GB2383584A

GB2383584A - Bioabsorbable cyanoacrylate tissue adhesives

Info

Publication number: GB2383584A
Application number: GB0302451A
Authority: GB
Inventors: Dimiter Kotzev
Original assignee: Chemence Inc
Current assignee: Chemence Inc
Priority date: 1999-09-29
Filing date: 2000-08-30
Publication date: 2003-07-02
Anticipated expiration: 2020-08-30
Also published as: GB2383584B; GB0302451D0

Abstract

Copolymers derived from glycolide and two or more other monomers selected from the group consisting of lactide, e -caprolactone, dioxanone, and trimethylene carbonate are disclosed. A bioabsorbable tissue adhesive made by the method of dissolving the copolymer in cyanoacrylate monomer(s) is also disclosed, along with an embolic agent, a sealant or void filler, and an adhesive for wound closure comprising the tissue adhesive. The cyanoacrylates may be alkyl 2-cyanoacrylates, alkenyl 2-cyanoacrylates, alkoxyalkyl 2-cyanoacrylates, or carbalkoxyalkyl 2-cyanoacrylates, where the alkyl group may have 1 to 16 carbon atoms.

Description

BIOABSORBABLE CYANOACRYLATE TISSUE ADHESIVES This invention relates to cyanoacrylate tissue adhesives, and more particularly, to bioabsorbable cyanoacrylate tissue adhesive compositions and to methods for making and using these compositions. The compositions are useful in medical applications, including, but not limited to, wound and surgical incision closure, implants, medical device fixation, sealants and void fillers, embolic agents and other general medical applications.

Surgical incisions and wounds can be closed by three general methodssuturing, stapling and adhesive bonding.

U. S. Pat. No. 5,578, 046 teaches that sutures are bioabsorbable when the material that they are made from is capable of being broken down into smaller constituents, which can be metabolized and excreted by the living organism. Such materials are useful for temporarily holding tissues in a desired position during healing and are absorbed by the organism after a period of time. The teachings of U. S. Pat. No. 5,578, 046 as well as the patents and literature in turn referenced by U. S. Pat. No. 5,578, 046 are incorporated as reference herein.

Wound suturing has the advantage of producing bioabsorbable, non-toxic degradation products. It however also has disadvantages. Suturing requires time and skill. It causes additional trauma to the tissue by piercing and does not provide a hermetic closure.

Cyanoacrylates posses the unique property to bond living tissue. They have been widely and successfully tested for closing wounds and incisions, especially in cases where suturing does not provide satisfactory results. See Lijoi A. et al,"Subacute left ventricular free wall rupture complicating acute myocardial infarction. Successful surgical repair with a sutureless technique", J. Cardiovascular Surgery, 1996 Dec, 37 (6), 627-630; Tebala G. D. et al,"The use of cyanoacrylate tissue adhesive in high-risk intestinal anastomoses", Surgery Today, 1995,25 (12), 1069-72 and Zaki I. et al, "Split skin grafting on severely damaged skin. A technique using absorbable tissue adhesive", J. of Dermatologic Surgery and Oncology, 1994 Dec, 20 (12), 827-9.

Cyanoacrylate tissue adhesive have the following advantages over suturing: they save time; they can bond difficult to suture tissues ; they can provide a hermetic closure; they have haemostatic action; they produce better cosmetic results; they are indispensable in emergencies.

A major disadvantage of cyanoacrylate adhesives is that one of the degradation products is formaldehyde, which is toxic to the surrounding tissues (see Pani K. C. et al,"The degradation of n-butyl alpha-cyanoacrylate tissue adhesive. II.", Surgery, 1968 March, 63 (3), 481-9). For this reason

cyanoacrylates have not found favor with the FDA for internal tissue closure. Only topical skin closure applications have been FDA approved.

Other disadvantages of cyanoacrylate tissue adhesives are their runniness (low viscosity) in uncured form and stiffness when cured.

The present invention overcomes the problems and disadvantages associated with current cyanoacrylate adhesives and provides compositions useful as bioabsorbable tissue adhesives. The adhesives of the present invention are quickly biodegradable with reduced formaldehyde generation, and provide hermetic closure and haemostatic action. Additional benefits include increased application viscosity and increased flexibility in the cured state of the adhesives.

