Two-component encapsulation system including synthetic matrix and biosynthetic adhesive

Abstract

The present invention is directed to a hemostatic patch comprising a porous substrate and at least one pair of co-reactive polymeric reagents comprising at least one nucleophilic polyalkylene oxide-based component and at least one electrophilic polyalkylene oxide-based component on the porous substrate in a molar ratio of excess primary nucleophilic groups to available electrophilic groups of about 0.2 to about 0.9:1. The present invention is also directed to processes for the manufacture and use of such hemostatic patches.

Description

[Technical Field]

[0001] This patent application relates, in general, to surgical procedures, and more specifically to systems, devices, and methods for sealing tissues and organs to control bleeding, fluid leakage, and air leakage. [Background technology]

[0002] Resection is a surgical procedure that involves removing a portion of tissue or organ. Performed on a wide variety of organs, including the liver, lungs, and gastrointestinal system, resection presents surgeons with numerous unique challenges related to effectively managing postoperative bleeding, as well as fluid and air leakage.

[0003] During organ resection procedures, surgeons manage massive bleeding at the resection surface by using tourniquets, extensive sutures, etc. Some surgeons use adhesive fluids (e.g., synthetic adhesives, fibrin adhesive gels), but these are limited because they may leak from the resection surface before fully curing, or they may easily peel off after curing due to insufficient adhesion to the underlying tissue or lack of appropriate elastic properties.

[0004] Hepatectomy. A surgical procedure involving the removal of all or part of the liver is generally referred to as hepatectomy. Partial hepatectomy is the preferred approach for removing solid tumors from the liver. During hepatectomy, the tissue boundaries within the resected area are disrupted, exposing the internal parenchyma and fluid system. Re-establishment of proper boundaries does not occur immediately but requires a long tissue healing process that can last from several days to several weeks. During the tissue healing process, the resected tissue may ooze blood and / or leak organ-specific fluids (e.g., bile), which can lead to postoperative complications. One study found that the bile leakage rate after hepatectomy was approximately 5%, which dramatically increased the likelihood of postoperative complications in patients.

[0005] Lung resection. Lung resection procedures typically involve a considerable amount of tissue manipulation and processing, resulting in a high incidence of postoperative air leakage. Standardized techniques used to address air leakage involve suturing or stapling the lung tissue. However, these techniques are often ineffective in creating an airtight seal due to the inherent fragmentation of the lung parenchyma, particularly in emphysema patients. In some cases, topical adhesives are applied directly either over the pleural detachment or along the staple line, but these techniques are often insufficient to prevent air leakage.

[0006] GI resection. Gastrointestinal (GI) procedures often involve the removal of a large portion of the patient's intestinal anatomical structure to effectively treat the disease. After removing the GI tissue, the surgeon must reconstruct the patient's digestive system. GI reconstruction is complex due to the delicate structure of the intestine, limited blood supply to the lower colon, limited surgical access to complex anatomical structures, and the disease condition that typically affects surrounding tissues. However, even when surgeons exercise the utmost care during GI reconstruction procedures, a certain percentage of patients experience complications resulting from leakage at the surgically created anastomosis site. GI leakage can have catastrophic consequences, often requiring additional surgery and treatment if the leakage is not managed.

[0007] In light of the above complications, much effort has been made to effectively manage intraoperative and postoperative bleeding, as well as fluid and air leakage. For example, when resecting solid organs, surgeons typically manage massive bleeding at the resection surface by using tourniquets and extensive sutures. Small amounts of bleeding and fluid leakage are often managed by using adhesive fluids (e.g., synthetic adhesives, fibrin adhesives) to cover the resection surface; however, these methodologies have achieved limited success because the adhesive fluids tend to leak from the resection surface before hardening and / or peel off after hardening, due to the lack of sufficient adhesion to the underlying tissue or appropriate elastic properties of the hardened adhesive.

