WO1992015341A1 - Kleber zum verkleben von biologischen geweben - Google Patents
Kleber zum verkleben von biologischen geweben Download PDFInfo
- Publication number
- WO1992015341A1 WO1992015341A1 PCT/CH1992/000036 CH9200036W WO9215341A1 WO 1992015341 A1 WO1992015341 A1 WO 1992015341A1 CH 9200036 W CH9200036 W CH 9200036W WO 9215341 A1 WO9215341 A1 WO 9215341A1
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- WO
- WIPO (PCT)
- Prior art keywords
- adhesive
- fibrinogen
- adhesive according
- enzyme
- cleaving
- Prior art date
Links
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- 229940012952 fibrinogen Drugs 0.000 claims abstract description 26
- 239000003998 snake venom Substances 0.000 claims abstract description 18
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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
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/106—Fibrin; Fibrinogen
-
- 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
- A61L24/0015—Medicaments; Biocides
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
Definitions
- the present invention relates to a fibrinogen-containing adhesive which is intended for bonding biological tissues, in particular human body tissues.
- Physiological wound healing is based on a complex, multi-phase interaction between proteins, cells and corpuscles of the blood on the one hand and structural proteins, polysaccharides and cells of the tissue on the other hand and ultimately leads to the closing of the surface and the filling of the wound with tissue.
- Mechanical measures are often used to connect and restore tissue structures that have been interrupted by surgical interventions, traumatic or pathological influences, such as e.g. Sewing, clamping, nailing and screwing techniques using natural or synthetic, organic or inorganic aids.
- Synthetic resin adhesives based on polyacrylic acid esters such as 2-cyanoacrylic acid isobutyl ester (Bucrylat TM)
- Bucrylat TM 2-cyanoacrylic acid isobutyl ester
- polyacrylic adhesive results in a foreign, rigid adhesive zone that does not adapt to the plasticity and elasticity of soft tissues and organs and causes inflammation through mechanical irritation.
- the use of such synthetic resin adhesives is therefore limited today to the field of dentistry and a few special orthopedic-surgical indications.
- a commercial product (Tissucol Kit, Immuno AG, Vienna, Austria) is made up of A) a so-called cryoprecipitate of human blood, a mixture of plasminogen-containing fibrinogen, fibronectin and the clotting factor XIII present as an inactive proenzyme, B) bovine thrombin, C) aprotinin solution and D ) Calcium chloride solution together.
- Components A and B are lyophilisates which, before use in water, with the addition of components C, respectively. D, be solved.
- the viscous solution A / C containing 75 to 115 mg of clottable protein per ml and the solution B / D containing 4 to 500 units of thrombin, depending on the application, are then applied either simultaneously or in succession to the wound surface and allowed to polymerize .
- the thrombin contained in the system catalyzes the cleavage of fibrinopeptides (A and B) from fibrinogen and the formation of fibrin monomers as well as the activation of the fibrin-stabilizing factor XIII.
- an adhesive adhesive zone that seals the wound defect is formed within a few seconds, which, depending on the aprotinin concentration added, is more or less rapidly broken down and dissolved by fibrinolytic means.
- bovine thrombin contained in adhesive systems is an unstable, heat-sensitive enzyme in which viruses and prions cannot be inactivated or weakened by physical or chemical measures without destroying their enzyme activity, and which is why it carries carriers of bovine spongiform encephalopathy (BSE) and of can be mammalian pathogenic viruses.
- BSE bovine spongiform encephalopathy
- Bovine thrombin is also a powerful antigen that can trigger anaphylactic reactions in the human organism.
- human thrombin is not antigenic, it carries the risk of transmission of hepatitis and HIV viruses because, because of its sensitivity, it cannot be freed from viruses by heat or chemical measures.
- antithrombin III an inhibitor of thrombin in the blood, the so-called antithrombin III, which can neutralize the thrombin of the adhesive. Since this thrombin-inhibiting effect of antithrombin III is potentiated by the anticoagulant heparin, an adhesive containing thrombin cannot be used in patients who are being treated with heparin, or can only be used using high thrombin concentrations. However, the higher the thrombin concentration in the adhesive, the greater the risk of anaphylactic and thrombo-embolic reactions. Thrombin migrating from the adhesive site triggers activation of the platelet adhesion, aggregation and release reactions and therefore has a thrombogenic effect.
