WO2005016616A1 - Methods for preparing medical implants from calcium phosphate cement and medical implants - Google Patents
Methods for preparing medical implants from calcium phosphate cement and medical implants Download PDFInfo
- Publication number
- WO2005016616A1 WO2005016616A1 PCT/US2004/022309 US2004022309W WO2005016616A1 WO 2005016616 A1 WO2005016616 A1 WO 2005016616A1 US 2004022309 W US2004022309 W US 2004022309W WO 2005016616 A1 WO2005016616 A1 WO 2005016616A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phosphate
- calcium
- paste
- liquid
- calcium phosphate
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 163
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 title claims abstract description 151
- 239000001506 calcium phosphate Substances 0.000 title claims abstract description 131
- 229910000389 calcium phosphate Inorganic materials 0.000 title claims abstract description 122
- 235000011010 calcium phosphates Nutrition 0.000 title claims abstract description 121
- 239000007943 implant Substances 0.000 title claims abstract description 72
- 239000004568 cement Substances 0.000 title claims abstract description 65
- 230000001054 cortical effect Effects 0.000 claims abstract description 47
- 239000007788 liquid Substances 0.000 claims description 158
- 239000000843 powder Substances 0.000 claims description 116
- 229960001714 calcium phosphate Drugs 0.000 claims description 113
- 210000000988 bone and bone Anatomy 0.000 claims description 49
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 36
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 239000007864 aqueous solution Substances 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- 239000011575 calcium Substances 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims description 19
- 229910001868 water Inorganic materials 0.000 claims description 19
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 16
- ZBZJARSYCHAEND-UHFFFAOYSA-L calcium;dihydrogen phosphate;hydrate Chemical compound O.[Ca+2].OP(O)([O-])=O.OP(O)([O-])=O ZBZJARSYCHAEND-UHFFFAOYSA-L 0.000 claims description 15
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 15
- 229910000388 diammonium phosphate Inorganic materials 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 239000003929 acidic solution Substances 0.000 claims description 14
- 239000003637 basic solution Substances 0.000 claims description 14
- 230000007423 decrease Effects 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 13
- GBNXLQPMFAUCOI-UHFFFAOYSA-H tetracalcium;oxygen(2-);diphosphate Chemical compound [O-2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GBNXLQPMFAUCOI-UHFFFAOYSA-H 0.000 claims description 13
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 12
- 229910019142 PO4 Inorganic materials 0.000 claims description 10
- 238000002441 X-ray diffraction Methods 0.000 claims description 10
- YYRMJZQKEFZXMX-UHFFFAOYSA-L calcium bis(dihydrogenphosphate) Chemical compound [Ca+2].OP(O)([O-])=O.OP(O)([O-])=O YYRMJZQKEFZXMX-UHFFFAOYSA-L 0.000 claims description 10
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium phosphate dihydrate Substances O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 claims description 10
- 235000019691 monocalcium phosphate Nutrition 0.000 claims description 10
- 238000000465 moulding Methods 0.000 claims description 10
- 229910000392 octacalcium phosphate Inorganic materials 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 10
- YIGWVOWKHUSYER-UHFFFAOYSA-F tetracalcium;hydrogen phosphate;diphosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[Ca+2].OP([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O YIGWVOWKHUSYER-UHFFFAOYSA-F 0.000 claims description 10
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 9
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 9
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 8
- 229910052791 calcium Inorganic materials 0.000 claims description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 8
- 229910017604 nitric acid Inorganic materials 0.000 claims description 8
- 238000005192 partition Methods 0.000 claims description 8
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 239000011148 porous material Substances 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
- JUNWLZAGQLJVLR-UHFFFAOYSA-J calcium diphosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])(=O)OP([O-])([O-])=O JUNWLZAGQLJVLR-UHFFFAOYSA-J 0.000 claims description 6
- 235000019838 diammonium phosphate Nutrition 0.000 claims description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical group [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 238000005245 sintering Methods 0.000 claims description 6
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims description 6
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 6
- 239000004132 Calcium polyphosphate Substances 0.000 claims description 5
- 229940062672 calcium dihydrogen phosphate Drugs 0.000 claims description 5
- ROPDWRCJTIRLTR-UHFFFAOYSA-L calcium metaphosphate Chemical compound [Ca+2].[O-]P(=O)=O.[O-]P(=O)=O ROPDWRCJTIRLTR-UHFFFAOYSA-L 0.000 claims description 5
- 235000019827 calcium polyphosphate Nutrition 0.000 claims description 5
- 229940043256 calcium pyrophosphate Drugs 0.000 claims description 5
- 229910000394 calcium triphosphate Inorganic materials 0.000 claims description 5
- HUSUHZRVLBSGBO-UHFFFAOYSA-L calcium;dihydrogen phosphate;hydroxide Chemical compound O.[Ca+2].OP([O-])([O-])=O HUSUHZRVLBSGBO-UHFFFAOYSA-L 0.000 claims description 5
- VEJCUEBBRSCJRP-UHFFFAOYSA-L calcium;hydron;phosphonato phosphate Chemical compound [Ca+2].OP(O)(=O)OP([O-])([O-])=O VEJCUEBBRSCJRP-UHFFFAOYSA-L 0.000 claims description 5
- 235000019821 dicalcium diphosphate Nutrition 0.000 claims description 5
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 5
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 5
- 229910000150 monocalcium phosphate Inorganic materials 0.000 claims description 5
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 5
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 5
- RFWLACFDYFIVMC-UHFFFAOYSA-D pentacalcium;[oxido(phosphonatooxy)phosphoryl] phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O RFWLACFDYFIVMC-UHFFFAOYSA-D 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- 235000021317 phosphate Nutrition 0.000 claims description 5
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 5
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 5
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 5
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 5
- VQNBUJAEBQLLKU-UHFFFAOYSA-H tricalcium;diphosphate;hydrate Chemical compound O.[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VQNBUJAEBQLLKU-UHFFFAOYSA-H 0.000 claims description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 claims description 4
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007836 KH2PO4 Substances 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- 235000011054 acetic acid Nutrition 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 239000000908 ammonium hydroxide Substances 0.000 claims description 4
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- XQGPKZUNMMFTAL-UHFFFAOYSA-L dipotassium;hydrogen phosphate;trihydrate Chemical compound O.O.O.[K+].[K+].OP([O-])([O-])=O XQGPKZUNMMFTAL-UHFFFAOYSA-L 0.000 claims description 4
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 claims description 4
- PYLIXCKOHOHGKQ-UHFFFAOYSA-L disodium;hydrogen phosphate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O PYLIXCKOHOHGKQ-UHFFFAOYSA-L 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- 239000004310 lactic acid Substances 0.000 claims description 4
- 235000014655 lactic acid Nutrition 0.000 claims description 4
- 239000001630 malic acid Substances 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 4
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 4
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 claims description 4
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- DDXPLCBTGWFAIG-UHFFFAOYSA-N triazanium;phosphate;trihydrate Chemical compound [NH4+].[NH4+].[NH4+].O.O.O.[O-]P([O-])([O-])=O DDXPLCBTGWFAIG-UHFFFAOYSA-N 0.000 claims description 4
- 235000019798 tripotassium phosphate Nutrition 0.000 claims description 4
- ASTWEMOBIXQPPV-UHFFFAOYSA-K trisodium;phosphate;dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[O-]P([O-])([O-])=O ASTWEMOBIXQPPV-UHFFFAOYSA-K 0.000 claims description 4
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- HLCFGWHYROZGBI-JJKGCWMISA-M Potassium gluconate Chemical compound [K+].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O HLCFGWHYROZGBI-JJKGCWMISA-M 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 238000004140 cleaning Methods 0.000 claims description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 150000004676 glycans Chemical class 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 235000016337 monopotassium tartrate Nutrition 0.000 claims description 3
- 229920001282 polysaccharide Polymers 0.000 claims description 3
- 239000005017 polysaccharide Substances 0.000 claims description 3
- KYKNRZGSIGMXFH-ZVGUSBNCSA-M potassium bitartrate Chemical compound [K+].OC(=O)[C@H](O)[C@@H](O)C([O-])=O KYKNRZGSIGMXFH-ZVGUSBNCSA-M 0.000 claims description 3
- 229940081543 potassium bitartrate Drugs 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000004224 potassium gluconate Substances 0.000 claims description 3
- 235000013926 potassium gluconate Nutrition 0.000 claims description 3
- 229960003189 potassium gluconate Drugs 0.000 claims description 3
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 claims description 3
- 229940074439 potassium sodium tartrate Drugs 0.000 claims description 3
- 235000011151 potassium sulphates Nutrition 0.000 claims description 3
- 239000011697 sodium iodate Substances 0.000 claims description 3
- 239000001540 sodium lactate Substances 0.000 claims description 3
- 235000011088 sodium lactate Nutrition 0.000 claims description 3
- 229940005581 sodium lactate Drugs 0.000 claims description 3
- 235000011006 sodium potassium tartrate Nutrition 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- -1 K3PO Chemical compound 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims 2
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 claims 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 claims 1
- 239000008280 blood Substances 0.000 abstract description 4
- 210000004369 blood Anatomy 0.000 abstract description 4
- 210000001124 body fluid Anatomy 0.000 abstract description 4
- 239000010839 body fluid Substances 0.000 abstract description 4
- 230000009977 dual effect Effects 0.000 abstract description 4
- 230000035515 penetration Effects 0.000 abstract description 4
- 230000008467 tissue growth Effects 0.000 abstract 1
- 238000007654 immersion Methods 0.000 description 13
- 230000000694 effects Effects 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 229910000831 Steel Inorganic materials 0.000 description 4
- 239000002131 composite material Substances 0.000 description 4
- 230000006835 compression Effects 0.000 description 4
- 238000007906 compression Methods 0.000 description 4
- 239000002105 nanoparticle Substances 0.000 description 4
- 239000010959 steel Substances 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 229910052586 apatite Inorganic materials 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 230000003014 reinforcing effect Effects 0.000 description 2
- 230000003319 supportive effect Effects 0.000 description 2
- 229910014771 Ca4(PO4)2O Inorganic materials 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229910000393 dicalcium diphosphate Inorganic materials 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/28—Bones
-
- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B28/00—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements
- C04B28/34—Compositions of mortars, concrete or artificial stone, containing inorganic binders or the reaction product of an inorganic and an organic binder, e.g. polycarboxylate cements containing cold phosphate binders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2/46—Special tools for implanting artificial joints
- A61F2/4644—Preparation of bone graft, bone plugs or bone dowels, e.g. grinding or milling bone material
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
- A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C39/00—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
- B29C39/02—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor for making articles of definite length, i.e. discrete articles
-
- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B38/00—Porous mortars, concrete, artificial stone or ceramic ware; Preparation thereof
- C04B38/04—Porous mortars, concrete, artificial stone or ceramic ware; Preparation thereof by dissolving-out added substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/02—Prostheses implantable into the body
- A61F2/30—Joints
- A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
- A61F2002/30316—The prosthesis having different structural features at different locations within the same prosthesis; Connections between prosthetic parts; Special structural features of bone or joint prostheses not otherwise provided for
- A61F2002/30535—Special structural features of bone or joint prostheses not otherwise provided for
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B2111/00—Mortars, concrete or artificial stone or mixtures to prepare them, characterised by specific function, property or use
- C04B2111/00241—Physical properties of the materials not provided for elsewhere in C04B2111/00
- C04B2111/00413—Materials having an inhomogeneous concentration of ingredients or irregular properties in different layers
-
- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B2111/00—Mortars, concrete or artificial stone or mixtures to prepare them, characterised by specific function, property or use
- C04B2111/00474—Uses not provided for elsewhere in C04B2111/00
- C04B2111/00612—Uses not provided for elsewhere in C04B2111/00 as one or more layers of a layered structure
-
- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B2111/00—Mortars, concrete or artificial stone or mixtures to prepare them, characterised by specific function, property or use
- C04B2111/00474—Uses not provided for elsewhere in C04B2111/00
- C04B2111/00836—Uses not provided for elsewhere in C04B2111/00 for medical or dental applications
Definitions
- the present invention is related to a medical implant made from calcium phosphate cement, and in particular to a method of preparing a molded and hardened calcium phosphate cement article having a superior compressive strength for use as medical implant.
- the molded and hardened calcium phosphate cement block may be in the forms of a dense block, a porous block for use as tissue-engineered scaffold, or a dual function block comprising a dense cortical portion bearing the majority of load and a porous cancellous portion allowing a rapid blood/body fluid penetration and tissue ingrowth.
- a prosthetic bone implant is bioresorbable and is supportive at the same time. Accordingly, an article made of calcium phosphate will be preferable than that made of a metal, if the former has strength which is comparable to a human cortical bone.
- One way of making such a bone implant is by sintering a calcium phosphate powder, particularly a hydroxyapatite (HA) powder, into a block material at a temperature generally greater than 1000°C.
- HA hydroxyapatite
- the conventional spinal fusing device is composed of a metallic cage and a bioresorbable material disposed in the metal cage, for example the one disclosed in US patent No. 5,645,598.
