A combination, medical kit and medical device for treating and / or preventing tissue leakage

Abstract

The invention relates to a combination for treating tissue leakage, comprising - a collagen material and - a cyanoacrylate component. Further, the invention relates to a medical kit and medical device for treating and / or preventing tissue leakage.

Description

[0001] P 62282 WO November 17, 2025

[0002] - 1 - CG / CG

[0003] A combination, medical kit and medical device for treating and / or preventing tissue leakage

[0004] FIELD OF INVENTION

[0005] The present invention refers to a combination, a medical kit and a medical device for treating and / or preventing tissue leakage.

[0006] BACKGROUND OF THE INVENTION

[0007] It is known to apply stapler lines to prevent tissue leakage. However, even if correctly placed, micro holes may occur enhancing the risk of leakage, which can have devastating conseguences for animals and human patients.

[0008] A composition containing collagen for cultivating biological cells is known from WO 2009 / 024280 A2.

[0009] OBJECT AND SOLUTION

[0010] In view of the foregoing, an object underlying the present invention is therefore to make available a combination, a medical kit and a medical device useful for treating and / or preventing tissue leakage, which in particular addresses disadvantages or risk as described above.

[0011] This object is accomplished by a combination according to independent claim 1, a medical kit according to claim 21 and a medical device according to claim 22. Preferred embodiments of the invention are defined in the dependent claims and the description. The subject-matter and wording, respectively, of all claims is hereby incorporated into the description by explicit reference.

[0012] According to a first aspect, the present invention refers to a combination, in particular medical, preferably surgical, combination, in particular for treating and / or preventing tissue leakage.

[0013] The combination comprises the following:

[0014] - a collagen material and

[0015] - a cyanoacrylate component. P 62282 - 2 -

[0016] The term “tissue leakage” as used according to the present invention refers to any trauma of tissue, in particular human and / or animal tissue, resulting in the exit of body fluids such as intestinal liquids, bile, feces and blood.

[0017] The tissue leakage according to the present invention may be selected from the group consisting of skin leakage, liver leakage, spleen leakage, pancreas leakage, kidney leakage, lung leakage, adrenal gland leakage, stomach leakage, gall bladder leakage and intestines leakage such as small intestines leakage. More preferably, the tissue leakage refers to a leakage of the digestive tract.

[0018] The term “collagen material” as used according to the present invention refers to a material comprising or consisting of collagen.

[0019] The present invention is based on the surprising finding that a combination comprising collagen material and a cyanoacrylate component may be used for treating and / or preventing tissue leakages, in particular in human beings or animals. In that regard, it was especially surprising that a collagen material equipped with the cyanoacrylate component exhibited flexibility, impermeability to body fluids such as blood and tissue adherence. Further, it surprisingly turned out that the combination according to the present invention is able to withstand severe conditions especially in the digestive tract such as for example billiary fluid. Further, collagen is part of healthy tissues. In particular, depending on the type of collagen, the collagen may have or mimic vessel-like structures. Thus, the collagen material may advantageously foster tissue healing processes such as granulation. Further, the cyanoacrylate component and the collagen are biodegradable / bioabsorbable materials and may therefore be degraded / absorbed in vivo, in particular when a mechanical support of the collagen material is no longer needed.

[0020] In an embodiment of the invention, the collagen of the collagen material has a proportion of 50 % by weight to 70 % by weight, in particular 55 % by weight to 70 % by weight, preferably 60 % by weight to 70 % by weight, based on the total weight of the collagen material.

[0021] In a further embodiment of the invention, the collagen material further comprises a fat. Preferably, the fat is a vegetable oil. Vegetable oil advantageously improves the flexibility of the combination. In addition, the use of vegetable oil helps to avoid signs of rancidity, thereby improving manufacture and in particular storage of the combination. The vegetable oil may particularly be a seed oil, i.e. a vegetable oil obtained from seed (endosperm) rather than other parts of plants. Particularly, the vegetable oil may be selected from the group consisting of soybean oil, grape seed oil, cocoa butter, olive oil, palm oil, rice bran oil, sunflower oil, corn oil, sesame oil, palm P 62282 - 3 -

[0022] kernel oil, coconut oil, peanut oil, and mixtures of at least two of the aforementioned vegetable oils.

[0023] In a further embodiment of the invention, the fat has a proportion of 1 % by weight to 7 % by weight, in particular 2 % by weight to 6 % by weight, preferably 3 % by weight to 5 % by weight, based on the total weight of the collagen material.

[0024] In a further embodiment of the invention, the collagen material further comprises a polyol. The polyol may advantageously act as a plasticizer and additionally increases flexibility of the collagen material. The polyol may be in particular glycerol and / or a sugar alcohol. More specifically, the polyol may be preferably selected from the group consisting of glycerol, ethylene glycol, maltitol, sorbitol, xylitol, erythritol, isomalt, inositol, myoinositol, pinitol, mannitol, and mixtures of at least two of the aforementioned polyols.

