Methods for tissue repair using adhesive materials

• US 20030119985A1
• Filed: 09/30/2002
• Published: 06/26/2003
• Est. Priority Date: 12/18/1995
• Status: Active Grant

• Current Assignee: Angiodevice International GmbH
• Original Assignee: Angiotech Pharmaceuticals Incorporated
• Inventors: Trollsas, Olof Mikael, Sehl, Louis C., Toman, David, Wallace, Donald G., Schroeder, Jacqueline A., Chu, George H., DeLustro, Frank A.
• Granted Patent: US 6,833,408 B2
• Time in Patent Office: Days
• US Class Current: 525/54.1
• CPC Class Codes: A61F 2/0063 Implantable repair or support meshes, e.g. hernia meshes
• CPC Class Codes: A61L 24/043 Mixtures of macromolecular materials
• CPC Class Codes: A61L 24/08 Polysaccharides A61L24/043 takes precedence
• CPC Class Codes: A61L 24/102 Collagen
• CPC Class Codes: A61L 27/24 Collagen
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/044 Collagen
• CPC Class Codes: C08B 37/0075 Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: C08F 283/00 Macromolecular compounds obtained by polymerising monomers on to polymers provided for in subclass C08G
• CPC Class Codes: C08F 283/04 on to polycarbonamides, polyesteramides or polyimides C08F283/004 takes precedence
• CPC Class Codes: C08F 283/06 on to polyethers, polyoxymethylenes or polyacetals C08F283/004 takes precedence
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08G 75/045 from mercapto compounds and unsaturated compounds
• CPC Class Codes: C08G 75/26 Polythioesters
• CPC Class Codes: C08H 1/00 Macromolecular products derived from proteins food proteins A23; glue, gelatine C09H
• CPC Class Codes: C08H 1/06 derived from horn, hoofs, hair, skin or leather
• CPC Class Codes: C08L 2666/26 Natural polymers, natural resins or derivatives thereof according to C08L1/00 - C08L5/00, C08L89/00, C08L93/00, C08L97/00 or C08L99/00
• CPC Class Codes: C08L 5/16 Cyclodextrin; Derivatives thereof
• CPC Class Codes: C08L 51/003 grafted on to macromolecular compounds obtained by reactions only involving unsaturated carbon-to-carbon bonds C08L51/04, C08L51/06 take precedence
• CPC Class Codes: C08L 53/00 : Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 67/06 : Unsaturated polyesters
• CPC Class Codes: C08L 71/00 : Compositions of polyethers obtained by reactions forming an ether link in the main chain of polyacetals C08L59/00; of epoxy resins C08L63/00; of polythioether-ethers C08L81/02; of polyether-sulfones C08L81/06; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 71/02 : Polyalkylene oxides
• CPC Class Codes: C08L 81/02 : Polythioethers; Polythioether-ethers
• CPC Class Codes: C08L 89/06 : derived from leather or skin , e.g. gelatin
• CPC Class Codes: C08L 91/06 : Waxes
• CPC Class Codes: C09D 167/02 : Polyesters derived from dicarboxylic acids and dihydroxy compounds C09D167/06 takes precedence
• CPC Class Codes: C09J 151/003 : grafted on to macromolecular compounds obtained by reactions only involving unsaturated carbon-to-carbon bonds C09J151/04, C09J151/06 take precedence
• CPC Class Codes: C09J 153/00 : Adhesives based on block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Adhesives based on derivatives of such polymers
• CPC Class Codes: C09J 189/06 : derived from leather or skin

Abstract

A method of tissue repair is provided using a biocompatible nonimmunogenic adhesive composition. The adhesive composition comprises collagen and a plurality of crosslinkable components having reactive functional groups thereon, with the functional groups selected so as to enable inter-reaction between the components, i.e., crosslinking. Kits for use in carrying out the method of the invention are also provided, as are pretreated surgically acceptable patches that have been coated with the aforementioned adhesive composition.

Claims

1. A method of repairing damaged tissue in a patient comprising the steps of:

placing into contact with the damaged tissue an adhesive composition comprised of

(i) a hydrophilic polymer;

(ii) a crosslinkable component A having m nucleophilic groups, wherein m≧

2; and

(iii) a crosslinkable component B having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds, wherein n≧

2 and m+n>

4;

wherein each of components A and B is biocompatible and nonimmunogenic, and at least one of components A and B is hydrophilic polymer, and crosslinking of the composition results in a biocompatible, nonimmunogenic, crosslinked matrix.

2. The method of claim 1, wherein the damaged tissue is herniated tissue and the method further comprises placing a surgically acceptable patch in contact with the herniated tissue.

3. The method of claim 1, wherein the adhesive is placed into contact with the damaged tissue via laparoscopic techniques.

4. The method of claim 3, wherein the surgically acceptable patch is a mesh plug or mesh sheet.

5. The method of claim 2, wherein the herniated tissue is a result of a condition selected from the group consisting inguinal hernia, femoral hernia, scrotal hernia, ventral hernia, umbilical hernia, ventral/epigastric hernia, incisional hernia, spigelian hernia, recurrent hernia, recurrent incisional hernia, bilateral hernia, stoma hernia, and hiatus hernia.

