Fleece-coated wound dressing

Abstract

This invention relates to an absorbable hemostatic patch that utilizes a biocompatible fiber fabric substrate that is melt-blown and has a napped or loose surface, and that has a low profile, high flexibility, strength and porosity suitable for coating crosslinkable active molecules and ultimately effective as a hemostatic agent in cases of problematic bleeding.

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 available units capable of covalently crosslinking with corresponding co-reactive groups on the substrate. 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 resilient layered nonwoven matrix substrate composed of napped or loosely packed meltblown microfibers at the surface to achieve high tissue adhesion. In the development of highly functional, low-profile hemostatic patches, napped substrates uniquely possess high surface area and suitability for coating with crosslinkable active molecules (e.g., PEG) that would otherwise lack good tissue adhesion properties.

[0003] This invention relates to an absorbable hemostatic nonwoven patch and wound dressing that utilizes a biocompatible fiber fabric substrate meltblown and brushed or loosely packed on its surface; and the substrate has a low profile, high flexibility, strength and porosity suitable for coating with crosslinkable active molecules and ultimately effective as a hemostatic agent in cases of problematic bleeding. Attached Figure Description

[0004] Figure 1 It is a schematic exploded view of a single meltblown patch with raised surface fibers and increased matrix bulkiness through a napping process.

[0005] Figure 2 A comparison of cross-sectional images of un-brushed and different degrees of brushing as substrates is shown.

[0006] Figure 3 The images show suspended (left) and cross-sectional (right) SEM images of un-brushed (top) and brushed (bottom) substrates with the same coating.

[0007] Figure 4 Images of the same coated non-pile (top) and pile (bottom) substrates obtained via micro-CT are shown. Detailed Implementation

[0008] This invention relates to substrates particularly suitable for coating because the napped surface has an increased surface area for coating individual meltblown fibers in a nonwoven substrate. Preferred high substrate bulk is achieved via a napping method that loosens tightly entangled fibers, increasing substrate bulk and overall volume, which allows for greater penetration depth of the subsequently applied coating.

[0009] One of the benefits of this invention is that the resulting wound dressing has multiple sides because the already brushed surface can be easily identified as the brushed and coated side that should be applied to the tissue surface.

[0010] The wound dressing of the present invention exhibits strong patch adhesion to tissue because the brushed surface results in a higher amount of coated fibers and greater surface roughness, both of which together enhance adhesion at the patch-tissue interface.

[0011] Another advantage of this invention is the easy-to-handle low-profile patch, which has a relatively low thickness and density that does not compromise functionality when brushed, and can be easily handled in smaller spaces. The patch may also require reduced sealing compression time.

[0012] Another advantage of the invention is that the degree of napping can be adjusted to allow for specific features, such as reducing stiffness as the degree of napping increases.

[0013] The wound dressing of the present invention exhibits high tissue conformability because the combination of elastic layering and roughened matrix allows for high compliance with tissue should tissue expand or move.

[0014] In one embodiment, the invention can be produced with customized absorption time / biocompatibility because the meltblown nonwoven matrix can be manufactured using biocompatible and absorbable materials by, for example, pre-irradiation and / or adjustment of fiber diameter and polymer structure during melt extrusion and crystallization, respectively.

[0015] In one embodiment, the nonwoven base material is made of an absorbable and biocompatible polyester material such as A copolymer of glycolide and ε-caprolactone is produced by extrusion through a linear die containing hundreds of small holes. A converging stream of hot air refines the molten polymer to form extremely fine fibers. 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 cylinder and the die surface, are selected to obtain preferred fiber diameter and orientation on the formed web, which in turn controls the fiber diameter, pore size, and density of the resulting nonwoven matrix.

[0016] While the cylinder size 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 density of the nonwoven matrix per unit area and is inherently related to fiber diameter, specific surface area, and overall porosity within the layer. Increasing the gap between the polymer extrusion die and the cylinder also affects matrix characteristics, thereby better randomizing fiber thickness and orientation.

