napped coated wound dressing

Abstract

The present invention relates to an absorbent hemostatic patch using a biocompatible fibrous fabric substrate that is melt-blown, napped, or loosened on the surface, wherein the substrate has a low profile, high flexibility, strength, and porosity suitable for coating crosslinkable active molecules and is ultimately effective for use as a hemostatic agent in problematic bleeding situations.

Description

Background Technology

[0001] Absorbable hemostatic patches containing two crosslinkable components are described in literature including U.S. Patent Application Publication No. 2011 / 0045047 A1. The crosslinkable component for such patches may be a pair of co-reactive compounds, or a substrate coated with a co-reactive compound having available units capable of forming covalent crosslinks with corresponding co-reactive groups on the substrate. Plasma-derived biological components that initiate, enhance, and / or support the hemostatic cascade for the formation of fibrin clots have also been applied to substrates of various compositions and materials.

[0002] The present invention relates to an absorbable hemostatic patch for sealing, and more specifically, to an economically feasible elastic-layered nonwoven matrix substrate composed of melt-blown microfibers that are napped or loosened on the surface for high tissue adhesion. The napped substrate has an inherently high surface area and suitability for coating crosslinkable active molecules (e.g., PEG) in the development of high-performance low-profile hemostatic patches, otherwise excellent tissue adhesion properties would be lacking.

[0003] The present invention relates to an absorbent hemostatic nonwoven patch and wound dressing using a biocompatible fibrous fabric substrate that is melt-blown or loosened on the surface, wherein the substrate has a low profile, high flexibility, strength, and porosity suitable for coating crosslinkable active molecules and ultimately effective for use as a hemostatic agent in bleeding situations where bleeding is problematic. Brief explanation of the drawing

[0004] Figure 1 is a schematic exploded view of a freestanding melt-blown patch in which the matrix loft is increased and the surface fibers are raised by a napping method. Figure 2 is a cross-sectional image of a substrate, illustrating a comparison between an unbrushed substrate and a substrate brushed to varying degrees. Figure 3 illustrates planar (left) and cross-sectional (right) SEM images of an unbrushed substrate (top) and a brushed substrate (bottom) coated in the same way. Figure 4 illustrates images of an unbrushed substrate (top) and an unbrushed substrate (bottom) coated identically through micro CT. Specific details for implementing the invention

[0005] The present invention relates to a matrix particularly suitable for coating because the napped surface has an increased surface area for coating individual melt-blown fibers in a nonwoven matrix. A desirable high matrix loft is produced through a napping process that loosens tightly intertwined fibers, thereby enabling a greater penetration depth for a subsequently applied coating layer and increasing the matrix loft and overall volume.

[0006] One of the advantages of the present invention is that the resulting wound dressing has laterality, because the napped surface can be easily identified as the napped and coated surface to be applied to the tissue surface.

[0007] The wound dressing of the present invention exhibits strong patch adhesion to tissue because the napped surface results in both a larger amount of coated fibers and greater surface roughness, which enhance adhesion together at the patch-tissue interface.

[0008] Another advantage of the present invention is an easy-to-handle, low-profile patch having a relatively low thickness and density that can be easily handled in a smaller space without compromising functionality when napped. The patch may also need to reduce the compression time for sealing.

[0009] Another advantage of the present invention is that specific characteristics can be enabled by adjusting the degree of napping, for example, stiffness can be reduced by increasing the degree of napping.

[0010] Since the combination of the elastic layer and the roughened matrix enables high conformity with the tissue when the tissue expands or moves, the wound dressing of the present invention exhibits high tissue conformability.

[0011] In one embodiment, since a melt-blown nonwoven matrix can be produced using biocompatible and absorbent materials by controlling, for example, fiber diameter and polymer structure during melt extrusion and crystallization and / or by pre-irradiation, the present invention can be produced to have customized absorption time / biocompatibility.

[0012] In one embodiment, the nonwoven base material is produced from an absorbent and biocompatible polyester material, such as Monocryl (trademark), a copolymer of glycolide and epsilon-caprolactone, by extrusion through a linear die containing hundreds of small orifices. A converging stream of hot air elongates the molten polymer to form fibers of extremely fine diameter. High-speed air blows the fibers onto a collecting drum to form a single sheet of melt-blown nonwoven fabric. Process factors, such as drum speed and the distance between the drum and the surface of the die, are selected to obtain a desired fiber diameter and the orientation of the fibers in the formed web, which ultimately controls the resulting fiber diameter, pore size, and density of the nonwoven matrix.

