Bioabsorbable implant of hyaluronic acid derivative for treatment of osteochondral and chondral defects

Abstract

A method for treating an osteochondral defect or a chondral defect in a subject includes implanting a composite in a site of the osteochondral or chondral defect. The composite includes a hyaluronic acid derivative; and at least one member of the group consisting of a cell, a cellular growth factor and a cellular differentiation factor, which is impregnated in, or coupled to, the hyaluronic acid derivative. In one embodiment, carboxyl functionalities of the hyaluronic acid derivative are each independently derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea. In another embodiment, the hyaluronic acid derivative is prepared by reacting an uncrosslinked hyaluronic acid with a biscarbodimide in the presence of a pH buffer in a range of between about 4 and about 8. The composite can be used for regenerating or stimulating regeneration of meniscal tissues in a subject in need thereof.

1 . A method for treating an osteochondral defect or a chondral defect in a subject, comprising implanting a composite in a site of the osteochondral or chondral defect, the composite including: 
 a) a hyaluronic acid derivative, wherein carboxyl functionalities of the hyaluronic acid derivative are each independently derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea; and    b) at least one member of the group consisting of a cell, a cellular growth factor and a cellular differentiation factor, which is impregnated in, or coupled to, the hyaluronic acid derivative.    
   
   
       2 . The method of  claim 1 , wherein the composition includes at least one member selected from mesenchymal stem cells, fibrochondrocytes, osteochondrocytes, chondrocytes, TGFβ supergene family members, tissue growth hormones, encoding genes thereof, and synthetic peptide analogues thereof.  
   
   
       3 . The method of  claim 2 , wherein the composite includes a cartilage chondrocyte, osteochondrocyte or mesenchymal stem cell.  
   
   
       4 . The method of  claim 1 , further including the step of stabilizing the composite within the site of the osteochondral or chondral defect so that the composite does not move during the regeneration or repair of the osteochondral or chondral defect.  
   
   
       5 . The method of  claim 1 , wherein at least about 1% by mole of the carboxyl functionalities have been derivatized.  
   
   
       6 . The method of  claim 5 , wherein at least about 25% by mole of the derivatized carboxyl functionalities are O-acyl isoureas and/or N-acylureas.  
   
   
       7 . The method of  claim 5 , wherein the hyaluronic acid derivative includes at least one crosslink represented by the following structural formula:  
       HA′—U—R 2 —U—HA′ 
     wherein: 
 each HA′ is the same or a different hyaluronic acid molecule;  
 each U is independently an optionally substituted O-acyl isourea or N-acyl urea; and  
 each R 2  is independently a substituted or unsubstituted hydrocarbylene group optionally interrupted by one or more heteroatoms.  
 
   
   
       8 . The method of  claim 1 , wherein the composite has interconnected pores of sizes that can provide molecular cuing for the impregnated or coupled cell to migrate through, or a path for migration of the impregnated or coupled cellular growth or differentiation factor.  
   
   
       9 . The method of  claim 1 , wherein the composite further includes a biocompatible, biodegradable support, wherein the hyaluronic acid derivative is at the support.  
   
   
       10 . The method of  claim 9 , wherein the support includes at least one member selected from the group consisting of crosslinked alginates, gelatin, collagen, crosslinked collagen, collagen derivatives, crosslinked hyaluronic acid, chitosan, chitosan derivatives, cellulose and derivatives thereof, dextran derivatives, polyanionic polysaccharides and derivatives thereof, polylactic acid (PLA), polyglycolic acid (PGA), a copolymer of a polylactic acid and a polyglycolic acid (PLGA), lactides, glycolides, polyoxanones, polyoxalates, copolymer of poly(bis(p-carboxyphenoxy)propane)anhydride (PCPP) and sebacic acid, poly(l-glutamic acid), poly(d-glutamic acid), polyacrylic acid, poly(dl-glutamic acid), poly(l-aspartic acid), poly(d-aspartic acid), poly(dl-aspartic acid), polyethylene glycol, copolymers of polyamino acids with polyethylene glycol, polypeptides, polycaprolactone, poly(alkylene succinates), poly(hydroxy butyrate) (PHB), poly(butylene diglycolate), nylon-2/nylon-6-copolyamides, polydihydropyrans, polyphosphazenes, poly(ortho ester), poly(cyano acrylates), polyvinylpyrrolidone and polyvinylalcohol.  
   
   
       11 . The method of  claim 1 , wherein the composition further includes a material that enhances adherence of the composite to tissue.  
   
   
       12 . The method of  claim 11 , wherein the material that enhances adherence of the composite to tissue is a polymer selected from the group consisting of fibrin, collagen, crosslinked collagen, collagen derivative and a polymer that includes a peptide sequence having arginine, glycine and aspartic acid.  
   
   
       13 . The method of  claim 1 , further including the step of fabricating the composite in the shape of the osteochondral or chondral defect.  
   
