Minimally invasive treatment of vertebra (mitv) using a calcium phosphate combination bone cement

Abstract

Featured are a biocompatible, injectable, self-setting, cohesive, bone-bonding and remodeling calcium phosphate composite material and its use in methods of repairing defective bone, e.g., in vertebroplasty augmentation and kyphoplasty.

What is claimed is: 
     
         1 . A method for performing vertebroplasty on a vertebral body comprising:
 a) injecting a flowable bone cement into at least one said vertebral body, said flowable bone cement comprising a nanocrystalline apatitic calcium phosphate, a radio-opaque agent, carboxymethyl cellulose in an amount of 10% or less by weight, and a pharmaceutically acceptable fluid in an amount sufficient to produce said flowable bone cement; and   b) allowing said flowable bone cement to harden, wherein said flowable bone cement, when hardened, has a compressive strength of 1 mPa or greater and is resorbable in vivo.   
     
     
         2 . The method of  claim 1 , wherein said flowable bone cement further comprises:
 a) at least one agent that promotes bone growth or inhibits bone resorption;   b) one or more crystal growth inhibitors;   c) demineralized bone matrix;   d) benzoyl peroxide powder;   e) hydroxyethyl methacrylate (HEMA);   f) a cohesiveness agent, an osteopenic agent, or a medicinal agent; or   q) a biologically active agent.   
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the pharmaceutically acceptable fluid is selected from water, saline, a phosphate buffer, a biological fluid, in particular, blood or a fluid that includes blood components, and glycerol. 
     
     
         5 . The method of  claim 1 , wherein said vertebral body:
 a) is in a human or non-human mammal; or   b) comprises fractured or osteoporotic bone.   
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1  further comprising:
 a) injecting said flowable bone cement into two or more vertebral bodies; or 
 b) creating a cavity in said vertebral body and injecting said flowable bone cement into said cavity. 
 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein said nanocrystalline apatitic calcium phosphate comprises crystals within the range of 30-80 nm, optionally wherein said nanocrystalline apatitic calcium phosphate comprises crystals within the range of 30-50 nm. 
     
     
         10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein said nanocrystalline apatitic calcium phosphate:
 a) has a crystallinity index value of less than 60% relative to hydroxyapatite; or   b) is selected from amorphous calcium phosphate, poorly crystalline calcium phosphate, hydroxyapatite, carbonated apatite (calcium-deficient hydroxyapatite), monocalcium phosphate, calcium metaphosphate, heptacalcium phosphate, dicalcium phosphate dihydrate, tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate, and tricalcium phosphate, or mixtures thereof.   
     
     
         12 - 17 . (canceled) 
     
     
         18 . The method of  claim 2 , wherein said cohesiveness agent is selected from the group consisting of:
 a) one or more polymers selected from polysaccharides, nucleic acids, carbohydrates, proteins, polypeptides, poly(α-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(anhydride-co-imides), poly(orthocarbonates), poly(α-hydroxy alkanoates), poly(dioxanones), poly(phosphoesters), poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA), poly(lactide-co-glycolide (PLGA), poly(L-lactide-co-D, L-lactide), poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (PHB), poly(ε-caprolactone), poly(δ-valerolactone), poly(γ-butyrolactone), poly(caprolactone), polyacrylic acid, polycarboxylic acid, poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride), poly(ethyleneimine), polypropylene fumarate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene, polymethylmethacrylate, carbon fibers, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, poly(ethylene terephthalate)polyamide, and copolymers thereof;   b) a homo- or co-polymer having one or more monomers selected from the group consisting of acrolein potassium, (meth)acrylamides, (meth)acrylic acid and salts thereof, (meth)acrylates, acrylonitrile, ethylene, ethylene glycol, ethyleneimine, ethyleneoxide, styrene sulfonate, vinyl acetate, vinyl alcohol, vinyl chloride, and vinylpyrrolidone);   c) a polyphenolic complexing agent selected from gallotannins, ellagitannins, taragallotannins, caffetannins, proanthocyanidins, catechin, epicatechin, chlorogenic acid, and arbutin; and   d) an agent selected from alginic acid, arabic gum, guar gum, xantham gum, gelatin, chitin, chitosan, chitosan acetate, chitosan lactate, chondroitin sulfate, N,O-carboxymethyl chitosan, a dextran, fibrin glue, glycerol, hyaluronic acid, sodium hyaluronate, a cellulose, in particular, carboxymethyl cellulose, a glucosamine, a proteoglycan, a starch, lactic acid, a pluronic, sodium glycerophosphate, collagen, glycogen, a keratin, silk, and mixtures thereof;   said osteogenic agent is selected from the group consisting of transforming growth factors-beta (TGF-β), activins, inhibins, and bone morphogenetic proteins (BMPs);   said medicinal agent is selected from the group consisting of antibiotics, enzyme inhibitors, antihistamines, anti-inflammatory agents, muscle relaxants, anti-spasmodics, analgesics, prostaglandins, anti-depressants, trophic factors, and hormones; and   said biologically active agent is selected from the group consisting of organic molecules, inorganic materials, proteins, peptides, nucleic acids, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, antibodies, growth factors, and anti-cancer agents.   
     
