MXPA00002116A - Methods of applying monomeric compositions effective as wound closure devices - Google Patents

Abstract

A method of joining together i(in vivo) living tissue surfaces includes (a) holding together at least two tissue surfaces to form abutted tissue surfaces;(b) applying across said abutted tissue surfaces an excessive amount of an adhesive composition comprising at least one monomer that forms a medically acceptable polymer with an applicator having a porous applicator tip;and (c) maintaining said tissue surfaces in contact i(in vivo) until said composition polymerizes to form a thick film of polymerized composition on said abutted tissue surface.

Description

METHODS FOR APPLYING EFFECTIVE MONOMERIC COMPOSITIONS AS DEVICES FOR THE CLOSURE OF WOUNDS FIELD OF THE INVENTION This invention relates to monomeric and polymeric compositions useful for forming biomedical adhesives and sealants, and to methods for applying them. More particularly, this invention relates to methods for applying monomeric and polymeric compositions and to their use for medical, surgical and other in vivo applications.

BACKGROUND OF THE INVENTION The products in primary use for wound closure are sutures and surgical staples. Sutures are recognized for providing adequate support to wounds. However, sutures cause additional trauma to the site of the wound (due to the need for the needle and suture to pass through the tissue and the need to anesthetize the wound area via needle application) and are time consuming to be placed , and at the level of REF .: 32977 the skin, can cause unattractive or unsightly wound closure marks. Surgical staples have been developed for rapid apposition of wounds and to provide improved cosmetic results. However, surgical staples also impose trauma to additional wounds and require the use of auxiliary and often costly devices to place and apply the staples. Both sutures and staples are especially problematic in pediatric cases where the patient may have a strong anxiety response and refuse to cooperate with their placement, and in geriatric cases where the skin tissue is thin or weak and is willing to split or tear . Alternatively, adhesives have been proposed as wound closure devices. One group of such adhesives is the monomeric form of alpha-cyanoacrylates. Reference is made, for example, to U.S. Patent Nos. 5,328,687 to Leung et al; 3,527,841 to ic er et al .; 3,722,599 to Robertson et al .; 3,995,641 to Kronenthal et al .; and 3,940,362 from Overhults, which describe alpha-cyanoacrylates which are useful as surgical adhesives. All the above references are incorporated herein by reference. Typically, the cyanoacrylate surgical adhesive is applied to one or both surfaces of the wounds or incisions, including the internal portions of the wound, with any excess adhesive that is rapidly removed from the joined surfaces. Accordingly, the edges of the wound are held together until they adhere. See U.S. Patent No. 3,559,652 to Coover, Jr. et al. Two adhesive coatings can be applied to the wound surfaces. However, this method of application produces significant levels of histoxicity due to the surgical adhesive that is trapped within the wound site. An additional method of applying cyanoacrylate surgical adhesive to wounds or incisions involves the formation of a bridge over the wound site. As described in U.S. Patent No. 3,667,472 to Halpern, the cut tissues are held together and held in fixed relationship until a cyanoacrylate adhesive has been applied over the incision and the time necessary to develop a bond is allowed. The excess adhesive is removed from the incision. However, the composition used in this process suffers from inadequate film resistance and flexibility with high histotoxicity at wound sites. These conventional adhesive web application methods generally do not specify a particular method that is preferred, nor is mention made of placement other than in minimal amounts of glue in wounds. Conventional application techniques seek to reduce the application of excessive amounts of tissue adhesive to the wound due to histoxicity. A commercially available topical tissue adhesive is Histoacryl® available from B. Braun Melsungen AG of Germany. The manufacturer recommends the use of this adhesive only for the closure of minor skin wounds and not for internal use. Nevertheless, the manufacturer recommends that the adhesive be used sparingly or in thin films because the thick films do not increase the film's resistance and can lead to necrosis of the surrounding tissue due to the thermogenic reaction. However, the films formed from this adhesive are brittle, allowing several wound dehiscence. The plasticizers have been added to surgical cyanoacrylate adhesive compositions. See, for example, US Pat. Nos. 3,759,264 to Coover, Jr et al., 3,667,472 to Halpern, 3,559,652 to Banitt, the subject of which is incorporated herein by reference. However, the incorporation of plasticizers in such compositions has led to decrease the strength of the film of the polymerized material. Accordingly, such compositions have been used only within the site of the wound and not over the site of the wound as a bridge. Other adhesives have been used in surgical cyanoacrylate adhesives for the purposes of modifying the cure speed and shelf life of the adhesives. For example, cyanoacrylate polymerization inhibitors or stabilizers including Lewis acids, such as sulfur dioxide, nitric oxide, boron trifluoride and other acidic substances, including hydroquinone monomethyl ether, hydroquinone, nitrohydroquinone, catechol and hydroquinone monoethyl ether . See, for example, US Patent No. 3,559,652 to Banitt, the subject of which is incorporated herein by reference. These compositions contain significant amounts of impurities and, therefore, require substantial amounts of stabilizer to inhibit the premature polymerization of the monomer. Other adhesives include both plasticizers and stabilizing agents. For example, U.S. Patent No. 5,480,935 to Greff et al., Discloses a tissue adhesive having a plasticizer and a polymerization inhibitor. However, the plasticizers described herein (ie, alkyl phthalates) are highly toxic and are not suitable for use in biocompatible medical adhesives.

