Compositions and methods for tissue repair

Abstract

Implants for repairing tissue defects, such as cartilage tissue defects, and methods of their preparation and use are disclosed. A mold of a tissue defect is prepared by pressing upon the defect a substrate having shape memory, such as aluminum foil. The mold, which has contours substantially conforming to those of the defect, is removed from the defect, and tissue particles are added to the mold ex vivo. A biological carrier such as biocompatible glue is also added to the mold. The combination of tissue particles and the biological carrier thereby form an implant, which retains its shape after separation from the mold. The implant can be transferred to the tissue defect, with contours of the mold matching corresponding contours of the defect.

1 . A method of repairing a tissue defect, the method comprising:
 a) forming, on a tissue defect, a mold conforming to the contours of at least a portion of the tissue defect; removing the mold from the defect;   b) forming in the mold an implant comprising: i) one or more tissue particles and ii) a biocompatible carrier, whereby the implant has a shape substantially conforming to the contours of at least the portion of the tissue defect;   c) separating the implant from the mold; and   d) applying the implant to at least the portion of the tissue defect.   
     
     
         2 . The method of  claim 1 , wherein the mold comprises a pliable substrate having shape memory. 
     
     
         3 . The method of  claim 2 , wherein the substrate having shape memory is a metal foil. 
     
     
         4 . The method of  claim 2 , wherein the substrate having shape memory is a plastic. 
     
     
         5 . The method of  claim 2 , wherein the substrate having shape memory is a polymer. 
     
     
         6 . The method of  claim 1 , wherein the one or more tissue particles are initially suspended in a liquid medium. 
     
     
         7 . The method of  claim 6 , wherein forming the implant comprises removing an amount of the liquid medium from the mold. 
     
     
         8 . The method of  claim 6  further comprising introducing one or more perforations in the mold, thereby promoting draining of the liquid medium from the mold. 
     
     
         9 . The method of  claim 1 , wherein the biocompatible carrier is selected from the group consisting of a fibrinogen, a fibrin, a thrombin, a type I collagen, a type II collagen, a type III collagen, a gelatin, a fibronectin, a laminin, a hyaluronic acid, a hydrogel a pegylated hydrogel and a chitosan. 
     
     
         10 . The method of  claim 9 , wherein the biocompatible carrier comprises at least one biocompatible adhesive. 
     
     
         11 . The method of  claim 10 , wherein the biocompatible adhesive is a fibrin adhesive. 
     
     
         12 . The method of  claim 1 , wherein the implant further comprises at least one bioactive agent. 
     
     
         13 . The method of  claim 12 , wherein the at least one bioactive agent is a bioactive peptide. 
     
     
         14 . The method of  claim 1 , wherein the implant comprises a first layer comprising one or more tissue particles and a second layer comprising a biocompatible carrier. 
     
     
         15 . The method of  claim 1 , wherein the applying the implant to the tissue defect comprises inserting the implant at the tissue defect. 
     
     
         16 . The method of  claim 15 , wherein the applying the implant to the tissue defect further comprises affixing the implant to the tissue defect. 
     
     
         17 . The method of  claim 15 , wherein the implant is inserted using a minimally invasive surgical (MIS) technique. 
     
     
         18 . The method of  claim 15 , wherein the applying the implant to the tissue defect further comprises affixing the implant to the tissue defect. 
     
     
         19 . The method of  claim 15 , wherein the implant is inserted using a minimally invasive surgical (MIS) technique. 
     
     
         20 . The method of  claim 31 , wherein the implant is inserted arthroscopically. 
     
     
         21 . The method of  claim 1 , wherein the tissue defect is a cartilage defect. 
     
     
         22 . The method of  claim 1 , wherein the tissue particles are cartilage tissue particles. 
     
     
         23 . An apparatus for forming an implant for repairing a tissue defect, the apparatus comprising:
 a) a mold having a shape substantially conforming to the contours of a tissue defect of a subject; and   b) a composition comprising one or more tissue particles and a biocompatible carrier, the composition disposed in the mold wherein the shape of the composition substantially conforms to the contours of the tissue defect.   
     
     
         24 . The apparatus of  claim 23 , wherein the mold comprises a substrate having shape memory. 
     
     
         25 . The apparatus of  claim 24 , wherein the substrate having shape memory is a metal foil. 
     
     
         26 . The apparatus of  claim 24 , wherein the substrate having shape memory is a plastic. 
     
     
         27 . The apparatus of  claim 24 , wherein the substrate having shape memory is a polymer. 
     
     
         28 . The apparatus of  claim 23 , wherein the mold has one or more perforations therethrough. 
     
     
         29 . The apparatus of  claim 23 , wherein the biocompatible carrier comprises at least one biocompatible adhesive. 
     
     
         30 . The apparatus of  claim 23 , wherein the biocompatible carrier comprises a biocompatible adhesive. 
     
     
         31 . The apparatus of  claim 30 , wherein the biocompatible adhesive comprises a fibrin adhesive. 
     
     
         32 . The apparatus of  claim 23 , wherein the biocompatible carrier comprises a biocompatible gel. 
     
     
         33 . The apparatus of  claim 23 , wherein the implant further comprises at least one bioactive agent. 
     
     
         34 . The apparatus of  claim 33 , wherein the at least one bioactive agent is a growth factor. 
     
