Devices and Methods for Nerve Regeneration

Abstract

The present invention is directed to a nerve regeneration conduit including a resorbable tube having a matrix therein. The matrix is characterized by substantially parallel, axially aligned pores extending the length of the matrix. The matrix is formed by the axial freezing of a slurry having little or no significant radial thermal gradient during the freezing process. The matrix is used to bridge the gap between the severed ends of a nerve and provide a scaffold for nerve regeneration.

1 . A method for making a matrix having substantially parallel axially aligned pores comprising
 freezing a slurry of a material capable of forming a matrix and a liquid along an axial direction of the slurry, with the slurry having little or no significant radial thermal gradient, to form a frozen slurry and   freeze drying the frozen slurry to form the matrix having substantially parallel axially aligned pores.   
     
     
         2 . The method of  claim 1  wherein the step of freezing includes contacting a proximal end of the slurry to a heat sink with the slurry freezing from the proximal end of the slurry to a distal end of the slurry to form the frozen slurry. 
     
     
         3 . The method of  claim 1  wherein the pores have an average diameter of about 10 μm to about 300 μm. 
     
     
         4 . The method of  claim 1  wherein the step of freezing the slurry comprises providing a cooling gradient in the axial direction of the slurry by rapid heat transfer from the slurry to a cooling medium, wherein the cooling gradient has substantially no radial component. 
     
     
         5 . The method of  claim 1  including the step of insulating the slurry to provide little or no substantial thermal gradient during the step of freezing the slurry. 
     
     
         6 . The method of  claim 1  wherein the slurry is placed in a mold which is insulated. 
     
     
         7 . The method of  claim 1  wherein the slurry is placed in a conduit which is insulated. 
     
     
         8 . The method of  claim 1  wherein the step of freezing the slurry comprises rapid heat transfer from the slurry to a cooling medium through a thermally conducting plug or pole contacting a proximal end of the slurry and the cooling medium, with the freezing moving from the proximal end of the slurry to the distal end of the slurry. 
     
     
         9 . The method of  claim 1  wherein the matrix is substantially cylindrical. 
     
     
         10 . The method of  claim 9  wherein the matrix has a length from about 1 cm to about 15 cm. 
     
     
         11 . The method of  claim 1  wherein the slurry comprises collagen and water. 
     
     
         12 . The method of  claim 1  wherein the slurry further comprises glycosaminoglycan. 
     
     
         13 . The method of  claim 12  wherein the glycosaminoglycan is chondroitin sulfate, dermatan sulfate, keratin sulfate or hyaluronic acid. 
     
     
         14 . The method of  claim 12  wherein the glycosaminoglycan is chondroitin sulfate. 
     
     
         15 . The method of  claim 4  wherein the cooling medium is liquid nitrogen or dry ice. 
     
     
         16 . The method of  claim 1  wherein the matrix formed by freeze drying is contained within a conduit. 
     
     
         17 . A method for regenerating a severed nerve comprising contacting each severed end of the nerve to a matrix produced according to  claim 1  and promoting growth of nerve tissue through each end of the matrix until the nerve tissue combines together within the matrix. 
     
     
         18 . The method of  claim 17  wherein the matrix is contained within a conduit. 
     
     
         19 . The method of  claim 18  wherein each severed end of the nerve is inserted into the conduit to contact the matrix. 
     
     
         20 . The method of  claim 17  wherein each severed end of the nerve is connected to the matrix by a connector overlapping the conduit and the nerve. 
     
     
         21 . The method of  claim 18  wherein the matrix and the conduit are biodegradable. 
     
     
         22 . The method of  claim 17  wherein the gap between the ends of the severed nerve is less than 15 cm. 
     
     
         23 . A system for making a matrix comprising
 a liquid cooling medium,   an insulated tube having a heat sink at a proximal end, with the heat sink contacting the liquid cooling medium.   
     
     
         24 . The system of  claim 23  wherein the insulated tube is a collagen tube surrounded by an insulating material with the heat sink protruding from the insulating material. 
     
     
         25 . The system of  claim 24  wherein the insulating material is buoyant when placed in the liquid cooling medium. 
     
     
         26 . A method for making a matrix having substantially parallel axially aligned pores comprising
 freezing a liquid slurry of a material capable of forming a matrix, so that the formation of ice crystal occurs in a predetermined axial direction, with the slurry experiencing little or no significant radial thermal gradient during the axial freezing; and   freeze drying the frozen slurry to form the matrix having substantially parallel axially aligned pores.   
     
     
         27 . A nerve regeneration conduit comprising
 a resorbable conduit having a first end and a second end,   a matrix within the resorbable conduit having a plurality of substantially parallel axially aligned pores.   
     
     
         28 . The nerve regeneration conduit of  claim 27  wherein the resorbable conduit is a tube comprising collagen. 
     
     
         29 . The nerve regeneration conduit of  claim 28  wherein the matrix comprises collagen, laminin, fibronectin, merosin, hyaluronic acid, chitin, chitosan, keratin, polyglycolic acid, polylactic acid, or cellulose. 
     
     
         30 . The nerve regeneration conduit of  claim 28  wherein the matrix further includes a glycosaminoglycan. 
     
     
         31 . The nerve regeneration conduit of  claim 30  wherein the glycosaminoglycan is chondroitin sulfate, dermatan sulfate, keratin sulfate or hyaluronic acid. 
     
