WO2000040277A1 - Tissue adhesive for treating vigorously bleeding surfaces - Google Patents
Tissue adhesive for treating vigorously bleeding surfaces Download PDFInfo
- Publication number
- WO2000040277A1 WO2000040277A1 PCT/US1999/000504 US9900504W WO0040277A1 WO 2000040277 A1 WO2000040277 A1 WO 2000040277A1 US 9900504 W US9900504 W US 9900504W WO 0040277 A1 WO0040277 A1 WO 0040277A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- adhesive
- collagen
- albumin
- tissue
- tissue adhesive
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/043—Mixtures of macromolecular materials
Definitions
- the present invention relates generally to adhesives, more specifically it relates to medical adhesives, and particularly it relates to tissue adhesives which exhibit high bio-compatibility, excellent tensile properties, are bio-absorbable, do not interfere with the healing processes and are easily applied to various tissues.
- the present invention is also particularly well suited for controlling complex, vigorous bleeding emanating from large surface areas, specifically the visceral organs, lungs and the vascular system.
- Fibrin tissue adhesives have attracted considerable attention due to the high bio- compatibility associated with fibrin monomers. Fibrin tissue adhesives are administered as two components and work by forming an artificial fibrin clot over the effected area. The fibrinogen and Factor XL ⁇ I component is delivered to the wound site followed by a thrombin and calcium ion solution which initiates the conversion of fibrinogen into fibrin monomers. Fibrin tissue adhesives exhibit relatively weak tissue binding properties, have a fairly long set-up time and are not suitable for use in treating large, aggressively bleeding surfaces. The amount of fibrin required to produce a satisfactory adhesive requires multiple blood donors which increases the risk of transmitting blood borne diseases.
- Fibrin based tissue adhesives have been described in a number of U.S. patents, the most relevant of those include 4,414,976, 4,909,251, 5,219,328, 5,395,923, 5,407,671, 5,464,471, 5,804,428 and 5,814,022.
- Patent number 4,414,976 describes the basic fibrin based tissue sealant and discloses the fundamental theory associated with its biological activity. The remaining patents cited above are primarily directed at novel means for delivering fibrin and the required clotting agents to the wound site in a convenient fashion making the use of this tissue adhesive more acceptable to physicians.
- Patent number 5,407,671 addresses the transmission of blood borne pathogens and is directed at minimizing this inherent risk, while patent 5,464,471 is directed to recombinant forms of fibrin and application techniques thereof. However, none of these patents discuss the use of a fibrin based tissue adhesive for controlling vigorous bleeding tissues.
- Gelatin Resorcin Aldehyde Tissue Adhesives are currently available in Germany for use in conjunction with cardiovascular surgery. These compounds are generally used as reinforcement or leathering agents on fragile tissues.
- Gelatin Resorcin Aldehyde Tissue Adhesives are composed of heated gelatin that is mixed in situ with a cross-linking agent such as glutaraldehyde or formaldehyde.
- GRATAs are relatively easy to apply and have moderately good adhesive qualities.
- GRATA do not possess adhesive qualities sufficient to seal large areas of vigorously bleeding tissues and there are reports of post surgical inflammation in rabbits indicating problems with bio-compatibility.
- U.S. patent number 5,292,333 describes a more recent GRATA development but does not suggest that the claimed tissue adhesive would be suitable for sealing large surface areas of vigorously bleeding tissues. The examples described therein are limited to vascular grafts.
- United States Patent number 5,583,114 discloses an albumin based tissue adhesive prepared using an alkaline solution of human serum albumin that is cross-linked with polyethylene glycol.
- the resulting tissue adhesive is intended for use as an adjunct or replacement of sutures, stables, tapes and/or bandages.
- Other proposed uses include post-surgical applications to reduce tissue adhesions, sealing tissues to prevent or control blood or other fluid leaks at suture or staple sites and for controlling leaks in the pulmonary system. Treating large surface areas of vigorously bleeding tissues is not described.
- Acrylates are semi-crystalline compounds that tend to fracture under stress which can result in wound healing inhibition. The cyanoacrylates have been exhaustively studied and is the most successful acrylate class used as tissue adhesives.
- N-isobutyl and N-butylcyanoacrylate were initially selected for development after animal tests suggested that these compounds demonstrated superior tissue adhesiveness and minimal tissue inflammation.
- N- butylcyanoacrylate is available outside the U.S. for human applications and as an approved veterinary compound within the U.S.
- Tissue welding is an area where significant research and development has been focused. Numerous U.S. patents have been issued in this area including four assigned to Fusion Medical Technologies, Inc. of Mountain View, CA. Patent 5,669,934 describes the use of a preformed sheet made of collagen, gelatin and mixtures thereof combined with a plastisizer which is sealed to the injured tissue using radio frequencies between 20 and 120 watts. The principle application for this device is the repair of severed and torn tissues including blood vessels, ducts, muscle, fascia, tendon and bone. Although bleeding is often a collateral consequence of injuries to these tissues, control of vigorous bleeding over large surface areas is not disclosed in the '934 patent.
