Abstract:
A granule or particle made of a chitosan material either carries within it a polymer mesh material of poly-4-hydroxy butyrate, or has interspersed with it a polymer mesh material of poly-4-hydroxy butyrate. The granule or particle can be carried within a polymer mesh socklet made of a material consisting essentially of poly-4-hydroxy butyrate. The granule or particle can be used to treat intracavity bleeding.

Description:
RELATED APPLICATIONS  
       [0001]     This application claims the benefit of U.S. Provisional Application Ser. No. 60/698,734, filed Jul. 13, 2005, and entitled “Hemostatic Compositions, Assemblies, Systems, and Methods Employing Particulate Hemostatic Agents Formed from Hydrophilic Polymer Foam Such as Chitosan.” 
     
    
     FIELD OF THE INVENTION  
       [0002]     The invention is generally directed to agents applied externally or internally on a site of tissue injury or tissue trauma to ameliorate bleeding, fluid seepage or weeping, or other forms of fluid loss.  
       BACKGROUND OF THE INVENTION  
       [0003]     Hemorrhage is the leading cause of death from battlefield trauma and the second leading cause of death after trauma in the civilian community. Non-compressible hemorrhage (hemorrhage not readily accessible to direct pressure, such as intracavity bleeding) contributes to the majority of early trauma deaths. Apart from proposals to apply a liquid hemostatic foam and recombinant factor VIIa to the non-compressible bleeding sites, very little has been done to address this problem. There is a critical need to provide more effective treatment options to the combat medic for controlling severe internal hemorrhage such as intracavity bleeding.  
         [0004]     Control of intracavity bleeding is complicated by many factors, chief among which are: lack of accessibility by conventional methods of hemostatic control such as application of pressure and topical dressings; difficulty in assessing the extent and location of injury; bowel perforation, and interferences caused by blood flow and pooling of bodily fluids.  
       SUMMARY OF THE INVENTION  
       [0005]     The invention provides a chitosan hemostatic agent matrix in the form of a granule or particle that carries within it a polymer mesh material formed from poly-4-hydroxy butyrate (TephaFLEX™ Material manufactured by Tepha Inc.).  
         [0006]     The invention also provides a chitosan hemostatic agent matrix as just described that can be applied within a polymer mesh socklet formed from poly-4-hydroxy butyrate (TephaFLEX™ Material manufactured by Tepha Inc.).  
         [0007]     The improved hemostatic agents as just described can be used to stanch, seal, or stabilize a site of noncompressible hemorrhage, e.g., at a site of intracavity bleeding. The invention provides rapid delivery of a safe and effective hemostatic agent to a general site of bleeding; enhanced promotion of strong clot formation at the site of bleeding; and ability (if necessary) to apply tamponade over the field of injury. The invention also provides an enhanced rate of wound healing with reduced fibrotic adhesion and reduced opportunity for wound infection. The invention therefore addresses many of the significant issues related to current difficulties in controlling intracavitary hemorrhage and recovery from this type of injury.  
         [0008]     Other features and advantages of the invention shall be apparent based upon the accompanying description, drawings, and listing of key technical features. 
     
    
     DESCRIPTION OF THE DRAWINGS  
       [0009]      FIG. 1A  is a schematic anatomic view of an intracavity site of noncompressible hemorrhage, into which a hemostatic agent has been applied to stanch, seal, or stabilize the site.  
         [0010]      FIG. 1B  is an enlarged view of the hemostatic agent shown in  FIG. 1A , showing the granules or particles that comprise the agent.  
         [0011]      FIG. 2  is a further enlarged view of the granules or particles shown in  FIG. 1B  showing strips of a polymer mesh material formed from poly-4-hydroxy butyrate (TephaFLEX™ Material manufactured by Tepha Inc.) that have been added to the granules or particles.  
         [0012]      FIG. 3  is a schematic flow chart view of a process of manufacturing the granules or particles shown in  FIG. 2  from a chitosan material.  
         [0013]      FIG. 4  shows a step in the manufacturing process shown in  FIG. 3 , in which strips of the polymer mesh material formed from poly-4-hydroxy butyrate (TephaFLEX™ Material manufactured by Tepha Inc.) are added to the granules or particles.  
         [0014]      FIG. 5  shows a composite hemostatic agent comprising hemostatic granules or particles mixed with strips of polymer mesh material formed from poly-4-hydroxy butyrate (TephaFLEX™ Material manufactured by Tepha Inc.).  
         [0015]      FIG. 6  shows a bolus of the granules or particles shown in  FIG. 2  contained for delivery in a socklet of polymer mesh material formed from poly-4-hydroxy butyrate (TephaFLEX™ Material manufactured by Tepha Inc.).  
