Patent Application
20060004314
The application of continuous pressure with gauze bandage remains a primary intervention technique used to stem blood flow, especially flow from severely bleeding wounds. However, this procedure neither effectively nor safely stanches severe blood flow. This has been, and continues to be, a major survival problem in the case of severe life-threatening bleeding from a wound.
Hemostatic bandages such as collagen wound dressings or dry fibrin thrombin wound dressings or chitosan and chitosan dressings are available, such dressings are not sufficiently resistant to dissolution in high blood flow. They also do not possess enough adhesive properties to serve any practical purpose in the stanching of severe blood flow. These currently available surgical hemostatic bandages are also delicate and thus prone to failure should they be damaged by bending or loading with pressure. They are also susceptible to dissolution in hemorrhagic bleeding. Such dissolution and collapse of these bandages may be catastrophic, because it can produce a loss of adhesion to the wound and allow bleeding to continue unabated.
Along with adequately preventing and limiting bleeding and hemorrhaging, care must be taken to prevent bacterial infections from arising on and around the wound or lesion. Current bandages do not adequately prevent the growth of such infections and do not treat such infections.
There remains a need for improved hemostatic dressings with robustness and longevity to resist dissolution during use that will assist in the treatment of bacterial infections.
The invention provides antimicrobial barriers, systems and methods formed from a structure including a chitosan biomaterial. The antimicrobial barriers can be used, e.g., (i) to stanch, seal, or stabilize a site of tissue injury, tissue trauma, or tissue access; or (ii) to form an anti-microbial barrier; or (iii) to form an antiviral patch; or (iv) to intervene in a bleeding disorder; or (v) to release a therapeutic agent; or (vi) to treat a mucosal surface; or (vii) combinations thereof.
In one embodiment, the antimicrobial barrier structure is desirably densified by compression.
Other features and advantages of the invention shall be apparent based upon the accompanying description, drawings, and claims.
FIGS. 8 to 9A/B are perspective views of the antimicrobial barrier pad assembly being applied to a targeted tissue site to stanch bleeding.
FIGS. 15, 16A/B, and 17A/B are perspective views of an embodiment of the steps for conditioning a hydrophilic polymer structure to create micro-fractures, which provide improved flexibility and compliance.
To facilitate an understanding of this disclosure, the following listing summarizes the topical areas covered, arranged in the order in which they appear:
I. The Antimicrobial Barrier Pad Assembly
A. Overview
B. Use of the Antimicrobial Barrier Pad Assembly
C. Manufacture of the Tissue Dressing Pad Assembly
D. Altering the Compliance Properties of a Hydrophilic Polymer Structure
A. Overview
B. Use of Tissue Dressing Sheet Assembly
C. Manufacture of the Tissue Dressing Sheet Assembly
III. Further Indications and Configurations for Hydrophilic Polymer Structures
A. Anti-Microbial Barriers
IV. Conclusion
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 structures. While the preferred embodiment has been described, the details may be changed without departing from the invention, which is defined by the claims.
I. Tissue Dressing Pad Assembly
A. Overview
The size, shape, and configuration of the antimicrobial barrier pad assembly 10 can vary according to its intended use. The pad assembly 10 can be rectilinear, elongated, square, round, oval, or a composite or complex combination thereof. Desirably, as will be described later, the shape, size, and configuration of pad assembly 10 can be formed by cutting, bending, or molding, either during use or in advance of use. In
1. The Tissue Dressing Matrix
The tissue dressing matrix 12 is preferably formed from a low modulus hydrophilic polymer matrix, i.e., an inherently “uncompressed” tissue dressing matrix 12, which has been densified by a subsequent densification process, which will be described later. The tissue dressing matrix 12, preferably, includes a biocompatible material that reacts in the presence of blood, body fluid, or moisture to become a strong adhesive or glue. Desirably, the tissue dressing matrix also possesses other beneficial attributes, for example, anti-bacterial and/or anti-microbial anti-viral characteristics, and/or characteristics that accelerate or otherwise enhance the body's defensive reaction to injury.
The tissue dressing matrix 12 may comprise a hydrophilic polymer form, such as a polyacrylate, an alginate, chitosan, a hydrophilic polyamine, a chitosan derivative, polylysine, polyethylene imine, xanthan, carrageenan, quaternary ammonium polymer, chondroitin sulfate, a starch, a modified cellulosic polymer, a dextran, hyaluronan or combinations thereof. The starch may be of 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, which is most preferably poly [β-(1→4)-2-amino-2-deoxy-D-glucopyranose, which is more commonly referred to as chitosan. The chitosan selected for the matrix 12 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.
