Patent Grant
9004918
The invention is generally directed to compositions, assemblies, and methods applied during or after a dental procedure to ameliorate bleeding, fluid seepage or weeping, or other forms of fluid loss, as well as promote healing and to limit secondary problems associated with the dental procedures.
The crown of the tooth is exposed above the gum. A hard shiny outer surface, called the enamel, covers the crown. Below the enamel is dentin, which is microscopically porous hard tissue. At the center of the tooth is the pulp chamber, which houses the pulp consisting of blood vessels and nerve tissues.
A tooth may become damaged, or decayed, e.g., due to erosion of the calcium in the tooth's enamel by bacteria. This, in turn, can lead to erosion of the dentin beneath the enamel. As the decay continues, bacteria can migrate through the porous dentin and infect the pulp. An immune response to the infection can follow, causing the blood vessels around the tooth to enlarge and press against the nerves entering the tooth. The result is tooth ache.
There are various dental procedures for intervening when these or other conditions affecting the oral cavity and its anatomic structures arise. These procedures are routinely performed by dentists including general practitioners, oral and maxillofacial surgeons, endodontists and periodontists.
For example, endodontic therapy, also called root canal therapy, can, under many circumstances, intervene to remove the bacteria, nerve tissue, organic debris, and bacterial toxins from within the inner aspects of a decaying tooth. Following this, the practitioner fills in and seals off the interior of the tooth. Currently, there are about 16 million root canals performed annually in the USA.
If the decay has progressed too far, removal or extraction of the tooth may be indicated. Currently, there are more than 30 million extractions performed each year in the USA. During a simple extraction, a dentist will grasp the tooth with an instrument, e.g., forceps, and rock the tooth back and forth. This rocking motion loosens the tooth from the alveolar bone by breaking the periodontal ligaments that hold the tooth in place. The tooth is then extracted from the socket, leaving the tooth socket open.
Removal or extraction of the tooth may also be indicated when the presence of the tooth is causing crowding, or malocclusion, or preventing another tooth (e.g., a wisdom tooth) from erupting, or in preparation for orthodontic treatment (“braces”). A tooth extraction may also be indicated because of advanced periodontal (gum) disease. Sometimes, if the tooth selected for extraction is not fully erupted above the gum, it may be necessary to first remove some of the overlying gum and bone tissue in order to access the tooth for extraction.
During and after such conventional dental procedures—e.g., endodontic surgery, or periodontal surgery, orthodontic treatment, tooth extractions, orthognathic surgery, biopsies, and other oral surgery procedures—bleeding, fluid seepage or weeping, or other forms of fluid loss typically occur. Bleeding, fluid seepage or weeping, or other forms of fluid loss can also occur in the oral cavity as a result of injury or trauma to tissue and structures in the oral cavity. In this regard, there are about two million teeth lost each year due to accidents. Swelling and residual bleeding can be typically expected to persist during the healing period following the procedure or injury. During the healing period, new gum tissue will grown into the gap left by the extraction.
It is thereby desirable during the healing period to take steps to stanch, seal, and/or stabilize the site of surgical intervention—or the site of tissue injury or trauma—against fluid loss due to bleeding, fluid seepage or weeping. During and after dental procedures or injury to the oral cavity, there is a need for quick and effective hemostasis.
For example, following a tooth extraction, the quick cessation of bleeding and the formation of a blood clot on the wound in the open tooth socket are very desirable. Indeed, during the entire healing period following an extraction—which can take from one to six weeks—it is important to preserve conditions conducive to hemostasis, so that the blood clot that forms within the socket does not break down and/or dislodge. If the clot breaks down and/or dislodges, a condition known as a dry socket (also called alveolar osteitis) results. Dry socket conditions can also occur for the same reason during the treatment of cystic cavity defects in the jaw. Dry socket can cause pain and discomfort, which will subside only as the socket heals through a secondary healing process.
Conventionally, cotton packs and rolled or folded cotton gauze pads are commonly used to stem the bleeding precipitated during and after dental procedures. While the presence of such materials may absorb blood and fluids, they do not promote or create conditions conducive to rapid and long term hemostasis or healing. There still remains a need for improved hemostatic compositions, assemblies, and methods that can be applied during or after dental procedures.
Along with damage to the tooth itself, there may also be damage to the gums and gingival material surrounding the tooth or teeth. For example, people may have problems associated with inadequate amounts of gingival material surrounding a tooth or teeth. If there is inadequate attached gingiva, spontaneous recession of the gum and bone will occur over time. Typically the normal attached gingiva has been worn away with improper brushing, although some people are born with very little attached gingiva.
Surgeries are performed on these areas to provide added gingiva to the area, typically by adding a gingival graft from another area located in the person's mouth. These procedures are frequently performed, yet they are also some of the most sensitive surgical wounds that must be managed by periodontists. Post operative pain, recurrent bleeding, delayed secondary healing, associated with these types of wounds and the open nature of these wounds all contribute to the problematic post operative issues associated with these types of wounds. Treatment generally has been done using protective stents and/or periodontal dressings placed over the wound area, but these treatments do not necessarily promote hemostasis and secondary healing for the wound site as effectively as desired. Consequently, there has been a long felt need for processes and assemblies that can be used to promote hemostasis, enhance blood clot stability after surgery and shorten healing times.
The invention provides assemblies, systems and methods for treating tissue or bone in an oral cavity or an adjacent anatomic structure, comprising the placement of a hydrophilic polymer sponge structure.
