WO2013177242A1 - Oxidized regenerated cellulose hemostatic powders and methods of making - Google Patents
Oxidized regenerated cellulose hemostatic powders and methods of making Download PDFInfo
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- WO2013177242A1 WO2013177242A1 PCT/US2013/042149 US2013042149W WO2013177242A1 WO 2013177242 A1 WO2013177242 A1 WO 2013177242A1 US 2013042149 W US2013042149 W US 2013042149W WO 2013177242 A1 WO2013177242 A1 WO 2013177242A1
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/418—Agents promoting blood coagulation, blood-clotting agents, embolising agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
Definitions
- the present invention is directed to resorbable hemostatic powders with improved efficacy, particularly compacted powders made of oxidized regenerated cellulose, and to methods for manufacturing such powders,
- TAHs Topical Absorbable Hemostats
- OC oxidized cellulose
- ORC oxidized regenerated cellulose
- gelatin gelatin
- collagen ehitin
- chitosan chitosan
- scaffolds based on the above materials can be combined with biologically-derived clotting factors, such as thrombin and fibrinogen.
- oxidized cellulose As well as oxidized regenerated cellulose has long been used as a topical hemostatic wound dressing 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 procedures.
- a number of methods for forming various types of hemostats based on oxidized cellulose materials are known, whether made in powder, woven, non-woven, knit, and other forms.
- Currently utilized hemostatic wound dressings include knitted or non-woven fabrics comprising oxidized regenerated cellulose (ORC ), which is oxidized cellulose with increased homogeneity of the cellulose fiber.
- ORC oxidized regenerated cellulose
- hemostatic wound dressings examples include SURGICEL* resorbable hemostat; SURGICEL* ' NU-KNIT* resorbable hemostat; SURGICEL*
- FIBRILLAR resorbable hemostat and SURGICEL ® SNoWTM resorbable hemostat all available from Johnson & Johnson Wound Management Worldwide, a division of Ethicon, inc., Somerville, N.J., a Johnson & Johnson Company.
- Other examples of commercial resorbable hemostats containing oxidized cellulose include GelitaCel* resorbable cellulose surgical dressing from Gelita Medical BV, Amsterdam, The Netherlands, The commercially available oxidized cellulose hemostats noted above are knitted or nonwoven fabrics having a porous structure for providing hemostasis.
- U.S. Patent No. 3,364,200 to Ashton and Moser describes a resorbable, surgical hemostat in the form of pledgets of integrated oxidized cellulose staple fibers
- compressible, shapeable mass that is formed into a sheet for placement on a bleed site and further having a slee ve in a form of a tubular shell dimensioned to receive a limb.
- hemostatic wound dressings utilizing a fibrous fabric substrate made from carboxylic -oxidized cellulose and containing a porous, polymeric matrix homogeneously distributed through the fabric and made of a biocompatible, water-soluble or water-sweJlable cellulose polymer, wherein the fabric contains about 3 percent by weight or more of water- soluble oligosaccharides.
- POSTOPERATIVE ILEUS AND GASTRIC STASIS discloses milling of ORC, particularly cryogenic milling, using a cutting blade of a motor-driven mill.
- the process of reerystallization of the ball-milled samples was studied under various conditions and compared to the hydrolytically induced recrystailization of rayons.
- the reference discloses effect of fine structure on the decrystaliization process which results from the ball-milling of cellulose fibers.
- U.S. Patent No. 6,627,749 discloses a process for grinding oxidized cellulose using a pestle and mortar or in a ball mill or any other conventional laboratory grinder. It further discloses that when cotton linter sheet is used as the starting cellulose source, the fiber length of the product decreases with increasing reaction time. When ball-milled, the long fibrous structures of the product turn into smaller fibers, to loosely-packed spherical aggregates. No significant change in the crystallinity of these samples occurs as a result of ball milling. The reference discloses long fibrous oxidized cellulose ball milled to form small fibers or loosely packed spherical aggregates.
- Oxycelodex a ew hemostatic preparation, Pharmaceutical Chemistry Journal, 18, 506-5; discloses an Oxycelodex paste that consists of two components, oxidized cellulose powder and a 20% aqueous solution of dextran.
- the present invention is directed to a hemostatic material comprising a compacted ORC powder that has particles with an average aspect ratio from about 1 to about 18.
- the compacted ORC powder is preferably made by ball milling. More particularly, the compacted ORC powder can be roller compaction processed ORC powder or hammer mill processed ORC powder.