[0017] The preferred cylinder speed determined by the present invention is in the range of 0.08 m / s to 0.41 m / s, more preferably 0.12 m / s to 0.37 m / s, most preferably 0.15 m / s to 0.2 m / s, and the distance is in the range of 10 inches to 40 inches, more preferably 15 to 35 inches, and most preferably 20 to 30 inches, in order to customize and generate microporous, waterproof and low profile (thickness) nonwoven membranes.

[0018] These ranges are used The established material properties (e.g., intrinsic viscosity of 1.67) may slightly influence fiber characteristics, 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 (Both Polyglactin 910 and polyglycolic acid) Increasing the cylinder speed will reduce the patch density, and at least the range we have determined is a feasible starting point. Meltblown biodegradable polymers of interest include, but are not limited to, polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), poly(p-dioxanone) (PDS), and caprolactone / glycolic acid polyesters, such as poly(caprolactone-co-glycolic acid).

[0019] The preferred thickness range determined by the present invention before brushing is 0.30 mm to 1.5 mm, more preferably 0.6 mm to 0.95 mm, and most preferably 0.85 mm to 90 mm. Although this initial thickness can vary, after brushing, the present invention determines that the preferred increase in matrix height is approximately 50% to 250% of the original thickness, more preferably 55% to 175%, and most preferably 125% to 165%.

[0020] The preferred density determined by this invention is 140 mg / cm³. 3 -250mg / cm 3 More preferably 140 mg / cm 3 -200mg / cm 3 The optimal concentration is 140 mg / cm³. 3 -150mg / cm 3 Within the expected range. The density is not expected to change significantly after brushing.

[0021] 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 ​​approximately 85%.

[0022] Meltblown polymers offer unique advantages in the production of ultrafine fibers. The meltblown nonwovens of the present invention define fine fibers with a diameter in the range of 1 micrometer to 250 micrometers, preferably in the range of 1 micrometer to 90 micrometers.

[0023] In one embodiment, prior to napping, separate meltblown patches are generated by extruding another sheet of meltblown polyester-based nonwoven fabric onto a collection cylinder before the former sheet crystallizes. Multiple discrete sheets are deposited onto the cylinder to create a multilayer matrix. The surface is then modified by napping to increase the surface area for coating and multi-sided applications. The napping effect is achieved by using abrasive techniques to mechanically raise the fiber ends on the patch surface and simultaneously increasing the matrix bulkiness as the underlying fiber entanglement is loosened during the process.

[0024] Current napping methods employ both manual and automatic tools. For manual napping, the surface of the nonwoven fabric is brushed unidirectionally several times using a steel file card (e.g., 3.75") until the fibers begin to detach from the surface (5-15 times is the preferred working range for this method). For automatic napping, a bench drill with a coiled wire wheel attachment (e.g., 0.25" bar, 3" diameter) is used. Different degrees of napping can also be achieved using other instruments such as glass, wire brushes, and abrasive discs. Additionally, high-pressure air, vacuum, or water jets can be used to loosen the matrix. To achieve extensive napping without destructive abrasion, the matrix can be heated before brushing to soften the fibers. Nailing increases the cross-sectional area and specific surface area available for coating crosslinkable active molecules. Figure 1 This ultimately provides the potential for excellent structural integration of the hemostatic patch with the tissue to enhance adhesion.

[0025] The degree of napping can be characterized by measuring the increased cross-sectional height and area per density produced by this method. The preferred method for a moderately napped surface is to increase the average fiber height to provide a 161% increase in matrix height. Figure 2 (Table 1).

[0026] Table 1. Increasing matrix height from the start of napping

[0027] condition <![CDATA[Density (mg / cm 2 )]]> Matrix height Δ (%) Substrate A; No napping 13.6 - Substrate A; lightly brushed 13.2 54.70 Substrate B; No napping 13.3 - Substrate B; Medium brushing 13.3 161.11 Substrate C; No napping 12.9 - Substrate C; Highly brushed 12.8 252.81

[0028] The optimal method for medium-brushed surfaces increases the cross-sectional area by 152%. Figure 2(See Table 2). In all cases, the density change is minimal.

