WO2015013106A1 - Compositions de pâte osseuse et méthodes d'utilisation associés - Google Patents

Compositions de pâte osseuse et méthodes d'utilisation associés Download PDF

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Publication number
WO2015013106A1
WO2015013106A1 PCT/US2014/047058 US2014047058W WO2015013106A1 WO 2015013106 A1 WO2015013106 A1 WO 2015013106A1 US 2014047058 W US2014047058 W US 2014047058W WO 2015013106 A1 WO2015013106 A1 WO 2015013106A1
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composition
bone
nanoparticles
agent
bone paste
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PCT/US2014/047058
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English (en)
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Charles R. Bridges
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Bridges Charles R
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Publication of WO2015013106A1 publication Critical patent/WO2015013106A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
    • A61L24/0094—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing macromolecular fillers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/102—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/104—Gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/624—Nanocapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/12—Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the presently disclosed invention relates generally to thrombogenic bone paste compositions including a matrix material, at least one of an antibiotic or growth factor, and a hemostatic agent.
  • Hemostasis is attained during surgeries by different procedures depending on the anatomical situation. In a number of surgeries in the region of the skull and,
  • bone wax is used to seal the capillary vessels and thus to achieve hemostasis, because of the strong bleeding that occurs in these locations due to the anatomical situation.
  • the bone wax is first kneaded by the surgeon to soften the bone wax.
  • the softened bone wax is then pressed directly onto and/or into the bleeding bone areas. This approach blocks the flow of blood, which causes hematomas to arise and the supply vessels to ultimately become closed by fibrin.
  • Bone wax has been known since the 19th century and generally contains bleached bees wax and a plasticizer. Substances including almond oil, Vaseline, palmitic acid, isopropyl ester, and myristic acid isopropyl ester, can be used as plasticizer.
  • a thrombogenic bone paste composition that can simultaneously provide a mechanical barrier to blood loss, an antibiotic action to prevent infection, and a consistency (e.g., kneadable and/or malleable at body temperature) that enables conformation and adherence to cut bone surfaces and holes in bones.
  • thrombogenic bone paste compositions including a matrix material that provides a platform for clot formation of blood, a plurality of nanoparticles comprising at least one antibiotic agent to prevent infections and/or at least one growth factor, and at least one hemostatic agent to facilitate blood clot formation.
  • the hemostatic agent is an active hemostatic agent such as one or more thrombins.
  • the present invention provides methods of decreasing bleeding from a bone that has been cut, broken, or punctured, such as due to an accident or a surgical procedure.
  • a thrombogenic bone paste composition as disclosed herein can be applied onto one or more cut/broken surfaces of the bone or filled within the holes formed in the bone.
  • the step of applying the thrombogenic bone paste composition comprises filling any holes or crevices imparted to the bone during a surgical procedure or due to an accident.
  • the thrombogenic bone paste composition can be densely packed into the crevices and holes in one application or over the course of a series of applications.
  • embodiments of the present invention are directed to present invention provide thrombogenic bone paste compositions including a matrix material that provides a platform for clot formation of blood, a plurality of nanoparticles comprising at least one antibiotic agent to prevent infections and/or at least one growth factor, and at least one hemostatic agent to facilitate blood clot formation.
  • the hemostatic agent is an active hemostatic agent such as one or more thrombins.
  • compositions according to embodiments of the present invention are preferably kneadable and/or malleable at room (e.g., about 68°F) or body temperature (e.g., about 98.6°F).
  • the compositions are kneadable and/or malleable from about 60°F to about 105°F (e.g. 60-100°F).
  • embodiments of the present invention can be continually molded, deformed, or shaped by hand before, during, or after application of the composition onto cuts or within
  • the thrombogenic bone paste compositions can both readily conform to the contours of the cuts and/or holes while simultaneously having enough consistency to remain in the place of application or deposition (e.g., the composition preferably does not leak or ooze out of or from the spots of application).
  • certain embodiments of the present invention comprise a viscosity that is large enough such that the composition can withstand the pressure associated with bleeding from the bone. That is, bleeding from the bone tissue will generally not dislodge or displace the bone paste composition from the site of application.
  • thrombogenic bone paste compositions can beneficially provide a mechanical barrier to bleeding while also providing an antibiotic effect that remains in place over the course of a surgical procedure and until sufficient clot formation has prevented the risk of further bleeding.
  • the bone paste composition according to certain embodiments can both prevent bone bleeding and prevent infection at the location of interest (e.g., cut/broken/punctured bone surfaces)
  • thrombogenic bone paste compositions can comprise a matrix material.
  • the matrix material can provide a material network or platform for blood clot formation, while a hemostatic agent can actively induce thrombosis.
  • a hemostatic agent can actively induce thrombosis.
  • the matrix material need not necessarily be limited, certain preferred matrix materials include collagen or derivatives thereof.
  • Collagen comprises a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of vertebrates.
  • collagen is the main component of connective tissue, and is the most abundant protein in mammals.
  • Collagen in the form of elongated fibrils, is mostly found in fibrous tissues such as tendon, ligament and skin, and is also abundant in cornea, cartilage, bone, blood vessels, the gut, and intervertebral disc.
  • the use of collagen or a derivative thereof as a matrix material according to certain embodiments of the present invention should be safely accepted by the patient's body.
  • the matrix material can comprise a gelatin powder.
  • Gelatin is derived from collagen and has been used as a gelling agent in food, pharmaceuticals, photography, and cosmetic applications.
  • gelatin comprises a mixture of peptides and proteins produced by partial hydrolysis of collagen extracted from mammals. When water is added to gelatin, it can form a semi-solid colloid gel.
  • gelatin gels typically exist over only a small temperature range with the upper limit being the melting point of the gel (e.g., typically slightly less than 35°C) and the lower limit the freezing point at which ice crystallizes.
  • the matrix materials e.g., collagens and derivatives thereof
  • the partially swollen particles of the matrix material can restrict blood flow and provide a stable matrix around which a clot can form.