In forming the matrix 12, the chitosan is desirably placed into solution with an acid, such as glutamic acid, lactic acid, formic acid, hydrochloric acid and/or acetic acid. Among these, hydrochloric acid and acetic acid are most preferred, because chitosan acetate salt and chitosan chloride salt resist dissolution in blood whereas chitosan lactate salt and chitosan glutamate salt do not. Larger molecular weight (Mw) anions disrupt the para-crystalline structure of the chitosan salt, causing a plasticization effect in the structure (enhanced flexibility). Undesirably, they also provide for rapid dissolution of these larger Mw anion salts in blood.
One preferred form of the matrix 12 comprises an “uncompressed” chitosan acetate matrix 12 of density less than 0.035 g/cm3 that has been formed by freezing and lyophilizing a chitosan acetate solution, which is then densified by compression to a density of from 0.6 to 0.25 g/cm3, with a most preferred density of about 0.20 g/cm3. This chitosan matrix 12 can also be characterized as a compressed, hydrophilic structure. The densified chitosan matrix 12 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.
The chitosan matrix 12 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 12. The cellular membranes fuse to chitosan matrix 12 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 12 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 12 also binds bacteria, endotoxins, and microbes, and can kill bacteria, microbes, and/or viral agents on contact.
Further details of the structure, composition, manufacture, and other technical features of the chitosan matrix 12 will be described later.
2. The Backing
The tissue dressing pad assemble is sized and configured for manipulation by a caregiver's fingers and hand. The backing 14 isolates a caregiver's fingers and hand from the fluid-reactive chitosan matrix 12 (see, e.g.,
Other polymers suitable for backing use in temporary wound applications include, but are not limited to, cellulose polymers, polyethylene, polypropylene, metallocene polymers, polyurethanes, polyvinylchloride polymers, polyesters, polyamides or combinations thereof.
For internal wound applications, a resorbable backing may be used in hydrophilic sponge bandage forms. Preferably such bandage forms would use a biodegradable, biocompatible backing material. Synthetic biodegradable materials may include, but are not limited to, poly(glycolic acid), poly(lactic acid), poly(e-caprolactone), poly(β-hydroxybutyric acid), poly (β-hydroxyvaleric acid), polydioxanone, poly(ethylene oxide), poly(malic acid), poly(tartronic acid), polyphosphazene, copolymers of polyethylene, copolymers of polypropylene, and the copolymers of the monomers used to synthesize the above-mentioned polymers or combinations thereof. Naturally occurring biodegradable polymers may include, but are not limited to, chitin, algin, starch, dextran, collagen and albumen.
3. The Pouch
As
The pouch 16 is configured to be peeled opened by the caregiver (see
B. Use of the Antimicrobial Barrier Pad Assembly 10
Once removed from the pouch 16 (see
Desirably, the antimicrobial barrier pad assembly 10 is applied to the injury site within one hour of opening the pouch 16. As
Desirably, as
Due to unique mechanical and adhesive characteristics, two or more dressing pad assemblies can be overlapped, if needed, to occupy the wound or tissue site. The chitosan matrix 12 of one pad assembly 10 will adhere to the backing 14 of an adjacent dressing pad assembly 10.
The dressing pad assembly 10 can also be torn or cut on site (see
If the tissue pad dressing assembly fails to stick to the injury site, it can be removed and discarded, and another fresh dressing pad assembly 10 applied. In wounds with substantial tissue disruptions, with deep tissue planes or in penetrating wounds, peeling away the backing 14 and stuffing the chitosan matrix 12 into the wound, followed by covering the wound with a second dressing, has been shown to be very effective.
Once pressure has been applied for two to five minutes, and/or control of the bleeding has been accomplished with good dressing adhesion and coverage of the wound or tissue site, a second conventional dressing (e.g., gauze) is desirably applied to secure the dressing and to provide a clean barrier for the wound (see
Desirably, in the case of FDA cleared temporary dressing forms, the antimicrobial barrier pad assembly 10 is removed within forty-eight hours of application for definitive surgical repair. The antimicrobial barrier pad assembly 10 can be peeled away from the wound and will generally separate from the wound in a single, intact dressing. In some cases, residual chitosan gel may remain, and this can be removed using saline or water with gentle abrasion and a gauze dressing. Chitosan is biodegradable within the body and is broken down into glucosamine, a benign substance. Still, it is desirable in the case of temporary dressings, that efforts should be made to remove all portions of chitosan from the wound at the time of definitive repair. As before discussed, biodegradable dressings can be formed for internal use.
Action reports by combat medics in operations in and during freedom operations in Afghanistan and Iraq have shown successful clinical utility for the dressing pad assemblies without adverse effects. The US Army Institute for Surgical Research at Fort Sam Houston in Texas evaluated the dressing pad assembly 10 in trauma models with severe life threatening bleeding and compared this dressing to standard 4×4 inch cotton gauze dressings. The antimicrobial barrier pad assembly 10 significantly decreased blood loss and decreased resuscitative fluid requirements. Survival at one hour was increased in the group to which the antimicrobial barrier pad assembly 10 was applied, compared to the cotton gauze survival group. Combat medics have successfully treated bullet wounds, shrapnel, land mine and other injuries, when conventional wound dressings have failed.
