JP4812630B2 - Tissue coating assemblies, systems and methods formed from hydrophilic polymer sponge structures such as chitosan - Google Patents

Description

(Related application)
This application is a US patent application filed December 23, 2004 entitled "Wound Dressing and Method of Controlling Life-Threating Breeding". No. 10 / 743,052, a continuation-in-part application entitled “Wound Dressing and Method of Controlling Life-Threening Breeding”, 2003 12 This is a continuation-in-part of US patent application Ser. No. 10 / 480,827 filed on Jan. 15, which is provisional application No. 60/298, filed Jun. 14, 2001. The international application PCT / U502 / 18757 filed June 14, 2002, claiming the benefit of No. 773, C.I. F. R. § 371 national phase applications, each of which is hereby incorporated by reference.

(Field of Invention)
The present invention as a whole is applied to a site of tissue injury or trauma or tissue invasion to improve bleeding, fluid leakage or exudation, or other forms of fluid loss while simultaneously covering the entire site. Related to the tissue dressing to be protected.

(Background of the Invention)
Continuously applying pressure with a gauze bandage is the first treatment technique used to stop blood flow, particularly outflow from severe bleeding wounds. However, this technique is neither efficient nor safe for stopping severe blood flow. This becomes a major survival problem in the case of severe and life-threatening bleeding from a wound and will continue to be a problem in the future.

  Although tourniquets such as collagen wound dressings or dried fibrin thrombin wound dressings or chitosan and chitosan dressings are commercially available, these dressings are not resistant to dissolution in a large amount of blood flow. They also do not have sufficient adhesive properties to achieve a practical purpose in preventing severe blood flow. These currently available surgical tourniquets are also delicate and therefore tend to be damaged by bending and twisting under pressure. They are also easily dissolved in the flowing blood. Such dissolution and disintegration of these bandages can be disastrous as they lose their stickiness to the wound and continue to bleed without weakening.

  There is a need for an improved hemostatic dressing that has robustness and long life that does not dissolve during use.

(Summary of Invention)
The present invention provides tissue dressing assemblies, systems and methods formed from hydrophilic polymer sponge structures. This tissue dressing assembly may be used, for example, (i) for hemostasis, sealing or stabilization at the site of tissue damage, tissue trauma or tissue intrusion; or (ii) for the formation of an anti-bacterial barrier; For the formation of viral patches; or (iv) for the treatment of bleeding disorders; or (v) for the release of therapeutic agents; or (vi) for the treatment of mucosal surfaces; or (vii) for their combination. it can.

  According to one aspect of the present invention, the hydrophilic polymer sponge structure comprises: (i) a microcrack in a critical part of the structure by mechanical manipulation prior to use, or (ii) a critical part of the structure prior to use. Or (iii) a fluid injection channel pattern formed in a significant portion of the structure prior to use.

  According to another aspect of the invention, the tissue dressing assembly includes at least one woven or non-woven or permeable membranous sheet present within the hydrophilic sponge structure.

  According to another aspect of the present invention, the tissue dressing assembly includes an absorbable component retained in a hydrophilic sponge structure.

  Having one or more of these aspects provides compatibility, flexibility, and long life.

  In one embodiment, the hydrophilic polymer sponge structure comprises chitosan biomaterial.

In one embodiment, the hydrophilic polymer sponge structure is desirably densified to a density of 0.6 to 0.1 g / cm ³ .

  Other features and advantages of the invention will be apparent based on the accompanying description, drawings, and claims.

(Detailed explanation)
To facilitate understanding of the present disclosure, the scope of the topics covered is summarized in the following list in the order listed.

(List of topic areas to be listed)
I. Tissue dressing pad assembly Overview 1. Tissue dressing matrix 1. 3. Support material Sachet B. Example 1 Use of Tissue Dressing Pad Assembly
C. Manufacture of tissue dressing pad assembly 1. Preparation of chitosan solution 2. Deaeration of chitosan aqueous solution 3. Freezing chitosan aqueous solution 4. Freeze-drying of chitosan / ice matrix 6. Densification of chitosan matrix 7. Fixing of support material 8. Placement in a pouch Final sterilization Evaluation of adhesive / adhesive sealing properties of hydrophilic polymer sponge structures 1. Arterial wound sealing test device Identification of aging phenomenon
Example 2
3. Identification of adhesion / adhesion properties between different shapes of hydrophilic polymer sponge structures Change in compatibility characteristics of hydrophilic polymer sponge structure Adjustable microcrack
Example 3
2. Adjustable microstructure
Example 4
3. Adjustable vertical channel formation
Example 5
II. Tissue dressing sheet assembly A. Overview B. Use of tissue dressing sheet assembly Fabrication of tissue dressing sheet assembly Examples 6 and 7
III. Further applications and shapes of hydrophilic polymer sponge structures Bodily fluid loss suppression (eg, burns)
1. Composite dressing assembly 76
B. Antimicrobial barrier Example 8
C. Antiviral patch Treatment of bleeding disorders Sustained release of therapeutic agents Treatment of mucosal surface IV. CONCLUSION While this disclosure is detailed and accurate to enable those skilled in the art to practice the invention, the physical embodiments disclosed herein are merely illustrative of the invention and other specific It may be embodied in the structure. While preferred embodiments have been described, the details may be changed without departing from the invention as defined in the claims.

(I. Tissue dressing pad assembly)
(A. Overview)
FIG. 1 shows a tissue dressing pad assembly 10. In use, the tissue dressing pad assembly 10 can adhere to tissue in the presence of blood, body fluid, or moisture. The tissue dressing pad assembly 10 stops and seals the site of tissue damage, tissue trauma, or tissue invasion (eg, a catheter or feeding tube) so that there is no bleeding, fluid leakage or exudation, or other form of fluid loss. Can be used to stop or stabilize. Tissue sites to be treated include, for example, arterial and / or venous bleeding, or lacerations, or entry / entrance wounds, or tissue punctures, or catheter entry sites, or burns, or sutures. The tissue dressing pad assembly 10 is also preferably capable of forming an antibacterial and / or antimicrobial and / or antiviral protection barrier at or around the tissue treatment site.

  FIG. 1 shows the tissue dressing pad assembly 10 prior to use. As best shown in FIG. 2, the tissue dressing pad assembly 10 includes a tissue dressing matrix 12 and a pad support 14 overlying one surface of the tissue dressing matrix 12. Desirably, the tissue dressing matrix 12 and support 14 have different colors, textures, or other visual and / or tactile differences to facilitate identification by the person performing the procedure.

  The size, shape, and structure of the tissue dressing pad assembly 10 can vary depending on its intended use. The pad assembly 10 may be linear, elongated, circular, elliptical, or a composite or composite combination thereof. Desirably, as described below, the shape, size, and structure of the pad assembly 10 can be formed by cutting, bending, or molding either during or prior to use. In FIG. 1, a representative structure of a tissue dressing pad assembly 10 is shown, which is extremely useful for temporary suppression of external bleeding or fluid loss. As an example, the size is 10 cm × 10 cm × 0.55 cm.

(1. Tissue coating material matrix)
The tissue dressing matrix 12 is preferably formed from a low modulus hydrophilic polymer matrix, ie, the originally “uncompressed” tissue dressing matrix 12 is densified by the following densification step described below. The tissue dressing matrix 12 preferably includes a biocompatible material that reacts in the presence of blood, body fluids, or moisture to form a strong adhesive or glue. Desirably, the tissue dressing matrix also has other advantageous properties such as promoting anti-bacterial and / or anti-microbial, anti-viral properties, and / or promoting body defense responses to injury.

  The tissue dressing matrix 12 is made of a hydrophilic polymer such as polyacrylate, alginate, chitosan, hydrophilic polyamine, chitosan derivative, polylysine, polyethyleneimine, xanthan, carrageenan, quaternary ammonium polymer, chondroitin sulfate, starch, modified Cellulose polymer, dextran, hyaluronan or combinations thereof may be included. The starch may comprise amylase, amylopectin, and a combination of amylopectin and amylase.

  In a preferred embodiment, the biocompatible material of the matrix 12 comprises a non-mammalian material, most preferably poly [β- (1 → 4) -2-amino-2-deoxy-D-glucopyranose, which is More commonly called chitosan. The chitosan selected for the matrix 12 preferably has a weight average molecular weight of at least about 100 kDa, more preferably at least about 150 kDa. Most preferably, the chitosan has a weight average molecular weight of at least about 300 kDa.

  In forming the matrix 12, chitosan is desirably placed in solution with an acid such as glutamic acid, lactic acid, formic acid, hydrochloric acid and / or acetic acid. Of these, hydrochloric acid and acetic acid are most preferred. This is because chitosan acetate and chitosan chloride are resistant to dissolution in blood, but chitosan lactate and chitosan glutamate are not. Larger molecular weight (Mw) anions destroy the para-crystal structure of the chitosan salt, creating a plasticizing effect on the structure (increasing flexibility), but undesirably, of these large Mw anion salts It also provides rapid dissolution in the blood.

One preferred form of matrix 12 includes an “uncompressed” chitosan acetate matrix 12 having a density of less than 0.035 g / cm ³ formed by freezing and lyophilization of a chitosan acetate solution, which is then reduced to 0. Densification to a density of 6 to 0.25 g / cm ³ , most preferably about 0.20 g / cm ³ . The chitosan matrix 12 is also characterized by a compressed, hydrophilic sponge structure. The densified chitosan matrix 12 exhibits all of the above properties that may be desirable. It also has certain structural and mechanical advantages, thereby imparting robustness and long life to the matrix in use, which will be described in more detail later.

  The chitosan matrix 12 presents a robust, permeable, high specific surface area, positively charged surface. A positively charged surface results in a surface that is highly responsive to red blood cell and platelet interactions. The erythrocyte membrane is negatively charged and is attracted to the chitosan matrix 12. The cell membrane fuses with the chitosan matrix upon contact. Clots are formed very quickly and usually require the clotting proteins needed for hemostasis, but this is no longer necessary. For this reason, the chitosan matrix 12 is effective not only for normal but also for individuals who have been subjected to anticoagulation, as well as for those who have coagulation injury such as hemophilia. The chitosan matrix 12 can also bind to bacteria, endotoxins, and microorganisms and kill bacteria, microorganisms, and / or viral substances upon contact.

  Further details of the structure, composition, manufacture, and other technical features of the chitosan matrix 12 will be described later.

(2. Support material)
The tissue dressing pad assembly is sized and configured to be manipulated by the finger and hand of the person performing the procedure. The support material 14 separates the finger and hand of the person performing the procedure from the fluid-responsive chitosan matrix 12 (see, eg, FIG. 8). The support 14 allows the chitosan matrix 12 to be handled, manipulated and applied to a tissue site without sticking or sticking to the finger or hand of the person performing the procedure. The support 14 can be a synthetic and natural polymer low modular mesh and / or a fill and / or a fabric. In a preferred embodiment for temporary application to an external wound, the support 14 comprises a fluid impermeable polymer material, such as polyethylene (3M 1774T polyethylene foam medical tape, thickness 0.056 cm), but other similar materials. Can also be used.

  Other polymers for the support material used in temporary application to the wound include, but are not limited to, cellulose polymers, polyethylene, polypropylene, metallocene polymers, polyurethanes, polyvinyl chloride polymers, polyesters, polyamides, or combinations thereof. .

  For application to an internal wound, a resorbable support may be used in the form of a hydrophilic sponge bandage. Preferably, such a bandage shape uses a biodegradable, biocompatible support material. Synthetic biodegradable materials include, but are not limited to, poly (glycolic acid), poly (lactic acid), poly (e-caprolactone), poly (β-hydroxybutyric acid), poly (β-hydroxyvaleric acid), poly Dioxane, poly (ethylene oxide), poly (malic acid), poly (tartronic acid), polyphosphazene, copolymers of polyethylene, copolymers of polypropylene, and copolymers of monomers used to synthesize the above polymers, or combinations thereof including. Natural product biodegradable polymers include, but are not limited to, chitin, algin, starch, dextran, collagen and albumin.

(3. Small bag)
As shown in FIG. 3, the chitosan matrix 12 is desirably vacuum packaged in a pouch 16 lined with a hermetically heat-sealed foil with a low moisture content, preferably 5% or less, prior to use. The tissue dressing pad assembly 10 is then finally sterilized using gamma irradiation within the pouch 16.