[0008] Covidien sells VERISET® hemostatic patches for sealing excised tissue surfaces. VERISET® hemostatic patches consist of an oxidized regenerated cellulose (ORC) layer and a reactive polyethylene glycol (PEG) layer. The patch is applied to the tissue surface by applying pressure to the surface. Due to the opacity of the ORC matrix, the surgeon cannot see through the VERISET® hemostatic patch to assess the condition of the excised surface while applying pressure to it. The patch is also rigid with low flexibility and therefore may not achieve good tissue conformability or may remain accommodating to tissue movement. [Overview of the project] [Problems that the invention aims to solve]

[0009] Given the aforementioned shortcomings, there is a continuing need for improved systems, devices, and methods that enable surgeons to effectively seal the resection surfaces of organs and tissues, and to successfully prevent and / or manage intraoperative and postoperative bleeding, fluid leakage, and / or air leakage from the resection surfaces of tissues and organs.

[0010] To date, much effort has been made to seal the resected surface of organs to control intraoperative and postoperative bleeding, fluid leakage, and air leakage. Some of these efforts involve applying a mesh to the resected surface, followed by the application of fibrin adhesive to seal the surface. However, animal model experiments have shown that fibrin adhesive does not have sufficient tissue bonding strength to adhere the mesh to the resected surface of the organ. [Means for solving the problem]

[0011] The present invention relates to a system and process for continuously depositing at least two different crosslinkable polyalkylene oxide components, preferably PEG-NHS and PEG-NH2, onto an absorbent matrix. In aqueous environments, such as in the presence of blood, 1) the PEG-NHS and PEG-NH2 components tend to crosslink to form a gel-like mechanical barrier that can stop bleeding, and 2) PEG-NHS crosslinks with NH2 groups of tissue proteins, thereby leading to adhesion of the prototype to the tissue. Despite this tissue adhesion function, the applicants have found it advantageous to deposit an excess of the PEG-NH2 component using a selected matrix structure.

[0012] The inventors observed that the molar ratio of these two polyoxyalkylene oxide reactive components is crucial for the hemostatic efficacy of the patch. The potential reason for the molar ratio criticality is the competition between two mechanisms: gel formation and tissue adhesion. Therefore, only at the optimal molar ratio of PEG-NHS and PEG-NH2 do the two mechanisms coexist in a way that the prototype satisfies its hemostatic criteria.

[0013] In addition, the total PEG density demonstrated novel behavior, with an optimized range identified for sufficient adhesion to the tissue. Furthermore, it was discovered that the total amount of polyalkylene oxide reactive components has an upper limit, as excess amounts form a gel-like mechanical barrier that is largely impermeable to the plasma / liquid phase, preventing the resulting polymer clumps from integrating with the substrate.

[0014] This patent application discloses preferred systems, devices, and methods for overcoming the defects identified above and for effectively sealing tissue to control bleeding, fluid leakage, and air leakage.

[0015] In one embodiment, the first component of the system is a carrier matrix (e.g., mesh or nonwoven) or a substrate. In one embodiment, the matrix is ​​a nonwoven matrix. In one embodiment, the synthetic matrix is ​​a biodegradable synthetic matrix.

[0016] In one embodiment, the matrix may be made from a synthetic substrate or patch, such as an absorbent synthetic substrate, made from polyglactin 910 (PG910) material manufactured and sold by Ethicon, Inc. (Somerville, New Jersey) under the trademark VICRYL® Polyglactin 910 material, in a structured combination with woven or nonwoven layers of oxidized cellulose, preferably oxidized regenerated cellulose. In one embodiment, the polyglactin 910 material may be a copolymer material of about 90% glycolide and 10% L-lactide, attached to a layer of woven oxidized cellulose material by needle punching.

[0017] In one embodiment, the synthetic matrix may be a flexible or conformable nonwoven matrix that is placed on the tissue surface of an organ and adapted to conform to the shape of the tissue surface and / or the organ. In one embodiment, the synthetic matrix is ​​bioabsorbable.

