Meltblown layings with gradient density

Abstract

This invention relates to an absorbable hemostatic nonwoven patch that utilizes a biocompatible substrate composed of meltblown microfibers as a mesh sheet, which is laminated and bonded / entangled with decreasing density and increasing porosity; wherein the substrate has high flexibility, strength and porosity, suitable for coating with crosslinkable active molecules and has the ability to be used for laparoscopic use or cannula deployment, ultimately serving as a highly effective hemostatic agent for resolving problematic bleeding during open and minimally invasive surgical procedures.

Description

Background Technology

[0001] Absorbable hemostatic patches comprising two crosslinkable components have been described in the literature, including in U.S. Publication 2011 / 0045047A1. The crosslinkable components used in such patches can be a pair of co-reactive compounds or a substrate coated with a co-reactive compound having usable units capable of covalently crosslinking with corresponding co-reactive groups on the substrate and / or the target bleeding site tissue. Plasma-derived bio-components that initiate, enhance, and / or support the formation of fibrin clots in hemostatic cascades have also been applied to substrates of various constructions and materials. Summary of the Invention

[0002] This invention relates to an absorbable hemostatic patch for sealing, and more specifically, to an economically viable elastic layered matrix substrate composed of meltblown nonwoven microfibers as a mesh sheet, which is laminated and bonded / entangled with decreasing density and increasing porosity. The gradient-based construct improves the coating properties of crosslinkable active molecules (e.g., reactive polyethylene glycol-based compounds (PEG) or bio-components), while the lamination introduces a unique distribution of stiffness within the matrix structure, allowing cannula deployment without compromising the patch's overall stretchability / compliance and / or hemostatic effectiveness. The result is a highly functional hemostatic patch suitable for both open and minimally invasive surgical procedures to stop problematic bleeding.

[0003] This invention relates to wound dressings comprising a meltblown multilayer substrate having at least two main facing surfaces and a coating layer applied to at least one of the main facing surfaces of a sealant selected from the group consisting of co-reactive hydrogel forming materials, one or more plasma-based hemostatic agents, and combinations thereof, wherein the meltblown substrate has a porosity gradient distribution. The substrate is preferably a multilayer monolithic composite material of polymeric material layers, each layer having a decreasing density and increasing porosity relative to adjacent layers. The substrate preferably consists substantially of 4 to 14 discrete and monolithic layers. Each discrete and monolithic layer may be about 0.05 mm to 0.2 mm thick. The substrate preferably has pores with a diameter in the range of 0.01 mm to 0.5 mm on an overall basis, more preferably most of the pores have a diameter in the range of 0.1 mm to 0.3 mm.

[0004] The total / overall open porosity of the substrate can range from 30% to 90%. In one embodiment, the bottom third of the substrate has an open porosity of about 30%, the middle third has an open porosity of about 80%, and the top third of the substrate to the coated main surface has an open porosity of about 85%.

[0005] Preferably, the coating is applied such that at least a portion of the coating remains on at least one main surface of the substrate and penetrates to a depth greater than 90% of the substrate thickness, while the overall substrate porosity is greater than 60%. In one embodiment, the coating may penetrate to a depth greater than 95%. In another embodiment, the coating penetrates to a depth of at least 97%. The overall substrate porosity may be greater than 65%, preferably greater than 70%.

[0006] In one embodiment, the substrate has an average stiffness of at least 0.50 N / mm, for example, an average stiffness of about 0.53 N / mm.

[0007] In one embodiment, the polymer material is selected from biodegradable polymers selected from the group consisting of polyglycolic acid (PGA), polylactic-co-glycolic acid copolymer (PLGA), poly(lactic acid)(PLA), poly(dioxane)(PDS), polycaprolactone, caprolactone / glycolic acid copolymer, and combinations thereof.

[0008] In one embodiment, the polymer material is a copolymer of glycolide and ε-caprolactone (Monocryl), polyglactin 910 (Vicryl), or a combination thereof.

[0009] The hydrogel-forming material can be at least two different multifunctional polymers or polymer precursors containing two or more electrophilic or nucleophilic functional groups. In one embodiment, at least one of the hydrogel-forming materials has two or more nucleophilic functional groups that react with electrophilic functional groups on a second hydrogel-forming material to form covalent bonds.

