Multiphasic Bone Graft Substitute
The invention provides a particulate composition adapted for forming a bone graft substitute cement upon mixing with an aqueous solution, comprising i) a calcium sulfate hemihydrate powder, wherein the calcium sulfate hemihydrate is present at a concentration of at least about 50 weight percent based on the total weight of the particulate composition; ii) a monocalcium phosphate monohydrate powder; iii) a non-porous β-tricalcium phosphate powder; and iv) a porous β-tricalcium phosphate powder. Bone graft substitute cements made therefrom, a bone graft substitute kit comprising the particulate composition, methods of making and using the particulate composition, and articles made from the bone graft substitute cement are also provided.
1 . A particulate composition adapted for forming a bone graft substitute cement upon mixing with an aqueous solution, comprising:
i) a calcium sulfate hemihydrate powder, wherein the calcium sulfate hemihydrate is present at a concentration of at least about 50 weight percent based on the total weight of the particulate composition;
ii) a monocalcium phosphate monohydrate powder;
iii) a non-porous β-tricalcium phosphate powder; and
iv) a porous β-tricalcium phosphate powder.
2 . The particulate composition of claim 1 , wherein the calcium sulfate hemihydrate is present at a concentration of at least about 70 weight percent based on the total weight of the particulate composition.
3 . The particulate composition of claim 1 , wherein the calcium sulfate hemihydrate powder has a bimodal particle distribution.
4 . The particulate composition of claim 3 , wherein the calcium sulfate hemihydrate powder has a median particle size of about 5 to about 20 microns.
5 . The particulate composition of claim 1 , wherein the non-porous β-tricalcium phosphate powder has a median particle size of less than about 20 microns.
6 . The particulate composition of claim 1 , wherein the porous β-tricalcium phosphate powder exhibits a bimodal particle size distribution.
7 . The particulate composition of claim 6 , wherein the porous β-tricalcium phosphate powder comprises less than 50% by weight of particles having a particle size up to about 63 microns and greater than 50% by weight of particles having a particle size greater than about 63 microns.
8 . The particulate composition of claim 6 , wherein the porous β-tricalcium phosphate powder comprises about 25% by weight of particles having a particle size up to about 63 microns and about 75% by weight of particles having a particle size greater than about 63 microns.
9 . The particulate composition of claim 1 , further comprising non-porous β-tricalcium phosphate granules having a median particle size of at least about 75 microns.
10 . The particulate composition of claim 9 , wherein the non-porous β-tricalcium phosphate granules have a median particle size of about 75 to about 1,000 microns.
11 . The particulate composition of claim 9 , wherein the non-porous β-tricalcium phosphate granules are present at a concentration of up to about 20 weight percent based on the total weight of the particulate composition.
12 . The particulate composition of claim 9 , wherein the non-porous β-tricalcium phosphate granules are present at a concentration of up to about 12 weight percent based on the total weight of the particulate composition.
13 . The particulate composition of claim 1 , wherein the calcium sulfate hemihydrate is α-calcium sulfate hemihydrate.
14 . The particulate composition of claim 1 , wherein the calcium sulfate hemihydrate powder has a bimodal particle distribution comprising about 30 to about 60 volume percent of particles having a mode of about 1.0 to about 3.0 microns and about 40 to about 70 volume percent of particles having a mode of about 20 to about 30 microns, based on the total volume of the calcium sulfate hemihydrate powder.
15 . The particulate composition of claim 1 , wherein the porous β-tricalcium phosphate powder is present at a concentration of between about 5 and about 15 weight percent.
16 . The particulate composition of claim 1 , wherein the non-porous β-tricalcium phosphate powder has a bimodal particle size distribution comprising about 30 to about 70 volume percent of particles having a mode of about 2.0 to about 6.0 microns and about 30 to about 70 volume percent of particles having a mode of about 40 to about 70 microns based on the total volume of the non-porous β-tricalcium phosphate powder.
