CN101472564A

CN101472564A - High performance reticulated elastomeric matrix

Info

Publication number: CN101472564A
Application number: CNA200780023043XA
Authority: CN
Inventors: A·达塔; 小劳伦斯·P·拉韦尔; C·弗里德曼; J·D·麦吉利瓦里; A·森迪贾尔维克
Original assignee: Biomerix Corp
Current assignee: Biomerix Corp
Priority date: 2006-06-22
Filing date: 2007-06-15
Publication date: 2009-07-01

Abstract

This invention relates to reticulated elastomeric matrices, their manufacture, their post-processing, such as their reinforcement, compressive molding or annealing, and uses including uses for implantable devices into or for topical treatment of patients, such as humans and other animals, for surgical devices, tissue augmentation, tissue repair, therapeutic, nutritional, or other useful purposes.

Description

High performance reticulated elastomeric matrix

The application is the U. S. application US10/848 that submitted on May 17th, 2004,624 part continuation application, and request this application, the U.S. Provisional Application US60/816 that on June 22nd, 2006 submitted to, the U.S. Provisional Application US60/849 that on October 3rd, 120 and 2006 submitted to, 328 interests are incorporated herein by reference the content intact that each application is disclosed.

Invention field

The present invention relates to reticulated elastomeric matrix, its preparation comprises by so-called " craft " technology and " machine " method, its post processing, such as its reinforcement, compression molded or annealing and application comprise being used for implantable device is implanted or the topical therapeutic patient, such as people and other animal, be used for operation device, tissue is strengthened, tissue repair, treatment, nutrition or other useful purpose.With regard to these and other objects, but product of the present invention can use or be loaded with one or more substance for delivery separately.

Background of invention

Tissue engineered (" TE ") means generally comprise sending of biocompatible tissue substrate, and this substrate is as cell attachment, and the support or the holder of growth and/or propagation pass through the synthetic new organization of regeneration or growth of new tissue thus so that repair wound or defective.Generally acknowledged that open cytocompatibility foam has the important potential that is used to repair with regenerating tissues.Yet, because it is decomposed by health and absorbs, but can be in the synthetic new organization of health to produce the ability of any side effect after repairing the neutralization of wound process, so work has formerly concentrated on the tissue engineered support that is made of the synthesising biological absorbent material in the art.

The main weakness that relates to these means of the bioresorbable 3-dimension porous support that is used for tissue regeneration is in this unwanted tissue reaction of product life cycle process, because polymer biological degraded and can not transform the degradation characteristic of TE support in vivo, their abilities have seriously been limited thus as effective support.In addition, to for example passing through conduit, endoscope, arthroscope (arthoscope) or syringe delivery are delivered to the implant that can resist the compression in the delivery apparatus in the biological part process and are still had demand, this implant can be recovered to expand so that occupy and be retained in the biological part and have specific aperture by resilience, make that this implant can be with organizing inwardly growth, so that be applicable to useful therapeutic purposes on described position.In addition, from the viewpoint of biodurable, many materials that the polyurethane foam of the formation of bubbling in polymerization process constitutes are not attractive, because may generate the unwanted material that can produce bad biological respinse in polymerization process, carcinogen for example, cytotoxin etc.On the contrary, biodurable reticulated elastomeric matrix material of the present invention is suitable for using such as this class of long-term TE implant, especially wherein such as dynamic load and/or the stretching, extension experienced in the relevant orthopedic applications of soft tissue.

Present most organization bracket is made of Biodegradable polymeric, such as polyglycolic acid (" PGA "), the homopolymer of polylactic acid (" PLA ") etc. and copolymer or such as collagen protein, elastin laminin, based on the product of animal tissue, based on these class biopolymers such as product of people's tissue.There are many shortcomings in these materials, for example, are difficult to transform its characteristic with near in the various target tissue those.In addition, keep time limit of ability of its performance shorter in vivo, especially relate to its elasticity and rebound characteristics.In order to spend a few weeks or months regeneration, reinvent and/or callus, such as orthopedic applications soft tissue or vascular tissue, can not use the support that constitutes by biodegradable polymer and biopolymer, because they can not keep the desired potential performance of effective support, and particularly with regard to biopolymer, degrade in week at about 2-4.Some biodegradable polymer can exist at the most more than 1 year or 1 year in vivo, but they are easily crisp usually, easy fracture, in vivo or have in the external environment and be lower than about 5% tensile elongation.The tissue engineered substrate of the support that constitutes by biopolymer, and in some cases with regard to biodegradable polymer, the height probability that exists unwanted tissue reaction and device to repel usually.The latter is for especially serious based on the product of animal or human's tissue.The biodegradable polymer implant is decomposed in their long-term chronic tissue defective agglutinations usually and observed unwanted tissue reaction during degraded.

Selectively, use freeze drying technology at present and can leach hole life technology (porogens),, thereby make porous support by biodegradable polymer such as salt and sugar; But, be difficult to control the characteristic of gained support, control porous and structure.

The implantable device that the present invention includes reticulated elastomeric matrix has overcome biological absorptive material, the above-mentioned difficult problem of biodegradable polymer and biopolymer.Can transform these reticulated elastomeric matrix materials so that mate basically or satisfy with the tissue characteristics of targeting reparation and cause tissue regeneration, reinvent or the particular requirement of the concrete application of healing.This paper has disclosed and has successfully transformed its characteristic so that near the mode of those or characteristic in the various target tissue, makes tissue regeneration, transforms and/or healing is promoted.

This paper has disclosed the method for transforming reticulated elastomeric matrix form of the present invention and/or characteristic, by controlling its chemistry, processing and post processing feature, such as crosslinked amount, the amount of degree of crystallinity, chemical composition, condition of cure, netted degree and/or back nettedization processing, such as annealing, compression molded and/or mix reinforcement.Be different from biodegradable polymer, reticulated elastomeric matrix in vivo long term maintenance its physical characteristic and performance.Therefore, it can't start unwanted tissue reaction, as what the biodegradable implant was observed when they decompose and degrade.

Be different from biodegradable polymer or biopolymer, the implantable device that the present invention includes reticulated elastomeric matrix is its physical characteristic of long term maintenance and performance in vivo.It can't start unwanted tissue reaction, as what the biodegradable implant was observed when they decompose and degrade.The high-voidage amount of reticulated elastomeric matrix of the present invention and nettedization degree make tissue ingrowth and cell breed in the substrate.Do not wish to be subjected to any theory constraint, think that the high-voidage amount of reticulated elastomeric matrix and nettedization degree not only make tissue ingrowth and substrate inner cell breed, and the directed and transformation of tissue that can after initial tissue growth is gone into implantable device, heal.Passing in time, reticulated elastomeric matrix and/or implantable device provide repair or alternate original structure functional, such as having load-carrying ability.Do not wish to be subjected to any theory constraint, think because reticulated elastomeric matrix or comprise the high-voidage amount of its implantable device, in case so organization healing and biointegration take place, then most of regeneration or the position of repairing are formed by the reticulated elastomeric matrix of new organization and small size part or by the implantable device that it constitutes.

In addition, transform the compression set of implantable device, the ability that resilience and/or dynamic compression are recovered is to provide the high restoring force of reticulated elastomeric matrix after periodically loading repeatedly.This category feature advantageous particularly in application, for example in orthopedic applications, wherein the periodicity of implantable device loads and can also compress reticulated elastomeric matrix enduringly, prevents that thus it from promoting best infiltration of cell and the necessary surrounding soft tissue of tissue ingrowth tangible Continuous Contact taking place.In another limiting examples, the density of transformation implantable device of the present invention and aperture are so that make reticulated elastomeric matrix be issued to maximum permeability in compression.If high carrying capacity is placed on the implantable device, then this category feature is favourable.In another limiting examples, transform the characteristic of reticulated elastomeric matrix so that make its " soft conformal match " maximization, this is advantageous particularly in aesthetic surgery is used.

The U.S. Pat 5 of Bell etc., 891,558, the US6 of Vyakarnam etc., 306,424, the US6 of Plouhar etc., 638,312 and the US6 of Melican etc., 599,323 and the Application No. US 2002/0131989 of Brown etc., each self-described of US2004/0175408 of the US 2004/0078077 of US2003/0147935 and Binette etc. and Chun etc. composite implant or support.

A.E.S.Clarke etc. are at list of references proceedings of Blowing Agentsand Foaming Processes 2006, in May, 2006 16-17 day (Munich, Germany) 17 pages paper " Innovative Manufacture of Olefin Foams ", the middle description by the routine heating so that material surface expands and make inner the expansion prepare the alkene foam by microwave heating.

The description of above-mentioned background technology can comprise the insight of disclosure content, finds, and understanding or disclosure or dependency each other, we do not understand before the present invention, but by association area provided by the invention.Particularly pointed out the contribution of the present invention of some this class in this article, and other this class contribution of the present invention is apparent from context.Only because this paper has quoted from documents, so be not the field that allows to constitute documents, it is very different with the field of the invention, and is similar with the field of the invention.The list of references of citation is not to allow this list of references to be the prior art at the application in the application's background technology part.

Summary of the invention

Implantable device of the present invention is used for many application as long-term TE implant, especially wherein experience dynamic load and/or stretching, extension in such as the reparation of the relevant orthopedic applications of soft tissue and regeneration.

The present invention relates to comprise the implantable device of the netted resilience-compressible elastomeric substrate that contains a plurality of holes, wherein this implantable device further comprises with the reinforcement of 1-dimension mode at least.This implantable device can be reinforced preceding or annealing afterwards.This implantable device can be reinforced preceding or be compressed molded afterwards.

The invention still further relates to the implantable device that comprises the netted resilience-compressible elastomeric substrate that contains a plurality of holes, wherein this implantable device is compressed molded at it after nettedization.This implantable device can be compressed molded before or afterwards annealing.This implantable device can be compressed molded before or be reinforced afterwards.

The invention still further relates to the implantable device that comprises the netted resilience-compressible elastomeric substrate that contains a plurality of holes, wherein this implantable device is at its nettedization after annealing.This implantable device can be reinforced before annealing or afterwards.This implantable device can be before annealing or is compressed molded afterwards.

The invention still further relates to the polymerization of preparation elastomeric matrices, this method has the step of mixing following composition:

A) polyol component of 100 weight portions,

B) isocyanate prepolymer composition of about 90 weight portions of about 10-,

C) foaming agent of about 6.0 weight portions of about 0.5-,

D) optional about 8.0 parts by weight of cross-linking agent of about 0.05-,

E) cahin extension agent of optional about 8.0 weight portions of about 0.05-,

F) at least a catalyst of optional about 3.0 weight portions of about 0.05-,

G) at least a compartment opener of optional about 8.0 weight portions of about 0.1-,

H) surfactant of about 8.0 weight portions of about 0.1-and

I) the optional viscosity improver that reaches 15 weight portions approximately; Thereby obtain elastomeric matrices.

The invention still further relates to and prepare the method for partial mesh elastomeric matrices at least, this method has following steps:

1) following composition is mixed into mixture:

A) elastomeric material of 100 weight portions,

B) optional about 70 weight portions of about 2-have more hydrophilic polymer material,

C) crosslinking group of optional about 20 weight portions of about 0.1-and

D) foaming agent of optional about 20 weight portions of about 1-;

2) make microwave irradiation under the about 6.0GHz frequency of this mixture about 2.2GHz-of contact, also simultaneously with this mixture heated about 70 ℃-Yue 225 ℃ temperature extremely;

Thereby obtain the elastomeric matrices of partial mesh at least.

The invention still further relates to the implantable device that contains reticulated elastomeric matrix, wherein prepare this reticulated elastomeric matrix so that cell is inwardly grown and propagation is gone into annealed reticulated elastomeric matrix.

The invention still further relates to the method for treated tissue defective, this method has following steps:

A) optionally make implantable device of the present invention be compressed into first compressing structure from relaxed configuration;

B) by delivery apparatus the implantable device that compresses is delivered to rejected region in the body; And

C) optionally make described implantable device in described body, expand into second work structuring on the position.

The invention still further relates to the method for treated tissue defective, this method has the step of inserting implantable device of the present invention by the open surgery operation.

Tissue defects can relate to orthopedic applications, and common surgical procedures is used, and aesthetic surgery is used, and tissue engineered application or its be mixture arbitrarily.Described orthopedic applications can relate to reparation, rebuilds, and regeneration is strengthened, and breach insertion or its be the tendon of mixture arbitrarily, ligament, and cartilage, meniscus, spinal disc or its be mixture arbitrarily.Described common surgical procedures is used can relate to inguinal hernia, the veutro hernia, and thigh portion hernia, umbilical hernia or its be mixture arbitrarily.

The invention still further relates to the elastomeric matrices of the partial mesh at least product of any means preparation described herein.

The accompanying drawing summary

Be described in more detail below certain embodiments of the present invention and preparation of the present invention and used embodiment, read this description with foregoing description and according to them, as an example, with reference to accompanying drawing, wherein through view in the same or analogous key element of the similar character representation that relates to, and wherein:

Fig. 1 is the sketch map of a kind of possibility form of the part microstructure of a kind of embodiment of expression multiporous biological durability Resilient product of the present invention;

Fig. 2 is the schematic procedure block diagram of preparation multiporous biological durability elasticity implantable device of the present invention;

Fig. 3 illustration the typical compression molded process of cylindrical prefabricated form;

Fig. 4 illustration the typical compression molded process of the prefabricated form of cube;

Fig. 5 illustration several different typical reticulated elastomeric matrixes strengthen grids;

Fig. 6 illustration several different typical reticulated elastomeric matrixes strengthen grids;

Fig. 7 illustration the geometric graph of suture pull off strength test;

Fig. 8 illustration be easy to use implantable device of the present invention to carry out minimum infringement and other to build the zone of the face cosmetic surgery of application again;

Fig. 9 illustration make the implantable device of reinforcement and two kinds of methods of tuberosity anchoring;

Figure 10 is the scanning electron micrograph image of embodiment 5 reticulated elastomeric matrixes 1;

The sketch map of Figure 11 for concerning between the darcy permeability of several reticulated elastomeric matrixes and the available circulating area;

Figure 12 is the scanning electron micrograph image of embodiment 7 reticulated elastomeric matrixes 3;

Figure 13 represents the pattern of the rectangle implantable device of embodiment 14;

Figure 14 represents the dimension amount of the rectangle implantable device pattern feature of embodiment 14; And

Figure 15 represents the histologic analysis photo of the device of embodiment 15.

Detailed Description Of The Invention

Certain embodiments of the present invention comprise gauze bio durability elastomer product, they also are compressible and show resilience in it recover, have multiple application and can be used for biological the implantation as an example, especially the long-term TE implant of implant into body is especially wherein such as experience dynamic load and/or stretching, extension in the relevant orthopedic applications of soft tissue; Be used for tissue and strengthen, support and reparation; Be used for the treatment of application; Be used for beauty treatment, build again Urology Surgery or stomach oesophagus purpose; Or as pharmaceutically active agents, drug delivery matrix for example. Other embodiment comprises passes through conduit, endoscope, arthroscope, laparoscope, cystoscope, syringe or other suitable delivery apparatus carry out the gauze bio durability elastomer product sent in the body, and can implant satisfactorily, otherwise be exactly that what be exposed to that living tissue and fluid prolong is time limit, for example at least 29 days.

Generally acknowledge as the present invention, need the implantable device of innocuousness at medical domain, it can be delivered to position in the patient body, position in the human patient body for example, it can occupy time limit that this position prolongs and can be harmful to the host. In one embodiment, this class implantable device finally can also become integration, such as biointegration, for example with organizing inwardly growth or biointegration. Propose various biodegradables or absorbability porous polymer material and be used for tissue reinforcement and reparation.

It is desirable to form the implantable device that is suitable for as tissue engineered support or other matrix very nearly the same, so that support inner cell propagation is used, for example especially in the soft tissue connection of prosthese organ, regenerate, strengthen, in a large amount of orthopedic applications in support and the inside growth. Not retrained by any particular theory, think that having nettedization of high-voidage amount height can make implantable device become and cell, comprise and organize together at least part of inside growth and/or propagation, in some cases basically inwardly growth and propagation, in some cases fully inwardly growth and propagation, described cell, comprise tissue such as fibroblast, fibr tissue, synovial cell, marrow stromal cell, stem cell and/or fibrocartilage cells. Inside the organizing to provide thus and be repaired or the defect repair of alternative original structure functional of growth and/or propagation is such as having load-carrying ability. Yet, before the present invention occurs, not yet be met material and/or the product of this class implantable device requirement.

In a broad sense, the embodiment of some gauze bio durability Resilient product of the present invention comprises the high osmosis pseudostructure that is made of the biodurable polymer elastomer or if not fully, be exactly mainly to be consisted of by it so, described biodurable polymer elastomer is resilience-compressible, in order to recover its shape after being delivered to biological part. In one embodiment, elastomeric matrices has the good fatigue strength relevant with dynamic load. In another embodiment, elastomeric matrices is chemically fully being characterized. In another embodiment, elastomeric matrices is fully characterized physically. In another embodiment, elastomeric matrices the chemistry and physically all fully characterized.

Certain embodiments of the present invention can supportint cell growth and allow cell inwardly to grow in vivo and breed and be used as the interior biological implantable device of body, for example for can in external or body, using in order to the tissue engineered support of cell proliferation matrix is provided.

Implantable device of the present invention is used for many application as long-term tissue engineered implant, is especially wherein experiencing dynamic load and/or stretching, extension such as being used for repairing with the relevant orthopedic applications of soft tissue of regeneration. In certain embodiments, the U.S. Patent application US10/848 that reticulated elastomeric matrix of the present invention was submitted to such as on May 17th, 2004, described in 624 (the announcing on February 24th, 2005 as U.S. Patent Application Publication No. US 2005-0043816-A1), for all purposes intactly are incorporated herein by reference the document.

In one embodiment, reticulated elastomeric matrix of the present invention is by providing the cell adhesion, and migration is bred and/or the surface of coating (for example collagen) deposition is conducive to tissue ingrowth. In another embodiment, the tissue of any type all can be grown into the implantable device that comprises reticulated elastomeric matrix of the present invention, comprise that as an example epithelial tissue (comprises, squamous (squamous) for example, cube and columnar epithelium), connective tissue (comprises, (areolar) tissue for example loosens, fine and close regular and irregular tissue, desmachyme, adipose tissue, cartilage and bone) and musculature (comprise, skeletal muscle for example, smooth muscle and cardiac muscle) or its any combination, for example fiber vascular tissue. In another embodiment of the invention, the implantable device that comprises reticulated elastomeric matrix of the present invention can have basically the tissue ingrowth through its intercommunicating pore volume.

In one embodiment, the present invention includes and have enough resilience-compressibilities so that by " delivery apparatus ", namely has the implantable device that the device of the chamber that comprises the elasticity implantable device is sent, for example use simultaneously conduit, endoscope, arthroscope, laparoscope, cystoscope or syringe are delivered to desired area with it, then discharge at this position. In another embodiment, the elasticity implantable device of sending thus after being delivered to biological part, basically recover its shape and have enough biodurable and Biocompatibility to be suitable for long-term implantation. In another embodiment, the elasticity implantable device of sending thus can be crossed over defective and be used as the bridge of breach in the natural tissues.

Can in the popularity energy range, transform or customize by changing material and/or processing conditions the structure of elastomeric matrices of the present invention, form with characteristic so that different function or treat application.

Not retrained by any particular theory, think and the object of the present invention is to provide light-duty durable construction, it can the filled biomass volume or chamber and comprise enough porous that is distributed in the overall volume, can satisfy this purpose by allowing in the following situation one or more: sealing, embolism, cell is inwardly grown, cell proliferation, regeneration, the cell adhesion, drug delivery is by the enzyme effect of immobilized enzyme generation with such as said other the useful process of this paper, particularly including the application of request priority.

In one embodiment, elastomeric matrices of the present invention has enough resiliences in order to can basically recover, for example for implant into body compress after with 1-dimension mode at least return to the relaxed configuration size at least about 50%, low compression set for example, for example under 25 ℃ or 37 ℃ and for being used for pharmaceutically active agents, such as enough intensity and the circulation of medicine and other medical use controlled release. In another embodiment, elastomeric matrices of the present invention have enough resiliences in case can for implant into body compress after with 1-dimension mode at least return to the relaxed configuration size at least about 60%. In another embodiment, elastomeric matrices of the present invention have enough resiliences in case can for implant into body compress after with 1-dimension mode at least return to the relaxed configuration size at least about 90%.

In this application, term " biodurable " has been described and has been suitable for stable elastomer and other products of time limit time expand in biotic environment. This series products with respect to its duty and Yan Buying shows and decomposes or degraded, corrodes or the obvious deterioration of mechanical performance when the biotic environment in the contact time limit suitable with using this implantable device. Implanting the time limit can be several weeks, some months or several years; In the life-span of host's product, wherein mixed Resilient product of the present invention, such as graft or prosthese; Or for the life-span of Resilient product for the patient. In one embodiment, should understand the desirable contact time limit is at least about 29 days. In another embodiment, should understand the desirable contact time limit is at least 29 days. In one embodiment, described implantable device was biodurable at least 2 months. In another embodiment, described implantable device was biodurable at least 6 months. In another embodiment, described implantable device was biodurable at least 12 months. In another embodiment, described implantable device more than at least 12 months is being biodurable. In another embodiment, described implantable device was biodurable at least 24 months. In another embodiment, described implantable device was biodurable at least 5 years. In another embodiment, described implantable device more than at least 5 years is being biodurable.

In one embodiment, biodurable product of the present invention also is biocompatibility. In this application, term " biocompatibility " means can induce hardly the product of (if any also seldom) any bad biological respinse when implanting host patient. The similar consideration that is suitable for " biodurable " also is applied to " biocompatibility " characteristic.

The biotic environment of estimating can be interpreted as in vivo, for example in described product patients with implantation host's the body or in the body of local application, mammalian hosts for example is such as people or other primate, pet or motion animal, livestock or edible animal or laboratory animal. All these classes are used all to be concerned and are scope of the present invention. " patient " used herein is animal. In one embodiment, described animal is bird, includes, but are not limited to chicken, turkey, duck, goose or quail or mammal. In another embodiment, described animal is mammal, includes, but are not limited to ox, horse, sheep, goat, pig, cat, dog, mouse, rat, hamster, rabbit, cavy, monkey and people. In another embodiment, described animal is primate or people. In another embodiment, described animal is behaved.

In one embodiment, the structural material that is used for porous elastomers of the present invention is synthetic polymer, especially, but be not limited to anti-biodegradable elastomeric polymer, for example, in one embodiment, the Merlon polyurethanes, Merlon urea-carbamates, polyethers polyurethanes, poly-(carbonic ester common-ether) urea-carbamates, polysiloxane-based etc., in another embodiment, Merlon polyurethanes, Merlon urea-carbamates, poly-(carbonic ester-altogether-ether) urea-carbamates and polysiloxane-based, in another embodiment, Merlon polyurethanes, Merlon urea-carbamates and polysiloxane-based. This class elastomer is generally hydrophobic, but according to the present invention, they can be processed into to have low hydrophobicity or certain hydrophilic surface. In another embodiment, can produce this class elastomer with low hydrophobicity or certain hydrophilic surface.

Gauze bio durability Resilient product of the present invention can be described as having " macrostructure " and " microstructure ", the general sense of this term used herein is described in the following paragraph.

" macrostructure " means the goods that are made of biodurable Resilient product of the present invention or the overall physical characteristic of article, such as: by the outer perimeter that the geometrical boundary of goods or article is described, ignore hole or space; " macrostructure surface area " refers to outmost surface area, although any Kong Jun is filled on it, ignored the surface area in the hole; " the macrostructure volume " that described goods or article occupy or abbreviation " volume " are the volume of macrostructure or the restriction of abbreviation " greatly " surface area; And " bulk density " is the weight in per unit volume goods or the article self, and it is different from the density of structural material.

" microstructure " means to consist of the inner structural features of the biodurable elastomeric material of product of the present invention, such as the size in hole; Aperture surface area, it is the gross area of material surface in the hole; Tang and intersection point structure with the entity structure that consists of some embodiment of Resilient product of the present invention.

With regard to Fig. 1, what facility showed is the schematic diagram of the concrete form of reticulated polymer foam. Fig. 1 is some the convenient manner in illustration certain embodiments of the invention microstructure characteristic and the principle. This figure is not appointed as the ideal of Resilient product embodiment of the present invention and describes, and is not appointed as the detailed description of Resilient product specific embodiments of the present invention yet. The further feature of microstructure and principle are apparent from this specification, or apparent in from the inventive method of the said poroelasticity product of preparation this paper one or more.

Form

General description the microstructure of multiporous biological biodurable elastomeric matrix 10 of illustration, it can be the discrete component of continuous or amorphous body with difformity or stretching, extension especially, comprise the netted entity phase 12 that consists of and disperse therein or determine thus by suitable biodurable elastomeric material, continuous interconnected space phase 14, the latter is cancellated principal character.

In one embodiment, the elastomeric material of formation elastomeric matrices 10 can be mixture or the admixture of multiple material. In another embodiment, elastomeric material is single synthetic polymer elastomer, such as more specifically describing hereinafter. In other embodiments, although elastomeric matrices 10 carries out rear nettedization processing, such as annealing, compression molded and/or reinforcement it should be understood that elastomeric matrices 10 has kept its feature of determining, and it has kept biodurable, nettedization and elasticity.

The space mutually 14 is generally before use and fills air or inflation. In application, the space is mutually 14 in many situations, but is not to have filled liquid in all situations, for example filled biofluid or body fluid.

The entity phase 12 of elastomeric matrices 10 as shown in fig. 1 has organic structure and comprises the tang 16 of a plurality of relative thin, and they extend between a plurality of X-sections 18 and be interconnected. X-section 18 is main locations of structures, and three or three above tangs 16 meet each other herein. Can observe four or five above tangs 16 meets or meets can observing the position that two X-sections 18 merge each other at X-section 18. In one embodiment, tang 16 stretches in 3-dimension mode between paper plane X-section 18 up and down, is not partial to specific plane. Therefore, the tang 16 of any appointment can be to stretch from this X-section 18 with respect to any direction that is connected to other tang 16 on the X-section 18. Tang 16 and X-section 18 generally can have curved shape and limit a plurality of holes 20 or the entity gap in 12 mutually between them. Tang 16 consists of interconnected continuous entity mutually with X-section 18.

As shown in fig. 1, the entity of elastomeric matrices 10 is 12 structural detail mutually, be that tang 16 and X-section 18 can demonstrate and have certain layer structure, just as from monolithic, downcut some, be appreciated that this outward appearance can part owing to the difficulty of the complicated 3-dimension structure of expression in 2-dimension figure. Tang 16 and X-section 18 can have and have in many cases non-stratiform shape, comprise circle, ellipse and non-circular transverse cross-section and the cross section that on area, changes along ad hoc structure, for example, their tapers change into less and/or larger cross section, pass along its longest dimension simultaneously.

The compartment of elastomeric matrices 10 by hole 20 bunch or group consist of, they can form compartment, but except compartment 22 in most of hole 20 do not exist because of nettedization or non-existent situation basically. Especially, a small amount of hole 20 can have the structural material compartment that is also referred to as " window " or " glass pane ", such as compartment 22. When reaching when blocking degree by hole 20 of fluid and/or tissue propagation and propagation, this class compartment is undesirable. In one embodiment, compartment 22 can be removed in suitable procedure of processing, such as nettedization step as described below.

Each compartment that consists of reticulated elastomeric matrix is characterised in that its average cell diameter, or with regard to non-spherical compartment, is its greatest cross-section size. Reticulated elastomeric matrix comprises mutually 14 reticulated structure of the interconnected space of the compartment that consists of 3-dimension space structure or the open bore by wherein 20. In one embodiment, compartment consists of 3-dimension superstructure. In Figure 10 and 12, can be from the border that tang 16 and/or the X-section 18 in display white cross section are observed each compartment. Hole 20 is generally 2-or 3-dimension structure. The hole provides between each compartment or has consisted of the hole bunch of compartment or the connectivity between the group.

Except the terminal point of the lip-deep border of macrostructure, in the embodiment depicted in fig. 1, the entity phase 12 of elastomeric matrices 10 comprises that hardly (if any) stretches from tang 16 or X-section 18, but the free-end that is not connected with another tang or X-section, cecum or outstanding " tang-sample " structure.

Yet in selectable embodiment, entity phase 12 can be furnished with a plurality of these class fibrillation (not shown)s, about 5 fibrillation of 1-of for example having an appointment in each tang 16 or the X-section 18. In some applications, it is long-pending that this class fibrillation for example can be used for the additional surface that they provide.

Space mutually shape and the structure (or vice versa) in 14 hole 20 tang 16 and X-section 18 can be considered as determining consisting of. With regard to disperseing to determine, the many opening because of at least part of disappearance compartment 22 in the hole 20 enters and communicates with at least two extra holes 20. On X-section 18, three or three above holes 20 can be regarded as meeting and intercommunication. In certain embodiments, space phase 14 this means the compartment hole (if any) that has hardly sealing for passing through continuously elastomeric matrices 10 continuously or basically. The compartment hole of this class sealing separately volume of inside is not communicated with any other compartment, for example by compartment 22 and adjacent compartments isolation, expression lacks useful volume and may block the passage that useful fluid enters elastomeric matrices 10 inner tangs and

X-section structure

16 and 18.

In one embodiment, if exist, Feng Bi compartment hole comprises and is lower than about 90% elastomeric matrices 10 volumes so.In another embodiment, if exist, the enclosed compartment hole comprises and is lower than about 80% elastomeric matrices 10 volumes so.In another embodiment, if exist, the enclosed compartment hole comprises and is lower than about 70% elastomeric matrices 10 volumes so.In another embodiment, if exist, the enclosed compartment hole comprises and is lower than about 50% elastomeric matrices 10 volumes so.In another embodiment, if exist, the enclosed compartment hole comprises and is lower than about 30% elastomeric matrices 10 volumes so.In another embodiment, if exist, the enclosed compartment hole comprises and is lower than about 25% elastomeric matrices 10 volumes so.In another embodiment, if exist, the enclosed compartment hole comprises and is lower than about 20% elastomeric matrices 10 volumes so.In another embodiment, if exist, the enclosed compartment hole comprises and is lower than about 15% elastomeric matrices 10 volumes so.In another embodiment, if exist, the enclosed compartment hole comprises and is lower than about 10% elastomeric matrices 10 volumes so.In another embodiment, if exist, the enclosed compartment hole comprises and is lower than about 5% elastomeric matrices 10 volumes so.In another embodiment, if exist, the enclosed compartment hole comprises and is lower than about 2% elastomeric matrices 10 volumes so.The existence in enclosed compartment hole can be noticed in the influence that reduction is inwardly grown by the fluidic volume flow rate of elastomeric matrices 10 and/or as cell and propagation is gone in elastomeric matrices 10 minimizings according to it.

In another embodiment, elastomeric matrices 10 is by nettedization.In another embodiment, elastomeric matrices 10 nettedization basically.In another embodiment, elastomeric matrices 10 complete nettedization.In another embodiment, many compartment 22 of elastomeric matrices 10 are removed: in another embodiment, most of compartment 22 of elastomeric matrices 10 is removed.In another embodiment, elastomeric matrices 10 basically all compartment 22 be removed.

In another embodiment, can be described as the continuous net-shaped structure that netted entity phase 12 comprises entity structure, such as minor connector 16 and X-section 18, there are not any tangible termination, isolating district or discontinuity, this border with elastomeric matrices is different, in the reticulated structure of elastomeric matrices, the false line of intending can be from any another point that is a bit tracked to this reticulated structure fully of reticulated structure by the material of entity phase 12.

In another embodiment, the space is mutually 14 also for the continuous net-shaped structure in gap or be used for gas or the intercommunication fluid passage of liquid, this fluid passage omnipresence stretch and by the entity of elastomeric matrices 10 mutually 12 structure define (or determining) and open and enter all its outer surfaces.As mentioned above, in other embodiments, only exist several, essentially no or do not have fully with space reticulated structure at least one other hole 20 disconnected closure or the compartment hole of sealing.In addition, in this space phase reticulated structure, the false line of intending can be by space phase 14 any another points that a bit tracked to this reticulated structure fully from reticulated structure.

Consistent with purpose of the present invention, in one embodiment, constitute the microstructure of elastomeric matrices 10 so that allow or impel cell 20 and entity 12 surface adhering mutually, neointima formation and cell are gone into 14 hole 20 mutually, space with tissue ingrowth and propagation on it, and this moment, elastomeric matrices 10 resided in the position certain hour time limit in the suitable body.

In another embodiment, comprise that with regard to some purpose Fibrotic this class cell or tissue is inwardly grown and propagation can occur or impelled the skin that only enters hole 20, and enter the darkest inside and the omnipresence elastomeric matrices 10 of whole elastomeric matrices 10.Therefore, in this embodiment, the space that elastomeric matrices 10 occupies becomes fully by fibrosis, and the cell of cicatrix or other type of organization and tissue are filled to growth and propagation, but except elasticity entity 12 spaces that occupy mutually.In another embodiment, implantable device of the present invention works, and makes ingrown for example organizing keep vitality because of supportive microvasculature prolongs to exist.

In order to reach this purpose, particularly with regard to the form of space phase 14, in one embodiment, elastomeric matrices 10 is because of having open nettedization of intercommunicating pore.

Be not subjected to any concrete theory constraint, think and allow the elastomeric matrices 10 inner body fluid of being used, for example blood nature lavation, even also be so after cell mass resides in elastomeric matrices 10 inside is so that by providing nutrient to keep this colony and from wherein removing refuse to it.In another embodiment, elastomeric matrices 10 is because of having open nettedization of intercommunicating pore of certain size range.In another embodiment, elastomeric matrices 10 is because of open nettedization of intercommunicating pore of distribution with magnitude range.

Estimate to select the various physics and the chemical parameters of elastomeric matrices 10, particularly comprise parameter as described below, so that the application-specific of elastomeric matrices 10 is impelled cell inwardly growth and propagation according to expectation.

Be appreciated that this class provide inner cell lavation elastomeric matrices 10 structure can for fluid penetrable and can provide by and arrive the fluid passage of substrate inside, but purpose and acellular lavation, for example be used for the eluted substance activating agent, for example medicine or other biological useful materials.This class material can be chosen the inner surface that is fixed to elastomeric matrices 10 wantonly.

In another embodiment of the invention, but gas phase 12 can be filled or contact delivery treatments gas, antibacterial for example, such as ozone or wound healant, such as nitric oxide, as long as the macrostructure surface is sealed by the biological example resorbable membrane, so that in implanting product, comprise described gas, corrode up to described film, thereby discharge described gas so that provide topical therapeutic or other effect.

Useful embodiment of the present invention comprises: randomized to a certain extent as shown in fig. 1 structure, and wherein minor connector 16, and the shape and the size in X-section 18 and hole 20 change basically; More orderly structure, they also show, and entity and space 3-dimension mutually interpenetrates, the described feature of structural complexity and high fluid permeability.Can produce the more orderly structure of this class by method of the present invention, just as described further below.

Porous

After nettedization, space phase 14 can comprise the elastomeric matrices 10 that is low to moderate 10% volume, volume that provides such as elastomeric matrices 10 gaps before reticulated elastomeric matrix being used any optional inner bore surface coating or layering is provided for this, after nettedization, described reticulated elastomeric matrix is compressed molded as described in detail herein and/or strengthens.In another embodiment, space phase 14 can comprise the elastomeric matrices 10 that is low to moderate 20% volume.In another embodiment, space phase 14 can comprise the elastomeric matrices 10 that is low to moderate 35% volume.In another embodiment, space phase 14 can comprise the elastomeric matrices 10 that is low to moderate 50% volume.In one embodiment, as determined, the volume of space phase 14 is about the elastomeric matrices 10 of about 99% volume of 10%-.In another embodiment, as determined, the volume of space phase 14 is about the elastomeric matrices 10 of about 99% volume of 20%-.In another embodiment, as determined, the volume of space phase 14 is about the elastomeric matrices 10 of about 97% volume of 30%-.In another embodiment, as determined, the volume of space phase 14 is about the elastomeric matrices 10 of about 99% volume of 50%-.In another embodiment, as determined, the volume of space phase 14 is about the elastomeric matrices 10 of about 99% volume of 70%-.In another embodiment, the volume of space phase 14 is about the elastomeric matrices 10 of about 98% volume of 80%-.In another embodiment, the volume of space phase 14 is about the elastomeric matrices 10 of about 98% volume of 90%-.

As used herein, in the hole for spherical or when being essentially sphere, its maximum lateral dimension is equivalent to the diameter in hole.When the Kong Weifei sphere, for example when ellipse or tetrahedron, the ultimate range in its maximum transverse size is equivalent to from a hole surface to the hole of another hole surface, for example long side length of the long axis length of oval body opening or tetrahedron Kongzui." average diameter or other maximum transverse size " used herein means sphere or the number average diameter of spherical pore or the longest lateral dimension of number average of non-spherical pore basically.

In an embodiment that relates to orthopedic applications etc., in order to impel cell inwardly growth and propagation and enough fluid permeabilities are provided, the average diameter in hole 20 or other maximum transverse size are at least about 10 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are at least about 20 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are at least about 50 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are at least about 100 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are at least about 150 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are at least about 250 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are greater than about 250 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are greater than 250 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are at least about 450 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are greater than about 450 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are greater than 450 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are at least about 500 μ m.

In an embodiment that relates to orthopedic applications etc., the average diameter in hole 20 or other maximum transverse size are not more than about 600 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are not more than about 500 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are not more than about 450 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are not more than about 350 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are not more than about 250 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are not more than about 150 μ m.In another embodiment, the average diameter in hole 20 or other maximum transverse size are not more than about 20 μ m.