[0010] Hemostatic agents may be selected from prothrombin, thrombin, fibrin, fibronectin, factors (factors) X / Xa, factor VII / VIIa, factor IX / IXa, factor XI / XIa, factor XII / XIIa, tissue factor, von Willebrand factor, elastin, albumin, platelet surface glycoprotein, vasopressin and the vasopressin group consisting of analogues, adrenaline, selectin, plasminogen activator inhibitors, platelet activators, synthetic peptides, and any combination thereof.

[0011] The present invention also relates to a method for preparing the wound dressing described herein, the method comprising meltblowing microfibers into a mesh sheet, laminating the meltblown sheet, and bonding layers of the meltblown sheet.

[0012] The present invention also relates to a method for sealing a tissue surface by applying the above-described wound dressing to an injured and / or moist tissue surface.

[0013] This invention relates to an absorbable hemostatic nonwoven patch and wound dressing that utilizes a biocompatible substrate composed of meltblown microfibers as a mesh sheet, which is laminated and bonded / entangled with decreasing density and increasing porosity; the substrate has high flexibility, strength and porosity, suitable for coating with crosslinkable active molecules and has the ability to be used for laparoscopic use or cannula deployment, ultimately serving as a highly effective hemostatic agent for resolving problematic bleeding during open and minimally invasive surgical procedures. Attached Figure Description

[0014] Figure 1 This is an exploded diagram of a gradient patch, in which meltblown nonwoven sheets are stacked with decreasing density and increasing porosity.

[0015] Figure 2 This is a microscopic (30x) image of a cross-section of a gradient distribution construct, which allows for greater interpenetration of coatings within the matrix structure compared to agglomerated / agglomerated coatings on a non-gradient substrate. Detailed Implementation

[0016] The present invention provides a wound dressing that advantageously forms a matrix particularly suitable for coating, having a highly porous layer on the surface, which increases the surface area available for coating and allows for deeper coating penetration. Preferably, the wound dressing ultimately provides a means of coating individual meltblown fibers within the matrix of a complex nonwoven network rather than agglomerating or forming a film on the surface.

[0017] Preferred wound dressings have a substrate layer characterized by tortuous pathways and high matrix bulkiness throughout the substrate prior to coating. Lamination and stacking of meltblown sheets with decreasing density and increasing porosity create a complex nonwoven network, which not only increases the mechanical integrity of the matrix but also provides the additional benefit of allowing blood penetration while the hydrogel reactive components and / or biological components hydrate and react to produce an integral seal with the substrate and outer surface. The desired tortuosity throughout the matrix also prevents the patch from bulging when attempting to stop high-pressure bleeding.

[0018] The preferred wound dressing exhibits tactile appeal and ease of handling. Due to the increased stiffness resulting from the unique lamination of meltblown sheets, the patch of the present invention has a robust, strong, and resilient structure that provides tactile advantages during use and conforms to tissue upon application.

[0019] Preferred wound dressings can be unfolded laparoscopically because the unique distribution of stiffness in the matrix structure (especially after application) provides "shape memory," which allows the patch to roll up, unfold through the cannula, and return to its original shape without permanent deformation upon delivery.

[0020] The preferred wound dressing is a relatively robust patch that provides good adhesion to tissue. Based on available data, it appears that the reactive component has high permeability to the substrate layer, while the porous nature at the surface level provides the ability to adhere effectively at the patch-tissue interface.

[0021] Preferred wound dressing properties can be customized by the number of layers and fiber structure to allow for specific properties, such as increased stiffness with increasing layers, increased meltblown extrusion process factors (e.g., cylinder speed), and altered porosity by increasing the distance between the extrusion die surface and the collection cylinder.

[0022] Preferred wound dressings exhibit high tissue compliance because the combination of an elastic layer and an open porous interface allows for high tissue compliance if tissue expands or moves without compromising adhesion enhanced by a denser backing.

[0023] Preferred wound dressings can have customized absorption times / biocompatibility. Meltblown nonwoven matrices can use biocompatible absorbable materials such as... The material is manufactured in a way that allows for the adjustment of properties by modifying the fiber diameter and polymer structure, respectively, during melt extrusion and post-crystallization treatment (e.g., smaller fiber diameters will result in faster absorption).

