Melt broadening with gradient density

Abstract

The present invention is directed to an absorbable hemostatic nonwoven patch utilizing a biocompatible substrate comprised of meltblown microfibers as layered, bonded / entangled web-like sheets of decreasing density and increasing porosity, with the substrate having high flexibility, strength, and porosity suitable for coating crosslinkable active molecules, as well as the capability for laparoscopic or trocar deployment, and ultimately to an absorbable hemostatic nonwoven patch and wound dressing for functional use as a highly effective hemostat to address problematic bleeding in both incisional and minimally invasive surgical procedures.

Description

[Background technology]

[0001] Absorbable hemostatic patches containing two cross-linking moieties have been described in the literature, such as US Patent Application Publication No. 2011 / 0045047(A1). The cross-linking moieties for such patches can be pairs of co-reactive compounds or substrates coated with co-reactive compounds having available units capable of forming covalent cross-links with corresponding co-reactive groups on the substrate and / or in the target bleeding site tissue. Plasma-derived biological components that initiate, enhance, and / or support the hemostatic cascade to produce a fibrin clot have also been applied onto substrates of various configurations and materials. Summary of the Invention [Means for solving the problem]

[0002] The present invention relates to an absorbent hemostatic patch for sealing, and more specifically to an economically viable elastic layered matrix substrate consisting of meltblown nonwoven microfibers as laminated, bonded / entangled web-like sheets of descending density and increasing porosity. The gradient-based composition improves the coating properties of crosslinkable active molecules such as reactive polyethylene glycol-based compounds (PEGs) or biological moieties, while the laminate introduces a unique distributed stiffness into the matrix structure that allows for trocar deployment, all without compromising the overall malleability / compliance and / or hemostatic effectiveness of the patch. The end result is a highly functional hemostatic patch that can be utilized in both open and minimally invasive surgical procedures to stop problematic bleeding.

[0003] The present invention is directed to a wound dressing comprising a meltblown multi-layer substrate having at least two major opposing surfaces and a coating layer applied to at least one of the major opposing surfaces of a sealant selected from the group consisting of a co-reactive hydrogel-forming material, one or more plasma-based hemostatic agents, and combinations thereof, wherein the meltblown substrate has a gradient porosity profile. The substrate is preferably a multi-layer integrated composite of layers of polymeric material, each layer having a descending density and an increasing porosity relative to adjacent layers. The substrate preferably consists essentially of 4-14 discrete and integrated layers. Each discrete and integrated layer may be about 0.05-0.2 mm thick. The substrate preferably has pores generally with a pore size in the range of 0.1-0.5 mm, more preferably the majority of the pores have a pore size in the range of 0.01-0.3 mm.

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

[0005] The coating is preferably applied such that at least a portion of the coating is on at least one major surface of the substrate and penetrates to a depth of greater than 90% of the substrate thickness, while the overall substrate porosity is greater than 60%. In one embodiment, the coating can penetrate to a depth of greater than 95% penetration. In another embodiment, the coating penetrates to a depth of at least 97%. The overall substrate porosity can 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, such as an average stiffness of about 0.53 N / mm.

[0007] In one embodiment, the polymeric material is selected from a biodegradable polymer selected from the group consisting of polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), polydioxanone (PDS), polycarolactone, caprolactone / glycolide copolymers, and combinations thereof.

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

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

[0010] The hemostatic agent may be selected from 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 glycoproteins, the vasopressin group consisting of vasopressin and analogs, epinephrine, selectins, plasminogen activator inhibitors, platelet activators, synthetic peptides, and any combination thereof having hemostatic activity.

[0011] The present invention is also directed to a method for preparing the wound dressings described herein by meltblowing the microfiber into a web-like sheet, laminating the meltblown sheets, and bonding the laminated meltblown sheets.