- the hemostatic material preferably has a tapped density of at least 0.45 g cm ' ', and/or a flowability of at least 7.5 cm/ ' s; and/or an average particle size of 1.75 microns to 1 16 microns with a median size of 36 microns.
- the hemostatic material is a powder with particles having average aspect ratio from about 1 to about 5: a tapped density of at least 0.67 g/cm 3 and flowability of at least 70.
- the hemostatic material further includes an additive, such as earboxymethyl cellulose (CMC) or other polysaccharides, calcium salt, anti-infective agent, hemostasis promoting agent, gelatin, collagen, or combinations thereof,
- CMC earboxymethyl cellulose
- other polysaccharides such as calcium salt, anti-infective agent, hemostasis promoting agent, gelatin, collagen, or combinations thereof,
- the hemostatic material is in the form of a paste that comprises the hemostatic materials of described above and a saline solution.
- the paste preferably has a viscosity greater than 10000 Pa-s at room temperature.
- the present invention is directed to a method of making the hemostatic materials described above by compacting an ORC-based material into a powder, until said powder reaches an aspect ratio of from about 1 to about 18.
- the ORC-based material can be ORC in fabric form, ORC in non-woven form, or a sliredded ORC material.
- the compacting is performed by ball milling.
- the compacting is performed by roller compaction or by hammer milling.
- the ORC-based material can be combined with an additive, such as CMC, calcium salt, anti-infective agent, hemostasis promoting agent, gelatin, collagen, saline, or combinations thereof.
- the present invention is directed to a method of treating a wound by applying hemostatic po wders described above onto and/or into the wound of a patient.
- Figure 1 is a graph of particle size distribution of ball milled material as measured by dynamic light scattering.
- Figure 2 is a graph of particle size distribution of ball milled material as measured by SEM.
- Figure 3 is a graph of the results of in-vitro blood clotting testing shown as clotting time versus aspect ratio for shredded and ball milled ORG powders.
- Figure 4 is a graph of in-vitro blood clotting testing shown as clotting time versus aspect ratio for shredded and bail milled ORG powders.
- Figure 5 is a graph of the time to hemostasis for several different powders.
- Figure 6 is a graph showing average viscosity of flowable materials
- Figure 8 is a graph of hemostatic efficacy study- time to hemostasis (TTH) of various materials in a spleen biopsy punch model.
- the inventors discovered a process for making compacted ORC powder having specific properties from ORC-based materials or from pre-shredded ORC-based materials, whereby the resulting powder can be used for various surgical and wound healing topical applications, such as anti-adhesion barriers, hemostats, tissue sealants, etc.
- Oxidized regenerated cellulose materials which are used as a starting material for making compacted ORC powder of the present invention are known and commercially a v ailable.
- the materials include absorbable woven or knitted fabric or non-woven materials comprising oxidized polysaccharides, in particular oxidized cellulose and the neutralized derivatives thereof.
- the cellulose may be carboxylic-oxidized or aldehyde-oxidized cellulose.
- Oxidized regenerated polysaccharides including, but without limitation, oxidized regenerated cellulose may be used. Oxidized regenerated cellulose is preferred due to its higher degree of uniformity versus cellulose that has not been regenerated. Regenerated cellulose and a detailed description of how to make oxidized regenerated cellulose are set forth in U.S. Pat. Nos. 3,364,200, 5, 180,398 and 4,626,253, the contents each of which is hereby incorporated by reference as if set forth in its entirety.
- Examples of materials that may ⁇ be utilized as the include, but are not limited to, INTERCEED* absorbable adhesion barrier, SURGICEL ® absorbable hemostai, SURGICEL ® NU-KNIT ® absorbable hemostai, SURGICEL ® FIBRILLAR absorbable hemostat, or SURGICEL ® S oWTM absorbable hemostat (each available from Johnson & Johnson Wound Management Worldwide, a division of Ethicon, Inc., Somervbook, N.J.).
- the resulting ORG powders can perform as a hemostat in either a paste or powder form with superior hemostatic properties and good tissue conformability and flowability.
- the ORG materials can be physically incorporated with other agents and biopolymers to improve adherence to tissues, sealing properties, and/or anti-adhesions properties.
- the inventive method is used to make particles of ORG having these specific aspect ratios directly from ORG materials, such as ORG fabric or non-wovens as characterized above utilizing the ball milling process.
- the particulates of the present invention have overall size (largest dimension) less than 500 microns, such as less than 300, 200, and less than 100 microns.