         [0016]      FIG. 7  shows one way of delivering the bolus of the granules or particles shown in  FIG. 6  in the socklet of polymer mesh material to an injury site.  
         [0017]      FIGS. 8A and 8B  show a way of delivering a bolus of the granules or particles shown in  FIG. 2  into a releasable polymer mesh socklet formed from poly-4-hydroxy butyrate (TephaFLEX™ Material manufactured by Tepha Inc.) at an injury site.  
         [0018]      FIG. 9  is an alternative way of delivering a bolus of the granules or particles shown in  FIG. 2  to an injury site without use of a containment socklet or the like. 
     
    
     DETAILED DESCRIPTION  
       [0019]     Although the disclosure hereof is detailed and exact to enable those skilled in the art to practice the invention, the physical embodiments herein disclosed merely exemplify the invention, which may be embodied in other specific structure. While the preferred embodiment has been described, the details may be changed without departing from the invention, which is defined by the claims.  
         [0020]      FIG. 1A  shows a site  10  of an intracavity abdominal injury, where severe internal bleeding will occur if steps are not taken to stanch, seal, or stabilize the site. The site  10  is the location of a noncompressible hemorrhage, meaning that the hemorrhage is not readily accessible to direct pressure.  
         [0021]     As shown in  FIGS. 1A and 1B , a hemostatic agent  12  that embodies the features of the invention has been applied to stanch, seal, or stabilize the site  10  without the application of direct pressure or compression. The agent  12  takes the form of discrete particles  14  of a biodegradable hydrophilic polymer (best shown in  FIG. 1B  and  FIG. 2 ).  
         [0022]     The polymer of which the particles  14  are formed has been selected to include a biocompatible material that reacts in the presence of blood, body fluid, or moisture to become a strong adhesive or glue. Desirably, the polymer from which the particles  14  are formed also desirably possess other beneficial attributes, for example, anti-bacterial and/or anti-microbial anti-viral characteristics, and/or characteristics that accelerate or otherwise enhance the body&#39;s defensive reaction to injury. The polymer material comprising the particles  14  has desirably been densified or otherwise treated to make the particles  14  resistant to dispersal away from the site  10  by flowing blood and/or other dynamic conditions affecting the site  10 .  
         [0023]     The agent  12  thereby serves to stanch, seal, and/or stabilize the site  10  against bleeding, fluid seepage or weeping, or other forms of fluid loss. The agent  12  also desirably forms an anti-bacterial and/or anti-microbial and/or anti-viral protective barrier at or surrounding the tissue treatment site  10 . The agent  12  can applied as temporary intervention to stanch, seal, and/or stabilize the site  10  on an acute basis. The agent  12  can also be augmented, as will be described later, to make possible more permanent internal use.  
         [0024]     The particles  14  shown in  FIG. 2  comprise a chitosan material, most preferably poly [β-(1→4)-2-amino-2-deoxy-D-glucopyranose. The chitosan selected for the particles  14  preferably has a weight average molecular weight of at least about 100 kDa, and more preferably, of at least about 150 kDa. Most preferably, the chitosan has a weight average molecular weight of at least about 300 kDa.  
         [0025]     The chitosan can be manufactured in the manner described in U.S. patent application Ser. No. 11/020,365 filed on Dec. 23, 2004, entitled “Tissue Dressing Assemblies, Systems, and Methods Formed From Hydrophilic Polymer Sponge Structures Such as Chitosan”; U.S. patent application Ser. No. 10/743,052, filed on Dec. 23, 2004, entitled “Wound Dressing and Method of Controlling Severe Life-Threatening Bleeding”; U.S. patent application Ser. No. 10/480,827, filed on Dec. 15, 2003, entitled “Wound Dressing and Method of Controlling Severe Life-Threatening Bleeding,” which was a national stage filing under 37 C.F.R. § 371 of International Application No. PCT/US02/18757, filed on Jun. 14, 2002, which are each incorporated herein by reference.  
         [0026]     Generally speaking the chitosan particles  14  are formed by the preparation of a chitosan solution by addition of water to solid chitosan flake or powder at 25° C. ( FIG. 3 , Step A), the solid being dispersed in the liquid by agitation, stirring or shaking. On dispersion of the chitosan in the liquid, the acid component is added and mixed through the dispersion to cause dissolution of the chitosan solid. The chitosan biomaterial  16  is desirably degassed of general atmospheric gases ( FIG. 3 , Step B). The structure or form producing steps for the chitosan material  16  are typically carried out from solution and can be accomplished employing techniques such as freezing (to cause phase separation) ( FIG. 3 , Step C). In the case of freezing, where two or more distinct phases are formed by freezing (typically water freezing into ice with differentiation of the chitosan biomaterial into a separate solid phase), another step is required to remove the frozen solvent (typically ice), and hence produce the chitosan matrix  16  without disturbing the frozen structure. This may be accomplished by a freeze-drying and/or a freeze substitution step ( FIG. 3 , Step D).  
