HK1231786A1 - Reinforced absorbable synthetic matrix for hemostatic applications - Google Patents

Description

Enhanced absorbent synthetic matrices for hemostatic applications

The present application is a divisional application of the invention patent application entitled "enhanced absorbent synthetic matrix for hemostatic applications" filed as 16/5/2011 with application number 201180024421.2.

Technical Field

The present invention relates to bioabsorbable hemostatic devices that may be used as a construct suitable for use in medical devices.

Background

In surgery, controlling bleeding is crucial to improve the outcome of the surgery and to shorten the duration of the surgery in the operating room. A variety of hemostatic materials, including oxidized cellulose-based materials, have been used as dressings in a variety of surgical procedures, including neurosurgery, abdominal surgery, cardiovascular surgery, thoracic surgery, head and neck surgery, pelvic surgery, and skin and subcutaneous tissue surgery.

The use of multi-layer fabrics in conjunction with surgery is generally accepted. For example, the multilayered fabric is used as a universal pad, wound dressing, surgical mesh (including hernia repair mesh, adhesion prevention mesh, and tissue reinforcement mesh), defect closure device, and hemostat.

U.S. patent No.5,593,441 to Lichtenstein et al describes a composite prosthesis preferably having tissue-allowing inward facingGrowing sheets of polypropylene, e.g.And (3) a net. This reference discloses that other surgical materials suitable for tissue augmentation and defect closure may be utilized, including absorbent meshes such as hydroxy lactic acid polymer 910And (3) a net. The composite prosthesis of Lichtenstein et al also has an adhesion barrier, preferably a piece of silicone elastomer. This reference generally teaches oxidizing regenerated cellulose such as(TC7) an absorbent adhesion barrier (commercially available from Ethicon, Inc. (Somerville, n.j.)) can be used as an adhesion barrier to create a composite prosthesis with short term efficacy.

U.S. patent No.5,686,090 to Schilder et al describes the use of a fleece in combination with a non-absorbent or absorbent film to prevent adjacent tissue overgrowth and reduce adhesions. Schilder et al generally disclose that polypropylene, polyester, hydroxy lactic acid polymer, polydioxanone, or poliglecaprone 25 may be used as the fleece material or membrane material.

Published U.S. patent application 2006/00084930 to dharaj et al describes an enhanced absorbent multilayered fabric that may be used in medical devices particularly suited for tissue engineering applications. The basic content includes first preparing a repair site for implantation, and then placing a reinforced absorbent multilayer fabric at the site. The first absorbent nonwoven comprises fibers comprising an aliphatic polyester polymer, copolymer or blend thereof; and the second absorbent woven or knitted fabric comprises oxidized regenerated cellulose fibers. But cells were seeded onto the 9010PLGA component of the matrix before the 9010PLGA component of the matrix migrated through the non-woven matrix and contacted with the ORC component. The ORC component typically degrades in about two weeks and the degrading component creates an acidic environment that may be detrimental to cell proliferation or survival. The present invention solves the above problem by providing a synthetic matrix which is fully absorbent, i.e. does not create such an environment which is detrimental to cell survival.

U.S. patent No.4,626,253 to Broadnax et al describes a device relating to a surgical hemostat (SURGICEL) for controlling bleeding, and more particularly to a knitted fabric of oxidized cellulose having excellent handling and hemostatic properties. U.S. patent No.7,666,803 to Shetty et al describes a process for making an enhanced absorbent multi-layer web useful as a hemostat. The basic content includes first preparing a repair site for implantation, and then placing a reinforced absorbent multilayer fabric at the site. The first absorbent nonwoven comprises fibers comprising an aliphatic polyester polymer, copolymer or blend thereof; and the second absorbent woven or knitted fabric comprises oxidized regenerated cellulose fibers. The method also describes the appropriate density and thickness of the matrix that can be used to make the particular invention described above. However, in certain applications where a longer duration of hemostatic function and increased mechanical properties are required, the above-mentioned matrix will not meet both requirements, mainly due to its weaker mechanical properties.