17 . The particulate composition of claim 1 , wherein the non-porous β-tricalcium phosphate powder has a bimodal particle size distribution comprising about 50 to about 65 volume percent of particles having a mode of about 4.0 to about 5.5 microns and about 35 to about 50 volume percent of particles having a mode of about 60 to about 70 microns based on the total volume of the non-porous β-tricalcium phosphate powder.
18 . The particulate composition of claim 1 , further comprising an accelerant adapted for accelerating the conversion of calcium sulfate hemihydrate to calcium sulfate dihydrate.
19 . The particulate composition of claim 18 , wherein the accelerant is selected from the group consisting of calcium sulfate dihydrate particles, potassium sulfate particles, and sodium sulfate particles, wherein the accelerant is optionally coated with sucrose.
20 . The particulate composition of claim 18 , wherein the accelerant is present at a concentration of up to about 1 weight percent based on the total weight of the particulate composition.
21 . The particulate composition of claim 1 , comprising:
i) a calcium sulfate hemihydrate powder having a bimodal particle distribution and a median particle size of about 5 to about 20 microns, wherein the calcium sulfate hemihydrate is present at a concentration of at least about 70 weight percent based on the total weight of the particulate composition;
ii) a monocalcium phosphate monohydrate powder;
iii) a non-porous β-tricalcium phosphate powder having a median particle size of less than about 20 microns, the monocalcium phosphate monohydrate powder and the non-porous β-tricalcium phosphate powder being present at a combined concentration of about 3 to about 20 weight percent based on the total weight of the particulate composition;
iv) non-porous β-tricalcium phosphate granules having a median particle size of at least about 75 microns and present at a concentration of up to about 20 weight percent based on the total weight of the particulate composition;
v) porous β-tricalcium phosphate powder, in an amount of up to about 15 weight percent based on the total weight of the particulate composition; and
vi) an accelerant adapted for accelerating the conversion of calcium sulfate hemihydrate to calcium sulfate dihydrate, the accelerant being present at a concentration of up to about 1 weight percent based on the total weight of the particulate composition.
22 . The particulate composition of claim 1 , comprising:
i) an α-calcium sulfate hemihydrate powder having a bimodal particle distribution and a median particle size of about 5 to about 20 microns, wherein the calcium sulfate hemihydrate is present at a concentration of at least about 70 weight percent based on the total weight of the particulate composition, and wherein the calcium sulfate hemihydrate powder has a bimodal particle distribution comprising about 30 to about 60 volume percent of particles having a mode of about 1.0 to about 3.0 microns and about 40 to about 70 volume percent of particles having a mode of about 20 to about 30 microns, based on the total volume of the calcium sulfate hemihydrate powder;
ii) a monocalcium phosphate monohydrate powder;
iii) a β-tricalcium phosphate powder having a median particle size of less than about 20 microns, the monocalcium phosphate monohydrate powder and the β-tricalcium phosphate powder being present at a combined concentration of about 3 to about 20 weight percent based on the total weight of the particulate composition;
iv) β-tricalcium phosphate granules having a median particle size of about 100 to about 400 microns and present at a concentration of up to about 12 weight percent based on the total weight of the particulate composition;
v) porous β-tricalcium phosphate powder, in an amount of up to about 15 weight percent based on the total weight of the particulate composition, wherein the porous β-tricalcium phosphate powder comprises less than 50% by weight of particles having a particle size up to about 63 microns and greater than 50% by weight of particles having a particle size greater than about 63 microns; and
vi) an accelerant adapted for accelerating the conversion of calcium sulfate hemihydrate to calcium sulfate dihydrate, the accelerant being present at a concentration of up to about 1 weight percent based on the total weight of the particulate composition.
23 . The particulate composition of any of claims 1 - 22 , further comprising a biologically active agent.
24 . The particulate composition of claim 23 , wherein the biologically active agent is selected from the group consisting of cancellous bone chips, growth factors, antibiotics, pesticides, chemotherapeutic agents, antivirals, analgesics, and anti-inflammatory agents.