- thrombin-containing wound adhesive In order to reduce the risk of anaphylactic and thromboembolic complications to a minimum, care must be taken when applying thrombin-containing wound adhesive to ensure that thrombin is kept away from tissue that is not to be supplied to the wound environment. Under no circumstances should thrombin enter the bloodstream because it can trigger thromboses and embolisms due to its diverse activating effects on platelets, plasma coagulation factors and endothelial cells. Even with careful application, however, the adhesive site forms a thrombin depot which triggers intravascular coagulation and against which the organism can direct immunological defense reactions. For these reasons, thrombin-containing fibrin glues can only be used with significant restrictions and are in no way suitable for use in surgical interventions on blood vessels.
- the present invention relates to an adhesive for gluing human body tissues, which (a) fibrinogen, (b) a fibrinogen-cleaving enzyme,
- (d) contains coagulation factor XIII and is characterized in that it contains the coagulation factor XIII in activated form (factor Xllla) and as a fibrinogen-cleaving enzyme a fibrinogen-cleaving snake venom enzyme.
- Fibrinogen-cleaving snake venom enzymes can be obtained from the venom of the snake family Viperidae.
- 27 fibrinogen-cleaving enzymes have been isolated and characterized from snake venoms of the snake family Viperidae (H. Pirkle and K. Stocker, Thrombin-like enzymes fro snake venoms: An inventory. Thromb. Hae ostas., In press) .
- Two of these enzymes, Ancrod and Batroxobin are used in human medicine as antithrombotic drugs for therapeutic defibrinogenization.
- the adhesive according to the invention is therefore not only suitable for use in the conventional indications for fibrin adhesive, but also in endoscopic operations, for example in the joint area and in particular in vascular surgery operations.
- the adhesive capacity of the adhesive according to the invention can be increased significantly by adding fibronectin to the adhesive mixture. It has also been found that the strength of the tissue bonds can be considerably increased if a reducing agent is added to the adhesive mixture.
- Suitable reducing agents are preferably thiol compounds such as cysteine, dithiothreitol, dithioerythritol, glutathione, thioredoxin or similar compounds.
- the strengthening effect of these thiol compounds may be due to their stabilizing effect on the active, reduced form of factor Xllla and possibly also to trigger disulfide exchange reactions in the polymerized adhesive material.
- dithiothreitol can be used in concentrations of 0.1-1 mM per liter of the total adhesive.
- the coagulation factor XIII is activated before the addition to the adhesive mixture by means of thrombin, trypsin or the snake venom enzyme thrombocytin.
- the activation can be carried out as follows: 10 ml of a solution of 500 units of factor XIII, in buffered (pH 7.4) 0.05 molar sodium chloride solution, are incubated with 100 units of thrombin or 20 units of thrombocytin.
- the enzymes used to activate factor XIII are preferably fixed to an insoluble carrier, e.g. Sepharose 4B (Pharmacia, Sweden), insolubilized. After activation is complete, the insolubilized enzymes can be separated from the activated factor XIII simply by centrifugation or filtration.
- the snake venom enzymes which have a good shelf life in solution, do not need to be lyophilized, which simplifies the use of the adhesive and reduces its production costs.
- the fibrinogen-cleaving snake venom enzymes can be dissolved in aqueous electrolyte solutions, for example in sodium chloride or calcium chloride solutions. Because snit venom enzymes, which are not very antigenic, are not inhibited by antithrombin even in the presence of heparin, they can be used in very low doses even in patients who are treated with heparin, which practically eliminates the risk of anaphylactic reactions.
- the snake venom enzymes do not activate endogenous or exogenous prothrobin nor do they cause adhesion, aggregation and Triggering release reactions in platelets, there is also no risk of thromboembolic complications when using the adhesive according to the invention.
- the venom gland secretions of solenoglyphic snakes i.e. those with movable, tubular fangs belonging to the family of the vipers (Viperidae), in particular the tribe of pit vipers (Crotalinae), are suitable as the starting material for obtaining fibrinogen-cleaving snake venom enzymes.
- the poison of Bothrops atrox, Bothrops moojeni and Calloselasma (Agkistrodon) rhodostoma are particularly suitable, from which the fibrinogen-cleaving enzymes Batroxobin and Ancrod, which are already used in human medicine, are produced (Stocker, K. Defibrinogenation with thro bin-like snake venom enzymes, in Fibrinolytics and Antifibrinolytics, Markwardt, F., Ed., Springer-Verlag, Berlin, 1978, 451).
