WO2021148851A1

WO2021148851A1 - Bio-resorbable wound filler for deep tissue wound closure

Info

Publication number: WO2021148851A1
Application number: PCT/IB2020/056044
Authority: WO
Inventors: Timothy Mark Robinson; Christopher Brian Locke; Alexander WAITE
Original assignee: Kci Licensing, Inc.; Systagenix Wound Management, Limited
Priority date: 2020-01-21
Filing date: 2020-06-25
Publication date: 2021-07-29

Abstract

The present disclosure relates generally to wound fillers that may include two or more bio-resorbable film sheets adjoined in a manifold configuration that may be used in the therapy of deep wounds and for facilitating wound healing. Kits for use in practicing the methods are also provided.

Description

BIO RESORBABLE WOUND FILLER FOR DEEP TISSUE WOUND CLOSURE

TECHNICAL FIELD

[0001] The present technology relates generally to wound fillers and methods for facilitating wound healing. Kits for use in practicing the methods are also provided.

BACKGROUND

[0002] The following description of the background of the present technology is provided simply as an aid in understanding the present technology and is not admitted to describe or constitute prior art to the present technology. [0003] A wide variety of materials and devices, generally characterized as “dressings,” are generally known in the art for use in treating an injury or other disruption of tissue. Such wounds may be the result of trauma, surgery, or disease, and may affect skin or other tissues. In general, dressings may control bleeding, absorb wound exudate, ease pain, assist in debriding the wound, protect wound tissue from infection, or otherwise promote healing and protect the wound from further damage. [0004] The application of negative pressure to deep wounds is intended to bring about effective reverse-expansion, to reduce trauma and edema, and allow for bottom-up closure of the wound. Present treatment materials (such as gauze or foam) are ill-suited to this task and present problems with removal or are unable to manifold fluids or pressure.

SUMMARY [0005] In an aspect, a wound filler that includes a two or more bio-resorbable film sheets adjoined in a manifold configuration. Each bio-resorbable film sheet includes collagen and one or more stiffening agents, and the wound filler exhibits a modulus of elasticity of about 0.5 MPa to about 5.0 MPa.

[0006] In an aspect, methods for treating a wound in a subject in need thereof are provided, wherein the method includes administering a wound filler of any embodiment disclosed herein to the wound.

[0007] In a further related aspect, a method of manufacturing a wound filler that includes: fabricating a bio-resorbable film sheet from a slurry that includes collagen and a stiffening agent; removing residual water from the bio-resorbable film sheet; repeating the fabricating and removing steps to form additional bio-resorbable film sheets; forming the bio-resorbable film sheets into a corrugated shape that includes a plurality of flutes; adjoining two or more bio-resorbable film sheets to form a manifold configuration; wherein the wound filler has a modulus of elasticity from about 0.5 MPa to about 5.0 MPa.

[0008] In a further related aspect, the present disclosure provides kits that include a wound filler of any embodiment disclosed herein and instructions for use.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1 shows a perspective view of the an embodiment of the wound filler of the present technology having a manifold configuration.

[0010] FIG. 2 shows a top view of an embodiment of the wound filler of the present technology having a manifold configuration.

DETAILED DESCRIPTION

[0011] It is to be appreciated that certain aspects, modes, embodiments, variations, and features of the present methods are described below in various levels of detail in order to provide a substantial understanding of the present technology.

Definitions

[0012] The definitions of certain terms as used in this specification are provided below. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this present technology belongs.

[0013] The following terms are used throughout as defined below.

[0014] As used herein and in the appended claims, singular articles such as “a”, “an”, and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0015] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term - for example, “about 10 wt.%” would mean “9 wt.% to 11 wt.%.” It is to be understood that when “about” precedes a term, the term is to be construed as disclosing “about” the term as well as the term without modification by “about” - for example, “about 10 wt.%” discloses “9 wt.% to 11 wt.%” as well as discloses “10 wt.%.”

[0016] As used herein, the term “modulus of elasticity” (also known as ‘Young’s modulus”) refers to the measure of an object or a substance’s resistance to being deformed elastically (i.e., non- permanently) upon the application of a stress. The modulus of elasticity of an object is defined by the following formula:

wherein “stress” is the force causing the deformation divided by the area to which the force is applied, and wherein “strain” is the ratio of the change in some parameter caused by the defbrmation to the original value of the parameter.

[0017] As used herein, the term “mammalian recombinant collagen” refers to collagen manufactured by culturing a non-human organism or mammalian or non-mammalian cells to express at least one exogenous gene encoding a collagen in the culturing system. The term “human recombinant collagen” refers to collagen manufactured by culturing a non-human organism or mammalian or non-mammalian cells to express at least one human gene encoding a collagen. The human recombinant collagen may be selected from the group consisting of collagen type I, type II, type III, type IV, type V, type VI, type VII, type VIII, type IX, type X, type XI, type XII, type XIII, type XTV, type XV, type XVI, type XVII, type XVIII, type XIX, type XX, type XXI, type XXII, type XXIII, type XXIV, type XXV, type XXVI, type XXVII, and mixtures of any two or more thereof. The human recombinant collagen can be collagen of one type free of any other type, or can be a mixture of collagen types. Suitably, the human recombinant collagen includes collagens selected from collagen type I, collagen type Π, or mixtures thereof. The term “bovine recombinant collagen” refers to collagen manufactured by culturing a non-human organism or mammalian or non- mammalian cells to express at least one bovine gene encoding a collagen. The bovine recombinant collagen may be selected from collagen type I, type II, type III, type IV, or mixtures of any two or more thereof. The bovine recombinant collagen can be collagen of one type free of any other type, or can be a mixture of collagen types. Suitably, the bovine recombinant collagen includes collagens selected from collagen type I, collagen type III, and mixtures thereof.

[0018] As used herein, the “administration” of a wound filler to a subject includes any route of introducing or delivering to a subject a wound filler to perform its intended function. Administration can be carried out by any suitable route, including, but not limited to, topical administration. Administration includes self-administration and the administration by another.

[0019] As used herein, the term “effective amount” refers to a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, e.g. , an amount which results in the decrease in a wound described herein or one or more signs or symptoms associated with a wound described herein. In the context of therapeutic and/or prophylactic applications, the amount of an filler administered to the subject will vary depending on the composition, the degree, type, and severity of the wound and on the characteristics of the individual. The fillers can also be administered in combination with one or more additional therapeutic compounds. In the methods described herein, the therapeutic fillers may be administered to a subject having one or more wounds.

[0020] As used herein, the terms “individual”, “patient”, or “subject” can refer to an individual organism, a vertebrate, a mammal, or a human. In some embodiments, the individual, patient, or subject is a human.

[0021] “Treating” or “treatment” as used herein covers the treatment of a wound described herein, in a subject, such as a human, and includes: (i) inhibiting a wound, i.e., arresting its development; (ii) relieving a wound, i.e., causing regression of the wound; (iii) slowing progression of the wound; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the wound. In some embodiments, treatment means that the symptoms associated with the wound are alleviated, reduced, cured, or placed in a state of remission.

[0022] It is also to be appreciated that the various modes of treatment of wounds as described herein are intended to mean “substantial,” which includes total but also less than total treatment, and wherein some biologically or medically relevant result is achieved. The treatment may be a continuous prolonged treatment for a chronic wound or a single administration, or a few administrations fbr the treatment of an acute wound.

The Present Technology

[0023] Application of negative pressure to deep wounds may bring about effective reverse- expansion, reducing trauma and edema and allowing bottom-up closure of the wound. However, mainstream wound care treatment and materials may pose risks, such as loss of structural integrity of wound dressings, which may granulate in the wound.