         [0027]     The chitosan material  16  comprise an “uncompressed” chitosan acetate matrix of density less than 0.035 g/cm 3  that has been formed by freezing and lyophilizing a chitosan acetate solution, which is then densified by compression ( FIG. 3 , Step E) to a density of from 0.6 to 0.5 g/cm 3 , with a most preferred density of about 0.25 to 0.5 g/cm 3 . This chitosan matrix can also be characterized as a compressed, hydrophilic sponge structure. The densified chitosan matrix  16  exhibits all of the above-described characteristics deemed to be desirable. It also possesses certain structural and mechanical benefits that lend robustness and longevity to the matrix during use, as will be described in greater detail later.  
         [0028]     The densified chitosan biomaterial  16  is next preferably preconditioned by heating chitosan matrix  16  in an oven to a temperature of preferably up to about 75° C., more preferably to a temperature of up to about 80° C., and most preferably to a temperature of preferably up to about 85° C. ( FIG. 3 , Step F).  
         [0029]     After formation in the manner just described, the sponge structure is granulated, e.g., by a mechanical process, to a desired particle diameter, e.g., at or near 0.9 mm. Simple mechanical granulation of the chitosan matrix  16  through a suitable mechanical device  18  (as shown in  FIG. 3 , Step G) can be used to prepare chitosan sponge particles  14  of close to 0.9 mm in diameter. Other granulation methodologies can be used. For example, off the shelf stainless steel grinding/granulating laboratory/food processing equipment can be used. More robust, purpose designed, and more process-controlled systems can also be used. Granulation of the chitosan matrix  16  can be conducted under ambient temperature or liquid nitrogen temperature conditions.  
         [0030]     Preferably, a well defined particle size distribution of particle granulate  14  is prepared. The particle size distribution can be characterized using, e.g., Leica ZP6 APO stereomicroscope and Image Analysis MC software. The granulated particles are sterilized ( FIG. 3 , Step H), for example, by irradiation, such as by gamma irradiation.  
         [0031]     The chitosan matrix from which the particles  14  are formed presents a robust, permeable, high specific surface area, positively charged surface. The positively charged surface creates a highly reactive surface for red blood cell and platelet interaction. Red blood cell membranes are negatively charged, and they are attracted to the chitosan matrix. The cellular membranes fuse to chitosan matrix upon contact. A clot can be formed very quickly, circumventing immediate need for clotting proteins that are normally required for hemostasis. For this reason, the chitosan matrix is effective for both normal as well as anti-coagulated individuals, and as well as persons having a coagulation disorder like hemophilia. The chitosan matrix also binds bacteria, endotoxins, and microbes, and can kill bacteria, microbes, and/or viral agents on contact. Furthermore, chitosan is biodegradable within the body and is broken down into glucosamine, a benign substance.  
         [0032]     The interior of the particles  14  can be reinforced by the inclusion of small strips or pieces of a bioresorbable polymer mesh material  24  (as shown in  FIG. 2 ) formed from poly-4-hydroxy butyrate (TephaFLEX™ Material manufactured by Tepha Inc.). These strips of mesh material  24  can be added to the viscous chitosan solution  16  immediately before the freezing step (as  FIG. 4  shows). Alternatively (as  FIG. 5  shows), loose small strips or pieces of the bioresorbable poly-4-hydroxy butyrate (TephaFLEX™ Material manufactured by Tepha Inc.) mesh material  24  can be added after granulation and prior to pouching and sterilization. In this arrangement, the strips or pieces of the mesh material  24  reside between the individual particles  14  contained within the pouch  22  (as shown in  FIG. 5 ).  
         [0033]     The presence of the poly-4-hydroxy butyrate (TephaFLEX™ Material manufactured by Tepha Inc.) mesh material  24  enhances hemostasis by overall reinforcement of the complex composite of chitosan granule particle  14 , blood, and the mesh material  24 .  
         [0034]     The poly-4-hydroxy butyrate (TephaFLEX™ Material manufactured by Tepha Inc.) mesh material is a biosynthetic absorbable polyester produced through a fermentation process rather than by chemical synthesis. It can generally be described as a strong, pliable thermoplastic with a tensile strength of 50 MPa, tensile modulus of 70 MPa, elongation to break of ˜1000%, and hardness (Shore D) of 52.8. Upon orientation the tensile strength increases approximately 10-fold (to a value about 25% higher than commercial absorbable monofilament suture materials such as PDSII™).  
