WO2022013345A1

WO2022013345A1 - Kit composed of a two-component tissue adhesive and a textile structure for strengthening the connective tissue after an operation, and use thereof

Info

Publication number: WO2022013345A1
Application number: PCT/EP2021/069740
Authority: WO
Inventors: René H. TOLBA; Marius ROSENBERG; Steve GOTZEN
Original assignee: Adhesys Medical Gmbh
Priority date: 2020-07-17
Filing date: 2021-07-15
Publication date: 2022-01-20

Abstract

The present invention relates to a mesh implantation system in the field of hernia surgery, said system comprising a textile fabric and a tissue adhesive, wherein the textile fabric is composed of a polymer selected from the group comprising or consisting of polyethersulphones, polysulphones, polyolefins, polyesters, fluoropolymers, silicones or mixed polymers and/or mixtures thereof, wherein the system is characterised in that the fabric adhesive is a two-component adhesive having as a first component at least one amino-functional aspartic acid ester acting as a curing agent and having as a second component an isocyanate-functional prepolymer. The invention also relates to: a planar composite material suitable for use as a mesh implant in the field of hernia surgery, obtained or obtainable from the aforementioned system; a method for producing such a planar composite material; and a mesh implantation method in the field of hernia surgery using such a system.

Description

Kit consisting of a two-component tissue adhesive and a textile structure to strengthen the connective tissue after an operation and its use

The present invention relates to a system for mesh implantation in the context of hernia surgery, comprising a textile fabric and a tissue adhesive, the textile fabric being composed of a polymer selected from the group comprising or consisting of polyether sulfones, polysulfones, polyolefins, polyesters, fluoropolymers , Silicones or mixed polymers and/or mixtures of these. The invention also relates to a flat composite material suitable for use as a mesh implant in the context of hernia surgery, obtained or obtainable from the aforementioned system, a method for producing such a flat composite material and a method for mesh implantation in the context of hernia surgery with such a system.

State of the art:

Devices and methods for mesh implantation in the context of hernia surgery are known from the prior art, for example in the case of an inguinal hernia. The operations are carried out endoscopically, laparoscopically or openly. The treating surgeon introduces net-like implants made of a polymer fiber into the body at the required location and fixes them there, which can be done, for example, by sewing or stapling.

Although these fastening methods are widespread in the medical field, they are associated with various disadvantages in connection with mesh implantation. Thus, additional tissue damage is caused by both suturing and stapling. In addition, the fasteners used, such as threads and staples, increase the foreign body sensation at the operated site. A further disadvantage can be seen in the fact that the tissue is fixed at certain points or at most in sections, which reduces the mechanical support properties of the tissue.

Based on this, a further development of this treatment method consists in fastening the mesh implant generally over the entire surface using a surgical adhesive based on cyanoacrylates instead of sewing or stapling. An example of an adhesive that is customary for this purpose is Glubran2®, Dahlhausen GmbH, Germany. However, investigations that led to the present invention have shown that when cyanoacrylates are used as tissue adhesive, healing is not always satisfactory, particularly with regard to body cells growing through the bonded mesh implant.

Task:

The object of the present invention was therefore to provide a system for mesh implantation in the context of hernia surgery of the type mentioned at the outset, which on the one hand has good adhesion properties on the usual substrates and on the other hand improved growth of body cells through the bonded mesh implant allowed, especially within a period of one week.

Solution:

The object is achieved by a system for mesh implantation in the context of hernia surgery, comprising a textile fabric and a tissue adhesive, the textile fabric being composed of a polymer selected from the group comprising or consisting of polyether sulfones, polysulfones, polyolefins, polyesters, Fluorine polymers, silicones or mixed polymers and/or mixtures of these, the system being characterized in that the tissue adhesive is a two-component adhesive with at least one amino-functional aspartic acid ester as a hardener as the first component and an isocyanate-functional prepolymer as the second component.

The invention is based on the finding that when using the two-component adhesive according to the invention instead of a cyanoacrylate-based system previously used in the prior art, when using the mesh implant, comparable adhesion properties can be achieved on a wide variety of organic tissue types of the human or animal body, but clearly Improved growth of body cells through the glued-in mesh implant takes place, especially after a period of 7 or 21 days. As a result, the mesh implant is integrated more quickly into the body and can therefore develop its full support function more quickly.

A further advantage of the two-component adhesive according to the invention is that there are fewer postoperative complications such as inflammation and the like compared to prior art cyanoacrylate-based systems. It was also found that the two-component adhesives according to the invention made from amino-functional aspartic acid ester as hardener and isocyanate-functional prepolymer generally release less thermal energy per unit of time during polymerization than cyanoacrylate-based systems, which means less stress for the affected tissue parts.

In addition, cyanoacrylates usually become relatively hard after polymerisation, so that the mesh implant becomes more rigid, which increases the foreign body sensation. In contrast, the polyurethaneurea systems according to the invention remain considerably more flexible.

In addition, the two-component adhesives according to the invention are distinguished by good biodegradability, which, depending on the amount of aspartic acid ester used, can be 4 weeks to 6 months, for example.

A further advantage of the two-component adhesive according to the invention is that the cured tissue adhesive according to ISO 10993-5:2009 has no cytotoxicity.

In principle, all systems that can be used in the medical field in the context of hernia surgery can be used as textile fabrics. Such textile fabrics can be in the form of a woven, non-woven or knitted fabric.

According to the invention, the textile fabric is constructed from a polymer that is selected from the group comprising or consisting of polyether sulfones, polysulfones, polyolefins, polyesters, fluoropolymers, silicones or mixed polymers and/or mixtures of these. It is thus possible, for example, to use fibers made from polymer blends and/or mixed textiles, such as mixed fabrics or knitted fabrics made from different polymer fibers. Accordingly, the textile fabric can be formed from at least two different polymer fibers, in particular from polypropylene and polyvinylidene fluoride fibers.

The polymer is preferably selected from the group comprising or consisting of polypropylene and/or polyvinylidene fluoride, preferably polyvinylidene fluoride. These polymers are particularly preferred because they show relatively few physiological interactions even after they have remained in the body for a long time.

