GB2102811A - A tissue adhesive and a method of producing the same - Google Patents
A tissue adhesive and a method of producing the same Download PDFInfo
- Publication number
- GB2102811A GB2102811A GB08219500A GB8219500A GB2102811A GB 2102811 A GB2102811 A GB 2102811A GB 08219500 A GB08219500 A GB 08219500A GB 8219500 A GB8219500 A GB 8219500A GB 2102811 A GB2102811 A GB 2102811A
- Authority
- GB
- United Kingdom
- Prior art keywords
- fibrinogen
- factor
- antibiotic
- tissue adhesive
- factor xiii
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/106—Fibrin; Fibrinogen
Abstract
A tissue adhesive based on human or animal proteins contains factor XIII, fibrinogen and an antibiotic. In order to achieve a high straining capacity of the adherences and a retarded antimicrobial efficacy, the ratio of factor XIII to fibrinogen, expressed in units of factor XIII per gram of fibrinogen, amounts to at least 500. The antibiotic is chosen among amino-glucosides, beta- lactams, polypeptides or tetracyclines. In a method of producing the tissue adhesive the concentration ratio of factor XIII to fibrinogen is adjusted in a fibrinogen-containing blood plasma fraction by the addition of factor XIII. The antibiotic is added either before deepfreezing or lyophilization of the resulting preparation, or after thawing or reconstitution of the same.
Description
SPECIFICATION
Improvements in or relating to a tissue adhesive and a method of producing the same
The invention relates to a tissue adhesive based on human or animal proteins, containing factor XIII, fibrinogen and an antibiotic, as well as to a method of producing the same.
From British Patent application No. 8003775 and British patent application No. 8003776 methods are already known for producing a tissue adhesive containing fibrinogen and factor XIII, in which certain concentration ratios of factor XIII to fibrinogen and, if desired, albumin are adjusted, and the preparations are deepfrozen or lyophilized. These preparations basically exhibited satisfactory properties, i.e. a high straining capacity of the adherences and a good absorbability; however, it is desirable to improve these preparations with a view to an antimicrobial efficacy.
To be sure, it has already been proposed in U.S. patent No. 2,533,004 as well as by Fellinger et al. in the journal "Der Tuberkulosearzt" (6111,1952) to add antibiotics to fibrinogen solutions and to use them as wound adhesives, yet these solutions to be prepared directly at the beside do not give the fibrin clots formed therefrom a sufficient durability and straining capacity.
Furthermore, it is known from the work by Bösch et al., Archiv für orthopadische und Unfall-Chirurgie, Vol.
90 (1977), pages 63 to 75, to apply a fibrin adhesive system for filling bone defects in connection with bone transplants, with the fibrin forming at the chosen site immediately at the bone cavity by the addition of thrombin to a fibrinogen solution. As required, commonly available combination preparations of pulverized neomycin were added.
Finally, it was proposed according to the PCT application No. 80/00083 to prepare a fibrinogen antibiotic gel, wherein a mixture of cryoprecipitate with tobramycin and gentamicin as antibiotics to be prepared at the bedside is used.
According to experiments carried out by Applicant it was found that the described and known tissue adhesives that contain fibrinogen, factor XIII and antibiotic do not possess the desired combination of properties, i.e. a high straining capacity of the adherences and an antimicrobial efficacy, but that an adverse interaction between the antibiotics and factor Xlil takes place, which results in a strong decrease of the cross-linking ability of fibrinogen and a negative effect on the coagulability. Consequently, the adhesive exhibits a poorer rigidity and adhering capacity on the wound and tissue surfaces.
A further disadvantage of the known preparations resides in that the release of the antibiotic to the tissue takes place too quickly so that the retardation of the antibiotic does not suffice to be effective over a longer period of time and to achieve a high active substance release.
The invention aims at avoiding these disadvantages and difficulties and has as its object to provide a tissue adhesive of human or animal origin that meets the above-mentioned combination of properties and guarantees an improved efficacy of the antibiotic.
The set object is achieved with a tissue adhesive of the initially defined kind in that the ratio of factor XIII to fibrinogen, expressed in units of factor XIII per gram of fibrinogen, amounts to at least 500 and that an antibiotic selected from the group consisting of aminoglucosides, betalactams, polypeptides and tetracyclines is contained therein.