C. Manufacture of the Tissue Dressing Pad Assembly
A desirable methodology for making the antimicrobial barrier pad assembly 10 will now be described. This methodology is shown schematically in
1. Preparation of a Chitosan Solution
The chitosan used to prepare the chitosan solution preferably has a fractional degree of deacetylation greater than 0.78 but less than 0.97. Most preferably the chitosan has a fractional degree of deacetylation greater than 0.85 but less than 0.95. Preferably the chitosan selected for processing into the matrix has a viscosity at 25° C. in a 1% (w/w) solution of 1% (w/w) acetic acid (AA) with spindle LVI at 30 rpm, which is about 100 centipoise to about 2000 centipoise. More preferably, the chitosan has viscosity at 25° C. in a 1% (w/w) solution of 1% (w/w) acetic acid (AA) with spindle LVI at 30 rpm, which is about 125 centipoise to about 1000 centipoise. Most preferably, the chitosan has viscosity at 25° C. in a 1% (w/w) solution of 1% (w/w) acetic acid (AA) with spindle LV1 at 30 rpm, which is about 400 centipoise to about 800 centipoise.
The chitosan solution is preferably prepared at 25° C. by addition of water to solid chitosan flake or powder and the solid 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 rate of dissolution will depend on the temperature of the solution, the molecular weight of the chitosan and the level of agitation. Preferably the dissolution step is performed within a closed tank reactor with agitating blades or a closed rotating vessel. This ensures homogeneous dissolution of the chitosan and no opportunity for high viscosity residue to be trapped on the side of the vessel. Preferably the chitosan solution percentage (w/w) is greater than 0.5% chitosan and less than 2.7% chitosan. More preferably the chitosan solution percentage (w/w) is greater than 1% chitosan and less than 2.3% chitosan. Most preferably the chitosan solution percentage is greater than 1.5% chitosan and less than 2.1% chitosan. Preferably the acid used is acetic acid. Preferably the acetic acid is added to the solution to provide for an acetic acid solution percentage (w/w) at more than 0.8% and less than 4%. More preferably the acetic acid is added to the solution to provide for an acetic acid solution percentage (w/w) at more than 1.5% (w/w) and less than 2.5%.
The structure or form producing steps for the chitosan matrix 12 are typically carried out from solution and can he accomplished employing techniques such as freezing (to cause phase separation), non-solvent die extrusion (to produce a filament), electro-spinning (to produce a filament), phase inversion and precipitation with a non-solvent (as is typically used to produce dialysis and filter membranes) or solution coating onto a preformed sponge-like or woven product. 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 12 without disturbing the frozen structure. This may be accomplished by a freeze-drying and/or a freeze substitution step. The filament can he formed into a non-woven sponge-like mesh by non-woven spinning processes. Alternately, the filament may he produced into a felted weave by conventional spinning and weaving processes. Other processes that may be used to make the biomaterial sponge-like product include dissolution of added porogens from a solid chitosan matrix 12 or boring of material from said matrix.
2. Degassing the Aqueous Chitosan Solution
Preferably (see
In one embodiment, certain gases can be added back into the solution to controlled partial pressures after initial degassing. Such gases would include but are not limited to argon, nitrogen and helium. An advantage of this step is that solutions containing partial pressures of these gases form micro-voids on freezing. The microvoid is then carried through the sponge as the ice-front advances. This leaves a well defined and controlled channel that aids sponge pore interconnectivity.
3. Freezing the Aqueous Chitosan Solution
Next (see
Freezing of the chitosan solution in this way enables the preferred structure of the wound-dressing product to be prepared.
As will be demonstrated below, the plate freezing temperature affects the structure and mechanical properties of the final chitosan matrix 12. The plate freezing temperature is preferably not higher than about −10° C., more preferably not more than about −20° C., and most preferably not more than about −30° C. When frozen at −10° C., the structure of the uncompressed chitosan matrix 12 is very open and vertical throughout the open sponge structure. When frozen at −25° C., the structure of the uncompressed chitosan matrix 12 is more closed, but it is still vertical. When frozen at −40° C., the structure of the uncompressed chitosan matrix 12 is closed and not vertical. Instead, the chitosan matrix 12 comprises more of a reinforced, inter-meshed structure. The adhesive/cohesive sealing properties of the chitosan matrix 12 are observed to improve as lower freezing temperatures are used. A freezing temperatures of about −40° C. forms a structure for the chitosan matrix 12 having superior adhesive/cohesive properties.
During the freezing step, the temperature may be lowered over a predetermined time period. For example, the freezing temperature of a chitosan biomaterial solution may he lowered from room temperature to −45° C. by plate cooling application of a constant temperature cooling ramp of between about −0.4° C./mm to about −0.8° C./mm for a period of about 90 minutes to about 160 minutes.