DESCRIPTION OF THE INVENTION The present invention provides a process for the application of a surgical adhesive composition in a bridge structure that provides unexpectedly improved bond strength over conventional application techniques of the polymerized composition, at the site of the wound or incision, which increases the effectiveness of monomers and polymers in in vivo applications. The surgical adhesive forms a flexible and resistant bond or union on wounds and incisions. In addition, the method for applying a surgical adhesive to a wound or incision provides a strong and flexible biocompatible bond. The present invention is also directed to methods for applying a monomeric composition with a porous applicator tip and with a tip of the applicator having a non-uniform distribution of the initiator or speed modifier.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES One embodiment of the present invention provides the monomeric composition for wound closure, comprising: A) at least one monomer, which forms a medically acceptable wound closure polymer; B) at least one plasticizing agent; and C) at least one acid stabilizing agent. In other embodiments, the present invention is directed to methods for using the monomers, copolymers and polymers described above made therefrom for biomedical purposes. See the North American Patent Series No. 08 / 609,921, incorporated herein in its entirety as reference. In such an embodiment, the edges of a wound or incision are held together and an excessive amount of the surgical adhesive composition described above is applied to the edges of the opposing wound spliced or squeezed, preferably using more than one application stroke. This process forms a bridge over opposite edges of the wound spliced or supported, which is flexible and has high resistance to tension. The excessive amount of adhesive placed on the opposite edges of the spliced wound forms a thick film therein and unexpectedly increases the strength of the film. For example, the present invention includes a method for forming a biococtable film through spliced tissue surfaces, comprising: (a) holding together at least two tissue surfaces to form spliced tissue surfaces, (b) applying to through the spliced tissue surfaces a biocompatible adhesive monomer composition, and (c) allow the composition to polymerize and form a biocompatible film on spliced tissue surfaces having an in vivo film strength of at least 70 mmHg pressure at vacuum required to induce wound deterioration, generally from 70 mmHg to 400 mmHg vacuum pressure required to induce wound deterioration, preferably from 90 mmHg to 400 mmHg vacuum pressure required to induce wound deterioration, and more preferably from 100 mmHg to 400 mmHg of pressure required to induce wound deterioration. Preferably, the monomer is an alpha-cyanoacrylate. The monomeric compositions of this invention and polymers formed thereof are useful as tissue adhesives, sealants to prevent blood flow or to cover open wounds, and in other biomedical applications. They find use in, for example, juxtaposing tissues with surgical incisions or traumatically lacerated; retarding blood flow from wounds; and helping to repair and grow back the living tissue. As conventional surgical adhesive compositions, mentioned above, plasticizers have been included with the adverse effect of reducing the strength of the film. It has been found that, contrary to the previous opinion, the strength of the film (for example, firmness) under certain conditions is not adversely reduced until the addition of large amounts of the plasticizing agent. Depending on the particular acid stabilizing agent and the purity of the monomer used in the adhesive composition, the addition of large amounts of plasticizing agent can increase the strength or strength of the resulting bond formed in the wound. It has been found that weak acid stabilizing agents do not significantly affect the polymerization of the monomer in the present composition and provide increased resistance to the film with the increase of amounts of plasticizing agents.

The monomers that can be used in this invention are easily polymerizable, for example polymerizable or anionically polymerizable free radicals, to form polymers. Such monomers include those which form polymers, which may, but need not be, biodegradable. Reference is made, for example, to U.S. Patent No. 5,328,687, which is incorporated herein by reference. As defined herein, "histotoxicity" refers to the response of the adverse tissue, such as inflammation due to the presence of toxic materials in the tissue. Useful 1, 1-disubstituted ethylene monomers include, but are not limited to, monomers of the formula: (i; CHR = CXY wherein X and Y are each strong electron separation groups, and R is H, -CH = CH2 or, provided that X and Y are both cyano groups, an alkyl group of 1 to 4 carbon atoms. Examples of monomers within the scope of formula (I) include alpha-cyanoacrylates, vinylidene cyanides, alkyl homologs of 1 to 4 carbon atoms of vinylidene cyanides, dialkyl methylene malonates, acrylacrylonitriles, vinyl sulphinates and vinyl sulfonates of the formula CH2 = CX'Y 'where X' is -S02R 'or -SO3R' and Y 'is -CN, -COOR', -COCH3, -SO2R 'or -SO3R' and R 'is H or hydrocarbyl. The preferred monomers of the formula (I) for use in this invention are alpha-cyanoacrylates. These monomers are known in the art and have the formula CN / (II) CHR2 «C \ COOR" 1 wherein R is hydrogen and R is a hydrocarbyl or substituted hydrocarbyl group; a group having the formula -R -OR -0-R, wherein R4 is a 1,2-alkylene group having 2-4 carbon atoms, R5 is an alkylene group having 2-4 carbon atoms, and R6 is an alkyl group having 1-6 carbon atoms; or a group that R'-C O-R * has the formula I I where R7 is O CH3 -CH2"• CB-, or -C (CH3) 2- and R is an organic radical.