- the l ow aspect ratio (1-20) particles should comprise the majority of the particl es constituting the powdered material, i.e. over 50%, such as over 80% or over 90% of particles.
- the particulates having overall size (largest dimension) less than 500 microns, such as less than 300, 200, and less than 100 microns should comprise the majority of the particles constituting the powdered material, i.e. over 50%, such as over 80% or over 90% of particles.
- the product resul ting from the ball-milling process comprising low aspect ratio and high tapped density particles of ORG are shown to have superior hemostatic or blood clotting properties.
- ORG is an absorbable hemostatic material .known to these skilled the art. A number of methods are known for forming various types of hemostats based on oxidized cellulose materials into powder, woven, non-woven, knit, and other forms and combinations thereof. Currently utilized hemostatic wound dressings include knitted or non-woven fabrics comprising oxidized regenerated cellulose (ORG), which is oxidized cellulose with increased homogeneity of the cellulose fiber.
- ORG oxidized regenerated cellulose
- hemostatic wound dressings commercially available include SURGICEL* absorbable hemostat, SURGICEL '® NLI-KNIT ® absorbable hemostat, SURGICEL ® FIBRILLAR absorbable hemostat, or SURGICEL ® SNoWTM absorbable hemostat; all available from Johnson & Johnson Wound Management Worldwide, a division of Ethicon, Inc., Somervbook, N.J.
- the ball milled ORC particles can be combined with various additives to further improve the hemostatic properties, wound healing properties, and handling properties, utilizing additives known to these skilled in the art, including: hemostatic additives, such as gelatin, collagen, cellulose, chitosan,
- biologies based hemostatic agents as exemplified by thrombin, fibrinogen, and fibrin
- additional biologies hemostatic agents include, without limitation, procoagulant enzymes, proteins and peptides, each such agent can be naturally occurring, recombinant, or synthetic, and may be further selected from the group consisting of fibronectin, heparinase, Factor X/Xa, Factor Vfl/VIIa, Factor IX/IXa, Factor Xl/XIa, Factor XH/XIla, tissue factor, batroxobin, ancrod, ecarin, von Willebrand Factor, albumin, platelet surface glycoproteins, vasopressin and vasopressin analogs, epinephrine, selectin, procoagulant venom, plasminogen activator inhibitor, platelet activating agents, synthetic peptides having hemostatic activity, derivatives of the above and
- Preferred biologic hemostatic agents that can used in combination with the bail- milled ORC particles are thrombin, fibrinogen and fibrin; Anti-infective agents, such as chiorhexidine gluconate (CHG), triclosan, silver, and similar anti-bacterial microbial agents that are known in the art; and additives that increase the stickiness of the hemostat; diluents, saline solutions, and similar additives that known in the art.
- the aspect ratio of powder is defined as a v erage aspect ratio of particles comprising the pow der, with the aspect ratio of particles determmed by a measurement of the longest dimension of the particle (length) divided by the shortest dimension of the particle (width), as visible under appropriate magnification under SEM or optical microscope.
- the lowest aspect ratio (AR) of 1 corresponds to a round particle, having longest dimension equal to the shortest dimension.
- An aspect ratio of about 20 corresponds to a fibrous particle having length 20 times diameter.
- the aspect ratios of experimental samples were determined by SEM imaging.
- Preferred aspect ratios according to the present invention are from 1 to 20, more specifically from about 1.5 to about 17.5,
- the flowability of hemostatic particles is a parameter that influences the deployment of powders during surgical procedures. High flowability is preferred in a surgical setting for ease of deployment. Bulk density is the ratio of the mass of an untapped powder sample and its volume including the contribution of the interparticulate v oid volume. Tapped density is a measure of increased bulk density of powder that is obtained by mechanically tapping a container of the powder. Tapped density appears to be correlated with flowability. High tapped density is preferred for ease of deployment and mixing. Preferred tapped density is from about 0.35 to about 1 g/cm 3 , more preferably 0.4-0.9 g/cm 3 , such as 0.42-0.78 g/cm J .
- Tapped density for purposes of this appiication except as otherwise noted, is measured using a modified USP 616 method in which one (1 ) gram of powder is introduced into a dry graduated cylinder of 10 ml,, and manually tapped with 100 taps for approximately 2 minutes.
- the expression force for hemostatic powders is also an important parameter related to deployment of powders or paste during surgical procedures.