One embodiment of the invention is directed to a method for making a bioabsorbable tissue adhesive composition comprising the step of dissolving one or more copolymers, the copolymers derived from glycolide and two other monomers, into a cyanoacrylate monomer or blend of cyanoacrylate monomers. The one or more copolymers possess amorphous structure and are in a rubbery state at body temperature. The two other monomers are selected from the group consisting of lactide, e-caprolactone, dioxanone and trimethylene carbonate. The cyanoacrylate monomer or monomers are selected from the group consisting of alkyl 2-cyanoacrylate, alkenyl 2-cyanoacrylate, alkoxyalkyl 2-cyanoacrylate, or carbalkoxyalkyl 2cyanoacrylate. The alkyl group of the cyanoacrylate monomer or monomers preferably has 1 to 16 carbon atoms, and includes cycloalkyl functionality.

Another embodiment is directed to a bioabsorbable tissue adhesives made by this method.

Other embodiments and advantages of the invention are set forth in part in the description which follows, and in part, will be obvious from this description, or may be learned from the practice of the invention.

As embodied and broadly described herein, the present invention is directed to cyanoacrylate-based tissue adhesives which combine the advantages of bioabsorbable suturing with the advantages of adhesive bonding. The compositions of the present invention are quickly biodegradable with reduced formaldehyde generation, and provide hermetic closure and haemostatic action. Additional benefits of the present invention include increased application viscosity and increased flexibility in the cured state of the adhesives.

The present invention is useful in medical applications, including veterinary and other applications where a biodegradable bond is desired. Compositions of the invention may be used to bond tissue to tissue, tissue to a foreign object such as an implant, or even two foreign objects to each other. They can also be used as implants.

Although lactide - e-caprolactone copolymers were added to cyanoacrylate for thickening and plasticising of the resultant polymer with good experimental results (See Tseng Y.-C. et al,"Physical modification of acyanoacrylate for application as surgical adhesives", Progress in Biomedical Polymers, Ed. By C. G. Gebelein and R. L. Dunn, Plenum Press, New York, 1990, pp. 53-63), the lactide- B-caprolactone copolymer is not as easily biodegradable as glycolide-based copolymers and not easily soluble into cyanoacrylate at high concentrations.

In contrast, the present invention provides for an adhesive bond with enhanced biodegradability.

The present invention describes a series of terpolymers derived from glycolide and two or more of the following monomers: lactide, 8- caprolactone, dioxanone, and trimethylene carbonate. The monomers are copolymerized in ratios, which yield an amorphous and rubbery copolymer.

This is in contrast to typical copolymers used for suture manufacture, which generally posses high degree of crystallinity in order to be suitable for producing fibres. Additional feature of this class of copolymers is that they

contain at least 10% glycolide moiety in their chains, which renders them quickly biodegradable.

Catalysts useful in the copolymerization are cationic anhydrous catalysts, such as SnCl2, stannous octoate and antimony salts. Other useful catalysts are these described for polymerization of cyclic carbonates in U. S. Pat. No.

3, 301, 824, which is incorporated herein by reference.

Suitable initiators for the copolymerization may be selected from a large range of protonic and Lewis acids, amines, phosphines, hydrides, alkoxides, alkali derivatives of alkali and alkaline earth metals, as well as, hydrogen donor substances such as carboxylic acids, alcohols, glycols and alkanolamins.

The copolymers are obtained by combining the catalyst (s), initiator (s) and monomers, mixing and heating at predetermined temperature and time to ensure polymerization. The resultant copolymer could be post-treated by conventional methods to remove any unreacted monomers.

The bioabsorbable cyanoacrylate adhesives of the present invention are obtained by dissolving one or more of the above-described copolymers into one or more of the above-described cyanoacrylate monomers. Unexpectedly high amounts of copolymers (s) can easily be dissolved into the composition due to the nature of the copolymers. The dissolution can take place by agitation at room temperature or elevated temperature.

The bioabsorbable cyanoacrylate adhesives of the present invention can be stabilized against premature polymerization with anionic and free-radical polymerization inhibitors. Anionic polymerization inhibitors, known in the art include soluble acidic gases (for example sulfur dioxide), and phosphoric, carboxylic and organic sulphonic acids. Free-radical polymerization inhibitors include hydroquinone, t-butyl catechol, hydroxyanisole, butylated hydroxyanisole and butylated hydroxytoluene.

