Medical material for wound sealing with a removable intermediate separation layer

Abstract

The present invention relates to a medical device having a first porous substrate layer having at least a surface coating of a first co-reactive component thereon, a second substrate layer having at least a surface coating layer of a second co-reactive component that reacts with the first co-reactive component, and a removable barrier layer positioned between the first and second substrate layers and in contact with the first and second substrate layers.

Description

Background Art

[0001] Absorbent hemostatic patches containing two crosslinkable components are described in documents including US Patent Application Publication No. 2011 / 0045047A1. Such crosslinkable components for patches can be pairs of co-reactive compounds or substrates coated with co-reactive compounds having available units capable of forming covalent crosslinks with corresponding co-reactive groups on the substrate. The main limitation of such patents is that the co-reactive components can react in an aqueous / wet environment, which can reduce patch efficacy over time. One approach to overcome this problem was to process and package the co-reactive-containing patches under low moisture conditions. Another approach was to create some space or gap between the co-reactive layers by applying a coating on the opposing side of the trauma pharmaceutical material or by placing a film barrier layer between the co-reactive components.

[0002] The Applicants have identified an alternative method of placing an inert and removable separator barrier layer between the co-reactive components to function as an impermeable and chemically inert physical barrier to prevent interaction. Such a separator layer can also function as a desiccant to remove moisture from the environment in the immediate vicinity of the trauma pharmaceutical material. The separation layer can be removed in a way that does not change the patch configuration and does not require additional procedural steps by the user. In this method, each of the two coated layers can be separated by the primary package material (without additional barriers within the system) in a way that when the device is removed from the package, the barrier (part of the package) is removed from the layer, allowing their proximity prior to application of the device. The Applicants have also identified a way for the two layers to be positioned flat within the primary package while being connected along one of their edges (e.g., as a visible one) and separated from each other.

Brief Description of the Drawings

[0003] [Figure 1a] One embodiment of the present invention is shown in which a single substrate is separately coated onto two halves, folded at their boundary, and a removable barrier layer or film placed in between can be used to physically separate the two coreactive layers, or optionally, can be stored open without the barrier layer. [Figure 1b] One embodiment of the present invention is shown in which a single substrate is separately coated onto two halves, folded at their boundary, and a removable barrier layer or film placed in between can be used to physically separate the two coreactive layers, or optionally, can be stored open without the barrier layer. [Figure 2] One embodiment of the present invention is shown in which two separate substrate layers are physically separated by a removable barrier layer or film placed in between. [Figure 3a] One embodiment of the present invention is shown in which two separate substrate layers are coated separately, joined by hinges, and a removable barrier layer or film placed in between can be used to physically separate the two coreactive layers, or optionally, can be stored open without the barrier layer. [Figure 3b] One embodiment of the present invention is shown in which two separate substrate layers are coated separately, joined by hinges, and a removable barrier layer or film placed in between can be used to physically separate the two coreactive layers, or optionally, can be stored open without the barrier layer. [Figure 4] One embodiment of the present invention is shown in which two separate substrate layers are joined at a specific "welding" point, and a removable barrier layer or film placed in between is used to physically separate the two layers. [Figure 5] One embodiment of the present invention is described in which two separate substrate layers are joined at a specific "welding" point, a removable barrier layer or film placed in between is used to physically separate the two layers, and the separating layer is fixed or integrated with the device package so that removal of the device from the package ensures the removal of the barrier layer. [Figure 6a] A barrier layer and an embodiment of the present invention are shown, wherein the barrier layer has holes and cuts along its surface, thereby allowing sublayers to be connected to each other to enhance structural integrity. [Figure 6b] A barrier layer and an embodiment of the present invention are shown, wherein the barrier layer has holes and cuts along its surface, thereby allowing sublayers to be connected to each other to enhance structural integrity. [Overview of the project] [Means for solving the problem]

[0004] In one embodiment, the present invention relates to a medical device comprising: a first porous substrate layer having at least one main opposing surface having at least a surface coating of a first co-reactive component; a second porous substrate layer having at least one main opposing surface having at least a surface coating of a second co-reactive component that reacts with the first co-reactive component; and a removable barrier layer disposed between the first substrate layer and the second substrate layer, in contact with at least one main opposing surface or surface coating, each independent of the first and second substrate layers. The first substrate layer may be a porous nonwoven mesh composed of one or more synthetic polymers or copolymers, cellulosic materials, and blends thereof. The second substrate layer is a porous nonwoven mesh composed of one or more synthetic polymers or copolymers, cellulosic materials, and blends thereof. The second substrate layer may optionally be a non-porous film applied to the upper opposing surface of the second substrate layer.

[0005] In one embodiment, at least one main surface of the first substrate layer may be coated with a nucleophilic group-containing compound as a first co-reactive component. Alternatively, at least one main surface of the second substrate layer may be coated with an electrophilic group-containing compound as a second co-reactive component. Alternatively, at least one main surface of the substrate layer may be coated PEG-NHS, which may be coated on the tissue-facing surface. Furthermore, the PEG-NHS-containing substrate may be coated on both sides, but the PEG-amine component may be coated on only one side of the opposing porous substrate layer (sublayer).

[0006] In another embodiment, the second co-reactive component may further include an activator for the first co-reactive component, the activator being selected from the group consisting of enzymes, buffers, carbodiimides, catalysts, and combinations thereof.

[0007] In one embodiment, the first base layer, the second base layer, and the barrier layer may be assembled in a sandwich configuration with at least three layers stacked on top of each other. Furthermore, in any embodiment, the first base layer and the second base layer may be maintained in a common relative position by a plurality of connection points or welds.

[0008] In one embodiment, the first and second base material layers may be formed by folding a common base material along a hinge.

[0009] In one embodiment, the first and second substrate layers have peripheral edge regions, and the plurality of connection points or welds are provided at separate points along at least one peripheral edge region on each of the first and second substrate layers. At least the plurality of connection points or welds may be provided penetrating the inert film along the axes of the first and second substrate layers. The barrier layer may have one or more slits corresponding to the plurality of connection points or welds, at least along its length, which allow the inert film to be removed from between the first and second substrate layers by pulling without having to tear the barrier layer.

