JP6035623B2 - Control of solubility and sinterability of biomaterial ceramics made of tricalcium phosphate by the amount of trivalent metal ions dissolved - Google Patents
Control of solubility and sinterability of biomaterial ceramics made of tricalcium phosphate by the amount of trivalent metal ions dissolved Download PDFInfo
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- JP6035623B2 JP6035623B2 JP2010125011A JP2010125011A JP6035623B2 JP 6035623 B2 JP6035623 B2 JP 6035623B2 JP 2010125011 A JP2010125011 A JP 2010125011A JP 2010125011 A JP2010125011 A JP 2010125011A JP 6035623 B2 JP6035623 B2 JP 6035623B2
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- 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 description 153
- 229910021645 metal ion Inorganic materials 0.000 title claims description 95
- 235000019731 tricalcium phosphate Nutrition 0.000 title claims description 52
- 239000001506 calcium phosphate Substances 0.000 title claims description 40
- 229910000391 tricalcium phosphate Inorganic materials 0.000 title claims description 40
- 229940078499 tricalcium phosphate Drugs 0.000 title claims description 40
- 239000012620 biological material Substances 0.000 title claims description 25
- 239000000919 ceramic Substances 0.000 title claims description 25
- 239000011575 calcium Substances 0.000 claims description 47
- 239000006104 solid solution Substances 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 23
- 239000013078 crystal Substances 0.000 claims description 17
- 230000003247 decreasing effect Effects 0.000 claims description 9
- -1 yttrium ion Chemical class 0.000 claims description 8
- 229910052727 yttrium Inorganic materials 0.000 claims description 6
- 230000007423 decrease Effects 0.000 claims description 5
- 150000001768 cations Chemical group 0.000 claims description 4
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910001451 bismuth ion Inorganic materials 0.000 claims description 3
- 229910001424 calcium ion Inorganic materials 0.000 claims description 3
- 230000006641 stabilisation Effects 0.000 claims description 3
- 238000011105 stabilization Methods 0.000 claims description 3
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 claims description 2
- 239000011148 porous material Substances 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 description 125
- 238000010304 firing Methods 0.000 description 28
- 238000002441 X-ray diffraction Methods 0.000 description 20
- 239000012071 phase Substances 0.000 description 18
- 230000008859 change Effects 0.000 description 16
- 238000010586 diagram Methods 0.000 description 16
- 238000010828 elution Methods 0.000 description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 210000000988 bone and bone Anatomy 0.000 description 10
- 238000002329 infrared spectrum Methods 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 238000005259 measurement Methods 0.000 description 10
- 238000000465 moulding Methods 0.000 description 10
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 238000005452 bending Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000002156 mixing Methods 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000007974 sodium acetate buffer Substances 0.000 description 8
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 8
- 230000007704 transition Effects 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- 239000011701 zinc Substances 0.000 description 7
- 238000001354 calcination Methods 0.000 description 6
- 230000011164 ossification Effects 0.000 description 6
- 238000005498 polishing Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 230000001737 promoting effect Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000003462 bioceramic Substances 0.000 description 4
- 239000004568 cement Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 4
- 229910000388 diammonium phosphate Inorganic materials 0.000 description 4
- 235000019838 diammonium phosphate Nutrition 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229910052742 iron Inorganic materials 0.000 description 4
- 229910001416 lithium ion Inorganic materials 0.000 description 4
- 229910044991 metal oxide Inorganic materials 0.000 description 4
- 150000004706 metal oxides Chemical class 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 229910052697 platinum Inorganic materials 0.000 description 4
- 229910001414 potassium ion Inorganic materials 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000005245 sintering Methods 0.000 description 4
- 229910001415 sodium ion Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007580 dry-mixing Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229910001425 magnesium ion Inorganic materials 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 238000010298 pulverizing process Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000007088 Archimedes method Methods 0.000 description 2
- 229910015902 Bi 2 O 3 Inorganic materials 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- ODINCKMPIJJUCX-UHFFFAOYSA-N Calcium oxide Chemical compound [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 2
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 description 2
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 2
- 238000003991 Rietveld refinement Methods 0.000 description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 2
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910000416 bismuth oxide Inorganic materials 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 229910003460 diamond Inorganic materials 0.000 description 2
- 239000010432 diamond Substances 0.000 description 2
- TYIXMATWDRGMPF-UHFFFAOYSA-N dibismuth;oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Bi+3].[Bi+3] TYIXMATWDRGMPF-UHFFFAOYSA-N 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229910003440 dysprosium oxide Inorganic materials 0.000 description 2
- NLQFUUYNQFMIJW-UHFFFAOYSA-N dysprosium(iii) oxide Chemical compound O=[Dy]O[Dy]=O NLQFUUYNQFMIJW-UHFFFAOYSA-N 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000001683 neutron diffraction Methods 0.000 description 2
- CVPJXKJISAFJDU-UHFFFAOYSA-A nonacalcium;magnesium;hydrogen phosphate;iron(2+);hexaphosphate Chemical compound [Mg+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Fe+2].OP([O-])([O-])=O.OP([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O CVPJXKJISAFJDU-UHFFFAOYSA-A 0.000 description 2
- AHKZTVQIVOEVFO-UHFFFAOYSA-N oxide(2-) Chemical compound [O-2] AHKZTVQIVOEVFO-UHFFFAOYSA-N 0.000 description 2
- KFAFTZQGYMGWLU-UHFFFAOYSA-N oxo(oxovanadiooxy)vanadium Chemical compound O=[V]O[V]=O KFAFTZQGYMGWLU-UHFFFAOYSA-N 0.000 description 2
- SIWVEOZUMHYXCS-UHFFFAOYSA-N oxo(oxoyttriooxy)yttrium Chemical compound O=[Y]O[Y]=O SIWVEOZUMHYXCS-UHFFFAOYSA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 238000013001 point bending Methods 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229910052591 whitlockite Inorganic materials 0.000 description 2
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 229910052692 Dysprosium Inorganic materials 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000002639 bone cement Substances 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- 239000004068 calcium phosphate ceramic Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 229910001430 chromium ion Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910001431 copper ion Inorganic materials 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000005530 etching Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 229910001437 manganese ion Inorganic materials 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002138 osteoinductive effect Effects 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000001028 reflection method Methods 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000003746 solid phase reaction Methods 0.000 description 1
- 238000004544 sputter deposition Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 229910001456 vanadium ion Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Description
本発明はリン酸三カルシウムのリン酸サイトに生体必須元素又は生体微量必須元素に分類される三価金属イオンを置換固溶させた生体材料セラミックスに関する。 The present invention relates to a biomaterial ceramic in which a trivalent metal ion classified as a biological essential element or a biological trace essential element is substituted and dissolved in a phosphate site of tricalcium phosphate.
現代の急激な少子高齢化社会への移行にともない増加傾向にある高齢者の骨粗鬆症や骨折の治療に用いる医療材料、特に人工骨をはじめとする硬組織用代替材料としてリン酸三カルシウム[TCP;Ca3(PO4)2]が利用されている。リン酸三カルシウムは、生体親和性や骨誘導能に優れるだけでなく、生体内で次第に溶解しながら患者自身の骨(自家骨)と置換し、最終的には自家骨と完全に置換する生体吸収性セラミックスとして臨床応用されている。一方、その結晶構造中のカルシウムイオンおよびリン酸イオンと金属イオンが置換固溶する特徴を有し、金属イオンの置換固溶にともない材料化学的性質や生物学的性質が変化する。 Medical materials used to treat osteoporosis and fractures in the elderly, which are on the rise due to the transition to a rapidly aging society with a declining birthrate, especially tricalcium phosphate [TCP; as an alternative material for hard tissues including artificial bones Ca 3 (PO 4 ) 2 ] is used. Tricalcium phosphate not only has excellent biocompatibility and osteoinductive ability, but also replaces the patient's own bone (autologous bone) while gradually dissolving in vivo, and eventually replaces the autologous bone completely. It is clinically applied as an absorbent ceramic. On the other hand, calcium ions and phosphate ions in the crystal structure are characterized by substitutional solid solution, and the material chemical properties and biological properties change with substitutional solid solution of metal ions.
β型リン酸三カルシウム(β-TCP)およびα型リン酸三カルシウム(α-TCP)のカルシウムイオンと陽イオンを置換固溶した人工骨材としては、亜鉛イオン(Zn2+イオン)を置換した亜鉛含有TCP(特許文献１)が報告されている。in vitro(生体外)およびin vivo(生体内)評価により、この物質は、Zn2+イオンの溶出(除放)にともない通常のβ-TCPよりも優れた骨形成促進作用を有することが明らかにされている。 Replacement of zinc ion (Zn 2+ ion) as an artificial aggregate containing β-type tricalcium phosphate (β-TCP) and α-type tricalcium phosphate (α-TCP) as a solid solution Zinc-containing TCP (Patent Document 1) has been reported. In vitro (in vitro) and in vivo (in vivo) evaluation reveals that this substance has a better bone formation promoting effect than normal β-TCP as Zn 2+ ions are eluted (released) Has been.
また、二価金属イオンであるマグネシウムイオン(Mg2+イオン)または前述のZn2+イオンが置換固溶したβ-TCPの溶解性(生体吸収性)および溶解速度は、Mg2+イオンまたはZn2+イオンの置換固溶にともないともに低下することが明らかにされている。 In addition, the solubility (bioabsorbability) and dissolution rate of β-TCP in which the divalent metal ion magnesium ion (Mg 2+ ion) or the above-mentioned Zn 2+ ion was substituted and dissolved were Mg 2+ ion or Zn It has been clarified that it decreases with the substitutional solid solution of 2+ ions.