- Proteins fibrinogen and factor XIII are obtained from blood from controlled donors and treated by chemical and physical methods for virus inactivation known per se.
- the adhesive according to the invention can be ready for use
- Tris-hydroxymethylaminomethane e.g. Tris-hydroxymethylaminomethane (TRIS), and 1 to 100
- KIE units contain aprotinin per ml. Immediately before such mixtures are applied to tissue to be bonded, the polymerisation and gelation of the fibrinogen is carried out
- Batroxobin concentration of the solution is adjusted so that the ready-to-use total adhesive 5 - 100 units
- Batroxobin contains. With batroxobin amounts of 10 to 50 units per ml of adhesive mixture, gel times of
- the adhesive according to the invention can be composed, for example, of three separate ampouled components that are to be mixed when the adhesive is used.
- Ampoule 1 contains 20 mg fibrinogen, 1 mg fibronectin, 1 unit (KIE) aprotinin and 1 unit activated factor XIII in lyophilized form.
- Ampoule 2 contains 1 ml of 0.02 molar calcium chloride solution, which serves as a solvent for the contents of ampoule 1.
- Ampoule 3 contains 0.2 ml of an aqueous solution containing 50 batroxobin units and 4 ⁇ g dithiothreitol pe ml.
- the content of the ampoule 1 is dissolved in the content of the ampoule 2.
- the solution is drawn into a sterile syringe.
- the solution from ampoule 3 is taken up in a second injection syringe.
- the contents of both syringes are simultaneously applied to the tissue surfaces to be glued and the latter are combined using appropriate force.
- the properties of the adhesive mixtures according to the invention can be examined on the one hand by chemical and physico-chemical tests of the fibrin produced and on the other hand by measurements of mechanical parameters, such as stiffness, tensile strength and adhesiveness of the adhesive to different tissues.
- Chemical methods for examining the adhesive properties include the determination of the protein mass by amino acid analysis and the degree of crosslinking by electrophoretic procedures. By turbidometric measurements and by determining the permeability according to Blombburg et al. (Biochim. Biophys. Acta 997, 96-110, 1989), the porosity and the average thickness of the fibrin fibers in polymers of different adhesive mixtures can be determined.
- a circular disk of a selected biological tissue is mounted on one end of a metal cylinder.
- This cylinder end is covered with a metal mesh of a defined mesh size, around which prevent applied tissue sample from sliding into the cylinder.
- the other end of the cylinder is hermetically sealed with a dense metal plate.
- a second circular disk of the same biological tissue is mounted on a second metal cylinder.
- the adhesive to be tested is now applied to the exposed surface of the one tissue disc, whereupon the two tissue discs mounted on their metal cylinders are pressed firmly against one another.
- both cylinders are placed under vacuum, as a result of which the two tissue samples are drawn with known force against the metal nets attached to the cylinder ends. Then a tensile force is exerted on both metal cylinders at constant speed and the tensile movement is recorded digitally and graphically via a force measuring cell connected to the system. These records objectify the mechanical properties of the mechanical connection created between the biological tissue and the adhesive. The same test principle is used to determine the mechanical properties of the adhesive itself, but the tissue samples are replaced by circular disks made of polymerized adhesive.
- Component I 2 g of plasminogen-free, human fibrinogen, 0.1 g of human fibronectin, 100 units of factor Xllla and 100 kallikrein inhibitor units (KIE) aprotinin were dissolved in 100 ml of an aqueous, sterile, pyrogen-free buffer solution containing 0.05 mol per L contained tris-hydroxymethylaminomethane, 0.1 mol per L sodium chloride and 1 mmol per L ethylenediaminetetraacetic acid and had a pH of 7.4.
- KIE kallikrein inhibitor units
- the solution was given by a Membrane bacterial filters with a pore size of 0.2 ⁇ are sterile filtered, filled into 10 ml ampoules in 1.0 ml portions under sterile conditions and lyophilized under sterile conditions. The ampoules were then welded.
- Component II An aqueous 0.02 molar calcium chloride solution was prepared as solvent for the lyophilized component I. The solution was filtered through a Membran ⁇ filter fiber-free, ml dispensed into ampoules 1 each and sterilized for 30 minutes in an autoclave at 120 "C Component III.
- component I in component II containing calcium ions protein solution two batroxobin solutions (lilac and Illb) with two batroxobin concentrations which catalyze the polymerization of the fibrinogen at different speeds, in order to achieve slow polymerization
- the lilac component consisted of 0.2 ml of a sterile aqueous solution of 10 units of batroxobin and 4 ⁇ g of dithiothreitol per ml and to achieve rapid polymerization
- component Illb contained 0.2 ml of a solution of 50 units batroxobin and 4 ⁇ g dithiothreitol per ml.
