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Publication numberCA2082427 C
Publication typeGrant
Application numberCA 2082427
PCT numberPCT/US1991/003106
Publication date31 Oct 2000
Filing date6 May 1991
Priority date7 May 1990
Also published asCA2082427A1, DE69126971D1, DE69126971T2, EP0527936A1, EP0527936A4, EP0527936B1, US5108438, WO1991016867A1
Publication numberCA 2082427, CA 2082427 C, CA 2082427C, CA-C-2082427, CA2082427 C, CA2082427C, PCT/1991/3106, PCT/US/1991/003106, PCT/US/1991/03106, PCT/US/91/003106, PCT/US/91/03106, PCT/US1991/003106, PCT/US1991/03106, PCT/US1991003106, PCT/US199103106, PCT/US91/003106, PCT/US91/03106, PCT/US91003106, PCT/US9103106
InventorsKevin R. Stone
ApplicantKevin R. Stone, Regen Corporation, Regen Biologics, Inc.
Export CitationBiBTeX, EndNote, RefMan
External Links: CIPO, Espacenet
Prosthetic intervertebral disc
CA 2082427 C
Abstract
A prosthetic intervertebral disc (200) is disclosed which can be implanted in the human skeleton, and which can at as a scaffold for regrowth of intervertebral disc material. The disc (200), includes a dry, porous, volume matrix of biocompatible and bioresorbable fibers which may be interspersed with glycosaminoglycan molecules.
The matrix is adapted to have in vivo an outer surface contour substantially the same as that of a natural intervertebral disc, whereby said matrix establishes an at least partially bioresorbable scaffold adapted for ingrowth of intervertebral fibrochondrocytes.
Cross-links may be provided by a portion of the GAG molecules.
Claims(69)
1. A prosthetic intervertebral disc comprising a dry, porous volume matrix of biocompatible and bioresorbable fibers, said matrix being adapted to have in vivo an outer surface contour substantially the same as that of a natural intervertebral disc, whereby said matrix establishes an at least partially bioresorbable scaffold adapted for ingrowth of vertebral fibrochondrocytes, and wherein said scaffold and said ingrown fibrochondrocytes support natural intervertebral disc load forces.
2. The disc of claim 1 wherein said fibers comprise polymers.
3. The disc of claim 1 wherein said fibers are selected from the group consisting of natural polymers, analogs of said natural polymers, synthetic fibers, and mixtures thereof.
4. The disc of claim 3 wherein said natural polymers are selected from the group consisting of collagen, elastin, reticulin, cellulose, analogs thereof, and mixtures thereof.
5. The disc of claim 4 wherein said natural polymers are collagen-based polymers.
6. The disc of claim 1 further comprising cross-links between at least a portion of said fibers.
7. The disc of claim 1 further comprising a plurality of glycosaminoglycan molecules interspersed with said fibers.
8. The disc of claim 7, wherein said glycosaminoglycan molecules are selected from the group consisting of chondroitin 4-sulfate, chondroitin 6-sulfate, keratin sulfate, dermatan sulfate, heparan sulfate, heparin, hyaluronic acid, and mixtures thereof.
9. The disc of claim 7 wherein at least a portion of said molecules provide cross-links between said fibers.
10. The disc of claim 7 wherein said fibers are present at a concentration of 75-100% by dry weight, and said glycosaminoglycan molecules are present at a concentration of 0-25% by dry weight.
11. The prosthetic disc of claim 6 wherein said cross-links are formed by a chemical cross-linking agent.
12. The prosthetic disc of claim 11 wherein said cross-linking agent is selected from the group consisting of glutaraldehyde, formaldehyde, biocompatible bifunctional aldehydes, carbodiimides, hexamethylene diisocyanate, bis-imidates, polyglycerol polyglycidyl ether, glyoxal, acyl azide, and mixtures thereof.
13. The prosthetic disc of claim 12 wherein said cross-linking agent comprises 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide.
14. The disc of claim 1 wherein said intervertebral disc has a density of 0.07 to 0.50 gram matrix per cubic centimeter.
15. The disc of claim 1 wherein said intervertebral disc has an intrafibrillary and interfibrillary space of 2 - 25 cm3/g matrix.
16. The disc of claim 1 wherein said fibers are oriented in a substantially random fashion throughout said matrix.
17. The disc of claim 1 wherein said fibers are oriented in a substantially ordered fashion throughout said matrix.
18. The disc of claim 17 wherein said matrix comprises substantially circumferentially extending fibers.
19. The disc of claim 17 wherein said matrix comprises substantially radially extending fibers.
20. The disc of claim 1 wherein the density of said fibers is substantially uniform throughout said matrix.
21. The disc of claim 1 wherein said fibers are oriented in a substantially ordered fashion in the region adjacent to the peripheral edge of said disc, said orientation being substantially circumferential.
22. The disc of claim 21 wherein said fibers are oriented in a substantially random fashion in the central region of said disc.
23. The disc of claim 7 wherein said glycosaminoglycan molecules are dispersed substantially uniformly throughout said matrix.
24. The disc of claim 7 wherein said glycosaminoglycan molecules are dispersed nonuniformly throughout said matrix.
25. The disc of claim 1 further comprising a mesh extending from a portion of the outer surface of said matrix, said mesh being resorbable and biocompatible.
26. A method for fabricating a prosthetic intervertebral disc comprising the steps of:
(a) placing a plurality of biocompatible and bioresorbable fibers into a mold, said mold having a shape that enables disc space function;
(b) subjecting said fibers to a first and a second cycle of freezing and thawing;
(c) contacting said fibers with a chemical cross-linking agent such that said fibers assume the shape of said mold; and (d) lyophilizing said cross-linked fibers, said prosthetic intervertebral disc thus formed comprising a dry porous volume matrix being adapted to have in vivo an outer surface countour substantially the same as that of a natural intervertebral disc, whereby said matrix establishes an at least partially bioresorbable scaffold adapted for ingrowth of vertebral fibrochondrocytes.
27. The method of claim 26 wherein said placing step comprises placing a plurality of fibers into a mold, said fibers being selected from the group comprising a natural material, an analog thereof, and a synthetic material.
28. The method of claim 27 wherein said analog of said natural material is a biosynthetic analog.
29. The method of claim 26 wherein said placing step further comprises placing a plurality of polymeric fibers into said mold.