[0024] In one embodiment, the nonwoven base material is made of absorbable, biocompatible polyester material such as It is produced by extrusion through a linear die containing hundreds of tiny holes. A converging stream of hot air refines the molten polymer to form fibers with extremely fine diameters. High-speed air blows the fibers onto a collecting cylinder, forming a sheet of meltblown nonwoven fabric. Process factors, such as cylinder speed and the distance between the extrusion die surface and the collecting cylinder, are selected to obtain preferred fiber diameters and orientations, which in turn control the pore size and density of the resulting nonwoven matrix.

[0025] While the width of the cylinder depends on the length of the polymer extrusion die, it is arbitrary and can be scaled up for mass production of meltblown sheets. The cylinder speed is inversely proportional to the patch density per unit area and is inherently related to fiber diameter, specific surface area, and overall porosity within the layer. The collector distance also affects matrix properties when the gap between the polymer extrusion die and the collecting cylinder is increased, thereby better randomizing fiber thickness and orientation on the fiber web.

[0026] This invention identifies preferred cylinder speeds in the range of 4-20 RPM and distances in the range of 10-40 inches. Different combinations within these ranges are used to produce layers with decreasing density and increasing porosity. The collector cylinder distance is set in the range of 10-40 inches, and the preferred settings for each layer are determined to achieve a target porosity distribution in the matrix structure.

[0027] These ranges are used The established material properties (e.g., intrinsic viscosity of 1.67) may slightly influence fiber properties, and consequently affect the porosity, density, and stiffness of the entire matrix. However, regardless of material properties, these ranges should show the same trend (e.g., for...). and Increasing the cylinder speed will reduce the patch density, and at least the range we have identified is a feasible starting point. Other biodegradable polymers of interest that can be meltblown include, but are not limited to, PGA, PLGA, PLA, PDS, PCL, and caprolactone / glycolic acid copolymers.

[0028] These ranges represent a set of methods for achieving all desired densities and porosities in matrices found to be functional hemostatic agents. However, these density and porosity properties can be achieved by adjusting other process factors (e.g., screw speed and extrusion temperature) during meltblown extrusion.

[0029] The preferred thickness range determined by this invention is 0.30 mm to 2.5 mm, more preferably 0.6 mm to 1.1 mm, and most preferably 0.9 mm to 1.1 mm. More important than the wide range of thicknesses is that the gradient and top porous structure are created by stacking individual sheets, each with a thickness of less than 0.5 mm, and most preferably in the range of 0.05 mm to 0.2 mm.

[0030] Based on micro-CT analysis, this invention determines that the preferred pore size distribution is in the range of 0.01 mm to 0.5 mm, with most pores in the range of 0.1 mm to 0.3 mm. Furthermore, according to micro-CT analysis, this invention determines that the total open porosity of the matrix is ​​in the range of 30% to 90%. This wide range of total porosity is attributed to the gradient-based stacking of the construct, where the porosity of the bottom third of the matrix is ​​approximately 30%, the middle third is 80%, and the top third (surface) is 85%.

[0031] Meltblown polymers offer unique advantages in producing ultrafine fibers; conversely, spunbond filaments do not possess the fineness of meltblown fibers. The meltblown nonwovens of this invention define fine fibers, with fiber diameters ranging from 1 micrometer to 250 micrometers in all layers, preferably from 1 micrometer to 90 micrometers. Assuming a gradient-based construction, finer fibers are generally preferred to be located in the upper region of the matrix, closer to the surface. In this regard, the optimal fiber diameter range for the bottom third of the matrix is ​​determined to be 10 micrometers to 80 micrometers, for the middle third 10 micrometers to 40 micrometers, and for the top third (surface) 1 micrometer to 30 micrometers.

[0032] Once each sheet of meltblown polyester-based nonwoven material with the desired density and porosity is produced, it is used as a building block in a gradient-based multilayer patch concept.

[0033] One advantage of the gradient design described herein is that it creates complex, tortuous paths for any substance flowing through the matrix; one can imagine blood seeping from the coating layer placed in contact with the moist tissue surface and coagulating before reaching the densest and preferably water-impermeable layer furthest from the coating layer. Additionally, the matrix has a relatively soft / fluffy and “cushion-like” high loft, which end users will find useful and easy to handle.