An aspect of the invention contemplates systems and methods that can be used in conjunction with stents and periodontal dressings to promote hemostasis and secondary healing in gingival surgery, such as surgery utilizing free gingival graft palatal donor sites. The systems and methods utilize hydrophilic polymer sponge structures that will be placed within the area that will receive the gingival graft material.
One aspect of the invention provides a hydrophilic polymer sponge structure that is shaped, sized, and configured for placement in association with tissue or bone in an oral cavity or an adjacent anatomic structure, as well as a method for placing the hydrophilic polymer sponge structure in association with the tissue or bone in the oral cavity or the adjacent anatomic structure.
Another aspect of the invention includes systems and methods for performing a dental surgical procedure, which can comprise, e.g., a tooth extraction; or endodontic surgery; or periodontal surgery; or orthodontic treatment; or orthognathic surgery; or a biopsy; or gingival surgery; or osseous surgery; or scaling or root planning; or periodontal maintenance; or complete maxillary or mandibular denture; or complete or partial denture adjustment; or denture rebase or reline; or soft tissue surgical extraction; or bony surgical extraction; or installation of an occlusal orthotic device or occlusal guard or occlusal adjustment; or oral surgery involving jaw repair; treatment of cystic cavity defects in the jaw; or new bone growth or bone growth promotion; or any other surgical procedure or intervention affecting tissue in the oral cavity, anatomic structures in the oral cavity, or alveolar (jaw) bone, or treatment of any acute or chronic oral trauma or condition. According to this aspect of the invention, the systems and methods place a hydrophilic polymer sponge structure in association with tissue or bone affected by the surgical procedure.
Another aspect of the invention provides systems and methods for treating tissue in the oral cavity or alveolar (jaw) bone as a result of an accident that causes injury or trauma to the tissue or bone. According to this aspect of the invention, the systems and methods place a hydrophilic polymer sponge structure in association with the treated tissue or bone.
The assemblies, systems and methods that make use of the hydrophilic polymer sponge structure stanch, seal, or stabilize a site of tissue or bone injury, tissue or bone trauma, or tissue or bone surgery. The use of hydrophilic polymer sponge structure can also form an anti-microbial or anti-viral barrier; and/or promote coagulation; and/or release a therapeutic agent; and/or treat a periodontal or bone surface; and/or combinations thereof.
In accordance with all aspects of the invention, the hydrophilic polymer sponge structure desirably includes a chitosan biomaterial which has been densified by compression prior to use to a density of between 0.6 to 0.1 g/cm3.
Other features and advantages of the invention shall be apparent based upon the accompanying description, drawings, and claims.
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.
The present invention provides a dental pad assembly 10 (see
The dental pad assembly 10 comprises a tissue dressing matrix 12. The tissue dressing matrix 12 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 and/or anti-viral characteristics, and/or characteristics that accelerate or otherwise enhance coagulation, soft tissue healing and the body's defensive reaction to injury. The dressing matrix 12 will be described in further detail, below.
Below are two examples of possible dental procedures where the dental assembly 10 can be used to promote healing and minimize post-surgical issues related to the dental procedures.
In
Once in place, the dental assembly 10 will be placed with the opening 116 over the graft 114.
As
The pouch 16 is configured to be peeled opened by the caregiver at the instant of use. The pouch 16 provides peel away access to the tissue dressing pad assembly 10 along one end. The opposing edges of the pouch 16 are grasped and pulled apart to expose the tissue dressing pad assembly 10 for use.
Once removed from the pouch 16 (see
After the dental assembly 10 is in place over the graft 114, a periodontal dressing 122 (
It should be understood that either arrangement of
As
Desirably, as
The site treated by the pad assembly 10 can involve arterial and/or venous bleeding caused by a surgical instrument or trauma or injury; or by the placement during surgery or a dental procedure of a wire, staples, fasteners, or sutures; or caused accidentally by a laceration, or a wound, or a puncture, or a burn, or a bone fracture, or crush injury. The dental pad assembly 10 can be sized and configured to be inserted or placed in association with any type of tissue disruption, trauma, or injury in the oral cavity or on or in proximity to adjacent anatomic structures.
Regardless of the cause, the properties of the matrix 12 of the pad assembly 10 serve to moderate bleeding, fluid seepage or weeping, or other forms of fluid loss, while also promoting healing.
Due to the properties of the matrix 12, the dental pad assembly 10 can also desirably form an anti-bacterial and/or anti-microbial and/or anti-viral protective barrier at or surrounding the tissue treatment site in an oral cavity.
Due to the special properties of the chitosan matrix 12, the dental pad assembly 10 also may be indicated for use with individuals undergoing dental procedures or suffering tissue trauma in the oral cavity, who have various types of bleeding or coagulation disorders, such as hemophilia, or idiopathic thrombocytopenic purpura (ITP) (which can itself lead to bleeding gums). The presence of the chitosan matrix 12 attracts red blood cell membranes, which fuse to chitosan matrix 12 upon contact. A clot can be formed very quickly and does not need the clotting proteins that are normally required for coagulation. Even in individuals without bleeding or coagulation disorders, the presence of the chitosan matrix 12 can accelerate the clotting process independent of the clotting cascade. For this reason, the matrix 12 can be used with no loss of efficacy in conjunction with anticoagulants/blood thinners such as heparin, clopidogrel bisulfate (PLAVIX®), acetylsalicylic acid, dipyridamole, etc.