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

[0013] The present invention is directed to absorbent hemostatic nonwoven patches and wound dressings utilizing a biocompatible substrate of meltblown microfibers as layered, descending density and increasing porosity bonded / entangled web-like sheets, with the substrate having high flexibility, strength, and porosity suitable for coating crosslinkable active molecules, as well as the capability for laparoscopic or trocar deployment, and ultimately for functional use as a highly effective hemostatic agent to address problematic bleeding in both incisional and minimally invasive surgical procedures. [Brief description of the drawings]

[0014] [Figure 1] FIG. 1 is an exploded schematic of a gradient patch in which meltblown nonwoven sheets are layered with descending density and increasing porosity. [Diagram 2] FIG. 2 is a microscopic (30x) image of a cross-section of a gradient profiling construct that allows for a larger interpenetrating coating within the matrix structure compared to an agglomerated / coherent coating on a non-gradient substrate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The present invention provides a wound dressing that advantageously forms a matrix particularly suitable for coating, having a highly porous layer on the surface that increases the surface area available for coating, allowing deeper coating penetration. Preferably, the wound dressing ultimately provides a means to coat individual meltblown fibers within the body of a complex nonwoven network, instead of agglomerating or forming a film layer on the surface.

[0016] A preferred wound dressing has a substrate layer characterized by a tortuous path and high matrix loft throughout the substrate prior to coating. Layering and stacking of meltblown sheets with descending density and increasing porosity results in a complex nonwoven network that not only enhances the mechanical integrity of the matrix, but also provides the added benefit of allowing blood to penetrate while the hydrogel reactive components and / or biological components hydrate and react to create an integral seal between the substrate and the exterior surface. The desired tortuosity throughout the substrate may also prevent the patch from bulging when attempting to stop higher pressure bleeding.

[0017] Preferred wound dressings exhibit tactility and ease of handling. Due to the increased stiffness resulting from the unique lamination of the meltblown sheets, the patch of the present invention, when applied, has a strong, robust, and resilient structure that provides tactile benefits and is able to conform to tissue during use.

[0018] Preferred wound dressings are laparoscopically deployable in that the unique distribution of stiffness in the matrix construct and structure (especially after coating) provides a "shape memory" that allows the patch to be rolled up, deployed through a trocar, and upon delivery, return to its original shape without permanent deformation.

[0019] A preferred wound dressing is a relatively strong patch that provides good adhesion to tissue. Based on available data, it appears that higher penetration of the reactive components into the backing layer and the porous nature at the surface level provide effective adhesion at the patch-tissue interface.

[0020] Preferred wound dressing properties can be tailored by managing the number of layers along with the fiber structure to allow for specific characteristics, such as increasing stiffness with increasing layers, increasing meltblown extrusion process factors such as drum speed, and the distance between the extrusion die surface and the collection drum to vary porosity.

[0021] Preferred wound dressings have high tissue conformability as a result of the combination of an elastic layer and an open porous interface, which allows for high conformity to tissue as the tissue expands or moves without compromising the enhanced adhesion properties provided by the denser backing.

[0022] Preferred wound dressings can have tailored absorption times / biocompatibility. Meltblown nonwoven matrices can be fabricated using biocompatible and absorbent materials such as Monocryl® that have the ability to tailor properties by adjusting fiber diameter and polymer structure during melt extrusion and post crystallization processing, respectively (e.g., smaller fiber diameters absorb faster).

[0023] In one embodiment, the nonwoven substrate is produced from an absorbent and biocompatible polyester material such as Monocryl® by extrusion through a linear die containing hundreds of small orifices. The molten polymer is attenuated with a converging stream of hot air to form extremely fine diameter fibers. The high velocity air blows the fibers onto a collection drum to form a sheet of meltblown nonwoven. Process factors such as drum speed and the distance between the extrusion die surface and the collection drum are selected to obtain the preferred fiber diameter and orientation that govern the resulting pore size and density of the nonwoven matrix.

[0024] The drum width, while dependent on the length of the polymer extrusion die, is optional and can be scaled up for large-scale production of meltblown sheets. The drum speed is inversely proportional to the patch density per unit area, which is intrinsically related to the fiber diameter, specific surface area, and overall porosity of the layer. The collector distance also affects the matrix properties, since increasing the gap between the polymer extrusion die and the collector drum results in better randomization of the thickness and orientation of the fibers on the web.

[0025] The present invention has identified preferred drum speeds ranging from 4 to 20 RPM, and distances ranging from 10 to 40 inches. Various combinations within these ranges have been utilized to produce layers with descending density and increasing porosity. The collector drum distance is set in the range of 10 to 40 inches, with preferred settings for each layer being identified to achieve the target porosity distribution of the matrix construct.