30. The method of claim 26 wherein said fibers are selected from the group consisting of collagen, elastin, reticulin, cellulose, analogs thereof, and mixtures thereof.
31. The method of claim 26 wherein said placing step further comprises placing a plurality of glycosaminoglycan molecules into said mold.
32. The method of claim 31 wherein said glycosaminoglycan molecules are selected from the group consisting of chondroitin 4-sulfate, chondroitin 6-sulfate, keratin sulfate, dermatan sulfate, heparin, heparan sulfate, hyaluronic acid, and mixtures thereof.
33. The method of claim 26 wherein said placing step further comprises the step of orienting said fibers substantially circumferentially.
34. The method of claim 33 wherein said orienting step comprises compressing said fibers in said mold with a piston, directed along a compression axis, while during said compressing step said piston is rotated with respect to said mold about said compression axis.
35. The method of claim 33 wherein said orienting step comprises rotating said mold as said fibers are placed therein.
36. The method of claim 26 wherein said placing step further comprises the step of orienting said fibers substantially radially.
37. The method of claim 26 further comprising the step of compressing said fibers prior to said second cycle of freezing and thawing.
38. The method of claim 31 further comprising the step of compressing said fibers and said glycosaminoglycan molecules prior to said second cycle of freezing and thawing.
39. The method of claim 37 wherein said compressing step comprises applying a predetermined amount of pressure to a region of said matrix with a piston, said piston having a predetermined shape.
40. The method of claim 26 wherein said chemical cross-linking agent is selected from the group consisting of glutaraldehyde, formaldehyde, biocompatible and bifunctional aldehydes, carbodiimides, hexamethylene diisocyanate, bis-imidates, polyglycerol polyglycidylether, glyoxal, acyl azide, and mixtures thereof.
41. The method of claim 26 further comprising the additional step of subjecting said lyophilized matrix to dehydrothermal cross-linking.
42. The use of a prosthetic intervertebral disc for regeneration of intervertebral tissue in vivo wherein said disc comprises a dry porous volume matrix of biocompatible and bioresorbable fibers, said matrix being adapted to have in vivo an outer surface contour substantially the same as that of a natural intervertebral disc, whereby said matrix establishes an at least partially bioresorbable scaffold adapted for ingrowth of vertebral fibrochondrocytes, and wherein said scaffold and said ingrown fibrochondrocytes support natural intervertebral disc load forces.
43. The use of claim 42 wherein at least a portion of said fibers are cross-linked.
44. The use of claim 42 wherein a plurality of glycosaminoglycan molecules are interspersed with said fibers.
45. The use of claim 42 wherein said disc further comprises a mesh extending from a portion of the outer surface of said disc, said mesh being resorbable and biocompatible.
46. The use of any one of claims 42 to 45, wherein said fibers are selected from the group consisting of natural polymers, and analogs and mixtures thereof.
47. The disc of claim 1, wherein said fibers are selected from the group consisting of natural polymers, and analogs and mixtures thereof.
48. The disc of claim 47 wherein said natural polymers are selected from the group consisting of collagen, elastin, reticulin, cellulose, analogs thereof, and mixtures thereof.
49. The disc of claim 48 wherein said natural polymers are collagen-based polymers.
50. The disc of claim 47 further comprising cross-links between at least a portion of said fibers.
51. The disc of claim 47 further comprising a plurality of glycosaminoglycan molecules interspersed with said fibers.
52. The disc of claim 51, wherein said glycosaminoglycan molecules are selected from the group consisting of chondroitin 4-sulfate, chondroitin 6-sulfate, keratin sulfate, dermatan sulfate, heparan sulfate, heparin, hyaluronic acid, and mixtures thereof.
53. The disc of claim 51 wherein at least a portion of said molecules provide cross-links between said fibers.
54. The disc of claim 51 wherein said fibers are present at a concentration of 75-100% by dry weight, and said glycosaminoglycan molecules are present at a concentration of 0-25% by dry weight.
55. The prosthetic disc of claim 50 wherein said cross-links are formed by a chemical cross-linking agent.
56. The prosthetic disc of claim 55 wherein said cross-linking agent is selected from the group consisting of glutaraldehyde, formaldehyde, biocompatible bifunctional aldehydes, carbodiimides, hexamethylene diisocyanate, bis-imidates, polyglycerol polyglycidyl ether, glyoxal, acyl azide, and mixtures thereof.
57. The prosthetic disc of claim 56 wherein said cross-linking agent comprises 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide.
58. The disc of claim 47 wherein said intervertebral disc has a density of 0.07 to 0.50 gram matrix per cubic centimeter.
59. The disc of claim 47 wherein said intervertebral disc has an intrafibrillary and interfibrillary space of 2 - 25 cm3/g matrix.
60. The disc of claim 47 wherein said fibers are oriented in a substantially random fashion throughout said matrix.
61. The disc of claim 47 wherein said fibers are oriented in a substantially ordered fashion throughout said matrix.
62. The disc of claim 61 wherein said matrix comprises substantially circumferentially extending fibers.
63. The disc of claim 61 wherein said matrix comprises substantially radially extending fibers.
64. The disc of claim 47 wherein the density of said fibers is substantially uniform throughout said matrix.
65. The disc of claim 47 wherein said fibers are oriented in a substantially ordered fashion in the region adjacent to the peripheral edge of said disc, said orientation being substantially circumferential.
66. The disc of claim 65 wherein said fibers are oriented in a substantially random fashion in the central region of said disc.
67. The disc of claim 51 wherein said glycosaminoglycan molecules are dispersed substantially uniformly throughout said matrix.
68. The disc of claim 51 wherein said glycosaminoglycan molecules are dispersed nonuniformly throughout said matrix.
69. The disc of claim 47 further comprising a mesh extending from a portion of the outer surface of said matrix, said mesh being resorbable and biocompatible.
Description  (OCR text may contain errors)