  • the matrix materials can include platelet rich plasma (PRP), also sometimes referenced as autologous platelet gel, as a component.
  • PRP platelet rich plasma
  • PRP is blood plasma that has been enriched with platelets (e.g., 3-5 times more than native blood). That is, PRP can comprise an increased concentration of autologous platelets suspended in a small amount of plasma after centrifugation.
  • patient or third party's blood e.g., whole blood
  • PRP platelet poor plasma
  • red blood cells red blood cells.
  • the separation of the blood into these three (3) layers can be performed well in advance of, immediately prior to, or during a procedure according to embodiments of the present invention.
  • two (2) spins are utilized to provide a desired level of separation.
  • a first spin e.g., a "hard spin” separates the platelet poor plasma (PPP) from the red fraction and platelet rich plasma (PRP).
  • a second spin e.g., a "soft spin” separates the red fraction from the PRP.
  • the PRP material has the highest specific gravity and will be deposited at the bottom of the tube.
  • PRP contains several different growth factors and other cytokines that stimulate healing of bone tissue and/or enhance bone regeneration.
  • the platelets collected in PRP can be activated by the addition of thrombin, calcium chloride, and/or collagen, which induces the release of these factors from alpha granules.
  • the growth factors and other cytokines present in PRP include: platelet-derived growth factor; transforming growth factor beta; fibroblast growth factor; insulin-like growth factor 1 ; insulin-like growth factor 2; vascular endothelial growth factor; epidermal growth factor; Interleukin 8; keratinocyte growth factor; and connective tissue growth factor.
  • the activation of the platelets collected in the PRP can be carried out prior to or during the addition of the PRP to the collagen or derivatives thereof (e.g., gelatin) or other components (e.g., thrombin).
  • the platelet activator/agonist thrombin, collagen, and/or calcium chloride
  • the platelet activator/agonist is added to activate the platelets to facilitate formation of a platelet gel.
  • concentration of the matrix material in the thrombogenic bone paste compositions can comprise a wide range concentrations depending, for example, on the final intended purpose of the composition. In certain embodiments, however, the thrombogenic bone paste compositions can comprise a matrix material in an amount of about at least any of the following: 20, 30, 40, 50, 60, 70, 80, and 90% and/or at most about any of the following 99, 95, 90, 80, 70 and 60% by weight of the thrombogenic bone paste compositions.
  • the matrix material in the thrombogenic bone paste compositions can comprise PRP.
  • the matrix material e.g., collagen plus PRP
  • the matrix material can comprise PRP in an amount of about at least any of the following: 1 , 10, 20, 30, 40, and 50% and/or at most about any of the following 99, 90, 80, 70 and 60% by weight of the matrix material (e.g., 1-20%, 10-60%, 40-70%, etc... of PRP by weight of the matrix material).
  • certain embodiments of the present invention can include a plurality of nanoparticles comprising at least one antibiotic agent.
  • the incorporation of a plurality of nanoparticles comprising at least one antibiotic agent can beneficially enable compositions according to certain embodiment of the present invention to provide immediate, localized, controlled release and/or sustained release of the antibiotic agent at or to the area of interest (e.g., cut or broken bone surfaces).
  • the nanoparticles encapsulate the antibiotic agent while other embodiments the antibiotic agent can be embedded in (e.g., including the surface of the nanoparticles and throughout the interior of the nanoparticles) the nanoparticles.
  • the delivery of the antibiotic agent can be customized according to the needs of an individual patient's need. Customization of the compositions can be achieved, for instance, by varying the entrapped (e.g., encapsulated) and/or embedded (e.g., a solid-solid mixture) antibiotic agents and their respective concentrations. Moreover, a combination of different nanoparticles (e.g., sizes and materials) can be used in a single bone paste composition. For instance, a combination of different types of nanoparticles in a bone paste
  • the composition can provide a tailorable controlled release of antibiotic agents, and the desired efficacy.
  • the nanoparticles incorporated into bone paste compositions comprise biomaterials that are already proven to be safe in many FDA approved drug delivery systems.
  • Prolonged and controlled release of antibiotic agents can be controlled by manipulating the properties and sizes of nanoparticles utilized for housing the antibiotic agents.
  • a single type or a combination of different types of nanoparticles can be used for the delivery of the antibiotic agents, including but not limited to micelles, inverse micelles, liposomes and a variety of known polymeric nanoparticles.
  • Each type of such nanoparticles for example, can have a different half-life for drug release and a different particle size.
  • Typical micelles have a hydrophobic core and a hydrophilic surface allowing the encapsulation of hydrophobic molecules in an aqueous solution.
  • Inverse (or reverse) micelles, with a hydrophilic core can be produced via a micro-emulsion method.
  • micro-emulsions two immiscible phases (water and ⁇ ) are present with a surfactant, the surfactant molecules can form a monolayer at the interface between the oil and water, with the hydrophobic tails of the surfactant molecules dissolved in the oil phase and the hydrophilic head groups in the aqueous phase.
  • the binary systems As in the binary systems
  • water/surfactant or oil/surfactant self-assembled structures of different types can be formed, ranging, for example, from (inverted) spherical and cylindrical micelles to lamellar phases and bicontinuous micro-emulsions, which may coexist with predominantly oil or aqueous phases.
  • This type of micelle for example, is particularly useful in encapsulating hydrophilic molecules.
  • Liposomes comprise colloidal lipid bilayer vesicles ranging from a few nanometers to several micrometers in diameter. They can safely entrap hydrophilic molecules in the core, and hydrophobic molecules in the lipid bilayer in an aqueous solution. Liposomes can be composed of naturally-derived phospholipids with mixed lipid chains (like egg phosphatidylethanolamine), or of pure surfactant components like DOPE
  • Liposomes that contain low (or high) pH can be constructed such that dissolved aqueous drugs (e.g., antibiotic agent) will be charged in solution (i.e., the pH is outside the drug's pH range). As the pH naturally neutralizes within the liposome (protons can pass through some membranes), the drug (e.g. , antibiotic agent) will also be neutralized, allowing it to freely pass through a membrane. These liposomes work to deliver drugs by diffusion rather than by direct cell fusion. Another strategy for liposome drug delivery is to target endocytosis events. Liposomes can be made in a particular size range that makes them viable targets for natural macrophage phagocytosis. These liposomes may be digested while in the macrophage's phagosome, thus releasing its drug. Liposomes can also be decorated with opsonins and ligands to activate endocytosis in other cell types.
