US2016354518A1PendingUtilityA1

Bone pastes comprising biofunctionalized calcium phosphate cements with enhanced cell functions for bone repair

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Assignee: XU HUAKUNPriority: Oct 21, 2011Filed: Aug 19, 2016Published: Dec 8, 2016
Est. expiryOct 21, 2031(~5.3 yrs left)· nominal 20-yr term from priority
Inventors:Huakun Xu
A61L 27/3834A61L 27/20A61L 2430/02A61L 27/227A61L 24/0036A61L 24/0042A61L 2400/06A61L 24/02A61L 27/225A61L 27/56A61L 27/54A61L 24/08A61L 27/3616A61L 27/12A61L 24/0005A61L 24/0015A61L 24/106A61L 27/365A61L 24/0031A61L 27/3633C04B 2111/00836C04B 28/34A61L 24/108A61L 24/043
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Claims

Abstract

The invention provides injectable, biofunctional agent-containing calcium phosphate cement bone pastes for bone tissue engineering, and methods of making and using the same.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A bone paste comprising calcium phosphate cement and one or more biofunctional agents, wherein the biofunctional agents are selected from the group consisting of RGD-containing peptides, fibronectin, fibronectin-like engineered polymer protein (FEPP), derived extracellular matrix (dECM), and platelet concentrate. 
     
     
         2 . The bone paste of  claim 1 , wherein the bone paste comprises calcium phosphate cement and an RGD-containing peptide, wherein RGD-containing peptide is selected from the group consisting of RGD, G4RGDSP, RGDS, GRGD, GRGDGY, RGDSGGC, and GRGDS, and wherein RGD-containing peptide is present within a range of about 0.0005% to about 5% by mass. 
     
     
         3 . The bone paste of  claim 1 , wherein the bone paste comprises calcium phosphate cement and fibronectin, wherein fibronectin is present within a range of about 0.0005% to about 5% by mass. 
     
     
         4 . The bone paste of  claim 1 , wherein the bone paste comprises calcium phosphate cement and FEPP, wherein FEPP is present within a range of about 0.0005% to about 5% by mass. 
     
     
         5 . The bone paste of  claim 1 , wherein the bone paste comprises calcium phosphate cement and dECM, wherein dECM is present within a range of about 0.001% to about 10% by mass. 
     
     
         6 . The bone paste of  claim 1 , wherein the bone paste comprises calcium phosphate cement and platelet concentrate, wherein platelet concentrate is present within a range of about 0.001% to about 10% by mass. 
     
     
         7 . The bone paste of  claim 1 , wherein the bone paste comprises calcium phosphate cement and any two of the biofunctional agents. 
     
     
         8 . The bone paste of  claim 1 , wherein the bone paste comprises calcium phosphate cement and any three of the biofunctional agents. 
     
     
         9 . The bone paste of  claim 1 , wherein the bone paste comprises calcium phosphate cement and any four of the biofunctional agents. 
     
     
         10 . The bone paste of  claim 1 , wherein the bone paste comprises calcium phosphate cement and each of the five biofunctional agents. 
     
     
         11 . The bone paste of any one of  claims 1 - 10 , wherein the calcium phosphate cement comprises one or more ingredients selected from the group consisting of tetracalcium phosphate (TTCP) (Ca 4 (PO 4 ) 2 O), dicalcium phosphate anhydrous (DCPA) (CaHPO 4 ), dicalcium phosphate dihydrate (CaHPO 4 .2H 2 O), tricalcium phosphate (Ca 3 [PO 4 ] 2 ), α-tricalcium phosphate (α-Ca 3 (PO 4 ) 2 ), β-tricalcium phosphate (β-Ca 3 (PO 4 ) 2 ), octacalcium phosphate (Ca 8 H 2 (PO 4 ) 6 .5H 2 O), amorphous calcium phosphate (Ca 3 (PO 4 ) 2 ), calcium carbonate (CaCO 3 ), calcium hydroxide (Ca[OH] 2 ), and hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ), and mixtures thereof. 
     
     
         12 . The bone paste of any one of  claims 1 - 10 , wherein the calcium phosphate cement comprises tetracalcium phosphate and dicalcium phosphate anhydrous. 
     
     
         13 . The bone paste of  claim 12 , wherein the calcium phosphate cement comprises a molar ratio of tetracalcium phosphate to dicalcium phosphate anhydrous of about 1:5 to about 5:1. 
     
     
         14 . The bone paste of  claim 12 , wherein the calcium phosphate cement comprises a molar ratio of tetracalcium phosphate to dicalcium phosphate anhydrous of about 1:3 to about 1:1. 
     
     
         15 . The bone paste of  claim 12 , wherein the calcium phosphate cement comprises an approximately 1:1 molar ratio of tetracalcium phosphate to dicalcium phosphate anhydrous. 
     
     
         16 . The bone paste of any one of  claims 1 - 10 , wherein the calcium phosphate cement further comprises chitosan. 
     