25 . The particulate composition of claim 23 , wherein the biologically active agent is bone marrow aspirate.
26 . The particulate composition of claim 23 , wherein the biologically active agent is a growth factor selected from the group consisting of fibroblast growth factors, platelet-derived growth factors, bone morphogenic proteins, osteogenic proteins, transforming growth factors, LIM mineralization proteins, osteoid-inducing factors, angiogenins, endothelins; growth differentiation factors, ADMP-1, endothelins, hepatocyte growth factor and keratinocyte growth factor, heparin-binding growth factors, hedgehog proteins, interleukins, colony-stimulating factors, epithelial growth factors, insulin-like growth factors, cytokines, osteopontin, and osteonectin.
27 . The particulate composition of any of claims 1 - 22 , wherein the particulate composition has a Vicat set time upon mixing with an aqueous solution of about 3 to about 8 minutes.
28 . The particulate composition of any of claims 1 - 22 , wherein the particulate composition has a Gillmore set time upon mixing with an aqueous solution of about 6 to about 20 minutes.
29 . The particulate composition of any of claims 1 - 22 , wherein the pore sizes of the porous β-tricalcium phosphate powder are in the range of about 100 microns to about 400 microns.
30 . The particulate composition of any of claims 1 - 22 , wherein the porous β-tricalcium phosphate powder is characterized by an interconnected, multidirectional porosity.
31 . The particulate composition of any of claims 1 - 22 , wherein the porous β-tricalcium phosphate powder has a total porosity of at least about 50%.
32 . A bone graft substitute cement comprising the reaction product formed by mixing a particulate composition of any one of claims 1 to 22 with an aqueous solution, the reaction product comprising calcium sulfate dihydrate, brushite, and a porous β-tricalcium phosphate component.
33 . The bone graft substitute cement of claim 32 , comprising non-porous β-tricalcium phosphate granules.
34 . The bone graft substitute cement of claim 32 , wherein said cement is cast in a predetermined shape.
35 . The bone graft substitute cement of claim 34 , wherein said predetermined shape is selected from the group consisting of pellets, granules, wedges, blocks, and disks.
36 . The bone graft substitute cement of claim 32 , wherein the aqueous solution comprises a carboxylic acid.
37 . The bone graft substitute cement of claim 36 , wherein the carboxylic acid is a hydroxy carboxylic acid.
38 . The bone graft substitute cement of claim 37 , wherein the hydroxy carboxylic acid is glycolic acid.
39 . The bone graft substitute cement of claim 36 , wherein the carboxylic acid is neutralized to a pH of about 6.5 to about 7.5.
40 . The bone graft substitute cement of any one of claims 36 to 39 , wherein the aqueous solution further comprises sodium chloride.
41 . A method for treating a bone defect, comprising applying a bone graft substitute cement according to claim 32 to the site of the bone defect.
42 . A bone graft substitute kit, comprising one or more containers enclosing a particulate composition according to any one of claims 1 to 22 , a separate container enclosing a sterile aqueous solution, and a written instruction set describing a method of using the kit.
43 . The bone graft substitute kit of claim 42 , further comprising a mixing apparatus adapted for mixing the particulate composition and the aqueous solution.
44 . The bone graft substitute kit of claim 43 , further comprising a delivery device adapted for delivering a bone graft substitute cement mixture to the site of a bone defect.
45 . The bone graft substitute kit of claim 44 , wherein the delivery device comprises a Jamshidi needle.
46 . The bone graft substitute kit of claim 42 , wherein a portion of the particulate composition is enclosed in a first syringe and a portion of the particulate composition is enclosed in a second syringe, and wherein the kit further includes a syringe connector adapted to connect the first and second syringe such that the contents of each syringe can be mixed.
47 . The bone graft substitute kit of claim 42 , further comprising at least one syringe containing at least a portion of the particulate composition and a vial adaptor adapted to connect the syringe to the container enclosing the sterile aqueous solution.