  The pouch 16 is configured to be peeled and released by the person performing the procedure in use (see FIGS. 4 and 5). The pouch 16 is peeled along one end to utilize the tissue dressing pad assembly 10. The opposite end of the pouch 16 is grasped and pulled apart to expose the tissue dressing pad assembly 10 to be used.

(B. Use of tissue coating pad assembly)
Once the tissue dressing pad assembly 10 is removed from the pouch 16 (see FIG. 6), it can be immediately adhered to the targeted tissue site. There is no need to perform pre-application operations to promote adhesion. For example, it is not necessary to peel off the protective material to expose the sticky surface in use. Since the chitosan matrix 12 itself exhibits strong adhesive properties once in contact with blood, fluid, or moisture, the adhesive surface is formed in situ.

  Desirably, the tissue dressing pad assembly 10 is applied to the injury site within one hour of release of the pouch 16. As shown in FIG. 7, the tissue dressing assembly 10 can be preformed and deformed on the site to adapt to the shape and form of the site. As shown in FIGS. 14 and 15, the tissue dressing pad assembly 10 can be deliberately shaped into other shapes, such as cups, to best fit the particular shape and configuration of the treatment site. While the tissue dressing pad assembly 10 is molded or otherwise manipulated prior to placement at the treatment site, the caregiver must avoid hand or finger moisture coming into contact with the chitosan matrix 12. This is because the chitosan matrix 12 becomes sticky when it comes into contact, making it difficult to handle. This is the primary purpose of the support 14, but the support 14 also serves to add mechanical support and strength to the matrix.

  8-13 illustrate a tissue dressing pad assembly 10 applied for the treatment of arterial and / or venous hemorrhagic damage. As shown in FIGS. 8 and 9, the tissue dressing pad assembly 10 must be placed so that the chitosan matrix 12 is placed at the very bleeding site or other site where attachment is desired. The support 14 provides a non-stick surface so that the caregiver can apply pressure in a conventional manner. Desirably, caregivers should avoid repositioning the tissue dressing pad assembly 10 after it has been applied to the site where attachment is desired.

  Desirably, as shown in FIG. 8, a stable pressure is applied for at least two minutes so that the chitosan matrix 12 exhibits natural adhesive activity. The adhesive strength of the chitosan matrix 12 increases with the time the pressure is applied until about 5 minutes. The pressure applied to the tissue dressing pad assembly 10 during this time will also provide a more uniform adhesion and wound seal. It was found that applying pressure with a Kerrix roll 18 (see FIG. 10A) was extremely effective.

  Due to the unique mechanical properties and stickiness, two or more dressing pad assemblies can be stacked to close the wound or tissue site if necessary (see FIG. 11). The chitosan matrix 12 of one pad assembly 10 adheres to the support 14 of the adjacent dressing pad assembly 10.

  The dressing pad assembly 10 can also be torn or cut on the site to match the size of the wound or tissue site (see FIG. 12). In order to provide good tissue adhesion and sealing, the dressing pad assembly 10 preferably has a perimeter that is at least 1/2 inch larger than the wound or tissue site. If small, cut the patch pieces of the dressing assembly to the size of the site (see FIG. 13) to best approximate the topology and morphology of the processing site and fit and adhere to the periphery of the other pad assembly 10 You can also.

  If the tissue dressing pad assembly does not stick to the damaged site, it can be removed and discarded and another new dressing pad assembly 10 can be applied. In wounds with significant tissue destruction on deep tissue surfaces, i.e. penetrating wounds, it is very effective to exfoliate the support material 14 and pack the chitosan matrix 12 into the wound and then cover the wound with a second dressing I understood.

  After the pressure has been applied for 2-5 minutes and / or after the suppression of bleeding has been achieved with good dressing adhesion and coverage at the wound or tissue site, preferably a second conventional dressing (e.g. Gauze) is applied to cover and provide a clean barrier to the wound (see FIG. 10B). After this, if the wound is hidden in the undergarment, it is necessary to apply a watertight cover to prevent the dressing from being excessively hydrated.

  In the case of a temporary dressing shape that has passed through the FDA, preferably the woven dressing pad assembly 10 is removed within 48 hours of application in order to provide the most reliable surgical repair. The tissue dressing pad assembly 10 is peeled away from the wound and is usually separated from the wound as a single intact dressing. In some cases, the remaining chitosan gel may remain, but this can be removed using a saline or water loose friction and gauze dressing. Chitosan is biodegradable in the body and is broken down into glucosamine, a harmless substance. Furthermore, in the case of temporary covering, it is desirable to make an effort to remove all parts of chitosan from the wound at the point of reliable repair. As previously discussed, the biodegradable dressing can be shaped for internal use.

(Example 1)
(Use activity report)
Activity reports by combat medic in surgery on liberal combat in Afghanistan and Iraq showed that clinical use of the dressing pad assembly was successful without adverse effects. The United States Army Agency for Surgical Studies in Fort Sam Houston, Texas, evaluated the dressing pad assembly 10 in a trauma model for severe and life-threatening bleeding, and a standard 4x4 inch cotton gauze dressing Compared. Tissue dressing pad assembly 10 significantly reduced blood loss and reduced resuscitation fluid requirements. As for survival for 1 hour, the group to which the tissue dressing pad assembly 10 was applied increased in comparison with the cotton gauze survival group. Combat medic had successfully treated bullets, shrapnel, landmines and other wounds even though they could not be treated with conventional wound dressings.

(C. Manufacture of tissue coating pad assembly)
In the following, a preferred method for manufacturing the tissue dressing pad assembly 10 will be described. This method is schematically illustrated in FIG. Of course, other methods can be used.

(1. Preparation of chitosan solution)
The chitosan used to prepare the chitosan solution preferably has a deacetylation fraction greater than 0.78 and less than 0.97. Most preferably, the chitosan has a deacetylation fraction greater than 0.85 and less than 0.95. Preferably, the chitosan selected for processing into a matrix has a viscosity in a 1% (w / w) solution of 1% (w / w) acetic acid (AA) at 25 ° C. using a spindle LVI at 30 rpm. Is about 100 centipoise to about 2000 centipoise. More preferably, the chitosan has a viscosity in a 1% (w / w) solution of 1% (w / w) acetic acid (AA) at 25 ° C. using a spindle LVI at 30 rpm from about 125 centipoise to about 1000 It is a centipoise. Most preferably, the chitosan has a viscosity in a 1% (w / w) solution of 1% (w / w) acetic acid (AA) at 25 ° C. using a spindle LVI at 30 rpm from about 400 centipoise to about 800 It is a centipoise.

  The chitosan solution is preferably prepared by adding water to the solid chitosan flake or powder at 25 ° C., and the solid is dispersed in the liquid by stirring, stirring or shaking. When chitosan is dispersed in a liquid, an acidic component is added and mixed by dispersion to dissolve the chitosan solid. The dissolution rate depends on the temperature of the solution, the molecular weight of chitosan and the degree of stirring. Preferably, the dissolving step is carried out in a closed tank reactor or a rotating closed vessel equipped with a stirring blade. This ensures uniform dissolution of the chitosan and eliminates the opportunity for high viscosity residues to be captured on the side of the container. Preferably, the proportion of chitosan solution (w / w) is greater than 0.5% chitosan and less than 2.7% chitosan. More preferably, the ratio (w / w) of the chitosan solution is greater than 1% chitosan and less than 2.3% chitosan. Most preferably, the proportion of chitosan solution is greater than 1.5% chitosan and less than 2.1% chitosan. Preferably the acid used is acetic acid. Preferably, acetic acid is added to the solution to a ratio (w / w) of acetic acid solution greater than 0.8% and less than 4%. More preferably, acetic acid is added to the solution in a proportion (w / w) of acetic acid solution that is greater than 1.5% (w / w) and less than 2.5%.

  The structure or morphology manufacturing process of the chitosan matrix 12 is typically performed from solution, freezing (for phase separation generation), non-solvent mold extrusion (for filament manufacturing), electrospinning (for filament manufacturing) Can be achieved using techniques such as phase transformation and non-solvent precipitation (typically as used in dialysis and filter membrane manufacture), or solution coating on preformed sponge-like or woven products . In the case of freezing in which two or more different phases are formed upon freezing (typically when water is frozen in ice and the chitosan biomaterial is separated in different solid phases), the frozen solvent (typically In other words, another process is required to remove the ice) and manufacture the chitosan matrix 12 without destroying the frozen structure. This is accomplished by a lyophilization and / or freeze replacement process. The filament can be formed into a nonwoven sponge-like mesh by a nonwoven spinning method. Alternatively, the filaments can be manufactured as felted fabrics by conventional spinning and weaving methods. Other methods that can be used to make a sponge-like article of biological material include dissolution of the added pore former from the solid chitosan matrix 12 or perforation of the material from the matrix.

(2. Deaeration of chitosan aqueous solution)
Preferably (see FIG. 16, step B), normal atmospheric gas is degassed from the chitosan biological material. Typically, degassing removes sufficient residual gas from the chitosan biomaterial, leaving large voids or large trapped gas bubbles undesired in the primary wound dressing product without escaping gas in subsequent freezing operations. Avoid formation. The degassing step can be performed by heating the chitosan biomaterial, typically in solution, and applying a vacuum to it. For example, degassing may be performed by heating the chitosan solution to about 45 ° C. with stirring at just about 500 mTorr and just prior to applying a vacuum of about 5 minutes.

  In one embodiment, certain gases may be added to the solution after initial degassing while controlling the partial pressure. Such gases include but are not limited to argon, nitrogen and helium. The advantage of this process is that a solution containing these gases at a certain partial pressure forms minute voids when frozen. The microvoids are then carried through the sponge as the ice front advances. This helps interconnect the sponge pores and leaves a well-defined and controlled channel.

(3. Freezing chitosan aqueous solution)
Next (see FIG. 16, step C), the chitosan biomaterial—typically degassed in acid solution as described above—is subjected to a freezing step. Freezing can be performed preferably by cooling the chitosan biomaterial solution supported in the mold and lowering the temperature of the solution from room temperature to finally below the freezing point. More preferably, this freezing step is performed on a plate freezer, whereby a temperature gradient is introduced through the chitosan solution in the mold due to heat loss through the plate cooling surface. Preferably, the plate cooling surface is in good thermal contact with the mold. Preferably, the temperature of the chitosan solution and the mold before coming into contact with the plate freezer surface is around room temperature. Preferably, the surface of the plate freezer surface is less than -10 ° C before introducing the mold + solution. Preferably, the heat capacity of the mold + solution is less than the heat capacity of the plate shelf + heat transfer fluid. Preferably, the mold is not limited to metal elements such as iron, nickel, silver, copper, aluminum, aluminum alloys, titanium, titanium alloys, vanadium, molybdenum, gold, rhodium, palladium, platinum and / or combinations thereof. Formed from. The mold is also coated with a thin inert metal coating such as titanium, chromium, tungsten, vanadium, nickel, molybdenum, gold, and platinum to prevent reaction with the acidic components of the chitosan solution and the chitosan salt matrix. May be. A thermal barrier coating or member may be used in conjunction with a metal mold to control heat conduction within the mold. Preferably, the mold surface does not bind to the frozen chitosan solution. The inner surface of the mold is preferably a thin and permanently bonded fluorinated release formed from polytetrafluoroethylene (Teflon), fluorinated ethylene polymer (FEP), or other fluorinated polymer material. Covered with mold coating. Although a coated metal mold is preferred, a thin wall plastic mold is a convenient alternative as a support for the solution. Such plastic molds include, but are not limited to, molds made by injection molding, machining or thermoforming from polyvinyl chloride, polystyrene, acrylonitrile-butadiene-styrene copolymer, polyester, polyamide, polyurethane and polyolefin. Including. An advantage of combining metal molds with locally placed insulation is that they provide an opportunity to improve control of heat flow and structure inside the freezing sponge. This improvement in heat flow control is due to the large thermal conductivity difference between the heat conducting and heat insulating members in the mold.

  Freezing of the chitosan solution by this method allows the production of a wound dressing with a preferred structure.

  As will be shown later, the plate freezing temperature affects the structure and mechanical properties of the final chitosan matrix 12. The plate freezing temperature is preferably less than about −10 ° C., more preferably less than about −20 ° C., and most preferably less than about −30 ° C. When frozen at −10 ° C., the structure of the uncompressed chitosan matrix 12 is wide open and vertical throughout the open sponge structure. When frozen at −25 ° C., the structure of the uncompressed chitosan matrix 12 is denser but still vertical. When frozen at −40 ° C., the structure of the uncompressed chitosan matrix 12 is dense and not vertical. Instead, the chitosan matrix 12 includes more reinforced, interlocking structures. It was observed that the adhesion / adhesion properties of the chitosan matrix 12 were improved when lower freezing temperatures were used. A freezing temperature of about −40 ° C. forms a chitosan matrix 12 with excellent adhesion / adhesion properties.