  • drugs e.g., antibiotic agent
  • Polymeric nanoparticles may be prepared using a variety of polymers.
  • the polymeric nanoparticles are comprised of a biodegradable polymer.
  • exemplary biodegradable polymer that can be used according to certain embodiments of the present invention can include (but not limited to) poly (lactic-co-glycolic acid) (PLGA),
  • PCL polycaprolactone
  • PGA polyglycolide
  • PLA polylactic acid
  • PHB poly-3- hydroxybutyrate
  • PBS poly(alkyl cyanoacrylates
  • the bone paste compositions comprise PGLA nanoparticles containing one or more antibiotic agents.
  • PLGA is a copolymer synthesized by means of random ring-opening co- polymerization of two different monomers, the cyclic dimers (1 ,4-dioxane-2,5-diones) of glycolic acid and lactic acid.
  • Formula (1 ) sets for the general structure for PGLA:
  • x is the number of units of lactic acid and y is the number of units of glycolic acid.
  • y is the number of units of glycolic acid.
  • PLGA Depending on the ratio of lactide to glycolide used for the polymerization, different forms of PLGA can be obtained adding to the tailorable nature of the nanoparticles comprised of PLGA.
  • the different forms of PLGA are routinely identified by the monomers' ratio used (e.g. PLGA 75:25 identifies a copolymer whose composition is 75% lactic acid and 25% glycolic acid).
  • the ratio of lactic acid to glycolic acid can be varied to manipulate the degradation time (e.g., rate of delivery of the antibiotic agents) of the PLGA.
  • PLGA degrades by hydrolysis of its ester linkages in the presence of water and it has been shown that the time required for degradation of PLGA is related to the monomers' ratio used in production. In general, the higher the content of glycolide units, the lower the time required for degradation (e.g., complete delivery of the antibiotic agents will occur over a shorter time period). As such, a longer duration of delivery (e.g., delivery of the antibiotic agent slowly over a given period of time) can be achieved by simply utilizing a PLGA with a lower content of glycolide units relative to lactide units. In addition, PLGAs can optionally be end-capped with esters (as opposed to the free carboxylic acid) to provide a longer degradation half-life.
  • the PLGAs utilized can comprise a broad range of lactide to glycolide ratios.
  • bone paste compositions can comprise a plurality of PLGA nanoparticles comprising a lactide to glycolide ratio of at least any of the following: 5:95; 10:90; 15:85; 20:80; 25:75; 35:65: and 40:60 and/or at most about any of the following 50:50; 60; 40; 70; 30; and 80; 20.
  • the delivery of the antibiotic agents can be controlled such that the bone paste compositions can provide a controlled and/or sustained release of the antibiotic agent over a predetermined duration of time.
  • the time duration of delivery to the antibiotic agent e.g., the duration of time from application until all of the antibiotic agent has been released from the nanoparticles
  • the time duration of delivery to the antibiotic agent can comprise from at least any of the following: 1 hour, 3 hours, 8 hours, 24 hours, 3 days, 5 days, 7 days, and 10 days and/or at most about any of the following: 2 months, 1 month, 3 weeks, 2 weeks, and 1 week.
  • predetermined time duration is sufficient to provide a therapeutically effective amount of the antibiotic agent over the bulk (preferably the entire time duration) of the time duration of the sustained release.
  • therapeutically effective amount can comprise an amount sufficient to mitigate or eliminate the development of an infection at the location of interest (e.g., cut/broken bone surfaces to which the bone paste composition has been applied).
  • emulsification reverse salting-out and nano-precipitation. These methods generally include two main steps: (i) to prepare an emulsified system and (ii) to form nanoparticles.
  • To encapsulate lipophilic and hydrophilic reagents two types of preparation methods were commonly used. Oil in water (O/W) emulsification was used to load lipophilic drugs. Water in oil in water (W/O/W) double emulsification was used to load hydrophilic drugs.
  • the controlled and/or sustained release of antibiotic agents can be accomplished, at least in part, by manipulating the type and sizes of the nanoparticles of different properties.
  • the bone paste compositions can comprise a combination of unilamellar and multilamellar liposomes or micelles entrapping antibiotic agents. Having both types of liposomes can allow for better control of release rate.
  • the antibiotic clindamycin is hydrophilic, and therefore may be encapsulated in inverse micelles and liposomes.
  • Inverse micelles are generally smaller, tighter, and more stable than liposomes.
  • the controlled release of encapsulated antibiotics over time can be achieved.
  • the different release times of nanoparticles allows for sustained delivery of antibiotic agent over time.
  • a combination of the different types of nanoparticles e.g., liposomes, polymeric-based, etc.
  • can be just one way to provide a sustained release of one or more antimicrobial agents however, a sustained release can also be achieved by using a combination of different polymeric nanoparticles (for example) or a combination of different forms of PLGA (for example).
  • embodiments of the present invention can be easily customized according to the needs of each patient by, for example, varying the antibiotic agent(s), and the mixture (or using only a single type) of nanoparticles in the composition.
  • the nanoparticles can all be formed from the same material if so desired.
  • the size of the nanoparticles can comprise from at least any of the following: 50, 100, 200, 300, 400, and 500 nm and/or at most about any of the following: 1000, 900, 800, 700, 600, and 550 nm.
  • the plurality of nanoparticles can generally fall within one or more of the aforementioned ranges.
  • a first group of nanoparticles could have a range from 200 to 400 nm while a second group of nanoparticles can have a different range such as 500 to 800 nm.