The dental pad assembly 10, when used during or after a dental procedure or accidental trauma in the oral cavity, can also provide a topically applied platform for the delivery of one or more therapeutic agents into the blood stream in a controlled release fashion. The therapeutic agents can be incorporated into the hydrophilic polymer sponge structure, e.g., either before or after the freezing step, and before the drying and densification steps, as will be described later. Examples of therapeutic agents that can be incorporated into a hydrophilic polymer sponge structure (e.g., the chitosan matrix 12) include, but are not limited to, drugs or medications, stem cells, antibodies, anti-microbials, anti-virals, collagens, genes, DNA, and other therapeutic agents; hemostatic agents like fibrin; growth factors; Bone Morphogenic Protein (BMP); peptides; STAMPS; DNA vaccines and similar compounds.
The beneficial properties of chitosan matrix 12 includes adherence to mucosal surfaces within the body, such as those lining the mouth. This feature makes possible the incorporation of the chitosan matrix 12 in systems and devices directed to treating mucosal surfaces where the adhesive sealing characteristics, and/or accelerated clotting attributes, and/or anti-bacterial/anti-viral features of the chitosan matrix 12, as described, provide advantages. Such systems and methods can include the gum repairs and sealing about sutures placed in the oral cavity.
The chitosan matrix 12 of the pad assembly 10 does more than soak up blood as a clot forms within the socket. The adhesive strength of the chitosan matrix 12 causes it to adhere to tissue within the socket, so that mechanical properties of the pad assembly 10 apply direct pressure. Further, the presence of the chitosan matrix 12 attracts red blood cell membranes, which fuse to chitosan matrix 12 upon contact. A clot can be formed very quickly and does not depend solely upon the clotting proteins that are normally required for coagulation. The presence of the chitosan matrix 12 can accelerate the clotting process independent of the clotting cascade. Also further, the presence of the chitosan matrix 12 can provide an anti-bacterial and/or anti-microbial and/or anti-viral protective effect. Hemostasis occurs in about one minute using the chitosan matrix 12 in dental applications, compared to about seven minutes using conventional cotton packs and rolled or folded gauze pads.
The dental pad assembly 10 can be torn or cut on site to match the size of the extraction site, as previously described. Smaller, patch pieces of a pad assembly 10 can also be cut to size on site, and fitted and adhered in other pieces already placed to best approximate the topology and morphology of the treatment site.
Desirably, the dental pad assembly 10 is allowed to reside within the socket during the healing process for the prevention of pain and the promotion of rapid healing. The presence of chitosan matrix 12 within the socket provides an environment conducive to retention of the clot (thereby avoiding dry socket) as well as the general healing process, during which new bone and gum tissue grow into the gap left by the extraction. The physical presence of the chitosan matrix 12—which, desirably, is purposely densified during its manufacture to resist dissolution—acts as a bone covering obtundant and physiologic scaffolding for the conduction of normal alveolar bone heal process of fibroblast ingrowth, blood vessel formation, and reossification of the extraction site. The enhanced physical properties of the densified chitosan matrix 12 further enhanced by the adhesive strength of the chitosan matrix 12, its self-promotion of coagulation, and its anti-bacterial/anti-microbial/anti-viral properties.
As previously described, the pad assembly 10 can incorporate a medication or physiologic or pharmacologic agent that acts locally or systemically in the body, e.g., enzymes, organic catalysts, ribozymes, organometallics, proteins, glycoproteins, peptides, polyamino acids, antibodies, nucleic acids, steroidal molecules, antibiotics, antimycotics, cytokines, growth factors for tissue and/or bone, carbohydrates, oleophobics, lipids, extracellular matrix and/or individual components, mammalian cells, stem cells, genetically engineered cells, pharmaceuticals, peptides, STAMPS, DNA vaccines and therapeutics. The pad assembly 10 provides a physically stable, biocompatible, and non-cytotoxic environment promoting a rapid and pain-free recovery period.
Desirably, the pad assembly 10 is removed and, if indicated, replaced within forty-eight hours of application. The pad assembly 10 can be peeled away and will generally separate from the treatment site in a single, intact dressing. In some cases, residual chitosan gel may remain, and this can be removed using a saline or water wash, with gentle abrasion using a gauze dressing or irrigation syringe, if required.
Chitosan is biodegradable within the body and is broken down into glucosamine, a benign substance. Still, efforts should be made to remove all portions of chitosan from the wound at the time of definitive repair.
The tissue dressing matrix 12 desirably comprises 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.
Due to the special properties of the chitosan matrix 12, the dental pad assembly 10 is capable of adhering to tissue within the socket in the presence of blood, or body fluids, or moisture. The presence of the dental pad assembly 10 stanches, seals, and/or stabilizes the extraction site, while establishing conditions conducive to the formation and maintenance of a blood clot at the wound during the healing process.
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. As previously described, the tissue dressing matrix 12 may comprise a hydrophilic polymer form, which, in a preferred form, comprises a non-mammalian material 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 sponge 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.
Example 1 demonstrates the efficacy of a dental pad assembly as described above in free gingival procedures. The dressing assembly 10 was assessed for effectiveness of managing post-surgical sequelae, ease of handling; and comparing the dressing assembly 10 performance in oral surgery and periodontal surgery procedures. The primary objectives was to evaluate the effectiveness of using a 1″×3″ dressing pad assembly 10 for hemostasis and soft tissue healing response of maxillary donor sites during and after periodontal free gingival graft surgical procedures. The dressing pad assemblies 10 can be torn or cut to a desired size, as described, above, with respect to the description of the use of a dental pad assembly, or could be manufactured for the desired size.