According to a preferred embodiment of the system according to the invention, the textile fabric has a textile porosity of at least 40%, in particular at least 50%, preferably from 50 to 90%, determined according to Mühl T, Binnebösel M, Klinge U, Goedderz T: New Objective Measurement to Characterize the Porosity of Textile Implants, Journal of Biomedical Materials Research Part B: Applied Biomaterials: 176-183, DOI 10.1002/jbmb; ©Wiley Periodicals, Inc. (5/2007). This is advantageous because such flat structures are very well wetted over the entire surface by the adhesive used according to the invention, which enables good initial adhesion to the body tissue. In addition, these textile porosities later allow body cells to grow through and thus good integration into the body's own tissue.

In the context of the system according to the invention, it can be provided that the textile fabric has an average pore diameter of 100 to 3,000 μm, with the textile fabric essentially having two different average pore diameters, one of which has an average pore diameter of 100 to 600 μm and the other other mean pore diameter is 700 to 3000 μm, the mean pore diameters more preferably differing by a factor of at least 2. As a result, good adhesion of the adhesive according to the invention can be achieved in the freshly applied state, ie in a state in which the adhesive still has a low viscosity. In this way, it is also possible to prevent the adhesive from dripping down after application if the mesh is implanted overhead, ie the adhesive is applied against the force of gravity.

Adhesives preferred according to the invention are, for example, those disclosed in EP 2 145 634 B1 and EP 2 794 710 B1. Particular preference is given to those of examples 1 and 2 of EP 2 145 634 B1 and of example polyol 1 made from and prepolymer 2 of EP 2 794 710 B1 and a hardener made from aspartate A/PEG 200 in a ratio of 0.57/0.43. The disclosure of EP 2 145 634 B1 and EP 2 794 710 B1 is hereby incorporated by reference into the present disclosure.

According to a preferred embodiment of the system according to the invention, the tissue adhesive comprises or consists of the following components: an isocyanate-functional prepolymer as component A), obtainable by a) reacting an H-functional starter compound having at least one Zerewitinoff-active H atom with an alkylene oxide compound and a co - Monomer to a hydroxyl-bearing precursor, wherein the comonomer is selected from the group consisting of lactides, glycolides, and combinations thereof and combinations of lactides and / or glycolides with cyclic di- carboxylic acid anhydrides and wherein the comonomer is built into the polymer chain(s) of the hydroxyl-bearing precursor by a random copo lysis, and b) reaction of the hydroxyl-bearing precursor from step a) with a polyfunctional isocyanate to form the isocyanate-functional prepolymer, an amino-functional one Aspartic acid ester as component B) of the general formula (I)

whereby

X is an n-valent organic radical,

R1, R2 are identical or different organic radicals which do not have any Zerewitinoff-active H atoms, n is an integer >2, and optionally a reaction product of the isocyanate-functional prepolymer A) with the amino-functional aspartic acid ester B) as component C).

In other words, the isocyanate-functional prepolymer according to the invention contains ester groups in the polymer chains, which are generated by random copolymerization of alkylene oxide compounds and lactides, glycolides and/or cyclic dicarboxylic acid anhydrides on starter compounds containing Zerewitinoff-active H atoms. In particular, the ester groups are not incorporated in blocks. The indefinite article "a", "an" etc. is to be understood as meaning that several of these components can also be implemented with one another. The components mentioned, in particular the comonomer, can also be used in dimer, trimer, etc., for example as dilactide.

Such isocyanate-functional prepolymers are biodegradable in a patient's body. The degradation time is longer than the healing time for the wound to be closed, for example 4 weeks. The statistical distribution of the comonomer units in the polymer chain(s) in particular seems to have an advantageous effect on the construction speed, as these act as "predetermined breaking points" in the hardened adhesive. When the comonomer building blocks are attacked and broken down during biological degradation, the polymer chain length shortens particularly quickly.

At the same time, the isocyanate-functional prepolymers according to the invention are distinguished by high adhesion, in particular to human or animal tissue, and a high rate of curing. In addition, tissue adhesives with an isocyanate-functional prepolymer according to the invention meet the requirements with regard to histotoxicity, thrombogenicity and allergenic potential.

The present invention provides that the H-functional starter compound carries at least one Zerewitinoff-active H atom. In the context of the present invention, a Zerewitinoff-active H atom is understood as meaning an acidic H atom or “active” H atom. Such can be determined in a manner known per se by a reaction with a corresponding Grignard reagent. The amount of Zerewitinoff-active H atoms is typically measured via the methane released when the substance to be tested reacts with methylmagnesium bromide (CH3-MgBr) according to the following reaction equation:

Zerewitinoff-active H atoms are typically derived from C-H acidic organic groups, -OH, -SH, -NH2 or -NHR with R as an organic radical, and -COOH.

Particularly suitable H-functional starter compounds have an H functionality of 1 to 35, in particular 1 to 16, preferably 1 to 8, where the H functionality relates to the aforementioned Zerewitinoff-active H atoms.

Polyhydroxy-functional polymers are particularly suitable as H-functional starter compounds, which are selected in particular from straight-chain and/or branched polyethers, polyesters, polyether polyesters, polycarbonates, polyether polycarbonates, and combinations thereof.

If the polymer containing hydroxyl groups used as the H-functional starter compound is a polyether or has polyether groups, these more preferably contain ethylene oxide units, the proportion by weight of the ethylene oxide units in such a prefabricated alkylene oxide addition product being in particular at least 40% by weight. preferably at least 50% by weight. For example, the proportion by weight of ethylene oxide units is 40 to 90% by weight, preferably 50 to 80% by weight, based in each case on the mass of the polymer bearing hydroxyl groups. The remainder of the polyether structure or the polyether building blocks can each be made up of other alkylene oxide units such as in particular (polypropylene oxide, (poly)butylene oxide or other (poly)alkylene oxide groups and mixtures thereof. The molecular weights of the H-functional starter compound can vary over wide ranges For example, the average molecular weight can be from 17 to 10000 g/mol, in particular from more than 200 to 9000 g/mol development of the OH number can be determined. In other words, a monomeric starter compound can be selected as the H-functional starter compound for the prepolymer according to the invention, such as ammonia or ethylene glycol. Oligomeric starter compounds are also included, for example polyethers with an average molecular weight of 200 to 600g/ mol and polymeric starter compounds with higher molecular weights, for example from more than 600 to 10000 g/mol or 800 to 9000 g/mol.