Examples of suitable hydrocarbyl and substituted hydrocarbyl groups include straight chain or branched chain alkyl groups having 1-16 carbon atoms; alkyl groups of 1 to 16 straight-chain or branched-chain carbon atoms substituted with an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom, a cyano group, or a haloalkyl group; straight or branched chain alkenyl groups having 2 to 16 carbon atoms; straight chain or branched chain alkynyl groups having 2 to 12 carbon atoms; cycloalkyl groups; aralkyl groups; alkylaryl groups; and aryl groups. The organic radical R can be substituted or unsubstituted and can be straight chain, branched or cyclic, saturated, unsaturated or aromatic. Examples of such organic radicals include alkyl radicals of 1 to 8 carbon atoms, alkenyl radicals of 2 to 8 carbon atoms, alkynyl radicals of 2 to 8 carbon atoms, cycloaliphatic radicals of 3 to 12 carbon atoms, aryl radicals such as phenyl and substituted phenyl and aralkyl radicals such as benzyl, methylbenzyl and phenylethyl. Other organic radicals include substituted hydrocarbon radicals, such as halo substituted hydrocarbon radicals (eg, chloro-, fluoro- and bromo-substituted hydrocarbons) and oxy- (eg, alkoxy-substituted hydrocarbons). Preferred organic radicals are alkyl, alkenyl and alkynyl radicals having from 1 to about 8 carbon atoms, and halo substituted derivatives thereof. Alkyl radicals of 4 to 6 carbon atoms are particularly preferred. In the cyanoacrylate monomer of the formula (II), R is preferably an alkyl group having 1-10 carbon atoms or a group having the formula -AOR, wherein A is a straight chain alkylene or oxyalkylene radical or branched, divalent, having 2-8 carbon atoms, and R is a straight or branched alkyl radical having 1-8 carbon atoms. Examples of groups represented by the formula -AOR include l-methoxy-2-propyl, 2-butoxy ethyl, isopropoxy ethyl, 2-methoxy ethyl, and 2-ethoxy ethyl. The preferred alpha-cyanoacrylate monomers used in this invention are 2-octyl cyanoacrylate, dodecyl cyanoacrylate, 2-ethylhexyl cyanoacrylate, butyl cyanoacrylate, methyl cyanoacrylate, 3-methoxybutyl cyanoacrylate, 2-butoxyethyl cyanoacrylate, 2-isopropoxyethyl cyanoacrylate, or 1-methoxy -2-propyl cyanoacrylate. The alpha-cyanoacrylates of the formula (II) can be prepared according to methods known in the art. Reference is made, for example, to U.S. Patent Nos. 2,721,858 and 3,254,111, each of which is incorporated herein by reference. For example, alpha cyanoacrylates can be prepared by reacting an alkyl cyanoacetate with formaldehyde in a non-aqueous organic solvent and in the presence of a basic catalyst, followed by pyrolysis of the anhydrous intermediate polymer in the presence of a polymerization inhibitor. Alpha-cyanoacrylate monomers prepared with low moisture content and essentially free of impurities are preferred for biomedical use. The alpha-cyanoacrylates of the formula (II) wherein R is a group having the formula -R4-0-R5-0-R6 can be prepared according to the method described in the North American Patent No. 4,364,876 to Kimura et al. ., which is incorporated here as a reference. In the method of Kimura et al., Alpha-cyanoacrylates are prepared by producing a cyanoacetate by esterification of cyanoacetic acid with an alcohol or by transesterification of an alkyl cyanoacetate and an alcohol; condensing the cyanoacetate and formaldehyde or para-formaldehyde in the presence of a catalyst at a molar ratio of 0.5-1.5: 1, preferably 0.8-1.2: 1, to obtain a condensate; depolymerizing the condensation reaction mixture either directly or after removal of the condensation catalyst to give the crude cyanoacrylate; and distilling the crude cyanoacrylate to form a cyanoacrylate of high purity. The alpha-cyanoacrylates of the formula (II) in C-O-R where R is a group having the formula I I they can be prepared in accordance with the procedure described in U.S. Patent No. 3,995,641 to Kronenthal et al., which is incorporated herein by reference. In the method of Kronenthal et al., Such alpha-cyanoacrylate monomers are prepared by reacting an alkyl ester of an alpha-cyanoacrylic acid with a cyclic 1,3-diene to form a Diels-Alder adduct which is then subjected to to alkaline hydrolysis followed by acidification to form the corresponding alpha-cyanoacrylic acid adduct. The adduct of alpha-cyanoacrylic acid is preferably esterified by an alkyl bromoacetate to give the corresponding carbalkoxymethyl alpha-cyanoacrylate adduct. Alternatively, the alpha-cyanoacrylic acid adduct can be converted to the alpha-cyanoacryloyl halide adduct by the reaction with thionyl chloride. The alpha-cyanoacryloyl halide adduct is then reacted with an alkyl hydroxyacetate or a methyl substituted alkyl hydroxyacetate to give the corresponding carbalkoxymethyl alpha-cyanoacrylate adduct or carbalkoxy alkyl alpha-cyanoacrylate adduct, respectively. The cyclic 1,3-diene blocking group is finally removed and the carbalkoxy methyl alpha-cyanoacrylate adduct or the carbalkoxy alkyl alpha-cyanoacrylate adduct is converted to the corresponding alkyl carbalkoxy-alpha cyanoacrylate by heating the adduct in the presence of a slight deficit of maleic anhydride. Examples of monomers of the formula (II) include cyanopentadienoates and alpha-cyanoacrylates of the formula: CN / (III) CHZ = C \ COOR wherein Z is -CH = CH2 and R is as defined above. The monomers of the formula (III) wherein R is an alkyl group of 1 to 10 carbon atoms, ie the esters of 2-cyanopenta-2,4-dienoic acid, can be prepared by reacting an appropriate 2-cyanoacetate with acrolein in the presence of a catalyst such as zinc chloride. This method for preparing 2-cyanopenta-2,4-dienoic acid esters is described, for example, in U.S. Patent No. 3,554,990, which is incorporated herein by reference. Preferred monomers are alkyl alpha-cyanoacrylates and most preferably octyl cyanoacrylates, especially 2-octyl alpha-cyanoacrylates. The monomers used in the present application should be very pure and contain few impurities (eg, surgical grade). Component B) of the compositions of this invention is at least a plasticizing agent imparting flexibility to the polymerized monomer formed in the wound or incision. The plasticizing agent preferably contains little or no moisture and should not significantly affect the polymerization of the monomer. Examples of suitable plasticizers include acetyl tributyl citrate, dimethyl sebacate, triethyl phosphate, tri (2-ethylhexyl) phosphate, tri (p-cresyl) phosphate, glyceryl triacetate, glyceryl tributyrate, diethyl sebacate, dioctyl adipate, isopropyl myristate, butyl stearate, lauric acid, trioctyl trimellitate, dioctyl glutarate and mixtures thereof. Preferred plasticizers are tributyl citrate and acetyl tributyl citrate.

Component c) of the compositions of this invention is at least one acid stabilizing agent that inhibits polymerization. Such stabilizing agents may also include mixtures of anionic stabilizing agents and radical stabilizing agents. Examples of suitable anionic stabilizing agents include suldioxide, sulfonic acid, lactone, boron trifluoride, organic acid, alkyl sulfate, alkyl sulfite, 3-sulfolene, alkylsulfone, alkyl sulfoxide, mercaptan, and alkyl sulfide and mixtures thereof. Preferred anion stabilizing agents are acid stabilizing agents of organic acids such as acetic acid or phosphoric acid with acetic acid which is a more preferable acid stabilizing agent. The maximum amount of suldioxide present in the adhesive composition should be less than 50 ppm, and preferably less than 30 ppm. Examples of suitable radical stabilizing agents include hydroquinone, hydroquinone monomethyl ether, catechol, pyrogallol, benzoquinone, 2-hydroxybenzoquinone, p-methoxy phenol, t-butyl catechol, butylated hydroxy anisole, butylated hydroxy toluene, and hydroquinone -butyl.