[0026] This range was established using Monocryl®, where material properties (e.g., 1.67 intrinsic viscosity) have a slight effect on fiber properties, which in turn may affect overall matrix porosity, density, and stiffness. However, this range should show the same trends regardless of material details (e.g., increasing drum speed reduces patch density for both Monocryl® and Vicryl®, so at the very least, the determined range is a viable starting point). Other biodegradable polymers of interest that may be meltblown include, but are not limited to, PGA, PLGA, PLA, PDS, PCL, and caprolactone / glycolide copolymers.

[0027] These ranges are a set of methods for producing any desired density and porosity in a matrix that has been found to be a functional hemostat, however, these density and porosity characteristics can be achieved by adjusting other process factors during melt-blowing extrusion, such as screw speed and extrusion temperature.

[0028] The present invention has identified preferred thicknesses in the range of 0.30-2.5 mm, more preferably in the range of 0.6-1.1 mm, and most preferably in the range of 0.9-1.1 mm. More importantly than the wide range of thicknesses, the gradient and upper porous structures are produced by laminating individual sheets that are all less than 0.5 mm thick, most preferably in the range of 0.05-0.2 mm thick.

[0029] Based on micro-CT analysis, the present invention has identified a preferred pore size distribution in the range of 0.01-0.5 mm, with the majority of the pores in the range of 0.1-0.3 mm. Additionally, from the micro-CT analysis, the present invention has identified a total open porosity of the matrix in the range of 30-90%. The wide range of total porosity is due to the gradient layering of the constituents, with the bottom third of the matrix having a porosity of approximately 30%, the middle third 80%, and the top third (surface) 85%.

[0030] Meltblowing these polymers offers unique advantages in producing ultra-fine fibers, whereas spunbonded filaments, in contrast, do not have the fineness of the meltblowing process. The present invention of the meltblown nonwoven fabric has specified fine fibers in all layers with diameters ranging from 1 to 250 micrometers, preferably from 1 to 90 microns. Considering gradient-based construction, it is preferred that the finer fibers are generally in the upper region of the matrix near the surface. In this regard, it has been determined that the most preferred fiber diameter ranges for the bottom third of the matrix are 10 to 80 micrometers, the middle third 10 to 40 micrometers, and the top third (surface) 1 to 30 micrometers.

[0031] Individual sheets of meltblown polyester-based nonwoven fabric, once manufactured to the desired density and porosity, are used as building blocks in a multi-layer gradient-based patch concept.

[0032] One advantage of the gradient design described herein is the creation of a complex, tortuous path for any material flowing through the matrix. It is envisioned that blood will permeate through the coating layer that is placed in contact with the moist tissue surface and blood clot before reaching the most dense and preferably water-impermeable layer that is furthest from the coating layer. In addition, the matrix is ​​relatively soft / fluffy and has a high "cushion-like" loft that can be useful and easy to handle for the end user.

[0033] The gradient concept is essentially a multi-layer composite of layers constructed with descending density and increasing porosity (Figure 1). Each layer of meltblown polyester-based nonwoven sheet is produced on a collection drum and partially crystallized under an industrial blower for 15 minutes. Subsequent coated layers, either with lower density and / or higher porosity, are then applied on top of the previous layer and bonded to the partially crystallized previous layer.

[0034] In an alternative embodiment, the individual meltblown layers can also be produced separately and then stacked and bonded using either thermal or ultrasonic methods.

[0035] In one embodiment, the matrix has at least 4 discrete layers and up to 14 discrete layers, where each layer was about 0.05-0.2 mm thick. While a minimum number of layers (graded or not) is necessary so that the matrix has structural integrity, there is also a limit to how many meltblown sheets can be stacked together before the matrix substrate becomes too large and rigid for practical applications.

[0036] Substrates with 4 layers without gradient profile result in dramatically different topographies compared to 7 or 14 layers. Applicants have discovered that by increasing the number of layers, the depth of the voids / spaces that the coating can penetrate increases. Relative analysis of the 3D models (Table 1) reveals that the maximum height of the surface pores or void spaces increases by approximately 45% and 200% for 7 and 14 layers, respectively. Relative surface area and volume also increased substantially in the multilayer gradient constructs.