In addition to the hydroxy-functional starters which are to be used with preference, amino-functional starters can also be used. Examples of hydroxy-functional starter compounds are methanol, ethanol, 1-propanol, 2-propanol and higher aliphatic monols, especially fatty alcohols, phenol, alkyl-substituted phenols, propylene glycol, ethylene glycol, diethylene glycol, dipropylene glycol, 1,2-butanediol, 1,3-butanediol 1,4-butanediol, hexanediol, pentanediol, 3-methyl-1,5-pentanediol, 1,12-dodecanediol, glycerol, trimethylolpropane, pentaerythritol, sorbitol, sucrose, hydroquinone, catechol, resorcinol, bisphenol F, bisphenol A, 1,3,5-trihydroxybenzene, and methylol-containing condensates of formaldehyde and phenol or urea. Highly functional starter compounds based on hydrogenated starch hydrolysis products can also be used. Such are described in example in EP 1525244 A1.

Examples of H-functional starter compounds containing amino groups are ammonia, ethanolamine, diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, ethylenediamine, hexamethylenediamine, aniline, the isomers of toluidine, the isomers of diaminotoluene, the isomers of diaminodiphenylmethane and in the condensation of aniline with Formaldehyde to diaminodiphenylmethane accumulating polynuclear products, also methylol-containing condensates from formaldehyde and melamine and Mannich bases. In addition, as starter compounds, ring-opening products from cyclic Carboxylic anhydrides and polyols are used. Examples are ring opening products from phthalic anhydride or succinic anhydride on the one hand and ethylene glycol, diethylene glycol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, hexanediol, pentanediol, 3-methyl-1,5-pentanediol, 1,12 -dodecanediol, glycerol, trimethylolpropane, pentaerythritol or sorbitol on the other hand. In addition, it is also possible to use monofunctional or polyfunctional carboxylic acids directly as starter compounds.

Furthermore, prefabricated alkylene oxide addition products of the starter compounds mentioned, i.e. polyether polyols preferably with OH numbers of 5 to 1000 mg KOH/g, preferably 10 to 1000 mg KOH/g, can also be used as starter compounds in the process or added to the reaction mixture. It is also possible to use polyester polyols, preferably with OH numbers in the range from 6 to 800 mg KOH/g, as starters or co-starters in the process according to the invention. Polyester polyols suitable for this purpose can be prepared, for example, from organic dicarboxylic acids having 2 to 12 carbon atoms and polyhydric alcohols, preferably diols, having 2 to 12 carbon atoms, preferably 2 to 6 carbon atoms, by known processes.

Furthermore, polycarbonate polyols, polyester carbonate polyols or polyether carbonate polyols, preferably polycarbonate diols, polyester carbonate diols or polyether carbonate diols, preferably each with OH numbers in the range from 6 to 800 mg KOH/g, can be used as starters or co-starters as H-functional starter substances. These are produced, for example, by reacting phosgene, dimethyl carbonate, diethyl carbonate or diphenyl carbonate with difunctional or higher alcohols or polyester polyols or polyether polyols.

It is also possible to use polyether carbonate polyols, such as are obtainable, for example, by catalytically reacting alkylene oxides (epoxides) and carbon dioxide in the presence of H-functional starter substances (see, for example, EP-A 2046861). These polyether carbonate polyols preferably have an OH number of >5 mg KOH/g to <240 mg KOH/g, particularly preferably >9 to <200 mg KOH/g.

In step a) of the preparation of the prepolymer according to the invention, amino-group-free H-functional starter compounds with hydroxyl groups are preferably used as carriers for the active hydrogens, such as methanol, ethanol, 1-propanol, 2-propanol and higher aliphatic monols, in particular fatty alcohols, phenol, alkyl-substituted phenols, Propylene glycol, ethylene glycol, diethylene glycol, dipropylene glycol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, hexanediol, pentanediol, 3-methyl-1,5-pentanediol, 1,12-dodecane diol, glycerol, trimethylolpropane, pentaerythritol, sorbitol, sucrose, hydroquinone, pyrocatechol, resorcinol, bisphenol F, bisphenol A, 1,3,5-trihydroxybenzene, methylol-containing condensates of formaldehyde and phenol and hydrogenated starch hydrolysis products. Mixtures of different H-functional starter compounds can also be used.

Alkylene oxide compounds which can be used according to the invention can be those representatives which have 2 to 24 carbon atoms, in particular 2 to 12 carbon atoms, more preferably 2 to 6 carbon atoms, and the combination of different alkylene oxide compounds of the aforementioned type. In the case of the epoxides with 2 to 24 carbon atoms it is, for example, one or more compounds selected from the group consisting of ethylene oxide, propylene oxide, 1-butene oxide, 2,3-butene oxide, 2-methyl-1,2-propene oxide (isobutene oxide), 1-pentene oxide, 2,3- pentene oxide, 2-methyl-1,2-butene oxide, 3-methyl-1,2-butene oxide, 1-hexene oxide, 2,3-hexene oxide, 3,4-hexene oxide, 2-methyl-1,2-pentene oxide, 4- Methyl-1,2-pentene oxide, 2-ethyl-1,2-butene oxide, 1-heptene oxide, 1-octene oxide, 1-nonene oxide, 1-decene oxide, 1-undecene oxide, 1-dodecene oxide, 4-methyl-1,2- pentene oxide, butadiene monoxide, isoprene monoxide, cyclopentene oxide, cyclohexene oxide, cycloheptene oxide, cyclooctene oxide, styrene oxide, methyl styrene oxide, Pinene oxide, mono- or polyepoxidized fats as mono-, di- and triglycerides, epoxidized fatty acids, C1-C24 esters of epoxidized fatty acids, epichlorohydrin, glycidol, and derivatives of glycidol such as methyl glycidyl ether, ethyl glycidyl ether, 2-ethylhexyl glycidyl ether, allyl glycidyl cidyl ether, glycidyl methacrylate and epoxy-functional alkyloxysilanes such as 3-glycidyloxypropyltrimethoxysilane, 3-glycidyloxypropyltriethoxysilane, 3-glycidyloxypropyltripropoxysilane, 3-glycidyloxypropylmethyldimethoxysilane, 3-glycidyloxypropylethyldiethoxysilane and 3-glycidyloxypropyltriisopropoxysilane. Ethylene oxide and/or propylene oxide are preferably used. In particular, the proportion by weight of ethylene oxide, based on the total mass of the metered alkylene oxide compounds, can be at least 40% by weight, preferably at least 50% by weight. For example, the proportion by weight of ethylene oxide is 40-90%, preferably 50-80%, based in each case on the total mass of the metered alkylene oxide compounds.