- the effort required to expel a liquid from a syringe, and to draw liquid into the syringe, are known as the expression force and aspiration force respectively.
- the expression force measure is a more critical for dual-syringe mixing devices.
- Dual-syringe mixing devices produce a substantially homogenously paste mixture by combining initially separate liquid and solid carriers and then passing the blended contents back and forth between two connected syringes via interconnected outlets. Therefore, a low expression force for dispensing the paste from a syringe is preferred for ease of mixing and ultimately for deployment of the resulting paste.
- the desired expression force is less than 1.51 ibf at the similar aspect ratio as seen in Ta ble 3 when the 1 st or 2 nd 0.1 mL of paste is expressed using sterile Beckton Dickinson [male luer lock 1 mL swinges.
- ORC samples can be ball milled with 5 - 30 or more high-density ZrO? bails, such as 12 ZrO? balls (20 mm in diameter; Glen Mills Inc., Clifton, NJ, USA) by placing the balls and the samples in a grinding jar (250 mL; 500mL or larger). The jar can be clamped into the latching brackets and then counterbalanced on the mill (such as planetary ball mill PM100; Retsch, Inc., Newtown, PA, USA). The milling can be then performed at 150-500 rpm, e.g. at 300 rpm for 5-60 minutes, such as for 10 - 30 min.
- high-density ZrO? bails such as 12 ZrO? balls (20 mm in diameter; Glen Mills Inc., Clifton, NJ, USA
- the mill can be then performed at 150-500 rpm, e.g. at 300 rpm for 5-60 minutes, such as for 10 - 30 min.
- Rolling compaction refers to the continuous compaction of powders by roll mills.
- the powder is usually delivered by feed screw to rolls and densified by the pressure and shear force.
- Roll compaction is a powder agglomeration process used in variety of industries including the pharmaceutical , mineral and chemical industries.
- Roll compaction of poor flowability powder mixtures requires screw feed of the powder between two counter-rotating rolls. These then draw the powder into the compaction zone and apply a high pressure forming a strip of compacted powder. Powders compacted to such strips or ribbons by pressure between two-counter rotating rolls are then further milled into granules of low aspect ratio.
- woven or non-woven ORC material, or shredded or ball milled ORC material can be further roller compacted to reach desired low aspect ratios and high density OR C particles.
- a hammer mill is another method that can be used to make an ORC particle having sufficient low aspect ratio and high tapped density.
- a hammer mill operates by impact action and will pulverize most dry, free-flowing materials. Material is fed into the hammer mill from the top and then falls into the grinding chamber. The material is contacted by a series of hardened steel hammers rotating at high speed. The material is ground by repeated contact with these hammers, contact with the walls of the grinding chamber, and particle to particle contact. The material remains in the hammer mill grinding chamber until the particles become small enough to escape by passing through the perforated screen that covers the bottom half of the grinding chamber.
- a hammermill is essentially a steel drum containing a vertical or horizontal rotating shaft or dram on which hammers are mounted.
- the hammers are free to swing on the ends of the cross, or fixed to the central rotor.
- the rotor is spun at a high speed inside the drum while material is fed into a feed hopper.
- the material is impacted by the hammer bars and is thereby shredded and expelled through screens in the dram of a selected size.
- the hammer mill can be used as a primary, secondary, or tertiary crusher, i.e. ORC can be hammer milled from woven or non-woven material ORC source, or from shredded or ball milled ORC material.
- the milled powder then was dried in a vacuum oven (Fisher Scientific Model 280A Isotemp vacuum oven) with a vacuum pump (LabCare America Pump PV-35) at 65°C for 2.5 h.
- the milled powder was finally stored in a nitrogen box.
- the milling was performed at 300 rpm for 30 minutes with same rotation. Milled ORC powder was removed from the grinding jar and dried in a vacuum oven (Fisher Scientific Model 280A Isotemp vacuum oven) and a vacuum pump (LabCare America Pump PV-35) at 65 °C for 2.5 hours.
- a vacuum oven Fisher Scientific Model 280A Isotemp vacuum oven
- a vacuum pump LabCare America Pump PV-35
- ORC-based SURGICEL NU-KN T absorbable hemostat was utilized in preparing the powders of this invention, using the same methods as described above.
- Shredded ORG powders were obtained by shredding ORC fabric through a Fitz Mill equipped with a screen mesh 1726-150.
- the raw bulk density and tapped densit '- were 0.2g/mL and 0.26g/mL, respectively, measured with a standard USP 616.