  During the freezing process, the temperature is lowered over a predetermined time. For example, the freezing temperature of chitosan biomaterial can be increased from room temperature by applying plate cooling with a constant cooling temperature gradient of about −0.4 ° C./mm to about −0.8 ° C. for about 90 to about 160 minutes. The temperature is lowered to -45 ° C.

(4. Freeze-drying of chitosan / ice matrix)
The frozen chitosan / ice matrix is desirably subjected to moisture removal from the interior of the interstices of the frozen material (see FIG. 16, step D). This moisture removal step can be performed without harming the overall structure of the frozen chitosan biological material. This can be done without producing a liquid phase that can disrupt the structural arrangement of the final chitosan matrix 12. That is, the ice in the frozen chitosan biological material moves from the solid frozen phase to the gas phase (sublimation) without forming an intermediate liquid phase. The sublimated gas is trapped as ice in a vacuum condensing tank at a temperature well below that of the frozen chitosan biomaterial. The preferred method for performing the moisture removal step is by freeze drying or freeze drying. Freeze drying of the frozen chitosan biomaterial can be performed by further cooling the frozen chitosan biomaterial. Typically, a vacuum is then applied. Next, the evacuated frozen chitosan biological material is gradually heated.

  More particularly, the frozen chitosan biomaterial is preferably at about -15 ° C, more preferably at about -25 ° C, most preferably at about -45 ° C, at least about 1 hour, more preferably about 2 hours, most preferably It is subsequently frozen for an appropriate time of about 3 hours. This step may be followed by cooling the condenser to a temperature of about -45 ° C, more preferably about -60 ° C, and most preferably less than about -85 ° C. Next, a vacuum with a magnitude of preferably up to about 100 mTorr, more preferably up to about 150 mTorr, and most preferably at least about 200 mTorr is applied. The evacuated frozen chitosan material is preferably at about −25 ° C., more preferably at about −15 ° C., most preferably at about −10 ° C., for at least 1 hour, more preferably at least about 5 hours, most preferably at least about Heat for an appropriate time of 10 hours.

  Further, while maintaining a vacuum near 200 mTorr, at a shelf temperature of about 20 ° C., more preferably about 15 ° C., most preferably about 10 ° C., at least 36 hours, more preferably at least about 42 hours, most preferably at least about Lyophilization is performed for an appropriate time of 48 hours.

(5. Densification of chitosan matrix)
The chitosan matrix before densification (density of about 0.03 g / cm ³ ) is referred to as “uncompressed chitosan matrix”. This uncompressed matrix is not effective in hemostasis because it dissolves quickly in blood and has poor mechanical properties. The chitosan matrix needs to be compressed (see FIG. 16, step E). To compress the dried “uncompressed” chitosan matrix 12 to reduce the thickness and increase the density of the matrix, a compressive load on the hydrophilic matrix polymer surface can be used, typically with a heated plate. The compression process is sometimes expressed as “densification”, but significantly improves the dissolution resistance of the chitosan matrix 12. Properly frozen chitosan matrix 12 compressed above the threshold density (near 0.1 g / cm ³ ) is not easily dissolved in blood flowing at 37 ° C.

  The compression temperature is preferably 60 ° C. or higher, more preferably about 75 ° C. or higher and less than about 85 ° C.

After densification, the density of the matrix 12 differs between the bottom (“active”) surface of the matrix 12 (ie, the surface exposed to tissue) and the top surface of the matrix 12 (the surface to which the support 14 is applied). . For example, in a typical matrix 12 where the average density measured on the active surface is at or near the most preferred density value of 0.2 g / cm ³ , the average density measured on the upper surface is significantly lower, for example 0. It can be set to 05 g / cm ³ . The desired density range described herein for the densified matrix 12 is the density range on or near the active side of the matrix 12 where exposure to blood, fluid, or moisture first occurs.

  The densified chitosan biomaterial then preferably heats the chitosan matrix 12 in an oven to a temperature of preferably about 75 ° C, more preferably to a temperature of about 80 ° C, and most preferably to a temperature of about 85 ° C. Preconditioning is performed (see FIG. 16, step F). Preconditioning is typically performed for up to about 0.25 hours, preferably up to about 0.35 hours, more preferably up to about 0.45 hours, and most preferably up to about 0.50 hours. This preconditioning process loses 20-30% adhesive properties, but provides a more significant improvement in dissolution resistance at low cost.

(6. Fixing of support material to densified chitosan matrix)
Support material 14 is secured to chitosan matrix 12 to form tissue dressing pad assembly 10 (see FIG. 16, step G). The support material 14 can be adhered or adhered by directly adhering to the upper layer of the chitosan matrix 12. Alternatively, an adhesive such as 3M9942 acrylate skin adhesive, fibrin glue, or cyanoacrylate glue can also be used.

(7. Placement in a small bag)
The tissue dressing pad assembly 10 is subsequently packaged in a sachet 16 (see FIG. 16, step H). The pouch is preferably purged with an inert gas such as argon or nitrogen, depressurized and heat sealed. The pouch 16 keeps the interior sterile for long periods (at least 24 months) and also provides a very high barrier to moisture and ambient air over the same period.

(8. Final sterilization)
After being accommodated in the pouch, the processed tissue dressing pad assembly 10 is preferably subjected to a sterilization process (see FIG. 16, process I). The tissue dressing pad assembly 10 can be sterilized in a number of ways. For example, a preferred method is by irradiation, such as gamma irradiation, which further improves the blood dissolution resistance, tensile properties and adhesive properties of the wound dressing. Irradiation is performed at a level of at least about 5 kGy, more preferably at least about 10 kGy, and most preferably at least 15 kGy.

(D. Evaluation of adhesive / adhesive sealing properties of hydrophilic polymer sponge structure)
(1. Arterial wound sealing test device)
The tissue dressing pad assembly 10 is only one example, but the adhesive properties can be reliably tested using a test device specifically designed to test and verify the adhesive properties for any of the hydrophilic polymer sponge structures. And can be verified. A typical test apparatus 20 is shown in FIG.

  The test apparatus 20 includes a table that simulates an arterial wound sealing environment. The test apparatus 20 is a reproducibly and statistically correct method for the environment (exposure time) and the fracture (or rupture) strength of a hydrophilic polymer sponge structure such as the pad assembly 10 or the same structure of a manufacturing lot. Can be evaluated. Prior to final labeling and product shipment, the test apparatus 20 determines the relative adhesive and adhesive properties of the tissue dressing pad assembly 10 or a pad assembly of a manufacturing lot as a predetermined strength criterion. Can be installed as part of the entire manufacturing process. The test device 20 provides fracture strength data with reproducibility, which is statistically related to in vivo use.

  The test apparatus 20 includes a test block 22 simulating an external arterial wound site. Test block 22 includes a test surface 24 made of a material that mimics tissue. The test surface 24 can be made, for example, from rigid polyvinyl chloride plastic. The test surface 24 has an opening 44 with a diameter of about 4 mm, which mimics the entrance of an arterial wound. The test surface 24 is treated to mimic the tissue, for example, by sanding the test surface 24 with a paper file of particle size 400 to draw a small circle around the opening 44.

  A load arm 26 is disposed above the test surface 24 along with the opening. The load arm 26 forms part of an air cylinder that communicates with a pneumatic source 28. A controller 30 (eg, a programmed microprocessor) manages communication with the pneumatic source and operates the load arm 26. The air pressure advances the load arm 26 toward the test surface 24 and loads a predetermined pressure.

  As shown in FIG. 17, a test size sample 32 of a hydrophilic polymer sponge structure (eg, tissue dressing pad assembly 10) is pre-soaked in a test fluid 34 and placed on the test surface 24. The chitosan matrix 12 is disposed on the opening. The load arm 26 is then manipulated (see FIG. 18A) and an initial pressure is applied to the pre-soaked test size sample 32 on the test surface 24.

  The test fluid 34 includes a fluid that activates the adhesive properties of the chitosan matrix 12. The test fluid 34 can include, for example, bovine whole blood that has been anticoagulated (eg, with citric acid). As for the blood to be used as the test fluid 34 in the test apparatus 20, no significant difference was observed in the test results regardless of whether the blood was fresh or the blood on the 10th day.

  A supply tube 36 is connected to the test block 22. Supply tube 36 can carry test fluid 34 to test block 22 and contact chitosan matrix 12 through openings 44. The other end of the supply pipe 36 is connected to a syringe drive pump 38.

  The syringe drive pump 38 is operated by a motor 40 in a suction and discharge cycle. On the other hand, the motor 40 is connected to the controller 30. Through the motor 40, the controller 30 instructs the operation of the syringe drive pump 38 while synchronizing with the air pressure source.

  In the aspiration cycle, the motor 40 operates the syringe pump 38 to aspirate the test fluid 34 from the test fluid source 42 into the syringe drive pump 38. Blood backflow from the test block 22 to the syringe drive pump 38 during the aspiration cycle is prevented by an in-line one-way check valve 46B. In the discharge cycle, the motor 40 operates the syringe drive pump 38 such that the test fluid 34 is discharged from the syringe drive pump 38 through the opening 44 in the test surface 24. Test fluid backflow to the test fluid source 42 during the discharge cycle is prevented by an in-line one-way check valve 46A. The controller 30 manages the speed of the test fluid 34 conveyed through the opening 44 during the discharge cycle.

  In use, referring to FIG. 18A, a test size sample 32 previously immersed in test fluid 34 (eg, less than about 10 seconds) is placed on test surface 24. The controller 30 is operated to apply pressure (eg, about 60 kPa) to the test size sample 32 over the opening with the load arm 26. The predetermined load time is desirably measured in imitation of actual use conditions, and is, for example, 3 minutes. During this time, the controller 30 can operate the syringe drive pump 38 in a suction cycle and direct the test fluid 32 into the syringe drive pump 38.

  At the end of the load time (see FIG. 18B), the controller 30 releases the air pressure on the load arm 26 and pulls the load arm 26 away from the test surface 24. The controller 30 immediately operates the syringe drive pump 38 in the discharge cycle. The controller 30 ramps the pressure of citrated bovine whole blood flowing to the test block 22 at a predetermined rate, for example between 3 and 16 mmHg / s, preferably 10 mmHg / s. The pressure in the supply pipe 36 is continuously monitored and recorded by the controller 30 over the entire time.

  The controller 30 continues the blood pressure ramp at a predetermined rate until the final test size sample is finally destroyed (see FIG. 18C). The time from the highest point of the increased pressure indicates the final failure. Final failure is shown in and indicates that the test size sample has lost its adhesion to the test surface 24 and can no longer withstand the pressure applied through the opening. The controller 30 records the highest pressure condition at which the final failure occurred for the test size sample. This pressure is the breaking strength of the pad assembly 10.

  The observed maximum pressure state (breaking strength) is compared to a predetermined “pass / fail” criterion. In a representative example, a fracture strength greater than 750 mmHg is “pass”. A fracture strength of less than 750 mmHg indicates “fail”. This criterion represents a pressure level that is six times higher than normal human systolic blood pressure, and therefore imposes a strict “pass” criterion.

  As an alternative to continuously ramping the pressure until final failure, ramp to a constant high blood pressure (eg 250 mmHg) at 3 to 16 mmHg / s (preferably 10 mmHg / s) for a predetermined time (eg 10 minutes). In this test, the pass / fail criterion is to treat a sample of a test size with blood pressure held for 10 minutes holding test time as “pass”, and a test size for which blood pressure was not held for 10 minutes holding time. Are treated as “failed”.

  A statistically significant sample of the entire production lot of tissue dressing pad assembly can be identified using the test apparatus 20 and test method described above. For efficient verification, several test blocks 22 each having a dedicated load arm 26 and a test fluid supply pipe 36 are connected to one air pressure source and a syringe drive pump 38 by a manifold. Can be operated in series using a single controller 30. A pass / fail criterion is determined by combining pass / fail ratios for all lots. For example, if the final breaking strength is greater than 750 mmHg and is 75% or more of the lot, it can be correlated that all lots are statistically correct “pass”. If the final break strength is greater than 750 mmHg and less than 75% of the lot, then all lots can be correlated to be statistically correct “fails”.