  • the plurality of nanoparticles can comprise one or more groups having respective (or possibly somewhat overlapping) particle size distributions. Such an approach can be employed to further tailor a particular bone paste composition for a specific application.
  • certain embodiments of the present invention can include one or more antibiotic agents encapsulated and/or embedded with one or more types of nanoparticles to prevent the occurrence of an infection.
  • the presence of an antibiotic agent beneficially allows effective local infection protection to be realized via application of the thrombogenic bone paste compositions to sites of bones that have been cut or punctured (e.g., holes).
  • many traditional bone waxes or pastes are devoid of any antibacterial activity.
  • suitable antibiotic agents can include aminoglycoside antibiotics, glycopeptide antibiotics, lincosamide antibiotics, and peptide antibiotics.
  • the antibiotic agent comprises a glycopeptide antibiotic.
  • exemplary glycopeptide antibiotic in accordance with certain embodiments of the present invention can comprise vancomycin (Vancocin), linezolid (Zyvox), daptomycin (Cubicin), quinupristin-dalfopristin (Synercid), teicoplanin (Targocid), or combinations thereof.
  • the antibiotic agent can include (but not limited to) silver ion, Imipenem, rifampicin, chloramphenicol, novobiocin, spectinomycin, trimethoprim, erythromycin, doxycycline, minocycline, vancomycin, acyclovir,
  • amphotericin B gentamicin, gentamicin sulfate, tobramycin, ampicillin, penicillin, ethambutol, clindamycin, and cephalosporins including cefazolin, ceftriaxone, cefotaxime, and combinations thereof.
  • concentration of the antibiotic agent in the thrombogenic bone paste compositions can comprise a wide range of concentrations. In certain embodiments, however, the thrombogenic bone paste compositions can comprise one or more antibiotic agents in an amount of about at least any of the following: 0.1 , 1 , 3, 5, 10, 20, and 30% and/or at most about any of the following 60, 50, 40, 30, 25 and 20 % by weight of the thrombogenic bone paste compositions.
  • the thrombogenic bone paste compositions according to certain embodiments of the present invention can also comprise one or more hemostatic agents (e.g., topical hemostatic agents).
  • the one or more hemostatic agents comprise a topical hemostatic agent(s).
  • a topical hemostatic agent is preferable since it can be applied directly to the bleeding site (e.g., cut or punctured bone surface) and can prevent or mitigate continuous unrelenting bleeding throughout a procedure and into the post-operative recovery period.
  • incorporation of one or more hemostatic agents into the thrombogenic bone paste compositions can significantly reduce blood loss in patients undergoing a variety of procedures.
  • the hemostatic agent can comprise an active hemostatic agent, passive hemostatic agent, or a combination thereof.
  • the thrombogenic bone paste compositions include at least an active hemostatic agent (e.g., thrombin).
  • Passive hemostatic agents act passively through contact activation and promotion of platelet aggregation.
  • Passive hemostatic agents can include collagens, celluloses (e.g., cellulose-based agents including regenerated oxidized cellulose), and gelatins. In this regard, these passive hemostatic agents can double as a matrix material for facilitating blood clot formation. Passive hemostatic agents, however, do not actively cause thrombosis. Accordingly, preferred embodiments include at least one active hemostatic agent.
  • Active hemostatic agents' exhibit biological activity and can directly participate at the end of the coagulation cascade to induce a clot at the site of bleeding.
  • Preferred active hemostatic agents according to embodiments of the present invention can comprise thrombin.
  • the hemostatic agent comprises recombinant human thrombin.
  • Thrombin-JMI® thrombin, Topical, Bovine Origin, USP
  • EvithromTM thrombin, topical [Human]
  • RecothromTM thrombin, topical [Recombinant]
  • Certain preferred embodiments of the present invention utilize RecothromTM (thrombin, topical [Recombinant]) from ZymoGenetics®, Inc.
  • the one or more hemostatic agents can comprise one or more antifibrinolytic agents.
  • Antifibrinolytic agents are typically lysine- like compounds that interfere with the formation of the fibrinolytic enzyme plasmin from its precursor plasminogen by plasminogen activators (primarily t-PA and u-PA). As such, these drugs block the binding sites of the enzymes or plasminogen respectively and thus stop plasmin formation.
  • Plasmin is the enzyme responsible for fibrinolysis (the process that prevents blood clots from growing in which fibrin -the protein that forms the framework of blood clots - is degraded).
  • Suitable antifibrinolytic agents can include aminocaprioc acid (Amicar®), tranexamic acid (Cyklokapron®), and aprotinin (Trasylol®).
  • the at least one antifibrinolytic agent comprises aminocaprioc acid (also known as Amicar®, ⁇ - aminocaproic acid, ⁇ - ⁇ , or 6-aminohexanoic acid).
  • Aminocaprioc acid has the following structure:
  • aminocaproic acid or another antifibrinolytic agent or suitable lysine analog
  • incorporation of aminocaproic acid (or another antifibrinolytic agent or suitable lysine analog) into the thrombogenic bone paste compositions can facilitate the prevention or mitigation of continuous bleeding throughout a procedure and into the post-operative recovery period.
  • the at least one antifibrinolytic agent comprises tranexamic acid (trans-4- (aminomethyl)cyclohexanecarboxylic acid), which is a synthetic derivative of the amino acid lysine.
  • Tranexamic acid has the following structure:
  • Incorporation of the hemostatic agents, particularly the active hemostatic agents, into the thrombogenic bone paste compositions according to certain embodiments of the present invention improves blood conservation by reducing blood loss.
  • the use of thrombin is particularly desirable as thrombin acts at the end of the clotting cascade. As such, the thrombin is less likely to be susceptible to coagulopathies caused by clotting factor deficiencies or platelet malfunction.