[0018] In one embodiment, the wound dressing further comprises at least two layers of reactive components that are co-reactive and deposited sequentially to minimize the reaction. In one embodiment, the reactive components may include a biocompatible reactive electrophile and a nucleophile. In one embodiment, the electrophile may include PEG-SG. In one embodiment, the nucleophile may be selected from any polymer source of amine (NH2) groups (e.g., primary amine moieties), preferably polyethylene glycolamine (PEG-NH2), and combinations thereof.

[0019] In one embodiment, the present invention relates to a hemostatic patch comprising a porous substrate having available acidic carboxyl groups, and at least one pair of co-reactive polymer reagents comprising at least one nucleophilic polyalkylene oxide component and at least one electrophilic polyalkylene oxide component. The polymer reagent components are arranged on the porous substrate in a molar ratio of about 0.2 to about 0.9:1 of primary electrophilic (NHS) groups to nucleophilic (NH2) groups. At least one of the co-reactive polymer reagents may be a 3-arm or 4-arm polyethylene glycol nucleophile. At least one of the co-reactive polymer reagents may be a 3-arm or 4-arm polyethylene glycol electrophile. The at least one electrophilic polyalkylene oxide component may have an average molecular weight Mw of about 5 kD to 30 kD, preferably 10 kD to 20 kD. At least one nucleophilic polyalkylene oxide component may have an average Mw of about 4 kD to 20 kD, preferably less than about 10 kD, and more preferably about 4 kD to 5 kD. The electrophilic component may be a polymer material composed of polyethylene glycol succinimidyl glutarate ester (PEG-SG). The nucleophilic component may be a polymer material selected from the group consisting of any polymer source having a primary amine (NH2) group.

[0020] A hemostatic patch may be characterized by having a porous substrate constructed primarily from oxidized cellulose or oxidized regenerated cellulose material. The porous substrate may be a bilayer structure having at least a first layer of oxidized cellulose-containing material or oxidized regenerated cellulose-containing material together with at least a second layer of polyglutin-containing polymer. The porous substrate is preferably a biodegradable and flexible layer, preferably constructed from a blend of synthetic and cellulose components.

[0021] In one embodiment, the porous substrate comprises at least one layer of a non-woven mesh made from polyglactin 910 and a second adherent layer of a non-woven mesh composed primarily of oxidized cellulose or oxidized regenerated cellulose material that provides localized acidic groups upon tissue application.

[0022] In one embodiment, the present invention is directed to a method for manufacturing a hemostatic patch as described herein, wherein at least one pair of co-reactive polymer reagents is applied to a substrate from a non-aqueous solvent spray, which can use air or gas as an example, or via ultrasonic spraying. The non-aqueous solvent can be wholly or partially an organic solvent such as acetone. The at least one pair of co-reactive polymer reagents can be applied continuously with a drying step intervening during the application of the unobtrusive layer of alternative co-reactive polymer reagents. The at least one pair of co-reactive polymers is preferably applied as a continuous unobtrusive layer of a first co-reactive polymer and a second co-reactive polymer. A layer of at least one polyethylene glycol-based electrophile can be applied as the first unobtrusive layer in the sequence.

[0023] As described in more detail herein, the materials for constructing the non-woven blend matrix have been determined to contribute to localized acidic groups in a manner that provides adequate support and forms an excellent level of adhesion for the combination of reactive components to form a fluid and / or gas seal.

[0024] In addition, it has been found that continuously depositing a co-reactive adhesive component onto an absorbent matrix in a minimal aqueous environment produces a suitable wound dressing. Furthermore, the Applicants have discovered that controlling the molar ratio of the co-reactive adhesive components is important for the hemostatic efficacy of the patch. Without being bound by theory, the preferred molar ratio of the co-reactive adhesive components is such that polymer electrophiles such as PEG-NHS and polymer nucleophiles such as PEG-NH2 tend to crosslink to form a gel-like mechanical barrier, and the polymer electrophiles such as PEG-NHS crosslink with the NH2 groups of tissue proteins, and it is considered that the balance of two reaction mechanisms is maintained. In addition, the total density of the co-reactive adhesive components has demonstrated a novel behavior where the selected range provides sufficient adhesion to tissue.