Published U.S. patent application 2008/0033333 to MacPhee et al describes the use of DEXON (polyglycolic acid woven matrix) as the substrate material for fibrinogen and thrombin. U.S. patent No.6,762,336 describes the use of a glycolic acid or lactic acid based polymer or copolymer (VICRYL) as a monolayer to support the sandwich of fibrinogen and thrombin. Similarly, Fibrin Sealant pads described as being developed by The American Red Cross are described in a number of articles, such as Bijan Kheirabadi et al, "The positional availability of fibre Sealant repair in repair of vacuum repair in Swine" (Journal of transaction, Infection and diagnostic Care, 2007, 1 month, pages 94-103) and Jill Sonder et al, "company of10 differential biological repair in an atomic repair" (Journal of transaction, Injury, Infection and diagnostic Care, 2003, 2 months, page 280-.

Disclosure of Invention

The present invention relates to an enhanced absorbent hemostat comprising a single layer nonwoven synthetic fabric. The absorbent nonwoven is comprised of fibers comprising aliphatic polyester polymers, copolymers or blends thereof. Aliphatic polyesters are typically synthesized by ring-opening polymerization of monomers including, but not limited to, lactic acid, lactide (including L-, D-, meso-, and D, L mixtures), glycolic acid, glycolide, -caprolactone, p-dioxanone (1, 4-dioxan-2-one), and trimethylene carbonate (1, 3-dioxan-2-one). In one embodiment, the nonwoven synthetic fabric consists essentially of a blend of polyglycolide/polylactide copolymer and polydioxanone. The invention also relates to a hemostatic fabric comprising at least one hemostatic agent in a non-woven layer of a first absorbable fabric comprising a polyglycolide/polylactide copolymer and a second absorbable fabric comprising polydioxanone, wherein both fabrics are in the form of staple fibers.

The first absorbent fabric may consist essentially of a copolymer of glycolide/lactide in a ratio of 90 moles/10 moles in the composition. The first absorbent web may be in the form of staple fibers having a length of about 0.75 to 2.5 inches. The second absorbent fabric may be in the form of staple fibers having a length of 0.75 to 2.5 inches. One or both of these staple fibers may be chemically or mechanically crimped. The weight ratio of the first textile staple fibers to the second textile staple fibers may be about 70: 30. The mixture of staple fiber material may be pressed to a thickness of about 1.5mm and a density of about 100 mg/cc.

In one embodiment, the hemostatic device is substantially free of any oxidized polysaccharide material. In one embodiment, the hemostatic agent comprises thrombin. In another embodiment, the hemostatic agent on the hemostatic device comprises thrombin and fibrinogen.

The invention also relates to a method of using the hemostatic textile as a medical device. The medical devices described above preferably provide hemostasis when applied to a tissue or wound requiring hemostasis. More specifically, the device can control and reduce mild to moderate bleeding over an effective period of time of about 1 to about 10 minutes.

The invention also relates to a method for manufacturing the hemostatic textile, comprising the following steps: suspending thrombin and fibrinogen in perfluorinated hydrogen fluoride to form a suspension, and applying the suspension to an absorbent nonwoven. The thrombin activity on the hemostatic textile may be from about 20 to 500IU/cm²And fibrinogen on the dressing may be in the range of about 2 to 15mg/cm²Within the range of (1). The method further comprises the step of sterilizing the hemostatic textile, for example by radiation.