(2. Identification of aging phenomenon)
Using the test apparatus 20 and the method described above, it can be seen that a surprising and more beneficial aging phenomenon exists in the densified tissue dressing pad assembly. Briefly, during storage time prior to use--that is, after manufacture, sterilization, packaging in sachets 16 and storage without use--as described above--adhesion of the densified tissue dressing pad assembly The characteristics are significantly improved. Due to the aging phenomenon, lots of tissue dressing pad assemblies that fail the acceptance criteria when tested within a few days after manufacture, sterilization, and sachet acceptance pass the acceptance criteria when retested more than two months later.

(Example 2)
(Aging phenomenon)
The method started by retesting the lot that failed the first test, which showed better performance after 6 months and 12 months than immediately after production. This is because a clear increase in adhesive effect performance was observed.

  The following data was obtained from seven lots of tissue dressing pad assemblies that failed the final product test and were retested after aging for at least 2 months. “Pressure” in Tables 1 and 2 is the maximum pressure state (ie, breaking strength) at which the final failure occurred in the test sample, as described above. As shown in Tables 1 and 2, six of the seven lots showed improved performance, most of which were dramatic improvements.

次のロットを同様に評価した。下記の表３は、この後続時間中のロット合否の統計をまとめたものである。ロットの半分は、ガンマ線照射による滅菌から戻された直後に実施された最初の試験で合格した。最初に合格しなかったロットの５０パーセント（５０％）を、最低２ヶ月の老化時間の後に再試験した。これらのロットのうち７９パーセント（７９％）が合格し、老化現象の存在が確認され、ロットの合計の合格率を９０パーセント（９０％）とした。

The next lot was similarly evaluated. Table 3 below summarizes the lot acceptance statistics during this subsequent time. Half of the lot passed the first test performed immediately after returning from sterilization by gamma irradiation. Fifty percent (50%) of the first failing lots were retested after a minimum aging time of 2 months. Of these lots, 79 percent (79%) passed and the presence of the aging phenomenon was confirmed, and the total acceptance rate of the lots was 90 percent (90%).

上記のロットのうちの１４個のロットには、データテンプレートに入れた最初及び老化処理した試験について、試験装置２０を用いた検証データがある。それらを表４に集計した。合否基準を満たす被試験パッドアセンブリ１０のロット平均破壊圧力及び割合における変化は、効果の増大を示している。表４は、老化後でも合格しなかった２つのロット（１５６及び１６２）であっても粘着効果に増大が見られたことを示している。破壊圧力における平均増加割合は３８パーセント（３８％）である。合否基準を満たす被試験組織被覆材パッドアセンブリの数は最初の試験データより５９パーセント（５９％）増加した。

Of the above lots, 14 lots have verification data using the test apparatus 20 for the initial and aging tests put in the data template. They are tabulated in Table 4. A change in the lot average failure pressure and rate of the pad assembly 10 under test that meets the pass / fail criteria indicates an increase in effectiveness. Table 4 shows that the two sticks (156 and 162) that did not pass even after aging showed an increase in the sticking effect. The average increase in burst pressure is 38 percent (38%). The number of tested tissue dressing pad assemblies meeting pass / fail criteria increased by 59 percent (59%) over the initial test data.

貯蔵時間に亘る組織被覆材パッドアセンブリ１０の性能向上は、老化現象と呼ばれ、劇的で真実である。老化現象は、上述したキトサンマトリクス１２組成物の溶解に対する耐性の堅牢性及び寿命が経時的に向上することを示している。

The improved performance of the tissue dressing pad assembly 10 over storage time is called the aging phenomenon and is dramatic and true. The aging phenomenon indicates that the above-mentioned resistance to dissolution of the chitosan matrix 12 composition and the lifetime are improved.

(3. Identification of adhesion / adhesion characteristics between different shapes of hydrophilic polymer sponge structures)
Using the test apparatus 20 and method described above, differences in the densified tissue dressing pad assembly produced by different methods can be identified and quantified.

  For example, using the test apparatus 20 and method described above, it will be understood that the temperature at which the chitosan matrix 12 is frozen during manufacture affects not only the structure of the matrix, but also its adhesion and adhesion characteristics.

  Differences in the structure of the uncompressed chitosan matrix 12 frozen at different temperatures can be visually observed. When frozen at a shelf temperature of −10 ° C. in a 5 cm diameter aluminum mold coated with Teflon (registered trademark), the structure of the uncompressed chitosan matrix 12 is stepped and open pores throughout the sponge structure. And has a vertical lamella. When frozen at a shelf temperature of −25 ° C. in a 5 cm diameter aluminum mold coated with Teflon®, the structure of the uncompressed chitosan matrix 12 is smaller in steps and more closely spaced, It also has a vertical lamella. When frozen at a shelf temperature of −40 ° C. in a 5 cm diameter aluminum mold coated with Teflon®, the structure of the uncompressed chitosan matrix 12 is the finest, most closely spaced mold edge Radial lamellae from the upper part toward the upper middle part of the sponge. In this latter condition, the uncompressed chitosan matrix 12 contains more reinforced interdigitated structures, which are usually more suitable for densification processes where the matrix surface is subjected to a compressive load.

  Using the test apparatus 20 and method described above to evaluate the breaking strength of the three types of chitosan matrix, it was shown that the adhesion properties of a given chitosan matrix 12 improve as the freezing temperature decreases. FIG. 35 is a graphical representation of the underlying data. FIG. 19 shows the X axis as the freezing temperature (−10 ° C., −25 ° C., and −40 ° C., the temperature decreases to the right), and the Y axis as the breaking pressure (mmHg) measured using the test apparatus 20 and method described above. Plot three data sets. Analysis of variance for three data sets (n = 10, n = 10, and n = 18 for −10 ° C., −25 ° C., and −40 ° C., respectively) showed a very small p value (p = 11.77 E− 11) was produced. As can be seen from FIG. 35, the adhesive properties of the chitosan matrix 12 are improved by changing the physical structure of the matrix from a stepped and open vertical lamellar structure to a fine and reinforced cross mesh lamellar structure.

  FIG. 19 also shows that the test apparatus 20 and method described above provide reproducible data with sufficient sensitivity to identify “low effectiveness” and “high effectiveness” chitosan matrices 12. ing.

(E. Change in compatibility characteristics of hydrophilic polymer sponge structure)
Immediately before use, the tissue dressing pad assembly 10 is removed from its pouch 16 (as shown in FIGS. 4-6). Due to its low moisture content, the tissue dressing pad assembly 10 is relatively inflexible when removed from the pouch 16 and does not readily conform well to the curved irregular surface of the targeted lesion site. Looks like. It has already been mentioned and recommended to bend and / or mold the pad assembly 10 before placing it on the targeted lesion site. Since it is necessary to immediately press the pad assembly 10 against the damage defect in order to suppress severe bleeding, the molding ability of the pad assembly 10 is particularly important in suppressing strong bleeding. In general, these bleeding vessels are deep inside irregularly shaped wounds.

  In the hydrophilic polymer sponge structure in which the pad assembly 10 is an example, the structure is manufactured to conform to the shape of the wound and to achieve placement of the underlying irregular surface of the wound and the sponge structure. Thus, the greater the flexibility and conformability of the structure, the greater the resistance to splitting and collapsing. Resistance to division and collapse is advantageous to maintain wound sealing and hemostatic efficiency. Compatibility and flexibility provide the ability to add deep or torn shaped wounds to hydrophilic polymer sponge structures (eg, pad assembly 10) without causing cracks or significant pad assembly 10 dissolution. To do.

  Certain plasticizers may alter other structural characteristics of the pad assembly 10 if certain plasticizers are used in the chitosan solution to improve flexibility and compatibility. This can cause problems. For example, chitosan glutamate and chitosan lactate are more compatible than chitosan acetate. However, glutamic acid and lactic acid chitosan salts dissolve immediately in the presence of blood, but chitosan acetate does not. That is, improved suitability and flexibility is offset by reduced robustness and melt resistant lifetime.

  Improved compatibility and flexibility is achieved by mechanically manipulating any hydrophilic polymer sponge structure after manufacture, without losing the advantageous characteristics of fastness and dissolution resistant lifetime. Several ways in which such mechanical operations are performed after manufacture are described herein. Although the method will be described on the assumption of the chitosan matrix 12, the method is widely applicable to the formation of a hydrophilic polymer sponge structure, and the chitosan matrix 12 is merely an example.

(1. Adjustable microcracks in hydrophilic polymer sponge structure)
Adjustment of microcracks in the base structure of a hydrophilic polymer sponge structure such as the chitosan matrix 12 can be performed by mechanical preconditioning of the drying pad assembly 10 step by step. This form of adjusting the pad assembly 10 by mechanical preconditioning can achieve improved flexibility and conformity without causing overall failure during use of the pad assembly 10.

  Desirably, as shown in FIG. 20, preconditioning can be performed with a pad assembly 10 sealed in a pouch 16. As shown in FIG. 20, the active surface of the pad assembly 10 (ie, the chitosan matrix 12) is faced up, and finger indentations 48, 1 to 1.5 mm deep, are manually applied repeatedly across the surface. After applying local pressure, one end of a square pad assembly with the active surface facing upward is applied to the side of a cylinder 50 that is 7.5 cm in diameter and 12 cm long as shown in FIG. 21A. The cylinder 50 is then rolled over the pad assembly 10 to give the pad assembly 10 a concave shape with a diameter of 7.5 cm. The cylinder 50 is removed, and the pad assembly 10 is rotated 90 ° (see FIG. 21B) to form another 7.5 cm diameter concave shape formed in the pad assembly 10. After this treatment, the pad assembly 10 is inverted (i.e., this time the support 14 is facing upward (see FIGS. 21C and 21D) and a 90 ° correction is made to form a concave shape with a diameter of 7.5 cm on the pad assembly 10. Formed on the support material 14. The operation of the pad assembly 10 described herein may be performed mechanically during its processing, just prior to loading and sealing for final shipping packaging.

  The mechanical preconditioning described above is not limited to finger probing and / or wrapping around a cylinder. Preconditioning also includes any technique that causes a mechanical change within any hydrophilic polymer sponge structure that results in an improvement in the flexural modulus of the sponge without significantly impairing the hemostatic effect of the sponge. Such preconditioning includes mechanical manipulation of any hydrophilic polymer sponge structure including but not limited to mechanical manipulation by bending, twisting, rotation, vibration, exploration, compression, stretching, shaking and kneading.

(Example 3)
(Porcine femoral artery injury experiment)
The chitosan pad assembly was mechanically preconditioned to improve flexibility and suitability, as described above, for 240 minutes for use in a severe hemorrhagic injury model. Each approximately 45 kg pig (N = 14) was anesthetized while monitoring mean arterial pressure and cardiovascular protection with crystalline and hypertonic saline (terazole, buprenorphine, isoflurane in oxygen). A transcutaneous cut of the skin and muscle that does not follow the tissue plane as done in normal surgery to simulate a wound is made in the left and right groin area of each animal to expose or partially separate the left and right femoral artery I let you. The exposed femoral artery was 2.5 cm to 4.0 cm below the external tissue surface. Prior to wound formation, bupivacaine was administered as an analgesic and to reduce vasospasm throughout the exposed femoral artery. At 1-2 cm from the inguinal canal, a femoral artery wound was formed by perforation with a 2.7 mm vascular punch, the wound was protected with gauze for 1 minute, and persistent strong bleeding occurred after the gauze was removed. Two sponges of Medline gauze sponge (7.5 cm × 7.5 cm and 12 layers) were folded in two to form a 48-layer gauze control test piece of 7.5 cm × 3.8 cm. This is called 48PG. The preconditioned chitosan pad assembly 10 was cut into four specimens measuring 5 cm × 5 cm × 0.55 cm. This is called HCB. Two of the four HCB pieces of each chitosan pad assembly 10 were randomly selected for use in each injury test. To achieve hemostasis, HCB or 48PG was supported immediately with 7.5 cm gauze roll and immediately pressed against the perforated area and held in the damaged area for 3 minutes. The pressure used to suppress the injury was just sufficient to stop the arterial blood flow observed by monitoring the pulse distal to the injury. The pressure was released after 3 minutes, but the 7.5 cm gauze roll was left on the specimen. The hemostatic time was recorded for each specimen. If an attempt with the first specimen failed to achieve hemostasis within 30 minutes, an attempt with a second specimen of the same pad assembly 10 was allowed. If an attempt at the second specimen failed to achieve and maintain hemostasis for at least 240 minutes, the HCB or 48PG was recorded as a failure. If 48PG was used for the first application and it was unsuccessful in the first 30 minutes, then the HCB pad assembly 10 could be used as a rescue pad assembly 10. Conversely, if HCB was used for the first application and it was unsuccessful in the first 30 minutes, 48PG could be used as the rescue pad assembly 10. If neither HCB or 48PG was successful in achieving hemostasis of a lesion for at least 30 minutes, the lesion was stopped with forceps and another artery was used. At 240 minutes of hemostasis, the specimen was evaluated for success in long-term surgery. The pulse was checked distally to confirm that the artery was patency and a specimen (HCB or 48PG) was removed to check for clot durability or bleeding. The specimens were tested for overallity, gelation and tissue adhesion. Blood loss from the femoral artery was recorded. Samples were collected for histological examination. When the second thigh injury was applied to the animal, it was reversed from the first thigh injury. All 14 animals (28 injuries) were tested in this way.