4. Freeze Drying the Chitosan/Ice Matrix
The frozen chitosan/ice matrix desirably undergoes water removal from within the interstices of the frozen material (see
The preferred manner of implementing the water removal step is by freeze-drying, or lyophilization. Freeze-drying of the frozen chitosan biomaterial can be conducted by further cooling the frozen chitosan biomaterial. Typically, a vacuum is then applied. Next, the evacuated frozen chitosan material may be gradually heated.
More specifically, the frozen chitosan biomaterial may be subjected to subsequent freezing preferably at about −15° C., more preferably at about −25° C., and most preferably at about −45° C., for a preferred time period of at least about 1 hour, more preferably at least about 2 hour, and most preferably at least about 3 hour. This step can be followed by cooling of the condenser to a temperature of less than about −45° C., more preferably at about −60° C., and most preferably at about −85° C. Next, a vacuum in the amount of preferably at most about 100 mTorr, more preferably at most about 150 mTorr, and most preferably at least about 200 mTorr, can be applied. The evacuated frozen chitosan material can be heated preferably at about −25° C., more preferably at about −15° C., and most preferably at about −10° C., for a preferred time period of at least about 1 hour, more preferably at least about 5 hour, and most preferably at least about 10 hour.
Further freeze drying, maintaining vacuum pressure at near 200 mTorr, is conducted at a shelf temperature of about 20° C., more preferably at about 15° C., and most preferably at about 10° C., for a preferred time period of at least about 36 hours, more preferably at least about 42 hours, and most preferably at least about 48 hours.
5. Densification of the Chitosan Matrix
The chitosan matrix before densification (density near 0.03 g/cm3) will be called an “uncompressed chitosan matrix.” This uncompressed matrix is ineffective in stanching bleeding since it rapidly dissolves in blood and has poor mechanical properties. The chitosan biomaterial is necessarily compressed (see
The compression temperature is preferably not less than about 60° C., more preferably it is not less than about 75° C. and not more than about 85° C.
After densification, the density of the matrix 12 can be different at the base (“active”) surface of the matrix 12 (i.e., the surface exposed to tissue) than at the top surface of the matrix 12 (the surface to which the backing 14 is applied). For example, in a typical matrix 12 where the mean density measured at the active surface is at or near the most preferred density value of 0.2 g/cm3, the mean density measured at the top surface can be significantly lower, e.g., at 0.05 g/cm3. The desired density ranges as described herein for a densified matrix 12, are intended to exist at are near the active side of the matrix 12, where exposure to blood, fluid, or moisture first occurs.
The densified chitosan biomaterial is next preferably preconditioned by heating chitosan matrix 12 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. (
6. Secure the Backing to the Densified Chitosan Matrix
The backing 14 is secured to the chitosan matrix 12 to form the antimicrobial barrier pad assembly 10 (see
7. Placement in the Pouch
The antimicrobial barrier pad assembly 10 can he subsequently packaged in the pouch 16 (see
8. Sterilization
After pouching, the processed antimicrobial barrier pad assembly 10 is desirably subjected to a sterilization step (see
D. Altering the Compliance Properties of a Hydrophilic Polymer Structure
Immediately prior to use, the antimicrobial barrier pad assembly 10 is removed from its pouch 16 (as shown in FIGS. 4 to 6). Due to its low moisture content, the antimicrobial barrier pad assembly 10, upon removed from the pouch 16, can seem to be relatively inflexible and may not immediately mate well with curved and irregular surfaces of the targeted injury site. Bending and/or molding of the pad assembly 10 prior to placement on the targeted injury site has been already described and recommended. The ability to shape the pad assembly 10 is especially important when attempting to control strong bleeding, since apposition of the pad assembly 10 immediately against an injured vessel is necessary to control severe bleeding. Generally, these bleeding vessels are deep within irregularly shaped wounds.
In hydrophilic polymer sponge structure, of which the pad assembly 10 is but one example, the more flexible and compliant the structure is, the more resistant it is to tearing and fragmentation as the structure is made to conform to the shape of the wound and achieve apposition of the sponge structure with the underlying irregular surface of the injury. Resistance to tearing and fragmentation is a benefit, as it maintains wound sealing and hemostatic efficacy. Compliance and flexibility provide an ability to load a hydrophilic polymer sponge structure (e.g., the pad assembly 10) against a deep or crevice shaped wound without cracking or significant pad assembly 10 dissolution.
Improved flexibility and compliance by the use of certain plasticizing agents in solution with the chitosan may be problematic, because certain plasticizers can change other structural attributes of the pad assembly 10. For example, chitosan glutamate and chitosan lactate are more compliant than chitosan acetate. However, glutamate and lactate chitosan acid salts rapidly dissolve in the presence of blood, while the chitosan acetate salt does not. Thus, improved compliance and flexibility can be offset by reduced robustness and longevity of resistance to dissolution.