. M.-.

2 0 8 2 4 2 l PCT/US91/03106 PROSTHETIC INTERVERTEBRAL DISC
BACKGROUND OF THE DISCLOSURE
The present invention is in the field of implantable medical devices, and more particularly,.
is directed to devices useful as a prosthetic intervertebral disc.
The intervertebral disc acts in the spine as a crucial stabilizer, and as a mechanism for force distribution between the vertebral bodies. Without the disc, collapse of the intervertebral space occurs in conjunction with abnormal joint mechanics and premature development of arthritic changes.
Prior art methods of treating injured or diseased discs have included chemical disintegration procedures and surgical ezcision, often followed by bony fusion to prevent spinal collapse or instability. With ezcision, no significant ,._ W~~1/16867 ~ ~ ~ ~ ~ ~ 7 PCT/US91/03106 ,.
regeneration of vertebral tissue occurs. Replacement of an injured disc in an otherwise healthy spine may prevent arthritic changes and may stabilize the spinal segments. In disease8 spines replacement of the disc may reduce the progression of the disease process, and may provide pain relief.
In alternative prior art replacement approaches, discs have been replaced with prostheses compose3 of a: tificial ~:ater VaIJ. :'::c uss of gurelr artificial materials in the spine minimizes the possibility of an immunological response. In addition, such materials permit construction of a structure which can withstand the high and repeated loads seen by the spinal vertebral joints. and can alter the joint mechanics in beneficial ways that biological materials would not tolerate. For ezample. titanium, (Albrektsson et al. (1981) Acta Ortop. Scan. x:155-170), acrylic (Cleveland (1955) Marquette Med. Rev. ~"Q:62: Hamby et al.(1959) J.
Neurosurg. x,:311). polytetrafluorothylene-carbon fiber (Alitalo (1979) Acta Veterinaria Scandinavica Suppl. ~:1-58), and steel discs (Fenstrom (1973) Acta Chir. Stand. 4:165-186: French Patent No.
4,349.921) have been used to replace the resected disc. Each of these efforts have met with failure due to continued collapse of the disc space or erosion of the metal prosthesis into the surrounding bone.
A prosthetic intervertebral disc has also been constructed from resilient materials such as silicone rubber (e. g., Edeland (1985) J. Hiomed Eng.
7:57-62; Schneider et al. (1974) 2. Orthop.

WO 91/16867 2 o a 2 4 ~ 7 P~/US91/03106 x:1078-1086; Urbaniak et al. (1973) J. Hiomed.
Mater. Res. Symposium q:165-186). A disc has also '. been made from resilient plastic materials to form a bladder as disclosed in U.S. Patent Nos. 3.875.595 and 4,772,287; however, failure to restore full stability and normal joint biomechanics has prevented success. Porous elastomeric materials as described in U.S. Patent No. 4,349.921 have failure to recapitulate the normal vertebral body mechanics.
Generally, the replacement of intervertebral tissue With structures consisting of artificial materials has been unsuccessful principally because the opposing vertebral end plates of human and animal joints are fragile. The end plates in the spine will not withstand abrasive interfaces nor variances from normal compliance. which evidently result from the implantation of prior art artificial discs.
Additionally, joint forces are multiples of body weight which, in the case of the spine, are typically over a million cycles per year. Thus far, prior art artificial discs have not been soft or durable enough, nor have they been able to be positioned securely enough to withstand such routine forces.
Prostheses, in general, have been devised out of at least some of the constituents of the structures which they are replacing, or out of materials not considered to be immunogenic to the body. For ezample, Yannas et al. fashioned blood vessel grafts (U. S. Patent No. 4,350.629), synthetic epidermis (U. S. Patent No. 4,448,718), and sciatic nerve guides (WO 89/10728; Yannas (1979) Am. Chem.
Soc. x:209) out of collagen and glycosaminoglycans, wQ 91 ~' ~' 2 0 8 2 4 2 l P~~US91 /03106 biochemical components of many body organs. Hy adjusting the pore size and azes of the pores and fibers comprising these structures, regrowth of natural tissue could be stimulated. Further regrowth has been advanced by seeding of the nerve guide with Schwann cells prior to implantation (see U.S. Fatent No. 4,458,678). However, even with the foregoing technologies which have been applied to the reconstruction of anatomical structures other than intervertebral discs, a structure suitable as a prosthetic disc and constructed from natural materials has not yet been successfully developed.
Accordingly, it is an object of this invention to provide an intervertebral disc replacement or prosthesis.
Another object is to provide an improved disc replacement or prosthesis that does not interfere With normal vertebral segment motion as such interference could lead to a reduced range of motion or to focal concentration of force at other sites within the spinal column or instability of the opposing vertebral bodies, therefore enhancing the chances of progressive arthritic destruction.
Yet another object is to pzovide an improved disc replacement or prosthesis that is biomechanically able to withstand normal spinal column forces and is able to function at those loads to protect the opposing end plates and stabilize the joints.

W O 91/16867 2 p 8 2 4 2 7 P~/US91/03106 --Still another object is to provide an improved disc replacement or prosthesis Which promotes regrowth of intervertebral disc material and Which acts as a scaffold for fibrocartilage infiltration.
A further object is to provide an improved disc replacement or prosthesis does not evoke an immunologic reaction or aggrevate other joint structures.
Still a further object is to provide an improved meniscal replacement or prosthesis which can be easily implanted by standard operative techniques.