[0034] The gradient concept is essentially a multilayer composite material constructed with decreasing density and increasing porosity. Figure 1 Each layer of meltblown polyester-based nonwoven sheet is produced on a collecting cylinder and partially crystallized for 15 minutes under an industrial blower. A subsequent capping layer with lower density and / or higher porosity is then applied over the previous layer and bonded to the partially crystallized previous layer.

[0035] In an alternative implementation, individual meltblown layers can also be produced separately and then stacked and bonded using thermal or ultrasonic methods.

[0036] In one embodiment, the matrix has at least four and no more than fourteen discrete layers, each layer being approximately 0.05 mm to 0.2 mm thick. A minimum number of layers (with or without gradients) is required to ensure the matrix has structural integrity, while for practical applications, there are also limitations on how many meltblown sheets can be stacked before the matrix substrate becomes too large and too rigid.

[0037] Compared to seven or fourteen layers, a substrate with four layers and no gradient distribution produces a significantly different morphology. The applicant found that increasing the number of layers increased the depth of the voids / spaces into which the coating could penetrate. Relative analysis of the 3D model (Table 1) shows that 7 layers and 14 layers increased the maximum height of pores or voids at the surface by approximately 45% and 200%, respectively. In the multilayer gradient structure, the relative surface area and volume also increased significantly.

[0038] Table 1

[0039]

[0040] Coating a substrate without a gradient distribution results in poor material permeability and aggregation or clumping, while a gradient-distributed substrate exhibits effective coating of individual fibers and improved permeability to the substrate. Advanced microscopy and depth composition analysis revealed that increasing porosity produces a unique depth coating that individually encapsulates more nonwoven fibers rather than agglomerating them on the surface. Cross-sectional microscopy at 30x magnification confirmed that gradient constructs allow coatings to interpenetrate within the matrix structure compared to agglomerated / agglomerated coatings on a substrate without a gradient; using gradient constructs, the proportion of coatings penetrating into the matrix increased by 42%. Images also show that mass-dependent coatings on gradient-based surfaces better maintain matrix height and bulk, while the same coating might compress a substrate without a gradient.

[0041] To further confirm the matrix characteristics, porosity was assessed via micro-CT imaging and analysis (Table 2).

[0042] Table 2. Porosity assessment via micro-CT imaging and analysis .

[0043] ID Patch status Porosity (%) %change 1 No gradient 85 - 2 Gradient-free coating 62 - 3 gradient 90 5 (compared to 1) 4 Gradient Coating 72 10 (compared to 2)

[0044] The gradient substrate increases the porosity of the entire matrix by 5%, despite the higher material bulkiness. After coating, the gradient patch increases the porosity of the entire matrix by 10%, despite the higher material bulkiness.

[0045] In one embodiment, a hemostatic patch composed of a nonwoven, gradient-based meltblown substrate is combined with a crosslinkable coating. Exemplary meltblown microfiber sheets utilize absorbable, biocompatible polyester materials, such as… (IV is 1.67) is prepared and layered onto a collection cylinder. After melt extrusion, each layer is partially crystallized under an air-circulating fan, preferably for 15 minutes. In the most preferred embodiment, subsequent layers are immediately covered after fifteen (15) minutes of cooling, at which point the previously partially crystallized layer bonds and creates fiber entanglement at the two fiber point-to-point contact areas. In this embodiment, the entangled layered structure is again partially crystallized, and the cycle is repeated to construct the most preferred gradient-based matrix as described in Table 5.

[0046] Table 5. Sequential Lamination of Meltblown Nonwoven Sheets

[0047]

[0048] The final construct is allowed to fully crystallize in a vacuum chamber for at least 12 hours, and then stored in a moisture-free environment.

[0049] The most preferred substrate has 7 layers, with a coating penetration depth greater than 90% of the thickness, more preferably greater than 95%, and most preferably at least 97%, and a total substrate porosity greater than 60%, more preferably greater than 65%, and most preferably about 72%. The most preferred patch has an average hardness of 0.53 N / mm.