Relate in the embodiment of orthopedic applications etc. at another, the average diameter in hole 20 or other maximum transverse size are about the about 50 μ m of 10 μ m-.In another embodiment, the average diameter in hole 20 or other maximum transverse size are about the about 150 μ m of 20 μ m-.In another embodiment, the average diameter in hole 20 or other maximum transverse size are about the about 250 μ m of 150 μ m-.In another embodiment, the average diameter in hole 20 or other maximum transverse size are about the about 500 μ m of 250 μ m-.In another embodiment, the average diameter in hole 20 or other maximum transverse size are about the about 600 μ m of 450 μ m-.In another embodiment, the average diameter in hole 20 or other maximum transverse size are about the about 500 μ M of 10 μ m-.In another embodiment, the average diameter in hole 20 or other maximum transverse size are about the about 600 μ m of 20 μ m-.In another embodiment, the average diameter in hole 20 or other maximum transverse size are about the about 600 μ m of 50 μ m-.

In another embodiment, the average diameter in hole 20 or other maximum transverse size are about the about 500 μ m of 100 μ m-.In another embodiment, the average diameter in hole 20 or other maximum transverse size are about the about 350 μ m of 150 μ m-.

In an embodiment that relates to orthopedic applications etc., in order to impel cell inwardly growth and propagation and enough fluid permeabilities are provided, compartment average diameter or other the longest lateral dimension of elastomeric matrices 10 are at least about 100 μ m.In another embodiment, its compartment average diameter or other the longest lateral dimension are at least about 150 μ m.In another embodiment, its compartment average diameter or other the longest lateral dimension at least 200 μ m.In another embodiment, its compartment average diameter or other the longest lateral dimension at least 250 μ m.

Relate in the embodiment of orthopedic applications etc. at another, the compartment average diameter of elastomeric matrices 10 or other the longest lateral dimension are not more than about 1000 μ m.In another embodiment, its compartment average diameter or other the longest lateral dimension are not more than about 850 μ m.In another embodiment, its compartment average diameter or other the longest lateral dimension are not more than about 450 μ m.In another embodiment, its compartment average diameter or other the longest lateral dimension are not more than about 700 μ m.In another embodiment, its compartment average diameter or other the longest lateral dimension are not more than about 650 μ m.

Relate in the embodiment of orthopedic applications etc. at another, the compartment average diameter of elastomeric matrices 10 or other the longest lateral dimension are about the about 1000 μ m of 100 μ m-.In another embodiment, its compartment average diameter or other the longest lateral dimension are about the about 850 μ m of 150 μ m-.In another embodiment, its compartment average diameter or other the longest lateral dimension are about the about 700 μ m of 200 μ m-.In another embodiment, its compartment average diameter or other the longest lateral dimension are about the about 650 μ m of 250 μ m-.

In another embodiment, the implantable device that is made of elastomeric matrices 10 can comprise the little hole size that changes big to 500 μ m for example from for example 20 μ m in single device.In another embodiment, the implantable device that is made of elastomeric matrices 10 can comprise the little size of compartments that changes big to 1000 μ m for example from for example 100 μ m in single device.In another embodiment, this class version can occur in any inferior cross section of the cross section or the cross section of whole material.In another embodiment, this class version occurs with the form of regular progressively transition.In another embodiment, this class version in a step-wise fashion occurs.For example, pore size distribution can be about the about 70 μ m of 20 μ m-on an end of implantable device, and is about the about 500 μ m of 300 μ m-on the other end of this device.The change of this pore size distribution can be carried out in one or more continuous transitions or one or more dispersion steps.The version of this class pore size distribution produces continuous transition district or dispersion steps, promptly from a kind of pore size distribution carry out the transition to another kind of pore size distribution with regard to continuous transition situation for more progressive, or in the situation of dispersion steps or a plurality of steps for more distinguishing.With regard to the direction in hole, similarly transition can take place on the direction in hole, wherein has more the lower hole of the hole transition Inbound of directivity and even enters the hole of the direction in essentially no inferior cross section by cross section or cross section.The pore size distribution by the implantable device cross section that is made of elastomeric matrices 10 and/or the difference of direction can be so that this device be transformed at cell type, cell adhesion, and cell is inwardly grown and/or the cell proliferation aspect has preferred properties.Selectively, different pore size distribution and/or hole direction by the implantable device cross section that is made of elastomeric matrices 10 make this device be transformed at types of organization, the tissue adhesion, and tissue ingrowth and/or hyperblastosis aspect have preferred properties.

Well-known cell can be along also structure outline adhesion, propagation and the differentiation by being formed by pore size distribution.Cell directional and cellular morphology can produce to be transformed or the new tissue that forms, and it can duplicate or simulate actual tissue basically, for example substitutes the anatomical features of tissue.This preferably owing to continuously or progressively pore size distribution version cellular morphology and orientation, wherein have or take place when the foraminous orientation of tool can not have formerly cell inoculation in that implantable device is put into tissue repair and regeneration site.Thisly preferably can also carry out after cell in vitro is cultivated implantable device being put into the patient, for example take place when human or animal tissues reparation and regeneration site owing to continuously or the progressively cellular morphology and the orientation of pore size distribution version.These are the pore size distribution version continuously or progressively, wherein have or not the foraminous orientation of tool can be the key character of TE support in many orthopedic applications, especially comprising spinal column, shoulder, knee joint, the soft tissue in the growth of hands or joint and prosthese organ is connected, and repairs, regeneration is in reinforcement and/or the support.

Size and shape

Be easy to elastomeric matrices 10 is made any required size and shape.Helpfulness of the present invention is that elastomeric matrices 10 is adapted to pass through the block raw material, for example by cutting, and stamping, cut or pressing mold carry out mass production by this class piece raw material.In one embodiment, can use the area of heating surface to carry out the piece raw material cuts apart.Extra helpfulness of the present invention is that the shape of elastomeric matrices 10 and structure can in very large range change and be easy to be suitable for required anatomic form.

The size of elastomeric matrices 10, shape is constructed relevant detailed description with other and can be specifically designed to specific application or patient or be the mass production standardization.Yet standardization is tended in economic consideration.In order to reach this purpose, elastomeric matrices 10 can be made for the test kit of the elasticity implantable device sheet that comprises different sizes and shape.In addition, disclose in the application as other part discussion and request priority in this description, can be with a plurality of, for example two, three or four single elastomeric matrices 10 usefulness act on the implantable device system at single target biology position, its for a certain size or be shaped or both had that a certain size also is shaped so that be collaborative its effect of the individual targeting moiety of treatment.

Can be surgeon or other medical treatment or veterinary practitioner, the practitioner of the enforcement operation technique of research worker etc. can select one or more implantable devices to be used for concrete treatment from utilizing subsequently the scope, for example described in the application of request priority.

As an example, the minimum dimension of elastomeric matrices 10 is low to moderate 0.5mm and full-size up to 100mm and even more than the 100mm.Yet, in one embodiment, pay close attention to and specify the elastomeric matrices 10 of this class size that is used to implant can have the shape of prolongation, such as cylinder, the body of rod, pipe or prolongation prism shape or folding are curled, and spiral or other are constructed more closely.Similarly, little size to 0.5mm can be the lateral dimension of elongated shape or bar or sheet-sample implantable device.

In a selectable embodiment, has sphere, cube, tetrahedron, annular or can have effectiveness at diameter or other the maximum sized elastomeric matrices 10 of comparing other form that do not possess the significant prolongation size and the about 500mm of about 0.5mm-with any other size for example is used for the orthopedic applications position.In another embodiment, the elastomeric matrices 10 with this class form has diameter or other full-size of the about 20mm of about 3mm-.

With regard to the application of most of implantable device, the macrostructure size of elastomeric matrices 10 comprises following embodiment: fine and close shape, such as spheroid, cube, pyramid, tetrahedron, cone, cylinder, trapezoidal, parallelepiped, ellipsoid, spindle, tubular or sleeve-shaped and many low regular shapes (in another embodiment, these lateral dimensions are about the about 100mm. of 5mm-) with the about 200mm lateral dimension of about 1mm-; And have about 0.5-about 20

The sheet of mm thickness (in another embodiment, these thickness are about the about 5mm of 1-) and the about 200mm lateral dimensions of about 5-(in another embodiment, these sizes are about the about 100mm of 10-)-or bar-sample shape.

With regard to orthopedic applications treatment, the invention has the advantages that can use implantable elastomeric matrices element effectively and need not be strictly with may be generally complicated and be difficult to modeled orthopedic applications position structure consistent.Therefore, in one embodiment, implantable elastomeric matrices element of the present invention has obvious difference and comparatively simply constructs, for example described in the application of request priority.

In addition, in one embodiment, if implantable device of the present invention or use more than one implantable device should not be full of the orthopedic applications position fully, even also be like this during complete expansion in position.In one embodiment, the implantable device of complete expansion of the present invention provides enough spaces dimensionally less than the orthopedic applications position and in the orthopedic applications position, guaranteeing vascularization, cell is inwardly grown and propagation and the blood possible passage by implantable device.In another embodiment, the implantable device of complete expansion of the present invention is similar with the orthopedic applications position basically dimensionally.In another embodiment, the implantable device of complete expansion of the present invention is dimensionally basically greater than the orthopedic applications position.In another embodiment, the implantable device of complete expansion of the present invention on volume less than the orthopedic applications position.In another embodiment, the implantable device of complete expansion of the present invention is identical with the orthopedic applications position basically on volume.In another embodiment, the implantable device of complete expansion of the present invention on volume greater than the orthopedic applications position.In another embodiment, after putting into the orthopedic applications position, the expansible implantable device of the present invention can swelling, for example, by absorption and/or adsorbed water or other body fluid swelling, in one embodiment, is swelling to many 1-20% in 1-dimension mode.In one embodiment, be swelling to many 1-30% in 1-dimension mode.Or be swelling to many 1-40% in 1-dimension mode in another embodiment.

Some useful implantable device shape can be near the appearance profile at targeting orthopedic applications position.In one embodiment, implantable device is configured as and relatively simply protrudes shape, the size of dish-sample or hemispherical or half-oval and a plurality of different parts that are suitable for treating different patients.

In another embodiment, can expect when implanting, in its hole by biofluid, before body fluid and/or tissue are full of, this class is used for the implantable device of orthopedic applications etc. and not exclusively fills, covers or cross over the biological part of their residences, although and not necessarily necessary in many cases, each elastomeric matrices 10 of implanting has at least that the 1-dimension is no more than 50% its biological part that enters or is repaired or alternate damaged tissues above 50%.In another embodiment, the aforesaid elastomeric matrices 10 of respectively implanting has at least the 1-dimension and is no more than 75% its biological part that enters or surpasses 75% and be repaired or alternate damaged tissues.In another embodiment, aforesaid single implantable elastomeric matrices 10 has at least the 1-dimension and is no more than 95% its biological part that enters or surpasses 95% and be repaired or alternate damaged tissues.

In another embodiment, when implanting, be filled biofluid in its hole, before body fluid and/or the tissue, this class is used for the implantable device of orthopedic applications etc. and fills, covers or cross over the biological part of their residences basically, although and not necessarily necessary in many cases, each elastomeric matrices 10 of implanting has at least 1-to be tieed up to be no more than about 100% its biological part that enters or to cover 100% and is repaired or alternate damaged tissues.In another embodiment, the aforesaid elastomeric matrices 10 of respectively implanting has at least the 1-dimension and is no more than 98% its biological part that enters or covers 98% and be repaired or alternate damaged tissues.In another embodiment, each is implanted elastomeric matrices 10 and has at least the 1-dimension and be no more than 102% its biological part that enters or cover 102% and be repaired or alternate damaged tissues.

In another embodiment, when implanting, be filled biofluid in its hole, before body fluid and/or the tissue, this class is used for the implantable device of orthopedic applications etc. and excessively fills, covers or cross over the biological part of their residences, although and not necessarily necessary in many cases, each elastomeric matrices 10 of implanting has at least 1-to be tieed up to be no more than about 105% its biological part that enters or to cover 105% and is repaired or alternate damaged tissues.In another embodiment, the aforesaid elastomeric matrices 10 of respectively implanting has at least the 1-dimension and is no more than 125% its biological part that enters or covers 125% and be repaired or alternate damaged tissues.In another embodiment, respectively implanting elastomeric matrices 10 as mentioned above has at least the 1-dimension and is no more than 150% its biological part that enters or covers 150% and be repaired or alternate damaged tissues.In another embodiment, respectively implanting elastomeric matrices 10 as mentioned above has at least the 1-dimension and is no more than 200% its biological part that enters or covers 200% and be repaired or alternate damaged tissues.In another embodiment, respectively implanting elastomeric matrices 10 as mentioned above has at least the 1-dimension and is no more than 300% its biological part that enters or covers 300% and be repaired or alternate damaged tissues.

Be used to implement one embodiment of the invention and be enough pliable and tough and resiliences, it is the compressible reticulated elastomeric matrix 10 of resilience, so that can be in environmental condition, for example be compressed into first compact texture from relaxed configuration at first under 25 ℃, thereby can send by delivery apparatus, described delivery apparatus is for example for being used for the external conduit of sending, endoscope, syringe, cystoscope, the trocar or other suitable introducer instrument; So that expand into second work structuring in position.In addition, in another embodiment, elastomeric matrices has resilience-compressibility as herein described after being compressed about 5-95% of original size (for example compression is about the 19/20-1/20 of original size).In another embodiment, elastomeric matrices has resilience-compressibility as herein described after being compressed about 10-90% of original size (for example compression is about the 9/10-1/10 of original size).Elastomeric matrices 10 used herein has " resilience-compressibility ", promptly is " resilience-compressible " in 50% o'clock of relaxed configuration size that external second work structuring is at least about the dimension of 1-at least form.In another embodiment, the resilience-compressibility of elastomeric matrices 10 makes second work structuring in 80% of the external relaxed configuration size that is at least about the dimension of 1-at least form.In another embodiment, the resilience-compressibility of elastomeric matrices 10 makes second work structuring in 90% of the external relaxed configuration size that is at least about the dimension of 1-at least form.In another embodiment, the resilience-compressibility of elastomeric matrices 10 makes second work structuring in 97% of the external relaxed configuration size that is at least about the dimension of 1-at least form.

In another embodiment, elastomeric matrices has resilience-compressibility as herein described after being compressed about 5-95% of initial volume (for example compression is about the 19/20-1/20 of initial volume).In another embodiment, elastomeric matrices has resilience-compressibility as herein described after being compressed about 10-90% of initial volume (for example compression is about the 9/10-1/10 of initial volume)." volume " used herein is the volume divided by elastomeric matrices outermost 3-dimension profile.In another embodiment, the resilience-compressibility of elastomeric matrices 10 makes second work structuring be at least about relaxed configuration in vivo and occupies 50% of volume.In another embodiment, the resilience-compressibility of elastomeric matrices 10 makes second work structuring be at least about relaxed configuration in vivo and occupies 80% of volume.In another embodiment, the resilience-compressibility of elastomeric matrices 10 makes second work structuring be at least about relaxed configuration in vivo and occupies 90% of volume.In another embodiment, the resilience-compressibility of elastomeric matrices 10 makes second work structuring be at least about elastomeric matrices in vivo and occupies 97% of volume with its relaxed configuration form.

Abundant elastomer and the elasticity implantable device that characterizes

In one embodiment, as separately or with the elastomer of elastomeric matrices 10 structural materials of admixture or solution combination be the abundant synthetic elastomeric polymer of sign, they have proper mechanical capacity, these mechanical performances are at chemistry, physics or biological nature aspect are fully characterized and are regarded as biodurable and the interior implantable device of body that be suitable for being used as patient, particularly mammal and especially people.In another embodiment, the elastomer that is used as elastomeric matrices 10 structural materials is at chemistry, physics or biological nature aspect are fully characterized and are regarded as biodurable and the interior implantable device of body that be suitable for being used as patient, particularly mammal and especially people.

The elastomeric matrices physical characteristic

Elastomeric matrices 10, reticulated elastomeric matrix comprises the implantable device of reticulated elastomeric matrix and/or comprises that the implantable device of compression molded reticulated elastomeric matrix can have any suitable bulk density consistent with its other characteristic, is also referred to as proportion.For example, in one embodiment, can be about the about 0.96g/cc of 0.005g/cc-(about 0.31 lb/ft as bulk density according to test determines described in the ASTM Standard D3574 ³-Yue 60 lb/ft ³).In another embodiment, bulk density can be about the about 0.56g/cc of 0.048g/cc-(about 3.0 lb/ft ³-Yue 35 lb/ft ³).In another embodiment, bulk density can be about the about 0.15g/cc of 0.005g/cc-(about 0.31 lb/ft ³-Yue 9.4 lb/ft ³).In another embodiment, bulk density can be about the about 0.127g/cc of 0.008g/cc-(about 0.5lb/ft ³-Yue 8 lb/ft ³).In another embodiment, bulk density can be about the about 0.115g/cc of 0.015g/cc-(about 0.93 lb/ft ³-Yue 7.2 lb/ft ³).In another embodiment, bulk density can be about the about 0.104g/cc of 0.024g/cc-(about 1.5 lb/ft ³-Yue 6.5 lb/ft ³).

It is long-pending that elastomeric matrices 10 can have any suitable microcosmic surface consistent with its other characteristic.For example, the plane that those skilled in the art can expose according to porous material usually is by the hole frequency, and it is long-pending that for example the hole number in every millimeter line estimates microcosmic surface, and can estimate to portal frequency by the average compartment side diameter in μ m usually.

Other suitable physical characteristic obviously or apparent to those skilled in the art.

The elastomeric matrices mechanical performance

In one embodiment, reticulated elastomeric matrix 10 has enough structural intergrities so that in external self-supporting and self-support.Yet, in another embodiment, the structural support thing is provided can for elastomeric matrices 10, such as rib or minor connector.

Reticulated elastomeric matrix 10 has enough hot strengths, make it to specify in the application process He in the post-treatment step process and withstand normal craft or mechanically actuated at it, described post-treatment step is not because of tearing, fracture, peel off, fragmentation or disintegrate, come off sheet or granule, or lose its structural intergrity but needs or ideal.The hot strength of raw material should be so not high, to such an extent as to can disturb manufacturing or other processing of elastomeric matrices 10.

Therefore, for example, in one embodiment, reticulated elastomeric matrix 10 can have about 700kg/m ²-Yue 350,000kg/m ²The hot strength of (the about 500psi of about 1psi-).In another embodiment, elastomeric matrices 10 can have about 700kg/m ²-Yue 70,000kg/m ²The hot strength of (the about 100psi of about 1psi-).In another embodiment, it is about 7 that reticulated elastomeric matrix 10 can have, 000kg/m ²-Yue 140,000kg/m ²The stretch modulus of (the about 200psi of about 10psi-).In another embodiment, it is about 17 that elastomeric matrices 10 can have, 500kg/m ²-Yue 70,000kg/m ²The stretch modulus of (the about 100psi of about 25psi-).

Limit tensile elongation also is ideal fully.For example, in another embodiment, reticulated elastomeric matrix 10 has and is at least about 25% limit tensile elongation.In another embodiment, elastomeric matrices 10 has and is at least about 200% limit tensile elongation.

In one embodiment, elastomeric matrices 10 expand into second work structuring from first compact texture in short-term, for example in one embodiment, in 90 seconds or 90 seconds, in another embodiment, in 40 seconds or 40 seconds, each recovers about 95% after 75% compression strain keeps reaching 10 minutes.In another embodiment, elastomeric matrices 10 expand into second work structuring from first compact texture in short-term, for example in one embodiment in 180 seconds or 180 seconds, in another embodiment in 90 seconds or 90 seconds, in 60 seconds or 60 seconds, each recovers about 95% after 75% compression strain keeps reaching 30 minutes in another embodiment.In another embodiment, after 75% compression strain keeps reaching 30 minutes, thereby elastomeric matrices 10 in about 10 minutes, recover to occupy the occupied volume of its relaxed configuration at least about 97%.

In one embodiment, it is about 7 that reticulated elastomeric matrix 10 can have, 000kg/m ²-Yue 140,000kg/m ²The modulus of compressibility of (the about 200psi of about 10psi-).In another embodiment, it is about 17 that elastomeric matrices 10 has, 500kg/m ²-Yue 70,000kg/m ²The modulus of compressibility of (the about 100psi of about 25psi-).In another embodiment, reticulated elastomeric matrix 10 has about 700kg/m under 50% compression strain ²-Yue 350,000kg/m ²The comprcssive strength of (the about 500psi of about 1psi-).In another embodiment, reticulated elastomeric matrix 10 has about 700kg/m under 50% compression strain ²-Yue 70,000kg/m ²The comprcssive strength of (the about 100psi of about 1psi-).In another embodiment, it is about 7 that reticulated elastomeric matrix 10 has under 75% compression strain, 000kg/m ²-420,000kg/m ²The comprcssive strength of (the about 600psi of about 10psi-).In another embodiment, it is about 7 that reticulated elastomeric matrix 10 has under 75% compression strain, 000kg/m ²-Yue 140,000kg/m ²The comprcssive strength of (the about 200psi of about 10psi-).

In another embodiment, reticulated elastomeric matrix 10 promptly is compressed to 50% o'clock of its thickness according to ASTMD3574 and has and be no more than about 30% compression set under about 25 ℃.In another embodiment, elastomeric matrices 10 has and is no more than about 20% compression set.In another embodiment, elastomeric matrices 10 has and is no more than about 10% compression set.In another embodiment, elastomeric matrices 10 has and is no more than about 5% compression set.

In another embodiment, as according to test determines described in the ASTM Standard D3574, reticulated elastomeric matrix 10 has the tearing toughness of the linear about 8.90kg/ linearity cm of cm-of about 0.18kg/ (about 1 lbs/ linear inch-Yue 50 lbs/ linear inches).In another embodiment, as according to test determines described in the ASTM Standard D3574, reticulated elastomeric matrix 10 has the tearing toughness of the linear about 1.78kg/ linearity cm of cm-of about 0.18kg/ (about 1 lbs/ linear inch-Yue 10 lbs/ linear inches).

In another embodiment, as according to test determines described in the embodiment 5, reticulated elastomeric matrix 10 has about 50 seconds-Yue 2,500 seconds static recovery time t-90%.In another embodiment, reticulated elastomeric matrix 10 has about 100 seconds-Yue 2,000 seconds static recovery time t-90%.In another embodiment, reticulated elastomeric matrix 10 has about 125 seconds-Yue 1,500 second static recovery time t-90%.

In another embodiment, as according to method of testing described in the embodiment 5 in air and measure after 5,000 circulations under the 1Hz frequency, reticulated elastomeric matrix 10 has about 5 seconds-Yue 200 seconds dynamic recovery time t-90%.In another embodiment, as in air and measure after 100,000 circulations under the 1Hz frequency, reticulated elastomeric matrix 10 has 4,000 seconds dynamic recovery time t-90%.In one embodiment, be less than about 1,750 second.In another embodiment, be less than about 200 seconds.In another embodiment, or about 50 seconds-Yue 4,000 seconds.In another embodiment, in water and measure after 100,000 circulations under the 1Hz frequency, reticulated elastomeric matrix 10 has about 3,000 seconds dynamic recovery time t-90%.In one embodiment, be less than about 1,500 second.In another embodiment, be less than about 100 seconds.In another embodiment, or about 50 seconds-Yue 3,000 seconds.

Table 1 has been summarized and has been suitable for reticulated elastomeric matrix 10, is included in the mechanical performance of embodiment and other characteristic of those reticulated elastomeric matrixes of nettedization after annealing.Extra suitable mechanical is apparent to those skilled in the art or become apparent.

Table 1: the characteristic of reticulated elastomeric matrix 10

Characteristic	Representative value
Characteristic	Representative value	Proportion/bulk density	0.31-9.41b/ft ³(0.005-0.15g/ cc)
Stretch modulus	10-200psi(7,000-140,000kg/ m ²)	Proportion/bulk density	0.31-9.41b/ft ³(0.005-0.15g/ cc)
Stretch modulus	10-200psi(7,000-140,000kg/ m ²)	Hot strength	1-500psi(700-350,000kg/m ²)
Limit tensile elongation	≥25％	Hot strength	1-500psi(700-350,000kg/m ²)
Limit tensile elongation	≥25％	Modulus of compressibility	10-200psi(7,000-140,000kg/ m ²)
Comprcssive strength under 50% compression	1-500psi(700-350,000kg/m ²)	Modulus of compressibility	10-200psi(7,000-140,000kg/ m ²)
Comprcssive strength under 50% compression	1-500psi(700-350,000kg/m ²)	Comprcssive strength under 75% compression	10-600psi(7,000-420,000kg/ m ²)
50% compression set, 22 hours, under 25 ℃	≤30％	Comprcssive strength under 75% compression	10-600psi(7,000-420,000kg/ m ²)
50% compression set, 22 hours, under 25 ℃	≤30％	Tearing toughness	1-501bs/ linear inch (the linear cm of 0.18-8.90kg/)
The static recovery time [t-90% (second) of 50% uniaxial compression after 120 minutes]	50-2,500	Tearing toughness	1-501bs/ linear inch (the linear cm of 0.18-8.90kg/)
	50-2,500	Dynamic recovery time [t-90% (second) under 1Hz after the period of 50% compression during ± 5% strain] 5,000 (in air) 100,000 circulations (in air) 100,000 circulations (in water) that circulate	5-200 50-4,000 50-3,000
			5-200 50-4,000 50-3,000

Unless otherwise stated, otherwise the mechanical performance of porous material described herein can be measured according to title " Standard TestMethods for Flexible CellularMaterials-Slab, Bonded and Molded Urethane Foams " or the suitable known method of other this class those skilled in the art of ASTMD3574-01.

In addition, if porous is endowed the elastomer that is used for elastomeric matrices 10 after non-polymeric course of reaction, so good processability also is ideal for polymerization postforming and manufacturing.For example, in one embodiment, elastomeric matrices 10 has low viscosity.

Biodurable and biocompatibility

In one embodiment, elastomer has enough biodurable, so that be suitable for implanting for a long time patient, for example animal or human.Biodurable elastomer and elastomeric matrices have chemistry, and physics and/or biological nature are so that provide the expection of rational biodurable, and promptly described elastomer is being implanted animal, for example can show at least 29 days time limits of stability during mammal.The long-term life expectancy of implanting can change according to the difference of application-specific.With regard to many application, need long-term implantation basically, and with regard to this class is used, may need at least 6,12 or the biodurable in time limit more than 24 months or 5 years or 5 years.What have special helpfulness is can be regarded as being the elastomer of biodurable in the life-span the patient.With regard to may the using of elastomeric matrices 10 embodiments for the treatment of spinal defect for example,, may be favourable so in its body, surpass the biodurable in 50 years because this class illness self may be present among suitable youngster's body patient.

In another embodiment, implant the time limit be enough at least make cell inwardly growth and propagation begin to take place, for example at least about 4-8 in week.In another embodiment, elastomer is enough to fully be characterized so that have the chemistry that this class provides the expection of reasonable biodurable because of demonstration, physics and/or biological nature are suitable for long-term implantation, and promptly elastomer can continue to show biodurable when implanting time limit time expand.

Not retrained by any particular theory, the biodurable of the elastomeric matrices that is formed by the method that comprises polymerization, crosslinked, foaming and nettedization comprises the material composition that is chosen as biodurable and the stoichiometric proportion of those compositions, makes elastomeric matrices keep the biodurable of its composition.For example, can by will be for example the chemical bond of facile hydrolysis and group under patient's rehydration temperature and pH, be reduced to bottom line such as the existence of ester group and formation and improve the elastomeric matrices biodurable.As another example, can after crosslinked and foaming, surpass about 2 hours curing schedule, so that the free amino that exists on the elastomeric matrices is reduced to bottom line.In addition, importantly degraded is reduced to bottom line, described degraded may occur in the elastomeric matrices preparation process, for example occur because of contacting shearing or heat energy, such as may be in the mixing as any method known in the art, dissolving occurs in the crosslinked and/or bubbling process.

As mentioned above, biodurable elastomer and elastomeric matrices are suitable for time limit time expand and are in the biotic environment.This series products can not show tangible decomposition, and degraded is corroded symptom or obviously relate to the mechanical performance degeneration of its application when the biotic environment of the contact time bar suitable with its application and/or body fluid stress.Yet some bursts apart, and it may not be relevant with other application with many orthopedic applications as described herein that the disappearance of cracking or toughness and intensity-be called sometimes ESC or environmental stress burst apart.Use in many bodies, for example when elastomeric matrices 10 is used for the treatment of the orthopedic applications position, is exposed to less (if any) mechanical stress, and can produce the mechanical damage that causes the severe patient consequence thus.Therefore, do not exist ESC for estimating that the suitable elastomeric biodurable in this class application of the present invention is not essential, because elastic importance degree reduction when endothelialization, encapsulation and cell are inwardly grown and bred progress.

In addition, in some implant to be used, estimate elastomeric matrices 10 process in time, parcel such as the wall that for example becomes comes off or is organized, scar tissue or mix with fully integrated or biointegration and for example go into the tissue of being repaired or the chamber of being treated in 2 week-1 year.In this case, elastomeric matrices 10 has reduced contact movement or circulation biofluid.Therefore, can't eliminate also and can be weakened even biochemical degradation or the deleterious product of unwanted possibility are released into the probability of host organisms.

In one embodiment, elastomeric matrices has good biodurable, and is attended by excellent biological compatibility, makes elastomer can induce (if any also seldom) untoward reaction hardly in vivo.In order to reach this purpose, be used for another embodiment of the invention, the biology that can induce untoward reaction or effect does not in vivo need or elastomer or other material of harmful substance or structure in order not contain when placing the prolongation of appointment implant site to implant the time limit.This class elastomer should lack or should only comprise biotoxin, mutagenic agent, carcinogen and/or the teratogen of extremely low biological tolerance amount thus fully.In another embodiment, the elastomeric biodurable biological characteristic that is used for making elastomeric matrices 10 comprises the antibiont degraded and does not exist or the following situation of extremely low amount at least a: cytotoxicity, hematotoxicity, carcinogenecity, mutagenicity or teratogenecity.

From the elastomer polymerization, crosslinked and blistered elastomeric matrices

In other embodiments, the invention provides multiporous biological durability elastomer and polymerization, crosslinked and their method of foaming, and they can be used to produce biodurable reticulated elastomeric matrix 10 as described herein.In another embodiment, nettedization is as follows.

More particularly, in another embodiment, the invention provides the method for preparing biodurable elastomeric polyurethane substrate, comprise by polycarbonate polyol composition and synthetic this substrate of isocyanate prepolymer composition, by polymerization, crosslinked and foaming is carried out, and forms the hole thus, makes nettedization of foam subsequently and obtains nettedization product.With this product called after Merlon polyurethanes, be the polymer of the carbamate groups that comprises that the NCO by the hydroxyl of for example polycarbonate polyol composition and isocyanate prepolymer composition forms.In this embodiment, described method has been used controlled chemistry so that the body of the reticulated elastomeric with good biological durability characteristics is provided.According to the present invention, carry out polymerization and avoid wherein biological and do not need or product that the chemical method of harmful components obtains so that provide to use.

In one embodiment, as a kind of raw material, described method is used at least a polyol component.With regard to the application's purpose, term " polyol component " comprises that average each molecule contains the molecule of about 2 hydroxyls, i.e. difunctionality polyhydric alcohol or dihydroxylic alcohols; And on average each molecule contains the molecule of about 2 above hydroxyls, i.e. polyhydric alcohol or multi-functional polyol.Average each molecule of typical case's polyalcohols contains about 5 hydroxyls of about 2-.In one embodiment, as a kind of raw material, described method is used the difunctionality polyol component.In this embodiment, because the hydroxy functionality of dihydroxylic alcohols is about 2, so it does not provide the so-called soft segments crosslinked " soft segments " that has.In another embodiment, as a kind of polyol component raw material, described method uses multi-functional polyol's composition of capacity so that provide the soft segments of controlled degree crosslinked.In another embodiment, this method provides enough soft segments crosslinked so that produce stable foam.In another embodiment, described soft segments is made of general relative low molecular weight polyols composition, in one embodiment, and about 6,000 dalton of about 350-, and in another embodiment, ' about 4,000 dalton of about 450-.Therefore, these polyalcohols are generally liquid or low melting point solid.This soft segments polyhydric alcohol is by uncle or secondary hydroxyl end-blocking.In another embodiment, each molecule of soft segments polyol component has about 2 hydroxyls.In another embodiment, each molecule of soft segments polyol component has about 2 above hydroxyls; It is that some polyhydric alcohol molecule is required crosslinked so that give soft segments that each polyhydric alcohol molecule has 2 above hydroxyls.

In one embodiment, the average number of hydroxyl in each molecule is about 2 in polyol component.In another embodiment, in polyol component the average number of hydroxyl in each molecule approximately greater than 2.In another embodiment, in polyol component the average number of hydroxyl in each molecule greater than 2.In one embodiment, polyol component comprises the tertiary carbon key.In one embodiment, polyol component comprises a plurality of tertiary carbon keys.

In one embodiment, polyol component is a polyether polyol, PEPA, polycarbonate polyol, the hydrocarbon polyhydric alcohol, polysiloxane polyhydric alcohol, poly-(ether-altogether-ester) polyhydric alcohol, poly-(ether-altogether-carbonic ester) polyhydric alcohol, poly-(ether-altogether-hydrocarbon) polyhydric alcohol, poly-(ether-altogether-siloxanes) polyhydric alcohol, poly-(ester-altogether-carbonic ester) polyhydric alcohol, poly-(ester-altogether-hydrocarbon) polyhydric alcohol, poly-(ester-altogether-siloxanes) polyhydric alcohol, poly-(carbonic ester-altogether-hydrocarbon) polyhydric alcohol, poly-(carbonic ester common-siloxanes) polyhydric alcohol, poly-(hydrocarbon-altogether-siloxanes) polyhydric alcohol or its mixture.

Polyethers-class polyhydric alcohol for for example with glycols or the polymeric alkylene oxide of polyalcohols, such as the oligomer of oxirane or expoxy propane, the latter causes hydroxy functionality crosslinked so that can carry out soft segments greater than 2.

Polyester-class polyhydric alcohol is the oligomer of the product of carboxylic acid and ethylene glycol or trihydroxylic alcohol, such as glycol adipate, and propylene glycol adipate ester, butanediol butanediol, diethylene glycol adipate ester, phthalate, pla-pcl and Oleum Ricini.When reactant comprises when having greater than those of 2 hydroxy functionality, polyalcohols for example, it is crosslinked to carry out soft segments.

Merlon-class polyhydric alcohol generally obtains for hydrocarbon binary acid alcohols and the carbonate monomer reaction that has different hydrocarbon chains length between each comfortable hydroxyl by a class hydrocarbon dihydroxylic alcohols or with regard to a plurality of polyhydric alcohol.The hydrocarbon chain length between the adjacent carbons esters of gallic acid and the hydrocarbon chain appearance of original dihydroxylic alcohols (class) are together.For example, can be by making 1,6-hexanediol and carbonate prepare the difunctionality polycarbonate polyol such as reaction of sodium bicarbonate, thereby obtain Merlon-class polyhydric alcohol 1,6-hexanediol carbonic ester.The molecular weight that is purchased product of this reaction changes between about 5,000 dalton of about 500-.If polycarbonate polyol is solid down at 25 ℃, it generally further is being melted before the processing so.Selectively, in one embodiment, can be by the mixture of hydrocarbon di-alcohols, for example 1, the 6-hexanediol, cyclohexyl dimethanol and 1, three kinds of all of 4-butanediol or any binary combination prepare liquid polycarbonate polyol composition.Be not subjected to any passage theory constraint, think that the mixture of this class hydrocarbon di-alcohols can destroy the degree of crystallinity of product polycarbonate polyol composition, thereby make that it is down to produce more softish relatively foam in liquid and the foam that is comprising it thus at 25 ℃.

Have greater than those of 2 hydroxy functionality when the reactant that is used for producing polycarbonate polyol comprises, for example during polyalcohols, it is crosslinked to carry out soft segments.Can have polycarbonate polyol class greater than 2 average number of hydroxyl, for example Merlon trihydroxylic alcohol by in preparation polycarbonate polyol composition, using hexanetriol for example to prepare each molecule.In order to prepare liquid Merlon trihydroxylic alcohol composition, can make the material with other hydroxyl, for example mixture of cyclohexyl front three alcohol and/or butantriol and carbonic ester and hexanetriol reaction.

Be purchased hydrocarbon-class polyhydric alcohol and generally produced by the radical polymerization of dienes and vinyl monomer, therefore, they are generally the hydroxy-end capped material of difunctionality.

Polysiloxane polyhydric alcohol is the alkyl of for example contain hydroxy end groups and/or the type siloxane that aryl replaces, such as dimethyl siloxane, and the oligomer of diphenyl siloxane or methyl phenyl siloxane.Can have polysiloxane polyhydric alcohol class greater than 2 average number of hydroxyl, for example polysiloxanes trihydroxylic alcohol by in preparation polysiloxane polyhydric alcohol composition, using methyl methylol siloxanes for example to prepare each molecule.

The polyhydric alcohol of particular type need not to be limited to those that are made of single monomeric unit.For example, polyethers-class polyhydric alcohol can be formed by oxirane and propylene oxide mixture.

In addition, in another embodiment, copolymer or polyol class can be formed by means commonly known in the art by any kind in the above-mentioned polyalcohols.Therefore, can use the polyol copolymer of following two metamembers: poly-(ether-altogether-ester) polyhydric alcohol, poly-(ether-altogether-carbonic ester) polyhydric alcohol, poly-(ether-altogether-hydrocarbon) polyhydric alcohol, poly-(ether-altogether-siloxanes) polyhydric alcohol, poly-(ester-altogether-carbonic ester) polyhydric alcohol, poly-(ester-altogether-hydrocarbon) polyhydric alcohol, poly-(ester-altogether-siloxanes) polyhydric alcohol, poly-(carbonic ester-be total to-hydrocarbon) polyhydric alcohol, poly-(carbonic ester-altogether-siloxanes) polyhydric alcohol and poly-(hydrocarbon-be total to-siloxanes) polyhydric alcohol.For example, poly-(ether-be total to-ester) polyhydric alcohol can be formed by polyether units, and described polyethers is formed by oxirane and the polyester unit combined polymerization that contains glycol adipate.In another embodiment, copolymer is poly-(ether-be total to-carbonic ester) polyhydric alcohol, poly-(ether-altogether-hydrocarbon) polyhydric alcohol, poly-(ether-altogether-siloxanes) polyhydric alcohol, poly-(carbonic ester-altogether-hydrocarbon) polyhydric alcohol, poly-(carbonic ester-altogether-siloxanes) polyhydric alcohol, poly-(hydrocarbon-altogether-siloxanes) polyhydric alcohol or its mixture.In another embodiment, copolymer is poly-(carbonic ester-be total to-hydrocarbon) polyhydric alcohol, poly-(carbonic ester-altogether-siloxanes) polyhydric alcohol, poly-(hydrocarbon-altogether-siloxanes) polyhydric alcohol or its mixture.In another embodiment, copolymer is poly-(carbonic ester-be total to-hydrocarbon) polyhydric alcohol.For example, can be by making 1, the 6-hexanediol, 1, that 4-butanediol and hydrocarbon-class polyhydric alcohol and carbonic ester polymerization form is poly-(carbonic ester-altogether-hydrocarbon) polyhydric alcohol.