[0025] In a further embodiment of the invention, the polyol has a proportion of 10 % by weight to 35 % by weight, in particular 15 % by weight to 30 % by weight, preferably 20 % by weight to 25 % by weight, based on the total weight of the collagen material.

[0026] In a further embodiment of the invention, the collagen material, by 100 % by weight, comprises or consists of the following:

[0027] 50 % by weight to 70 % by weight of collagen,

[0028] 1 % by weight to 7 % by weight of fat and

[0029] 10 % by weight to 35 % by weight of polyol.

[0030] It surprisingly turned out that especially a collagen material having the above composition in combination with a cyanoacrylate component resulted in a flexible, resistant and deformable structure, in particular membranous structure, being in particular useful for treating and / or preventing tissue leakage. With respect to further features of the collagen, fat and polyol, reference is made in its entirety to the preceding and still following description.

[0031] In a further embodiment of the invention, the collagen of the collagen material is or comprises native collagen. P 62282 - 4 -

[0032] The term "native collagen" as used according to the present invention refers to collagen which has not been denatured, hydrolyzed, or gelatinized, in particular totally or significantly.

[0033] Native collagen makes the collagen material especially suited to act as an impermeable barrier towards body fluids, to foster tissue adherence and tissue neogenesis as well as to withstand severe conditions within a body such as in the digestive tract.

[0034] The collagen of the collagen material may comprise fibers having a length, in particular determined by dynamic image analysis, in particular using a dynamic image analysis particle size analyzer commercially available under the name QICPIC / LIXELL (Sympatec GmbH), of 10 pm to 3000 pm, in particular 100 pm to 2000 pm, preferably 400 pm to 1500 pm.

[0035] Further, the collagen of the collagen material may comprise fibers having a diameter, in particular determined by dynamic image analysis, in particular using a dynamic image analysis particle size analyzer commercially available under the name QICPIC / LIXELL (Sympatec GmbH), of 5 pm to 30 pm, in particular 10 pm to 25 pm, preferably 15 pm to 20 pm.

[0036] In a further embodiment of the invention, the collagen of the collagen material is or comprises a collagen selected from the group consisting of collagen type I, collagen type II, collagen type III, collagen type IV, collagen type V, recombinant collagen and mixtures of at least two of the aforementioned collagen types.

[0037] Collagen type I is found in skin, tendon, vasculature, organs and bone. With respect to bone, collagen type I forms the main component of the organic part of bone.

[0038] Collagen type II is found in cartilage. Collagen type II forms the main collagenous component of cartilage.

[0039] Collagen type III is found in reticular fibers. Collagen type III forms the main component of reticular fibers. Commonly, collagen type III is found alongside collagen type I.

[0040] Collagen type IV is part of basal lamina and the epithelium-secreted layer of the basement membrane.

[0041] Collagen type V is found on cell surfaces, in hair and in placenta. P 62282 - 5 -

[0042] The recombinant collagen may be synthesized by biosynthetic methods, in particular by the aid of genetically modified microorganisms or in cell cultures. In particular, the recombinant collagen may be capable of forming tissue specific structures, including fibrils, networks, membrane structures etc.

[0043] In a further embodiment of the invention, the collagen of the collagen material is of xenogenic, in particular bovine, porcine, equine, ovine, or marine origin. Preferably, the collagen of the collagen material is of bovine origin.

[0044] In a further embodiment of the invention, the collagen of the collagen material is or comprises collagen type I, in particular native collagen type I, and preferably stems from bovine skin.

[0045] Further, the collagen material may comprise a biological tissue and / or an extracellular matrix (ECM) or the collagen of the collagen material may be part of a biological tissue and / or an extracellular matrix (ECM), in particular in a processed form. Preferably, the biological tissue and / or extracellular matrix (ECM) may be selected from the group consisting of pericardium, pericardium fibrosum, pericardium serosum, epicardium, squamous epithelium, tunica serosa, muscle such as myocardium, peritoneum, small intestine, small intestinal submucosa, gastric submucosa, urinary bladder submucosa, uterine submucosa, dermis, serosa dermis, and mixtures of at least two of the aforementioned biological tissues and extracellular matrices, respectively.

[0046] In a further embodiment of the invention, the collagen material has a pH value of 5 to 8, in particular 6 to 8, preferably 7 to 8.

[0047] In a further embodiment of the invention, the collagen material has a weight per unit area of 16 g / m2to 150 g / m2, in particular 20 g / m2to 45 g / m2, preferably 20 g / m2to 40 g / m2.

[0048] In a further embodiment of the invention, the collagen material has a tensile strength of 5 N / mm2to 25 N / mm2, in particular 5 N / mm2to 20 N / mm2, preferably 6 N / mm2to 15 N / mm2. The tensile strength may be in particular determined by means of a tensile testing system of Instron GmbH.

[0049] In a further embodiment of the invention, the collagen material, in a dry condition, has a thickness of 5 pm to 200 pm, in particular 10 pm to 30 pm, preferably 15 pm to 25 pm.