     
         17 . The bone paste of any one of  claims 1 - 10 , wherein the calcium phosphate cement further comprises fibers. 
     
     
         18 . The bone paste of  claim 17 , wherein the fibers are degradable. 
     
     
         19 . The bone paste of any one of  claims 1 - 10 , wherein the calcium phosphate cement further comprises chitosan and degradable fibers. 
     
     
         20 . The bone paste of any one of  claims 1 - 10 , wherein the calcium phosphate cement further comprises a porogen. 
     
     
         21 . The bone paste of  claim 20 , wherein the porogen is NaHCO 3  and citric acid. 
     
     
         22 . The bone paste of  claim 21 , wherein the mass fraction of NaHCO 3  is from about 5% to about 30%, and the mass fraction of citric acid is from about 50% to about 60%. 
     
     
         23 . The bone paste of  claim 16 , wherein the bone paste comprises calcium phosphate cement and a RGD-containing peptide, wherein the RGD-containing peptide is present within a range of about 0.0005% to about 0.05% by mass, and wherein the RGD-containing peptide is covalently linked to said chitosan. 
     
     
         24 . The bone paste of any one of  claims 1 - 10 , wherein the bone paste further comprises stem cells. 
     
     
         25 . The bone paste of  claim 24 , wherein the cells are selected from the group consisting of human umbilical cord mesenchymal stem cells, bone marrow stem cells, embryonic stem cells, pluripotent stem cells, induced pluripotent stem cells, multipotent stem cells, progenitor cells, and osteoblasts. 
     
     
         26 . The bone paste of  claim 24 , wherein the cells are attached to a surface of the bone paste, or the cells are interspersed throughout the bone paste, or both. 
     
     
         27 . The bone paste of any one of  claims 1 - 10 , wherein the bone paste is injectable. 
     
     
         28 . A bone paste comprising calcium phosphate cement, one or more biofunctional agents and cell-encapsulating microbeads, wherein the biofunctional agents are selected from the group consisting of RGD peptide, fibronectin, fibronectin-like engineered polymer protein (FEPP), derived extracellular matrix (dECM), and platelet concentrate. 
     
     
         29 . The bone paste of  claim 28 , wherein the bone paste comprises calcium phosphate cement and an RGD-containing peptide, wherein RGD-containing peptide is selected from the group consisting of RGD, G4RGDSP, RGDS, GRGD, GRGDGY, RGDSGGC, and GRGDS, and wherein RGD-containing peptide is present within a range of about 0.0005% to about 5% by mass. 
     
     
         30 . The bone paste of  claim 28 , wherein the bone paste comprises calcium phosphate cement and fibronectin, wherein fibronectin is present within a range of about 0.0005% to about 5% by mass. 
     
     
         31 . The bone paste of  claim 28 , wherein the bone paste comprises calcium phosphate cement and FEPP, wherein FEPP is present within a range of about 0.0005% to about 5% by mass. 
     
     
         32 . The bone paste of  claim 28 , wherein the bone paste comprises calcium phosphate cement and dECM, wherein dECM is present within a range of about 0.001% to about 10% by mass. 
     
     
         33 . The bone paste of  claim 28 , wherein the bone paste comprises calcium phosphate cement and platelet concentrate, wherein platelet concentrate is present within a range of about 0.001% to about 10% by mass. 
     
     
         34 . The bone paste of  claim 28 , wherein the bone paste comprises calcium phosphate cement and any two of the biofunctional agents. 
     
     
         35 . The bone paste of  claim 28 , wherein the bone paste comprises calcium phosphate cement and any three of the biofunctional agents. 
     
     
         36 . The bone paste of  claim 28 , wherein the bone paste comprises calcium phosphate cement and any four of the biofunctional agents. 
     
     
         37 . The bone paste of  claim 28 , wherein the bone paste comprises calcium phosphate cement and each of the five biofunctional agents. 
     
     
         38 . The bone paste of any one of  claims 28 - 37 , wherein the calcium phosphate cement comprises one or more ingredients selected from the group consisting of tetracalcium phosphate (TTCP) (Ca 4 (PO 4 ) 2 O), dicalcium phosphate anhydrous (DCPA) (CaHPO 4 ), dicalcium phosphate dihydrate (CaHPO 4 .2H 2 O), tricalcium phosphate (Ca 3 [PO 4 ] 2 ), α-tricalcium phosphate (α-Ca 3 (PO 4 ) 2 ), β-tricalcium phosphate (β-Ca 3 (PO 4 ) 2 ), octacalcium phosphate (Ca 8 H 2 (PO 4 ) 6 5H 2 O), amorphous calcium phosphate (Ca 3 (PO 4 ) 2 ), calcium carbonate (CaCO 3 ), calcium hydroxide (Ca[OH] 2 ), and hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ), and mixtures thereof. 
     
     
         39 . The bone paste of any one of  claims 28 - 37 , wherein the calcium phosphate cement comprises tetracalcium phosphate and dicalcium phosphate anhydrous. 
     