- the Bass patents disclose an adhesive comprising a first component of fibrous and/or globular proteins, preferably collagen and albumin, which can be used either together or separately and combined with a second component that is made of proteoglycans, glycoproteins, saccharides, polyalcohols, proteins, gels, or similar compounds.
- the second component provides a matrix, or foundation, for the first component to complex with and form a gel or solution.
- the resulting gel or solution can be subsequently modified with viscosity agents, bonding enhances and polar dyes which alter the tissue bonding effects when used in conjunction with a laser.
- Argon beam high electro-coagulation is a physical technique, not a tissue adhesive per se. High frequency energy is applied directly to the tissue surface causing the rapid evaporation of water resulting in coagulation. However, this process has not proven successful in treating large tissue surface areas and is especially ineffective in patients with coagulopathies.
- the present invention is directed to a composite tissue bonding and tissue modifying technology which fulfills the needs expressed above.
- This novel tissue adhesive technology comprises a combination of ultrasonically treated proteins including collagen and albumin which form a viscous material that develops adhesive properties when chemically cross-linked.
- a novel new cross-linking agent with surprisingly stable properties was developed in association with the tissue adhesive described and claimed herein and is considered to be within the scope of the present invention.
- This new cross-linking agent is a product of reacting glutaraldehyde with amino acids or peptides and allowing the reaction to proceed to completion.
- This chemical cross-linker is mixed with the ultrasonically treated proteins, allowed to react for a pre-determined time, then used to seal the large surface areas of vigorously bleeding tissues including, but not limited to, the liver, lungs and major vascular systems in patients with and without bleeding disorders.
- This same tissue adhesive has proven to work well in sealing suture sites to prevent leakage.
- Another surprising and exciting aspect of this invention is the versatility of the base adhesive.
- the cross-linked tissue adhesive of the present invention is mixed with magnesium carbonate under alkaline conditions the resulting compound becomes a powerful bone adhesive.
- This bone adhesive differs from the tissue adhesive in that it is much less malleable upon curing making it ideal for cementing rigid anatomical structures while maintaining the bio- absorbability and high bio-compatibility properties of the base adhesive.
- tissue bonding materials described in this patent include novel semi-liquid tissue adhesives, non-malleable bone adhesive, surprisingly stable and effective cross-linking agents and combinations thereof.
- Tissue adhesives formed by the methods of the present invention must possess the adhesive strength necessary to seal a vigorous bleeding tissue sufficiently to allow complete healing with minimal toxic side effects.
- Tissue adhesives of the present invention which develop a cohesive strength of at least 5 kg/cm 2 at five minutes post application with an adhesive bonding strength of at least 1 kg/cm 2 can adequately control vigorous bleeding in all body tissues including spleens, livers, lungs, the vascular system and bone.
- One embodiment of the present invention is prepared by mixing an ultrasonically treated fibrous protein with ultrasonically treated globular protein, adding a cross-linking agent and allowing the reaction to proceed for 1-3 minutes.
- the resulting adhesive can then be applied directly to vigorously bleeding tissues including visceral organs.
- the novel cross-linking agent is first prepared by mixing three parts glutamate solution (3-6 M in distilled water) with one part of a 7% aqueous glutaraldehyde solution. The resulting mixture is allowed to react for 48 hours at room temperature or until no discernible aldehyde signal is detectable using infrared spectroscopy, the solution has turned yellow-brown, pH is approximately 4.5-6.5 and all trace of characteristic aldehyde odor is eliminated.
- the fully reacted cross-linking agent is further examined using infrared analysis of aqueous and methanol solutions, a lower range infrared absorption signal is detected which is consistent with an incomplete pyrimidine compound. The importance of this signal in not known and is not intended to limit this invention.
- a one percent collagen solution preferably bovine or porcine collagen, is made in distilled water and sonicated at 0.5 to 1.5 watts/cm 2 at 17 kHz to 24 kHz for approximately 12 hours at 6°C to 10°C. The sonicated solution is then concentrated using cold lyophilization. The final concentration of the collagen solution is between 35% to 45%.
- the final adhesive is prepared by mixing four to eight parts of the collagen/albumin solution with one part of the cross-linking solution and 0.01% methylene blue.
- This adhesive can used as a stand alone sealant or in conjunction with tissue patches made from bio-compatible materials.
- approximately 9% to 20% by weight of hydroxyapatite was added to in addition to the alkaline magnesium carbonate. Both formulations were equally satisfactory. Experiments were conducted in vivo using porcine and rabbit models.
