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WO1991007951A1 - Composition de revêtement a base d'alginate comprenant de l'acide guluronique homologue destinee a etre appliquee et implantee in vivo et procede d'utilisation - Google Patents

Composition de revêtement a base d'alginate comprenant de l'acide guluronique homologue destinee a etre appliquee et implantee in vivo et procede d'utilisation Download PDF

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Publication number
WO1991007951A1
WO1991007951A1 PCT/US1990/007108 US9007108W WO9107951A1 WO 1991007951 A1 WO1991007951 A1 WO 1991007951A1 US 9007108 W US9007108 W US 9007108W WO 9107951 A1 WO9107951 A1 WO 9107951A1
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WO
WIPO (PCT)
Prior art keywords
alginate
guluronic acid
composition
barrier
acid
Prior art date
Application number
PCT/US1990/007108
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English (en)
Inventor
Gudmund Skjak-Braek
Olav Smidsrod
Terje Espevik
Marit Otterlei
Patrick Soon-Shiong
Original Assignee
Trancel Corporation
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Filing date
Publication date
Application filed by Trancel Corporation filed Critical Trancel Corporation
Publication of WO1991007951A1 publication Critical patent/WO1991007951A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/04—Alginic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
    • C12N11/02—Enzymes or microbial cells immobilised on or in an organic carrier
    • C12N11/04—Enzymes or microbial cells immobilised on or in an organic carrier entrapped within the carrier, e.g. gel or hollow fibres

Definitions

  • This invention relates to the fields of polymer chemistry, immunology and transplantation, and more particularly to the field of materials for use in conjunction with transplantation and implantation of foreign cells and biological materials.
  • Microencapsulation is a process in which small, discrete materials, viable biological tissue or cells, liquid droplets, or gases are completely enveloped by an intact membrane which is preferably compatible with the biological system in which it is placed.
  • the function of the microcapsule membrane is to protect the material within from immunological recognition by the host and to control the flow of materials inside and outside the microcapsule across the membrane.
  • islet cells In addition to islet cells, other materials such as tissue, charcoal, microbial cells, yeasts, chloroplasts, plant protoplasts, mitochondria and enzymes have been immobilized and entrapped using microencapsulation techniques. Attempts have been made to transplant such encapsulated material into a patient to perform the specific function of that material inside the recipient patient. For example, activated charcoal could be used to detoxify blood, while pancreatic tissue could supplement the patient's supply of insulin. See, e.g.. Lim and Sun (1980) Science 210, 908; O'Shea, et al. (1984) Bio ⁇ him. Biophys. Acta 804. 133.
  • fibroblasts A potential mechanism for the induction of fibroblasts is the activation of macrophages, and the resultant stimulation of cytokines by the capsule substance.
  • Cytokines are molecules secreted by the body in response to a new set of antigens, and are often toxic to the encapsulated cells. Some cytokines in turn stimulate the immune system of the patient. Thus, immune response can still be a limiting factor in the effective life of the encapsulated material.
  • fibroblast cells tend to overgrow the microcapsules, also apparently in response to the newly released cytokines. Dinerallo, in LYMPHOKINES AND THE IMMUNE RESPONSE (Cohen, ed. 1990) CRC Press, p. 156; Piela and Korn, in LYMPHOKINES AND THE IMMUNE RESPONSE (Cohen, ed. 1990) CRC Press, pp. 255-273.
  • This growth of fibroblasts causes the microcapsules to lose their porosity.
  • the cellular material inside the microcapsules cannot receive nutrients and the product of the cellular material cannot permeate the microcapsule wall. This can cause the encapsulated living material to die, and can impair the effectiveness of the microcapsules as a delivery system.
  • Alginate the principal material of the microcapsules, is a heterogeneous group of linear binary copolymers of 1-4 linked 0-D-mannuronic acid (M) and its C-5 epimer ⁇ -L-guluronic acid (G) .
  • the monomers are arranged in a blockwise pattern along the polymeric chain where homopolymeric regions (M blocks and G blocks) are interspaced with sequences containing both monomers (MG blocks) .
  • the proportion and sequential arrangement of the uronic acids in alginate depend upon the species of algae and the kind of algal tissue from which the material is prepared. Various properties of different types of alginates are based upon the guluronic acid makeup of the particular alginate.