Patients were used who required free gingival grafts or connective tissue grafts. The patients were required to return for a 7-day post-operative visit and had a willingness and availability to provide informed consent. Patient that were excluded from the study included patients that had scheduled dental or surgical procedure other than noted in inclusion criteria; required procedures involving primary closure of the dressing assembly 10 within the surgical wound; and inability to provide informed consent. The study was reviewed by an Investigational Review Board prior to the study, and was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2000.
The following potentially confounding variables of individual patients were considered if they were significant: prothrombin or other laboratory tests in patients taking blood thinning medication; age and gender; hypertension (defined as a systolic blood pressure greater than 140 mm mercury); patients who smoked or used tobacco products; patients taking birth control pills; and patients taking bisphosphonate therapies.
Example 1 was conducted as a 2-site, externally controlled study involving one or more periodontal surgery sites per patient. During each surgical procedure, the dressing assembly 10 was cut to size (based on each subject's individual wound size) within the sterile field using sterile scissors, and placed on the oral surgical wound without the use of sutures. The custom trimmed dressing assembly 10 was initially stabilized with either finger pressure or by using a clean dry surgical instrument so that the dressing did not adhere to the instrument. It should be noted that a clean dry surgical instrument is needed, so that the dressing assembly 10 will not adhere to the instrument when being inserted. The time to hemostasis was noted.
The wound was either covered with a standard periodontal dressing 54, as shown in
If a periodontal dressing was used, it was placed in such a manner to assure that the dressing assembly 10 was exposed to oral fluids and remained in place until the 7-day postoperative visit. Those patients using a vented or non-vented surgical stent were instructed to remove the stent 48 hours after surgery for cleaning, and then replace the stent to protect the surgical wound until the 7-day post operative appointment.
Surgical wounds were evaluated for time to hemostasis, immediate soft tissue response, post-surgery inflammation, pain, and 7-day healing response. If hemostasis was not achieved in 60 seconds, the surgeon observed the surgical site at designated intervals until hemostasis was achieved. The dressing assembly 10 was allowed to remain in place without sutures for a maximum of 7-days post surgery. If available, the number of days that a dressing remained on the wound (based on dressing exposure and tongue activity) was noted. Any remaining residual dressing material was removed by water irrigation at the 7-day post surgery follow-up visit. At the conclusion of the study, ease of handling and use by the practitioner during the surgical procedure was noted.
Digital pictures were taken immediately following the surgical procedure for all control and surgical sites, and again at the 7-day post-operative visit.
After all post-surgical follow-up visits were completed and photographs taken, an independent panel of nine (9) specially trained periodontists and general dentists evaluated the surgical site photographs for healing. The panelists were blinded to the treatment protocol used and whether the patient was a study subject or control. Three criteria were evaluated: pain, inflammation, and progression of healing. Wounds were graded from 0 (poor) to 5 (normal) to 10 (best). A pictorial evaluation guide was provided to each panelist to minimize evaluation variability.
Patient demographics are summarized in Table 1. 33 females and 15 males between the ages of 8 to 76 years of age (median age 49.5) were chosen for the study. Eight patients discontinued aspirin therapy 5 days prior to the surgery. One patient was under aspirin therapy at the time of the surgery. Twenty-five patients were treated using the dressing assembly 10 dressing covered with a periodontal dressing (with 9 controls); 7 were treated using the dressing assembly 10 and a solid stent (with 6 controls), and 4 were treated using the dressing assembly 10 dressing and a perforated stent (with no controls). One patient had two procedures.
Results
Hemostasis:
The dressing assembly 10 had a 1.5 minute average hemostasis time, which was a statistically significantly faster time than the control for both periodontal dressing and surgical stents. The dressing assembly 10 hemostasis time (p=0.0147) would have been even shorter except for the inclusion of a 9.4 minute dressing assembly 10 hemostasis time for one patient who suffered a possible bleeding event involving the greater palatine artery that was controlled using the dressing assembly 10 without suturing but had prolonged minor oozing. Control bleeding time averaged 3.2 minutes.
Inflammation:
Inflammation scores were reduced (p=0.1120) in patients treated with the dressing assembly 10 compared to control. Inflammation scores for those patients treated with dressing assembly 10 and periodontal dressing or perforated stents had minimal, if any, post operative inflammation.
Pain
Pain scores were reduced for patients treated with dressing assembly 10 (p=0.0993) compared to control. dressing assembly 10 patients treated with periodontal dressing experienced a 67% reduction in pain score compared to control patients.
Soft Tissue Healing
Soft tissue healing was statistically significantly improved for all patients treated with the dental assembly 10 compared to control patients (p<0.0001). Patients treated with the dental assembly using periodontal dressing (p=0.0029) and periodontal stent patients (p=0.0037) all healed statistically significantly better than surgical control patients.
Free gingival graft palatal donor sites are among the most common surgical wounds produced in periodontal surgery and most heal by secondary intent. Many hemostatic agents have been used to treat these surgical wounds including those that are porcine, bovine or human based materials that all have cultural, religious, biologic and allergic problems associated with their use and which are eliminated using the dressing assembly 10. Further, use of the dressing assembly 10 decreased pain scores (p=0.1120) and inflammation (p=0.0993) for the patients compared to control patients. Hemostasis (p=0.0147) and soft tissue healing (p<0.0001) times were statistically significantly reduced, as well. The dressing assembly 10 is also shown to be bacteriostatic, thereby limiting the growth of bacteria.