         [0035]     Despite its biosynthesis route, the structure of the polyester is very simple, and closely resembles the structures of other existing synthetic absorbable biomaterials used in medical applications. The polymer belongs to a larger class of materials called polyhydroxyalkanoates (PHAs) that are produced in nature by numerous microorganisms. In nature these polyesters are produced as storage granules inside cells, and serve to regulate energy metabolism. They are also of commercial interest because of their thermoplastic properties, and relative ease of production. Tepha, Inc. produces the TephaFLEX™ biomaterial for medical applications using a proprietary transgenic fermentation process specifically engineered to produce this homopolymer. The TephaFLEX™ biomaterial production process utilizes a genetically engineered  Escherichia coli  K12 microorganism that incorporates new biosynthetic pathways to produce the polymer. The polymer accumulates inside the fermented cells during fermentation as distinct granules, and can then be extracted at the end of the process in a highly pure form. The biomaterial has passed tests for the following: cytotoxicity; sensitization; irritation and intracutaneous reactivity; hemocompatibility; endotoxin; implantation (subcutaneous and intramuscular); and USP Class VI. In vivo, the TephaFLEX™ biomaterial is hydrolyzed to 4-hydroxybutyrate, a natural human metabolite, present normally in the brain, heart, lung, liver, kidney, and muscle. This metabolite has a half-life of just 35 minutes, and is rapidly eliminated from the body (via the Krebs cycle) primarily as expired carbon dioxide.  
         [0036]     Being thermoplastic, the TephaFLEX™ biopolymer can be converted into a wide variety of fabricated forms using traditional plastics processing technologies, such as injection molding or extrusion. Melt extruded fibers made from this novel absorbable polymer are at least 30% stronger, significantly more flexible and retain their strength longer than the commercially available absorbable monofilament suture materials. These properties make the TephaFLEX™ biopolymer an excellent choice for construction of a hemostatic dressing for controlling intracavity hemorrhage.  
         [0037]     The TephaFLEX™ biomaterial can be processed into fibers and fabrics suitable for use as an absorbable sponge.  
         [0038]     To provide for enhanced local delivery and potentially some pressure compaction (tamponade) of the encased granulate against the wound, the chitosan granulate particles  14  can be desirable housed for delivery within an open mesh socklet or bag  26  (see  FIG. 6 ) made from a TephaFLEX biomaterial above described.  
         [0039]     The mesh of the socklet  26  is sufficiently open to allow for the chitosan granulate particles  14  to protrude out of the socklet  26 , but not so open that granulate particles  14  could be flushed away by flowing blood through the mesh. The socklet  26  supports the chitosan granulate particles  14  during and after delivery and allows a more directed application of a bolus of the granulate particles  14 . The mesh socklet  26  should be sufficiently open to allow protrusion of chitosan particles  14  at the outer surface of the bolus from its outside surface without loss of individual chitosan granule particles  14 . The mechanical properties of the mesh socklet  26  are sufficient to allow local application of pressure over its surface without tearing or breaking.  
         [0040]     The tamponade of a socklet  26  filled with the particles  14  can be applied, e.g., through a cannula  28  (see  FIG. 7 ) by use of tamp  34  to advance the socklet  26  through the cannula  28  to the injury site  10 . Multiple socklets  26  can be delivered in sequence through the cannula  28 , if required. Alternatively, a caregiver can manually insert one or more of the socklets  26  into the treatment site  10  through a surface incision.  
         [0041]     Alternatively, as  FIGS. 8A and 8B  show, a mesh socklet  30  can be releasably attached to the end of a cannula  28 , e.g., by a releasable suture  32 . The cannula  28  guides the empty socklet  30  into the injury site  10 . In this arrangement, individual particles  14  (i.e., not confined during delivery within a mesh socklet  26  as shown in  FIG. 6 ) can be urged through the cannula  28 , using, e.g., a tamp, to fill the socklet  30  within the injury site. Upon filling the socklet  30  with particles  14 , the suture  32  can be pulled to release the cannula  28 , leaving the particle filled socklet  30  behind in the injury site  10 , as  FIG. 8B  shows.  
         [0042]     Alternatively, as  FIG. 9  shows, individual particles.  14  can be delivered to the injury site  10  through a syringe  36 . In this arrangement, means for targeting of the particles  14  at the injury site  10  and protection against disbursement of the particles  14  away from the injury site  10  due to blood flow may be required, using the already described confinement devices and techniques. It is believed that permanent internal use will require the use of a socklet or equivalent confinement technique.  
         [0043]     Therefore, it should be apparent that above-described embodiments of this invention are merely descriptive of its principles and are not to be limited. The scope of this invention instead shall be determined from the scope of the following claims, including their equivalents.