[0013] The drum size depends on the length of the polymer-extrusion die but is arbitrary and can be scaled up for the large-scale production of melt-blown sheets. Drum speed is inversely proportional to the nonwoven matrix density per unit area and is essentially related to the fiber diameter, specific surface area, and total porosity of the layer. Collector distance also affects matrix properties, as increasing the gap between the polymer-extrusion die and the drum better randomizes fiber thickness and orientation.

[0014] The present invention has determined that, in order to customize and produce a microporous, water-impermeable, and low-profile (thickness) nonwoven film, the preferred drum speed is in the range of 0.08 to 0.41 m / s, more preferably 0.12 to 0.37 m / s, most preferably 0.15 to 0.2 m / s, and the distance is in the range of 10 to 40 inches, more preferably 15 to 35 inches, most preferably 20 to 30 inches.

[0015] This range was established using Monocryl (Trademark), where material properties (e.g., intrinsic viscosity of 1.67) may have a small effect on fiber properties, which ultimately affect the porosity, density, and stiffness of the entire matrix. However, this range should exhibit the same trend regardless of material specifications (e.g., increasing drum speed will decrease patch density for Monocryl (Trademark), Vicryl (Trademark), Polyglactin 910, and Polyglycolic Acid, and at least the range determined by the inventors is a viable starting point). Biodegradable polymers of interest that can be melt-blown include, but are not limited to, Polyglycolic Acid (PGA), Poly(Lactic Acid-Co-Glycolic Acid) (PLGA), Polylactic Acid (PLA), Polydioxanone (PDS), and Caprolactone / Glycolide polyesters, such as Poly(Caprolactone-Co-Glycolide).

[0016] The present invention has determined that a preferred thickness is in the range of 0.30 to 1.5 mm before napping, more preferably 0.6 to 0.95 mm, and most preferably 0.85 to 0.90 mm. While this starting thickness may vary, the present invention has determined that, after napping, a preferred increase in matrix height is in the range of approximately 50 to 250% of the original thickness, more preferably 55 to 175%, and most preferably 125 to 165%.

[0017] The present invention has confirmed that the preferred density is in the range of 140 to 250 mg / cm³, more preferably 140 to 200 mg / cm³, and most preferably 140 to 150 mg / cm³. The density is not expected to change, particularly after napping.

[0018] Based on micro-CT analysis, the present invention confirmed that the preferred pore size distribution is in the range of 0.01 to 0.5 mm, and most pores are in the range of 0.1 to 0.3 mm. Additionally, from micro-CT analysis, the present invention confirmed that the total open porosity of the matrix is ​​approximately 85%.

[0019] Meltblowing of these polymers offers unique advantages in producing ultrafine fibers. The melt-blown nonwoven fabric of the present invention has been identified as a microfiber with a diameter in the range of 1 to 250 micrometers, preferably in the range of 1 to 90 micrometers.

[0020] In one embodiment, a standalone melt-blown patch prior to napping is created by extruding another sheet of melt-blown polyester nonwoven onto a collection drum prior to crystallization of the previous sheet. A plurality of distinct sheets are deposited onto the drum to create a multilayer matrix. Subsequently, the surface is modified by napping to increase the surface area and laterality for coating. The napping effect can be achieved by mechanically raising the ends of the fibers on the surface of the patch using a polishing technique, and simultaneously increasing the matrix loft as the entanglement of the fibers beneath the surface is loosened by the process.

[0021] Current mowing methods use both manual and automatic tools. For manual napping, a steel file card (e.g., 3.75") is used to brush the surface of the nonwoven fabric unidirectionally multiple times until the fibers begin to detach from the surface (5 to 15 times is the preferred working range for this method). For automatic napping, a bench-top drill press is used with a crimped wire wheel attachment (e.g., 0.25" stem, 3" diameter). Other devices, such as glass, wire brushes, and abrasive flap wheels, may also be used to achieve different degrees of napping. Additionally, high-pressure air, vacuum, or water jets may also be used to loosen the matrix. To achieve extensive napping without destructive abrasion, heat can be applied to the matrix prior to brushing to soften the fibers. Napping increases the cross-sectional area and specific surface area to coat crosslinkable active molecules, which ultimately provide the possibility for excellent structural integration between the hemostatic patch and the tissue for enhanced adhesion (Fig. 1).