In another embodiment, polyol component is a polyether polyol, polycarbonate polyol, hydrocarbon polyhydric alcohol, polysiloxane polyhydric alcohol, poly-(ether-altogether-carbonic ester) polyhydric alcohol, poly-(ether-altogether-hydrocarbon) polyhydric alcohol, poly-(ether-altogether-siloxanes) polyhydric alcohol, poly-(carbonic ester-altogether-hydrocarbon) polyhydric alcohol, poly-(carbonic ester-altogether-siloxanes) polyhydric alcohol, poly-(hydrocarbon-altogether-siloxanes) polyhydric alcohol or its mixture.In another embodiment, polyol component is a polycarbonate polyol, the hydrocarbon polyhydric alcohol, and polysiloxane polyhydric alcohol, poly-(carbonic ester-altogether-hydrocarbon) polyhydric alcohol, poly-(carbonic ester-altogether-siloxanes) polyhydric alcohol, poly-(hydrocarbon-altogether-siloxanes) polyhydric alcohol or its mixture.In another embodiment, polyol component is a polycarbonate polyol, poly-(carbonic ester-altogether-hydrocarbon) polyhydric alcohol, poly-(carbonic ester-altogether-siloxanes) polyhydric alcohol, poly-(hydrocarbon-altogether-siloxanes) polyhydric alcohol or its mixture.In another embodiment, polyol component is a polycarbonate polyol, poly-(carbonic ester-altogether-hydrocarbon) polyhydric alcohol, poly-(carbonic ester-altogether-siloxanes) polyhydric alcohol or its mixture.In another embodiment, polyol component is a polycarbonate polyol.

In addition, in another embodiment, can in elastomeric matrices of the present invention, use the mixture (mixtures) of polyalcohols and polyol class, mixture (admixtures) and/or admixture.In another embodiment, the molecular weight of polyhydric alcohol is variable.In another embodiment, the degree of functionality of polyhydric alcohol is variable.

In another embodiment, when difunctionality polycarbonate polyol class or difunctionality hydrocarbon polyalcohols because of himself can not induce soft segments crosslinked the time, introduce higher functionality in the preparation by having greater than being applied in of cahin extension agent of about 2 hydroxy functionality.In another embodiment, introduce higher functionality by having greater than the application of the isocyanate prepolymer composition of about 2 NCO degree of functionality.Commodity PCDL class with about 5,000 Dalton molecular weights of about 500-, such as from Arch Chemicals, ((Peabody, PC-1733 MA) is easy to obtain Inc. Inc. for Norwalk, POLY-CD CD220 CT) and from Stahl USA.Commodity hydrocarbon polyalcohols available from Sartomer (Exton, PA).Commodity polyether polyol class be easy to available from, such as PLURACOL, for example has degree of functionality and is 3 PLURACOL GP430 and from BASFCorp. (Wyandotte, MI) LUPRANOL series is from Dow ChemicalCorp. (Midland, VORANOL MI.), from Bayer Corp. (Leverkusen, Germany) and Huntsman Corp. (Madison Heights, MI) BAYCOLL B, DESMOPHEN and MULTRANOL.Commodity polyester polyols alcohols is easy to obtain, such as LUPRAPHEN from BASF, and from Dow, the TONE polycaprolactone of BAYCOLL A and VORANOL and from the DESMOPHEN U series of Bayer and Huntsman.Commodity polysiloxane polyhydric alcohol class is easy to obtain, such as from Dow.

Described method also uses at least a isocyanate prepolymer composition and optional at least a cahin extension agent composition so that so-called " hard segment " is provided.With regard to the application's purpose, term " isocyanate prepolymer composition " comprises that average each molecule contains the molecule of about 2 isocyanate groups and each molecule and on average contains those molecules greater than about 2 isocyanate groups.The reactive hydrogen radical reaction of the isocyanate groups of isocyanate prepolymer composition and other component, for example with hydroxyl in oxygen generation hydrogen bonding and with polyol component in amine in nitrogen, cahin extension agent, cross-linking agent and/or waterishlogging are given birth to hydrogen bonding.

In one embodiment, the isocyanate groups average in each molecule is about 2 in the isocyanate prepolymer composition.In another embodiment, in the isocyanate prepolymer composition isocyanate groups average in each molecule greater than about 2.In another embodiment, on the isocyanate prepolymer composition isocyanate groups average in each molecule greater than 2.

Isocyanate index, be quantity well-known in the art be in the goods that can be used for reacting isocyanate groups quantity with can with the mol ratio of group quantity in the goods of those isocyanate groups reaction, group in the goods of described and the reaction of those isocyanate groups for example is dihydroxylic alcohols if present, polyol component, the reactive group of cahin extension agent and water.In one embodiment, isocyanate index is about 0.9-about 1.1.In another embodiment, isocyanate index is about 0.9-about 1.02.In another embodiment, isocyanate index is about 0.98-about 1.02.In another embodiment, isocyanate index is about 0.9-about 1.0.In another embodiment, isocyanate index is about 0.9-about 0.98.

Typical diisocyanates comprises aliphatic diisocyanates, comprises the isocyanates of aromatic group, promptly so-called " aromatic diisocyanates " or its mixture.Aliphatic diisocyanates comprises two Carbimide. tetramethylene esters, cyclohexane extraction-1,2-vulcabond, cyclohexane extraction-1,4-vulcabond, two Carbimide .s, six methylene esters, two Carbimide. isophorone esters, methylene-two-(right-cyclohexyl isocyanate) (" H ₁₂MDI ") or its mixture.Aromatic diisocyanates comprises right-phenylene vulcabond, 4,4 '-'-diphenylmethane diisocyanate (" 4; 4 '-MDI "), 2,4 '-'-diphenylmethane diisocyanate (" 2; 4 '-MDI "), 2,4 toluene diisocyanate (" 2,4-TDI "), 2,6-toluene di-isocyanate(TDI) (" 2,6-TDI ") ,-tetramethylxylene diisocyanate or its mixture.

The typical isocyanate prepolymer composition that each molecule on average contains greater than about 2 isocyanate groups comprises: the adduct that contains about 3 isocyanate groups of two Carbimide .s, six methylene esters and water, and it is purchased from Bayer as DESMODUR N100; With the trimer (trirner) of two Carbimide .s, the six methylene esters that contain about 3 isocyanate groups, it is purchased from Bayer as MONDUR N3390.

In one embodiment, isocyanate prepolymer composition contains at least about 2 of 5% weight, 4 '-MDI and counterbalance 4, the mixture of 4 '-MDI.In another embodiment, isocyanate prepolymer composition contains 2 of at least 5% weight, 4 '-MDI and counterbalance 4, the mixture of 4 '-MDI.In another embodiment, isocyanate prepolymer composition contains 2 of about 50% weight of about 5%-, 4 '-MDI and counterbalance 4, the mixture of 4 '-MDI.In another embodiment, isocyanate prepolymer composition contains 2 of about 50% weight of 5%-, 4 '-MDI and counterbalance 4, the mixture of 4 '-MDI.In another embodiment, isocyanate prepolymer composition contains 2 of about 40% weight of about 5%-, 4 '-MDI and counterbalance 4, the mixture of 4 '-MDI.In another embodiment, isocyanate prepolymer composition contains 2 of about 40% weight of 5%-, 4 '-MDI and counterbalance 4, the mixture of 4 '-MDI.In another embodiment, isocyanate prepolymer composition contains 2 of about 35% weight of 5%-, 4 '-MDI and counterbalance 4, the mixture of 4 '-MDI.Not retrained by any particular theory, think a large amount of 2,4 '-MDI and 4, the application of the admixture of 4 '-MDI since destroyed asymmetric 2, the hard segment degree of crystallinity that 4 '-MDI structure produces and produce softer elastomeric matrices.

Suitable diisocyanates comprises: MDI, such as ISONATE 125M, from some member of the PAPI series of Dow with from ISONATE 50 OP of Dow; Contain 4,4 '-MDI and 2, the isocyanates of 4 '-MDI mixture, such as RUBI NATE 9433 and RUBINATE9258, they are separately from Huntsman and MONDUR MRS 2 with from the MRS 20 of Bayer; TDI, for example from Lyondell Corp. (Houston, TX); Isophorone diisocyanate is such as the VESTAMAT from Degussa (Germany); H ₁₂MDI is such as the DESMODUR W from Bayer; With various diisocyanates from BASF.

On average contain the '-diphenylmethane diisocyanate class that comprises following modification greater than the suitable isocyanate prepolymer composition of about 2 isocyanate groups in each molecule, they are separately available from Dow:ISOBIND 1088, and the isocyanate groups degree of functionality is about 3; ISONATE 143L, the isocyanate groups degree of functionality is about 2.1; PAPI 27, and the isocyanate groups degree of functionality is about 2.7; PAPI94, the isocyanate groups degree of functionality is about 2.3; PAPI 580N, the isocyanate groups degree of functionality is about 3; With PAPI 20, the isocyanate groups degree of functionality is about 3.2.

Typical cahin extension agent comprises di-alcohols, two amines, alkanolamine or its mixture.In one embodiment, cahin extension agent is the aliphatic dihydric alcohol with 2-10 carbon atom.In another embodiment, glycol chain extender is selected from ethylene glycol, and 1,2-propylene glycol, 1, ammediol, 1,4-butanediol, 1,5-pentanediol, diethylene glycol, 2,2'-ethylenedioxybis(ethanol). or its mixture.In another embodiment, cahin extension agent is the diamidogen with 2-10 carbon atom.In another embodiment, diamine chain extender is selected from ethylenediamine, and 1,3-diaminobutane, 1,4-diaminobutane, 1,5 diaminourea pentane, 1,1,7-diaminourea heptane, 1,8-diaminourea octane, isophorone diamine or its mixture.In another embodiment, cahin extension agent is the alkanolamine with 2-10 carbon atom.In another embodiment, alkanol amine chain extender is selected from diethanolamine, triethanolamine, isopropanolamine, dimethylethanolamine, methyl diethanolamine, diethyl ethylene diamine or its mixture.

Be purchased cahin extension agent and comprise two amines, the JEFFAMI NE of three amines series and from the polyether monoamine of Hunt sman, VERSAMIN isophorone diamine from Creanova, available from Air Products Corp. (Allentown, the VERSALI NK series of two amines PA), ethanolamine, diethyl ethylene diamine and available from the isopropanolamine of Dow with from Bayer, BASF and UOP Corp. (Des Plaines, various cahin extension agents IL).

In one embodiment, have a spot of optional components, have the cross-linking agent that surpasses 2 degree of functionality such as multifunctional hydroxy compounds or other, for example glycerol is so that crosslinked.In another embodiment, the amount of optional multifunctional cross-linking agent is enough to obtain stable foam just, promptly can disintegrate become the foam of non-foam sample.Selectively or in addition, the multifunctional adduct of aliphatic series and cyclic aliphatic isocyanates can be used to give with aromatic diisocyanates crosslinked.Selectively or in addition, the multifunctional adduct of aliphatic series and cyclic aliphatic isocyanates can be used to give with aliphatic diisocyanates crosslinked.Optional this method is used at least a catalyst in certain embodiments, and it is selected from the foaming catalyst, tertiary amine for example, gelation catalyst, for example dibutyl tin laurate or its mixture.In addition, known tertiary amine catalyst also can have gelation in this area, and promptly they can be used as and bubble and gelation catalyst works.Typical tertiary amine catalyst comprises the TOTYCAT series from Toyo Soda Co. (Japan), from Texaco Chemical Co. (Austin, TX) TEXACAT series, KOSMOS and TEGO series from Th.Goldschmidt Co. (Germany), from Rohm and Haas (Philadelphia, PA) DMP series, from the KAOLIZER series of Kao Corp. (Japan) with from Enterprise Chemical Co. (Altamonte Springs, QUINCAT series FL).Typical organotin catalysts comprises the (Middlebury from WitcoCorporation, CT) FOMREZ and FOMREZ UL series, from CosanChemical Co. (Carlstadt, COCURE NJ) and COSCAT series and from DABCO and the POLYCAT series of AirProducts.

In certain embodiments, described method is used at least a surfactant.Exemplary surfactants comprises TEGOSTAB BF2370, B-8300, B-8305 and B-5055, they are all from Goldschmidt, from Dow Corning (Midland, DC 5241 MI) and other nonionic organosilicon are such as available from Dow Corning, Air Pr oducts and General Electric (Water ford, polydimethylsiloxane class NY).

In certain embodiments, described method is used at least a compartment opener.Typical compartment opener comprises from Goldschmidt) ORTEGOL 501.

Can prepare crosslinked polyurethanes by the means that comprise prepolymer method and single pot process.The embodiment that relates to prepolymer is as follows.At first, by conventional method by at least a isocyanate prepolymer composition (for example MDI) with at least aly have multifunctional soft segments material greater than 2 degree of functionality (for example have degree of functionality be 3 a soft segments) preparation prepolymer based on polyethers.Then with prepolymer, optional at least a catalyst (for example dibutyl tin laurate) and at least a difunctional chain extenders (for example 1,4-butanediol) in mixer mixing so that this mixture solidified or crosslinked.In another embodiment, crosslinkedly in mould, carry out.In another embodiment, crosslinked and foaming, promptly the hole is shaped and carries out jointly.In another embodiment, crosslinked and foaming is carried out in mould jointly.

Selectively, can use so-called " single jar " means.Single jar of embodiment need not independent prepolymer preparation process.In one embodiment, with raw material, those described in epimere mix in mixer and foaming and crosslinked then.In another embodiment, heating before described component is mixed.In another embodiment, when being mixed, described component heats them.In another embodiment, crosslinkedly in mould, carry out.In another embodiment, bubble and crosslinkedly carry out jointly.In another embodiment, crosslinked and foaming is carried out in mould jointly.In another embodiment, all components of mixing except that isocyanate prepolymer composition in mixer.For example add isocyanate prepolymer composition and the crosslinked and generation thereupon of bubbling then with high-speed stirred.In another embodiment, with this foaming mixture impouring mould and make its emersion.In another embodiment, with polyol component and isocyanate prepolymer composition and other optional additive, such as viscosity improver, surfactant and/or compartment opener are mixed into first liquid.

In another embodiment, described polyol component is liquid under mixing temperature.In another embodiment, described polyol component is a solid, and therefore, the rising mixing temperature makes and mixing precedent as make polyol component liquefaction by heating.Next by mixed foaming agent and optional additive, form second liquid such as gelation catalyst and/or foaming catalyst.In mixer, mix first and second liquid and foaming and crosslinked then then.

In another embodiment, any or all manufacturing process of the present invention all can be used for the preparation have greater than 3.4 lbs/ft ³(0.054g/cc) foam of density.In this embodiment, use cross-linking agent, such as glycerol; The degree of functionality of isocyanate prepolymer composition is 2.0-2.4; Isocyanate prepolymer composition mainly is made up of MDI; And 4, the amount of 4 '-MDI is greater than the isocyanate prepolymer composition of about 50% weight.The molecular weight of polyol component is about 1, about 2,000 dalton of 000-.Adjust foaming agent, for example the amount of water is so that obtain density greater than 3.4 lbs/ft ³Non-reticulated polymer foam (0.054g/cc).The foaming agent of reduction can reduce the quantity of urea key in the material.Can be by using difunctional chain extenders, such as butanediol and/or increase foam density and/or compensate any hardness that less urea key produces and/or the decline of hot strength and/or comprcssive strength by the amount that increases used cross-linking agent.

In one embodiment, reduce crosslinked degree and increase foamy toughness thus and/or the range of extension that breaks should be able to carry out more effective nettedization.In another embodiment, the higher density foamed materials of generation can stand one or more nettedization steps better, for example the unexpected impact of two nettedization steps and minimal damage (if any) to minor connector 16 can be provided.In one embodiment, the invention provides the method for the flexible polyurethanes biodurable substrate of preparation, this substrate can prepare based on polycarbonate polyol composition and nettedization of isocyanate prepolymer composition raw material.In another embodiment, provide the multiporous biological durability elastomer polymerization of preparation resilience polyurethane matrix, this method comprises mixed polycarbonate polyol component and aliphatic isocyanate composition, for example H ₁₂MDI.

In another embodiment, described foam is substantially free of the Carbimide. ester bond.In another embodiment, described foam does not have the Carbimide. ester bond.In another embodiment, described foam is substantially free of biuret linkage.In another embodiment, described foam does not have biuret linkage.In another embodiment, described foam is substantially free of the allophanic acid ester bond.In another embodiment, described foam does not have the allophanic acid ester bond.In another embodiment, described foam is substantially free of chlorinated isocyanurates and biuret linkage.In another embodiment, described foam does not have chlorinated isocyanurates and biuret linkage.In another embodiment, described foam is substantially free of chlorinated isocyanurates and allophanic acid ester bond.In another embodiment, described foam does not have chlorinated isocyanurates and allophanic acid ester bond.In another embodiment, described foam is substantially free of chlorinated isocyanurates and biuret linkage.In another embodiment, described foam does not have allophanate and biuret linkage.In another embodiment, described foam is substantially free of allophanate, biuret and isocyanuric acid ester bond.In another embodiment, described foam does not have allophanate, biuret and isocyanuric acid ester bond.Not retrained by any particular theory, think not have allophanate, biuret and/or isocyanuric acid ester bond are because of than the crosslinked suppleness of strengthening that provides for elastomeric matrices of the hard segment of low degree.

In certain embodiments, can include the additive that helps obtain stable foam, for example surfactant and catalyst.Be limited in minimum demand by amount, keep the degree of functionality of each additive simultaneously, can control influence product toxicity with this class additive.

In one embodiment, produced the elastomeric matrices of various density, the about 0.15g/cc of for example about 0.005-(about 9.4 lb/ft of about 0.31- ³).By the amount of foaming agent in the goods for example or foaming agent, isocyanate index, the pressure of isocyanate prepolymer composition content, exothermic heat of reaction curve and/or foaming environment is controlled density.

Typical foaming agent comprises water and physics foaming agent, volatile organic chemistry material matter for example, such as hydro carbons, ethanol and acetone and various fluorocarbons and more favourable substitute thereof to environment, such as hydrofluorocarbon, Chlorofluorocarbons (CFCs) and HCFC.Water and isocyanate groups reaction produce the carbon dioxide as foaming agent.In addition, in certain embodiments, can use foaming agent, such as the combination of water and fluorocarbons.In another embodiment, water is used as foaming agent.The fluorine carbon foaming agent that is purchased is available from Huntsman, E.I.duPont deNemours and Co. (Wilmington, DE), Allied Chemical (Minneapolis, MN) and Honeywell (Morristown, NJ).

With regard to purpose of the present invention, just be used for by bubbling and the polyol component of per 100 weight portions of crosslinked preparation elastomeric matrices (or 100 restrain) (polycarbonate polyol for example, polysiloxane polyhydric alcohol), by weight other that exists in goods becomes component as follows: the isocyanate prepolymer composition of the isocyanate index with about 0.85-about 1.10 of about 10-about 90 parts (or grams) (MDIs for example, its mixture, H ₁₂MDI), about 6.0 parts (or gram) foaming agents (for example water) of about 0.5-, about 2.0 parts (or gram) foaming catalyst (for example tertiary amine) of about 0.1-, about 8.0 parts (or gram) compartment openers of about 8.0 parts (or gram) surfactants of about 0.1-and about 0.1-.Certainly, the amount of used actual isocyanate prepolymer composition relates to and depends on the order of magnitude of the isocyanate index of particular product.In addition, with regard to the polyol component that is used for per 100 weight portions (or 100 grams) by foaming and crosslinked preparation elastomeric matrices, if exist, the amount of following optional member is as follows by weight in the goods so: reach 20 parts of (or gram) cahin extension agents approximately, reach 20 parts of (or gram) cross-linking agent approximately, reach 0.5 part of (or gram) gelation catalyst (for example wrapping stanniferous chemical compound) approximately, reach 10.0 parts of (or gram) physics foaming agents (hydro carbons for example approximately, ethanol, acetone, fluorocarbons) peace treaty reaches 15 parts of (or gram) viscosity improvers.

In other embodiments, just be used for by bubbling and the polyol component of per 100 weight portions of crosslinked preparation elastomeric matrices (or 100 restrain) (polycarbonate polyol for example, polysiloxane polyhydric alcohol), by weight other that exists in goods becomes component as follows: about 10-about 90 parts (or grams) has about 0.85-about 1.2, in one embodiment, the isocyanate prepolymer composition of about 1.019 isocyanate index of about 0.85-(MDIs for example, its mixture, H ₁₂MDI).In another embodiment, about 6.0 parts (or gram) foaming agents (for example water) of about 0.5-, about 3.0 parts (or gram) catalyst (for example tertiary amine) of optional about 0.05-, such as foaming catalyst and/or gelation catalyst, about 8.0 parts (or gram) surfactants of about 0.1-, about 8.0 parts (or gram) compartment openers of optional about 0.1-, about 8.0 parts (or gram) cross-linking agent of optional about 0.05-, about 8.0 parts (or gram) cahin extension agents of glycerol and optional about 0.05-for example, for example 1, the 4-butanediol.

Can make then to have nettedization of substrate that is suitable for the object of the invention characteristic, described characteristic as by test case as acceptable compression set under in human body temperature, air-flow, hot strength and compression property are determined.

In another embodiment, omitted gelation catalyst, tin catalyst and optional use another kind of catalyst for example, for example tertiary amine is alternative.In one embodiment, tertiary amine catalyst comprises one or more non-aromatic amines.In another embodiment, reaction is carried out so that make tertiary amine catalyst (if you are using) complete reaction become polymer and avoid identical residue.In another embodiment, omitted gelation catalyst and replace and use higher nucleation temperature.

In another embodiment, in order to strengthen biodurable and biocompatibility, there is biological undesirable substance in the component of selecting to be used for polymerization process or is subject to the material of biological attack influence or this situation is reduced to bottom line at end-product avoiding.

The selectable preparation embodiment of the present invention relates to removable water solublity spheroid, filler or particulate fraction or replace water fully as foaming agent, and described for example removing makes the complete crosslinked back of substrate by washing, extracts or fusing is carried out.

The aspect of other method of the present invention

With reference now to Fig. 2,, shown process block sketch map has provided the extensive overview ot that the inventive method can be selected embodiment, can be comprised the implantable device of biodurable holey elastomeric matrices 10 thus by thick elastomer or elastomer reagent by one or another kind of preparation in several different processing approach.

In first approach, make the elastomer for preparing by method as described herein comprise a plurality of compartments by using one or more foaming agents that for example in its preparation process, use.Especially, can comprise for example polyol component, isocyanates, optional cross-linking agent and any required additive, raw material 40 such as surfactant etc. is used at synthesis step 42 synthetic required elastomeric polymers, and it has or do not have tangible foaming or other generates the activity in hole.Select raw material so that required mechanical performance is provided and promotes biocompatibility and biodurable.Then in step 48 in relevant chemical property and purity, physical and mechanical property aspect and the optional elastomeric polymer product that also aspect biological nature, all characterizes step 42 as mentioned above, thereby the elastomer that is fully characterized 50.The data of optional characterisation can be used for control or change step 42 so that strengthen processing or product as shown in approach 51.

Selectively, provide to process equipment by the abundant elastomer 50 that characterizes of raw material 40 generations and by commodity selling person 60.Synthesize this class elastomer and give its porous subsequently according to known method.The elastomer of this quasi-representative is that BIONATE 80A aromatic polycarbonate-urethane elastomers is (from Polymer Technology Group Inc., Berkeley, CA), CARBOTHANE PC 3575 A aliphatic series polyurethane elastomer (Noveon Inc., Cleveland, OH), CARBOSIL siloxanes Merlon carbamate (from PolymerTechnology Group), BIOSPAN segmentation polyurethanes (from PolymerTechnology Group) and CHRONOFLEX AL and CHRONOFLEX C are (from CardioTech International Inc., Wilmington, MA).Can give elastomer 50 porous by the foaming agent that uses in the step after polyreaction or polymerization.One or more foaming agents can be for example by wherein absorbing and/or absorption on it in the step after polymerization (being raw material to be purchased typical elastomeric or multiple elastomer for example), choose wantonly under the influence that heats up and/or boost incoming stockly, bubbling gas is discharged from foaming agent so that form the elastomeric matrices that comprises the hole.In one embodiment, described hole is interconnected.Interconnected amount depends on the temperature that for example puts on polymer, puts on the pressure of polymer, gas concentration, the gas concentration on the polymer surfaces, rate of gas release and/or gas release pattern in the polymer.

If desired, can select in the raw material 40 the elastomeric polymer reagent that uses avoiding bad by-product or residue, and if desired, purification in step 52.On the raw material of selection and purification, carry out polymer synthesis step 54 then, and carry out to avoid generating bad by-product or residue.Then as above-mentioned to characterize the elastomeric polymer that produces in the step 54 described in the step 48 in step 56, so that help the product that high-quality is fully determined, the elastomer 50 that promptly fully characterizes produces.In another embodiment, this characterization result is the feedback of approach 58 described process control, thereby helps producing high-quality, fully the product of determining, the i.e. elastomer 50 that fully characterizes.

In one embodiment, the invention provides the gauze bio biodurable elastomeric matrix, it comprises the polymer element that is in particular biomedical implantation design.Elastomeric matrices comprises the biodurable polymeric material and by avoiding making one or more method preparations of this polymer generation chemical modification, described chemical modification forms unwanted by-product and comprises the residue of unwanted unreacting material.In some cases, comprise polyurethanes and the foam that generates by known technology because of having unwanted unreacting material or unwanted by-product and being not suitable in the long-term blood vessel orthopedic applications and related application.In one embodiment, elastomeric matrices is by being purchased that biodurable polymer elasticity material constitutes and being avoided in forming one or more methods of porous and reticulated elastomeric matrix at the chemical modification of raw material elastomeric material.

In another embodiment, the chemical feature that is used to make the elastomeric biodurable of elastomeric matrices 10 comprises following one or more: good oxidation stability; Do not contain or be substantially free of and be easy to take place biodegradable key, the chemical characteristic of some polyethers key or hydrolyzable ester bond for example, described key can be introduced polyurethanes by adding polyethers or PEPA composition; Refining relatively or purification and do not contain or be substantially free of objectionable, reactant, the product of chemically fully determining of by-product; Oligomer etc.; Fully definite molecular weight, it is crosslinked removing inelastic body; With the dissolubility in the biocompatible solvent, certainly, unless this elastomer is crosslinked.

In another embodiment, relate to and be used to prepare entity 12 elastomeric method correlated characteristic mutually, the elastomeric biodurable that for example is used for making elastomeric matrices 10 comprises following one or more: the reproducibility of method; Process control to the product denseness; With avoid or remove basically objectionable, reactant, by-product, oligomer etc.

In certain embodiments, careful design and control the netted of following pore-forming of the present invention and other polymerization after process.For this purpose, in certain embodiments, method of the present invention avoids introducing unwanted residue, otherwise will produce harmful effect to the required biodurable of raw material.In another embodiment, can further process and/or characterize raw material, provide or characteristic that proof is relevant with biodurable so that promote.In another embodiment, can with elastomeric must the characteristic present be suitable, and according to the instruction of this description, technology characteristics can be for that be fit to or controlled.

Be formed up to the small part reticulated elastomeric matrix by microwave irradiation

Formation the present invention another kind of mode of partial mesh elastomeric matrices is at least undertaken by using the microwave irradiation technology.In the method, with the elastomeric material of 100 weight portions, be used as raw material such as Merlon carbamate or Merlon carbamate urea, preferably the form with granule or tablet provides.Suitable fusing blender or the blender of optional use, such as extruder, double screw extruder or Brabender PLASTOGRAPH are with elastomeric material and about 70 weight portions of for example about 2-(in one embodiment), about 35 weight portions of about 10-(in another embodiment) have more the hydrophilic polymers material, such as poly-(vinyl acetate) (PVA), polyethylene-altogether-vinyl acetate) (EVA), poly-(vinyl alcohol) or its mixture arbitrarily are mixed into mixture.Described blender or blender can have screw rod, oar or magnetic stirrer.In mixed process, also add about 20 weight portions of about 0.1-(in one embodiment), the cross-linking agent of about 5 weight portions of about 0.25-(in another embodiment).In mixed process, also add about 20 weight portions of about 1-(in one embodiment), one or more foaming agents of about 15 weight portions of about 5-(in another embodiment).In another embodiment, in mixed process, also add cross-linking agent and one or more foaming agents.

Can use at the about 6.0Giga Hertz of about 2.2-(GHz) (in the embodiment), in confined chamber, the gained mixture heated be become to have the interconnected and blistered elastomeric matrices of partial mesh at least structure intercommunicating porosity at about 2.45GHz (in another embodiment) or the microwave irradiation that under about 5.8GHz (in another embodiment) frequency, generates.Optional also in carrying out the identical confined chamber of microwave irradiation for example by heating or Convective Heating with this mixture heated to about 70 ℃-Yue 225 ℃ temperature (in one embodiment) or about 100 ℃-Yue 180 ℃ (in another embodiment) have interconnected and the blistered elastomeric matrices of partial mesh at least structure intercommunicating porosity so that help to form.Therefore, if exist, helpfulness is to have more the hydrophilic polymers material and is easy to heat in the microwave irradiation process so, promotes to comprise the heating or the foaming of its mixture thus.In one embodiment, select to have more the hydrophilic polymers material, make its dielectric loss and/or dielectric loss tangent enough big, make that having more the hydrophilic polymers material is easy to heat under used microwave irradiation frequency.

This method can be bulk method or continuous production method.The optional elastomeric matrices that forms can further nettedization as described below so that obtain required permeability.

According to other embodiment of the present invention, the biodurable elastomeric material is selected from Merlon polyurethanes urea, Merlon polyureas carbamate, the Merlon polyurethanes, Merlon polysiloxanes polyurethanes, Merlon polysiloxanes polyurethanes urea, the polysiloxanes polyurethanes, polysiloxanes polyurethanes urea, Merlon hydrocarbon polyurethanes, Merlon hydrocarbon polyurethanes urea or its be mixture arbitrarily.Special concern thermoplastic elastomer wherein, such as polyurethanes, its chemical characteristic is relevant with for example good biodurable.In one embodiment, this analog thermoplastic polyurethane elastomer comprises the Merlon polyurethanes, the polyester polyurethanes, the polyethers polyurethanes, the polysiloxanes polyurethanes, hydrocarbon polyurethanes (promptly on average comprising those thermoplastic elastomer polyurethanes that at least a isocyanate prepolymer composition of about 2 isocyanate groups and at least a hydroxy-end capped hydrocarbon oligomer and/or hydrocarbon polymer form by each molecule) has polyurethanes of so-called " mixing " soft segments and composition thereof.Blended soft segments polyurethanes is for well known to a person skilled in the art and comprising, polycarbonate-polyester polyurethanes for example, Merlon-polyethers polyurethanes, Merlon polysiloxanes polyurethanes, Merlon-hydrocarbon polyurethanes, polycarbonate-polysiloxane-hydrocarbon polyurethanes, polyester-polyethers polyurethanes, the polyester-polysiloxane polyurethanes, polyester-hydrocarbon polyurethanes, the polyether-polysiloxane polyurethanes, polyethers-hydrocarbon polyurethanes, polyether-polysiloxane-hydrocarbon polyurethanes and polysiloxanes-hydrocarbon polyurethanes.In another embodiment, the thermoplastic polyurethanes elastomer comprises the Merlon polyurethanes, polyethers polyurethanes, polysiloxanes polyurethanes, the hydrocarbon polyurethanes has polyurethanes or its mixture that these mix soft segments.In another embodiment, the thermoplastic polyurethanes elastomer comprises the Merlon polyurethanes, the polysiloxanes polyurethanes, and the hydrocarbon polyurethanes has polyurethanes or its mixture that these mix soft segments.In another embodiment, the thermoplastic polyurethanes elastomer is Merlon polyurethanes or its mixture.In another embodiment, the thermoplastic polyurethanes elastomer is polysiloxanes polyurethanes or its mixture.In another embodiment, the thermoplastic polyurethanes elastomer is polysiloxanes polyurethanes or its mixture.In another embodiment, the thermoplastic polyurethanes elastomer comprises at least a vulcabond in the isocyanate prepolymer composition, at least a cahin extension agent and at least a dihydroxylic alcohols and can be by diisocyanates as described in detail above, the combination in any of difunctional chain extenders and di-alcohols forms.

In one embodiment, the weight average molecular weight of thermoplastic elastomer (TPE) is about 30, about 500,000 dalton of 000-.In another embodiment, the weight average molecular weight of thermoplastic elastomer (TPE) is about 50, about 250,000 dalton of 000-.

In one embodiment, being used to implement some suitable thermoplastic that is suitable for sign as described herein of the present invention can comprise: as Pinchuk etc. in U.S. Pat 5,741,331 (and the U.S. Pat 6 of division, 102,939 and 6,197,240) described polyolefin polymer with alternately secondary and quaternary carbon; Have elastomeric block, the copolymer of the block of polyolefin and thermoplastic block for example, styrene for example, as Pinchuk etc. described in the U.S. Patent Application Publication No. US 2002/0107330A1; The polyether ester that thermoplasticity is segmented, the thermoplastic poly dimethyl siloxane, two-block polystyrene polybutadiene, three-block polystyrene polybutadiene, poly-(acrylic alkene ether sulfone)-poly-(Allyl carbonate) block copolymer, two-block copolymer of polybutadiene and polyisoprene, the copolymer of ethylene vinyl acetate (EVA), segmented block is total to-the polystyrene poly(ethylene oxide), two-block is common-polystyrene poly(ethylene oxide) and three-block be common-copolymer of polystyrene poly(ethylene oxide), for example as Penhasi described in U.S. Patent Application Publication No. US 2003/0208259 A1 (especially referring to wherein paragraph [0035]); With the polyurethanes with blended soft segments, described blended soft segments comprises polysiloxanes and polyethers and/or Merlon composition, as Meijs etc. in U.S. Pat 6,313, described in 254; With DiDomenico etc. in U.S. Pat 6,149, those polyurethanes described in 678,6,111,052 and 5,986,034.Be applicable to that in addition implementing of the present invention is by the synthetic new or known elastomer of the inventive method as described herein.In another embodiment, optional therapeutic agent can be written into and be used to implement other elastomeric suitable block of the present invention.

Be applicable to implement of the present invention some be purchased the Merlon polyurethanes series that thermoplastic elastomer (TPE) comprises to be provided under trade mark BIONATE by PolymerTechnology Group Inc..For example, obtain very fully characterizing the Merlon polyurethane polymer BIONATE 80A of grade, 55 and 90 is machinable, and they have the favorable mechanical performance according to reports, no cytotoxicity, no mutagenicity, non-carcinogenesis and non-hemolytic.Be applicable to that it is available from CardioTech International that enforcement another kind of the present invention is purchased elastomer, the Merlon aromatics polyurethane thermoplastic elastomer CHRONOFLEX C series of the biodurable medical grade of Inc..Be applicable to that it is the elastomeric PELLETHANE series of thermoplastic polyurethanes that enforcement another kind of the present invention is purchased elastomer, 2363 series of products particularly, and more particularly be those called afters 81A and 85A by Dow ChemicalCompany (Midland, the product that MI) provides.These commodity polyurethane polymers are linear, noncrosslinking polymer, and therefore, they are easy to analyze and are easy to and characterize.

Nettedization of elastomeric matrices

Elastomeric matrices 10 can carry out any kind in the various post-process treatment so that promote it to use, and wherein some is as described herein and wherein some other is apparent to those skilled in the art.In one embodiment, if be not the ingredient that becomes described production method, nettedization of elastomeric matrices 10 so of the present invention can be used to remove the inside " window " to any existence of small part, the i.e. residual compartment 22 of illustration among Fig. 1.Nettedization tends to increase porous and fluid permeability.

Porous or foamed materials with some compartment of breaking generally are called " opening the chamber " material or foam.On the contrary, the porous material that is called " nettedization " or " partial meshization at least " has many, promptly be removed at least about 40% compartment to the small part that should be present in the identical porous material, except only by the compartment of sealing form.To the place that small part is removed because of nettedization, adjacent netted compartment is open each other in compartment, interconnected and connection.More, promptly the porous material that is removed at least about 65% compartment is called " further nettedization ".If most of, promptly at least about 80% or basically all, promptly be removed at least about 90% compartment, the porous material of Bao Liuing is called " basically ' nettedization " or " complete nettedization " respectively so.According to the application of this area, be appreciated that Web materials or foam comprise to the reticulated structure of the open interconnected compartment of small part.

" nettedization " generally means to small part and removes compartment, it is broken or tears and be not only by breaking method.In addition, breaking method produces the chip that must remove by further processing very undesirablely.In another embodiment, nettedization method has been removed basically fully to the small part compartment.For example, can be by being partly dissolved compartment at least, be called " nettedization of solvent " or " chemical nettedization " respectively or by partial melting at least, burn and/or collapse out compartment, be called " nettedization of burning " respectively, " heat supply network shapeization " or " impacting nettedization " carry out nettedization.The molten material that derives from the fusing compartment is deposited on the minor connector.In one embodiment, this generic operation can be used for method of the present invention so that make elastomeric matrices 10 nettedization.In another embodiment, by before nettedization, applying vacuum-evacuate all air of holding back in elastomeric matrices 10 holes.In another embodiment, undertaken nettedization by a plurality of nettedization steps.In another embodiment, use nettedization step twice.In another embodiment, after nettedization of burning for the first time, carry out nettedization of burning the second time.In another embodiment, after nettedization of burning, carry out the chemical network shapeization.In another embodiment, after nettedization of chemistry, carry out the burning web shapeization.In another embodiment, carrying out the chemical nettedization second time after chemical nettedization for the first time.