[0029] Table 2 .

[0030] condition <![CDATA[Non-flocked area (px 2 )]]> <![CDATA[Area after brushing (px 2 )]]> Matrix area Δ (%) Base material A, lightly brushed 26.17 41.15 57.24 Substrate B, medium brushing 26.91 67.88 152.25 Substrate C, highly napped 24.31 129.86 434.18

[0031] Quantitative analysis of the preferred substrates showed that moderate brushing increased the substrate height, surface roughness, and volume by 642%, 672%, and 8999%, respectively (Table 3).

[0032] Table 3 .

[0033] brushed Maximum height (um) Surface roughness Sa (um) Volume (μm^3) none 1006 108 4.4E09 Mild 4635 759 2.7E11 moderate 7503 835 4.0E11 high 10465 1405 5.5E11 No vs. Mild (%) 361 602 5992 No vs. moderate (%Δ) 646 672 8999 No VS height (%Δ) 940 1198 12465

[0034] Coating a substrate without brushing results in poor material permeability and aggregation or clumping, while brushing shows improved coating of individual fibers and better penetration into the substrate. Cross-sectional SEM microscopy shows that brushing alleviates the problem of "flat films," where the coating clumps at the surface, blocking the benefits of the porous structure and increasing stiffness. Figure 3 ).

[0035] Furthermore, more cracks were observed in the non-textured coating. Image analysis confirmed that the non-textured group had only a small number of pores and the void space at the surface accounted for 12% of the total surface area, while the texturized group had 27% of the area.

[0036] The reduced agglomeration in the coated and brushed substrates of individual fibers revealed improved pore volume and void space (15%), which would facilitate blood penetration and enhance the interlocking of the coated fibers with tissue. To further confirm these matrix characteristics, micro-CT imaging was performed to examine the coating on the brushed surface. This visualization not only reaffirmed how brushing improves matrix bulkiness but also resulted in improved coating penetration and increased porosity at the surface. Cross-sectional analysis showed that brushing disrupted the uniform film-like coating seen under non-brushed conditions and effectively dispersed the crosslinking agent without clogging the microporous structure of the matrix substrate. Figure 4 Finally, the porosity increased, and the stiffness decreased by 13.8% and 50%, respectively (Table 4).

[0037] Table 4 .

[0038] Sample Name Total porosity (%) Average stiffness (N / mm) Non-fleece, coated 41.4 0.02 brushed, coated 55.2 0.01

[0039] Functional assessments were performed using a tissue peel test and an in vitro heparinized spleen hemorrhage model. For the qualified peel test, a patch was applied to the skin tissue of the lower leg and compressed in Tris-buffered saline before peeling, and the force was measured at 90°.

[0040] For in vitro assessment of hemostatic efficacy, brushed, coated, non-brushed coated, and uncoated non-brushed patches were used as nonwoven substrates to evaluate hemorrhage reduction. Briefly, each patch was cut into a 1"×1" square and placed on a 10mm circular biopsy defect in an in vitro spleen model (perfused with heparinized bovine blood) for 2 minutes. Quantitative analysis confirmed that hemorrhage in the in vitro model was minimized or completely stopped by using coated brushed meltblown patches.

[0041] These data confirm that, in addition to improved tissue adhesion, the hemostatic patches are fully functional and effective. Different degrees of fraying affected the effectiveness of the hemostatic agent. While all patches did reduce bleeding and ultimately seal to stop it, as previously mentioned, mild or high fraying had reduced effectiveness compared to moderate fraying.

[0042] In one embodiment, the highly adhesive hemostatic patch, composed of a combination of a brushed meltblown matrix substrate and a crosslinkable coating, may use absorbable and biocompatible polyester materials (such as... The meltblown microfiber web is prepared at a cylinder speed of 0.17 m / s (preferably within the test range of 0.09 m / s to 0.34 m / s) and a collector distance of 25 inches (preferably within the range of 12 inches to 25 inches). Four layers can be directly constructed on the collector cylinder, and preferably in the range of 2 to 10 layers. When using an equal to 1.6... At IV, the density of the four-layered structure was approximately 13 mg / cm³. 2 These material characteristics and densities are needed before brushing.