- An inevitable disadvantage of this fusion device is the sinking of the metallic cage sitting between two vertebrae to replace or repair a defect spinal disk, because the hardness and the relatively small size of the cage wear out or break the bone tissue, and in particular the endplate of the vertebra.
- a tissue-engineered scaffold (majority made from biodegradable polymers) has a very porous structure that allows living cells (usually taken from the patient being treated) to penetrate into the structure and be "seeded" in- vitro during a cell culture process.
- the cell-seeded scaffold is implanted into either an animal (e.g., rat) whose immune system has been removed, or into the patient himself (usually under the skin for easier later-on process).
- an animal e.g., rat
- the cells quickly multiply from absorbing nutrients from the animal or the patient's body, and, at the same time, the scaffold itself is gradually dissolved or resorbed.
- the implant now a real bone
- the implant is removed from under the skin of the animal or the patient and re-implanted into the (wounded or diseased) site being treated.
- tissue-engineered scaffold US 6,139,578; US 6,200,606; US 5,306,303; and US 6,132,463. It is advantageous if a tissue-engineered scaffold is bioresorbable, sufficiently porous and supportive at the same time.
- the conventional high temperature (usually >1000°C)-sintered porous hydroxyapatite (HA) block material does not possess sufficient micro/nano-sized porosity and is hardly bioresorbable.
- the conventional biodegradable polymer for scaffold application exhibits a relatively low strength and too high a dissolution rate.
- An objective of the invention is to provide a molded and hardened calcium phosphate cement (CPC) article or block having a superior compressive strength for use as medical implant, which is free from the aforesaid drawbacks in the prior art.
- Another objective of the invention is to provide a porous hardened CPC article or block for use as a tissue-engineered scaffold, which is free from the aforesaid drawbacks in the prior art, or as a functional implant other than the tissue-engineered scaffold.
- Another objective of the invention is to provide a dual function hardened calcium phosphate cement (CPC) article or block for use as a prosthetic bone implant comprising a dense cortical portion and a porous cancellous portion, which is free from the aforesaid drawbacks in the prior art.
- the prosthetic bone implant constructed according to the present invention is made of a hardened calcium phosphate cement having an apatitic phase as a major phase, which comprises a dense cortical portion bearing the majority of load and a porous cancellous portion allowing a rapid blood/body fluid penetration and tissue ingrowth.
- the prosthetic bone implant of the present invention is made by a novel technique, which involves immersing an article molded from two different pastes of calcium phosphate cement (CPC), one of them having an additional pore-forming powder, in a liquid for a period of time, so that the compressive strength of the molded CPC article is significantly improved after removing from the liquid while the pore-forming powder is dissolved in the liquid, creating pores in a desired zone or zones of the molded article.
- CPC calcium phosphate cement
- the dense cortical portion of the prosthetic bone implant made according to the present invention exhibits a high strength comparable to that of human cortical bone (about 110-170 MPa). The strength is adjustable by adjusting process parameters. 3.
- the dense cortical portion of the prosthetic bone implant made according to the present invention contains significant amount of micro- and nano-sized porosity, that improves bioresorbability thereof.
- the porous cancellous portion of the prosthetic bone implant made according to the present invention possesses a porosity greater than 40% in volume, prepferably 40-90%, allowing rapid blood/body fluid penetration and tissue ingrowth, thereby anchoring the prosthetic bone implant. 5.
- a wide range of medical application includes bone dowel, spacer, cavity filler, artificial disc and fixation devices for spine and other locations, to name a few.
- a novel method for making a hardened CPC article for use as medical implant involves impregnating an article molded from a paste of CPC in a liquid for a period of time, so that the compressive strength of the CPC block is significantly improved after removing from the liquid. It is apparent that the medical implant prepared according to this novel method has the features and advantages recited in the above-mentioned Items 3 and 5.
- a novel method for making a porous hardened CPC article for use as a tissue-engineered scaffold which involves preparing a shaped article from a paste comprising a calcium phosphate cement, a pore-forming powder and a setting liquid; and immersing said shaped article in an immersing liquid for a period of time so that said pore-forming powder is dissolved in the immersing liquid, creating pores in said shaped article.
- the porous hardened CPC article made according to the present invention has the following features and advantages: - The porous hardened CPC article can transform into an apatite-dominated material shortly after immersion in physiological solution or after implantation. - The porous hardened CPC article exhibits a higher strength than most other bioactive or biodegradable porous blocks with a similar porosity level.
- Figs. 2a to 2f are schematic cross sectional views showing steps of a method for preparing a prosthetic bone implant according to one embodiment of the present invention.
- Figs. 3a and 3b are schematic vertical and horizontal cross sectional views of a prosthetic bone implant prepared according to another embodiment of the present invention, respectively.
- the present invention discloses a method for making a hardened molded calcium phosphate cement (CPC) article comprising impregnating a rigid shaped article of calcium phosphate with an impregnating liquid for a period of time so that a compressive strength of the resulting impregnated article removed from the impregnating liquid is increased compared to that of the rigid shaped article without said impregnating treatment.
- the impregnating liquid is an acidic solution, a basic solution, a physiological solution, an organic solvent, or a substantially pure water.
- the impregnating liquid comprises at least one of Ca and P sources.
- the impregnating liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH 4 ) 2 HPO 4 .
- the rigid shaped article of calcium phosphate is a molded article from a paste of calcium phosphate cement.
- the impregnating is carried out for a period longer than 10 minutes, and more preferably for about 12 hours to 96 hours.
- the impregnating is carried out 30-90°C, and more preferably at room temperature.
- a method for making a molded calcium phosphate article comprises the following steps: (a) preparing a powder of a calcium phosphate cement; (b) mixing said powder with a setting liquid to form a paste, wherein said paste undergoes a hardening reaction; (c) molding said paste into an article in a mold of a desired shape and size before said hardening reaction is complete; (d) impregnating the resulting hardened article from step (c) with an impregnating liquid to allow strength of said article to increase; and (e) removing said article from said impregnating liquid.
- said calcium phosphate cement comprises at least one Ca source and at least one P source, or more preferably at least one calcium phosphate source.
- Said calcium phosphate source comprises one or more calcium phosphates selected from the group consisting of alpha-tricalcium phosphate ( ⁇ -TCP), beta-tricalcium phosphate ( ⁇ -TCP), tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA), octacalcium phosphate (OCP), calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium pyrophosphate, calcium triphosphate, calcium phosphate tribasic, calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium phosphate, tricalcium phosphate, tri
- the calcium phosphate source comprises at least one calcium phosphate particle having calcium phosphate whiskers on the surface of said calcium phosphate particle, wherein said calcium phosphate whiskers have a length of about 1-5000 nm and a width of about 1-500 nm.
- the setting liquid in step (b) is an acidic solution, a basic solution, or a substantially pure water.
- An acidic solution suitable for use in the present invention is selected from the group consisting of nitric acid (HNO 3 ), hydrochloric acid (HCl), phosphoric acid (H 3 PO ), carbonic acid (H 2 CO 3 ), sodium dihydrogen phosphate (NaH PO 4 ), sodium dihydrogen phosphate monohydrate (NaH PO 4 » H 2 O), sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dehydrate, potassium dihydrogen phosphate (KH 2 PO 4 ), ammonium dihydrogen.phosphate (NH 4 H PO 4 ), malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture.
- a basic solution suitable for use in the present invention is selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na 2 HPO 4 ), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na 3 PO » 12H 2 O), dipotassium hydrogen phosphate (K 2 HPO 4 ), potassium hydrogen phosphate trihydrate (K 2 HPO *3H 2 O), potassium phosphate tribasic (K 3 PO 4 ), diammonium hydrogen phosphate ((NH 4 ) 2 HPO 4 ), ammonium phosphate trihydrate ((NH ) 3 PO 4 *3H 2 O), sodium hydrogen carbonate (NaHCO ), sodium carbonate Na 2 CO 3 , and their mixture.
- Step (c) of the method of the present invention preferably further comprises removing said article from said mold.
- Step (c) of the method of the present invention preferably further comprises removing a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases.
- Step (c) of the method of the present invention preferably further comprises pressurizing said paste in said mold, preferably between 1 and 500 MPa, before said hardening reaction is complete to remove a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases. More preferably, step (c) further comprises heating said paste during said pressurizing.
- Step (c) of the method of the present invention preferably further comprises heating said paste during molding.
- Step (d) of the method of the present invention preferably further comprises heating the impregnating liquid, preferably at a temperature between 30 and 90°C during said impregnating.
- the method of the present invention may further comprise drying said article after removing said article from said impregnating liquid.
- the method of the present invention may further comprise heating said article, preferably at a temperature between 50 and 500°C, after removing said article from said impregnating liquid.
- the molded calcium phosphate article made according to the method of the present invention may be used as a medical implant or a reinforcing constituent of a composite. According to a second preferred embodiment of the present invention, a method for making a porous hardened CPC article is provided.
- the second preferred embodiment is similar to the first embodiment with a major difference in that a pore-forming powder is mixed with the powder of calcium phosphate cement used in step (a).
- the method for making a porous hardened CPC article according to the second preferred embodiment comprises: i) preparing a shaped article from a paste comprising a calcium phosphate cement, a pore-forming powder and a setting liquid; ii) immersing said shaped article in an immersing liquid for a first period of time so that said pore-forming powder is dissolved in the immersing liquid, creating pores in said shaped article; iii) removing the resulting porous shaped article from said immersing liquid; and iv) immersing the porous shaped article from step iii) in an impregnating liquid for a second period of time so that a compressive strength of the resulting article removed from the impregnating liquid is increased compared to that of said porous shaped article without said impregnating treatment, wherein step i
- Said pore-forming powder preferably is selected from the group consisting of LiCl, KC1, NaCI, MgCl 2 , CaCl 2 , NaIO 3 , KI, Na 3 PO 4 , K 3 PO 4 , Na 2 CO 3 , amino acid-sodium salt, amino acid-potassium salt, glucose, polysaccharide, fatty acid-sodium salt, fatty acid-potassium salt, potassium bitartrate (KHC H 4 O 6 ), potassium carbonate, potassium gluconate (KC 6 H ⁇ O 7 ), potassium-sodium tartrate (KNaC 4 H O 6 '4H 2 O), potassium sulfate (K 2 SO ), sodium sulfate, and sodium lactate.
- LiCl, KC1, NaCI, MgCl 2 , CaCl 2 , NaIO 3 , KI, Na 3 PO 4 , K 3 PO 4 , Na 2 CO 3 amino acid-sodium salt, amino acid-potassium salt, glucose, poly
- said immersing liquid in step ii) and said impregnating liquid in step iv) independently are an acidic aqueous solution, a basic aqueous solution, a physiological solution, an organic solvent, or a substantially pure water.
- Said immersing liquid may comprises at least one of Ca and P sources.
- Said immersing liquid may be a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH 4 ) 2 HPO 4 .
- Said impregnating liquid in step iv) may be different from or the same as the immersing liquid in step i).
- the first period of time in step ii) is longer than 10 minutes, and more preferably longer than 1 day.
- the second period of time in step iv) is longer than 10 minutes, and more preferably longer than 1 day.
- the immersing in step ii) and iv) is carried out at room temperature or at a temperature between about 30 and 90°C.
- said paste in step i) further comprises living cells.
- said immersing liquid in step ii) comprises living cells.
- said impregnating liquid in step iv) comprises living cells.
- said porous shaped article having an increased compressive strength removed from said impregnating liquid in step iv) has a porosity of at least 20 vol%, and more preferably of 40-90 vol%.
- the porous hardened CPC article made according to the method of the present invention may be used as a tissue-engineered scaffold, medical implant or a reinforcing constituent of a composite.
- a method for making a dual function hardened CPC article for use as a prosthetic bone implant is provided.
- the third preferred embodiment basically is a combination of the first embodiment and the second embodiment, wherein a first CPC paste without the pore-forming powder and a second CPC paste containing the pore-forming powder are used to mold an integral article and immersing the integral article in the impregnating liquid, so that the pore-forming powder is dissolved in the immersing liquid, creating pores in the integral article while the hardened CPC gaining compressive strength.
- a prosthetic bone implant comprising a cortical portion having two opposite sides, and a cancellous portion integrally disposed in said cortical portion and being exposed through said two opposite sides, wherein said cortical portion comprises a hardened calcium phosphate cement has a porosity of less than 40%) in volume, and said cancellous portion comprises a porous hardened calcium phosphate cement having a porosity greater than 20% in volume, and greater than that of said cortical portion.
- the prosthetic bone implant according to Feature 2 further comprising a transitional portion between said column and said hollow disk surrounding said central cylinder, which has properties range from those of said cancellous portion to said cortical portion.