[0025] As disclosed in more detail herein, the order in which the first and second components are deposited onto the substrate, as well as the specific composition of the biosynthetic adhesive, can affect the efficacy of the sealant and can therefore be modified and / or adjusted for effective use in a particular application.

Mode for Carrying Out the Invention

[0026] Polyethylene glycol succinimidyl glutarate (PEG-SG) has a well-established safety profile in medical devices and is used in sealant products such as Duraseal and Coseal. Succinimidyl glutarate reacts with amine groups on proteins, such as collagen, under weakly alkaline conditions to form amide bonds. The cleavable ester linker designed into the PEG allows the polymer to be degradable in vivo. This form of PEG also provides the ability to crosslink across multiple collagen fibers due to its long spacer region that allows intermolecular crosslinking.

[0027] In one embodiment, the two-reactive component encapsulant preferably includes a synthetic matrix adapted to be placed on the tissue of a soft organ. In one embodiment, the synthetic matrix may be a mesh matrix or a nonwoven matrix placed on the tissue surface together with the reactive components. In one embodiment, the nonwoven matrix is ​​flexible and / or conformable and adapted to be placed on the tissue surface with the biosynthetic adhesive applied to the synthetic matrix.

[0028] In one embodiment, the synthetic matrix preferably includes fibers and gaps arranged between the fibers.

[0029] In one embodiment, a biosynthetic or synthetic adhesive is applied to a biodegradable synthetic matrix (e.g., VICRYL® nonwoven PG910) in a manner that substantially prevents the reaction of co-reactive components. The biosynthetic adhesive component may be a solution of PEG-NH2 and polyethylene glycol succinimidyl glutarate (PEG-SG) pre-mixed immediately before use, with one component having a protective leaving group that prevents the reaction at a pH for delivery. Alternatively, the biosynthetic adhesive component can be provided on the matrix by the sequential application and drying of individual solutions of the co-reactive components. Furthermore, the biosynthetic adhesive component can be provided on the matrix individually or as a blend in powder form.

[0030] Comparative Examples 1 and 2: Since PEG-NHS is an electrophile that is highly likely to react with amine nucleophiles present in blood proteins and tissues, it was expected that individually coating a fabric substrate with PEG-NHS would promote adhesion of the substrate to bleeding wounds. However, it was found that applying only the electrophile PEG-NHS without the nucleophile PEG-NH2 was not effective in adhering the patch to the bleeding surface.

[0031] For example, 16.0 mg / cm³ 2Four-arm (10kDa) PEG-NHS was deposited onto a nonwoven carboxylmethylcellulose (CMC) substrate and evaluated in a porcine spleen biopsy punch bleeding model. In this model, the exemplary CMC patch was not effective in providing hemostatic efficacy.

[0032] Similarly, applying only the nucleophile PEG-NH2 without the electrophile PEG-NHS was not effective in adhering the patch to the bleeding surface. For example, 6.5 mg / cm² 2 Applying 4-arm (4kDa)PEG-NH2 to a nonwoven carboxymethylcellulose (CMC) substrate was not effective in providing hemostatic efficacy.

[0033] Total 25.5mg / cm 2 PEGs (PEG-NHS, 10 kDa 4-arm [4ARM-SG-10K] and PEG-NH2, 5 kDa 4-arm [4ARM-NH2-5000]) were applied to a 4-inch x 2-inch substrate (double-layer substrate) consisting of layers of woven oxidized regenerated cellulose and nonwoven absorbent polymer (PG910). The total PEG loading density remained the same, but the molar ratio of PEG-NHS to PEG-NH2 changed to 0.6, 1.2, and 1.8.

[0034] [Table 1]

[0035] Our research results show that hemostatic efficacy decreases as the molar ratio of PEG-NHS to PEG-NH2 increases between 0.6 and 1.8. In addition, the results indicate that the PEG molar ratio is an important variable in the hemostatic performance of these prototypes in this model.