[0022] The degree of napping can be characterized by measuring the increased cross-sectional height and area per density resulting from the process. The most desirable process for moderately napping the surface is to raise the average fibers to provide a 161% increase in matrix height (Fig. 2; Table 1).

[0023] [Table 1]

[0024]

[0025] The most desirable process for moderately napping the surface increases the cross-sectional area by 152% (Fig. 2, Table 2). In all cases, the change in density is minimal.

[0026] [Table 2]

[0027]

[0028] Quantitative analysis of the desirable substrate showed that the moderate napping increased the matrix height, surface roughness, and volume by 642%, 672%, and 8999%, respectively (Table 3).

[0029] [Table 3]

[0030]

[0031] When the matrix was coated without napping, penetration was poor and the material clumped or aggregated, whereas napping exhibited improved coating of individual fibers and superior penetration into the matrix. Cross-sectional SEM microscopy showed that napping mitigated the problem of a "flat film" where the coating caked on the surface, blocking the benefits of the porous structure and increasing stiffness (Fig. 3).

[0032] Additionally, more cracks were observed in the non-brushed coating. Image analysis confirmed that the non-brushed group had a small number of pores and void spaces only on the surface covering 12% of the total surface area, whereas the brushed group had 27% of the surface area.

[0033] The coating of individual fibers and reduced clumping in the napped substrate exemplified improved pore volume and pore space (15%), which are beneficial for blood percolation and enhanced interlocking of coated fibers with tissue. To further confirm these matrix characteristics, micro-CT imaging was performed to understand the coating on the napped surface. Through visualization, it was reconfirmed how napping improved matrix loft, as well as resulting in improved penetration of the coating and increased porosity on the surface. Cross-sectional analysis revealed that napping effectively dispersed the crosslinking agent and disrupted the uniform film-like coating visible in the unnapping state without blocking the microporous structure of the matrix substrate (Fig. 4). Finally, porosity was improved, and stiffness was reduced by 13.8% and 50%, respectively (Table 4).

[0034] [Table 4]

[0035]

[0036] Functional evaluations were performed using tissue dissection tests and a heparin-treated spleen in vitro hemorrhage model. For the qualified dissection test, a patch was applied to calf dermal tissue, dissected after compression in Tris-buffered saline, and the force was measured at 90°.

[0037] For in vitro evaluation of hemostatic efficacy, napped and coated nonwoven substrates, unnapping and coated nonwoven substrates, and unnapping and uncoated nonwoven substrates were evaluated for the reduction of bleeding. Briefly, each patch was cut into a 1"x1" square and placed over a 10 mm circular biopsy defect in an in vitro spleen model (perfused with heparin-treated bovine blood) with tamponade for 2 minutes. Quantitative analysis confirmed that bleeding was minimized or completely stopped in the in vitro model by the use of the coated napped melt-blown patch.

[0038] These data confirmed that the hemostatic patches were fully functional and effective, in addition to improved tissue adhesion. Various levels of napping affected the efficacy of the hemostatic agent. While all patches reduced bleeding and ultimately sealed and stopped it, mild or high napping, as previously described, showed reduced efficacy compared to moderate napping.

[0039] In one embodiment, a high-adhesion hemostatic patch can be manufactured from a melt-blown microfiber web using an absorbent and biocompatible polyester material such as Monocryle (Trademark), with a drum speed within a tested range of 0.17 m / s, preferably 0.09 to 0.34 m / s, and a collector distance within a range of 25 inches, preferably 12 to 25 inches, comprising a napped melt-blown matrix substrate combined with a crosslinkable coating. Four layers, preferably in the range of 2 to 10 layers, can be directly constructed on the collector drum. When using Monocryle (Trademark) with an IV of 1.6, the density obtained of the four-layer structure is approximately 13 mg / cm². These material characteristics and densities are required prior to napping.