   
       14 . The method of  claim 1 , further including the steps of: forming the composite in a sheet or film; and cutting, trimming and contouring the sheet or film to fill the osteochondral or chondral defect.  
   
   
       15 . A method for regenerating or promoting regeneration of cartilage and/or bone in an osteochondral or chondral defect in a subject, comprising: 
 a) forming a scaffold that includes a hyaluronic acid derivative and a support, wherein carboxyl functionalities of the hyaluronic acid derivative are each independently derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea;    b) impregnating in, or coupling to, the scaffold at least one member of the group consisting of a cell, and a cellular growth and differentiation factor in the scaffold; and    c) implanting the scaffold that is impregnated or coupled with said at least one member of the group consisting of a cell, and a cellular growth and differentiation factor at a site of the osteochondral or chondral defect of the subject, thereby providing a mechanism for delivery of the cell, cellular growth factor or cellular differentiation factor to the site of the osteochondral or chondral defect to regenerate or promote regeneration of cartilage and bone in the osteochondral or chondral defect.    
   
   
       16 . The method of  claim 15 , wherein the cell, cellular growth factor and cellular differentiation factor include at least one member selected from the group consisting of mesenchymal stem cells, fibrochondrocytes, osteochondrocytes, chondrocytes, TGFβ supergene family members, and hormones that stimulate tissue growth.  
   
   
       17 . The method of  claim 16 , wherein the scaffold include a cartilage chondrocyte, osteochondrocyte or mesenchymal stem cell.  
   
   
       18 . The method of  claim 15 , further including the step of stabilizing the composite within the osteochondral or chondral defect so that the composite does not move during the regeneration or repair of the osteochondral or chondral defect.  
   
   
       19 . The method of  claim 15 , wherein at least 1% by mole of the carboxyl functionalities have been derivatized.  
   
   
       20 . The method of  claim 19 , wherein at least 25% by mole of the derivatized carboxyl functionalities are O-acyl isoureas and/or N-acylureas.  
   
   
       21 . The method of  claim 15 , wherein the hyaluronic acid derivative includes at least one crosslink represented by the following structural formula:  
       HA′—U—R 2 —U—HA′ 
     wherein: 
 each HA′ is the same or a different hyaluronic acid molecule;  
 each U is independently an optionally substituted O-acyl isourea or N-acyl urea; and  
 each R 2  is independently a substituted or unsubstituted hydrocarbylene group optionally interrupted by one or more heteroatoms.  
 
   
   
       22 . The method of  claim 15 , wherein the scaffold has interconnected pores of sizes that can provide molecular cuing for the impregnated or coupled cell to migrate through, or a path for migration of the impregnated or coupled cellular growth factor or cellular differentiation factor.  
   
   
       23 . The method of  claim 15 , wherein the support is a biocompatible and biodegradable support.  
   
   
       24 . The method of  claim 23 , wherein the support includes at least one member selected from the group consisting of crosslinked alginates, gelatin, collagen, crosslinked collagen, collagen derivatives, crosslinked hyaluronic acid, chitosan, chitosan derivatives, cellulose and derivatives thereof, dextran derivatives, polyanionic polysaccharides and derivatives thereof, polylactic acid (PLA), polyglycolic acid (PGA), a copolymer of a polylactic acid and a polyglycolic acid (PLGA), lactides, glycolides, polyoxanones, polyoxalates, copolymer of poly(bis(p-carboxyphenoxy)propane)anhydride (PCPP) and sebacic acid, poly(l-glutamic acid), poly(d-glutamic acid), polyacrylic acid, poly(dl-glutamic acid), poly(l-aspartic acid), poly(d-aspartic acid), poly(dl-aspartic acid), polyethylene glycol, copolymers of polyamino acids with polyethylene glycol, polypeptides, polycaprolactone, poly(alkylene succinates), poly(hydroxy butyrate) (PHB), poly(butylene diglycolate), nylon-2/nylon-6-copolyamides, polydihydropyrans, polyphosphazenes, poly(ortho ester), poly(cyano acrylates), polyvinylpyrrolidone and polyvinylalcohol.  
   
   
       25 . The method of  claim 15 , wherein the scaffold further includes a material that enhances adherence of the composite to tissue.  
   
   
       26 . The method of  claim 25 , wherein the material that enhances adherence of the composite to tissue is a polymer selected from the group consisting of fibrin, collagen, crosslinked collagen, collagen derivative and a polymer that includes a peptide sequence having arginine, glycine and aspartic acid.  
   
   
       27 . The method of  claim 15 , further including the step of fabricating the scaffold in the shape of the osteochondral or chondral defect.  
   
   
       28 . The method of  claim 15 , further including the steps of: forming the scaffold in a sheet or film; and cutting, trimming and contouring the sheet or film to fill the osteochondral or chondral defect.