[0050] Alternatively, the collagen material may have a thickness, in a dry condition, of 0.5 mm to 10 mm. P 62282 - 6 -

[0051] Further, the collagen material may have a mean pore diameter, in particular determined by microscopy, preferably by environmental scanning electron microscopy (ESEM), of > 6 pm, in particular 6 pm to 480 pm, preferably 10 pm to 65 pm.

[0052] Further, the collagen material may be impermeable to cells.

[0053] The term “cells” as used according to present invention typically means cells of the body, in particular cells of the human and / or animal body.

[0054] Alternatively, the collagen material may be permeable to cells.

[0055] Further, the collagen material may have a cross-linked structure, in particular physically and / or chemically cross-linked structure. Thus, the tensile strength of the collagen material may be advantageously increased. In particular, the collagen material may be cross-linked via crosslinking agent, in particular selected from the group consisting of diamine, carbodiimide, diisocyanate, dicarboxylic acids, dialdehydes, polyaldehydes and mixtures of at least two of the aforementioned cross-linking agents. The polyaldehydes may preferably be polysaccharides carrying aldehyde groups (polyaldehydic polysaccharides). The polyaldehydic polysaccharides can in particular have a degree of oxidation of 10 % to 50 %, preferably 10 % to 30 %, for example 25 %. The carbodiimide may be EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), for example.

[0056] Alternatively, the collagen material may have a non-cross-linked structure.

[0057] Further, the collagen material may have a lyophilized structure.

[0058] Further, the collagen material may be in an extruded form. Advantageously, extrusion allows adjustment of layer thickness of the collagen material. Principally, different collagen manufacturing processes may be used for manufacturing the collagen material.

[0059] Further, the collagen material may be advantageously translucent.

[0060] Further, the collagen material may have a layered structure, in particular mono-layered or multilayered structure, for example two-layered, three-layered, four-layered or five-layered structure. P 62282 - 7 -

[0061] Preferably, the collagen material is in the form of a two-dimensional surface structure, in particular flat or planar two-dimensional surface structure.

[0062] Principally, the collagen material may comprise or be in the form of a patch, fabric, non-woven, membrane, sponge or a combination of at least two of the aforementioned forms. Particularly, the collagen material may comprise or be in the form of a membrane and / or sponge. The size of the aforementioned forms of the collagen material may be especially adjustable to the treating site to be addressed.

[0063] In a further embodiment of the invention, the collagen material comprises a membranous structure. In particular, the collagen material may be in the form of a membranous structure. A useful collagen material having a membranous structure is, for example, commercialized under Collagen Cell Carrier (CCC).

[0064] The term “membranous structure” as used according to the present invention refers to a two-dimensional surface structure, in particular flat or planar two-dimensional surface structure, in particular having a thickness of 10 pm to 200 pm. Further, the collagen material may comprise a membranous structure and a spongy structure. Preferably, the membranous structure is impermeable to cells and the spongy structure is preferably permeable to cells. Further, the spongy structure may have in particular columnar pores, in particular extending along a thickness direction of the spongy structure. Further, the membranous structure may have a thickness, in particular layer thickness, of 0.1 mm to 5 mm, in particular 0.5 mm to 2 mm, while the spongy structure may preferably have a thickness, in particular layer thickness, of 1 mm to 10 mm, in particular 2 mm to 5 mm. Further, the membranous structure may have weight per unit area of 50 g / m2to 180 g / m2, in particular 80 g / m2to 110 g / m2, while the spongy structure may preferably have a weight per unit area, of 30 g / m2to 300 g / m2, in particular 80 g / m2to 120 g / m2. Preferably, the membranous component is pericardium, while the spongy component is preferably collagen, in particular selected from the group consisting of collagen type I, collagen type II, collagen type III, collagen type IV, collagen type V, recombinant collagen and mixtures of at least two of the aforementioned collagen types.

[0065] Further, the collagen material may be in the form of a collagen membrane, i.e. a membrane comprising or consisting of collagen, preferably skin collagen (so-called skin collagen membrane), P 62282 - 8 -

[0066] in particular bovine skin collagen (so-called bovine skin collagen membrane). In particular, the collagen material may be in the form of an extruded bovine skin collagen membrane.

[0067] Further, the collagen material may be in the form of a pericardium and / or collagen membrane, i.e. a membrane comprising or consisting of pericardium and / or collagen, in particular bovine pericardium and / or bovine collagen, (so-called bovine pericardium and / or collagen membrane), preferably lyophilized pericardium and / or collagen (so-called lyophilized bovine pericardium and / or collagen membrane). Useful membranes are, for example, commercialized under Lyograft or Lyoplant.

[0068] Further, the collagen material may be in the form of particles, in particular in the form of a powder.

[0069] Further, the collagen material may be in the form of a gel, in particular hydrogel. Preferably, the gel is an injectable gel, in particular viscoelastic injectable gel.

[0070] In a further embodiment of the invention, the collagen material is in the form of an implant, preferably a surgical implant, in particular a surgical mesh.