  • viscosity depends mainly upon the molecular size, whereas the affinity for divalent ions essential for the gel-forming properties are related to the guluronic acid content. Specifically, two consecutive di-axially linked G residues provide binding sites for calcium ions and long sequences of such sites form cross-links with similar sequences in other alginate molecules, giving rise to gel networks.
  • alginates may be obtained from certain bacteria.
  • Azotobacter vinelandii produces O-acetylated alginate with a content of L-guluronic acid ranging from
  • M residues may be obtained from specific portions of algal tissue.
  • alginate having a high content of guluronic acid may be obtained from the outer cortex of old stipes of L. hyperborea.
  • Alginate having a high content of guluronic acid can also be prepared by chemical fractionation or by enzymatic modification using mannuronan C-5 epimerase. This enzyme is able to introduce G-blocks into an existing alginate polymer, producing polymers with high G-block content.
  • alginate itself is one of the materials of the microcapsules which causes fibrosis, such that attempted implantation or transplantation of alginate encapsulated material is viable only for a short term.
  • a measure of the potential to cause fibrosis can be obtained from the ability of certain substances to induce cytokine production, including tumor necrosis factor- ⁇ (TNF- ⁇ ) , interleukin-1 (IL-1) and interleukin-6 (IL-6) .
  • TNF- ⁇ tumor necrosis factor- ⁇
  • IL-1 interleukin-1
  • IL-6 interleukin-6
  • a possible mechanism for the fibrotic reaction to implanted microcapsules is the activation of macrophages, either by a contaminant within commercial alginate (e.g., polyphenols or lipopolysaccharides (LPS) ) , or by alginate monomers directly, with subsequent release of cytokines responsible for fibroblast migration and proliferation.
  • LPS lipopolysaccharides
  • LPS lipopolysaccharides
  • polysaccharides other than LPS have been reported to have an immunostimulating effect, including antitumor activity and stimulation of monocyte functions. However, little is known about the effects of polysaccharides on cytokine production from monocytes.
  • the present invention provides a successful approach to microencapsulation and implantation which has not heretofore been discovered.
  • TNF tumor necrosis factor
  • the present invention provides a material comprised of alginate, and particularly, alginate comprising primarily guluronic acid, with minimal amounts of mannuronic acid, the material being useful in vivo for implantation and transplantation in mammalian bodies.
  • the material may take many forms, such as sheets, organ capsulation and the like, but is preferably used for microencapsulation of living cells and tissue which are foreign to the host in which they are implanted.
  • the present invention also protects islet cells or other transplanted tissue from immunological cell rejection.
  • the present invention also provides a microencapsulation system which limits fibroblast overgrowth.
  • the present invention also acts to depress production in vivo of cytokines such as TNF, IL-1 and IL-6. As such, it is useful as a pharmaceutical to inhibit the production of these cytokines for such purposes as the treatment of sepsis, immune rejection, and inflammatory response.
  • the present invention relates to encapsulation of cells or other biological material with an outer coating of alginate which is completely or substantially comprised of guluronic acid and is completely or substantially free of mannuronic acid. Additionally, the same alginate can be used in various forms to inhibit cytokine production.
  • FIGURE 1 is a graph showing the induction of TNF by Poly M, heterologous GMGM polymeric and Poly G alginates.
  • FIGURE 2 is a graph showing the dampening effect of induction of TNF by Poly G when combined with Poly M.
  • FIGURE 3 is a graph showing the induction of IL-1 by Poly M, heterologous GMGM polymeric and Poly G alginates.
  • FIGURE 4 is a graph showing the dampening effect of induction of IL-1 by Poly G when combined with Poly M.
  • FIGURE 5 is a graph showing the induction of IL-6 by Poly M, heterologous GMGM polymeric and Poly G alginates.
  • FIGURE 6 is a graph showing the dampening effect of induction of IL-6 by Poly G when combined with Poly M.
  • the present invention comprises material which can be implanted or transplanted in vivo into mammals without inducing any substantial immunogenic reaction or fibroblast formation.
  • One important use for this material is for encapsulation of biological materials, such as in microcapsules.
  • the present invention is also a process for microencapsulating biological cells and other materials for use in implantation or transplantation as a drug or biological material delivery system.
  • biological materials includes prokaryotic and eukaryotic cells which are either naturally occurring or genetically engineered, drugs or pharmaceuticals. enzymes, parts of cells such as mitochondria and protoplasts or any other naturally occurring or synthesized material which may be implanted.
