COMPOSITIONS, SYSTEMS, AND METHODS FOR ARRESTING OR CONTROLLING BLEEDING OR FLUID LEAKAGE IN BODY TISSUE

• US 20020032463A1
• Filed: 04/01/1999
• Published: 03/14/2002
• Est. Priority Date: 11/06/1998
• Status: Active Grant

• Current Assignee: Neomend, Inc. (Becton, Dickinson & Co)
• Original Assignee: Neomend, Inc. (Becton, Dickinson & Co)
• Inventors: CRUISE, GREGORY M., HNOJEWYJ, OLEXANDER
• Granted Patent: US 6,458,147 B1
• Time in Patent Office: Days
• US Class Current: 606/214
• CPC Class Codes: A61B 17/00491 Surgical glue applicators surgical adhesives A61L24/00; two-component delivery syringes A61M5/19
• CPC Class Codes: A61B 17/0057 Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect sutures A61B17/04; closing rectum or urethra near body surface A61F2/0009
• CPC Class Codes: A61B 17/3415 for introducing tubes or catheters, e.g. gastrostomy tubes, drain catheters A61B17/3417 takes precedence; body piercing catheter guide needles A61M25/06
• CPC Class Codes: A61B 18/1482 having a long rigid shaft for accessing the inner body transcutaneously in minimal invasive surgery, e.g. laparoscopy
• CPC Class Codes: A61B 18/1487 Trocar-like, i.e. devices producing an enlarged transcutaneous opening
• CPC Class Codes: A61B 2017/00084 Temperature
• CPC Class Codes: A61B 2017/00495 for two-component glue
• CPC Class Codes: A61B 2017/005 hardenable using external energy source, e.g. laser, ultrasound
• CPC Class Codes: A61B 2017/00637 for sealing trocar wounds through abdominal wall
• CPC Class Codes: A61B 2017/0065 the implement being an adhesive
• CPC Class Codes: A61B 2017/3492 against the outside of the body
• CPC Class Codes: A61B 2090/064 for measuring force, pressure or mechanical tension
• CPC Class Codes: A61M 25/0662 Guide tubes
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: B01F 25/4231 using baffles
• CPC Class Codes: B01F 25/4233 using plates with holes, the holes being displaced from one plate to the next one to force the flow to make a bending movement
• CPC Class Codes: B01F 33/50112 of the syringe or cartridge type

Abstract

A biocompatible and biodegradable hydrogel compound, which is free of a hemostatic agent, is applied to arrest the flow of blood or fluid from body tissue. The compound preferably includes a protein comprising recombinant or natural serum albumin, which is mixed with a polymer that comprises poly(ethylene) glycol (PEG), and, most preferably, a multi-armed PEG polymer.

Claims

1. A biocompatible and biodegradable material applied to arrest the flow of blood or fluid from body tissue comprising a hydrogel compound free of a hemostatic agent.

2. A material according to claim 1

wherein the hydrogel compound includes a protein.

3. A material according to claim 2

wherein the protein includes recombinant or natural serum albumin.

4. A material according to claim 1

wherein the compound includes a polymer.

5. A material according to claim 4

wherein the polymer includes poly(ethylene) glycol (PEG).

6. A material according to claim 5

wherein the PEG comprises a multi-armed polymer.

62. A system to arrest the flow of blood or fluid from body tissue comprising

a first dispenser containing a first liquid component,

a second dispenser containing a second liquid component,

a mixer coupled to the first and second dispensers for mixing the first and second liquid components to form the material as defined in claim 1 or 7.

63. A system according to claim 62

wherein the mixer includes a spray head.

64. A system according to claim 62

wherein the mixer includes a cannula.

7. A biocompatible and biodegradable material applied to arrest diffuse bleeding comprising a hydrogel compound free of a hemostatic agent.

8. A material according to claim 7

wherein the hydrogel compound includes a protein.

9. A material according to claim 8

wherein the protein includes recombinant or natural serum albumin.

10. A material according to claim 7

wherein the compound includes a polymer.

11. A material according to claim 10

wherein the polymer includes poly(ethylene) glycol (PEG).