- the batroxobin / dithiothreitol solutions purple and illb were sterilized by sterile filtration and in aseptic conditions in ampoules of 0.1 2 ml bottled Glue was dissolved in component I (lyophilisate) in component II (solvent) and component III was added to the solution.
- the ready-to-use adhesive contained 0.0167 g fibrinogen, 0.0008 g fibronectin, 0.833 unit factor Xllla, 0.833 KIE aprotinin, 0.0018 g CaCl_, 8.333 or 33.333 units batroxobin and 0.66 ⁇ g dithiothreitol per ml.
- Fbg fibrinogen
- Ba batroxobin
- Thr thrombin
- fibrinogen contained 0.4 units of FXIII per ml.
- Endothelial samples were obtained from porcine aorta.
- FXIIIa represent essential components of the adhesive polymerized using Batroxobin and that the endothelium
- Adhesion of this mixture is at least as good as that of the glue activated by thrombin.
- Fbg fibrinogen
- FN fibronectin
- Ba batroxobin
- Thr thrombin
- Pig skin was used to conduct these experiments. Anesthetized pigs were removed with a dermatome 1 mm thick skin flap, from which o slices were cut out. The panes were glued together as described in Example 3, adhesive mixtures activated with batroxobin having different fibrinogen and fibronectin concentrations being passed to test 5 with or without dithiothreitol (DTT, final concentration 0.5 mM). In the experiments summarized in Table III, the clotting time of the activated adhesive was 30 to 40 seconds. Adhesive strength, expressed as
- Fbg fibrinogen
- DTT dithiothreitol
- FN fibronectin
- Ba Batroxobin
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH0606/91-6 | 1991-02-28 | ||
| CH606/91A CH681693A5 (en, 2012) | 1991-02-28 | 1991-02-28 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US30184094A Continuation | 1991-02-28 | 1994-09-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992015341A1 true WO1992015341A1 (de) | 1992-09-17 |
Family
ID=4190893
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CH1992/000036 WO1992015341A1 (de) | 1991-02-28 | 1992-02-21 | Kleber zum verkleben von biologischen geweben |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU1251592A (en, 2012) |
| CH (1) | CH681693A5 (en, 2012) |
| WO (1) | WO1992015341A1 (en, 2012) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994002182A1 (en) * | 1992-07-18 | 1994-02-03 | Opperbas Holding B.V. | A two component fibrin-glue composition for improving in vitro fertilization |
| EP0592242A1 (en) * | 1992-10-08 | 1994-04-13 | E.R. Squibb & Sons, Inc. | Fibrin sealant compositions and method for utilizing same |
| WO1994022503A1 (en) * | 1993-03-30 | 1994-10-13 | Opperbas Holding B.V. | Two component fibrin glue |
| US5989215A (en) * | 1995-01-16 | 1999-11-23 | Baxter International Inc. | Fibrin delivery device and method for forming fibrin on a surface |
| WO1999065536A1 (en) * | 1998-06-18 | 1999-12-23 | The Microsearch Foundation Of Australia | Method of tissue repair ii |
| EP0534178B1 (en) * | 1991-09-27 | 2001-04-18 | Omrix Biopharmaceuticals S.A. | Improved tissue glue prepared by using cryoprecipitate |
| US7135027B2 (en) | 2002-10-04 | 2006-11-14 | Baxter International, Inc. | Devices and methods for mixing and extruding medically useful compositions |
| US7226657B1 (en) | 1998-11-04 | 2007-06-05 | Baxter International Inc. | Element provided with a fibrin layer, preparation and use thereof |
| US9358318B2 (en) | 2004-10-20 | 2016-06-07 | Ethicon, Inc. | Method of making a reinforced absorbable multilayered hemostatic wound dressing |
| US9439997B2 (en) | 2004-10-20 | 2016-09-13 | Ethicon, Inc. | Reinforced absorbable multilayered hemostatis wound dressing |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20021917A1 (it) * | 2002-09-10 | 2004-03-11 | New Dawn Consultores E Servicos L Da | Attivatore per la formazione di gel piastrinico, gel di plasma povero di piastrine o gel di plasma ricco di piastrine. |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2201993A1 (de) * | 1971-01-18 | 1972-08-10 | Pentapharm Ag | Enzympraeparat und Verfahren zu dessen Herstellung |