[0024] The present disclosure is directed to wound fillers that include two or more bio-resorbable film sheets adjoined in a manifold configuration. The wound fillers of the present technology advantageously may have radial contraction properties such that they communicate greater level of force over or across a wound area, and especially for large area or deep wounds. The components of the wound filler may stimulate tissue growth and/or prevent bacterial infection. The components of the wound filler are bio-resorbable, bio-compatible, and bio-absorbable and may remain in the wound for up to about 7 days. For example, in any embodiment disclosed herein, the wound filler may remain in the wound for up to about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 1.5 weeks, about 2 weeks, or any range including and/or between any two of these values. The components of the wound filler may reduce the inflammatory phase, may stimulate granulation tissue growth, and/or may reduce bacterial bioburden.

[0025] Thus, in an aspect, a wound filler that includes a two or more bio-resorbable film sheets adjoined in a manifold configuration. Each bio-resorbable film sheet independently includes collagen and one or more stiffening agents, and the wound filler exhibits a modulus of elasticity of about 0.5 MPa to about 5.0 MPa. In any embodiment disclosed herein, the wound filler may exhibits a modulus of elasticity of about 0.5 MPa, about 0.6 MPa, about 0.7 MPa, about 0.8 MPa, about 0.9 MPa, about 1.0 MPa, about 1.3 MPa, about 1.4 MPa, about 1.5 MPa, about 1.6 MPa, about 1.7 MPa, about 1.8 MPa, about 1.9 MPa, about 2.0 MPa, about 2.1 MPa, about 2.2 MPa, about 2.3 MPa, about 2.4 MPa, about 2.5 MPa, about 2.6 MPa, about 2.7 MPa, about 2.8 MPa, about 2.9 MPa, about 3.0 MPa, about 3.1 MPa, about 3.2 MPa, about 3.3 MPa, about 3.4 MPa, about 3.5 MPa, about 3.6 MPa, about 3.7 MPa, about 3.8 MPa, about 3.9 MPa, about 4.0 MPa, about 4.1 MPa, about 4.2 MPa, about 4.3 MPa, about 4.4 MPa, about 4.5 MPa, about 4.6 MPa, about 4.7 MPa, about 4.8 MPa, about 4.9 MPa, about 5.0 MPa, or any range including and/or in between any two of these values. For example, in any embodiment disclosed herein, the wound filler may exhibit a modulus of elasticity of about 0.5 MPa to about 5.0 MPa, about 1.0 MPa to about 2.5 MPa, or about 1.2 MPa to about 2.3 MPa. FIG. 1 provides a non-limiting representative illustration of an embodiment of a wound filler of the present technology, illustrating the manifold configuration of the wound filler.

[0026] FIGs. 1 and 2 provide non-limiting representative illustrations of embodiments of a wound filler of the present technology, illustrating the two or more bio-resorbable film sheets (110 and 210, respectively), the corrugated shape or wave pattern of the bio-resorbable sheet (120 and 220, respectively), the adjoined flutes of the bio-resorbable film sheets (130 and 230, respectively) of such a wound filler, and the open channels (240) of the wound filler. FIG. 1 provides an illustrative perspective view illustration of a wound filler 100 that includes two or more bio-resorbable film sheets 110 having a corrugated shape 120, where the sheets are adjoined at the flutes (130) of the bioresorbable film sheets. FIG. 2 provides an illustrative top view illustration of a wound filler 200 that includes two or more bio-resorbable film sheets 210 having a corrugated shape 220, where the sheets are adjoined at the flutes (230) of the bio-resorbable film sheets, and the wound filler 200 includes open channels 240.

Bio-resorbable Film Sheets

[0027] In any embodiment disclosed herein, each bio-resoibable film sheet may independently include about 0.01 weight percent (“wt.%”) to about 80 wt.% of collagen based on the weight of the bio-resorbable film sheet. Thus, each bio-resorbable film sheet may independently include collagen in an amount (based on the total weight of the bio-resorbable sheet) of about 0.01 wt.%, about 0.1 wt.%, about 1 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 12 wt.%, about 14 wt.%, about 16 wt.%, about 18 wt.%, about 20 wt.%, about 25 wt.%, about 30 wt.%, about 35 wt.%, about 40 wt.%, about 45 wt.%, about 50 wt.%, about 55 wt.%, about 60 wt.%, about 65 wt.%, about 70 wt.%, about 75 wt.%, about 80 wt.%, or any range including and/or in between any two of these values. In any embodiment disclosed herein, the bio-resoibable sheet may include from about 10 wt.% to about 50 wt.% collagen.

[0028] In any embodiment disclosed herein, the collagen of each bio-resorbable film sheet may independently include a mammalian collagen, such as a bovine collagen, a human collagen, or a combination thereof. The collagen of any embodiment herein may be a Type I collagen, a Type Π collagen, a Type ΠΙ collagen, may be obtained from any natural source, may be chemically-modified collagen (e.g., an atelocollagen obtained by removing the immunogenic telopeptides from natural collagen), or may be a combination of any two or more thereof. For example, the collagen may include collagen obtained from bovine corium that has been rendered largely free of non-collagenous components, for example, including fat, non-collagenous proteins, polysaccharides, and other carbohydrates, such as by procedures described in U.S. Pat. Nos. 4,614,794 and 4,320,201, each of which is incorporated herein by reference. The bovine collagen may include one or both of bovine collagen type I and bovine collagen type ΠΙ. In any embodiment disclosed herein, each bioresorbable film sheet may independently include a weight ratio of human collagen type I to human collagen type ΙΠ of about 100:0, about 90: 10, about 80:20, about 70:30, about 60:40, about 50:50, about 40:60, about 30:70, about 20:80, about 10:90, about 0: 100, or any range including and/or in between any two of these values. The ratio by weight of human collagen type I to human collagen type ΙΠ may be greater than about 50:50, or greater than about 70:30. The collagen of any embodiment herein may include a weight ratio of type I bovine collagen to type III bovine collagen of about 95:5, about 85:15, about 75:25, about 65:35, about 55:45, about 50:50, about 45:55, about 65:35, about 75:25, about 85:15, about 95:5, or any range including and/or in between any two of these values. The ratio by weight of the type I bovine collagen to type III bovine collagen may be about 85:15.

[0029] The collagen included in the bio-resorbable film sheet of any embodiment herein may have a weight-average molecular weight of about 5,000, about 6,000, about 7,000, about 8,000, about 9,000, about 10,000, about 12,000, about 14,000, about 16,000, about 18,000, about 20,000, about 22,000, about 24,000, about 26,000, about 28,000, about 30,000, about 32,000, about 34,000, about 36,000, about 38,000, about 40,000, about 45,000, about 50,000, about 55,000, about 60,000, about 65,000, about 70,000, about 75,000, about 80,000, about 85,000, about 90,000, about 95,000, about 100,000, or any range including and/or in between any two of these values.

[0030] In any embodiment disclosed herein, the one or more stiffening agents may include bioabsorbable polymers, cross-linking agents, or combinations thereof. In any embodiment disclosed herein, the stiffening agent may be a bioabsorbable polymer. Exemplary bioabsorbable polymers may include, but are not limited to, polylactic acid (PLA), gelatin, polyglycolide, polycaprolactone, or a combination of any two or more thereof. In any embodiment disclosed herein, the bioabsorbable polymer may be PLA, gelatin, or a combination thereof. In any embodiment herein, the bioabsorbable polymer may be PLA. In any embodiment disclosed herein, the bioabsorbable polymer may be gelatin.

[0031] In any embodiment disclosed herein, each bio-resorbable film sheet may independently include about 1 wt.% to about 20 wt.% of the bioabsorbable polymer. Thus, the total amount of the bioresorbable polymer in each bio-resorbable film sheet may independently be about 1 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, or any range including and/or in between any two of these values based on the weight of the bio-absorbable film sheet.