Advantageously, factor XIII is contained in a deepfrozen tissue adhesive in an amount of at least 40 units/ml.
According to another embodiment at least 33 % of fibrinogen is contained in a lyophilized tissue adhesive, factor XIII being present in an amount of at least 170 units/g of lyophilisate.
Suitably, a plasmin inhibitor or plasminogen-activator inhibitor selected from the group consisting of aprotinin, a2-antiplasmin, a2-macroglobulin, a1-antitrypsin, E-aminocaproic acid and tranexamic acid is additionally contained.
Advantageously, the tissue adhesive is a two-component preparation, factor XIII, fibrinogen and the plasmin inhibitor or plasminogen-activator inhibitor being contained in the first component and the antibiotic, thrombin and bivalent calcium being contained in the second component.
Preferably, the antibiotic is contained in the form of a hardly soluble derivative. A variant of this embodiment consists in that, in addition to the hardly soluble derivative, also an easily soluble one is used, if desired distributed in the two components of the tissue adhesive. This embodiment has the advantage that the easily soluble derivative is released quickly, thus ensuring a high initial efficacy, whereas the hardly soluble derivative causes a lasting efficacy.
Moreover, the invention comprises a method of producing the tissue adhesive with a modification consisting in that a concentration ratio of factor XIII to fibrinogen, expressed in units offactorXllllg of fibrinogen, of at least 500 is adjusted in a fibrinogen-containing blood plasma fraction by the addition of factor XIII, whereupon the antibiotic is added and the preparation is deepfrozen or lyophilized.
According to another modification a concentration ratio of factor XIII to fibrinogen, expressed in units of factor Xlil/g of fibrinogen, of at least 500 is adjusted in a fibrinogen-containing blood plasma fraction by the addition of factor XIII, whereupon the preparation is deepfrozen or lyophilized and, after thawing or reconstitution, is combined with an antibiotic-containing solution. With this em bodiment the antibiotic may be added after thawing or to the reconstituted solution. However, with these embodiments it has to be taken care that the concentration of factor XIII does not fall below a minimum concentration; it is to be above 40 units/ml.
According to preferred embodiment in which the fibrinogen-containing blood plasma fraction is washed with a buffer solution, the washing procedure is carried out until a factor XIII concentration of 200 units of factor Xlil/g of fibrinogen is reached, whereupon factor Xlil is supplied in an amount of at least 300 units/g of fibrinogen in the form of a concentrate of lyophilisate.
The tissue adhesive according to the invention and the method of producing the same will be explained in more detail by way ofthefollowing examples.
Example 1: Cryoprecipitate (100 g) was gained from frozen fresh human plasma by heating to 2" C, separated by centrifugation and washed twice in a buffer solution containing Na3 citrate, NaCI, glycine, glucose, aprotinin and heparin at a pH of 6.5, and the separated precipitate was dissolved in a glycine-containing buffer solution (255 ml) at a pH of 7.9. It was found that a ratio of factor XIII to fibrinogen of 226 units of factor XllI/g of fibrinogen was contained in this solution. To adjust the ratio desired according to the invention, of more than 500 U/g of fibrinogen, a pulverized factor Xlil preparation with 9,000 units was added to the solution, the concentration ratio of the solution thus having been increased to 826 units offactorXlll/g of fibrinogen.This solution was sterile-filtered; then 1.7g of gentamicin were added under sterile conditions, the mixture was filled into final containers (2.5 milk, deepfrozen and lyophilized.
Example 2: The preparation of the tissue adhesive basis from cryoprecipitate was effected in the same manner as in
Example 1, with the difference that the precipitation was liquefied by heating to 37" C after a single washing, and 13,600 units of pulverized facter XIII were added. A ratio of factor XIII to fibrinogen of 967 factor XIII units/g of fibrinogen was obtained.
5.67 g 7-i(thienyl)-(2)-acetamidoj-cephalosporanic acid were added to the solution as an antibiotic. The suspension thus obtained was filled into final containers (1 ml) and deepfrozen. The filled-in preparation has a content of factor Xlli amounting to 87 U/ml.