Suitable acid stabilizing agents include those having pKa ionization constants ranging from about 0 to about 7, preferably from about 1 to about 6, and most preferably from about 2 to about 5.5. For example, suitable acid stabilizing agents include: acid sulfide (pKa 7.0), carbonic acid (pKa 6.4), triacetylmethane (pKa 5.9), acetic acid (pKa 4.8), benzoic acid (pKa 4.2), 2,4-dinitrophenol (pKa 4.0), formic acid (pK 3.7), nitrous acid (pKa 3.3), hydrofluoric acid (pKa 3.2), chloroacetic acid (pKa 2.9), phosphoric acid (pKa 2.2), dichloroacetic acid (pKa 1.3), trichloroacetic acid ( pKa 0.7), 2, 4, 6-trinitrophenol (picric acid) (pKa 0.3), trifluoroacetic acid (pKa 0.2), and mixtures thereof. When the aforementioned weak acid stabilizing agents are added to the adhesive composition, it has been found that the addition of the plasticizing agents in amounts ranging from about 0.5% by weight to about 16% by weight, preferably from about 3% by weight a about 9% by weight, and most preferably from about 5% by weight to about 7% by weight provides increased film strength (e.g., hardness or firmness) of the polymerized monomer over polymerized monomers which have amounts of plasticizing agents and acid stabilizing agents outside the above ranges. The concentration of the acid stabilizing agents used may vary depending on the strength of the acid. For example, when acetic acid is used, a concentration of 80-200 ppm (weight / weight), preferably 90-180 (weight / weight), and more preferably 100-150 ppm (weight / weight) may be used. When using a stronger acid, such as phosphoric acid, a concentration range of 20-80 ppm can be used. (weight / weight), preferably, 30-70 ppm (w / w) and more preferably 40-60 ppm (w / w). The compositions of this invention may also include at least one biocompatible agent effective to reduce the concentration levels of active formaldehyde produced during the in vivo biodegradation of the polymer (also referred to herein as "formaldehyde concentration reducing agents"). Preferably, this component is a formaldehyde purification compound. Examples of formaldehyde purification compounds useful in this invention include sulfites, bisulfites, mixtures of sulfites and bisulfites; Ammonium sulphite salts; amines; amides; imides; nitriles; carbamates; alcohols; mercaptans; proteins; mixtures of amines, amides, and proteins; active methylene compounds such as cyclic ketones and compounds having a b-dicarbonyl group; and free heterocyclic ring compounds of a carbonyl group and containing an NH group, with the ring made of nitrogen or carbon atoms, the ring is unsaturated or, when fused to a phenyl group, is unsaturated or saturated, and the group NH is attached or bonded to a carbon atom or a nitrogen atom, this atom is directly linked by a double bond to another carbon or nitrogen atom. The bisulfites and sulfites useful as the formaldehyde purifying compound in this invention include alkali metal salts such as lithium, sodium and potassium salts, and ammonium salts, for example, sodium bisulfite, potassium bisulfite, lithium bisulfite, ammonium bisulfite, sodium sulfite, potassium sulfite, lithium sulfite, ammonium sulfite, and the like. Examples of amines useful in this invention include the aliphatic and aromatic amines such as, for example, aniline, benzidine, aminopyrimidine, toluenediamine, triethylenediamine, diphenylamine, diaminodiphenylamine, hydrazines and hydrazide.

Suitable proteins include collagen, gelatin, casein, soy protein, vegetable protein, keratin and glue. The preferred protein for use in this invention is casein. Suitable amides for use in this invention include urea, cyanamide, acrylamide, benzamide, and acetamide. Urea is the preferred amide. Suitable alcohols include phenols, 1,4-butanediol, d-sorbitol, and polyvinyl alcohol. Examples of suitable compounds having a b-dicarbonyl group include malonic acid, acetylacetone, ethylacetone, acetate, malonamide, diethylmalonate or other malonic ester. Preferred cyclic ketones for use in this invention include cyclohexanone or cyclopentanone. Examples of suitable heterocyclic compounds for use as the formaldehyde purifier in this invention are described, for example, in U.S. Patent No. 4,127,382 (Perry) which is incorporated herein by reference. Such heterocyclic compounds include, for example, benzimidazole, 5-methyl benzimidazole, 2-methylbenzimidazole, indole, pyrrolo, 1,2,4-triazole, indoline, benzotriazole, indoline, and the like. A preferred formaldehyde purifier for use in this invention is sodium bisulfite.