In an embodiment that relates to orthopedic applications etc., elastomeric matrices 10 can nettedly change into the intercommunicating pore structure, and the hole with average diameter or other maximum transverse size is at least about 10 μ m.

In another embodiment, elastomeric matrices can nettedization have the hole that is at least about 20 μ m average diameters or other maximum transverse size with proposition.In another embodiment, elastomeric matrices can nettedization have the hole that is at least about 50 μ m average diameters or other maximum transverse size with proposition.In another embodiment, elastomeric matrices can nettedization have the hole that is at least about 150 μ m average diameters or other maximum transverse size with proposition.In another embodiment, elastomeric matrices can nettedization have the hole that is at least about 250 μ m average diameters or other maximum transverse size with proposition.In another embodiment, elastomeric matrices can nettedization to propose to have at least hole greater than about 250 μ m average diameters or other maximum transverse size.In another embodiment, elastomeric matrices can nettedization to propose to have at least hole greater than about 250 μ m average diameters or other maximum transverse size.In another embodiment, elastomeric matrices can nettedization to propose to have hole at least about 450 μ m average diameters or other maximum transverse size.In another embodiment, elastomeric matrices can nettedization to propose to have at least hole greater than about 450 μ m average diameters or other maximum transverse size.In another embodiment, elastomeric matrices can nettedization to propose to have at least hole greater than 450 μ m average diameters or other maximum transverse size.In another embodiment, elastomeric matrices can nettedization to propose to have hole at least about 500 μ m average diameters or other maximum transverse size.

Relate in the embodiment of orthopedic applications etc. at another, elastomeric matrices can nettedization to propose have the hole that is not more than about 600 μ m average diameters or other maximum transverse size.In another embodiment, elastomeric matrices can nettedization have the hole that is not more than about 450 μ m average diameters or other maximum transverse size with proposition.In another embodiment, elastomeric matrices can nettedization have the hole that is not more than about 250 μ m average diameters or other maximum transverse size with proposition.In another embodiment, elastomeric matrices can nettedization have the hole that is not more than about 150 μ m average diameters or other maximum transverse size with proposition.In another embodiment, elastomeric matrices can nettedization have the hole that is not more than about 20 μ m average diameters or other maximum transverse size with proposition.

Relate in the embodiment of orthopedic applications etc. at another, elastomeric matrices can nettedization to propose hole with the about 50 μ m average diameters of about 10 μ m-or other maximum transverse size.In another embodiment, elastomeric matrices can nettedization to propose hole with the about 150 μ m average diameters of about 20 μ m-or other maximum transverse size.In another embodiment, elastomeric matrices can nettedization to propose hole with the about 250 μ m average diameters of about 150 μ m-or other maximum transverse size.In another embodiment, elastomeric matrices can nettedization to propose hole with the about 500 μ m average diameters of about 250 μ m-or other maximum transverse size.In another embodiment, elastomeric matrices can nettedization to propose hole with the about 600 μ m average diameters of 450 μ m-or other maximum transverse size.In another embodiment, elastomeric matrices can nettedization to propose hole with the about 500 μ m average diameters of about 10 μ m-or other maximum transverse size.In another embodiment, elastomeric matrices can nettedization to propose hole with the about 600 μ m average diameters of about 10 μ m-or other maximum transverse size.

For example, can choose wantonly before nettedization or afterwards by solvent extraction purification reticulated elastomeric matrix.In one embodiment, any this class such as the solvent extraction of using isopropyl alcohol or other purification process be appropriate relatively method, and carrying out it is for fear of being reduced to bottom line to the possible harmful effect of the machinery that satisfies the requisite elastomeric matrices of the object of the invention or physical property or with it.

An embodiment is used chemical nettedization, wherein elastomeric matrices nettedization in the acid bath that comprises mineral acid.Another embodiment is used chemical nettedization, wherein elastomeric matrices nettedization in the corrosivity of bag inorganic base is bathed.Another embodiment is used nettedization of solvent, and the volatile solvent of wherein not leaving over residue is used for this method.Another embodiment is used being higher than under 25 ℃ the temperature and is used nettedization of solvent.In another embodiment, use solvent that the elastomeric matrices that comprises the Merlon polyurethanes is carried out nettedization of solvent, described solvent is selected from oxolane (" THF "), dimethyl acetylamide (" DMAC "), dimethyl sulfoxine (" DMSO "), dimethyl formamide (" DMF "), the N-N-methyl-2-2-pyrrolidone N-is also referred to as m-pyrol or its mixture.In another embodiment, use THF that the elastomeric matrices that comprises the Merlon polyurethanes is carried out nettedization of solvent.In another embodiment, use the N-N-methyl-2-2-pyrrolidone N-that the elastomeric matrices that comprises the Merlon polyurethanes is carried out nettedization of solvent.In another embodiment, use highly basic that the elastomeric matrices that comprises the Merlon polyurethanes is carried out chemical nettedization.In another embodiment, alkaline pH is at least about 9.

In these chemistry or nettedization of solvent embodiment, can the optionally washing reticulated polymer foam.In these chemistry or nettedization of solvent embodiment, can the optionally drying reticulated polymer foam.

In one embodiment, can use burning nettedization, wherein electricity consumption spark ignition inflammable gas, for example mixture of hydrogen and oxygen or methane and oxygen.In another embodiment, nettedization of in pressure chamber, burning.In another embodiment, by importing hydrogen, aerofluxus was reduced to the pressure in the pressure chamber basically at least about 2 minutes and for example is lower than about 50-150 millitorr before oxygen or its mixture.In another embodiment, reduced the pressure in the pressure chamber basically in cocycle, for example reduced pressure basically at one, import not reacting gas, such as argon or nitrogen, importing hydrogen, reduce pressure before oxygen or its mixture once more basically then.The temperature that nettedization carried out for example can be subjected to keep this moment the influence of the ratio of the temperature of chamber and/or indoor hydrogen/oxygen.In another embodiment, nettedization of burning back is the annealing phase.In in these burn nettedization embodiment any one, can the optionally washing reticulated polymer foam.In in these burn nettedization embodiment any one, can the optionally drying reticulated polymer foam.

In one embodiment, the reticulated elastomeric matrix convection cell, for example the permeability of liquid is greater than the permeability to the not nettedization substrate convection cell that constitutes reticulated elastomeric matrix.In another embodiment, carry out nettedization process and be beneficial to the elastomeric matrices structure that cell is inwardly grown and propagation is gone into substrate inside so that provide.In another embodiment, carry out nettedization process so that the elastomeric matrices structure is provided, it helps, and cell is inwardly grown and propagation spreads all over for implanting the elastomeric matrices of configuration.

Term " configuration " etc. is used to represent the arrangement of the applied corresponding construction of this term, is shaped and dimensioning.Therefore, the purpose that relates to " configuration " structure is to specify to be related to and is applicable to described purpose and selects or the dependency structure that designs or the holonmic space geometry of structure division.

Give the internal holes feature

In hole 20, elastomeric matrices 10 can be chosen the feature that has except the volume of above-mentioned space or blanketing gas wantonly.In one embodiment, elastomeric matrices 10 can have herein be called " internal holes " feature as its microstructural ingredient, that is, and the feature of elastomeric matrices 10 " in the hole ".In one embodiment, the inner surface in hole 20 can " endoporus be coated ", i.e. coating or handle so that give those surfaces required feature to a certain degree, for example hydrophilic.Coating or treatment media can have additionally gives or the ability of bonding active component, and active component preferably is delivered to hole 20 then.In one embodiment, can use the covalent bonding of this coating media or processing promotion material and internal surface of hole, for example described in the application of request priority.In another embodiment, coating comprises biodegradable or absorbable polymer and inorganic constituents, such as hydroxyapatite.Can be by on the reticulated elastomeric matrix of making 10, carrying out chemistry or treatment with irradiation, by in the elastomer assembling process, making elastomer contact hydrophilic, water environment or for example by well known to a person skilled in the art that alternate manner carries out hydrophilic and handles.

In addition, can be by at liquid coating solution or be suitable for forming that contact film forming biocompatible polymer is coated with one or more coatings in the molten state under the condition of biocompatible polymer thin film on endoporus.In one embodiment, be used for the polymer of this type coating for having enough high-molecular weight film forming biocompatible polymer, so that can not become wax shape or sticking shape.Polymer also should adhere to entity phase 12.In another embodiment, bonding strength makes thin polymer film can not break or deviate from reticulated elastomeric matrix 10 processing or expansion process.

Suitable biocompatible polymer comprises polyamide-based, TPO (polypropylene for example, polyethylene), absorbability polyesters (for example polyethylene terephthalate) and bioresorbable aliphatic polyester class (lactic acid for example, glycolic, lactide not, Acetic acid, hydroxy-, bimol. cyclic ester, to-diethyleno dioxide ketones, plutonium carbonate propyl ester, the homopolymer of s-caprolactone and copolymer or its mixture).In addition, biocompatible polymer comprises film forming bioresorbable polymer; They comprise the aliphatic polyester class, poly-(aminoacid), copolymerization (ether-ester), the polyalkylene oxalic acid ester, polyamide-based, poly-(iminocarbonic acid esters), poe class, the polyoxaesters class, the polyoxaesters class that comprises phosphinylidyne-containing amine group, polyamidoamines esters, poly-anhydrides, group of polyphosphazenes, biomolecule or its mixture.With regard to purpose of the present invention, the aliphatic polyester class comprises polymer and lactide (comprising lactic acid d-, 1-and Study of Meso-Lactide), 6-caprolactone, Acetic acid, hydroxy-, bimol. cyclic ester (comprising glycolic), butyric ester, hydroxyl valerate, to-diethyleno dioxide ketones, plutonium carbonate propyl ester (and alkyl derivative), 1,4-two oxa-ring-2-in heptan ketone, 1,5-two oxa-ring-2-in heptan ketone, 6,6-dimethyl-1, the copolymer of 4-diox-2-ketone or its mixture.In one embodiment, stiffener can be by biopolymer, such as collagen protein, and formations such as elastin laminin.Biopolymer can be biodegradable or biological absorbable.

Biocompatible polymer further comprises the film forming biodurable polymer with low relatively long-term tissue reaction, such as polyurethanes, siloxanes, poly-(methyl) esters of acrylic acid, polyesters, poly-alkyl epoxy (for example poly(ethylene oxide)), polyvinyl alcohol, polyethylene glycols and polyvinylpyrrolidone and hydrogel, those that form by crospolyvinylpyrrolidone and polyesters such as those.Other polymer also can be used as biocompatible polymer, as long as they can dissolve, solidifies or polymerization.This base polymer and copolymer comprise TPO, polyisobutylene and ethene-alpha-olefin copolymer; Acrylate copolymer (comprising methyl acrylic ester) and copolymer; Vinyl halide polymer and copolymer are such as polrvinyl chloride; Glymes is such as polyvinyl methyl ether; Poly-vinylidene halide such as Kynoar and polyvinylidene chloride; Polyacrylonitrile; The polyethylene ketone; The polyethylene aromatic compounds is such as polystyrene; The polyethylene esters is such as polyvinyl acetate; Vinyl monomer each other and with the copolymer of ε-olefines, such as ethylene-methyl methacrylate methyl terpolymer and vinyl-vinyl acetate copolymer; Acrylonitritrile-styrene resin; ABS resin; Polyamide-based, such as nylon 66 and polycaprolactam; Alkyd resins; Polycarbonate-based; The polyformaldehyde class; Polyimide; Polyethers; Epoxy resin; Polyurethanes; Artificial silk; Artificial silk-triacetate; The plug fine jade cellophane; Cellulose and derivant thereof, such as cellulose acetate, cellulose acetate-butyrate, celluloid, cellulose propionate and cellulose ethers (for example carboxymethyl cellulose and hydroxy alkyl cellulose); Or its mixture.With regard to purpose of the present invention, polyamide-basedly comprise the polyamide-based of following general formula:

-N (H)-(CH ₂) _n-C (O)-and-N (H)-(CH ₂) x-N (H)-C (O)-(CH ₁₂) _y-C (O)-, wherein n is the integer of about 4-about 13; X is the integer of about 4-about 16 for integer and the y of about 4-about 12.It is illustrative should understanding the above-mentioned material catalogue, but not determinate.

General by using polymer, the optional pharmaceutically active agents that comprises carries out simple dip coating or sprays the device that coating is made of reticulated elastomeric matrix 10 such as therapeutic agent or medicine.In one embodiment, coating is that solution and the polymer content in coating solution are about about 40% weight of 1%-.In another embodiment, polymer content is about about 20% weight of 1%-in the coating solution.In another embodiment, polymer content is about about 10% weight of 1%-in the coating solution.

Be suitably coating entity mutually 12, select to be used to apply the solvent or the solvent blends of solution especially according to the consideration of the solvent speed of the deposition level of suitable viscosity balance, polymer, moistening speed and evaporation, as well known in the art.In one embodiment, selective solvent makes this base polymer dissolve in solvent.In another embodiment, from coating, remove fully basically and desolvate.In another embodiment, described solvent is avirulent, and is non-carcinogenic and favourable to environment.Mixed solvent system is favourable to control viscosity and evaporation rate.In all situations, solvent all should not react with coat polymers.Solvent includes, but are not limited to: acetone, N-Methyl pyrrolidone (" NMP "), DMSO, toluene, dichloromethane, chloroform, vinyl trichloride (" TCE "), various freon class ， dioxs, ethyl acetate, THF, DMF and DMAC.

In another embodiment, the film forming coat polymers is a thermoplastic polymer, and its fusing enters the hole 20 of elastomeric matrices 10 and forming coating to the solid material 12 of small part elastomeric matrices 10 when cooling or curing.In another embodiment, the processing temperature of thermoplasticity coat polymers under its fusing form is approximately higher than 60 ℃.In another embodiment, the processing temperature of thermoplasticity coat polymers under its fusing form is approximately higher than 90 ℃.In another embodiment, the processing temperature of thermoplasticity coat polymers under its fusing form is approximately higher than 120 ℃.

In as another embodiment of the invention of hereinafter more specifically describing, give some or all coating or the inside growth promoter of tytosis in the hole 20 of elastomeric matrices 10.In another enforcement side, can make promoter foaming.In another embodiment, promoter can be the form of film.Promoter can be for biodegradable or absorbable material so that promote elastomeric matrices 10 cell in vivo to invade.Promoter comprises naturally occurring material, they can be in human body enzymatic degradation, or in human body hydrolytically unstable, as fibrin, Fibrinogen, collagen protein, elastin laminin, hyaluronic acid and absorbability biocompatibility polysaccharide, such as chitosan, starch, fatty acid (and esters), glucose-polysaccharide class (glucoso-glycans) and hyaluronic acid.In certain embodiments, the hole surface of coating or dipping elastomeric matrices 10 described in above-mentioned part, but join in the biocompatible polymer with promoter replacement biocompatible polymer or with promoter, so that impel cell inwardly growth and propagation.

In one embodiment, apply or infusion process to guarantee product used herein " composite elastic implantable device ", promptly reticulated elastomeric matrix and coating keep enough resiliences after compression, make that it can be by delivery apparatus, delivery catheter for example, syringe or endoscope send.Describe some embodiment of this class composite elastic implantable device referring now to collagen protein,, as mentioned above, should understand other material and can be used for substituting collagen protein as limiting examples.

One embodiment of the invention comprise for preparing the method for composite elastic implantable device:

A) make moisture collagen protein slurry soak into mesh structural porous elastomer, such as the hole of elastomeric matrices 10, it is chosen wantonly and is the hole of biodurable elastomer product; With

B) optional removing by lyophilizing anhydrated, and to produce collagen coating, wherein collagen coating is chosen the interconnected network structure that comprises the hole on mesh structural porous at least elastomeric part hole surface wantonly.

Can impel the collagen protein aqueous slurries by for example working pressure, suspension or solution enter the elastomeric matrices hole and soak into collagen protein.Collagen protein can be I, II or III type or its mixture.In one embodiment, the collagen protein type comprises at least 90% collagen protein I.The concentration of collagen protein be about about 2.0% weight of 0.3%-and when lyophilizing with slurry, the pH of suspension or solution is adjusted to about 2.6-about 5.0.Selectively, can soak into collagen protein by elastomeric matrices being immersed the collagen protein slurry.

With the reticulated elastomeric bulk phase ratio of uncoated, the composite elastic implantable device can have the space phase 14 that appropriateness reduces on volume.In one embodiment, the composite elastic implantable device has kept good fluid permeability and enough porous to grow and propagation so that fibroblast or other cell are inside.

Choose wantonly and can make freeze dried collagen cross-linking so that control the interior enzymatic degradation rate of the body of collagen coating and/or control the ability of collagen coating in conjunction with elastomeric matrices 10.Can for example pass through at evacuated chamber's internal heating by means commonly known in the art, by in the inert gas environment of essentially no humidity, heating, by making collagen protein contact formaldehyde steam or coming crosslinked with collagen albumen by the use glutaraldehyde.Not retrained by any particular theory, think when implanting the composite elastic implantable device, to collagen protein, the texturizer that has the height affinity such as fibroblast is easier to invade the elastomeric matrices 10 that floods collagen protein than the substrate of uncoated.In addition, not retrained by any particular theory, think that further new organization is invaded and is full of the space that degrade collagen albumen is left over, and also soaks into and be full of other available space in the elastomeric matrices 10 simultaneously along with the degraded of collagen protein enzymatic.Not retrained by any particular theory, think that the structural intergrity that this class collagen protein coating or the elastomeric matrices 10 that floods provide the proteic booster actions of collagen in the hole 20 of elastomeric matrices 10 is extra favourable, it can give the bigger rigidity and the structural stability of various structures of elastomeric matrices 10.

The method of the composite elastic implantable device of preparation collagen protein coating is being the typical case in embodiment 3 and 12.Other method is apparent to those skilled in the art.

The implantable device of coating

In some applications, the device that is made of elastomeric matrices 10 can have to the outermost or the macro surface of small part coating or fusion, so that provide less macro surface to amass, because the internal surface area in subsurface hole is no longer influenced.Be not bound by any particular theory, think that this surface area that reduces provides more predictability and sending and transporting by minister's bending channel in the delivery apparatus more easily.Surface applied or fusion have changed " porous on surface ", promptly reduced the percentage ratio in the hole that the surface is opened to small part, or in limit, completely cut off coating fully or merge the hole on surface, promptly surface is non-hole, does not apply or merges lip-deep hole because do not have to be retained in.Yet surface applied or fusion still make the interconnected loose structure of elastomeric matrices 10 inwardly keep and are open on the surface of other uncoated or not fusion; For example can inside growth of cultured cell and propagation in this lip-deep part coating or hole maintenance of merging and the open surface that other hole is interconnected and those are left over.In one embodiment, coating and uncoated surface are orthogonal.In another embodiment, coating and uncoated surface are each other in the oblique angle.In one embodiment, coating and uncoated surface are adjacent one another are.In another embodiment, coating and uncoated surface are not adjacent to each other.In another embodiment, coating and uncoated surface contact with each other.In another embodiment, coating does not contact each other with uncoated surface.

In other is used, can apply, merge or melt one or more planes of the implantable device macro surface that constitutes by reticulated elastomeric matrix 10, so that improve itself and connecting device, for example anchor or sutural joint efficiency are not torn or are pulled out so that connecting device can not pass from implantable device.Be not bound by any particular theory, think generate grappling as mentioned above on the implantable device the extra contact of macro surface tear or pull out by providing less space and bigger resistance to suppress to pass.

Can cause the fusion and/or the selective melting of the macro surface layer of elastomeric matrices 10 according to several different modes.In one embodiment, can be used to prepare final implantable device size and the cutter of shape or the temperature that blade is heated to rising with being used for 10 of elastomeric matrices are cut into, for example, being the typical case among the embodiment 9.In another embodiment, be cut into the device of required form and size by using laser cutting device by relatively large elastomeric matrices 10, and merge the surface that contacts laser beam in the method.In another embodiment, the cold laser cutter sweep is used to cut the device of required size and shape.In another embodiment, heated mold can be used for by adding hot press method with required size and shape applicator.Can will put into heating mould from the relatively large bigger elastomeric matrices 10 that is cut into.Mould covers section so that its overall dimension is decreased to required size with shape and merge the surface that these contact heating mould, for example, and being the typical case among the embodiment 10.In above-mentioned each embodiment, be used to be shaped and the processing temperature of sizing in one embodiment, greater than about 15 ℃.In another embodiment, be used to be shaped and the processing temperature of sizing above about 100 ℃.In another embodiment, be used to be shaped and the processing temperature of finalizing the design above about 130 ℃.In another embodiment, macro surface layer that does not merge and/or part are by covering them to prevent its exposure in merging the macro surface process.

Can make coating on the macro surface by biocompatible polymer, described biocompatible polymer can comprise that biodegradable maybe can absorb and biological can not degrade or nonabsorbable polymer.Suitable absorbable polymer is included in the biocompatible polymer described in the previous section.It is illustrative should understanding this catalog of materials, but indefiniteness.In one embodiment, by absorbable polymer being melted confining surface hole on the elastomeric matrices that coating is coated on shaping.Elastomeric matrices and coating form device jointly.In another embodiment, the confining surface hole forms device on the elastomeric matrices that coating is coated on shaping by absorbable polymer is melted.In another embodiment, coating and elastomeric matrices occupy the volume greater than the independent elastomeric matrices of uncoated jointly.

For example, can on elastomeric matrices 10, be coated with coating by the coating solution that dipping or spraying contain polymer or be mixed with the polymer of pharmaceutically active agents.In one embodiment, the polymer content in coating solution is about about 40% weight of 1%-.In another embodiment, the polymer content in coating solution is about about 20% weight of 1%-.In another embodiment, the polymer content in coating solution is about about 10% weight of 1%-.In another embodiment, the macro surface layer and/or the part of not carrying out solution coating prevents its exposure by cover them in macro surface solution coating process.For example, select to be used to apply the solvent or the solvent blends of solution based on the consideration of above-mentioned part (promptly in " giving interior hole characteristic " part).

In one embodiment, can by fusing film forming coat polymers and by dip coated will melt polymer-coated in the coating that is coated with on the elastomeric matrices 10 on the elastomeric matrices 10, being the typical case among the embodiment 11.In another embodiment, can on elastomeric matrices 10, be coated with coating by fusing film forming coat polymers and by the polymer of in such as extruding or coextrusion this class process, using fusing, as the melt polymer thin layer on the axle of elastomeric matrices 10 formation by punch die.In arbitrary these embodiments, the polymer-coated macro surface of fusing and bridging or block this surperficial hole do not reach any effective depth but can not penetrate inside.Be not bound by any particular theory, think it be because of the fusing the polymer high viscosity due to.Therefore, keep the part elastomeric matrices that takes out from macro surface and the netted character of the part elastomeric matrices macro surface of contact melting polymer not.When cooling and curing, the polymer of fusing forms the solid coating layer on elastomeric matrices 10.In one embodiment, the processing temperature of melting heat plastic coating polymer is at least about 60 ℃.In another embodiment, the processing temperature of melting heat plastic coating polymer is at least about 90 ℃.In another embodiment, the processing temperature of melting heat plastic coating polymer is at least about 120 ℃.In another embodiment, macro surface layer and/or the part that melts coating prevents to expose by cover them in macro surface fusing coating process.

Another embodiment of the invention has been used the complex elasticity implantable device of collagen protein coating, and this device is configured to the sleeve pipe of stretching, extension around implantable device as mentioned above.The collagen matrices sleeve pipe can be implanted on tissue repair and the regeneration site, adjacent with this position with contact.Localized thus collagen matrices sleeve pipe can be used for the auxiliary elastomeric matrices 10 that keeps, and helps tissue sealing formation and helps to prevent seepage.In one embodiment, exist collagen protein to promote the inside growth of cell and to breed and improve mechanical stability in the elastomeric matrices 10 by promoting fibroblast to be attached to collagen protein.Exist collagen protein can stimulate early and/or more fully soaking into of elastomeric matrices 10 intercommunicating pores.

Tissue culture

Biodurable reticulated elastomeric matrix of the present invention can the sustenticular cell type, comprises the proteic cell of secretory structure and produces the proteinic cell that characterizes organ dysfunction.Elastomeric matrices help the ability that the various kinds of cell type coexists each other and support the ability of the cell of secretory protein show elastomeric matrices at organ the application in growth and the organ reconstruction in the external and body.In addition, described biodurable reticulated elastomeric matrix can also be used to the human cell line that increases, so that many application that human body is implanted comprise being implanted to fibrocyte, chondrocyte, osteoblast, osteoclast, osteocyte, the synovial cell, marrow stromal cell, stem cell, fibrocartilage cells, endotheliocyte, smooth muscle cell, adipose cell, myocardial cell, the myocyte, horn cell, hepatocyte, leukocyte, macrophage, endocrine cell, urogenital cell, the lymphatic vessel cell, islet cells, myocyte, Interstitial cell, nephrocyte, vascular cell, thyroid cell, parathyroid gland cell, adrenal gland-hypothalamic pituitary axis cell, bile duct cell, ovary or testicular cell, salivation cell, nephrocyte, epithelial cell, neurocyte, stem cell, progenitor cell, sarcoplast and small intestine cells.

Can obtain to transform neoblastic means (before implantation or simultaneously or afterwards) by being implanted in the cell inoculated in the elastomeric matrices.In this case, can dispose elastomeric matrices preventing to implant cells contacting health immune system, or make and new cell can be mixed in the body to open mode in the sealing mode.Therefore, in another embodiment, can be before elastomeric matrices be implanted the patient, simultaneously or afterwards cell is mixed, promptly cultivate and breed on elastomeric matrices.

In one embodiment, can cultivate, be beneficial to the purpose of tissue repair or tissue regeneration to the implantable device inoculating cell type of making by the biodurable reticulated elastomeric matrix and before optional use delivery apparatus inserts the patient.Be necessary containing or do not containing stimulus object, such as stress or directed proper culture medium in organize or cell culture.Described cell comprises fibroblast, chondrocyte, osteoblast, osteoclast, osteocyte, synovial cell, bone marrow stromal cell, stem cell, fibrocartilage cells, endotheliocyte and smooth muscle cell.

Different pore morphology can be had, size, so that research and develop the engineered implantable device of cell tissue, their target is especially comprising spinal column particularly in orthopedic applications with dissimilar cell culture on surface on the biodurable reticulated elastomeric matrix of shape and orientation, shoulder, knee joint, hands or joint are connected with soft tissue in the prosthese organ growth, repair, regeneration is in reinforcement and/or the support.In another embodiment, can so cultivate and have similar pore morphology, size, all surface on shape and the directed biodurable reticulated elastomeric matrix.

In other embodiments, biodurable reticulated elastomeric matrix of the present invention can be at the mammary gland prosthese, and the pacemaker cover is in the LVAD field of air bags or as the application of organizing bridging substrate.

Pharmaceutically active agents is sent

In another embodiment, the film forming polymer that is used to apply reticulated elastomeric matrix 10 can provide to be sent and/or the controlled release drug activating agent, the carrier of medicine for example, such as the application of request priority described in.In another embodiment, pharmaceutically active agents is mixed with the coating of elastomeric matrices 10, covalent bonding adsorbs thereon and/or absorption obtains pharmaceutical composition within it.In another embodiment, be used to form foamy composition, polymer and/or admixture comprise pharmaceutically active agents.In order to form these foams, with mentioned component, polymer and/or admixture mix with pharmaceutically active agents, after this form foam or make pharmaceutically active agents be written into foam after it forms.

In one embodiment, coat polymers and pharmaceutically active agents have solvent commonly used.This can be provided as the coating of solution.In another embodiment, pharmaceutically active agents can be used as solid dispersion and is present in the solution of coat polymers in solvent.

Can be by mixing one or more pharmaceutically active agents and being used to form foamy polymer, solvent or polymer-solvent mixture preparation comprises the reticulated elastomeric matrix and the foaming of pharmaceutically active agents.Selectively, in one embodiment, can use pharmaceutically acceptable carrier that pharmaceutically active agents is coated on the foam.In another embodiment, if use the fusing coating, pharmaceutically active agents tolerates melt-processed temperature so, and can not reduce its effect basically.

The preparation that comprises pharmaceutically active agents can mix with reticulated elastomeric matrix 10 coatings by making one or more pharmaceutically active agents, covalent bonding adsorbs thereon and/or absorption prepares within it or by pharmaceutically active agents being mixed extra hydrophobicity or hydrophilic coating.Pharmaceutically active agents can be used as liquid, and finely-divided solid or another kind of nonlimiting examples of suitable physical exist.Typically, but optional described substrate can comprise one or more typical additives, such as diluent, and carrier, excipient, stabilizing agent etc.

In another embodiment, can application of coatings discharge so that delay pharmaceutically active agents.In another embodiment, last coating can be as the delivery matrices of second pharmaceutically active agents.The stratification coating that comprises quick and slow hydrating polymer equivalent layer can be used for stage by stage or controlled release places the different pharmaceutical activating agent of different layers.Polymer blend can also be used to control the rate of release of different pharmaceutical activating agent or the balance of required coating characteristic (for example elasticity, toughness) and medicine delivery characteristics (for example release characteristics) is provided.Have the deliquescent polymer of different solvents and can be used to constitute different polymeric layers, these layers can be used to send the release characteristics of different pharmaceutically active agents or control pharmaceutically active agents.

The amount of pharmaceutically active agents depends on used certain drug activating agent and medical disorder to be treated.In one embodiment, pharmaceutically active agents exists with effective dose.In another embodiment, the amount of pharmaceutically active agents accounts for about 0.01%-about 60% of coating weight.In another embodiment, the amount of pharmaceutically active agents accounts for about 0.01%-about 40% of coating weight.In another embodiment, the amount of pharmaceutically active agents accounts for about 0.1%-about 20% of coating weight.

Many different pharmaceutically active agents can with the reticulated elastomeric matrix coupling.Generally speaking, can comprise by pharmaceutical composition administered agents activating agent of the present invention, but be not limited to anyly have the treatment or the pharmaceutically active agents that are applied to implant position or the required physiological property by pharmaceutical composition administration of the present invention and (comprise, but be not limited to nucleic acid, protein, lipid and carbohydrate).Therapeutic agent includes, but are not limited to: anti-infective, such as antibiotic and antiviral agents; Chemotherapeutics (for example anticarcinogen); The anti-medicine that repels; Analgesic and analgesic drug combination; Anti-inflammatory agent; Hormone is such as steroid; Somatomedin (including, but are not limited to cytokine, chemotactic factor and interleukin) and other be natural derives or protein, polysaccharide, glycoprotein and the lipoprotein of genetic modification.These somatomedin are described in The Cellular and Molecular Basis of BoneFormation and Repair, Vicki Rosen and R.Scott Thies, and R.G.LandesCompany publishes, and the document is incorporated herein by reference.Extra therapeutic agent comprises thrombin inhibitor, antithrombotic drug, thrombolytic medicine, fibrinolytic agent, the vasospasm inhibitor, calcium channel blocker, vasodilation, antihypertensive, antimicrobial drug, antibiotic, surface glycoprotein acceptor inhibitor, antiplatelet drug, antimitotic drug, microtubule inhibitor, antisecretory drug, the actin inhibitor is reinvented inhibitor, antisense nucleotide, antimetabolite, antiproliferative agents, anti-cancer chemotherapeutic agents, anti-inflammatory steroids, nonsteroid anti-inflammatory drugs, immunosuppressant, growth hormone antagonist, somatomedin, dopamine agonist, radiotherapeutic agents, peptide class, protein, enzyme, extracellular matrix composition, angiotensin converting enzyme (ACE) inhibitor, free radical scavenger, chelating agen, antioxidant, anti-polymerase, antiviral agents, optical dynamic therapy agent and gene therapeutic agents.

In addition, can in foam, add range protein (comprising the short-chain peptide class) in the course of processing after foam forms, growth stimulator, chemoattractant, growth factor receptors or ceramic particle adsorb from the teeth outwards it or backfill charges into foam.For example, in one embodiment, can partially or completely fill biocompatibility in the foamy hole and absorb synthetic polymer or biopolymer (such as collagen protein or elastin laminin) again, biocompatibility ceramic material (such as hydroxyapatite) and combination thereof and can choose wantonly to comprise and promote the material of tissue by the device growth.This class tissue growth material includes, but are not limited to autotransplantation, allograft or xenograft bone, bone marrow and morphogenetic proteins.Biopolymer can also or be used as the delivery vector somatomedin as conductive material or chemotactic material.Example comprises recombined collagen, the collagen protein of animal derived, elastin laminin and hyaluronic acid.Pharmaceutically active agents coating or surface treatment also may reside on the material surface.For example, can make biologically active peptide sequence (RGD ' s) with surface combination so that help protein adsorption and cell tissue is subsequently adhered to.

Bioactive molecule includes, but are not limited to protein, collagen protein (comprising IV and XVIII type), the fibril collagen protein (comprises I, II, III, V, the XI type), FACIT collagen protein (IX, XII, the XIV type), other collagen protein (VI, VII, the XIII type), short chain collagen protein (VIII, the X type), elastin laminin, nestin-1, fibrillin, fibronectin, fibrin, fibrinogen, fibroglycan, fibromodulin, fine albumen, glypican, vitronectin, laminin, nestin, extracellular matrix protein, perlecan, heparin, heparitin sulfate Dan Baijutang, decorin, the cutin fibril is assembled albumen, keratin, syndecan is assembled albumen, integrin, aggrecan, biglycan, bone sialoprotein, cartilage matrix protein, Cat-301 Dan Baijutang, CD44, acetylcholine esterase, HB-GAM, hyaluronan, hyaluronan is conjugated protein, mucin, osteopontin, plasminogen, plasminogen activator inhibitor, limit protein, serglycan, tendon glycoprotein, thrombospondin, tissue plasminogen activator, urokinase type plasminogen activator, versican, Feng's von willebrand's factor, glucosan, arabinogalactan, chitosan, polylactide (polyactide)-Acetic acid, hydroxy-, bimol. cyclic ester, alginate, pullulan, gelatin and albumin.

Extra bioactive molecule includes, but are not limited to cell adhesion molecule and blast cell albumen, comprises immunoglobulin (Ig; Comprise monoclonal and polyclonal antibody), calcium is according to Fibronectin, and integrin is selected in albumen and the H-CAM superfamily those.Example includes, but are not limited to AMOG, CD2, CD4, CD8, C-CAM (CELL-CAM 105), the cell surface galactosyltransferase connects albumen, desmocollin, desmoglein, fasciclin, F11, the GP1b-IX complex, intercellular adhesion molecule, phosphoric acid LCA protein-tyrosine (LCA, CD45), LFA-1, LFA-3, mannose-binding protein (MBP), MTJC 18, myelin associated glucoprotein (MAG), N-CAM (NCAM), neurofascin, neuroglian, neural chemotactic factor, nerve growth factor, PECAM-1, PH-20, brain signal albumen, TAG-1, VCAM-1, the SPARC/ osteonectin, CCN1 (CYR61), CCN2 (CTGF; Connective Tissue Growth Factor), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2), CCN6 (WISP-3), locking albumen and close albumen.Somatomedin comprises, but be not limited to BMP ' s (1-7), BMP-albuminoid (GFD-5,-7,-8), epidermal growth factor (EGF), erythropoietin (EPO), fibroblast growth factor (FGF), growth hormone (GH), somatotropin releasing factor (GHRF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony stimutaing factor (GM-CSF), insulin, insulin like growth factor (IGF-I, IGF-II), insulin-like growth factor binding protein (IGFBP), M-CSF (M-CSF), Multi-CSF (II-3), platelet-derived somatomedin (PDGF), tumor growth factor (TGF-α, TGF-β), tumor necrosis factor (TNF-α), vascular endothelial cell growth factor (VEGF ' s), angiogenin, placental growth factor (PIGF), interleukin and receptor protein or known other molecule in conjunction with the above-mentioned factor, the short-chain peptide class comprises, but be not limited to (the single letter amino acid code of called after), RGD, EILDV, RGDS, RGES, RFDS, GRDGS, GRGS, GRGDTP and QPPRARI.

Compression molded

Except that the chemistry and/or processing that change elastomeric matrices 10 for the required or targeting implantable device performance that obtains certain limit, nettedization back step also can be used for obtaining ' the required or targeting implantable device performance of certain limit such as giving interior hole characteristic (as mentioned above).In the embodiment after another nettedization, in compression process with reticulated elastomeric matrix in the dimension of 1-at least, for example 1-dimension compression, compression of 2-2-dimension or 3-2-dimension are compressed, if and, in carrying out intensifies process, still keep compressible so as hereinafter describing the reinforcement of use stiffener in detail.

In one embodiment, implantable device is made by reticulated elastomeric matrix, makes this device density be about 2.0 lbs/ft ³-Yue 4.0 lbs/ft ³(the about 0.064g/cc of about 0.032g/cc-).In another embodiment, make implantable device, make this device density be about 4.01bs/ft ³-Yue 8.01bs/ft ³(the about 0.128g/cc of about 0.064g/cc-).In another embodiment, make implantable device, make this device density be about 2.51bs/ft ³-Yue 261bs/ft ³(the about 0.417g/cc of about 0.040g/cc-.

In one embodiment, implantable device is by making with the substrate of 1-dimension form orientation.In another embodiment, implantable device is by making with the substrate of 2-dimension form orientation.In another embodiment, implantable device is by making with the substrate of 3-dimension form orientation.In another embodiment, essentially no preferred orientation in substrate.In another embodiment, in initial foam forming process the substrate orientation takes place.In another embodiment, the substrate orientation takes place in nettedization process.In another embodiment, such as the substrate orientation occurring in the secondary processing process by compression molded (may take place) in nettedization back.The characteristic that directed result is shown as in the orientation direction strengthens and/or the performance enhancing.For example, tensile properties can rise on the direction at foam such as hot strength and to be strengthened, and occurs on the hot strength MC on the rectangular direction of direction or do not have obviously changing rising with foam simultaneously.