また、一価金属イオンであるリチウムイオン、ナトリウムイオンおよびカリウムイオン(Li+イオン、Na+イオン、K+イオン)または二価金属イオンであるマグネシウムイオン(Mg2+イオン)、亜鉛イオン(Zn2+イオン)、鉄イオン(Fe2+イオン)、銅イオン(Zn2+イオン)などの置換固溶したβ-TCPの固溶のメカニズムと溶解性の制御については特許文献２において公開されている。 Also, lithium ion, sodium ion and potassium ion (Li + ion, Na + ion, K + ion) which are monovalent metal ions, magnesium ion (Mg2 + ion), zinc ion (Zn 2 ion) which is divalent metal ion Patent Document 2 discloses the solid solution mechanism and solubility control of substituted solid solution β-TCP such as + ion), iron ion (Fe 2+ ion), copper ion (Zn 2+ ion), etc. .
上記の一価金属イオンであるリチウムイオン、ナトリウムイオンおよびカリウムイオン(Li+イオン、Na+イオン、K+イオン)または二価金属イオンであるマグネシウムイオン(Mg2+イオン)を置換固溶するβ-TCP構造中のカルシウムサイトについてはすでに知られている。 Β that dissolves and replaces the monovalent metal ions lithium ion, sodium ion and potassium ion (Li + ion, Na + ion, K + ion) or divalent metal ion magnesium ion (Mg 2+ ion) -The calcium site in the TCP structure is already known.
しかしながら、三価金属イオンを置換固溶するβ-TCP構造中の固溶サイトについては未だ報告がなく、固溶サイトへの金属イオン固溶による材料の機械的性質や生体内溶解性等の物性評価の報告もない。このため、生体材料として臨床応用することが難しかった。 However, there are no reports on solid-solution sites in the β-TCP structure where trivalent metal ions are substituted and dissolved, and the physical properties such as mechanical properties and in-vivo solubility of the metal ions due to the solid-solution sites. There is no report of evaluation. For this reason, it was difficult to apply clinically as a biomaterial.
（１）本発明は、生体必須元素又は生体微量必須元素に分類される三価金属イオンを固溶したリン酸三カルシウムからなる生体材料セラミックスを提供する。 (1) The present invention provides a biomaterial ceramic made of tricalcium phosphate in which a trivalent metal ion classified as a biological essential element or a biological trace essential element is dissolved.
（２）本発明は、三価金属イオンの固溶量によって溶解性及び焼結性を制御された上記（１）に記載の生体材料セラミックスを提供する。 (2) The present invention provides the biomaterial ceramic according to (1), wherein the solubility and the sinterability are controlled by the solid solution amount of the trivalent metal ion.
（３）本発明は、三価金属イオンは、イットリウムイオン、ジスプロシウムイオン、ビスマスイオンのいずれか一である上記（１）又は上記（２）に記載の生体材料セラミックスを提供する。 (3) The present invention provides the biomaterial ceramic according to (1) or (2) above, wherein the trivalent metal ion is any one of yttrium ion, dysprosium ion, and bismuth ion.
（４）本発明は、リン酸三カルシウムの全カルシウムイオンに対して９．１ｍｏｌ％以下の三価金属イオンを固溶した上記（３）に記載の生体材料セラミックスを提供する。 (4) The present invention provides the biomaterial ceramic according to (3) above, in which 9.1 mol% or less of trivalent metal ions are dissolved in total calcium ions of tricalcium phosphate.
（５）本発明は、上記（１）から（４）のいずれか一に記載のリン酸三カルシウムの焼結体からなる生体材料セラミックスを提供する。 (5) The present invention provides a biomaterial ceramic comprising the sintered body of tricalcium phosphate according to any one of (1) to (4) above.
（６）本発明は、上記（１）から（４）のいずれか一に記載の生体材料セラミックスであって、その性状が粉体である生体材料セラミックスを提供する。 (6) The present invention provides the biomaterial ceramic according to any one of (1) to (4) above, wherein the biomaterial ceramic is a powder.
（７）本発明は、上記（１）から（４）のいずれか一に記載の生体材料セラミックスであって、その性状が顆粒体である生体材料セラミックスを提供する。 (7) The present invention provides the biomaterial ceramic according to any one of (1) to (4) above, wherein the biomaterial ceramic has a granular shape.
（８）本発明は、上記（１）から（４）のいずれか一に記載の生体材料セラミックスであって、その性状が膜状である生体材料セラミックスを提供する。 (8) The present invention provides the biomaterial ceramic according to any one of (1) to (4) above, wherein the property is a film-like ceramic.
（９）本発明は、リン酸水素二アンモニウムと炭酸カルシウムと三価金属酸化物を乾式混合し、得られた混合物を焼成して合成される上記（１）に記載のリン酸三カルシウムからなる生体材料セラミックスを提供する。 (9) The present invention comprises tricalcium phosphate according to the above (1) synthesized by dry mixing diammonium hydrogen phosphate, calcium carbonate, and a trivalent metal oxide, and firing the resulting mixture. Provide biomaterial ceramics.
（１０）本発明は、リン酸水素二アンモニウムと炭酸カルシウムと三価金属酸化物とを湿式混合した後、得られた混合物から溶媒エタノールを除去する混合工程と、混合工程で得られた混合体を溶媒中で粉砕した後、前記溶媒を除去する粉砕工程と、粉砕工程で得られた粉体を一軸加圧成型して成型体を作成する成型工程と、成型工程で得られた成型体を焼成する焼成工程と、を有するリン酸三カルシウム焼結体製造方法を提供する。 (10) The present invention includes a mixing step in which diammonium hydrogen phosphate, calcium carbonate, and a trivalent metal oxide are wet-mixed, and then the solvent ethanol is removed from the resulting mixture, and the mixture obtained in the mixing step Crushed in a solvent, and then a pulverizing step for removing the solvent, a molding step for forming a molded body by uniaxial pressure molding of the powder obtained in the pulverizing step, and a molded body obtained in the molding step. There is provided a method for producing a tricalcium phosphate sintered body having a firing step of firing.
（１１）本発明は、混合工程における三価金属酸化物の混合量によってリン酸三カルシウム焼結体の溶解性及び焼結性を制御する上記（１０）に記載のリン酸三カルシウム焼結体製造方法を提供する。 (11) The tricalcium phosphate sintered body according to the above (10), wherein the present invention controls the solubility and sinterability of the tricalcium phosphate sintered body by the mixing amount of the trivalent metal oxide in the mixing step. A manufacturing method is provided.
本発明により、他の価数の金属イオンでは発現しない三価金属イオン独特の生体への作用、例えば骨生成促進作用などを有した新たな硬組織代替用バイオセラミックスの作製が可能となる。 The present invention makes it possible to produce a new bioceramic for substituting hard tissue having an action on a living body peculiar to a trivalent metal ion that is not expressed by other valence metal ions, for example, an action for promoting bone formation.
また、本発明は、固溶させる三価金属イオンの種類や固溶量で焼結性や溶解性などが制御可能でもあることから、これまでの金属イオン固溶TCPでは実現できなかった焼結性や溶解性などを有する硬組織代替材料が作製可能となる。また、理想的な生体硬組織代替材料とされる埋入する患者の年齢や性別、および患部に合わせた骨補填剤や生体骨セメントなどの作製を促進する発明である。 In addition, since the present invention can control sinterability and solubility by the type and amount of trivalent metal ions to be dissolved, sintering that has not been realized by conventional metal ion solid solution TCP It becomes possible to produce a hard tissue substitute material having properties such as solubility and solubility. In addition, the present invention promotes the production of a bone filling agent, a living bone cement, or the like suitable for the age and sex of the patient to be implanted, which is an ideal living hard tissue substitute material, and the affected part.
また、本発明では、一般的なリン酸三カルシウムの製造方法である固相法を用いていることから、実用性および汎用性が高く、高温相のα-TCPではなく低温相のβ-TCPに三価金属イオンを固溶させたバイオセラミックスを、厳密な製造条件の制御、熟練した製造方法および高温処理(焼成)や新たな製造装置を必要としない。このため、現在のリン酸三カルシウムの製造ラインをそのまま用いて製造でき、少ない設備投資やコストで三価金属イオンに起因する骨生成促進効果などを有したβ-TCPの製造が可能となる。 Further, in the present invention, since a solid phase method, which is a general method for producing tricalcium phosphate, is used, it is highly practical and versatile, and not a high temperature phase α-TCP but a low temperature phase β-TCP In addition, bioceramics in which trivalent metal ions are solid-dissolved do not require strict control of production conditions, skilled production methods, high-temperature treatment (firing), or new production equipment. For this reason, it is possible to produce β-TCP that can be produced using the present production line of tricalcium phosphate as it is, and has an effect of promoting bone formation caused by trivalent metal ions with a small capital investment and cost.
また、本発明での三価金属イオン固溶TCPは、その結晶相がTCP単相であり、生体に悪影響を及ぼすとされる金属酸化物や他のリン酸塩などの不純物を含まないため、十分にバイオセラミックスとしての応用が期待できる発明である。 In addition, the trivalent metal ion solid solution TCP in the present invention has a single crystal phase of TCP and does not contain impurities such as metal oxides and other phosphates that are considered to adversely affect the living body. It is an invention that can be sufficiently applied as bioceramics.
以下、本件発明の実施の形態について、添付図面を用いて説明する。なお、本件発明は、これら実施形態に何ら限定されるべきものではなく、その要旨を逸脱しない範囲において、種々なる態様で実施し得る。
<<実施形態１>>
<実施形態１：概要>
Hereinafter, embodiments of the present invention will be described with reference to the accompanying drawings. In addition, this invention should not be limited to these embodiments at all, and can be implemented in various modes without departing from the gist thereof.