[0036] In addition, the molar ratio of PEG-NHS to PEG-NH2 is 0.25 (30.6 mg / cm³). 2 PEG-NH2, 19.2 mg / cm³ 2It is a PEG-NHS (Percutaneous Endoscopic Protein-Hemostatic Stimulant) and has been found to demonstrate hemostatic efficacy in heparinized pig hemorrhage models (spleen and liver biopsy punch, and partial nephrectomy). (PEGamine PEG-AM-4K, PEG-NHS-4-arm N-hydroxysuccinimide glutarate ester-terminated PEG, Mw approximately 10,000 g / mol, 4ARM-SG-10K)

[0037] Observations from the three summarized studies allowed the inventors to discover that the molar ratio of PEG does not follow a linear trend. As the PEG-NHS to PEG-NH2 molar ratio approaches 0, the hemostatic efficacy of the prototype does not continue to increase compared to 0.25, but decreases to a hemostatic efficacy of 0. As the PEG-NHS to PEG-NH2 molar ratio approaches infinity, the hemostatic efficacy decreases to 0, and two PEGs are required to form an adhesive gel composite. The data support an optimal PEG-NHS to PEG-NH2 molar ratio range of 0.25 to 1.8.

[0038] To demonstrate the functionality of samples within the suggested PEG ratio range in relevant acute hemorrhagic animal models, the following studies were conducted. The test substances demonstrated hemostatic efficacy in heparinized porcine hemorrhagic models (spleen biopsy punch and splenectomy). These included PEG-NH2 (4-arm and 4K molecular weight) and PEG-NHS (4-arm, n-hydroxysuccinimide glutarate ester-terminated PEG, 10K molecular weight, 4ARM-SG-10K). The substrate used was a bilayer substrate, onto which acetone solutions of each component—first the PEG-NH2 solution, then the PEG-NHS solution—were ultrasonically sprayed. Coating levels and hemostatic models are listed below:

[0039] [Table 2]

[0040] At a fixed molar ratio of 1.2:1:0 between the succinimidyl group PEG-SG and the amine groups on PEG-amine, the PEG deposition density (mass of total PEG deposited per substrate surface area) was evaluated for its effect on tissue detachment force. 0 mg / cm 2 (uncoated) to 51.0 mg / cm 2 For bilayer prototypes with deposition densities in the range of (uncoated) to 200% of the standard S1 deposition density, the peel adhesion force was evaluated. Interestingly, the detachment force initially increased with an increase in PEG deposition density, but reached a plateau at a density of 6.4 mg / cm 2 to a maximum of 25.5 mg / cm 2 (25% to 100% of the standard S1 deposition density). Above a deposition density of 25.5 mg / cm 2 , the detachment force began to decrease.

[0041] This trend indicates that the interfacial chemical adhesion of PEMs coated with PEG to tissue and subsequent gel formation are a low threshold depending on the PEG deposition density at the above fixed ratio, while above a threshold of 6.4 mg / cm 2 , the PEG layer has sufficient functionality to adhere to tissue and form strong cross-linked gels with each other. However, above a PEG density of 25.5 mg / cm 2 , the ability to form a strongly interconnected gel between the tissue surface and both PEGs can be hindered by excessive spatial separation of the individual PEG layers.

[0042]

Table 3

[0043] Example: Production via continuous solution spraying (ultrasonic) In this process, individual PEG coating layers are applied using an ultrasonic atomizer until the target density of that PEG is reached. Dry air is used as the carrier gas for the atomized polymer solution, but inert gases such as nitrogen or argon can also be used. In one embodiment, a PEG-NH2 layer is first coated onto the matrix until the target density is reached, the matrix is ​​then dried under vacuum, and then layers of PEG-SG are coated until their respective target densities are reached. The fully coated matrix is ​​then dried under vacuum and packaged.

[0044] The sealing systems disclosed herein are independent of the patient's coagulation system. Therefore, surgeons can achieve hemostasis and sealing independent of the patient's coagulation state, which can be impaired in resected patients because most coagulation proteins are produced in the liver. The sealing systems may also be used in patients receiving antiplatelet and anticoagulant therapy, such as aspirin, heparin, or warfarin.