[0071] In a further embodiment of the invention, the cyanoacrylate component includes cyanoacrylate monomers represented by the formula

[0072] CH2=CH(CN)-COOR (formula I)

[0073] wherein R is an alkyl, alkoxyalkyl, cycloalkyl, alkenyl, aralkyl, aryl, allyl or haloalkyl group.

[0074] In particular, the cyanoacrylate component may include cyanoacrylate monomers selected from the group consisting of alkyl 2-cyanoacrylate monomers, alkoxyalkyl 2-cyanoacryla-te monomers, multifunctional cyanoacrylate monomers and mixtures of at least two of the aforementioned cyanoacrylate monomers.

[0075] In a further embodiment of the invention, the cyanoacrylate component includes alkyl 2-cyanoacrylate monomers. The alkyl 2-cyanoacrylate monomers are in particular selected from the group consisting of methyl 2-cyanoacrylate monomers, ethyl 2-cyanoacrylate monomers, n-propyl 2-cyanoacrylate monomers, isopropyl 2-cyanoacrylate monomers, n-butyl 2-cyanoacrylate monomers, isobutyl 2-cyanoacrylate monomers such as, for example, 1 -butyl 2-cyanoacrylate monomers and / or 2-butyl 2-cyanoacrylate monomers, n-pentyl 2-cyanoacrylate monomers, isopentyl 2-cyanoacrylate monomers such as, for example, 1 -pentyl 2-cyanoacrylate monomers, P 62282 - 9 -

[0076] 2-pentyl 2-cyanoacrylate monomers and / or 3-pentyl 2-cyanoacrylate monomers, cyclopentyl 2-cyanoacrylate monomers, n-hexyl 2-cyanoacrylate monomers, isohexyl 2-cyanoacrylate monomers such as, for example, 1 -hexyl 2-cyanoacrylate monomers, 2-hexyl 2-cyanoacrylate monomers, 3-hexyl 2-cyanoacrylate monomers and / or 4-hexyl 2-cyanoacrylate monomers, cyclohexyl 2-cyanoacrylate monomers, n-heptyl 2-cyanoacrylate monomers, isoheptyl 2-cyanoacrylate monomers such as, for example, 1 -heptyl 2-cyanoacrylate monomers, 2-heptyl 2-cyanoacrylate monomers, 3-heptyl 2-cyanoacrylate monomers and / or 4-heptyl 2-cyanoacrylate monomers, n-octyl 2-cyanoacrylate monomers, isooctyl 2-cyanoacrylate monomers such as, for example, 1 -octyl 2-cyanoacrylate monomers, 2-octyl 2-cyanoacrylate monomers, 3-octyl 2-cyanoacrylate monomers and / or 4-octyl 2-cyanoacrylate monomers, n-nonyl 2-cyanoacrylate monomers, isononyl 2-cyanoacrylate monomers, n-decyl 2-cyanoacrylate monomers, isodecyl 2-cyanoacrylate monomers, n-undecyl 2-cyanoacrylate monomers, isoundecyl 2-cyanoacrylate monomers, n-dodecyl 2-cyanoacrylate monomers, isododecyl 2-cyanoacrylate monomers and mixtures of at least two of the afore-mentioned alkyl 2-cyanoacrylate monomers.

[0077] Preferably, the cyanoacrylate component includes n-butyl 2-cyanoacrylate monomers and / or n-octyl 2-cyanoacrylate monomers, more preferably n-butyl 2-cyanoacrylate monomers. N-butyl 2-cyanoacrylate monomers have the advantage that they are especially histocompatible and bactericidal and are further fully absorbable by hydrolysis and decarboxylation.

[0078] Further, the collagen material may have a coating. The coating may be in particular formed on two opposite surfaces, in particular main surfaces, of the collagen material. The coating may comprise a polymer and / or therapeutic agent, in particular as detailed in the following paragraphs.

[0079] Further, the combination may further comprise a polymer. The polymer may be part of a coating of the collagen material and / or dispersed in the collagen material. Accordingly, the collagen material may be coated with a polymer. Alternatively or in combination, for manufacture of the collagen material, collagen may be mixed with a polymer.

[0080] In particular, the polymer may be selected from the group consisting of polyvinyl alcohol, polyglycolide or polyglycolic acid, polylactide or polylactic acid, polydioxanone, polyhydroxybutyrate or polyhydroxybutyric acid, poly-3-hydroxybutyrate or poly-3-hydroxybutyric acid, poly-4-hydroxybutyrate or poly-4-hydroxybutyric acid, polytrimethylene carbonate, poly-s-caprolactone, polyethylene glycol, elastin, reticulin, fibronectin, laminin, fibrin, albumin, starch, amylose, amylopectin, dextran, dextrin, cellulose, cellulose derivatives such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, chitin, chitosan, hyaluronic acid, dextran sulfate, heparin, heparan sulfate, chondroitin sulfate, P 62282 - 10 -

[0081] dermatan sulfate, polyethylene glycol and mixtures of at least two of the aforementioned polymers.

[0082] Further, the combination may further comprise a therapeutic agent. The therapeutic agent may be part of a coating of the collagen material and / or dispersed in the collagen material. Accordingly, the collagen material may be coated with the therapeutic agent. Alternatively or in combination, for manufacture of the collagen material, collagen may be mixed with the therapeutic agent.