A desirable methodology for making the tissue dressing pad assembly 10 will now be described. This methodology is shown schematically in
A. Preparation of a Chitosan Solution
The chitosan used to prepare the chitosan solution (designated CS in
The chitosan solution CS 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 (see
The structure or form producing steps for the chitosan matrix 12 are typically carried out from solution and can be 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 be formed into a non-woven sponge-like mesh by non-woven spinning processes. Alternately, the filament may be 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.
B. 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.
C. Freezing the Aqueous Chitosan Solution
Next (see
Freezing of the chitosan solution in this way (forming a frozen chitosan solution, designed FCS in
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 be 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.
D. Freeze Drying the Chitosan/Ice Matrix
The frozen chitosan/ice matrix (FCS) 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 FCS 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.
E. 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 not ideal in stanching bleeding, since it may rapidly dissolve in blood and possess poor mechanical properties. The chitosan biomaterial is therefore desirably 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. 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. (
F. Placement in the Pouch
The tissue dressing pad assembly 10 can be subsequently packaged in the pouch 16 (see
G. Sterilization
After pouching, the processed tissue dressing pad assembly 10 is desirably subjected to a sterilization step (see
H. Improving Compliance and Flexibility
Bending and/or molding of the pad assembly 10 prior to placement on the targeted treatment of injury site has been already described and recommended. In hydrophilic polymer sponge structures, 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 targeted treatment site and achieve apposition of the sponge structure with the underlying (typically) irregular surface of the injury. Resistance to tearing and fragmentation is a benefit, as it maintains wound sealing and hemostatic efficacy. Improved compliance and flexibility can be achieved by mechanical manipulation of any hydrophilic polymer sponge structure during or after manufacture, without loss of beneficial features of robustness and longevity of resistance to dissolution.
There are several ways in which such mechanical manipulation can be accomplished during or after manufacture; for example, (i) by controlled micro-fracturing of the substructure of a hydrophilic polymer sponge structure by rolling, bending, twisting, rotating, vibrating, probing, compressing, extending, shaking and kneading; (ii) controlled macro-texturing (by the formation of deep relief patterns) in a given hydrophilic polymer sponge structure by thermal compression techniques at 80° C.; and (iii) by controlled formation of vertical channels into a given hydrophilic polymer sponge structure 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.
Further details of mechanical manipulations that can be performed to improve compliance and flexibility are shown in co-pending U.S. patent application Ser. No. 11/020,365, filed Dec. 23, 2004, and entitled “Tissue Dressing Assemblies, Systems, and Methods Formed From Hydrophilic Polymer Sponge Structures Such as Chitosan,” which is incorporated herein by reference.
The dental pad assembly 10 can be provided in various alternative forms.
For example, as shown in
Further details of the sheet assembly 64 can be founding in co-pending U.S. patent application Ser. No. 11/020,365, filed Dec. 23, 2004, and entitled “Tissue Dressing Assemblies, Systems, and Methods Formed From Hydrophilic Polymer Sponge Structures Such as Chitosan,” which is incorporated herein by reference.
The dental assembly of the present invention can also provide a topically applied platform for the delivery of one or more therapeutic agents into the blood stream in a controlled release fashion. The therapeutic agents can be incorporated into the hydrophilic polymer sponge structure, e.g., either before or after the freezing step, and before the drying and densification steps, as will be described later. Examples of therapeutic agents that can be incorporated into a hydrophilic polymer sponge structure (e.g., the chitosan matrix 12) include, but are not limited to, drugs or medications, stem cells, antibodies, anti-microbials, anti-virals, collagens, genes, DNA, and other therapeutic agents; hemostatic agents like fibrin; growth factors; Bone Morphogenic Protein (BMP); peptides; STAMPS; DNA vaccines and similar compounds.
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 association with dental procedures or trauma involving the oral cavity—in pad form, in sheet form, or in otherwise compliant form. The dental assembly 10 of the present invention also provides improved hemostasis and healing capabilities at free gingival graft palatal donor sites.
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 of application Ser. No. 12/592,124 filed on Nov. 19, 2009, now abandoned, which is a continuation-in-part of U.S. patent application Ser. No. 11/261,351, filed on Oct. 28, 2005, issued as U.S. Pat. No. 7,897,832, which is a continuation-in-part of U.S. application Ser. No. 10/743,052, filed on Dec. 23, 2003, issued as U.S. Pat. No. 7,371,403, which is a continuation-in-part of U.S. patent application Ser. No. 10/480,827 filed Oct. 6, 2004, filed as International Application No. PCT/US02/18757 on Jun. 14, 2002, issued as U.S. Pat. No. 7,482,503, which claims the benefit of provisional patent application Ser. No. 60/298,773 filed Jun. 14, 2001. Each of these applications is incorporated herein by reference.