In the practice of this invention, the formaldehyde concentration reducing agent, for example, formaldehyde purifying compound, is added in an effective amount to the cyanoacrylate. The "effective amount" is that amount sufficient to reduce the amount of formaldehyde generated during the subsequent in vivo biodegradation of the polymerized cyanoacrylate. This amount will depend on the type of active formaldehyde concentration reducing agent, and can be easily determined without undue experimentation by those skilled in the art. The formaldehyde concentration reducing agent can be used in this invention in the free form or in the microencapsulated form. When microencapsulated, the formaldehyde concentration reducing agent is released from the microcapsule continuously for a period of time during the biodegradation of the cyanoacrylate polymer in vivo. For purposes of this invention, the microencapsulated form of the formaldehyde concentration reducing agent is preferred, because this mode prevents or substantially reduces the polymerization of the cyanoacrylate monomer by the formaldehyde concentration reducing agent, which It increases its useful life and facilitates the manipulation of the monomeric composition during its use. Microencapsulation of the formaldehyde purifier can be achieved by many known microencapsulation techniques. For example, microencapsulation can be performed by dissolving a coating polymer in a volatile solvent, for example, methylene chloride, at a polymer concentration of about 6% by weight; adding a formaldehyde purifying compound in the particulate form to the polymer / coating solvent solution under stirring to produce a purifier concentration of 18% by weight; slowly add a solution of mineral oil containing surfactant to the polymer solution under rapid stirring; allow the volatile solvent to evaporate with stirring; remove the agitator; Separate the solids from the mineral oil; and washing and drying the microparticles. The size of the microparticles will vary depending on approximately 0.001 to approximately 1000 microns. The coating polymer for microencapsulating the formaldehyde concentration reducing agent should be polymers that undergo bioerosion in vivo, preferably at speeds similar to or greater than the cyanoacrylate polymer formed by the monomer, and should have low inherent moisture content . Such "bioerosion" can occur as a result of the physical or chemical decomposition of the encapsulation material, for example, by the encapsulation material passing from solid to solute in the presence of body fluids, or by biodegradation of the encapsulation material by agents present in the body. Examples of coating materials which can be used to microencapsulate the formaldehyde concentration reducing agent include polyesters, such as polyglycolic acid, polylactic acid, polyglycolic acid and polylactic acid copolymers, polycaprolactone, poly-b-hydroxybutyrate, copolymers of epsilon-caprolactone and delta-valerolactone, copolymers of epsilon-caprolactyl and DL-dilute, and polyester hydrogels; polyvinyl pyrrolidone; polyamides; jelly; albumin; proteins; collagen; poly (orthoesters); poly (anhydrides); poly (alkyl-2-cyanoacrylates); poly (dihydropyrans); poly (acetals); poly (phosphazenes); poly (urethanes); poly (dioxinones), cellulose; and starches. Examples of the surfactant that can be added to the mineral oil include those commercially available under the designations Triton x-100, Tween 20 and Tween 80. The composition of this invention may additionally contain one or more adjuvants, such as thickening agents, medicaments., or the like, to improve the medical utility of the monomer for particular medical applications. Suitable thickeners include, for example, polycyanoacrylates, polylactic acid, polyglycolic acid, lactic-glycolic acid copolymers, polycaprolactone, lactic acid-caprolactone copolymers, poly-3-hydroxybutyric acid, polyorthoesters, polyalkyl acrylates, alkyl acrylate copolymers. and vinyl acetate, polyalkyl methacrylates and copolymers of alkyl and butadiene methacrylates. To improve the cohesive strength of adhesives formed from the compositions of this invention, dysfunctional monomeric crosslinking agents can be added to the monomer compositions of this invention. Such crosslinking agents are known. Reference is made, for example, to U.S. Patent No. 3,940,362 to Overhults, which is incorporated herein by reference. Examples of suitable crosslinking agents include alkyl bis (2-cyanoacrylates), triallyl isocyanurates, alkylene diacrylates, alkylene dimethacrylates, trimethylol propane triacrylate, and alkyl bis (2-cyanoacrylates). A catalytic amount of an amine activated free radical initiator or speed modifier is added to initiate the polymerization or to modify the polymerization rate of the cyanoacrylate monomer / crosslinking agent mixture. The compositions of this invention may additionally contain fibrous reinforcement and colorants, i.e., dyes and pigments. Examples of suitable fibrous reinforcement include PGA microfibrils, collagen microfibrils, cellulosic microfibrils, and olefinic microfibrils. Examples of suitable dyes include l-hydroxy-4- [4-methylphenyl-amino] -9, 10 anthracene (D + C violet No. 2); disodium salt of 6-hydroxy-5- [(4-sulfophenyl) axo] -2-naphthalene sulfonic acid (FD + C Yellow No. 6); 9- (o-carboxyphenyl) -6-hydroxy-2,4,5,7-tetraiodo-3H-xanthen-3-one, disodium salt, monohydrate (FD + C Red No. 3); disodium salt of 2- (1, 3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene) -2,3-dihydro-3-oxo-lH-indol-5-sulfonic acid (FD + C Blue No. 2); and copper [phthalocyaninate (2-)]. The compositions of this invention can be used to join together two surfaces by applying the present composition to opposing wound surfaces which are held together. Depending on the particular requirements of the user, the adhesive compositions of this invention can be applied by known means such as with a glass stir bar, sterile brush or medicine dropper. However, in many situations a pressurized aerosol dispensing package is preferred in which the adhesive composition is in solution with a compatible anhydrous propellant. In one embodiment, the present invention is directed to a method of joining two surfaces together in vivo, which comprises (a) holding the tissue surfaces of a wound or incision together to form a spliced tissue surface; (b) applying to the spliced tissue surface a composition of the present invention, for example, a composition comprising 1) at least one monomer (e.g., a monomer of the formula (I)) which forms a medically acceptable polymer , 2) a plasticizing agent and 3) a suitable acid stabilizing agent; and (b) keeping the surfaces in contact until the composition polymerizes. As conventional surgical adhesive compositions, mentioned above, they have been applied in very small amounts to wound surfaces before they are spliced, taking care to remove the excess adhesive. Thick films formed on wound surfaces have resulted, in the past, in increased histotoxicity of the wound tissues and increased film brittleness without increasing the strength of the film. However, the present invention is directed to a method for joining together in vivo two tissue surfaces by applying to a surface of the already spliced tissue of a wound or incision, a composition of this invention, preferably in more than one application or coating in the tissue surfaces spliced to provide a liberal or excess amount of the adhesive composition that is uniformly distributed on the surfaces of the spliced fabric. Any excess adhesive applied directly to the surface of the spliced tissue or in the immediate vicinity of the wound or incision is preferably not removed, although the excess applied to surrounding tissue not close to the region of the wound can be removed. A subsequent coating can be applied immediately after the application of a precoat or after a precoat has been fully polymerized. Preferably, the monomer composition applied to the surface of the spliced fabric is allowed to at least partially polymerize prior to subsequent coatings or applications of additional monomeric composition. A coating of an adhesive composition of the present invention having a monomer different from the monomer of the former or precoating may be applied as the second or subsequent coating. Due to the addition of the plasticizing agent and the spliced stabilizing agent, the polymer formed on the surface of the spliced fabric possesses sufficient bond or bond strength and flexibility even with the significant film or coating thickness. The thickness range of the film is suitable from 0.1 mm to 2.0 mm or 3.0 mm or greater, preferably from 0.2 mm to 1.5 mm and more preferably from 0.4 mm to 0.8 mm. In another embodiment, the present invention is directed to a method of joining two tissue surfaces together in vivo by applying the present adhesive composition using several applicators. Such applicators include foldable brush applicators, syringes and bottles with several nozzles or dispensing tips.