[0083] In particular, the therapeutic agent may be selected from the group consisting of antimicrobial, in particular antibiotic, agents, disinfecting agents, anti-inflammatory agents, wound healing promoting agents, cellular growth agents, morphogenetic agents, cytokines, peptides, proteins, extracellular components, cellular differentiating agents, cellular adhesion agents, cellular recruiting agents, anesthetic agents, and mixtures of at least two of the afore-mentioned therapeutic agents.

[0084] The growth agents may be selected from the group consisting of fibroblast growth factor (FGF), transforming growth factor (TGF), platelet derived growth factor (PDGF), epidermal growth factor (EGF), granulocyte-macrophage colony stimulation factor (GMCSF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), hepatocyte growth factor (HGF), interleucin-1B (IL-1B), interleucin-8 (IL-8), nerve growth factor (NGF), and mixtures of at least two of the aforementioned growth agents.

[0085] Further, the combination may preferably be in the form of a medical, in particular surgical, kit, wherein the collagen material and the cyanoacrylate component are spatially separated from each other.

[0086] Further, the combination may preferably be in the form of a medical, in particular surgical, device, wherein the collagen material comprises or is equipped, in particular soaked, with the cyanoacrylate component.

[0087] In a further embodiment of the invention, the combination is for use in the treatment and / or prevention of tissue leakage, in particular leakage from intestinal wounds and / or anastomotic leakage, in particular in colorectal surgery.

[0088] According to a second aspect, the invention refers to a medical, in particular surgical, kit, in particular for treating and / or preventing tissue leakage. The tissue leakage may be selected from the group consisting of skin leakage, liver leakage, spleen leakage, pancreas leakage, kidney P 62282 - 11 -

[0089] leakage, lung leakage, adrenal gland leakage, stomach leakage, gall bladder leakage and intestines leakage such as small intestines leakage. More preferably, the tissue leakage refers to a leakage of the digestive tract.

[0090] The medical kit comprises a combination comprising

[0091] - a collagen material and

[0092] - a cyanoacrylate component,

[0093] wherein the collagen material and cyanoacrylate component are spatially separated from each other.

[0094] In addition, the medical kit may comprise at least one further component, in particular instructions for use and / or a suture material.

[0095] With respect to further features and advantages of the medical kit, in particular with respect to the collagen material and cyanoacrylate component, reference is made in its entirety to the first aspect of the present invention. The features and advantages described under the first aspect of the present invention, in particular with respect to the collagen material and cyanoacrylate component, do apply, mutatis mutandis, with respect to the medical kit according to the second aspect of the invention.

[0096] According to a third aspect, the invention refers to a medical, in particular surgical, device, in particular for treating and / or preventing tissue leakage. The tissue leakage is in particular selected from the group consisting of skin leakage, liver leakage, spleen leakage, pancreas leakage, kidney leakage, lung leakage, adrenal gland leakage, stomach leakage, gall bladder leakage and intestines leakage such as small intestines leakage. More preferably, the tissue leakage refers to a leakage of the digestive tract.

[0097] The medical device comprises a combination comprising

[0098] - a collagen material and

[0099] - a cyanoacrylate component, P 62282 - 12 -

[0100] wherein the collagen material comprises the cyanoacrylate component and / or is equipped, in particular soaked, with the cyanoacrylate component.

[0101] With respect to further features and advantages of the collagen material and cyanoacrylate component, reference is made in its entirety to the first aspect of the invention. The features and advantages described under the first aspect of the invention, in particular with respect to the collagen material and cyanoacrylate component, do also apply, mutatis mutandis, with respect to the medical device according to the third aspect of the invention.

[0102] According to a fourth aspect, the invention refers to a medical, in particular surgical, kit for use in the treatment and / or prevention of tissue leakage. The tissue leakage is in particular selected from the group consisting of skin leakage, liver leakage, spleen leakage, pancreas leakage, kidney leakage, lung leakage, adrenal gland leakage, stomach leakage, gall bladder leakage and intestines leakage. More preferably, the tissue leakage refers to a leakage of the digestive tract.

[0103] The medical kit comprises a combination comprising

[0104] - a collagen material and

[0105] - a cyanoacrylate component,

[0106] wherein the collagen material and cyanoacrylate component are spatially separated from each other.

[0107] In addition, the medical kit may comprise at least one further component, in particular instructions for use and / or a suture material.

[0108] With respect to further features and advantages of the medical kit, in particular the collagen material and cyanoacrylate component, reference is made in its entirety to the first aspect of the invention. The features and advantages described under the first aspect of the invention, in particular with respect to the collagen material and cyanoacrylate component, do also apply, mutatis mutandis, with respect to the medical kit according to the fourth aspect of the invention.