[0043] The preferred brushing degree is achieved through a polishing technique that loosens fiber entanglement, increasing the surface fiber and overall matrix height by approximately 161%, and preferably in the range of 55%–253%, while the cross-sectional area subsequently increases by approximately 152%, and preferably in the range of 57%–434%. The resulting substrate can have increases in surface roughness and volume of approximately 676% and 8999%, respectively.

[0044] Pile brushing methods include both manual and automatic tools. Manual pile brushing can be achieved using, but is not limited to, wire brushes, steel file cards, glass, or similar tools / materials with rough edges that can be used to produce abrasion. To achieve a preferred degree of pile brushing, the surface of the nonwoven fabric is brushed unidirectionally several times using a steel file card (3.75") until the fibers begin to tear off from the surface (for this method, 5-15 strokes are a preferred working range, where 5 strokes result in “light” pile brushing and 15 strokes result in “heavy pile brushing”). Alternatively, automatic pile brushing methods include, but are not limited to, bench drills used with coiled wire wheels (e.g., 0.25" bar, 3" diameter) or other brush-based attachments. Other power-operated equipment and attachments, such as wire brushes and abrasive disc wheels, can also be used to achieve different degrees of pile brushing.

[0045] To achieve a higher degree of napping without damaging abrasion, the matrix can be heated before brushing to soften the fibers. The degree of heating can vary depending on the polymer; for Heat the building block to 50°C for 15 minutes before applying the nap.

[0046] Crosslinkable active materials, such as polyethylene glycol active esters (e.g., PEG-succinimide glutarate), are preferably coated sequentially with or without buffers and additives to form a fully functional hemostatic agent. For practical considerations, a 2-inch by 4-inch meltblown matrix after brushing is ultrasonically sprayed (dissolving method) or dip-coated (non-dissolving method) with a shallow buffer solution deeply embedded in a porous substrate: working examples include 1.25 mg / cm³. 2 Sodium borate, or 2 mg / cm³ 2 Bis-Tris or 1 mg / cm 2 Sodium bicarbonate. Then, ultrasonically coated with 15 mg / cm³. 2 The 4-arm PEG-amine-HCl (molecular weight: 10 kDa) was then ultrasonically coated with 18 mg / cm³. 2 The 4-arm PEG-SG (molecular weight: 10 kDa) has a brushed structure that allows for the unique deposition of crosslinkable active substances, resulting in enhanced tissue adhesion.

[0047] Exemplary plasma-derived (or related) hemostatic agents include proteins and peptides, and are therefore not limited to natural hemostatic agents, and may be in recombinant or synthetic forms; prothrombin, thrombin, fibrin, fibronectin, 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.

[0048] 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 D-lactic acid, L-lactic acid, lactide (including L-, D-, and meso forms), glycolic acid, glycolide, caprolactone, p-dioxanone, and trimethylene carbonate, as well as mixtures or blends thereof.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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".

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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).

[0058] 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.

[0059] 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.

[0060] In one embodiment, a multifunctional electrophilic polymer, such as a multi-arm PEG functionalized with multiple NHS groups, can be used as a first co-reactive component, and a multifunctional nucleophilic component, such as trilysine, can be used as a second co-reactive component. In other embodiments, a multifunctional electrophilic polymer, such as a multi-target PEG functionalized with multiple NHS groups, can be used as a first co-reactive component, and a multifunctional nucleophilic polymer, such as collagen and / or collagen derivatives, can be used as a second co-reactive component. The multi-arm PEG functionalized with multiple NHS groups can, 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.

[0061] For patch implementations, the co-reactive components can be deposited as a single 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).

[0062] 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.

[0063] 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.

[0064] 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 adding 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 hydrogel 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 in clot stabilization, tissue inward growth, and remodeling during scaffold degradation. 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.