[0010] In one embodiment, at least one periphery of the barrier layer may extend beyond the periphery of at least one of the first and second substrate layers. Furthermore, the device may further comprise one or more package components, the barrier layer being attached to the package and removed when the medical device is separated from the associated one or more package components. At least one of the package components may be a housing compartment having two spatially separated compartments for the first and second substrate layers. The housing compartment may be formed as a single compartment for holding the first and second substrate layers.

[0011] In one embodiment, the present invention relates to a method for achieving hemostasis on a bleeding site, comprising applying the device described herein to the bleeding tissue site. Alternatively, a PEG-NHS coated substrate may be applied directly to the bleeding tissue site.

[0012] In one embodiment, the present invention relates to a method for sealing tissue, which includes applying the device described herein to a damaged tissue site. In another method, a PEG-NHS coated substrate may be applied directly to the damaged tissue site. [Modes for carrying out the invention]

[0013] The traumatic medical material 100 of the present invention comprises a medical device having a substrate structure of at least two fibrous and / or porous sublayers 102 and 104 containing co-reactive crosslinkable components. A further non-porous outer layer (not shown) (e.g., a continuous film) may be applied to the surface of the medical device, which is intended to face away from the tissue surface, for multiple purposes, e.g., to provide lateral features that enable appropriate directional arrangement or to provide a barrier layer that retains and redirects fluids passing through the medical device.

[0014] Each sublayer 102, 104 has a main opposing surface, one or more peripheral regions, and one or more side depth regions. The number of peripheral regions and side depth regions depends on the shape of the medical device.

[0015] Furthermore, each sublayer 102, 104 is provided at least as a surface coating, more preferably as a coating of a surface-reactive crosslinkable component extending to all or part of the depth of the sublayer. These reactive component coatings are physically separated from each other by a removable barrier layer or the like placed in between. The medical device or trauma pharmaceutical material 100 may consist of a single substrate structure (e.g., matrix) material that is differently coated on two subcompartments, preferably about half, so as to fold along a boundary 108 between two active materials, as shown in Figure 1b, and produce a trauma pharmaceutical material 100 with stacked sublayers 102 and 104 separated by a removable layer 106, as shown in Figure 1a. In another embodiment, the substrate structure may have at least two distinct, separated, coreactive-containing sublayers 102, 104 having a removable barrier layer 106 placed in between, as shown in Figure 2.

[0016] Sublayers 102 and 104 may be structurally integrated with each other via ultrasonic welding, needle punching, thermal welding, chemical bonding, or suture attachment, as indicated by welding point 108 in Figure 4, thereby maintaining relative positional stability by each layer, otherwise being physically separate and isolated. The medical device 100 may be configured as a double structure having two hinges 110 between coated sublayers 102 and 104 with a removable separator barrier layer 106 positioned in between, as shown in Figures 3a and 3b. In an alternative embodiment, the base structure may have at least two separate, isolated, coreactive sublayers 102 and 104 structurally integrated at a specific point 108, and have a removable barrier layer 106 positioned in between, as shown in Figure 4 or 5, where the barrier layer 106 is integrated with the device's secondary package 112.

[0017] The co-reactive carrier layer of the substrate structure may be in the form of a woven fabric, nonwoven fabric, or porous sponge material. Exemplary structural materials include cellulose-based materials, synthetic polymers, gelatin, collagen, and extracellular matrix. The substrate may consist of components selected from gelatin, collagen, oxidized polysaccharides, aliphatic polyester polymers, and / or copolymers of one or more monomers selected from the group consisting of D-lactic acid, L-lactic acid, lactide (including L-, D-, and meso forms), glycolic acid, glycolide, caprolactone, p-dioxanone, and trimethylene carbonate, and mixtures or blends thereof. Degradable polyurethanes prepared using (but not limited to) diisocyanates (e.g., 2,6-diisocyanate ethyl hexanoate (ELDI) and 2,6-diisocyanate methyl hexanoate (MLDI)) together with degradable aliphatic polyester diols and degradable chain extenders (e.g., 2-hydroxyethyl-2-hydroxypropanoate, 4-((1-(1-amino-2-phenylethoxy)ethoxy)methylcyclohexyl)methyl-2-amino-3-phenylpropanoate, 1,1-(hexane-1,6-diyl)bis(3-(2-hydroxyethylurea, ethane-1,2-diylbis(3-(4-hydroxyphenyl)propanoate, bis(2-hydroxyethyl)phosphate, and bis(2-hydroxyhexyl)phosphate)) may also be suitable for the production of substrates.

[0018] In one form, the substrate structure can consist of a layer of an oxidized polysaccharide, particularly oxidized cellulose and neutralized derivatives thereof. For example, the cellulose can be carboxyl-oxidized cellulose or aldehyde-oxidized cellulose. In one form, an oxidized regenerated polysaccharide including but not limited to oxidized regenerated cellulose may be used. Regenerated cellulose has a higher uniformity compared to non-regenerated cellulose. Detailed descriptions of regenerated cellulose and methods for making oxidized regenerated cellulose are described in U.S. Patent Nos. 3,364,200, 5,180,398, and 4,626,253, the contents of which are incorporated herein by reference as if fully set forth herein. Examples of fabrics that can be utilized include, but are not limited to, Interceed absorbent adhesion barriers, Surgicel® absorbent hemostats, Surgicel® Nu-Knit absorbent hemostats, and Surgicel® fibrous absorbent hemostats (each available from Ethicon, Somerville, NJ). U.S. Patent No. 5,007,916 discloses the aforementioned Interceed absorbent adhesion barrier and methods for making the same, the contents of which are incorporated herein by reference for all that they disclose.