     
         32 . The nerve regeneration conduit of  claim 30  wherein the glycosaminoglycan is chondroitin sulfate. 
     
     
         33 . The nerve regeneration conduit of  claim 28  wherein the tube includes a glycosaminoglycan. 
     
     
         34 . The nerve regeneration conduit of  claim 33  wherein the glycosaminoglycan is chondroitin sulfate, dermatan sulfate, keratin sulfate or hyaluronic acid. 
     
     
         35 . The nerve regeneration conduit of  claim 33  wherein the glycosaminoglycan is chondroitin sulfate. 
     
     
         36 . The nerve regeneration conduit of  claim 27  wherein the nerve regeneration conduit is crosslinked. 
     
     
         37 . The nerve regeneration conduit of  claim 27  wherein the resorbable conduit is crosslinked. 
     
     
         38 . The nerve regeneration conduit of  claim 27  wherein the matrix is crosslinked. 
     
     
         39 . The nerve regeneration conduit of  claim 27  wherein the resorbable conduit and the matrix are crosslinked. 
     
     
         40 . The nerve regeneration conduit of  claim 36  wherein the nerve regeneration conduit is crosslinked to an extent that it is completely resorbed within about 1 to about 3 months. 
     
     
         41 . The nerve regeneration conduit of  claim 36  wherein the nerve regeneration conduit is crosslinked by heating under vacuum or by treatment with a chemical crosslinking agent. 
     
     
         42 . The nerve regeneration conduit of  claim 41  wherein the chemical crosslinking agent is glutaraldehyde, formaldehyde, chromium sulfate, carbodiimide or adipyl dichloride. 
     
     
         43 . The nerve regeneration conduit of  claim 27  wherein the matrix within the resorbable conduit having a plurality of substantially parallel axially aligned pores is formed by freezing a slurry of a material capable of forming a matrix and a liquid along an axial direction of the slurry, with the slurry having little or no significant radial thermal gradient, to form a frozen slurry and freeze drying the frozen slurry to form the matrix having substantially parallel axially aligned pores. 
     
     
         44 . A system for nerve regeneration comprising a nerve regeneration conduit and at least one connector with the nerve regeneration conduit comprising
 a resorbable conduit having a first end and a second end, and   a matrix within the resorbable conduit having a plurality of substantially parallel axially aligned pores.   
     
     
         45 . The system for nerve regeneration of  claim 44  including two connectors. 
     
     
         46 . The system of  claim 44  wherein the connector is a resorbable tube having a first open end and a second open end and a diameter sufficient to overlap the resorbable conduit and a nerve to be inserted into the tube. 
     
     
         47 . The system of  claim 44  wherein the connector is a collagen sheet having a length or width sufficient to wrap around the connector and a nerve. 
     
     
         48 . The system of  claim 44  wherein the connector is comprised of collagen, laminin, fibronectin, merosin, hyaluronic acid, chitin, chitosan, keratin, polyglycolic acid, polylactic acid, or cellulose. 
     
     
         49 . The system of  claim 44  wherein the resorbable conduit is a tube including collagen. 
     
     
         50 . The system of  claim 44  wherein the matrix is comprised of collagen, laminin, fibronectin, merosin, hyaluronic acid, chitin, chitosan, keratin, polyglycolic acid, polylactic acid, or cellulose. 
     
     
         51 . The system of  claim 50  wherein the matrix further includes a glycosaminoglycan. 
     
     
         52 . The system of  claim 51  wherein the glycosaminoglycan is chondroitin sulfate, dermatan sulfate, keratin sulfate or hyaluronic acid. 
     
     
         53 . The system of  claim 51  wherein the glycosaminoglycan is chondroitin sulfate. 
     
     
         54 . The system of  claim 49  wherein the tube further includes a glycosaminoglycan. 
     
     
         55 . The system of  claim 54  wherein the glycosaminoglycan is chondroitin sulfate, dermatan sulfate, keratin sulfate or hyaluronic acid. 
     
     
         56 . The system of  claim 54  wherein the glycosaminoglycan is chondroitin sulfate. 
     
     
         57 . The system of  claim 44  wherein the matrix within the resorbable conduit having a plurality of substantially parallel axially aligned pores is formed by freezing a slurry of a material capable of forming a matrix and a liquid along an axial direction of the slurry, with the slurry having little or no significant radial thermal gradient, to form a frozen slurry and freeze drying the frozen slurry to form the matrix having substantially parallel axially aligned pores. 
     
     
         58 . The system of  claim 44  wherein the nerve regeneration conduct is crosslinked. 
     
     
         59 . The system of  claim 44  wherein the resorbable conduit is crosslinked. 
     
     
         60 . The system of  claim 44  wherein the matrix is crosslinked. 
     
     
         61 . The system of  claim 44  wherein the resorbable conduit and the matrix are crosslinked. 
     
     
         62 . The system of  claim 58  wherein the nerve regeneration conduit is crosslinked to an extent that it is completely resorbed within about 1 to about 3 months. 
     
     
         63 . The system of  claim 58  wherein the nerve regeneration conduit is crosslinked by heating under vacuum or by treatment with a chemical crosslinking agent. 
     
     
         64 . The system of  claim 63  wherein the chemical crosslinking agent is glutaraldehyde, formaldehyde, chromium sulfate, carbodiimide or adipyl dichloride.