  • the material used in the present invention is alginate comprised substantially of ⁇ -L-guluronic acid (G) which may be referred to herein as guluronic acid.
  • G ⁇ -L-guluronic acid
  • M mannuronic acid
  • Alginate so comprised elicits a very low response from monocytes in the production of tumor necrosis factor (TNF) and of IL-1 and IL-6, which, as a result, does not elicit fibrosis.
  • TNF tumor necrosis factor
  • This high-G alginate is used in the formation of microcapsules for the transplantation or implantation of foreign material into a mammal.
  • the high-G alginate is used in place of at least one layer of polyanionic polymer, such as low-G alginate, in the microcapsule membrane.
  • the high-G alginate can be used as the inner or first layer surrounding the encapsulated material. In some microcapsules this may be the only layer surrounding the encapsulated material.
  • a second layer of polyanionic polymer can be used, either immediately surrounding the gelled first layer, or surrounding a second layer made of a polycationic polymer.
  • the polyanionic polymer layer can be used as the second layer surrounding a first layer made of either a polycationic polymer or a basement membrane.
  • the outermost layer of polyanionic polymer is high-G alginate.
  • Any other layer of polyanionic polymer can also be composed of high-G alginater.
  • Material to be implanted or transplanted is first coated with a negatively charged material such as alginate to form a gel coating therearound, as described above.
  • the cellular material is coated with a tissue basement membrane such as Matrigel (Collaborative
  • the solubilized tissue basement membrane contains proteoglycans, collagen, and laminin and/or intactin.
  • the proteoglycan forms a matrix which permits transfer of selected materials inside and out of the cells.
  • the use of the tissue basement membrane eliminates the need for a gelling and then reliquification of the gel material surrounding the cell.
  • the tissue basement membrane provides both structural elements supporting the cells and also mediates various significant cellular events and cellular functions including proliferation and differentiation.
  • the structural elements of the extracellular matrix of the tissue basement membrane or an equivalent thereof into a microencapsulated bioenvironment, the viability and functionality of the immuno-isolated islet cells is enhanced.
  • the molecular weight of the proteoglycans used as the tissue basement membrane have a molecular weight of 200,000 to 300,000 Daltons.
  • the transplantable material is next coated with a positively charged material such as poly-L-lysine.
  • a positively charged material such as poly-L-lysine.
  • poly-L-lysine as a coating material is well-known in the art and is described in various references referred to above. It has been found, however, that the use of poly-L-lysine having a molecular weight of less than 20,000 is particularly advantageous in that it minimizes the induction of fibroblast formation.
  • a positively charged polysaccharide such as chitosan may be used as the second layer of the coating.
  • the positively charged second layer is coated with a layer of alginate of the present invention comprising high G content, greater than 65% and preferably greater than 85% G residues, as described above.
  • a layer of alginate of the present invention comprising high G content, greater than 65% and preferably greater than 85% G residues, as described above.
  • any minimization of mannuronic acid residues, with the equivalent increase in G residues in the alginate is contemplated by the present invention and will enhance the decrease of fibrosis.
  • the composition comprising alginate having a high G content may be used in the form of organ capsulation, sheets of alginate for implantation, hollow fibers, microcapsules and membranes formed of the subject composition.
  • the present invention comprises the use of Poly G alginate as a coating material for any biological materials which may be implanted or transplanted.
  • the material to be implanted or transplanted can include living tissue, living cells, activated charcoal, or any other material of the appropriate size which is useful when transplanted within immunoisolation systems.
  • Material to be transplanted is preferably chosen for its ability to function in vivo when transplanted into a recipient body.
  • Living cells can include, but are not limited to, islets of Langerhans cells which can produce insulin, hepatic cells or liver tissue, and red blood cells.
  • cells such as islet cells from the Islets of Langerhans may be purified in accordance with co-pending application Serial No.
  • Microcapsules with at least one outer layer composed of high-G alginate were found to elicit the lowest amounts of the various cytokines. See Figures 1-6. As a result, such microcapsules would be the most effective for implantation or transplantation of material into a mammalian body, because they would minimize the immune response by the body to the microcapsules.
  • alginate can be prepared according to methods well known in the art.
  • alginate can be commercialy obtained from numerous outlets including Sigma (St. Louis, MO) and Protan A/S (Drammen, Norway) .