Detailed Description

The reinforced absorbent fabric is a nonwoven material comprising at least two synthetic polymeric fibers and one or more hemostatic agents. The fabric preferably does not contain an effective amount of cellulosic or oxidized polysaccharide as a separate layer or in combination as part of a nonwoven layer. Examples of cellulose or oxidized polysaccharides that have previously been used in hemostatic devices include oxidized cellulose and its neutralized derivatives. For example, the cellulose may be carboxyl-oxidized cellulose or aldehyde-oxidized cellulose. Regenerated cellulose and a detailed description of how to prepare oxidized regenerated oxidized cellulose are shown in the following patents: U.S. Pat. No.3,364,200, U.S. Pat. No.5,180,398, and U.S. Pat. No.4,626,253, the entire contents of each of which are hereby incorporated by reference. Although these cellulose-derived materials have been shown to enhance hemostasis, the present invention has certain advantages, particularly when used in conjunction with particulate or lyophilized hemostatic agents such as thrombin and fibrinogen.

The first absorbent nonwoven is comprised of fibers comprising aliphatic polyester polymers, copolymers or blends thereof. Aliphatic polyesters are typically synthesized by ring-opening polymerization of monomers including, but not limited to, lactic acid, lactide (including L-, D-, meso-, and D, L mixtures), glycolic acid, glycolide, -caprolactone, p-dioxanone (1, 4-dioxan-2-one), and trimethylene carbonate (1, 3-dioxan-2-one). In one embodiment, the first polymeric fiber material consists essentially of a blend of copolymers of glycolide and lactide, such as the copolymer poly (glycolide-lactide) copolymer (PGLA, 90 moles/10 moles) and Polydioxanone (PDO). The two materials are processed into a single layer of nonwoven fibrous material and are preferably mixed at a weight ratio of about 80: 20 to about 60: 40, more preferably about 70: 30, of PGLA and PDO. The weight ratio of PLGA to PDO in the nonwoven blend may be from 10: 90 to 90: 10, most preferably in the range of 70: 30.

In one embodiment, poly (glycolide-lactide) copolymer (PGLA, 90 moles/10 moles) is melt spun into polymer fibers. The multifilament yarn of PGLA is consolidated, crimped, and cut into staple fibers having a length of 0.1 to 3.0 inches, preferably 0.75 to 2.5 inches. PDO was melt spun into polymer fibers. The multifilament yarn of PDO is consolidated, crimped, and cut into staple fibers having a length of 0.1 to 3.0 inches, preferably 0.75 to 2.5 inches. A mixture of these staple fiber materials consisting essentially of PGLA/PDO at 70/30 weight ratio is carded to produce a nonwoven batt which is then compressed to a thickness of about 0.25 to 2.5mm, preferably 1.25 to 1.75mm and a density of about 50 to 200mg/cc, preferably 75 to 125 mg/cc.

One method of making the fabrics described herein is by the following process. Absorbent polymer fibers having a denier per fiber size of about 1 to 4 can be consolidated into multifilament yarns of about 80 to 120 denier, then consolidated into yarns of about 800 to 1200 denier, thermally crimped, and then cut into staple fibers having a length of about 0.75 to 2.5 inches. The staple fibers may be fed to a multi-roll dry-laid card one or more times and carded into a uniform nonwoven batt while controlling the moisture content between about 20-60% at room temperature of 15 to 24 ℃. For example, a single cylinder roller flat card having a main cylinder covered by alternating rollers and stripping rollers may be used to produce a uniform nonwoven batt, wherein the batt is stripped from the surface of the cylinder by a doffer roller and deposited onto a collector roller. The enhanced absorbent fabric can then be scoured by washing in a suitable solvent and dried under mild conditions for 10-30 minutes.

The fabric is scrubbed with a solvent suitable for dissolving any spin finish. Solvents include, but are not limited to, isopropanol, hexane, ethyl acetate, and dichloromethane. The fabric is then dried under conditions that provide sufficient drying while minimizing shrinkage.

The hemostat described herein provides and maintains effective hemostasis when applied to a wound requiring hemostasis. As used herein, effective hemostasis is the ability to control and/or reduce mild to moderate bleeding within an effective time as recognized by those skilled in the art of hemostasis. Other indications of effective hemostasis may be provided by government regulatory standards and the like. Examples of mild to moderate bleeding include, but are not limited to, bleeding due to splenectomy, hepatectomy, blunt liver injury, and blunt spleen injury.