Be called in the compression molded secondary processing method at a kind of this paper, by using different temperatures densification and/or 1-dimension, 2-dimension or 3-dimension orientation obtain required reinforcing property.In one embodiment, can under the situation of not using mould, carry out densification and/or orientation.In another embodiment, by using mould to promote densification and/or orientation.As described below, densification and/or orientation are being higher than 25 ℃ usually, and for example about 105 ℃-Yue 180 ℃ are carried out in time bar depends on the time bar of used temperature.In another embodiment, compression molded process is carried out in batch methods.In another embodiment, the compression process process is carried out in continuation method.

" prefabrication type product " not compression reticulated elastomeric matrix for being shaped, it is from the cutting-out of reticulated elastomeric matrix piece or with the machine manufacturing, to be used for secondary operations, such as compression molded.The prefabrication type product can have predetermined size and shape.In one embodiment, the size of prefabrication type product and shape are determined according to the final or required compression ratio that is endowed in compression molded process.

When using mould, die cavity can have fixed shape, such as cylinder, and cube, spheroid or ellipsoid or it can have irregularly shaped.Cross-linked network biodurable elasticity Merlon urea-carbamate substrate is being compressed when molded and the geometry of densification and/or the orientation step mould when finishing has concordance significantly.

Compression molded can also carrying out in the mould that its profile can change in compression molded process for example changes over final shape and/or size from initial shape and/or size.The change of this die size can start or activates by applying heat or using load.In this class example, the cylindrical prefabrication type product of reticulated elastomeric matrix that will have diameter d 3 is put into thin-walled PTFE (poly-(tetrafluoroethene)) shrinkage-parcel pipe that has greater than the initial diameter d1 of d3.When applying external heat and/or load, PTFE shrinkage-parcel Guan Congqi initial diameter d1 shrinkage is to less final diameter d2.The cylindrical prefabrication type product that will have diameter d 3 is compressed into the final diameter that is substantially equal to or equals d2.The reticulated elastomeric matrix of compression is with the mould geometry for the PTFE tube that heats shrinkage is consistent to a great extent in this embodiment.

In one embodiment, think by compression molded with densification and/or directed give that characteristic that reticulated elastomeric matrix causes the reticulated elastomeric matrix that compresses strengthens and/or performance strengthens, such as in its mechanical properties, hot strength for example, stretch modulus, comprcssive strength, modulus of compressibility and/or tearing toughness.In another embodiment, think and give reticulated elastomeric matrix with densification and/or orientation and cause relating on the organization healing position and send by compression molded, concordance, the performance of operability and/or fillibility strengthens.

In compression molded process, in one embodiment, the 1-at least of prefabrication type product ties up size, and the length and/or the diameter of for example cylindrical prefabrication type product reduce dimensionally.Being used for application by mould reduces cylindrical prefabrication type product diameter and the constant basically non-limiting compression molded method of length is illustrated in Fig. 3.The typical cylindrical prefabrication type product of 61mm diameter among Fig. 3 can be put into by cylindrical flexible sheets for example thin aluminum, the mould inside that steel or plastic sheet constitute.In any suitable manner one side of sheet is fixed, and at the other end, promptly afterbody is outstanding.Apply power then so that afterbody is pulled out from the cylindrical part of sheet, reduce the internal diameter of sheet thus, and reduce to remain on the diameter of the prefabrication type product in the sheet simultaneously, as illustration among Fig. 3.As illustration wherein, the typical 61mm diameter circle of Fig. 3 cylindricality prefabrication type product can be decreased to for example 42mm.In this compression molded process, think that mould inner surface moves or displacement with respect to the outer surface of the prefabrication type product that contacts mould inner surface, after this afterbody is drawn out; Therefore, this compression molded method can also be described as " motion mold wall " compression molded method.

In another embodiment, in compression molded process, the 1-of prefabrication type product dimension reduces such as the cube gauge, and bidimensional remains unchanged basically in addition.This as a result illustration in Fig. 4.Typical cube prefabrication type product can be put into by two relative quite inflexible for example thick aluminum the mould inside that the die face of steel or plastics constitutes.The power that applies then to be to impel the two sides close to each other, reduces the cubical gauge that keeps between the two sides thus, as illustration among Fig. 4.In this compression molded process, think that each face moves hardly or be fixed when impelling them closer to each other for the outer surface of the prefabrication type product of this face of contact; Therefore, this compression molded method can also be described as " fixed mould wall " compression molded method.

In another embodiment, the institute that occurs when compression molded of prefabrication type small product size changes and can change owing to size only occurs in 1-dimension basically.In another embodiment, the prefabrication type small product size when compression molded, occur change and can change owing to the size that only in 1-dimension form, occurs.In another embodiment, changing basically that the prefabrication type small product size occurs when compression molded can change owing to the size that only occurs in gauge.In another embodiment, the prefabrication type small product size when compression molded, occur change and can change owing to the size that only in gauge, occurs.In another embodiment, changing basically that the prefabrication type small product size occurs when compression molded can change owing to the size that only occurs in length or height dimension.In another embodiment, the prefabrication type small product size when compression molded, occur change and can change owing to the size that only in length or height dimension, occurs.

This paper is defined as the size that reduces in compression molded process original size is about 1.1-about 9.9 with the compression molded linear compression ratio of the ratio of the size of final size afterwards.In another embodiment, the linear compression ratio is about 1.5-about 8.0.In another embodiment, the linear compression ratio is about 2.5-about 7.0.In another embodiment, the linear compression ratio is about 2.0-about 6.0.

If be reduced reducing with the linear compression strain of size in the compression molded process, promptly the size on original size changes expression, and the linear compression strain is about 3%-about 97% so.In another embodiment, the linear compression strain is about 15%-about 95%.In another embodiment, the linear compression strain is about 25%-about 90%.In another embodiment, the linear compression strain is about 30%-about 85%.In another embodiment, the linear compression strain is about 40%-about 75%.

In another embodiment, in compression molded process, the radial dimension of cylindrical prefabrication type product reduces, and promptly circumference reduces, and make that size reduces on two directions, and cylindrical height remains unchanged basically on another direction.In another embodiment, in compression molded process, the radial dimension of cylindrical prefabrication type product reduces, and on other direction, this cylindrical height remains unchanged.

In another embodiment, changing basically that the prefabrication type small product size occurs when compression molded can change owing to the size that only occurs in the 2-dimension.In another embodiment, the prefabrication type small product size when compression molded, occur change and can change owing to the size dimension that only in 2-dimension, occurs.In another embodiment, changing basically that the prefabrication type small product size occurs when compression molded can change owing to the size that only occurs in radial dimension.In another embodiment, the prefabrication type small product size when compression molded, occur change and can change owing to the size that only in radial dimension, occurs.

The original size that this paper is defined as cylindrical prefabrication type product radius is about 1.2-about 6.7 with the compression molded back finally radial compression ratio of the ratio of the size of radius.In another embodiment, the radial compression ratio is about 1.5-about 6.0.In another embodiment, the radial compression ratio is about 2.5-about 6.0.In another embodiment, the radial compression ratio is about 2.0-about 5.0.

In another embodiment, this paper original size of being defined as cylindrical prefabrication type product cross-sectional area is about 1.5-about 47 with the cross section compression ratio of the ratio of the size of the final cross-sectional area in compression molded back.In another embodiment, the cross section compression ratio is about 1.5-about 25.In another embodiment, the cross section compression ratio is about 2.0-about 9.0.In another embodiment, the cross section compression ratio is about 2.0-about 7.0.

If with the cross section compression strain, promptly the cross-sectional area on original cross-sectional area basis changes and represents reducing of cross-sectional area in the compression molded process of cylindrical prefabrication type product, and the cross section compression strain is about 25%-about 90% so.In another embodiment, the cross section compression strain is about 33%-about 88%.In another embodiment, the cross section compression strain is about 50%-about 88%.

The compression molded of biodurable reticulated elastomeric matrix material of the present invention carries out and in one embodiment, can carry out under about 100 ℃-Yue 190 ℃ being higher than under 25 ℃ the temperature.Or in another embodiment, about 110 ℃-Yue 180 ℃.In another embodiment, about 120 ℃-Yue 145 ℃.In another embodiment, when the temperature of carrying out compression molded process increases, carry out the time decreased of this compression molded process.The compression molded time was about 10 seconds-Yue 10 hours usually.In another embodiment, the compression molded time was about 30 seconds-Yue 5 hours.In another embodiment, the compression molded time was about 30 seconds-Yue 3 hours.When the temperature of carrying out compression molded process raises, be used for compression molded time decreased.Under higher temperature, the compression molded time must lack, because the long compression molded time may cause reticulated elastomeric matrix generation thermal degradation.For example, in one embodiment, under about temperature more than 160 ℃ or 160 ℃, the compression molded time is about in 30 minutes or 30 minutes.In one embodiment, be about in 10 minutes or 10 minutes.Or in another embodiment, be about in 5 minutes or 5 minutes.In another embodiment, under about 150 ℃ of temperature, under for example about 145 ℃-Yue 155 ℃, the compression molded time is about in 60 minutes or 60 minutes.In one embodiment, be about in 20 minutes or 20 minutes.Or in another embodiment, be about in 10 minutes or 10 minutes.In another embodiment, under about 130 ℃ of temperature, under for example about 125 ℃-Yue 135 ℃, the compression molded time is about in 240 minutes or 240 minutes.In one embodiment, be about in 120 minutes or 120 minutes.Or in another embodiment, be about in 30 minutes or 30 minutes.

After compression molded, the reticulated elastomeric matrix density of compression with compression molded before the ratio of reticulated elastomeric matrix density can increase about 1.05 times-Yue 25 times.In another embodiment, the reticulated elastomeric matrix density of compression can increase about 1.20 times-Yue 7.5 times; For example, in one embodiment, from 3.5 lbs/ft ³Initial density (0.056g/cc) is increased to 4.2 lbs/ft after compression molded ³(0.067g/cc) density.Or in one embodiment, be increased to 26.3 lbs/ft after compression molded ³(0.421g/cc) density.In another embodiment, the density of the reticulated elastomeric matrix of compression can be from for example 3.4 lbs/ft ³Initial density (0.054g/cc) is increased to 7.9 lbs/ft after compression molded ³(0.127g/cc).

After compression molded, the hot strength of the reticulated elastomeric matrix of compression can increase about 1.05 times-Yue 5.0 than the hot strength of the molded preceding reticulated elastomeric matrix of compression.In another embodiment, the hot strength of the reticulated elastomeric matrix of compression can increase about 1.20 times-Yue 2.5 times, for example, in one embodiment, from initial 52psi (36,400kg/m ²) hot strength increase to 62.4psi after compression molded (43,700kg/m ²) hot strength.Or in one embodiment, increase to 130psi after compression molded (91,000kg/m ²) hot strength.In another embodiment, the hot strength of the reticulated elastomeric matrix of compression can be for example from initial 52psi (36,400kg/m ²) hot strength increase to 120psi after compression molded (84,000kg/m ²) hot strength.In other embodiments, the increase of hot strength appears at the 1-dimension, on the direction of 2-dimension or the compression molded middle preferred orientation of 3-dimension.

After compression molded, the comprcssive strength of the reticulated elastomeric matrix of compression can increase about 1.05 times-Yue 4.5 times than the comprcssive strength of the molded preceding reticulated elastomeric matrix of compression.In another embodiment, the comprcssive strength of the reticulated elastomeric matrix of compression can increase about 1.20 times-Yue 3.5 times; For example, in one embodiment, under 50% compression strain from 2.4psi (1,700kg/m ²) initial compressive strength increase to 2.9psi under 50% compression strain of compression molded back (2,000kg/m ²), or in another embodiment, increase under 50% compression strain after compression molded 8.4psi (5,900kg/m ²).In other embodiments, the increase of comprcssive strength appears at the 1-dimension, on the direction of 2-dimension or the compression molded middle preferred orientation of 3-dimension.

After compression molded, the permeability of the reticulated elastomeric matrix of compression reduces usually, and the reticulated elastomeric matrix that may reduce compression thus provides the ability of tissue ingrowth and propagation.Therefore, importantly keep excellent permeability after compression molded.For example, in one embodiment, cross-sectional area reduces at about 50% o'clock in the compression molded back of this reticulated elastomeric matrix, and initial reticulated elastomeric matrix convection cell is reduced at least about the permeability of 450 darcies and is not less than about 250 darcies.In another embodiment, cross-sectional area reduces at about 60% o'clock in the compression molded back of this reticulated elastomeric matrix, and initial reticulated elastomeric matrix convection cell is reduced at least about the permeability of 450 darcies and is not less than 100 darcies.In another embodiment, cross-sectional area reduces at about 80% o'clock in the compression molded back of this reticulated elastomeric matrix, and initial reticulated elastomeric matrix convection cell is reduced at least about the permeability of 450 darcies and is not less than about 20 darcies.

In another embodiment, cross-sectional area reduces at about 50% o'clock in the compression molded back of this reticulated elastomeric matrix, and the permeability of about 300 darcies of initial reticulated elastomeric matrix is reduced to and is not less than about 100 darcies.In another embodiment, cross-sectional area reduces at about 60% o'clock in the compression molded back of this reticulated elastomeric matrix, and initial reticulated elastomeric matrix convection cell is reduced at least about the permeability of 300 darcies and is not less than about 80 darcies.In another embodiment, cross-sectional area reduces at about 75% o'clock in the compression molded back of this reticulated elastomeric matrix, and initial reticulated elastomeric matrix convection cell is reduced at least about the permeability of 300 darcies and is not less than about 15 darcies.

In another embodiment, cross-sectional area reduces at about 50% o'clock in the compression molded back of this reticulated elastomeric matrix, and initial reticulated elastomeric matrix convection cell is reduced at least about the permeability of 200 darcies and is not less than about 40 darcies.In another embodiment, cross-sectional area reduces at about 50% o'clock in the compression molded back of this reticulated elastomeric matrix, and initial reticulated elastomeric matrix convection cell is reduced at least about the permeability of 200 darcies and is not less than about 80 darcies.In another embodiment, cross-sectional area reduces at about 60% o'clock in the compression molded back of this reticulated elastomeric matrix, and initial reticulated elastomeric matrix convection cell is reduced at least about the permeability of 200 darcies and is not less than about 40 darcies.In another embodiment, cross-sectional area reduces at about 70% o'clock in the compression molded back of this reticulated elastomeric matrix, and initial reticulated elastomeric matrix convection cell is reduced at least about the permeability of 200 darcies and is not less than about 15 darcies.

Reinforcement is mixed

Elastomeric matrices 10 removes and carries out nettedly outside the pale of civilizationly can also carrying out further one or more nettedization post-treatment steps, thus give aforesaid in hole characteristic and compression molded.For example, in another embodiment, use stiffener to strengthen reticulated elastomeric matrix.In other embodiments, described stiffener is at least 1-dimension, 1-dimension stiffener (such as fiber) for example, 2-dimension stiffener (such as the 2-2-dimension network structure that is made of the 1-dimension reinforcing element that intersects) or 3-dimension stiffener (such as 3-dimension grid).

Can pass through stiffener, for example fiber comprises or mixes cross-linked network biodurable elasticity Merlon urea-carbamate substrate, prepares the multi-functional reinforcement elastomeric matrices of the concrete application purpose that is used for various implantable devices and/or the reinforcement elastomeric matrices of compression.Can comprise by the enhanced function of using stiffener to give, but be not limited to intensifier with operative process in sew up the ability that relevant tension goes out load, device comes localized ability and the ability of holding device on reparation position when organization healing takes place after operation by sew up anchor in operative process repairing on the position.In another embodiment, enhanced functional for device provides the ability with additional load in operation process, so that reparation that helps organizing or regeneration.In another embodiment, enhanced functional for device provides the ability with additional load by postoperative initial several days at least, so that reparation that helps organizing or regeneration.In another embodiment, enhanced functional for the back device of performing the operation provides the ability with additional load, so that reparation that helps organizing or regeneration.

A kind of mode that obtains enhancement function is by with stiffener, fiber for example, and fibrous reticular structure, tinsel and/or stitching thread mix elastomeric matrices to carry out.The another kind of typical way that obtains enhancement function is undertaken by using at least a stiffener to strengthen substrate.The stiffener doped matrix can be undertaken by variety of way, include, but are not limited to suture needle, sew up, weaving and braiding.In one embodiment, can stiffener be connected with substrate by sewing needle.In another embodiment, can stiffener be connected with substrate.In another embodiment, can be by the elastomeric matrices component being bubbled and making that the composite construction that forms thus is netted to change into intercommunication and intercommunicating pore structure and with the stiffener doped matrix.In one embodiment, used stiffener can not disturb substrate to adapt to the ability of tissue ingrowth and propagation.

The elastomeric matrices that fiber is mixed cross-linked network biodurable elasticity Merlon urea-carbamate substrate can change aspect directed at its density and/or its.The density of elastomeric matrices can change, in one embodiment, and about 2 lbs/ft ³-Yue 25 lbs/ft ³(about 0.401 g/cc of about 0.032g/cc-), or in another embodiment, about 2.5 lbs/ft ³-Yue 10 lbs/ft ³(the about 0.160g/cc of about 0.040g/cc-).In another embodiment, about 3 lbs/ft ³-Yue 8.5 lbs/ft ³(the about 0.136g/cc of about 0.480g/cc-).Orientation can occur in the nettedization process or in the secondary processing process after nettedization and the foam thermal curing in initial foam forming process.The characteristic that directed result is expressed as on orientation direction strengthens and/or the performance enhancing.In one embodiment, make the device that constitutes by the reinforcement reticulated elastomeric matrix be positioned tissue to be repaired, make enhanced characteristic of directed substrate and/or enhanced performance arrange by this way with the direction that tolerance has the high loads direction.The performance that the mixing of stiffener can cause substrate strengthens, and it is better than substrate by making reinforcement with the directed performance that obtains of one or more directions.

Stiffener can comprise monfil, multifilament, and braiding mixes monfil, multifilament yarn, pencil monfil, pencil multifilament etc.Stiffener can comprise amorphous polymer, the semi-crystal polymer, and for example polyester or nylon, carbon, carbon fiber for example, glass, glass fibre for example, pottery, crosslinked polymer fibers etc. or its be mixture arbitrarily.Described fiber can be by absorbing or nonabsorbable material is made.In one embodiment, fiber stiffener of the present invention is made by biocompatible materials.

In one embodiment, stiffener can by at least a can not absorbent material, can not degrade or can not make by absorbable polymer such as biology.Suitable example that can not absorbable polymer includes, but are not limited to polyesters (such as polyethylene terephthalate and PA polybutyleneterephthalate); TPO (such as polyethylene and polypropylene, comprise atactic, complete same, same and admixture and polyisobutylene and ethene-alpha-olefin copolymer); Acrylate copolymer and copolymer; Vinyl halide polymer and copolymer (such as polrvinyl chloride); Glymes (such as polyvinyl methyl ether); Poly-vinylidene halide (such as Kynoar and Vingon); Polyacrylonitrile; The polyethylene ketone; Polyethylene aromatic compounds (such as polystyrene); Polyethylene esters (such as polyvinyl acetate); Vinyl monomer each other with the copolymer (such as the ethylene-methyl methacrylate methyl terpolymer, acrylonitritrile-styrene resin, ABS resin and vinyl-vinyl acetate copolymer) of olefines; Polyamide-based (such as nylon 4, nylon 6, nylon 66, NYLON610, nylon 11, nylon 12 and polycaprolactam); Alkyd resins; Polycarbonate-based; The polyformaldehyde class; Polyimide; Polyethers; Ethylene oxide resin; Polyurethanes; Artificial silk; Artificial silk-triacetate; And mixture arbitrarily.With regard to the application's purpose, polyamide-based also comprising-NH-(CH ₂) _n-C (O)-and-NH-(CH ₂) _x-NH-C (O)-(CH ₂) _y-C (O)-the polyamide form, wherein n is the integer of 6-13, comprises two-end-point; X is the integer of 6-12, comprises two-end-point; And y is the integer of 4-16, comprises two-end-point.

In another embodiment, stiffener can be by at least a biodegradable, and biology can absorb or absorbable polymer is made.The example of suitable absorbable polymer includes, but are not limited to the aliphatic polyester class, lactic acid for example, and glycolic, lactide, Acetic acid, hydroxy-, bimol. cyclic ester, to-diethyleno dioxide ketones, plutonium carbonate propyl ester, the homopolymer of 6-caprolactone and admixture thereof and copolymer.Other typical biocompatible polymer comprises film forming bioresorbable polymer, such as the aliphatic polyester class, poly-(aminoacid), copolymerization (ether-ester class), the polyalkylene oxalic acid ester, polyamide-based, poly-(iminocarbonic acid esters), the poe class, the polyoxaesters class comprises the polyoxaesters class of phosphinylidyne-containing amine group, the polyamidoamines esters, poly-anhydrides, group of polyphosphazenes, biomolecule and mixture arbitrarily thereof.With regard to purpose of the present invention, the aliphatic polyester class comprises polymer and lactide (comprising lactic acid d-, 1-and Study of Meso-Lactide), 6-caprolactone, Acetic acid, hydroxy-, bimol. cyclic ester (comprising glycolic), butyric ester, hydroxyl valerate, to-diethyleno dioxide ketones, plutonium carbonate propyl ester (and alkyl derivative), 1,4-two oxa-ring-2-in heptan ketone, 1,5-two oxa-ring-2-in heptan ketone, 6,6-dimethyl-1, the copolymer of 4-diox-2-ketone and mixture arbitrarily thereof.

Can be by melt-extruded, anneal and stretch after melt-extruded, solvent spinning, electrostatic spinning and other method well known in the art prepare this fibrid/silk.Every kind of fiber all can be for bilayerization, has inner core and epitheca; Or multiple stratification, have inner core, epitheca and one or more layers intermediate layer.In two-and many-layer fiber, core, sheath or core random layer outward all can comprise degradable or soluble polymer.Can not apply or with comprising amorphous polymer, the semi-crystal polymer, carbon, glass, pottery etc. or its is the coating coated fiber of mixture arbitrarily.

Stiffener can be by carbon, glass, pottery, bioresorbable glass, contain the calcium phosphate glass of silicate or its arbitrarily mixture make.The calcium phosphate glass that can be controlled at interior degraded of human body and/or soak time can comprise metal, such as ferrum, and magnesium, sodium, potassium or its be mixture arbitrarily.

In another embodiment, described 1-dimension stiffener comprises the amorphous polymer fiber, the semi-crystalline polymer fiber, crosslinked polymer fibers, biopolymerization fibres, collagen fiber, elastic fiber, carbon fiber, glass fibre, the bioresorbable glass fibre contains the calcium phosphate glass fiber of silicate, ceramic fibre, polyester fiber, nylon fiber, amorphous polymer silk, the semi-crystalline polymer silk, cross linked polymer silk, biopolymer silk, collagenous shreds, elastin laminin silk, carbon filament, glass fiber, the bioresorbable glass fiber contains the calcium phosphate glass silk of silicate, ceramic wire, polyester capillaries, nylon yarn or its be mixture arbitrarily.In another embodiment, 2-dimension stiffener comprises intersection 1-dimension reinforcing element, and it comprises the amorphous polymer fiber, the semi-crystalline polymer fiber, crosslinked polymer fibers, biopolymerization fibres, carbon fiber, glass fibre, bioresorbable glass fibre, the calcium phosphate glass fiber that contains silicate, ceramic fibre, polyester fiber, nylon fiber, the amorphous polymer silk, semi-crystalline polymer silk, cross linked polymer silk, the biopolymer silk, carbon filament, glass fiber, bioresorbable glass fiber, the calcium phosphate glass silk that contains silicate, ceramic wire, polyester capillaries, nylon yarn or its be mixture arbitrarily.

Can stiffener be mixed reticulated elastomeric matrix with different mode.In one embodiment, stiffener is placed along the border of device, thereby kept apart from the fixed range at device edge.In another embodiment, stiffener is placed along the device border, thereby kept apart from the variable range at device edge.In another embodiment, along girth, for example circular device girth is placed, thereby has kept apart from the fixed range at device edge with stiffener.In another embodiment, stiffener is placed along the girth of device, thereby kept apart from the variable range at device edge.In another embodiment, stiffener, exists such as parallel fiber for example as a plurality of parallel lines as a plurality of parallel and/or substantially parallel 1-dimension reinforcing elements.In another embodiment, stiffener can be strengthened the grid placement as 2-or 3-dimension, wherein said 1-dimension reinforcing element passes through passage each other.Described grid can have one or more reinforcing elements.Strengthen in the embodiment of grid at 2-or 3-dimension, the element of stiffener is arranged with the geometry pattern, such as square, rectangle, trapezoidal, triangle, rhombus, parallelogram, circle, ellipse, pentagon, hexagon and/or have lateral polygon more than 7 or 7.Comprise the reinforcing element of strengthening grid all can be of similar shape with the size maybe can have different shapes and size.Comprise that the reinforcing element of strengthening grid can also comprise frame, girth and/or parallel lines element in addition.Strengthen the performance of grid or pattern, geometry and the quantity that characteristic depends on the substrate of this stiffener doped matrix and reinforcement thus the intrinsic characteristic and the grating element of stiffener.

Some is typical, but nonrestrictive reinforcement grid illustration is in Fig. 5 and 6.Fig. 5 a-5c and 6a-6d comprise frame or one or more girth reinforcing element separately.Fig. 5 a illustration the oval reinforcing element that on the square-grid reinforcing element, stacks.Fig. 5 b illustration on the square-grid reinforcing element eclipsed two oval reinforcing elements.Fig. 5 c illustration the square-grid reinforcing element.Fig. 6 a illustration on the square-grid reinforcing element eclipsed rhombus grid reinforcing element.Fig. 6 b illustration on the square-grid reinforcing element eclipsed 4-face polygon grid reinforcing element.Fig. 6 c and 6d illustration on the square-grid reinforcing element rhombus grid reinforcing element of eclipsed different spacing and oblique angle (diagional) reinforcing element.

In one embodiment, any one side of single grating element can be about the about 20mm length of 0.25mm-or be about the about 15mm of 5mm-in another embodiment long.

In other embodiments, gap between the reinforcing element or spacing can be about the about 20mm of 0.25mm-such as the gap between the adjacent linear reinforcing element in one embodiment.Or be about the about 15mm of 0.5mm-in another embodiment.In other embodiments, the space between the reinforcing element is substantially the same.In other embodiments, the space difference between the different reinforcing element.In other many-Wei stiffener embodiment, the space between the space between the 1-dimension reinforcing element and any other dimension reinforcing element is independently of one another.

In one embodiment, diameter with the reinforcing element that is essentially circular cross section can be about the about 0.50mm of 0.03mm-, or in another embodiment, the about 0.30mm of about 0.07mm-, or in another embodiment, the about 1.0mm of about 0.05mm-, or the about 1.0mm of about in another embodiment 0.03mm-.In another embodiment, the diameter with the reinforcing element that is essentially circular cross section can equal about 8-0 number-Yue No. 0 USP suture diameters.In one embodiment, about 8-0 number-Yue No. 2 USP suture diameters.In another embodiment, about 8-0 number-Yue 2-0 USP suture diameters.

Reinforcing element, for example fiber or stitching thread reinforcement layout or distribution and the pattern in substrate depends on that stand-by Design of device requires and/or uses.Be used for embodiment in stitching with the stiffener doped matrix, the suture needle spacing, promptly the distance between the junction point is about about 4mm of 0.25mm-or the about 3mm of about in another embodiment 1mm-in running suture or the same line.

In one embodiment, use, be used for the rotator cuff repair of booster action such as implantable device at some, may need not accurate cooperate to mate or be fit to repair or regenerated tissue.In another embodiment, before use, be shaped such as the implantable device that makes the reticulated elastomeric matrix that comprises reinforcement before surgical repair tendon and the ligament.A kind of typical manufacturing process is a Trimming.When needs are shaped, can be along the line or reinforcing fibre the reticulated elastomeric matrix of strengthening is repaired on length and/or width.In one embodiment, carry out this finishing so that keep about 2mm external reinforcing border, the stitching that for example helps in operation process connects.

With regard to the device of the reticulated elastomeric matrix that the present invention includes reinforcement, in one embodiment, be about the about 100mm of 0.25mm-with the full-size of the vertical any cross section of device thickness.In another embodiment, the maximum ga(u)ge of device is about the about 20mm of 0.25mm-.

In one embodiment, one or more bioactive molecules that describe in detail for implantable device and/or its stiffener coating this paper are such as protein, collagen protein, elastin laminin, nestin-1, fibrillin, fibronectin, cell adhesion molecule, blast cell albumen, calcium is according to Fibronectin, integrin is selected albumen, H-CAM superfamily etc.

In one embodiment, the device that stiffener is mixed reticulated elastomeric matrix has at least a feature in the following performance range.The stitching thread pull off strength is about about 17 lbs/ft of 1.1 lbs/ft-(about 5 newton-Yue 75 newton) or about 9.0 lbs/ft of about in another embodiment 2.3 lbs/ft-(about 10 newton-Yue 40 newton) in one embodiment.Fracture strength is about about 100 lbs/ft of 2.0 lbs/ft-(about 8.8 newton-Yue 440 newton) or about 45 lbs/ft of about in another embodiment 3.4 lbs/ft-(about 15 newton-Yue 200 newton) or the about 22.5lbs/ft of about in another embodiment 6.8 lbs/ft-(about 30 newton-Yue 100 newton) in one embodiment.The ball bursting strength is about about 75 lbsf of 3 lbsf-(the about 34Kgf of about 1.35Kgf-) or about 50 lbsf of about in another embodiment 8 lbsf-(the about 22.5Kgf of about 3.65Kgf-) in one embodiment.

Use has been installed the INSTRON Tester (Model3342) that the pneumatic handle of 1kN clamps the jaw folder up and down and has been carried out the test of stitching thread pull off strength, the handle surface that described jaw folder has relative 25mm x25mm rubber coated separately.Fig. 7 illustration strengthen sample and sutural geometry in the stitching thread pull off strength test embodiment.Testing sutural length is 2-0ETHIBOND Woven polyester stitching thread.With standard of instruments specification length setting to 60mm (2.36 inches), an end of reinforcement reticulated elastomeric matrix device to be tested (end 2) clamping is gone into the fixed jaw folder in instrument bottom.By using syringe needle ETHIBOND is tested the other end (end 1) that stitching thread inserts the reticulated elastomeric matrix device of strengthening.Test stitching thread two ends form ring.Make the test stitching thread at the horizontal line feeder 2-3mm that is lower than the most approaching device edge and preferably is connected with stiffening device in the face of device width center, as to Fig. 7 illustration of the device of use fiber square-grid reinforcement.

The length of testing the reticulated elastomeric matrix device junction point of sutural free-end distance test (DT) stitching thread and reinforcement is about 50-60mm.Sutural free-end is clamped into the removable jaw clip in instrument top.After this, use and to move up and (3.94 inches/min) speed is carried out stitching thread maintenance strength test with 100mm/min away from the removable jaw folder of fixing jaw folder.The maximum, force that reaches in the application of force-elongation relation curve is labeled as stitching thread keeps intensity, as long as tearing in the reticulated elastomeric matrix device of strengthening is limited to the zone near the end 1 HORIZONTAL PLAID grid line of contiguous stitching thread link position.According to meansigma methods and standard deviation are determined in the test of multiple sample.

Carry out fracture strength test according to the mode identical, but do not use the polyester stitching thread of braiding and the reticulated elastomeric matrix device of the reinforcement that fixedly clamping is tested between the removable jaw folder of jaw folder and top in the instrument bottom with above-mentioned stitching thread pull off strength.After this, use and to move up and press from both sides away from the fixing removable jaw of jaw folder that (3.94 inches/min) speed is carried out fracture strength test with 100mm/min.The maximum, force that reaches in the application of force-elongation relation curve is labeled as fracture strength.

According to the determination of test method ball bursting strength described in the ASTM Standard 3787, have the 10mm diameter but use, 18mm diameter retaining hole and 102mm/min (4 inches/min) crosshead speed than bead.

Other post-treatment of reticulated elastomeric matrix

Except that above-mentioned those that described, elastomeric matrices 10 can also carry out further procedure of processing or a plurality of step.For example, elastomeric matrices 10 or can anneal so that Stability Analysis of Structures by the product that elastomeric matrices 10 is made.

In one embodiment, at high temperature annealing can promote the crystallinity that increases in the polyurethanes.In another embodiment, annealing can promote the crystallinity that increases in the crosslinked polyurethanes under heating up.Annealing can also promote Stability Analysis of Structures and the secular bin stability in crosslinked polyurethanes and the long term store time limit stability under heating up.Stability Analysis of Structures and/or extra crystallinity can provide the bin stability of raising to the implantable device of being made by elastomeric matrices 10.In one embodiment, be not bound by any particular theory, annealing cause foam to form and/or nettedization process in the stress relaxation that forms in the reticulated elastomeric matrix structure.

In one embodiment, annealing above under about 50 ℃ temperature.In another embodiment, annealing above under about 100 ℃ temperature.In another embodiment, annealing above under about 125 ℃ temperature.In another embodiment, under about 100 ℃-Yue 135 ℃ temperature, anneal.In another embodiment, under about 100 ℃-Yue 130 ℃ temperature, anneal.In another embodiment, under about 100 ℃-Yue 120 ℃ temperature, anneal.In another embodiment, under about 105 ℃-Yue 115 ℃ temperature, anneal.

In another embodiment, annealing was carried out at least about 2 hours.In another embodiment, with about 15 hours of the about 2-of annealing.In another embodiment, with about 10 hours of the about 3-of annealing.In another embodiment, with about 8 hours of the about 4-of annealing.

In restriction or do not anneal under the situation of restraint device.In another embodiment, elastomeric matrices 10 is unfettered on geometry when annealing, for example is not surrounded by mould around the elastomeric matrices.In another embodiment, elastomeric matrices 10 suffers restraints on geometry when annealing, and for example elastomeric matrices is subjected to the surface on one or more sides, such as the die surface constraint, makes its size, can not change basically in annealing process such as its thickness.In this embodiment, elastomeric matrices 10 is not compressed to any tangible degree because of it is tied, and therefore, is different from compression molded in this class annealing aspect this.

In one embodiment, can choose wantonly in compression molded back under about 110 ℃-Yue 140 ℃ of temperature and about 15 minutes-Yue 4 hours time bars the reticulated elastomeric matrix of compression further anneal ().With compression molded the same, can be limited under the situation of in the mould or not using mould in substrate and anneal compression.In another embodiment, can be limited under the situation in the mould in substrate that will compression and anneal.If initial compression moldedly carry out under about temperature more than 150 ℃ or 150 ℃, annealing time should be lacked the probability with the thermal degradation when the long annealing time of the reticulated elastomeric matrix avoiding compressing so.For example, about temperatures more than 150 ℃ or 150 ℃ contract molded after, under about 125 ℃-Yue 135 ℃ of temperature, about 30 minutes-Yue 3 hours time bars are carried out in the annealing of reticulated elastomeric matrix of compression.

Elastomeric matrices 10 can be molded as different shape and size in its shaping or production process.Shape can be work structuring, such as arbitrary shape and the structure of request described in the priority application, or shape can at be deposit material in bulk.Can cut subsequently, finishing, punching press deposit material, or make its shaping so that final the application.For example, can be by the use blade, drift, drill bit or laser carry out sizing and shaping.In in these embodiments every kind, be used to be shaped and one or more processing temperatures of the cutting tool of sizing can be higher than about 100 ℃.In another embodiment, be used to be shaped and the processing temperature of the cutting tool of typing can be higher than about 130 ℃.In one embodiment, final step can comprise the macrostructure surface protuberance that finishing may biological tissue stimulation, such as the finishing of minor connector etc.In another embodiment, final step can comprise heating anneal.Can or anneal afterwards before final cutting and shaping.

Be shaped and typing can comprise the shaping of customization and typing so that implantable device and concrete patient's concrete therapentic part coupling, as by imaging or other technical measurement well known in the art.Especially, elastomeric matrices 10 one or peanut in one embodiment for example is less than approximately 6, and is less than about 2 in another embodiment and can comprises and be used for the treatment of that needs are repaired and/or the implantable device system of regenerated damaged tissues.

The shaping of being made by elastomeric matrices 10 and the size of calibrator can be repaired with regeneration the different of site according to treatment particular organization and be changed.In one embodiment, compress and send before the device key dimension be about the about 500mm of 0.5mm-.In another embodiment, compress and send before the device key dimension be about the about 500mm of 10mm-.In another embodiment, compress and send before the device key dimension be about the about 200mm of 50mm-.In another embodiment, compress and send before the device key dimension be about the about 100mm of 30mm-.Elastomeric matrices 10 is passing through delivery apparatus, and for example conduit shows compression set when syringe or endoscope's compression and transhipment.In another embodiment, before the compression of design apparatus, consider compression set and standard deviation thereof during size.

In one embodiment, use implantable device or apparatus system treatment patient, with reference to the volume that limits to implantation site in the inlet of described position, described implantable device or apparatus system not or target chamber or other position of himself this apparatus system residence of complete filling.Wherein even after biofluid or tissue occupy the elastomeric matrices hole, implantable device or apparatus system are also not exclusively filled target chamber or other position that implant system is still resided in one embodiment.In another embodiment, the volume of implantable device or the complete expansion of apparatus system original position is lower than 1% of described position volume at least.In another embodiment, the volume of implantable device or the complete expansion of apparatus system original position is lower than 15% of described position volume at least.In another embodiment, the volume of implantable device or the complete expansion of apparatus system original position is lower than 30% of described position volume at least.