[0045] In one embodiment, the electrophile may include PEG-SG. In one embodiment, the nucleophile may be selected from polyethylene glycolamine (PEG-NH2) and any polymer source of NH2 groups, such as a combination of albumin and PEG-NH2.

[0046] While the above description applies to embodiments of the present invention, other and further embodiments of the present invention can be devised without departing from the basic scope of the present invention, and the scope of the present invention is limited only by the appended claims. For example, in the present invention, any of the features shown in any of the embodiments described herein or incorporated by reference herein can be incorporated together with any of the features shown in any of the other embodiments described herein or incorporated by reference herein, and may still be included within the scope of the present invention.

[0047] [Implementation Method] (1) A hemostatic patch comprising a porous substrate having available acidic carboxyl groups, and at least one pair of coreactive polymer reagents comprising at least one nucleophilic polyalkylene oxide component and at least one electrophilic polyalkylene oxide component, wherein both components are arranged on the porous substrate in a molar ratio of approximately 0.2 to approximately 0.9:1 of primary electrophiles to nucleophiles. (2) The hemostatic patch according to Embodiment 1, wherein at least one of the coreactive polymer reagents is a 3-arm polyethylene glycol-based nucleophile. (3) The hemostatic patch according to Embodiment 1, wherein at least one of the coreactive polymer reagents is a 3-arm polyethylene glycol-based electrophile. (4) The hemostatic patch according to Embodiment 1, wherein at least one of the coreactive polymer reagents is a 4-arm polyethylene glycol-based nucleophile. (5) The hemostatic patch according to Embodiment 1, wherein at least one of the coreactive polymer reagents is a 4-arm polyethylene glycol-based electrophile.

[0048] (6) A method for producing a hemostatic patch according to Embodiment 1, wherein at least one pair of the coreactive polymer reagents is applied to the substrate from a non-aqueous solvent spray via ultrasonic air atomization. (7) The method according to Embodiment 6, wherein the non-aqueous solvent includes an organic solvent. (8) The method according to Embodiment 6, wherein the non-aqueous solvent includes acetone. (9) The method according to Embodiment 6, wherein at least one pair of the coreactive polymer reagents are applied sequentially with a drying interval in between. (10) The method according to embodiment 9, wherein at least one pair of the coreactive polymers are applied in a continuous, inconspicuous layer of the first coreactive polymer and the second coreactive polymer.

[0049] (11) The method according to Embodiment 10, wherein at least one layer of polyethylene glycol-based electrophile is sequentially applied as the first layer. (12) The hemostatic patch according to Embodiment 1, wherein the porous substrate comprises oxidized cellulose or oxidized regenerated cellulose. (13) The hemostatic patch according to Embodiment 1, wherein the porous substrate is a bilayer structure comprising at least a first layer of an oxidized cellulose-containing material or an oxidized regenerated cellulose-containing material together with at least a second layer of a polyglutin-containing polymer. (14) The hemostatic patch according to Embodiment 1, wherein the at least one electrophilic polyalkylene oxide component has an average molecular weight Mw of about 10 kD. (15) The hemostatic patch according to Embodiment 1, wherein the at least one nucleophilic polyalkylene oxide component has an average Mw of about 4 kD to 5 kD.

[0050] (16) The hemostatic patch according to Embodiment 1, wherein the porous substrate is a synthetic biodegradable and flexible matrix. (17) The hemostatic patch according to Embodiment 16, wherein the porous substrate comprises at least one layer of nonwoven mesh made from polyglutin 910 and a second adhesive layer of nonwoven mesh made of essentially oxidized cellulose or oxidized regenerated cellulose material that provides localized acidic groups when applied to tissue. (18) The hemostatic patch according to Embodiment 1, wherein the electrophilic component comprises polyethylene glycol succinimidyl glutarate ester (PEG-SG). (19) The hemostatic patch according to Embodiment 1, wherein the nucleophile is selected from the group consisting of any polymer source of primary amine (NH2) groups. (20) The at least two coreactive polymer reagents are present in an amount of about 6.4 mg polymer / cm² of substrate. 2 ~25.5 mg / cm³ 2 A hemostatic patch according to Embodiment 1, deposited on the substrate at a density of .