The nonwoven substrate described above may comprise one or more hemostatic agents. For the purposes of this application, a hemostatic agent is an agent that has a hemostatic effect, and more preferably, slows, stops, and ultimately stops bleeding at the site of injury. One method for producing hemostasis at the site of injury is to introduce one or more factors present in the coagulation cascade, which may react with another or other factors naturally present in the body. Thrombin has been used to produce hemostasis, and in another embodiment, thrombin is used in combination with fibrinogen to produce the desired hemostasis. Additional components such as calcium may also be provided to further enhance hemostasis.

In one embodiment, the bioabsorbable nonwoven remains in powder, granular form with no spacing and minimal powder loss from its surface, due in part to the manner in which the hemostatic agent is added and the nonwoven nature of the substrate. In a preferred method for applying thrombin and/or fibrinogen to a substrate, solutions comprising one or more biological agents are separately lyophilized. The lyophilized material is then ground to a powder using a superfine mill, a ball mill, or a cooled knife mill. The powders are weighed and suspended together in a carrier fluid in which the proteins are not soluble. Preferred carrier fluids are perfluorinated hydrogens, including but not limited to HFE-7000, HFE-7100, HFE-7300, and PF-5060 (commercially available from 3M company (Minnesota)). Any other carrier fluid in which the protein is not soluble may be used, such as alcohols, esters, or other organic fluids. The suspension is mixed thoroughly and applied to the absorbent nonwoven by conventional means (e.g., wet coating, dry coating, or electrostatic spraying, dipping, painting, or sprinkling) while maintaining a room temperature of about 15 to 24 ℃ and a relative humidity of about 10 to 60% (preferably not more than 30%). The single layer dressing is then dried at ambient room temperature and packaged in a suitable moisture-proof container. The dressing with thrombin and/or fibrinogen contains no more than 25% moisture, preferably no more than 15% moisture, and most preferably no more than 5% moisture.

The thrombin and/or fibrinogen may be of animal origin, human, or may be recombinant. The thrombin activity on the dressing may be in the range of about 20 to 500IU/cm²Preferably about 20 to 200IU/cm²And most preferably about 50 to 200IU/cm²Within the range of (1). The fibrinogen activity on the dressing may be between about 2 and 15mg/cm²Preferably about 3 to 12mg/cm²And most preferably about 5 to 10mg/cm²Within the range of (1). The amount of thrombin and/or fibrinogen powder applied to the nonwoven is preferably a sufficient amount to cover its surface such that there are no visible uncovered areas. The powder may be located primarily on top of the nonwoven or more preferably impregnated into the nonwoven.

As a surgical dressing, the dressings described herein may be used as an adjunct to primary wound closure devices, such as arterial closure devices, staples, and sutures, to seal potential leaks of gas, liquid, or solids, as well as to provide hemostasis. For example, the dressing may be utilized to seal gas from tissue or to seal fluid from organs and tissues including, but not limited to, bile, lymph, cerebrospinal fluid, gastrointestinal fluid, interstitial fluid, and urine.

The hemostat described herein has additional medical applications and may be used for a variety of clinical functions including, but not limited to, matrix/substrate (i.e., fibrinogen/thrombin) coating, tissue reinforcement and support (i.e., for gastrointestinal or vascular anastomosis), tissue approximation (i.e., anastomosis where the connection is difficult to perform (i.e., in tension)), and tension release. In all of the above cases, the hemostatic matrix may additionally facilitate and possibly improve the natural tissue healing process. The dressing may be used in vivo for a variety of surgical procedures including, but not limited to, cardiovascular, peripheral vascular, cardio-thoracic, gynecological, neurological, and general surgery. The hemostat may also be used to attach medical devices (e.g., meshes, clips, and membranes) to tissue, to attach tissue to tissue, or to attach medical devices to medical devices.