- a method for preparing a prosthetic bone implant comprising a cortical portion having two opposite sides, and a cancellous portion integrally disposed in said cortical portion and being exposed through said two opposite sides, said method comprises the following steps: a) preparing a first paste comprising a first calcium phosphate cement and a first setting liquid; b) preparing a second paste comprising a second calcium phosphate cement, a pore-forming powder and a second setting liquid; c) i) preparing a shaped article in a mold having two or more cells separated by one more partition walls comprising introducing said first paste and said second paste into said two or more cells separately, and removing said one or more partition walls from said mold, so that said second paste in the form of a single column or two or more isolated columns is integrally disposed in the first paste in said mold; or ii) preparing a shaped article comprising introducing one of said first paste and said second paste into a first mold to form an intermediate in said first mold, placing said intermediate into a
- said first calcium phosphate cement comprises at least one Ca source and at least one P source, or at least one calcium phosphate source; and said second calcium phosphate cement comprises at least one Ca source and at least one P source, or at least one calcium phosphate source.
- step c-i) further comprises allowing said first paste and said second paste undergoing a hardening reaction in said mold.
- step c-i) further comprises pressurizing said first paste and said second paste in said mold after removing said one or more partition walls from said mold to remove a portion of liquid from said first paste and said second paste, so that a liquid/powder ratio of said first paste and of said second paste decreases; and allowing said first paste and second paste undergoing a hardening reaction in said mold.
- step c-ii) further comprises allowing said intermediate undergoing a hardening reaction in said first mold, and allowing said another one of said first paste and said second paste undergoing a hardening reaction in said second mold.
- step c-ii) further comprises pressurizing said one of said first paste and said second paste in said first mold to remove a portion of liquid therefrom before the hardening reaction of said intermediate is completed; allowing said intermediate undergoing a hardening reaction in said first mold; pressuring said another one of said first paste and said second paste in said second mold, so that a liquid/powder ratio of said another one of said first paste and of said second paste decreases; and allowing said another one of said first paste and second paste undergoing a hardening reaction in said second mold.
- 31. The method according to Feature 28, wherein said pressuring is about 1 to 500 MPa.
- the immersing liquid is an acidic aqueous solution, a basic aqueous solution, a physiological solution, an organic solvent, or a substantially pure water.
- the immersing liquid comprises at least one of Ca and P sources.
- the immersing liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH 4 ) 2 HPO 4 .
- step d) The method according to Feature 16, wherein the immersing in step d) is carried out for a period longer than 1 day.
- step d) is carried out at a temperature of about 10 and 90°C.
- Figs, la to Id Four different designs of prosthetic bone implants constructed according to the present invention are shown in Figs, la to Id.
- the prosthetic bone implant of the present invention has a dense cortical portion DI in the tubular form and a porous cancellous portion PI formed in the central through hole of the tubular cortical portion DI .
- Both the dense cortical portion DI and the porous cancellous portion PI are made of a hardened calcium phosphate cement having an apatitic phase as a major phase.
- Fig. la the dense cortical portion DI in the tubular form and a porous cancellous portion PI formed in the central through hole of the tubular cortical portion DI .
- Both the dense cortical portion DI and the porous cancellous portion PI are made of a hardened calcium phosphate cement having an apatitic phase as a major phase.
- the prosthetic bone implant of the present invention has a dense cortical portion DI in the tubular form; a cylindrical porous cancellous portion PI in the center of the tubular cortical portion DI ; and an annular transitional portion P2 connecting the tubular cortical portion DI and the cylindrical cancellous portion PI .
- the transitional portion P2 is made of a hardened calcium phosphate cement having an apatitic phase as a major phase, and a porosity gradient increasing from the lower porosity of the cylindrical cancellous portion PI to the higher porosity of the tubular cortical portion DI, which may be formed in-situ during molding of two different two different CPC pastes, one of them having an additional pore-forming powder for forming the cylindrical cancellous portion PI, and another one being a regular CPC powder for forming the dense cortical portion DI.
- the porous cancellous portion PI may be in the forms of isolated columns surrounded by the dense cortical portion DI as shown in Figs, lc and Id.
- a suitable method for preparing the prosthetic bone implant of the present invention includes placing a tubular partition wall 10 in a hollow cylindrical mold 20, as shown in Fig. 2a; pouring a first paste comprising a calcium phosphate cement and a setting liquid in the annular cell and a second paste comprising the calcium phosphate cement, a pore-forming powder and the setting liquid in the central cell, as shown in Fig. 2b; removing the partition wall and pressing the CPC pastes before hardening, as shown in Fig. 2c, wherein a portion of the setting liquid is removed from the gap between the mold 20 and the press 30 and/or holes (not shown in the drawing) provided on the press 30.
- the CPC paste will undergo a hardening reaction to convert into apatitic phase.
- the hardened disk is removed from the mold and is subjected to surface finishing to expose the central portion hardened from the second paste, as shown in Fig. 2d, followed by immersing in a bath of an immersing liquid as shown in Fig. 2e, where the pore-forming powder is dissolved in the immersing liquid while the hardened CPC thereof gaining compressive strength.
- the immersing may last from 10 minutes to several days.
- the composite disk so formed is washed with water after being removed from the bath, and dried and heated in an oven to obtain the prosthetic bone implant as shown in Fig. 2f.
- An alternative method for preparing the prosthetic bone implant of the present invention from the same raw materials includes pouring the second paste in a first mold, pressing the second paste to remove a portion of the setting liquid from the second paste before the hardening reaction is completed, so that the liquid/powder ratio in the second paste decreases, and allowing the hardening reaction undergo in the mold for a period of time, e.g. 15 minutes starting from the mixing of the CPC powder, the pore-forming powder and the setting liquid, to obtain a cylindrical block having a diameter of 7 mm.
- the cylindrical block is removed from the first mold, and placed in the center of a second mold having a diameter of 10 mm.
- the first paste is poured into the annular space in the second mold, and a press having a dimension corresponding to the annular shape is used to pressure the first paste to remove a portion of the setting liquid from the first paste before the hardening reaction is completed, so that the liquid/powder ratio in the first paste decreases.
- the first paste will undergo a hardening reaction to convert into apatitic phase.
- the hardened cylinder having a diameter of 10 mm is removed from the second mold, followed by immersing in an immersing liquid, where the pore-forming powder contained in the second paste is dissolved in the immersing liquid while the hardened CPC thereof gaining compressive strength, to obtain the prosthetic bone implant of the present invention, as shown in Figs. 3a and 3b.
- the prosthetic bone implant shown in Figs. 3a and 3b can also be prepared by changing the sequence of the molding of the first paste and the second paste with modifications to the second mold used in this alternative method.
- the following examples are intended to demonstrate the invention more fully without acting as a limitation upon its scope, since numerous modifications and variations will be apparent to those skilled in this art.
- PREPARATIVE EXAMPLE 1 Preparation of TTCP Powder A Ca (PO ) 2 O (TTCP) powder was prepared by mixing Ca 2 P 2 O powder with CaCO 3 powder uniformly in ethanol for 24 hours followed by heating to dry. The mixing ratio of Ca 2 P 2 O 7 powder to CaCO 3 powder was 1 : 1.27 (weight ratio) and the powder mixture was heated to 1400°C to allow two powders to react to form TTCP.
- PREPARATIVE EXAMPLE 2 Preparation of conventional TTCP/DCPA-based CPC powder (abbreviated as C-CPC) The resulting TTCP powder from PREPARATIVE EXAMPLE 1 was sieved and blended with dried CaHPO 4 (DCPA) powder in a ball mill for 12 hours. The blending ratio of the TTCP powder to the DCPA powder was 1 : 1 (molar ratio) to obtain the conventional CPC powder. Particles of this C-CPC powder have no whisker on the surfaces thereof.
- PREPARATIVE EXAMPLE 3 Preparation of non-dispersive TTCP/DCPA-based CPC powder (abbreviated as ND-CPC)
- the TTCP powder prepared according to the method of PREPARATIVE EXAMPLE 1 was sieved and blended with dried CaHPO (DCPA) powder in a ball mill for 12 hours.
- the blending ratio of the TTCP powder to the DCPA powder was 1 : 1 (molar ratio).
- the resultant powder mixture was added to a 25 mM diluted solution of phosphate to obtain a powder/solution mixture having a concentration of 3 g powder mixture per 1 ml solution while stirring.
- the resulting powder/solution mixture was formed into pellets, and the pellets were heated in an oven at 50°C for 10 minutes. The pellets were then uniformly ground in a mechanical mill for 20 minutes to obtain the non-dispersive
- TTCP/DCPA-based CPC powder (ND-CPC).
- the particles of this ND-CPC powder have whisker on the surfaces thereof.
- Dense blocks EXAMPLE 1 Effect of immersion time on compressive strength of CPC block
- the ND-CPC powder from PREPARATIVE EXAMPLE 3 was added in a liquid/powder ratio (L/P ratio) of 0.4, i.e. 4 ml liquid/10 g powder, while stirring.
- the resulting paste was filled into a cylindrical steel mold having a length of 12 mm and a diameter of 6 mm, and was compressed with a gradually increased pressure until a maximum pressure was reached. The maximum pressure was maintained for one minute, and then the compressed CPC block was removed from the mold.
- the compressed CPC block was immersed in a Hanks' solution for 1 day, 4 days, and 16 days.
- Each test group of the three different periods of immersion time has five specimens, the compressive strength of which was measured by using a AGS-500D mechanical tester (Shimadzu Co., Ltd., Kyoto, Japan) immediately following the removal thereof from the Hanks' solution without drying.
- the CPC paste in the mold was compressed with a maximum pressure of 166.6 MPa, and in the course of the compression the compression speeds were about 5 mm/min during 0-104.1 MPa; 3 mm/min during 104.1-138.8 MPa; 1 mm/min during 138.8-159.6 MPa: and 0.5 mm/min during 159.6-166.6 MPa.
- the measured wet specimen compressive strength is listed Table 1.
- CPC blocks is increased remarkably after one-day immersion in comparison with the non-immersed block, and declines a little for a longer immersion time.
- EXAMPLE 2 Effect of whiskers on compressive strength of TTCP/DCPA-based CPC block The procedures of EXAMPLE 1 were repeated by using the C-CPC powder prepared in PREPARATIVE EXAMPLE 2 and the ND-CPC powder prepared in PREPARATIVE EXAMPLE 3. The maximum pressure used to compress the CPC paste in the mold in this example was 156.2 MPa. The results for one-day immersion time are listed in Table 2.
- EXAMPLE 3 Effect of whiskers on compressive strength of TTCP-based CPC block Ca 4 (PO 4 ) 2 O (TTCP) powder as synthesized in PREPARATIVE EXAMPLE 1 was sieved with a #325 mesh. The sieved powder has an average particle size of about 10 ⁇ m.
- the TTCP powder was immersed in the HCl aqueous solution for 12 hours, filtered rapidly and washed with deionized water, and filtered rapidly with a vacuum pump again. The resulting powder cake was dried in an oven at 50°C.
- the dried powder was divided into halves, ground for 20 minutes and 120 minutes separately, and combined to obtain the non-dispersive TTCP-based CPC powder, the particles of which have whisker on the surfaces thereof.
- a setting solution of diammonium hydrogen phosphate was prepared by dissolving 20 g of diammonium hydrogen phosphate, (NH ) HPO 4 , in 40 ml deionized water.
- the procedures in EXAMPLE 1 were used to obtain the wet specimen compressive strength for one-day immersion time, wherein the maximum pressure to compress the CPC paste in the mold was 156.2 MPa. The results are shown in Table 3.
- EXAMPLE 4 Effect of molding pressure on compressive strength of ND-CPC block (in low pressure regime: 0.09-3.5 MPa) The procedures of EXAMPLE 1 were repeated except that the maximum pressure used to compress the CPC paste in the mold was changed from 166.6 MPa to the values listed in Table 4. The period of immersion was one day. The results are listed in Table 4.
- EXAMPLE 5 Effect of reducing liquid/powder ratio during compression of the CPC paste in the mold on compressive strength of ND-CPC block The procedures of EXAMPLE 1 were repeated except that the maximum pressure used to compress the CPC paste in the mold was changed from 166.6 MPa to the values listed in Table 5. The liquid leaked from the mold during compression was measured, and the liquid/powder ratio was re-calculated as shown in Table 5. The period of immersion was one day. The results are listed in Table 5.
- EXAMPLE 6 Effect of post-heat treatment on compressive strength of CPC block The procedures of EXAMPLE 1 were repeated. The period of immersion was one day. The CPC blocks after removing from the Hanks' solution were subjected to post-heat treatments: 1) 50°C for one day; and 2) 400°C for two hours with a heating rate of 10°C per minute. The results are listed in Table 6. Table 6
- EXAMPLE 7 Effect of KCl content and immersion time on compressive strength of porous CPC block
- the ND-CPC powder from PREPARATIVE EXAMPLE 3 was added in a liquid/powder ratio (L/P ratio) of 0.4, i.e. 4 ml liquid/10 g powder, while stirring.
- KCl powder in a predetermined amount was mixed to the resulting mixture by stirring intensively.
- the resulting paste was filled into a cylindrical steel mold having a length of 12 mm and a diameter of 6 mm, and was compressed with a gradually increased pressure until a maximum pressure of 3.5 MPa was reached.
- EXAMPLE 8 Porosity and compressive strength of porous CPC blocks prepared from different pore-forming powders The procedures of EXAMPLE 7 were repeated by using sugar, KI, C 17 H 33 COONa and C 13 H 27 COOH instead of KCl. The immersion time was 14 days in deionized water. In the cases where the C 17 H 33 COONa and C 13 H 7 COOH were used, the CPC blocks were further immersed in ethanol for additional four days. The conditions and the results are listed in Table 8.
