WO2022013345A1 - Kit composé d'un adhésif tissulaire à deux composants et d'une structure textile pour renforcer le tissu conjonctif après une opération, et son utilisation - Google Patents

Kit composé d'un adhésif tissulaire à deux composants et d'une structure textile pour renforcer le tissu conjonctif après une opération, et son utilisation Download PDF

Info

Publication number
WO2022013345A1
WO2022013345A1 PCT/EP2021/069740 EP2021069740W WO2022013345A1 WO 2022013345 A1 WO2022013345 A1 WO 2022013345A1 EP 2021069740 W EP2021069740 W EP 2021069740W WO 2022013345 A1 WO2022013345 A1 WO 2022013345A1
Authority
WO
WIPO (PCT)
Prior art keywords
textile fabric
adhesive
tissue
component
fabric
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2021/069740
Other languages
German (de)
English (en)
Inventor
René H. TOLBA
Marius ROSENBERG
Steve GOTZEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Adhesys Medical GmbH
Original Assignee
Adhesys Medical GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Adhesys Medical GmbH filed Critical Adhesys Medical GmbH
Publication of WO2022013345A1 publication Critical patent/WO2022013345A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • cyanoacrylates usually become relatively hard after polymerisation, so that the mesh implant becomes more rigid, which increases the foreign body sensation.
  • the polyurethaneurea systems according to the invention remain considerably more flexible.
  • 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.
  • textile fabrics can be in the form of a woven, non-woven or knitted fabric.
  • 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.
  • 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, Binnebinatel 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.
  • these textile porosities later allow body cells to grow through and thus good integration into the body's own tissue.
  • the textile fabric has an average pore diameter of 100 to 3,000 ⁇ m, with the textile fabric essentially having two different average pore diameters, one of which has an average pore diameter of 100 to 600 ⁇ m and the other other mean pore diameter is 700 to 3000 ⁇ m, the mean pore diameters more preferably differing by a factor of at least 2.
  • 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.
  • 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).
  • 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.
  • 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.
  • the polymer chain length shortens particularly quickly.
  • 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.
  • tissue adhesives with an isocyanate-functional prepolymer according to the invention meet the requirements with regard to histotoxicity, thrombogenicity and allergenic potential.
  • the H-functional starter compound carries at least one Zerewitinoff-active H atom.
  • 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.
  • the polymer containing hydroxyl groups used as the H-functional starter compound is a polyether or has polyether groups
  • 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
  • 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.
  • 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.
  • hydroxy-functional starters which are to be used with preference, amino-functional starters can also be used.
  • 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
  • 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.
  • 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.
  • monofunctional or polyfunctional carboxylic acids directly as starter compounds.
  • 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
  • polyester polyols preferably with OH numbers in the range from 6 to 800 mg KOH/g
  • 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.
  • 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.
  • 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.
  • 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,
  • active hydrogens such as methanol, ethanol, 1-propano
  • 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.
  • 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, cyclohex
  • Ethylene oxide and/or propylene oxide are preferably used.
  • 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.
  • 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.
  • 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 .
  • 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).
  • DMC catalyst double metal cyanide catalyst
  • 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.
  • 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.
  • 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.
  • HDI hexamethylene diisocyanate
  • IPDI isophorone diisocyanate
  • BDI butylene diisocyanate
  • HMDI bisisocyanato cyclohexylmethan
  • hexamethylene diisocyanate HDI
  • isophorone diisocyanate IPDI
  • butylene diisocyanate BDI
  • bis(isocyanatocyclohexyl)methane HMDI
  • Hexamethylene diisocyanate, isophorone diisocyanate, butylene diisocyanate are particularly preferred
  • hexamethylene diisocyanate and isophorone diisocyanate are very particularly preferred.
  • 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).
  • TDI toluene diisocyanate
  • MDI diphenylmethane diisocyanate
  • 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.
  • 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.
  • the adhesive used is characterized by an aspartate hardener.
  • the tissue adhesive can preferably comprise at least one further hardener.
  • 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.
  • a polyethylene glycol 200 is preferably used.
  • 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.
  • 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.
  • 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.
  • components of this type support wound healing, and their continuous, almost uniform delivery in terms of quantity is particularly beneficial for wound healing.
  • 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 methamizol, Novalgin®, Phenazone, Antipyrin®, Isopropyl phenazone and very particularly preferably arylacetic acids and their derivatives, Heteroa rylessigklaren and their derivatives, arylpropionic acids and their derivatives and Her- teroarylpropionic acids and their derivatives, for example Indomethacin®, Diclophenac®, Ibuprofen®, Naxoprophen®, Indomethacin®, Ketoprofen®, Piroxicam®.
  • aFGF Acidic Fibroplast Growth Factor
  • EGF Epidermal growth Factor
  • PDGF PlaterhPDGF-BB (Becaplermin)
  • PDECGF Plater 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
  • 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,
  • 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.
  • antimicrobial metals in particular, can also be used as antiseptics.
  • silver, copper or zinc and their salts, oxides or complexes can be used in combination or alone as antimicrobial metals.
  • 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.
  • this has an effective porosity of at least 25%, in particular at least 45%, preferably from 45 to 85%, determined according to Mühl T, Binnebinatel 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).
  • the effective porosity describes the porosity of the system after the adhesive has been applied and allowed to harden.
  • the fabric adhesive covers the textile fabric as completely as possible on both flat sides.
  • 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.
  • 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.
  • 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.
  • component A 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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. Binnebinatel 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).
  • 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 ⁇ m, the textile fabric in particular essentially having two different average pore diameters, of which one average pore diameter is 100 to 600 ⁇ m and the other average pore diameter is 700 to 3000 ⁇ m, the average pore diameters more preferably differing by at least a factor of 2.
  • 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)
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 B penetratel 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).
  • 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%.
  • 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.
  • 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.
  • the invention relates to a method according to embodiment 18, wherein the method is performed laparoscopically.
  • 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.
  • 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, Dalhausentechnik, Germany)
  • 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).
  • GPC gel permeation chromatography
  • 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.
  • 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.
  • 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.
  • two more working trocars are placed step by step in the right (10mm) and left (5mm) middle abdomen.
  • abdominal wall defects were artificially created using surgical scissors to simulate a groin rupture.
  • a 10x5 cm large textile fabric is placed in the area of the abdominal wall in the right/left middle/lower abdomen.
  • the textile fabric 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.
  • 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.
  • Example 1 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.
  • 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.
  • inflammatory cells CD68
  • cell proliferation Ki67
  • T-lymphocyte infiltration CD3 expression
  • CD45 expression the identified leukocyte infiltration
  • tissue glue 2 group 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 ⁇
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Surgery (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Materials For Medical Uses (AREA)