[0040] A desirable degree of napping is achieved by a polishing technique that loosens fiber entanglement, raises surface fibers, and increases the cross-sectional area by approximately 152%, preferably 57% to 434%, while increasing the total matrix height by approximately 161%, preferably in the range of 55 to 253%. The resulting substrate may have surface roughness and volume increased by approximately 676% and 8999%, respectively.

[0041] The napping method includes both manual and automatic tools. Manual napping can be achieved by, but is not limited to, a wire brush, a steel pile card, glass, or similar tool / material having a rough edge that can be used to produce abrasion. To achieve a desired degree of napping, the surface of the nonwoven fabric is brushed unidirectionally several times using a steel pile card (3.75") until the fibers begin to tear from the surface (5 to 15 times is a preferred working range for this method, 5 times results in "light" napping and 15 times results in "heavy" napping). Alternatively, the automatic napping method includes, but is not limited to, a bench-top drill press used with a crimped wire wheel (e.g., 0.25" stem, 3" diameter) or other brush-based attachments. Other power devices and attachments, such as wire brushes and abrasive flap wheels, may also be used to achieve different degrees of napping.

[0042] To achieve a higher degree of napping without destructive abrasion, heat can be applied to the matrix before brushing to soften the fibers. The degree of heating may vary depending on the polymer; in the case of Monocrylic (registered trademark), the structure was heated to 50°C for 15 minutes before napping.

[0043] A fully functional hemostatic agent is developed by sequentially coating a crosslinking activator, such as a polyethylene glycol active ester (e.g., PEG-succinimidyl glutarate), preferably with or without a buffer and additive. To implement the idea, a 2-inch x 4-inch melt-blown matrix is ​​ultrasonically spray-coated (solubilization method) or dip-coated (insoluble method) with a light layer of buffer that is deeply embedded into the porous substrate: the example contains 1.25 mg / cm² of sodium borate, or 2 mg / cm² of Bis-Tris, or 1 mg / cm² of sodium bicarbonate. Subsequently, 15 mg / cm² of 4-ammonium-PEG-amine-HCl (MW:10Kda) is ultrasonically coated, followed by 18 mg / cm² of 4-ammonium-PEG-SG (MW:10Kda). The napped structure enables the unique deposition of crosslinking activators that result in enhanced tissue adhesion.

[0044] Exemplary plasma-derived (or plasma-related) hemostatic agents include proteins and peptides, and are therefore not limited to natural hemostatic agents and may be of the following recombinant or synthetic forms: 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 analogs, epinephrine, selectin, plasminogen activator inhibitors, platelet activators, synthetic peptides, and any combination thereof having hemostatic activity.

[0045] The carrier sublayers may be in the form of nonwoven materials. An exemplary constituent material is a synthetic polymer. The substrate may be composed of a component selected from 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.

[0046] The substrate may alternatively or additionally consist of a layer of fabric of an aliphatic polyester polymer, copolymer, or blend thereof. Aliphatic polyesters are typically synthesized from ring-opening polymerization of monomers including, but not limited to, lactide (including L- and D-, meso forms), glycolic acid, glycolide, caprolactone, p-dioxanone (1,4-dioxan-2-one), and trimethylene carbonate (1,3-dioxan-2-one). In some cases, aliphatic polyesters may be prepared, for example, by polycondensation of D-lactic acid, L-lactic acid, and / or glycolic acid. In one form, the fabric comprises a copolymer of glycolide and lactide, with an amount of glycolide in the range of about 70 to 95% by molar and the remainder being lactide.

[0047] The porous substrate of the dressing has openings or pores over at least a portion of its surface. As described in more detail below, materials suitable for forming the porous substrate include, but are not limited to, fibrous structures. In an embodiment, the pores may exist in a number and size sufficient to be interconnected across the entire thickness of the porous substrate.

[0048] One or more sublayers of the porous substrate may have a thickness of at least 0.1 cm, and in a given embodiment, a thickness of about 0.2 to about 1.5 cm. The size of the pores within the sublayers of the porous substrate may be about 2 micrometers to about 300 micrometers, and in an embodiment, about 50 micrometers to about 150 micrometers. It is considered that the pores of the sublayers of the substrate may be arranged in any manner within the substrate. For example, the pores may be configured in a random or uniform manner. In some embodiments, the pores may be formed using calcium or copper alginate to create a honeycomb-shaped porous substrate. In another embodiment, the pores may be configured to create a gradient in the porous substrate. The gradient may further enhance the ability of the porous substrate to absorb physiological fluid and guide the movement of the physiological fluid, which carries the first co-reactive component, toward the second co-reactive component.