12. A material according to claim 11

wherein the PEG comprises a multi-armed polymer.

14. A material according to claim 13, wherein the protein solution comprises a hydrophilic protein selected from a group consisting essentially of albumin, gelatin, antibodies, serum fractions, or serum.

15. A material according to claim 13, wherein the protein solution comprises a water soluble derivative of a hydrophobic protein selected from a group consisting essentially of collagen, fibrinogen, elastin, chitosan, or hyaluronic acid.

16. A material according to claim 13, wherein the protein solution comprises recombinant or natural human serum albumin.

17. A material according to claim 16, wherein the human serum albumin is at a concentration of about 25% or less.

18. A material according to claim 13, wherein the protein solution includes a buffer.

19. A material according to claim 18, wherein the buffer includes carbonate or phosphate.

20. A material according to claim 18, wherein the buffer has a concentration of about 0.3 M to about 0.4 M.

21. A material according to claim 20, wherein the buffer comprises carbonate at a concentration of about 0.3 M and a pH value of about 8 to about 10.

22. A material according to claim 13, wherein the protein solution has a pH value of between about 7 to about 10.

23. A material according to claim 22, wherein the pH value is about 8 to about 10.

24. A material according to claim 13, wherein the polymer is electrophilically derivatized.

25. A material according to claim 13, wherein the polymer solution includes a derivative of a polymer selected from a group consisting essentially of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene glycol)-co-poly(propylene glycol) block copolymers, or electrophilically derivatized polysaccharides, carbohydrates, or proteins.

26. A material according to claim 13, wherein the polymer is comprised of poly(ethylene glycol)(PEG).

27. A material according to claim 26, wherein the PEG has a molecular weight of between about 1,000 and about 30,000 g/mole.

28. A material according to claim 27, wherein the PEG has a molecular weight of between about 2,000 and about 15,000 g/mole.

29. A material according to claim 27, wherein the PEG has a molecular weight of between about 10,000 and 15,000 g/mole.

30. A material according to claim 26, wherein the PEG comprises a multi-armed polymer structure.

31. A material according to claim 13, wherein the polymer comprises a compound of the formula PEG-(DCR-CG)_n, where PEG is poly(ethylene glycol), DCR is a degradation control region, CG is a cross-linking group, and n is equal to or greater than three.

32. A material according to claim 31, wherein the compound comprises a multi-armed polymer structure.

33. A material according to claim 31, wherein the degradation control region (DCR) comprises a hydrolytically degradable moiety.

34. A material according to claim 33, wherein the hydrolytically degradable moiety includes saturated di-acids, unsaturated di-acids, poly(glycolic acid), poly(DL-lactic acid), poly(L-lactic acid), poly(ξ

-caprolactone), poly(δ

-valerolactone), poly(γ

-butyrolactone), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(orthocarbonates), or poly(phosphoesters).

35. A material according to claim 31, wherein the degradation control region (DCR) comprises an enzymatically degradable region.

36. A barrier according to claim 35, wherein the enzymatically degradable region includes Leu-Glyc-Pro-Ala (collagenes sensitive linkage) or Gly-Pro-Lys (plasmin sensitive linkage).

37. A material according to claim 31, wherein the degradable control region (DGR) includes ester containing linkages.

38. A material according to claim 37, wherein the degradable control region (GCR) includes succinic acid or glutaric acid.

39. A material according to claim 31, wherein the cross-linking group (CG) includes an active ester.

40. A material according to claim 39, wherein the active ester includes an ester of N-hydroxysuccinimide.

41. A material according to claim 31, wherein the cross-linking group (CG) selectively reacts with sulfhydryl groups.

42. A material according to claim 41, wherein the cross-linking group (CG) includes vinyl sulfone, N-ethyl maleimide, iodoacetamide, or orthopyridyl disulfide.

43. A material according to claim 31, wherein the cross-linking group (CG) selectively reacts with amino groups.

44. A material according to claim 43, wherein the cross-linking group (CG) includes aldehydes.

45. A material according to claim 31, wherein the cross-linking group (CG) reacts with sulfhydryl, primary amino, and secondary amino groups.