In another embodiment, the volume of implantable device or the complete expansion of apparatus system original position is greater than the about 1%-of cavity volume about 40%.In another embodiment, the volume of implantable device or the complete expansion of apparatus system original position is greater than the about 5%-of cavity volume about 25%.In another embodiment, the ratio of the volume that occupies of implantable device volume and orthopedic applications position is about 70%-about 90%.In another embodiment, the ratio of the volume that occupies of implantable device volume and orthopedic applications position is about 90%-about 100%.In another embodiment, the ratio of the volume that occupies of implantable device volume and orthopedic applications position is about 90%-and is lower than about 100%.In another embodiment, the ratio of the volume that occupies of implantable device volume and orthopedic applications position is about 100%-about 140%.In another embodiment, the ratio of the volume that occupies of implantable device volume and orthopedic applications position is about 100%-about 200%.In another embodiment, the ratio of the volume that occupies of implantable device volume and orthopedic applications position is about 100%-about 300%.

Can be by any method as known in the art to biodurable reticulated elastomeric matrix 10 or comprise that the implantable device system of this class substrate sterilizes, and comprises gamma-radiation, autoclaving, ethylene oxide sterilizing, infrared ray radiation and electron beam irradiation.In one embodiment, the biodurable elastomer that is used to make elastomeric matrices 10 tolerates this class sterilization and can not lose useful physical and mechanical property.It is extra crosslinked so that improve the performance of device that the application of gamma-radiation can provide.

In one embodiment, the product of sterilization can be packaged in paper, in the aseptic packaging of polymer or other suitable material.In another embodiment, in this class packing, elastomeric matrices 10 is compressed in the holding element so that it is written into delivery apparatus with the compressed configuration form, in conduit or endoscope.In another embodiment, elastomeric matrices 10 comprises the elastomer with compression set, and this compression set can make it be expanded to its compression front volume of larger proportion, for example under 25 ℃, is expanded at least 50% of its compression front volume.In another embodiment, elastomeric matrices 10 keeps being compressed in that typical commercial stores and expands after the distribution time in this class packing, and it surpasses 3 months usually and can reach 1 or 5 year from being prepared into application.

Radiopacity

In one embodiment, for example, implantable device can be by making the granule adhesion of radiopaque material, covalent bonding and/or mix elastomeric matrices self and be endowed radiopacity so that in-vivo imaging.The radiopaque material comprises titanium, tantalum, and tungsten, barium sulfate or other well known to a person skilled in the art suitable material.

Implantable device is used

Can described in the request priority application, use the implantable device system of mixing reticulated elastomeric matrix.In one embodiment, the implantable device that comprises reticulated elastomeric matrix can be used for the treatment of tissue defects, for example in orthopedic applications, common surgical procedures is used, and aesthetic surgery is used, and tissue engineered application or its are used for repairing in mixture arbitrarily, rebuild, regeneration is strengthened, and breach inserts or it makes up arbitrarily.

In another embodiment, comprise that the implantable device of reticulated elastomeric matrix can be used for orthopedic applications, so as tendon, ligament, cartilage, meniscus, spinal disc or its be the reparation of mixture arbitrarily, rebuilds, regeneration is strengthened, and breach inserts or it makes up arbitrarily.For example, comprise that the implantable device of reticulated elastomeric matrix can be used for orthopedic applications widely, include, but are not limited to comprise spinal column, shoulder, elbow, wrist, hands, knee joint, the reparation in ankle or other joints and regeneration are as what describe in detail in the priority application.The implantable device of being made by the biodurable reticulated elastomeric matrix provides platform for tissue ingrowth, described tissue ingrowth is treated so-called soft tissue orthopedic applications disease especially effectively, for example connect, regeneration is strengthened or the support soft tissue, comprises the tendon reinforcement, articular cartilage is repaired, meniscal repairs and reconstruction, ligament are rebuild, prolapse of intervertebral disc substrate stable and that repair as nuclear subsitution thing and annulus.

Can comprise that the implantable device reparation of reticulated elastomeric matrix or the ligament example in the regenerated shoulder zone comprise acromion clavicle ligament by use, glenohumeral ligaments, coracohumeral ligament, horizontal humerus ligament, coracoacromial ligament etc.Can comprise that the example of tendon in the implantable device reparation of reticulated elastomeric matrix or the regenerated shoulder zone comprises supraspinatus by use, infraspinatus, the long tendon of arm biceps etc.Can also comprise the implantable device reparation of reticulated elastomeric matrix or the cartilage in the regeneration shoulder zone by use.

Can comprise that the example of ligament in the implantable device reparation of reticulated elastomeric matrix or the regenerated elbow region comprises medial collateral ligament (" MCL "), lateral collateral ligament ligament and anular ligaments by use.Can comprise that the example of tendon in the implantable device reparation of reticulated elastomeric matrix or the regenerated elbow region comprises biceps and triceps tendon by use.Can also comprise the implantable device reparation of reticulated elastomeric matrix or the cartilage in the regeneration elbow region by use.

Can comprise that the example of ligament in the implantable device reparation of reticulated elastomeric matrix or the territory, regenerated knee comprises posterior cruciate ligament, anterior cruciate ligament (" ACL "), patellar ligament by use, the fibula side para-ligament, the tibial side ligamena collateralia, ligament meniscofemorale posterius, posterior clinoid process shin calf ligament etc.Can comprise that the example of tendon in the implantable device reparation of reticulated elastomeric matrix or the territory, regenerated knee comprises quadriceps tendon by use.Can comprise the implantable device reparation of reticulated elastomeric matrix or the articular cartilage in the regeneration territory, knee by use.

Can comprise that the example of ligament in the implantable device reparation of reticulated elastomeric matrix or the regenerated ankle joint area comprises horizontal inguinal ligament, groin ligamentaum cruciatum, flexor retinaculum etc. by use.Can comprise that the example of tendon in the implantable device reparation of reticulated elastomeric matrix or the regenerated ankle joint area comprises peroneus longus, peroneus brevis, Achelis tendon etc. by use.Can also comprise the implantable device reparation of reticulated elastomeric matrix or the cartilage in the regeneration ankle joint area by use.

Generally speaking, can comprise the implantable device reparation or the regeneration spinal column of reticulated elastomeric matrix by use, shoulder, elbow, wrist, hands, knee joint, any ligament, tendon and/or the cartilage of ankle or other body joints.

In one embodiment, the implantable device that comprises reticulated elastomeric matrix is suitable for being configured as locking device to seal the access portal in the annulus that produces because of discectomy (discotomy), thereby, be also referred to as in intervertebral disk hernia or slippage or the expanding disk situation and strengthen and stable plate-like annulus at prolapse of intervertebral disc.Can be by the intubate in the discectomy operating process, used with the locking device compression and send into the annulus opening.By following at least two kinds of mechanism this device is fixed into opening.At first, netted entity mutually 12 export-oriented resilience can provide and prevent the mechanical system that is offset.The second, netted entity mutually 12 can be as grow into interconnected space 14 the substrate mutually of elastomeric matrices of Muller's fibers chondrosin.Can be by using as anchor known in the art, stitching thread or biological glue and binding agent obtain extra fixing.Locking device can the Muller's fibers cartilage inwardly growth go into the elastomeric matrices of implantable device.

In another embodiment, will comprise that the implantable device of reticulated elastomeric matrix is made sticking patch, can be for example by sewing up, anchor, staple etc. are in place so that support when key heal is provided with its grappling, make the original position tendon strengthen and reinforcement.This is used in particular for rotator cuff or storehouse technology reparation, wherein tendinous tissue worsen or undercapacity that chronic defective and remaining tendon take place to support the required stitching of successful grappling tendon, wherein tendon and muscle contraction and can not fully stretch so that be connected (tendon of contraction) again or because of damage destructive tendon, muscle or tissue.The implantable device that comprises reticulated elastomeric matrix can be used as the substrate of tissue ingrowth so that strengthen tendon and provide support in agglutination.In one embodiment, comprise that the implantable device of reticulated elastomeric matrix can be as breach insert or bridge material so that tear ligament or tendon by providing the substrate of repairing position and tissue ingrowth to repair wholly or in part.This class implantable device can also be repaired tendon inoperable otherwise that just can not connect again.The implantable device that comprises reticulated elastomeric matrix can be used for the MCL reparation.Can use conventional sew up implantable device fixed (afixed) repair position (at tough leukorrhagia) go up (atop) or use permanent, for example metal or so-called Bioabsorbable staple or anchor/stitching thread be fixed on bone (near condyle of femur or near in tibia plature) on.Can also use biology-glue to make sticking patch be connected (such as tendon, ligament or cerebral dura mater) with the specified restoration position as stiffening device.

In another embodiment, supporting tissue is repaired and the regenerated implantable bioartificial durability of articular cartilage substrate when being formed in reticulated elastomeric matrix or the implantable device that comprises reticulated elastomeric matrix with acellular pattern, in the knee joint injury in treating, have application thus, for example be used for meniscal repairs and ACL and rebuild.Comprise reticulated elastomeric matrix implantable device can as near or side direction meniscus sample be shaped.The implantable device that comprises reticulated elastomeric matrix can be used for perfect joint dish or the displacement of part meniscus.Can sew up perfect joint dish or sections or fix with staple and bone or adjacent meniscal tissue.

The another kind that comprises the implantable device of reticulated elastomeric matrix is used the reparation be to repair weak position in the biological connective tissue, and these weak positions make to have the another kind of organ that causes biological damage or tract bulging or hernia and go out.In one embodiment, the feature of implantable device and functionally make it be suitable for common surgical procedures to use is such as the application in hernia repair.

Hernia can be described as groin position or veutro and other is more uncommon, but well-known change location, the i.e. hernia of femur or umbilicus.In one embodiment, hernia to be repaired is an inguinal hernia, the veutro hernia, and thigh portion hernia, umbilical hernia or its mix arbitrarily.Can be directly or by the peritoneoscope means near being arranged in the go forward hernia of stomach wall or flank wall of operation or wound front.Reparation will comprise that mainly the implantable device of reticulated elastomeric matrix places in the stomach wall, strengthen or strengthen sheath of rectus abdominis-transversus, the defective in the muscle/fascia of obliquus externus abdominis m. and/or obliquus internus abdominis m. thus.In one embodiment, the implantable device that comprises reticulated elastomeric matrix can be processed into and have at micropore on the abdominal cavity side or a level and smooth side and tissue ingrowth to go into towards another porous side of the implant in the outside.

Can be by means before the peritoneum near inguinal hernia, though before the described peritoneum means with inner loop as by anterior approach and " atonicity " Lichenstein or filling or selectively laparoscopic surgery directly enter preperitoneal space.

Do not have in the tension force reparation at Lichtenstein, cutting skin, behind scarpa's fascia and the obliquus externus abdominis m. aponeurosis (aponeuroses) by anterior approach near inguinal canal.Check the rope of indirect capsule, reduce any direct hernia and the implantable device reinforced bottom that comprises reticulated elastomeric matrix by sewing up with link to each other tendon and inguinal ligament bracket edge.Can make the implantable device crack that comprises reticulated elastomeric matrix or be designed to hold Cable Structure.In the Kugel technology, will comprise that the monolayer or the bilayer (having or do not have the memory external resilience ring of ego defense) of the implantable device of reticulated elastomeric matrix put into preperitoneal space by the 4cm muscle-splitting incision prepositionly.

Two kinds of laparoscopy technology commonly used comprise repairs (" TAPP ") and repairs (" TEP ") outside the peritoneum fully before the abdomen peritoneum.TAPP and TEP can put into preperitoneal space with the implantable device that comprises reticulated elastomeric matrix.In abdominal part, enter intraperitoneal and carry out the TAPP reparation by the preperitoneal space otch of in peritoneum, doing.In TEP repairs, in extraperitoneal space, begin to peel off fully.The purpose of suitably repairing in two kinds of operations comprises: (1) peels off muscle-muscle-aperture (MPO) and surrounding structure fully, wherein near fully middle pubis and the Lei Qiusi gap of exposing; (2) remove preceding fat of peritoneum and rope lipoma; (3) estimate all possible hernia position; (4) reduce hernical sac fully; (5) make the rope skeletonizing to guarantee reducing indirect capsule by deferent duct and gonaduct near-end.

In another embodiment, comprise that the implantable device of reticulated elastomeric matrix is used for the aesthetic surgery application, comprise maxillary surface, cranium, mammary gland, Urology Surgery, stomach esophagus or other are rebuild purpose.In this class is used, the filler that reticulated elastomeric matrix can play a part to take up space and the platform of tissue ingrowth is provided, it is treated this class shaping especially effectively and rebuilds disease.

In one embodiment, be in particular shaping and reconstruction operations, strengthen and prevent the implantable device of capsule formation design packet purse rope shape elastomeric matrices such as the mammary gland soft tissue.Owing to obtained reticulated elastomeric matrix unique biological durability/biocompatibility of the present invention, so it is used in particular for the mammary gland plastic operation.Its application can reduce the implant encapsulation and form.Usually the bag of putting into the mammary gland implant under the mammary gland self or generating with modus operandi under the muscle under the mammary gland.Mammary gland implant (even have grain surface those) can reach among the crowd of all cases 25% and form thick entity fibrous capsule or metaplasia (folding/gauffer).These capsules (grade according to 1-4 is categorized as 3 or 4 usually, and wherein 4 are " the worst situation ") have proposed serious clinical challenge to patient and plastic surgeon.What can fully accept from animal model and clinical experience is that above-mentioned polyurethane foam is successfully avoided or obviously weakened capsule formation; Yet those polyurethane foam coverings are defectiveness also.On the contrary, the implantable device that comprises reticulated elastomeric matrix is used to avoid and or obviously weakens capsule and form.

Implantable device can use with several different structures.For example, the square of embodiment or rectangle in fact can with fixedly coupling of standard procedures so that the fiber stiffener carefully is included in the tissue bond.The side breast that the example can be used for using the mammary gland of the standard mammary gland implant under the thoracic wall muscle group to rebuild is folding down.Another typically is configured to as Asia-gland or Asia-obducent implantable device of flesh mammary gland implant.Can customize the lip that has the cancellated implantable device of reinforcement or on its periphery, have existence, so that use standard mammary gland implant to cover in no stitching thread mode.Implantation can carried out on outer side or both sides, so that increase tissue ingrowth, and stabilisation implant and weaken and even prevent the organized implant fibrous capsule that thickens to form.

In another embodiment, implantable device be used for the face cosmetic surgery in case the bottom line invasive with other reconstruction application.In the face cosmetic applications, can use trocar (troacar) or other introducer that implantable device is conveyed into supportive fascia soft tissue.The implantable device that comprises reticulated elastomeric matrix is connected tissue and connects for example absorbability stitching thread in time in its whole process, anchor, barb, nail pin, screw, staple, plate, hobnail, glue etc., dispersion and implantable device supporting tissue are inwardly grown, and carry out the safety biological fixation thus.Modal is to solve and the special area of operation technique forehead, face middle part and neck by open or minimum level invasive/percutaneous technology, such as the nasolabial fold of illustration in Fig. 8, and the cheek crescent, cheek caves in and the lower jaw dewlap.

Implantable device of the present invention has general the application in all field of surgery, and wherein permanent biological fixation and/or the suspension of being undertaken by tissue ingrowth to reticulated elastomeric matrix also needs.

The implantable device that comprises reticulated elastomeric matrix is also as the holder of body outer cell proliferation application, and for example orthopedic applications connects such as tissue, and regeneration is strengthened or tendon, ligament, the holder during meniscus and annulus and prosthese organ-tissue are grown.

In one embodiment, implantable device can comprise cell, somatomedin and nutrient.In another embodiment, the biodurable implantable device can or be gathered template from patient's autogenous cell as non-autogenous cell, described cell can be cultivated and implant then patient's defective in the isolated experiment room environmental.In another embodiment, implantable device mixes osteoinductive agent, such as somatomedin, for example derive from platelet and leukocytic ability from the bulk-growth factor it is functionalized in case regulate cell function and energetically induced tissue inwardly grow.The basis that implantable device provides cell therapy to use thus so that support the wide region soft tissue, includes, but are not limited to the tissue repair and the regeneration of articular cartilage, and meniscal repairs and ACL rebuild.The gained implantable device is filled cartilage defects, supports autologous tissue's reparation and regeneration and can integrate reparation or regeneration site, for example impaired knee joint subsequently.

In another embodiment, implantable device is used for tissue engineered application, comprises generating the prosthese organ-tissue, for example is used for liver, the regeneration of kidney or mammary gland tissue.

In a limiting examples, be appointed part, select one or more to comprise the implantable device of reticulated elastomeric matrix such as target tissue healing position.Implantable device (or multiple arrangement) is written into delivery apparatus, such as conduit, endoscope, sleeve pipe, the trocar etc.In one embodiment, delivery apparatus is used to use bottom line invasive mode to send the implantable device that comprises reticulated elastomeric matrix.After implantable device discharges from delivery apparatus, can its grappling is in place so that resist from target reparation or regeneration site migration.Make the method for implantable device fix in position comprise the use suture, anchor, barb, contact pin, screw, staple, plate, tack pin, glue or its make up arbitrarily implantable device and target reparation position are fixed.The implantable device that comprises reticulated elastomeric matrix can overturn and insert the joint by arthroscopic cannula.In one embodiment, implantable device and target tissue healing position compare over dimensioning and reside on this position or remain on this position by compressed fit in place, the resilience by reticulated elastomeric matrix for example.In one embodiment, overdimensioned implantable device is consistent with tissue defects on form.Be not bound by any particular theory, the resilience and the restorability that produce the conformal match of this class can cause forming gapless basically closely border between implantable device wall and defective, and the interface that helps lend some impetus to inside growth of cell and hyperblastosis is provided thus.In case on this position, discharge, but the implantable device that then comprises reticulated elastomeric matrix is expanded in the resilience mode and is about its original size and shape is obeyed any compression set limit and any required flexing certainly, covers or meet the dissection and/or the geometry of the implant site that implantable device elasticity is fit to.In another embodiment, insert implantable device by the open operation operation.

In another embodiment, it is damaged reticulated elastomeric matrix 10 to be fixed to.This damaged may because of damage or disease causes or may produce because of modus operandi.Reticulated elastomeric matrix can be positioned at the damaged inside of target, and is adjacent with it and/or to cover target damaged.Reticulated elastomeric matrix can be used as the defective filler, substitutes tissue, organizes stiffener and/or eta patch.In another embodiment, reticulated elastomeric matrix can be crossed over defective and as the bridging thing of breach in the natural tissues.

Although can maybe can the implantable device that comprise reticulated elastomeric matrix is connected the method for undergoing surgery with tissue repair or regeneration site by many various criterions, two kinds of typical methods be as described below.These operational applications can be repaired regeneration and reconstructive procedure in other.

Use Hall orthopedic applications burr to peel off the soft tissue repair position, such as the crust of impaired tendon of infraspinatus muscle.Peel off the crust of the standard area of bone.4 Biosuture viscosity anchors are put into the square configuration of tuberosity.Hold with a firm grip tendon of infraspinatus muscle and use the recessed and Mason-Allen formula suture of two sutured to be attached to proximal humerus again.Implantable device placed repair top, position, make the 0.5cm-2cm jag of on the tuberosity side, having an appointment.The remainder of device stretches on tendon.Be used for anchor suture that tendon connects and also follow vertical matress suture by this device and this device is fixed on repair tendon, thereby generate the stratified structure of forming by implantable device and tendon.In the side, in addition two anchor sutures by device and with its downwards and tuberosity tighten.In one embodiment, will install anchor suture and be arranged in stiffener inside, for example along the device girth and/or strengthen the grid outermost component inner place reinforcing element inside.4 anchor suture ends intersect as shown in Fig. 9 a.

In another embodiment, repair and to carry out as mentioned above, repair top, position, make the 1cm jag of on the tuberosity side, having an appointment but implantable device is placed on.The remainder of implantable device stretches on tendon.The anchor suture that is used for the tendon connection is also as mentioned above by this device.In the side, in addition two anchor sutures as mentioned above by device and with its downwards and tuberosity tighten.To install anchor suture and as shown in Fig. 9 b, be arranged in device stiffener inside.

In one embodiment, the implantable device of being made by the biodurable reticulated elastomeric matrix provides splendid platform for tissue ingrowth.In another embodiment, the cell body can be invaded and grow into the implantable device that comprises reticulated elastomeric matrix such as fibroblast and tissue.Be in due course, this class is inwardly grown and is expanded the endoporus 20 and the little gap of the reticulated elastomeric matrix of going into to insert 10.Finally, the implantable device that comprises reticulated elastomeric matrix can be reproduced the cell filling of inwardly growing basically, and this inside growth has formed the agglomerate that can occupy described position or void space wherein.The type of tissue ingrowth includes, but are not limited to fibrous tissue, endothelial tissue and orthopedic applications soft tissue.

In another embodiment, implantable device promotes that cell is inwardly grown and tissue regeneration is dispersed throughout described position, is dispersed throughout the border, position or by some exposed surface, seals this position thus.Passing in time, this inductive fiber blood vessel body that produces because of tissue ingrowth can promote implantable device to mix target tissue healing position.In one embodiment, this inductive fiber blood vessel body that produces because of tissue ingrowth can cause implantable device to small part (even not being complete basically) biointegration to go into target tissue healing position.In another embodiment, tissue ingrowth can cause repair of damaged tissues or damaged tissues regeneration and/or rebuild.In another embodiment, tissue ingrowth can cause the effectively opposing migration of generation in time of implantable device.It can also fill space or defective.In another embodiment, tissue ingrowth is for continuing for a long time, the scar tissue of harmless and/or mechanically stable.In another embodiment, process in time, for example the reticulated elastomeric matrix 10 of implantation became and is organized fully, fibrous tissue, filling and/or encapsulations such as scar tissue to 1 year 2 weeks to 3 month.

In another embodiment, implantable device also has this useful permanent biological feature of implanting of biocompatibility.Biocompatibility includes, but are not limited to show non-carcinogenesis, mutagenicity, teratogenecity, cytotoxicity or other bad biological agent.

In another embodiment, the characteristic that will comprise the implantable device of reticulated elastomeric matrix is transformed into the tissue compatible with targeting, for example simulates it or satisfies the requirement of application-specific.Can be by control, for example crosslinked amount, the amount of degree of crystallinity, chemical composition, condition of cure, nettedization degree and/or nettedization post-treatment, such as annealing, compression molded and/or mix the characteristic that stiffener is transformed reticulated elastomeric matrix.Be different from biodegradable polymer, reticulated elastomeric matrix is kept its physical features and performance in vivo in the long-time time limit.Therefore, it can not cause unwanted tissue reaction, and is observed as possibility when biodegradable implant is decomposed and degrade.The high-voidage amount of reticulated elastomeric matrix and nettedization degree make tissue ingrowth and cell is bred in the substrate.In one embodiment, ingrown tissue and/or regenerated cell occupy the interconnected space of original implantable device about 25%-about 99% of 14 volumes mutually, in another embodiment, be about 51%-about 99%, provide thus repair or alternate original structure functional, such as having weight bearing power.

In a limiting examples, transform the compression set of implantable device, resilience and/or restorative after CYCLIC LOADING repeatedly so that the height restoring force of reticulated elastomeric matrix is provided.This category feature is for the orthopedic applications advantageous particularly, wherein the CYCLIC LOADING of implantable device can also persistency the compression reticulated elastomeric matrix, prevent thus it basically Continuous Contact allow optimum cell to soak into and the necessary surrounding soft tissue of tissue ingrowth.In another limiting examples, the density of transformation implantable device and aperture are so that provide the acceptable permeability of reticulated elastomeric matrix under compression.This category feature and advantage help spinal column and knee joint orthopedic applications, and wherein top load is placed on the implantable device.In another limiting examples, transform the characteristic of reticulated elastomeric matrix so that with its " soft conformal match " maximization, this is particularly conducive to aesthetic surgery and uses.In another limiting examples, the tensile property maximization that makes implantable device for example provides the maximum resistance that stitching thread is pulled out to replenish used technique for fixing.

In another embodiment, the implantable device of this paper disclosure can be as passing drug carrier.For example, therapeutic agent and biodurable entity 12 are mixed mutually, covalent bonding absorbs thereon and/or is absorbed into wherein.Can send any kind in the various therapeutic agents by implantable device, for example those therapeutic agents that above disclose.

The specific embodiment

Embodiment

List the following example and be in order to help to understand the present invention, but should not be regarded as limiting especially the present invention as herein described.This class version of the present invention comprises that the replacement scheme of all present known equivalence techniques schemes that belong to the change in those skilled in the art's scope and prescription change or the experimental design or the technical scheme of research and development subsequently all are regarded as falling into the scope of the invention that this paper discloses.

Embodiment 1: the manufacturing of crosslinked polyurethane matrix 1

Aromatic isocyanate RUBINATE 9258 (from Huntsman) is as isocyanate prepolymer composition.RUBINATE 9258 infra are liquid for 25 ℃.RUBINATE 9258 contains 4,4 '-MDI and 2,4 '-MDI and have about 2.33 isocyanate functionality.Have poly-(1, the 6-hexane carbonic ester) dihydroxylic alcohols (from the POLY-CD CD220 of Arch Chemicals) of about 2,000 daltonian dihydroxylic alcohols and be solid down as polyol component and at 25 ℃.Distilled water is as foaming agent.Used foaming catalyst is that the tertiary amine triethylenediamine is (in dipropylene glycol 33%; DABCO 33LV from AirProducts).Use is based on the surfactant (from the TEGOSTAB BF 2370 of Goldschmidt) of siloxanes.Use compartment opener (from the ORTEGOL 501 of Goldschmidt).Exist viscosity improver Allyl carbonate (from Sigma-Aldrich) to reduce viscosity.Used components in proportions is as shown in table 2.

Table 2

Component	Weight portion
Component	Weight portion	Polyol component
	100	Polyol component
	100	Viscosity improver	5.80
Surfactant	1.10	Viscosity improver	5.80
Surfactant	1.10	The compartment opener	1.00
Isocyanate prepolymer composition	62.42	The compartment opener	1.00
Isocyanate prepolymer composition	62.42	Isocyanate index	1.00
Distilled water	3.39	Isocyanate index	1.00
Distilled water	3.39	The foaming catalyst	0.53

Polyol component is liquefied under 70 ℃ and weigh up its 100g and put into the polyethylene cup.The 5.8g viscosity improver is joined in the polyol component so that reduce viscosity and use the mixing axle of boring blender that described component is formed " mixture-1 " with 3100rpm mixing 15 seconds.In mixture-1, add the 1.10g surfactant and as mentioned above component mixing 15 seconds is formed " mixture-2 ".After this in mixture-2, add 1.00g compartment opener and component mixed 15 seconds as mentioned above and form " mixture-3 ".In mixture-3, add the 62.42g isocyanate prepolymer composition and component mixed 60 ± 10 seconds and form " system A ".

Use Glass rod that the 3.39g distilled water was mixed in little plastic cup 60 seconds with 0.53g foaming catalyst and form " system B ".

With the A of B impouring system as quickly as possible of system, avoid simultaneously overflowing.Use the boring blender to mix 10 seconds component is violent as mentioned above, then the six-pack that covered by aluminium foil of impouring 22.9cm x 20.3cm x 12.7cm (9 inches x8 inch x5 inches) inner surface.Bubbling, it is as follows to distribute: 11 seconds incorporation times, 27 seconds one-tenth emulsion time and 100 second rise time.

Beginning to bubble back 2 minutes, and promptly when combination system A and B, foam was being entered maintain in the circulated air oven under 100-105 ℃ and solidified about 55-about 60 minutes.After this in baking oven, take out foam and descend cooling 10 minutes at about 25 ℃.Use band saw to take out adventitia from every side.After this, hand pressure is put on the every side of foam with open compartment's window.Make foam reenter circulated air oven and after fixing 4.5 hours again under 100-105 ℃.

As the foamy average pore size measured according to the observation by light microscope result greater than about 325 μ m.

Carry out following foam test according to ASTM D3574.Use the sample of 50mm x 50mm x 25mm size to measure bulk density.By using example weight divided by the sample volume bulk density.Obtain 2.29 lbs/ft ³Density value (0.037g/cc).

Carry out tension test to rising direction sample parallel or perpendicular cuts with foam.Downcut the tension force sample of Os Canitis shape from foam block.The about 12.5mm of each test sample is thick after measured, and the wide and about 140mm of about 25.4mm is long; The specification length of each sample is that the specification width of 35mm and each sample is 6.5mm.Use the crosshead velocity determination tension force (prolongation when hot strength and fracture) of INSTRON Universal Testing InstrumentModel 1122 with 500mm/min (19.6 inch per minute clock).With foam rise the parallel average tensile strength of direction measure be about 33.8psi (23,770kg/m ²).Rise the parallel extension at break degree mensuration of direction with foam and be about 123%.With foam rise the vertical average tensile strength of direction measure be about 27.2psi (19,150kg/m ²).Rise the vertical extension at break degree mensuration of direction with foam and be about 134%.

Embodiment 2: nettedization of crosslinked polyurethane matrix 1 and make implantable device by it

Carry out foamy nettedization described in the embodiment 1 by the operation described in the embodiment 6.

Measure reticulated polymer foam density as described in example 1 above.Obtain 2.13 lbs/ft ³Nettedization back density value (0.034g/cc).

As described in example 1 above the reticulated polymer foam sample is carried out tension test.With foam rise the parallel nettedization after-drawing average strength of direction measure be about 31.1psi (21,870kg/m ²).Rise the parallel nettedization back extension at break degree mensuration of direction with foam and be about 92%.With foam rise the vertical average nettedization after-drawing average strength of direction measure be about 22.0psi (15,480kg/m ²).Rise vertical nettedization of direction back elongation mensuration with foam and be about 110%.

The sample that use is determined as 50mm x 50mm x 25mm carries out compression test.Use INSTRON Universal Testing Instrument Model 1122 to test with the crosshead speed of 10mm/min (0.4 inch per minute clock).Will 50% with 75% compression under separately with foam rise parallel nettedization of direction afterwards comprcssive strength be determined as respectively 1.49psi (1,050kg/m ²) and 3.49psi (2,460kg ,/m ²).To under 50% and 75% compression, reticulated samples under 25 ℃, carry out described piezometric and contract 22 hours, discharge rising the parallel nettedization compression set of direction with foam and measuring respectively and be about 4.7% and 7.5% of measuring separately after the compression stress then.

Make the mushroom-shaped implantable device with machine by reticulated polymer foam, it has the smooth cylindric head of about 16mm diameter and about 8mm length or the narrow cylindrical bar of medicated cap and about 10mm diameter and about 8mm length.After this, by the gamma-rays that makes the about 2.3Mr ad dosage of its contact sample is sterilized.

Embodiment 3: the manufacturing of the implantable device of collagen protein coating

Washing is by extracting the type i collagen albumen that obtains and be chopped into fibril from Niu Laiyuan.By vigorous stirring collagen protein and water and add mineral acid is about 3.5 preparations, 1% weight to pH collagen protein aqueous slurries.The viscosity of this slurry is about 500 centipoises.

To immerse described collagen protein slurry fully according to the mushroom-shaped implantable device of embodiment 2 preparations, flood each implantable device with this slurry thus.After this device with collagen protein-slurry dipping is placed on the metal tray, and this pallet is placed on the lyophil apparatus frame that is precooled to-45 ℃.After slurry in device is freezing, make the pressure in the cryodesiccation chamber reduce to about 100 millitorrs, make water leave refrigerated collagen protein slurry distillation thus, be retained in the sedimentary porous collagen albumen substrate in the nettedization implantable device hole.After this, make temperature slowly rise to about 25 ℃, make pressure return to 1 atmospheric pressure then.Total processing time in lyophil apparatus is about 21-22 hour.

After from lyophil apparatus, taking out implantable device, made collagen cross-linking in about 21 hours by implant contact formaldehyde steam with exsiccant collagen protein dipping.The gamma-rays of the about 2.3Mrad dosage of its contact is sterilized to sample.

Embodiment 4: implant is implanted pig L1-L4 interspace of lumbar vertebrae

The mini pig of Yucatan that is about 55-65kg of weighing carries out LI-L4 (interspace of lumbar vertebrae) discectomy.Discectomy is by forming with acceptable human clinical's operation technique similar rear flank annular otomy and vertebral pulp extraction (nuclectomy).To in the annular otomy of 3mm front side, implant by the mushroom-shaped implantable device of the preparation of operation described in embodiment 2 and 3 so that repair ring defect.Carry out the standard " locked in " operation subsequently.Implantable device of the present invention fully works separately, and for example its adaptability expands, closed ring defective and keep its position.Do not exist bad acute reaction relevant and the equal impunity of all animal subjects old place to recover with this operation.

Embodiment 5: the synthetic and characteristic of reticulated elastomeric matrix 1

Prepare cross-linked network biodurable elasticity Merlon urea-carbamate substrate by following operation.

Aromatic isocyanate MONDUR MRS-20 (from Bayer Corporation) is as isocyanate prepolymer composition.MONDUR MRS-20 infra is a liquid for 25 ℃.MONDUR MRS-20 contains 4,4 '-'-diphenylmethane diisocyanate (MDI) and 2,4 '-MDI and have the isocyanate functionality of about 2.2-2.3.Have poly-(1, the 6-hexane carbonic ester) dihydroxylic alcohols (from the POLY-CD220 of Arch Chemicals) of about 2,000 daltonian dihydroxylic alcohols and be solid down as polyol component and at 25 ℃.Distilled water is as foaming agent.Used foaming catalyst is amine triethylenediamine (33% weight in dipropylene glycol; DABCO 33LV from Air Products) and two (2-dimethylaminoethyl) ether (23% weight in dipropylene glycol; NIAXA-133 from GE Silicones).Use is used as the cytotostatic agent based on the surfactant TEGOSTAB BF 2370 and the TEGOSTABB-8305 (from Goldschmidt) of siloxanes.Use compartment opener (from the ORTEGOL 501 of Goldschmidt).Exist viscosity improver Allyl carbonate (from Sigma-Aldrich) to reduce viscosity.In this mixture, add glycerol (99.7% USP Grade) and 1 as crosslinking group and cahin extension agent respectively, 4-butanediol (99.75% weight purity is from Lyondell).The ratio of used component is as shown in following table 3.

Table 3

Component	Weight portion
Component	Weight portion	Polyol component
	100	Polyol component
	100	Isocyanate prepolymer composition	52.96
Isocyanate index	1.00	Isocyanate prepolymer composition	52.96
Isocyanate index	1.00	Viscosity improver	5.80
The compartment opener	2.00	Viscosity improver	5.80
The compartment opener	2.00	Distilled water	1.95
The B-8305 surfactant	0.70	Distilled water	1.95
The B-8305 surfactant	0.70	BF 2370 surfactants	0.70
The 33LV catalyst	0.45	BF 2370 surfactants	0.70
The 33LV catalyst	0.45	The A-133 catalyst	0.12
Glycerol	2.00	The A-133 catalyst	0.12
Glycerol	2.00	1, the 4-butanediol	0.80

Isocyanate index, be amount well-known in the art be isocyanate groups in preparation, can be used for the quantity of reacting with can with group in the preparation of those isocyanate groups reactions, dihydroxylic alcohols for example, polyol component, the mol ratio of reactive groups such as cahin extension agent, water (if existence) quantity.Isocyanate prepolymer composition in the preparation is put into the composition A metering system of Edge Sweets Bench Top type carbamate mixing apparatus and maintain under about 20-25 ℃ temperature.

Polyhydric alcohol is liquefied in about 70 ℃ baking oven and be merged into uniform mixing according to aforementioned proportion with viscosity improver and compartment opener.This mixture is put into the composition B metering system of Edge Sweets equipment.This polyol component is maintained in the composition B system under about 65-70 ℃ temperature.

To be mixed into single even batch according to aforementioned proportion from the remaining ingredient of table 3 and put into the composition C metering system of Edge Sweets equipment.This composition is maintained under about 20-25 ℃ temperature.In the foam forming process, from composition A: composition B: the flow velocity ratio in gram/minute of composition C supply is about 8:16:1.

Mentioned component is merged in the 250cc mixing chamber of Edge Sweets equipment in a continuous manner, and this equipment has been installed the 10mm diameter nozzle that places under the mixing chamber.Promote to mix by the high shear disk mixer that in mixing chamber, moves.Blending constituent is injected the mould of rectangular cross section processing release paper wall coating from nozzle.After this foam is raised up to and fills mould basically.The gained mixture began into emulsion in about 10 seconds behind the contact mould, and rose fully in 120 seconds.Repair the foamy top of gained and foam was put into 100 ℃ of curing ovens 5 hours.

After the curing, foam is put into the netted device that comprises pressure chamber then in the side and the bottom of finishing foam block, its inner and surrounding air isolation.Room pressure is reduced so that remove air all in the cured foam basically.Make hydrogen and the oxygen mixture inlet chamber of supporting that to be enough to incendiary ratio exists.Keeping room pressure is higher than the atmospheric pressure time enough time limit and penetrates foam to guarantee gas.By spark ignitor indoor gas and this igniting the admixture of gas in the foam is exploded then.For any combustion products of Min. ground contact and cooling foam, remove the burning gases of generation and alternative with about 25 ℃ nitrogen immediately after blast from indoor.More than repeating above-mentioned nettedization process once then.Be not bound by any particular theory, thinking explodes has removed the many compartment between the adjacent compartments or " window " in the foam to small part, generates open hole thus and produces the reticulated elastomeric matrix structure.

As what measure according to the observation by light microscope result, the average cell diameter of reticulated elastomeric matrix 1 or other maximum transverse size are about 525 μ m.Figure 10 is scanning electron micrograph (SEM) image of reticulated elastomeric matrix 1, and wherein interconnected compartment reticulated structure and intercommunication and the interconnectivity of open bore for example passed through in its expression.Scale bar on the base of Figure 10 is equivalent to about 500 μ m.As what measure according to the SEM observed result, the average pore size of reticulated elastomeric matrix 1 or other maximum transverse size are about 205 μ m.

Use based on the method for testing of ASTM Standard D3574 to carrying out following test available from the foamy reticulated elastomeric matrix 1 that forms thus of nettedization.Use the reticulated elastomeric matrix sample of 5.0cm x 5.0cm x 2.5cm size to measure bulk density.By calculating nettedization back density divided by sample volume with sample weight.Obtain 3.29 lbs/ft ³Density value (0.053g/cc).