<< Embodiment 1 >>
<Embodiment 1: Overview>
生体必須元素又は生体微量必須元素に分類される三価金属イオンを固溶したリン酸三カルシウムからなる生体材料セラミックス及びその焼結体について説明する。
<実施形態１：構成>
A biomaterial ceramic made of tricalcium phosphate in which a trivalent metal ion classified as a biological essential element or a biological trace essential element is dissolved, and a sintered body thereof will be described.
<Embodiment 1: Configuration>
本発明の生体材料セラミックスとは、事故や病気などにより欠損、喪失した歯や骨などの生体硬組織の置換材料として用いられるものであって、三価の金属イオンが後述する形態で固溶したリン酸三カルシウム（以下、TCPという）からなる生体材料セラミックスであればその形状は特に限定しない。粉体、顆粒体、膜状のものや、多孔体、緻密体などの焼結体が該当する。また、固溶とは、２種類以上の元素が互いに溶け合い、全体が均一の固相になることをいい、焼結体とは融点より低い温度で加熱して固化したものをいう。 The biomaterial ceramics of the present invention is used as a replacement material for living hard tissues such as teeth and bones that have been lost or lost due to accidents or illnesses, and trivalent metal ions are dissolved in the form described later. The shape is not particularly limited as long as it is a biomaterial ceramic made of tricalcium phosphate (hereinafter referred to as TCP). A sintered body such as a powder, a granule, a film, a porous body or a dense body is applicable. In addition, solid solution means that two or more kinds of elements are melted together to form a uniform solid phase as a whole, and a sintered body means a material solidified by heating at a temperature lower than the melting point.
（１）固溶形態 (1) Solid solution form
本発明に係るTCPは、結晶中のCaサイトにイットリウム等の生体必須元素又は生体微量必須元素に分類される三価の金属イオンを固溶したものである。TCPの機械的強度や溶解性は、その結晶構造、結晶性（粒子サイズなど）に影響を受けるため、結晶中のCaサイトに上記三価の金属イオンで固溶することにより、当該TCPからなる生体材料セラミックスの機械的強度や溶解性を制御する。 The TCP according to the present invention is a solid solution of a trivalent metal ion classified as a biological essential element such as yttrium or a biological trace essential element at a Ca site in a crystal. Since the mechanical strength and solubility of TCP are affected by its crystal structure and crystallinity (particle size, etc.), it is composed of the TCP by solid-dissolving with the above trivalent metal ions at the Ca site in the crystal. Controls the mechanical strength and solubility of biomaterial ceramics.
（リン酸三カルシウムの性質）
リン酸三カルシウム〔Ca3(PO4)2：TCP〕には、低温からβ、α、α'の三つの相が存在する。α'-TCPは1450℃付近から高温で安定であり常温では得られない。α-TCPは1120-1180℃以下でβ-TCPに相転移するが、転移の速度が遅いため常温で準安定相として存在する。天然にはWhitlockite〔（Ca18(Mg、Fe)2H2(PO4)14、β相と類似）として存在する。α-TCPおよびβ-TCPはともに生体活性材料であり、バイオセラミックスとして利用されている。これらの生体内における挙動はHApと似ているが、溶解度はHApより大きく、β-TCPの溶解度はHApの約2倍、α-TCPはHApの約10倍である。
(Properties of tricalcium phosphate)
Tricalcium phosphate [Ca 3 (PO 4 ) 2 : TCP] has three phases β, α and α ′ from low temperature. α'-TCP is stable at high temperatures from around 1450 ° C and cannot be obtained at room temperature. α-TCP undergoes phase transition to β-TCP at temperatures below 1120-1180 ° C, but exists as a metastable phase at room temperature due to the slow transition rate. Naturally, it exists as Whitlockite [(Ca 18 (Mg, Fe) 2 H 2 (PO 4 ) 14 , similar to β phase)]. α-TCP and β-TCP are both bioactive materials and are used as bioceramics. These in vivo behaviors are similar to HAp, but the solubility is greater than HAp, β-TCP has a solubility of about twice that of HAp, and α-TCP is about 10 times that of HAp.
β-TCPは HApよりCa/Pモル比が低い(Ca/Pモル比=1.50)ため、β-TCPは他のリン酸カルシウム系セラミックスと比較して生体中での溶解および吸収速度が大きく、新生骨の生成とともに自家骨と置換するため人工歯根や骨充填材として臨床応用されている。また、β-TCPはα-TCPへの転移温度である1150℃以下の温度で焼結体が作製でき、このような焼成プロセスにより分解などを起こさず、吸水性もある。材料の吸収速度が周囲に形成する骨生成速度と適合し、新たに形成した骨が十分な強度をもつことが理想的なバイオセラミックスと考えられるため、β-TCPはこの条件を満たす可能性を有する数少ない材料である。 Since β-TCP has a lower Ca / P molar ratio than HAp (Ca / P molar ratio = 1.50), β-TCP has a higher dissolution rate and resorption rate in the living body than other calcium phosphate ceramics. It is clinically applied as an artificial tooth root and bone filler to replace autogenous bone with the generation of bone. In addition, β-TCP can produce a sintered body at a temperature of 1150 ° C. or lower, which is a transition temperature to α-TCP, and does not cause decomposition or the like by such a firing process, and has water absorption. Β-TCP has the possibility of satisfying this condition because the resorption rate of the material is compatible with the bone formation rate formed in the surrounding area, and it is considered that the newly formed bone has sufficient strength. There are few materials to have.
一方、α-TCPは水和してHApとなり、その時に硬化する性質があるため生体用セメントとして応用されている。しかし、水のみによる硬化では硬化時間が生体用セメントの使用条件にくらべて長すぎるため、硬化促進のためクエン酸、ポリアクリル酸などの酸を硬化剤として添加する方法も用いられている。しかし、生体用セメントとして酸を用いた場合、充填部位周辺に炎症性の反応が生じるため、酸を用いないかまたは酸を積極的に中和させるタイプのセメントが開発されている。 On the other hand, α-TCP is hydrated into HAp and hardens at that time, so it is used as a bio-cement. However, since the curing time is too long in the case of curing with water as compared with the use conditions of the biological cement, a method of adding an acid such as citric acid or polyacrylic acid as a curing agent to accelerate the curing is also used. However, when an acid is used as a biological cement, an inflammatory reaction occurs around the filling site. Therefore, a type of cement that does not use an acid or actively neutralizes the acid has been developed.
（β型リン酸三カルシウムの結晶構造）
β-TCPの空間群はR3cで菱面体晶系に属する。格子定数は六方格子設定でa=1.04352(2)nm、c=3.74029(5)nmである。図１、図２にβ-TCPの結晶構造を示す。β-TCPは結晶構造(単位格子)中にCaとPO4四面体からなる結晶学的に独立なA、B 2本のカラムが存在し、これら2本のカラムがｃ軸に平行に存在している。カラムAはｃ軸(3回軸)上に存在し、P(1)-Ca(4)-Ca(5)-P(1)-空孔-Ca(5)の繰り返しである。天然鉱物であるWhitlockiteではCa(4)およびCa(5)サイトにはMgやFeといった他の金属イオンが置換する。また、Ca(4)サイトは席占有率が約0.5であるため、カラムAに空孔が存在する特異な結晶構造をもっている。カラムBはP(2)-Ca(3)-Ca(1)-Ca(2)-P(3)の繰り返しであるが、三つのCaは一直線上にのらずに1/3ずつずれるため折れ線を形成する。下記の表１と表２に空孔を考慮したβ-TCP単位格子中の各Ca2+イオンサイトおよびPO4 3-イオンサイトの割合を示した。
［表１］
［表２］
(Crystal structure of β-type tricalcium phosphate)
The space group of β-TCP is R3c and belongs to the rhombohedral system. The lattice constants are a = 1.04352 (2) nm and c = 3.74029 (5) nm in the hexagonal lattice setting. 1 and 2 show the crystal structure of β-TCP. β-TCP has two crystallographically independent A and B columns consisting of Ca and PO 4 tetrahedra in the crystal structure (unit cell), and these two columns exist parallel to the c-axis. ing. Column A exists on the c-axis (three-fold axis) and is a repetition of P (1) -Ca (4) -Ca (5) -P (1) -hole-Ca (5). In Whitlockite, a natural mineral, Ca (4) and Ca (5) sites are replaced by other metal ions such as Mg and Fe. In addition, since the Ca (4) site has a seat occupancy of about 0.5, it has a unique crystal structure in which vacancy exists in column A. Column B is a repetition of P (2) -Ca (3) -Ca (1) -Ca (2) -P (3), but the three Ca's do not fall on a straight line but shift by 1/3. A polygonal line is formed. Tables 1 and 2 below show the ratio of each Ca 2+ ion site and PO 4 3- ion site in the β-TCP unit cell in consideration of vacancies.
[Table 1]
[Table 2]
（三価金属イオン固溶β型リン酸三カルシウム） (Trivalent metal ion solid solution β-type tricalcium phosphate)
本発明で生体材料セラミックス等に固溶させる三価金属イオンとしては、主として生体必須元素又は生体微量必須元素に分類されるものである。生体必須元素又は生体微量必須元素とは、生体分子の立体構造を維持したり、重要な生体反応や独特の生理作用を発揮する元素である。生体必須元素又は生体微量必須元素に分類される三価金属イオンとしては、例えばイットリウムイオン（Ｙ3+）、ビスマスイオン（Ｂｉ3+）、ジスプロシウムイオン（Ｄｙ3+）、バナジウムイオン（Ｖ3+）、ランタンイオン（Ｌａ3+）などが考えられる。また、マンガンイオン（Ｍｎ3+）、鉄イオン（Ｆｅ3+）、クロムイオン（Ｃｒ3+）等も考えられる。これらの三価金属イオンを用いることにより、生体に適した生体材料セラミックス等を生成することが可能になる。 The trivalent metal ions that are solid-solved in the biomaterial ceramics and the like in the present invention are mainly classified into essential biological elements or essential biological trace elements. A biological essential element or a biological trace essential element is an element that maintains a three-dimensional structure of a biological molecule, or exhibits an important biological reaction or a unique physiological action. Examples of trivalent metal ions classified as essential biological elements or essential biological elements include yttrium ions (Y 3+ ), bismuth ions (Bi 3+ ), dysprosium ions (Dy 3+ ), vanadium ions (V 3+ ). ), Lanthanum ions (La 3+ ) and the like. Manganese ions (Mn 3+ ), iron ions (Fe 3+ ), chromium ions (Cr 3+ ), and the like are also conceivable. By using these trivalent metal ions, biomaterial ceramics suitable for the living body can be generated.