Improved compliance and flexibility can be achieved by mechanical manipulation of any hydrophilic polymer sponge structure after manufacture, without loss of beneficial features of robustness and longevity of resistance to dissolution. Several ways in which such mechanical manipulation can be accomplished after manufacture will now be described. While the methodologies are described in the context of the chitosan matrix 12, it should be appreciated that the methodologies are broadly applicable for use with any form of hydrophilic polymer sponge structure, of which the chitosan matrix 12 is but one example.
1. Controlled Micro-Fracturing of a Hydrophilic Polymer Sponge Structure
Controlled micro-fracturing of the substructure of a hydrophilic polymer sponge structure such as the chitosan matrix 12 can be accomplished by systematic mechanical pre-conditioning of the dry pad assembly 10. This form of controlled mechanical pre-conditioning of the pad assembly 10 can achieve improved flexibility and compliance, without engendering gross failure of the pad assembly 10 at its time of use.
Desirably, as
The mechanical pre-conditioning described above is not limited to the pre-conditioning by digital probing and/or drawing over cylinders. The pre-conditioning may also include any technique which provides for mechanical change inside any hydrophilic polymer sponge structure resulting in enhanced sponge flexural modulus without significant loss of sponge hemostatic efficacy. Such pre-conditioning would include mechanical manipulations of any hydrophilic sponge structure including, but not limited to, mechanical manipulations by bending, twisting, rotating, vibrating, probing, compressing, extending, shaking and kneading.
2. Controlled Macro-Texturing of a Hydrophilic Polymer Sponge Structure
Controlled macro-texturing (by the formation of deep relief patterns) in a given hydrophilic polymer sponge structure can achieve improved flexibility and compliance, without engendering gross failure of the pad assembly 10 at its time of use. With regard to the chitosan matrix 12, the deep relief patterns can be formed either on the active surface of the chitosan matrix 12, or on the backing 14, or both sides.
As
The purpose of the patterns 52 is to enhance dry pad assembly compliance by reduction in flexural resistance orthogonal to the relief 52, so that the relief pattern acts much like a local hinge to allow enhanced flexure along its length.
It is preferred that this relief 52 is applied in the backing 14 of the pad assembly 10 and not in the chitosan matrix 12, whose role is to provide hemostasis by injury sealing and promoting local clot formation. Macro-textured deep relief patterns 52 in the base chitosan matrix 12 can provide for loss of sealing by providing channels for blood to escape through the chitosan matrix 12.
In order to mitigate this possibility, alternative relief patterns 52 of the type shown in
Mechanical flexure testing was carried out on a test pad assemblies (each 10 cm×10 cm×0.55 cm, with adherent backing 14—3M 1774T polyethylene foam medical tape 0.056 cm thick). One pad assembly 10 (Pad 1) comprised a chitosan matrix 12 having a predominantly vertical lamella structure (i.e., manufactured at a warmer relative freezing temperature, as described above). The other pad assembly 10 (Pad 2) comprised a chitosan matrix 12 having a predominantly horizontal, intermeshed lamella structure (i.e., manufactured at a colder relative freezing temperature, as described above).
Each Pad 1 and 2 was cut in half. Two halves (5 cm×10 cm×0.55 cm) of each compressed chitosan pads 1 and 2, were locally compressed at 80° C. to produce the relief pattern on the backing 14, in the form of
Three test pieces (10 cm×1.27 cm×0.55 cm) were cut from each half of the pad assembly 10 using a scalpel. These test pieces were subjected to three point flex testing. The test pieces had relief indentations 0.25 cm deep and 0.25 cm wide at the top surface. Each indentation was separated from its neighbor by 1.27 cm. Three point flex testing on an Instron uniaxial mechanical tester, model number 5844, with a 50 N load cell was performed to determine flexural modulus for the 0.55 cm thick test pieces with span 5.8 cm and crosshead speed of 0.235 cm/s. Flexural load was plotted against mid-point flexural displacement for the two pads 1 and 2 (treated and untreated) and are shown, respectively, in
The flexural testing demonstrates a significant improvement in flexibility with controlled macro-texturing of either type of the dry pad assembly 10.
3. Controlled Formation of Vertical Channels in a Hydrophilic Polymer Sponge Structure
A controlled introduction of blood into, and through the bulk of a given hydrophilic polymer sponge structure, of which the chitosan matrix 12 is but one example, is desirable for improved initial structural compliance and also for longevity of resistance to structure dissolution. Controlled formation of vertical channels into a given hydrophilic polymer sponge structure can achieve improved flexibility and compliance, without engendering gross failure of the structure at its time of use.
A controlled introduction of blood into, and through the bulk of a hydrophilic polymer sponge structure is desirable for improved initial compliance of the structure and also for longevity of resistance to dissolution of the structure. Improved absorption of blood into a hydrophilic polymer sponge structure can be accomplished by the introduction of vertical channels into the structure. Channel cross sectional area, channel depth and channel number density can be controlled to ensure an appropriate rate of blood absorption and distribution of blood absorption into the hydrophilic polymer sponge structure. With respect to the chitosan matrix 12, typically, a 200% increase in chitosan matrix 12 mass associated with blood absorption from 5 g to 15 g can cause a flexural modulus reduction of near 72%, from 7 MPa to 2 MPa. Also, controlled introduction of blood into the chitosan matrix 12 can result in a more cohesive matrix.