According to the invention, the isocyanate-functional prepolymer contains building blocks originating from lactides, glycolides and/or cyclic dicarboxylic acid anhydrides, which are built into the polymer chain of the hydroxyl-bearing precursor by statistical copolymerization. The molar ratio of the alkylene oxide compound to this comonomer is preferably in the hydroxyl-bearing group Precursor is 200: 1 to 1: 1, in particular 10: 1 to 5: 1. These molar ratios are particularly preferred because a tissue adhesive containing such a prepolymer precursor has good adhesion with a short curing time and also degrades quickly under physiological conditions .

In principle, it is also possible to incorporate other co-monomers, such as e.g. cyclic anhydrides or carbon dioxide, into the polymer chain of the hydroxyl-bearing prepolymer by statistical copolymerization.

The preparation of component A) can be carried out without catalysis, but the use of a catalyst is preferred. In particular, step a) can be catalyzed via a double metal cyanide catalyst (DMC catalyst) which contains in particular zinc hexacyanocobaltate (III), zinc hexacyanoiridate (III), zinc hexacyanoferrate (III) or cobalt(II) hexacyanocobaltate (III). A particular advantage of this embodiment is that the hydroxyl-bearing precursor obtained as an intermediate of step a) has a comparably narrow distribution of molecular chain lengths. One of the reasons can be seen in the use of DMC catalysis, because such catalysts show so-called “catch-up” kinetics. This means that as the chain length increases, the catalytic activity for attaching the next monomer building block gradually decreases, and with it the reaction rate.

As explained above, the preferred amino-functional aspartic acid ester used is one of the general formula (I). More preferred is an amino-functional aspartic acid ester of the general formula (II)

where R1, R2, R3 are identical or different organic radicals which have no Zerewitinoff-active H atoms.

To improve the biological compatibility, the polyfunctional isocyanate is preferably selected from aliphatic isocyanates, in particular from hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), butylene diisocyanate (BDI), bisisocyanato cyclohexylmethane (HMDI), 2,2,4-trimethylhexamethylene diisocyanate, bisisocyanatomethylcyclohexane, bisisocyanatomethyltricyclodecane, xylene diisocyanate, tetramethylxylylene diisocyanate, norbornane diisocyanate, cyclohexane diisocyanate, diisocyanatododecane, or combinations thereof. Here, hexamethylene diisocyanate (HDI), isophorone diisocyanate (IPDI), butylene diisocyanate (BDI) and bis(isocyanatocyclohexyl)methane (HMDI) are preferred. Hexamethylene diisocyanate, isophorone diisocyanate, butylene diisocyanate are particularly preferred, hexamethylene diisocyanate and isophorone diisocyanate are very particularly preferred.

In principle, however, the invention is not limited to the use of aliphatic isocyanates, so conventional aromatic isocyanates can also be used, for example toluene diisocyanate (TDI) or diphenylmethane diisocyanate (MDI).

The reaction of the hydroxyl-bearing prepolymer obtained after step a) with the polyfunctional isocyanate in step b) can be carried out at an NCO/OH ratio of 4:1 to 12:1, preferably 8:1, and then the proportion of unreacted Isocyanate are separated by suitable methods. Thin-film distillation is usually used for this, giving a prepolymer having a residual monomer content of less than 1% by weight, preferably less than 0.1% by weight, very particularly preferably less than 0.03% by weight.

Optionally, stabilizers such as benzoyl chloride, isophthaloyl chloride, dibutyl phosphate, 3-chloropropionic acid, or methyl tosylate may be added during preparation of the isocyanate-functional prepolymer.

The reaction temperature in the reaction in step b) is preferably from 20 to 120.degree. C. and more preferably from 60 to 100.degree.

The isocyanate-functional prepolymer preferably has an average NCO content, measured according to DIN EN ISO 11909, of from 2 to 10% by weight, preferably from 2.5 to 8% by weight.

The average NCO functionality of the isocyanate-functional prepolymer is preferably from 1.5 to 6, more preferably from 1.6 to 5, even more preferably from 1.7 to 4, very particularly preferably from 1.8 to 3.5 and in particular 3.

According to the invention, the adhesive used is characterized by an aspartate hardener. However, the tissue adhesive can preferably comprise at least one further hardener. Thus, according to a particularly preferred embodiment, the tissue adhesive according to the invention also comprises a further hardener, which consists in particular of polyols with a numerical average molar mass of 1000 Da or less, in particular 600 Da or less, more preferably 400 Da or less or even 300 Da or less. PEG or PPG, for example, are suitable as polyols. The addition of these additional hardeners can influence the curing speed of the tissue adhesive according to the invention, ie it can generally be shortened, so that the tissue adhesive can be manufactured as required. For example, a polyethylene glycol 200 is preferably used.

Of course, pharmacologically active ingredients such as analgesics with and without anti-inflammatory effects, antiphlogistics, antimicrobial substances, antimycotics, antiparasitic substances can also be incorporated into the tissue adhesive.

The active ingredients can be present as a pure active ingredient or in encapsulated form, for example in order to achieve a time-delayed release. Within the scope of the present invention, a large number of types and classes of active substances can be used as medicinal active substances.

Such a medicinal active substance can, for example, comprise a component which releases nitrogen monoxide under in vivo conditions, preferably L-arginine or an L-arginine-containing component or an L-arginine-releasing component, particularly preferably L-arginine hydrochloride. Proline, ornithine and/or other biogenic intermediates such as biogenic polyamines (spermine, spermite, putrescine or bioactive artificial polyamines) can also be used. As is known, components of this type support wound healing, and their continuous, almost uniform delivery in terms of quantity is particularly beneficial for wound healing.

Other active ingredients that can be used according to the invention include at least one substance selected from the group of vitamins or provitamins, carotenoids, analgesics, antiseptics, haemostatics, antihistamines, antimicrobial metals or their salts, plant substances or mixtures of substances that promote wound healing, plant extracts, enzymes, growth factors, enzyme inhibitors and combinations thereof.

Analgesics include, in particular, non-steroidal analgesics, in particular salicylic acid, acetylsalicylic acid and their derivatives, e.g. Aspirin®, aniline and its derivatives, acetaminophen, e.g. Paracetamol®, antranilic acid and its derivatives, e.g. mefenamic acid, pyrazole or its derivatives, e.g. methamizol, Novalgin®, Phenazone, Antipyrin®, Isopropyl phenazone and very particularly preferably arylacetic acids and their derivatives, Heteroa rylessigsäuren and their derivatives, arylpropionic acids and their derivatives and Her- teroarylpropionic acids and their derivatives, for example Indomethacin®, Diclophenac®, Ibuprofen®, Naxoprophen®, Indomethacin®, Ketoprofen®, Piroxicam®.