For example, the tip of the applicator may be removable from the container of the applicator while maintaining the crosslinkable and / or polymerizable material. A tip of the applicator could be attached to the applicator container prior to use and disassembly of the applicator container subsequent to its use to prevent premature polymerization or cross-linking of the non-applied material in the applicator container. At this point the tip of the applicator can be discarded and a new tip of the applicator can be fixed to the applicator container for subsequent use or the tip of the applicator can be reused. Additionally, the tip of the applicator according to the present invention may comprise multiple parts, with at least one part comprising the initiator or speed modifier. For example, the component comprising the initiator or speed modifier can be manufactured separately from the other component (s) of the tip of the applicator and is assembled prior to joining or fixing with the applicator. applicator container. The tip of the applicator may also be in the form of a nozzle for atomizing polymerizable liquid and / or crosslinkable materials. Condensate or extended spray, conical nozzles are suitable. The tip of the applicator according to the present invention can be used in several devices. For example, manual methods of application may include the use of grasping devices such as syringes, adhesive guns, pipettes, eye droppers and the like. The tip of the applicator and the applicator container can also be an integral unit. The unit can also be preformed as a single piece and loaded with polymerizable and / or crosslinkable material. After the application of material from the applicator container, the unit can be discarded. Additionally, a tip of the integral applicator / unit of the applicator container can be adapted to provide the ability to recharge the unit with new materials such as a multipurpose device. The tip of the applicator can be composed of any variety of materials including polymerized materials such as plastics, foams, rubber, thermo assemblies, films or membranes. Additionally, the tip of the applicator may be composed of materials such as metal, glass, paper, ceramics, mineral coal and the like. The material of the tip of the applicator may be porous, absorbent or adsorbent in its nature to improve and facilitate loading of the initiator or speed modifier at or within the tip of the applicator. For example, the tip of the applicator may be composed of a material having random pores, a honeycomb material, a material having a fabric configuration, etc. The degree of porosity will depend on the materials to be used. In the embodiments, the tip of the applicator can be porous and have an average pore size of about 1 μm to approximately 500 μm. Generally, according to the present invention, an end of the applicator having an average pore size of about 20 μm is used with a polymerizable material having a viscosity of about 7 cPs at 25 ° C. When the crosslinkable and / or polymerizable material has a viscosity greater than 7 cPs, the average pore size of the tip of the applicator is generally increased. For example, an extremity of the one having an average pore size of about 140 μm is preferably used with a polymerizable material having a viscosity of about 250 cPs at 25 ° C. Porosity is the open volume within the pores of an extremity of the applicator divided by the total volume of the tip of the applicator. In embodiments, one extremity of the applicator has a porosity of less than or equal to 80 percent. The tip of the applicator according to the present invention, wherein it is connected to the container of the applicator, it may have an elongated tubular portion, out of which the mixed polymerization and / or crosslinking material is issued. A portion of the tip of the applicator which is immediately below the container of the applicator is advantageously porous to avoid a drop of the acute pressure and ensures a profile of constant mixing ratio. The structure can preferably trap any barriers or materials used to separate multiple components within the applicator container. Thus, any barriers will not hinder the device. Initiators that initiate the polymerization and / or crosslinking of the material, or speed modifiers that modify the rate of polymerization of the material, can be applied to a portion of the surface or to the entire surface of the tip of the applicator, including the interior and the outside of the limb. Alternatively, the velocity initiator or modifier can be coated only on an internal surface of the tip of the applicator. Preferably, only a portion of the interior of the tip of the applicator is coated with the initiator or speed modifier. The initiator or velocity modifier at the tip of the applicator may be in the form of a solid, such as a powder or a solid film, or in the form of a liquid, such as a viscous or cake-like material. The initiator or speed modifier may also include a variety of additives, such as surfactants or emulsifiers. Preferably, the initiator is soluble in the polymerizable and / or crosslinkable material, and / or comprises or is accompanied by at least one surfactant which, in modalities, assists the initiator to co-elute with the polymerizable and / or crosslinkable material. In embodiments, the surfactant can help solubilize the initiator in the polymerizable and / or crosslinkable material. Particular primers for particular systems can be easily selected by one of ordinary skill in the art without undue experimentation. Suitable initiators include, but are not limited to, detergent compositions; surfactants: for example, nonionic surfactants such as polysorbate 20 (eg, Tween 20 ™), polysorbate 80 (eg, Tween 80 ™) and poloxamers, cationic surfactants such as benzalkonium chloride and tetrabutylammonium bromide, anionic surfactants such as sodium tetradecyl sulfate, and amphoteric or zwitterionic surfactants such as dodecyldimethyl (3-sulfopropyl) ammonium hydroxide, internal salt; amines, imines and amides, such as imidazole, tryptamine, urea, arginine and povidin; salts of phosphines, phosphites and phosphonium, such as triphenylphosphine and triethyl phosphite; alcohols such as ethylene glycol, methyl gallate, ascorbic acid, tannins and tannic acid; bases and inorganic salts, such as sodium bisulfite, magnesium hydroxide, calcium sulfate and sodium silicate; sulfur compounds such as thiourea and polysulfides; ethers polymeric cyclics such as monensin, nonactin, coronation ethers, calixarenes and polymeric epoxides; cyclic and acyclic carbonates, such as diethyl carbonate; phase transfer catalysts such as Aliquat 336; organometallics such as cobalt naphthenate and manganese acetylacetonate; and initiators of radicals and radicals, such as di-t-butyl peroxide and azobisisobutyronitrile. The polymerizable and / or crosslinkable material may also contain an initiator which is inactive until activated by a catalyst or accelerator (included within the scope of the term "initiator" as used herein) at the tip of the applicator. Initiators activated by stimulation such as heat and / or light (e.g., ultraviolet light or visible light) are also suitable if the limb and / or applicator is appropriately subjected to such stimulation. The initiator or speed modifier can be applied to the surface of the tip of the applicator or it can be impregnated or incorporated into the matrix or internal portions of the tip of the applicator. In embodiments, when a porous applicator is used, the amount of initiator or velocity modifier necessary to initiate and / or modify the polymerization and / or crosslinking rate is increased when the pore size of the tip of the applicator is increased. The initiator or speed modifier can be applied to the tip of the applicator by spraying, immersing, or brushing the tip of the applicator with a liquid medium containing the initiator or speed modifier. The liquid medium may include non-aqueous solvents, such as ethers, acetone, ethanol, pentane or mixtures thereof; or they can include aqueous solutions. Preferably, the liquid medium is a lower or lower boiling point solvent. In some embodiments of the present invention, the distribution of the initiator or velocity modifier may be uniform within the tip of the applicator. In other embodiments, it may be an anisotropic distribution or concentration gradient of the initiator or velocity modifier at the tip of the applicator. In the modalities, the concentration gradient can be increased or decreased from the beginning of the extremity of the applicator to the extremity of the extremity. The distribution of the initiator or speed modifier can be varied depending on the solvent used to apply the initiator and the desired wetting characteristics. Applicable applicators for the application of the adhesive of the present invention include those described in co-pending Application Serial No. 08 / 488,411, the subject of which is incorporated herein by reference. A preferred applicator is a foldable brush applicator. Specific methods that can use an adhesive composition of the present invention include methods for repairing damaged living tissue to prevent the escape of fluids through it by keeping the edges of the damaged tissue together in a splice relationship, applying to the tissue of splicing the monomeric composition of the present invention, and allowing the polymerization of the composition; and methods for stopping the blood flow of the vessels which comprise maintaining damaged regions of the blood vessels together, applying the present monomeric composition to the damaged regions and allowing the composition to polymerize. When a limb of the porous applicator is used to apply the adhesive composition, the composition is preferably not expressed directly through the tip of the applicator in a continuous motion. In accordance with the embodiments of the present invention, the adhesive composition is (1) expressed at the end or remote from the end of the tip of the applicator, (2) the pressure is released to direct the composition back to the applicator, and (3) ) the composition is then expressed subsequently through the tip of the applicator in a continuous motion. This is called a new suction method for applying the adhesive composition of the present invention. As a result, the adhesive composition polymerizes more slowly than if it had been expressed directly through the limb. Repair of damaged tissues (for example, to control blood flow) comprises, in general, sponge cleaning to remove superficial body fluids, keeping damaged tissue surfaces together in a splice relationship and subsequent application to spliced tissue exposed of the present adhesive composition. The composition is polymerized to a thin film of polymer while in contact with the surface of the spliced fabric. Tissues that are not bodily fluids or otherwise covered by body fluids do not need to be sponged first. More than one coating or application of the monomeric composition can be applied to the surface of the spliced fabric. The monomers are easily polymerized to addition type polymers and copolymers, which are generally optically clear (like films). In more binding or binding applications using the compositions of this invention, the polymerization of the monomers is catalyzed by small amounts of moisture on the surface of the adherents. Similarly, the polymerization rate modifiers are catalyzed by small amounts of moisture. Thus, the desired binding or binding of tissues or hemostasis proceeds well in the presence of blood and other body fluids. The bonds formed are of adequate flexibility and resistance to withstand normal tissue movement. In addition, the strength of the bond or union is maintained as the natural wound healing proceeds.