The bioabsorbable cyanoacrylate adhesives of the present invention will contain any additives necessary to impart desired properties to the adhesive as viscosity, color, X-ray opacity, as well as antimicrobial agents, antibiotics, growth promoting factors, anti-cancer drugs, immune system enhancing drugs, and leachable inorganic fillers.

For example dyes contemplated for use in the present invention are D & C Violet No. 2, D & C Green No. 6, carbon black and bone black.

For example growth factors contemplated for use in the adhesives of the present invention are fibroblast growth factor, bone growth factor, epidermal growth factor, platelet derived growth factor, macrophage derived growth factor, alveolar derived growth factor, monocyte derived growth factor, magainin, and so forth.

For example inorganic leachable fillers contemplated for use in the adhesives of the present invention are tricalcium phosphate, hydroxyapatite, calcium carbonate, calcium chloride.

The adhesive compositions of the present invention can be heat sterilized by following the teachings of U. K. Pat. GB 2 306 469B, which is incorporated herein by reference.

One embodiment is directed to bioabsorbable tissue adhesive compositions obtained by dissolving copolymers derived from glycolide and two other monomers selected from lactide, e-caprolactone, dioxanone and trimethylene carbonate, the copolymers possessing amorphous structure and being in rubbery state at body temperature, into cyanoacrylate monomer or a blend of cyanoacrylate monomers, wherin the cyanoacrylate monomer are selected from alkyl 2-cyanoacrylate, alkenyl 2-cyanoacrylate, alkoxyalkyl 2cyanoacrylate, or carbalkoxyalkyl 2-cyanoacrylate, and wherein the alkyl group may have I to 16 carbon atoms. Preferably, the cyanoacrylates are selected from methyl 2-cyanoacrylate, ethyl 2-cyanoacrylate, n-propyl 2cyanoacrylate, iso-propyl 2-cyanoacrylate, n-butyl 2-cyanoacrylate, isobutyl 2-cyanoacrylate, hexyl 2-cyanoacrylate, n-octyl 2-cyanoacrylate, 2octyl 2-cyanoacrylate, 2-methoxyethyl 2-cyanoacrylate, 2-ethoxyethyl 2cyanoacrylate and 2-propoxyethyl 2-cyanoacrylate.

Applications of the present invention include, but are not limited to, wound closure (including surgical incisions and other wounds), adhesives for medical devices, implants, sealants and void fillers in human and animal medical applications and embolic agents.

The following examples are offered to illustrate embodiments of the invention, and should not be viewed as limiting the scope of the invention.

Example 1 - Preparation and properties of amorphous and rubbery terpolymers The monomers, stannous octoate and dodecanol are added to a reactor in quantities specified in Table 1. The mixture is heated to 165 C with stirring under nitrogen atmosphere for 24 hours. The reaction product is discharged and treated at 45 oC under vacuum of less than 1 mmHg for 48 h to remove any unreacted monomers. Glass transition (Tg) of the copolymers was determined by Differential Scanning Calorimetry with heating rate of 20 C/min. As can be seen from Table 1 the synthesized copolymers were completely amorphous with low glass transition points and were rubbery at room temperature.

Table 1 Polymerization ratios and properties of copolymers

Copo s-lactide glycolide stannous dodec Tg Physical Soluble lymer caprola (g) (g) octoate anol (oC) appearance into No. ctone (g) (g) of NBCA (g) copolymer Cl 666 666 666 0.4 5 1.1 rubbery yes C2 800 800 400 0.4 5 12.9 rubbery yes C3 800 400 800 0.4 5-3. 4 rubbery yes C4 1000 500 500 0.4 5-16. 0 rubbery Yes Example 2 Preparation of adhesives Bioabsorbable cyanoacrylate tissue adhesive compositions were obtained by mixing by stirring a measured amount of copolymer into n-butyl 2cyanoacrylate (NBCA) at room temperature for 24 hours. The quantities of copolymers and cyanoacrylate are shown in Table 2. The copolymers were completely dissolved, forming homogeneous, viscous products.

Table 2 Adhesive formulations

Adhesive Quantity of NBCA Type of copolymer Quantity of No. (g) copolymer (g) Al 175 Cl A2 175 C3 25 A3 175 C4 A6 166 C3 34 Example 3 Elasticity of cured adhesives Specimens of 35 mm in length, 6.5 mm in width and 2 mm in thickness were prepared by curing the adhesives in polytetrafluoroethylene molds.