[0050] In an alternative embodiment, each meltblown sheet / layer may be produced individually and crystallized in a vacuum chamber for at least 12 hours. These layers are then stacked and thermally or ultrasonically bonded at pinhole-sized contact points on a matrix. The dressing of the present invention comprises a carrier layer having multiple fibrous sublayers containing co-reactive crosslinkable components. Crosslinkable active substances, such as reactive PEGS, are preferably applied sequentially with or without buffers and additives to form a fully functional hemostatic agent. The top sublayer has co-reactive crosslinkable components and / or at least one plasma-derived or plasma-related hemostatic agent, preferably fibrinogen. In another embodiment, the hemostatic agent may be thrombin or fibrinogen, each used alone or in combination.

[0051] Exemplary plasma-derived (or related) hemostatic agents include proteins and peptides, and are therefore not limited to only natural hemostatic agents, as these hemostatic agents can be recombinant or synthetic forms of prothrombin, thrombin, fibrin, fibronectin, factor (factor) X / Xa, factor VII / VIIa, factor IX / IXa, factor XI / XIa, factor XII / XIIa, tissue factor, von Willebrand factor, elastin, albumin, platelet surface glycoprotein, vasopressin and the vasopressin group consisting of analogues, adrenaline, selectin, plasminogen activator inhibitors, platelet activators, synthetic peptides, and any combination thereof.

[0052] The carrier sublayer can be in the form of a nonwoven material. An exemplary constructing material is a synthetic polymer. The substrate can consist of a component selected from copolymers of aliphatic polyester polymers and / or one or more monomers, wherein the monomers are 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.

[0053] The substrate may alternatively or additionally consist of a fabric layer of 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 (including L- and D-, meso-forms), glycolic acid, glycolide, caprolactone, p-dioxane-2-one (1,4-dioxane-2-one), and trimethylene carbonate (1,3-dioxane-2-one). In some cases, aliphatic polyesters may be prepared by polycondensation of, for example, D-lactic acid, L-lactic acid, and / or glycolic acid. In one form, the fabric comprises a copolymer of glycolide and lactide in an amount of about 70 mol% to 95 mol% of glycolide and the remaining lactide.

[0054] The porous substrate of the dressing has openings or pores on at least a portion of its surface. As described in more detail below, suitable materials for forming the porous substrate include, but are not limited to, fibrous structures. In embodiments, the pores may have a sufficient number and size to be interconnected across the entire thickness of the porous substrate.

[0055] One or more sublayers of the porous substrate may be at least 0.1 cm thick, and in some embodiments, from about 0.2 cm to about 1.5 cm thick. The pore size in the sublayers of the porous substrate may be from about 2 micrometers to about 300 micrometers, and in some embodiments, from about 50 micrometers to about 150 micrometers. It is conceivable that the pores in the sublayers of the substrate can be arranged in any manner within the substrate. For example, the pores can be constructed in a random or uniform manner. In some embodiments, calcium alginate or copper alginate can be used to form the pores to produce a honeycomb-shaped porous substrate. In other embodiments, the pores can be configured to create a gradient within the porous substrate. This gradient can further enhance the ability of the porous substrate to absorb physiological fluids and guide the physiological fluids carrying a first co-reactive component to migrate towards a second co-reactive component.

[0056] In one embodiment, the substrate has a first co-reactive component applied to a first sublayer and a second co-reactive component applied thereon. The terms "first co-reactive component" and "second co-reactive component" each refer to a polymer, functional polymer, macromolecule, small molecule, or crosslinking agent that can participate in the reaction to form a crosslinked molecular network, such as a hydrogel.

[0057] In one embodiment, the first coreactive component and the second coreactive component are each multifunctional, meaning they contain two or more electrophilic or nucleophilic functional groups, such that, for example, a nucleophilic functional group on the first coreactive component can 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 component includes two or more functional groups, such that the precursor binds to form a crosslinked polymer product due to an electrophilic-nucleophilic reaction. This type of reaction is referred to as a "crosslinking reaction".

[0058] In some embodiments, the first and second co-reactive components each contain only one type of functional group, or only nucleophilic groups, or only electrophilic functional groups, provided that both nucleophilic and electrophilic precursors are used simultaneously in the crosslinking reaction. Thus, 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. 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 a thiol. Therefore, functional polymers such as proteins, poly(allylamine), styrene sulfonic acid, or amine-terminated difunctional or polyfunctional poly(ethylene glycol) (“PEG”) can be used.