  • Poly G alginate may be obtained from Protan (Norway or Seattle) , or may be obtained by isolation of the material from natural sources or by chemical conversion by methods reported in the literature.
  • Some alginate is relatively high in M residues and must be converted to low M for use in this invention.
  • An example of a procedure which can be used for reducing the level of M in alginate follows.
  • composition of this invention is to inhibit .in vivo production of cytokines such as TNF, IL-1 and IL-6.
  • cytokines such as TNF, IL-1 and IL-6.
  • FIGs 2, 4, and 6 show, the high-G alginate depresses production of both of these cytokines.
  • These cytokines play a role in a number of disease states, including but not limited to inflammatory response, transplant rejection, and sepsis. Therefore, this high- G alginate composition can be administered to treat such disease states.
  • the concentration of high-G alginate useful for such treatment is shown in Figures 2, 4 and 6, Table 1, and described in Examples 5 and 6, below.
  • 1% (w/v) OBDG was added to 1% (w/v) LF 10/60 solution (dissolved in elution buffer consisting of NaHC0 3 pH 8.5), and mixed for 30 min. at room temperature.
  • Equal volumes of the PB-Seph 4B-gel and OBDG/alginate solution were mixed and transferred to- a dialysis bag (MW 12-14000) .
  • the bag was then placed in a container with phosphate buffered saline (PBS) and dialyzed for 48 hours at room temperature. Subsequently, the PB-Seph 4B-gel was removed by centrifugation at 2750 r.p.m., for 10 min. at 4 ⁇ C.
  • PBS phosphate buffered saline
  • Monocytes were isolated from human A+ blood buffy coat (The Bloodbank, University of Trondheim, Norway) as described by Boyum ("Separation of monocytes and lymfocytes.” Scan J Immunol 1976; 5:9). Monocytes in 24 well culture plates (Costar, Cambridge, MA, USA) were cultured in complete medium consisting of RPMI 1640 (Gibco, Paisley, U.K.) with 1% glutamine, 40 mg/ml garamycin and 25% A- serum. (The Bloodbank, University of Trondheim) .
  • the alginate, the M-blocks, the G-blocks and the MG blocks were dissolved in PBS and sterile filtered through 0.2 ⁇ m filter (Nuclepore, Pleasanton, CA, USA). Commercial unfiltered alginate was sterilized by autoclaving.
  • the polysaccharide solutions were diluted in complete medium and added to the monocytes for 16-24 hours before the supernatants were harvested.
  • E. coli (strain 026:06) derived LPS (Sigma) , or b/1-3 D polyglucose (obtained from Professor R. Seljelid, University of Troms ⁇ , Norway) were added to some monocyte cultures.
  • Alginate gels were made in 24-well culture plates (Costar) by adding 0.5 ml 10 mg/ml sterile filtered alginate solution in the wells. Then 1 ml of 0.1 M CaCl 2 was added for 10 min. before the supernatant over the gel was removed. The gels were then washed twice with 1.5 ml saline, and finally twice with complete medium. Human monocytes at a concentration of 0.5 x 10 6 cells/well were added to the alginate gels, and the plate was incubated for 16-24 hours before the supernatants were harvested.
  • TNF- ⁇ was determined by its cytotoxic effect on the fibrosarcoma cell line WEHI 164 clone 13, as described in Espevik et al ("A highly sensitive cell line, WEHI 163 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes.” Immunol Methods 1986; 95:99.) Dilutions of recombinant TNF- ⁇ (r-TNF- ⁇ , Genentech, Inc. South San Francisco) were included as a standard. The TNF- ⁇ specificity of the assay was verified by a monoclonal antibody against rTNF- ⁇ which completely neutralized the recorded activity (data not shown) .
  • IL-1 Assay for Detection of IL-1 in Supernatants From Monocytes Amount of IL-1 was determined by a two stage assay. The first stage involves the mouse thymocyte EL-4 NOB-I cell line which produces high concentrations of IL-2 (interleukin-2) in response to human IL-1, as described by Gaering et al. Dilutions of r-IL-1 (Glaxo, Geneva, Switzerland) were included as standard. After incubation in C0 2 for 24 hours, 100 ml of each of the supernatants were transferred into replicate 96-well microplates. The second stage in this assay involves the IL-2 dependent mouse T cell line HT-2 as described by Mosmann, T.