- Test animals were anti-coagulated with intravenous heparin (300 unit/kg) and measured bleeding times (PTT) exceeded 250 seconds.
- a pig's liver is severely lacerated and the surface disrupted using multiple strokes with a scalpel. This heavily bleeding, flat disrupted surface represents the worst-case scenario for a wound closure agent.
- the surface of the liver is coated with the tissue adhesive to a thickness of approximately one to three millimeters, and after a short application time, the bleeding is completely stopped.
- Postmortem studies of tissues from pigs sacrificed at six weeks following the application of the tissue adhesive to vigorously bleeding visceral organs demonstrated minimal adhesions, normal wound healing and ongoing resorbtion of these adhesive materials. Similar results were achieved with rabbits.
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- Health & Medical Sciences (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Materials For Medical Uses (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99903029A EP1140233A1 (en) | 1999-01-08 | 1999-01-08 | Tissue adhesive for treating vigorously bleeding surfaces |
CA002358567A CA2358567A1 (en) | 1999-01-08 | 1999-01-08 | Tissue adhesive for treating vigorously bleeding surfaces |
PCT/US1999/000504 WO2000040277A1 (en) | 1999-01-08 | 1999-01-08 | Tissue adhesive for treating vigorously bleeding surfaces |
AU23147/99A AU2314799A (en) | 1999-01-08 | 1999-01-08 | Tissue adhesive for treating vigorously bleeding surfaces |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US1999/000504 WO2000040277A1 (en) | 1999-01-08 | 1999-01-08 | Tissue adhesive for treating vigorously bleeding surfaces |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000040277A1 true WO2000040277A1 (en) | 2000-07-13 |
Family
ID=22271962
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/000504 WO2000040277A1 (en) | 1999-01-08 | 1999-01-08 | Tissue adhesive for treating vigorously bleeding surfaces |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1140233A1 (en) |
AU (1) | AU2314799A (en) |
CA (1) | CA2358567A1 (en) |
WO (1) | WO2000040277A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006032847A1 (en) * | 2004-09-20 | 2006-03-30 | Photopharmica Limited | Wound healing |
JP2006528518A (en) * | 2003-07-23 | 2006-12-21 | コヴァレント メディカル インコーポレイテッド | Tissue adhesive sealant |
CN113876997A (en) * | 2021-09-27 | 2022-01-04 | 广东省科学院健康医学研究所 | Albumin composite adhesive and preparation method thereof |
WO2023191176A1 (en) * | 2022-03-28 | 2023-10-05 | 주식회사 덴하우스 | Bone regeneration composition and dosage form |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010146582A2 (en) | 2009-06-15 | 2010-12-23 | Technion- Research And Development Foundation Ltd. | Reinforced surgical adhesives and sealants and their in-situ application |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5292362A (en) * | 1990-07-27 | 1994-03-08 | The Trustees Of Columbia University In The City Of New York | Tissue bonding and sealing composition and method of using the same |
WO1997024090A1 (en) * | 1995-12-19 | 1997-07-10 | Nova-Sorb Ltd. | Apparatus and methods for producing superabsorbent foams |
-
1999
- 1999-01-08 EP EP99903029A patent/EP1140233A1/en not_active Withdrawn
- 1999-01-08 CA CA002358567A patent/CA2358567A1/en not_active Abandoned
- 1999-01-08 WO PCT/US1999/000504 patent/WO2000040277A1/en not_active Application Discontinuation
- 1999-01-08 AU AU23147/99A patent/AU2314799A/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5292362A (en) * | 1990-07-27 | 1994-03-08 | The Trustees Of Columbia University In The City Of New York | Tissue bonding and sealing composition and method of using the same |
WO1997024090A1 (en) * | 1995-12-19 | 1997-07-10 | Nova-Sorb Ltd. | Apparatus and methods for producing superabsorbent foams |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006528518A (en) * | 2003-07-23 | 2006-12-21 | コヴァレント メディカル インコーポレイテッド | Tissue adhesive sealant |
WO2006032847A1 (en) * | 2004-09-20 | 2006-03-30 | Photopharmica Limited | Wound healing |
US7407953B2 (en) | 2004-09-20 | 2008-08-05 | Photopharmica Limited | Wound healing |
CN113876997A (en) * | 2021-09-27 | 2022-01-04 | 广东省科学院健康医学研究所 | Albumin composite adhesive and preparation method thereof |
WO2023191176A1 (en) * | 2022-03-28 | 2023-10-05 | 주식회사 덴하우스 | Bone regeneration composition and dosage form |
Also Published As
Publication number | Publication date |
---|---|
AU2314799A (en) | 2000-07-24 |
CA2358567A1 (en) | 2000-07-13 |
EP1140233A1 (en) | 2001-10-10 |
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