- & S Pore-forming powder/CPC by volume.
- C.S. dry compressive strength (hereinafter abbreviated as C.S.).
- Porosity Porosity (vol%) was measured by Archimedes' method, and calculated as in ASTM C830. It can be seen from Table 8 that various powders which are soluble in • water can be used in the preparation of a porous CPC block according to the method of the present invention.
- KCl powder in a ratio of KCl powder/CPC by volume of 2 was mixed to the resulting mixture by stirring intensively.
- the resulting paste was filled into a cylindrical steel mold having a length of 12 mm and a diameter of 7 mm, and was compressed with a gradually increased pressure until a maximum pressure of 3.5 MPa was reached. The maximum pressure was maintained for one minute, and then the compressed CPC block was removed from the mold at the 15 th minute following the mixing of the liquid and powders.
- the resulting cylinder having a diameter of 7 mm was placed in another cylindrical steel mold having a diameter of 10 mm.
- KCl powder was dissolved in the deionized water, and a dual-functional CPC block having a porous CPC cylinder surround by a dense CPC annular block was obtained.
- the compressive strength of the specimen was measured by using a AGS-500D mechanical tester (Shimadzu Co., Ltd., Kyoto, Japan) after the specimens were dry.
- the measured dry specimen compressive strength is 68.8 MPa.
- the porosities of the porous CPC cylinder and the dense CPC annular block were measured by Archimedes' method, and calculated as in ASTM C830, after the dual-functional CPC block was broken intentionally, and the results are 74% and 30%, respectively.
- the results indicate that the powder is a mixture of apatite and TTCP with apatite as a major portion.
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Abstract
The present invention discloses a medical implant made from calcium phosphate cement, and in particular to a method of preparing a molded and hardened calcium phosphate cement article having a superior compressive strength for use as medical implant. The molded and hardened calcium phosphate cement article may be in the forms of a dense block, a porous block for use as tissue-engineered scaffold, or a dual function block comprising a dense cortical portion (D1) bearing the majority of load and a porous cancellous portion (P1) allowing a rapid blood/body fluid penetration and tissue growth.
Description
Methods for Preparing Medical Implants from Calcium Phosphate Cement and Medical Implants
Field of the Invention The present invention is related to a medical implant made from calcium phosphate cement, and in particular to a method of preparing a molded and hardened calcium phosphate cement article having a superior compressive strength for use as medical implant. The molded and hardened calcium phosphate cement block may be in the forms of a dense block, a porous block for use as tissue-engineered scaffold, or a dual function block comprising a dense cortical portion bearing the majority of load and a porous cancellous portion allowing a rapid blood/body fluid penetration and tissue ingrowth.
Background of the Invention It is advantageous if a prosthetic bone implant is bioresorbable and is supportive at the same time. Accordingly, an article made of calcium phosphate will be preferable than that made of a metal, if the former has strength which is comparable to a human cortical bone. One way of making such a bone implant is by sintering a calcium phosphate powder, particularly a hydroxyapatite (HA) powder, into a block material at a temperature generally greater than 1000°C. Despite the fact that the high temperature-sintered HA block material has an enhanced strength, the bioresorbability of the material is largely sacrificed, if not totally destroyed, due to the elimination of the micro- and nano-sized porosity during the sintering process. The conventional spinal fusing device is composed of a metallic cage and a bioresorbable material disposed in the metal cage, for example the one disclosed in US patent No. 5,645,598. An inevitable disadvantage of this fusion device is the sinking of the metallic cage sitting between two vertebrae to replace or repair a defect spinal disk, because the hardness and the relatively small size of the cage wear out or break the bone tissue, and in particular the endplate of the vertebra.
A tissue-engineered scaffold (majority made from biodegradable polymers) has a very porous structure that allows living cells (usually taken from the patient being treated) to penetrate into the structure and be "seeded" in- vitro during a cell culture process. After a period of time (days or weeks) of cell culture, the cell-seeded scaffold is implanted into either an animal (e.g., rat) whose immune system has been removed, or into the patient himself (usually under the skin for easier later-on process). During this period of time (weeks to months) the cells quickly multiply from absorbing nutrients from the animal or the patient's body, and, at the same time, the scaffold itself is gradually dissolved or resorbed. When this process is substantially "mature", the implant (now a real bone) is removed from under the skin of the animal or the patient and re-implanted into the (wounded or diseased) site being treated. The following are some references describing some details about the background, requirements, applications, etc. of tissue-engineered scaffold: US 6,139,578; US 6,200,606; US 5,306,303; and US 6,132,463. It is advantageous if a tissue-engineered scaffold is bioresorbable, sufficiently porous and supportive at the same time. The conventional high temperature (usually >1000°C)-sintered porous hydroxyapatite (HA) block material does not possess sufficient micro/nano-sized porosity and is hardly bioresorbable. On the other hand, the conventional biodegradable polymer for scaffold application exhibits a relatively low strength and too high a dissolution rate.
Summary of the Invention An objective of the invention is to provide a molded and hardened calcium phosphate cement (CPC) article or block having a superior compressive strength for use as medical implant, which is free from the aforesaid drawbacks in the prior art. Another objective of the invention is to provide a porous hardened CPC article or block for use as a tissue-engineered scaffold, which is free from the aforesaid drawbacks in the prior art, or as a functional implant other than the tissue-engineered scaffold.
Another objective of the invention is to provide a dual function hardened calcium phosphate cement (CPC) article or block for use as a prosthetic bone implant comprising a dense cortical portion and a porous cancellous portion, which is free from the aforesaid drawbacks in the prior art. The prosthetic bone implant constructed according to the present invention is made of a hardened calcium phosphate cement having an apatitic phase as a major phase, which comprises a dense cortical portion bearing the majority of load and a porous cancellous portion allowing a rapid blood/body fluid penetration and tissue ingrowth. The prosthetic bone implant of the present invention is made by a novel technique, which involves immersing an article molded from two different pastes of calcium phosphate cement (CPC), one of them having an additional pore-forming powder, in a liquid for a period of time, so that the compressive strength of the molded CPC article is significantly improved after removing from the liquid while the pore-forming powder is dissolved in the liquid, creating pores in a desired zone or zones of the molded article. Features and advantages of the present invention are as follows: 1. Easy process for different shape and size of the prosthetic bone implant of the present invention, so that the outer circumferential dense portion thereof can sit over the circumferential cortical portion of a bone and the porous portion thereof can contact the cancellous portion of the bone adjacent to a bone receiving treatment. 2. The dense cortical portion of the prosthetic bone implant made according to the present invention exhibits a high strength comparable to that of human cortical bone (about 110-170 MPa). The strength is adjustable by adjusting process parameters. 3. The dense cortical portion of the prosthetic bone implant made according to the present invention contains significant amount of micro- and nano-sized porosity, that improves bioresorbability thereof. Conventional high temperature-sintered HA block, on the other hand, does not possess sufficient micro/nano-sized porosity and is not bioresorbable. 4. The porous cancellous portion of the prosthetic bone implant made
according to the present invention possesses a porosity greater than 40% in volume, prepferably 40-90%, allowing rapid blood/body fluid penetration and tissue ingrowth, thereby anchoring the prosthetic bone implant. 5. A wide range of medical application includes bone dowel, spacer, cavity filler, artificial disc and fixation devices for spine and other locations, to name a few. In another aspect of the present invention, a novel method for making a hardened CPC article for use as medical implant is provided, which involves impregnating an article molded from a paste of CPC in a liquid for a period of time, so that the compressive strength of the CPC block is significantly improved after removing from the liquid. It is apparent that the medical implant prepared according to this novel method has the features and advantages recited in the above-mentioned Items 3 and 5. In a further aspect of the present invention, a novel method for making a porous hardened CPC article for use as a tissue-engineered scaffold, which involves preparing a shaped article from a paste comprising a calcium phosphate cement, a pore-forming powder and a setting liquid; and immersing said shaped article in an immersing liquid for a period of time so that said pore-forming powder is dissolved in the immersing liquid, creating pores in said shaped article. In addition to the above-mentioned Item 4, the porous hardened CPC article made according to the present invention has the following features and advantages: - The porous hardened CPC article can transform into an apatite-dominated material shortly after immersion in physiological solution or after implantation. - The porous hardened CPC article exhibits a higher strength than most other bioactive or biodegradable porous blocks with a similar porosity level.
Brief Description of the Drawings Figs, la to Id show schematic cross sectional views of four different designs of prosthetic bone implants constructed according to the present invention.
Figs. 2a to 2f are schematic cross sectional views showing steps of a method for preparing a prosthetic bone implant according to one embodiment of the present invention. Figs. 3a and 3b are schematic vertical and horizontal cross sectional views of a prosthetic bone implant prepared according to another embodiment of the present invention, respectively.
Detailed Description of the Invention The present invention discloses a method for making a hardened molded calcium phosphate cement (CPC) article comprising impregnating a rigid shaped article of calcium phosphate with an impregnating liquid for a period of time so that a compressive strength of the resulting impregnated article removed from the impregnating liquid is increased compared to that of the rigid shaped article without said impregnating treatment. Preferably, the impregnating liquid is an acidic solution, a basic solution, a physiological solution, an organic solvent, or a substantially pure water. Preferably, the impregnating liquid comprises at least one of Ca and P sources. Preferably, the impregnating liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH4)2HPO4. Preferably, the rigid shaped article of calcium phosphate is a molded article from a paste of calcium phosphate cement. Preferably, the impregnating is carried out for a period longer than 10 minutes, and more preferably for about 12 hours to 96 hours. Preferably, the impregnating is carried out 30-90°C, and more preferably at room temperature. According to a first preferred embodiment of the present invention, a method for making a molded calcium phosphate article comprises the following steps: (a) preparing a powder of a calcium phosphate cement; (b) mixing said powder with a setting liquid to form a paste, wherein said paste undergoes a hardening reaction; (c) molding said paste into an article in a mold of a desired shape and size
before said hardening reaction is complete; (d) impregnating the resulting hardened article from step (c) with an impregnating liquid to allow strength of said article to increase; and (e) removing said article from said impregnating liquid. Preferably, said calcium phosphate cement comprises at least one Ca source and at least one P source, or more preferably at least one calcium phosphate source. Said calcium phosphate source comprises one or more calcium phosphates selected from the group consisting of alpha-tricalcium phosphate (α-TCP), beta-tricalcium phosphate (β-TCP), tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA), octacalcium phosphate (OCP), calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium pyrophosphate, calcium triphosphate, calcium phosphate tribasic, calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium phosphate, tricalcium phosphate hydrate, and amorphous calcium phosphate. Preferably, the calcium phosphate source comprises at least one calcium phosphate particle having calcium phosphate whiskers on the surface of said calcium phosphate particle, wherein said calcium phosphate whiskers have a length of about 1-5000 nm and a width of about 1-500 nm. Preferably, the setting liquid in step (b) is an acidic solution, a basic solution, or a substantially pure water. An acidic solution suitable for use in the present invention is selected from the group consisting of nitric acid (HNO3), hydrochloric acid (HCl), phosphoric acid (H3PO ), carbonic acid (H2CO3), sodium dihydrogen phosphate (NaH PO4), sodium dihydrogen phosphate monohydrate (NaH PO4 »H2O), sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dehydrate, potassium dihydrogen phosphate (KH2PO4), ammonium dihydrogen.phosphate (NH4H PO4), malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture.
A basic solution suitable for use in the present invention is selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na2HPO4), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na3PO »12H2O), dipotassium hydrogen phosphate (K2HPO4), potassium hydrogen phosphate trihydrate (K2HPO *3H2O), potassium phosphate tribasic (K3PO4), diammonium hydrogen phosphate ((NH4)2HPO4), ammonium phosphate trihydrate ((NH )3PO4*3H2O), sodium hydrogen carbonate (NaHCO ), sodium carbonate Na2CO3, and their mixture. Step (c) of the method of the present invention preferably further comprises removing said article from said mold. Step (c) of the method of the present invention preferably further comprises removing a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases. Step (c) of the method of the present invention preferably further comprises pressurizing said paste in said mold, preferably between 1 and 500 MPa, before said hardening reaction is complete to remove a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases. More preferably, step (c) further comprises heating said paste during said pressurizing. Step (c) of the method of the present invention preferably further comprises heating said paste during molding. Step (d) of the method of the present invention preferably further comprises heating the impregnating liquid, preferably at a temperature between 30 and 90°C during said impregnating. The method of the present invention may further comprise drying said article after removing said article from said impregnating liquid. The method of the present invention may further comprise heating said article, preferably at a temperature between 50 and 500°C, after removing said article from said impregnating liquid. The molded calcium phosphate article made according to the method of the present invention may be used as a medical implant or a reinforcing constituent of a composite.