[0109] According to a fifth aspect, the invention refers to a medical, in particular surgical, device for use in the treatment and / or prevention of tissue leakage. The tissue leakage is in particular selected from the group consisting of skin leakage, liver leakage, spleen leakage, pancreas leakage, kidney leakage, lung leakage, adrenal gland leakage, stomach leakage, gall bladder leakage and P 62282 - 13 -

[0110] intestines leakage such as small intestines leakage. More preferably, the tissue leakage refers to a leakage of the digestive tract.

[0111] The medical device comprises a combination comprising

[0112] - a collagen material and

[0113] - a cyanoacrylate component,

[0114] wherein the collagen material comprises the cyanoacrylate component and / or is equipped, in particular soaked, with the cyanoacrylate component.

[0115] With respect to further features and advantages of the medical device, in particular collagen material and cyanoacrylate component, reference is made in its entirety to the first aspect of the invention. The features and advantages described under the first aspect of the invention, in particular with respect to the collagen material and cyanoacrylate component, do also apply, mutatis mutandis, with respect to the device according to the fifth aspect of the invention.

[0116] According to a sixth aspect, the invention refers to a method for treating and / or preventing tissue leakage in a subject comprising the steps of

[0117] - equipping, in particular soaking, a collagen material with a cyanoacrylate component and

[0118] - applying the collagen material equipped with the cyanoacrylate component to the tissue leakage.

[0119] The subject is preferably a human subject. Alternatively, the subject may be an animal subject such as a horse, a cattle, a pig, a sheep, a goat, a dog, a cat or a rodent.

[0120] The tissue leakage is in particular selected from the group consisting of skin leakage, liver leakage, spleen leakage, pancreas leakage, kidney leakage, lung leakage, adrenal gland leakage, stomach leakage, gall bladder leakage and intestines leakage such as small intestines leakage. More preferably, the tissue leakage refers to a leakage of the digestive tract.

[0121] With respect to further features and advantages of the method, in particular collagen material and cyanoacrylate component, reference is made in its entirety to the first aspect of the invention. The features and advantages described under the first aspect of the invention, in particular with P 62282 - 14 -

[0122] respect to the collagen material and cyanoacrylate component, do also apply, mutatis mutandis, with respect to the method according to the sixth aspect of the invention.

[0123] Further features and advantages of the invention will become clear from the following description of preferred embodiments in form of examples in conjunction with the subject-matter of the dependent claims. The individual features can be realized either singularly or severally in combination in one embodiment of the invention. The preferred embodiments merely serve for illustration and better understanding of the invention and are not to be understood as in any way limiting the invention.

[0124] Example section

[0125] 1. Several in vitro testings were performed evaluating the inventive concept using completely different surfaces like meat, a rubber tube and sheep intestines. Using the rubber tube and sheep intestines filled with a colored solution allow the observation of the patch impermeability in function of time. Using meat as support allows the simulation of patch adherence on a moist surface.

[0126] 2. A pilot trial was performed using a published animal model with pigs to confirm the feasibility of the concept. An intestinal anastomosis was created using a stapler, in a second step a defect in the anastomotic line of 2 cm was created simulating an anastomotic dehiscence.

[0127] A collagen membrane was soaked in Histoacryl (n-butyl 2-cyanoacrylate monomers) for approximately 30 seconds (every site, in total approximately 60 seconds) in a petri dish and applied on the defect. The collagen membrane used is commercially available under the labelling Collagen Cell Carrier (CCC).

[0128] The combined medical device should also help to perform physiological remodeling of the tissue at the damaged site. It allows fibroblast migration, followed by subsequent native collagen deposition. After a follow-up of 7 days euthanasia took place, confirming the partial healing of the intestinal defect. The histological tissue examination revealed that tissue granulation took place during the healing phase (see fig. 1).

[0129] 3. A study was performed to assess the feasibility and safety of using collagen mesh combined with cyanoacrylate as an anatomical reinforcement method to prevent P 62282 - 15 -

[0130] anastomotic leakage in colorectal surgery. This was evaluated using an experimental pig model.

[0131] Characterization of the applied materials

[0132] A collagen mesh commercially available under the name Collagen Cell Carrier® (CCC) was applied. The CCC mesh comprises type I collagen fibers, isolated in their complex form, from bovine skin, represent a natural environment for adherent cells. They are thin (20 pm), translucent and biocompatible membranes, individually prepared under sterile conditions.

[0133] Histoacryl® is an n-butyl-cyanoacrylate-based tissue adhesive that is used to connect tissues in a wide range of procedures: in this case, for fixation of collagen meshes. It is histocompatible and bactericidal, and is fully absorbed by hydrolysis and decarboxylation.

[0134] Test item preparation

[0135] The CCC mesh and the n-butyl-cyanoacrylate-based tissue were combined in an operating room on the day of the test, at the time of use, and under sterile conditions. The procedure was the following:

[0136] Twelve vials of the n-butyl-cyanoacrylate-based tissue (each containing 0.5 mL of n-butyl-cyanoacrylate) were poured into a sterile petri dish. The CCC mesh was placed in the dish and soaked for approximately 60 seconds on each side, turning it with sterile tweezers. After letting any excess cyanoacrylate drip onto a gauze pad, the mesh was applied over the defect created in the anastomosis. Although the protocol contemplated customization of the mesh dimensions, it was not necessary in any case.