     
         19 - 20 . (canceled) 
     
     
         21 . The method of  claim 1 , comprising injecting said flowable bone cement into said vertebral body using a needle having a size of 16 gauge or less, optionally wherein the needle is an 11 gauge needle. 
     
     
         22 - 45 . (canceled) 
     
     
         46 . A method of preparing a bone cement comprising admixing a calcium phosphate material comprising crystals within the range of 30-80 nm, a radio-opaque agent, and carboxymethyl cellulose in an amount of 10% or less by weight. 
     
     
         47 . The method of  claim 46 , wherein:
 a) the method comprises high energy grinding the calcium phosphate material prior to said admixing; or   b) the radio-opaque agent is selected from the group consisting of barium, iodine, lanthanum oxide, zirconium oxide, and sodium alginate, optionally wherein the barium is barium carbonate, barium sulfate, or barium apatite; or the iodine is methyl methacrylate, 2-(2-iodobenzoyl)-ethyl methacrylate, Renografin-60, or ISOVUE.   
     
     
         48 . The method of  claim 46 , wherein the calcium phosphate material:
 a) comprises a nanocrystalline apatite or nano-low crystalline apatite;   b) has a calcium to phosphate ratio (Ca/P) of less than 1.67;   c) comprises amorphous calcium phosphate and dicalcium phosphate dihydrate;   d) comprises crystals within the range of 30-50 nm;   e) has a crystallinity index value of less than 60% relative to hydroxyapatite; or   f) is selected from amorphous calcium phosphate, poorly crystalline calcium phosphate, hydroxyapatite, carbonated apatite (calcium-deficient hydroxyapatite), monocalcium phosphate, calcium metaphosphate, heptacalcium phosphate, dicalcium phosphate dihydrate, tetracalcium phosphate, octacalcium phosphate, calcium pyrophosphate, and tricalcium phosphate, or mixtures thereof.   
     
     
         49 . The method of  claim 46 , wherein the method further comprises:
 a) admixing a pharmaceutically acceptable fluid with the bone cement to produce a flowable bone cement, optionally wherein the pharmaceutically acceptable fluid is selected from the group consisting of water, saline, a phosphate buffer, a biological fluid, in particular, blood or a fluid that includes blood components, and glycerol;   b) admixing at least one agent that promotes bone growth or inhibits bone resorption with the bone cement;   c) admixing one or more crystal growth inhibitors with the bone cement;   d) admixing demineralized bone matrix with the bone cement;   e) admixing benzoyl peroxide powder with the bone cement;   f) admixing hydroxyethyl methacrylate (HEMA with the bone cement); or   g) admixing a supplemental material selected from the group consisting of a cohesiveness agent, an osteogenic agent, a biologically active agent, and a medicinal agent with the bone cement.   
     
     
         50 . The method of  claim 49 , wherein the method further comprises loading the flowable bone cement into a delivery syringe configured for vertebral injection. 
     