The application of the tissue adhesives prepared according to Examples 1 and 2 advantageously is realized by mixing the thawed or reconstituted mixture with thrombin and calcium chloride and applying it onto the tissue to be connected. It is also possible to apply the two components separately onto the tissue to be connected or filled.
Example 3:
The method according to Example 1 was repeated except for adding the antibiotic. The washed precipitate, after dissolving in a buffer solution, was sterile-filtered, filled into final containers (2,5 ml), deepfrozen and lyophilized, the first component of the tissue adhesive according to the invention thus having been made storable. The second component was prepared prior to application from a solution of thrombin and calcium chloride by adding 7-[(thienyl)-(2)-acetamidoj-cephalosporanic acid (30 mg/ml).
Example 4:
The procedure according to Example 2 was repeated, wherein gentamicin (1.89 g) was added after dissolving the cryoprecipitate, the solution was filled into final containers (1 ml) and deepfrozen. Thus, the first component of the adhesive according to the invention is present in a storable form. The second component containing 30 mg of7-[(thienyl)-2(2)-acetamidoj-cephalosporanic acid per ml of a calcium chloride thrombin solution was prepared prior to application.
Instead of the aprotinin added in accordance with Examples 1 to 4, one or more of the following compounds may be used as plasmin inhibitor or plasminogen-activator inhibitor: cx2-antiplasmin, a2-macroglobulin, a1-antitrypsin, E-aminocaproic acid and tranexamic acid.
The tissue adhesives prepared according to the invention are generally applicable for the seamless connection of human of animal tissue or organ parts, to dress wounds and stop bleedings, their antimicrobial efficacy being substantially improved.
The improved adhesive properties with an equally improved antimicrobial efficacy of the tissue adhesives according to the invention can be taken from the following comparative examples summarized in a table; the degree of crosslinking of tissue adhesives according to the invention with an increased factor Xlll/fibrinogen ratio was compared to the crosslinking degree of known tissue adhesives without an increased factor Xlil/fibrinogen ratio, using different antibiotics for each case.The a-crosslinking degree has been determined according to the sodiumlaurylsulfate (SDS) polyacrylamide gel electrophoresis method, which is carried out in a mannerthat, after having mixed the tissue adhesive with an equal volume of a solution containing 40 I*Mol CaCI2 and 15 NIH units U.S. National Institute of Health units) of thrombin per ml, the mixture is incubated at 37" C. The a-crosslinking degree is determined after stopping the reaction and reductive cleavage of the disulfide bridges contained in the proteins, by the addition of a mixture of urea, sodiumdodecylsulfate and -mercaptoethanol by means of gel electrophoresis.
In a further part of the table the clot rigidity of a tissue adhesive according to the invention was compared to a known one in a thrombelastograph, with gentamicin having been added as antibiotic.
Finally, the table includes comparative values of the tearing resistance of a tissue adhesive according to the invention and of a known one, with gentamicin being used as an antibiotic.
Fibrin a-crosslinking (at 37"C after 60 min.)
Addition of Tissue adhesive of in- Tissue adhesive
antibiotic vention with increased without increased
factor XIII content factor XIII content
> 500 U/g fibrinogen
Gentamicin 70 % 30 % Neomycin 41% 21% Fosfomycin 47 % 24% Axlocillin 66 % 42 % Doxycyclin 65 % 26 % Cefoxitin 54% 44% Clot rigidity in thrombelastograph (37" C - 60 min.) = elasticity module
Gentamicin 1150 426
Teari- esistance in g/cm2 (37" L - 30 min.) Gentamicin 1283 999
Finally, a comparative example was carried out with respect to the antibiotics release of a tissue adhesive prepared according to Example 4, 85 % of gentamicin having been released from a clot produced by this tissue adhesive already after 72 hours in an in vitro test. After 96 hours a release of gentamicin was not recognized any more, while 7-[(thienyl)-(2)-acetamido]-cephalosporanic acid was still detectable even after 8 days.
Claims (12)
1. A deepfrozen or lyophilized tissue adhesive based on human or animal proteins which comprises factor XIII, fibrinogen and an antibiotic, wherein the ratio of factor XIII to fibrinogen, expressed in units of factor Xlil per gram of fibrinogen, amounts to at least 500, and said antibiotic is selected from the group consisting of aminoglucosides, betalactams, polypeptides and tetracyclines.