  In this experiment, 100% of the HCB test (N = 25) was hemostatic after 30 minutes, but only 21% of 48PG (N = 14) was hemostatic after that time. As a result of 100% and 21% hemostasis of HCB and 48PG, respectively, at 30 minutes, 48PG was not suitable for rescue, while HCB was suitable for 11 rescue. At 240 minutes, 84% of HCB tests were hemostatic, but only 7% of 48PG were hemostatic. Statistical analysis by Fisher's exact test showed that there was a significant (P <0.001) difference in hemostatic effect between the 48PG and HCB groups in this model. The results are summarized in Table 5 and Table 6 below.

また、曲げ試験及び（「ＳＡＷＳ（ｓｉｍｕｌａｔｅｄ ａｒｔｅｒｉａｌ ｗｏｕｎｄ ｓｅａｌ）」又は「ＳＡＷＳ試験」と呼ばれることもある、上述した試験装置２０及び方法を用いた）急性のインビトロで模した動脈創傷封止試験も、操作したパッドアセンブリ及び操作しないパッドアセンブリについて実施した。１０ｃｍ×１．２７ｃｍ×０．５５ｃｍの細片を各パッドアセンブリの二分の一から取った。これらを三点曲げ試験における曲げ弾性率を試験するのに用いた。５０Ｎ負荷セルを備えるインストロン（Ｉｎｓｔｒｏｎ）一軸機械的検査装置、モデル番号５８４４での三点曲げ試験は、０．５５厚の試験片のスパン５．８ｃｍ及びクロスヘッド速度０．２３５ｃｍ／ｓでの曲げ弾性率を測定するために実施された。パッドアセンブリの他の半分はＳＡＷＳ試験で使用した。曲げ試験の結果を下記の表７に示す。曲げ試験は、機械的プレコンディショニングでの可撓性の有意な向上を示している。ＳＡＷＳ試験の結果は下記の表８に示す。

Also, a bending test and an acute in vitro simulated arterial wound sealing test (using the test apparatus 20 and method described above, sometimes referred to as “SAWS (simulated arterial wound seal)” or “SAWS test”), This was carried out on an operated pad assembly and a non-operated pad assembly. A 10 cm × 1.27 cm × 0.55 cm strip was taken from one-half of each pad assembly. These were used to test the flexural modulus in a three point bend test. A three-point bend test on an Instron uniaxial mechanical inspection device with a 50N load cell, model number 5844, was performed at a span of 5.8 cm and a crosshead speed of 0.235 cm / s with a 0.55 thick specimen. This was done to measure the flexural modulus. The other half of the pad assembly was used in the SAWS test. The results of the bending test are shown in Table 7 below. Bending tests show a significant improvement in flexibility with mechanical preconditioning. The results of the SAWS test are shown in Table 8 below.

  The results of the SAWS test show that the treated test sample has a 32.4% decrease in average burst pressure resistance from 1114 mmHg to 753.7 mmHg compared to the untreated control. This in vitro test is performed on the flat test bench surface of the SAWS tester, but as shown in the femoral artery model, on the irregularly curved surface of the injury, the treated sample is It was highly effective. The 63% reduction in stiffness caused by mechanical manipulation makes the chitosan matrix 12 more susceptible to damage, which clearly offsets the 32.4% reduction in SAWS efficiency.

（２．親水性ポリマースポンジ構造体の調整的な微小構造化）
任意の親水性ポリマースポンジ構造体を（深いレリーフパターン形成によって）調整し微小構造化すると、パッドアセンブリ１０の使用時に大きな不具合を起こすことなく、可撓性及び適合性の向上を達成できる。キトサンマトリクス１２には、深いレリーフパターンを、キトサンマトリクスの活性表面、又は支持材１４、あるいは両方に形成することができる。

(2. Adjusting microstructure of hydrophilic polymer sponge structure)
When any hydrophilic polymer sponge structure is adjusted and microstructured (by forming a deep relief pattern), increased flexibility and conformability can be achieved without causing major failures when using the pad assembly 10. In the chitosan matrix 12, a deep relief pattern can be formed on the active surface of the chitosan matrix, the support 14, or both.

  As shown in FIGS. 23A and 23B, a deep (0.25-0.50 cm) relief surface pattern 52 (microstructured surface) can be formed in the pad assembly 10 by thermally compressing a sponge at 80 ° C. Sponge thermal compression can be performed using a positive relief press platen 54 with a controlled heater assembly 56. Various representative examples of the types of relief patterns 52 that can be used are shown in FIGS. 24A-24D. A negative relief pattern is formed from the positive relief provided on the heated platen 54.

  The purpose of the pattern 52 is to improve the suitability of the dry pad assembly by reducing the bending resistance perpendicular to the relief 52 and to allow the relief pattern to act like a local hinge and flex along its length. Is to improve the performance.

  This relief 52 is preferably applied to the support 14 of the pad assembly 10 and not to the chitosan matrix 12 which is responsible for hemostasis by damage sealing and local clot formation. Providing a micro-structured deep relief pattern 52 in the base chitosan matrix 12 can provide a channel through which blood leaks through the chitosan matrix 12, thereby reducing sealing properties.

  To reduce this possibility, an alternative relief pattern 52 of the type shown in FIGS. 24E and 24F can also be used for the basic relief, which will reduce the likelihood of a loss of sealing properties. Thus, the relief 52 can also be used on a matrix basis, but is still not preferred compared to use on the support 14 or the upper surface of the matrix. During sponge compression, it is also possible to apply relief patterns to the top and bottom surfaces of the pad assembly 10 simultaneously by using two positive relief patterns provided above and below the platen. However, as FIGS. 18A and 18B show, it is more preferred to use a single positive relief on the upper surface of the chitosan matrix 12 to form a single, deep relief.

Example 4
A mechanical bend test was performed on the test pad assemblies (each 10 cm × 10 cm × 0.55 cm, with adhesive support 14--3M 1774T polyethylene foam medical tape 0.056 cm thick). One pad assembly 10 (pad 1) was provided with a chitosan matrix 12 having a predominantly vertical lamellar structure (ie, manufactured at a relatively high freezing temperature as described above). The other pad assembly 10 (pad 2) was provided with a chitosan matrix 12 (i.e., manufactured at a relatively low freezing temperature as described above) having a lamellar structure that was primarily horizontal and interdigitated.

  Each of pads 1 and 2 was cut in half. Two halves (5 cm × 10 cm × 0.55 cm) of each of the compressed chitosan pads 1 and 2 were locally compressed at 80 ° C. to form a relief pattern having the shape shown in FIG. The other half of pads 1 and 2 were left untreated and used as a control.

  Three specimens (10 cm × 1.27 cm × 0.55 cm) were cut from each half of the pad assembly 10 using a scalpel. A three-point bending test was performed on these specimens. The test specimen had relief depressions with a depth of 0.25 cm and a width of 0.25 cm on the upper surface, and each depression was spaced 1.27 cm from the adjacent depression. A three-point bend test with an Instron uniaxial mechanical inspection device, model number 5844 with a 50N load cell, was performed at a 0.55 mm specimen span of 5.5 cm and a crosshead speed of 0.235 cm / s. This was done to measure the flexural modulus. The bending load was plotted against the midpoint bending displacement of the two pads 1 and 2 (treated and untreated) and are shown in FIGS. 25A and 25B, respectively. The specimen treated versus untreated flexural modulus for pads 1 and 2 (treated and untreated) are shown in Tables 9A and 9B, respectively.

  Bending tests showed a significant increase in flexibility due to tuned microstructures in either type of dry pad assembly 10.

（３．親水性ポリマースポンジ構造体における調整的な垂直チャンネルの形成）
キトサンマトリクス１２を一例とする任意の親水性ポリマースポンジ構造体のバルク内へ及びバルクを通じて血液を調整的に導入すると、初期の構造的適合の向上及び構造体溶解に対する耐性の寿命の向上にも望ましい。与えられた親水性ポリマースポンジ構造体への垂直チャンネルの制御された形成は、使用時における構造体の全体的な不具合を生ずることなく、向上した可撓性及び適合性を達成できる。

(3. Formation of adjustable vertical channel in hydrophilic polymer sponge structure)
Coordinated introduction of blood into and through the bulk of any hydrophilic polymer sponge structure, such as the chitosan matrix 12, is also desirable for improved initial structural fit and improved lifetime of structure dissolution resistance. . Controlled formation of vertical channels in a given hydrophilic polymer sponge structure can achieve improved flexibility and conformity without causing the overall failure of the structure in use.

  Coordinated introduction of blood into and through the bulk of the hydrophilic polymer sponge structure is also desirable to improve the initial structural fit of the structure and increase the lifetime of resistance to structure dissolution. Improved blood absorption into the hydrophilic polymer sponge structure can be achieved by the introduction of vertical channels into the structure. The channel cross-sectional area, channel depth, and channel number density can be adjusted to ensure the proper rate of blood absorption and the distribution of blood absorption to the hydrophilic polymer sponge structure. For the chitosan matrix 12, typically, when the weight of the chitosan matrix 12 increases by 200% with blood absorption from 5 g to 15 g, the flexural modulus decreases by about 72% from 7 MPa to 2 MPa. In addition, the regulatory introduction of blood into the chitosan matrix 12 results in a more sticky matrix.

  This increase in strength in the hydrophilic polymer matrix is the result of the reaction of blood components such as platelets and red blood cells with the matrix. When sufficient time has elapsed until blood is introduced into the sponge structure and the sponge structure and blood components react to form an “amalgam” of blood and a hydrophilic polymer sponge structure, the resulting sponge structure The body is resistant to dissolution in body fluids, especially in the case of a chitosanate matrix, which does not dissolve easily even when saline is introduced. Typically, especially in the case of a chitosanate matrix, when saline is introduced prior to the reaction between blood and the hydrophilic polymer sponge structure, the hydrophilic sponge structure rapidly swells, gels and Causes dissolution.

  In addition, when blood is excessively introduced into any hydrophilic polymer sponge structure such as the chitosan matrix 12, liquefaction collapse may occur. Therefore, the average channel cross-sectional area, average channel depth, and channel number density must be adjusted to ensure that the blood absorption rate does not crush the structure of the hydrophilic polymer sponge structure.

  Regulated distribution of vertical channels in a hydrophilic polymer sponge structure can be performed during the freezing process of the sponge structure manufacture, or it can be performed mechanically by perforation of the sponge structure during the compression (densification) process. Good.

  During the freezing process in which nuclei are formed at the bottom, vertical channels can be introduced by supersaturating the solution with residual gas in the frozen solution. When freezing is started, the gas becomes a bubble nucleus at the bottom of the solution in the mold. Air bubbles rise through the solution during the freezing process, leaving a vertical channel. Sublimation of ice around the channels during lyophilization preserves the channels in the final sponge matrix.

  Alternatively, the channel can also be formed by placing a vertical rod member at the bottom of the mold during the freezing process. Preferably, the mold is from a metal component such as but not limited to iron, nickel, silver, copper, aluminum, aluminum alloy, titanium, titanium alloy, vanadium, molybdenum, gold, rhodium, palladium, platinum and / or combinations thereof. Composed. The metal rod member is preferably a metal such as, but not limited to, iron, nickel, silver, copper, aluminum, aluminum alloy, titanium, titanium alloy, vanadium, molybdenum, gold, palladium, rhodium or platinum and / or combinations thereof Consists of ingredients. The mold should also be coated with a thin and inert metal coating such as titanium, chromium, tungsten, vanadium, nickel, molybdenum, gold and platinum so as not to react with the acidic components of the chitosan solution and chitosan salt matrix. You can also. Thermal barrier coatings or members may be used in combination with metal molds and vertical rod members to control heat conduction within the mold and vertical rod members. Metal molds and vertical metal rod members are preferred, but plastic molds and vertical plastic rod members are convenient alternatives for forming channels. The advantages of metal molds and their metal rod members in combination with locally disposed insulation members are that they provide an opportunity to facilitate control of heat flow and structure within the frozen sponge structure. is there. The improvement in heat flow control is due to the large difference in thermal conductivity between the thermally and thermally insulating members in the mold, as well as the local thermal gradient in the bulk of the hydrophilic polymer sponge structure via the rod member. Brought about by the ability to generate.