- the shredded ORC powders were fed into a roller compactor (WP 120x 40V, #900-0071 , Alexandertechnik, Inc, PA). 5 Liter high flow hopper with helical band screw mounted horizontally above feed screw inlet. High output feed screw with reliefs for friction pins. Single helix in hopper inlet and double helix in the vacuum area were towards the front of the feeding screw.
- a Vacuum de-aeration filter pipe ( ⁇ lum) was installed around the feed screw for removing entrained air before the rollers.
- the sample flew well enough to achieve a flake of 2.2-2.7mm.
- Higher pressure was required to force the fibers to break around 180 bars, 16.2 Kn cm of roller width.
- the pressure was around 6Kg/hour for the procedure of feed scre w transportation in order to move the sample smoothly.
- Standard rotor angle starting with a 1.25mm screen for coarse breaking and a 0.63mm screen for the fine granulation. Round screens (1.25mm round) were used to start and then 0.80mm square screens were used for more aggressive shear.
- samples were sieved through a screen sieves set of 80, 100, 120, 140, 170, 230, and 270 meshes, with a amplitude-modulated ATM sonic sifter for 5 minutes.
- the particle distributions were 31.1% (>18() mesh), 0.7% (>150 mesh), 0% (>125 mesh), 0.1% (106 mesh), 3,6% (90 mesh), 20.2% (63 mesh), 5% (53 mesh), and 37.6% in the bottom pan. Except for the sample (>! 80 mesh), the rest of the sieved samples were in fiber formats.
- the aspect ratio and tapped density of the sample (>180 mesh) were approximately 1.5 and 0.44g/mL, respectively.
- shredded/chopped ORC powder was prepared from the same starting ORC fabric as follows. A quantity of ORC fabric was placed into a shredder
- EXAMPLE 2 Physical charaeterizaiion of compacted ORC powders or Brown-Milled Powders (BMP).
- Shredded ORC powder was made having substantially the same aspect ratios as the inventive ball milled powders.
- the shredded ORC powders were obtained by shredding ORC fabric through a Fitz Mill at 6000 rpm and equipped with a screen mesh followed by sieving through a screen sieves set of 45, 80, 120, 400, with a sieve shaker (W.S. Tyler, OH, USA, Model: RX-29, SN: 10-1046). Aspect ratio characterizations were performed using optical measurement technique as described above.
- EXAMPLE 3 Effects of particles aspect ratio on tapped density and flowability: BMP vs. shredded/chopped powders
- Particle flowability was measured using a modified USP 1 174 method- Powder flow.
- Four digits of Scale (Mettler Toledo Excellent XS204, ETHICON BA-046) was used to measure the weight of the powder as it traveled through a glass tube (ODi 0.8cm, ID: 0.6cm, length: 31cm).
- the flow rate of powder was determined by the travel time and total travel distance (40cm).
- An ST4 Coagulation Analyzer was used to determine the in-vitro blood clotting time. Each cuveite contained 200uL of diluted blood followed by ihe applicaiion of 2mg of each test article. Each sample was tested in triplicate.
- FIG. 3 shows the results of the testing shown as clotting time vs. aspect ratio for shredded ORC powders and BMP.
- Figure 4 shows the same data as Figure 3 but for a narrow range of aspect ratios. Analysis of data presented indicates that at low aspect ratios, particularly at aspect ratios from about 1 to about 18, BMP exhibit much better blood clotting relative to shredded ORC powders, with up to 3 times faster time to clotting at some aspect ratios.
- TTPI time to hemostasis
- inventive materials which included BMP, as well as BMP Plus
- BMP is a powder made of SURGICEL ⁇ fabric by ball milling as described above.
- BMP Plus is a powder made of SURGiCEX ⁇ fabric mixed with carhoxymethyl cellulose (CMC) and calcium citrate by bail milling as described above.
- SURGIFLO ® Hemostatic Matrix is commercially available from Johnson & Johnson Wound Management Worldwide, a division of Ethicon, Inc., Somervbook, N.J., a Johnson & Johnson Company.
- Biopsy punch incisions (6 mm long and 3 mm deep) were made on a swine spleen.
- BMP was prepared as described above (Example 5) and utilized for making paste. To each 6mL syringe, lgram of BMP was added. The plunger was pre -positioned to 2.2 mL. The syringe was then mixed with 2 mL of sterile saline by connecting to another syringe and transferring the BMP/ saline mixture back and forth between the syringes, with 10 transfers to reach ready-to-use consistency. Additional transfers were applied if necessary.
