Elastic biopolymer and use as a tissue adhesive

Patent metadata

Field	Value
Publication number	US-2017232138-A1
Application number	US-201515502347-A
Country	US
Kind code	A1
Filing date	Aug 6, 2015
Priority date	Aug 8, 2014
Publication date	Aug 17, 2017
Grant date	—

Abstract

The present invention provides an improved tissue adhesive to repair defects in soft tissue. Following ASTM standard tests, crosslinked methacryloyl-substituted gelatin hydrogels of the present invention (GelSEAL) were shown to exhibit adhesive properties, i.e. wound closure strength, shear resistance and burst pressure, that were superior to clinically used fibrin- and poly(ethylene glycol)-based glues. Chronic in vivo experiments in rats proved GelSEAL to effectively seal large lung leakages without additional sutures or staples, presenting improved performance as compared to fibrin and poly(ethylene glycol) glues. Furthermore, subcutaneous implantation in rats revealed high biocompatibility of GelSEAL as evidenced by low inflammatory host response. Advantageously, the tissue adhesives of the present invention are low cost and easy to produce, making them a promising substance to be used as a sealant for fluid leakages in soft tissue, as well as an easily tunable platform to further optimize the adhesive characteristics.

First claim

1 . A tissue adhesive comprising a light activated methacryloyl-substituted gelatin, a photoinitiator and a pharmaceutically acceptable carrier.

2 . The tissue adhesive of claim 1 , wherein the methacryloyl-substituted gelatin has a degree of methacryloyl substitution between 50% and 90%.

3 .- 4 . (canceled)

5 . The tissue adhesive of claim 1 , wherein the methacryloyl-substituted gelatin is present at a concentration between 10% and 40% (w/v).

6 .- 8 . (canceled)

9 . The tissue adhesive of claim 1 , wherein the photoinitiator is selected from the group consisting of: 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propane-1-one, azobisisobutyronitrile, benzoyl peroxide, di-tert-butyl peroxide, 2,2-dimethoxy-2-phenylacetophenone, Eosin Y, and any combination thereof.

10 . (canceled)

11 . The tissue adhesive of claim 1 , further comprising:
(i) a hemostatic agent selected from the group consisting of blood coagulation factors, prothrombin, thrombin, silicate nanoparticles, and any combination thereof; or (ii) an antibacterial agent selected from the group consisting of silver nanoparticles, copper oxide nanoparticles, nanoparticle-carried antibiotic drugs, penicillins, cephalosporins, penems, carbapenems, monobactams, aminoglycosides, sulfonamides, macrolides, tetracyclins, lincosides, quinolones, chloramphenicol, vancomycin, metronidazole, rifampin, isoniazid, spectinomycin, trimethoprim sulfamethoxazole, chitosan, and any combination thereof.

12 . (canceled)

13 . A tissue adhesive comprising a crosslinked methacryloyl-substituted gelatin hydrogel and a pharmaceutically acceptable carrier, wherein the crosslinked methacryloyl-substituted gelatin hydrogel has a degree of methacryloyl substitution between 50% and 90% and a concentration between 10% and 40% (w/v) in the pharmaceutically acceptable carrier.

14 .- 15 . (canceled)

16 . The tissue adhesive of claim 13 , having a wound closure strength of >20 kPa, or a shear resistance strength of >200 kPa, or a burst pressure of >5 kPa.

17 .- 24 . (canceled)

25 . The tissue adhesive of claim 13 , further comprising:
a hemostatic agent selected from the group consisting of blood coagulation factors, prothrombin, thrombin, silicate nanoparticles, and any combination thereof; or (ii) an antibacterial agent selected from the group consisting of silver nanoparticles, copper oxide nanoparticles, nanoparticle-carried antibiotic drugs, penicillins, cephalosporins, penems, carbapenems, monobactams, aminoglycosides, sulfonamides, macrolides, tetracyclins, lincosides, quinolones, chloramphenicol, vancomycin, metronidazole, rifampin, isoniazid, spectinomycin, trimethoprim, sulfamethoxazole, chitosan, and any combination thereof.

26 . (canceled)

27 . A method for adhering or sealing soft tissue, comprising the steps of:
a. Applying a composition comprising a light activated methacryloyl-substituted gelatin, a photoinitiator and a pharmaceutically acceptable carrier to the soft tissue to be adhered or sealed; and b. Exposing the composition to UV or visible light.

28 . The method of claim 27 , wherein the soft tissue is a highly stressed elastic tissue.

29 . (canceled)

30 . The method of claim 27 , wherein the method provides a seal against leakage of a fluid through the soft tissue.

31 .- 35 . (canceled)

36 . The method of claim 27 , wherein the composition is exposed to UV or visible light for a time period between 1 minute and 5 minutes.

37 .- 39 . (canceled)

40 . The method of claim 27 , wherein the methacryloyl-substituted gelatin has a degree of methacryloyl substitution between 50% and 90%.

41 .- 42 . (canceled)

43 . The method of claim 27 , wherein the methacryloyl-substituted gelatin is present at a concentration between 10% and 40% (w/v).

44 .- 46 . (canceled)

47 . The method of claim 27 , wherein the photoinitiator is selected from the group consisting of: 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propane-1-one, azobisisobutyronitrile, benzoyl peroxide, di-tert-butyl peroxide, 2,2-dimethoxy-2-phenylacetophenone, Eosin Y, and any combination thereof.

48 . (canceled)

49 . The method of claim 27 , wherein the composition further comprises:
a hemostatic agent selected from the group consisting of blood coagulation factors, prothrombin, thrombin, silicate nanoparticles, and any combination thereof; or (ii) an antibacterial agent selected from the group consisting of silver nanoparticles, copper oxide nanoparticles, nanoparticle-carried antibiotic drugs, penicillins, cephalosporins, penems, carbapenems, monobactams, aminoglycosides, sulfonamides, macrolides, tetracyclins, lincosides, quinolones, chloramphenicol, vancomycin, metronidazole, rifampin, isoniazid, spectinomycin, trimethoprim, sulfamethoxazole, chitosan, and any combination thereof.

50 . (canceled)

51 . The method of claim 27 , wherein the method does not comprise suturing or stapling the soft tissue to be adhered or sealed.

52 . The tissue adhesive of claim 1 , wherein the methacryloyl-substituted gelatin further comprises dopamine conjugated to the gelatin.

53 .- 57 . (canceled)

58 . The tissue adhesive of claim 13 , wherein the methacryloyl-substituted gelatin hydrogel further comprises dopamine conjugated to the gelatin.

59 .- 68 . (canceled)

69 . The method of claim 27 , wherein the methacryloyl-substituted gelatin further comprises dopamine conjugated to the gelatin.

70 .- 75 . (canceled)

Assignees

• Brigham & Womens Hospital Inc

Inventors

• Khademhosseini Ali
• Annabi Nasim
• Assmann Alexander

Classifications

• A61L24/104 Primary

  Gelatin · CPC title

• A61L24/0015

  Medicaments; Biocides · CPC title

• A61L2300/418

  Agents promoting blood coagulation, blood-clotting agents, embolising agents · CPC title

• A61K31/137

  Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone} · CPC title

• A61L2300/404

  Biocides, antimicrobial agents, antiseptic agents · CPC title