The compositions employed in the invention are preferably sterilizable by conventional methods including, but not limited to, aseptic filtration or autoclaving techniques.

EXAMPLES I-VI The compositions according to the present invention are prepared using conventional mixing equipment. For example, the process can be conducted as follows: For a surgical grade cyanoacrylate in a round bottom flask, add the plasticizer, the acid stabilizer, and other formulation components as described herein. The resulting mixture is mechanically stirred until it is homogeneous. The present invention is further illustrated by the following non-limiting examples. In the following examples, various amounts of plasticizer (ie, acetyl tributyl citrate) are used in adhesive compositions of the present invention that illustrate the effects on the strengths of the bonds formed by the adhesive. The data presented in Table I are generated using the following method: A 2"incision is made on a 5 W x 5 V (1/16" thick) latex sheet. An adhesive composition (i.e., 2-octyl cyanoacrylate) is applied topically to the incision with a collapsible or compressible brush with an initiated polymerization tip. The interface surface of the incision should not be inadvertently stuck. 10 After healing for one hour, the sheet is fixed between two sheets of plexillium. The lower blade is equipped with a gas inlet and pressure transducer. The top sheet has a 3 5/8"hole centrally located in this one. The test piece is placed so that the glued side faces the top sheet of the plexifold that contains the 3 5/8"hole 20 The valve that controls the gas flow opens to pressurize the test material. Pressure is increased until it declines.Peak pressure is recorded by the transducer and recorded in a chart.Ten determinations are made per test material.The results are as follows: TABLE I: EXAMPLES VII-X To demonstrate the unexpected superiority of the resistance of the in vivo film provided by the adhesive composition and method of application according to the present invention, various methods and materials for wound closure and topical administration of various devices for surgical wound closure are evaluated (Examples VII-XI). In vivo resistance is objectively defined by the amount of final pressure required to induce a lack or decline of the wound (ie, the amounts of vacuum pressure required to open the wound). The biomedical analysis is done using the Dimensional Analysis Systems (DAS), (DIMENSIONAL ANALYSIS SYSTEMS, LEONIA, NEW JERSEY). This technology is specifically designed for in vivo biomedical characterization of linear incision wounds. . In contrast to previous biomechanical methods of analysis (for example, uniaxial stresses), the DAS applies a multiaxial stress to a wound that is more analogous to stresses experienced in clinical conditions. In addition, the DAS does not require tissue manipulation or destructive incision of specimens prior to testing. Therefore, sensitive, reproducible and reliable measures of fragile wounds can be obtained in the initial phase of healing. The DAS further eliminates artifact error and experimental variables introduced by extirpation methods such as non-viable tissue samples, inconsistent variation of sample dimensions, and cracked edges of excised tissues. The male Sprague Dawley rat is selected for the animal model because of its genetic homogeneity, ease of handling and lodging, and overall popularity as a model for linear incision wounds, thus allowing the comparison of data for other similar studies. This model has been widely used in the search for incisional wounds, which is well documented in the literature. Male Sprague Dawley rats, purchased from Harlan Sprague Dawley. Inc. (Indianapolis, Indiana) are used in tests. All animals are kept seven days prior to the procedures for stabilization of diet and behavior. Four groups of rats (Groups A-D), each with a different wound closure method and / or surgical adhesive, are tested under identical conditions. Each of the specimens is tested for film strength one hour after wound closure by linear incision.

EXAMPLE VII In the first group of rats, designated as Group A, an attack or blow technique is applied for the application of the adhesive on the tissue. An adhesive of the present invention containing about 6% by weight of plasticizer with acetic acid as an acid stabilizer (pKa = 4.8) in 2-octyl alpha-cyanoacrylate is applied with a compressible ampoule with an extremity of A 6. broom (foldable brush applicator) and is passed along the edges of the opposing wounds in a "one hit" manner for topical administration.

EXAMPLE VIII In the second group of rats, designated as Group B, the linear incisions are closed with the same adhesive using a multiple shot technique. The adhesive is applied with a compressible ampule that passes more than once along the opposite edges of the wound in a form of "multiple strokes" resulting in 2-3 different applications of adhesive.

EXAMPLE IX In the third group of rats, designated as Group C, the linear incision wounds are closed with the same adhesive using a minimal surface exposure technique. The adhesive is applied with a UniJect ™ syringe (available from Horixon, Santa Ana, CA, USA) with approximately 3-4 drops in an attempt to limit the amount of adhesive exposed to the surface of the skin, so the adhesive is administered to the opposite edges of the wound only.

EXAMPLE X In the fourth group of rats, designated as Group D, the linear incision wounds are closed with Histoacril® (a surgical adhesive available from B. Braun Melsungen AG of Germany) using the application technique of Example IX. The results of the in vivo biomechanical analysis are shown in Table II below. As illustrated in Table II, there are significant differences observed among all the groups in a time period of one hour studied. Group B, the multiple shot technique, demonstrates a significant increase in final pressure compared to Groups A & C. These data suggest that increasing the amount of adhesive applied may allow higher in vivo resistance. Group D reveals a highly significant decrease in in vivo resistance compared to all the groups evaluated.

TABLE II: Statistical results surveyed by direct comparison of alternating methods and other techniques in 1 hour post-application.