  • concentration of the hemostatic agent in the thrombogenic bone paste compositions can comprise a wide range of concentrations. In certain embodiments, however, the thrombogenic bone paste compositions can comprise one or more hemostatic agents in an amount of about at least any of the following: 0.1 , 1 , 3, 5, 10, 20, and 30% and/or at most about any of the following 60, 50, 40, 30, 25 and 20 % by weight of the
  • thrombogenic bone paste compositions can include one or more growth factors.
  • the one or more growth factors can be generally provided within the paste or incorporated on or within a plurality of nanoparticles.
  • the thrombogenic bone paste compositions comprise a plurality of nanoparticles comprising one or more growth factors.
  • nanoparticles including one or more growth factors. That is, the nanoparticles comprising one or more growth factors can provide a controlled and/or sustained release of the one or more growth factors using a variety of differing types of nanoparticles as discussed above. Such embodiments can beneficially provide localized delivery of the one or more growth factors.
  • the nanoparticles encapsulate the one or more growth factors while other embodiments the one or more growth factors can be embedded in (e.g., including the surface of the nanoparticles and throughout the interior of the nanoparticles) the nanoparticles.
  • the delivery of the one or more growth factors can be customized according to the needs of an individual patient's need. Customization of the compositions can be achieved, for instance, by varying the entrapped (e.g., encapsulated) and/or embedded (e.g., a solid-solid mixture) the one or more growth factors and their respective concentrations. Moreover, a combination of different nanoparticles (e.g., sizes and materials) can be used in a single bone paste composition. For instance, a combination of different types of nanoparticles in a bone paste composition can provide a taiiorable controlled release of the one or more growth factors, and the desired efficacy. In certain preferred embodiments, the nanoparticles incorporated into bone paste compositions comprise biomaterials that are already proven to be safe in many FDA approved drug delivery systems.
  • Prolonged (sustained) and controlled release of one or more growth factors can be controlled by manipulating the properties and sizes of nanoparticles utilized for housing the one or more growth factors.
  • a single type or a combination of different types of nanoparticles can be used for the delivery of the one or more growth factors, including but not limited to micelles, inverse micelles, liposomes and a variety of known polymeric nanoparticles.
  • Each type of such nanoparticles for example, can have a different half-life for drug release and a different particle size.
  • Exemplary types of nanoparticles have previously been discussed with respect to the at least one antibiotic agent and each of these types are suitable for delivery of one or more growth factors. As such, a discussion of each is not reproduced under this section.
  • the thrombogenic bone paste compositions can include nanoparticles comprising both one or more antibiotic agents and one or more growth factors.
  • the thrombogenic bone paste compositions can include a first group of nanoparticles comprising one or more antibiotic agents and a second group of nanoparticles comprising one or more growth factors.
  • the delivery profile (e.g., percentage release of an agent over a given time period) of the one or more antibiotic agents can be different than the delivery profile of one or more growth factors if desired. For a particular indication, for instance, it can be more beneficial to deliver a greater dosage or percentage of the one or more antibiotic agents in a quicker or shorter duration of time as compared to the delivery of the one or more growth factors (or vice versa).
  • PLGA nanoparticles can be formulated by manipulating the lactide to glycolide ratio to selectively control the release of the agent (e.g., antibiotic agent or growth factor) carried therein/thereon.
  • the agent e.g., antibiotic agent or growth factor
  • the thrombogenic bone paste compositions can be devoid of an antibiotic agent, but include nanoparticles comprising one or more growth factors (or vice versa).
  • a growth factor can comprise a naturally occurring substance capable of stimulating cellular growth, proliferation and/or cellular differentiation.
  • a growth factor is a protein or a steroid hormone.
  • Growth factors often promote cell differentiation and maturation, which varies between growth factors. For example, bone morphogenic proteins (BMP) stimulate bone cell differentiation, while fibroblast growth factors (FGF) and vascular endothelial growth factors (VEGF) stimulate blood vessel differentiation (angiogenesis).
  • BMP bone morphogenic proteins
  • FGF fibroblast growth factors
  • VEGF vascular endothelial growth factors
  • Growth factors suitable for inclusion in certain embodiments of the present invention include, but not necessarily limited to growth factors that can assist (or enhance) in the healing of bone tissue (e.g., BMP, FGF, VEGF, etc.) and/or recruit the development of new blood vessels (e.g., FGF, VEGF, etc.) or to chemo-attract stem cells (SDF).
  • Exemplary growth factors can include BMP (bone morphogenetic proteins), FGF (fibroblast growth factors), VEGF (vascular endothelial growth factors), TGF-beta
  • transforming growth factor beta transforming growth factor beta
  • SDF stromal derived growth factor
  • hepatocyte growth factor hepatocyte growth factor
  • the thrombogenic bone paste compositions provide a sustained release of the one or more growth factors.
  • Such embodiments that is, release one or more growth factors upon application of the bone paste composition onto a patient slowly over an extended period of time.
  • respective growth factors included in the composition can be released serially (e.g., substantially all of a first growth factor can be released prior to the onset of releasing a second growth factor and so on) or in an overlapping nature.
  • a time release profile of a first growth factor (e.g., substantially all of a first growth factor can be released between about 1 minute to 1 hour after application of the bone paste composition to the patient) can be overlapping to a second growth factor having a different (second) time release profile (e.g., substantially all of a second growth factor can be released between about 30 minutes to 3 hours after application of the bone paste composition to the patient).
  • one or more growth factors can be released immediately upon application of the bone paste composition onto a patient (e.g., release initiates within 0.5 minutes - 10 minutes and/or substantially all of the growth factor is released within 3-15 minutes of application of the bone paste composition).
  • the bone paste composition preferably (not necessarily) includes the same or different growth factors that can (or are) be released in a sustained manner over a desired time frame (e.g. , substantially all or all of the growth factor released, for example, within a time duration of 30 minutes to 3 hours).
  • the bone paste compositions include one or more growth factors that are (or can be) substantially all or completely released upon application of the bone paste composition onto a patient slowly over an extended period of time.