  After lyophilization of the sponge structure, the vertical channels can be introduced during the compression (densification) process. For example, as shown in FIGS. 26A and 26B, the compression device 58 may be a geometrically patterned pincushion for placing short (2.5 mm deep) equally spaced perforations 62 at the bottom of the sponge structure. (See FIG. 27).

  The purpose of the perforations 62 is to allow blood to enter locally at a slow controlled rate through and through the bottom of the hydrophilic polymer sponge structure. The purpose of this intrusion is to cause a rapid change in the bendability of the matrix by first plasticizing the dry sponge with blood. Second, the blood is more evenly dispersed and mixed through the matrix to stabilize the matrix against the lysing agent present in the body cavity. If there is no perforated bottom, blood will only penetrate the surface of the sponge structure (depth <1.5 mm) after 1, 6, 16 and 31 minutes, but if perforated is present, blood will flow after 31 minutes. Penetrates to a depth of 1.8 to 2.3 mm. A perforated matrix has a further reduction in flexural modulus compared to a matrix without perforations. FIG. 28 shows the absorption characteristics at 1, 6, 16, and 31 minutes for each matrix type.

(Example 5)
Both perforated and non-perforated chitosan matrices were tested in an in vitro SAWS test and, as shown in Table 10, both types were shown to be effective in sealing against strong blood flow.

図２７のピンクッションデザインで穿孔されたサンプルの試験結果は、穿孔していないコントロールに比較して血液の吸収速度の有意な上昇を示した。パッドアセンブリ１０の適用での最初の３０秒間に亘る穿孔された試験片における血液吸収速度は、コントロールサンプルより２から３倍高く、従って、穿孔した場合にはパッドアセンブリ１０の適合性の迅速な向上が得られ、複雑な創傷領域での重大な出血性損傷への親水性ポリマースポンジ構造体の配置を促進することができる。

Test results for samples perforated with the pincushion design of FIG. 27 showed a significant increase in blood absorption rate compared to unperforated controls. The blood absorption rate in the perforated specimen over the first 30 seconds with the application of the pad assembly 10 is 2 to 3 times higher than the control sample, and thus a rapid improvement in the suitability of the pad assembly 10 when perforated. And can facilitate the placement of the hydrophilic polymer sponge structure to severe hemorrhagic damage in complex wound areas.

(II. Tissue dressing sheet assembly)
(A. Overview)
FIG. 29 shows a tissue dressing sheet assembly 64. Similar to the tissue dressing pad assembly 10 previously described and shown in FIG. 1, the tissue dressing sheet assembly 64 adheres to the tissue in use in the presence of blood or bodily fluids or moisture. With the tissue dressing sheet, the assembly 64 can also be used to stop, seal, and / or stabilize the site of tissue damage or trauma or tissue ingress against bleeding or other forms of fluid loss. Like tissue dressing pad assembly 10, tissue sites treated with tissue dressing sheet assembly 64 can be, for example, arterial and / or venous bleeding, or lacerations, or entry / entrance wounds, or tissue punctures, or catheter intrusions. Includes site, or burn, or suture. The tissue dressing sheet assembly 64 can also form an antibacterial and / or antimicrobial and / or antiviral protection barrier at or near the tissue treatment site.

  FIG. 29 shows the tissue dressing assembly 64 prior to use. As best shown in FIG. 30, the tissue dressing sheet assembly 64 includes a sheet 66 of woven or non-woven mesh material sandwiched between layers of a tissue dressing matrix 68. The tissue dressing matrix 68 includes a sheet 66. Tissue dressing matrix 68 desirably includes chitosan matrix 12 as described with respect to tissue dressing pad assembly 10. However, other hydrophilic polymer sponge structures can be used.

  The size, shape, and configuration of the tissue dressing sheet assembly 64 can vary depending on its intended use. The sheet assembly 64 may be linear, elongated, circular, elliptical, or a composite or composite combination thereof.

The tissue dressing sheet assembly 64 achieves a quick fit of the hydrophilic polymer sponge structure in the bleeding region. The tissue dressing sheet assembly 64 is preferably thin (compared to the pad assembly 10) and ranges from 0.5 mm to 1.5 mm thick. A preferred form of thin reinforcement structure for sheet assembly 64 is a chitosan matrix 12 or sponge reinforced with an absorbent band such as cotton gauze, typically a chitosan matrix with a density of 0.10 to 0.20 g / cm ^3. The final thickness of the band is 1.5 mm or less.

  The sheet assembly 64 may be a small sheet (eg, 10 cm × 10 cm × 0.1 cm), or small (as shown in FIG. 31B) so as to be packaged in a multi-sheet flat plate shape 70 (as shown in FIG. 31A). Can be prepared in a long sheet shape (for example, 10 cm × 150 cm × 0.1 cm) so as to be packaged in a rolled sheet shape 72. The sheet 66 reinforces the entire assembly 64 but also provides a large specific surface area of the hydrophilic polymer sponge structure that can be utilized for blood absorption. The presence of the woven or non-woven sheet 66 also strengthens the entire hydrophilic polymer sponge structure.

  The sheet 66 can include, for example, a woven or non-woven mesh material formed from a cellulose-derived material such as cotton mesh gauze. Examples of preferred reinforcing materials include absorbable low modulus meshes and / or porous films and / or porous sponges and / or fabrics of synthetic and naturally derived polymers. Synthetic biodegradable materials include, but are not limited to, poly (glycolic acid), poly (lactic acid), poly (e-caprolactone), poly (β-hydroxybutyric acid), poly (β-hydroxyvaleric acid), polydioxane, poly (Ethylene oxide), poly (malic acid), poly (tartronic acid), polyphosphazene, polyhydroxybutyrate and copolymers of monomers used to synthesize the above polymers. Natural product polymers include, but are not limited to, cellulose, chitin, algin, starch, dextran, collagen and albumin. Non-biodegradable synthetic reinforcing materials include, but are not limited to, polyethylene, polyethylene copolymers, polypropylene, polypropylene copolymers, metallocene polymers, polyurethanes, polyvinyl chloride polymers, polyesters and polyamides.

(B. Use of tissue dressing sheet assembly)
The thin sheet assembly 64 has a very good fit and allows immediate and powerful placement of a hydrophilic polymer sponge structure (eg, chitosan matrix 12) at the site of injury. Also, strengthening the sheet allows the entire assembly to withstand dissolution in a strong bleeding area. The sheet assembly 64 layers and miniaturizes the hydrophilic polymer sponge structure (eg, chitosan matrix 12) using pressure that boosts the entire structure against strong arterial and venous bleeding within the wound site. And / or rotation—ie, “stuffing” (as shown in FIG. 32). As shown in FIG. 32, when the entire sheet structure is packed, the interaction between the hydrophilic polymer (for example, chitosan) injected into the bandage and blood is particularly deep or otherwise difficult to approach. This is advantageous for application of. The packing and pressing of the sheet assembly 64 into the hemorrhagic wound is highly tacky, provides an insoluble and very good bandage configuration.

(C. Manufacture of tissue dressing sheet assembly)
A tissue dressing sheet assembly 64 (10 cm × 10 cm × 0.15 cm) having a chitosan matrix 12 with a density of about 0.15 gm / cm ³ is a 2 percent (2%), 11 cm × 11 cm × 2 cm deep aluminum mold. It can be prepared by filling the chitosan acetate solution to a depth of 0.38 cm (see FIG. 33, step A).

  As shown in FIG. 33 (Step B), a sheet 66—for example, containing an absorbent gauze bandage 10 cm × 10 cm—is placed on the solution in the mold and immersed in chitosan. Chitosan is impregnated into the sheet 66.

  As shown in FIG. 33 (step C), chitosan having a depth of 0.38 cm is poured onto the impregnated gauze sheet 66.

  As shown in FIG. 33 (Step D), the mold is placed in, for example, a Virtis Genesis 25XL freeze dryer on a shelf at 30 ° C. The solution is frozen and then the ice is sublimed by lyophilization.

  As shown in FIG. 33 (Step E), the resulting gauze reinforced sheet assembly 64 is pressed between platens at 80 ° C. to a thickness of 0.155 cm. Next, the pressed sheet assembly 64 is baked at 80 ° C. for 30 minutes (FIG. 33, step F). The resulting sheet assembly is sterilized as previously described. For final sterilization and storage, one or more sheet assemblies are packaged in a heat sealed foil lined sachet 74 or the like into sheet or roll form (see FIG. 34).

(Example 6)
(Bending characteristics of tissue dressing sheet assembly)
A three point bend test of the tissue dressing sheet assembly 64 was performed. The three-point bending test is an Instron uniaxial mechanical inspection device with a 50N load cell, model number 5844, measuring the flexural modulus at a specimen span of 5.8 cm and a crosshead speed of 0.235 cm / s. To be carried out. The results are shown in FIG. FIG. 35 shows that the 1.5 mm thick tissue dressing sheet assembly tested fits significantly better than the 5.5 mm thick tissue dressing pad assembly.

(Example 7)
(Adhesive properties of tissue dressing sheet assembly)
A specimen (5 cm × 5 cm × 0.15 cm) of tissue dressing assembly 64 was cut out within 96 hours of its manufacture. The sheet assembly 64 was not subjected to gamma irradiation sterilization prior to testing. The test piece was immersed in citrated bovine whole blood for 10 seconds and immediately subjected to the SAWS test. Three specimens were layered during the test and the composite chitosan density was 0.15 g / cm 3. The result of this test is shown in FIG.

  As FIG. 36a shows, the three-layer tissue dressing sheet assembly 64 maintained a substantially physiological blood pressure of approximately 80 mm Hg for an extended period of time (ie, about 400 seconds). This indicates the presence of sealing and clot formation.

  Based on experience with the pad assembly, better adhesion / adhesion properties are expected to result after the tissue dressing sheet assembly 64 has been subjected to gamma irradiation. FIG. 36B confirms this: after gamma irradiation, the three-layer sheet assembly 64 performed very similar to the 0.55 cm thick chitosan tissue pad 10.

(III. Further application and shape of hydrophilic polymer sponge structure)
The previous disclosure has focused primarily on the use of the tissue dressing pad assembly 10 and the tissue dressing sheet assembly 64 in a hemostatic setting of blood and / or fluid loss at the wound site. Although other applications have been mentioned, some of these and further applications are described in more detail below.

  Of course, the outstanding technical features of compressed hydrophilic polymer sponge structures, such as chitosan matrix, are incorporated into a wide variety of shapes, sizes and forms of coating structures, and a diverse number of different applications Should be understood to be provided. As shown, the shapes, sizes, and configurations that a given hydrophilic polymer sponge structure (eg, chitosan matrix 12) can take are not limited to the described pad assembly 10 and sheet assembly 64, and may be of particular application. It can be modified as required. Some representative examples are shown below, but all included are not intended to be limiting.

(A. Suppression of body fluid loss (for example, burns))
Suppression of bleeding may mean that preservation of body fluids is synonymous with maintaining health and sometimes life. An example of this is the treatment of burns.

  Burns can be caused by heat and flame, radiation, sunlight, electricity, or chemical exposure. Thin or superficial burns (also called first degree burns) are red and painful. They are slightly raised and become white when pressed, and the skin on the burn peels off in one or two days. Deeper burns, superficial interlayer burns and deep interlayer burns (also called second-degree burns), have blisters and are more painful. There are also full-thickness burns (also called third-degree burns) that cause damage to all layers of the skin. Burned skin is white or charred. These burns cause little or no pain if the nerve is damaged.

  The presence of a tissue burn area compromises the skin's ability to suppress fluid loss (which leads to dehydration) and the ability of the skin to block bacterial and microbial invasion in that area. Thus, in all burn treatments, the dressing is used to cover the burn area. The dressing keeps air away from the area, relieves pain and protects blistered skin. The dressing also absorbs fluid when the tissue burn is healed. Antimicrobial creams or ointments and / or moisturizers are used to prevent drying and combat infections.