The following growth factors should be mentioned in particular: aFGF (Acidic Fibroplast Growth Factor), EGF (Epidermal) Growth Factor), PDGF (Platelet Derived Growth Factor), rhPDGF-BB (Becaplermin), PDECGF (Platelet Derived Endothelial Cell Growth Factor), bFGF ( basic fibroblast growth factor), TGF a; (Transforming Growth Factor alpha), TGF ß (Transforming Growth Factor beta), KGF (Keratinocyte Growth Factor), IGF1/IGF2 (Insulin-Like Growth Factor) and TNF (Tumor Necrosis Factor).

Vitamins or provitamins are in particular the fat-soluble or water-soluble vitamins vitamin A, group of retinoids, provitamin A, group of carotenoids, in particular special ß-carotene, vitamin E, group of tocopherols, in particular a tocopherol, ß-tocopherol, y-tocopherol, d-tocopherol and a-tocotrienol, ß-tocotrienol, y-tocotrienol and d-tocotrienol, vitamin K, phylloquinone, in particular phytomenadione or vegetable vitamin K, vitamin C, L-ascorbic acid, vitamin B1, thiamine, vitamin B2, riboflavin, vita min G, vitamin B3, niacin, nicotinic acid and nicotinamide, vitamin B5, pantothenic acid, provitamin B5, panthenol or dexpanthenol, vitamin B6, vitamin B7, vitamin H, biotin, vitamin B9, folic acid and combinations thereof.

An antiseptic should be an agent that has a gemicidal, bactericidal, bacteriostatic, fungicidal, virucidal, virustatic and/or generally microbiocidal effect.

Substances that are particularly suitable are those selected from the group consisting of resorcinol, iodine, iodine-povidone, chlorhexidine, benzalkonium chloride, benzoic acid, benzoyl peroxide or cethylpyridinium chloride. In addition, antimicrobial metals, in particular, can also be used as antiseptics. In particular, silver, copper or zinc and their salts, oxides or complexes can be used in combination or alone as antimicrobial metals.

In connection with the present invention, herbal active ingredients that promote wound healing are, in particular, chamomile extracts, witch hazel extracts, for example Hamamelis virgina, calendula extract, aloe extract, for example aloe vera, aloe barbadensis, aloe feroxoder or aloe vulgaris, green tea extracts, seaweed -Extract, for example red algae or green algae extract, avocado extract, myrrh extract, for example Commophora molmol, bamboo extracts and combinations thereof. The content of the active ingredients is based primarily on the medically required dose and also on the compatibility with the other components of the tissue adhesive according to the invention.

The present invention also relates to a flat composite material suitable for use as a mesh implant in the context of hernia surgery, obtainable from a system according to the invention. The flat composite material can be obtained, for example, from the system according to the invention by applying the adhesive according to the invention to the textile fabric and optionally subsequent curing.

In a preferred development of the composite material according to the invention, this has an effective porosity of at least 25%, in particular at least 45%, preferably from 45 to 85%, determined according to Mühl T, Binnebösel M, Klinge U, Goedderz T: New Objective Measurement to Characterize the Porosity of Textile Implants, Journal of Biomedical Materials Research Part B: Applied Biomaterials: 176-183, DOI 10.1002/jbmb; ©Wiley Periodicals, Inc. (5/2007). In contrast to the textile porosity, the effective porosity describes the porosity of the system after the adhesive has been applied and allowed to harden.

In the case of the composite material according to the invention, it is preferred that the fabric adhesive covers the textile fabric as completely as possible on both flat sides. This means that the fiber surface of the textile fabric is preferably at least 80% covered with the adhesive, preferably at least 85% or even at least 90%. This is advantageous because it allows the mesh implant to adhere particularly well to the body's own tissue.

Another subject of the present invention relates to a method for producing a composite material from a system according to the invention, the method comprising the following steps: a) placing the textile fabric on a substrate b) mixing the components of the fabric adhesive comprising at least two components, in particular by means of a static mixer; c) applying the mixture produced in step b) to the textile fabric; d) allowing the tissue adhesive to cure.

To carry out the method, a dosing system with at least two chambers, such as a two-chamber syringe, is preferably used, at the outlet of which a static mixer can be attached. In one chamber of the dosing system is component A) and in the other chamber contains component B) and optionally component C) of the tissue adhesive. By actuating the two-chamber syringe, the components of the fabric adhesive are mixed in the static mixer and applied evenly to the textile fabric.

The invention further relates to a method for mesh implantation in the context of hernia surgery using a system according to the invention, the method comprising the following steps: a) placing the textile fabric on an area of human or animal tissue inside the body; b) Mixing the components of the tissue adhesive comprising at least two components, in particular by means of a static mixer; c) applying the mixture produced in step b) to the textile fabric; d) allowing the tissue adhesive to cure.

Here, too, the above-mentioned dosing system with at least two chambers with an optional static mixer can preferably be used. The procedure is preferably performed laparoscopically.

Another subject of the present invention relates to tissue adhesive for use in a method for mesh implantation in the context of hernia surgery, characterized in that the tissue adhesive is a two-component adhesive with at least one amino-functional aspartic acid ester as a hardener as the first component and an isocyanate-functional second component is prepolymer.

The invention relates in particular to the following embodiments:

According to a first embodiment, the invention relates to a system for mesh implantation in the context of hernia surgery, comprising a textile fabric and a tissue adhesive, the textile fabric being composed of a polymer selected from the group comprising or consisting of polyether sulfones, polysulfones, polyolefins, polyesters , Fluoropolymers, silicones or mixed polymers and / or mixtures of these, the system being characterized in that the tissue adhesive is a two-component adhesive with at least one amino-functional aspartic acid reester as a hardener as the first component and as the second component an isocyanate-functional prepolymer.

According to a second embodiment, the invention relates to a system according to embodiment 1, characterized in that the textile fabric is in the form of a woven fabric, a non-woven fabric or a knitted fabric.

According to a third embodiment, the invention relates to a system according to embodiment 1 or 2, characterized in that the polymer is selected from the group comprising or consisting of polypropylene and/or polyvinylidene fluoride, preferably polyvinylidene fluoride.

According to a fourth embodiment, the invention relates to a system according to one of the above embodiments, characterized in that the textile fabric is formed from at least two different polymer fibers, in particular from polypropylene and polyvinylidene fluoride fibers.

