Fluidized intestinal submucosa and its use as an injectable tissue graft

• US 5,275,826 A
• Filed: 11/13/1992
• Issued: 01/04/1994
• Est. Priority Date: 11/13/1992
• Status: Expired due to Term

• Current Assignee: Methodist Hospitals of Dallas, Purdue Research Foundation (The Trustees of Purdue University (d/b/a Purdue University))
• Original Assignee: Methodist Hospitals of Dallas
• Inventors: Voytik, Sherry, Hiles, Michael, Demeter, Robert J., Knapp, Peter M. Jr., Badylak, Stephen F.
• Primary Examiner(s): Robinson, Douglas W.
• Assistant Examiner(s): Witz, Jean C.
• Application Number:
  US07/976,156
• Time in Patent Office: 417 Days
• Field of Search: 424/551, 623/14
• US Class Current: 424/551
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2002/2835 Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
• CPC Class Codes: A61F 2002/30062 (bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• CPC Class Codes: A61F 2002/30677 Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61K 35/38 Stomach; Intestine; Goblet cells; Oral mucosa; Saliva
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 27/3629 Intestinal tissue, e.g. small intestinal submucosa
• CPC Class Codes: A61L 27/3645 Connective tissue
• CPC Class Codes: A61L 27/365 Bones
• CPC Class Codes: A61L 27/367 Muscle tissue, e.g. sphincter
• CPC Class Codes: A61L 27/3683 subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• CPC Class Codes: A61L 27/3691 characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
• CPC Class Codes: A61L 27/3695 characterised by the function or physical properties of the final product, where no specific conditions are defined to achieve this A61L27/3687, A61L27/3691 take precedence
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A fluidized, injectable tissue graft composition is described. The composition comprises comminuted intestinal submucosa or protease-digested intestinal submucosa. Methods for the preparation and use of injectable tissue graft compositions are described. In preferred embodiments the tissue graft material is prepared from the intestinal submucosa comprising the tunica submucosa, the muscularis mucosa and the stratum compactum of a segment of intestinal tissue of a warm-blooded vertebrate. Effective amounts of the fluidized graft compositions can be injected to promote repair tissue defects by inducing formation of endogenous tissues.

Claims

1. A method of preparing an injectable tissue graft composition, said method comprising the steps of comminuting intestinal tissue consisting essentially of the tunica submucosa, the muscularis mucosa and stratum compactum of the tunica mucosa of the intestine of a warm-blooded vertebrate and hydrating the resultant comminuted intestinal tissue to provide said tissue graft composition as a fluid having a viscosity of about 2 to about 300,000 cps at 25°

C.

2. The method of claim 1, wherein the comminuting step includes the step of freezing the intestinal tissue and grinding the frozen intestinal tissue.

3. The method of claim 1 wherein the comminuting step includes the steps of freeze-drying the intestinal tissue and grinding the freeze-dried intestinal tissue.

4. The method of claim 1 wherein the comminuting step includes the step of processing the intestinal tissue in a high shear blender.

5. The method of claim 1 further comprising the step of sterilizing the tissue graft composition.

6. The method of claim 1 further comprising the step of digesting the comminuted intestinal tissue with a protease for a period of time sufficient to solubilize said tissue to provide the tissue graft composition as a substantially homogeneous solution.

7. The method of claim 6, further comprising the step of neutralizing the substantially homogeneous solution to inactivate the protease.

8. The method of claim 6, further comprising the step of isolating the solubilized tissue from the substantially homogeneous solution.

9. A method of preparing an injectable tissue graft composition, said method comprising the step of digesting intestinal tissue consisting essentially of the tunica submucosa, the muscularis mucosa and stratum compactum of the tunica mucosa of the intestine of a warm-blooded vertebrate in aqueous solution with a protease for a period of time sufficient to solubilize said intestinal tissue to form a substantially homogeneous solution.

10. The method of claim 9, further comprising the step of neutralizing the substantially homogeneous solution to inactivate the protease.

11. The method of claim 9, further comprising the step of isolating the solubilized tissue from the substantially homogeneous solution.

12. An injectable, non-immunogenic tissue graft composition comprising a suspension of comminuted intestinal tissue consisting essentially of the tunica submucosa, the muscularis mucosa and stratum compactum of the tunica mucosa of the intestine of a warm-blooded vertebrate in an aqueous carrier.

13. The composition of claim 12 having a viscosity of about 2 to about 300,000 cps at 25°

C.

17. A method of promoting wound healing in a patient in need thereof comprising the step of applying to a wound an effective amount of the injectable tissue graft composition of claim 12.

18. The injectable tissue graft composition of claim 12, dried and in powder form.

20. A method for inducing the formation of endogenous connective tissue in a warm-blooded vertebrate in need thereof comprising administering an effective amount of the tissue graft composition of claim 12 in an amount effective to induce endogenous tissue growth at the site the composition is administered.

21. The method of claim 20 wherein the growth induced endogenous tissue is bone or connective tissue comprising collagen, elastin or muscle.

22. The method of claim 20 wherein the tissue graft composition is injected into tissue forming a sphincter in a warm-blooded mammal and the growth induced tissue is tissue forming the sphincter.

23. A method for augmenting sphincter function in a mammal in need thereof comprising the step of injecting an effective amount of the tissue graft composition of claim 12 into tissue forming said sphincter.

14. An injectable, non-immunogenic tissue graft composition comprising a suspension of protease-digested intestinal tissue consisting essentially of the tunica submucosa, the muscularis mucosa and stratum compactum of the tunica mucosa of the intestine of a warm-blooded vertebrate in an aqueous carrier.

15. The composition of claim 14 having a viscosity of about 2 to about 300,000 cps at 25°

C.

16. The composition of claim 14, wherein the composition is substantially free of protease.

19. The injectable tissue graft composition of claim 14, dried and in powder form.

24. A method of promoting wound healing in a patient in need thereof comprising the step of applying to a wound an effective amount of the injectable tissue graft composition of claim 14.

25. A method for inducing the formation of endogenous connective tissue in a warm-blooded vertebrate in need thereof comprising administering an effective amount of the tissue graft composition of claim 14 in an amount effective to induce endogenous tissue growth at the site the composition is administered.

26. A method for augmenting sphincter function in a mammal in need thereof comprising the step of injecting an effective amount of the tissue graft composition of claim 14 into tissue forming said sphincter.