| Number | Name | Date | Kind |
|---|---|---|---|
| 2610625 | Sifferd et al. | Sep 1952 | A |
| 2858830 | Robins | Nov 1958 | A |
| 2923664 | Cook et al. | Feb 1960 | A |
| 3551556 | Kliment et al. | Dec 1970 | A |
| 3632754 | Balassa | Jan 1972 | A |
| 3800792 | McKnight et al. | Apr 1974 | A |
| 3801675 | Russell | Apr 1974 | A |
| 3849238 | Gould et al. | Nov 1974 | A |
| 3902497 | Casey | Sep 1975 | A |
| 3911116 | Balassa | Oct 1975 | A |
| 3954493 | Battista et al. | May 1976 | A |
| 3977406 | Roth | Aug 1976 | A |
| 4040884 | Roth | Aug 1977 | A |
| 4056103 | Kaczmarzyk et al. | Nov 1977 | A |
| 4068757 | Casey | Jan 1978 | A |
| 4094743 | Leuba | Jun 1978 | A |
| 4195175 | Peniston et al. | Mar 1980 | A |
| 4292972 | Pawelchak et al. | Oct 1981 | A |
| 4373519 | Errede et al. | Feb 1983 | A |
| 4394373 | Malette et al. | Jul 1983 | A |
| 4452785 | Malette et al. | Jun 1984 | A |
| 4460642 | Errede et al. | Jul 1984 | A |
| 4501835 | Berke | Feb 1985 | A |
| 4524064 | Nambu | Jun 1985 | A |
| 4532134 | Malette et al. | Jul 1985 | A |
| 4533326 | Anthony | Aug 1985 | A |
| 4541426 | Webster | Sep 1985 | A |
| 4599209 | Dautzenberg et al. | Jul 1986 | A |
| 4651725 | Kifune et al. | Mar 1987 | A |
| 4684370 | Barrett | Aug 1987 | A |
| 4699135 | Motosugi et al. | Oct 1987 | A |
| 4759348 | Cawood | Jul 1988 | A |
| 4772419 | Malson et al. | Sep 1988 | A |
| 4833237 | Kawamura et al. | May 1989 | A |
| 4948540 | Nigam | Aug 1990 | A |
| 4952618 | Olsen | Aug 1990 | A |
| 4956350 | Mosbey | Sep 1990 | A |
| 4958011 | Bade | Sep 1990 | A |
| 4960413 | Sagar et al. | Oct 1990 | A |
| 4973493 | Guire | Nov 1990 | A |
| 4977892 | Ewall | Dec 1990 | A |
| 5006071 | Carter | Apr 1991 | A |
| 5024841 | Chu et al. | Jun 1991 | A |
| 5035893 | Shioya et al. | Jul 1991 | A |
| 5062418 | Dyer et al. | Nov 1991 | A |
| 5110604 | Chu et al. | May 1992 | A |
| 5116824 | Miyata et al. | May 1992 | A |
| 5154928 | Andrews | Oct 1992 | A |
| 5206028 | Li | Apr 1993 | A |
| 5252275 | Sultze et al. | Oct 1993 | A |
| 5254301 | Sessions et al. | Oct 1993 | A |
| 5300494 | Brode, II et al. | Apr 1994 | A |
| 5376376 | Li | Dec 1994 | A |
| 5378472 | Muzzarelli | Jan 1995 | A |
| 5420197 | Lorenz et al. | May 1995 | A |
| 5454719 | Hamblen | Oct 1995 | A |
| 5525710 | Unger et al. | Jun 1996 | A |
| 5571181 | Li | Nov 1996 | A |
| 5597581 | Kaessmann et al. | Jan 1997 | A |
| 5643596 | Pruss et al. | Jul 1997 | A |
| 5700476 | Rosenthal et al. | Dec 1997 | A |
| 5738860 | Schønfeldt et al. | Apr 1998 | A |
| 5756111 | Yoshikawa et al. | May 1998 | A |
| 5797960 | Stevens et al. | Aug 1998 | A |
| 5821271 | Roenigk | Oct 1998 | A |
| 5827265 | Glinsky et al. | Oct 1998 | A |
| 5836970 | Pandit | Nov 1998 | A |
| 5840777 | Eagles et al. | Nov 1998 | A |
| 5858292 | Dragoo et al. | Jan 1999 | A |
| 5858350 | Vournakis et al. | Jan 1999 | A |
| 5952618 | Deslauriers | Sep 1999 | A |
| 5961478 | Timmermans | Oct 1999 | A |
| 6042877 | Lyon et al. | Mar 2000 | A |
| 6054122 | MacPhee et al. | Apr 2000 | A |
| 6103369 | Lucast et al. | Aug 2000 | A |
| 6124273 | Drohan et al. | Sep 2000 | A |
| 6156330 | Tsukada et al. | Dec 2000 | A |
| 6162241 | Coury et al. | Dec 2000 | A |
| 6225521 | Gueret | May 2001 | B1 |
| 6270515 | Linden et al. | Aug 2001 | B1 |
| 6406712 | Rolf | Jun 2002 | B1 |
| 6448462 | Groitzsch et al. | Sep 2002 | B2 |
| 6454787 | Maddalo et al. | Sep 2002 | B1 |
| 6485667 | Tan | Nov 2002 | B1 |
| 6486285 | Fujita | Nov 2002 | B2 |
| 6548569 | Williams et al. | Apr 2003 | B1 |
| 6552244 | Jacques et al. | Apr 2003 | B1 |
| 6565878 | Schoenfeldt et al. | May 2003 | B2 |
| 6566577 | Addison et al. | May 2003 | B1 |
| 6599891 | North et al. | Jul 2003 | B2 |
| 6693180 | Lee et al. | Feb 2004 | B2 |
| 6726712 | Raeder-Devens et al. | Apr 2004 | B1 |
| 6855860 | Ruszczak et al. | Feb 2005 | B2 |
| 6863924 | Ranganathan et al. | Mar 2005 | B2 |
| 6864245 | Vournakis et al. | Mar 2005 | B2 |
| 6992233 | Drake et al. | Jan 2006 | B2 |
| 7019191 | Looney et al. | Mar 2006 | B2 |
