CA1205013A - Method of producing a tissue adhesive - Google Patents
Method of producing a tissue adhesiveInfo
- Publication number
- CA1205013A CA1205013A CA000449868A CA449868A CA1205013A CA 1205013 A CA1205013 A CA 1205013A CA 000449868 A CA000449868 A CA 000449868A CA 449868 A CA449868 A CA 449868A CA 1205013 A CA1205013 A CA 1205013A
- Authority
- CA
- Canada
- Prior art keywords
- flat material
- collagen
- fibrinogen
- tissue
- 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.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims abstract description 19
- 239000003106 tissue adhesive Substances 0.000 title claims abstract description 9
- 239000000463 material Substances 0.000 claims abstract description 26
- 108010049003 Fibrinogen Proteins 0.000 claims abstract description 19
- 102000008946 Fibrinogen Human genes 0.000 claims abstract description 19
- 229940012952 fibrinogen Drugs 0.000 claims abstract description 19
- 108010071289 Factor XIII Proteins 0.000 claims abstract description 18
- 229940012444 factor xiii Drugs 0.000 claims abstract description 18
- 235000021120 animal protein Nutrition 0.000 claims abstract description 5
- 102000008186 Collagen Human genes 0.000 claims description 22
- 108010035532 Collagen Proteins 0.000 claims description 22
- 229920001436 collagen Polymers 0.000 claims description 22
- 239000004745 nonwoven fabric Substances 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 7
- 239000003242 anti bacterial agent Substances 0.000 claims description 4
- 230000003115 biocidal effect Effects 0.000 claims description 4
- 239000001828 Gelatine Substances 0.000 claims description 3
- 229940122791 Plasmin inhibitor Drugs 0.000 claims description 3
- 230000001427 coherent effect Effects 0.000 claims description 3
- 239000000824 cytostatic agent Substances 0.000 claims description 3
- 230000001085 cytostatic effect Effects 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 239000011159 matrix material Substances 0.000 claims description 3
- 239000002806 plasmin inhibitor Substances 0.000 claims description 3
- 150000004676 glycans Chemical class 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 229960005188 collagen Drugs 0.000 claims 9
- 229920001282 polysaccharide Polymers 0.000 claims 1
- 206010052428 Wound Diseases 0.000 description 12
- 208000027418 Wounds and injury Diseases 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- 235000018102 proteins Nutrition 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 4
- YBHYYFYQHRADCQ-UHFFFAOYSA-N 2-aminoacetic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound NCC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O YBHYYFYQHRADCQ-UHFFFAOYSA-N 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229960002897 heparin Drugs 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 229960004072 thrombin Drugs 0.000 description 3
- YWMSSKBMOFPBDM-UHFFFAOYSA-N 4-carbamoylbenzenesulfonyl chloride Chemical compound NC(=O)C1=CC=C(S(Cl)(=O)=O)C=C1 YWMSSKBMOFPBDM-UHFFFAOYSA-N 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N Glutamine Chemical compound OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 229960001656 amikacin sulfate Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 208000034158 bleeding Diseases 0.000 description 2
- 231100000319 bleeding Toxicity 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000007493 shaping process Methods 0.000 description 2
- 229940075469 tissue adhesives Drugs 0.000 description 2
- 108010039627 Aprotinin Proteins 0.000 description 1
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical group OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 1
- 108010014173 Factor X Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000002759 woven fabric Substances 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Materials For Medical Uses (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE:
In a method of producing a tissue adhesive based on human or animal proteins, a tissue compatible flat material is impregnated with a solution of fibrinogen and Factor XIII, and lyophilized.
In a method of producing a tissue adhesive based on human or animal proteins, a tissue compatible flat material is impregnated with a solution of fibrinogen and Factor XIII, and lyophilized.
Description
The invention relates to a method of producing a tissue adhesive based on human or animal proteins having a content of fibrinogen and Factor XIII and, if desired, a content of a plasmin inhibitor, an antibiotic and a cytostatic.
It has been known to use blood cl~tting substances for stopping bleedings and for covering wounds. Accord-ing to the first suggestions of this kind, fibrin tampons and fibrin platelets have been used. A method of pro-ducing tissue adhesives of fibrinogen and Factor X~IIhas been described in US.patents Nos. 4,362,567 and 4,298,598 and 4,377,572.
Furthermore, it is known to use tissue adhesives having a porous structure based on collagen for covering wounds, wherein a non-woven fabric consisting of col]agen fibres is applied to the wound.