[0019] The substrate can alternatively or additionally consist of a layer of a fabric of an aliphatic polyester polymer, copolymer, or blend thereof. Aliphatic polyesters are typically synthesized in the ring-opening polymerization of monomers including but not limited to lactide (L- and D-, including the meso form), glycolic acid, glycolide, caprolactone, p-dioxanone (1,4-dioxane-2-one), and trimethylene carbonate (1,3-dioxane-2-one). Aliphatic polyesters can in some cases be made, for example, by polycondensation of D-lactic acid, L-lactic acid, and / or glycolic acid. In one form, the fabric contains a copolymer of glycolide and lactide in an amount in the range of about 70 - 95% on a molar basis of glycolide and the remaining lactide.

[0020] The substrate structure may also include an oxidized regenerated cellulose / polypropylene / polydioxanone (PDS) mesh commercially available under the trademark Proceed from Ethicon, Inc. U.S. Patent Publications Nos. 2005 / 0113849 A1 and 2008 / 0071300 A1 disclose the aforementioned Proceed oxidized regenerated cellulose / polypropylene / PDS mesh substrate and methods for making the same, the contents of which are incorporated herein by reference in their entirety. In one form, both outer surfaces of the oxidized regenerated cellulose / polypropylene / PDS mesh may be substantially coated with a polymer coating, and in another form, only one outer surface of the substrate may be substantially coated with a polymer coating. The cloth used to form the substrate may include an aliphatic polyester polymer, copolymer, or blend thereof alone or in combination with oxidized polysaccharide fibers.

[0021] In one embodiment, the substrate is made of a layer of a biomaterial, preferably a protein, biopolymer, or polysaccharide matrix, particularly selected from the group consisting of a collagen, gelatin, fibrin, starch, or chitosan matrix. Preferably, the matrix of the present invention is biodegradable, i.e., after a period of time, it is naturally absorbed by the patient's body. In any case, the material (including the matrix) must be biocompatible, i.e., the material does not affect the patient to whom it is administered. Such biodegradable materials are particularly suitable in situations where hemostasis is achieved in the body, i.e., during the surgical procedure, and the site is closed after surgery.

[0022] Therefore, in one embodiment, one or more sublayers of the substrate structure are preferably biomaterials selected from biopolymers such as proteins or polysaccharides. Particularly preferably are biomaterials selected from the group consisting of collagen, gelatin, fibrin, polysaccharides, e.g., hyaluronic acid, chitosan, and derivatives thereof, more preferably gelatin, collagen, and chitosan, and especially preferably gelatin and collagen. Such gelatin or collagen matrix used in the present invention may be any collagen-derived material suitable for forming a gel, including porous matrix or fibrous matrix, and materials from liquid, paste, fibrous or powdered collagen materials that can be processed into particles. Preparation of a collagen gel for the manufacture of a sponge or sheet may include acidification until gel formation occurs and subsequent pH neutralization. To improve gel-forming ability or solubility, collagen may be (partially) hydrolyzed or modified, as long as the property of forming a stable sponge or sheet when dry is not reduced. The matrix used to couple the thrombin receptor activator may be a biopolymer, i.e., a naturally occurring polymer or its derivative, or a synthetic polymer. Examples of biopolymers useful in hemostatic materials according to the present invention include polypeptides such as collagen, collagen derivatives such as gelatin, elastin, and elastin derivatives.

[0023] Embodiments containing collagen according to this disclosure include a porous substrate having a first co-reactive and / or crosslinkable component applied to a first portion of the porous substrate, and a second co-reactive and / or crosslinkable component applied to a second portion of the porous substrate. Although the different components do not crosslink with each other, one component coated on one layer may activate and strengthen other components coated on separate layers, resulting in hemostasis upon application.

[0024] Porous substrates for traumatic medical materials have openings or pores over at least a portion of their surface. Suitable materials for forming porous substrates include, but are not limited to, fibrous structures (e.g., braided structures, woven structures, nonwoven structures, etc.) and / or foams (e.g., open-cell foams or closed-cell foams), as will be described in more detail below. In some embodiments, the pores may be numerous and of sufficient size to interconnect over the entire thickness of the porous substrate. Woven fabrics, braided fabrics, and open-cell foams are exemplary examples of structures in which the pores may be numerous and of sufficient size to interconnect over the entire thickness of the porous substrate. In some embodiments, the pores do not interconnect over the entire thickness of the porous substrate. Closed-cell foams or fused nonwoven materials are exemplary examples of structures in which the pores do not need to interconnect over the entire thickness of the porous substrate. The pores of a foamed porous substrate may extend over the entire thickness of the porous substrate. In yet other embodiments, the pores do not extend over the entire thickness of the porous substrate, but rather are present in only a portion of its thickness. In some embodiments, the openings or pores are located on a portion of the surface of the porous substrate, while the rest of the porous substrate has a non-porous texture.

[0025] When the porous substrate or its sublayer is fibrous, the porous substrate or sublayer may be formed using any method suitable for forming a fibrous structure, including but not limited to braiding, weaving, nonwoven fabric technology, wet spinning, electrospinning, extrusion, co-extrusion, etc. Suitable techniques for producing fibrous structures are within the scope of those skilled in the art. In some embodiments, the fabric has a three-dimensional structure, such as the fabrics described in U.S. Patents No. 7,021,086 and No. 6,443,964, and these disclosures are incorporated herein in their entirety.

[0026] In embodiments, the porous substrate or its sublayer is made from oxidized cellulose fibers. Such materials are well known, including oxidized cellulose hemostatic materials commercially available under the trademark name SURGICEL®. Methods for preparing oxidized cellulose hemostatic materials are well known to those skilled in the art and are disclosed, for example, in U.S. Patents 3,364,200, 4,626,253, 5,484,913, and 6,500,777, which are incorporated herein by reference in their entirety.

[0027] If the porous substrate or sublayer is a foam, the porous substrate or sublayer may be formed using any method suitable for forming a foam or sponge, including but not limited to lyophilization or freeze-drying of the composition. The foam may be crosslinkable or non-crosslinkable, and may contain covalent or ionic bonds. Suitable techniques for producing the foam are within the scope of those skilled in the art.