| 7371403 | McCarthy et al. | May 2008 | B2 |
| 7402172 | Chin et al. | Jul 2008 | B2 |
| 7546812 | Eastin et al. | Jun 2009 | B2 |
| 7637934 | Mangiardi et al. | Dec 2009 | B2 |
| 7671102 | Gaserod et al. | Mar 2010 | B2 |
| 7820872 | Gregory et al. | Oct 2010 | B2 |
| 7850709 | Cummins et al. | Dec 2010 | B2 |
| 7897832 | McAdams et al. | Mar 2011 | B2 |
| 8063265 | Beck et al. | Nov 2011 | B2 |
| 20010045177 | Harvey et al. | Nov 2001 | A1 |
| 20020071855 | Sadozai et al. | Jun 2002 | A1 |
| 20020161376 | Barry et al. | Oct 2002 | A1 |
| 20040243043 | McCarthy et al. | Dec 2004 | A1 |
| 20050036955 | DeGould | Feb 2005 | A1 |
| 20050038369 | Gregory et al. | Feb 2005 | A1 |
| 20050123581 | Ringeisen et al. | Jun 2005 | A1 |
| 20050137512 | Campbell et al. | Jun 2005 | A1 |
| 20050147656 | McCarthy et al. | Jul 2005 | A1 |
| 20050240137 | Zhu et al. | Oct 2005 | A1 |
| 20060004314 | McCarthy et al. | Jan 2006 | A1 |
| 20060008419 | Hissink et al. | Jan 2006 | A1 |
| 20060083710 | Joerger et al. | Apr 2006 | A1 |
| 20060184224 | Angel | Aug 2006 | A1 |
| 20060211973 | Gregory et al. | Sep 2006 | A1 |
| 20070021703 | McCarthy | Jan 2007 | A1 |
| 20070066920 | Hopman et al. | Mar 2007 | A1 |
| 20070083137 | Hopman et al. | Apr 2007 | A1 |
| 20070237811 | Scherr | Oct 2007 | A1 |
| 20070255194 | Gudnason et al. | Nov 2007 | A1 |
| 20070255243 | Kaun et al. | Nov 2007 | A1 |
| 20070276308 | Huey et al. | Nov 2007 | A1 |
| 20080132990 | Richardson | Jun 2008 | A1 |
| 20080147019 | Song et al. | Jun 2008 | A1 |
| 20080241229 | Li et al. | Oct 2008 | A1 |
| Number | Date | Country |
|---|---|---|
| 0353972 | Feb 1990 | EP |
| 0477979 | Sep 1991 | EP |
| 0643963 | Apr 1994 | EP |
| 1462123 | Sep 2004 | EP |
| 60-142927 | Jul 1985 | JP |
| 62-039506 | Feb 1987 | JP |
| 60-090507 | Apr 1988 | JP |
| 63-090507 | Apr 1988 | JP |
| 07-116241 | May 1995 | JP |
| 11-342153 | Dec 1999 | JP |
| 2002-233542 | Aug 2002 | JP |
| WO 9505794 | Mar 1995 | WO |
| WO 9902587 | Jan 1999 | WO |
| WO 0056256 | Sep 2000 | WO |
| WO 02102276 | Dec 2002 | WO |
| WO 03047643 | Jun 2003 | WO |
| WO 03079946 | Oct 2003 | WO |
| WO 03092756 | Nov 2003 | WO |
| WO 03101310 | Dec 2003 | WO |
| WO 2004047695 | Jun 2004 | WO |
| WO 2004060412 | Jul 2004 | WO |
| WO 2005062880 | Jul 2005 | WO |
| WO 2006049463 | May 2006 | WO |
| WO 2006071649 | Jul 2006 | WO |
| WO 2007009050 | Jan 2007 | WO |
| WO 2007056066 | May 2007 | WO |
| WO 2007074327 | Jul 2007 | WO |
| WO 2008033462 | Mar 2008 | WO |
| WO 2008036225 | Mar 2008 | WO |
| Entry |
|---|
| Park et al., Platelet derived growth factor releasing chitosan sponge for periodontal bone regeneration, Biomaterials 21 (2000) 153-159. |
| Allan et al,, “Biomedical Applications of Chitin and Chitosan.” Chitin, Chitosan, and Related Enzymes—Accademic Press, Inc.: 119-133, 1984. |
| Anema et al., “Poental Uses of Absobable Fibrin Adhesive Bandage for Genitourinary Trauma.” World Journal of Surgery, vol. 25: 1573-1577, 2001. |
| Bégin et al., “Antimicrobial films produced from chitosan.” International Journal of Biological Macromolecules, vol. 26: 63-67, 1999. |
| Belman et al,, “From the Battlefield to the Street,” Per declaration submitted in U.S. Appl. No. 10/480,827, dated Dec. 17, 2007, poster presentation was made at the ATACCC Conference, Aug. 2006. |
| CNN Transcript—3pp., Jun. 8, 2006. |
| HemCon Manufacturing Materials. Per declaration submitted in U.S. Appl. No. 10/480,827, dated Dec. 17, 2007, materials were submitted as supporting evidence for declaration. |
| Horesh et al., “Pre-hospital use of the HemCon bandage,” Per declaration submitted in U.S. Appl. No. 10/480,827, dated Dec. 17, 2007, poster presentation was made at the WCDEM Conference, May 2007. |
| Kiley, Kevin, “Department of the Army memo.” Jul. 20, 2005. |
| Kumar, Ravi, “Chitin and chitosan fibres: A review.” Bulletin of Material Science: vol. 22, No, 5: 905-915, Aug. 1999. |
| Luo et al., “The role of poly(ethylene glycol) in the formation of silver nanoparticles.” Journal of Colloid and Interface Science, vol. 288: 444-448, 2005. |