（３）三価金属イオン添加β-TCPの合成 (3) Synthesis of β-TCP added with trivalent metal ions
本発明に係る三価金属イオン固溶β-TCPの合成は既存の方法に従い、固相反応による乾式法と、水溶液反応による湿式法のどちらでもよいが、不純物相の生成を抑制できる点で、乾式法が好ましい。例えば、既存の方法に従い、リン酸源及びカルシウム源としてリン酸水素二アンモニウム（(ＮＨ4)2ＨＰＯ4）と、酸化カルシウム（ＣａＯ）を出発原料として用い、三価金属イオン源として酸化イットリウム（Ｙ2Ｏ3）（又は酸化ビスマス（Ｂｉ2Ｏ3）、酸化ジスプロシウム（Ｄｙ2Ｏ3）、酸化バナジウム（Ｖ2Ｏ3））を用いた。各出発原料を乾式混合し、得られた混合物を焼成して生成される。一例を図３に示す。各出発原料を１時間乾式混合（Ｓ０３０１）する。これを昇温速度３℃／min、焼成温度１０００℃、保持時間１２時間、大気雰囲気中の条件下で焼成する（Ｓ０３０２）。続いて再度１時間の乾式混合を行う（Ｓ０３０３）。そして再度、昇温速度３℃／min、焼成温度１０００℃、保持時間１２時間、大気雰囲気中の条件下で焼成し（Ｓ０３０４）、得られた焼成体が本発明に係る三価金属イオン固溶β-TCPとなる。 The synthesis of the trivalent metal ion solid solution β-TCP according to the present invention may be either a dry method using a solid phase reaction or a wet method using an aqueous solution reaction in accordance with an existing method. A dry method is preferred. For example, in accordance with an existing method, diammonium hydrogen phosphate ((NH 4 ) 2 HPO 4 ) and calcium oxide (CaO) are used as starting materials, and yttrium oxide (Trivalent metal ion source ( Y 2 O 3 ) (or bismuth oxide (Bi 2 O 3 ), dysprosium oxide (Dy 2 O 3 ), vanadium oxide (V 2 O 3 )) was used. Each starting material is dry mixed and the resulting mixture is calcined. An example is shown in FIG. Each starting material is dry-mixed for 1 hour (S0301). This is fired under conditions of a temperature increase rate of 3 ° C./min, a firing temperature of 1000 ° C., a holding time of 12 hours, and in an air atmosphere (S0302). Subsequently, dry mixing is performed again for 1 hour (S0303). Then, again, the firing rate is 3 ° C./min, the firing temperature is 1000 ° C., the holding time is 12 hours, and the firing is performed in the atmosphere (S0304). β-TCP.
なお、後述する実施例１において評価される三価金属イオン固溶β-TCPは、図３に示す方法で合成されたものである。 The trivalent metal ion solid solution β-TCP evaluated in Example 1 described later is synthesized by the method shown in FIG.
（４）三価金属イオン固溶β-TCPの焼結 (4) Sintering of trivalent metal ion solid solution β-TCP
本発明に係る三価金属イオン固溶β-TCPの焼結は既存の方法に従い行えばよい。一例を図４に示す。リン酸源及びカルシウム源としてリン酸水素二アンモニウム（ＣａＨＰＯ4・２Ｈ2Ｏ）と、酸化カルシウム（ＣａＣＯ3）を出発原料として用い、三価金属イオン源として酸化イットリウム（Ｙ2Ｏ3）（又は酸化ビスマス（Ｂｉ2Ｏ3）、酸化ジスプロシウム（Ｄｙ2Ｏ3）、酸化バナジウム（Ｖ2Ｏ3））を用いた。上記出発原料をボールミルで４８時間湿式混合する（Ｓ０４０１）。溶媒としてエタノールなどの有機溶媒を用いる。その後、エバポレータなどを用いて溶媒を除去する（Ｓ０４０２）（混合工程）。溶媒除去後の混合体を再度溶媒に入れて粉砕し（Ｓ０４０３）、その後再度溶媒を除去する（Ｓ０４０４）（粉砕工程）。ここで得られた粉体を一軸加圧成型して成型体を作成し（成型工程）（Ｓ０４０５）、当該成型体を焼成し（焼成工程）（Ｓ０４０６）、焼結体を得る。ここで、一軸加圧成型（Ｓ０４０５）は、３２ＭＰａで１分間加圧する。使用する金型は４５ｍｍ×２０ｍｍである。また、焼成（Ｓ０４０６）は、昇温速度３℃／min、焼成温度１１００℃、保持時間２４時間、大気雰囲気中の条件下で行う。 The sintering of the trivalent metal ion solid solution β-TCP according to the present invention may be performed according to an existing method. An example is shown in FIG. Using diammonium hydrogen phosphate (CaHPO 4 .2H 2 O) and calcium oxide (CaCO 3 ) as starting materials as the phosphate and calcium sources, and yttrium oxide (Y 2 O 3 ) as the trivalent metal ion source (or Bismuth oxide (Bi 2 O 3 ), dysprosium oxide (Dy 2 O 3 ), and vanadium oxide (V 2 O 3 )) were used. The above starting materials are wet-mixed with a ball mill for 48 hours (S0401). An organic solvent such as ethanol is used as the solvent. Thereafter, the solvent is removed using an evaporator or the like (S0402) (mixing step). The mixture after removal of the solvent is again put in the solvent and pulverized (S0403), and then the solvent is removed again (S0404) (pulverization step). The powder obtained here is uniaxially pressed to form a molded body (molding step) (S0405), and the molded body is fired (firing step) (S0406) to obtain a sintered body. Here, uniaxial pressure molding (S0405) pressurizes at 32 MPa for 1 minute. The mold used is 45 mm × 20 mm. Further, the firing (S0406) is performed under conditions in an air atmosphere at a heating rate of 3 ° C./min, a firing temperature of 1100 ° C., a holding time of 24 hours.
なお、図５に示すように、ボールミルで湿式混合し（Ｓ０５０１）、溶媒を除去（Ｓ０５０２）した後、仮焼工程（Ｓ０５０３）を行ってもよい。また、一軸加圧成型（Ｓ０５０６）後にCIP成型工程（Ｓ０５０７）を行ってもよい。当該仮焼工程（Ｓ０５０３）は、昇温速度３℃／min、焼成温度８００℃〜１０００℃、保持時間１２時間、大気雰囲気中の条件下行う。また、CIP成型工程（Ｓ０５０７）は２００ＭＰａで１分間加圧成型する。なお、仮焼工程における仮焼温度の違いにより、焼結性及び焼結体の機械的強度に明らかな差異が見られるため、仮焼工程を行うことによりこれらを調整することが可能である。また、CIP成型工程により、より均一な焼結体の製造が可能である。 In addition, as shown in FIG. 5, after carrying out wet mixing with a ball mill (S0501) and removing a solvent (S0502), you may perform a calcination process (S0503). Further, the CIP molding step (S0507) may be performed after the uniaxial pressure molding (S0506). The calcination step (S0503) is performed under conditions of a temperature increase rate of 3 ° C./min, a baking temperature of 800 ° C. to 1000 ° C., a holding time of 12 hours, and an air atmosphere. In the CIP molding step (S0507), pressure molding is performed at 200 MPa for 1 minute. In addition, since a clear difference is seen in sinterability and the mechanical strength of a sintered compact by the difference in the calcination temperature in a calcination process, these can be adjusted by performing a calcination process. Further, a more uniform sintered body can be produced by the CIP molding process.
<実施形態１：効果> <Embodiment 1: Effect>
三価の金属イオンがβ-TCPに固溶することを明らかにした本発明は、β-TCPに固溶させる金属イオンの選択範囲を増加させるだけでなく、固溶した金属イオンに起因する材料の溶解性制御、骨生成促進作用なども有する新規な硬組織代替用生体材料として応用範囲の拡大につながる。 The present invention, which clarifies that trivalent metal ions are dissolved in β-TCP, not only increases the selection range of metal ions to be dissolved in β-TCP, but also a material resulting from the dissolved metal ions. As a new biomaterial for hard tissue replacement that has solubility control and bone formation promoting action, it will lead to expansion of application range.
本発明では、一般的なリン酸三カルシウムの製造方法である固相法を用いて、高温相のα-TCPではなく低温相のβ-TCPに三価の金属イオンを固溶させるため、厳密な製造条件の制御、熟練した製造方法および高温処理(焼成)を必要とせず、現在のリン酸三カルシウムの製造ラインで製造できるため、少ない設備投資やコストで固溶させた陰イオンに起因する骨生成促進効果などを有したβ-TCPの製造が可能となる。 In the present invention, a solid phase method, which is a general method for producing tricalcium phosphate, is used to dissolve trivalent metal ions in β-TCP in a low temperature phase instead of α-TCP in a high temperature phase. Control of manufacturing conditions, skilled manufacturing methods and high temperature treatment (firing) are not required, and because it can be manufactured on the current production line of tricalcium phosphate, it is caused by anion dissolved in less equipment investment and cost It is possible to produce β-TCP having an effect of promoting bone formation.