[0028] One or more sublayers of the porous substrate may be at least 0.1 cm thick, and in certain embodiments, may be about 0.2 to about 1.5 cm thick. The size of the pores in the sublayers of the porous substrate may be about 2 micrometers to about 300 micrometers, and in certain embodiments, may be about 50 micrometers to about 150 micrometers. It is assumed that the pores of the sublayers of the substrate may be arranged in any manner within the substrate. For example, the pores may be arranged in a random or uniform manner. In some embodiments, copper alginate may be used to form the pores and create a honeycomb-shaped porous substrate. In yet other embodiments, the pores may be configured to create a gradient in the porous substrate. The gradient can further enhance the ability of the porous substrate to absorb physiological fluids and direct the movement of physiological fluids carrying a first co-reactive component toward a second co-reactive component.

[0029] In embodiments, the traumatic medicinal material and its base structure are made from undenatured collagen, mainly consisting of non-hydrolyzed α-chains with a molecular weight of approximately 100 kDa, or collagen in which its helical structure is at least partially lost by heating or any other method. The term “undenatured collagen” means collagen in which its helical structure is not lost. The collagen used in the traumatic medicinal materials herein may be natural collagen or, in particular, atelocollagen obtained by pepsin digestion and / or after moderate heating as defined above. The collagen may be pre-chemically modified by oxidation, methylation, ethylation, succinylation, or any other well-known process. The collagen may also be crosslinked with any suitable crosslinking agent such as genipin, isocyanates, and aldehydes. The origin and type of collagen may be as shown above for the non-traumatic medicinal materials.

[0030] In other embodiments, gelatin or collagen (including any collagen described herein) may be used as one of the precursors. As described in more detail below, amine groups on the collagen precursor (which are nucleophilic) may freely react with electrophilic groups on the first co-reactive component to form the substrate of the present disclosure.

[0031] In embodiments, the substrate or its porous collagen layer can be obtained by freeze-drying an acidic aqueous solution of collagen at a concentration of 2 to 50 grams / liter (g / l) and an initial temperature of 4 to 25°C. The concentration of collagen in the solution may be about 1 g / l to about 30 g / l, and in embodiments, about 10 g / l. The solution is advantageously neutralized to a pH of about 6 to 8. Traumatizing medicinal materials can also be prepared from a solution of collagen or heated collagen and obtained by freeze-drying a fluid foam emulsified in the presence of a variable volume of air (the air-to-water volume varies from about 1 to about 10).

[0032] In one embodiment, the substrate structure comprises a first co-reactive component applied to a first sublayer and a second co-reactive component applied thereto. The terms "first co-reactive component" and "second co-reactive component" refer to polymers, functional polymers, macromolecules, small molecules, or crosslinking agents, respectively, that can participate in reactions that form a network of crosslinked molecules such as hydrogels.

[0033] In one embodiment, each of the first and second coreactive components is polyfunctional, meaning that it contains two or more electrophilic or nucleophilic functional groups, for example, a nucleophilic functional group on the first coreactive component may react with an electrophilic functional group on the second coreactive component to form a covalent bond. At least one of the first or second coreactive components contains three or more functional groups, such that precursors combine to form a crosslinked polymer product as a result of an electrophilic-nucleophilic reaction. Such a reaction is referred to as a "crosslinking reaction".

[0034] In certain embodiments, each of the first and second co-reactive components contains only one category of functional groups, either nucleophilic groups only or electrophilic functional groups only, insofar as both the nucleophilic and electrophilic precursors are used in the crosslinking reaction. For example, if the first co-reactive component has a nucleophilic functional group such as an amine, the second co-reactive component may have an electrophilic functional group such as N-hydroxysuccinimide (NHS). On the other hand, if the first co-reactive component has an electrophilic functional group such as sulfosuccinimide, the second co-reactive component may have a nucleophilic functional group such as an amine or thiol. Therefore, functional polymers such as proteins, poly(allylamine), sulfhydryl (or thiol)-terminated PEG, or amine-terminated di- or polyfunctional poly(ethylene glycol) (PEG) can be used.

[0035] The first and second co-reactive components may have a biologically inert and water-soluble core. When the core is a water-soluble polymer region, preferred polymers that may be used include polyethers, polyalkylene oxides such as polyethylene glycol ("PEG"), polyethylene oxide ("PEO"), polyethylene oxide-co-polypropylene oxide ("PPO"), co-polyethylene oxide blocks or random copolymers, and polyvinyl alcohol ("PVA"), poly(vinylpyrrolidinone) ("PVP"), poly(amino acids), poly(saccharides) such as dextran, chitosan, alginic acid, carboxymethylcellulose, oxidized cellulose, hydroxyethylcellulose, hydroxymethylcellulose, and hyaluronic acid, and proteins such as albumin, collagen, casein, and gelatin. Polyethers, more specifically poly(oxyalkylene) or poly(ethylene glycol), or polyethylene glycol are particularly useful. If the core is essentially a low molecular weight, the first and second co-reactive components can be made water-soluble by using any of the various hydrophilic functionalities. For example, the precursor may be made water-soluble by using water-soluble functional groups such as hydroxyl, amine, sulfonic acid, and carboxylic acid. Although the N-hydroxysuccinimide ("NHS") ester of subaric acid is insoluble in water, the NHS ester of subaric acid can be made water-soluble without affecting its reactivity to the amine group by adding a sulfonate group to the succinimide ring.

[0036] In embodiments, both the first and second co-reactive components may be large molecules that can be crosslinked. For example, in embodiments, one of the precursors may be a polyfunctional PEG having a molecular weight of about 2,000 to about 20,000 daltons. In embodiments having electrophilic groups, this polyfunctional PEG may react with collagen having a molecular weight of about 100,000 daltons. In other embodiments, gelatin having a molecular weight of about 50,000 to about 100,000 daltons may be used instead of collagen.