According to a second preferred embodiment of the present invention, a method for making a porous hardened CPC article is provided. The second preferred embodiment is similar to the first embodiment with a major difference in that a pore-forming powder is mixed with the powder of calcium phosphate cement used in step (a). The method for making a porous hardened CPC article according to the second preferred embodiment comprises: i) preparing a shaped article from a paste comprising a calcium phosphate cement, a pore-forming powder and a setting liquid; ii) immersing said shaped article in an immersing liquid for a first period of time so that said pore-forming powder is dissolved in the immersing liquid, creating pores in said shaped article; iii) removing the resulting porous shaped article from said immersing liquid; and iv) immersing the porous shaped article from step iii) in an impregnating liquid for a second period of time so that a compressive strength of the resulting article removed from the impregnating liquid is increased compared to that of said porous shaped article without said impregnating treatment, wherein step iii) is omitted and a compressive strength of the resulting porous shaped article removed from the immersing liquid after the first and the second periods of time is increased compared to that of the resulting porous shaped article removed after the first period of time, when the immersing liquid and the impregnating liquid are the same. Said pore-forming powder preferably is selected from the group consisting of LiCl, KC1, NaCI, MgCl2, CaCl2, NaIO3, KI, Na3PO4, K3PO4, Na2CO3, amino acid-sodium salt, amino acid-potassium salt, glucose, polysaccharide, fatty acid-sodium salt, fatty acid-potassium salt, potassium bitartrate (KHC H4O6), potassium carbonate, potassium gluconate (KC6HπO7), potassium-sodium tartrate (KNaC4H O6'4H2O), potassium sulfate (K2SO ), sodium sulfate, and sodium lactate. Preferably, said immersing liquid in step ii) and said impregnating liquid in step iv) independently are an acidic aqueous solution, a basic aqueous solution, a physiological solution, an organic solvent, or a substantially pure
water. Said immersing liquid may comprises at least one of Ca and P sources. Said immersing liquid may be a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH4)2HPO4. Said impregnating liquid in step iv) may be different from or the same as the immersing liquid in step i). Preferably, the first period of time in step ii) is longer than 10 minutes, and more preferably longer than 1 day. Preferably, the second period of time in step iv) is longer than 10 minutes, and more preferably longer than 1 day. Preferably, the immersing in step ii) and iv) is carried out at room temperature or at a temperature between about 30 and 90°C. Preferably, said paste in step i) further comprises living cells. Preferably, said immersing liquid in step ii) comprises living cells. Preferably, said impregnating liquid in step iv) comprises living cells. Preferably, said porous shaped article having an increased compressive strength removed from said impregnating liquid in step iv) has a porosity of at least 20 vol%, and more preferably of 40-90 vol%. The porous hardened CPC article made according to the method of the present invention may be used as a tissue-engineered scaffold, medical implant or a reinforcing constituent of a composite. According to a third preferred embodiment of the present invention, a method for making a dual function hardened CPC article for use as a prosthetic bone implant is provided. The third preferred embodiment basically is a combination of the first embodiment and the second embodiment, wherein a first CPC paste without the pore-forming powder and a second CPC paste containing the pore-forming powder are used to mold an integral article and immersing the integral article in the impregnating liquid, so that the pore-forming powder is dissolved in the immersing liquid, creating pores in the integral article while the hardened CPC gaining compressive strength. Features of the third preferred embodiments of the present invention includes (but not limited to) the following: 1. A prosthetic bone implant comprising a cortical portion having two opposite sides, and a cancellous portion integrally disposed in said cortical portion and
being exposed through said two opposite sides, wherein said cortical portion comprises a hardened calcium phosphate cement has a porosity of less than 40%) in volume, and said cancellous portion comprises a porous hardened calcium phosphate cement having a porosity greater than 20% in volume, and greater than that of said cortical portion.
2. The prosthetic bone implant according to Feature 1, wherein the cortical portion is in the form of a hollow disk, and the cancellous portion is in the form of a column surrounded by the hollow disk.
3. The prosthetic bone implant according to Feature 2 further comprising a transitional portion between said column and said hollow disk surrounding said central cylinder, which has properties range from those of said cancellous portion to said cortical portion.
4. The prosthetic bone implant according to Feature 1, wherein the cortical portion is in the form of a disk having one or more longitudinal through holes, and the cancellous portion is in the form of one or more columns surrounded by said one or more longitudinal through holes.
5. The prosthetic bone implant according to Feature 1, wherein said hardened calcium phosphate cement of said cortical portion comprises an apatitic phase as a major phase giving rise to broadened characteristic X-ray diffraction peaks in comparison with a high-temperature sintered apatitic phase.
6. The prosthetic bone implant according to Feature 5, wherein said broadened characteristic the X-ray diffraction peaks are at 2-Theta values of 25-27° and 30-35°.
7. The prosthetic bone implant according to Feature 1, wherein said hardened calcium phosphate cement of said cortical portion is prepared without a high temperature sintering.
8. The prosthetic bone implant according to Feature 1, wherein said hardened calcium phosphate cement of said cortical portion comprises an apatitic phase as a major phase having a Ca/P molar ratio of 1.5-2.0. 9. The prosthetic bone implant according to Feature 1, wherein said hardened calcium phosphate cement of said cancellous portion comprises an apatitic phase as a major phase giving rise to broadened characteristic X-ray
diffraction peaks in comparison with a high-temperature sintered apatitic phase.
10. The prosthetic bone implant according to Feature 9, wherein said broadened characteristic the X-ray diffraction peaks are at 2-Theta values of 25-27° and 30-35°.
11. The prosthetic bone implant according to Feature 1 , wherein said hardened calcium phosphate cement of said cancellous portion is prepared without a high temperature sintering.
12. The prosthetic bone implant according to Feature 1, wherein said hardened calcium phosphate cement of said cancellous portion comprises an apatitic phase as a major phase having a Ca/P molar ratio of 1.5-2.0.
13. The prosthetic bone implant according to Feature 1, wherein said cortical portion comprises 10-90% in volume of said implant.
14. The prosthetic bone implant according to Feature 1, wherein said cortical portion has a porosity of less than 30% in volume.
15. The prosthetic bone implant according to Feature 1, wherein said cancellous portion has a porosity greater than 40-90% in volume.
16. A method for preparing a prosthetic bone implant comprising a cortical portion having two opposite sides, and a cancellous portion integrally disposed in said cortical portion and being exposed through said two opposite sides, said method comprises the following steps: a) preparing a first paste comprising a first calcium phosphate cement and a first setting liquid; b) preparing a second paste comprising a second calcium phosphate cement, a pore-forming powder and a second setting liquid; c) i) preparing a shaped article in a mold having two or more cells separated by one more partition walls comprising introducing said first paste and said second paste into said two or more cells separately, and removing said one or more partition walls from said mold, so that said second paste in the form of a single column or two or more isolated columns is integrally disposed in the first paste in said mold; or ii) preparing a shaped article comprising introducing one of said first paste
and said second paste into a first mold to form an intermediate in said first mold, placing said intermediate into a second mold after a hardening reaction thereof undergoes at least partially, and introducing another one of said first paste ad said second paste into said second mold, so that said second paste as a single column or as two or more isolated columns is integrally disposed in the first paste in said second mold; d) immersing the resulting shaped article from step c) in an immersing liquid for a first period of time so that said pore-forming powder is dissolved in the immersing liquid, creating pores in said single column or said two or more isolated columns; and e) removing the immersed shaped article from said immersing liquid.
17. The method according to Feature 16 further comprising f) drying the immersed shaped article.
18. The method according to Feature 16, wherein said pore-forming powder is the same as that used in the second preferred embodiment of the present invention.
19. The method according to Feature 16, wherein said first calcium phosphate cement comprises at least one Ca source and at least one P source, or at least one calcium phosphate source; and said second calcium phosphate cement comprises at least one Ca source and at least one P source, or at least one calcium phosphate source.
20. The method according to Feature 19, wherein said first calcium phosphate cement comprises at least one calcium phosphate source, and said second calcium phosphate cement comprises at least one calcium phosphate source. 21. The method according to Feature 20, wherein said calcium phosphate source is the same as that used in the first preferred embodiment of the present invention. 22. The method according to Feature 21, wherein said first calcium phosphate cement and said second calcium phosphate cement are identical. 23. The method according to Feature 22, wherein said first calcium phosphate cement and said second calcium phosphate cement are tetracalcium phosphate.
24. The method according to Feature 16, wherein the first setting liquid and the second setting liquid independently are an acidic solution, a basic solution, or a substantially pure water.
25. The method according to Feature 24, wherein said acidic solution is the same as that used in the first preferred embodiment of the present invention.
26. The method according to Feature 22, wherein said basic solution is the same as that used in the first preferred embodiment of the present invention.
27. The method according to Feature 16, wherein step c-i) further comprises allowing said first paste and said second paste undergoing a hardening reaction in said mold.
28. The method according to Feature 16, wherein step c-i) further comprises pressurizing said first paste and said second paste in said mold after removing said one or more partition walls from said mold to remove a portion of liquid from said first paste and said second paste, so that a liquid/powder ratio of said first paste and of said second paste decreases; and allowing said first paste and second paste undergoing a hardening reaction in said mold.
29. The method according to Feature 16, wherein step c-ii) further comprises allowing said intermediate undergoing a hardening reaction in said first mold, and allowing said another one of said first paste and said second paste undergoing a hardening reaction in said second mold.
30. The method according to Feature 16, wherein step c-ii) further comprises pressurizing said one of said first paste and said second paste in said first mold to remove a portion of liquid therefrom before the hardening reaction of said intermediate is completed; allowing said intermediate undergoing a hardening reaction in said first mold; pressuring said another one of said first paste and said second paste in said second mold, so that a liquid/powder ratio of said another one of said first paste and of said second paste decreases; and allowing said another one of said first paste and second paste undergoing a hardening reaction in said second mold. 31. The method according to Feature 28, wherein said pressuring is about 1 to 500 MPa. 32. The method according to Feature 30, wherein said pressuring is about 1 to
500 MPa. 33. The method according to Feature 16, wherein the immersing liquid is an acidic aqueous solution, a basic aqueous solution, a physiological solution, an organic solvent, or a substantially pure water. 34. The method according to Featur 33, wherein the immersing liquid comprises at least one of Ca and P sources. 35. The method according to Feature 33, wherein the immersing liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH4)2HPO4. 36. The method according to Feature 16, wherein the immersing in step d) is carried out for a period longer than 10 minutes.
37. The method according to Feature 16, wherein the immersing in step d) is carried out for a period longer than 1 day.
38. The method according to Feature 16, wherein the immersing in step d) is carried out at a temperature of about 10 and 90°C.
39. The method according to Feature 38, wherein the immersing in step d) is carried out at room temperature.
40. The method according Feature 17 further comprising cleaning said immersed shaped article before said drying; and heating the resulting dried shaped article at a temperature between 50 and 500°C. Four different designs of prosthetic bone implants constructed according to the present invention are shown in Figs, la to Id. In Fig. la, the prosthetic bone implant of the present invention has a dense cortical portion DI in the tubular form and a porous cancellous portion PI formed in the central through hole of the tubular cortical portion DI . Both the dense cortical portion DI and the porous cancellous portion PI are made of a hardened calcium phosphate cement having an apatitic phase as a major phase. In Fig. lb, the prosthetic bone implant of the present invention has a dense cortical portion DI in the tubular form; a cylindrical porous cancellous portion PI in the center of the tubular cortical portion DI ; and an annular transitional portion P2 connecting the tubular cortical portion DI and the cylindrical cancellous portion PI . The transitional portion P2 is made of a hardened calcium phosphate cement having
an apatitic phase as a major phase, and a porosity gradient increasing from the lower porosity of the cylindrical cancellous portion PI to the higher porosity of the tubular cortical portion DI, which may be formed in-situ during molding of two different two different CPC pastes, one of them having an additional pore-forming powder for forming the cylindrical cancellous portion PI, and another one being a regular CPC powder for forming the dense cortical portion DI. The porous cancellous portion PI may be in the forms of isolated columns surrounded by the dense cortical portion DI as shown in Figs, lc and Id. Other designs are also possible in addition to those shown in Figs, la to Id. A suitable method for preparing the prosthetic bone implant of the present invention includes placing a tubular partition wall 10 in a hollow cylindrical mold 20, as shown in Fig. 2a; pouring a first paste comprising a calcium phosphate cement and a setting liquid in the annular cell and a second paste comprising the calcium phosphate cement, a pore-forming powder and the setting liquid in the central cell, as shown in Fig. 2b; removing the partition wall and pressing the CPC pastes before hardening, as shown in Fig. 2c, wherein a portion of the setting liquid is removed from the gap between the mold 20 and the press 30 and/or holes (not shown in the drawing) provided on the press 30. The CPC paste will undergo a hardening reaction to convert into apatitic phase. The hardened disk is removed from the mold and is subjected to surface finishing to expose the central portion hardened from the second paste, as shown in Fig. 2d, followed by immersing in a bath of an immersing liquid as shown in Fig. 2e, where the pore-forming powder is dissolved in the immersing liquid while the hardened CPC thereof gaining compressive strength. The immersing may last from 10 minutes to several days. The composite disk so formed is washed with water after being removed from the bath, and dried and heated in an oven to obtain the prosthetic bone implant as shown in Fig. 2f. The heating is conducted at a temperature between 50 and 500°C for a period of several hours to several days, which enhance the compressive strength of the cortical portion of the prosthetic bone implant. An alternative method for preparing the prosthetic bone implant of the present invention from the same raw materials includes pouring the second paste
in a first mold, pressing the second paste to remove a portion of the setting liquid from the second paste before the hardening reaction is completed, so that the liquid/powder ratio in the second paste decreases, and allowing the hardening reaction undergo in the mold for a period of time, e.g. 15 minutes starting from the mixing of the CPC powder, the pore-forming powder and the setting liquid, to obtain a cylindrical block having a diameter of 7 mm. Then, the cylindrical block is removed from the first mold, and placed in the center of a second mold having a diameter of 10 mm. The first paste is poured into the annular space in the second mold, and a press having a dimension corresponding to the annular shape is used to pressure the first paste to remove a portion of the setting liquid from the first paste before the hardening reaction is completed, so that the liquid/powder ratio in the first paste decreases. Again, the first paste will undergo a hardening reaction to convert into apatitic phase. The hardened cylinder having a diameter of 10 mm is removed from the second mold, followed by immersing in an immersing liquid, where the pore-forming powder contained in the second paste is dissolved in the immersing liquid while the hardened CPC thereof gaining compressive strength, to obtain the prosthetic bone implant of the present invention, as shown in Figs. 3a and 3b. It is apparently to people skilled in the art that the prosthetic bone implant shown in Figs. 3a and 3b can also be prepared by changing the sequence of the molding of the first paste and the second paste with modifications to the second mold used in this alternative method. The following examples are intended to demonstrate the invention more fully without acting as a limitation upon its scope, since numerous modifications and variations will be apparent to those skilled in this art.