46. A material according to claim 31, wherein the cross-linking group (CG) include active esters, epoxides, carbonylimidazole, nitrophenyl carbonates, tresylate, mesylate, tosylate, or isocyanate.

47. A material according to claim 31, wherein the cross-linking group (CG) is present in a concentration of less than about 5% of total mass of the compound.

48. A material according to claim 31, wherein the cross-linking group (CG) is present in a concentration of about 1% or less of total mass of the compound.

49. A material according to claim 31, wherein the PEG comprises a 4-arm PEG, the degradation control region comprises glutaric acid, and the cross-linking group includes a N-hydroxysuccinimide ester.

50. A material according to claim 47, wherein the 4-arm PEG has a molecular weight of about 10,000 g/mole.

51. A material according to claim 31, wherein the compound comprises poly(ethylene glycol) tetra-succinimidyl glutarate.

52. A material according to claim 31, wherein the compound comprises poly(ethylene glycol)tetra-succinimidyl succinate.

53. A material according to claim 49 or 51 or 52, wherein the protein solution includes recombinant or natural human serum albumin.

54. A material according to claim 53, wherein the human serum albumin is present in a concentration of about 25% or less.

55. A material according to claim 13, wherein the polymer solution includes poly(ethylene glycol)tetra-succinimidyl glutarate.

56. A material according to claim 55, wherein the polymer solution includes water.

57. A material according to claim 55, wherein the protein solution includes recombinant or natural human serum albumin.

58. A material according to claim 57, wherein the human serum albumin is present in a concentration of about 25% or less.

59. A material according to claim 13, wherein the polymer has a functionality of four.

60. A material according to claim 13, wherein the polymer solution includes poly(ethylene glycol)tetra-succinimidyl succinate.

61. A material according to claim 13, wherein the polymer solution has a concentration that ranged from about 5% to about 35% w/w.

13. A biocompatible and biodegradable material applied to arrest the flow of blood or to seal tissue comprising a mixture of a protein solution and a polymer solution including a derivative of a hydrophilic polymer with a functionality of at least three, wherein, upon mixing, the protein solution and the polymer solution cross-link to form a mechanical non-liquid covering structure.

65. A system to arrest the flow of blood or to seal tissue comprising

a first dispenser containing a first liquid component comprising a protein solution,

a second dispenser containing a second liquid component comprising a polymer solution including a derivative of a hydrophilic polymer with a functionality of at least three,

a mixer coupled to the first and second dispensers for mixing the first and second liquid components, wherein, upon mixing, the protein solution and the polymer solution cross-link to form a mechanical non-liquid tissue covering structure.

66. A system according to claim 65

wherein the mixer includes a spray head.

67. A system according to claim 65

wherein the mixer includes a cannula.

69. A method according to claim 68 wherein the dispersing step includes spraying the material on the body tissue.

70. A method according to claim 68 wherein the dispersing step includes flowing the material on the body tissue through a cannula.

76. A method according to claim 68 wherein the dispersing step includes flowing the mixture on the body tissue through a cannula.

68. A method for arresting the flow of blood or fluid from body tissue comprising the step of dispersing on the body tissue a biocompatible and biodegradable material comprising a hydrogel compound free of a hemostatic agent.

71. A method for arresting diffuse bleeding comprising the step of dispersing on the body tissue a biocompatible and biodegradable material comprising a hydrogel compound free of a hemostatic agent.

72. A method according to claim 71 wherein the dispersing step includes spraying the material on the body tissue.

73. A method according to claim 71 wherein the dispersing step includes flowing the material on the body tissue through a cannula.

74. A method for arresting the flow of blood or to seal tissue comprising the step of dispersing on the body tissue a biocompatible and biodegradable material comprising a mixture of a protein solution and a polymer solution including a derivative of a hydrophilic polymer with a functionality of at least three, wherein, upon mixing, the protein solution and the polymer solution cross-link to form a mechanical non-liquid covering structure.

75. A method according to claim 74 wherein the dispersing step includes spraying the mixture on the body tissue.