[0037] If it is desirable that the biocompatible crosslinked polymer resulting from the reaction of a first co-reactive component and a second co-reactive component be biodegradable or absorbable, one or more of the first and second co-reactive components may have a biodegradable bond present between their functional groups. The biodegradable bond may also optionally function as a water-soluble core of one or more precursors. Alternatively, or in addition, the functional groups of the first and second co-reactive components may be selected such that the product of their reaction yields a biodegradable bond. In each approach, the biodegradable bond may be selected such that the resulting biodegradable biocompatible crosslinked polymer degrades, dissolves, or is absorbed within a desired period. Preferably, a biodegradable bond that degrades to a non-toxic product under physiological conditions is selected.

[0038] The biodegradable bond may be chelate, or chemically or enzymatically hydrolyzable or absorbable. Exemplary chemically hydrolyzable biodegradable bonds include polymers, copolymers, and oligomers of glycosides, d-lactide, lactide, caprolactone, dioxanone, and trimethylene carbonate. Exemplary enzymatically hydrolyzable biodegradable bonds include peptide bonds cleavable by metalloproteinases and collagenases. Further exemplary biodegradable bonds include polymers and copolymers of poly(hydroxy acids), poly(orthocarbonates), poly(anhydrides), poly(lactones), poly(amino acids), poly(carbonates), poly(saccharides), and poly(phosphonates), and similarly biodegradable polyurethanes. In embodiments, the biodegradable bond may include ester bonds. Some non-limiting examples include esters of succinic acid, glutaric acid, propionic acid, adipic acid, or amino acids, and carboxymethyl esters.

[0039] In some embodiments, a polyfunctional electrophilic polymer, such as multi-armed PEG functionalized with multiple NHS groups, may be used as a first co-reactive component, and a polyfunctional nucleophilic component, such as trilysine, may be used as a second co-reactive component. In other embodiments, a polyfunctional electrophilic polymer, such as multi-armed PEG functionalized with multiple NHS groups, may be used as a first co-reactive component, and a polyfunctional nucleophilic polymer, such as collagen and / or collagen derivatives, may be used as a second co-reactive component. Multi-armed PEG functionalized with multiple NHS groups may have, for example, four, six, or eight arms and may have a molecular weight of about 5,000 to about 25,000. Many other examples of preferred first and second precursors are described in U.S. Patents 6,152,943, 6,165,201, 6,179,862, 6,514,534, 6,566,406, 6,605,294, 6,673,093, 6,703,047, 6,818,018, 7,009,034, and 7,347,850, the entire contents of each of these are incorporated herein by reference.

[0040] Referring to Figure 1, the first co-reactive component may be applied to the first portion 102 of the porous substrate, and the second co-reactive component may be applied to the second portion 104 of the porous substrate. For example, the precursor may be applied in a dry form such as particulate matter, or in a solid or semi-solid state such as a film or foam. In the embodiment, at least one of the first co-reactive component or the second co-reactive component is coated onto the porous substrate as a film. The first co-reactive component may be applied to the porous substrate using any preferred method well known to those skilled in the art, including but not limited to spraying, brushing, dipping, injection, lamination, etc. In the embodiment, the first co-reactive component may be applied as a coating on the substrate at any concentration, size, and composition that can form a hemostatic or traumatic medical material.

[0041] In certain embodiments, the first co-reactive component coating may penetrate into the pores of a porous substrate structure. The coating may form a non-porous or porous layer. In certain embodiments, the first co-reactive component may be applied as a laminated film on at least one side of the substrate.

[0042] Similarly, the second co-reactive component may be applied to the porous substrate using any suitable method well known to those skilled in the art, including but not limited to spraying, brushing, dipping, injection, lamination, etc.

[0043] In some embodiments, the second co-reactive component may be incorporated into the porous substrate before its formation. In other embodiments, the second co-reactive component may be positioned within the pores of the porous substrate or on the surface of the porous substrate after its formation. In yet another embodiment, the porous substrate may be rolled before the application of the second co-reactive component, thereby allowing the second precursor to penetrate into openings on the substrate created by the rolling process. In yet another embodiment, the second co-reactive component may be applied to the porous substrate in solution, followed by evaporation or freeze-drying of the solvent. In certain embodiments, the second co-reactive component may be applied to the porous substrate as a coating on at least one side of the substrate, or as a laminated film on at least one side of the substrate.

[0044] It should be understood that, as an alternative to foamed collagen or gelatin, the porous substrate structure or its sublayer may be a fibrous structure. Therefore, in embodiments, the porous substrate or sublayer may be a fibrous structure, i.e., a woven or nonwoven fabric structure. The first and second co-reactive components can be applied to a fibrous porous substrate structure or a portion thereof using substantially the same techniques as those described above with respect to the foamed porous substrate. Therefore, similar to the foamed porous substrate described above in which the porous substrate or sublayer is fibrous, the first and / or second co-reactive components may be applied, for example, as particles deposited from a solution, as a non-porous film formed by drying a film-forming solution, or as a foam applied to at least a portion of a fibrous porous substrate.

[0045] The barrier layer is non-porous and inert to or has pore sizes that inhibit the passage of co-reactive components, such as those provided on each sublayer, thereby preventing interaction between materials in different layers. The barrier may be or contain a desiccant by appropriate selection of materials that reduce moisture levels within the medical device to improve shelf life. The barrier layer 106 prevents adhesion of sublayers 102 and 104. In some embodiments, such as those illustrated in Figure 5, the barrier layer 106 may be formed as part of or integrated with the primary or secondary package for the medical device. The barrier layer 106 is generally a flat film layer, but may be textured to provide some additional space and spacing between the coated sublayers.

[0046] The barrier layer 106 may be positioned between the sublayers 102 and 104 such that the barrier layer 106 extends beyond the periphery of at least one of the coated sublayers 102 and 104, and so that the user can grasp and remove the barrier layer 106 before use. In the integrated package embodiment of Figure 5, the barrier layer 106 may be attached to at least a portion of the package material 112 such that when the device 100 is removed from the package 112, the barrier layer 106 is removed in the same motion from between the coated sublayers 102 and 104. The barrier layer 106 may have holes 114 and cuts 116 along its surface to connect the sublayers 102 and 104 to each other to obtain greater structural integrity. As shown in Figure 6, such holes 114 and cuts 116 at selected points along the peripheral region of the barrier layer 106 are designed so that the barrier layer 106 can be easily removed from between the sublayers 102 and 104 by tensile force. In another embodiment, slits and optionally openings may be provided along at least a portion of the axis of the barrier layer to allow interconnection in the space other than the peripheral region of the sublayers.