2. A deepfrozen tissue adhesive as set forth in claim 1, wherein factor XIII is contained in an amount of at least 40 units/ml.
3. A lyophilized tissue adhesive as set forth in claim 1, wherein at least 33 % by weight of fibrinogen is contained, factor Xlil being present in an amount of at least 170 units/gram of lyophilisate.
4. A tissue adhesive as set forth in claim 1, further comprising a plasmin inhibitor or plasminogenactivator inhibitor selected from the group consisting of aprotinin, a2-antiplasmin, a2-macroglobulin, a1-antitrypsin, e-aminocaproic acid and tranexamic acid.
5. A tissue adhesive as set forth in claim 1, comprising a first component and a second component, said first component containing factor XIII and fibrinogen and said second component containing said antibiotic, thrombin and bivalent calcium.
6. A tissue adhesive as set forth in claim 4, comprising a first component and a second component, said first component containing factor XIII, fibrinogen and said plasmin inhibitor or plasminogen-activator inhibitor and said second component containing said antibiotic, thrombin and bivalent calcium.
7. A tissue adhesive as set forth in claim 1,wherein said antibiotic is present in the form of a hardly soluble derivative.
8. A method of producing a tissue adhesive based on human or animal proteins and comprising factor
XIII, fibrinogen, a plasmin inhibitor or plasminogen-activator inhibitor, and an antibiotic selected from the group consisting of aminoglucosides, betalactams, polypeptides and tetracyclines, which method comprises the steps of adjusting in a fibrinogen-containing blood plasma fraction a concentration ratio of factor XIII to fibrinogen, expressed in units of factor Xlil/gram of fibrinogen, of at least 500 by adding factor XIII, adding said antibiotic, and deepfreezing or lyophilizing the resulting preparation.
9. A method of producing a tissue adhesive based on human or animal proteins and comprising factor
XIII, fibrinogen, a plasmin inhibitor or plasminogen-activator inhibitor, and an antibiotic selected from the group consisting of aminoglucosides, betalactams, polypeptides and tetracyclines, which method comprises the steps of
adjusting in a fibrinogen-containing blood plasma fraction a concentration ratio of factor Xlil to fibrinogen, expressed in units of factor Xlil/gram of fibrinogen, of at least 500 by adding factor XIII,
deepfreezing or lyophilizing the resulting preparation,
thawing or reconstituting the preparation, and
combining the preparation with a solution containing said antibiotic.
10. A method as set forth in claim 8 or 9, further comprising washing said fibrinogen-containing blood plasma fraction with a buffer solution in a washing procedure, and wherein said washing procedure is carried out until a factor Xlil concentration of 200 units of factor Xlil/gram of fibrinogen is reached, whereupon factor Xlil is added in an amount of at least 300 units/gram of fibrinogen in the form of a concentrate or lyophilisate.