Commercially available cyanoacrylate activator Ritelok (RTM) AC69, Chemence Inc. , was used to facilitate bulk polymerization. The specimens were subjected to dynamic mechanical analysis at frequency of 1 Hz. The value of the modulus of elasticity at 37 C was recorded. The results presented in Table 3 show that the cured adhesives of the present invention are almost two times more flexible at body temperature than cured unmodified n-butyl 2-cyanoacrylate (NBCA).

Table 3 Modulus of elasticity of cured adhesives

Cured adhesive E' at 37 C (108Pa) NBCA 13. 8 Al72 A2 7. 3 A3 5. 9 Example 4 Strength properties of cured adhesives

Test specimens were prepared as described in Example 3. They were tested in tensile mode with crosshead speed of I mm/min. The peak stress was recorded. N-butyl 2-cyanoacrylate (NBCA), n-hexyl 2-cyanoacrylate (NHCA) and 2-octyl 2-cyanoacrylate (2-OCA) were tested alongside the adhesives of the present invention for comparison. The data presented in Table 4 are average of 10 measurements. The results show that the adhesives of the present invention posses substantial bulk strength surpassing that of NHCA and 2-OCA.

Table 4 Tensile strength properties of cured adhesives

Cured adhesive Peak stress (kg/mm2) NBCA 2. 0 NHCA 0. 9 2-OCA 0. 5 Al 1. 6 A2 0. 9 A3 1. 6 Example 5 Set time of adhesives Specimens with dimensions according to ASTM D 1002-94 were made of Nylon 6,6. The area to be bonded (see ASTM D 1002-94) was degreased with acetone. A drop of adhesive was applied to one surface, which was overlapped with another coupon. The joint was clamped with two bulldog clips. After a measured period of time, in 15-second increments, the clips were removed and the joint was subjected to 2 kg load. The set time was determined as the time, measured after clamping, when the bonded assembly can withstand a 2 kg weight for 30 seconds. At least 5 consecutively bonded joints have to meet the test requirement in order to establish the set time. The adhesive bonding was performed at 21-22 C and 55-65 % relative humidity. Joints bonded with NBCA, NHCA and 2-OCA were tested for comparison purposes. The results presented in Table 5 show that the adhesives of the present invention have similar set times to unmodified cyanoacrylates.

Table 5 Settimeofadhesives

Adhesive Set time (sec) NBCA 90 NHCA 90 2-OCA 195 A2 90 A6 120 Example 6 In-vitro mass loss of adhesive film Cured adhesive film was prepared by spreading 0.07g of adhesive on the surface of a microscope glass slide. The adhesive was left to cure. Film with average thickness of 0.045 mm was scraped from the glass slide, placed at 37 OC under vacuum for 4 hours, followed by 12 hours in a desiccator cabinet. Approximately 0.04 g of the film was weighed precisely and placed in Sorensen's buffer solution of pH of 7.2 at 37 oC. Samples were removed from the buffer solution at measured periods of time, washed with deionized water, dried at 37 C under vacuum for 4 hours and placed in a desiccator cabinet for 12 hours. Then the weight of the sample was measured and the weight loss calculated. The results are presented in Table 6. For comparison, films of NBCA, NHCA and 2-OCA were tested alongside the adhesives.

The results clearly demonstrate 2 to 19 fold increase in degradability of the adhesives of the present invention compared to unmodified cyanoacrylates.

It is expected that at"in-vivo"conditions the bioabsorbed copolymer phase in the adhesive film will create pathways for tissue growth connecting the bonded surfaces, leading to quick healing.

In-vitro weight loss of adhesive films

Adhesive Weight loss (%) after aging in buffer at 37 Oc for 7 weeks 12 weeks 20 weeks NBCA 2. 4 4. 3 5. 3 NHCA 0. 7 1. 5 2. 6 2-OCA 0. 2 0. 7 1. 4 Al 6. 2 13. 5 16. 2 A2 10. 8 15. 4 17. 4 A3 7. 7 8. 0 10. 5 Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. All references cited herein, including patents, are specifically and entirely incorporated by reference. It is intended that the specification and examples be considered exemplary only, with the true scope and spirit of the invention indicated by the following claims.