     
         35 . The apparatus of  claim 23 , wherein the implant comprises a first layer and at least a second layer. 
     
     
         36 . The apparatus of  claim 23 , wherein the subject is a human. 
     
     
         37 . The apparatus of  claim 23 , wherein the tissue defect is a cartilage defect. 
     
     
         38 . The apparatus of  claim 37 , wherein the tissue particles are cartilage tissue particles. 
     
     
         39 . A method of forming an implant for repairing a tissue defect, the method comprising:
 a) forming a substrate having shape memory into a mold of a tissue defect of a subject, wherein the mold substantially conforms to contours of at least a portion of the tissue defect;   b) removing the mold from the tissue defect; and   c) disposing in the mold a composition comprising at least one biological agent and a biocompatible carrier, thereby forming the implant having a shape substantially conforming to the contours of at least the portion of the tissue defect.   
     
     
         40 . The method of  claim 39 , wherein the at least one biological agent comprises a plurality of tissue particles. 
     
     
         41 . The method of  claim 39 , wherein the at least one biological agent comprises a population of cells. 
     
     
         42 . The method of  claim 41 , wherein the population of cells comprises a plurality of chondrocytes. 
     
     
         43 . The method of  claim 39 , wherein the biological agent comprises a plurality of tissue particles. 
     
     
         44 . The method of  claim 43 , wherein the plurality tissue particles comprise juvenile cartilage particles. 
     
     
         45 . The method of  claim 39 , further comprising introducing one or more perforations in the mold. 
     
     
         46 . The method of  claim 39 , wherein the biocompatible carrier comprises at least one biocompatible adhesive. 
     
     
         47 . The method of  claim 46 , wherein the biocompatible adhesive is a fibrin adhesive. 
     
     
         48 . The method of  claim 39 , further comprising mixing into the composition in the mold at least one bioactive agent. 
     
     
         49 . The method of  claim 48 , wherein the at least one bioactive agent is a growth factor. 
     
     
         50 . The method of  claim 48 , wherein the at least one bioactive agent comprises a plurality of cells. 
     
     
         51 . The method of  claim 39 , further comprising separating the implant from the mold. 
     
     
         52 . An implant for repairing a tissue defect of a subject, comprising a biological agent and a biocompatible carrier, wherein the shape of the implant substantially conforms to the contours of a mold wherein the mold substantially conforms to at least a portion of a tissue defect of a subject. 
     
     
         53 . The implant of  claim 52 , wherein the at least one biological agent comprises a plurality of tissue particles. 
     
     
         54 . The implant of  claim 52 , wherein the at least one biological agent comprises a population of cells. 
     
     
         55 . The implant of  claim 54 , wherein the population of cells comprises a plurality of chondrocytes. 
     
     
         56 . The implant of  claim 52 , wherein the biocompatible carrier comprises at least one biocompatible adhesive. 
     
     
         57 . The implant of  claim 56 , wherein the biocompatible adhesive is a fibrin adhesive. 
     
     
         58 . The implant of  claim 57 , wherein the implant further comprises at least one bioactive agent. 
     
     
         59 . The implant of  claim 58 , wherein the at least one bioactive agent is a growth factor. 
     
     
         60 . The implant of  claim 52 , wherein the implant comprises a first layer and at least a second layer. 
     
     
         61 . The implant of  claim 60 , wherein the second layer comprises at least one biocompatible carrier. 
     
     
         62 . The implant of  claim 52 , wherein the tissue defect is a cartilage tissue defect. 
     
     
         63 . The implant of  claim 62 , wherein the tissue particles are cartilage tissue particles. 
     
     
         64 . A kit for forming an implant for repairing a tissue defect, comprising:
 a) a pliable substrate having shape memory and which can be shaped to substantially conform to the contours of at least a portion of a tissue defect, thereby serving as a mold of at least the portion of the tissue defect in a subject;   b) a biological agent; and   c) a biocompatible carrier.   
     
     
         65 . The kit of  claim 64 , wherein the biological agent comprises a plurality of tissue particles. 
     
     
         66 . The kit of  claim 64 , wherein the pliable substrate having shape memory is a metal foil. 
     
     
         67 . The kit of  claim 64 , wherein the pliable substrate having shape memory is a plastic. 
     
     
         68 . The kit of  claim 64 , wherein the pliable substrate having shape memory is a polymer. 
     
     
         69 . The kit of  claim 64 , wherein the biological agent comprises one or more tissue particles in a liquid medium. 
     
     
         70 . The kit of  claim 69 , wherein the liquid medium is a cell, tissue or organ storage medium. 
     
     
         71 . The kit of  claim 64 , wherein the biocompatible carrier comprises at least one biocompatible adhesive. 
     
     
         72 . The kit of  claim 71 , wherein the biocompatible adhesive is a fibrin adhesive. 
     
     
         73 . The kit of  claim 64 , further comprising at least one bioactive agent. 
     
     
         74 . The kit of  claim 73 , wherein the at least one bioactive agent is a growth factor. 
     
     
         75 . The kit of  claim 64 , wherein the tissue particles are cartilage particles. 
     
     
         76 . The kit of  claim 75 , wherein the cartilage particles are selected from the group consisting of neocartilage particles, juvenile cartilage particles, cadaver cartilage particles and a combination thereof.