三価の金属イオンを添加したβ-TCPの評価 Evaluation of β-TCP added with trivalent metal ions
図３に示す方法により作成した三価金属イオンを添加したβ-TCP（以下、単に「試料」とする）について、Ｘ線回折、ＦＴ−ＩＲ、生体吸収性等の試験を行った。なお、本実施例の三価金属イオン添加β-TCPの乾式混合時の原料のモル配合比を下記表３に示す。
［表３］
Tests such as X-ray diffraction, FT-IR, and bioabsorbability were performed on β-TCP (hereinafter simply referred to as “sample”) to which trivalent metal ions prepared by the method shown in FIG. 3 were added. In addition, Table 3 below shows the molar mixing ratio of the raw materials during dry mixing of the trivalent metal ion-added β-TCP of this example.
[Table 3]
（１）Ｘ線回折 (1) X-ray diffraction
リガク製RAD-2C型Ｘ線回折装置を用いて、試料の結晶相の同定を行った。測定条件は、ターゲット：CuKαモノクロメーター、走査範囲（2θ）：10-60°、スキャンステップ：0.020°、スキャンスピード：8°／min、使用管電圧：40kV、使用管電流：30mA、である。 The crystal phase of the sample was identified using Rigaku RAD-2C type X-ray diffractometer. The measurement conditions are: target: CuKα monochromator, scan range (2θ): 10-60 °, scan step: 0.020 °, scan speed: 8 ° / min, tube voltage: 40 kV, tube current: 30 mA.
三価金属イオンを0〜12mol%添加して作製した試料のX線回折結果を図６〜図１３に示す。図６および図７より、Y3+イオン添加量の増加にともなう回折ピークのシフトはほとんど見られなかった。しかし、Y 3+イオン9.09mol%添加β-TCPでは、β-TCPにY 3+イオンが9.09mol%固溶したときの理論組成であるCa9Y(PO4)7（ICDD46-0402）の回折線と一致した。Y 3+イオン添加量10mol%以降では、YPO4（ICDD 11-0254）の回折ピークが確認された。 The X-ray diffraction results of the samples prepared by adding 0 to 12 mol% of trivalent metal ions are shown in FIGS. From FIG. 6 and FIG. 7, the shift of the diffraction peak with the increase in Y 3+ ion addition amount was hardly seen. However, in β-TCP with 9.09 mol% Y 3+ ions added, the theoretical composition of Y9 + ions in 9.09 mol% in β-TCP is Ca 9 Y (PO 4 ) 7 (ICDD46-0402). Consistent with diffraction lines. The diffraction peak of YPO 4 (ICDD 11-0254) was confirmed when the Y 3+ ion addition amount was 10 mol% or more.
図８および図９より、Y3+イオンの場合と同様に、Dy3+イオン添加量の増加にともなう回折ピークのシフトは見られなかった。Dy3+イオン9.09mol%添加β-TCPでは、β-TCPにDy3+イオンが9.09mol%固溶したときの理論組成であるCa9Dy(PO4)7（ICDD 49-1086）の回折線と一致した。Dy3+イオン添加量10mol%以降では、DyPO4（ICDD 26-0591）の回折ピークが確認された。 From FIG. 8 and FIG. 9, as in the case of Y 3+ ions, no shift of the diffraction peak was observed as the Dy 3+ ion addition amount increased. In Dy 3+ ions 9.09Mol% added β-TCP, Ca 9 Dy ( PO 4) Dy 3+ ions in beta-TCP is the stoichiometric composition when dissolved 9.09mol% 7 diffraction (ICDD 49-1086) Matched the line. When the Dy 3+ ion addition amount was 10 mol% or more, a diffraction peak of DyPO 4 (ICDD 26-0591) was confirmed.
図１０および図１１より、Bi3+イオン添加量9.09mol%までは、添加量の増加にともない、ピークがわずかに低角度側にシフトし、Bi3+イオン9.09mol%添加β-TCPでは、β-TCPにBi3+イオンが9.09mol%固溶したときの理論組成であるCa9Bi(PO4)7（ICDD44-0187）の回折線と一致した。それ以降はピークのシフトは見られなかった。Bi3+イオン添加量10mol%以降では、Ca3Bi(PO4)3（ICDD44-0187）の回折ピークが確認された。 From 10 and 11, until the Bi 3+ ion amount 9.09Mol%, with the increase of the addition amount, the peak is shifted slightly lower angle side, the Bi 3+ ion 9.09Mol% added beta-TCP, This coincided with the diffraction line of Ca 9 Bi (PO 4 ) 7 (ICDD44-0187), which is the theoretical composition when Bi 3+ ions were dissolved in β-TCP at 9.09 mol%. After that, no peak shift was observed. The diffraction peak of Ca 3 Bi (PO 4 ) 3 (ICDD44-0187) was confirmed at a Bi 3+ ion addition amount of 10 mol% or more.
図１２および図１３より、La3+イオン添加量9.09mol%までは、添加量の増加にともない、ピークがわずかに低角度側にシフトした。それ以降はピークのシフトは見られなかった。ICDDカードデータにはないが、添加量9.09mol%のときにはCa9La(PO4)7という組成になっていると考えられる。La3+イオン添加量10mol%以降では、LaPO4（ICDD32-0493）の回折ピークが確認された。以上のことから、三価金属イオンはβ-TCP構造中に9.09mol%まで固溶すると考えられる。 From FIG. 12 and FIG. 13, the peak slightly shifted to the lower angle side as the addition amount increased up to 9.09 mol% of La 3+ ion addition amount. After that, no peak shift was observed. Although not in the ICDD card data, it is considered that the composition is Ca 9 La (PO 4 ) 7 when the addition amount is 9.09 mol%. When the La 3+ ion addition amount was 10 mol% or more, a diffraction peak of LaPO 4 (ICDD32-0493) was confirmed. From the above, it is considered that trivalent metal ions are solid-solved up to 9.09 mol% in the β-TCP structure.
三価金属イオンを固溶したリン酸三カルシウムの構造安定性は、Ca(5)サイトの酸化物イオンとの配位状態(6配位)に依存する。すなわち、β-TCPのCa(5)サイトの6配位の結晶化学的な安定性は熱的安定性に一致し、さらにリン酸三カルシウムの溶解性および固体の拡散(焼結性)にも依存する。すなわち、Ca(5)サイトの安定化によるブロッキング効果の増大によって物質移動は抑制され、バルクを構成する粒子成長を抑制することに寄与する。一方、α-TCPに三価金属イオンを固溶させると、3Ca2+イオン=2M3+イオン+□で部分的に置換固溶する。生じた空孔濃度は物質移動に寄与する。このように三価金属イオンを固溶させることによってリン酸三カルシウム構造の安定性と空孔濃度を制御することができ、それによってリン酸三カルシウムの溶解性や固体反応を制御するものである。 The structural stability of tricalcium phosphate in which a trivalent metal ion is dissolved depends on the coordination state (6-coordinate) with the oxide ion at the Ca (5) site. That is, the 6-coordination crystal chemical stability of the Ca (5) site of β-TCP matches the thermal stability, and also the solubility of tricalcium phosphate and the diffusion of solids (sinterability). Dependent. That is, mass transfer is suppressed by an increase in the blocking effect due to stabilization of the Ca (5) site, which contributes to suppressing growth of particles constituting the bulk. On the other hand, when trivalent metal ions are dissolved in α-TCP, they are partially substituted by 3Ca 2+ ions = 2M 3+ ions + □. The generated vacancy concentration contributes to mass transfer. Thus, by dissolving the trivalent metal ions, the stability of the tricalcium phosphate structure and the vacancy concentration can be controlled, thereby controlling the solubility and solid reaction of the tricalcium phosphate. .
（２）格子定数 (2) Lattice constant
格子定数の測定には、リガク製回転対陰極型X線回折装置RINT-1500を使用し、内部標準試料としてSi(99.99%、三津和化学薬品株式会社)を用い、β-TCPの回折線(2 0 10)、(2 1 8)、(2 2 0)、(3 2 8)、(2 0 20)の5本とSiの回折線(1 1 1)、(2 2 0)、(3 1 1)、(2 0 20)の4本について最適な条件下で予備測定した。測定は、使用管電圧:40kV、使用管電流:200mA、にて行った。また、測定したX線回折図についてピークトップ法を用いた内部標準法で角度補正を行い、次式を用いて最小二乗法で格子定数の精密化を行った。
［数１］
The lattice constant was measured using a Rigaku rotating anti-cathode X-ray diffractometer RINT-1500, using Si (99.99%, Mitsuwa Chemical Co., Ltd.) as an internal standard sample, and β-TCP diffraction lines ( (2 0 10), (2 1 8), (2 2 0), (3 2 8), (2 0 20) and Si diffraction lines (1 1 1), (2 2 0), (3 1 Preliminary measurement was performed under the optimum conditions for 4) (1 0) and (2 0 20). The measurement was performed at a working tube voltage: 40 kV and a working tube current: 200 mA. In addition, the measured X-ray diffraction diagram was subjected to angle correction by the internal standard method using the peak top method, and the lattice constant was refined by the least square method using the following equation.