  • Viability in the assays for TNF- ⁇ , IL-1 and IL-6 was measured in a colorimetric assay for growth and survival by using a tetrazoli ⁇ m salt as described by Mosmann, supra.
  • three separate alginate compositions were tested for their ability to induce monocytes to release TNF.
  • the alginate compositions included Poly G alginate, heterologous GMGM alginate comprising linear binary copolymers of 1-4 linked jS-D-mannuronic acid (M) and its C-5 epimer ⁇ -L-guluronic acid (G) , and Poly M ( / 8-D-mannuronic acid) alginate.
  • FIG. 1 shows that Poly M and GMGM alginate induced substantial TNF production by the monocytes on the order of 7000 to 10,000 picograms of TNF per milliliter, whereas Poly G alginate induced TNF production two orders of magnitude less, or at approximately 200 pg/ml of TNF. TNF is known as an inducer of fibroblast growth.
  • Figure 3 shows the equivalent results with respect to IL-1 production by the monocytes.
  • Figure 5 shows the equivalent results with respect to IL-6 production.
  • FIG. 2 shows the results of an experiment in which Poly M and Poly M plus 1 mg/ml of Poly G was added to a culture of monocytes and the TNF production was measured.
  • the Poly M plus Poly G sample induced substantially lower TNF production than Poly M alone.
  • Figure 4 shows the equivalent results with respect to IL-I production by the monocytes.
  • Figure 6 shows the equivalent results with respect to IL-6 production.
  • Table 1 shows the results of an experiment which demonstrates cytokine release from monocytes cultured on alginate gels.
  • Monocytes on tissue culture plates were detached by a rubber policeman, washed once in Hanks Balanced Salt Solution, and added to culture wells with alginate gel, or culture wells with LPS or growth media. Alginate gels were made as described above. Supernatants were harvested after 16-24 hours and assayed for TNF, IL-6 and IL-1.
  • the monocytes cultured on LF 10/60 which has a 64% G residue content, induced substantially less production of each of TNF, IL-1 and IL-6 compared with A. nodosum alginate gel, which has a G residue content of 46%. LPS also showed a great capacity to induce cytokine production.
  • the gelled droplets were incubated for 6 minutes in 0.05% (w/w) polylysine having a molecular weight of 17,000.
  • the supernatant was decanted and the polylysine capsules were washed with dilute CHES, 1.1% calcium chloride solution and physiological saline.
  • the washed polylysine capsules were incubated for 4 minutes in 30 ml of 0.03% sodium alginate to permit the formation of an outer alginate membrane on the initial polylysine membrane, by ionic interaction between the negatively charged alginate and the positively charged polylysine.
  • the alginate used in the outer and inner coating is poly G alginate produced as described above.
  • microcapsules were washed with saline, 0.05M citrate buffer for 6 minutes to reliquify the inner calcium alginate, and washed again with saline.
  • the microcapsules were found to be perfectly spherical and each to contain from 1 to 2 viable islets.
  • the microcapsules had diameters of 700 ⁇ 50 ⁇ m and wall thicknesses of about 5 ⁇ m.
  • the microcapsules were suspended in nutrient medium at 37 ⁇ C. It will be obvious to a person of ordinary skill in the art that the present invention is not limited in its application to specific biological materials to be encapsulated, such as the islet cells described in detail above, or by the specifically described other inner layers of microcapsule discussed herein.
  • the subject invention is not limited to only three layer microcapsules, but that two layer capsules may also be employed using the high G content alginate of the present invention, and if desired, the low molecular weight poly-L-lysine (below 20,000 daltons) .
  • the only limitations of the present invention are set forth in the claims appended hereto and any equivalents thereof.

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Abstract

On décrit une composition de greffe ou d'implantation qui entraîne une réponse immunitaire réduite comprenant du matériau ancapsulé à l'intérieur d'une barrière semi-perméable. Au moins la couche la plus externe de la barrière contient de l'alginate comprenant essentiellement de l'acide guluronique α-1 avec des quantités minimes d'acide mannuronique β-D. On décrit également les procédés permettant de fabriquer une telle composition et l'utilisation de celle-ci.