According to a fifth embodiment, the invention relates to a system according to one of the above embodiments, characterized in that the textile fabric has a textile porosity of at least 40%, in particular at least 50%, preferably from 50 to 90%, determined according to Mühl T. Binnebösel M, Klinge U, Goedderz T: New Objective Measurement to Characterize the Porosity of Textile Implants, Journal of Biomedical Materials Research Part B: Applied Biomaterials: 176-183, DOI 10.1002/jbmb; ©Wiley Periodicals, Inc. (5/2007).

According to a sixth embodiment, the invention relates to a system according to one of the preceding embodiments, characterized in that the textile fabric has an average pore diameter of 100 to 3,000 μm, the textile fabric in particular essentially having two different average pore diameters, of which one average pore diameter is 100 to 600 μm and the other average pore diameter is 700 to 3000 μm, the average pore diameters more preferably differing by at least a factor of 2.

According to a seventh embodiment, the invention relates to a system according to one of the above embodiments, characterized in that the tissue adhesive comprises or consists of the following components: an isocyanate-functional prepolymer as component A), obtainable by a) Reaction of a bifunctional starter compound having at least one Zerewitinoff-active H atom with an alkylene oxide compound and a comonomer to give a hydroxyl-bearing precursor, the comonomer being selected from the group consisting of lactides, glycolides and combinations thereof and combinations of lactides and/or glycolides with cyclic dicarboxylic acid anhydrides and wherein the co-monomer is built into the polymer chain(s) of the hydroxyl-bearing precursor by a random copo lysis, and b) reacting the hydroxyl-bearing precursor from step a) with a polyfunctional isocyanate to the isocyanate-functional prepolymer, an amino-functional aspartic acid ester as component B) of general formula (I)

whereby

X is an n-valent organic radical,

According to an eighth embodiment, the invention relates to a system according to embodiment 7, characterized in that the amino-functional aspartic acid ester is one of the general formula (II)

is, where R1, R2, R3 are identical or different organic radicals which have no Zerewitinoff-active H atoms.

According to a ninth embodiment, the invention relates to a system according to embodiment 7 or 8, characterized in that the alkylene oxide compound is selected from ethylene oxide and/or propylene oxide, the proportion of ethylene oxide units in the polymer chain of the hydroxyl-bearing precursor being at least 40% by weight amounts to.

According to a tenth embodiment, the invention relates to a system according to one of embodiments 7 to 9, characterized in that the polyfunctional isocyanate is selected from aliphatic isocyanates.

According to an eleventh embodiment, the invention relates to a system according to one of the preceding embodiments, characterized in that the tissue adhesive comprises at least one further hardener, which is selected in particular from polyols with a number-average molar mass of 1000 Da or less, in particular 600 Da or less eng.

According to a twelfth embodiment, the invention relates to a system according to one of the above embodiments, characterized in that the tissue adhesive contains at least one pharmacologically active ingredient selected from the group comprising analgesics with and without anti-inflammatory effects, anti-inflammatory drugs, antimicrobial substances, antimycotics , antiparasitic substances or mixtures of these, the active ingredients are present in particular as a pure active ingredient or in encapsulated form.

According to a thirteenth embodiment, the invention relates to a system according to embodiment 12, characterized in that the active substance is selected from components which release nitrogen monoxide under in vivo conditions, preferably L-arginine or an L-arginine-containing or an L-arginine-releasing one component, particularly preferably L-arginine hydrochloride,

proline, ornithine and/or biogenic polyamines, in particular spermine, spermite, putrescine or bioactive artificial polyamines, Vitamins or provitamins, carotenoids, analgesics, antiseptics, haemostatics, antihistamines, antimicrobial metals or their salts, herbal substances or mixtures of substances that promote wound healing, plant extracts, enzymes, growth factors, enzyme inhibitors and combinations thereof.

According to a fourteenth embodiment, the invention relates to a flat composite material suitable for use as a mesh implant in the context of hernia surgery, obtainable from a system according to one of embodiments 1 to 13.

According to a fifteenth embodiment, the invention relates to a composite material according to embodiment 14, characterized in that the composite material has an effective porosity of at least 25%, in particular at least 45%, preferably from 45 to 85%, determined according to Mühl T, Binne Bösel M, Klinge U , Goedderz T: New Objective Measurement to Characterize the Porosity of Textile Implants, Journal of Biomedical Materials Research Part B: Applied Biomaterials: 176-183, DOI 10.1002/jbmb; ©Wiley Periodicals, Inc. (5/2007).

According to a sixteenth embodiment, the invention relates to a composite material according to embodiment 14 or 15, characterized in that the fabric adhesive covers the textile fabric as completely as possible on both flat sides, the fiber surface of the textile fabric being preferably at least 80% covered with the fabric adhesive, preferably at least 85% or even at least 90%.

According to a seventeenth embodiment, the invention relates to a method for producing a composite material from a system according to one of embodiments 1 to 13, the method comprising the following steps: a) placing the textile fabric on a substrate b) mixing the components of the at least two Tissue adhesive comprising components, in particular by means of a static mixer; c) applying the mixture produced in step b) to the textile fabric; d) allowing the tissue adhesive to cure.

According to an eighteenth embodiment, the invention relates to a method for mesh implantation in the context of hernia surgery with a system according to one of embodiments 1 to 13, the method comprising the following steps: a) laying the fabric onto an area of human or animal tissue within the body; b) Mixing the components of the tissue adhesive comprising at least two components, in particular by means of a static mixer; c) applying the mixture produced in step b) to the textile fabric; d) allowing the tissue adhesive to set.

According to a nineteenth embodiment, the invention relates to a method according to embodiment 18, wherein the method is performed laparoscopically.

Example:

The present invention is explained in more detail below using an exemplary embodiment.

Materials used:

Tissue adhesive 1 (according to the invention): two-component tissue adhesive based on the polyol 1 of EP 2 794 710 B1, which is converted into the prepolymer 2 and then with the aspartate A and PEG 200 in the following mixing ratio (aspartate AI PEG 200; 0.57/ 0.43) is formulated.

Tissue Adhesive 2 (According to the Invention): Two-component tissue adhesive based on Examples 1 and 2 of EP 2 145634 B1. The application was carried out using a commercially available two-chamber applicator with a static mixer. One chamber contained a mixture of 0.45 g PEG 200 and 0.55 g aspartate B. The second chamber contained 4 g of prepolymer A.