11. A tissue adhesive substantially as hereinbefore described with reference to the accompanying examples.
12. A method substantially as hereinbefore described with reference to the accompanying examples.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT0333781A AT369990B (en) | 1981-07-28 | 1981-07-28 | METHOD FOR PRODUCING A TISSUE ADHESIVE |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2102811A true GB2102811A (en) | 1983-02-09 |
GB2102811B GB2102811B (en) | 1985-01-30 |
Family
ID=3548998
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08219500A Expired GB2102811B (en) | 1981-07-28 | 1982-07-06 | A tissue adhesive and a method of producing the same |
Country Status (14)
Country | Link |
---|---|
JP (1) | JPH0696039B2 (en) |
AR (1) | AR227252A1 (en) |
AT (1) | AT369990B (en) |
BE (1) | BE893851A (en) |
CA (1) | CA1168982A (en) |
CH (1) | CH659187B (en) |
DE (1) | DE3225102A1 (en) |
DK (1) | DK157977C (en) |
ES (1) | ES514441A0 (en) |
FR (1) | FR2510408B1 (en) |
GB (1) | GB2102811B (en) |
IT (1) | IT1157313B (en) |
NL (1) | NL192665C (en) |
SE (1) | SE459848B (en) |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4837379A (en) * | 1988-06-02 | 1989-06-06 | Organogenesis Inc. | Fibrin-collagen tissue equivalents and methods for preparation thereof |
EP0401004A3 (en) * | 1989-06-01 | 1991-03-20 | Life Technologies Inc. | A composition for use in the treatment of fish material during the preparation of a processed fish product, to a method of preparing such a fish product and to an improved fish product |
EP0470431A2 (en) * | 1990-07-31 | 1992-02-12 | Nunzio Rapisarda | Use of fosfomycin pharmaceutically acceptable salts as a topical cicatrizer |
WO1994002182A1 (en) * | 1992-07-18 | 1994-02-03 | Opperbas Holding B.V. | A two component fibrin-glue composition for improving in vitro fertilization |
US5330974A (en) * | 1993-03-01 | 1994-07-19 | Fibratek, Inc. | Therapeutic fibrinogen compositions |
WO1994022503A1 (en) * | 1993-03-30 | 1994-10-13 | Opperbas Holding B.V. | Two component fibrin glue |
EP0696201A1 (en) † | 1993-03-12 | 1996-02-14 | American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
US6054122A (en) * | 1990-11-27 | 2000-04-25 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
US6117425A (en) * | 1990-11-27 | 2000-09-12 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, method of their production and use |
US6197325B1 (en) | 1990-11-27 | 2001-03-06 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
US6559119B1 (en) | 1990-11-27 | 2003-05-06 | Loyola University Of Chicago | Method of preparing a tissue sealant-treated biomedical material |
US6762336B1 (en) | 1998-01-19 | 2004-07-13 | The American National Red Cross | Hemostatic sandwich bandage |
US6960463B2 (en) | 1999-12-23 | 2005-11-01 | Csl Limited | Separation of fibrinogen from plasma proteases |
US7009039B2 (en) * | 2001-07-19 | 2006-03-07 | Prochon Biotech Ltd. | Plasma protein matrices and methods for their preparation |
US7189410B1 (en) | 1990-11-27 | 2007-03-13 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
US7459295B2 (en) * | 1997-08-28 | 2008-12-02 | Baxter Aktiengesellschaft | Fibrinogen-based tissue adhesive containing an elastase inhibitor |
US8268362B2 (en) | 1997-11-12 | 2012-09-18 | Bio-Products & Bio-Engineering Aktiengesellschaft | Medicinal product for the promotion of wound healing |
US8383776B2 (en) | 2004-08-27 | 2013-02-26 | Novo Nordisk Health Care Ag | Purification of factor XIII polypeptides from biological materials |
US8445009B2 (en) | 2006-08-04 | 2013-05-21 | Stb, Ltd | Processes for the production of solid dressings for treating wounded tissue |
US8461302B2 (en) | 2004-11-23 | 2013-06-11 | Zymogenetics, Inc. | Purification of recombinant human factor XIII |
US8679528B2 (en) | 2002-09-10 | 2014-03-25 | American National Red Cross | Hemostatic dressing |
US9131929B2 (en) | 2007-08-06 | 2015-09-15 | Stb, Ltd. | Methods and dressings for sealing internal injuries |
