Hybrid matrix implants and explants
First Claim
Patent Images
1. A composition comprising a body of matrix material comprising insoluble collagen fibrils, there being embedded within the body of matrix material(a) a population of cultured vertebrate cells genetically engineered to express a polypeptide;
- (b) a plurality of microspheres; and
(c) an agent selected from the group consisting of a factor which promotes vascularization, a cytokine, a growth factor and ascorbic acid.
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Abstract
A composition having a body of matrix material made up of insoluble collagen fibrils, and disposed therewithin
(a) a plurality of vertebrate cells;
(b) a plurality of microspheres; and
(c) an agent such as a factor that promotes vascularization, a cytokine, a growth factor, or ascorbic acid.
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Citations
66 Claims
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1. A composition comprising a body of matrix material comprising insoluble collagen fibrils, there being embedded within the body of matrix material
(a) a population of cultured vertebrate cells genetically engineered to express a polypeptide; -
(b) a plurality of microspheres; and
(c) an agent selected from the group consisting of a factor which promotes vascularization, a cytokine, a growth factor and ascorbic acid. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 64, 65, 66)
forming a mixture comprising: (a) a plurality of cultured vertebrate cells genetically engineered to express a polypeptide;
(b) a plurality of microspheres;
(c) a solution comprising soluble collagen; and
(d) an agent selected from the group consisting of a factor that promotes vascularization, a cytokine, a growth factor, and ascorbic acid;
subjecting the soluble collagen in the mixture to conditions effective to form a gel; and
exposing the gel to culture conditions which cause the gel to contract, thereby forming the body of the composition.
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39. The method of claim 38, wherein the agent is associated with a solid substrate.
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40. The method of claim 39, wherein the solid substrate comprises beads of agarose with heparin or heparan sulfate proteoglycan bound thereto.
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41. The method of claim 39, wherein the solid substrate further comprises calcium alginate.
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42. The method of claim 40, wherein the solid substrate comprises calcium alginate.
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43. The method of claim 39, wherein the solid substrate comprises a substance selected from the group consisting of collagen, gelatin, ethylene-vinyl acetate, polylactide/glycolic acid co-polymer, fibrin, sucrose octasulfate, dextran, polyethylene glycol, an alginate, polyacrylamide, cellulose, latex, and polyhydroxyethylmethacrylate.
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44. The method of claim 43, wherein heparin or heparan sulfate proteoglycan is bound to the substance.
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45. The method of claim 38, wherein the microspheres are porous collagen beads.
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46. The method of claim 38, wherein the microspheres are porous gelatin beads.
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47. The method of claim 38, wherein the mixture additionally comprises a substance selected from the group consisting of a second type of collagen, agarose, alginate, fibronectin, laminin, hyaluronic acid, heparan sulfate, dermatan sulfate, sulfated proteoglycans, fibrin, elastin, and tenascin.
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48. The method of claim 38, wherein the solution is an acidic aqueous solution of soluble collagen, and gelation is accomplished by raising the pH of the solution.
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49. The method of claim 38, wherein the gelation step takes place in a mold, so that, prior to the contracting step, the gel is in the shape of the mold.
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50. The method of claim 38, wherein the cultured vertebrate cells are cultured in the presence of the microspheres prior to being mixed with the solution.
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51. A method of administering a polypeptide to a patient in need thereof, comprising
providing the composition of claim 32, wherein the cultured vertebrate cells secrete the polypeptide; - and
implanting the composition in the patient, wherein the cultured vertebrate cells secrete the polypeptide after implanting the composition in the patient.
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52. The method of claim 51, wherein the cultured vertebrate cells are derived from one or more cells removed from the patient, and have been genetically engineered in vitro to express and secrete the polypeptide.
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53. The method of claim 51, wherein the implanting is carried out at a subcutaneous site in the patient.
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54. The method of claim 51, wherein the implanting is carried out at an intraperitoneal, sub-renal capsular, inguinal, intramuscular, intraventricular, intraomental, or intrathecal site in the patient.
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55. The method of claim 51, wherein the polypeptide is one which promotes wound healing, and the implanting is carried out at the site of a preexisting wound of the patient.
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56. The method of claim 51, wherein each of the plurality of microspheres consists primarily of one or more substances selected from the group consisting of collagen, polystyrene, dextran, polyacrylamide, cellulose, calcium alginate, latex, polysulfone, and glass.
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57. The method of claim 51, wherein each of the plurality of microspheres consists primarily of gelatin.
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58. The method of claim 38, wherein the gel is formed in a flat-bottomed mold filled with the mixture to a depth of about 0.18 cm.
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59. A composition produced by the method of claim 58.
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60. The method of claim 38, wherein the gel is formed in a flat-bottomed cylindrical mold with an internal radius (r);
- the mixture has a volume (V); and
when r is expressed in cm and V is expressed in ml, r2/V is about 1.8.
- the mixture has a volume (V); and
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64. The composition of claim 1, wherein the polypeptide is selected from the group consisting of interferon-α
- (IFN-α
), interferon-β
(IFN-β
), interferon-γ
(IFN-γ
), follicle stimulating hormone (FSH), α
-galactosidase, β
-gluceramidase, α
-iduronidase, α
-L-iduronidase, glucosamine-N-sulfatase, α
-N-acetylglucosaminidase, acetylcoenzyme A;
α
-glucosaminide-N-acetyltransferase, N-acetylglucosamine-6-sulfatase, β
-galactosidase, N-acetylgalactosamine-6-sulfatase, and β
-glucuronidase.
- (IFN-α
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65. The composition of claim 1, wherein the matrix material additionally comprises a substance selected from the group consisting of heparin, cellulose, starch and dextran.
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66. The method of claim 38, wherein the mixture additionally comprises a substance selected from the group consisting of heparin, cellulose, starch, and dextran.
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61. A method of making a composition, the method comprising
forming a mixture comprising: -
(a) a plurality of cultured vertebrate cells genetically engineered to express a polypeptide;
(b) a plurality of microspheres; and
(c) a solution comprising soluble collagen;
subjecting the soluble collagen in the mixture to conditions effective to form a gel; and
exposing the gel to culture conditions which cause the gel to contract, thereby forming the body of the composition, wherein the gel is formed in a flat-bottomed mold filled with the mixture to a depth of about 0.18 cm. - View Dependent Claims (62)
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63. A method of making a composition, the method comprising
forming a mixture comprising: -
(a) a plurality of cultured vertebrate cells genetically engineered to express a polypeptide;
(b) a plurality of microspheres; and
(c) a solution comprising soluble collagen;
subjecting the soluble collagen in the mixture to conditions effective to form a gel; and
exposing the gel to culture conditions which cause the gel to contract, thereby forming the body of the composition, wherein the gel is formed in a flat-bottomed cylindrical mold with an internal radius (r);
the mixture has a volume (V); and
when r is expressed in cm and V is expressed in ml, r2/V is about 1.8.
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Specification