Both tissue adhesives according to the invention were used with a two-chamber syringe with an attached static mixer.

Tissue adhesive 3 (comparison): commercial medical cyanoacrylate adhesive (Glubran®2, Dalhausen Medizintechnik, Germany)

Merfasern DynaMesh ^® -IPOM consisting of two different poly, polypropylene, and polyvinylidene fluoride fibers (PP-12% / PVDF 88%): textile fabric. 1 The composite material has an effective porosity of 43% and a textile porosity of 58%, determined according to Mühl T, Binnebösel M, Klinge U, Goedderz T: New Objective Measurement to Characterize the Porosity of Textile Implants, Journal of Biomedical Materials Research Part B: Applied Biomaterials: 176-183, DOI 10.1002/jbmb; ©Wiley Periodicals, Inc.

(5/2007).

Measurement methods:

The OH numbers were determined in accordance with the provisions of DIN 53240.

The viscosities of the polyols were determined using a rotational viscometer (Physica MCR 51, manufacturer: Anton Paar) in accordance with DIN 53019. The number average M _n and the weight _{average M w of} the molecular weight and the polydispersity (M _w /M _n ) were determined by means of gel permeation chromatography (GPC). The procedure was according to DIN 55672-1: "Gel permeation chromatography, part 1 - tetrahydrofuran as eluent" (SECurity GPC system from PSS Polymer Service, flow rate 1.0 ml/min; columns: 2xPSS SDV linear M, 8x300 mm, 5 pm; RID -Detector). Polystyrene samples of known molar mass were used for calibration.

Unless expressly stated otherwise, NCO contents were determined volumetrically in accordance with DIN EN ISO 11909.

The residual monomer content was determined according to DIN ISO 17025:2018-03.

Example 1 Application of the tissue adhesives 1 to 3 and the textile fabric 1 in an in vivo small animal model - rat; Preparation of samples for the cell penetration test:

The rats were operated on under general anesthesia and sterile surgical conditions. The rats were then placed in a supine position, their abdomens shaved and disinfected with iodine solution. After a longitudinal section, textile fabrics were implanted subcutaneously in the left and right abdominal wall and fixed with tissue adhesive. The abdominal wall of the rats was closed using commercially available sutures.

Histopathological evaluation of the rats: When the animals were finalized after 7 or 21 days, samples with the adhesive/textile fabric interface and adjacent tissue were isolated. The samples were embedded in paraffin and cut into 3 pm sections after formaldehyde fixation.

Example 2 Application of the tissue adhesive 1 and the textile fabric 1 in the in vivo large animal model - pig:

For the evaluation in the minipig model, the animals were subjected to a minimally invasive laparotomy under general anesthesia. The test animals were placed in the supine position and a 10mm camera trocar was inserted in the mid-abdomen. After applying the pneumoperitoneum with 15mmHg, two more working trocars are placed step by step in the right (10mm) and left (5mm) middle abdomen. After that, abdominal wall defects were artificially created using surgical scissors to simulate a groin rupture. Then a 10x5 cm large textile fabric is placed in the area of the abdominal wall in the right/left middle/lower abdomen. After stretching the textile fabric and fixing it in the middle using an absorbable holding dens, the textile fabric is bonded against the force of gravity at certain points at the end and in the middle of the textile fabric using fabric adhesive, which is introduced and applied laparoscopically. The trocars were then removed and the abdominal wall closed again with sutures. After 90 days, the animals were finalized and the fabric was securely attached to the abdominal wall.

Adhesion test (tensile testing machine):

The different tissue adhesives 1-3 were checked for their adhesion properties by mechanical testing. A ZwickRoell tensile testing machine with the appropriate software was used for this purpose. Pork skin from the abdominal area was selected as the natural tissue substrate for this comparative experiment and cut into 10×2 cm strips. These substrates were then glued to the textile fabric 1 using fabric adhesive 1-3. The samples prepared in this way were clamped into the tensile testing machine with the textile fabric on top and the pigskin substrate on the bottom and pulled at a constant feed rate of 2 cm/min and the maximum force required was determined. No significant difference in maximum adhesion was found between the tissue adhesive according to the invention and the comparison adhesive. The maximum adhesive strength of all tested samples was between 15 and 20 N and thus offers sufficient adhesive strength for use in mesh-reinforcing hernia surgery.

Growth of the cells through the mesh implant (cell penetration test):

The samples and sections produced according to Example 1 were analyzed histopathologically and immunohistochemically. Specimens were stained with hematoxylin and eosin to reduce variation in internal staining. Cell penetration at the interface between tissue adhesive and textile fabric was determined semi-quantitatively using combined samples using the TissueFAXS system and bright field microscopy and image analysis software. To analyze the foreign body reaction, the cells were identified by means of markers and measured.

After 7 days, both tissue adhesives 1 and 2 showed a significantly higher cell penetration than comparative tissue adhesive 3. Between the tissue adhesives according to the invention however, no significant difference in cell penetration was found. In the 21-day group, tissue glue 1 showed increased and tissue glue 2 significantly increased ingrowth of cell strands compared to tissue glue 3.

The characterization of the foreign body reaction with regard to the tissue adhesive/textile fabric combination was carried out by analyzing the presence of inflammatory cells (CD68), cell proliferation (Ki67), T-lymphocyte infiltration (CD3 expression) and the identified leukocyte infiltration (CD45 expression) near the tissue adhesive/fabric interface and tissue ingrowth. For this purpose, a further control group was created, in which the textile fabric 1 was introduced into the animal body without tissue adhesive but otherwise as described in Example 1. This group is referred to below as the “untreated control group”.

After 7 days, CD68 positive cells were increased in tissue glue 3 (comparison) and tissue glue 1 group compared to the untreated control group (21.0±4.9 vs. 12.4±3.5 (p<0.01); 19.3 ± 5.7 vs. 12.4 ± 3.5 (p=0.01 )). In addition, a significantly lower number of CD68-positive cells could be observed after the application of tissue adhesive 2 compared to the comparison group of tissue adhesive 3 (14.9±4.2 vs. 21.0±4.9; p=0.04). After 21 days, only tissue glue 1 showed an increased infiltration with CD68-positive cells compared to tissue glue 3 (18.0 ± 4.4 vs. 12.1 ± 3.0; p=0.01). Analysis of cellular proliferation by measuring Ki67-positive cells showed an increase after 7 days in all three tissue glue groups compared to the untreated control (tissue glue 3: 2.2 ± 1.5 (p=0.04); Tissue glue 2: 2.3±1.2 (p<0.01), tissue glue 1: 1.8±1.1 (p=0.01) vs. control 0.9±1.1).