- Concentrations of 1 gram/1.6 mL, lgram/ 1.8 mL, 1 gram/2 mL and lgram 2.2mL were evaluated; however, the first two concentrations of samples were very difficult to mix and gel block was found in the syringes. Concentration of Igrarn per 2.2mL was too dilute compared to 1 gram/2 mL. The data presented corresponds to 1 gram/2 ml_.
- Commercially available SURG1FLO ® Hemostatic Matrix (Control) was mixed with 2 mL of sterile saline.
- TTH time to hemostasis
- BMP was prepared as described in Example 5.
- the milled GelitaCel powder with aspect ratio of 1.92 required 2-hour grinding process.
- Analysis of the data presented in Figure 8 indicates that BMP exhibited better hemostatic effsciency relative to the comparative powders at the same aspect ratios of the powders.
- the SURGICEL ® powder AR 20 data point on the plot Figure 8 corresponds to the shredded ORC powder (comparative example).
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Abstract
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Priority Applications (19)
Application Number | Priority Date | Filing Date | Title |
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BR122019014998A BR122019014998B1 (en) | 2012-05-25 | 2013-05-22 | hemostatic powders of oxidized regenerated cellulose and methods for making them |
EP18196090.7A EP3466455B1 (en) | 2012-05-25 | 2013-05-22 | Oxidized regenerated cellulose hemostatic powders and methods of making |
CN201380027487.6A CN104321085B (en) | 2012-05-25 | 2013-05-22 | Oxidized regenerated cellulose haemostatic powder and preparation method |
JP2015514141A JP6165849B2 (en) | 2012-05-25 | 2013-05-22 | Oxidized regenerated cellulose hemostatic powder and production method |
MX2018003025A MX358625B (en) | 2012-05-25 | 2013-05-22 | Oxidized regenerated cellulose hemostatic powders and methods of making. |
ES13725889T ES2702714T3 (en) | 2012-05-25 | 2013-05-22 | Haemostatic powders of oxidized regenerated cellulose and processing methods |
MX2014014322A MX354596B (en) | 2012-05-25 | 2013-05-22 | Oxidized regenerated cellulose hemostatic powders and methods of making. |
IN9514DEN2014 IN2014DN09514A (en) | 2012-05-25 | 2013-05-22 | |
EP22151814.5A EP4043042A1 (en) | 2012-05-25 | 2013-05-22 | Oxidized regenerated cellulose hemostatic powders and methods of making |
AU2013266416A AU2013266416B2 (en) | 2012-05-25 | 2013-05-22 | Oxidized regenerated cellulose hemostatic powders and methods of making |
EP13725889.3A EP2854882B1 (en) | 2012-05-25 | 2013-05-22 | Oxidized regenerated cellulose hemostatic powders and methods of making |
KR1020207018980A KR102254305B1 (en) | 2012-05-25 | 2013-05-22 | Oxidized regenerated cellulose hemostatic powders and methods of making |
RU2014152706A RU2629199C2 (en) | 2012-05-25 | 2013-05-22 | Hemostatic powders of oxided regenerated cellulose and methods of their production |
KR1020147036146A KR102131601B1 (en) | 2012-05-25 | 2013-05-22 | Oxidized regenerated cellulose hemostatic powders and methods of making |
BR112014029206A BR112014029206B1 (en) | 2012-05-25 | 2013-05-22 | hemostatic material comprising oxidized regenerated cellulose, its method of manufacture and hemostatic paste |
CA2874622A CA2874622C (en) | 2012-05-25 | 2013-05-22 | Oxidized regenerated cellulose hemostatic powders and methods of making |
IL235549A IL235549B (en) | 2012-05-25 | 2014-11-06 | Oxidized regenerated cellulose hemostatic powders and methods of making |
ZA2014/09429A ZA201409429B (en) | 2012-05-25 | 2014-12-19 | Oxidized regenerated cellulose hemostatic powders and methods of making |
IL261869A IL261869B (en) | 2012-05-25 | 2018-09-20 | Oxidized regenerated cellulose hemostatic powders and methods of making |
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US13/480,842 US8815832B2 (en) | 2012-05-25 | 2012-05-25 | Oxidized regenerated cellulose hemostatic powders and methods of making |
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US11883554B2 (en) | 2017-11-08 | 2024-01-30 | Ethicon, Inc. | Hemostatic paste having surface enriched with hemostasis-promoting agents and devices for delivery |
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