Carry out tension test to being cut into parallel or vertical reticulated elastomeric matrix 1 sample of foam rise direction.Downcut the tension force sample of Os Canitis shape from reticulated elastomeric matrix foam piece.The about 1.25cm of each test sample is thick after measured, and the wide and about 14cm of about 2.54cm is long; The specification length of each sample is that the specification width of 3.5cm and each sample is 6.5mm.Use the crosshead velocity determination tensile properties (prolongation when hot strength and fracture) of INSTRONUniversal Testing Instrument Model 3342 with 50cm/min (19.6 inch per minute clock).With foam rise the vertical average nettedization after-drawing strength detection of direction be about 34.3psi (24,115kg/m ²).Rise vertical nettedization of direction back extension at break degree mensuration with foam and be about 124%.With foam rise the parallel average nettedization after-drawing strength detection of direction be about 61.4psi (43,170kg/m ²).Rise the parallel nettedization back extension at break degree mensuration of direction with foam and be about 122%.

Reticulated elastomeric matrix 1 sample that use is determined as 5.0cm x 5.0cm x 2.5cm carries out compression test.Use INSTRON Universal Testing Instrument Model1122 to test with the crosshead speed of 1mm/min (0.4 inch per minute clock).Will be under 50% compression with foam rise parallel nettedization of direction afterwards compressive strength determination be 2.1psi (1,475kg/m ²).Nettedization sample carries out 50% compression 22 hours under 25 ℃, discharge the nettedization back compression set mensuration of measuring after the compression stress parallel with foam rise direction then and be about 8.5%.

At Q800Dynamic Mechanical Analyzer (TA Instruments, NewCastle, DE) using the standard compression fixture to rise direction by the cylindrical sample that makes each 12mm diameter and 6mm thickness along foam in and carried out 50% uniaxial compression 120 minutes, is the static recovery that measured reticulated elastomeric matrix 1 recovery time in 120 minute subsequently.Measure that 6mm (" t-90% ") original depth sample returns to the required time of initial thickness 90% and the meansigma methods of mensuration is 1406 seconds.

Rise direction by the cuboid sample that makes each 1 inch (2.54cm) high (rising direction) x1.25 inch x1.25 inch (3.18cm x 3.18cm) along foam and carry out 50% uniaxial compression along foam, then when keeping this uniaxial compression in air ambient and also rise direction under the 1Hz frequency and give along foam ± dynamic load 5 of 5% stress, the resilience of 000 circulation or 100,000 circulation mensuration reticulated elastomeric matrixes 1 recovers.In addition, also test 100,000 circulation cuboid samples as mentioned above, but in whole test process, sample is immersed water.Measure and write down 67% (" t-67% ") and 90% (" t-90% ") the required time that returns to 1 inch (2.54cm) sample initial height.The result who obtains is as shown in table 4.

Table 4

In 50% compression ± period under 5% strain under the 1Hz	Rise the test sample book orientation of direction with respect to foam	T-67% (second)	T-90% (second)
In 50% compression ± period under 5% strain under the 1Hz		T-67% (second)	T-90% (second)	5,000 (in air)	Parallel	0.7	46
100,000 (in air)	Parallel	84	2370	5,000 (in air)	Parallel	0.7	46
100,000 (in air)	Parallel	84	2370	100,000 (in water)	Parallel	---	3400

Use automatic fluid permeameter-LP-101-A type (, Inc.) to be determined at foam and to rise the fluid of direction by reticulated elastomeric matrix 1, for example permeability for liquids also from PorousMaterials.The diameter of the cylindrical reticulated elastomeric matrix sample of test is that 7.0-7.7mm and length are 13-14mm.The flush end of sample is placed on the metallic plate that is placed on liquid infiltration instrument bottom.In order to measure permeability for liquids, by from the pressure-driven of fluid reservoir from the sample end along its axle by the sample water of compaction that makes progress.Measure relevant operation full automation and be subjected to Capwin automatic fluid permeameter (6.71.92 version) and the Microsoft Excel software control of all in permeability calculates, carrying out with permeability.Reticulated elastomeric matrix 1 permeability rises on the direction at foam and is determined as 498 darcies.

Also measure permeability so that reduce available circulation area, thus the molded sample of analog compression in reticulated elastomeric matrix 1 compression (vertical) back with foam rise direction.This step is inserted support greater than the cylindrical sample of the diameter of rustless steel sample holder diameter and is carried out by having, and thus sample is carried out radial compression.The unpressed cylindrical reticulated elastomeric matrix 1 sample diameter of test is about 7.0mm and length is about 13-14mm, and the diameter of the sample of compression to be pressed into about 7.0mm diameter stainless steel stent precontract at it be the about 16.0mm of 9.0mm-.Figure 11 is the darcy permeability and the sketch map that can utilize the circulation area relation of different goods reticulated elastomeric matrixes; Line 2 among Figure 11 is the sketch map of this class reticulated elastomeric matrix 1.Figure 11,100% can utilize circulation area to represent unpressed reticulated elastomeric matrix 1 and show at foam rises high osmosis 498 darcies on the direction.Use can utilize the permeability of circulation area to change illustration in Figure 11.For example, reticulated elastomeric matrix 1 rises permeability on the direction at foam and can utilize circulation area to reduce to 47.9% o'clock of original area after compression to reduce to 329 darcies, and can utilize circulation area to reduce to 19.4% o'clock of original area after compression and reduce to 28 darcies.

Embodiment 6: the synthetic and characteristic of reticulated elastomeric matrix 2

By the preparation of operation described in the embodiment 5 cross-linked network biodurable elasticity Merlon urea-carbamate substrate, but component utilized and ratio thereof are as shown in following table 5.

Table 5

Component	Weight portion
Component	Weight portion	Polyol component
	100	Polyol component
	100	Isocyanate prepolymer composition	52.37
Isocyanate index	1.00	Isocyanate prepolymer composition	52.37
Isocyanate index	1.00	Viscosity improver	5.80
The compartment opener	2.00	Viscosity improver	5.80
The compartment opener	2.00	Distilled water	2.15
The B-8305 surfactant	0.70	Distilled water	2.15
The B-8305 surfactant	0.70	BF 2370 surfactants	0.72
The 33LV catalyst	0.55	BF 2370 surfactants	0.72
The 33LV catalyst	0.55	Glycerol	2.00
1, the 4-butanediol	1.95	Glycerol	2.00

As what measure according to the observation by light microscope result, the average cell diameter of reticulated elastomeric matrix 2 or other maximum transverse size are about 576 μ m.The SEM image of reticulated elastomeric matrix 2 has for example shown by the interconnected compartment reticulated structure of open bore wherein.As what measure according to the SEM observed result, the average pore size of reticulated elastomeric matrix 2 or other maximum transverse size are about 281 μ m.

Use based on the method for testing of ASTM Standard D3574 to carrying out following test available from the foamy reticulated elastomeric matrix 2 that forms thus of nettedization.Measure the density of reticulated elastomeric matrix 2 as described in example 5 above; Obtain 3.23 lbs/ft ³Density value (0.053g/cc).

As described in example 5 above reticulated elastomeric matrix 2 is carried out tension test.With foam rise the vertical average nettedization after-drawing strength detection of direction be about 40psi (28,120kg/m ²).Rise vertical nettedization of direction back extension at break degree mensuration with foam and be about 135%.With foam rise the parallel average nettedization after-drawing strength detection of direction be about 55psi (38,665kg/m ²).Rise the parallel nettedization back extension at break degree mensuration of direction with foam and be about 126%.

As described in example 5 above reticulated elastomeric matrix 2 is carried out compression test.Will be under 50% compression with foam rise parallel nettedization of direction afterwards compressive strength determination be about 2.0psi (1,406kg/m ²).Under 25 ℃, carry out 50% compression 22 hours, discharge the nettedization back compression set mensuration of measuring after the compression stress parallel then and be about 7.5% with foam rise direction.

The resilience of measuring reticulated elastomeric matrix 2 as described in example 5 above recovers.The result who obtains is as shown in table 6.

Table 6

In 50% compression ± period under 5% strain under the 1Hz	Rise the test sample book orientation of direction with respect to foam	T-67% (second)	T-90% (second)
In 50% compression ± period under 5% strain under the 1Hz		T-67% (second)	T-90% (second)	5,000 (in air)	Parallel	---	123
100,000 (in air)	Parallel	50	3845	5,000 (in air)	Parallel	---	123
100,000 (in air)	Parallel	50	3845	100,000 (in water)	Parallel	---	2350

Use automatic fluid permeameter-LP-101-A type to rise the fluid permeability of measuring on the direction by reticulated elastomeric matrix 2 at foam as described in example 5 above.The permeability of reticulated elastomeric matrix 2 is determined as 314 darcies on foam rise direction.

As described in example 5 above, also measure permeability so that reduce available circulation area in reticulated elastomeric matrix 2 compressions (vertical) back with foam rise direction.Line 3 among Figure 11 is the sketch map of the circulation area the utilized relation of darcy permeability and reticulated elastomeric matrix 2.In Figure 11,100% can utilize circulation area to represent unpressed reticulated elastomeric matrix 2, and shows that the high osmosis that rises on the direction at foam is 314 darcies.Reticulated elastomeric matrix 2 rises permeability on the direction at foam and can utilize circulation area to reduce to 43.9% o'clock of original area after compression to reduce to 224 darcies, and can utilize area to reduce to 25.5% o'clock of original area after compression and reduce to 54 darcies.

Embodiment 7: the synthetic and characteristic of reticulated elastomeric matrix 3

By the preparation of operation described in the embodiment 5 cross-linked network biodurable elasticity Merlon urea-carbamate substrate, but component utilized and ratio thereof are as shown in following table 7.

Table 7

Component	Weight portion
Component	Weight portion	Polyol component
	100	Polyol component
	100	Isocyanate prepolymer composition	46.90
Isocyanate index	1.00	Isocyanate prepolymer composition	46.90
Isocyanate index	1.00	Viscosity improver	5.80
The compartment opener	2.00	Viscosity improver	5.80
The compartment opener	2.00	Distilled water	1.00
The B-8305 surfactant	1.00	Distilled water	1.00
The B-8305 surfactant	1.00	BF 2370 surfactants	1.00
The 33LV catalyst	0.45	BF 2370 surfactants	1.00
The 33LV catalyst	0.45	The A-133 catalyst	0.15
Glycerol	3.00	The A-133 catalyst	0.15
Glycerol	3.00	1, the 4-butanediol	2.00
		1, the 4-butanediol	2.00

As what measure according to the observation by light microscope result, the average cell diameter of reticulated elastomeric matrix 3 or other maximum transverse size are about 300 μ m.Figure 12 is the SEM image of reticulated elastomeric matrix 3, and wherein interconnected compartment reticulated structure and intercommunication and the interconnectivity of open bore for example passed through in its expression.As what measure according to the SEM observed result, the average pore size of reticulated elastomeric matrix 3 or other maximum transverse size are about 175 μ m.

Use based on the method for testing of ASTM Standard D3574 to carrying out following test available from the foamy reticulated elastomeric matrix 3 that forms thus of nettedization.Measure the density of reticulated elastomeric matrix 3 as described in example 5 above; Obtain 5.92 lbs/ft ³Density value (0.095g/cc).

As described in example 5 above reticulated elastomeric matrix 3 samples are carried out tension test.With foam rise the vertical average nettedization after-drawing strength detection of direction be about 71.7psi (50,405kg/m ²).Rise vertical nettedization of direction back extension at break degree mensuration with foam and be about 161%.With foam rise the parallel average nettedization after-drawing strength detection of direction be about 104psi (73,110kg/m ²).Rise the parallel nettedization back extension at break degree mensuration of direction with foam and be about 169%.

As described in example 5 above reticulated elastomeric matrix 3 is carried out compression test.Under 50% compression with foam rise parallel nettedization of direction afterwards compressive strength determination be 3.65psi (2,565kg/m ²).

Measure the static recovery of reticulated elastomeric matrix 3 as described in example 5 above.Measuring T-90% and measuring meansigma methods is 166 seconds.

The resilience of measuring reticulated elastomeric matrix 3 as described in example 5 above recovers.The result who obtains is as shown in table 8.

Table 8

In 50% compression ± period under 5% strain under the 1Hz	Rise the test sample book orientation of direction with respect to foam	T-67% (second)	T-90% (second)
In 50% compression ± period under 5% strain under the 1Hz		T-67% (second)	T-90% (second)	5,000 (in air)	Parallel	---	13.6
100,000 (in air)	Parallel	---	175	5,000 (in air)	Parallel	---	13.6
100,000 (in air)	Parallel	---	175	100,000 (in water)	Parallel	---	108

Use automatic fluid permeameter LP-101-A type to rise the fluid permeability of measuring on the direction by reticulated elastomeric matrix 3 at foam as described in example 5 above.The permeability of reticulated elastomeric matrix 3 rises on the direction at foam and is determined as 103 darcies.

Embodiment 8: the synthetic and characteristic of reticulated elastomeric matrix 4

By the preparation of operation described in the embodiment 5 cross-linked network biodurable elasticity Merlon urea-carbamate substrate, but component utilized and ratio thereof are as shown in following table 9.

Table 9

Component	Weight portion
Component	Weight portion	Polyol component
	100	Polyol component
	100	Isocyanate prepolymer composition	45.64
Isocyanate index	1.00	Isocyanate prepolymer composition	45.64
Isocyanate index	1.00	Viscosity improver	5.80
The compartment opener	2.00	Viscosity improver	5.80
The compartment opener	2.00	Distilled water	1.60
The B-8305 surfactant	1.00	Distilled water	1.60
The B-8305 surfactant	1.00	The BF2370 surfactant	1.00
The 33LV catalyst	0.45	The BF2370 surfactant	1.00
The 33LV catalyst	0.45	The A-133 catalyst	0.15
Glycerol	1.00	The A-133 catalyst	0.15
Glycerol	1.00	1, the 4-butanediol	1.50

As what measure according to the observation by light microscope result, the average cell diameter of reticulated elastomeric matrix 4 or other maximum transverse size are about 353 μ m.The wherein interconnected compartment reticulated structure of open bore is for example passed through in the SEM image demonstration of the reticulated elastomeric matrix of present embodiment.As what measure according to the SEM observed result, the average pore size of reticulated elastomeric matrix 4 or other maximum transverse size are about 231 μ m.

Use based on the method for testing of ASTM Standard D3574 to carrying out following test available from the foamy reticulated elastomeric matrix 4 that forms thus of nettedization.Measure the density of reticulated elastomeric matrix 4 as described in example 5 above; Obtain 3.81 lbs/ft ³Density value (0.061g/cc).

As described in example 5 above reticulated elastomeric matrix 4 samples are carried out tension test.With foam rise the vertical average nettedization after-drawing strength detection of direction be about 40.9psi (28,753kg/m ²).Rise vertical nettedization of direction back extension at break degree mensuration with foam and be about 216%.With foam rise the parallel average nettedization after-drawing strength detection of direction be about 52.5psi (36,910kg/m ²).Rise the parallel nettedization back extension at break degree mensuration of direction with foam and be about 206%.

As described in example 5 above reticulated elastomeric matrix 4 specimen are carried out compression test.Rising the parallel nettedization back compressive strength determination of direction with foam under 50% compression is 1.3psi (914kg/m ²).

Measure the static recovery of reticulated elastomeric matrix 4 as described in example 5 above.Measuring T-90% and measuring meansigma methods is 466 seconds.

The resilience of measuring reticulated elastomeric matrix 4 as described in example 5 above recovers.The result who obtains is as shown in table 10.

Table 10

In 50% compression ± period under 5% strain under the 1Hz	Rise the test sample book orientation of direction with respect to foam	T-67% (second)	T-90% (second)
In 50% compression ± period under 5% strain under the 1Hz		T-67% (second)	T-90% (second)	5,000 (in air)	Parallel	0.6	7.0
100,000 (in air)	Parallel	3.0	761	5,000 (in air)	Parallel	0.6	7.0
100,000 (in air)	Parallel	3.0	761	100,000 (in water)	Parallel	---	382
				100,000 (in water)	Parallel	---	382

Use automatic fluid permeameter LP-101-A type to rise the fluid permeability of measuring on the direction by reticulated elastomeric matrix 4 at foam as described in example 5 above.The permeability of reticulated elastomeric matrix 4 rises on the direction at foam and is determined as 380 darcies.

Embodiment 9 has the implantable device on the non-porous surface of selectivity

Use is according to the Web materials sheet of embodiment 5 preparations.The heating blade that will have the edge of a knife is used for from the cylinder of this sheet cutting 10mm diameter and 15mm length.The blade temperature is higher than 170 ℃.Merge and imporosity because of contact heating blade shows on the material piece surface of contact heating blade.Those surfaces of this material piece that the appointment retaining porosity does not promptly merge do not contact the heating blade.

Embodiment 10 has the implantable device on the non-porous surface of selectivity

Use is according to the appropriate overdimensioned Web materials sheet of embodiment 5 preparations.The overdimensioned material piece of appropriateness is put into the mould that is heated above 170 ℃ of temperature.On this material piece, cover mould then so that overall size is decreased to required size.When taking out this material piece from mould, merge and imporosity because of the contact mould shows on the material piece surface of contact mould.Prevent to specify those surface contact heating moulds of this material piece that retaining porosity promptly do not merge.Heating blade with edge of a knife is used for from the cylinder of this sheet cutting 10mm diameter and 15mm length.

Embodiment 11 has the implantable device of the dip coating on selectivity imporosity surface

Use is according to the Web materials sheet of embodiment 5 preparations.The following copolymer coated macro surface of coating that will contain 90mole%PGA and 10mole%PLA.Melt the PGA/PLA copolymer under 205 ℃ and in the extruder and this material piece is immersed melt so that apply it.Cover the desire retaining porosity of this material piece, promptly without those surfaces of melt coating to protect them and to make its not contact melting thing.When taking out, melt solidifies and forms thin imporosity coating on the material piece surface that it contacted.

The manufacturing of the elastomeric matrices of embodiment 12 collagen protein coating

Washing is by extracting the type i collagen albumen that obtains and being chopped into fibril from Corii Bovis seu Bubali.By vigorous stirring collagen protein and water and add mineral acid is about 3.5 preparations, 1% weight to pH collagen protein aqueous slurries.

To be cut into the sheet of 60mm * 60mm * 2mm according to the nettedization polyurethane matrix of embodiment 5 preparations.This sheet is put into shallow pallet and the collagen protein slurry is inclined thereon, make this sheet immerse slurry fully about 15 minutes and optional jolting pallet.If necessary, decantation goes out excessive slurry and the sheet of slurry dipping is placed on the plastic pallet from this sheet, and this pallet is placed on the lyophil apparatus pallet that remains on 10 ℃.Make lyophil apparatus pallet temperature reduce to-35 ℃ and make the pressure in the lyophil apparatus reduce to about 75 millitorrs from 10 ℃ with about 1 ℃/minute cooldown rate.Remaining on-35 ℃ after following 8 hours, making the pallet temperature rise to 10 ℃ and make temperature reach 25 ℃ with about 2.5 ℃/hour speed then with about 1 ℃/hour speed.In freeze-drying process, water distils from freezing collagen protein slurry, leaves over the porous collagen albumen substrate in reticulated polyurethane substrate film perforation.Make pressure return to 1 atmospheric pressure.

Choose wantonly under about 110 ℃, make porous collagen albumen coating the polyurethane matrix sheet further in nitrogen current about 24 hours of heat treated so that crosslinked with collagen albumen provides extra structural intergrity thus.

Embodiment 13: the synthetic and characteristic of reticulated elastomeric matrix 5 and be used to repair the rat stomach wall Application in the implantable device

Aromatic isocyanate MONDUR MRS 20 is (from Bayer; Comprise 4,4 '-MDI and 2, the mixture of 4 '-MDI) as isocyanate prepolymer composition.MONDUR MRS 20 contains 4 of about 65%-70% weight, 4 '-MDI, and 2 of about 30%-35% weight, 4 '-MDI has the isocyanate functionality of about 2.2-2.3 and is liquid down at 25 ℃.Dihydroxylic alcohols with about 2,000 Dalton molecular weights, (POLY-CD CD220 ArchChemicals) is solid down as polyol component and at 25 ℃ to poly-(1,6-hexane carbonic ester) dihydroxylic alcohols.Distilled water is as foaming agent.The foaming catalyst is tertiary amine triethylenediamine (33% weight in dipropylene glycol; DABCO 33LV from AirProducts).Glycerol (99.7%USP/EP is from Dow Chemical) is as crosslinking group and 1, and 4-butanediol (from BASF Chemical) is as cahin extension agent.Use is based on the surfactant (TEGOSTAB BF2370 is from Goldschmidt) of siloxanes.Use compartment opener (ORTEGOL 501, from Goldschmidt).There is viscosity improver Allyl carbonate (from Sigma-Aldrich) so that reduce viscosity.The ratio of used component is as shown in following table 11.

Table 11

Component	Weight portion
Component	Weight portion	Polyol component
	100	Polyol component
	100	Isocyanate prepolymer composition	51.32
Isocyanate index	1.00	Isocyanate prepolymer composition	51.32
Isocyanate index	1.00	Viscosity improver	5.80
The compartment opener	2.0	Viscosity improver	5.80
The compartment opener	2.0	Surfactant	1.5
Distilled water	1.89	Surfactant	1.5
Distilled water	1.89	The foaming catalyst	0.56
Glycerol	2.15	The foaming catalyst	0.56
Glycerol	2.15	1, the 4-butanediol	0.72

Dihydroxylic alcohols is liquefied in about 70 ℃ air circulation oven and its 100g is weighed into the polyethylene cup.5.8g viscosity improver (Allyl carbonate) is joined in the polyhydric alcohol and use in the boring blender that mixing rod has been installed and mix 15 seconds (mixture-1) with 3100rpm.Join 1.5g surfactant (TEGOSTAB BF-2370) in the mixture-1 and remix 15 seconds (mixture-2).Join 2.0g compartment opener (ORTEGOL 501) in the mixture-2 and mix 15 seconds (mixture-3).Join 2.15g cross-linking agent (glycerol) in the mixture-3 and mix 15 seconds (mixture-4).Join 0.72g cahin extension agent (1, the 4-butanediol) in the mixture-4 and mix 15 seconds (mixture-5).Join 51.32g isocyanates (MONDUR MRS 20) in the mixture-5 and mix 60 seconds (system A).By using little Glass rod that the 1.89g distilled water is mixed 60 seconds (system B) with 0.56g foaming catalyst (DABCO 33LV) in little plastic cup.

With the A of B impouring system as quickly as possible of system, nothing is overflowed and was used the violent mixing of boring blender 10 seconds and the six-pack of 9 inches x8 inches of impouring x5 inch (23cm x 20cm x 13cm) size, covers with aluminium foil in carton interior.Bubbling process is as follows: incorporation time 10-12 second, become 28 seconds emulsion time and 120 seconds rise times.

Beginning back 2 minutes of the mixing of bubbling, foam is being put into the baking oven that maintains under 100-105 ℃ solidified about 60 minutes.In baking oven, take out elastomeric matrices and descend cooling 10 minutes at about 25 ℃.With saw take out adventitia and with hands from all side compression elasticity substrate with open compartment's window.Elastomeric matrices is put back in the air circulation oven under 100 ℃-105 ℃, carries out 3.5 hours after fixing again.Physics and chemical crosslinking all are present in the final elastomeric matrices.

After the curing, the side and the bottom of finishing foam block make nettedization of elastomeric matrices then as described in example 5 above.As what measure by the observation by light microscope result, the average pore size of reticulated elastomeric matrix 5 or other maximum transverse size are about 220 μ m.

Use is being carried out following test based on the method for testing of ASTM Standard D3574 available from the foamy reticulated elastomeric matrix 5 that forms thus of nettedization.Measure the density of reticulated elastomeric matrix 5 as described in example 5 above; Obtain 4.27 lbs/ft ³Density value (0.068g/cc).

As described in example 5 above reticulated elastomeric matrix 5 samples are carried out tension test.With foam rise the vertical average nettedization after-drawing strength detection of direction be about 36.8psi (25,870kg/m ²).Rise vertical nettedization of direction back extension at break degree mensuration with foam and be about 114%.With foam rise the parallel average nettedization after-drawing strength detection of direction be about 66.6psi (46,805kg/m ²).Rise the parallel nettedization back extension at break degree mensuration of direction with foam and be about 117%.

Use to measure to be about 152mm length, the wide and high sample of 12.7mm of 25mm is according to the tearing toughness of the test determines reticulated elastomeric matrix 5 described in the ASTM St andard D3574.On each sample one side, make the 40mm otch.Use (19.6 inches/min) crosshead velocity determination tearing toughness of INSTRON UniversalTesting Instrument Model 1122 and 50cm/min.Tearing toughness mensuration is about 3.15 lbs/ linear inches (the linear cm of 526g/).

Using reticulated elastomeric matrix 5 and mix the example that 4-0 multifilament polyester (TelflexMedical) prepares implantable device of the present invention therein, is the long and high square sticking patch of wide x2mm of 1cm after measured.Viking PlatinumModel 730 sewing machines that use has 1 groove part line and 3mm spacing mix square implantable device with the polyester fiber (having the 4-0 number sutural diameter that is equivalent to have 0.20mm maximum gauge and the minimum hot strength of 1.65 lbs (748g)) that weaves.

Implantable device is put into Sprague-Dawley rat stomach wall.The stomach wall defective has segment thickness and leaves over fascia of abdomen and peritoneum and skin complete.Scarcely be downcut in and outer oblique abdominal muscle and in rat tested implantable device alternative.Therefore, no device enters the abdominal cavity and implements surgical closure postoperative skin complete at operative site.Natural muscle tissue, subcutaneous tissue and fascia are arranged around the device.In 16 whens week, put to death rat after implantation.

Histologic analysis when 16 weeks is presented at tissue ingrowth and propagation in the whole implanting device.The device of implanting promotes stomach wall defect repair in the rat.Device demonstrate favourable reaction and with the inside abundant biointegration of growth of good organization.

Embodiment 14: prepare implantable device by reticulated elastomeric matrix 4 and braided fiber stiffener

Prepare reticulated elastomeric matrix 4 according to method described in the embodiment 8.Downcut from this reticulated elastomeric matrix and be configured as orthogonal implantable device, such as the operation sticking patch, it is long that it has 29mm, the size of the wide and 2mm thickness of 34mm.Use has polyester fiber (the Telflex Medical of the embroidery machine (BabyLockEsante BLN type) of pattern shown in Figure 13 with braiding; Be equivalent to the 5-0 stitching thread and have the 0.15mm maximum gauge and the diameter of the minimum hot strength of 0.88 lbs (399g)) mix the rectangle implantable device.The characteristic size of this pattern is provided among Figure 14.

Use intersection suture and the following polyester fiber that will weave that is provided with to mix the rectangle implantable device: suture motion spacing=1.5mm; Zone sewing density=3.9 lines/mm; Machine tension force sets=1.4.Grid size is 10mm x 8mm, each has the 2mm border along four sides.

The stitching strength retention (SRS) of each implantable device of braided fiber is mixed in test, it is defined as pulls out the standard stitching thread and cause the required maximum, force of its fracture from device.Also tested the tensile strength (TBS) of each device that mixes braided fiber, it has been defined as the required maximum, force of intact device tension failure.Use INSTRON Universal Testing InstrumentModel 3342 to carry out two kinds of tests.

In the SRS test, the polyester stitching thread of 2-0 ETHIBOND braiding is inserted implantable device one end and makes this stitching thread to be lower than the first HORIZONTAL PLAID grid line 2mm-3mm and to be connected with device near the device centrage by using syringe needle.Form the ring of about 50mm-60mm length by the stitching thread two ends.Make the free end (not being connected) of device be fixed on the fixedly interior and clamping of plane surface of the rubber coated of jaw folder of bottom with stitching thread.(3.94 inches/min) crosshead speed under displacement model, use and isolate or move up and carry out SRS away from the fixing removable jaw folder of jaw folder and test with 100mm/min.These mix the implantable device of Woven polyester fiber to 21 newton's SRS meansigma methods available from test.

In the TBS of these implantable devices test, an end that installs is installed between the face that is fixed in the rubber coated on the fixing pneumatic handle, and the other end of device is fixed between the face that is fixed in the rubber coated on the removable pneumatic handle.This test (3.94 inches/min) crosshead speed under displacement model, is used to isolate or move up and press from both sides away from the fixing removable jaw of jaw folder and is carried out with 100mm/min.Obtain 57 newton's TBS meansigma methods.

Embodiment 15: the implantable device with reticulated elastomeric matrix 4 and braided fiber stiffener is greatly The Mus rotator cuff adds the application of persistent erection of the penis

According to making the implantable device of the rectangular patch shapes of polyester fiber, but use 7-0 Woven polyester fiber with reticulated elastomeric matrix 4 and braiding with the similar mode of method described in the embodiment 14.The little square of cutting-out 2mm length and wide 1mm Mangnolia officinalis sheet form and implantation from device are so that make the tendon of supraspinatus muscle healing of rat.

Traditional tendon prosthesis treatment of using stitching thread to be undertaken by bone, but by using the implantable device described in the above-mentioned paragraph to strengthen.Generating the bilateral tendon of supraspinatus muscle with modus operandi in rat tears.In the right shoulder of rat, implement the complete crosscut of through thickness of tendon of supraspinatus muscle.Device is sewn on the top of tendon and use two 5-0PROLENE through bone suture with tendon-sticking patch structure repair to bone.Put to death rat and carry out the histologic analysis that tendon is repaired in thick 8 weeks of surgical repair.

The histologic analysis of photo illustration shows in Figure 15 does not have the obviously inflammation or the unsuitable vascularization of amount.The implantable device void space percentage ratio that the tissue ingrowth of determining according to the analysis of the area that occupies such as tissue ingrowth in this class photo of Figure 15 occupies is at least about 80%.With regard to implantable device inner tissue inwardly grows, as Chang GuiH ﹠amp; E dyeing shows, the cellular morphology of approaching device with in collagen matrices produces, have active connective tissue cell, such as the fibroblast unanimity, simultaneously the cell of far-end (or near the cell farther place of implantable device) be shown as static.Make the implantable device obvious systematism of tissue on every side.Tissue regions in the device is in any designation hole inner tissueization of the reticulated elastomeric matrix of device.Yet, be organized in when putting to death rat still not complete organizationization in the implantable device, because healing time long enough not.

Embodiment 16: the synthetic and characteristic of reticulated elastomeric matrix 6 and in the application of the implantable device with braided fiber stiffener that is used for repairing the rat rotator cuff

By preparing cross-linked network biodurable elasticity Merlon Semicarbazido formic acid esters substrate with similar method described in the embodiment 13, but with aromatic isocyanate RUBINATE 9258 (from Huntsman, comprise 4,4 '-MDI and 2, the mixture of 4 '-MDI) be used as isocyanate prepolymer composition and do not use cross-linking agent and cahin extension agent.RUBINATE 9258 contains 4 of about 68% weight, 4 '-MDI, and 2 of about 32% weight, 4 '-MDI has about 2.33 isocyanate functionality and be liquid under 25 ℃.Polyhydric alcohol with about 2,000 Dalton molecular weights, 1,6-gathers carbonic acid hexa-methylene ester (POLY-CD CD220), and promptly dihydroxylic alcohols is down a solid as polyol component and at 25 ℃.The ratio of used component is as shown in following table 12.

Table 12

Component	Weight portion
Component	Weight portion	Polyol component
	100	Polyol component
	100	Isocyanate prepolymer composition	47.25
Isocyanate index	1.00	Isocyanate prepolymer composition	47.25
Isocyanate index	1.00	Viscosity improver	5.80
The compartment opener	1.45	Viscosity improver	5.80
The compartment opener	1.45	Surfactant	0.66
Distilled water	2.38	Surfactant	0.66
Distilled water	2.38	Catalyst	0.53

Bubbling process is as follows: incorporation time 10 seconds becomes 16 seconds emulsion time and 80 seconds rise times.

Beginning back 2 minutes of the mixing of bubbling, elastomeric matrices is being put into the baking oven that maintains under 100-105 ℃ solidified 60 minutes.In baking oven, take out elastomeric matrices and descend cooling 10 minutes at about 25 ℃.Use saw remove adventitia and with hands from all side compression elasticity substrate with open compartment's window.Elastomeric matrices is put back under 100 ℃, carries out 4.0 hours after fixing in the air circulation oven again.

Using makes nettedization of foam once obtain reticulated elastomeric matrix 6 with the similar method of nettedization method described in the embodiment 5 basically.As what measure according to the observation by light microscope result, the average pore size of reticulated elastomeric matrix 6 or other maximum transverse size are 275 μ m-350 μ m.

Use based on the method for testing of ASTM Standard D3574 to carrying out following test available from the foamy reticulated elastomeric matrix 6 that forms thus of nettedization.Measure the density of reticulated elastomeric matrix 6 as described in example 5 above; Obtain 2.99 lbs/ft ³Density value (0.046g/cc).

As described in example 5 above reticulated elastomeric matrix 6 samples are carried out tension test.With foam rise the vertical average nettedization after-drawing strength detection of direction be about 33.6psi (23,625kg/m ²).Rise vertical nettedization of direction back extension at break degree mensuration with foam and be about 220%.

As described in example 5 above reticulated elastomeric matrix 6 is carried out compression test.Under 50% compression, rise the parallel nettedization back compressive strength determination of direction and be about 1.25psi (878kg/m with foam ²).

For the implantation of performing the operation, use the piece of the reticulated elastomeric matrix 6 of γShe Xianmiejun that substrate is suitably finalized the design and shaping in advance by cutting.Sprague-Dawley rat (body weight is about the about 275g of 250g-) is used for this experiment.Use intramuscular injection ketamine (100mg/kg) and xylazine (5mg/kg) to anaesthetize all rats.After this shaving upper limb is prepared and the shop operation towel with sterile manner.Provide and amount to 7 days antibiotic prophylaxis.

Surgical exposure is included in the 2cm otch on the back side of bilateral shoulder and scapula.In every side shoulder, identify spine of scapula and interior along its fiber concordance separation triangular muscle in the 1cm distance.Open subacromial bursa, but do not excise.Tendon of supraspinatus muscle shows, because it passes through to its insertion point on the proximal humerus greater tubercle under coraco-acromial arch.

In organizing extension group (1 group), downcut the wide tendon of supraspinatus muscle of 2mm zone at bilateral, position near-end 1mm begins and further proximal extension 2mm from inserting, and produces 2mm * 2mm defective.This has represented about 50% tendon of supraspinatus muscle wide, and the big through thickness rotator cuff that is equivalent to the people is torn.

Make this defective and present embodiment insert the 2mm * 2mm and the 6 implantable device bridgings of 1mm thickness reticulated elastomeric matrix of inserting on tendon edge and the greater tubercle between the position.Use two 5-0 PROLENE (Ethicon Inc.) interrupted suture line to pass through through the bone passage in the greater tubercle distal end fixture.Use two 5-0 PROLENE stitching thread that the near side (ns) of device is connected with the lateral edges of tendon then.Use interruption 4-0 VICRYL (Ethicon Inc.) stitching thread that triangular muscle is reacceesed then and take on and use 3-0 MONOCRYL (Ethicon Inc.) sealing skin.

In organizing reinforcement group (2 groups), use the #15 knife blade to generate bilateral through thickness defective at tendon of supraspinatus muscle insert division near-end 1mm, but opposite with 1 group, do not take out the tendon sections.Use then two 5-0 PROLENE stitching thread by through the bone passage with the insertion position of defect repair to the greater tubercle.Also by strengthening repairing, thereby generate the layered structure of forming by reticulated elastomeric matrix and tendon with the reticulated elastomeric matrix implantable device opposite joint of present embodiment.Use interruption 4-0VICRYL (Ethicon Inc.) stitching thread that triangular muscle is reacceesed then and take on and use 3-0MONOCRYL (Ethicon Inc.) sealing skin.

In 1 group and 2 groups was tested, 6 weeks sucked by carbon dioxide and put to death all animals after surgery.Estimate the overall healing evidence of rat shoulder and take out tendon of supraspinatus muscle and proximal humerus is used for histologic analysis by naked eyes.Overall inspection when convalescent period discloses good integration and goes into tendon and bone, and it is minimum not have obvious inflammation change and scar tissue.Under acromion, find adhesion in space and the triangular muscle lower area, change consistent with postoperative.On the histology, shoulder does not show inflammatory cell or unsuitable vascularization.Arrangement of collagen fibers in any given pore chamber of implanting device and systematism be to have the systematism of the regular connective tissue of fine and close collagen fiber.Generally speaking, notice that the cell that further takes out is similar with those of direct foil device generally from device, show that reticulated elastomeric matrix material pair cell form do not have tangible adverse effect.The histomorphometricall evaluation of 1 group of sample confirms that the mean cut-off ratio that repair tissue is soaked in the device is 77.6% (standard deviation+/-8.3%).

With 1 category seemingly, do not show that inflammation changes or unsuitable vascularization after being used to organize the implanting device (2 groups) of reinforcement to implant for 6 weeks in vivo.In addition, run into the cicatrization that changes consistent minimum level with postoperative.The histologic analysis of the device of implanting confirms and 1 group of substantially the same result.Especially, do not exist tangible inflammation to change.Be also noted that the repair tissue and tendon of supraspinatus muscle and the abundant biointegration of the tendon that is connected humerus of infiltration apparatus.It is 79.9% (standard deviation+/-7.7%) that meansigma methods is soaked in the histomorphometric display device.

Embodiment 17: reticulated elastomeric matrix 2 is in the implantable device with braided fiber stiffener Use

Prepare reticulated elastomeric matrix 2 according to the operation described in the embodiment 6.From reticulated elastomeric matrix 2, downcut and be configured as that to have a 54mm long, the implantable device of the rectangular patches of the wide and 2mm gauge of 34mm.Use polyester fiber (the Telflex Medical of Viking Platinum 730 sewing machines with the multifilament braiding; Be equivalent to have 4-0 number sutural filament diameter of 0.20mm diameter and the minimum hot strength of 1.65 lbs (748 gram)) insert rectangular patches shape device with the form of grid.Use intersection suture and the following polyester fiber that will weave that is provided with to insert rectangular patches: to have 2.5mm spacing and 6.5 tensile 1 groove part lines.Square grid be of a size of 10mm x10mm with along 2mm border separately, 4 sides.