SL~~Rv OF THE INVENTION
The present invention provides a biocompatable and bioresorbable structure for implantation into the spine which assumes the form and role of an intervertebral disc. This matrix may promote regrowth of intervertebral fibrochondrocytes and provides a scaffold for the regenerating intervertebral disc tissue.
Tne prosthetic disc is composed of a dry, porous. volume matrix of biocompatable and bioresorbable fibers. The matrix is adapted to have ~ v'v an outer surface contour substantially the same as that of a natural intervertebral disc. A
portion of the fibers may be cross-linked.
The fibers include a natural fiber or an analog of a natural fiber such as a biosynthetic analog, or a synthetic fiber. or mixtures thereof. A
biosynthetic fiber is one which may be produced by recombinant DNA technology including the transfection of an appropriate host cell capable of protein expression with a gene encoding, for example, a recombinant protein such as collagen. A synthetic fiber is one which may be produced by chemical methods such as. automated peptide synthesis. In one preferred embodiment of the invention, the fibers of the matrix are polymers of, for example, natural molecules such as those obtained from animal or human tissue. Natural fibers useful for the same purpose preferably include collagen, elastin, reticulin, cellulose, analogs thereof, and mixtures thereof.
A

7 2 0 8 2 4 2 7 p~/US91/03106 _7-In some forms of the invention, the fibers may be randomly orientated throughout the matrix, or '. may be ordered at specified regions. Alternatively, the fibers may assume substantially circumferentially extending or substantially radially extending orientations throughout the prosthetic disc.
The matrix may also include glycosaminoglycan molecules (GAGS) interspersed with the fibers. GAGs are mucopolysaccharide molecules Which provide lubrication and may be included in cross-links for the prosthetic disc. In one preferred aspect of the invention, GAGS such as chondroitin 4-sulfate, chondroitin 6-sulfate, keratin sulfate. dermatan sulfate, heparan-sulfate, heparin, hyaluronic acid, and mixtures thereof form a component of the disc. The GAGS may be uniformly dispersed throughout the prosthetic disc as individual molecules, or may be present in varying amounts in different regions of the structure.
In various forms of the invention, GAGS may directly participate in covalent cross-linking with the fibers, or may interact with the fibers mechanically in the form of entanglement or through interlocking mechanisms, thereby forming various stable fiber-GAG complexes.
The matrix may include about 75-100% natural ' 30 and/or synthetic fibers and about 0-25% GAGS by dry weight, the proportions of which may be constant ' throughout the structure or may be variable.

WO 91/16867 . 2 0 8 2 4 2 l P~/US91/03106 _g_ In a preferred embodiment of the invention, the matriz has a density of about 0.07 to 0.50 g matriz/cm3, Where "g matriz/cm3" is a unit connoting .' the number of grams in a cubic centimeter of the matriz. In addition, the matriz may have an interfibrillary and intrafibrillary space of about 2 to 25 cm3/g matriz.
In another form of the invention, the prosthetic disc may further include a mesh composed of a bioresorbable. biocompatible material which is attached to lateral portions of the outer surface of the matriz. The mesh aids in the successful implantation of the prosthetic intervertebral disc into the intervertebral spaces by providing a temporary anchoring mechanism.
The present invention also includes a method of regenerating intervertebral disc tissue ~p vivo.
This method includes fabricating a prosthetic intervertebral disc of the type described above, and implanting it into the spine by surgical procedures.
The presence of the prosthetic disc stimulates disc tissue growth.
Further, the invention includes a method for fabricating a prosthetic intervertebral disc of the type described above. Generally, the method includes placing a plurality of fibers or fibers and GAGS into a mold having a shape useful for spine function, subjecting the fibers (and GAGs) in the mold to two cycles of freezing and thawing, contacting the fibers ' or the fibers and GAGs with a chemical cross-linking reagent such that the fibers then assume the shape of -~w 2082421 the mold, and lyophilizing the resulting structure to obtain a dry, porous. volume matriz.
The fibers may be laid down in a circumferential orientation by rotating the mold as they are placed therein. Alternatively, the fibers in the mold may be compressed with a rotating piston. Radial orientation of the fibers is produced by manually painting t3~e fibers in a linear, radially 1_f~ di rLsrtori f g=~li~.~..
Specific densities and pore sizes may be obtained in various regions of the matriz by compressing the fibers or fibers and GAGS in the mold prior to the second freeze-thaw cycle. and subsequent to the chemical cross-linking step. This may be accomplished by applying pressure to a specific region of the matriz with a piston of a predetermined shape.
In a preferred aspect of the invention, the cross-linking step is performed using chemical agents which form intramolecular and intermolecular cross-links. Useful chemical agents include, for ezample, glutaraldehyde, formaldehyde, biocompatible bifunctional aldehydea, carbodiimides, hezamethylene diisocyanate, bis-imidates, glyozal, polyglycerol polyglycidyl ether, glyozal, and miztures thereof.
Particularly useful cross-linking agents are 1-ethyl, 3-(3-dimethylami,nopropyl) carbodiimide, polyglycerol polyglycidyl ether, acyl azide, and glutaraldehyde.
In other aspects of the invention, an additional cross-linking step is performed by A

lyophilizing the chemically cross-linked disc and then subjecting it to dehydrothermal cross-linking procedures.
In yet another aspect, the present invention provides the use of a prosthetic intervertebral disc for regeneration of intervertebral tissue in vivo by surgical implantation of said disc into a spine, wherein said disc comprises a dry porous volume matrix of biocompatible and bioresorbable fibers, said matrix being adapted to have in vivo an outer surface contour substantially the same as that of a natural intervertebral disc, whereby said matrix establishes an at least partially bioresorbable scaffold adapted for ingrowth of vertebral fibrochondrocytes, and wherein said scaffold and said ingrown fibrochondrocytes support natural intervertebral disc load forces.
The invention will next be described in connection with certain illustrated embodiments.
However, it should be clear that various modifications, additions, and deletions can be made without departing from the spirit or scope of the invention.
A

VfO 91/16867 2 p 8 2 4 2 7 P~/US91/0310G

BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing and other objects of this invention, the various features thereof, as well as the invention. itself, may be more fully understood from the following description, When read together with the accompanying drawings in which:
FIG. 1 is a simplified diagrammatic representation of the normal positioning of an intervertebral disc in native position in the human spine:
FIG. 2 shows a perspective view of an exemplary prosthetic intervertebral disc in accordance with the present invention;
FIG. 3 shows a sectional view along line 3-3 of the prosthetic intervertebral disc of FIG. 2;
FIG. 4 shows a perspective view of another exemplary prosthetic intervertebral disc;
FIG. 5A shows a perspective view of another exemplary prosthetic intervertebral disc including a mesh member; and FIG. 5B shows a sectional view along line 5B-5B of the prosthetic disc of FIG 5A;
FIG. 6 shows in section an exemplary mold for constructing a prosthetic intervertebral disc; and FIG. 7 shows in section an alternative mold for constructing a prosthetic intervertebral disc.