Claims

CLAIMS 1. A method for making a bioabsorbable adhesive composition comprising the steps of dissolving one or more copolymers, said copolymers derived from glycolide and two other monomers, into cyanoacrylate monomer or blend of cyanoacrylate monomers, wherein said one or more copolymers possess amorphous structure and are in a rubbery state at body temperature, and wherein said two monomers are selected from the group consisting of lactide, e-caprolactone, dioxanone and trimethylene carbonate, and wherein the cyanoacrylate monomer or monomers are selected from the group consisting of alkyl 2-cyanoacrylate, alkenyl 2- cyanoacrylate, alkenyl 2-cyanoacrylate, alkoxyalkyi 2-cyanoacrylate, and carbalkoxyalkyl 2-cyanoacrylate, wherein the alkyl group of said cyanoacrylate has I to 16 carbon atoms.
2. The composition of Claim 1 wherein the cyanoacrylate monomer or monomers having an alkyl group of 1 to 16 carbon atoms are selected from a group consisting of methyl 2-cyanoacrylate, ethyl 2- cyanoacrylate, n-propyl 2-cyanoacrylate, iso-propyl 2-cyanoacrylate, n- butyl 2-cyanoacrylate, iso-butyl 2-cyanoacrylate, hexyl 2-cyanoacrylate, n-octyl 2-cyanoacrylate, 2-octyl 2-cyanoacrylate, 2-methoxyethyl 2- cyanoacrylate, 2-ethoxyethyl 2-cyanoacrylate and 2-propoxyethyl 2- cyanoacrylate.
3. A bioabsorbable tissue adhesive made by the method of Claim 1.
4. A bioabsorbable adhesive composition comprising one or more copolymers, said copolymers derived from glycolide and two other monomers, dissolved into a cyanoacrylate monomer or blend of monomers, wherein said one or more copolymers possess amorphous structure and are in a rubbery state at body temperature, and wherein said two other monomers are selected from the group consisting of lactide, e- caprolactone, dioxanone, and trimethylene carbonate. And wherein the cyanoacrylate monomer or monomers are selected from the group consisting of alkyl 2-cyanoacrylate, alkenyl 2-cyanoacrylate, alkenyl 2- cyanoacrylate, alkoxyalkyl 2-cyanoacrylate, and carbalkoxyalkyl 2-

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cyanoacrylate, wherein the alkyl group of said cyanoacrylate has 1 to 16 carbon atoms.
5. The composition of Claim 4 wherein the cyanoacrylate monomer or monomers having an alkyl group of 1 to 16 carbon atoms are selected from a group consisting of methyl 2-cyanoacrylate, ethyl 2- cyanoacrylate, n-propyi 2-cyanoacrylate, iso-propyi 2-cyanoacrylate, n- butyl 2-cyanoacrylate, iso-butyl 2-cyanoacrylate, hexyl 2-cyanoacrylate, n-octyl 2-cyanoacrylate, 2-octyl 2-cyanoacrylate, 2-methoxyethyl 2- cyanoacrylate, 2-ethoxyethyl 2-cyanoacrylate and 2-propoxyethyl 2- cyanoacrylate.
6. The composition of Claim 4 further comprising one or more additives necessary to impart desired properties to the adhesive, said properties selected from the group consisting of viscosity, color, and X-ray opacity.
7. The composition of Claim 4 further comprising one or more additives selected from the group consisting of antimicrobial agents, antibiotics, growth promoting factors, anti-cancer drugs, immune system enhancing drugs, and leachable inorganic fillers.
8. A method for closing a wound comprising the step of applying the composition of Claims 4,5, 6,7 to said wound.
9. The method of Claim 8 wherein the wound is a surgical incision.
10. A method of adhering a medical device to a surface comprising the steps of: applying the composition of Claims 4,6, 6,7 to either or both said device or said surface; bringing the device, composition and surface into contact with each other; and allowing the composition to set thereby adhering the device and surface to each other.
11. The method of Claim 10 wherein said medical device is an implant.
12. An embolic agent comprising the composition of Claims 4,5, 6,7.

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13. A sealant or void filler for use in medical applications comprising the composition of Claims 4,5, 6,7.
14. An adhesive for wound closure comprising the composition of Claims 4,5, 6,7.
15. An implant comprising the composition of Claim 7.

