Tissue Sealant for Use in Non Compressible Hemorrhage

• US 20110066182A1
• Filed: 03/30/2010
• Published: 03/17/2011
• Est. Priority Date: 04/07/2009
• Status: Active Grant

• Current Assignee: George D. Falus
• Original Assignee: Biomedica Management Corporation
• Inventors: Falus, George
• Granted Patent: US 8,314,211 B2
• 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: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 24/043 Mixtures of macromolecular materials
• CPC Class Codes: A61L 24/106 Fibrin; Fibrinogen
• CPC Class Codes: A61L 2400/04 Materials for stopping bleeding
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C08L 89/06 derived from leather or skin , e.g. gelatin

Abstract

ClotFoam is a surgical sealant and hemostatic agent designed to be used in cases of non-compressible hemorrhage. It can be applied in the operating room through laparoscopic ports, or directly over lacerated tissue in laparotomy procedures or outside the operating room through a mixing needle and/or a spray injection method following abdominal, chest, extremities or other intracavitary severe trauma to promote hemostasis. Its crosslinking technology generates an adhesive three-dimensional polymeric network or scaffold that carries a fibrin sealant required for hemostasis. When mixed, Clotfoam produces a foam that spreads throughout a body cavity reaching the lacerated tissue to seal tissue and promote the coagulation cascade.

The viscoelastic attachment properties of the foam as well as the rapid formation of a fibrin clot that ensure that the sealant remains at the site of application without being washed away by blood or displaced by movement of the target tissue .

Claims

1. A four-part composition of a hydrogel carrier for a fibrin sealant (fibrin monomer) to be used as a non-compressible haemostatic agent for the control of bleeding and prevention of haematoma formation.

2. The composition set forth in claim 1 that can stop bleeding in cases of severe hemorrhage and seal lacerated tissue without the need of sutures, stitches, or other elements of compression.

3. A four-part hemostatic composition including a hydrogel carrier and a fibrin monomer, in combination, for cessation of blood loss from injured tissue of a patient'"'"'s body without application of a compressive force independently therefrom, the composition comprising:

a first component (Part A), in a liquid form, of Teleostean (fish) gelatin type A mixed with sucrose, polyvinylpyrrolidone, and Bovine serum albumin in a selected buffer solution at a pH of about 8.3 in the presence of metallic ions;

a second component (Part B) of a selected, relatively high molecular weight acrilyc acid of carbomer and divalent ions in a pH 3.4 solution;

a third component (Part C) of a fibrin monomer in a selected acidic solution that polymerizes upon change in pH; and

a fourth component (Part D) having a selected calcium independent transglutaminase enzyme and calcium chloride for stabilizing the fibrin polymer.

4. The composition set forth in claim 3, wherein the alkaline buffer in solution has a concentration generally within a range of 0.5M and 0.75M sodium carbonate/bicarbonate.

5. The composition set forth in claim 3, wherein Part D comprises a source of calcium ions in a concentration of about 20 mM solution suitable for polymerization of the fibrin monomer.

6. The composition set forth in claim 3, wherein the divalent ions include calcium, zinc and magnesium ions for substantially increasing the rate of fibrin polymerization, the length and strength of fibrin filaments, and fastening scaffold polymerization.

7. The composition set forth in claim 3, wherein Parts A-D retain their physical and chemical properties during sterilization.

8. The composition set forth in claim 3, wherein the fibrin monomer concentration is generally within a range of 12 mg/ml and 20 mg/ml of acteic acid.

9. The composition set forth in claim 3, wherein Parts A-D and the composition are bio-compatible with tissue on which they are applied.

10. The composition set forth in claim 3, wherein the blood loss is a result of hematoma formation during a selected procedure or event of the patient that results in blood loss including, but not limited to, internal trauma, general surgery, laparoscopic procedure(s) and liposuction.

11. The composition set forth in claim 3, wherein the polyvinylpyrrolidone, sucrose, albumin and gelatin are macromolecules which, upon mixture, produce a 3-D polymer that enhances the longevity and quality of the foam, while improving tissue adhesivity through matrix formation.

12. The composition set forth in claim 3, wherein the fibrin monomer is a non-dynamic fibrin monomer that is substantially free of thrombin and any exogenous enzymes which catalyze the formation of fibrin from fibrinogen.