  • substantially all or all of a growth factor (or multiple growth factors) can be released in a desired time duration (e.g., the duration of time from application until all of the growth factor(s) has been released from the bone past composition) can comprise from at least any of the following: 1 minute, 30 minutes, 1 hour, 3 hours, 8 hours, 24 hours, 3 days, 5 days, 7 days, and 10 days and/or at most about any of the following: 2 months, 1 month, 3 weeks, 2 weeks, 1 week, 3 days, 1 day, 8 hours, 4 hours, and 3 hours (e.g., from 1 minute to 1 hour, 30 minutes to 8 hours, 3 hours to 2 weeks, etc.).
  • the onset of releasing the one or more growth factors can be either immediate (e.g., upon application of the bone paste composition onto a patient) or delayed for a desired period of time.
  • certain embodiments of the present invention provide both a sustained and delayed release of at least one growth factor.
  • the time period in which the onset of release of the growth factor(s) can comprise from at least any of the following: 1 minute, 30 minutes, 1 hour, 3 hours, and 8 hours and/or at most about any of the following: 48 hours, 36 hours, 24 hours, and 12 hours.
  • the thrombogenic bone paste compositions can also include one or more adhesive agents, preferably a biological- based adhesive (e.g., bioadhesives).
  • Adhesive agents can be incorporated into the thrombogenic bone paste compositions to facilitate initial and/or prolonged adherence to the location of deposition (e.g., bone surface, hole, etc.).
  • the adhesion strength of the biological-based adhesive between the adhesive (e.g., bone paste composition including such a biological-based adhesive) and the targeted substrate (e.g., bone surface of a subject) is strong enough to help ensure that the bone paste
  • compositions remains in place upon application, during a medical procedure, and/or for a desired time period subsequent to the medical procedure.
  • the viscosity of certain embodiments of the present invention facilitate the composition's ability to "packed” either into the bone marrow, onto the surface of a bone, and/or into spaces between fractured bones (for example), while the adhesive agent can promote adherence of the "packed” bone paste composition in or on the place of deposition.
  • certain embodiments of the present invention include a biological adhesive (e.g., bioadhesives).
  • Biological adhesives generally include natural polymeric materials that act as adhesives and glues formed synthetically from biological monomers (e.g., sugars).
  • Biological adhesives can include of a variety of substances (e.g., proteins, carbohydrates, plant residues, compounds secreted from organisms).
  • one or more bio-based component can be mixed prior to or during a medical procedure to form a resulting biological adhesive to be incorporated into the bone paste compositions.
  • the adhesive e.g., biological adhesive
  • the adhesive is incorporated into the bone paste compositions prior to application of the bone paste composition onto the targeted substrate (e.g., bone surface).
  • BioGlue® is a composition including bovine serum albumin and glutaraldehydeare dispensed via a double-chambered syringe. Once dispensed, the adhesive components mix within an applicator tip where the cross- linking begins (within 20 to 30 seconds; it reaches bond strength within 2 minutes).
  • compositions including polycarbophil includes compositions including polycarbophil.
  • Polycarbophil is lightly cross-linked with divinyl glycol and contains multiple carboxyl radicals (COO-), which are the source of its negative charges. These acid radicals permit hydrogen bonding with cell surfaces. Despite the relative weakness of hydrogen bond,
  • polycarbophil enables numerous hydrogen bonds to provide an appropriate adhesion strength according to certain embodiments of the present invention.
  • concentration of the biological adhesive (e.g., bioadhesive) in the thrombogenic bone paste compositions can comprise a wide range of concentrations.
  • the thrombogenic bone paste compositions can comprise one or more biological adhesive (e.g., bioadhesive) in an amount of about at least any of the following: 0.1 , 1 , 3, 5, 10, 20, and 30% and/or at most about any of the following 60, 50, 40, 30, 25 and 20 % by weight of the thrombogenic bone paste compositions.
  • biological adhesive e.g., bioadhesive
  • the targeted substrate e.g., bone surface
  • an adhesive e.g., biological adhesive
  • the targeted substrate e.g., bone surface
  • an adhesive e.g., biological adhesive
  • certain embodiments can include an additional optional component (e.g., an expanding agent) that expands the "volume" of the thrombogenic bone paste compositions. That is, the expanding agent(s) is an optional feature.
  • an expanding agent e.g., an expanding agent
  • such thrombogenic bone paste compositions can be applied within holes or crevices formed on/in the surface of a bone that may either be currently bleeding or susceptible to bleeding.
  • the expanding agent incorporated within the thrombogenic bone paste composition can absorb moisture/water from blood at the application site (e.g., cut, hole, etc.) and swell, thereby expanding the "volume" of composition that has been previously positioned on/in the site of interest (e.g., surface cut on a bone, hole on or through a bone, etc.).
  • the expansion of the thrombogenic bone paste composition (which has already been applied to the bone wound) can further fill any air voids in the crevice or hole and effectively lock the bone paste composition in place.
  • the expanded bone paste composition provides an increased mechanical barrier to promote thrombosis.
  • suitable expanding agents can comprises a water swellable oligomer or polymer.
  • the water swellable oligomer or polymer is degradable.
  • Degradable oligomers or polymers can comprise disaccharides (e.g., sucrose), oligosaccharides (e.g., p-nitrophenyl-penta-N-acetyl-chitopentaoside) and polysaccharides, all of them being enzymatically cleavable.
  • Such di-, oligo- and polysaccharides can have any molecular weight ranging from about 100 to about 1 ,000,000, preferably from about 200 to about 200,000, and more preferably from about 1 ,000 to 40,000.
  • the expanding agent can comprise an in vivo degradable polymer hydrogel such as a modified dextran hydrogel which is enzymatically cleavable by dextranase.
  • Dextran is a high molecular weight (about 15,000 to 150,000) polysaccharide containing alpha-glucopyranose units which may be produced from the action of Leuconostoc mesenteroides onto saccharose. Dextran may be chemically modified by reaction with functional alpha-beta ethylenically unsaturated acid esters such as functional acrylates and methacrylates.