| Martin et al., “Medical application of poly-4-hydroxybutyrate: a strong flexible absorbable biomaterial.” Biochemical Engineering Journal, vol. 16: 97-105, 2003. |
| Moody, Robin J., “HemCon bandage stakes claim to soldier's kit bag.” Portland Business Journal, Nov. 4, 2005. |
| Ohshima et al., “Clinical Application of Chitin Non-Woven Fabric as Wound Dressing.” European Journal of Plastic Surgery, vol. 10: 66-69, 1987. |
| Oshima et al., “Clinical application of new chitin non-woven fabric and new chitin sponge sheet as wound dressing.” European Journal of Plastic Surgery, vol. 14: 207-211, 1991. |
| Percot et al., “Optimization of Chitin Extraction from Shrimp Shells.” Biomacromolecules, vol. 4: 12-18, 2003. |
| Pusateri et al., “Advanced Hemostatic Dressing Development Program: Animal Model Selection Criteria and Results of a Study of Nine Hemostatic Dressings in a Model of Severe Large Venous Hemorrhage and Hepatic Injury in Swine.” The Journal of Trauma, vol. 55: 518-526, 2003. |
| Sandford, Paul A., “Chitosan: Commercial Uses and Potential Applications.” Chitin and Chitosan: Proceedings from the 4th International Conference on Chitin and Chitosan, 51-69, 1988. |
| Sandford, Paul A., “Biomedical Applications of New Forms of Chitin/Chitosan.” Chitin Derivatives in Life Science, 12pp., 1992. |
| Siekman, Philip, “A Shrimp Bandage?” Fortune Small Business, pp. 67-68, 2006. |
| Sondeen et al., “Comparison of 10 Different Hemostatic Dressings in an Aortic Injury.” The Journal of Trauma, vol. 54, No. 2: 280-285, 2003. |
| Wedmore et al ., “A Special Report on the Chitosan-based Hemostatic Dressing: Experience in Current Combat Operations.” The Journal of Trauma, vol. 60: 655-658, 2006. |
| Wilson, J,R., “The Army's Greatest Inventions.” U.S. Army Materiel Command, pp. 30-37, 2005. |
| Fwu-Long Mi et al., “Fabrication and characterization of a sponge-like asymmetric chitosan membrane as a wound dressing.” Biomaterials 22 pp. 165-173 (2001), Elsevier Science Ltd., London and New York. |
| Michele W. Chan et al., “Comparison of Poly-N-acetyl Glucosamine (P-GlcNAc) with Absorbable Collagen (Actifoam), and Fibrin Sealant (Bolheal) for Achieving Hemostatis in a Swine Model of Splenic Hemorrhage.”The Journal of Trauma 48(3) pp. 454-458 (2000) Lippincott Williams & Wilkins, Inc. U.S.A. |
| Paul A. Sanford et al., “Biomedical Applicants of High-Purity Chitosan,” ACS Symposium Series 467 pp. 430-445 (1991) American Chemical Society, Washington D.C. |
| William G. Malette et al., “Chitosan: A New Hemostatic,” The Annals of Thoracic Surgery 36(1) pp. 55-58 (1983). |
| Roger Olsen et al., “Biomedical Applicants of Chitin and Its Derivatives,” Chitin and Chitosan pp. 813-829 (1988) Elsevier Applied Science, London and New York. |
| David J. Cole et al., “A pilot study evaluating the efficacy of a fully acetylated ply-N-acetyl glucosamine membrane formulation as a topical hemostatic agent,” Surgery 126(3) pp. 510-517 (1999) Mosby, Inc. U.S.A. |
| Bendix., “Chemical synthesis of polyactide and its copolymers for medical applications.” Polymer Degradation and Stability, vol. 59: 129-135, 1998. |
| Schoof et al., “Control of Pore Structure and Size in Freeze-Dried Collagen Sponges.” Journal of Biomedical Material Research, vol. 58: 352-357, 2001. |
| Wu et al., “Development of In Vitro Adhesion Test for Chitosan Bandages.” Society for Biomaterials 30th Annual Meeting Transactions, 2005, 1 pg. |
| Database WPI, Week 200873 Thomson Scientific, London GB, AN 2008-M34232, XP002695569 & CN 101138648, Mar. 12, 2008. |
| Number | Date | Country | |
|---|---|---|---|
| 20110143312 A1 | Jun 2011 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60298773 | Jun 2001 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12592124 | Nov 2009 | US |
| Child | 12804010 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11261351 | Oct 2005 | US |
| Child | 12592124 | US | |
| Parent | 10743052 | Dec 2003 | US |
| Child | 11261351 | US | |
| Parent | 10480827 | US | |
| Child | 10743052 | US |