[0032] In any embodiment disclosed herein, the stiffening agent may be a cross-linking agent. Exemplary cross-linking agents may include epichloihydrin, carbodiimide (e.g., 1 -ethyl-3 -[3- dimethylaminopropyl]carbodiimide), hexamethylene diisocyanate (HMDI), glutaraldehyde, or a combination of any two or more thereof. Each bio-resorbable film sheet may independently include about 0.01 wt.% to about 10 wt.% of the cross-linking agent based on the weight of the bio-resorbable film sheet. Thus, each bio-resorbable film sheet may independently include the cross-linking agent (based on the total weight of the bio-resorbable film sheet) of about 0.01 wt.%, about 0.1 wt.%, about 1 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, or any range including and/or in between any two of these values.

[0033] In any embodiment disclosed herein, each bio-resorbable film sheet may independently include about 1 wt.% to about 20 wt.% of plasticizers. Thus, the total amount of plasticizers in each bio-resorbable film sheet may independently be about 1 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, or any range including and/or in between any two of these values. Exemplary plasticizers in any embodiment disclosed herein may include, but are not limited to, glycerin, polyethylene oxide, or a combination thereof.

[0034] In any embodiment disclosed herein, each bio-resorbable film sheet may independently further include one or more of functional agents. Exemplary functional agents may include, but are not limited to, antimicrobial agents, growth factors, peptides, antioxidants, or combinations of any two or more thereof. Exemplary antimicrobial agent(s) may include a penicillin, a streptomycin, a silver compound (such as ionic silver or a source for ionic silver), chloihexidine, a poly(hexamethylene biguanide) (PHMB), iodine, or a combination of any two or more thereof.

[0035] In any embodiment disclosed herein, each bio-resorbable film sheet may independently include one or more growth factors. Exemplary growth factors in each bio-resorbable film sheet may independently include, but are not limited to, one or more of fibroblast growth factors (FGFs), insulinlike growth factor (IGF), keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), transforming growth factor β (ΤGFβ), epidermal growth factor (EGF), hepatocyte growth factor (HGF), or platelet-derived growth factor (PDGF). Additionally or alternatively, in some embodiments, the fibroblast growth factors comprise one or more of fibroblast growth factor 1 (FGF1), fibroblast growth factor 2 (FGF2), fibroblast growth factor 3 (FGF3), fibroblast growth factor 4 (FGF4), fibroblast growth factor 5 (FGFS), fibroblast growth factor 6 (FGF6), fibroblast growth factor 7 / keratinocyte growth factor (FGF7/KGF), fibroblast growth factor 8 (FGFS), fibroblast growth factor 9 (FGF9), fibroblast growth factor 10 / keratinocyte growth factor 2 (FGF10/KGF2), fibroblast growth factor 11 (FGF11), fibroblast growth factor 12 (FGF12), fibroblast growth factor 13 (FGF13), fibroblast growth factor 14 (FGF14), fibroblast growth factor 15 (FGF15), fibroblast growth factor 16 (FGF16), fibroblast growth factor 17 (FGF17), fibroblast growth factor 18 (FGF18), fibroblast growth factor 19 (FGF19), fibroblast growth factor 20 (FGF20), fibroblast growth factor 21 (FGF21), fibroblast growth factor 22 (FGF22), fibroblast growth factor 23 (FGF23), or any combination thereof. [0036] In any embodiment disclosed herein, each bio-resorbable film sheet may independently include one or more peptides; for example, in any embodiment disclosed herein, the one or more peptides may include defensins, histatins, cathelicidin LL-37, or any combination of two or more thereof.

[0037] In any embodiment disclosed herein, each bio-resoibable film sheet may independently include one or more antioxidants. Exemplary antioxidants include, but are not limited to, anthocyanins, astaxanthin, bilirubin, canthaxanthin, capsaicin, curcumin, coenzyme Q10, eugenol, flavanol, flavonolignans, flavanone, flavone, flavonol, iodide, isoflavone phytoestrogen, lutein, lycopene, manganese, melatonin, N-acetylcysteine, oxalic acid, phenolic acid, phytic acid, R -α-lipoic acid, stilbenoid, tocopherol, tocotrienol, vitamin A, vitamin C, vitamin E, xanthones, zeaxanthin, α- carotene, β-carotene, as well as a combination of any two or more thereof.

[0038] In any embodiment disclosed herein, each bio-resorbable film sheet may independently include about 0.001 wt.% to about 5 wt.% of functional agents. Thus, the total amount of functional agents in each bio-resorbable film sheet may independently be about 0.001 wt.%, about 0.002 wt.%, about 0.003 wt.%, about 0.004 wt.%, about 0.005 wt.%, about 0.006 wt.%, about 0.007 wt.%, about 0.008 wt.%, about 0.009 wt.%, about 0.01 wt.%, about 0.02 wt.%, about 0.03 wt.%, about 0.04 wt.%, about 0.05 wt.%, about 0.06 wt.%, about 0.07 wt.%, about 0.08 wt.%, about 0.09 wt.%, about 0.1 wt.%, about 0.2 wt.%, about 0.3 wt.%, about 0.4 wt.%, about 0.5 wt.%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, about 1 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, or any range including and/or in between any two of these values.

[0039] For example, when a bio-resorbable film sheet includes a silver compound, it may include about 0.1 wt.% to about 3 wt.% of the silver compound. Thus, the silver compound may be included in a bio-resorbable film sheet in an amount (by weight of the bio-resorbable film sheet) of about 0.1 wt.%, about 0.11 wt.%, about 0.12 wt.%, about 0.13 wt.%, about 0.14 wt.%, about 0.15 wt.%, about 0.16 wt.%, about 0.17 wt.%, about 0.18 wt.%, about 0.19 wt.%, about 0.2 wt.%, about 0.22 wt.%, about 0.24 wt.%, about 0.26 wt.%, about 0.28 wt.%, about 0.3 wt.%, about 0.32 wt.%, about 0.34 wt.%, about 0.36 wt.%, about 0.38 wt.%, about 0.4 wt.%, about 0.42 wt.%, about 0.44 wt.%, about 0.46 wt.%, about 0.48 wt.%, about 0.50 wt.%, about 0.52 wt.%, about 0.54 wt.%, about 0.56 wt.%, about 0.58 wt.%, about 0.6 wt.%, about 0.62 wt.%, about 0.64 wt.%, about 0.66 wt.%, about 0.68 wt.%, about 0.7 wt.%, about 0.72 wt.%, about 0.74 wt.%, about 0.76 wt.%, about 0.78 wt.%, about 0.8 wt.%, about 0.82 wt.%, about 0.84 wt.%, about 0.86 wt.%, about 0.88 wt.%, about 0.9 wt.%, about 0.92 wt.%, about 0.94 wt.%, about 0.96 wt.%, about 0.98 wt.%, about 1 wt.%, about 1.1 wt.%, about 1.15 wt.%, about 1.2 wt.%, about 1.25 wt.%, about 1.3 wt.%, about 1.35 wt.%, about 1.4 wt.%, about 1.45 wt.%, about 1.5 wt.%, about 1.55 wt.%, about 1.6 wt.%, about 1.65 wt.%, about 1.7 wt.%, about 1.75 wt.%, about 1.8 wt.%, about 1.85 wt.%, about 1.9 wt.%, about 1.95 wt.%, about 2 wt.%, about 2.05 wt.%, about 2.1 wt.%, about 2.15 wt.%, about 2.2 wt.%, about 2.25 wt.%, about 2.3 wt.%, about 2.35 wt.%, about 2.4 wt.%, about 2.45 wt.%, about 2.5 wt.%, about 2.55 wt.%, about 2.6 wt.%, about 2.65 wt.%, about 2.7 wt.%, about 2.75 wt.%, about 2.8 wt.%, about 2.85 wt.%, about 2.9 wt.%, about 2.95 wt.%, about 3 wt.%, or any range including and/or in between any two of the preceding values.