[0037] [Table 1]

[0038] Coating the matrix substrate without the gradient profile resulted in poor penetration and agglomeration or cohesion of the material, whereas the matrix with the gradient profile showed effective coating of individual fibers and improved penetration into the matrix. Advanced microscopy and in-depth compositional analysis showed that the increasing porosity resulted in a unique in-depth coating that individually encapsulated more non-woven fibers instead of agglomerating at the top of the surface. Cross-sectional microscopy at 30x magnification confirmed the gradient construct capable of interpenetrating coating in the matrix structure compared to the agglomerated / coherent coating on the matrix without the gradient. The coating penetrated the matrix with the gradient construct by 42% more. Images also suggested that the mass-dependent coating on the gradient-based surface could better preserve the height and loft of the matrix, whereas the same coating may compact the matrix without the gradient.

[0039] To further corroborate the matrix properties, porosity was assessed by micro-CT imaging and analysis (Table 2).

[0040] [Table 2]

[0041] Despite the higher bulk material, the gradient substrate resulted in 5% more porosity throughout the matrix. The coated gradient patch resulted in 10% more porosity throughout the matrix despite the higher bulk material.

[0042] In one embodiment, a hemostatic patch consisting of a nonwoven gradient-based meltblown substrate is combined with a crosslinkable coating. An exemplary meltblown microfiber sheet is made using an absorbent and biocompatible polyester material such as Monocryl® (IV of 1.67) and layered on a collection drum. Each layer is partially crystallized after melt extrusion, preferably for 15 minutes under an air circulating fan. In the most preferred embodiment, successive layers are layered immediately after a fifteen (15) minute cool down, at which point the previously partially crystallized former layer bonds at both fiber point and point contact areas, creating fiber entanglement. In this embodiment, the entangled laminate structure is partially crystallized again, and the cycle is repeated to build the most preferred gradient-based matrix described in Table 5.

[0043] [Table 3]

[0044] The final construct is allowed to fully crystallize for at least 12 hours in a vacuum chamber and is subsequently stored in a moisture-free environment.

[0045] The most preferred matrix has 7 layers, each with a coating penetration depth of greater than 90%, more preferably greater than 95%, and most preferably at least 97% of the thickness, and a total matrix porosity of greater than 60%, more preferably greater than 65%, and most preferably about 72%. The most preferred patch had an average stiffness of 0.53 N / mm.

[0046] In an alternative embodiment, each meltblown sheet / layer can be produced separately and crystallized in a vacuum chamber for at least 12 hours. The layers are then stacked and either thermally or ultrasonically bonded at pinhole-sized contact points across the 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 coated sequentially with or without buffers and additives to develop a fully functional hemostatic agent. In the top sublayer, co-reactive and crosslinkable components and / or at least one plasma-derived or plasma-related hemostatic agent are provided, with fibrinogen being preferred. In another embodiment, the hemostatic agent may be thrombin or fibrinogen, each individually or in combination.

[0047] Exemplary plasma-derived (or related) hemostatic agents include proteins and peptides, and thus are not limited to only naturally occurring, as the agent can be recombinant or synthetic forms of 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 glycoproteins, the vasopressin group consisting of vasopressin and analogs, epinephrine, selectins, plasminogen activator inhibitors, platelet activators, synthetic peptides, and any combination thereof that have hemostatic activity.

[0048] The carrier sublayer may be in the form of a nonwoven material. Exemplary construction materials are synthetic polymers. The substrate may be comprised 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.

[0049] The substrate may alternatively or additionally comprise a layer of woven aliphatic polyester polymer, copolymer, or blend thereof. Aliphatic polyesters are typically synthesized in a ring-opening polymerization of monomers including, but not limited to, lactide (L- and D-, including meso forms), glycolic acid, glycolide, caprolactone, p-dioxanone (1,4-dioxan-2-one), and trimethylene carbonate (1,3-dioxan-2-one). Aliphatic polyesters may in some cases be made by polycondensation of, for example, D-lactic acid, L-lactic acid, and / or glycolic acid. In one form, the woven fabric comprises a copolymer of glycolide and lactide in an amount ranging from about 70-95% on a molar basis of glycolide and remaining lactide.

[0050] The porous substrate of the dressing has openings, i.e., pores, across 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 some embodiments, the pores may be of sufficient number and size to interconnect 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 certain embodiments, may be about 0.2 to about 1.5 cm thick. The size of the pores in the sublayers of the porous substrate may be about 2 micrometers to about 300 micrometers, in embodiments, about 50 micrometers to about 150 micrometers. It is contemplated that the pores of the sublayers of the substrate may be arranged in any manner in the substrate. For example, the pores may be configured in a random or uniform manner. In some embodiments, calcium alginate or copper alginate may be used to form the pores to create a honeycomb shaped porous substrate. In yet other embodiments, the pores may be configured to create a gradient in the porous substrate. The gradient may further enhance the ability of the porous substrate to absorb physiological fluid and direct the movement of the physiological fluid carrying the first co-reactive component towards the second co-reactive component.