PREPARATIVE EXAMPLE 1 : Preparation of TTCP Powder A Ca (PO )2O (TTCP) powder was prepared by mixing Ca2P2O powder with CaCO3 powder uniformly in ethanol for 24 hours followed by heating to dry. The mixing ratio of Ca2P2O7 powder to CaCO3 powder was 1 : 1.27 (weight ratio) and the powder mixture was heated to 1400°C to allow two powders to react to form TTCP.
PREPARATIVE EXAMPLE 2: Preparation of conventional TTCP/DCPA-based CPC powder (abbreviated as C-CPC) The resulting TTCP powder from PREPARATIVE EXAMPLE 1 was sieved and blended with dried CaHPO4 (DCPA) powder in a ball mill for 12 hours. The blending ratio of the TTCP powder to the DCPA powder was 1 : 1 (molar ratio) to obtain the conventional CPC powder. Particles of this C-CPC powder have no whisker on the surfaces thereof.
PREPARATIVE EXAMPLE 3 : Preparation of non-dispersive TTCP/DCPA-based CPC powder (abbreviated as ND-CPC) The TTCP powder prepared according to the method of PREPARATIVE EXAMPLE 1 was sieved and blended with dried CaHPO (DCPA) powder in a ball mill for 12 hours. The blending ratio of the TTCP powder to the DCPA powder was 1 : 1 (molar ratio). The resultant powder mixture was added to a 25 mM diluted solution of phosphate to obtain a powder/solution mixture having a concentration of 3 g powder mixture per 1 ml solution while stirring. The resulting powder/solution mixture was formed into pellets, and the pellets were heated in an oven at 50°C for 10 minutes. The pellets were then uniformly ground in a mechanical mill for 20 minutes to obtain the non-dispersive
TTCP/DCPA-based CPC powder (ND-CPC). The particles of this ND-CPC powder have whisker on the surfaces thereof.
Dense blocks EXAMPLE 1 : Effect of immersion time on compressive strength of CPC block To a setting solution of 1M phosphoric acid solution (pH = 5.89) the ND-CPC powder from PREPARATIVE EXAMPLE 3 was added in a liquid/powder ratio (L/P ratio) of 0.4, i.e. 4 ml liquid/10 g powder, while stirring. The resulting paste was filled into a cylindrical steel mold having a length of 12 mm and a diameter of 6 mm, and was compressed with a gradually increased pressure until a maximum pressure was reached. The maximum pressure was maintained for one minute, and then the compressed CPC block was removed
from the mold. At the 15th minute following the mixing of the liquid and powder, the compressed CPC block was immersed in a Hanks' solution for 1 day, 4 days, and 16 days. Each test group of the three different periods of immersion time has five specimens, the compressive strength of which was measured by using a AGS-500D mechanical tester (Shimadzu Co., Ltd., Kyoto, Japan) immediately following the removal thereof from the Hanks' solution without drying. The CPC paste in the mold was compressed with a maximum pressure of 166.6 MPa, and in the course of the compression the compression speeds were about 5 mm/min during 0-104.1 MPa; 3 mm/min during 104.1-138.8 MPa; 1 mm/min during 138.8-159.6 MPa: and 0.5 mm/min during 159.6-166.6 MPa. The measured wet specimen compressive strength is listed Table 1.
Table 1
CPC blocks is increased remarkably after one-day immersion in comparison with the non-immersed block, and declines a little for a longer immersion time.
EXAMPLE 2: Effect of whiskers on compressive strength of TTCP/DCPA-based CPC block The procedures of EXAMPLE 1 were repeated by using the C-CPC powder prepared in PREPARATIVE EXAMPLE 2 and the ND-CPC powder
prepared in PREPARATIVE EXAMPLE 3. The maximum pressure used to compress the CPC paste in the mold in this example was 156.2 MPa. The results for one-day immersion time are listed in Table 2.
Table 2
It can be seen from Table 2 that the compressive strength, 62.3 MPa, of the immersed compressed CPC block prepared from the conventional CPC powder (no whisker) is about 1.7 times of that (37.3 MPa) of the non-immersed compressed CPC block in Table 1, and the compressive strength, 138.0 MPa, of the immersed compressed CPC block prepared from the non-dispersive CPC powder (with whisker) is about 3.7 times of that of the non- immersed compressed CPC block in Table 1
EXAMPLE 3 : Effect of whiskers on compressive strength of TTCP-based CPC block Ca4(PO4)2O (TTCP) powder as synthesized in PREPARATIVE EXAMPLE 1 was sieved with a #325 mesh. The sieved powder has an average particle size of about 10 μm. To the TTCP powder HCl aqueous solution (pH = 0.8) was added according to the ratio of lg TTCP/13ml solution. The TTCP powder was immersed in the HCl aqueous solution for 12 hours, filtered rapidly and washed with deionized water, and filtered rapidly with a vacuum pump again. The resulting powder cake was dried in an oven at 50°C. The dried powder was divided into halves, ground for 20 minutes and 120 minutes separately, and combined to obtain the non-dispersive TTCP-based CPC powder, the particles of which have whisker on the surfaces thereof. A setting solution of diammonium hydrogen phosphate was prepared by dissolving 20 g of diammonium hydrogen phosphate, (NH ) HPO4, in 40 ml deionized water. The procedures in EXAMPLE 1 were used to obtain the wet specimen compressive strength for
one-day immersion time, wherein the maximum pressure to compress the CPC paste in the mold was 156.2 MPa. The results are shown in Table 3.
Table 3
The trend same as the TTCP/DCPA-based CPC powder in Table 2 of EXAMPLE 2 can be observed in Table 3.
EXAMPLE 4: Effect of molding pressure on compressive strength of ND-CPC block (in low pressure regime: 0.09-3.5 MPa) The procedures of EXAMPLE 1 were repeated except that the maximum pressure used to compress the CPC paste in the mold was changed from 166.6 MPa to the values listed in Table 4. The period of immersion was one day. The results are listed in Table 4.
Table 4
The data in Table 4 indicate that the compressive strength of the CPC block increases as the pressure used to compress the CPC paste in the mold increases.
EXAMPLE 5: Effect of reducing liquid/powder ratio during compression of the CPC paste in the mold on compressive strength of ND-CPC block The procedures of EXAMPLE 1 were repeated except that the maximum pressure used to compress the CPC paste in the mold was changed from 166.6 MPa to the values listed in Table 5. The liquid leaked from the mold during compression was measured, and the liquid/powder ratio was re-calculated as shown in Table 5. The period of immersion was one day. The results are listed in Table 5.
Table 5
The data in Table 5 show that the compressive strength of the CPC block increases as the liquid/powder ratio decreases during molding.
EXAMPLE 6: Effect of post-heat treatment on compressive strength of CPC block The procedures of EXAMPLE 1 were repeated. The period of immersion was one day. The CPC blocks after removing from the Hanks' solution were subjected to post-heat treatments: 1) 50°C for one day; and 2) 400°C for two hours with a heating rate of 10°C per minute. The results are listed in Table 6.
Table 6
It can be seen from Table 6 that the post-heat treatment enhances the compressive strength of the CPC block.
Porous blocks
EXAMPLE 7: Effect of KCl content and immersion time on compressive strength of porous CPC block To a setting solution of 1M phosphoric acid solution (pH = 5.89) the ND-CPC powder from PREPARATIVE EXAMPLE 3 was added in a liquid/powder ratio (L/P ratio) of 0.4, i.e. 4 ml liquid/10 g powder, while stirring. KCl powder in a predetermined amount was mixed to the resulting mixture by stirring intensively. The resulting paste was filled into a cylindrical steel mold having a length of 12 mm and a diameter of 6 mm, and was compressed with a gradually increased pressure until a maximum pressure of 3.5 MPa was reached. The maximum pressure was maintained for one minute, and then the compressed CPC block was removed from the mold. At the 15th minute following the mixing of the liquid and powders, the compressed CPC block was immersed in a deionized water at 37°C for 4 days, 8 days, and 16 days. The compressive strength of the specimens of the three different periods of immersion time was measured by using a AGS-500D mechanical tester (Shimadzu Co., Ltd., Kyoto, Japan) after the specimens were dry. The measured dry specimen compressive strength is listed Table 7.
Table 7
It can seen from Table 7 that the dry compressive strength of the porous CPC blocks decreases as the KC1/CPC ratio by weight increases.
EXAMPLE 8: Porosity and compressive strength of porous CPC blocks prepared from different pore-forming powders The procedures of EXAMPLE 7 were repeated by using sugar, KI, C17H33COONa and C13H27COOH instead of KCl. The immersion time was 14 days in deionized water. In the cases where the C17H33COONa and C13H 7COOH were used, the CPC blocks were further immersed in ethanol for additional four days. The conditions and the results are listed in Table 8.
Table 8
Claims
1. A prosthetic bone implant comprising a cortical portion having two opposite sides, and a cancellous portion integrally disposed in said cortical portion and being exposed through said two opposite sides, wherein said cortical portion comprises a hardened calcium phosphate cement has a porosity of less than 40% in volume, and said cancellous portion comprises a porous hardened calcium phosphate cement having a porosity greater than 20% in volume, and greater than that of said cortical portion.
2. The implant according to claim 1, wherein the cortical portion is in the form of a hollow disk, and the cancellous portion is in the form of a column surrounded by the hollow disk.
3. The implant according to claim 2 further comprising a transitional portion between said column and said hollow disk surrounding said central cylinder, which has properties range from those of said cancellous portion to said cortical portion.
4. The implant according to claim 1, wherein the cortical portion is in the form of a disk having one or more longitudinal through holes, and the cancellous portion is in the form of one or more columns surrounded by said one or more longitudinal through holes.
5. The implant according to claim 1, wherein said hardened calcium phosphate cement of said cortical portion comprises an apatitic phase as a major phase giving rise to broadened characteristic X-ray diffraction peaks in comparison with a high-temperature sintered apatitic phase.
6. The implant according to claim 5, wherein said broadened characteristic the X-ray diffraction peaks are at 2-Theta values of 25-27° and 30-35°.
7. The implant according to claim 1, wherein said hardened calcium phosphate cement of said cortical portion is prepared without a high temperature sintering.
8. The implant according to claim 1, wherein said hardened calcium phosphate cement of said cortical portion comprises an apatitic phase as a major phase having a Ca/P molar ratio of 1.5-2.0.
9. The implant according to claim 1, wherein said hardened calcium phosphate cement of said cancellous portion comprises an apatitic phase as a major phase giving rise to broadened characteristic X-ray diffraction peaks in comparison with a high-temperature sintered apatitic phase.
10. The implant according to claim 9, wherein said broadened characteristic the X-ray diffraction peaks are at 2-Theta values of 25-27° and 30-35°.
11. The implant according to claim 1, wherein said hardened calcium phosphate cement of said cancellous portion is prepared without a high temperature sintering.
12. The implant according to claim 1, wherein said hardened calcium phosphate cement of said cancellous portion comprises an apatitic phase as a major phase having a Ca/P molar ratio of 1.5-2.0.