[0040] In any embodiment disclosed herein, the silver compound may be one or more pharmaceutically acceptable salts. Additionally or alternatively, in some embodiments, the one or more pharmaceutically acceptable silver salts may include, but are not limited to, silver oxide, silver chromate, silver allantoinate, silver borate, silver glycerolate, silver nitrate, silver acetate, silver chloride, silver sulfate, silver lactate, silver bromide, silver iodide, silver carbonate, silver citrate, silver laurate, silver deoxycholate, silver salicylate, silver />-aminobenzoate, silver /7-aminosalicylate, nanocrystalline silver, any pharmaceutically acceptable salt thereof, a silver oxysalt (e.g., Ag_?NOn), or a combination of any two or more thereof.

[0041] In any embodiment disclosed herein, each bio-resorbable film sheet may independently further include one or more of an oxidized cellulose, an oxidized regenerated cellulose (ORC), a polysaccharide, elastin, fibronectin, fibrin, laminin, a chitosan, hyaluronic acid, or a combination of any two or more thereof. In any embodiment disclosed herein, each bio-resorbable film sheet may independently include elastin.

[0042] In any embodiment disclosed herein, each bio-resorbable film sheet may independently include collagen and ORC. ORC may be produced by the oxidation of cellulose, for example with dinitrogen tetroxide and/or as described in U.S. Pat. No. 3,122,479 (incorporated herein by reference). Not intending to be bound by theory, it is believed that this process may convert primary alcohol groups on the saccharide residues of the cellulose to carboxylic acid groups, for example, forming uronic acid residues within the cellulose chain. The oxidation may not proceed with complete selectivity, and as a result hydroxyl groups on carbons 2 and 3 of the saccharide residue may be converted to the keto form. These ketone units may introduce an alkali labile link, which at pH 7 or higher initiates the decomposition of the polymer via formation of a lactone and sugar ring cleavage. As a result, oxidized regenerated cellulose is biodegradable and bioresorbable under physiological conditions. ORC is available with a variety of degrees of oxidation and hence rates of degradation. The ORC may include particles, fibers, or both; in any embodiment disclosed herein, the ORC may be in the form of particles, such as fiber particles or powder particles. In embodiments that include ORC fibers, the ORC fibers may have a volume fraction such that at least 80% of the fibers have lengths in the range from about 5 pm to about 1000 pm, or from about 250 pm to about 450 pm.

[0043] The bio-resorbable film sheet of any embodiment herein may include about 0.01 wt.% to about 70 wt.% ORC with a weight-average molecular weight of about 50,000 to about 1,000,000. Thus, the ORC of any embodiment disclosed herein may be included in an amount of about 30 wt.%, about 32 wt.%, about 34 wt.%, about 36 wt.%, about 38 wt.%, about 40 wt.%, about 42 wt.%, about 44 wt.%, about 46 wt.%, about 48 wt.%, about 50 wt.%, about 52 wt.%, about 54 wt.%, about 56 wt.%, about 58 wt.%, about 60 wt.%, about 62 wt.%, about 64 wt.%, about 66 wt.%, about 68 wt.%, about 70 wt.%, or any range including and/or in between any two of these values. The ORC may have a weight-average molecular weight of about 50,000, about 100,000, about 150,000, about 200,000, about 250,000, about 300,000, about 350,000, about 400,000, about 450,000, about 500,000, about 550,000, about 600,000, about 650,000, about 700,000, about 750,000, about 800,000, about 850,000, about 900,000, about 950,000, about 1,000,000, or any range including and/or in between any two of these values.

[0044] In any embodiment herein including collagen along with ORC in the bio-resoibable film sheet, a weight ratio of collagen to ORC may be about 60:40 to about 40:60 in bio-resoibable film sheet. The weight ratio of collagen to ORC may be about 60:40, about 59:41, about 58:42, about 57:43, about 56:44, about 55:45, about 54:46, about 53:47, about 52:48, about 51:49, about 50:50, about 49:51, about 48:52, about 47:53, about 46:54, about 45:55, about 44:56, about 43:57, about 42:58, about 41:59, about 40:60, or any range including and/or in between any two of these values.

[0045] In any embodiment herein, each bio-resoibable film sheet may independently further include an outer coating that may include an ORC, an antimicrobial agent, or a combination thereof. Additionally or alternatively, in some embodiments, the outer coating of each bio-resorbable film sheet may independently include one or more of the functional agents as disclosed herein in any embodiment.

[0046] In any embodiment herein, the bio-resorbable sheet may further include powders, porous matrices, or combinations thereof. Such powders in any embodiment herein, fbr example, may include freeze-dried collagen/ORC in powder form. Such porous matrix materials may include a freeze -dried collagen/ORC matrix.

The Wound Filler

[0047] As provided previously, the present technology provides a wound filler that includes two or more bio-resorbable film sheets adjoined in a manifold configuration. Each bio-resorbable film sheet may independently have a corrugated shape. As described herein, a “corrugated shape” refers to a wave -shaped patter of the bio-resorbable film sheets, where the arches of the wave -shaped patter are referred to as flutes. In any embodiment disclosed herein, the corrugated shape of each bioresorbable film sheet may independently include a plurality of flutes. In any embodiment disclosed herein, the plurality of flutes of the two or more bio-resorbable film sheets may be adjoined to form the manifold configuration of the wound filler (see, e.g., FIG. 1). The wound filler may include two or more bio-resorbable film sheets adjoined as disclosed herein in any embodiment. For example, in any embodiment disclosed herein, the wound filler may include 2 to about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, or any range including and/or in between any two of these values of bioresorbable film sheets.

[0048] In any embodiment disclosed herein, the wound filler of the present technology may include one or more open channels. The bio-resorbable film sheets are adjoined such that the flutes of the corrugated shape of the bio-resorbable film sheets forms the open channels (see, e.g., FIG. 2). In any embodiment disclosed herein, the bio-resorbable film sheets are vertically aligned to form the open channels. In any embodiment disclosed herein, the open channels of the wound filler may facilitate communication of forces (e.g. , vacuum, pressure, etc.) applied to a wound. In any embodiment disclosed herein, the open channels of the wound filler may allow for lateral or vertical communication of forces. Additional or alternatively, in any embodiment disclosed herein, the open channels may allow flee flow of fluids, such as wound fluid. Without being bound by theory, it is believed that the manifold design provides structural support to the wound filler such that the wound filler maintains its structural integrity during treatment of deep wounds. The geometry of each channel and the number of channels may vary depending on the desired use of the wound filler. For example, the channels may be sized such that, together, the channels produce lateral and/or vertical communication of forces or fluid flow.

[0049] In any embodiment disclosed herein, the wound filler of the present technology may be in any shape; for example, the wound filler may be shaped and sized for use in treating large area and/or deep wounds. In any embodiment disclosed herein, the wound filler may be in in a shape of a wafer, a mat, or other suitable three-dimensional (3D) shape.