PCT/US1990/007108 1989-12-05 1990-12-04 Composition de revêtement a base d'alginate comprenant de l'acide guluronique homologue destinee a etre appliquee et implantee in vivo et procede d'utilisation WO1991007951A1 (fr)

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US446,462 1989-12-05

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4204012A1 (de) * 1992-02-12 1993-08-19 Ulrich Prof Dr Zimmermann Mitogenfreie substanz, deren herstellung und verwendung
WO1993018649A1 (fr) * 1992-03-23 1993-09-30 Clover Consolidated, Limited Copolymeres greffes du genre polycationique, polymeres solubles dans l'eau et utilisations de ces substances
US5334640A (en) * 1992-04-08 1994-08-02 Clover Consolidated, Ltd. Ionically covalently crosslinked and crosslinkable biocompatible encapsulation compositions and methods
EP0641196A1 (fr) * 1992-05-29 1995-03-08 Vivorx, Incorporated Microencapsulation de cellules
WO1996002285A1 (fr) * 1994-07-15 1996-02-01 E.R. Squibb & Sons Inc. Fibres en alginate, leur production et leur utilisation
WO1996021351A2 (fr) * 1995-01-12 1996-07-18 The Governors Of The University Of Alberta Cryoconservation en masse de matieres biologiques et utilisation de matieres biologiques a cryoconservation et encapsulees
JPH08507747A (ja) * 1992-12-30 1996-08-20 クローバー コンソリデイテッド，リミテッド 生物学的活性物質用の細包を保護し生体に適合する、再利用可能なマクロカプセル封入システム
EP0741550A1 (fr) * 1994-01-24 1996-11-13 The Regents Of The University Of California Revetements multicouche d'alginate pour tissus biologiques de transplantation
US5639275A (en) * 1993-08-12 1997-06-17 Cytotherapeutics, Inc. Delivery of biologically active molecules using cells contained in biocompatible immunoisolatory capsules
US5738876A (en) * 1995-03-03 1998-04-14 Metabolex, Inc. Method of solution overcoating with gelling polymer
US5798113A (en) * 1991-04-25 1998-08-25 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
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WO1998047948A1 (fr) * 1997-04-18 1998-10-29 California Institute Of Technology Recouvrement de tissu en polymere multifonctionnel
US5840777A (en) * 1992-06-19 1998-11-24 Albany International Corp. Method of producing polysaccharide foams
US5876742A (en) * 1994-01-24 1999-03-02 The Regents Of The University Of California Biological tissue transplant coated with stabilized multilayer alginate coating suitable for transplantation and method of preparation thereof
US5908623A (en) * 1993-08-12 1999-06-01 Cytotherapeutics, Inc. Compositions and methods for the delivery of biologically active molecules using genetically altered cells contained in biocompatible immunoisolatory capsules
US5916790A (en) * 1995-03-03 1999-06-29 Metabolex, Inc. Encapsulation compositions, and methods
WO2000022105A1 (fr) * 1998-10-13 2000-04-20 Yissum Research Development Company Of The Hebrew University Of Jerusalem Revetement hydrocolloide de cellules
FR2793693A3 (fr) * 1999-05-18 2000-11-24 Martine Bulette Prothese vasculaire impregnee par un biopolymere d'origine vegetale ou bacterienne et procede pour la realisation d'une telle prothese
EP1413298A1 (fr) * 2002-09-24 2004-04-28 Cognis Deutschland GmbH & Co. KG Macrocapsules
WO2006116546A1 (fr) * 2005-04-27 2006-11-02 Baxter International Inc. Microparticules a surface modifiee et procedes de formation et d'utilisation associes
US7964574B2 (en) 2006-08-04 2011-06-21 Baxter International Inc. Microsphere-based composition for preventing and/or reversing new-onset autoimmune diabetes
US8529890B2 (en) 2009-03-23 2013-09-10 Ntnu Technology Transfer As Composition for the administration of polymeric drugs
US8673878B2 (en) 2005-10-06 2014-03-18 Ntnu Technology Transfer As Mucosal treatment
US8841279B2 (en) 2007-04-12 2014-09-23 Norwegian University Of Science And Technology Oligo-guluronate and galacturonate compositions
US8987215B2 (en) 2009-03-23 2015-03-24 Ntnu Technology Transfer As Composition for use in gene therapy
EP3174906A1 (fr) * 2014-08-01 2017-06-07 Massachusetts Institute Of Technology Alginates modifiés pour matériaux anti-fibrotiques et applications associées