[0052] In one embodiment, the substrate has a first co-reactive component applied onto the first sublayer and a second co-reactive component applied thereto. The terms "first co-reactive component" and "second co-reactive component" refer to a polymer, functional polymer, macromolecule, small molecule, or crosslinker, respectively, that can participate in a reaction to form a network of crosslinked molecules, such as a hydrogel.

[0053] In one embodiment, each of the first and second co-reactive components is multifunctional, meaning that it contains 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. At least one of the first or second co-reactive components contains three or more functional groups, such that the precursors combine to form a crosslinked polymer product as a result of an electrophilic-nucleophilic reaction. Such a reaction is referred to as a "crosslinking reaction."

[0054] In certain embodiments, each of the first and second co-reactive components contains only one category of functional groups, either only nucleophilic groups or only electrophilic functional groups, so long as both nucleophilic and electrophilic precursors 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 an N-hydroxysuccinimide. On the other hand, if the first co-reactive component has an electrophilic functional group such as a 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 di- or multifunctional poly(ethylene glycol)s ("PEGs") can be used.

[0055] The first and second coreactive components may have a biologically inert, water-soluble core. When the core is a water-soluble polymeric region, preferred polymers that may be used include polyethers, e.g., 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); e.g., dextran, chitosan, alginate, carboxymethylcellulose, oxidized cellulose, hydroxyethylcellulose, hydroxyethylcellulose (hyd), ... Examples of suitable core reactive components include poly(saccharides), such as hyaluronic acid, roxynethylcellulose, and hyaluronic acid; and proteins, such as albumin, collagen, casein, and gelatin. Particularly useful are polyethers, more specifically poly(oxyalkylenes) or poly(ethylene glycols), or polyethylene glycols. When the core is essentially small molecule, any of a variety of hydrophilic functionalities can be used to render the first and second coreactive components water soluble. For example, functional groups such as hydroxyl, amine, sulfonic acid, and carboxylic acid, which are water soluble, may be used to render the precursor water soluble. In addition, N-hydroxysuccinimide ("NHS") esters of subaric acid are insoluble in water, but the addition of a sulfonic acid group to the succinimide ring can render the NHS esters of subaric acid water soluble without affecting their reactivity towards amine groups.

[0056] In certain embodiments, both the first and second co-reactive components can be large molecules capable of crosslinking. For example, in embodiments, one of the precursors can be a multifunctional PEG having a molecular weight of about 2,000 to about 20,000 daltons. This multifunctional PEG can react with collagen having a molecular weight of about 100,000 daltons in embodiments having electrophilic groups. In other embodiments, gelatin having a molecular weight of about 50,000 to about 100,000 daltons can be used in place of collagen.

[0057] In an alternative embodiment, the co-reactive component and buffer are provided on the patch. An exemplary occlusive patch / pad is PEG-NH2 * It comprises HCl and PEG-NHS, a buffer salt, preferably an alkaline buffer (borax) deposited on an absorbent substrate.

[0058] If it is desired that the biocompatible crosslinked polymer resulting from the reaction of the first and second co-reactive components is biodegradable or absorbable, one or more of the first and second co-reactive components may have a biodegradable bond present between their functional groups. The biodegradable bond may also optionally serve as the water-soluble core of one or more precursors. Alternatively, or in addition, the functional groups of the first and second co-reactive components may be selected such that the product of the reaction between them results in a biodegradable bond. In each approach, the biodegradable bond may be selected such that the resulting biodegradable biocompatible crosslinked polymer is degraded, dissolved, or absorbed within a desired period of time. Preferably, a biodegradable bond is selected that degrades under physiological conditions into non-toxic products.

[0059] The biodegradable linkages may 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, dioxanone, and trimethylene carbonate. Exemplary enzymatically hydrolyzable biodegradable linkages include peptidic linkages cleavable by metalloproteinases and collagenases. Further exemplary biodegradable linkages 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, the biodegradable linkages may contain ester linkages. Some non-limiting examples include succinic acid, glutaric acid, propionic acid, adipic acid, or amino acid esters, and carboxymethyl esters.