[0050] In any embodiment disclosed herein, the depth of the wound filler of the present technology may be about 1 mm to about 10 mm. Thus, the width and/or height of the wound filler may be about 1.0 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2.0 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, about 2.5 mm, about 2.6 mm, about 2.7 mm, about 2.8 mm, about 2.9 mm, about 3.0 mm, about 3.2 mm, about 3.4 mm, about 3.6 mm, about 3.8 mm, about 4.0 mm, about 4.2 mm, about 4.4 mm, about 4.6 mm, about 4.8 mm, about 5.0 mm, about 5.5 mm, about 6.0 mm, about 6.5 mm, about 7.0 mm, about 7.5 mm, about 8.0 mm, about 8.5 mm, about 9.0 mm, about 9.5 mm, about 10.0 mm or any range including and/or in between any two of these values. [0051] In any embodiment disclosed herein, the length of the wound filler of the present technology may be about 0.1 in. to about 12 in. Thus, the length of the wound filler may be about 0.1 in., about 0.2 in., about 0.3 in., about 0.4 in., 0.5 in., about 0.6 in., about 0.7 in., about 0.8 in., about 0.9 in., 1 in., about 1.1 in., about 1.2 in., about 1.3 in., about 1.4 in., about 1.5 in., about 1.6 in., about 1.7 in., about 1.8 in., about 1.9 in., about 2.0 in., about 2.2 in., about 2.4 in., about 2.6 in., about 2.8 in., about 3.0 in., about 3.2 in., about 3.4 in., about 3.6 in., about 3.8 in., about 4.0 in., about 4.2 in., about 4.4 in., about 4.6 in., about 4.8 in., about 5.0 in., about 5.5 in., about 6.0 in., about 6.5 in., about 7.0 in., about 7.5 in., about 8.0 in., about 8.5 in., about 9.0 in., about 9.5 in., about 10.0 in., about 11.0 in., about 12.0 in., or any range including and/or in between any two of these values.

[0052] In any embodiment disclosed herein, the height and/or width of the wound filler of the present technology may be about 0.01 in. to about 8 in.. Thus, the height and/or width of the wound filler may be about 0.01 in., about 0.02 in., about 0.03 in., about 0.04 in., 0.05 in., about 0.06 in., about 0.07 in., about 0.08 in., about 0.09 in., 0.1 in., about 0.2 in., about 0.3 in., about 0.4 in., 0.5 in., about 0.6 in., about 0.7 in., about 0.8 in., about 0.9 in., about 1.0 in., about 1.1 in., about 1.2 in., about 1.3 in., about 1.4 in., about 1.5 in., about 1.6 in., about 1.7 in., about 1.8 in., about 1.9 in., about 2.0 in., about 2.1 in., about 2.2 in., about 2.3 in., about 2.4 in., about 2.5 in., about 2.6 in., about 2.7 in., about 2.8 in., about 2.9 in., about 3.0 in., about 3.2 in., about 3.4 in., about 3.6 in., about 3.8 in., about 4.0 in., about 4.2 in., about 4.4 in., about 4.6 in., about 4.8 in., about 5.0 in., about 5.5 in., about 6.0 in., about 6.5 in., about 7.0 in., about 7.5 in., about 8.0 in., or any range including and/or in between any two of these values.

[0053] In any embodiment disclosed herein, the wound filler of the present disclosure may be sterile and packaged in a microorganism-impermeable container.

Neeative-Pressure Therapy

[0054] The wound filler of any embodiment described herein may be employed in therapy in which a wound is treated with reduced pressure. Treatment of a wound with reduced pressure may be commonly referred to as “negative-pressure therapy,” but is also known by other names, including “negative-pressure wound therapy,” “reduced-pressure therapy,” ‘Vacuum therapy,” ‘Vacuum-assisted closure,” and “topical negative-pressure,” for example. Negative-pressure therapy may provide a number of benefits, including migration of epithelial and subcutaneous tissues, improved blood flow, and/or micro-deformation of tissue at a wound site. Together, these benefits may increase development of granulation tissue and reduce healing times.

[0055] Generally, the system may be configured to provide negative-pressure to a wound in accordance with this specification. In any embodiment herein, the system may generally include a negative-pressure supply, and may include or be configured to be coupled to a distribution component. In general, a distribution component may refer to any complementary or ancillary component configured to be fluidly coupled to a negative-pressure supply in a fluid path between a negative-pressure supply and a wound.

[0056] In any embodiment herein, the wound filler may be configured to distribute negative pressure. Additionally or alternatively, the fluid path(s) may be reversed or a secondary fluid path may be provided to facilitate movement of fluid across a wound. Additionally or alternatively, the fluid pathways of the through-holes may be interconnected to improve distribution or collection of fluids.

[0057] The fluid mechanics associated with using a negative-pressure source to reduce pressure in another component or location, such as within a sealed therapeutic environment, can be mathematically complex. However, the basic principles of fluid mechanics applicable to negative- pressure therapy are generally well-known to those skilled in the art. The process of reducing pressure may be described generally and illustratively herein as “delivering,” “distributing,” or “generating” negative pressure, for example.

[0058] In general, a fluid, such as wound fluid (for example, wound exudates and other fluids), flows toward lower pressure along a fluid path. Thus, the term “downstream” typically implies something in a fluid path relatively closer to a source of negative pressure or further away flora a source of positive pressure. Conversely, the term “upstream” implies something relatively further away from a source of negative pressure or closer to a source of positive pressure. This orientation is generally presumed for purposes of describing various features and components herein. However, the fluid path may also be reversed in some applications (such as by substituting a positive-pressure source for a negative-pressure source) and this descriptive convention should not be construed as a limiting convention.

[0059] “Negative pressure” may generally refer to a pressure less than a local ambient pressure, such as the ambient pressure in a local environment external to a sealed therapeutic environment provided by the wound filler. In many cases, the local ambient pressure may also be the atmospheric pressure proximate to or about a wound. Alternatively or additionally, the pressure may be less than a hydrostatic pressure associated with the tissue at the wound. While the amount and nature of negative pressure applied to a wound may vary according to therapeutic requirements, the pressure is generally a low vacuum, also commonly referred to as a rough vacuum, between -5 mm Hg (-667 Pa) and -500 mm Hg (-66.7 kPa), gauge pressure. Common therapeutic ranges are between -50 mm Hg (-6.7 kPa) and -300 mm Hg (-39.9 kPa), gauge pressure. [0060] Additionally or alternatively, in any embodiment herein, a negative-pressure supply may be a reservoir of air at a negative pressure, or may be a manual or electrically-powered device that can reduce the pressure in a sealed volume, such as a vacuum pump, a suction pump, a wall suction port available at many healthcare facilities, or a micro-pump, for example. A negative-pressure supply may be housed within or used in conjunction with other components, such as sensors, processing units, alarm indicators, memory, databases, software, display devices, or user interfaces that further facilitate therapy. A negative-pressure source may be combined with a controller and other components into a therapy unit. A negative-pressure supply may also have one or more supply ports configured to facilitate coupling and de-coupling of the negative-pressure supply to one or more distribution components.

[0061] In any embodiment herein, components may be fluidly coupled to each other to provide a path for transferring fluids (i.e., liquid and/or gas) between the components. For example, components may be fluidly coupled through a fluid conductor, such as a tube. As used herein, the term “fluid conductor” may include a tube, pipe, hose, conduit, or other structure with one or more lumina or open passages adapted to convey a fluid between two ends thereof. Typically, a fluid conductor may be an elongated, cylindrical structure with some flexibility, but the geometry and rigidity may vary. Additionally or alternatively, in any embodiment herein, the negative-pressure source may be operatively coupled to the wound filler via an interface.

Treatment Methods of the Present Technology

[0062] In an aspect, methods for treating a wound in a subject in need thereof are provided, wherein the method includes administering a wound filler of any embodiment disclosed herein to the wound. The wound may be a tunneling wound, a dermal wound, a diabetic wound, an acute wound, a chronic wound, or a combination of any two or more thereof. Exemplary chronic wounds include, but are not limited to, infectious wounds, venous ulcers, decubitus ulcers, or diabetic ulcers. In any embodiment herein, the wound is a tunneling wound. The method may include administering two or more wound fillers to the wound.