  • the expanding agent can comprises a super absorbent polymer (SAP).
  • SAPs super absorbent polymer
  • SAPs include a variety of water-insoluble, but water-swellable polymers capable of absorbing relatively large quantities of fluids. SAPs are capable of absorbing and retaining amounts of aqueous fluids equivalent to many times their own weight. As is known in the art, SAPs can absorb several hundreds of times its own weight (e.g., 50-1000, 200-500, 200-300 times its own weight) in water that can be stored within the molecular structure of the SAP. As water travels into an SAP particle, the SAP particle swells to accommodate the additional water molecules. SAPs are most commonly available as dry, granular powders, but gradually turn into a soft gel upon absorbing water.
  • SAP may be of one type (i.e., homogeneous) or mixtures of polymers.
  • the SAPs may have a size, shape, and/or morphology varying over a wide range.
  • the particles may not have a large ratio of greatest dimension to smallest dimension. Suitable particle sizes and methods for determining particle sizes of the SAP particles are well known.
  • SAPs may fall into the following types: (1 ) substituted and unsubstituted natural and synthetic polymers including polysaccharides, such as carboxymethyl starch, carboxymethyl cellulose, and hydroxypropyl cellulose; (2) nonionic types such as polyvinyl alcohol, and polyvinyl ethers; (3) cationic types such as polyvinyl pyridine, polyvinyl morpholinione, and ⁇ , ⁇ -dimethylaminoethyl or ⁇ , ⁇ -diethylaminopropyl acrylates and methacrylates, and the respective quaternary salts thereof.
  • polysaccharides such as carboxymethyl starch, carboxymethyl cellulose, and hydroxypropyl cellulose
  • nonionic types such as polyvinyl alcohol, and polyvinyl ethers
  • cationic types such as polyvinyl pyridine, polyvinyl morpholinione, and ⁇ , ⁇ -dimethylaminoethyl or ⁇ , ⁇ -die
  • SAPs may comprise a homo-polymer of partially neutralized alpha, beta-unsaturated carboxylic acid or a copolymer of partially neutralized alpha, beta- unsaturated carboxylic acid copolymerized with a monomer co-polymerizable therewith.
  • the homo-polymer or copolymer can comprise aliphatic groups, wherein at least some of the aliphatic groups are at least partially comprised by the surface of the SAP particles.
  • SAPs utilized comprise cross-linked networks of flexible polymer chains. Small amounts of cross-linkers can play a major role in improving the swelling and mechanical properties of SAPs.
  • SAPs comprise polymer networks that carry dissociated ionic functional groups to facilitate further water absorption. Examples of suitable SAPs that can be used in accordance with certain embodiments of the present invention may comprise one or more of the following polymers (i.e., types of SAP): (1 ) alkali metal salts of polyacrylic acids, (2)
  • polyacrylamides (3) unsaturated carboxylic acid anhydride copolymers, for example, ethylene/maleic anhydride copolymers and isobutylene/maleic anhydride copolymer, (4) polyvinyl ethers, (5) cellulose-based SAPs, for example, hydroxypropylcellulose and carboxy-methyl-cellulose, (6) polyvinyl morpholinone, (7) polymers and copolymers of vinyl sulfonic acid, (8) polyacrylates, (9) polyvinyl pyridine, (10) isobutylene maleic anhydride copolymers, and combinations thereof.
  • unsaturated carboxylic acid anhydride copolymers for example, ethylene/maleic anhydride copolymers and isobutylene/maleic anhydride copolymer
  • polyvinyl ethers (5) cellulose-based SAPs, for example, hydroxypropylcellulose and carboxy-methyl-cellulose, (6) polyvinyl morpholinone, (7) polymers and copo
  • the SAP comprises an alkali metal salt of a cross-linked polyacrylate (e.g., sodium polyacrylate) or carboxy-methyl-cellulose.
  • polymer materials for use in making such SAPs include slightly network cross linked polymers of partially neutralized polyacrylic acids and starch derivatives thereof.
  • the SAP may comprise from 25% to 95% by weight, more preferably from 50% to 80% by weight, neutralized, slightly network cross-linked, polyacrylic acid. Network cross-linking renders the polymer substantially water-insoluble and, in part, determines the absorptive capacity and extractable polymer content characteristics of the hydrogel-forming absorbent polymers.
  • a SAP incorporated into a thrombotic bone paste composition is biodegradable and can be safely resorbed into the body of a patient.
  • certain embodiments of the present invention can comprise a disintegrate (e.g., often referred to as a disintegrating agent in the
  • Disintegrates can also absorb water and swell to effectively expand the bone paste composition.
  • Exemplary disintegrates that can be used in certain embodiments of the present invention include microcrystalline cellulose, starches, cross-linked polyvinylpyrrolidone, or combinations thereof.
  • concentration of the optional expanding agent in the thrombogenic bone paste compositions can comprise a wide range of concentrations and can vary depending on the particular expanding agent employed. In certain embodiments, however, the thrombogenic bone paste compositions can comprise one or more expanding agents in an amount of about at least any of the following: 0.1 , 1 , 3, 5, 10, 20, and 30% and/or at most about any of the following 40, 30, 25 and 20 % by weight of the thrombogenic bone paste compositions.
  • the expanding agent can be provided in the form of particulates preferably have a mass median particulate size of between about 1 micron and about 2 mm, preferably between about 1 micron and about 500 microns, preferably between about 1 microns and about 50 microns.
  • the thrombotic bone paste compositions can optionally include one or more hardening agents.
  • one suitable hardening agent can comprise calcium sulfate dehydrate.
  • the extra moisture/water concentration absorbed into the thrombotic bone paste composition initiates a process of solidifying the composition within several minutes. For instance the thrombotic bone paste composition can start "setting" or hardening with 10-15 minutes with a completion of "setting” or hardening with 30-60 minutes.
  • the "setting" of the bone paste composition is not immediate so as to allow time for adsorption of sufficient water to allow the bone paste composition to expand if an expanding agent is present.