[0060] In certain embodiments, a multifunctional electrophilic polymer, such as a multiarm PEG functionalized with multiple NHS groups, may be used as the first co-reactive component, and a multifunctional nucleophilic component, such as trilysine, may be used as the second co-reactive component. In other embodiments, a multifunctional electrophilic polymer, such as a multiarm PEG functionalized with multiple NHS groups, may be used as the first co-reactive component, and a multifunctional nucleophilic polymer, such as collagen and / or collagen derivatives, may be used as the second co-reactive component. The multiarm PEG functionalized with multiple NHS groups may have, for example, 4, 6, or 8 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 described in U.S. Patent Nos. 6,152,943; 6,165,201; 6,179,862; 6,514,534; 6,566,406; 6,605,294; 6,673,093; 6,703,047; 6,818,018; 7,009,034; and 7,347,850, the entire contents of each of which are incorporated herein by reference.

[0061] In patch embodiments, the coreactive components can be deposited onto the matrix as individual layers. Alternatively, the coreactive components can be deposited as a mixture. The order of layers can vary, but a preferred order of occlusive patch or pad is a matrix, followed by a layer of buffer salt, a layer of protected PEG-amine, and a layer of PEG-NHS, followed by a layer of PEG-NH2. * HCl (or any other halide), PEG-NHS, and buffer salts (sodium tetraborate, MES, TRIS, Bis-Tris, sodium bicarbonate, etc.). Additionally, the number of arms and molecular weight of the material may vary, but from the standpoint of efficacy and stability, 4-arm-10K-NH2 *HCl and 4-arm-10K-NHS are the preferred variants. The embodiment was evaluated with different coating sequences. Performance and stability are greatly affected by the position of the deposition buffer on the matrix using the 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 was applied).

[0062] The first co-reactive component may be applied to the porous substrate using any suitable method known to one of skill in the art, including, but not limited to, spraying, brushing, dipping, pouring, laminating, etc. In embodiments, the first co-reactive component may be applied as a coating on the substrate in any concentration, size, and configuration capable of forming a hemostatic dressing. In embodiments, the first co-reactive component coating may penetrate the pores of the porous substrate. In embodiments, the first co-reactive component may be applied to the porous substrate as a film laminated to at least one side of the substrate.

[0063] Similarly, the second coreactive component may be applied to the porous substrate using any suitable method known to those of skill in the art, including, but not limited to, spraying, brushing, dipping, pouring, laminating, etc. In yet other embodiments, the second coreactive component may be applied to the porous substrate in solution, followed by evaporation of the solvent or freeze-drying. In embodiments, the second coreactive component may be applied to the porous substrate as a coating on at least one side of the substrate, or as a film laminated onto at least one side of the substrate.

[0064] In use, the patch dressing is oriented with the co-reactive component applied directly onto the tissue. In embodiments, the first and second portions may be distinguishable from one another by adding contrast dyes, surface textures, coloring, or other visual cues. Upon contact with tissue, such as injured tissue, the dressing will wick up physiological fluids and the first co-reactive component will be dissolved by the fluid. As the fluid is wicked into the dressing and moves through the dressing, the fluid will carry the dissolved first co-reactive component to the second co-reactive component and buffer. Ultimately, the first and second co-reactive components react to form a biocompatible crosslinked material, thereby aiding in tissue ingrowth and remodeling as the scaffold degrades. In some embodiments, the biocompatible crosslinked material produced by the reaction of the first and second co-reactive components also provides 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 the disclosure.

[0066] Working Example: The improvement of blood percolation within the matrix was illustrated in an ex vivo bleeding model where the gradient conditions were highly effective in stopping bleeding. The gradient patch also became highly compliant after hydration and adhered well to tissue. Qualified peel tests confirmed substantially higher tissue adhesion compared to fibrin-thrombogenic patches.

[0067] Patches with comparable or inferior performance were identified in an ex vivo bleeding model. Applicants found that the number of layers affected efficacy: 5 or fewer layers resulted in poor adhesion and cohesion, while 14 or more layers resulted in high adhesion failure; 7 layers were identified as most preferred.