Abstract

La présente invention concerne un système d'implantation de maille dans le domaine de la chirurgie des hernies, ledit système comprenant un tissu textile et un adhésif tissulaire, le tissu textile étant composé d'un polymère choisi dans le groupe comprenant ou constitué des polyéthersulfones, des polysulphones, des polyoléfines, des polyesters, des fluoropolymères, des silicones ou des polymères mixtes et/ou des mélanges de ceux-ci, le système étant caractérisé en ce que l'adhésif textile est un adhésif à deux composants ayant comme premier composant au moins un ester d'acide aspartique à fonction amino agissant en tant qu'agent de durcissement et ayant comme second composant un prépolymère à fonction isocyanate. L'invention concerne également : un matériau composite plan adapté pour être utilisé en tant qu'implant maillé dans le domaine de la chirurgie des hernies, obtenu ou pouvant être obtenu à partir du système susmentionné ; un procédé de fabrication d'un tel matériau composite plan ; et un procédé d'implantation de maille dans le domaine de la chirurgie des hernies à l'aide d'un tel système.
PCT/EP2021/069740 2020-07-17 2021-07-15 Kit composé d'un adhésif tissulaire à deux composants et d'une structure textile pour renforcer le tissu conjonctif après une opération, et son utilisation Ceased WO2022013345A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP20186562 2020-07-17
EP20186562.3 2020-07-17

Publications (1)

Publication Number Publication Date
WO2022013345A1 true WO2022013345A1 (fr) 2022-01-20

Family

ID=71670170

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2021/069740 Ceased WO2022013345A1 (fr) 2020-07-17 2021-07-15 Kit composé d'un adhésif tissulaire à deux composants et d'une structure textile pour renforcer le tissu conjonctif après une opération, et son utilisation

Country Status (1)