[0047] Upon removal of the barrier layer 106 and subsequent contact with tissue, the physiological fluid penetrates and moves through the traumatic medicinal material, interacting with co-reactive components on the different sublayers 102 and 104. As the fluid is carried toward the first portion 102, it is assumed that the solution comes into contact with the second co-reactive component, is dissolved by the physiological fluid, and mixes with it. This mixing will activate the first and second precursors, allowing them to interact and / or crosslink to form a sealing portion that assists in the sealing and hemostatic functions of the traumatic medicinal material 100. If one of the components is an activator for the other components, the physiological fluid may enable the activation of the components, resulting in sealing or hemostasis when the components come into contact with tissue or physiological fluid. In certain embodiments, this newly formed hydrogel / physiological fluid traumatic medicinal material may also act as an adhesion barrier.

[0048] In one embodiment, one or more sublayers 102 or 104 include a nonwoven fabric and a reinforcing fabric. The reinforcing fabric provides a backing to which the nonwoven fabric can be directly or indirectly attached. The nonwoven fabric functions as the first absorbent nonwoven fabric of the reinforced absorbent multilayer fabric described herein. The first absorbent nonwoven fabric consists of fibers comprising an aliphatic polyester polymer, copolymer, or blend thereof. The aliphatic polyester is typically synthesized by ring-opening polymerization of monomers including, but not limited to, lactic acid, lactide (including L-, D-, mesoform, and D,L mixtures), glycolic acid, glycolide, ε-caprolactone, p-dioxanone (1,4-dioxan-2-one), and trimethylene carbonate (1,3-dioxan-2-one). Preferably, the first absorbent nonwoven fabric contains a copolymer of glycolide and lactide in an amount ranging from about 70 to 95% on a molar basis of glycolide and the remaining lactide.

[0049] In alternative embodiments, the first absorbent nonwoven fabric comprises fibers consisting of aliphatic polyester polymers, copolymers, or blends thereof, in combination with oxidized polysaccharide fibers. Preferably, the nonwoven fabric is produced by a process other than spinning, weaving, or braiding. For example, the nonwoven fabric may be prepared from yarns, scrims, nets, or filaments produced by a process including spinning, weaving, or braiding. The yarns, scrims, nets, and / or filaments are crimped to enhance their entanglement with each other and adhesion to the second absorbent woven or knitted fabric. Such crimped yarns, scrims, nets, and / or filaments may then be cut into staples of sufficient length to entangle. The staples may be about 0.1 to 3.0 inches in length, preferably about 0.75 to 2.5 inches, and most preferably about 1.5 to 2.0 inches. The staples may be carded to produce a nonwoven vat, which may then be needle-punched or calendered to produce the first absorbent nonwoven fabric. The staples may be twisted or stacked.

[0050] The thickness of the sublayer of the nonwoven fabric may be in the range of approximately 0.25 to 2 mm. The basis weight of the nonwoven fabric is approximately 0.01 to 0.2 g / in. 2Preferably about 0.03 to 0.1 g / in 2 Most preferably about 0.04-0.08 g / in 2 The weight percentage of the first absorbent nonwoven fabric may be in the range of approximately 10-80%, based on the total weight of the reinforced absorbent multilayer fabric.

[0051] The second absorbent woven or knitted fabric functions as a reinforcing fiber and also contains oxidized polysaccharides, particularly oxidized cellulose and its neutralized derivatives. For example, the cellulose may be carboxyl-oxidized or aldehyde-oxidized cellulose. More preferably, the second absorbent woven or knitted fabric may be prepared using oxidized regenerated polysaccharides, including but not limited to oxidized regenerated cellulose. Regenerated cellulose is preferred over unregenerated cellulose due to its higher uniformity. Detailed descriptions of methods for producing regenerated cellulose and oxidized regenerated cellulose are found in U.S. Patents 3,364,200, 5,180,398, and 4,626,253, the contents of each of these patents being incorporated herein by reference as containing all their contents.

[0052] The reinforcing fabrics used in the present invention may be woven or knitted, provided that the fabric has the physical properties necessary for use in the intended application. Such fabrics are described, for example, in U.S. Patents 4,626,253, 5,002,551, and 5,007,916, the contents of which are incorporated herein by reference as if described in their entirety. In a preferred embodiment, the reinforcing fabric is a warp-knit tricot fabric composed of bright rayon yarn, which is subsequently oxidized to contain an amount of carboxyl or aldehyde moiety effective in giving the fabric biodegradability.

[0053] In another embodiment, the second absorbent woven or knitted fabric comprises oxidized polysaccharide fibers in combination with fibers made of aliphatic polyester polymers, copolymers, or blends thereof.

[0054] The second absorbent woven or knitted fabric preferably contains oxidized regenerated cellulose in an amount of about 0.001 to 0.2 g / in 2 The range is preferably about 0.01 to 0.1 g / in. 2 The range is most preferably about 0.04 to 0.07 g / in. 2 It may have a basis weight within the range of [specify range].

[0055] The first absorbent nonwoven fabric is attached to the second absorbent woven or knitted fabric either directly or indirectly. For example, the nonwoven fabric may be incorporated into the second absorbent woven or knitted fabric by needle punching, calendering, embossing, hydroentanglement, or by chemical or thermal bonding. The staples of the first absorbent nonwoven fabric may be intertwined with each other and embedded in the second absorbent woven or knitted fabric. More specifically, by methods other than chemical or thermal bonding, the first absorbent nonwoven fabric may be attached to the second absorbent woven or knitted fabric such that at least about 1%, preferably about 10-20%, and preferably no more than about 50% of the staples of the first absorbent nonwoven fabric are exposed on the other side of the second absorbent woven or knitted fabric. This ensures that the first absorbent nonwoven fabric and the second absorbent woven or knitted fabric remain bonded and do not delaminate under normal handling conditions. The reinforced absorbent multilayer fabric is uniform, so that, substantially, neither the second absorbent woven fabric nor the knitted fabric visually lacks coverage by the first absorbent nonwoven fabric.