[Equation 1]
つぎに、三価金属イオン添加β-TCPの格子定数変化を図１４〜図１７に示す。図１４より、Y3+イオンを添加すると、a軸は添加量9.09mol%までわずかに増加し、その後一定となった。一方、c軸はY 3+イオン添加量9.09mol%まで減少し、その後一定となった。 Next, changes in lattice constant of trivalent metal ion-added β-TCP are shown in FIGS. As shown in FIG. 14, when Y 3+ ions were added, the a-axis slightly increased to the added amount of 9.09 mol%, and then became constant. On the other hand, the c-axis decreased to a Y 3+ ion addition amount of 9.09 mol% and became constant thereafter.
図１５より、Dy3+イオンを添加すると、a軸は添加量9.09mol%までわずかに増加し、その後一定となった。一方、c軸はDy3+イオン添加量9.09mol%まで減少し、その後一定となった。 From FIG. 15, when Dy 3+ ions were added, the a-axis slightly increased to the added amount of 9.09 mol% and thereafter became constant. On the other hand, the c-axis decreased to a Dy 3+ ion addition amount of 9.09 mol% and became constant thereafter.
図１６より、Bi3+イオンを添加すると、a軸は添加量9.09mol%まで増加し、その後一定となった。一方、c軸はBi3+イオン添加量6 mol%まで増加し、その後一定となった。 As shown in FIG. 16, when Bi 3+ ions were added, the a-axis increased to the added amount of 9.09 mol% and thereafter became constant. On the other hand, the c-axis increased to a Bi 3+ ion addition amount of 6 mol% and became constant thereafter.
図１７より、La3+イオンを添加すると、a軸、c軸ともに、La3+イオン添加量9.09mol%まで増加し、その後一定となった。 From FIG. 17, when La 3+ ions were added, both the a-axis and c-axis increased to a La 3+ ion addition amount of 9.09 mol%, and then became constant.
格子定数変化と三価金属イオンの電荷の関係から、β-TCPに三価金属イオンが3Ca2+＋□＝2M3+＋2□という形で9.09mol%まで固溶すると考えられる。 From the relationship between the change in lattice constant and the charge of the trivalent metal ion, it is considered that the trivalent metal ion in β-TCP forms a solid solution up to 9.09 mol% in the form of 3Ca 2+ + □ = 2M 3+ + 2 □.
（３）ＦＴ−ＩＲ (3) FT-IR
日本分光製FT/IR-230型フーリエ変換型赤外分光光度計を用いて定性分析を行った。測定範囲は、400-4000ｃｍ−１、積算回数は68回である。試料の測定はKBrを用いた拡散反射法により行い、試料とKBrの混合重量比は試料１に対し、KBrが約２０の比率である。 Qualitative analysis was performed using a FT / IR-230 Fourier transform infrared spectrophotometer manufactured by JASCO. The measurement range is 400-4000 cm −1 and the number of integrations is 68 times. The sample is measured by the diffuse reflection method using KBr, and the mixing weight ratio of the sample and KBr is about 20 with respect to the sample 1.
β-TCPのFT-IRスペクトルでは一般的に945cm-1(ν1)、432cm-1(ν2)、1010cm-1(ν3)、550cm-1(ν4)付近にPO4 3-イオンの4つの基準振動の吸収が認められる。ここでν1とν3は伸縮振動、ν2とν4は変角振動である。 In FT-IR spectrum of beta-TCP generally 945cm -1 (ν 1), 432cm -1 (ν 2), 1010cm -1 (ν 3), 550cm -1 (ν 4) near the PO 4 3- ions Absorption of the four standard vibrations is recognized. Here, ν 1 and ν 3 are stretching vibrations, and ν 2 and ν 4 are bending vibrations.
図１８〜図２５に三価金属イオン添加β-TCPのIRスペクトルを示す。図１８および図１９より、Y 3+イオン添加量の増加にともない、ν1およびν3を含む吸収帯がブロードになった。 18 to 25 show IR spectra of trivalent metal ion-added β-TCP. From FIG. 18 and FIG. 19, the absorption band containing ν 1 and ν 3 became broader as the Y 3+ ion addition amount increased.
図２０および図２１より、Y3+イオンの場合と同様に、Dy3+イオン添加量の増加にともない、ν1およびν3を含む吸収帯がブロードになった。Y3+イオンとDy3+イオンはイオン半径がほぼ等しいため、同じような変化をしたと考えられる。 From FIG. 20 and FIG. 21, as in the case of Y 3+ ions, the absorption band containing ν 1 and ν 3 became broader as the amount of Dy 3+ ions added increased. Y 3+ ions and Dy 3+ ions have the same ionic radius and are considered to have changed in the same way.
図２２および図２３より、Bi3+イオン添加量の増加にともない、ν1およびν3を含む吸収帯が低波数側に広がり、1000cm-1付近の吸収が広がった。 22 and 23, the absorption band including ν 1 and ν 3 spreads toward the low wavenumber side with the increase of the Bi 3+ ion addition amount, and the absorption near 1000 cm −1 spread.
図２４および図２５より、La3+イオン添加β-TCPのIRスペクトルにおいて、La3+イオン添加量が増加しても、ν1およびν3を含む吸収帯に大きな変化は見られなかった。 24 and 25, in the IR spectrum of La 3+ ion-doped β-TCP, even if the amount of La 3+ ion addition increased, no significant change was observed in the absorption band including ν 1 and ν 3 .
三価金属イオンは空孔を含めると2つのサイトに対して1つの金属イオンしか固溶しないと考えられ、このときに空孔が形成されなければ、O2-イオンの配位は大きく変化し、PO4 3-イオンの対称性の低下が予想される。しかし、上記三価金属イオン添加β-TCPは、PO4 3-イオンの対称性の低下は見られなかった。このことからも、三価金属イオンを固溶した際に、空孔が形成されると考えられる。 Trivalent metal ions are considered to contain only one metal ion at two sites when vacancies are included. If no vacancies are formed at this time, the coordination of O 2- ions changes greatly. , PO 4 3- ion symmetry is expected to decrease. However, the trivalent metal ion-added β-TCP did not show a decrease in the symmetry of PO 4 3- ion. From this, it is considered that vacancies are formed when the trivalent metal ions are dissolved.
（４）リートベルト解析 (4) Rietveld analysis
Y3+イオンを9.09 mol%固溶した試料をX線回折測定した。
（結晶学データ : 中性子回折測定データM. Yashima et al.、 Journal of Solid State Chemistry、 175、 272-277 (2003).）
An X-ray diffraction measurement was performed on a sample prepared by dissolving 9.09 mol% of Y 3+ ions.
(Crystallographic data: Neutron diffraction measurement data M. Yashima et al., Journal of Solid State Chemistry, 175, 272-277 (2003).)
高速収束器を装着したX線回折装置（Rigaku Ultima III）により測定したβ-TCPと中性子回折測定データとでフィッティングし、得たプロファイル関数をY3+イオン固溶β型リン酸三カルシウム（以下、Y-TCPという）でのリートベルト解析の際に用いた。 Fitting with β-TCP measured by an X-ray diffractometer (Rigaku Ultima III) equipped with a high-speed converging device and neutron diffraction measurement data, the obtained profile function was converted to Y 3+ ionic solid solution β-type tricalcium phosphate Used for Rietveld analysis in Y-TCP).
図２６に示すように、プロファイル関数を用いてY-TCPのフィッティングを行った結果、３０．５°付近の最大ピーク強度がβ―ＴＣＰの１．５倍であり、ガウス関数が増大するとともに、それに影響されローレンツ関数が幅を持った。 As shown in FIG. 26, as a result of fitting Y-TCP using a profile function, the maximum peak intensity around 30.5 ° is 1.5 times that of β-TCP, and the Gaussian function increases. As a result, the Lorentz function has a width.
Ca(4)サイトの空孔(□)の席占有率を0として、Ca(5)サイトのY原子の席占有率を求めると、解析するとプログラムは収束し、電荷補償のためにCa(5)サイトのY原子の席占有率は約1.0の値になり、フィッテングパラメータCHI**=3.98となった。さらにリートベルトシミュレーションによる回折プロフィールと実験による回折プロフィールとがほぼ一致した結果を得た。このことから、図２７に示すように、固溶する三価金属イオンの置換する位置はCa(5)サイトであり、一方のCa(4)サイトはすべて空孔になることを明らかにした。その固溶メカニズムはAカラムの陽イオンを対象に考えると2Ca(5)+Ca(4)+□=2MIII+2□で固溶し、その固溶限界は全Caサイトに対して計算から求められる9.09 mol%とも一致した。 When the seat occupancy of the vacancies (□) at the Ca (4) site is set to 0 and the seat occupancy of the Y atom at the Ca (5) site is obtained, the program converges when analyzed, and Ca (5 ) Site occupancy of Y atoms at the site is about 1.0, and the fitting parameter CHI ** = 3.98. In addition, the diffraction profile obtained by Rietveld simulation and the experimental diffraction profile were almost consistent. From this, as shown in FIG. 27, it was clarified that the position of substitution of the solid solution trivalent metal ion is a Ca (5) site, and one Ca (4) site is all vacant. The solution mechanism is 2Ca (5) + Ca (4) + □ = 2M III + 2 □, considering the cation of the A column, and the solution limit is calculated from all Ca sites. It also agreed with the required 9.09 mol%.
（５）機械的性質 (5) Mechanical properties
a) 体積収縮率変化 a) Volume shrinkage change
作製した焼結体の焼成前後における試料体積から算出したY3+イオン添加量に対する体積収縮率変化を図２８に示す。この図が示すように、体積収縮率についてはY3+イオン添加量の増加にしたがい低下した。 FIG. 28 shows the volume shrinkage change with respect to the Y 3+ ion addition amount calculated from the sample volume before and after firing of the sintered body produced. As shown in this figure, the volume shrinkage decreased as the Y 3+ ion addition amount increased.