[0049] In one embodiment, the substrate has a first co-reactive component applied on a first sublayer and a second co-reactive component applied thereto. The terms "first co-reactive component" and "second co-reactive component" each mean a polymer, functional polymer, macromolecule, small molecule, or crosslinking agent capable of participating in a reaction to form a network of crosslinked molecules such as a hydrogel.

[0050] In one embodiment, each of the first co-reactive component and the second co-reactive component is polyfunctional, meaning that it comprises two or more electrophilic or nucleophilic functional groups such that, for example, a nucleophilic functional group on the first co-reactive component can react with an electrophilic functional group on the second co-reactive component to form a covalent bond. Since at least one of the first or second co-reactive components comprises more than two functional groups, the precursors are combined to form a cross-linked polymer product as a result of an electrophilic-nucleophilic reaction. This reaction is referred to as a "cross-linking reaction."

[0051] In a given embodiment, each of the first co-reactive component and the second co-reactive component comprises only one category of functional group, namely only nucleophilic or only electrophilic functional group, as long as both the nucleophilic precursor and the electrophilic precursor are used 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. Thus, functional polymers such as proteins, poly(allylamine), styrene sulfonic acid, or amine-terminated difunctional or polyfunctional poly(ethylene glycol) ("PEG") may be used.

[0052] The first co-reactive component and the second co-reactive component may have a water-soluble core that is biologically inert. Where the core is a water-soluble polymer region, preferred polymers that may be used include polyethers, for example, polyalkylene oxides, such as polyethylene glycol ("PEG"), polyethylene oxide ("PEO"), polyethylene oxide-co-polypropylene oxide ("PPO"), co-polyethylene oxide block or random copolymers, and polyvinyl alcohol ("PVA"); poly(vinylpyrrolidinone) ("PVP"); poly(amino acids); poly(saccharides), such as dextran, chitosan, alginate, carboxymethylcellulose, cellulose oxide, hydroxyethylcellulose, hydroxymethylcellulose, hyaluronic acid; and proteins, such as albumin, collagen, casein, and gelatin. Polyethers, and more specifically poly(oxyalkylene) or poly(ethylene glycol) or polyethylene glycol, are particularly useful. When the core is effectively a small molecule, any various hydrophilic functional groups can be used to make the first co-reactive component and the second co-reactive component water-soluble. For example, water-soluble functional groups such as hydroxyl, amine, sulfonate, and carboxylate can be used to make the precursor water-soluble. Additionally, although the N-hydroxysuccinimide ("NHS") ester of suberic acid is insoluble in water, the NHS ester of suberic acid can be made water-soluble by adding a sulfonate group to the succinimide ring without affecting its reactivity to the amine group.

[0053] In a given embodiment, both the first co-reactive component and the second co-reactive component may be large molecules capable of crosslinking. For example, in an embodiment, one of the precursors may be a polyfunctional PEG having a molecular weight of about 2,000 to about 20,000 daltons. In an embodiment having an electrophilic group, this polyfunctional PEG may be reacted with collagen having a molecular weight of about 100,000 daltons. In another embodiment, gelatin having a molecular weight of about 50,000 to about 100,000 daltons may be used instead of collagen.

[0054] In an alternative embodiment, a co-reactive component and a buffer are provided on the patch. An exemplary sealing patch / pad comprises PEG-NH2*HCl and PEG-NHS, buffer salt formulations, preferably as an alkaline buffer (Borax) deposited on an absorbent substrate.

[0055] If it is required that the biocompatible cross-linked polymer produced from the reaction of the first co-reactive component and the second co-reactive component be biodegradable or absorbable, one or more of the first co-reactive component and the second co-reactive component may have biodegradable bonds present between their functional groups. The biodegradable bonds may optionally also serve as a water-soluble core of one or more precursors. Alternatively or additionally, the functional groups of the first co-reactive component and the second co-reactive component may be selected such that the product of the reaction between them forms biodegradable bonds. For each approach, the biodegradable bonds may be selected so that the resulting biodegradable biocompatible cross-linked polymer degrades, dissolves, or is absorbed within a desired period. Preferably, biodegradable bonds that degrade into non-toxic products under physiological conditions are selected.