WO 91/16867 PC?/US91/03106 20824?7 p~SCRIPTION OF TH~ INVENTION
It has been discovered that a prosthetic intervertebral disc fabricated from biocompatible and bioresorbable fibers can be surgically implanted into the intervertebral space so as to provide normal joint motion and strength. This prosthetic intervertebral disc also acts as a scaffold for regenerating disc tissue whose ingrowth is encouraged by the physical C!:aractezistics of tre implanted device. Following implantation, tissue ingrowth, regeneration, and finally resorption of the scaffold.
natural intervertebratal tissue remains.
FIG. 1 shows the normal positioning of an intervertebral disc 100 in the human intervertebral space 110 between the vertebral bodies 120 and 130.
An exemplary prosthetic intervertebral disc 200 is shown in FIG. 2. The disc 200 is a generally porous, dry volume matriz which eztends circumferentially in about a central azis 10. As used herein, the term "volume matriz" refers to a porous array characterized by relatively comparable (but not necessarily equal) outer dimensions in three orthogonal directions (as contrasted with a sheet matriz which would have relatively comparable dimensions in two orthogonal directions but relatively small dimensions in a third orthogonal direction).
In the preferred form, prior to implantation, the prosthetic intervertebral disc 200 has the shape of a cylindrical pad, eztending circumferentially about the azis 10, and comprising a relatively high compliance central region 12 disposed about a relatively low compliance peripheral region 14. In FIG. 2, the separation of regions 14 and 12 is indicated generally by broken line 17, although the transition is normally gradual. In the preferred form, the top and bottom (as shown) surfaces of disc 200 are concave so that disc 200 has maximum height A
at its peripheral edge,of approximately 8 mm and a maximum radial dimension C of approximately 35 mm.
iu FIG. 3 shows a sectional view along line 3-3 of the prosthetic disc 200 shown in FIG. 2.
FIG. 4 shows an additional embodiment 220 of the present invention which is similar in composition to the prosthetic disc 200 depicted in FIG. 2. The prosthetic intervertebral disc 220 is similar to disc 200, but includes convex top and bottom surfaces and further includes a mesh member ZO extending from its lateral surface. The mesh member 20 is composed of a biocompatible, bioresorbable material. Following implantation, the mesh member 20 may be sutured to adjacent tissue to anchor the disc 220 in place. The mesh member 20 may function in this capacity until sufficient tissue ingrowth occurs to provide that function. Since the anchor function of mesh member 20 is only temporary, the mesh member 20 may be a ~1 mesh screen composed of absorbable suture materials such as polyglyconate, Dezon; or polydiozane (PDS) woven into a mesh. Alternatively, nonabsorbable suture materials such as expanded polytetrafluoroethylene (PTF'E) may be used.
FIGS. 5A and 5B show yet another embodiment 230 Which is similar to that of FIG. I but having * Trade mark Wp 91/1686? 2 0 ~ 2 4 2 l P~/US91/0310G