6. The method of claim 1, wherein the hydrophilic polymer is synthetic.

7. The method of claim 1, wherein the hydrophilic polymer is naturally occurring.

8. The method of claim 7, wherein the naturally occurring hydrophilic polymer is selected from the group consisting of proteins, carboxylated polysaccharides, aminated polysaccharides, glycosaminoglycans, and activated polysaccharides.

9. The method of claim 8, wherein the naturally occurring polymer is a protein.

10. The method of claim 8, wherein the naturally occurring polymer is collagen.

11. The method of claim 10, wherein the collagen is nonfibrillar collagen.

12. The method of claim 11, wherein the nonfibrillar collagen is a chemically modified collagen.

13. The method of claim 12, wherein the chemically modified collagen is methylated collagen.

14. The method of claim 11, wherein the nonfibrillar collagen is selected from the group consisting of:

type IV collagen, type VI collagen, and type VII collagen.

15. The method of claim 10, wherein the collagen is fibrillar collagen.

16. The method of claim 10, wherein the collagen comprises a mixture of nonfibrillar collagen and fibrillar collagen.

17. The method of claim 15, wherein the collagen comprises a mixture of particulate crosslinked fibrillar collagen and noncrosslinked fibrillar collagen.

18. The method of claim 17, wherein the particulate crosslinked fibrillar collagen comprises glutaraldehyde-crosslinked collagen.

19. The method of claim 17, wherein the particulate crosslinked fibrillar collagen comprises between about 25% to about 95% and the noncrosslinked fibrillar collagen comprises between about 5% to about 75% by weight of the composition.

20. The method of claim 6, wherein the collagen is denatured collagen.

21. The method of claim 1, wherein the adhesive composition further comprises a third crosslinkable component C that is biocompatible and nonimmunogenic and has at least one functional group selected from

(a) nucleophilic groups capable of reacting with the electrophilic groups of component B and,

(b) electrophilic groups capable of reacting with the nucleophilic groups of component,

wherein the total number of functional groups on component C is represented by p, such that m+n+p>

5.

22. The method of claim 1, wherein component A has the structural formula (I) and component B has the structural formula (II)

R¹(—

[Q¹]_q—

X)_m 

 

(I)R²(—

[Q²]_r—

Y)_n 

 

(II)

wherein;

R¹ and R² are independently selected from the group consisting of C₂ to C₁₄ hydrocarbyl, heteroatom-containing C₂ to C₁₄ hydrocarbyl, hydrophilic polymers, and hydrophobic polymers;

X represents one of the m nucleophilic groups of component A;

Y represents one of the n electrophilic groups of component B;

Q¹ and Q² are linking groups; and

q and r are independently zero or 1.

23. The method of claim 21, wherein component C has the structural formula (III)

R³(—

[Q³]_s—

Fn)_p 

 

(III)

wherein;

R³ is selected from the group consisting of C₂ to C₁₄ hydrocarbyl, heteroatom-containing C₂ to C₁₄ hydrocarbyl, hydrophilic polymers, and hydrophobic polymers;

Fn represents a functional group on component C; and

s is zero or 1.

24. The method of claim 22, wherein at least one of R¹ and R² is a synthetic hydrophilic polymer.

25. The method of claim 24, wherein:

(a) R¹ is a first synthetic hydrophilic polymer; and

(b) R² is selected from the group consisting of (i) a second synthetic hydrophilic polymer that may or may not be the same as R¹ and (ii) C₂ to C₁₄ hydrocarbyl groups containing zero to 2 heteroatoms selected from N, O and S.

26. The method of claim 25, wherein the synthetic hydrophilic polymer is of a linear, branched, dendrimeric, hyperbranched, or star polymer.

27. The method of claim 25, wherein the synthetic hydrophilic polymer is selected from the group consisting of:

polyalkylene oxides;

polyglycerols;

poly(oxyalkylene)-substituted polyols;

polyacrylic acid and analogs thereof;

polymaleic acid;

polyacrylamides;

poly(olefinic alcohol)s;

poly(N-vinyl lactams);

polyoxazolines;

polyvinylamines; and

copolymers thereof.

28. The method of claim 27, wherein the synthetic hydrophilic polymer is a polyalkylene oxide or polyglycerol.

31. The method of claim 27, wherein the synthetic hydrophilic polymer is a poly(oxyalkylene)-substituted diol or polyol.

32. The method of claim 31, wherein the synthetic hydrophilic polymer is selected from the group consisting of mono-poly(oxyalkylene)-substituted propylene glycol, di-(polyoxyalkylene)-substituted propylene glycol, mono-poly(oxyalkylene)-substituted trimethylene glycol, di-(polyoxyalkylene)-substituted trimethylene glycol, mono-poly(oxyalkylene)-substituted glycerol, di-(polyoxyalkylene)-substituted glycerol, and tri-(polyoxyalkylene)-substituted glycerol.