[0068] The final uniqueness of this construct comes from the matrix stiffness and ability of trocar deployment. The matrix architecture and unique distribution of stiffness within the structure (especially after coating) provides a "shape memory" that allows the patch to be rolled up and deployed through a trocar without deformation. To test this, a 2x2 inch patch was rolled up onto the tip of an 11 mm trocar (Endopath® XCEL Bladeless Trocar) and inserted through an Instron, and the push through force was measured.

[0069] The average stiffness, insertion force, and average force were measured through the trocar: the gradient and non-gradient patches had lower average forces and subsequently less deformation during trocar deployment compared to the non-woven non-gradient substrate. The gradient profiling substrate had higher stiffness, lower insertion force, and lower average force (Table 3).

[0070] [Table 4]

[0071] The gradient patches were also observed after deployment (roll-opening after insertion) and rated for deformation based on maximum lift at the edge (Table 4).

[0072] [Table 5]

[0073] [Table 6]

[0074] Coating process examples: A 2 inch by 4 inch meltblown gradient-based matrix is ​​either ultrasonically spray coated (solubilizing method) or dip coated (insoluble method) with a thin layer of buffer solution embedded deeply into the porous substrate.

[0075] As an example, 1.25 mg / cm 2 of sodium borate, 2 mg / cm 2 of Bis-Tris, or 1 mg / cm 2 Examples of sodium bicarbonate include sodium bicarbonate.

[0076] Then, 15 mg / cm 2 of 4-arm-PEG-amine-HCl (MW: 10 Kda) was ultrasonically coated, followed by 18 mg / cm 2 Ultrasonic coating of 4-arm-PEG-SG (MW: 10 Kda).

[0077] The gradient composition allows for the unique deposition of crosslinkable active agents deep within the matrix, ultimately resulting in a highly effective hemostatic agent.

[0078] [Embodiment] (1) A wound dressing comprising: a meltblown multi-layer substrate having at least two major opposing surfaces; and a coating layer applied to at least one of the major opposing surfaces of a sealant selected from the group consisting of a co-reactive hydrogel-forming material, one or more plasma-based hemostatic agents, and combinations thereof, wherein the meltblown substrate has a gradient porosity profile. (2) The wound dressing of embodiment 1, wherein the substrate is a multi-layered integrated composite of layers of polymeric material, each layer having a decreasing density and increasing porosity relative to adjacent layers. (3) The wound dressing of claim 2, wherein the substrate consists essentially of 4 to 14 discrete layers and an integral layer. (4) The wound dressing of embodiment 3, wherein each of the discrete layers and the integrated layer is about 0.05 to 0.2 mm thick. (5) The wound dressing of claim 1, wherein the substrate has an overall pore size in the range of 0.01 to 0.5 mm.

[0079] (6) The wound dressing of embodiment 5, wherein the majority of the pores have a pore diameter in the range of 0.1 to 0.3 mm. (7) The wound dressing of claim 1, wherein the total open porosity of the substrate is in the range of 30 to 90%. (8) The wound dressing of embodiment 1, wherein 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 up to the coated major surface has an open porosity of about 85%. (9) The wound dressing of embodiment 1, wherein the coating is on at least one major surface of the substrate and penetrates to a depth of greater than 90% of the thickness of the substrate, and the overall porosity of the substrate is greater than 60%. (10) The wound dressing of embodiment 9, wherein the coating penetrates to a depth of greater than 95% penetration.

[0080] (11) The wound dressing of embodiment 9, wherein the coating penetrates to a depth of at least 97%. (12) The wound dressing of embodiment 9, wherein the overall porosity of the substrate is greater than 65%. (13) The wound dressing of embodiment 11, wherein the overall porosity of the substrate is greater than 70%. (14) The wound dressing of embodiment 7, having an average stiffness of at least 0.50 N / mm. (15) The wound dressing of embodiment 13, having an average stiffness of about 0.53 N / mm.

[0081] (16) The wound dressing of embodiment 1, wherein the polymeric material is selected from the biodegradable polymers selected from the group consisting of polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), polydioxanone (PDS), polycaprolactone, caprolactone / glycolide polyester, and combinations thereof. (17) The wound dressing of embodiment 1, wherein the polymeric material is a copolymer of glycolide and epsilon-caprolactone (Monocryl), polyglactin 910 (Vicryl), or a combination thereof. (18) The wound dressing of embodiment 1, wherein the hydrogel-forming materials are at least two different multifunctional polymers or polymer precursors, each containing two or more electrophilic or nucleophilic functional groups. (19) The wound dressing of embodiment 18, wherein 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. (20) The wound dressing of embodiment 1, wherein the hemostatic agent is selected from 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 glycoproteins, the vasopressin group consisting of vasopressin and analogs, epinephrine, selectins, plasminogen activator inhibitors, platelet activators, synthetic peptides, and any combination thereof having hemostatic activity.