[0056] Biodegradable bonds may be chelates, or may be chemically or enzymatically hydrolyzable or absorbable. Exemplary chemically hydrolyzable biodegradable bonds include polymers, copolymers, and oligomers of glycolide, 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). In embodiments, biodegradable bonds may include 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.

[0057] In an embodiment, a polyfunctional electrophilic polymer, such as multi-arm PEG functionalized with multiple NHS groups, may be used as the first co-reactive component, and a polyfunctional nucleophilic component, such as trilysine, may be used as the second co-reactive component. In another embodiment, a polyfunctional electrophilic polymer, such as multi-arm PEG functionalized with multiple NHS groups, may be used as the first co-reactive component, and a polyfunctional nucleophilic polymer, such as collagen and / or collagen derivatives, may be used as the second co-reactive component. Multi-arm 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 suitable first and second precursors are U.S. Patents No. 6,152,943; No. 6,165,201; No. 6,179,862; No. 6,514,534; Described in No. 6,566,406; No. 6,605,294; No. 6,673,093; No. 6,703,047; No. 6,818,018; No. 7,009,034; and No. 7,347,850, the full contents of each of which are incorporated herein by reference.

[0058] In the case of patch embodiments, co-reactive components may be deposited on the matrix as individual layers. Alternatively, co-reactive components may be deposited as a mixture. The order of the layers may be changed, but a preferred order is a sealing patch or pad comprising PEG-NH2*HCl (or any other hydrohalide), PEG-NHS, and a buffer salt (e.g., sodium tetraborate, MES, TRIS, Bis-Tris, sodium bicarbonate) in the matrix, followed by a layer of buffer salt, a layer of protected PEG-amine, and a layer of PEG-NHS. Additionally, while the number of arms and molecular weight of the materials may be changed, 4-arm-10K-NH2*HCl and 4-arm-10K-NHS are preferred variations in terms of efficacy and stability. Embodiments were evaluated with different coating orders. Performance and stability are significantly affected by the location of the buffer deposited on the matrix using a spray-coating process. Performance and stability were optimal when the buffer was deposited under both PEGs (i.e., furthest from the tissue when the matrix is ​​applied).

[0059] The first co-reactive component may be applied to a porous substrate using any suitable method known to those skilled in the art, including but not limited to spraying, brushing, dipping, pouring, laminating, etc. In an embodiment, the first co-reactive component may be applied as a coating on the substrate at any concentration, dimension, and composition capable of forming a hemostatic dressing. In an embodiment, the coating of the first co-reactive component may penetrate into the pores of the porous substrate. In an embodiment, the first co-reactive component may be applied to the porous substrate as a film that is laminated onto at least one surface of the substrate.

[0060] The second co-reactive component may likewise 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, pouring, laminating, etc. In another embodiment, after applying the second co-reactive component as a solution to the porous substrate, the solvent may be evaporated or freeze-dried. In an embodiment, the second co-reactive component may be applied to the porous substrate as a coating on at least one surface of the substrate or as a film laminated on at least one surface of the substrate.

[0061] During use, the patch dressing is oriented so that the co-reactive components are applied directly onto the tissue. In embodiments, the first and second parts may be distinguished from one another by the addition of contrast dyes, surface texturing, coloring, or other visual cues. For example, upon contact with tissue, such as damaged tissue, the dressing will absorb physiological fluid, and the first co-reactive hydrogel component will be dissolved by the fluid. As the fluid wicks into the dressing and moves through it, it will transport the dissolved first co-reactive component into the second co-reactive component and the buffer. Eventually, the first co-reactive component and the second co-reactive component react to form a biocompatible cross-linked material that will assist in clot stabilization, tissue regeneration, and remodeling as the scaffold degrades. In some embodiments, the biocompatible cross-linked material produced by the reaction of the first and second co-reactive components also provides anti-adhesion properties to the dressing.