  A hydrophilic polymer sponge structure (eg, a chitosan matrix 12 of the type previously described) can be used to treat a tissue burn area in the form of either the pad assembly 10 or the sheet assembly 64. A hydrophilic polymer sponge structure (eg, chitosan matrix 12) absorbs and adheres to the fluid and covers the burn area. The hydrophilic polymer sponge structure (eg, chitosan matrix 12) also provides an antibacterial / antimicrobial protection barrier in the burn area.

(1. Composite coating assembly)
FIGS. 37 and 38 show a composite dressing assembly 76 that can also be used to treat tissue burn areas and other damaged tissue areas where relatively large volumes of fluid leakage and / or bleeding are expected. The composite dressing assembly 76 includes a fluid absorbent member 78 or a hydrophilic polymer sponge structure (eg, chitosan matrix 12) carried on the carrier and fluid absorbent member 78.

  The fluid absorbent member 78 may include a woven or non-woven mesh material formed from a cellulose-derived material such as, for example, a cotton gauze mesh. Other examples of fluid absorbing members 78 include synthetic and naturally derived polymer absorbent low modulus meshes and / or porous films and / or porous sponges and / or fabrics. Synthetic biodegradable materials include, but are not limited to, poly (glycolic acid), poly (lactic acid), poly (e-caprolactone), poly (β-hydroxybutyric acid), poly (β-hydroxyvaleric acid), polydioxane, poly (Ethylene oxide), poly (malic acid), poly (tartronic acid), polyphosphazene, polyhydroxybutyrate and copolymers of monomers used to synthesize the above polymers. Natural product polymers include, but are not limited to, cellulose, chitin, algin, starch, dextran, collagen and albumin. Non-biodegradable synthetic reinforcing materials include, but are not limited to, polyethylene, polyethylene copolymers, polypropylene, polypropylene copolymers, metallocene polymers, polyurethanes, polyvinyl chloride polymers, polyesters and polyamides.

  The hydrophilic polymer sponge structure can include, for example, a chitosan matrix 12 of the type previously described, which is desirably densified. Other types of chitosan structures or other shaped hydrophilic polymer sponge structures or tissue dressing matrices can also be generally used. The hydrophilic polymer sponge structure (for example, chitosan matrix 12) is fixed to the absorbent member, for example, by direct adhesion and / or adhesion to the hydrophilic polymer sponge structure, or by fibrin glue or cyanoacrylate glue.

  The primary function of the absorbent member when disposed with a hydrophilic polymer sponge structure (eg, chitosan matrix 12) is to absorb fluid remaining in or near the tissue burn area (or other wound site). is there. This eliminates the need for the hydrophilic polymer sponge structure (eg, chitosan matrix 12) to assume the overall fluid retention function of the composite assembly. As shown in FIG. 37, the outer periphery of the fluid absorbing member 78 desirably extends beyond the outer periphery of the hydrophilic polymer sponge structure (for example, the chitosan matrix 12), and the range and capacity of the fluid absorbing function of the absorbing member 78. Increase.

  The absorbent member 78 thereby supplements and shares the fluid retention function of the hydrophilic polymer sponge structure (eg, chitosan matrix 12). The absorbent member 78 reduces the fluid holding load of the hydrophilic polymer sponge structure (eg, chitosan matrix 12), so that the hydrophilic polymer sponge structure does not cause overhydration that jeopardizes its structural integrity. Do not become supersaturated with fluid or blood.

  As shown in FIG. 39, the interface between the absorbent member 78 and the hydrophilic polymer sponge structure (eg, chitosan matrix 12) is permeabilized with perforations 80 or other methods to provide a hydrophilic polymer sponge structure. The fluid retained in the fluid can easily move to the absorbent member 78, thereby reducing the fluid retention load of the hydrophilic polymer sponge structure.

  In use, the fluid absorbing member 78 may comprise an adhesive and be adhered to the tissue. Alternatively, other conventional dressings (eg, gauze) may be combined and applied to secure the composite dressing assembly 76 and provide a clean barrier to the wound. If the wound is subsequently hidden in the undergarment, a watertight cover must be applied to prevent the composite dressing assembly 76 from being overly hydrated.

(B. Antimicrobial barrier)
In certain applications, the focus of treatment is becoming to prevent the entry of bacteria and / or microorganisms through tissue areas that have been damaged by injury or due to the need to secure an entrance to the internal tissue area. Examples of the latter situation include, for example, placement of an indwelling catheter to accommodate peritoneal dialysis, or connection to an external urine or colon fistula bag, or parenteral nutrition, or connection of a sampling or monitoring device; After tracheostomy, or laparoscopic or endoscopic procedures, or after formation of an incision for entry into an internal body region in the introduction of a catheter device into a blood vessel.

  40 and 41, one exemplary embodiment of an antimicrobial gasket assembly 82 is shown. The gasket assembly 82 is sized and configured to be placed over the entry site, particularly the entry site where the indwelling catheter 88 is disposed. The antimicrobial assembly 82 includes a tissue adhesive carrier member 84 to which the antimicrobial member is secured. Desirably, the antimicrobial member comprises a chitosan matrix 12 of the type previously described, which has been densified. Other types of chitosan structures, or other hydrophilic polymer sponge structures, or tissue dressing matrices can also be generally used.

  The carrier member 84 includes an adhesive surface 86 and an antimicrobial member (preferably the chitosan matrix 12) is attached across the entry site. 40 and 41, the antimicrobial member 12 and the carrier 84 include a through hole 90, and an indwelling catheter 88 can be passed through the through hole. In this arrangement, the inner diameter of the through-hole 90 is substantially the same as the outer diameter of the indwelling catheter 88 and is firmly and closely fitted. In situations where there is no catheter placement and only an incision or entry site, it is understood that the antimicrobial member does not have a through hole.

  In an alternative arrangement (see FIG. 42), the previously described tissue dressing pad assembly 10 is sized and shaped in proportion to the area of the entry site to constitute the antimicrobial gasket assembly 82. In this configuration, the pad assembly 10 can include a through-hole 90 to provide, for example, an indwelling catheter passage.

  In another alternative arrangement (see FIG. 43), the previously described tissue dressing sheet assembly 64 is sized and shaped in proportion to the area of the entry site to constitute the antimicrobial gasket assembly 82. In this configuration, the seat assembly 64 can include a through hole 90 to provide, for example, an indwelling catheter passage.

(Example 8)
(Antimicrobial properties)
The densified chitosan acetate matrix and the various forms of dressings into which the chitosan acetate matrix can be introduced have antimicrobial effects as shown by the in vitro tests summarized in Table 11.

緻密化されたキトサンマトリクス１２の優れた粘着性及び機械的特性は、該マトリクスを四肢上（表皮的用途）及び身体内部での抗微生物用途での使用に極めて適したものにする。そのような用途は、短期から中期（０−１２０時間）の感染抑制、カテーテルの入／出口点での出血、サンプリング及び供給用途のためのバイオメディカル装置の入／出口点での出血、及び患者がショック状態で確実な外科手術による支援を受けられない場合の重大な損傷部位における出血の抑制を含む。

The excellent tack and mechanical properties of the densified chitosan matrix 12 make it very suitable for use in antimicrobial applications on the limbs (epidermal application) and within the body. Such applications include short- to medium-term (0-120 hours) infection control, bleeding at catheter entry / exit points, bleeding at the entry / exit points of biomedical devices for sampling and delivery applications, and patients Inhibition of bleeding at the site of critical injury when the patient is in shock and cannot receive reliable surgical assistance.

(C. Antiviral patch)
There are recurrent conditions caused by viral substances.

  For example, herpes simplex virus type 1 (“HSV1”) generally only infects body tissues above the waist. In most cases, it is HSV1 that causes herpes simplex. Herpes simplex (or lesion) is a type of facial erosion that is found in other skin near the lips or mouth. Some other terms used for herpes simplex are “rash” and the medical term “recurrent cleft lip”.

  Herpes simplex virus type 2 ("HSV2") typically only infects body tissues below the waist. It is this virus, also known as “genital herpes”. Both HSV2 (as well as HSV1) cause erosion (also called lesions) in the perivaginal region, penis, anal opening, buttocks or thigh. Occasionally, eros may appear in other parts of the body where the virus has entered through torn skin.

  Figures 44 and 45 show an exemplary embodiment of an antiviral patch assembly. The antiviral patch assembly 92 is sized and configured to be placed over a surface lesion of the type associated with HSV1 or HSV2, or other forms of viral skin infections such as infectious molluscum and sputum. The Antiviral patch assembly 92 includes a tissue adhesive carrier member 94 to which the antiviral member is secured. Desirably, the antiviral member comprises a chitosan matrix 12 of the type already described, which has been densified. Other types of chitosan structures, or other hydrophilic polymer sponge structures, or tissue dressing matrices can also be generally used.

  The carrier member 94 has an adhesive surface 96 to which an antiviral member (preferably chitosan matrix 12) covering the lesion is attached.

  In other alternative arrangements (not shown), the previously described tissue dressing pad assembly 10 or tissue dressing sheet assembly 64 or composite dressing assembly 76 may be used at the lesion site to constitute an antiviral patch assembly. It is possible to make the size and shape corresponding to the area. The excellent tack and mechanical properties of the densified compressed chitosan matrix 12 make it very suitable for use in antiviral applications on the extremities (epidermal application) and within the body. The presence of antiviral patch assembly 92 can kill viral material and promote healing in the lesion area.

(D. Treatment of bleeding disorders)
There are various types of bleeding or coagulopathy. For example, hemophilia is a disorder of genetic bleeding or coagulation. People with hemophilia lack the ability to stop bleeding because their blood does not have low or certain levels of specific proteins required for clotting called “factors”. Due to the loss of clotting factors, people with hemophilia will bleed for longer periods of time than those with normal or correct blood factor action. Idiopathic thrombocytopenic purpura (ITP) is another blood coagulation disorder characterized by an abnormal decrease in the number of platelets in the blood. Platelet depletion is prone to sputum, gingival bleeding, and internal bleeding.

  A hydrophilic polymer sponge structure (eg, chitosan matrix 12) incorporated into tissue dressing pad assembly 10 or tissue dressing sheet assembly 64 or composite dressing assembly 76, as all described above, can be used in hemophilia or other It is sized and shaped to be used as a treatment dressing to treat bleeding symptoms that appear in persons with coagulopathy. As already mentioned, the presence of the chitosan matrix 12 attracts the erythrocyte membrane, which fuses upon contact with the chitosan matrix 12. The clot is formed very quickly and eliminates the clotting proteins normally required for clotting. The coagulation cascade of a person with hemophilia or other coagulation disorder is somehow impaired, but if the chitosan matrix 12 is present while a person with such a disease has bleeding symptoms, what is the coagulation cascade? It can accelerate the coagulation process independently. For this reason, the presence of the chitosan matrix 12 in the dressing is effective as an intervention means for people with coagulation disorders such as hemophilia.

(E. Sustained release of therapeutic agent)
A hydrophilic polymer sponge structure (eg, the previously described chitosan matrix 12) can provide a topically applied platform for delivering one or more therapeutic agents into the bloodstream in a controlled release manner. . The therapeutic agent can be introduced into the hydrophilic polymer sponge structure, for example, before or after the freezing step and before the drying and densification steps. The rate at which the therapeutic agent is released from the hydrophilic polymer sponge structure can be controlled by the degree of densification. If the hydrophilic polymer sponge structure is further densified, the release rate of the therapeutic agent introduced into the structure will be slower.

  Examples of therapeutic agents that can be introduced into a hydrophilic polymer sponge structure (eg, chitosan matrix 12) include, but are not limited to, drugs or pharmaceuticals, stem cells, antibodies, antimicrobials, antivirals, collagen, genes, DNA, and Other therapeutic agents; hemostatic agents such as fibrin; growth factors; and similar compounds.

(F. Mucosal surface)
The advantageous properties of the chitosan matrix 12 include adhesion to mucosal surfaces within the body covering the esophagus, gastrointestinal tract, ureter, mouth, nasal and respiratory tracts, lungs and the like. This feature allows the chitosan matrix 12 to be introduced into, for example, systems and devices for the treatment of mucosal surfaces, where the adhesive sealing properties and / or facilitation of the chitosan matrix 12 as described. Improved clotting properties and / or antibacterial / antiviral properties are beneficial. Such systems and methods include gut junctions and other gastrointestinal surgical methods, esophageal or gastric function regeneration, suture sealing, and the like.