EXAMPLE 1 monolayer matrix of PGLA/PDO

Poly (glycolide-lactide) copolymer (PGLA, 90 moles/10 moles) was melt spun into polymer fibers. The multifilament yarn was consolidated, crimped, and cut into PGLA staple fiber material having a length of 2.0 inches. Polydioxanone (PDO) was melt spun into polymer fibers. The monofilament yarns were consolidated, crimped, and cut into PDO staple fiber material having a length of 2.0 inches. A mixture of PGLA/PDO staple fiber material was mixed at a weight ratio of 70/30 and carded to produce a nonwoven batt and compressed to a thickness of about 1.5mm and a density of about 100 mg/cc.

Example 2

A mild to moderate bleeding model was prepared by making a 15mm long and 3mm deep incision on the pig spleen. A PGLA/PDO matrix as described in example 1 was applied to the surgical site and packed for two minutes. The hemostatic effect was checked within 30 seconds after two minutes of tamponade. If no free-flow bleeding was observed within 30 seconds, the hemostasis time was recorded. If spontaneous bleeding is observed, the plug is refilled for 30 seconds until hemostasis is achieved or until the test period reaches ten minutes (which is defined as blood failure). All three test samples achieved hemostasis at 3.14 ± 1.26 minutes (table 1).

TABLE 1 hemostasis of PGLA/PDO matrices in spleen model

Sample numbering	1	2	3	Mean value of	SD
						Hemostasis time (minutes)	2.00	2.92	4.50	3.14	1.26

Example 3

The mechanical properties of the reinforced fabric were characterized in an in vitro test. The PGLA/PDO matrix material described in example 1 was cut into strips (approximately 3/8 inches wide by 2 inches long). The tensile strength of the fabric was then evaluated using an instron tensile tester in both dry and wet conditions. In wet condition, the strips were placed in a conical tube containing PBS buffer at pH 7.4 at 37 ℃. The tensile strength of the strips was then measured at 120 minutes, 4 days, 7 days, 11 days and 14 days. Tensile strength values for the PGLA/PDO material described in example 1 are shown in table 2.

TABLE 2 tensile strength of PGLA/PDO in dry and wet conditions

Example 4

A hemostatic device combining a PGLA/PDO matrix material and one or more hemostatic agents for controlling severe bleeding may be prepared by coating fibrinogen and thrombin onto the PGLA/PDO matrix material of example 1. This "combination product" was constructed by coating porcine fibrinogen and thrombin onto a PGLA/PDO matrix as described in example 1.PGLA/PDO matrices were cut to 5X 10cm size and sterilized by gamma irradiation (25 to 35 kGy). Different amounts of porcine fibrinogen and thrombin (see table 3) were mixed well with about 6.5ml of HFE-7000. The slurry was poured into a 5.5X 10.5cm tray and the PGLA/PDO matrix was immersed in the tray. The coated hemostatic device was air dried for about 30 minutes. The ambient conditions were maintained at 24 ℃ and 45% RH throughout the process. The dressing was vacuum dried and packaged in a plastic bag with nitrogen. The packaged dressing is again sterilized by electron beam (8 to 12.5 kGy). The efficacy of the dressing was tested in a severe bleeding model (pig kidney resection model). The results are shown in table 3.

TABLE 3 hemostatic time of PGLA/PDO with varying amounts of fibrinogen and thrombin

Sample ID	Substrate	Fibrinogen (mg/cm)2)	Thrombin (IU/cm)2)	Hemostasis time (minutes)
					A	PGLA/PDO	0	0	9.5±4.0
B	PGLA/PDO	0	100	6.5±5.2
					C	PGLA/PDO	9	0	6.1±2.2
D	PGLA/PDO	5	20	3.8±1.6
					E	PGLA/PDO	5	50	≤3.0
F	PGLA/PDO	5	100	3.8±1.5
					G	PGLA/PDO	9	20	6.1±0.1
H	PGLA/PDO	9	50	6.2±0.1
					I	PGLA/PDO	9	100	6.2±2.6