This improvement in the strength of a hydrophilic polymer matrix is a consequence of reaction of blood components, such as platelets and erythrocytes, with the same matrix. After introduction of blood into the sponge structure and allowance for time for the sponge structure and blood components to react to produce a blood and hydrophilic polymer sponge structure “amalgam,” the subsequent sponge structure is resistant to dissolution in body fluids and cannot be dissolved readily, especially in the case of a chitosan acid salt matrix, by the introduction of saline solution. Typically, prior to the reaction between blood and the hydrophilic polymer sponge structure, especially in the case of a chitosan acid salt matrix, the introduction of saline causes rapid swelling, gelling and dissolution of the hydrophilic polymer sponge structure.
Still, excessive introduction of blood into a given hydrophilic polymer sponge structure such as the chitosan matrix 12 can result in fluidized collapse. Therefore, mean channel cross-sectional area, mean channel depth and channel number density should be controlled to ensure that rate of blood absorption does not overwhelm the structure of the hydrophilic polymer sponge structure.
Controlled distribution of vertical channels in the hydrophilic polymer sponge structure can be achieved during the freezing step of the sponge structure preparation, or alternatively it may be achieved mechanically by perforation of the sponge structure during the compression (densification) step.
During the base nucleated freezing step, vertical channels can be introduced in the freezing solution by super-saturation of the same solution with residual gas. The same gas nucleates bubbles at the base of the solution in the mold as it begins to freeze. The bubbles rise through the solution during the freezing step leaving vertical channels. Sublimation of the ice around the channels during the lyophilization preserves the channels within the resultant sponge matrix.
Alternatively, channels may also be formed during the freezing step by the positioning of vertical rod elements in the base of the molds. Preferably the molds are formed from, but are not limited to, a metallic element such as iron, nickel, silver, copper, aluminum, aluminum alloy, titanium, titanium alloy, vanadium, molybdenum, gold, rhodium, palladium, platinum and/or combinations thereof. The metallic rod elements are preferably formed from, but not limited to, a metallic element such as iron, nickel, silver, copper, aluminum, aluminum alloy, titanium, titanium alloy, vanadium, molybdenum, gold, palladium, rhodium or platinum and/or combinations thereof. The molds may also be coated with thin, inert metallic coatings such as titanium, chromium, tungsten, vanadium, nickel, molybdenum, gold and platinum in order to ensure there is no reaction with the acid component of the chitosan solution and the chitosan salt matrix. Thermally insulating coatings or elements may be used in conjunction with the metallic molds and vertical rod elements to control heat transfer in the molds and in the vertical rod elements. Although metallic molds and vertical metallic rod elements are preferable, plastic molds and vertical plastic mold rod elements can be a convenient alternative for creating channels. An advantage of the metallic molds and their metallic rod elements combined with local placement of thermally insulating elements is that they also provide opportunity for improved control of heat flow and structure within the freezing sponge structure. This improvement in heat flow control results from large thermal conductivity differences between thermally conducting and thermally insulating elements in the mold and also the ability to create local thermal gradients within the bulk of the hydrophilic polymer sponge structure solution through the rod elements.
After lyophilization of the sponge structure, vertical channels can be introduced during the compression (densification) process. For example, as shown in
The intent of the perforations 62 is to allow local infiltration of blood at a slow controlled rate into and through the base of the hydrophilic polymer sponge structure. The purpose of this infiltration is first to allow for a more rapid flexural change in the matrix by plasticization of the dry sponge with blood. Secondly, it is intended to provide for a more uniform dispersion and mixing of blood through the matrix in order to stabilize the matrix to resist subsequent dissolution agents present within the body cavity. In the absence of the perforated base surface, it is seen after 1, 6, 16 and 31 minutes that blood only penetrates superficially into the sponge structure (<1.5 mm depth) while in the presence of the perforations that blood penetrates from 1.8 to 2.3 mm depth after 31 minutes. There is a resultant more rapid decrease in flexural modulus in the perforated matrix compared to a matrix without perforations.
II. Tissue Dressing Sheet Assembly
A. Overview
The size, shape, and configuration of the tissue dressing sheet assembly 64 can vary according to its intended use. The sheet assembly 64 can be rectilinear, elongated, square, round, oval, or composite or complex combinations thereof.