33. The method of claim 27, wherein the synthetic hydrophilic polymer is selected from the group consisting of poly(acrylic acid) and analogs and copolymers thereof.

34. The method of claim 33, wherein the synthetic hydrophilic polymer is selected from the group consisting of poly(acrylic acid), poly(methacrylic acid), poly(hydroxyethylmethacrylate), poly(hydroxyethylacrylate), poly(methylalkylsulfoxide acrylates), poly(methylalkylsulfoxide methacrylates), and copolymers thereof.

35. The method of claim 27, wherein the synthetic hydrophilic polymer is polymaleic acid.

36. The method of claim 27, wherein the synthetic hydrophilic polymer is a polyacrylamide.

37. The method of claim 36, wherein the synthetic hydrophilic polymer is selected from the group consisting of polyacrylamide, poly(methacrylamide), poly(dimethylacrylamide), poly(N-isopropylacrylamide), and copolymers thereof.

38. The method of claim 27, wherein the synthetic hydrophilic polymer is a poly(olefinic alcohol).

39. The method of claim 38, wherein the poly(olefinic alcohol) is polyvinyl alcohol or a copolymer thereof.

40. The method of claim 27, wherein the synthetic hydrophilic polymer is a poly(N-vinyl lactam).

41. The method of claim 40, wherein the poly(N-vinyl lactam) is selected from the group consisting of poly(vinyl pyrrolidone), poly(vinyl caprolactam), and copolymers thereof.

42. The method of claim 21, wherein component A has the structural formula (I) and component B has the structural formula (II)

R¹(—

[Q¹]_q—

X)_m 

 

(I)R²(—

[Q²]_r—

Y)_n 

 

(II)

wherein;

R¹ and R² are independently selected from the group consisting of C₂ to C₁₄ hydrocarbyl, heteroatom-containing C₂ to C₁₄ hydrocarbyl, hydrophilic polymers, and hydrophobic polymers;

X represents one of the m nucleophilic groups of component A;

Y represents one of the n electrophilic groups of component B;

Q¹ and Q² are linking groups; and

q and r are independently zero or 1.

43. The method of claim 42, wherein component C has the structural formula (III)

R³(—

[Q³]_s—

Fn)_p 

 

(III)

wherein;

R³ is selected from the group consisting of C₂ to C₁₄ hydrocarbyl, heteroatom-containing C₂ to C₁₄ hydrocarbyl, hydrophilic polymers, and hydrophobic polymers;

Fn represents a functional group on component C; and

s is zero or 1.

44. The method of claim 43, wherein r and s are zero.

45. The method of claim 43, wherein at least one of r and s is 1.

46. The method of claim 1, wherein the nucleophilic groups on component A are selected from the group consisting of —

NH₂, —

NHR⁴, —

N(R⁴)₂, —

SH, —

OH, —

COOH, —

C₆H₄—

OH,—

PH₂, —

PHR⁵, —

P(R⁵)₂, —

NH—

NH₂, —

CO—

NH—

NH₂, and —

C₅H₄N, wherein R⁴ and R⁵ are C₁-C₁₂ hydrocarbyl.

47. The method of claim 46, wherein the nucleophilic groups are selected from —

NH₂ and —

NHR⁴ where R⁴ is lower hydrocarbyl.

48. The method of claim 47, wherein the electrophilic groups on component B are amino-reactive groups.

49. The method of claim 48, wherein the amino-reactive groups contain an electrophilically reactive carbonyl group susceptible to nucleophilic attack by a primary or secondary amine.

50. The method of claim 49, wherein the amino-reactive groups are carboxylic acid esters.

51. The method of claim 49, wherein the amino-reactive groups are carboxylic acids or aldehydes.

52. The method of claim 1, wherein the adhesive composition further comprises a biologically active agent.

53. The method of claim 1, wherein the adhesive composition further is a cell.

29. The method of 28, wherein the synthetic hydrophilic polymer is a polyalkylene oxide selected from the group consisting of polyethylene glycol and poly(ethylene oxide)-poly(propylene oxide) copolymers.

30. The method of claim 29, wherein the polyalkylene oxide is polyethylene glycol.

54. A kit for effecting tissue repair, comprising an adhesive composition comprised of

(a) a hydrophilic polymer;

(b) a crosslinkable component A having m nucleophilic groups, wherein m≧

2;

(c) a crosslinkable component B having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds, wherein n≧

2 and m+n>

4; and

wherein each of components A and B is biocompatible and nonimmunogenic and crosslinking of the adhesive composition results in a biocompatible, nonimmunogenic, crosslinked matrix.

55. A pretreated surgically acceptable patch for use in the repair of herniated tissue comprising a surgically acceptable patch and an adhesive composition comprised of

(a) a hydrophilic polymer;

(b) a crosslinkable component A having m nucleophilic groups, wherein m≧

2;

(c) a crosslinkable component B having n electrophilic groups capable of reaction with the m nucleophilic groups to form covalent bonds, wherein n≧

2 and m+n>

4; and

wherein each of components A and B is biocompatible and crosslinking of the adhesive composition upon contact with moisture results in a biocompatible, crosslinked matrix.