US9701940B2 (en) | 2005-09-19 | 2017-07-11 | Histogenics Corporation | Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof |
US10077420B2 (en) | 2014-12-02 | 2018-09-18 | Histogenics Corporation | Cell and tissue culture container |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06102628B2 (en) * | 1984-03-27 | 1994-12-14 | イムノ・アクチエンゲゼルシャフト | Tissue adhesive manufacturing method |
JPS6185304A (en) * | 1984-10-01 | 1986-04-30 | Green Cross Corp:The | Auxiliary for dental treatment |
DE3622642A1 (en) * | 1986-07-05 | 1988-01-14 | Behringwerke Ag | ONE-COMPONENT TISSUE ADHESIVE AND METHOD FOR THE PRODUCTION THEREOF |
AT397203B (en) * | 1988-05-31 | 1994-02-25 | Immuno Ag | FABRIC ADHESIVE |
DE19521324C1 (en) * | 1995-06-12 | 1996-10-31 | Immuno Ag | Tissue adhesive and use thereof as a hemostatic |
DE19617369A1 (en) * | 1996-04-30 | 1997-11-06 | Immuno Ag | Storage-stable fibrinogen preparations |
US6506365B1 (en) | 2000-09-25 | 2003-01-14 | Baxter Aktiengesellschaft | Fibrin/fibrinogen binding conjugate |
US7067123B2 (en) | 2003-04-29 | 2006-06-27 | Musculoskeletal Transplant Foundation | Glue for cartilage repair |
US7901457B2 (en) | 2003-05-16 | 2011-03-08 | Musculoskeletal Transplant Foundation | Cartilage allograft plug |
US7837740B2 (en) | 2007-01-24 | 2010-11-23 | Musculoskeletal Transplant Foundation | Two piece cancellous construct for cartilage repair |
US7815926B2 (en) | 2005-07-11 | 2010-10-19 | Musculoskeletal Transplant Foundation | Implant for articular cartilage repair |
US8435551B2 (en) | 2007-03-06 | 2013-05-07 | Musculoskeletal Transplant Foundation | Cancellous construct with support ring for repair of osteochondral defects |
CA2717725A1 (en) | 2008-03-05 | 2009-09-11 | Musculoskeletal Transplant Foundation | Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles |
WO2023129802A1 (en) | 2021-12-30 | 2023-07-06 | Baxter International Inc. | Fibrinogen and thrombin solutions for a fibrin sealant and fibrin sealant kit |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT359652B (en) * | 1979-02-15 | 1980-11-25 | Immuno Ag | METHOD FOR PRODUCING A TISSUE ADHESIVE |
AT359653B (en) * | 1979-02-15 | 1980-11-25 | Immuno Ag | METHOD FOR PRODUCING A TISSUE ADHESIVE |
JPS56501129A (en) * | 1979-08-31 | 1981-08-13 |
-
1981
- 1981-07-28 AT AT0333781A patent/AT369990B/en not_active IP Right Cessation
-
1982
- 1982-07-01 SE SE8204064A patent/SE459848B/en not_active IP Right Cessation
- 1982-07-05 DE DE19823225102 patent/DE3225102A1/en active Granted
- 1982-07-05 CH CH409482A patent/CH659187B/de unknown
- 1982-07-05 DK DK300682A patent/DK157977C/en active
- 1982-07-06 GB GB08219500A patent/GB2102811B/en not_active Expired
- 1982-07-13 CA CA000407154A patent/CA1168982A/en not_active Expired
- 1982-07-16 BE BE0/208601A patent/BE893851A/en not_active IP Right Cessation
- 1982-07-21 AR AR290039A patent/AR227252A1/en active
- 1982-07-22 JP JP57126829A patent/JPH0696039B2/en not_active Expired - Lifetime
- 1982-07-23 NL NL8202982A patent/NL192665C/en not_active IP Right Cessation
- 1982-07-23 FR FR8212918A patent/FR2510408B1/en not_active Expired
- 1982-07-27 ES ES514441A patent/ES514441A0/en active Granted
- 1982-07-27 IT IT22595/82A patent/IT1157313B/en active
Cited By (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4837379A (en) * | 1988-06-02 | 1989-06-06 | Organogenesis Inc. | Fibrin-collagen tissue equivalents and methods for preparation thereof |
EP0401004A3 (en) * | 1989-06-01 | 1991-03-20 | Life Technologies Inc. | A composition for use in the treatment of fish material during the preparation of a processed fish product, to a method of preparing such a fish product and to an improved fish product |
US5314881A (en) * | 1990-07-31 | 1994-05-24 | Nunzio Rapisarda | Use of phosphomycin and the pharmaceutically acceptable salts thereof as a topical cicatrizer |
EP0470431A2 (en) * | 1990-07-31 | 1992-02-12 | Nunzio Rapisarda | Use of fosfomycin pharmaceutically acceptable salts as a topical cicatrizer |