US10709818B2 (en) 2015-11-01 2020-07-14 Massachusetts Institute Of Technology Modified alginates for anti-fibrotic materials and applications

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US6322804B1 (en) 1991-04-25 2001-11-27 Neurotech S.A. Implantable biocompatible immunoisolatory vehicle for the delivery of selected therapeutic products
US5800828A (en) * 1991-04-25 1998-09-01 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
US5800829A (en) * 1991-04-25 1998-09-01 Brown University Research Foundation Methods for coextruding immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US5798113A (en) * 1991-04-25 1998-08-25 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
US5874099A (en) * 1991-04-25 1999-02-23 Brown University Research Foundation Methods for making immunoisolatary implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US5871767A (en) * 1991-04-25 1999-02-16 Brown University Research Foundation Methods for treatment or prevention of neurodegenerative conditions using immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core
US6960351B2 (en) 1991-04-25 2005-11-01 Brown University Research Foundation Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products
US6083523A (en) * 1991-04-25 2000-07-04 Brown University Research Foundation Implantable biocompatable immunoisolatory vehicle for delivery of selected therapeutic products
US5869077A (en) * 1991-04-25 1999-02-09 Brown University Research Foundation Methods for treating diabetes by delivering insulin from biocompatible cell-containing devices
DE4204012A1 (de) * 1992-02-12 1993-08-19 Ulrich Prof Dr Zimmermann Mitogenfreie substanz, deren herstellung und verwendung
US5578442A (en) * 1992-03-23 1996-11-26 Vivorx, Inc. Graft copolymers of polycationic species and water-soluble polymers, and use therefor
WO1993018649A1 (fr) * 1992-03-23 1993-09-30 Clover Consolidated, Limited Copolymeres greffes du genre polycationique, polymeres solubles dans l'eau et utilisations de ces substances
US5834556A (en) * 1992-03-23 1998-11-10 Vivorx, Inc. Graft copolymer of polycationic species and water-soluble polymers, and uses therefor
EP0635040A4 (fr) * 1992-04-08 1995-10-04 Vivorx Inc Procedes d'encapsulage et compositions d'encapsulage reticulees biocompatibles.
EP0635040A1 (fr) * 1992-04-08 1995-01-25 Vivorx, Incorporated Procedes d'encapsulage et compositions d'encapsulage reticulees biocompatibles
US5334640A (en) * 1992-04-08 1994-08-02 Clover Consolidated, Ltd. Ionically covalently crosslinked and crosslinkable biocompatible encapsulation compositions and methods
US5578314A (en) * 1992-05-29 1996-11-26 The Regents Of The University Of California Multiple layer alginate coatings of biological tissue for transplantation
EP0641196A4 (fr) * 1992-05-29 1995-05-03 Vivorx Inc Microencapsulation de cellules.
EP0641196A1 (fr) * 1992-05-29 1995-03-08 Vivorx, Incorporated Microencapsulation de cellules
US5840777A (en) * 1992-06-19 1998-11-24 Albany International Corp. Method of producing polysaccharide foams
EP0762874A1 (fr) * 1992-12-30 1997-03-19 Clover Consolidated Ltd Systemes de conditionnement de substances biologiquement actives dans des macrocapsules recuperables, biocompatibles et cytoprotectrices
EP0762874A4 (fr) * 1992-12-30 1997-08-06 Clover Cons Ltd Systemes de conditionnement de substances biologiquement actives dans des macrocapsules recuperables, biocompatibles et cytoprotectrices
JPH08507747A (ja) * 1992-12-30 1996-08-20 クローバー コンソリデイテッド，リミテッド 生物学的活性物質用の細包を保護し生体に適合する、再利用可能なマクロカプセル封入システム
US5639275A (en) * 1993-08-12 1997-06-17 Cytotherapeutics, Inc. Delivery of biologically active molecules using cells contained in biocompatible immunoisolatory capsules
US5908623A (en) * 1993-08-12 1999-06-01 Cytotherapeutics, Inc. Compositions and methods for the delivery of biologically active molecules using genetically altered cells contained in biocompatible immunoisolatory capsules
US6264941B1 (en) 1993-08-12 2001-07-24 Neurotech S.A. Compositions for the delivery of biologically active molecules using genetically altered cells contained in biocompatible immunoisolatory capsules