For fixing the collagen non-woven fabric, either a fibrinogen-thrombin mixture was applied to the wound area or to the inner side of the collagen non-woven fabric, whereupon the non-woven fabric was pressed onto the wound. This method has, however, the disadvantage that the fibrinogen coagulates very rapidly due to the thrombin, and a penetration into the collagen is not possible. Also, it is very difficult to achieve an optimum timing of the fixing procedure with the help of the fibrinogen-thrombin mixture.
Furthermore, a material for healing wounds is ~4 ~
known (German Offenlegungsschrift No. 29 14 822) which material has a fibrous structure, e.g., of collagen or of synthetic polymers, to which Factor XIII is fixed.
This material is not suited as a wound adhesive,since it is only able to function with the cooperation of the coagulation-active factors present in the wound area.
However, these factors are present in a slight amount only and therefore do not suffice.
The invention aims at avoiding these disadvantages and difficulties and has as its object to provide a method of the initially defined kind, by which a tissue adhesive can be formed such that it is applicable with-out limitations, i.e~, that it can be used for stopping bleedings, covering wounds and uniting tissues, for the application of which no special preparation of the wound area is necessary and which guarantees a tighter wound cover or connection.
According to the invention, this object is achieved in that an a~ueous mixture containing a tissue-compatible ~0 material, in particular collagen, gelatine or poly-saccharide, as well as fibrinogen and Factor XIII is prepared and shaped to a plane structure, which under the formation of a flat material, such as a non-woven fabric or a sheet with a coherent matrix of a tissue-compatible material is lyophilized.
According to a preferred embodiment, the mixture and its shaping to a plane structure is effected by impregnating a porous collagen non-woven fabric with an aqueous solution containing fibrinogen and Factor XIII.
Suitably, a pre-fabricated porous collagen non-woven fabric is used.
Preferably, as the porous collagen non~woven fabric such a non-woven fabric is used which has been obtained by lyophili~ing an aqueous solution of collagen in layers.
According to an advantayeous ernbodiment, for a multi-layered formation of the flat material, the shaping of the mixture to a plane structure and its lyophilization are repeated at least once.
The method according to the invention will be ex-plained in more detail in the following examples.
Exarnple 1:
10 l of frozen hurnan fresh plasma are heated to -~ 2 C, and the cryoprecipitate containing Factor XIII
as well as fibrinogen is obtained by centrifugation.
The cold-soluble proteins are extracted from the cryoprecipitate by extraction with a buffer solution and removed. The remaining proteins are dissolved at 37 C in 100 rnl of a citrate-glycine buffer which contains aprotinin (2,500 KIU), heparin (20 IU) and amikacin sul-fate (2,000 mg), and sterile filtered. The filtrate con tains at least 1,000 units of Factor XIII and at least 7,500 mg of fibrinogen~
Commersially available collagen non-woven fabrics are partitioned into flat pieces having sizes of about _ ~ _ 70 cm2, and each flat piece is treated under sterile conditions ~ith 15 ml of the Factor XIII and fibrinogen-containing solution. Thereupon the flat pieces are frozen, the swollen pieces are lyophilized and sterile packed.
Instead of using prefabricated collagen flat pieces or non-woven materials, the same can be formed in situ by lyophilization in a Petri dish, whereupon the impregnating procedure with a solution containing Factor XIII and fibrinogen is carried out as described above.
Example 2:
10 l of frozen human fresh plasma are heated to
It has been known to use blood cl~tting substances for stopping bleedings and for covering wounds. Accord-ing to the first suggestions of this kind, fibrin tampons and fibrin platelets have been used. A method of pro-ducing tissue adhesives of fibrinogen and Factor X~IIhas been described in US.patents Nos. 4,362,567 and 4,298,598 and 4,377,572.
Furthermore, it is known to use tissue adhesives having a porous structure based on collagen for covering wounds, wherein a non-woven fabric consisting of col]agen fibres is applied to the wound.
For fixing the collagen non-woven fabric, either a fibrinogen-thrombin mixture was applied to the wound area or to the inner side of the collagen non-woven fabric, whereupon the non-woven fabric was pressed onto the wound. This method has, however, the disadvantage that the fibrinogen coagulates very rapidly due to the thrombin, and a penetration into the collagen is not possible. Also, it is very difficult to achieve an optimum timing of the fixing procedure with the help of the fibrinogen-thrombin mixture.
Furthermore, a material for healing wounds is ~4 ~
known (German Offenlegungsschrift No. 29 14 822) which material has a fibrous structure, e.g., of collagen or of synthetic polymers, to which Factor XIII is fixed.
This material is not suited as a wound adhesive,since it is only able to function with the cooperation of the coagulation-active factors present in the wound area.
However, these factors are present in a slight amount only and therefore do not suffice.