13. A method of sealing injured tissue of a patient'"'"'s body that utilizes a four-part hemostatic composition including a hydrogel carrier and a fibrin monomer, in combination, for cessation of blood loss from the injured tissue without application of a compressive force independently therefrom, the method comprising the steps of:

(i) mixing a first component (Part A), in a liquid form, of Teleostean (fish) gelatin type A mixed with sucrose, polyvinylpyrrolidone, and Bovine serum albumin in a selected buffer solution at a pH of about 8.3 in the presence of metallic ions, with a second component (Part B) of a selected, relatively high molecular weight acrylic acid of carbomer and divalent ions in a pH 3.4 solution, in a selected mixing device;

(ii) mixing the mixture of step (i) with a third component (Part C) of a fibrin monomer in a selected acidic solution that polymerizes upon change in pH, in the mixing device;

(iii) mixing the mixture of step (ii) with a fourth component (Part D) having a selected calcium independent transglutaminase enzyme and calcium chloride for stabilizing the fibrin polymer, in the mixing device so as to create a foam;

(iv) delivering and/or dispersing the foam through an outlet of the mixing device to a surgical site of a body cavity, organ or tissue so as to place the foam in contact with the site such that the non-dynamic, non-crosslinked fibrin monomer of the foam sticks to wet tissue of the site and forms a matrix in the patient'"'"'s blood; and

(v) rendering the non-crosslinked fibrin monomer dynamic by neutrilizing its pH such that the non-crosslinked fibrin is converted to a fibrin sealant, thereby inducing coagulation of the blood and adhesive properties of severed tissue.

14. The method set forth in claim 13, wherein the surgical site includes the patient'"'"'s skin, abdominal cavity, thorax, cardiovascular system, lymphatic system, pulmonary system, ear(s), nose, throat, eye(s), liver, spleen, cranial, spinal, maxillo-facial, bone, tendon, pancreas, genito-urinary tract or alimentary tract.

15. The method set forth in claim 13, further comprising the steps of mixing the water-solubilized components of the four-part composition adhesive, and then polymerizing/crosslinking the adhesive by a selected polymerizing/crosslinking reaction effected by a mixing device.

16. The method set forth in claim 13, wherein the mixing device of steps (i)-(iii) is a pneumatically operated, four-barreled syringe, each barrel containing one of component Parts A, B, C and D.

17. The method set forth in claim 13, wherein the cross-linked matrix formed by Teleostean (fish) gelatin type A, Bovine serum albumin, carrageenan (sulfonated polysaccharide) polyvinylpyrrolidinone, sucrose, carbomer 934 and ACTIVA in buffer solution serves as scaffold for the fibrin components to bind tissue together without compression independently therefrom or the addition of a suture, a staple, a tape, or a bandage.

18. The method set forth in claim 13, further comprising the step of dispersing the mixture of Parts A, B, C and D, upon its formation into an adhesive foaming hydrogel, into the patient'"'"'s body cavity such that the mixture minimizes blood loss from the injured tissue for a selected period of time as is suitable to form a fibrin clot and, thereby, seal the wound.

19. The method set forth in claim 18, wherein the adhesive foaming hydrogel is formed in less than about 10 seconds of mixing component Parts A, B, C and D.

20. The method set forth in claim 18, wherein the adhesive foaming hydrogel formed attains a storage moduli (G′

) of about 6000 dyn/cm2 monitored by rheometry as a function of time at a frequency of around 5 Hz and a about 2% stress strain at approximately 37°

C.

21. The method set forth in claim 13, wherein in step (ii) the solution of component Part C includes a fibrin monomer dissolved in acetic acid.

22. The method set forth in claim 13, wherein step (iii) further comprises the step of maintaining the fibrin monomer, polymerized and stabilized, in the four-part solution so as to form a fibrin sealant.

23. The method set forth in claim 13, wherein polymerization of the fibrin monomer is effected by the acid solution upon the addition of alkaline Part A to the fibrin monomer.

24. The method set forth in claim 13, wherein step (iii) further comprises the step of maintaining the fibrin polymer, as stabilized through activity of the transglutaminase enzyme in Part D, for over 90 days.

25. The method set forth in claim 13, wherein foam formation is induced by a chemical reaction of carbomer 934 and sodium monobasic phosphate (NaH₂\PO₄) in mixture with a simple buffer solution of sodium bicarbonate (NaHCO₃) such that carbon dioxide (CO₂) is released in the presence of divalent ions or surfactants.

26. The method set forth in claim 13, wherein the foam produced upon mixing of component Parts A, B, C and D is a non-exothermic foam having a volume about 400% greater than that of the component Parts before mixing step (i).

27. A medical kit for preparation and application of a four-part hemostatic composition including a hydrogel carrier and a fibrin monomer, in combination, for cessation of blood loss from injured tissue of a patient'"'"'s body without application of a compressive force independently therefrom, the kit comprising:

a first component (Part A), in a liquid form, of Teleostean (fish) gelatin type A mixed with sucrose, polyvinylpyrrolidone, and Bovine serum albumin in a selected buffer solution at a pH of about 8.3 in the presence of metallic ions;

a second component (Part B) of a selected, relatively high molecular weight acrilyc acid of carbomer and divalent ions in a pH 3.4 solution;

a third component (Part C) of a fibrin monomer in a selected acidic solution that polymerizes upon change in pH;

a fourth component (Part D) having a selected calcium independent transglutaminase enzyme and calcium chloride for stabilizing the fibrin polymer; and

a device for mixing, delivering and/or dispersing the composition, upon mixing, through an outlet of the mixing device to a site at the patient'"'"'s body.