[0063] The wound filler may be administered directly to the wound. Any method known to those in the art for administering a wound filler to a tunneling wound, a dermal wound, a diabetic wound, an acute wound, or a chronic wound disclosed herein may be employed. Suitable methods include in vitro or in vivo methods. In vivo methods typically include the administration of one or more wound fillers to a subject in need thereof, suitably a human. When used in vivo for therapy, the one or more wound fillers described herein are administered to the subject in effective amounts (i.e., amounts that have desired therapeutic effect). The dose and dosage regimen will depend upon the state of the wound of the subject and the characteristics of the particular wound filler used. [0064] The effective amount may be determined during pre-clinical trials and clinical trials by methods familiar to physicians and clinicians. An effective amount of one or more wound fillers useful in the methods may be administered to a subject in need thereof by any number of well-known methods for administering wound fillers.

[0065] In any embodiment disclosed herein, the wound fillers may be administered daily for 1 hour or more, for 2 hours or more, for 3 hours or more, for 4 hours or more, for 5 hours or more, for 6 hours or more, or for 12 hours or more. In any embodiment disclosed herein, the wound fillers may be administered one, two, three, four, or five times per day. In any embodiment disclosed herein, the wound fillers may be administered daily for one, two, three, four, or five weeks. In any embodiment disclosed herein, the wound fillers may be administered daily for less than 6 weeks. In any embodiment disclosed herein, the wound fillers may be administered daily for 6 weeks or more. In any embodiment disclosed herein, the wound fillers may be administered daily for 12 weeks or more. In any embodiment disclosed herein, the wound fillers may be administered every day, every other day, every third day, every fourth day, every fifth day, or every sixth day. In any embodiment disclosed herein, the wound fillers may be administered weekly, bi-weekly, tri-weekly, or monthly.

In any embodiment disclosed herein, the wound fillers may be administered for a chronic wound as appropriate.

[0066] In any embodiment herein, the method may include employing the wound filler in the context of a negative-pressure therapy, where the negative-pressure therapy may include positioning the wound filler in and/or proximate to the wound. The negative-pressure therapy may further include sealing the wound filler to tissue surrounding the wound to form a sealed space. For example, the wound filler may be positioned in and/or proximate to the wound and sealed to an attachment surface near the wound, for example, to undamaged epidermis peripheral to a wound.

[0067] The negative-pressure therapy method in any embodiment herein may further include fluidly coupling a negative-pressure source to the sealed space and operating the negative-pressure source to generate a negative pressure in the sealed space. For example, the negative-pressure source may be coupled to the wound filler such that the negative-pressure source may be used to reduce the pressure in the sealed space. For example, negative pressure applied across the wound, for example, via the wound filler may be effective to induce macrostrain and microstrain at the wound site, as well as remove exudates and other fluids from the wound.

Methods of Manufacturing a Wound Filler of the Present Technology

[0068] In a further related aspect, a method of manufacturing a wound filler that includes: fabricating a bio-resorbable film sheet from a slurry that includes collagen and a stiffening agent; removing residual water from the bio-resorbable film sheet; repeating the fabricating and removing steps to form additional bio-resorbable film sheets; forming the bio-resorbable film sheets into a corrugated shape that includes a plurality of flutes; adjoining two or more bio-resorbable film sheets to form a manifold configuration; wherein the wound filler has a modulus of elasticity from about 0.5 MPa to about 5.0 MPa.

[0069] In any embodiment herein, the fabricating may include casting the slurry to form the bioresorbable film sheet. Additionally or alternatively, in some embodiments, fabricating each bioresorbable film sheet may independently include extruding the slurry into a sheet.

[0070] In any embodiment herein, the slurry may have a pH from about 3 to 7. For example, in any embodiment herein, the slurry may have a pH of about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, or any range including and/or in between any two or more of the preceding values. In any embodiment herein, the pH of the slurry may be from about 4.5 to about 5.5.

[0071] In any embodiment herein, the slurry corresponds to the resultant bio-resorbable film sheet. In any embodiment disclosed herein, the slurry may include may include about 0.01 wt.% to about 80 wt.% of collagen based on dry weight of the slurry. Thus, the slurry may include collagen in an amount (based on the total dry weight of the slurry) of about 0.01 wt.%, about 0.1 wt.%, about 1 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 12 wt.%, about 14 wt.%, about 16 wt.%, about 18 wt.%, about 20 wt.%, about 25 wt.%, about 30 wt.%, about 35 wt.%, about 40 wt.%, about 45 wt.%, about 50 wt.%, about 55 wt.%, about 60 wt.%, about 65 wt.%, about 70 wt.%, about 75 wt.%, about 80 wt.%, or any range including and/or in between any two of these values. In any embodiment disclosed herein, the slurry may include from about 10 wt.% to about 50 wt.% of collagen. In any embodiment disclosed herein, the collagen of the slurry may include a mammalian collagen, such as a bovine collagen, a human collagen, or a combination thereof as described herein in any embodiment.

[0072] The collagen included in the slurry of any embodiment herein may have a weight-average molecular weight of about 5,000, about 6,000, about 7,000, about 8,000, about 9,000, about 10,000, about 12,000, about 14,000, about 16,000, about 18,000, about 20,000, about 22,000, about 24,000, about 26,000, about 28,000, about 30,000, about 32,000, about 34,000, about 36,000, about 38,000, about 40,000, about 45,000, about 50,000, about 55,000, about 60,000, about 65,000, about 70,000, about 75,000, about 80,000, about 85,000, about 90,000, about 95,000, about 100,000, or any range including and/or in between any two of these values.

[0073] In any embodiment disclosed herein, the slurry may further include one or more bioabsorbable polymers, plasticizers, cross-linking agents, functional agents, or combinations of two or more thereof. In any embodiment disclosed herein, the one or more stiffening agents may include bioabsorbable polymers, cross-linking agents, or combinations thereof. In any embodiment disclosed herein, the stiffening agent may be a bioabsorbable polymer. Exemplary bioabsorbable polymers may include, but are not limited to, polylactic acid (PLA), gelatin, polyglycolide, polycaprolactone, or a combination of any two or more thereof. In any embodiment disclosed herein, the bioabsorbable polymer may be PLA, gelatin, or a combination thereof. In any embodiment herein, the bioabsorbable polymer may be PLA. In any embodiment disclosed herein, the bioabsorbable polymer may be gelatin.

[0074] In any embodiment disclosed herein, the slurry may include about 1 wt.% to about 20 wt.% of the bioabsorbable polymer. Thus, the total amount of the bioabsorbable polymer in the slurry may be about 1 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, or any range including and/or in between any two of these values based on dry weight of the slurry.

[0075] In any embodiment disclosed herein, the stiffening agent may be a cross-linking agent. Exemplary cross-linking agents may include epichlorhydrin, carbodiimide (e.g., 1 -ethyl-3 -[3- dimethylaminopropyl]carbodiimide), hexamethylene diisocyanate (HMDI), glutaraldehyde, or a combination of any two or more thereof. The slurry may include about 0.01 wt.% to about 10 wt.% of the cross-linking agent based on dry weight of the slurry. Thus, the slurry may include the cross- linking agent (based on the total dry weight of the slurry) of about 0.01 wt.%, about 0.1 wt.%, about 1 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, or any range including and/or in between any two of these values.

[0076] In any embodiment disclosed herein, the slurry may include about 1 wt.% to about 20 wt.% of plasticizers based on the dry weight of the slurry. Thus, the total amount of plasticizers in the slurry may be about 1 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 18 wt.%, about 19 wt.%, about 20 wt.%, or any range including and/or in between any two of these values. Exemplary plasticizers in any embodiment disclosed herein may include, but are not limited to, glycerin, polyethylene oxide, or a combination thereof.