ｂ) 焼結体の曲げ強度測定 b) Measurement of bending strength of sintered body
曲げ強度はJIS R 1601に基づき、オートグラフ(AG-1、島津製作所製)を使用し、以下の条件で三点曲げ試験を行い測定した。 The bending strength was measured by performing a three-point bending test under the following conditions using an autograph (AG-1, manufactured by Shimadzu Corporation) based on JIS R 1601.
支点間距離：30mm
クロスヘッド速度：0.5 mm・min-1
試料片本数：2〜6本
試料片サイズ：3.0×4.0×36mm
試験温度：室温
試験雰囲気：大気中
試料の加工：焼結切断には低速切断機(ISOMETtm、BUEHLER製)を、表面研磨には研磨機(ダイアラップML-150、マルトー製)を使用し、耐水研磨紙♯200、♯400で研磨と面取りを行った。
Distance between fulcrums: 30mm
Crosshead speed: 0.5 mm · min -1
Number of sample pieces: 2 to 6 Sample piece size: 3.0 x 4.0 x 36 mm
Test temperature: Room temperature Test atmosphere: In the air Sample processing: Low-speed cutting machine (ISOMETtm, manufactured by BUEHLER) is used for sintering cutting, and polishing machine (Dialap ML-150, manufactured by Marto) is used for surface polishing. Polishing and chamfering were performed with abrasive paper # 200 and # 400.
測定した焼結体の最大荷重から曲げ強度をJIS-R-1601に基づき、次式より求めた。
［数２］
ここで、σは三点曲げ強さ(MPa)、Pは試験片が破壊したときの最大荷重(N)、Lは支点間距離(mm)、wは試験片の幅(mm)、tは試験片の厚さ(mm)である。
Based on the measured maximum load of the sintered body, the bending strength was obtained from the following equation based on JIS-R-1601.
[Equation 2]
Where σ is the three-point bending strength (MPa), P is the maximum load when the specimen breaks (N), L is the distance between supporting points (mm), w is the specimen width (mm), and t is The thickness of the test piece (mm).
作製した焼結体の曲げ強度変化を図２９に示す。この図が示すように、Y3+イオン添加β-TCP焼結体の曲げ強度は、Y3+イオン添加量の増加にしたがい低下した。 The bending strength change of the produced sintered body is shown in FIG. As shown in this figure, the bending strength of Y 3+ ion-doped beta-TCP sintered body was reduced with increasing Y 3+ ion amount.
ｃ) アルキメデス法による開気孔率およびかさ密度の測定 c) Measurement of open porosity and bulk density by Archimedes method
開気孔率およびかさ密度は、アルキメデス法(JIS R 1634)で溶媒には純水を用いて行った。開気孔率およびかさ密度は下記の式より求めた。
［数３］
ここで、W1は試料の乾燥重量(g)、W2は飽水試料の水中重量(g)、W3は飽水試料の空中質量(g)、Sは純水の密度(1.0g・cm-3)である。
The open porosity and bulk density were measured by the Archimedes method (JIS R 1634) using pure water as a solvent. The open porosity and bulk density were obtained from the following formulas.
[Equation 3]
Where W 1 is the dry weight of the sample (g), W 2 is the weight of the saturated sample in water (g), W 3 is the saturated mass of the saturated sample (g), and S is the density of pure water (1.0 g cm -3 ).
Y3+イオン添加量を変化させて作製した焼結体の開気孔率変化を図３０に、かさ密度変化を図３１にそれぞれ示す。これらの図が示すように、Y3+イオン添加β-TCP焼結体の開気孔率はY3+イオン添加量9.09mol%まで増加し、かさ密度についてはY3+イオン添加量の増加にしたがい低下した。 FIG. 30 shows a change in open porosity and FIG. 31 shows a change in bulk density of a sintered body produced by changing the amount of added Y 3+ ions. As these figures show, the open porosity of the Y 3+ ion-added β-TCP sintered body increased to the Y 3+ ion addition amount of 9.09 mol%, and the bulk density increased to the Y 3+ ion addition amount. Therefore, it decreased.
ｄ) 焼結体の微構造の観察 d) Observation of the microstructure of the sintered body
焼結体の微構造観察には走査型電子顕微鏡(SEM)、(VE-7800、KEYENCE製)を使用した。試料の加工として、研磨機(ダイアラップML-150、マルトー製)を使用し、耐水研磨紙♯200、 ♯400、♯800、♯1500、ラッピングダイヤ液MM-130、ポリシングダイヤMM-140を用いて鏡面研磨を行った試料を昇温速度5℃・min-1、保持時間5時間、大気雰囲気、1000℃でサーマルエッチングを行った。イオンスパッタ装置 (FINE CORT FC-1100、日本電子製)を使用し、金を蒸着させ(0.75ｋV、75mA)、それを検鏡試料とした。以下に測定条件を示す。 A scanning electron microscope (SEM) (VE-7800, manufactured by KEYENCE) was used to observe the microstructure of the sintered body. For sample processing, a polishing machine (Dialap ML-150, manufactured by Marto) was used, and water-resistant abrasive paper # 200, # 400, # 800, # 1500, lapping diamond fluid MM-130, and polishing diamond MM-140 were used. The samples subjected to mirror polishing were subjected to thermal etching at a heating rate of 5 ° C./min −1 , a holding time of 5 hours, and an atmospheric atmosphere at 1000 ° C. An ion sputtering apparatus (FINE CORT FC-1100, manufactured by JEOL Ltd.) was used to deposit gold (0.75 kV, 75 mA), and this was used as a microscopic sample. The measurement conditions are shown below.
フィラメント：W(タングステン)
加速電圧：1〜3kV
Filament: W (tungsten)
Accelerating voltage: 1-3kV
作製した焼結体の微構造を図３２に示す。微構造からは、Y3+イオン添加β-TCP焼結体の粒子径に大きな変化はみられなかったが、添加量の増加にともない9.09mol%まで気孔が増加していることを確認した。これらのことから、Y3+イオン固溶で焼結体の焼結性は低下することが示唆され、これにともない曲げ強度が低下したと考えられた。 The microstructure of the produced sintered body is shown in FIG. From the microstructure, the particle size of the Y 3+ ion-added β-TCP sintered body was not significantly changed, but it was confirmed that the pores increased to 9.09 mol% with the increase of the addition amount. From these facts, it was suggested that the sinterability of the sintered body was lowered by the solid solution of Y 3+ ions, and it was considered that the bending strength was lowered accordingly.
Y3+イオンを添加した焼結体はY3+イオン添加量9.09mol%までβ-TCP構造であることを確認した。また、その曲げ強度はY3+イオン添加量の増加にしたがい低下した。微構造観察からは、Y3+イオン添加量の増加にともないY3+イオン添加量9.09mol%まで焼結性の低下を確認した。 It was confirmed that the sintered body to which Y 3+ ions were added had a β-TCP structure up to a Y 3+ ion addition amount of 9.09 mol%. The bending strength decreased with increasing amount of Y 3+ ions. From microstructure examination revealed a reduction of sinterability up along Y 3+ ion amount 9.09Mol% the increase in Y 3+ ion amount.
以上の機械的性質についてDy3+イオンやBi3+イオンの三価金属イオン固溶β-TCP焼結体についても同様に試験を行った。表４は、Y3+イオン、Dy3+イオン、Bi3+イオンをそれぞれ9.09mol%まで固溶したβ-TCP焼結体と、通常のβ-TCP焼結体の物性を比較するものである。この表が示すように、これらの三価金属イオンを固溶したβ-TCP焼結体は、三価金属イオン添加量にしたがいその加工性は向上することが分かる。
［表４］
The above mechanical properties were also tested in the same manner for trivalent metal ion solid solution β-TCP sintered bodies of Dy 3+ ions and Bi 3+ ions. Table 4 compares the physical properties of a β-TCP sintered body in which Y 3+ ions, Dy 3+ ions, and Bi 3+ ions are each dissolved to 9.09 mol%, and a normal β-TCP sintered body. is there. As shown in this table, it can be seen that the β-TCP sintered body in which these trivalent metal ions are solid-solubilized improves its workability according to the amount of trivalent metal ions added.
[Table 4]
（６）三価金属イオンを固溶させたＴＣＰの溶解性 (6) Solubility of TCP with solid solution of trivalent metal ions
pH5.50の酢酸-酢酸ナトリウム緩衝液を用いて生体吸収性試験を行った。図３３〜図３６には、各種三価金属イオン固溶量を変化させた試料を酢酸-酢酸ナトリウム緩衝溶液中に3時間浸漬した後の各種イオン溶出濃度を示す。三価金属イオン固溶β-TCPを酢酸-酢酸ナトリウム緩衝溶液中へ浸漬した場合、陽イオン[(Ca+0.67M)：M=Y、Dy、Bi]およびPO4 3-イオン溶出濃度は、三価金属イオン固溶量の増加にともないそれぞれ低下した。したがって、β-TCPへの三価金属イオン固溶は、その溶解性を抑制することが明らかになった。 A bioabsorbability test was performed using a pH 5.50 acetic acid-sodium acetate buffer. 33 to 36 show various ion elution concentrations after immersing a sample in which the amount of each trivalent metal ion solid solution is changed in an acetic acid-sodium acetate buffer solution for 3 hours. When trivalent metal ion solid solution β-TCP is immersed in an acetic acid-sodium acetate buffer solution, the cation [(Ca + 0.67M): M = Y, Dy, Bi] and PO 4 3- ion elution concentration are It decreased as the amount of trivalent metal ion solid solution increased. Therefore, it was revealed that trivalent metal ion solid solution in β-TCP suppresses its solubility.