[0059] The first and second co-reactive components can have a bioinert and water-soluble core. When the core is a water-soluble polymeric region, preferred polymers that can be used include: polyethers, such as polyepoxides like polyethylene glycol (“PEG”), polyethylene oxide (“PEO”), polyethylene oxide-polypropylene oxide copolymers (“PPO”), polyethylene oxide block copolymers or random copolymers, and polyvinyl alcohol (“PVA”); poly(vinylpyrrolidone”) (“PVP”); poly(amino acids); polysaccharides such as dextran, chitosan, alginate, carboxymethyl cellulose, oxidized cellulose, hydroxyethyl cellulose, hyaluronic acid; and proteins such as albumin, collagen, casein, and gelatin. Polyethers, and more particularly poly(oxyene oxides) or poly(ethylene glycol) or polyethylene glycol, are particularly useful. When the core is inherently a small molecule, any of a variety of hydrophilic functional groups can be used to make the first and second co-reactive components water-soluble. For example, water-soluble functional groups such as hydroxyl, amine, sulfonate, and carboxylic acid esters can be used to prepare water-soluble precursors. Furthermore, the N-hydroxysuccinimide (“NHS”) ester of succinic acid is insoluble in water, but by adding a sulfonate group to the succinimide ring, the NHS ester of succinic acid can be made water-soluble without affecting its reactivity with the amine group.

[0060] In some embodiments, both the first and second co-reactive components can be cross-linkable macromolecules. For example, in one embodiment, one of the precursors can be a multifunctional PEG with a molecular weight of about 2,000 to about 20,000 Daltons. In embodiments with electrophilic groups, the multifunctional PEG can react with collagen with a molecular weight of about 100,000 Daltons. In other embodiments, gelatin with a molecular weight of about 50,000 to about 100,000 Daltons can be used instead of collagen.

[0061] In another embodiment, co-reactive components and buffers are provided on the patch. Exemplary sealing patches / gaskets include PEG-NH2*HCl and PEG-NHS, i.e., buffer salt reagents, which are preferably deposited on an absorbable substrate as alkaline buffers (borax).

[0062] If it is desired that the biocompatible crosslinked polymer resulting from the reaction of the first and second coreactive components is biodegradable or absorbable, then one or more of the first and second coreactive components may have biodegradable linkages present between functional groups. The biodegradable linkages may also optionally serve as a water-soluble core of one or more precursors in the precursors. Alternatively, or further, the functional groups of the first and second coreactive components may be selected such that the reaction products between them form biodegradable bonds. For each method, biodegradable bonds may be selected such that the resulting biodegradable biocompatible crosslinked polymer will degrade, dissolve, or be absorbed within a desired time period. Preferably, biodegradable bonds that degrade into non-toxic products under physiological conditions are selected.

[0063] Biodegradable linkages can be chelates or chemically or enzymatically hydrolyzable or absorbable. Exemplary chemically hydrolyzable biodegradable linkages include polymers, copolymers, and oligomers of glycolide, d-lactide, lactide, caprolactone, dioxane, and trimethylene carbonate. Exemplary enzymatically hydrolyzable biodegradable linkages include peptide bonds that can be cleaved by metalloproteinases and collagenases. Other exemplary biodegradable linkages include polymers and copolymers of poly(hydroxy acids), poly(orthocarbonates), poly(anhydrides), poly(lactones), poly(amino acids), poly(carbonates), poly(sugars), and poly(phosphonates). In embodiments, biodegradable linkages may contain ester bonds. Some non-limiting examples include esters of succinic acid, glutaric acid, propionic acid, adipic acid, or amino acids, as well as carboxymethyl esters.

[0064] In some embodiments, a multifunctional electrophilic polymer, such as a multi-arm PEG functionalized with multiple NHS groups, may be used as a first co-reactive component, and a multifunctional nucleophilic component, such as trilysine, may be used as a second co-reactive component. In other embodiments, a multifunctional electrophilic polymer, such as a multi-arm PEG functionalized with multiple NHS groups, may be used as a first co-reactive component, and a multifunctional nucleophilic polymer, such as collagen and / or collagen derivatives, may be used as a second co-reactive component. The multi-arm PEG functionalized with multiple NHS groups may, for example, have four, six, or eight arms and have a molecular weight of about 5,000 to about 25,000. Numerous other examples of suitable 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 which are incorporated herein by reference.