The invention aims at avoiding these disadvantages and difficulties and has as its object to provide a method of the initially defined kind, by which a tissue adhesive can be formed such that it is applicable with-out limitations, i.e~, that it can be used for stopping bleedings, covering wounds and uniting tissues, for the application of which no special preparation of the wound area is necessary and which guarantees a tighter wound cover or connection.
According to the invention, this object is achieved in that an a~ueous mixture containing a tissue-compatible ~0 material, in particular collagen, gelatine or poly-saccharide, as well as fibrinogen and Factor XIII is prepared and shaped to a plane structure, which under the formation of a flat material, such as a non-woven fabric or a sheet with a coherent matrix of a tissue-compatible material is lyophilized.
According to a preferred embodiment, the mixture and its shaping to a plane structure is effected by impregnating a porous collagen non-woven fabric with an aqueous solution containing fibrinogen and Factor XIII.
Suitably, a pre-fabricated porous collagen non-woven fabric is used.
Preferably, as the porous collagen non~woven fabric such a non-woven fabric is used which has been obtained by lyophili~ing an aqueous solution of collagen in layers.
According to an advantayeous ernbodiment, for a multi-layered formation of the flat material, the shaping of the mixture to a plane structure and its lyophilization are repeated at least once.
The method according to the invention will be ex-plained in more detail in the following examples.
Exarnple 1:
10 l of frozen hurnan fresh plasma are heated to -~ 2 C, and the cryoprecipitate containing Factor XIII
as well as fibrinogen is obtained by centrifugation.
The cold-soluble proteins are extracted from the cryoprecipitate by extraction with a buffer solution and removed. The remaining proteins are dissolved at 37 C in 100 rnl of a citrate-glycine buffer which contains aprotinin (2,500 KIU), heparin (20 IU) and amikacin sul-fate (2,000 mg), and sterile filtered. The filtrate con tains at least 1,000 units of Factor XIII and at least 7,500 mg of fibrinogen~
Commersially available collagen non-woven fabrics are partitioned into flat pieces having sizes of about _ ~ _ 70 cm2, and each flat piece is treated under sterile conditions ~ith 15 ml of the Factor XIII and fibrinogen-containing solution. Thereupon the flat pieces are frozen, the swollen pieces are lyophilized and sterile packed.
Instead of using prefabricated collagen flat pieces or non-woven materials, the same can be formed in situ by lyophilization in a Petri dish, whereupon the impregnating procedure with a solution containing Factor XIII and fibrinogen is carried out as described above.
Example 2:
10 l of frozen human fresh plasma are heated to
2 C, and the cryoprecipitate containing Factor XIII
as well as fibrinogen is obtained by centrifugatiorl.
The cold-soluble proteins are extracted from the cryoprecipitate by means of a buffer solution and re-moved. The remaining proteins are dissolved in 100 ml of a citrate-glycine buffer which contains ~protinin (2,500 KIU3, heparin (20 IU) and amikacin sulfate (~,000 mg) and sterile filtered. The filtrate contains at least 1,000 units of Factor XIII and at least 7,500 mg of fibrinogen.
To this mixture is added under sterile conditions 100 ml of sterile 1 % collagen solution. Thereupon this mixture is partitioned into 20 ml portions and distrib-uted into Petri dishes, layers having a thickness of 2 to 5 mm being formed. Then the portions present in the -- 5 ~
Petri dishes are frozen and lyophilized, porous flat structures forming. The~ are sterile packed in the Petri dishes as the final containers. When applied, they are taken from the Petri dishes and laid onto the wound region.
Example 3:
In the same manner as described in Exa~ple 1, the protein base material containing Faxtor XIII and fibrino-gen is obtained from frozen human fresh plasma by ob-taining the cryoprecipitate and separation of the cold-soluble proteins, is dissolved in a citrate-glycine-buffer containing C1-inactivator (35 P~), heparin (20 IU) and glutamin sulfate (2,500 mg), and is sterile filtered.
To the dissolving buffer, additional amounts of 1S Factor XIII up to twice the amount of the natively con tained amount may be added, which is preferred if an antibiotic is contained.
To this mixture there is added under sterile con-ditions the same amount of a commercially available
as well as fibrinogen is obtained by centrifugatiorl.
The cold-soluble proteins are extracted from the cryoprecipitate by means of a buffer solution and re-moved. The remaining proteins are dissolved in 100 ml of a citrate-glycine buffer which contains ~protinin (2,500 KIU3, heparin (20 IU) and amikacin sulfate (~,000 mg) and sterile filtered. The filtrate contains at least 1,000 units of Factor XIII and at least 7,500 mg of fibrinogen.