[0082] (21) A method for preparing the wound dressing of embodiment 1, comprising meltblowing microfiber into a web-like sheet, laminating the meltblown sheets, and bonding the laminated meltblown sheets. (22) A method of sealing a tissue surface, comprising applying to a damaged tissue surface the wound dressing of embodiment 1.

Claims

1. A wound dressing comprising: a meltblown multilayer substrate having a gradient porosity profile, the meltblown multilayer substrate having an upper major opposing surface and a lower major opposing surface having a lower open porosity than the upper major opposing surface; and a coating layer applied to the upper major opposing surface, the coating layer being a sealant selected from the group consisting of co-reactive hydrogel forming materials, one or more plasma-based hemostatic agents, and combinations thereof.

2. 10. The wound dressing of claim 1, wherein the meltblown multi-layer substrate is a multi-layer integrated composite of layers of polymeric material, each layer having a decreasing density and increasing porosity relative to an adjacent layer.

3. 3. The wound dressing of claim 2, wherein the meltblown multi-layer substrate consists essentially of 4 to 14 discrete and integral layers.

4. 4. The wound dressing of claim 3, wherein each discrete layer and each integrated layer is about 0.05 to 0.2 mm thick.

5. 10. The wound dressing of claim 1, wherein the meltblown multi-layer substrate generally has pores having a pore size in the range of 0.01 to 0.5 mm.

6. 6. The wound dressing of claim 5, wherein the majority of the pores have a pore diameter in the range of 0.1 to 0.3 mm.

7. 10. The wound dressing of claim 1, wherein the meltblown multi-layer substrate has a total open porosity in the range of 30-90%.

8. 2. The wound dressing of claim 1, wherein a lower third of the meltblown multilayer substrate has an open porosity of about 30%, a middle third has an open porosity of about 80%, and an upper third of the meltblown multilayer substrate to the upper major opposing surface has an open porosity of about 85%.

9. 10. The wound dressing of claim 1, wherein the coating layer penetrates to a depth of greater than 90% of the thickness of the meltblown multi-layer substrate and the overall porosity of the meltblown multi-layer substrate is greater than 60%.

10. 10. The wound dressing of claim 9, wherein the coating layer penetrates to a depth of greater than 95% of the thickness of the meltblown multi-layer substrate.

11. 10. The wound dressing of claim 9, wherein the coating layer penetrates to a depth of at least 97% of the thickness of the meltblown multi-layer substrate.

12. 10. The wound dressing of claim 9, wherein the meltblown multi-layer substrate has an overall porosity of greater than 65%.

13. 12. The wound dressing of claim 11, wherein the meltblown multi-layer substrate has an overall porosity of greater than 70%.

14. 8. The wound dressing of claim 7 having an average stiffness of at least 0.50 N / mm.

15. 14. The wound dressing of claim 13 having an average stiffness of about 0.53 N / mm.

16. 3. The wound dressing of claim 2, wherein the polymeric material is selected from a biodegradable polymer selected from the group consisting of polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), polydioxanone (PDS), polycaprolactone, caprolactone / glycolide polyester, and combinations thereof.

17. 3. The wound dressing of claim 2, wherein the polymeric material is a copolymer of glycolide and epsilon-caprolactone (Monocryl), polyglactin 910 (Vicryl), or a combination thereof.

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

19. 20. The wound dressing of claim 18, wherein 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.

20. 2. The wound dressing of claim 1, wherein the hemostatic agent is selected from 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 glycoproteins, the vasopressin group consisting of vasopressin and analogs, epinephrine, selectins, plasminogen activator inhibitors, platelet activators, synthetic peptides, and any combination thereof having hemostatic activity.

21. A method for preparing the wound dressing of claim 1, comprising meltblowing microfiber into a web-like sheet, stacking the web-like sheets, and bonding the stacked web-like sheets.

22. A wound dressing as described in claim 1 for use in a method of sealing a damaged tissue surface, the method comprising applying the wound dressing to the tissue surface.

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