[0137] Surgical Procedure

[0138] Control group: Animals assigned to the control colorectal suture dehiscence group, to which a 21 mm hole was made in the colorectal anastomosis, left uncovered.

[0139] Experimental group: Animals assigned to the colorectal suture dehiscence group with reinforcement, to which a 21 mm hole was made in the colorectal P 62282 - 16 -

[0140] anastomosis, which was covered with the CCC mesh and n-butyl- cyanoacrylate.

[0141] Detailed steps of the surgical intervention:

[0142] 1. Median laparotomy skin incision with scalpel: opening of abdominal wall planes with electric scalpel.

[0143] 2. Preparation of a colorectal anastomosis site. Assessment of an avascular plane through transillumination of the mesocolon with the Rutilight. Transitory blockade of intestinal transit using a rubber piece from a sterile surgical glove.

[0144] 3. Creation of an anastomosis at approximately 15 cm from the anal margin, using a 25-mm or 29-mm circular stapler by inserting a transrectal head.

[0145] 4. Marking of an approximately 21-mm defect on the antimesenteric site of the anastomosis and creation of the 21-mm colorectal defect to all anastomoses with electrocoagulation.

[0146] 5. Checking the size of the defect with a 21-mm Hegar stem.

[0147] 6. Application of test item (CCC mesh plus n-butyl-cyanoacrylate) in the Experimental group.

[0148] 7. Closure by planes of the median laparotomy with Monosyn® 0 with continuous sutures.

[0149] Findings:

[0150] The feasibility and safety of the reinforcement method could be successfully demonstrated considering the following:

[0151] The test item placement was easy and quick, and no incidents occurred at the time of application in any of the animals used. P 62282 - 17 -

[0152] All anatomical reinforcements were placed correctly, covering each previous defect created.

[0153] The positive post-operative follow-up of the animals in the Experimental group confirms the safety of the method; there were no complications or adverse events that could be associated with the test item and no animal unexpectedly died.

[0154] A foreign body granuloma containing mesh debris was observed in all the subjects of the Experimental groups, being more evident in 90-day animals. It is considered to be part of the normal degradation of the mesh within the body.

[0155] Clinical and histopathological differences between the Control group (7-day) and Experimental group (7-day):

[0156] The alterations in the leukocyte formula detected, indicate a low level of infection in the first 2-3 days post-intervention, with a higher incidence in control animals than in experimental animals.

[0157] The post-operative follow-up of all animals showed no significant differences between groups.

[0158] At the end of the study, macroscopic findings at necropsies were more significant in animals in the Control group (laparotomy wound, free fluid, macroscopic tissue assessments, etc.) than in the Experimental group. The PAI (Peritoneal Adhesion Index) result was very similar between both groups.

[0159] Histopathologically, no significant differences were found in the microscopic observations in the intestinal anastomosis samples between the animals in Control group 7-day and Experimental group at 7-day.

[0160] The experimental group at 90-day was intended to validate the safety and long-term degradability of the test item. With the results of the Experimental group at 90-day the duration of the test product and its correct degradation (both macroscopically and microscopically) could be confirmed.

Claims

P 62282 - 18 -Claims1. A combination for treating and / or preventing tissue leakage, comprising- a collagen material and- a cyanoacrylate component.

2. The combination of claim 1 , characterized in that the collagen of the collagen material has a proportion of 50 % by weight to 70 % by weight, in particular 55 % by weight to 70 % by weight, preferably 60 % by weight to 70 % by weight, based on the total weight of the collagen material3. The combination according to claim 1 or 2, characterized in that the collagen material further comprises a fat, preferably a vegetable oil, in particular selected from the group consisting of soybean oil, grape seed oil, cocoa butter, olive oil, palm oil, rice bran oil, sunflower oil, corn oil, sesame oil, palm kernel oil, coconut oil, peanut oil, and mixtures of at least two of the afore-mentioned vegetable oils.

4. The combination according to 3, characterized in that the fat has a proportion of 1 % by weight to 7 % by weight, in particular 2 % by weight to 6 % by weight, preferably 3 % by weight to 5 % by weight, based on the total weight of the collagen material.

5. The combination according to any of the preceding claims, characterized in that the collagen material further comprises a polyol, in particular selected from the group consisting of glycerol, ethylene glycol, maltitol, sorbitol, xylitol, erythritol, isomalt, inositol, myoinositol, pinitol, mannitol, and mixtures of at least two of the aforementioned polyols.

6. The combination according to claim 5, characterized in that the polyol has a proportion of 10 % by weight to 35 % by weight, in particular 15 % by weight to 30 % by weight,P 62282 - 19 -preferably 20 % by weight to 25 % by weight, based on the total weight of the collagen material.

7. The combination according to any of the preceding claims, characterized in that the collagen material, by 100 % by weight, comprises or consists of the following:50 % by weight to 70 % by weight of collagen,1 % by weight to 7 % by weight of fat and10 % by weight to 35 % by weight of polyol.