15. An implant comprising the composition of Claim 7.

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Amendments to the claims have been filed as follows CLAIMS

1. A method for making a bioabsorbable adhesive composition comprising the steps of dissolving one or more copolymers, said copolymers derived from glycolide and two other monomers, into cyanoacrylate monomer or blend of cyanoacrylate monomers, wherein said one or more copolymers possess amorphous structure and are in a rubbery state at body temperature, and wherein said two monomers are selected from the group consisting of lactide, -caprolacton, dioxanone and trimethylene carbonate, and wherein the cyanoacrylate monomer or monomers are selected from the group consisting of a1kyI2-cyanoacry1ate, alkenyl 2- cyanoacrylate, alkenyl 2-cyanoacrylate, alkoxyalkyl 2-cyanoacrylate, and carbalkoxyalkyl 2-cyanoacrylate, wherein the alkyl group of said cyanoacrylate has 1 to 16 carbon atoms.

2. The composition of Claim 1 wherein the cyanoacrylate monomer or monomers having an alkyl group of 1 to 16 carbon atoms are selected from a group consisting of methyl 2-cyanoacrylate, ethyl 2- cyanoacrylate, n-propyl 2-cyanoacrylate, iso-propyl 2-cyanoacrylate, n- butyl 2-cyanoacrylate, iso-butyl 2-cyanoacrylate, hexyl 2-cyanoacrylate, n-octyl 2-cyanoacrylate, 2-octyl 2-cyanoacrylate, 2-methoxyethyl 2- cyanoacrylate, 2-ethoxyethyl 2-cyanoacrylate and 2-propoxyethyl 2- cyanoacrylate.

3. A bioabsorbable tissue adhesive made by the method of Claim 1.

4. A bioabsorbable adhesive composition comprising one or more copolymers, said copolymers derived from glycolide and two other monomers, dissolved into a cyanoacrylate monomer or blend of monomers, wherein said one or more copolymers possess amorphous structure and are in a rubbery state at body temperature, and wherein said two other monomers are selected from the group consisting of lactide, E- caprolactone, dioxanone, and trimethylene carbonate, and wherein the cyanoacrylate monomer or monomers are selected from the group consisting of alkyl 2-cyanoacrylate, alkenyl 2-cyanoacrylate, alkenyl 2- cyanoacrylate, alkoxyalkyi 2-cyanoacrylate, and carbalkoxyalkyl2-

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cyanoacrylate, wherein the alkyl group of said cyanoacrylate has 1 to 16 carbon atoms.

5. The composition of Claim 4 wherein the cyanoacrylate monomer or monomers having an alkyl group of 1 to 16 carbon atoms are selected from a group consisting of methyl 2-cyanoacrylate, ethyl 2- cyanoacrylate, n-propyi 2-cyanoacrylate, iso-propyi 2-cyanoacrylate, n- butyl 2-cyanoacrylate, iso-butyl 2-cyanoacrylate, hexyl 2-cyanoacrylate, n-octyl 2-cyanoacrylate, 2-octyl 2-cyanoacrylate, 2-methoxyethyl 2- cyanoacrylate, 2-ethoxyethyl 2-cyanoacrylate and 2-propoxyethyl 2- cyanoacrylate.

6. The composition of Claim 4 further comprising one or more additives necessary to impart desired properties to the adhesive, said properties selected from the group consisting of viscosity, color, and X-ray opacity.

7. The composition of Claim 4 further comprising one or more additives selected from the group consisting of antimicrobial agents, antibiotics, growth promoting factors, anti-cancer drugs, immune system enhancing drugs, and leachable inorganic fillers.

8. A method for closing a wound comprising the step of applying the composition of Claims 4, 5, 6,7 to said wound.

9. The method of Claim 8 wherein the wound is a surgical incision.

10. A method of adhering a medical device to a surface comprising the steps of: applying the composition of Claims 4, 5,6, 7 to either or both said device or said surface; bringing the device, composition and surface into contact with each other; and allowing the composition to set thereby adhering the device and surface to each other.

11. The method of Claim 10 wherein said medical device is an implant.

12. An embolic agent comprising the composition of Claims 4,5, 6,7.

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13. A sealant or void filler for use in medical applications comprising the composition of Claims 4,5, 6,7.

14. An adhesive for wound closure comprising the composition of Claims 4, 5, 6, 7.