21 days after the tissue glue application, the positive cells of CD45 in the tissue glue 2 group (2.6 ± 1.1%) and tissue glue 1 group (2.7 ± 0.8%) compared to the untreated control (4.5 ± 1.6) and for comparison tissue adhesive 3 (5.2 ±

2.8) significantly lower. The examination of the lymphocyte infiltration by CD3 measurement after 7 days showed a significant upregulation in the comparison group tissue adhesive 3 compared to the untreated control (9.1 ± 4.8% vs. 4.4 ± 1.9%; p<0.01 ). CD3-positive cells were reduced in tissue glue 2 (3.4 ± 3.2%) and tissue glue 1 (4.3 ± 2.4%) compared to tissue glue 3 group.

When analyzing the biocompatibility, the tissue adhesives 1 and 2 according to the invention showed increased ingrowth of cell strands compared to the comparison group tissue adhesive 3, which indicates superior tissue integration. Furthermore, the first Tissue adhesive 2 according to the invention showed reduced migration of inflammatory cells compared to the tissue adhesive 3 comparison group. In addition, a significantly lower leukocyte infiltrate was detectable after 21 days in tissue adhesives 1 and 2 according to the invention. These findings show a lower foreign body reaction and therefore improved biocompatibility compared to the tissue adhesive comparison group 3.

Claims

Expectations:

1. System for mesh implantation in the context of hernia surgery comprising a textile fabric and a tissue adhesive, wherein the textile fabric is constructed from a polymer selected from the group comprising or consisting of polyether sulfones, polysulfones, polyolefins, polyesters, fluoropolymers, silicones or Copolymers and/or mixtures of these, characterized in that the tissue adhesive is a two-component adhesive with at least one amino-functional aspartic acid ester as a hardener as the first component and as the second component an isocyanate-functional prepolymer.

2. System according to claim 1, characterized in that the textile fabric is in the form of a woven fabric, scrim or knitted fabric.

3. System according to claim 1 or 2, characterized in that the polymer is selected from the group comprising or consisting of polypropylene and/or polyvinylidene fluoride, preferably polyvinylidene fluoride.

4. System according to any one of the preceding claims, characterized in that the textile fabric is formed from at least two different polymer fibers, in particular from polypropylene and polyvinylidene fluoride fibers.

5. System according to any one of the preceding claims, characterized in that the textile fabric has a textile porosity of at least 40%, in particular at least 50%, preferably from 50 to 90%, determined according to Mühl T, Binne Bösel M, Klinge U , Goedderz T: New Objective Measurement to Characterize the Porosity of Textile Implants, Journal of Biomedical Materials Research Part B: Applied Biomaterials: 176-183, DOI 10.1002/jbmb; ©Wiley Periodicals, Inc. (5/2007).

6. System according to one of the preceding claims, characterized in that the textile fabric has an average pore diameter of 100 to 3,000 μm, wherein the textile fabric has in particular essentially two different average pore diameters, one of which has an average pore diameter of 100 to 600 μm and the other average pore diameter is 700 to 3000 μm, the average pore diameters more preferably differing by a factor of at least 2.

7. System according to any one of the preceding claims, characterized in that the tissue adhesive comprises or consists of the following components: an isocyanate-functional prepolymer as component A), obtainable by a) reacting a bifunctional starter compound having at least one Zerewitinoff-active H atom with a Alkylene oxide compound and a comonomer to a hydroxyl-bearing precursor, wherein the comonomer is selected from the group consisting of lactides, glycolides, and combinations thereof and combinations of lactides and / or glycolides with cyclic dicarboxylic acid anhydrides and wherein the comonomer by ei ne statistical copolymerization in the polymer chain (s) of the hydroxyl-bearing precursor is incorporated, and b) reaction of the hydroxyl-bearing precursor from step a) with a polyfunctional isocyanate to form the isocyanate-functional prepolymer, an amino-functional aspartic acid ester as component B) of the general to

Formula (I)

is where

X is an n-valent organic radical,

R 1 , R _{2 are} identical or different organic radicals which do not have any Zerewitinoff-active H atoms, n is an integer >2, and optionally a reaction product of the isocyanate-functional prepolymer A) with the amino-functional aspartic acid ester B) as component C).

8. System according to claim 7, characterized in that the amino-functional Aspartic acid ester is one of the general formula (II)

9. System according to claim 7 or 8, characterized in that the alkylene oxide compound is selected from ethylene oxide and/or propylene oxide, the proportion of ethylene oxide units in the polymer chain of the hydroxyl-bearing precursor being at least 40% by weight.

10. System according to any one of claims 7 to 9, characterized in that the polyfunctional isocyanate is selected from aliphatic isocyanates.

11. System according to any one of the preceding claims, characterized in that the tissue adhesive comprises at least one further hardener which is selected in particular from polyols having a number-average molar mass of 1000 Da or less, in particular 600 Da or less.

12. Flat composite material suitable for use as a mesh implant in the context of hernia surgery, obtainable from a system according to any one of claims 1 to 11.

13. Composite material according to claim 12, characterized in that the composite material has an effective porosity of at least 25%, in particular at least 45%, preferably from 45 to 85%, determined according to Mühl T, Binnebösel M, Klinge U, Goedderz T: New Objective Measurement to Characterize the Porosity of Textile Implants, Journal of Biomedical Materials Research Part B: Applied Biomaterials: 176-183, DOI 10.1002/jbmb; ©Wiley Periodicals, Inc. (5/2007).

14. Composite material according to claim 12 or 13, characterized in that the fabric adhesive covers the textile fabric as completely as possible on both flat sides.

15. A method for producing a composite material from a system according to any one of claims 1 to 11, the method comprising the following steps: a) placing the textile fabric on a substrate b) mixing the components of the fabric adhesive comprising at least two components, in particular by means of a static mixer; c) applying the mixture produced in step b) to the textile fabric; d) allowing the tissue adhesive to cure.

16. A method for mesh implantation in the context of hernia surgery using a system according to any one of claims 1 to 11, the method comprising the following steps: a) placing the textile fabric on an area of human or animal tissue inside the body; b) mixing the components of the tissue adhesive comprising at least two components, in particular by means of a static mixer; c) applying the mixture produced in step b) to the textile fabric; d) allowing the tissue adhesive to cure.