EP0470431A3 (en) * | 1990-07-31 | 1992-03-25 | Nunzio Rapisarda | Use of phosphomycin and the pharmaceutically acceptable salts thereof as a topical cicatrizer |
US6197325B1 (en) | 1990-11-27 | 2001-03-06 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
US7229959B1 (en) | 1990-11-27 | 2007-06-12 | The American National Red Cross | Supplemented fibrin matrix delivery systems |
US7208179B1 (en) | 1990-11-27 | 2007-04-24 | The American National Red Cross | Methods for treating disease and forming a supplemented fibrin matrix |
US6054122A (en) * | 1990-11-27 | 2000-04-25 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
US6117425A (en) * | 1990-11-27 | 2000-09-12 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, method of their production and use |
USRE39298E1 (en) * | 1990-11-27 | 2006-09-19 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
US6559119B1 (en) | 1990-11-27 | 2003-05-06 | Loyola University Of Chicago | Method of preparing a tissue sealant-treated biomedical material |
US7196054B1 (en) | 1990-11-27 | 2007-03-27 | The American National Red Cross | Methods for treating wound tissue and forming a supplemented fibrin matrix |
US7189410B1 (en) | 1990-11-27 | 2007-03-13 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
USRE39321E1 (en) * | 1990-11-27 | 2006-10-03 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
USRE39192E1 (en) * | 1990-11-27 | 2006-07-18 | American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
WO1994002182A1 (en) * | 1992-07-18 | 1994-02-03 | Opperbas Holding B.V. | A two component fibrin-glue composition for improving in vitro fertilization |
US5330974A (en) * | 1993-03-01 | 1994-07-19 | Fibratek, Inc. | Therapeutic fibrinogen compositions |
EP0696201B2 (en) † | 1993-03-12 | 2012-09-19 | The American National Red Cross | Supplemented tissue sealants, methods of their production and use |
EP0696201A1 (en) † | 1993-03-12 | 1996-02-14 | American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
WO1994022503A1 (en) * | 1993-03-30 | 1994-10-13 | Opperbas Holding B.V. | Two component fibrin glue |
US6019993A (en) * | 1993-03-30 | 2000-02-01 | Omrix Biopharmaceuticals S.A. | Virus-inactivated 2-component fibrin glue |
US7459295B2 (en) * | 1997-08-28 | 2008-12-02 | Baxter Aktiengesellschaft | Fibrinogen-based tissue adhesive containing an elastase inhibitor |
US8425947B2 (en) | 1997-08-28 | 2013-04-23 | Baxter Aktiengesellschaft | Fibrinogen-based tissue adhesive containing an elastase inhibitor |
US7892802B2 (en) | 1997-08-28 | 2011-02-22 | Baxter Aktiengesellschaft | Fibrinogen-based tissue adhesive containing an elastase inhibitor |
US8268362B2 (en) | 1997-11-12 | 2012-09-18 | Bio-Products & Bio-Engineering Aktiengesellschaft | Medicinal product for the promotion of wound healing |
US6762336B1 (en) | 1998-01-19 | 2004-07-13 | The American National Red Cross | Hemostatic sandwich bandage |
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Also Published As
Publication number | Publication date |
---|---|
DK157977C (en) | 1990-08-13 |
FR2510408A1 (en) | 1983-02-04 |
SE8204064D0 (en) | 1982-07-01 |
DE3225102A1 (en) | 1983-02-17 |
SE8204064L (en) | 1983-01-29 |
NL192665C (en) | 1997-12-02 |
SE459848B (en) | 1989-08-14 |
IT1157313B (en) | 1987-02-11 |
CA1168982A (en) | 1984-06-12 |
FR2510408B1 (en) | 1987-02-27 |
AR227252A1 (en) | 1982-09-30 |
DK157977B (en) | 1990-03-12 |
ATA333781A (en) | 1982-07-15 |
JPH0696039B2 (en) | 1994-11-30 |
CH659187B (en) | 1987-01-15 |
JPS5826821A (en) | 1983-02-17 |
AT369990B (en) | 1983-02-25 |
NL8202982A (en) | 1983-02-16 |
ES8306023A1 (en) | 1983-05-01 |
GB2102811B (en) | 1985-01-30 |
BE893851A (en) | 1982-11-16 |
ES514441A0 (en) | 1983-05-01 |
NL192665B (en) | 1997-08-01 |
DE3225102C2 (en) | 1990-05-31 |
IT8222595A0 (en) | 1982-07-27 |
DK300682A (en) | 1983-01-29 |
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PE20 | Patent expired after termination of 20 years |
Effective date: 20020705 |