concave top and flat bottom surfaces. Other combinations might also be used.
In alternative forms of the invention, still other shapes than full cylinders may be used. For eaample, it is not required that the full 360 (about azis 10) pad be used if partial disc replacement is undertaken. For angular segment type discs, the cylindrical form may subtend any angle between zero ?0 a~d 360 degrees abaut axis 10. It is however important that the matriz have characteristics so that when implanted, at least the top and bottom surfaces substantially assume the shape or contour of a natural intervertebral disc.
The various embodiments of the invention may have certain densities of collagen fibers and dispersions of GAG molecules and cross-links that permit accommodation of differing stress levels, rates of ingrowth, and resiliency. Differing densities may be obtained ~ vivo where a device having uniform density is implanted, and body loading causes non-uniform compression of the device.
Alternatively, the prosthetic disc may be initially configured with non-uniform construction of a type so that the i,n vivo configuration provides the desired spatial densities and dispersions necessary for the desired function.
The prosthetic intervertebral disc may be fabricated of any biocompatible, bioresorbable fibers such as a natural material, an analog thereof or a synthetic material. The fibers are preferably polymeric in structure so that they can provide H'O 91/16867 2 0 8 2 4 2 7 P~/US91/03106 mechanical strength, protection, and lubrication while encouraging tissue ingrowth. Such polymeric fibers include. for ezample, collagen, reticulin, elastin, cellulose, and biosynthetic analogs thereof. These fibers may be ordered in substantially circumferentially-eztending oz substantially radially-eztending orientations, with the density of fibers being substantially uniform throughout the matriz. Alternatively, the matriz fibers may be unordered. In either the ordered or unordered configuration, the density of the fibers may be non-uniform. In the non-uniform configuration. relatively high densities of fibers may be established at anticipated points of high stress.
In an alternative aspect of the invention, the intrafibrillary (i.e., the space within the fiber) and interfibrillary (the space between the fibers) space is relatively high, a condition which promotes ingrowth of regenerated disc tissue. For ezample, the density of the intervertebral disc may be in the range of about 10-25 g matriz/cm3.
Alternatively, the intrafibrillary and interfibrillary space may be relatively low, a condition which provides superior cushioning, lubrication, and mechanical support for the intervertebral space, and which retards tissue and cell ingrowth, thereby diminishing the rate of scaffold resorption (e.g., density is in the range of about 2-10 g matria/cm3).
The temporary stability of the shape of the structure when ~ yivo, and the rate of disc ~.. J 91/16867 PC?/US91/03106 resorption, are both attributed to the effective cross-link formation between at least one portion of the fibers. The cross-linking reagents used with the above-noted fiber materials may be any biocompatible, bifunctional reagents which interacts with amino, carbonyl, or hydrozyl groups on a single fiber forming intramolecular cross-links, or on multiple fibers or on the fibers and the GAGs, resulting in covalent bond formation between adjacent molecules (intermolecular cross-links). Useful cross-linking reagents include aldehydes, hezamethylene diisocyanate, bisimidates. polyglycerol polyglycidyl ether, acyl azide, and carbodiimides.
The cross-linked device maintains a sufficient degree of hydrophilicity and elasticity which simulates the properties of the natural intervertebral disc, i.e., ability to sustain mechanical stress and to protect and lubricate articular surfaces. In addition, the structure provides an ideal environment for cell infiltration and eztracellular matriz synthesis and deposition, resulting in regeneration of natural disc tissue.
GAGS may be dispersed throughout the fibers. Alternatively, they may act as intermolecular cross-links between fibers. These GAGS typically include at least one of the group of molecules consisting of chondroitin 4-sulfate, chondroitin 6-sulfate, keratin sulfate, dermatan sulfate. heparan sulfate, heparin. and hyaluronic acid. The dispersion of GAG cross-links is preferably uniform, but may be more concentrated at anticipated points of high stress, typically at the - '~ 2082427 peripheral region 14, and less concentrated in the central region 12 (FIG. 2). In such configurations, the GAG concentration may be in the range of about 0-25~ in the distal region 14, and in the range of about 0-10~C in the central region 12. However, When uniform, the dispersion of GAGS throughout the prosthetic intervertebral disc may be, for ezample, in the range of about 1-15~C.
Intermolecular cross-links can also be established through a dehydrothermal process (heat and vacuum) which results in peptide bond formation between an epsilon amino group of lysine or hydrozylysine and a carbozyl group of aspartic or glutamic acid.
The cross-linked disc has a relatively high thermal stability at between about 55-85C, and preferably at between about 65-75C foz sufficient ~
v'v stability. This may be achieved through manipulation of the cross-linking conditions, including zeagent concentration, temperature, pH, and t ime ( see 1=XAMPLir 1 ) .
In a one embodiment the prosthetic intervertebral disc is constructed mainly of Type I
collagen fibers without GAG cross-links. Type I
collagen fibers may be obtained from the Achilles tendons of animals. However, the fibers may also be obtained from animal skin or from the skin or tendon of humans. The tissues are treated with a series of mechanical and chemical means to either totally remove the non-collagenous materials or reduce them to a minimal level. In the preferred processing steps, the tendon or skin is mechanically disintegrated into fine pieces useful for further processing. The disintegration may be achieved by grinding the tissue at liquid nitrogen temperature, or by cutting the tissue into small pieces with a sharp knife. In certain applications, the tendons are mechanically disintegrated along the fiber direction in order to maintain the length of the fibers for mechanical strength.
Salt eztraction of tendon at neutral pH
removes a small portion of the collagen molecules that are newly synthesized and have not yet been incorporated into the stable fibrils. Salt also removes some glycoproteins and proteoglycans that are associated with collagen through electrostatic interactions. Other salts such as KCl can be used as a substitute for NaCl.
Lipids that are associated with the cell membranes or collagenous matrices may be removed by first eztracting with detergents such as Triton X-100 (Sigma Chemical Co., St. Louis, Missouri), followed by eztracting with ether-ethanol miztures. The concentration of Triton X-100*is usually about 2-4~, but is preferably about 3~. The preferred mizture of ether-ethanol is usually at about a l:l ratio (v/v).
The period of eztraction is usually from B hours to 96 hours. and is preferably from about 24 to 48 hours.
Further eztraction may be accomplished by matriz swelling conducted at two eztreme pHs. Both acidic and basic swelling weakens the non-covalent intermolecular interactions, thus facilitating the * Trade mark A

~..~ 91/16867 PCT/US91/03106 . 2082427 release of non-covalently attached glycoproteins, GAGS, and other non-collagenous molecules through the open pores of the collagenous matrices.
The swelling of the collagenous matriz at alkaline pH is performed by treating the collagen at high pH with Ca(OH)2, NaOH, or the like, for a period of about 8-96 hours. Alkali eztraction in the presence of triple-helical stabilizing salts such as (CH3)NC1 or NH3SOa_ reduces the potential risk of denaturation of the collagen. Alkali treatment dissociates the non-cross-linked glycoproteins and GAGs from the collagen matrices. The alkali also removes the residual lipids through saponification.
Acid swelling may be conducted at a low pH
in the presence of acetic acid, HC1. or similar acids. Like the alkali treatment, the swelling removes non-cross-linked glycoproteins and GAGS.
The non-triple helical portions of the molecule (telopeptides) are involved in intermolecular cross-linking formation. They are weak antigens and are susceptible to attack by proteases such as pepsin and trypsin. Prolonged digestion with such proteases dissociates the fibrils (fibers) into individual molecules. However, if the digestion process is properly controlled such that mazimal telopeptides are removed without complete dissociation, the immunogenic properties of the fibrils can be reduced to a minimal level without compromising the mechanical strength. For ezample, to isolate molecular collagen, the digestion of skin or tendon with pepsin is usually conducted at an ..O 91/16867 PCTlLS91/03106 enzyme:collagen ratio of about 1:10 for about 24-96 hours at below room temperature. In comparison, fibrils may be obtained by limited pepsin digestion achieved at a ratio of about 1:100 (enzyme: collagen) for about 24-96 hours at 4C.
Collagen fibers obtained according to this methodology are then used to fabricate the prosthetic intervertebral disc of the present invention.
However, it must be appreciated that collagen obtained from other sources, such as biosynthetically-produced collagen or analogs thereof, may also be used in the construction of the prosthetic intervertebral disc.
One method of fabrication includes molding the collagen fibers into a predetermined shape using, for ezample, the mold forms described below in conjunction With FIGS. 6 and 7. The fibers may be placed randomly in the mold, or may be oriented in specific directions to achieve a intervertebral disc having specific structure characteristics. Other components such as GAGs which may participate in the cross-linking reaction, can be mized in with the fibers in a random or non-random fashion before the structure is subjected to various cross-linking procedures including chemical methods and/or dehydrothermal methods.
By following the processes described in the ezamples set forth hereinbelow, a prosthetic intervertebral disc of the form shown in FIGs. 2 or 3 may be constructed having the characteristics listed below in TABLE 1.