US5653975A (en) * 1993-08-12 1997-08-05 Cytotherapeutics, Inc. Compositions and methods for the delivery of biologically active molecules using cells contained in biocompatible capsules
US5676943A (en) * 1993-08-12 1997-10-14 Cytotherapeutics, Inc. Compositions and methods for the delivery of biologically active molecules using genetically altered cells contained in biocompatible immunoisolatory capsules
US5656481A (en) * 1993-08-12 1997-08-12 Cyto Therapeutics, Inc. Compositions and methods for the delivery of biologically active molecules using cells contained in biocompatible capsules
US5876742A (en) * 1994-01-24 1999-03-02 The Regents Of The University Of California Biological tissue transplant coated with stabilized multilayer alginate coating suitable for transplantation and method of preparation thereof
EP0741550A4 (fr) * 1994-01-24 1998-09-09 Univ California Revetements multicouche d'alginate pour tissus biologiques de transplantation
EP0741550A1 (fr) * 1994-01-24 1996-11-13 The Regents Of The University Of California Revetements multicouche d'alginate pour tissus biologiques de transplantation
US5874100A (en) * 1994-07-15 1999-02-23 Bristol-Myers Squibb Company Alginate fibres, manufacture and use
WO1996002285A1 (fr) * 1994-07-15 1996-02-01 E.R. Squibb & Sons Inc. Fibres en alginate, leur production et leur utilisation
US5863715A (en) * 1995-01-12 1999-01-26 The Governors Of The University Of Alberta Methods for bulk cryopreservation encapsulated islets
WO1996021351A3 (fr) * 1995-01-12 1996-12-19 Univ Alberta Cryoconservation en masse de matieres biologiques et utilisation de matieres biologiques a cryoconservation et encapsulees
WO1996021351A2 (fr) * 1995-01-12 1996-07-18 The Governors Of The University Of Alberta Cryoconservation en masse de matieres biologiques et utilisation de matieres biologiques a cryoconservation et encapsulees
US5916790A (en) * 1995-03-03 1999-06-29 Metabolex, Inc. Encapsulation compositions, and methods
US6020200A (en) * 1995-03-03 2000-02-01 Metabolex, Inc. Encapsulation compositions and methods
US5738876A (en) * 1995-03-03 1998-04-14 Metabolex, Inc. Method of solution overcoating with gelling polymer
WO1998047948A1 (fr) * 1997-04-18 1998-10-29 California Institute Of Technology Recouvrement de tissu en polymere multifonctionnel
US7316845B2 (en) 1997-04-21 2008-01-08 California Institute Of Technology Multifunctional polymeric tissue coatings
WO2000022105A1 (fr) * 1998-10-13 2000-04-20 Yissum Research Development Company Of The Hebrew University Of Jerusalem Revetement hydrocolloide de cellules
FR2793693A3 (fr) * 1999-05-18 2000-11-24 Martine Bulette Prothese vasculaire impregnee par un biopolymere d'origine vegetale ou bacterienne et procede pour la realisation d'une telle prothese
EP1413298A1 (fr) * 2002-09-24 2004-04-28 Cognis Deutschland GmbH & Co. KG Macrocapsules
WO2006116546A1 (fr) * 2005-04-27 2006-11-02 Baxter International Inc. Microparticules a surface modifiee et procedes de formation et d'utilisation associes
US8673878B2 (en) 2005-10-06 2014-03-18 Ntnu Technology Transfer As Mucosal treatment
US8754063B2 (en) 2005-10-06 2014-06-17 NTNU Technology Transfers AS Use of oligouronates for treating mucus hyperviscosity
US7964574B2 (en) 2006-08-04 2011-06-21 Baxter International Inc. Microsphere-based composition for preventing and/or reversing new-onset autoimmune diabetes
US8841279B2 (en) 2007-04-12 2014-09-23 Norwegian University Of Science And Technology Oligo-guluronate and galacturonate compositions
US8987215B2 (en) 2009-03-23 2015-03-24 Ntnu Technology Transfer As Composition for use in gene therapy
US8529890B2 (en) 2009-03-23 2013-09-10 Ntnu Technology Transfer As Composition for the administration of polymeric drugs
EP3174906A1 (fr) * 2014-08-01 2017-06-07 Massachusetts Institute Of Technology Alginates modifiés pour matériaux anti-fibrotiques et applications associées
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JPH05502863A (ja) 1993-05-20
EP0502949A4 (en) 1993-02-24

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