     
         40 . The bone paste of  claim 39 , wherein the calcium phosphate cement comprises a molar ratio of tetracalcium phosphate to dicalcium phosphate anhydrous of about 1:5 to about 5:1. 
     
     
         41 . The bone paste of  claim 39 , wherein the calcium phosphate cement comprises a molar ratio of tetracalcium phosphate to dicalcium phosphate anhydrous of about 1:3 to about 1:1. 
     
     
         42 . The bone paste of  claim 39 , wherein the calcium phosphate cement comprises an approximately 1:1 molar ratio of tetracalcium phosphate to dicalcium phosphate anhydrous. 
     
     
         43 . The bone paste of any one of  claims 28 - 37 , wherein the calcium phosphate cement further comprises chitosan. 
     
     
         44 . The bone paste of any one of  claims 28 - 37 , wherein the calcium phosphate cement further comprises fibers. 
     
     
         45 . The bone paste of  claim 40 , wherein the fibers are degradable. 
     
     
         46 . The bone paste of any one of  claims 28 - 37 , wherein the calcium phosphate cement further comprises chitosan and degradable fibers. 
     
     
         47 . The bone paste of any one of  claims 28 - 37 , wherein the calcium phosphate cement further comprises a porogen. 
     
     
         48 . The bone paste of  claim 47 , wherein the porogen is NaHCO 3  and citric acid. 
     
     
         49 . The bone paste of  claim 48 , wherein the mass fraction of NaHCO 3  is from about 5% to about 30%, and the mass fraction of citric acid is from about 50% to about 60%. 
     
     
         50 . The bone paste of  claim 43 , wherein the bone paste comprises calcium phosphate cement and a RGD-containing peptide, wherein the RGD-containing peptide is present within a range of about 0.0005% to about 0.05% by mass, and wherein the RGD-containing peptide is covalently linked to said chitosan. 
     
     
         51 . The bone paste of any one of  claims 28 - 37 , wherein the microbeads are hydrogel microbeads. 
     
     
         52 . The bone paste of  claim 51 , wherein the microbeads are comprised of alginate, partially oxidized alginate, oxidized alginate, alginate-fibrin, partially oxidized alginate-fibrin, oxidized alginate-fibrin, poly(ethylene glycol diacrylate), poly(ethylene glycol)-anhydride dimethacrylate, gelatin, chemically cross-linked polymers, ionically cross-linked polymers, heat-polymerized polymers, or photopolymerized polymers. 
     
     
         53 . The bone paste of  claim 51 , wherein the microbeads are alginate-fibrin microbeads. 
     
     
         54 . The bone paste of  claim 53 , wherein the alginate-fibrin microbeads comprise a fibrinogen mass fraction of from about 0.05% to about 1%. 
     
     
         55 . The bone paste of  claim 53 , wherein the alginate-fibrin microbeads comprise a fibrinogen mass fraction of about 0.1%. 
     
     
         56 . The bone paste of  claim 53 , wherein the alginate is at about 7.5% oxidation. 
     
     
         57 . The bone paste of any one of  claims 28 - 37 , wherein the microbeads are present in a volume of about 40 to 60%. 
     
     
         58 . The bone paste of any one of  claims 28 - 37 , wherein the microbeads have an average diameter of less than about 2 millimeters. 
     
     
         59 . The bone paste of any one of  claims 28 - 37 , wherein the cells are stem cells. 
     
     
         60 . The bone paste of any one of  claims 28 - 37 , wherein the cells are selected from the group consisting of human umbilical cord mesenchymal stem cells, bone marrow stem cells, embryonic stem cells, pluripotent stem cells, induced pluripotent stem cells, multipotent stem cells, progenitor cells, and osteoblasts. 
     
     
         61 . The bone paste of any one of  claims 28 - 37 , wherein the bone paste is injectable. 
     
     
         62 . A method for preparing a bone paste, comprising covalently linking an RGD-containing peptide to chitosan to form RGD-grafted chitosan, dissolving the RGD-grafted chitosan in water to form a chitosan liquid, and mixing calcium phosphate cement into the chitosan liquid, thereby preparing a bone paste. 
     
     
         63 . The method of  claim 62 , wherein the RGD-containing peptide is selected from the group consisting of RGD, G4RGDSP, RGDS, GRGD, GRGDGY, RGDSGGC, and GRGDS. 
     
     
         64 . The method of  claim 62  or  63 , wherein the RGD-containing peptide is present within a range of about 0.0005% to about 5% by mass. 
     
     
         65 . The method of  claim 62  or  63 , wherein the chitosan is chitosan lactate. 
     
     
         66 . The method of  claim 62  or  63 , wherein a degradable fiber is added to the chitosan liquid prior to mixing calcium phosphate cement into the chitosan liquid. 
     
     
         67 . The method of  claim 62  or  63 , wherein the calcium phosphate cement comprises an approximately 1:1 molar ratio of tetracalcium phosphate to dicalcium phosphate anhydrous.

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