[0077] In any embodiment disclosed herein, the slurry may further include one or more functional agents as disclosed herein in any embodiment. Exemplary functional agents may include, but are not limited to, antimicrobial agents, growth factors, peptides, antioxidants, or combinations of any two or more thereof. In any embodiment disclosed herein, the slurry may include about 0.001 wt.% to about 5 wt.% of functional agents. Thus, the total amount of functional agents in the slurry may be about 0.001 wt.%, about 0.002 wt.%, about 0.003 wt.%, about 0.004 wt.%, about 0.005 wt.%, about 0.006 wt.%, about 0.007 wt.%, about 0.008 wt.%, about 0.009 wt.%, about 0.01 wt.%, about 0.02 wt.%, about 0.03 wt.%, about 0.04 wt.%, about 0.05 wt.%, about 0.06 wt.%, about 0.07 wt.%, about 0.08 wt.%, about 0.09 wt.%, about 0.1 wt.%, about 0.2 wt.%, about 0.3 wt.%, about 0.4 wt.%, about 0.5 wt.%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, about 1 wt.%, about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, or any range including and/or in between any two of these values.

[0078] In any embodiment disclosed herein, the slurry may further include one or more of an oxidized cellulose, an oxidized regenerated cellulose (ORC), a polysaccharide, elastin, fibronectin, fibrin, laminin, a chitosan, hyaluronic acid, or a combination of any two or more thereof. In any embodiment disclosed herein, the slurry may include elastin.

[0079] In any embodiment disclosed herein, the slurry may include collagen and ORC. As discussed above, the slurry may include ORC as described herein in any embodiment. The slurry of any embodiment herein may include about 30 wt.% to about 70 wt.% ORC with a weight-average molecular weight of about 50,000 to about 1,000,000. Thus, the ORC of any embodiment disclosed herein may be included in an amount of about 30 wt.%, about 32 wt.%, about 34 wt.%, about 36 wt.%, about 38 wt.%, about 40 wt.%, about 42 wt.%, about 44 wt.%, about 46 wt.%, about 48 wt.%, about 50 wt.%, about 52 wt.%, about 54 wt.%, about 56 wt.%, about 58 wt.%, about 60 wt.%, about 62 wt.%, about 64 wt.%, about 66 wt.%, about 68 wt.%, about 70 wt.%, or any range including and/or in between any two of these values. The ORC may have a weight-average molecular weight of about 50,000, about 100,000, about 150,000, about 200,000, about 250,000, about 300,000, about 350,000, about 400,000, about 450,000, about 500,000, about 550,000, about 600,000, about 650,000, about 700,000, about 750,000, about 800,000, about 850,000, about 900,000, about 950,000, about 1,000,000, or any range including and/or in between any two of these values.

[0080] In any embodiment herein including collagen along with ORC in the slurry, a weight ratio of collagen to ORC may be about 60:40 to about 40:60 in the first slurry and/or the second slurry. The weight ratio of the one or more of collagen and chitosan to ORC may be about 60:40, about 59:41, about 58:42, about 57:43, about 56:44, about 55:45, about 54:46, about 53:47, about 52:48, about 51:49, about 50:50, about 49:51, about 48:52, about 47:53, about 46:54, about 45:55, about 44:56, about 43:57, about 42:58, about 41:59, about 40:60, or any range including and/or in between any two of these values.

[0081] Following fabrication of bio-resorbable film sheet, the method includes removing residual water from the bio-resorbable film sheet. For example, in any embodiment herein, removing the residual water may include air drying, freeze drying, vacuum drying, heating, or filter-pressing the bio-resorbable film sheets. In any embodiment herein, each bio-resorbable film sheet may independently retain 0% to about 5% of residual moisture. Suitable amounts of residual moisture may include, but are not limited to, about 0.05%, about 0.1%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, or any range including and/or in between any two of the preceding values.

[0082] In any embodiment disclosed herein, Sinning the bio-resorbable film sheets into a corrugated shape may include extruding the bio-resoibable sheet in to the corrugated shape; for example, in any embodiment herein, each bio-resorbable film sheet may independently be extruded using corrugated rollers. In any embodiment disclosed herein, the corrugated shape of each bio-resorbable film sheet may independently include a plurality of flutes as disclosed herein.

[0083] In any embodiment disclosed herein, adjoining the two or more bio-resorbable film sheets may include lamination (e.g., hot lamination). For example, in any embodiment disclosed herein, the two or more bio-resorbable film sheets are adjoined (i.e., bound) vertically along the flutes of the bioresorbable film sheets’ corrugated shape. Upon adjoining the two or more bio-resorbable film sheets, the adjoined flutes form a manifold configuration that include open channels.

[0084] In any embodiment disclosed herein, the method may further include applying a coating to the bio-resorbable film sheet. As previously provided, the coating as disclosed herein in any embodiment may include ORC, antimicrobial agents, or a combination thereof. For example, in any embodiment herein, the applying may include coating techniques known in the art (e.g., curtain or spray techniques).

[0085] In a related aspect, the present disclosure provides a wound filler prepared according to the method of manufacturing said wound filler as described herein in any embodiment.

Kits Comprising the Wound Filler of the Present Technology

[0086] In a further related aspect, the present disclosure provides kits that include a wound filler of any embodiment disclosed herein and instructions for use. The kits of the present technology may also include methods for treating a wound in a subject in need thereof. The kit may optionally comprise components such as antiseptic wipes, ointment, adhesive tape, tweezers, scissors, etc.

EQUIVALENTS

[0087] While certain embodiments have been illustrated and described, a person with ordinary skill in the art, after reading the foregoing specification, can effect changes, substitutions of equivalents and other types of alterations to the compositions, systems, and methods of the present technology. Each aspect and embodiment described above can also have included or incorporated therewith such variations or aspects as disclosed in regard to any or all of the other aspects and embodiments.

[0088] The present technology is also not to be limited in terms of the particular aspects and embodiments described herein, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that this present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Thus, it is intended that the specification be considered as exemplary only with the breadth, scope and spirit of the present technology indicated only by the appended claims, definitions therein and any equivalents thereof.

[0089] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.

[0090] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the present disclosure. This includes the generic description of the present disclosure with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. [0091] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0092] All publications, patent plications, issued patents, and other documents (for example, journals, articles and/or textbooks) referred to in this specification are herein incorporated by reference as if each individual publication, patent plication, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety to the extent they are not inconsistent with the explicit teachings of this specification. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

[0093] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

Claims

What is claimed is:

1. A wound filler comprising two or more bio-resorbable film sheets adjoined in a manifold configuration; wherein: each bio-resorbable film sheet independently comprises collagen and one or more stiffening agents; and the wound filler exhibits a modulus of elasticity of about 0.5 MPa to about 5.0 MPa.

2. The wound filler of claim 1, wherein the wound filler exhibits a modulus of elasticity of about 1.0 MPa to about 2.5 MPa

3. The wound filler of claim 1 or claim 2, wherein each bio-resoibable film sheet independently comprises about 0.01 weight percent (“wt.%”) to about 80 wt.% of collagen based on the weight of the bio-resoibable film sheet.

4. The wound filler of any one of claims 1-3, wherein each bio-resorbable film sheet independently comprises about 10 wt.% to about 50 wt.% of collagen based on the weight of the bio-resorbable film sheet.

5. The wound filler of any one of claims 1-4, wherein the one or more stiffening agents comprise bioabsoibable polymers, cross-linking agents, or combinations thereof.

6. The wound filler of any one of claims 1-5, wherein the bioabsoibable polymers comprise polylactic acid (PLA), gelatin, polyglycolide, polycaprolactone, or a combination of any two or more thereof.

7. The wound filler of any one of claims 1-6, wherein the bioabsoibable polymer comprises PLA, gelatin, or a combination thereof.

8. The wound filler of any one of claims 1-7, wherein the bioabsoibable polymer comprises PLA.

9. The wound filler of any one of claims 1-8, wherein the bioabsoibable polymer comprises gelatin.

10. The wound filler of any one of claims 1-9, wherein each bio-resorbable film sheet independently comprises from about 1 wt.% to about 20 wt.% bioabsoibable polymer based on weight of the bio-resoibable film sheet.