[0056] In one embodiment, matrix A, a combination of a reinforcing layer and an absorbent layer, is sprayed with reactive PEG, preferably PEG-amine (NH2), meaning a polyprimary amine-functionalized polyethylene glycol derivative, and matrix B, a synthetic polymer nonwoven matrix, is sprayed with co-reactive PEG, preferably PEG-NHS, meaning polyN-hydroxysuccinimide (NHS)-functionalized polyethylene glycol. These two sublayers are connected to each other at several points along the surface area by ultrasonic welding, needle punching, thermal welding, chemical bonding, suture bonding, etc. A barrier film is positioned between the two matrices. The barrier layer is flexible and is removed before use either manually and / or by connecting to the outer package when the traumatic medicinal material is pulled from the package. The barrier layer may be made from, for example, polyethylene terephthalate (PET), polystyrene, or Tyvek.

[0057] During use, the traumatic medicinal material is oriented such that the portion to which the first co-reactive component is applied is closer to the tissue, and the portion having the second co-reactive component to be applied thereto is adjacent thereto but further away from the tissue. In embodiments, the first and second portions may be distinguishable from each other by adding contrast dyes, surface textures, colorings, or other visual cues. When in contact with tissue, such as injured tissue, for example, the traumatic medicinal material draws up physiological fluids, and the first hydrogel co-reactive component is dissolved by the fluid. As the fluid is drawn into the traumatic medicinal material and moves across it, the fluid carries the dissolved first co-reactive component along the traumatic medicinal material. Eventually, the fluid moves through the traumatic medicinal material sufficiently to reach the second portion to which the second co-reactive component is applied, thereby dissolving the second co-reactive component. The first and second co-reactive components then react to form a biocompatible crosslinked material, thereby assisting tissue endoplastic growth and reconstruction as the scaffold degrades. In some embodiments, the biocompatible crosslinked material produced by the reaction of the first and second co-reactive components also provides a traumatic medicinal material with anti-adhesion properties.

[0058] The following examples are provided for illustrative purposes only and are not intended to limit the scope of this disclosure. [Examples]

[0059] Using an ultrasonic atomizing machine, a 2-inch x 4-inch matrix (Matrix A) was treated with 11.59 mg / cm³. 2 The material was coated with PEG-NH2 5K (20 grams in 100 ml of acetone). Next, two 2-inch x 4-inch PG910 vats (matrix B), formed from a copolymer of 90% glycolide and 10% L-lactide, were atomized using an ultrasonic atomizing machine at two different fiber densities (8.5 g / vat and 15.0 g / vat) to 13.91 mg / cm³. 2The two coated matrices were coated with PEG-NHS 10K (20 grams in 100 ml of acetone). The two coated matrices were dried overnight at room temperature in a nitrogen box, where they were not in physical contact with each other.

[0060] Two matrices (A and B) were cut into 3cm x 3cm squares and positioned on top of each other. Next, this overlay was placed on a 10mm circular biopsy defect in an ex vivo splenic hemorrhage model (perfused with heparinized bovine blood) for 2 minutes using tamponade. The level of bleeding before and after application was evaluated qualitatively (visual observation of bleeding) and quantitatively (measurement of blood volume perfused from the defect in grams / minute).

[0061] In the case of matrix B, an overlay structure matrix with a density of 8.5 g / bat, no blood flow was observed from the defect after application, and the measured blood flow decreased from 27.74 g of blood / min to 0 g of blood.

[0062] In the case of matrix B being the matrix of the overlay structure with a density of 15 g / bat, no blood flow was observed from the defect after application, and the measured blood flow decreased from 11.59 g of blood / min to 0 g of blood. Both bats coated with PEG-NHS (matrix B) at densities of 8.5 g / bat and 15 g / bat were shown to be effective in eliminating bleeding from the defect. Furthermore, although the two matrices were not mechanically or chemically adhered, no delamination was observed, as it appears that blood, and possibly activation of the two co-reactive PEGs by blood, bound the layers together at the defect site. However, separating the two co-reactive PEGs improved the stability of the product compared to patches co-coated with two co-reactive PEGs.

[0063] [Implementation Method] (1) A medical device, a. A first porous substrate layer having at least one main opposing surface having at least a surface coating of a first co-reactive component, b. A second substrate layer having at least one main opposing surface having at least a surface coating layer of a second coreactive component that reacts with the first coreactive component, c. A medical device comprising a removable barrier layer positioned between the first substrate layer and the second substrate layer, and in contact with at least one main opposing surface or surface coating, each independent of the first substrate layer and the second substrate layer. (2) The medical device according to Embodiment 1, wherein the first substrate layer is a porous nonwoven mesh composed of one or more synthetic polymers or copolymers, cellulose-based materials, and blends thereof. (3) The medical device according to Embodiment 2, wherein the second substrate layer is a porous nonwoven mesh composed of one or more synthetic polymers or copolymers, cellulose-based materials, and blends thereof. (4) The medical device according to Embodiment 1, wherein the second substrate layer is a nonporous film. (5) The medical device according to Embodiment 3, wherein a non-porous film is applied to the upper opposite surface of the second substrate layer.

[0064] (6) The medical device according to Embodiment 3, wherein at least one main surface of the first substrate layer is coated with a nucleophile-containing compound as the first co-reactive component. (7) The medical device according to Embodiment 3, wherein at least one main surface of the second substrate layer is coated with an electrophilic group-containing compound as the second co-reactive component. (8) The medical device according to Embodiment 1, wherein at least one main surface of the substrate layer is coated PEG-NHS. (9) The medical device according to Embodiment 8, wherein the PEG-NHS coated substrate is the tissue-facing surface. (10) The medical device according to Embodiment 8, wherein a PEG-NHS substrate is coated on both sides of the substrate layer, and PEG-amine is coated on only one side of the opposing porous substrate.