  • the hardening of the bone paste composition will provide an additional mechanism for locking or securing the bone paste composition into place within or on the wounded sites of the bone, particularly in embodiments including an expanding agent.
  • thrombotic bone paste compositions are preferably kneadable and/or malleable at room or body temperature.
  • embodiments of the present invention can be continually molded, deformed, or shaped by hand before, during, or after application of the composition onto cuts or within holes/crevices on the surface of a bone.
  • the thrombogenic bone paste compositions can both readily conform to the contours of the cuts and/or holes while simultaneously having enough consistency to remain in the place of application of deposition (e.g., the composition preferably does not leak or ooze out of or from the spots of application).
  • certain embodiments of the present invention comprise a viscosity that is large enough such that the composition can withstand the pressure associated with bleeding from the bone.
  • the viscosity of the thrombotic bone paste compositions can be high enough such that it does not disintegrate within minutes upon contact with blood or other aqueous media.
  • the viscosity of the thrombotic bone paste compositions should be such that the composition can be formed and reformed over the course of a surgical procedure.
  • the term "forming" should be understood to be any change of the shape or geometry of the thrombotic bone paste composition.
  • the forming/reforming of the thrombotic bone paste compositions can preferably be effected by at least one of the user's hands. The forming can also be carried out while the user wears gloves.
  • the forming/reforming of the bone paste composition can lead to heating of the composition, for example by kneading of the composition by a user. As the bone paste composition is heated due to handling by the user, the viscosity can drop slightly such that the bone paste composition becomes slightly more malleable.
  • the forming/reforming of the bone paste composition can serve, for example, to give the bone paste composition a shape that is suitable for mechanical sealing of bleeding bone tissue before, during, or subsequent to a surgical operation.
  • the viscosity of the thrombogenic bone paste compositions can comprise a wide range of viscosities depending upon their ultimate intended use. In certain embodiments, however, the thrombogenic bone paste compositions can comprise a viscosity of about at least any of the following: 100,000; 250,000; 500,000; 750,000; 1 ,000,000 centipoise and/or at most about any of the following 700,000,000; 600,000,000; 500,000,000; 300,000,000, 200,000,000, and 100,000,000 centipoise. It should be noted that the viscosity of the thrombogenic bone paste compositions can be tailored to the preference of the user or the intended use by the addition of water or saline.
  • the thrombogenic bone paste compositions can be manufactured by first placing all of the selected components of the thrombogenic bone paste compositions in a suitable mixing vessel. Subsequently, the individual components can be mixed, for example by stirring and/or kneading to preferably provide a homogeneous mix of the selected components.
  • each of the selected components can be added sequentially with mixing/kneading after each addition of a selected component.
  • the thrombogenic bone paste compositions can be provided in a variety of container forms.
  • all of the components can be provided in dry mix to which water or saline can be added to begin forming the bone paste composition having the desired viscosity.
  • Suitable containers include, for example, tins, bottles, bags, or cartridges, tubes, each of which can be provided with suitable closures.
  • one or more of the selected agents/components can be housed separate from the others.
  • one or more agents can be housed separately from the other agents and dispensed into a common mixing chamber where the formation of the thrombogenic bone paste composition can be carried out.
  • the thrombogenic bone paste compositions according to certain embodiments of the present invention can be used for a variety of different medical purposes.
  • the thrombogenic bone paste compositions are employed in methods of decreasing bleeding / conserving blood from a bone.
  • the thrombogenic bone paste compositions can be used for mechanical closure of bleeding bone wounds.
  • the thrombogenic bone paste compositions serve as a bone sealing agent. That is, the thrombogenic bone paste composition can be pressed onto or into bleeding bone areas by the user for this purpose.
  • the present provides methods of decreasing bleeding from a bone that has been cut or punctured, such as due to an accident or a surgical procedure.
  • a thrombogenic bone paste composition as disclosed herein can be applied onto one or more cut surfaces of the bone or filled within the holes formed in the bone.
  • the step of applying the thrombogenic bone paste composition comprises filling any holes or crevices imparted to the bone during a surgical procedure or due to an accident.
  • the thrombogenic bone paste composition can be densely packed into the crevices and holes in one application or over the course of a series of applications.
  • the bone treated is a sternum.
  • Example Composition - 1 A thrombogenic bone paste composition according to one embodiment of the present invention was produced by hand-mixing the following components: (1 ) 1 gram of "Surgifoam” made of absorbable Gelatin Sponge, U.S.P., manufactured by Ethicon, Inc. (USA); (2) 6 grams of sterile vancomycin hydrochloride; (3) 20,000 units of RECOTHROM, made by Zymogenetics (USA); and (4) 10 cc normal saline.
  • the resulting thrombogenic bone paste composition was inspected for kneadable and/or malleable at room temperature by hand.
  • the resulting composition was easily molded or shaped into various forms or shapes by light to moderate pressure from the fingertips of a single hand at room temperature (e.g. , about 68°F).
  • components e.g., Surgifoam, etc.
  • surgifoam e.g., Surgifoam, etc.
  • the amount of saline can simply be increased to reduce the viscosity to a desired level.

Abstract

L'invention concerne des compositions de pâte osseuse thrombogénique comprenant un matériau matrice, une pluralité de nanoparticules comprenant au moins un agent antibiotique. et au moins un agent hémostatique. L'invention concerne également des méthodes de réduction de saignement à partir d'un os dans lesquelles une composition de pâte osseuse peut être appliquée sur ou dans une ou plusieurs surfaces entaillées de l'os.
PCT/US2014/047058 2013-07-23 2014-07-17 Compositions de pâte osseuse et méthodes d'utilisation associés WO2015013106A1 (fr)

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US20070248675A1 (en) * 2005-09-08 2007-10-25 Gwangju Institute Of Science And Technology Composite comprising polysaccharide-functionalized nanoparticle and hydrogel matrix, a drug delivery system and a bone defect replacement matrix for sustained release comprising the same, and the preparation method thereof
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