[0065] The following examples are provided for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0066] Examples of substrate and napping methods :

[0067] Use absorbable and biocompatible polyester materials, such as The meltblown microfiber web is extruded onto a cylinder, with the preferred cylinder speed being 0.17 m / s and the distance between the cylinder and the die being 25 inches. When using an equal 1.6... During IV, four layers of this structure were directly constructed on the collector cylinder, resulting in a density of approximately 13 mg / cm³. 2 These material characteristics and densities are needed before brushing.

[0068] After cutting the 2-inch by 4-inch meltblown matrix, the nonwoven patch is gently heated to 50°C for 15 minutes to soften the fibers, and then the surface is brushed unidirectionally using a 4" steel file card to nap it until the overall matrix height increases by approximately 150%.

[0069] Coating method examples :

[0070] Ultrasonic spraying (dissolution method) or dip coating (insoluble material method) is used to coat a 2-inch x 4-inch meltblown textured substrate, embedding a thin layer of buffer deep into the porous substrate. 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. Then, ultrasonically coated with 15 mg / cm³. 2 The 4-arm PEG-amine-HCl (molecular weight: 10 kDa) was then ultrasonically coated with 18 mg / cm³. 24-arm PEG-SG (molecular weight: 10 kDa).

[0071] The brushed construct allows crosslinkable active substances to be uniquely deposited deep into the matrix, ultimately producing a highly effective hemostatic agent with enhanced adhesion.

Claims

1. A wound dressing that functions as a hemostatic agent, the wound dressing comprising a meltblown substrate having at least two main face surfaces and a coating, the coating being applied to at least one of the main face surfaces, the coating being a co-reactive hydrogel-forming material, wherein the coated main face surfaces are brushed, and wherein each of the co-reactive hydrogel-forming materials is at least two different multifunctional polymers or polymer precursors comprising two or more electrophilic or nucleophilic functional groups.

2. The wound dressing according to claim 1, wherein the wound dressing has a concentration of 140 mg / cm³. 3 -250mg / cm 3 Density within the range.

3. The wound dressing according to claim 2, wherein the wound dressing has a concentration of 140 mg / cm³. 3 -200mg / cm 3 The density.

4. The wound dressing according to claim 3, wherein the wound dressing has a concentration of 140 mg / cm³. 3 -150mg / cm 3 The density.

5. The wound dressing according to claim 1, wherein the wound dressing has pores, and most of the pores are in the range of 0.1 mm to 0.3 mm as measured by micro-CT analysis.

6. The wound dressing according to claim 1, wherein the wound dressing has a total open porosity of 85% as measured by micro-CT analysis.

7. The wound dressing according to claim 1, wherein the meltblown substrate is a bioabsorbable polymer material selected from polyglycolic acid, poly(lactic-co-glycolic acid), polylactic acid, polydioxane, caprolactone / glycolic acid polyester, poly(caprolactone-co-glycolic acid), and combinations thereof.

8. The wound dressing according to claim 1, wherein the meltblown substrate is a copolymer of glycolide and ε-caprolactone.

9. The wound dressing of claim 1, wherein at least one of the hydrogel-forming materials has two or more nucleophilic functional groups, the two or more nucleophilic functional groups reacting with electrophilic functional groups on the second hydrogel-forming material to form covalent bonds.

10. A method for preparing a wound dressing according to claim 1, comprising melting-blowing microfibers into a mesh sheet, layering the meltblown sheet, bonding the meltblown sheet layers, napping, and coating the main exposed surface of the bonded meltblown sheet layers.

11. The method of claim 10, wherein the wound dressing has an original thickness in the range of 0.30 mm to 1.5 mm and a matrix height increase in the range of 50% to 250% relative to the original thickness before being brushed.

12. The method of claim 10, wherein the wound dressing has an original thickness in the range of 0.6 mm to 0.95 mm and a matrix height increase in the range of 55% to 175% relative to the original thickness before being brushed.

13. The method of claim 10, wherein the wound dressing has an original thickness in the range of 0.85 mm to 0.90 mm and a matrix height increase in the range of 125% to 165% relative to the original thickness before being brushed.

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