-
1991
- 1991-02-28 CH CH606/91A patent/CH681693A5/de not_active IP Right Cessation
-
1992
- 1992-02-21 AU AU12515/92A patent/AU1251592A/en not_active Abandoned
- 1992-02-21 WO PCT/CH1992/000036 patent/WO1992015341A1/de unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2201993A1 (de) * | 1971-01-18 | 1972-08-10 | Pentapharm Ag | Enzympraeparat und Verfahren zu dessen Herstellung |
Cited By (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0534178B1 (en) * | 1991-09-27 | 2001-04-18 | Omrix Biopharmaceuticals S.A. | Improved tissue glue prepared by using cryoprecipitate |
| WO1994002182A1 (en) * | 1992-07-18 | 1994-02-03 | Opperbas Holding B.V. | A two component fibrin-glue composition for improving in vitro fertilization |
| US5804428A (en) * | 1992-10-08 | 1998-09-08 | Bristol-Myers Squibb Company | Fibrin sealant compositions and methods for utilizing same |
| US5962026A (en) * | 1992-10-08 | 1999-10-05 | Bristol-Myers Squibb Company | Solid compositions of fibrin monomer |
| US5739288A (en) * | 1992-10-08 | 1998-04-14 | Bristol-Myers Squibb Company | Fibrin sealant compositions |
| US5750657A (en) * | 1992-10-08 | 1998-05-12 | Bristol-Myers Squibb Company | Methods and compositions using fibrin monomer to make a fibrin sealant |
| US5763410A (en) * | 1992-10-08 | 1998-06-09 | Bristol-Myers Squibb Company | Kit for preparing a fibrin sealant |
| US5763411A (en) * | 1992-10-08 | 1998-06-09 | Bristol-Myers Squibb Company | Nondynamic fibrin monomer on bandages, sutures, prostheses and dressings |
| US5770194A (en) * | 1992-10-08 | 1998-06-23 | Bristol-Myers Squibb Company | Fibrin sealant compositions and methods for utilizing same |
| US5773418A (en) * | 1992-10-08 | 1998-06-30 | Bristol-Myers Squibb Company | Fibrin sealant compositions and methods for utilizing same |
| EP1266666A3 (en) * | 1992-10-08 | 2003-01-22 | E.R. Squibb & Sons, Inc. | Fibrin sealant compositions and method for utilizing same |
| ES2065294A1 (es) * | 1992-10-08 | 1995-02-01 | Squibb & Sons Inc | Composiciones acuosas oburadoras de fibrina y metodo para prepararlas. |
| EP0592242A1 (en) * | 1992-10-08 | 1994-04-13 | E.R. Squibb & Sons, Inc. | Fibrin sealant compositions and method for utilizing same |
| US6077507A (en) * | 1992-10-08 | 2000-06-20 | Bristol-Myers Squibb Company | Method of making a composition comprising a fibrin monomer |
| WO1994022503A1 (en) * | 1993-03-30 | 1994-10-13 | Opperbas Holding B.V. | Two component fibrin glue |
| US6074663A (en) * | 1995-01-16 | 2000-06-13 | Baxter International Inc. | Method of using cross-linked fibrin material |
| US5989215A (en) * | 1995-01-16 | 1999-11-23 | Baxter International Inc. | Fibrin delivery device and method for forming fibrin on a surface |
| WO1999065536A1 (en) * | 1998-06-18 | 1999-12-23 | The Microsearch Foundation Of Australia | Method of tissue repair ii |
| US7226657B1 (en) | 1998-11-04 | 2007-06-05 | Baxter International Inc. | Element provided with a fibrin layer, preparation and use thereof |
| US7135027B2 (en) | 2002-10-04 | 2006-11-14 | Baxter International, Inc. | Devices and methods for mixing and extruding medically useful compositions |
| US9358318B2 (en) | 2004-10-20 | 2016-06-07 | Ethicon, Inc. | Method of making a reinforced absorbable multilayered hemostatic wound dressing |
| US9439997B2 (en) | 2004-10-20 | 2016-09-13 | Ethicon, Inc. | Reinforced absorbable multilayered hemostatis wound dressing |
Also Published As
| Publication number | Publication date |
|---|---|
| AU1251592A (en) | 1992-10-06 |
| CH681693A5 (en, 2012) | 1993-05-14 |
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