The tissue dressing sheet assembly 64 achieves rapid compliance of the hydrophilic polymer sponge structure in a bleeding field. The tissue dressing sheet assembly 64 is preferably thin (compared to the pad assembly 10), being in the range of between 0.5 mm to 1.5 mm in thickness. A preferred form of the thin reinforced structure of the sheet assembly 64 comprises a chitosan matrix 12 or sponge, at the typical chitosan matrix density of 0.10 to 0.20 g/cm3, reinforced by absorbable bandage webbing such as cotton gauze and the resultant bandage thickness is 1.5 mm or less.
The sheet assembly 64 can be prepared as a compact sheet form (e.g. 10 cm×10 cm×0.1 cm) for packaging in a multi-sheet flat form 70 (as
The sheet 66 can comprise woven and non-woven mesh materials, formed, e.g., from cellulose derived material such as gauze cotton mesh. Examples of preferred reinforcing materials include absorbent low-modulus meshes and/or porous films and/or porous sponges and/or weaves of synthetic and naturally occurring polymers. Synthetic biodegradable materials may include, but are not limited to, poly(glycolic acid), poly(lactic acid), poly(e-caprolactone), poly(β-hydroxybutyric acid), poly(β-hydroxyvaleric acid), polydioxanone, poly(ethylene oxide), poly(malic acid), poly(tartronic acid), polyphosphazene, polyhydroxybutyrate and the copolymers of the monomers used to synthesize the above-mentioned polymers. Naturally occurring polymers may include, but are not limited to, cellulose, chitin, algin, starch, dextran, collagen and albumen. Non-degradable synthetic reinforcing materials may include but are not limited to polyethylene, polyethylene copolymers, polypropylene, polypropylene copolymers, metallocene polymers, polyurethanes, polyvinylchloride polymers, polyesters and polyamides.
B. Use of the Tissue Dressing Sheet Assembly
The thin sheet assembly 64 possesses very good compliance and allows for excellent apposition of the hydrophilic polymer sponge structure (e.g., the chitosan matrix 12) immediately against the injury site. Also the reinforcement of the sheet enables the overall assembly to resist dissolution in a strong bleeding field. The sheet assembly 64 accommodates layering, compaction, and/or rolling—i.e., “stuffing” (as
C. Manufacture of the Tissue Dressing Sheet Assembly
A tissue dressing sheet assembly 64 (10 cm×10 cm×0.15 cm), with chitosan matrix 12 density near 0.15 gm/cm3, can be prepared by filling 11 cm×11 cm×2 cm deep aluminum mold with a two percent (2%) chitosan acetate solution (see
As
As
As
As
Flexural three point bend testing of a tissue dressing sheet assembly 64 was performed. The three point flexural testing was performed on an Instron uniaxial mechanical tester, model number 5844, with a 50 N load cell to determine flexural modulus test pieces with span 5.8 cm and crosshead speed of 0.235 cm/s. The results are shown in
Test pieces (5 cm×5 cm×0.15 cm) of the tissue dressing sheet assembly 64 were cut within ninety-six hours of their production. The sheet assembly 64 was not subjected gamma radiation sterilization before testing. The test pieces were soaked in citrated bovine whole blood for 10 seconds and immediately subjected to SAWS testing. During the test, three test pieces were layered together, presenting a composite chitosan density near 0.15 g/cm3. The result of this testing is shown in
As
Based upon experience with the pad assemblies, better adhesion/cohesion properties were expected to result after the tissue dressing sheet assembly 64 underwent gamma irradiation.
III. Further Indications and Configurations for Hydrophilic Polymer Sponge Structures
The foregoing disclosure has focused upon the use of the antimicrobial barrier pad assembly 10 and the tissue dressing sheet assembly 64 principally in the setting of stanching blood and/or fluid loss at a wound site. Other indications have been mentioned and certain of these and other additional indications now will be described in greater detail.
Of course, it should be appreciated by now that the remarkable technical features that a compressed hydrophilic polymeric sponge structure, of which the chitosan matrix is but one example, possesses can be incorporated into dressing structures of diverse shapes, sizes, and configurations, to serve a diverse number of different indications. As will be shown, the shapes, sizes, and configurations that a given compressed hydrophilic polymer sponge structure (e.g., the chitosan matrix 12) can take are not limited to the pad assembly 10 and sheet assembly 64 described, and can transform according to the demands of a particular indication. Several representative examples follow, which are not intended to be all inclusive of limiting.
B. Antimicrobial Barriers
In certain indications, the focus of treatment becomes the prevention of ingress of bacteria and/or microbes through a tissue region that has been compromised, either by injury or by the need to establish an access portal to an interior tissue region. Examples of the latter situation include, e.g., the installation of an indwelling catheter to accommodate peritoneal dialysis, or the connection of an external urine or colostomy bag, or to accomplish parenteral nutrition, or to connect a sampling or monitoring device; or after the creation of an incision to access an interior region of the body during, e.g., a tracheotomy, or a laparoscopic or endoscopic procedure, or the introduction of a catheter instrument into a blood vessel.