Use and method identical described in the embodiment 14 test SRS and TBS.The SRS value is 36.5 newton, and the elongation of record was 25mm when wherein the implantable device of pulling out by 2-0 ETHIBOND stitching thread in experience ruptured.The TBS value is 56 newton, and the elongation when whole device tension failure is 7.1mm.

Embodiment 18: reticulated elastomeric matrix 1 compression molded

Prepare reticulated elastomeric matrix 1 according to the operation described in the embodiment 5.Use following operation with compression molded this substrate of 2-dimension.

From reticulated elastomeric matrix 1 downcut have 60.5mm diameter and a 62.0mm height be configured as cylindrical implantable device (" cylindrical prefabrication type product ").Make cylindrical prefabrication type product with machine, make that cylinder axis and foam rise direction is parallel.With cylindrical prefabrication type product by dry 70 ℃ of following cross-ventilation baking ovens (Blue M Inert Gas Oven Model DCA336F) internal heating 1.5 hours and be stored in the dry environment.

40.5mm the cylindrical die that diameter and 62.0mm are high (each free aluminum die substrate and covering are formed) is used for compression molded drying cylindrical prefabrication type product.Each mould is gone in exsiccant cylindrical prefabrication type product interference fit (under about 25 ℃), so that rising the vertical compression ratio of giving 1.49 times in the radial direction of direction with original foam.Cross-sectional area ratio before and after compression is 2.2 times.Use adjustable clamp that the mould of the cylindrical prefabrication type product of reticulated elastomeric matrix of inner each self-contained compression is held in place, put into baking oven then.Use the nitrogen purge baking oven.Mould was heated 3.0 hours in the nitrogen environment in baking oven under 130 ℃ of temperature.After this, in baking oven, take out mould and use compressed air cooling 15 minutes, after this lax clamp.The reticulated elastomeric matrix 1 cylindrical prefabrication type product of compression keeps the size and the shape of mould.The cylinder that these are compression molded is stored in the dry environment.

Use the characteristic of the compression molded reticulated elastomeric matrix of the time-and-motion study described in the embodiment 5 and 6.In following table 13, it has shown for example compression molded remarkable reinforcement of reticulated elastomeric matrix characteristic with the reticulated elastomeric matrix property column of compression molded front and back.

Table 13

Characteristic	Reticulated elastomeric matrix 1 (no compression molded)	Compression molded reticulated elastomeric matrix 1
Characteristic	Reticulated elastomeric matrix 1 (no compression molded)	Compression molded reticulated elastomeric matrix 1	Density	3.17lbs/ft ³(0.051g/cc)	7.42lbs/ft ³(0.119g/cc)
Rise the parallel hot strength of direction with foam	52.9psi(37,190kg/m ²)	115.9psi(81,480kg/m ²)	Density	3.17lbs/ft ³(0.051g/cc)	7.42lbs/ft ³(0.119g/cc)
Rise the parallel hot strength of direction with foam	52.9psi(37,190kg/m ²)	115.9psi(81,480kg/m ²)	Rise the parallel elongation of direction with foam	111％	95％
Rise the vertical hot strength of direction with foam	35.4psi(24,890kg/m ²)	45.9psi(32,270kg/m ²)	Rise the parallel elongation of direction with foam	111％	95％
Rise the vertical hot strength of direction with foam	35.4psi(24,890kg/m ²)	45.9psi(32,270kg/m ²)	Rise the vertical elongation of direction with foam	112％	175％
Under 50% stress, rise the parallel comprcssive strength of direction with foam	2.1psi(1,475kg/m ²)	8.2psi(5,765kg/m ²)	Rise the vertical elongation of direction with foam	112％	175％
	2.1psi(1,475kg/m ²)	8.2psi(5,765kg/m ²)	Permeability (darcy)	498	About 100

Embodiment 19: compression molded reticulated elastomeric matrix 1 and can what be used to repair the rat stomach wall Application in the implanting device

Use the compression molded reticulated elastomeric matrix 1 of preparation as described in example 18 above and mix the example that 5-0 multifilament CP cellosilk (C.P.Medical) is made implantable device of the present invention therein, promptly be determined as long and the wide and high square sticking patch of 2mm of 1cm.Use Viking Platinum Model 730 sewing machines and 1 groove part line and 3mm spacing that braided fiber is mixed rectangular devices.

Implantable device is put into 20 Sprague-Dawley rats stomach wall separately.The stomach wall defective is to have segment thickness and leave over fascia of abdomen and peritoneum and skin complete.Scarcely be downcut in and outer oblique abdominal muscle and alternative by implantable device to be measured in rat.Therefore, no device enter the abdominal cavity and behind operation closed surgery position skin be complete.Be natural muscle tissue, subcutaneous tissue and fascia around the device of implanting.In each 1,2,4,8 or 16 when week, put to death 4 rats after implantation.

On above-mentioned 20 different Sprague-Dawley rats stomach wall defective separately, implanted long and the wide and high square sticking patch of 2mm for 1cm after measured, it uses compression molded reticulated elastomeric matrix 1 to make as mentioned above, but does not mix 5-0 multifilament CP cellosilk.Also after implantation, the time respectively put to death 4 in these

rats

1,2,4,8 or 16 weeks.Also 1,2,4,8 or 16 weeks the time were put to death these rats after implantation.

, implant and estimate having and not having the filametntary implantable device of CP during the time in specified execution by histologic analysis to operative site+natural tissues is outer on every side.

There are similar host response in reinforcement and unstrengthened compression molded reticulated elastomeric matrix 1 implantable device.Healing reaction is characterised in that interact the inflammatory reaction on the position of in the 1st week main host-graft of being made up of monocyte infiltration.The quantity of multinucleated giant cell increases in whole research process.During to the 2nd week, the organized gradually connective tissue pockets around graft and the connective tissue begins to fill the hole of implantable device.The carrying out property increase in time of the systematism of connective tissue.Connective tissue is inner and very ripe on every side in graft material during to the 16th week.The amount of vascular system increased to for the 8th week in graft.Muscular tissue necrosis below in any animal, all not observing.

Embodiment 20: the reticulated elastomeric matrix 4 with selectivity imporosity surface has the multifibres volume Application in the implantable device of textured fiber

Prepare reticulated elastomeric matrix 4 according to the operation described in the embodiment 8.Has the square section that 50mm is long and wide and 2mm is high from this substrate cutting-out.In two surfaces of section with maximum surface area, make one side contact hot plate (maintain surpass 160 ℃ intensification) in nitrogen environment on a side of this section, generate relative non-permeable formation thus or have the layer of hypotonicity for reticulated elastomeric matrix so that the surface of fusing contact.Downcut implantable device from above-mentioned section with non-permeable formation subsequently, promptly 42mm grows and the wide and high square sticking patch of 2mm after measured.4-0 polyester fiber (Telflex Medical with the multifibres braiding; Be equivalent to sutural diameter 4-0 number) mix this square sticking patch so that form the implantable device that can use net as for example surgical operation with the form of grid.Square grid is of a size of 8mm x 8mm, and each has the 2mm border along the four sides.

Embodiment 21: the reticulated elastomeric matrix 4 with selectivity imporosity surface has degradable Application in the implantable device of multifibres braided fiber

Prepare reticulated elastomeric matrix 4 according to the operation described in the embodiment 8.Has the square section that 50mm is long and wide and 2mm is high from this substrate cutting-out.In two surfaces of the section with maximum surface area, one side applies the solution that the thermoplastic poly carbonic ether polyurethanes is dissolved in the dimethyl formamide of 97% oxolane and 3% volume.After solvent evaporation, shallow layer is retained on the hole of contact surface, generates relative non-permeable formation thus or have the layer of hypotonicity for reticulated elastomeric matrix on a side of section.Downcut implantable device from above-mentioned section with non-permeable formation subsequently, promptly 42mm grows and the wide and high square sticking patch of 2mm after measured.(Ethicon Inc with degradable multifibres braiding; The copolymer of Acetic acid, hydroxy-, bimol. cyclic ester and lactide and be equivalent to the sutural diameter of 4-0 VICRYL) fiber mix this square sticking patch with the form of grid can be so that form as surgical operation for example with the implantable device of net.Square grid is of a size of 8mm x 8mm, and each has the 2mm border along the four sides.

Embodiment 22: the reticulated elastomeric matrix 4 with braided fiber stiffener is being used for the sheep rotator cuff Application in the implantable device of strengthening

Constitute and be shaped as that 40mm is long after measured according to making polyester fiber by reticulated elastomeric matrix 4 and braiding described in the embodiment 14, the implantable device of the wide and rectangular patches that 2mm is thick of 20mm, but use the polyester fiber of 7-0 number braiding.As described below with this class implantable device implant 2 groups each sheep in case the rotator cuff in the healing sheep chronic model tear or tendon of infraspinatus muscle, thereby estimate the reinforcement of implantable device in connecting tendon of infraspinatus muscle and humerus.

On the shoulder of the right side of every sheep, generate chronic defective.Use the Rambouillet X Columbia ewe (sheep) more than 3.5 years old of skeletal maturation, its body weight is about the about 100Kg of 60Kg-.23 animals carry out this operation.In using the aseptic condition general anesthesia, on right shoulder joint, do the 6cm skin incision.Separate subcutaneous colonic muscle (colimuscle) with otch concordance ground.Separate triangular muscle along its acromion with tendon separated part between the omoplate head.Separate shallow head and tendon of infraspinatus muscle insert.Separate infraspinatus and use 5cm x 3cm PRECLUDE DuraSubstitute sheet (W.L.Gore and Associates, Flagstaff, AZ) parcel then from humerus.Use the conventional method wound closure.

After 4 weeks, anaesthetize sheep again and take out the PRECLUDE sheet.The crust at position is inserted in the front portion of using Hall orthopedic applications burr to peel off tendon of infraspinatus muscle.Peel off the crust of bone standard area (1cm x 1cm).In the matched group with 11 animals (1 group), after in the nodular 1cm x of infraspinatus 1cm square configuration, placing 4 Biosuture viscosity anchors (from the 3.0mm Biosuture viscosity anchor of Arthrex), hold tendon of infraspinatus muscle and use anchor suture to be connected again with proximal humerus with Mason-Allen groove part line.Be not use implantable device that tendon is connected with bone again in the another kind of mode described in the matched group.

In having another group of 12 animals (2 groups), implantable device is placed on reparation top, position, make on the tuberosity side, to have about 1cm jag.The remainder of device stretches on tendon.The anchor suture that is used for the tendon connection connects implantable device with vertical matress suture, generates the stratified structure of being made up of implantable device and tendon.On the side, in addition two anchor sutures by device and with implantable device downwards and tuberosity tighten.All implantable devices fixedly stitching thread all pass through on the fibre element of reinforcement grid in this device at least.

During 12

weeks

1 and 2 treated animals are implemented euthanasia for the second time connecting the operation back again.Collect from 9 of group (2 groups) shoulders accepting implantable device with from 8 shoulders of matched group (1 group) and prepare to be used for following bio-mechanical test at once.Removing outside soft tissue, after keeping humerus-tendon of infraspinatus muscle structural intergrity simultaneously, pierce proximal humerus and distal humerus with several screws, so that to use function (Purchase) probability of humerus in poly methyl methacrylate (PMMA) casting type material and the zone that metal fixture is connected further to increase.Use custom-designed handle each test sample book to be fixed in servo-hydraulic test machine (from MTSCorp., Eden Prairie, the Model 805 of MN) then.The bottom handle is supported the PMMA-casting end of humerus.Use is clamped on the tendon of infraspinatus muscle top handle as the preventive means that prevents slippage based on the ice-cold handle of ormolu of above-mentioned research research and development.The top handle to be moving for 0.5% stress/second so that tensile load is provided, and loses efficacy and is recorded in the final load (being defined as maximum load) that each sample reaches in the bio-mechanical process of the test up to sample.

The final load of average (from 8 animals) of matched group (1 group) is 762 newton, and standard deviation is 474 newton.Average (from 9 animals) final load of accepting implantable device (2 groups) is 1,328 newton, and standard deviation is 427 newton.The unidirectional ANOVA statistical analysis of use standard and p-value 0.05 time, the final load that will accept the group of implantable device (2 groups) are judged to be with the matched group of receiving device (1 group) not to have significant difference and is higher than matched group (1 group).

To takeing on from 3 reparations of the matched group (1 group) that is not used in the bio-mechanical test and carrying out histologic analysis from 3 reparation shoulders that are not used in the bio-mechanical test of accepting implantable device (2 groups).On the histology, find that the implantable device material is very inert.Inflammatory reaction is obviously extremely low.In all implantable devices, all found tissue ingrowth with collagen fiber formation.Organize also growth to go into humerus.

Embodiment 23: the synthetic and characteristic of reticulated elastomeric matrix 7

Prepare cross-linked network biodurable elasticity Merlon urea-carbamate substrate by the operation described in the embodiment 5, but component utilized and ratio thereof are as shown in following table 14.

Table 14

Component	Weight portion
Component	Weight portion	Polyol component
	100	Polyol component
	100	Isocyanate prepolymer composition	53.55
Isocyanate index	1.00	Isocyanate prepolymer composition	53.55
Isocyanate index	1.00	Viscosity improver	5.80
The compartment opener	2.00	Viscosity improver	5.80
The compartment opener	2.00	Distilled water	1.80
The B-8305 surfactant	1.20	Distilled water	1.80
The B-8305 surfactant	1.20	BF 2370 surfactants	1.20
The 33LV catalyst	0.35	BF 2370 surfactants	1.20
The 33LV catalyst	0.35	The A-133 catalyst	0.15
Glycerol	1.15	The A-133 catalyst	0.15
Glycerol	1.15	1, the 4-butanediol	3.00

As what measure according to the observation by light microscope result, the average cell diameter of reticulated elastomeric matrix 7 or other maximum transverse size are about 481 μ m.The SEM shadow table example of reticulated elastomeric matrix 7 is as passing through the wherein interconnected compartment reticulated structure of open bore.

Use based on the method for testing of ASTM Standard D3574 to carrying out following test available from the foamy reticulated elastomeric matrix 7 that forms thus of nettedization.Measure the density of reticulated elastomeric matrix 7 as described in example 5 above; Obtain 4.96 lbs/ft ³Density value (0.080g/cc).

As described in example 5 above reticulated elastomeric matrix 7 samples are carried out tension test.With foam rise the vertical average nettedization after-drawing strength detection of direction be about 50.2psi (35,300kg/m ²).Rise vertical nettedization of direction back extension at break degree mensuration with foam and be about 162%.With foam rise the parallel average nettedization after-drawing strength detection of direction be about 68.2psi (48,000kg/m ²).Rise the parallel nettedization back extension at break degree mensuration of direction with foam and be about 166%.

As described in example 5 above reticulated elastomeric matrix 7 is carried out compression test.Will be under 50% compression with foam rise parallel nettedization of direction afterwards compressive strength determination be about 3.31psi (2,325kg/m ²).

The resilience of measuring reticulated elastomeric matrix 7 as described in example 5 above recovers.The result who obtains is as shown in table 15.

Table 15

In 50% compression ± period under 5% strain under the 1Hz	Rise the test sample book orientation of direction with respect to foam	T-67% (second)	T-90% (second)
In 50% compression ± period under 5% strain under the 1Hz		T-67% (second)	T-90% (second)	100,000 (in air)	Parallel	---	1630
100,000 (in water)	Parallel	---	1140	100,000 (in air)	Parallel	---	1630

Use automatic fluid permeameter LP-101-A type to rise the fluid permeability of measuring on the direction by reticulated elastomeric matrix 7 at foam as described in example 5 above.The permeability of reticulated elastomeric matrix 7 rises on the direction at foam and is determined as 282 darcies.

As described in example 5 above, also measure permeability so that reduce after the available circulation area in reticulated elastomeric matrix 7 compressions (vertical) with foam rise direction.Line 1 among Figure 11 is the sketch map of the circulation area the utilized relation of darcy permeability and reticulated elastomeric matrix 7.In Figure 11,100% can utilize circulation area to represent unpressed reticulated elastomeric matrix 7 and show at foam rises high osmosis 282 darcies on the direction.Reticulated elastomeric matrix 7 rises permeability on the direction at foam and can utilize circulation area to reduce to 47.2% o'clock of original area after compression to reduce to 136 darcies, and can utilize area to reduce to 37.0% o'clock of original area after compression and reduce to 95 darcies.

Embodiment 24: the synthetic and characteristic of reticulated elastomeric matrix 8

Prepare cross-linked network biodurable elasticity Merlon urea-carbamate substrate by the operation described in the embodiment 7, but component utilized and ratio thereof are as shown in following table 16.Especially, use surfactant B-8300 and B-5055 (separately from Goldschmidt) to substitute and be used for the stable B-8305 surfactant of compartment.

Table 16

Component	Weight portion
Component	Weight portion	Polyol component
	100	Polyol component
	100	Isocyanate prepolymer composition	49.18
Isocyanate index	1.00	Isocyanate prepolymer composition	49.18
Isocyanate index	1.00	Viscosity improver	5.80
The compartment opener	2.00	Viscosity improver	5.80
The compartment opener	2.00	Distilled water	1.45
The B-8300 surfactant	0.45	Distilled water	1.45
The B-8300 surfactant	0.45	The B-5055 surfactant	0.45
The BF2370 surfactant	0.90	The B-5055 surfactant	0.45
The BF2370 surfactant	0.90	The 33LV catalyst	0.30
The A-133 catalyst	0.15	The 33LV catalyst	0.30
The A-133 catalyst	0.15	Glycerol	2.00
1, the 4-butanediol	2.00	Glycerol	2.00

As what measure according to the observation by light microscope result, the average cell diameter of reticulated elastomeric matrix 8 or other maximum transverse size are about 512 μ m.The SEM image of reticulated elastomeric matrix 8 has for example shown by the interconnected compartment reticulated structure of open bore wherein.

Use based on the method for testing of ASTM Standard D3574 to carrying out following test available from the foamy reticulated elastomeric matrix 8 that forms thus of nettedization.Measure the density of reticulated elastomeric matrix 8 as described in example 5 above; Obtain 5.25 lbs/ft ³Density value (0.084g/cc).

The piece of reticulated elastomeric matrix 8 was annealed in 110 ℃ baking oven 5 hours or 10 hours unfetteredly.

As described in example 5 above unannealed and annealed reticulated elastomeric matrix 8 samples are carried out rising vertical with parallel tension force and the compression test of direction with foam.In addition, calculate stretch modulus and modulus of compressibility separately by the ratio that is determined at stress and strain under the low strain, i.e. the initial slope of each corresponding stress and the relation between the strain curve.As according to what show in the following table 17, caused the mechanical performance of reticulated elastomeric matrix 8 significantly to increase in 5 hours and 10 hours at 110 ℃ of following nettedization after annealings.The density that should note reticulated elastomeric matrix 8 remains unchanged after annealing basically.

Table 17

Characteristic	After nettedization, there is not annealing	Annealed 5 hours down at 110 ℃	Annealed	10 hours down at 110 ℃
Characteristic	After nettedization, there is not annealing	Annealed 5 hours down at 110 ℃	Annealed	10 hours down at 110 ℃	Hot strength, vertical with the direction that foam rises	49.0psi	61.7psi	66.0psi
Stretch modulus, vertical with the direction that foam rises	30.3psi	34.7psi	40.2psi		Hot strength, vertical with the direction that foam rises	49.0psi	61.7psi	66.0psi
	30.3psi	34.7psi	40.2psi	Hot strength, parallel with foam rise direction	64.9psi	78.1	82.2
Stretch modulus, parallel with foam rise direction	46.8	46.1	60.2psi	Hot strength, parallel with foam rise direction	64.9psi	78.1	82.2
Stretch modulus, parallel with foam rise direction	46.8	46.1	60.2psi	Under 50% compression, rise the parallel compressive strength of direction with foam	2.1psi	3.8psi	4.4psi
Modulus of compressibility rises parallel with foam	30.7psi	56.2psi	61.4psi		2.1psi	3.8psi	4.4psi

The guiding open source literature of introducing

Especially with reference in this description separately with every piece of United States Patent (USP) and patent application, the content intacts ground that each outward appearance and international patent publication and each other open source literature and each undocumented patent application all disclose is incorporated herein conduct to its corresponding concrete reference of carrying out.

Although above described illustrative embodiment of the present invention, it should be understood that many and various modification are apparent for various equivalent modifications, or apparent when developing in this area.This class modification is paid close attention to belonging to the spirit and scope of the present invention that the present invention or this description disclose.

Claims

1. implantable device comprises the netted resilience-compressible elastomeric matrices that contains a plurality of holes, and wherein this implantable device further is included in the stiffener of 1-dimension form at least.

2. the described implantable device of claim 1, wherein said stiffener are 1-dimension stiffener.

3. the described implantable device of claim 2, wherein said 1-dimension stiffener comprises a plurality of substantially parallel 1-dimension reinforcing elements.

4. the described implantable device of claim 2, wherein said 1-dimension stiffener has circular basically cross section, and the about 1.0mm of the about 0.03mm-of its diameter chooses the about 0.30mm of about 0.07mm-wantonly.

5. the described implantable device of claim 2, wherein said 1-dimension stiffener has circular basically cross section, it with about 8-0 number-Yue No. 0, it is suitable to choose about 8-0 number-Yue No. 2 USP suture diameters wantonly.

6. the described implantable device of claim 2, wherein said 1-dimension stiffener comprises fiber, metal wire, suture, silk thread or its be mixture arbitrarily.

7. the described implantable device of claim 6, wherein said 1-dimension stiffener comprises monfil, multifilament, braided wires is mixed monfil, multifilament yarn, the pencil monfil, pencil multifilament or its be mixture arbitrarily.

8. the described implantable device of claim 6, wherein said 1-dimension stiffener comprises the amorphous polymer fiber, the semi-crystalline polymer fiber, crosslinked polymer fibers, biopolymerization fibres, collagen fiber, elastic fiber, carbon fiber, glass fibre, the bioresorbable glass fibre contains the calcium phosphate glass fiber of silicate, ceramic fibre, polyester fiber, nylon fiber, amorphous polymer silk, the semi-crystalline polymer silk, the cross linked polymer silk, biopolymer silk, carbon filament, glass fiber, the bioresorbable glass fiber contains the calcium phosphate glass silk of silicate, ceramic wire, polyester capillaries, nylon yarn or its be mixture arbitrarily.

9. the described implantable device of claim 6, wherein said 1-dimension stiffener comprises absorbable material.

10. the described implantable device of claim 6, wherein said 1-dimension stiffener comprises not resorbable material.

11. the described implantable device of claim 1, wherein said stiffener are 2-dimension stiffener.

12. the described implantable device of claim 11, wherein said 2-dimension stiffener comprises multicellular 1-dimension reinforcing element, and the path of wherein said 1-dimension reinforcing element is intersected with each other.

13. the described implantable device of claim 12, wherein said grid further comprises the border, and it comprises at least a 1-dimension reinforcing element apart from this about fixed range in device edge.

Any described implantable device during 14. aforesaid right requires, wherein said suture pull off strength is about 5 newton-Yue 75 newton, optional 10 newton-be about, 40 newton that are about.

Any described implantable device during 15. aforesaid right requires, wherein fracture strength is about 8.8 newton-Yue 440 newton, optional about 30 newton-Yue 100 newton.

Any described implantable device during 16. aforesaid right requires, wherein the ball bursting strength is about the about 34Kgf of 1.35Kgf-, the optional about 22.5Kgf of about 3.65Kgf-.

17. any described implantable device during aforesaid right requires wherein is configured to described reticulated elastomeric matrix allow the reticulated elastomeric matrix that cell is inwardly grown and propagation goes into to strengthen.

Any described implantable device during 18. aforesaid right requires, wherein this implantable device is being reinforced preceding annealing.

Any described implantable device during 19. aforesaid right requires, wherein this implantable device is being reinforced after annealing.

Any described implantable device during 20. aforesaid right requires, wherein this implantable device is compressed molded before being reinforced.

Any described implantable device during 21. aforesaid right requires, wherein this implantable device is compressed molded after being reinforced.

22. the method for treated tissue defective, this method comprises:

A) optional aforesaid right is required in the implantable device described in any be compressed into first compressing structure from relaxed configuration;

23. the described method of claim 22, wherein said tissue defects relates to orthopedic applications, and common surgical procedures is used, and aesthetic surgery is used, and tissue engineered application or its be mixture arbitrarily.

24. the described method of claim 23, wherein said orthopedic applications relates to tendon, ligament, and cartilage, meniscus, spinal disc or its be the reparation of mixture arbitrarily, rebuilds, and regeneration is strengthened, and breach insertion or its be mixture arbitrarily.

25. the described method of claim 23, wherein said common surgical procedures are used and are related to inguinal hernia, the veutro hernia, and thigh portion hernia, umbilical hernia or its be mixture arbitrarily.

26. as any described method among the claim 22-25, further comprise the use suture, anchor, barb, contact pin, screw, staple, plate, tack pin, glue or its arbitrarily mixture fixedly implantable device to described defective.

27. comprising by the open surgery operation, the method for treated tissue defective, this method insert as any described implantable device among the claim 1-21.

28. implantable device comprises the netted resilience-compressible elastomeric substrate that contains a plurality of holes, wherein this implantable device is compressed molded after nettedization.

29. the described implantable device of claim 28 is wherein compression molded at about 100 ℃-Yue 190 ℃, carries out under the optional about 110 ℃-Yue 180 ℃ temperature.

30. the described implantable device of claim 29, wherein compression molded carrying out about 10 seconds-Yue 10 hours, optional about 30 seconds-Yue 5 hours.

31. the described implantable device of claim 28, wherein compression molded under about temperature more than 160 ℃ or 160 ℃, carry out about below 30 minutes or 30 minutes, optional about time below 10 minutes or 10 minutes.

32. the described implantable device of claim 28, wherein compression molded carry out under about 130 ℃ temperature about below 240 minutes or 240 minutes, optional about time below 120 minutes or 120 minutes.

33. any described implantable device among the claim 28-32, wherein as measuring according to method of testing described in the ASTM Standard D3574, bulk density after compression molded is about the about 0.96g/cc of 0.005g/cc-, the optional about 0.56g/cc of about 0.048g/cc-.

34. any described implantable device among the claim 28-33, wherein Ya Suo reticulated elastomeric matrix density with compression molded before the ratio of reticulated elastomeric matrix density increased about 1.05 times-Yue 25 times, optional about 1.20 times-Yue 7.5 times.

35. any described implantable device among the claim 28-34, wherein the hot strength of Ya Suo reticulated elastomeric matrix has increased about 1.05 times-Yue 5.0 times with the ratio of the hot strength of compression molded preceding reticulated elastomeric matrix, optional about 1.20 times-Yue 2.5 times.

36. any described implantable device among the claim 28-35, wherein the comprcssive strength of Ya Suo reticulated elastomeric matrix has increased about 1.05 times-Yue 4.5 times with the ratio of the comprcssive strength of compression molded preceding reticulated elastomeric matrix, optional about 1.20 times-Yue 3.5 times.

37. any described implantable device among the claim 28-36, the permeability at least about 450 darcies of wherein initial reticulated elastomeric matrix convection cell is reduced to after this reticulated elastomeric matrix is compression molded and is not less than about 250 darcies, and this moment, cross-sectional area reduced about 50%.

38. any described implantable device among the claim 28-36, the permeability at least about 200 darcies of wherein initial reticulated elastomeric matrix convection cell is reduced to after this reticulated elastomeric matrix is compression molded and is not less than about 40 darcies, and this moment, cross-sectional area reduced about 50%.

39. any described implantable device among the claim 28-32 wherein compression moldedly carries out as fixed mold wall compression molding process.

The wall pressure moulding process that contracts carries out 40. any described implantable device among the claim 28-32, wherein compression molded conduct move moulds.

41. any described implantable device among the claim 28-32, wherein compression molded form with the compression of 1-dimension is carried out.

42. the described implantable device of claim 41, wherein to be about 1.1-about 9.9 for the linear compression ratio, optional about 1.5-about 8.0.

43. the described implantable device of claim 41, wherein to be about 3%-about 97% in the linear compression strain, optional about 15%-about 95%.

44. any described implantable device among the claim 28-32, wherein compression molded form with the compression of 2-dimension is carried out.

45. the described implantable device of claim 44, wherein said 2-dimension boil down to radial compression.

46. it is about 6.7 that the described implantable device of claim 45, wherein said radial compression ratio are about 1.2-, optional about 1.5-about 6.0.

47. the described implantable device of claim 45, wherein to be about 1.5-about 47 for the cross section compression ratio, optional about 1.5-about 25.

48. the described implantable device of claim 45, wherein to be about 25%-about 90% in the cross section compression strain, optional about 33%-about 88%.

49. any described implantable device among the claim 28-48 wherein is configured to described reticulated elastomeric matrix to allow cell inwardly to grow and propagation is gone into compression molded reticulated elastomeric matrix.

50. any described implantable device among the claim 28-48, wherein this implantable device is annealed before compression molded.

51. any described implantable device among the claim 28-48, wherein this implantable device is at compression molded after annealing.

52. any described implantable device among the claim 28-48, wherein this implantable device is reinforced before compression molded.

53. any described implantable device among the claim 28-48, wherein this implantable device is reinforced after compression molded.

54. the method for treated tissue defective, this method comprises:

A) choose wantonly and will be compressed into first compressing structure from relaxed configuration as any described implantable device among the claim 28-53;

C) optionally make this implantable device in described body, expand into second work structuring on the position.

55. the described method of claim 54, wherein said tissue defects relates to orthopedic applications, and common surgical procedures is used, and aesthetic surgery is used, and tissue engineered application or its be mixture arbitrarily.

56. the described method of claim 55, wherein said orthopedic applications relates to tendon, ligament, and cartilage, meniscus, spinal disc or its be the reparation of mixture arbitrarily, rebuilds, and regeneration is strengthened, and breach insertion or its be mixture arbitrarily.

57. the described method of claim 55, wherein said common surgical procedures are used and are related to inguinal hernia, the veutro hernia, and thigh portion hernia, umbilical hernia or its be mixture arbitrarily.

58. any described method further comprises the use suture among the claim 54-57, anchor, barb, contact pin, screw, staple, plate, tack pin, glue or its mixture arbitrarily make described implantable device be fixed to described defective to fix.

59. comprising by the open surgery operation, the method for treated tissue defective, this method insert as any described implantable device among the claim 28-53.

60. implantable device comprises the netted resilience-compressible elastomeric substrate that contains a plurality of holes, wherein this implantable device is at nettedization after annealing.

61. the described implantable device of claim 60, wherein said annealing is surpassing about 50 ℃ temperature, chooses wantonly and is carrying out above under about 100 ℃ temperature.

62. claim 60 or 61 described implantable devices, wherein said annealing was carried out at least about 2 hours, about 8 hours of optional about 4-.

63. any described implantable device among the claim 60-62, wherein this implantable device is unrestricted on geometry in the annealed while.

64. any described implantable device among the claim 60-62, wherein this implantable device is restricted on geometry in the annealed while.

65. any described implantable device among the claim 60-64 wherein is configured to described reticulated elastomeric matrix to allow cell inwardly to grow and propagation is gone into annealed reticulated elastomeric matrix.

66. any described implantable device among the claim 60-65, wherein this implantable device is reinforced before annealing.

67. any described implantable device among the claim 60-65, wherein this implantable device is reinforced after annealing.

68. any described implantable device among the claim 60-67, wherein this implantable device is compressed molded before annealing.

69. any described implantable device among the claim 60-67, wherein this implantable device is compressed molded after annealing.

70. the method for treated tissue defective, this method comprises:

A) choose wantonly and will be compressed into first compressing structure from relaxed configuration as any described implantable device among the claim 60-69;

C) optionally make described implantable device position in described body expand into second work structuring.

71. the described method of claim 70, wherein said tissue defects relates to orthopedic applications, and common surgical procedures is used, and aesthetic surgery is used, and tissue engineered application or its be mixture arbitrarily.

72. the described method of claim 71, wherein said orthopedic applications relates to tendon, ligament, and cartilage, meniscus, the reparation that spinal disc or its make up is arbitrarily rebuild, and regeneration is strengthened, and breach insertion or its be mixture arbitrarily.

73. the described method of claim 71, wherein said common surgical procedures are used and are related to inguinal hernia, the veutro hernia, and thigh portion hernia, umbilical hernia or its be mixture arbitrarily.

74. any described method further comprises the use suture among the claim 70-73, anchor, and barb, contact pin, screw, staple, plate, tack pin, glue or its mixture are arbitrarily fixed described implantable device and described defective.

75. comprising by the open surgery operation, the method for treated tissue defective, this method insert as any described implantable device among the claim 60-69.

76. the polymerization of preparation elastomeric matrices, this method comprise following composition is mixed so that described elastomeric matrices to be provided:

A) polyol component of 100 weight portions,

B) isocyanate prepolymer composition of about 90 weight portions of about 10-,

C) foaming agent of about 6.0 weight portions of about 0.5-,

D) crosslinking group of optional about 8.0 weight portions of about 0.05-,

E) cahin extension agent of optional about 8.0 weight portions of about 0.05-,

F) at least a catalyst of optional about 3.0 weight portions of about 0.05-,

H) surfactant of about 8.0 weight portions of about 0.1-and

I) the optional viscosity improver that reaches 15 weight portions approximately.

77. the described method of claim 76, wherein said isocyanate prepolymer composition has isocyanate index, and wherein this isocyanate index to be about 0.85-about 1.2, optional about 0.85-about 1.019.

78. the method described in claim 76 or 77, wherein said polyol component is liquefied before mixing.

79. any described method among the claim 76-78 wherein forms first mixture that comprises polyhydric alcohol and isocyanate prepolymer composition by polyols blend composition and isocyanate prepolymer composition; Form second mixture that comprises foaming agent and catalyst by mixed foaming agent and catalyst; And mix first mixture and second mixture.

80. any described method among the claim 76-78 is wherein mixed described polyol component, isocyanate prepolymer composition, foaming agent and catalyst in mixer.

81. any described method among the claim 76-78, wherein by polyols blend composition in mixer, foaming agent and catalyst form and comprise polyol component, first mixture of foaming agent and catalyst; And first mixture is mixed with described isocyanate prepolymer composition.

82. the product that obtains as method as described among the claim 76-81 any.

83. the described product of claim 82, the biodurable of wherein said elastomeric matrices at least 29 days, optional at least 6 months.

84. prepare the method for reticulated elastomeric matrix, this method comprises by nettedization method to be made as any described nettedization of elastomeric matrices among the claim 76-81 so that reticulated elastomeric matrix to be provided.

85. the described method of claim 84, the permeability of wherein said reticulated elastomeric matrix convection cell is greater than the permeability of the non-pseudostructure convection cell of this reticulated elastomeric matrix of preparation.

86. the product that the described method of claim 84 obtains.

87. the dynamic recovery time t-90% that has after 100,000 circulations in air and under the 1Hz frequency of the described product of claim 86, wherein said reticulated elastomeric matrix product is less than about 4,000 seconds, chooses wantonly to be less than about 1,750 second.

88. the described product of claim 87, the dynamic recovery time t-90% that wherein said reticulated elastomeric matrix product has is less than about 200 seconds.

89. the dynamic recovery time t-90% that has after 100,000 circulations in water and under the 1Hz frequency of the described product of claim 86, wherein said reticulated elastomeric matrix product is less than about 3,000 seconds, chooses wantonly to be less than about 1,500 second.

90. the described product of claim 89, the dynamic recovery time t-90% that wherein said reticulated elastomeric matrix product has is less than about 100 seconds.

91. the described product of claim 86, wherein said reticulated elastomeric matrix fills up the biological part that it is resided basically.

92. as claim 82,83 or 86-91 in any described product, inwardly growth and propagation are gone into this reticulated elastomeric matrix wherein described reticulated elastomeric matrix to be configured to allow cell.

93. the described product of claim 92 wherein makes described reticulated elastomeric matrix biointegration go into to be repaired or alternate tissue.

94. prepare the method for reticulated elastomeric matrix, this method comprises by the nettedization method of burning will use nettedization so that reticulated elastomeric matrix to be provided as any described substrate among the claim 76-81.

95. the described method of claim 94, the permeability of wherein said reticulated elastomeric matrix convection cell is greater than the permeability of the non-reticulated elastomeric matrix convection cell of this reticulated elastomeric matrix of preparation.

96. the product that the described method of claim 94 obtains.

97. prepare the method for partial mesh elastomeric matrices at least, this method comprises:

1) following composition is mixed so that mixture to be provided:

A) elastomeric material of 100 weight portions,

B) optional about 70 weight portions of about 2-have more the hydrophilic polymers material,

C) optional about 20 parts by weight of cross-linking agent of about 0.1-and

D) foaming agent of optional about 20 weight portions of about 1-;

2) make this mixture under the frequency of the about 6.0GHz of about 2.2GHz-, contact microwave irradiation, optional simultaneously also with this mixture heated to about 70 ℃-Yue 225 ℃ temperature; Thereby provide the elastomeric matrices of partial mesh at least.

98. the described method of claim 97, wherein said elastomeric material is selected from Merlon polyurethanes urea, Merlon polyureas carbamate, the Merlon polyurethanes, Merlon polysiloxanes polyurethanes, Merlon polysiloxanes polyurethanes urea, the polysiloxanes polyurethanes, polysiloxanes polyurethanes urea, Merlon hydrocarbon polyurethanes, Merlon hydrocarbon polyurethanes urea or its be mixture arbitrarily.

99. claim 97 or 98 described methods, the wherein said hydrophilic polymers material that has more is poly-(vinyl acetate), and poly-(ethylene-co-vinyl acetate) or its be mixture arbitrarily.

100. any described method among the claim 97-99, wherein said microwave irradiation is to carry out under the frequency of about 2.45GHz or about 5.8GHz.

101. any described method among the claim 97-100, wherein the temperature of optional heat is about 100 ℃-Yue 180 ℃.