     
         51 . The method of  claim 49 , wherein the flowable bone cement:
 a) is formulated for injection;   b) is formulated as a formable material or paste;   c) hardens in less than 1 hour at 37° C.;   d) has a compressive strength of 1 MPa after hardening; or   e) is resorbable in vivo.   
     
     
         52 . The method of  claim 51 , wherein said flowable bone cement is capable of being injected through a needle having a size of 16 gauge or less, optionally wherein said needle is an 11 gauge needle. 
     
     
         53 . The method of  claim 49 , wherein said cohesiveness agent is selected from the group consisting of:
 a) one or more polymers selected from the group consisting of polysaccharides, nucleic acids, carbohydrates, proteins, polypeptides, poly(α-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(anhydride-co-imides), poly(orthocarbonates), poly(α-hydroxy alkanoates), poly(dioxanones), poly(phosphoesters), poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA), poly(lactide-co-glycolide (PLGA), poly(L-lactide-co-D, L-lactide), poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (PHB), poly(ε-caprolactone), poly(δ-valerolactone), poly(γ-butyrolactone), poly(caprolactone), polyacrylic acid, polycarboxylic acid, poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride), poly(ethyleneimine), polypropylene fumarate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene, polymethylmethacrylate, carbon fibers, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, poly(ethylene terephthalate)polyamide, and copolymers thereof;   b) a homo- or co-polymer having one or more monomers selected from the group consisting of acrolein potassium, (meth)acrylamides, (meth)acrylic acid and salts thereof, (meth)acrylates, acrylonitrile, ethylene, ethylene glycol, ethyleneimine, ethyleneoxide, styrene sulfonate, vinyl acetate, vinyl alcohol, vinyl chloride, and vinylpyrrolidone;   c) a polyphenolic complexing agent selected from the group consisting of gallotannins, ellagitannins, taragallotannins, caffetannins, proanthocyanidins, catechin, epicatechin, chlorogenic acid, and arbutin; and   d) an agent selected from the group consisting of alginic acid, arabic gum, guar gum, xantham gum, gelatin, chitin, chitosan, chitosan acetate, chitosan lactate, chondroitin sulfate, N,O-carboxymethyl chitosan, a dextran, fibrin glue, glycerol, hyaluronic acid, sodium hyaluronate, and a cellulose, in particular, carboxymethyl cellulose, a glucosamine, a proteoglycan, a starch, lactic acid, a pluronic, sodium glycerophosphate, collagen, glycogen, a keratin, silk, and mixtures thereof;   said osteogenic agent is selected from the group consisting of transforming growth factors-beta (TGF-β), activins, inhibins, and bone morphogenetic proteins (BMPs);   said medicinal agent is selected from the group consisting of antibiotics, enzyme inhibitors, antihistamines, anti-inflammatory agents, muscle relaxants, anti-spasmodics, analgesics, prostaglandins, anti-depressants, trophic factors, and hormones; and   said biologically active agent is selected from the group consisting of organic molecules, inorganic materials, proteins, peptides, nucleic acids, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, antibodies, growth factors, and anti-cancer agents.   
     
     
         54 . A bone cement powder comprising a calcium phosphate material comprising crystals within the range of 30-80 nm, a radio-opaque agent, and carboxymethyl cellulose in an amount of 10% or less by weight, optionally wherein said calcium phosphate material comprises one or more of poorly crystalline calcium phosphate, amorphous calcium phosphate, and dicalcium phosphate dihydrate. 
     
     
         55 . The bone cement powder of  claim 55 , wherein the radio-opaque agent is selected from the group consisting of barium, iodine, lanthanum oxide, zirconium oxide, and sodium alginate, optionally wherein the barium is barium carbonate, barium sulfate, or barium apatite; or the iodine is methyl methacrylate, 2-(2-iodobenzoyl)-ethyl methacrylate, Renografin-60, or ISOVUE. 
     
     
         56 . A kit comprising the bone cement powder of  claim 54 .