WO 91/16867 2 O 8 2 4 ? l PCT/US91/03106 1?hysical Cha~acteristj,cs height A = 5 - 12 mm radius C = 10 - 25 mm density = 0.07 - 0.5 g/cm3 intra- and interfibrillary space = 2 - 25 cm3/g matziz Constituents fiber content = 75 - 100~C
glycosaminoglycan content = 0 - 25~
The prosthetic discs were evaluated ~ v'v and ~ vitro to determine ability to function physically, or to serve as a regeneration template for the fibrochondrocytes ezpected to serve as precursor cells for the subsequent fibrocartilaginous matriz. These studies demonstrate that the prosthetic disc allows for, and induces fibrochondrocyte infiltration and disc regeneration through the prosthetic material.
The following non-limiting ezamples describe methods of fabrication and ~ vivo use of the prosthetic intervertebral disc of the present invention.
FXAMPL~ 1 Mold Fabrication A mold useful for fabricating the prosthetic intervertebral disc is made of implantable stainless steel or biocompatible plastics such as polypropylene, delrin*, or combination of these materials. Exemplary molds 300 and 500 shown in Figures 6 and 7 respectively are composed of three pieces, labelled 302, 304, and 306 in Figure 6 and 502, 504 and 506 in Figure 7.
Hy way of ezample for the disc-shaped intervertebral disc illustrated in FIGS. 5A and 5B, the mold 300 of FIG. 6 is used. Piece 302 is disc-like and has a diameter substantially equal to that of the desired intervertebral disc. Piece 302 is perforated to allow liquid to pass through under pressure. The inner surface 303 of piece 302 has the desired shape of one side of the intervertebral disc-to-be-formed.
Piece 304 is a hollow cylinder which has the same inner dimension as piece 302. Piece 306 is a cylindrical piston which has an outer diameter .
slightly less than the inner diameter of piece 304.
The "top", or crown, surface 308 of piston 306 has the desired shape of one side of the intervertebral disc-to-be-formed.
For an intervertebral disc having flat top and bottom surfaces, the mold 500 of FIG. 7 is used where pieces 502 and 504 are.the same as pieces 302 and 304 in FIG. 6, and piece 506 is similar to piece 306 in FIG. 6 but has a flat crown surface 508.
During fabrication of the prosthetic disc 230, mold piece 302 is first assembled within piece 304, as shown in FIG. 6. The constituent fibers (in a fluid) are placed against the surface 303 of piece * Trade mark wo 9m ~ss~ 2 0 8 2 4 2 7 p~~US91 /03106 302. The crown surface 308 of piston 306 is then driven toward surface 303 along a compression azis until the fibers are compressed, the fluid is driven out through piece 302, and the desired azial dimension of the compressed fiber array is attained.
The mold is then frozen in pzeparation for cross-linking.
FXAMPL~ 2 1~ Pzeparatior. of Furified Type I CollagGr~
Bovine. porcine, or sheep Achilles tendon is obtained from USDA-approved slaughter houses. The preferred age of the animals is between 12 - 18 months. The tissue is kept cold during the purification process ezcept Where specified to minimize bacteria contamination and tissue degradation.
The adhering tissues of carefully selected tendons are first scrapped off mechanically. The tendons are then minced or cut into fine pieces and washed in ezcess quantities (about 10 volumes) of cold Water to remove residual blood proteins and water soluble materials.
The washed tendons are eztracted in ten volumes of 5$ NaCl, 0.01 M Tris, pH 7.4, for 24 (+/-4) hours to remove salt soluble materials. The salt-eztracted tendons are repeatedly washed in about 10 volumes of water to remove the salt.
To eztract lipid, the material is eztracted in 3$ Triton X-100 for 24 (+/- 2) hours. The ~~ 2082427 detergent is removed by extensive washing with water. The material is then extracted in 3-4 volumes of ether-ethanol (1:1 vol/vol) for 24 (+/- 2) hours to further minimize the lipid content. The lipid extracted material is extensively washed in water to remove the ether and ethanol.
The material is then subjected to two extreme pH eztractions to remove non-collagenous r.:aterials. Alkaline extraction is cornucted with 3-4 volumes of 0.2 M NaOH at pH 12.5 - 13.5 at room temperature in the presence of 1.0 M (CH3)NCl for 24 (+/- 2) hours with mild agitation.
Following alkaline extraction, the pH is neutralized with HC1, and the material is washed with Water. The pH is then adjusted to 2.5 - 3.0 by adding concentrated acetic acid to a final concentration of 0.5 M. The acid extraction is continued for 24 (+/- 2) hours with agitation.
The acid swollen tendon is then subjected to a limited proteolytic digestion with pepsin (enzyme:collagen = 1:100) for 24 (+/-) 2 hours. The pepsin and resulting telopeptides are removed through dialysis.
The swollen fibrillar material is then coacervated by adjusting the pH to its isoionic point with 1 M NaOH or HCl or by adjusting the ionic strength to 0.7 with NaCl. The aggregated collagen fibers are harvested by filtration, and the filtered material extensively washed with cold phosphate ffO 91 / 16867 2 0 8 2 4 2 7 P~/US91 /03106 buffered saline solution. The highly purified type I
collagen may be stored at -20 to -40C until used.