13. The implant according to claim 1, wherein said cortical portion comprises 10-90% in volume of said implant.
14. The implant according to claim 1, wherein said cortical portion has a porosity of less than 30% in volume.
15. The implant according to claim 1, wherein said cancellous portion has a porosity of 40-90% in volume.
16. A method for preparing a prosthetic bone implant comprising a cortical portion having two opposite sides, and a cancellous portion integrally disposed in said cortical portion and being exposed through said two opposite sides, said method comprises the following steps: a) preparing a first paste comprising a first calcium phosphate cement and a first setting liquid; b) preparing a second paste comprising a second calcium phosphate cement, a pore-forming powder and a second setting liquid; c) i) preparing a shaped article in a mold having two or more cells separated by one more partition walls comprising introducing said first paste and said second paste into said two or more cells separately, and removing said one or more partition walls from said mold, so that said second paste in the form of a single column or two or more isolated columns is integrally disposed in the first paste in said mold; or ii) preparing a shaped article comprising introducing one of said first paste and said second paste into a first mold to form an intermediate in said first mold, placing said intermediate into a second mold after a hardening reaction thereof undergoes at least partially, and introducing another one of said first paste ad said second paste into said second mold, so that said second paste as a single column or as two or more isolated columns is integrally disposed in the first paste in said second mold; d) immersing the resulting shaped article from step c) in an immersing liquid for a first period of time so that said pore-forming powder is dissolved in the immersing liquid, creating pores in said single column or said two or more isolated columns; and e) removing the immersed shaped article from said immersing liquid.
17. The method according to claim 16 further comprising f) drying the immersed shaped article.
18. The method according to claim 16, wherein said pore-forming powder is selected from the group consisting of LiCl, KCl, NaCI, MgCl2, CaCl2, NaIO3, KI, Na3PO4, K3PO , Na2CO3, amino acid-sodium salt, amino acid-potassium salt, glucose, polysaccharide, fatty acid-sodium salt, fatty acid-potassium salt, potassium bitartrate (KHC4H4O6), potassium carbonate, potassium gluconate (KC6HπO ), potassium-sodium tartrate (KNaC4H4O6 »4H2O), potassium sulfate (K2SO4), sodium sulfate, and sodium lactate.
19. The method according to claim 16, wherein said first calcium phosphate cement comprises at least one Ca source and at least one P source, or at least one calcium phosphate source; and said second calcium phosphate cement comprises at least one Ca source and at least one P source, or at least one calcium phosphate source.
20. The method according to claim 19, wherein said first calcium phosphate cement comprises at least one calcium phosphate source, and said second calcium phosphate cement comprises at least one calcium phosphate source.
21. The method according to claim 20, wherein said calcium phosphate source is selected from the group consisting of alpha-tricalcium phosphate (α-TCP), beta-tricalcium phosphate (β-TCP), tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA), octacalcium phosphate (OCP), calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium pyrophosphate, calcium triphosphate, calcium phosphate tribasic, calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium phosphate, tricalcium phosphate hydrate, and amorphous calcium phosphate.
22. The method according to claim 21, wherein said first calcium phosphate cement and said second calcium phosphate cement are identical.
23. The method according to claim 22, wherein said first calcium phosphate cement and said second calcium phosphate cement are tetracalcium phosphate.
24. The method according to claim 16, wherein the first setting liquid and the second setting liquid independently are an acidic solution, a basic solution, or a substantially pure water.
25. The method according to claim 24, wherein said acidic solution is selected from the group consisting of nitric acid (HNO3), hydrochloric acid (HCl), phosphoric acid (H3PO4), carbonic acid (H2CO3), sodium dihydrogen phosphate (NaH2PO4), sodium dihydrogen phosphate monohydrate (NaH PO4*H2O), sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dehydrate, potassium dihydrogen phosphate (KH2PO4), ammonium dihydrogen.phosphate (NH H2PO ), malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture.
26. The method according to claim 22, wherein said basic solution is selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na2HPO4), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na3PO4»12H2O), dipotassium hydrogen phosphate (K2HPO ), potassium hydrogen phosphate trihydrate (K2HPO4 »3H2O), potassium phosphate tribasic (K3PO ), diammonium hydrogen phosphate ((NH4)2HPO ), ammonium phosphate trihydrate ((NH4)3PO «3H2O), sodium hydrogen carbonate (NaHCO3), sodium carbonate Na2CO3, and their mixture.
27. The method according to claim 16, wherein step c-i) further comprises allowing said first paste and said second paste undergoing a hardening reaction in said mold.
28. The method according to claim 16, wherein step c-i) further comprises pressurizing said first paste and said second paste in said mold after removing said one or more partition walls from said mold to remove a portion of liquid from said first paste and said second paste, so that a liquid/powder ratio of said first paste and of said second paste decreases; and allowing said first paste and second paste undergoing a hardening reaction in said mold.
29. The method according to claim 16, wherein step c-ii) further comprises allowing said intermediate undergoing a hardening reaction in said first mold, and allowing said another one of said first paste and said second paste undergoing a hardening reaction in said second mold.
30. The method according to claim 16, wherein step c-ii) further comprises pressurizing said one of said first paste and said second paste in said first mold to remove a portion of liquid therefrom before the hardening reaction of said intermediate is completed; allowing said intermediate undergoing a hardening reaction in said first mold; pressuring said another one of said first paste and said second paste in said second mold, so that a liquid/powder ratio of said another one of said first paste and of said second paste decreases; and allowing said another one of said first paste and second paste undergoing a hardening reaction in said second mold.
31. The method according to claim 28, wherein said pressuring is about 1 to 500 MPa.
32. The method according to claim 30, wherein said pressuring is about 1 to 500 MPa.
33. The method according to claim 16, wherein the immersing liquid is an acidic aqueous solution, a basic aqueous solution, a physiological solution, an organic solvent, or a substantially pure water.
34. The method according to claim 33, wherein the immersing liquid comprises at least one of Ca and P sources.
35. The method according to claim 33, wherein the immersing liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH4)2HPO4.
36. The method according to claim 16, wherein the immersing in step d) is carried out for a period longer than 10 minutes.
37. The method according to claim 16, wherein the immersing in step d) is carried out for a period longer than 1 day.
38. The method according to claim 16, wherein the immersing in step d) is carried out at a temperature of about 10 and 90°C.
39. The method according to claim 38, wherein the immersing in step d) is carried out at room temperature.
40. The method according claim 17 further comprising cleaning said immersed shaped article before said drying; and heating the resulting dried shaped article at a temperature between 50 and 500°C.
41. A method for making a molded calcium phosphate article comprising impregnating a rigid shaped article of calcium phosphate with an impregnating liquid for a period of time so that a compressive strength of the resulting impregnated article removed from the impregnating liquid is increased compared to that of said rigid shaped article without said impregnating treatment.
42. The method according to claim 41, wherein the impregnating liquid is an acidic solution, a basic solution, a physiological solution, an organic solvent, or a substantially pure water.
43. The method according to claim 42, wherein the impregnating liquid comprises at least one of Ca and P sources.
44. The method according to claim 42, wherein the impregnating liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH4)2HPO4.
45. The method according to claim 41, wherein the rigid shaped article of calcium phosphate is a molded article from a paste of calcium phosphate cement.
46. The method according to claim 41, wherein the impregnating is carried out for a period longer than 10 minutes.
47. The method according to claim 46, wherein the impregnating is carried out for about 12 hours to 96 hours.
48. The method according to claim 1, wherein the impregnating is carried out at room temperature or at a temperature between about 30 and 90°C.
49. The method according to claim 45, wherein said calcium phosphate cement comprises one or more calcium phosphates selected from the group consisting of alpha-tricalcium phosphate (α-TCP), beta-tricalcium phosphate (β-TCP), tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA), octacalcium phosphate (OCP), calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium pyrophosphate, calcium triphosphate, calcium phosphate tribasic, calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium phosphate, tricalcium phosphate hydrate, and amorphous calcium phosphate.
50. The method according to claim 49, wherein the calcium phosphate cement comprises at least one calcium phosphate particle having calcium phosphate whiskers on the surface of said calcium phosphate particle, wherein said calcium phosphate whiskers have a length of about 1-5000 nm and a width of about 1-500 nm.
51. The method according to claim 45, wherein said paste is formed by mixing said calcium phosphate cement with a setting liquid.
52. A method for making a molded calcium phosphate article comprising the following steps: a) preparing a powder comprising at least one Ca source and at least one P source, or at least one calcium phosphate source; b) mixing said powder with a setting liquid to form a paste, wherein said paste undergoes a hardening reaction; c) molding said paste into an article in a mold of a desired shape and size before said hardening reaction is complete; d) impregnating the resulting hardened article from step (c) with an impregnating liquid to allow strength of said article to increase; and e) removing said article from said impregnating liquid.
53. The method according to claim 52, wherein said calcium phosphate source in step (a) comprises one or more calcium phosphates selected from the group consisting of alpha-tricalcium phosphate (α-TCP), beta- tricalcium phosphate (β-TCP), tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous. (DCPA), octacalcium phosphate (OCP), calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium pyrophosphate, calcium triphosphate, calcium phosphate tribasic, calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium phosphate, tricalcium phosphate hydrate, and amorphous calcium phosphate.
54. The method according to claim 52, wherein the calcium phosphate source comprises at least one calcium phosphate particle having calcium phosphate whiskers on the surface of said calcium phosphate particle, wherein said calcium phosphate whiskers have a length of about 1-5000 nm and a width of about 1-500 nm.
55. The method according to claim 52, wherein the setting liquid in step (b) is an acidic solution, a basic solution, or a substantially pure water.
56. The method according to claim 55, wherein said acidic solution is selected from the group consisting of nitric acid (HNO3), hydrochloric acid (HCl), phosphoric acid (H PO ), carbonic acid (H2CO3), sodium dihydrogen phosphate (NaH2PO4), sodium dihydrogen phosphate monohydrate (NaH2PO4»H2O), sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dehydrate, potassium dihydrogen phosphate (KH2PO4), ammonium dihydrogen.phosphate (NH4H2PO4), malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture.
57. The method according to claim 55, wherein said basic solution is selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na2HPO4), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na3PO4 #12H2O), dipotassium hydrogen phosphate (K2HPO4), potassium hydrogen phosphate trihydrate (K2HPO4»3H2O), potassium phosphate tribasic (K3PO4), diammonium hydrogen phosphate ((NH4)2HPO ), ammonium phosphate trihydrate ((NH4)3PO «3H2O), sodium hydrogen carbonate (NaHCO3), sodium carbonate Na2CO3, and their mixture.
58. The method according to claim 52, wherein step (c) further comprises removing said article from said mold.
59. The method according to claim 52, wherein step (c) further comprises removing a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases.
60. The method according to claim 52, wherein step (c) further comprises pressurizing said paste in said mold before said hardening reaction is complete to remove a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases.
61. The method according to claim 60, wherein step (c) further comprises heating said paste during said pressurizing.
62. The method according to claim 52, wherein step (c) further comprises heating said paste during molding.
63. The method according to claim 52, wherein step (d) further comprises heating the impregnating liquid during said impregnating.
64. The method according to claim 63, wherein step (d) further comprises heating the impregnating liquid at a temperature between about 30 and 90°C during said impregnating.
65. The method according to claim 52 further comprising drying said article after removing said article from said impregnating liquid.
66. The method according to claim 52 further comprising heating said article after removing said article from said impregnating liquid.
67. The method according to claim 66, wherein said article after being removed from said impregnating liquid is heated at a temperature between 50 and 500°C.
68. The method according to claim 52, wherein the impregnating liquid in step (d) is an acidic solution, a basic solution, a physiological solution, an organic solvent, or a substantially pure water.
69. The method according to claim 68, wherein the impregnating liquid comprises at least one of Ca and P sources.
70. The method according to claim 68, wherein the impregnating liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH4)2HPO4.
71. The method according to claim 52, wherein the impregnating in step (d) is carried out for a period longer than 10 minutes.
72. The method according to claim 71, wherein the impregnating is carried out for about 12 hours to 96 hours.
73. The method according to claim 52, wherein the impregnating in step (d) is carried out at room temperature.
74. A method for making a porous calcium phosphate article comprising the following steps: i) preparing a shaped article from a paste comprising a calcium phosphate cement, a pore-forming powder and a setting liquid; ii) immersing said shaped article in an immersing liquid for a first period of time so that said pore-forming powder is dissolved in the immersing liquid, creating pores in said shaped article; iii) removing the resulting porous shaped article from said immersing liquid; and iv) immersing the porous shaped article from step iii) in an impregnating liquid for a second period of time so that a compressive strength of the resulting article removed from the impregnating liquid is increased compared to that of said porous shaped article without said impregnating treatment, wherein step iii) is omitted and a compressive strength of the resulting porous shaped article removed from the immersing liquid after the first and the second periods of time is increased compared to that of the resulting porous shaped article removed after the first period of time, when the immersing liquid and the impregnating liquid are the same.
75. The method according to claim 74, wherein said pore-forming powder is selected from the group consisting of LiCl, KCl, NaCI, MgCl2, CaCl2, NaIO3, KI, Na3PO4, K3PO4, Na2CO3, amino acid-sodium salt, amino acid-potassium salt, glucose, polysaccharide, fatty acid-sodium salt, fatty acid-potassium salt, potassium bitartrate (KHC4H4O6), potassium carbonate, potassium gluconate (KC6HπO7), potassium-sodium tartrate (KNaC H4O6*4H2O), potassium sulfate (K2SO4), sodium sulfate, and sodium lactate.