Example 5

Poly (glycolide-lactide) copolymer (PGLA, 90 moles/10 moles) was melt spun into polymer fibers. The multifilament yarn was consolidated, crimped and cut into PGLA staple fiber material having a length of 2.0 inches. The staple fiber material of PGLA was carded to create a nonwoven batt and compressed to a thickness of about 2.3mm and a density of about 59 mg/cc. A mild to moderate bleeding model was prepared by making a 15mm long and 3mm deep incision on the pig spleen. PGLA matrix was applied to the surgical site and packed for two minutes. The hemostatic effect was checked within 30 seconds after two minutes of tamponade. If no free-flow bleeding was observed within 30 seconds, the hemostasis time was recorded. If spontaneous bleeding is observed, the plug is refilled for 30 seconds until hemostasis is achieved or until the test period reaches ten minutes (which is defined as blood failure). Both samples were tested and achieved (5.5 and 4.75 minutes) hemostasis for both samples.

Claims (19)

1. A synthetic hemostatic fabric comprising at least one hemostatic agent in a single non-woven layer comprised of a first absorbable fabric comprising a polyglycolide/polylactide copolymer and a second absorbable fabric comprising polydioxanone, wherein both fabrics are in staple fiber form, said single non-woven layer consisting essentially of a blend of polyglycolide/polylactide copolymer and polydioxanone.

2. The synthetic hemostatic fabric of claim 1, where the first absorbable fabric consists essentially of a copolymer of glycolide/lactide in a compositional ratio of 90 moles/10 moles.

3. The synthetic hemostatic fabric of claim 2, where the first absorbent fabric is comprised of staple fibers having a length of 0.75 to 2.5 inches.

4. The synthetic hemostatic fabric of claim 1, which is substantially free of any oxidized polysaccharide material and the hemostatic agent comprises thrombin.

5. The synthetic hemostatic fabric of claim 1, wherein the staple fibers are crimped.

6. The synthetic hemostatic fabric of claim 4, where the second absorbent fabric is comprised of staple fibers having a length of 0.75 to 2.5 inches.

7. The synthetic hemostatic fabric of claim 6, wherein the staple fibers are crimped.

8. The synthetic hemostatic fabric of claim 4, wherein the hemostatic agent further comprises fibrinogen.

9. The synthetic hemostatic fabric of claim 1, wherein the weight ratio of the first fabric staple fibers to the second fabric staple fibers is 70: 30.

10. The synthetic hemostatic fabric of claim 9, where the mixture of staple fibers is compressed to a thickness of 1.5 mm.

11. The synthetic hemostatic fabric of claim 10, where the blend of staple fibers is compressed to a density of 100 mg/cc.

12. Use of the synthetic hemostatic textile of claim 11 in the manufacture of a medical device.

13. The use of claim 12, wherein the medical device provides hemostasis when applied to a tissue or wound in need of hemostasis.

14. The use of claim 12, wherein the medical device controls and reduces mild to moderate bleeding over an effective period of1 to 10 minutes.

15. The synthetic hemostatic fabric of claim 1, having the following tensile strength (newtons/cm):

a. 63 in the dry condition;

b. 59 in wet condition for 120 minutes;

c. 50 in wet condition for 4 days;

d. 35 in wet condition for 7 days;

e. 18 in wet condition for 11 days;

f. 11 in the wet condition for 14 days.

16. A method for manufacturing the synthetic hemostatic fabric of claim 1, comprising the steps of:

a. suspending the thrombin and fibrinogen in a perfluorinated hydrocarbon to form a suspension; and

b. applying the suspension to the absorbent nonwoven.

17. The method of claim 16, wherein thrombin activity on the synthetic hemostatic textile is between 20 and 500IU/cm²And fibrinogen on the dressing is in the range of 2 to 15mg/cm²Within the range of (1).

18. The method of claim 17, further comprising the step of sterilizing the synthetic hemostatic textile.

19. The method of claim 18, wherein the wound dressing is sterilized by radiation.