[0051] (21) The hemostatic patch according to Embodiment 20, wherein the at least two coreactive polymer reagents are applied to a bilayer substrate that does not contain amine groups in a fixed molar ratio of 1.2:1.0 between succinimidyl groups (PEG-SG) and amine groups (PEG-amine).

Claims

1. A hemostatic patch comprising a porous substrate having available acidic carboxyl groups, and at least one pair of coreactive polymer reagents comprising at least one nucleophilic polyalkylene oxide component and at least one electrophilic polyalkylene oxide component, wherein both the nucleophilic polyalkylene oxide component and the electrophilic polyalkylene oxide component are arranged on the porous substrate in a molar ratio of primary electrophile to nucleophile of 0.2 to 0.9:

1.

2. The hemostatic patch according to claim 1, wherein at least one of the coreactive polymer reagents is a three-arm polyethylene glycol-based nucleophile.

3. The hemostatic patch according to claim 1, wherein at least one of the coreactive polymer reagents is a three-arm polyethylene glycol-based electrophile.

4. The hemostatic patch according to claim 1, wherein at least one of the coreactive polymer reagents is a four-arm polyethylene glycol-based nucleophile.

5. The hemostatic patch according to claim 1, wherein at least one of the coreactive polymer reagents is a four-arm polyethylene glycol-based electrophile.

6. A method for producing a hemostatic patch according to claim 1, wherein at least one pair of the coreactive polymer reagents is applied to the porous substrate from a non-aqueous solvent spray via ultrasonic air atomization.

7. The method according to claim 6, wherein the non-aqueous solvent of the non-aqueous solvent spray includes an organic solvent.

8. The method according to claim 6, wherein the non-aqueous solvent of the non-aqueous solvent spray comprises acetone.

9. The method according to claim 6, wherein at least one pair of the coreactive polymer reagents are applied continuously with an intervening drying period.

10. The method according to claim 9, wherein at least one pair of the coreactive polymer reagents are applied in a continuous, inconspicuous layer of the first coreactive polymer and the second coreactive polymer.

11. The method according to claim 10, wherein at least one layer of polyethylene glycol-based electrophile is sequentially applied as a first layer.

12. The hemostatic patch according to claim 1, wherein the porous substrate comprises oxidized cellulose or oxidized regenerated cellulose.

13. The hemostatic patch according to claim 1, wherein the porous substrate is a bilayer structure comprising at least a first layer of an oxidized cellulose-containing material or an oxidized regenerated cellulose-containing material together with at least a second layer of a polyglutin-containing polymer.

14. The hemostatic patch according to claim 1, wherein the at least one electrophilic polyalkylene oxide component has an average molecular weight Mw of 10 kD.

15. The hemostatic patch according to claim 1, wherein the at least one nucleophilic polyalkylene oxide component has an average Mw of 4 kD to 5 kD.

16. The hemostatic patch according to claim 1, wherein the porous substrate is a synthetic biodegradable and flexible matrix.

17. The hemostatic patch according to claim 16, wherein the porous substrate comprises at least one layer of nonwoven mesh made from polyglutin 910 and a second adhesive layer of nonwoven mesh made of essentially oxidized cellulose or oxidized regenerated cellulose material that provides localized acidic groups when applied to tissue.

18. The hemostatic patch according to claim 1, wherein the electrophilic polyalkylene oxide component comprises polyethylene glycol succinimidyl glutarate ester (PEG-SG).

19. The nucleophilic polyalkylene oxide component is a primary amine (NH ２ The hemostatic patch according to claim 1, which is selected from the group consisting of any polymer source of the ) group.

20. The aforementioned at least one pair of co-reactive polymer reagents is present in a concentration of 6.4 mg polymer / cm² of substrate. ２ ~25.5mg / cm ２ The hemostatic patch according to claim 1, wherein the hemostatic patch is deposited on the porous substrate at a density of [value].

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