(IV. Conclusion)
Hydrophilic polymer sponge structures such as chitosan matrix 12 are easily adapted as related to coatings or substrates of various sizes and forms--pad shapes, sheet shapes, composite shapes, laminated shapes, conform shapes- Those skilled in the medical and / or external sciences can adapt any hydrophilic polymer sponge structure, such as the chitosan matrix 12, for various uses on the body surface, inside the body, or the entire body. It has been shown that

  Thus, it will be appreciated that the above-described embodiments of the invention are merely descriptions of the concepts and are not limiting in any way. Instead, the scope of the invention should be defined by the following claims, including their equivalents.

FIG. 1 is a perspective view of an assembled tissue dressing pad assembly that can adhere to body tissue in the presence of blood, fluid, or moisture. FIG. 2 is an exploded perspective view of the tissue dressing pad assembly shown in FIG. FIG. 3 is a perspective view of the tissue dressing pad assembly shown in FIG. 1 packaged in a sealed sachet for final irradiation and storage. FIG. 4 is a perspective view of the sealed pouch shown in FIG. 3 opened and exposed for use with the tissue dressing pad assembly. FIG. 5 is a perspective view of the sealed pouch shown in FIG. 3 opened and exposed for use with the tissue dressing pad assembly. 6 and 7 are perspective views of what is held and manipulated by folding or folding prior to application to match the topology of the tissue site targeting the tissue dressing pad assembly. 6 and 7 are perspective views of what is held and manipulated by folding or folding prior to application to match the topology of the tissue site targeting the tissue dressing pad assembly. 8 to 10A / B are perspective views of a tissue dressing pad assembly applied to a targeted tissue site to stop bleeding. 8 to 10A / B are perspective views of a tissue dressing pad assembly applied to a targeted tissue site to stop bleeding. 8 to 10A / B are perspective views of a tissue dressing pad assembly applied to a targeted tissue site to stop bleeding. 8 to 10A / B are perspective views of a tissue dressing pad assembly applied to a targeted tissue site to stop bleeding. FIG. 11 is a perspective view of two tissue dressing pad assemblies applied in a laminate to a target tissue site to stop bleeding. FIG. 12 is a perspective view of a piece of tissue dressing pad assembly that has been cut and adapted to a targeted tissue site to stop bleeding. FIG. 13 is a perspective view of a fragment of a tissue dressing pad assembly that has been cut and adapted to a targeted tissue site to stop bleeding. 14 and 15 are perspective views of a tissue dressing pad assembly held and manipulated by molding into a concave or cup shape to conform to a target tissue site. 14 and 15 are perspective views of a tissue dressing pad assembly held and manipulated by molding into a concave or cup shape to conform to a target tissue site. FIG. 16 is a process diagram of the method of manufacturing the tissue dressing pad assembly shown in FIG. FIG. 17 is a partial diagram of a test device used to quantify the acute adhesion and adhesion of the tissue dressing pad assembly shown in FIG. 1 in a simulated arterial wound environment. FIGS. 18A-18C are partial diagrams of the test apparatus of FIG. 17 used to perform a destructive pressure test on a test sample of a tissue dressing pad assembly. FIGS. 18A-18C are partial diagrams of the test apparatus of FIG. 17 used to perform a destructive pressure test on a test sample of a tissue dressing pad assembly. FIGS. 18A-18C are partial diagrams of the test apparatus of FIG. 17 used to perform a destructive pressure test on a test sample of a tissue dressing pad assembly. FIG. 19 is a graph showing the difference in breaking pressure measured using the test apparatus shown in FIG. 17 between hydrophilic polymer sponge structures produced at different freezing temperatures. FIG. 20 is a perspective view of an embodiment of a conditioning process of a hydrophilic polymer sponge structure to create microcracks that impart improved flexibility and conformity. FIG. 21A is a perspective view of an embodiment of a conditioning process of a hydrophilic polymer sponge structure to create microcracks that impart improved flexibility and conformity. FIG. 21B is a perspective view of an embodiment of a conditioning process of a hydrophilic polymer sponge structure to create microcracks that impart improved flexibility and conformity. FIG. 22A is a perspective view of an embodiment of a conditioning process of a hydrophilic polymer sponge structure to create microcracks that provide improved flexibility and conformity. FIG. 22B is a perspective view of an embodiment of a conditioning process of a hydrophilic polymer sponge structure to create microcracks that provide improved flexibility and conformity. FIG. 23A is an illustration of an embodiment of a process for conditioning a hydrophilic polymer sponge structure by forming a deep relief pattern that imparts improved flexibility and conformity. FIG. 23B is an illustration of an embodiment of a process for conditioning a hydrophilic polymer sponge structure by forming a deep relief pattern that imparts improved flexibility and conformity. FIG. 24A is a plan view of a relief pattern that can be applied to condition a hydrophilic polymer sponge structure according to the steps shown in FIGS. 23A and 23B. FIG. 24B is a plan view of a relief pattern that may be applied to condition a hydrophilic polymer sponge structure according to the steps shown in FIGS. 23A and 23B. FIG. 24C is a plan view of a relief pattern that can be applied to condition a hydrophilic polymer sponge structure according to the steps shown in FIGS. 23A and 23B. FIG. 24D is a plan view of a relief pattern that can be applied to condition a hydrophilic polymer sponge structure according to the steps shown in FIGS. 23A and 23B. FIG. 24E is a plan view of a relief pattern that can be applied to condition a hydrophilic polymer sponge structure according to the steps shown in FIGS. 23A and 23B. FIG. 24F is a plan view of a relief pattern that can be applied to condition a hydrophilic polymer sponge structure according to the steps shown in FIGS. 23A and 23B. FIG. 25A is a graph showing the increased flexibility and conformability that the process steps shown in FIGS. 23A and 23B can provide. FIG. 25B is a graph showing the increased flexibility and conformability that the processing steps shown in FIGS. 23A and 23B can provide. FIG. 26A is an illustration of an embodiment of a process for conditioning a hydrophilic polymer sponge structure by forming vertical channels (perforations) that impart flexibility and conformity. FIG. 26B is an illustration of an embodiment of a process for conditioning a hydrophilic polymer sponge structure by forming vertical channels (perforations) that impart flexibility and conformity. FIG. 27 is a plan view of a vertical (perforated) channel that can be applied to condition a hydrophilic polymer sponge structure according to the process shown in FIGS. 26A and 26B. FIG. 28 is a graph showing the increased flexibility and conformability that the processing steps shown in FIGS. 26A and 26B can provide. FIG. 29 is a perspective view of the assembled tissue dressing sheet assembly that can adhere to body tissue in the presence of blood, fluid, or moisture. 30 is an exploded perspective view of the tissue dressing sheet assembly shown in FIG. FIG. 31A is a perspective view of a tissue dressing sheet assembly arranged in a sheet form. FIG. 31B is a perspective view of a tissue dressing sheet assembly arranged in a roll. FIG. 32 is a perspective view of a rolled tissue dressing sheet assembly for stopping bleeding to be packed into a targeted tissue region. FIG. 33 is a diagram of the steps of the method for manufacturing the tissue dressing sheet assembly shown in FIG. FIG. 34 is a perspective view of the tissue dressing pad assembly shown in FIG. 29 packaged in a sealed sachet for final irradiation and storage. FIG. 35 is a graph illustrating the flexibility and compatibility of the tissue dressing sheet assembly shown in FIG. 29 and the untreated tissue dressing pad assembly shown in FIG. FIG. 36A is a graph showing simulated wound seal characteristics of the tissue dressing sheet assembly shown in FIG. 29 before gamma irradiation. 36B is a graph showing simulated wound seal characteristics of the tissue dressing sheet assembly shown in FIG. 29 before and after gamma irradiation. FIG. 37 is a perspective view of an assembled composite tissue dressing assembly that can adhere to body tissue in the presence of blood, fluid, or moisture. 38 is an exploded perspective view of the composite tissue dressing assembly shown in FIG. 39 is a cross-sectional side view of the composite tissue dressing assembly shown in FIG. FIG. 40 is a perspective view of a composite tissue dressing assembly of the type shown in FIG. 37 that is shaped and configured to form a gasket assembly that adheres and seals to the entry site for placement of the catheter. 41 is a side cross-sectional view of the gasket assembly shown in FIG. FIG. 42 is a perspective view of a tissue dressing pad assembly of the type shown in FIG. 1 that is shaped and configured to form a gasket assembly that adheres and seals to an entry site for placement of a catheter. FIG. 43 is a perspective view of a tissue dressing sheet assembly of the type shown in FIG. 29 that is shaped and configured to form a gasket assembly that adheres and seals to the entry site for placement of the catheter.

Claims (12)

A tissue dressing comprising a hydrophilic polymer sponge structure, the hydrophilic polymer sponge structure comprising: (i) a microcrack in an important part of the structure by mechanical manipulation prior to use; or (ii) ) observed at least Tsuo含pattern of the fluid injection channel which is formed an important part of the use for the front of the structure,
A tissue dressing wherein the hydrophilic polymer sponge structure comprises a chitosan biomaterial . The hydrophilic polymer sponge structure is densified from 0.6 g / cm ³ by compression prior to use to a density of between 0.1 g / cm ^3, the tissue dressing according to claim 1.   The tissue dressing according to claim 1, wherein the microcrack is caused by one of bending, twisting, rotation, vibration, search, compression, stretching, shaking, or kneading.   The tissue dressing of claim 1, wherein the pattern of fluid injection channels has perforations.   The tissue dressing of claim 1, wherein the hydrophilic polymer sponge structure comprises a lower surface and an upper surface, and the fluid injection channel is formed in the lower surface.   The tissue coating material according to claim 1, wherein the hydrophilic polymer sponge structure includes a lower surface and an upper surface, and further includes a fluid-impermeable support material bonded to the upper surface.   The tissue dressing according to claim 1, wherein the hydrophilic polymer sponge structure includes a lower surface and an upper surface, and further includes a fluid-absorbing material bonded to the upper surface.   (I) hemostasis, sealing or stabilization at the site of tissue damage, tissue trauma, or tissue intrusion; or (ii) formation of an antibacterial barrier; or (iii) formation of an antiviral patch; or (iv) bleeding. The tissue of claim 1, used to perform at least one of treatment of sexually transmitted diseases; or (v) release of therapeutic agents; or (vi) treatment of mucosal surfaces; or (vii) combinations thereof. Coating material. A tissue covering material comprising a hydrophilic polymer sponge structure and at least one woven or non-woven or permeable membrane sheet present in the hydrophilic sponge structure, wherein the hydrophilic polymer sponge structure is compressed by compression. is the density until densification between .6g / cm ³ of 0.1 g / cm ^3, and the hydrophilic polymer sponge structure, a significant portion of the structure by (i) using the previous mechanical operation Comprising at least one of microcracks, or (ii) a pattern of fluid injection channels formed in a significant portion of the structure prior to use;
A tissue dressing wherein the hydrophilic polymer sponge structure comprises a chitosan biomaterial . (I) hemostasis, sealing or stabilization at the site of tissue damage, tissue trauma or tissue intrusion; or (ii) formation of an antibacterial barrier; or (iii) formation of an antiviral patch; or (iv) bleeding. 10. Tissue according to claim 9 , used to carry out at least one of treatment of sexual diseases; or (v) release of therapeutic agents; or (vi) treatment of mucosal surfaces; or (vii) combinations thereof. Coating material. A tissue covering material comprising a hydrophilic polymer sponge structure and an absorptive component held in the hydrophilic sponge structure, wherein the hydrophilic polymer sponge structure is compressed to 0.6 g / cm ³ to 0.1 g. Densified to a density of between / cm ³ and the hydrophilic polymer sponge structure is (i) microcracks in critical parts of the structure by mechanical manipulation before use, or (ii) before use Comprising at least one pattern of fluid injection channels formed in a significant portion of the structure of
A tissue dressing wherein the hydrophilic polymer sponge structure comprises a chitosan biomaterial . (I) hemostasis, sealing or stabilization at the site of tissue damage, tissue trauma or tissue intrusion; or (ii) formation of an antibacterial barrier; or (iii) formation of an antiviral patch; or (iv) bleeding. 12. Tissue according to claim 11 , used to carry out at least one of treatment of sexual diseases; or (v) release of therapeutic agents; or (vi) treatment of mucosal surfaces; or (vii) combinations thereof. Coating material.

Images