76. The method according to claim 74, wherein the immersing liquid is an acidic aqueous solution, a basic aqueous solution, a physiological solution, an organic solvent, or a substantially pure water.
77. The method according to claim 76, wherein the immersing liquid comprises at least one of Ca and P sources.
78. The method according to claim 76, wherein the immersing liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH4)2HPO4.
79. The method according to claim 76, wherein the immersing liquid and the impregnating liquid are the same.
80. The method according to claim 77, wherein the immersing liquid and the impregnating liquid are the same.
81. The method according to claim 78, wherein the immersing liquid and the impregnating liquid are the same.
82. The method according to claim 74, wherein the immersing liquid and the impregnating liquid are different.
83. The method according to claim 82, wherein the impregnating liquid is an acidic solution, a basic solution, a physiological solution, or a substantially pure water.
84. The method according to claim 83, wherein the impregnating liquid comprises at least one of Ca and P sources.
85. The method according to claim 83, wherein the impregnating liquid is a Hanks' solution, a HCl aqueous solution or an aqueous solution of (NH4)2HPO4.
86. The method according to claim 74, wherein the first period of time is longer than 10 minutes.
87. The method according to claim 86, wherein the first period of time is longer than 1 day.
88. The method according to claim 74, wherein the second period of time is longer than 10 minutes.
89. The method according to claim 88, wherein the second period of time is longer than 1 day.
90. The method according to claim 74, wherein the immersing in step ii) and iv) is carried out at room temperature or at a temperature between about 30 and 90°C.
91. The method according to claim 74, wherein said preparing of step i) comprises the following steps: (a) preparing a first powder as said calcium phosphate cement comprising at least one Ca source and at least one P source, or at least one calcium phosphate source; (b) mixing said first powder and the pore-forming powder with said setting liquid to form said paste, wherein said first powder and said setting liquid undergo a hardening reaction; (c) molding said paste into an article in a mold of a desired shape and size before said hardening reaction is complete; and (d) removing said molded article from said mold.
92. The method according to claim 91, wherein said calcium phosphate source in step (a) comprises one or more calcium phosphates selected from the group consisting of alpha-tricalcium phosphate (α-TCP), beta-tricalcium phosphate (β-TCP), tetracalcium phosphate (TTCP), monocalcium phosphate monohydrate (MCPM), monocalcium phosphate anhydrous (MCPA), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA), octacalcium phosphate (OCP), calcium dihydrogen phosphate, calcium dihydrogen phosphate hydrate, acid calcium pyrophosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate hydrate, calcium pyrophosphate, calcium triphosphate, calcium phosphate tribasic, calcium polyphosphate, calcium metaphosphate, anhydrous tricalcium phosphate, tricalcium phosphate hydrate, and amorphous calcium phosphate.
93. The method according to claim 92, wherein said calcium phosphate source in step (a) is tetracalcium phosphate (TTCP).
94. The method according to claim 92, wherein the calcium phosphate source comprises at least one calcium phosphate particle having calcium phosphate whiskers on the surface of said calcium phosphate particle, wherein said calcium phosphate whiskers have a length of about 1-5000 nm and a width of about 1-500 nm.
95. The method according to claim 92, wherein the setting liquid in step (b) is an acidic solution, a basic solution, or a substantially pure water.
96. The method according to claim 95, wherein said acidic solution is selected from the group consisting of nitric acid (HNO3), hydrochloric acid (HCl), phosphoric acid (H3PO4), carbonic acid (H2CO3), sodium dihydrogen phosphate (NaH2PO4), sodium dihydrogen phosphate monohydrate (NaH2PO4 »H2O), sodium dihydrogen phosphate dihydrate, sodium dihydrogen phosphate dehydrate, potassium dihydrogen phosphate (KH2PO4), ammonium dihydrogen.phosphate (NH H2PO ), malic acid, acetic acid, lactic acid, citric acid, malonic acid, succinic acid, glutaric acid, tartaric acid, oxalic acid and their mixture.
97. The method according to claim 95, wherein said basic solution is selected from the group consisting of ammonia, ammonium hydroxide, alkali metal hydroxide, alkali earth hydroxide, disodium hydrogen phosphate (Na2HPO ), disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate heptahydrate, sodium phosphate dodecahydrate (Na3PO4*12H2O), dipotassium hydrogen phosphate (K2HPO ), potassium hydrogen phosphate trihydrate (K2HPO4*3H2O), potassium phosphate tribasic (K3PO4), diammonium hydrogen phosphate ((NH )2HPO4), ammonium phosphate trihydrate ((NH4)3PO4 »3H2O), sodium hydrogen carbonate (NaHCO3), sodium carbonate Na CO3, and their mixture.
98. The method according to claim 91, wherein step (c) further comprises removing a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases.
99. The method according to claim 91, wherein step (c) further comprises pressurizing said paste in said mold before said hardening reaction is complete to remove a portion of liquid from said paste, so that a liquid/powder ratio of said paste decreases.
100. The method according to claim 99, wherein said pressuring is about 1 to 500 MPa.
101. The method according to claim 99, wherein step (c) further comprises heating said paste during said pressurizing.
102. The method according to claim 91, wherein step (c) further comprises heating said paste during molding.
103. The method according to claim 74 further comprising removing the resulting porous shaped article having an increased compressive strength from said impregnating liquid; and cleaning and drying said porous shaped article after removed from said impregnating liquid.
104. The method according to claim 103 further comprising heating the resulting cleaned and dried porous shaped article.
105. The method according to claim 104, wherein said heating is conducted at a temperature between 50 and 500°C.
106. The method according to claim 74, wherein said paste in step i) further comprises living cells.
107. The method according to claim 74, wherein said immersing liquid in step ii) comprises living cells.
108. The method according to claim 74, wherein said impregnating liquid in step iv) comprises living cells.
109. The method according to claim 74, wherein said porous shaped article having an increased compressive strength removed from said impregnating liquid in step iv) has a porosity of at least 30 vol%.
110. The method according to claim 74, wherein said porous shaped article having an increased compressive strength removed from said impregnating liquid in step iv) has a porosity of 50-90 vol%.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006522566A JP2007501054A (en) | 2003-08-05 | 2004-08-05 | Calcium phosphate cement medical implant manufacturing method and medical implant |
| AU2004265260A AU2004265260A1 (en) | 2003-08-05 | 2004-08-05 | Methods for preparing medical implants from calcium phosphate cement and medical implants |
| EP04778022A EP1660292A1 (en) | 2003-08-05 | 2004-08-05 | Methods for preparing medical implants from calcium phosphate cement and medical implants |
| CA002534826A CA2534826A1 (en) | 2003-08-05 | 2004-08-05 | Methods for preparing medical implants from calcium phosphate cement and medical implants |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/633,511 US7118705B2 (en) | 2003-08-05 | 2003-08-05 | Method for making a molded calcium phosphate article |
| US10/633,511 | 2003-08-05 | ||
| US10/780,728 | 2004-02-19 | ||
| US10/780,728 US7163651B2 (en) | 2004-02-19 | 2004-02-19 | Method for making a porous calcium phosphate article |
| US10/852,167 US6994726B2 (en) | 2004-05-25 | 2004-05-25 | Dual function prosthetic bone implant and method for preparing the same |
| US10/852,167 | 2004-05-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005016616A1 true WO2005016616A1 (en) | 2005-02-24 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2004/022309 WO2005016616A1 (en) | 2003-08-05 | 2004-08-05 | Methods for preparing medical implants from calcium phosphate cement and medical implants |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1660292A1 (en) |
| JP (1) | JP2007501054A (en) |
| KR (1) | KR20070028271A (en) |
| AU (1) | AU2004265260A1 (en) |
| CA (1) | CA2534826A1 (en) |
| TW (1) | TWI275386B (en) |
| WO (1) | WO2005016616A1 (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005079880A1 (en) * | 2004-02-19 | 2005-09-01 | Calcitec, Inc. | Methods for preparing medical implants from calcium phosphate cement and medical implants |
| WO2007044229A3 (en) * | 2005-09-28 | 2007-07-26 | Calcitec Inc | Surface treatments for calcium phosphate-based implants |
| US9463046B2 (en) | 2011-08-22 | 2016-10-11 | Ossdsign Ab | Implants and methods for using such implants to fill holes in bone tissue |
| US10076416B2 (en) | 2013-02-12 | 2018-09-18 | Ossdsign Ab | Mosaic implants, kits and methods for correcting bone defects |
| US10881519B2 (en) | 2014-08-14 | 2021-01-05 | Ossdsign Ab | Bone implants for correcting bone defects |
| CN114288192A (en) * | 2022-02-14 | 2022-04-08 | 浙江搏谷医疗科技有限公司 | Composition paste for tooth sealing treatment, preparation method and application |
| CN118121504A (en) * | 2024-05-06 | 2024-06-04 | 深圳柏垠生物科技有限公司 | Mussel mucin-based composition, preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100906545B1 (en) * | 2007-08-08 | 2009-07-07 | 퍼저 파마수티컬 컴퍼니 리미티드 | Biodegradable bone cement and its manufacturing method |
| JP4914308B2 (en) * | 2007-08-14 | 2012-04-11 | 瑞安大藥廠股▲分▼有限公司 | Cement for fracture treatment having biodegradability and method for producing the same |
| KR101627184B1 (en) | 2013-11-08 | 2016-06-07 | 한국기계연구원 | The preparing method of core-shell structured scaffold for hard tissue regeneration and the scaffold for hard tissue regeneration thereby |
| WO2015068908A1 (en) * | 2013-11-08 | 2015-05-14 | 한국기계연구원 | Method for manufacturing support for regenerating core-shell structured hard tissue and support for regenerating core-shell structured hard tissue manufactured thereby |
| KR101423129B1 (en) * | 2014-02-26 | 2014-07-25 | 주식회사 오쎄인 | High strength bone alternative synthetic bone for increasing compressive strength and supplementing blood circulation, and method for producing the same |
| TWI668002B (en) * | 2018-06-21 | 2019-08-11 | 財團法人亞洲大學 | Producing and stacking methods of cells containing blocks |
| KR102286084B1 (en) * | 2018-11-13 | 2021-08-06 | 한국재료연구원 | Control method of curing rate of calcium phosphate Support |
| JP7595337B2 (en) * | 2020-10-07 | 2024-12-06 | 国立研究開発法人理化学研究所 | Control device, method for manufacturing three-dimensional object, and control program |
| CN118206089B (en) * | 2024-03-20 | 2024-11-26 | 上海倍尔康生物医学科技有限公司 | A kind of hydroxyapatite microsphere and its preparation method and application |
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- 2004-08-04 TW TW093123389A patent/TWI275386B/en not_active IP Right Cessation
- 2004-08-05 EP EP04778022A patent/EP1660292A1/en not_active Withdrawn
- 2004-08-05 WO PCT/US2004/022309 patent/WO2005016616A1/en active Application Filing
- 2004-08-05 AU AU2004265260A patent/AU2004265260A1/en not_active Abandoned
- 2004-08-05 CA CA002534826A patent/CA2534826A1/en not_active Abandoned
- 2004-08-05 JP JP2006522566A patent/JP2007501054A/en active Pending
- 2004-08-05 KR KR1020067002571A patent/KR20070028271A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5820632A (en) * | 1988-04-20 | 1998-10-13 | Norian Corporation | Prepared calcium phosphate composition and method |
| US6547866B1 (en) * | 2000-10-30 | 2003-04-15 | Howmedica Osteonics Corp. | Porous calcium phosphate cement |
| US20030078317A1 (en) * | 2001-08-30 | 2003-04-24 | Jiin-Huey Lin | Process for preparing a paste from calcium phosphate cement |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005079880A1 (en) * | 2004-02-19 | 2005-09-01 | Calcitec, Inc. | Methods for preparing medical implants from calcium phosphate cement and medical implants |
| WO2007044229A3 (en) * | 2005-09-28 | 2007-07-26 | Calcitec Inc | Surface treatments for calcium phosphate-based implants |
| US9463046B2 (en) | 2011-08-22 | 2016-10-11 | Ossdsign Ab | Implants and methods for using such implants to fill holes in bone tissue |
| US10076416B2 (en) | 2013-02-12 | 2018-09-18 | Ossdsign Ab | Mosaic implants, kits and methods for correcting bone defects |
| US10881519B2 (en) | 2014-08-14 | 2021-01-05 | Ossdsign Ab | Bone implants for correcting bone defects |
| CN114288192A (en) * | 2022-02-14 | 2022-04-08 | 浙江搏谷医疗科技有限公司 | Composition paste for tooth sealing treatment, preparation method and application |
| CN118121504A (en) * | 2024-05-06 | 2024-06-04 | 深圳柏垠生物科技有限公司 | Mussel mucin-based composition, preparation method and application |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20070028271A (en) | 2007-03-12 |
| AU2004265260A1 (en) | 2005-02-24 |
| EP1660292A1 (en) | 2006-05-31 |
| CA2534826A1 (en) | 2005-02-24 |
| TW200509872A (en) | 2005-03-16 |
| JP2007501054A (en) | 2007-01-25 |
| TWI275386B (en) | 2007-03-11 |
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