11. The wound filler of any one of claims 1-10, wherein the cross-linking agent comprises epichlorhydrin, carbodiimide, hexamethylene diisocyanate (HMDI), glutaraldehyde, or a combination of any two or more thereof.

12. The wound filler of any one of claims 1-11, wherein each bio-resorbable film sheet independently comprises about 0.01 wt.% to about 10 wt.% cross-linking agent based on the weight of the bio-resorbable film sheet.

13. The wound filler of any one of claims 1-12, wherein each bio-resorbable film sheet independently further comprises about 1 wt.% to about 20 wt.% of one or more plasticizers based on weight of the bio-resorbable film sheet.

14. The wound filler of claim 13, wherein the one or more plasticizers are selected from glycerin, polyethylene oxide, or combinations thereof.

15. The wound filler of any one of claims 1-14, wherein each bio-resorbable film sheet independently further comprises one or more functional agents selected from the group consisting of antimicrobial agents, growth factors, peptides, and antioxidants, or combinations of any two or more thereof.

16. The wound filler of any one of claims 1-15, wherein each bio-resorbable film sheet independently comprises a silver compound.

17. The wound filler of any one of claims 1-16, wherein each bio-resorbable film sheet independently further comprises one or more selected from the group consisting of an oxidized cellulose, an oxidized regenerated cellulose (ORC), a polysaccharide, elastin, fibronectin, fibrin, laminin, a chitosan, and hyaluronic acid, or a combination of any two or more thereof.

18. The wound filler of any one of claims 1-17, wherein each bio-resorbable film sheet independently comprises collagen and ORC.

19. The wound filler of any one of claims 1-18, wherein each bio-resorbable film sheet independently comprises collagen and ORC in a weight ratio of collagen to ORC of about 60:40 to about 40:60.

20. The wound filler of any one of claims 1-19, wherein each bio-resorbable film sheet independently further comprises a coating comprising an ORC, an antimicrobial agent, or a combination thereof.

21. The wound filler of any one of claims 1-20, wherein each bio-resorbable film sheet independently has a corrugated shape comprising a plurality of flutes.

22. The wound filler of claim 21, wherein the flutes of the two or more bio-resorbable film sheets are adjoined to form the manifold configuration of the wound filler.

23. The wound filler of any one of claims 1-22, wherein the wound filler comprises open channels.

24. The wound filler of any one of claims 1-23, wherein the two or more bio-resorbable film sheets are vertically aligned.

25. The wound filler of any one of claims 1-24, wherein the wound filler is in a shape of a wafer, a mat, or other suitable three-dimensional (3D) shape.

26. The wound filler of any one of claims 1-25, wherein the wound filler has a length of about 0.1 in. to about 12 in.

27. The wound filler of any one of claims 1-26, wherein the wound filler has a length of about 4 in. to about 8 in.

28. The wound filler of any one of claims 1-27, wherein the wound filler has a width and/or height of about 0.01 in. to about 8 in.

29. The wound filler of any one of claims 1-28, wherein the wound filler has a depth of about 1 mm to about 10 mm.

30. A method for treating a wound in a subject in need thereof, the method comprising administering to the wound a wound filler of any one of claims 1-29.

31. The method of claim 30, wherein the wound is selected from the group consisting of a tunneling wound, a dermal wound, a diabetic wound, an acute wound, and a chronic wound, or a combination of any two or more thereof.

32. The method of claim 30 or claim 31, wherein the wound is a tunneling wound.

33. The method of any one of claims 30-32, wherein the wound filler is administered directly to the wound.

34. The method of any one of claims 30-33, further comprising providing negative pressure to the wound.

35. A method of manufacturing a wound filler comprising: fabricating a bio-resorbable film sheet from a slurry comprising collagen and a stiffening agent; removing residual water from the bio-resorbable film sheet; repeating the fabricating and removing steps to form additional bio-resorbable film sheets; forming the bio-resorbable film sheets into a corrugated shape; adjoining two or more bio-resorbable film sheets to form a manifold configuration; wherein the wound filler has a modulus of elasticity from about 0.5 MPa to about 5.0 MPa.

36. The method of claim 35, wherein the slurry comprises about 0.01 wt.% to about 80 wt.% of collagen based on dry weight of the slurry.

37. The method of claim 35 or claim 36, wherein the slurry comprises about 10 wt.% to about 50 wt.% of collagen based on dry weight of the slurry.

38. The method of any one of claims 35-37, wherein the one or more stiffening agents comprise bioabsorbable polymers, cross-linking agents, or combinations thereof.

39. The method of any one of claims 35-38, wherein the bioabsorbable polymers comprise PLA, gelatin, polyglycolide, polycaprolactone , or a combination of any two or more thereof.

40. The method of any one of claims 35-39, wherein the bioabsorbable polymer comprises PLA, gelatin, or a combination thereof.

41. The method of any one of claims 35-40, wherein the slurry comprises from about 1 wt.% to about 20 wt.% of the bioabsorbable polymer based on dry weight of the slurry.

42. The method of any one of claims 35-41, wherein the cross-linlring agent comprises epichlorhydrin, catbodiimide, hexamethylene diisocyanate (HMDI), glutaraldehyde, or a combination of any two or more thereof.

43. The method of any one of claims 35-42, wherein the slurry comprises about 0.01 wt.% to about 10 wt.% of the cross-linking agent based on dry weight of the slurry.

44. The method of any one of claims 35-43, wherein the slurry further comprises about 1 wt.% to about 20 wt.% of one or more plasticizers based on dry weight of the slurry.

45. The method of claim 44, wherein the one or more plasticizers are selected from glycerin, polyethylene oxide, or combinations thereof.

46. The method of any one of claims 35-45, wherein the slurry further comprises one or more functional agent selected from the group consisting of antimicrobial agents, growth factors, peptides, and antioxidants, or combinations of any two or more thereof.

47. The method of any one of claims 35-46, wherein the slurry comprises about 0.001 wt.% to about 5 wt.% of functional agents based on dry weight of the slurry.

48. The method of any one of claims 35-47, wherein the slurry further comprises one or more selected from the group consisting of an oxidized cellulose, an oxidized regenerated cellulose (ORC), a polysaccharide, elastin, fibronectin, fibrin, laminin, a chitosan, and hyaluronic acid, or a combination of any two or more thereof.

49. The method of any one of claims 35-48, wherein the slurry comprises collagen and ORC.

50. The method of any one of claims 35-49, wherein the slurry comprises collagen and ORC in a weight ratio of collagen to ORC of about 60:40 to about 40:60.

51. The method of any one of claims 35-50 further comprising degassing the slurry.

52. The method of any one of claims 35-51, wherein the degassing is performed under vacuum pressure.

53. The method of any one of claims 35-52, further comprising cross-linking the bio-resorbable film sheet.

54. The method of any one of claims 35-53, wherein removing residual water from the bioresorbable film sheet comprises air drying, freeze drying, vacuum drying, heating, or filter- pressing the bio-resorbable film sheets.

55. The method of any one of claims 35-54, wherein forming the bio-resorbable film sheets comprises extruding the bio-resorbable film sheet.

56. The method of any one of claims 35-55, wherein adjoining two or more bio-resorbable film sheets comprises laminating the bio-resorbable film sheets.

57. A wound filler prepared according to the method of any one of claims 35-56.

58. A kit comprising the wound filler of any one of claims 1-29; and instructions for use.

59. The kit of claim 56, wherein the instructions for use comprising instructions for a method according to any one of claims 30-34.

60. A kit comprising the wound filler of claim 57; and instructions for use.

61. The kit of claim 60, wherein the instructions for use comprising instructions for a method according to any one of claims 30-34.