Device I Fabrication A) The collagen content of the highly purified type I collagen fibrils from EXAMPLE 2 is determined either by gravimetric methods or by determining the hydrozyproline content assuming a 13.5~C by weight of hydrozyproline in Type I collagen The amount of purified material needed to fabricate a given density of a prosthetic intervertebral disc device is then determined and weighed out.
B) A solution of fibrillar collagen is carefully fit into a mold of desired, specified dimensions (see EXAMPLE I and FIG. 6 for a description of molds). Collagen fibers are laid down in random manner or in an oriented manner. In the oriented manner, circumferential orientation of the fibers is produced by rotation of the piston about its principal azis as the material is compressed in the mold; radial orientation is produced by manual painting of the collagen fibers in a linear, radially directed fashion.
C) The fibers are frozen at -20C, turned out of the mold, and thawed at room temperature.
D) The fibers are then resuspended in phosphate buffered saline, put back into the mold in the desired orientation(s), and compressed with the piston.

WO 91/16867 2 0 8 2 4 2 7 P~/US91/03106 E) The compressed fibers are then refrozen at -20C and then thawed at room temperature.
F) The resulting structure is cross-linked by soaking in a 0.2% glutaraldehyde solution, pH 7.6, for 24 (+/- 0.5) hours. Each glutaraldehyde-cross-linked prosthetic disc is subsequently rinsed repeatedly in 500 ml of phosphate buffered saline (PHS) solution pH 7.4, for 4, 8, 24 and 48 hours.
G) The rinsed matriz is then lyophilized.

Device Fabrication A)-E) (same as EXAMPLE 3) F) The structure is immersed in an aqueous solution of 0.5 M sodium nitrite, 0.3 M Hcl, and Nacl (OM, 0.34 M, 1.0 M, or 1.34 M) for 3 minutes at 4C.
~XBMPLE 5 Device II Fabrication A)-G) (same as in EXAMPLE 3) H) The lyophilized matriz is subjected to dehydrothermal cross-linking by vacuum and heat. The vacuum is first applied to reduce the residual water content to a minimal level. Some structural Water (about 3%) may still be associated With collagen triple-heliz as part of the structure stabilizing factor. The heat is increasing in steps to 110C

VVO 91 / 16867 ~ ~ ~ ~ ~ ~ ~ PCT/US91 /03106 (+/- 5), and continually applied at 110C under vacuum for 24 (+/- 2) hours.

Device III Fabrication A) (same as in EXAMPLE 3) H) The collagen material is dispersed in 0.01 M HCl at pH 2.0 - 2.5. Predetermined amounts of various GAGS are weighed and dissolved in water. For eaample, for a given density of 0.25 g/cm2, the collagen content will be 0.244 g, the hyaluronic acid content will be 0.003 g, and the chondroitin sulfate content will be 0.003 g for a 2.5~ GAG
content. The GAG solution is mined in with the collagen solution and placed in the mold in the desired orientation as described in EXAMPLE 2.
C)-G) (same as in EXAMPLE 3) Device IV Fabrication A)-C) (same as in EXAMPLE 3) D) (same as in EXAMPLE 3 ezcept that the . fibers laid down are not compressed.
E)-G) (same as in EXAMPLE 3) WO 91/16867 ~ ~ ~ ~ ~ ~ ~ PCT/US91/03106 EXAMPLE 8 v Device V Fabrication A)-E) (same as in EXAMPLE 3) F) The molded collagen is cross-linked in 5~ polyglycerol polyglycidyl ether in 50~C ethanol and 0.1 M Na2C03 at pH 10.0 for 24 (+/- 2) hours. The cross-linked device is rinsed for 4, 8, 24 and 48 ~ 0 hoLIB, A3Cf? ~rTlth 500 ml of PBS, pH ?.4.
G) (same as in EXAMPLE 3) Device VI Fabrication A)-E) (same as in EXAMPLE 3) F) The molded collagen is cross-linked in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (10 mg/g matriz) in 0.9~ NaCl, pH 4.7 at room temperature for 24 (+/- 2) hours. The addition of carbodiimide is made every 3 - 4 hours, and the pH
is adjusted to 4.7 after each addition of carbodiimide.
G) (same as in EXAMPLE 3) W~Q 91 / 16867 2 0 8 2 4 2 7 PCT/US91 /03106 Device VII Fabrication A)-D) (same as in EXAMPLE 2) E) For attachment purposes, a mesh of absorbable polyglyconate suture material, matched to the size of the mold, is laid in the dispersed collagen such that it protrudes from the structure's periphery to form a skirt which may eztend over the vertebral body. This mesh provides both immediate attachment sites and long term fibrous ingrowth.
F)-G) (same as in EXAMPLE 2) 33'~ vitro Testing Intervertebral discs are aseptically harvested from mature goats or dogs, trimmed of all adherent tissue, and placed into Gey's balanced saline solution. Each disc is bisected in the coronal plane and 3 mm full-thickness circular defects are made in each half. The defects are filled With a 3 mm diameter plug of one of two prototypes of a complez collagen-based matriz. The discs are placed in siz well culture plates containing 6 ml of Dulbecco's Modified Eagle's Medium supplemented with 10% fetal bovine serum, sodium ascorbate, and 0.1% penicillin/streptomycin.
Cultures are maintained at 37C in a humidified atmosphere of 10% C02/90% air, fed three times per week, and placed in fresh culture wells every week to prevent the formation of eaplant cell cultures. At WO 91/16867 PC?/US91/03106 = 2082421 intervals of one, four, and sir weeks after initiation of culture, three discs from each group are removed, fired, and evaluated with serial sections and staining. New collagen and glycosaminoglycan formation is evidenced histologically using Alcian Hlue and Masson's Trichrome stains.
The results demonstrate increasing cellular migration and irwasion over time. There is no apparent tozicity from the material. The depth of cellular penetration into the scaffold appears to be limited by the density of the prosthetic complez.
EXAMPL~ 12 In vivo Testing The cervical vertebral disc of a mature goat was primarily ezcised and surgically replaced by a prosthestic disc. The goat returned to full cage activities within a day after surgery. Serial radiographs have documented preservation of the interveztebral joint space.
The present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
A

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