[0062] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

[0063] Matrix and napping process examples:

[0064] Meltblown microfiber webs are extruded onto a drum using an absorbent and biocompatible polyester material, such as Monocryle (Trademark), at the most desirable drum speed of 0.17 m / s and a drum distance to the die of 25 inches. When using Monocryle (Trademark) with an IV of 1.6, four layers are constructed directly onto the collector drum in this configuration, with a resulting density of approximately 13 mg / cm². These material characteristics and densities are required prior to napping.

[0065] After cutting into a 2-inch x 4-inch melt-blown matrix, the nonwoven patch is gently heated to 50°C for 15 minutes to soften the fibers, and then the surface is napped by brushing it in one direction using a 4" steel pile card until the total matrix height increases by approximately 150%.

[0066] Coating process example:

[0067] A 2-inch x 4-inch melt-blown napped matrix is ​​ultrasonically spray-coated (solubilization method) or dip-coated (insoluble method) with a light layer of buffer embedded deep within the porous substrate. The example comprises 1.25 mg / cm² of sodium borate, 2 mg / cm² of Bis-Tris, or 1 mg / cm² of sodium bicarbonate. Subsequently, 15 mg / cm² of 4-arm-PEG-amine-HCl (MW:10Kda) is ultrasonically coated, followed by 18 mg / cm² of 4-arm-PEG-SG (MW:10Kda).

[0068] The napped structure allows for the unique deposition of crosslinking agents deep into the matrix, which ultimately results in highly effective hemostasis along with enhanced adhesion.

Claims

Claim 1 A wound dressing comprising a melt-blown matrix substrate having at least two melt-blown sheets, wherein the at least two melt-blown sheets are in a napped state and have a tissue-facing surface coated with a coating layer, the coating layer is selected from the group consisting of a co-reactive hydrogel-forming material, one or more plasma-based hemostatic agents and combinations thereof, the co-reactive hydrogel-forming material is formed by crosslinking of a first co-reactive component and a second co-reactive component, the first co-reactive component is a nucleophilic polymer selected from polymers containing amine or thiol functional groups, and the second co-reactive component is an electrophilic polymer containing N-hydroxysuccinimide or sulfosuccinimide functional groups. Claim 2 In claim 1, the wound dressing has an original thickness in the range of 0.30 to 1.5 mm before napping, and has an increase in matrix height in the range of 50 to 250% of the original thickness. Claim 3 In claim 1, the wound dressing has an original thickness in the range of 0.6 to 0.95 mm before napping and an increase in matrix height in the range of 55 to 175% of the original thickness. Claim 4 In claim 1, the wound dressing has an original thickness in the range of 0.85 to 0.90 mm before napping and an increase in matrix height in the range of 125 to 165% of the original thickness. Claim 5 A wound dressing according to claim 1, having a density in the range of 140 to 250 mg / cm³. Claim 6 A wound dressing having a density of 140 to 200 mg / cm³ in paragraph 2. Claim 7 In paragraph 3, a wound dressing having a density of 140 to 150 mg / cm³. Claim 8 A wound dressing according to claim 1, wherein the pore size distribution is in the range of 0.1 to 0.3 mm when measured by micro-CT analysis. Claim 9 A wound dressing according to claim 1, having a total open porosity of 85% when measured by micro-CT analysis. Claim 10 A wound dressing according to claim 1, wherein the melt-blown matrix substrate is a bioabsorbable polymer material selected from the group consisting of polyglycolic acid (PGA), poly(lactic acid-co-glycolic acid) (PLGA), polylactic acid (PLA), polydioxanone (PDS), caprolactone / glycolide polyester, poly(caprolactone-co-glycolide), and combinations thereof. Claim 11 A wound dressing according to claim 1, wherein the melt-blown matrix substrate is a copolymer of glycolide and epsilon-caprolactone. Claim 12 A wound dressing according to claim 1, wherein the hemostatic agent is selected from 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 analogs, epinephrine, selectin, plasminogen activator inhibitor, platelet activator, synthetic peptide, and any combination thereof having hemostatic activity. Claim 13 A method for manufacturing a wound dressing according to claim 1, comprising the steps of melt-blowing microfibers, laminating melt-blown sheets, bonding the layers of the melt-blown sheets, and napping and coating the exposed surface of the bonded layers of the melt-blown sheets. Claim 14 delete Claim 15 delete Claim 16 delete

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