8. The combination according to any of the preceding claims, characterized in that the collagen of the collagen material comprises native collagen.

9. The combination according to any of the preceding claims, characterized in that the collagen of the collagen material comprises a collagen selected from the group consistingP 62282 - 20 -of collagen type I, collagen type II, collagen type III; collagen type IV, collagen type V, recombinant collagen and mixtures of at least two of the aforementioned collagen types.

10. The combination according to any of the preceding claims, characterized in that the collagen of the collagen material is of xenogenic, in particular bovine, porcine, equine, ovine, or marine origin.

11. The combination according to any of the preceding claims, characterized in that the collagen of the collagen material comprises collagen type I, in particular native collagen type I, and stems from bovine skin.

12. The combination according to any of the preceding claims, characterized in that the collagen material has a pH value of 5 to 8, in particular 6 to 8, preferably 7 to 8.

13. The combination according to any of the preceding claims, characterized in that the collagen material has a weight per unit area of 16 g / m2to 150 g / m2, in particular 20 g / m2to 45 g / m2, preferably 20 g / m2to 40 g / m2.

14. The combination according to any of the preceding claims, characterized in that the collagen material has a tensile strength of 5 N / mm2to 25 N / mm2, in particular 5 N / mm2to 20 N / mm2, preferably 6 N / mm2to 15 N / mm2.

15. The combination according to any of the preceding claims, characterized in that the collagen material, in a dry condition, has a thickness of 5 pm to 200 pm, in particular 10 pm to 30 pm, preferably 15 pm to 25 pm.

16. The combination according to any of the preceding claims, characterized in that the collagen material comprises a membranous structure.

17. The combination according to any of the preceding claims, characterized in that the collagen material is in the form of a surgical implant, in particular a surgical mesh.

18. The combination according to any of the preceding claims, characterized in that the cyanoacrylate component includes cyanoacrylate monomers represented by the formula ICH2= CH(CN)-COOR (formula I)P 62282 - 21 -wherein R is an alkyl, alkoxyalkyl, cycloalkyl, alkenyl, aralkyl, aryl, allyl or haloalkyl group.

19. The combination according to any of the preceding claims, characterized in that the cyanoacrylate component includes alkyl 2-cyanoacrylate monomers, in particular selected from the group consisting of methyl 2-cyanoacrylate monomers, ethyl 2-cyanoacrylate monomers, n-propyl 2-cyanoacrylate monomers, isopropyl 2-cyanoacrylate monomers, n- butyl 2-cyanoacrylate monomers, isobutyl 2-cyanoacrylate monomers such as, for example, 1 -butyl 2-cyanoacrylate monomers and / or 2-butyl 2-cyanoacrylate monomers, n-pentyl 2-cyanoacrylate monomers, isopentyl 2-cyanoacrylate monomers such as, for example, 1 -pentyl 2-cyanoacrylate monomers, 2-pentyl 2-cyanoacrylate monomers and / or 3-pentyl 2-cyanoacrylate monomers, cyclopentyl 2-cyanoacrylate monomers, n-hexyl 2- cyanoacrylate monomers, isohexyl 2-cyanoacrylate monomers such as, for example, 1- hexyl 2-cyanoacrylate monomers, 2-hexyl 2-cyanoacrylate monomers, 3-hexyl 2- cyanoacrylate monomers and / or 4-hexyl 2-cyanoacrylate monomers, cyclohexyl 2- cyanoacrylate monomers, n-heptyl 2-cyanoacrylate monomers, isoheptyl 2-cyanoacrylate monomers such as, for example, 1 -heptyl 2-cyanoacrylate monomers, 2-heptyl 2- cyanoacrylate monomers, 3-heptyl 2-cyanoacrylate monomers and / or 4-heptyl 2- cyanoacrylate monomers, n-octyl 2-cyanoacrylate monomers, isooctyl 2-cyanoacrylate monomers such as, for example, 1 -octyl 2-cyanoacrylate monomers, 2-octyl 2- cyanoacrylate monomers, 3-octyl 2-cyanoacrylate monomers and / or 4-octyl 2- cyanoacrylate monomers, n-nonyl 2-cyanoacrylate monomers, isononyl 2-cyanoacrylate monomers, n-decyl 2-cyanoacrylate monomers, isodecyl 2-cyanoacrylate monomers, n- undecyl 2-cyanoacrylate monomers, isoundecyl 2-cyanoacrylate monomers, n-dodecyl 2- cyanoacrylate monomers, isododecyl 2-cyanoacrylate monomers and mixtures of at least two of the aforementioned alkyl 2-cyanoacrylate monomers.

20. The combination according to any of the preceding claims for use in the treatment and / or prevention of tissue leakage, in particular leakage from intestinal wounds and / or anastomotic leakage, in particular in colorectal surgery.

21. Medical kit for treating and / or preventing tissue leakage, comprising a combination according to any of the preceding claims.

22. Medical device for treating and / or preventing tissue leakage, comprising a combination according to any of the claims 1 to 20.

Images