[0065] For patch implementations, the co-reactive components can be deposited as a separate layer on the matrix. Alternatively, the co-reactive components can be deposited as a mixture. The layer order can be varied, but the preferred sequence for sealing patches or gaskets includes PEG-NH2*HCl (or any other hydrohalogen), PEG-NHS, and a buffer salt (e.g., sodium tetraborate, MES, TRIS, bis(2-hydroxyethyl)amino(tris(hydroxymethyl)methane) (Bis-Tris), sodium bicarbonate) with the matrix, followed by the buffer salt layer, the protected PEG-amine layer, and the PEG-NHS layer. Furthermore, the number of arms and the molecular weight of the materials can be varied, but 4-arm-10K-NH2*HCl and 4-arm-10K-NHS are preferred variants from the viewpoint of efficacy and stability. This implementation was evaluated with different coating sequences. The position of the buffer deposited using a spray coating process on the matrix significantly affects performance and stability. Optimal performance and stability are achieved when the buffer is deposited below both PEGs (i.e., furthest from the tissue when the matrix is ​​applied).

[0066] The first co-reactive component can be applied to the porous substrate using any suitable method known to those skilled in the art, including but not limited to spraying, brushing, dipping, casting, lamination, etc. In embodiments, the first co-reactive component can be applied to the substrate as a coating of any concentration, size, and configuration capable of forming a hemostatic dressing. In embodiments, the first co-reactive component coating can penetrate the pores of the porous substrate. In embodiments, the first co-reactive component can be applied to the porous substrate as a film laminated to at least one side of the substrate.

[0067] The second co-reactive component can also be applied to the porous substrate using any suitable method known to those skilled in the art, including but not limited to spraying, brushing, dipping, casting, lamination, etc. In other embodiments, the second co-reactive component can be applied to the porous substrate in solution form, followed by evaporation or lyophilization of the solvent. In embodiments, the second co-reactive component can be applied to the porous substrate as a coating on at least one side of the substrate or as a film laminated to at least one side of the substrate.

[0068] During use, the patch dressing is oriented to apply the co-reactive components directly to the tissue. In some embodiments, the first and second portions can be distinguished from each other by the addition of contrast dyes, surface textures, coloring, or other visual cues. Upon contact with tissue, such as injured tissue, the dressing absorbs physiological fluids, and the first co-reactive component is dissolved by the fluid. As the fluid penetrates and migrates through the dressing, it carries the dissolved first co-reactive component into the second co-reactive component and a buffer. Ultimately, the first and second co-reactive components react to form a biocompatible cross-linked material, thereby aiding tissue inward growth and remodeling as the scaffold degrades. In some embodiments, the biocompatible cross-linked material resulting from the reaction of the first and second co-reactive components also provides the dressing with anti-adhesion properties.

[0069] The following examples are provided for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0070] Example :

[0071] An ex vivo hemorrhage model illustrates improved blood permeation within the substrate, where gradient conditions proved highly effective in hemostasis. The gradient patch also became highly compliant and adhered well to the tissue after hydration. A qualified peel test confirmed significantly higher tissue adhesion compared to fibrin clot-forming patches.

[0072] In an ex vivo hemorrhage model, patches with performance below standard were identified. The applicant found that the number of layers affected efficacy: 5 or fewer layers led to cohesive and adhesive failure, while 14 or more layers led to high adhesive failure; 7 layers were considered the optimal choice.

[0073] The uniqueness of this construct ultimately stems from its matrix stiffness and cannula deployment capability. The unique distribution of stiffness within the matrix construction and structure (especially after coating) provides "shape memory," allowing the patch to roll up and unroll through the cannula without deformation. To test this, a 11mm cannula was used... The tip of the XCEL bladeless cannula needle is rolled up with a 2x2” patch and inserted via Instron, and then the propulsion force is measured.

[0074] Mean stiffness, insertion force, and mean force were measured using a cannula: compared to nonwoven, ungradient substrates, patches with and without gradients exhibited lower mean forces during cannula deployment and subsequently lower deformation. Gradient-distributed substrates showed high stiffness, low insertion force, and low mean force (Table 3).

[0075] Table 3

[0076]

[0077] Gradient patches were also observed after unfolding (after insertion and roll-up), and the presence or absence of deformation was assessed based on the maximum lift at the edge (Table 4).