To this mixture is added under sterile conditions 100 ml of sterile 1 % collagen solution. Thereupon this mixture is partitioned into 20 ml portions and distrib-uted into Petri dishes, layers having a thickness of 2 to 5 mm being formed. Then the portions present in the -- 5 ~
Petri dishes are frozen and lyophilized, porous flat structures forming. The~ are sterile packed in the Petri dishes as the final containers. When applied, they are taken from the Petri dishes and laid onto the wound region.
Example 3:
In the same manner as described in Exa~ple 1, the protein base material containing Faxtor XIII and fibrino-gen is obtained from frozen human fresh plasma by ob-taining the cryoprecipitate and separation of the cold-soluble proteins, is dissolved in a citrate-glycine-buffer containing C1-inactivator (35 P~), heparin (20 IU) and glutamin sulfate (2,500 mg), and is sterile filtered.
To the dissolving buffer, additional amounts of 1S Factor XIII up to twice the amount of the natively con tained amount may be added, which is preferred if an antibiotic is contained.
To this mixture there is added under sterile con-ditions the same amount of a commercially available
3.5 ~ gelatine solution. Subsequently the mixture is shaped to flat structures in Petri dishes, as described in Example 1, the swollen pieces are lyophilized and sterile packed.
Example 4:
Obtaining the protein base material containing Factor XIII and fibrinogen is effected in the same manner as in Examples 1 and 2, and so is the dissolving and ~5~3 Sterile filtration of t~le ci~rate-glycine-buffer solution.
To the filtrate the same amount of a 6 % hydroxy ethylene starch is admixed, the mixture is portioned into Petri dishes and shaped to flat structures, whereupon it is frozen, lyophilized and sterile packed.
Example 4:
Obtaining the protein base material containing Factor XIII and fibrinogen is effected in the same manner as in Examples 1 and 2, and so is the dissolving and ~5~3 Sterile filtration of t~le ci~rate-glycine-buffer solution.
To the filtrate the same amount of a 6 % hydroxy ethylene starch is admixed, the mixture is portioned into Petri dishes and shaped to flat structures, whereupon it is frozen, lyophilized and sterile packed.
Claims (7)
1. A method of producing a tissue adhesive based on human or animal proteins, said method comprising the steps of - impregnating a tissue-compatible flat material with a solution comprised of fibrinogen and Factor XIII, - lyophilizing said impregnated flat material having a coherent matrix of said tissue-compatible flat material.
2. A method as set forth in claim 1, wherein said tissue-compatible flat material comprises a non-woven fabric or sheet based on a material selected from the group consisting of collagen, gelatine and polysaccharide.
3. A method as set forth in claim 1, wherein said solution for impregnating said tissue-compatible, flat material further comprises at least one of a plasmin inhibitor, an antibiotic and a cytostatic.
4. A method of producing a tissue adhesive based on human or animal proteins, said method comprising the steps of - producing a flat material by lyophilizing an aqueous solution of collagen in layers so as to obtain a porous collagen flat material, - impregnating said porous collagen flat material with a solution comprised of fibrinogen and Factor XIII, - lyophilizing said impregnated collagen flat material having a coherent matrix of said collagen flat material.
5. A method of producing a tissue adhesive based on human or animal proteins, said method comprising lyophilizing an aqueous solution of fibrinogen, collagen and Factor XIII in layers so as to form a flat material containing fibrinogen, Factor XIII
and collagen.
and collagen.
6. A method as set forth in claim 5, wherein said aqueous solution further comprises at least one of a plasmin inhibitor, an antibiotic and a cyto-static.
7. A method as set forth in claim 5, further comprising the step of repeating at least once said lyophilizing said aqueous solution of fibrinogen, collagen and factor XIII to form a flat material by applying a further amount of said aqueous solution onto said flat material formed, and lyophilizing said further amount of said aqueous solution so as to form a multi-layered flat material.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000449868A CA1205013A (en) | 1984-03-19 | 1984-03-19 | Method of producing a tissue adhesive |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000449868A CA1205013A (en) | 1984-03-19 | 1984-03-19 | Method of producing a tissue adhesive |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1205013A true CA1205013A (en) | 1986-05-27 |
Family
ID=4127429
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000449868A Expired CA1205013A (en) | 1984-03-19 | 1984-03-19 | Method of producing a tissue adhesive |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1205013A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999065536A1 (en) * | 1998-06-18 | 1999-12-23 | The Microsearch Foundation Of Australia | Method of tissue repair ii |
-
1984
- 1984-03-19 CA CA000449868A patent/CA1205013A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999065536A1 (en) * | 1998-06-18 | 1999-12-23 | The Microsearch Foundation Of Australia | Method of tissue repair ii |
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|---|---|---|---|
| MKEX | Expiry |