Hydrogel-grafted degradable nerve guides

Abstract

The present invention is directed to the compositions and methods of preparing hydrogel-grafted nerve guides for peripheral nerve regeneration. Particularly, the present invention describes the nerve guides and methods for preparation of hydrogel-grafted nerve guides with encapsulated neurotrophic factors and a nanofiber mesh lining the inner surface of the guide. The present invention also provides methods for peripheral nerve repair using these hydrogel-grafted nerve guides.

1 . A nerve guide comprising a hollow body in the form of a tube having a wall with an external surface and an internal surface with defines a lumen, wherein the body comprises an outer biodegradable membrane, a hydrogel layer, and a nanofiber layer wherein the lumen is surrounded by the nanofiber layer. 
     
     
         2 . The nerve guide of  claim 1 , wherein the hydrogel layer comprises one or more neurotrophic factors. 
     
     
         3 . The nerve guide of  claim 2 , wherein the neurotrophic factors are selected from the group consisting of NGF, BDNF, NT3, CNTF, GDNF, FGF, pleiotrophin, osteopontin, neublastin and neurturin. 
     
     
         4 . The nerve guide of  claim 3 , wherein the hydrogel layer comprises GDNF and BDNF or GDNF and NT3. 
     
     
         5 . The nerve guide of  claim 1 , wherein the nanofibers are coated with one or more extracellular matrix molecules selected from laminin, fibronectin, collagen, and heparin. 
     
     
         6 . The nerve guide of  claim 5 , wherein the nanofibers are coated with one or more extracellular matrix molecules selected from laminin and heparin. 
     
     
         7 . The nerve guide of  claim 6 , wherein the nanofiber layer comprises laminin and heparin. 
     
     
         8 . The nerve guide of  claim 1 , wherein the biodegradable membrane is selected from a group consisting of biodegradable polyesters, poly(amino acid)s or derivatives thereof, and natural biodegradable polymers. 
     
     
         9 . The nerve guide of  claim 1 , wherein the biodegradable membrane is between about 50 and about 1000 μm thick. 
     
     
         10 . The nerve guide of  claim 1 , wherein the biodegradable membrane is porous. 
     
     
         11 . The nerve guide of  claim 1 , wherein the hydrogel layer is comprised of a material selected from the group consisting of PVA hydrogel or a mixture or PVA and one or more of pluronic polymers, heparin, heparan sulfate, chitosan, alginate, and dextran sulfate. 
     
     
         12 . The nerve guide of  claim 1 , wherein the thickness of the hydrogel is between about 200 μm and about 1.5 mm in its swollen state. 
     
     
         13 . The nerve guide of  claim 1 , wherein the nanofiber layer comprises one or more natural or synthetic biocompatible polymers comprising polymer fibers selected from the group consisting of biodegradable polyesters, proteins, polysaccharides and derivatives thereof. 
     
     
         14 . The nerve guide of  claim 13 , wherein the one or more polymer fibers comprise a polyester or derivative thereof. 
     
     
         15 . The nerve guide of  claim 13 , wherein the one or more polymer fibers comprise collagen, laminin, and derivatives thereof. 
     
     
         16 . The nerve guide of  claim 13 , wherein the one or more polymer fibers comprise chondroitin sulfate, alginate and derivatives thereof. 
     
     
         17 . The nerve guide of  claim 13 , wherein the one or more polymer fibers comprise polylactide, polyglycolide, polycaprolactone and their copolymers thereof. 
     
     
         18 . The nerve guide of  claim 1 , wherein the nanofiber layer comprises electrospun fibers. 
     
     
         19 . The nerve guide of  claim 18 , wherein the electrospun fibers are randomly oriented fibers. 
     
     
         20 . The nerve guide of  claim 18 , wherein the electrospun fibers are aligned fibers. 
     
     
         21 . The nerve guide of  claim 13 , wherein the average fiber diameter is between about 10 nm and 10 um. 
     
     
         22 . The nerve guide of  claim 21 , wherein the average fiber diameter is between about 100 um and 1 um. 
     
     
         23 . The nerve guide of  claim 2 , wherein the one or more neurotrophic factors are present in a gradient of lower concentration to higher concentration from the proximal end of the guide to the distal end of the guide. 
     
     
         24 . A process for making a nerve guide comprising:
 grafting a hydrogel onto a biodegradable polymer membrane;   coating the hydrogel layer with a solution of neurotropic factors;   applying a nanofiber mesh to the hydrogel surface; and   forming the composition into a tube.   
     
     
         25 . The process of  claim 24 , wherein the biodegradable polymer membrane is formed by solvent casting, hot-pressing or stretching. 
     
     
         26 . The process of  claim 24 , wherein the grafting is thermal melt-mixing or solvent swelling. 
     
     
         27 . The process of  claim 24 , further comprising freeze-drying the neurotrophic factors in place. 
     
     
         28 - 37 . (canceled) 
     
     
         38 . The process of  claim 24 , wherein the nanofiber layer comprises electrospun fibers. 
     
     
         39 . A method of treating peripheral nerve or spinal cord injury comprising:
 surgically implanting the nerve guide of  claim 1  at the site of a nerve injury;   thereby treating peripheral nerve or spinal cord injury.   
     
     
         40 - 42 . (canceled)