[0065] (11) The medical device according to Embodiment 1, wherein the second co-reactive component further comprises an activator for the first co-reactive component. (12) The medical device according to Embodiment 11, wherein the activator is selected from the group consisting of enzymes, buffers, carbodiimides, catalysts, and combinations thereof. (13) The medical device according to Embodiment 3, wherein the first substrate layer, the second substrate layer, and the barrier layer are assembled in a sandwich configuration in which at least three of the layers are stacked. (14) The medical device according to Embodiment 6, wherein the first base layer and the second base layer are maintained in a common relative position by a plurality of connection points or welds. (15) The medical device according to Embodiment 1, wherein the first substrate layer and the second substrate layer are formed by bending a common substrate material along a hinge.

[0066] (16) The medical device according to Embodiment 1, wherein the first base layer and the second base layer have peripheral edge regions, and the plurality of connection points or welds are provided at separate points along at least one peripheral edge region on each of the first base layer and the second base layer. (17) The medical device according to embodiment 16, wherein at least a plurality of connection points or welds are provided penetrating the inert film along the axes of the first substrate layer and the second substrate layer. (18) The medical device according to Embodiment 1, wherein the barrier layer has slits along at least a portion of its length corresponding to the plurality of connection points or welds, and the slits allow the inert film to be removed from between the first substrate layer and the second substrate layer by pulling without tearing the barrier layer. (19) The medical device according to Embodiment 1, wherein at least one peripheral edge of the barrier layer extends beyond at least one peripheral edge of the first substrate layer and the second substrate layer. (20) The medical device according to Embodiment 1, further comprising one or more package components, wherein the barrier layer is attached to the package and removed when the medical device is separated from the associated one or more package components.

[0067] (21) The kit according to Embodiment 20, wherein at least one of the package components is a housing compartment having two spatially separated compartments for the first substrate layer and the second substrate layer. (22) The kit according to embodiment 20, wherein the storage compartment is a single compartment for holding the first substrate layer and the second substrate layer. (23) A method for achieving hemostasis on a bleeding site, comprising applying the patch described in Embodiment 1 to the bleeding tissue site. (24) The method according to embodiment 23, wherein the PEG-NHS coated substrate is applied directly to the bleeding tissue site. (25) A method for sealing tissue, comprising applying the patch described in Embodiment 1 to a damaged tissue site.

[0068] (26) The method according to embodiment 25, wherein the PEG-NHS substrate is applied directly to the damaged tissue site.

Claims

1. It is a medical device, a. A first porous substrate layer having at least one main opposing surface having a surface coating containing a first co-reactive component, b. A second substrate layer having at least one main opposing surface having a surface coating layer containing a second co-reactive component that reacts with the first co-reactive component, c. A removable barrier layer positioned between the first porous substrate layer and the second substrate layer, and in contact with at least one independent main opposing surface or surface coating from the first porous substrate layer and the second substrate layer, At least one main surface of the first porous substrate layer is coated with a nucleophile-containing compound as the first co-reactive component, A medical device in which at least one main surface of the second substrate layer is coated with an electrophilic group-containing compound as the second co-reactive component.

2. The medical device according to claim 1, wherein the first porous substrate layer is a porous nonwoven mesh composed of one or more synthetic polymers or copolymers, cellulose-based materials, and blends thereof.

3. The medical device according to claim 2, wherein the second substrate layer is a porous nonwoven mesh composed of one or more synthetic polymers or copolymers, cellulose-based materials, and blends thereof.

4. The medical device according to claim 1, wherein the second substrate layer is a nonporous film.

5. The medical device according to claim 3, wherein a non-porous film is applied to the upper opposing surface of the second substrate layer.

6. The medical device according to claim 1, wherein at least one main surface of the substrate layer is coated PEG-NHS.

7. The medical device according to claim 6, wherein the PEG-NHS coated substrate is a tissue-facing surface.

8. The medical device according to claim 6, wherein a PEG-NHS substrate is coated on both sides of the substrate layer, and PEG-amine is coated on only one side of the opposing porous substrate.

9. The medical device according to claim 1, wherein the second co-reactive component further comprises an activator for the first co-reactive component.

10. The medical device according to claim 9, wherein the activator is selected from the group consisting of enzymes, buffers, carbodiimides, catalysts, and combinations thereof.

11. The medical device according to claim 3, wherein the first porous substrate layer, the second substrate layer, and the barrier layer are assembled in a sandwich configuration in which at least three of the layers are stacked.

12. The medical device according to claim 1, wherein the first porous substrate layer and the second substrate layer are maintained in a common relative arrangement by a plurality of connection points or welds.

13. The medical device according to claim 1, wherein the first porous substrate layer and the second substrate layer are formed by bending a common substrate material along a hinge.

14. The medical device according to claim 1, wherein the first porous substrate layer and the second substrate layer have peripheral edge regions, and the plurality of connection points or welds are provided at separate points along at least one peripheral edge region on each of the first porous substrate layer and the second substrate layer.

15. The medical device according to claim 14, wherein at least a plurality of connection points or welds are provided penetrating the inert film along the axes of the first porous substrate layer and the second substrate layer.

16. The medical device according to claim 1, wherein the barrier layer has slits along at least its length corresponding to the plurality of connection points or welds, and the slits allow the inert film to be removed from between the first porous substrate layer and the second substrate layer by pulling without tearing the barrier layer.

17. The medical device according to claim 1, wherein at least one peripheral edge of the barrier layer extends beyond the peripheral edge of at least one of the first porous substrate layer and the second substrate layer.

18. A kit comprising the medical device described in Claim 1 and one or more package components, wherein the barrier layer is attached to the package and removed when the medical device is separated from the one or more package components to which it relates.

19. The kit according to claim 18, wherein at least one of the package components is a housing compartment having two spatially separated compartments for the first porous substrate layer and the second substrate layer.

20. The kit according to claim 19, wherein the receiving compartment is a single section for holding the first porous substrate layer and the second substrate layer.

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