Country Link
WO (1) WO2022013345A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050054771A1 (en) * 1995-12-18 2005-03-10 Sehl Louis C. Adhesive tissue repair patch
EP1525244A1 (fr) 2002-07-22 2005-04-27 Basf Corporation Polyol de polyether pour mousses
EP2046861A1 (fr) 2006-07-24 2009-04-15 Bayer MaterialScience LLC Polyols de poly(éther-carbonate) fabriqués via la catalyse avec un cyanure métallique double (dmc)
EP2095832A1 (fr) * 2008-02-28 2009-09-02 Bayer MaterialScience AG Barrières d'adhésion postopératoires
EP2145634A1 (fr) 2008-07-17 2010-01-20 Bayer MaterialScience AG Colles médicales destinées à arrêter des saignements graves et à étanchéifier des fuites
EP2794710B1 (fr) 2011-12-20 2018-08-15 Adhesys Medical GmbH Prépolymère à isocyanate fonctionnel pour un adhésif tissulaire biodégradable

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050054771A1 (en) * 1995-12-18 2005-03-10 Sehl Louis C. Adhesive tissue repair patch
EP1525244A1 (fr) 2002-07-22 2005-04-27 Basf Corporation Polyol de polyether pour mousses
EP2046861A1 (fr) 2006-07-24 2009-04-15 Bayer MaterialScience LLC Polyols de poly(éther-carbonate) fabriqués via la catalyse avec un cyanure métallique double (dmc)
EP2095832A1 (fr) * 2008-02-28 2009-09-02 Bayer MaterialScience AG Barrières d'adhésion postopératoires
EP2145634A1 (fr) 2008-07-17 2010-01-20 Bayer MaterialScience AG Colles médicales destinées à arrêter des saignements graves et à étanchéifier des fuites
EP2794710B1 (fr) 2011-12-20 2018-08-15 Adhesys Medical GmbH Prépolymère à isocyanate fonctionnel pour un adhésif tissulaire biodégradable

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MÜHL TBINNEBÖSEL MKLINGE UGOEDDERZ T: "Journal of Biomedical Materials Research Part B: Applied Biomaterials", May 2007, WILEY PERIODICALS, INC., article "New Objective Measurement to Characterize the Porosity of Textile Implants", pages: 176 - 183

Similar Documents

Publication Publication Date Title
EP2794710B1 (fr) Prépolymère à isocyanate fonctionnel pour un adhésif tissulaire biodégradable
EP3097929B1 (fr) Barrières d'adhésion postopératoires
CN101549169B (zh) 使用点击化学法形成的生物粘合剂组合物
EP2454303B1 (fr) Adhésif tissulaire à base de polyurée
EP1064032B1 (fr) Composition de matiere pour la formation de tissu
DE10330971B4 (de) Verfahren zur Herstellung von Haut- oder Wundauflagen mit verkapselten, wundheilungsfördernden und/oder hautpflegenden Substanzen
EP2725044B1 (fr) Prépolymère à terminaison alkoxysilane à base de polyols de polyéther carbonate pour mousse à atomiser
DE10005433B4 (de) Biomaterialien
EP2802612B1 (fr) Durcissant (à base d'aspartate) modifié par ester d'acides bêta-aminés et son utilisation dans des adhésifs tissulaires en polyurée
EP2794798A1 (fr) Polymère hydroxy-amino et son utilisation dans des adhésifs de tissu à base de polyurée polyuréthane
DE4439994A1 (de) Wasseraushärtbarer Stützverband
WO2013104564A1 (fr) Ester d'acide bêta-aminé et son utilisation
WO2012107375A1 (fr) Adhésif tissulaire à base d'aspartates modifiés par azote
WO2022013345A1 (fr) Kit composé d'un adhésif tissulaire à deux composants et d'une structure textile pour renforcer le tissu conjonctif après une opération, et son utilisation
DE102021102484A1 (de) Kit für die Gefäßanastomose aus einem zwei-Komponenten Gewebekleber und einer Gefäßprothese sowie dessen Verwendung
EP4104870A1 (fr) Adhésif tissulaire sous la forme d'un adhésif à deux composants destiné à être utilisé comme barrière bactérienne dans le traitement des plaies, en particulier après les interventions chirurgicales
EP2699615B1 (fr) Adhésif médical pour stopper des saignements
DE102021106358A1 (de) Gewebekleber in Form eines Zweikomponenten-Klebstoffs zur Verwendung bei der Pankreasanastomose im Rahmen der Pankreasresektion
DE102014201889A1 (de) Medizinisches Produkt zur Anwendung bei der Behandlung von Hernien

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21745330

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21745330

Country of ref document: EP

Kind code of ref document: A1