In
The carrier component 84 desirably includes an adhesive surface 86, to attach the anti-microbial component (desirably, the chitosan matrix 12) over the access site. In
In an alternative arrangement (see
In another alternative arrangement (see
The densified chitosan acetate matrix and diverse forms of dressings that can incorporate the densified chitosan acetate matrix have anti-microbial efficacy as demonstrated by in vitro testing, as summarized in Table 11.
The excellent adhesive and mechanical properties of the densified chitosan matrix 12 make it eminently suitable for use in anti-microbial applications on the extremity (epidermal use) and inside the body. Such applications would include short to medium term (0-120 hour) control of infection and bleeding at catheter lead entry/exit points, at entry/exit points of biomedical devices for sampling and delivering application, and at severe injury sites when patient is in shock and unable to receive definitive surgical assistance.
Further in vivo testing of the densified chitosan acetate matrix 12 was carried out and compared to similar dressings and treatments, specifically alginate dressing and Ag sulfadiazine. The testing was performed on male mice, strain BALB/c, approximately 6 weeks old and weighing approximately 20-25 grams. The lower portion of the mice were depilated and were anesthetized by injection of a 9:1 ratio of ketamine HCL to xylazine (100 mg/kg). Full thickness excisional wounds of desired size were cut down to, but not through, the panniculus carnosus.
The mice were infected with the Gram-negative species Pseudomonas aeruginosa [strain 19660] and Proteus mirabilis [strain 51393] that had been stably transduced with the entire bacterial lux operon to allow in vivo bioluminescence imaging. The strains were used for a bacterial culture, and 1 ml of the culture was used in 30-40 ml of sterile brain.heart infusion (BHI) media. The bacteria was grown to exponential growth phase for 2 hours in a 37° C. incubator with shaking. The O.D. of the bacterial suspension was measured against the BHI media and the desired suspension of bacteria was prepared accordingly.
Bioluminescence imaging was performed using a Hamamtsu CCD camera to detect the emitted light from wound infections of the mice.
The excisional wounds (5×5 mm) were inoculated with 50×106 cells. In order to be able to measure luminescence transmission through the dressing pad assembly 10, a controlled thickness (1.6-2.4 mm) of densified chitosan matrix 12 structure was excised from the base surface of the dressing (nominally 5.5 mm thick) for use in the study. The chitosan matrix 12 test pieces used in the study were 10 mm×10 mm×2.1 mm in dimension. Three controls were used in the study: a positive control of silver sulfadiazine; a negative control of alginate sponge (10 mm×10 mm×2.0 mm); and another negative control of no treatment. All treatments were applied within 15 to 30 minutes of inoculation of the wound with bacteria.
The densified chitosan matrix 12 sponge test pieces were first wetted with Na acetate buffer (pH 4) before application. They were adhesive and conformed very well to the injury. The alginate control was wetted with PBS solution prior to application. It too adhered well to the injury. The silver sulfadiazine cream (50 mg) was rubbed on the infected wound with a gloved finger. Animal survival was followed over 15 days with observations of bioluminescence emission and animal activity at regular intervals (8-16 hours). In the case of the densified chitosan matrix 12 group (N=5), all animals survived and showed significant survival advantage over alginate (P<0.01), over no treatment (P<0.005) and over silver sulfadiazine (P<0.005) (see
The data suggest that the densified chitosan matrix 12 rapidly kills bacteria in the wound before systemic invasion can take place, and is superior to alginate dressing and silver sulfadiazine that may both encourage bacterial growth in the short term. As shown in
The chitsoan matrix 12 adheres well to wound areas and has rapid anti-microbial action. The combination of the anti-microbial and hemostatic qualities provides a superior wound dressing over the prior art, which is advantageous in early first aid treatment, such as in a combat, battlefield, or triage situation.
It has been demonstrated that a hydrophilic polymer sponge structure like the chitosan matrix 12 can be readily adapted for association with dressings or platforms of various sizes and configurations—in pad form, in sheet form, in composite form, in laminated form, in compliant form—such that a person of ordinary skill in the medical and/or surgical arts could adopt any hydrophilic polymer sponge structure like the chitosan matrix 12 to diverse indications on, in, or throughout the body.
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.
This application is a continuation-in-part of U.S. 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”, which is a continuation-in-part of U.S. patent application Ser. No. 10/743,052, filed on Dec. 23, 2003, entitled “Wound Dressing and Method of Controlling Severe Life-Threatening Bleeding,” which is a continuation-in-part of U.S. patent application Ser. No. 10/480,827, filed on Oct. 6, 2004, 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 claims the benefit of provisional patent application Ser. No. 60/298,773, filed Jun. 14, 2001, which are each incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60298773 | Jun 2001 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11020365 | Dec 2004 | US |
| Child | 11202558 | Aug 2005 | US |
| Parent | 10743052 | Dec 2003 | US |
| Child | 11020365 | Dec 2004 | US |
| Parent | 10480827 | Oct 2004 | US |
| Child | 10743052 | Dec 2003 | US |