[0078] Table 4

[0079]

[0080]

[0081] Coating method examples :

[0082] Ultrasonic spraying (dissolution method) or dip coating (insoluble material method) 2-inch x 4-inch gradient-based meltblown matrix, embedded deep within a porous substrate with a thin layer of buffer.

[0083] Working examples include 1.25 mg / cm³ 2 Sodium borate, 2 mg / cm 2 bis(2-hydroxyethyl)amino(tris(hydroxymethyl)methane or 1 mg / cm 2 Sodium bicarbonate.

[0084] Then, ultrasonically coat with 15 mg / cm 2 The 4-arm PEG-amine-HCl (molecular weight: 10 kDa) was then ultrasonically coated with 18 mg / cm³. 2 4-arm PEG-SG (molecular weight: 10 kDa).

[0085] Gradient constructs allow crosslinkable active substances to be uniquely deposited deep into the matrix, ultimately producing highly effective hemostatic agents.

Claims

1. A wound dressing for sealing tissue surfaces, comprising a meltblown multilayer substrate having at least two main face surfaces and a coating layer of a sealant, the coating layer being applied to at least one of the main face surfaces, the sealant being a co-reactive hydrogel-forming material, wherein the meltblown multilayer substrate has a porosity gradient distribution, and wherein the coating layer is applied to at least the main face surface having the highest porosity.

2. The wound dressing according to claim 1, wherein, The substrate is a multilayer monolithic composite material of polymer material layers, each layer having a decreasing density and increasing porosity relative to adjacent layers.

3. The wound dressing according to claim 2, wherein, The substrate consists of 4 to 14 discrete yet integral layers.

4. The wound dressing according to claim 3, wherein, Each discrete yet integral layer is 0.05mm-0.2mm thick.

5. The wound dressing according to claim 1, wherein, The substrate has a pore size in the range of 0.01 mm to 0.5 mm on an overall basis.

6. The wound dressing according to claim 5, wherein, Most of the holes in the substrate have a diameter in the range of 0.1 mm to 0.3 mm.

7. The wound dressing according to claim 1, wherein, The total open porosity of the substrate is in the range of 30%-90%.

8. The wound dressing according to claim 1, wherein, The bottom third of the substrate has an open porosity of 30%, the middle third has an open porosity of 80%, and the top third of the substrate to the coated main surface has an open porosity of 85%.

9. The wound dressing according to claim 1, wherein, The coating is located on at least one main surface of the substrate and penetrates to a depth greater than 90% of the substrate thickness, and the overall substrate porosity is greater than 60%.

10. The wound dressing according to claim 9, wherein, The coating penetrates to a depth greater than 95%.

11. The wound dressing according to claim 9, wherein, The coating penetrates to a depth of at least 97%.

12. The wound dressing according to claim 9, wherein, The overall substrate porosity is greater than 65%.

13. The wound dressing according to claim 11, wherein, The overall porosity of the substrate is greater than 70%.

14. The wound dressing of claim 7, wherein the wound dressing has an average stiffness of at least 0.50 N / mm.

15. The wound dressing according to claim 13, wherein the wound dressing has an average stiffness of 0.53 N / mm.

16. The wound dressing according to claim 2, wherein, The polymer material is selected from biodegradable polymers, which are selected from the group consisting of polyglycolic acid, polylactic acid-glycolic acid copolymer, polylactic acid, polydioxane, polycaprolactone, caprolactone / glycolic acid polyester, and combinations thereof.

17. The wound dressing according to claim 2, wherein, The polymer material is a copolymer of glycolide and ε-caprolactone, polyglactin 910, or a combination thereof.

18. The wound dressing according to claim 1, wherein, The hydrogel forming materials are each of at least two different multifunctional polymers or polymer precursors containing two or more electrophilic or nucleophilic functional groups.

19. The wound dressing according to claim 18, wherein, At least one of the hydrogel-forming materials has two or more nucleophilic functional groups, which react with electrophilic functional groups on the second hydrogel-forming material to form covalent bonds.

20. A method for preparing a wound dressing according to claim 1, comprising melting-blowing microfibers into a mesh sheet, stacking the meltblown sheet, and bonding layers of the meltblown sheet.

21. Use of the wound dressing of claim 1 in the preparation of a product for sealing a tissue surface, comprising applying the wound dressing of claim 1 to an injured tissue surface.

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