EXAMPLE XI The effectiveness of the same tissue adhesive according to the present invention is tested in its ability to close skin incisions in a pig model. The tissue adhesive, Histoacryl®, is used as a control. The incisions are made on each back side of these pigs with sterile scalpel blades at a controlled depth for the incisions. The incisions are closed with the test material or with the control material. The same adhesive of the present invention, incorporated in an applicator, is applied to the opposite spliced edges of the wound until the adhesive polymerizes (ie, the adhesive is no longer sticky on contact). The applicator is a plastic cylinder, flexible, transparent, with an absorbent head (folding steerer). Inside the cylinder is a glass vial containing the adhesive which is broken by compression of the cylinder. When the applicator is inverted, the adhesive is compressed out of the cylinder at the top and then into the skin. Histoacryl® is also applied with an applicator, which is a sealed plastic ampoule with a narrow neck. The ampoule is attached to a hypodermic calibration needle 27. The ampoule is inverted and the adhesive is applied by compressing the ampoule and dripping microdroplets from the end of the needle at the opposite edges of the incision. Care is taken not to touch the skin with the tip of the needle. The method for applying Histoacryl® by J. Quinn and J. Kissic (1994, "Tissue adhesives for laceration repair during sporting events", Clin J. Sport, Med., 4: 245-248) has been described. Observations are made frequently during the recovery phase, recorded approximately four hours postoperatively, and then daily to determine if any of the incisions are partially or completely separated (dehiscence), and if there is any adverse tissue response. If a wound is opened during the observation period, it does not close again.

TABLE III DEHYSCENCE OF INCISIONS IN THE SKIN OF PUERCO Invention TM HistoacrylM PIG 1 Number of incisions 4 Number of partial or complete dehiscences PIG 2 Number of incisions 4 Number of partial or complete dehiscences PIG 3 Number of incisions Number of partial or complete dehiscences The pigs were observed for wound dehiscence for 10 days. The dehiscence is not observed in any closed incision with the adhesive of the invention. Partial or complete dehiscence is observed in 7 of the 12 closed incisions with Histoacryl®. No complications such as infection or necrosis were observed.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property

Claims (20)

1. A device for distributing a crosslinkable or polymerizable monomer composition, characterized in that it comprises: an applicator having a porous applicator tip, wherein the tip of the applicator has an anisotropic distribution of a crosslinking initiator or polymerization or velocity modifier disposed therein , and which contains a composition of reticular or polymerizable monomeric material.

2. A device according to claim 1, characterized in that the anisotropic distribution forms a concentration gradient of the velocity modifier or initiator of the crosslinking or polymerization at the end of the applicator.

3. A device according to claim 1, characterized in that the tip of the applicator comprises a first end and a second end, the second end is located downstream in a direction of fluid flow from the first end, and a concentration of the speed modifier or polymerization initiator or crosslinking at the tip of the applicator is greater at the second end than at the first end.

4. A device according to claim 1, characterized in that the tip of the applicator comprises a first end and a second end, the second end located downstream in a flow direction of the fluid from the first end, and a concentration of the speed modifier. or crosslinking initiator or polymerization at the tip of the applicator is greater at the first end than at the second end.

5. A device according to claim 1, characterized in that the tip of the applicator has an average pore size of 1 μm to 500 μm.

6. A device according to claim 1, characterized in that the tip of the applicator has an average pore size of 20 to 140 μm and the composition of the monomeric material has a viscosity of 7 to 250 cPs at 25 ° C.

7. A device according to claim 1, characterized in that the tip of the applicator has an average pore size of about 20 μm and the composition of monomeric material has a viscosity of about 7 cPs at 25 ° C.

8. A device according to claim 1, characterized in that the tip of the applicator has an average pore size of about 140 μm and the composition of monomeric material has a viscosity of about 250 cPs at 25 ° C.

9. A device according to claim 1, characterized in that the end of the applicator has a porosity defined by the open volume of the pores of the tip of the applicator divided by the total volume of the tip of the applicator, of less than or equal to 80 times. hundred.

10. A device according to claim 1, characterized in that the polymerization or crosslinking speed modifier or initiator is an initiator or modifier of the polymerization or crosslinking speed for the composition of the monomeric material.

11. A device according to claim 1, characterized in that the tip of the applicator is integral with the applicator.

12. A device according to claim 1, characterized in that the applicator is selected from the group consisting of a syringe, a flexible cylinder, a tube, a pipette and an eye dropper.

13. A device according to claim 1, characterized in that the monomer is at least one monomer located in the applicator in a non-contacting relationship with the end of the porous applicator prior to the distribution of the monomer.

14. A device according to claim 1, characterized in that the applicator contains an adhesive composition, comprised of at least one monomer that forms a medically acceptable polymer; at least one plasticizer present in the composition in an amount from 0.5% by weight to 16% by weight of the composition; and at least one acid stabilizing agent having an ionization constant pKa from 0 to 7.

15. A device according to claim 1, characterized in that the monomeric material comprises a 1, 1-disubstituted monomer.

16. A device according to claim 1, characterized in that the monomeric material comprises an a-cyanoacrylate monomer

17. A device according to claim 1, characterized in that the monomeric material comprises at least one element selected from the monomer of butyl α-cyanoacrylate and octyl α-cyanoacrylate monomer.

18. The fabrication of the device according to claim 1, for use in a method characterized in that it comprises: (a) holding together at least two tissue surfaces in vivo to form spliced tissue surfaces, (b) applying through the surfaces of the spliced tissue, with the applicator having a porous applicator tip, an excess amount of a uniformly distributed adhesive composition comprising at least one monomer that forms a medically acceptable polymer, and (c) keeping the boundary surfaces in contact until that the composition is polymerized to form a thin film of medically acceptable polymerized composition on the spliced tissue surfaces.

19. The fabrication according to claim 18, characterized in that the method comprises more than one application of the adhesive composition through the spliced tissue surfaces.

20. The fabrication according to claim 19, characterized in that the method comprises allowing the adhesive composition to be applied across the surfaces of the spliced fabric to polymerize at least partially prior to subsequent coatings or applications of the adhesive composition. METHODS FOR APPLYING EFFECTIVE MONOMERIC COMPOSITIONS AS DEVICES FOR WOUND CLOSURE SUMMARY OF THE INVENTION A method for jointly joining tissue surfaces in vivo which includes (a) holding together at least two tissue surfaces to form spliced tissue surfaces, (b) applying an excess amount of an adhesive composition through the spliced tissue surfaces. comprising at least one monomer that forms a medically acceptable polymer with an applicator having a porous applicator tip, and (c) keeping tissue surfaces in contact in vivo until the composition is polymerized to form a thick film of polymerized composition on the surface of spliced tissue.