一方、Y3+イオン、Bi3+イオン、Dy3+イオン溶出濃度においては、理論組成から求めた全陽イオン溶出量に対する金属イオン溶出量 [0.67M/(Ca+0.67M)]よりも低くなった。 三価金属イオンは水溶液中で加水分解して不溶性物質になると分かっている。 したがって、溶出した三価金属イオンは酢酸-酢酸ナトリウム緩衝溶液中で加水分解し、それにともない不溶性物質が生成したため、三価金属イオンの溶出がほとんど認められなかったと考えた。 On the other hand, the elution concentrations of Y 3+ ions, Bi 3+ ions, and Dy 3+ ions are lower than the metal ion elution amount [0.67M / (Ca + 0.67M)] relative to the total cation elution amount obtained from the theoretical composition. became. Trivalent metal ions are known to hydrolyze into aqueous solutions in aqueous solutions. Therefore, the eluted trivalent metal ions were hydrolyzed in an acetic acid-sodium acetate buffer solution, and an insoluble material was generated. Accordingly, it was considered that almost no elution of the trivalent metal ions was observed.
一方、V3+イオン固溶β-TCPからは、理論組成から求めた理論値以上のV3+イオンの溶出を確認した。 それは固溶量の増加にしたがい増加した。 これらの三価金属イオン固溶β-TCPの違いは、三価金属のイオン半径が関係していると考えた。 三価金属イオンが固溶するCa(5)サイトの配位数である六配位における各種三価金属イオンのイオン半径比を表５に示す。イオン半径比は、各種三価金属イオンの六配位におけるイオン半径と、陰イオンであるO2-イオンのイオン半径との比であり、六配位でもっともその構造が安定するイオン半径比は0.414〜0.732である。 各種三価金属イオンのイオン半径比はY3+イオン、Bi3+イオン、Dy3+イオン、V3+イオンの順に、0.743、0.736、0.750、0.557となり、最密状態である0.732のときとの絶対値は、Bi3+イオン固溶β-TCP<Dy3+イオン固溶β-TCP≒Y3+イオン固溶β-TCP<V3+イオン固溶β-TCPとなる。 これは上記の各種イオン溶出量の順と一致している。 これらの結果から、イオン半径の小さいV3+イオンは他の三価金属イオンに比べて優先的に溶出したと考えられる。 On the other hand, from the V 3+ ion solid solution β-TCP, elution of V 3+ ions exceeding the theoretical value obtained from the theoretical composition was confirmed. It increased as the amount of solid solution increased. These trivalent metal ion solid solution β-TCP is considered to be related to the ionic radius of the trivalent metal. Table 5 shows ionic radius ratios of various trivalent metal ions in hexacoordination, which is the coordination number of the Ca (5) site where the trivalent metal ions are dissolved. The ionic radius ratio is the ratio of the ionic radius of various trivalent metal ions in the hexacoordination to the ionic radius of the anion O 2− ion. 0.414 to 0.732. The ionic radius ratio of various trivalent metal ions is 0.743, 0.736, 0.750, 0.557 in the order of Y 3+ ion, Bi 3+ ion, Dy 3+ ion, V 3+ ion, and 0.732, which is the most dense state. the absolute value of, the Bi 3+ ion solid solution β-TCP <Dy 3+ ions dissolved β-TCP ≒ Y 3+ ions dissolved β-TCP <V 3+ ions dissolved beta-TCP. This is consistent with the above-mentioned order of various ion elution amounts. From these results, it is considered that V 3+ ions having a small ion radius were preferentially eluted as compared with other trivalent metal ions.
［表５］
[Table 5]
（７）熱安定性評価 (7) Thermal stability evaluation
熱安定性を評価するために縦型管状炉を用いて加熱した。加熱条件は金属イオン無添加β-TCPの場合では焼成温度1100、1150、1170、1200℃にて焼成し、各種金属イオン固溶のβ-TCPの場合は焼成温度1200、1250、1300、1350℃にて焼成し、それぞれ焼成時間は30〜240分間とした。図３７に縦型管状炉の概略図を示す。ニラコ製の白金線および白金るつぼを使用した。 In order to evaluate thermal stability, it heated using the vertical tubular furnace. In the case of β-TCP without addition of metal ions, the heating conditions are firing at firing temperatures of 1100, 1150, 1170, and 1200 ° C. In the case of β-TCP that is a solid solution of various metal ions, firing temperatures of 1200, 1250, 1300, and 1350 ° C. The firing time was 30 to 240 minutes. FIG. 37 shows a schematic view of a vertical tubular furnace. Nilaco's platinum wire and platinum crucible were used.
測定方法としては、管状炉を所定の温度まで昇温し安定するまで待機した。安定したら管状炉を下へ移動させ、試料を入れた白金るつぼを白金線で吊るし、管状炉の中心にくるように上から入れた。その時、R熱電対と白金るつぼの距離を5ｍｍとした。それぞれ所定の時間になったら、管状炉を下げて試料の入った白金るつぼを取り出し、氷の中に入れて急冷した。冷却後、粉砕した。 As a measuring method, the tubular furnace was heated to a predetermined temperature and waited until it was stabilized. When stabilized, the tubular furnace was moved down, and the platinum crucible containing the sample was hung with a platinum wire and placed from above so as to come to the center of the tubular furnace. At that time, the distance between the R thermocouple and the platinum crucible was 5 mm. At each predetermined time, the tubular furnace was lowered and the platinum crucible containing the sample was taken out and placed in ice for rapid cooling. After cooling, it was pulverized.
リガク製RAD‐2C型X線回折装置を用いて、得られた生成物の結晶相の同定を以下の測定条件で行った。 Using the Rigaku RAD-2C type X-ray diffractometer, the crystalline phase of the obtained product was identified under the following measurement conditions.
ターゲット：Cu (Cu‐Kα線)
走査範囲：10〜60°
スキャンステップ：0.010°
スキャンスピード：8.000°/min
使用管電圧：40kV
使用管電流：30ｍA
モノクロメーター使用
Target: Cu (Cu-Kα ray)
Scanning range: 10-60 °
Scan step: 0.010 °
Scan speed: 8.000 ° / min
Working tube voltage: 40kV
Tube current: 30mA
Use of monochromator
金属イオン無添加β-TCPを焼成温度1100、1130、1150、1170、1200℃において所定の時間焼成し、得られた生成物の結晶相の同定を行った。焼成温度1100℃では240分間焼成してもβ-TCPに帰属する回折ピークのみが確認され、β-TCP単相であることが確認できた。金属イオン無添加β-TCPのβ-α相転移温度は1120〜1180℃と報告されている。焼成温度の上昇に連れてα-TCPに帰属される回折ピーク強度が増大したのが確認された。また、同じ焼成温度でも焼成時間の増加に連れてα-TCPの回折ピーク強度が増大した。焼成温度1150℃、1170℃および1200℃では焼成温度30分でもα-TCPに帰属されるピークが現れているため、β-TCPからα-TCPへの相転移は速いと考えられる。 Β-TCP without addition of metal ions was fired at firing temperatures of 1100, 1130, 1150, 1170, and 1200 ° C. for a predetermined time, and the crystalline phase of the obtained product was identified. At a firing temperature of 1100 ° C., only diffraction peaks attributed to β-TCP were confirmed even after firing for 240 minutes, confirming that it was a β-TCP single phase. The β-α phase transition temperature of β-TCP without added metal ions is reported to be 1120-1180 ° C. It was confirmed that the diffraction peak intensity attributed to α-TCP increased as the firing temperature increased. In addition, the diffraction peak intensity of α-TCP increased with increasing firing time even at the same firing temperature. At the firing temperatures of 1150 ° C, 1170 ° C and 1200 ° C, a peak attributed to α-TCP appears even at a firing temperature of 30 minutes, and therefore the phase transition from β-TCP to α-TCP is considered to be fast.
Y3+イオン3mol％固溶β-TCPを焼成温度1200、1250、1300、1350℃において所定の時間焼成し、得られた生成物をX線回折により結晶相の同定を行い、図３９〜図４２に示す結果を得た。図３９に示す焼成温度1200℃では焼成時間30分でα-TCPに帰属される回折ピークが確認された。図３８に示す金属イオン無添加β-TCPの1200℃で加熱した時のX線回折図と比較すると、金属イオン無添加β-TCPではほぼα-TCPに帰属する回折ピークが確認されたが、Y3+イオンを3mol％固溶させることで、α-TCPとβ-TCPの混合相ではあるもののβ-TCPの回折ピークが占める割合が高いことから、β-α相転移が抑制され、相転移温度が高温側に幅が広がり、相転移速度が遅くなったことが分かった。 Y 3+ ion 3 mol% solid solution β-TCP was calcined at a calcining temperature of 1200, 1250, 1300, 1350 ° C. for a predetermined time, and the obtained product was identified for crystal phase by X-ray diffraction. The result shown in 42 was obtained. At a firing temperature of 1200 ° C. shown in FIG. 39, a diffraction peak attributed to α-TCP was confirmed after a firing time of 30 minutes. Compared with the X-ray diffraction pattern of β-TCP without metal ion addition shown in FIG. 38 when heated at 1200 ° C., the diffraction peak attributed to α-TCP was almost confirmed with β-TCP without metal ion addition. By dissolving 3 mol% of Y 3+ ions, the proportion of the diffraction peak of β-TCP is high although it is a mixed phase of α-TCP and β-TCP. It was found that the transition temperature widened to the higher temperature side and the phase transition rate became slower.
（８）まとめ (8) Summary
本発明は、過去の報告とは異なり、β-TCPに三価金属イオンを固溶させるとCa(5)サイトにだけ置換することを明らかにした。また、三価金属イオンは、2Ca(5)+Ca(4)+□=2MIII+2□で固溶し、その固溶限界は全Caサイトに対して9.09mol%であることが分かった。しかし、三価金属イオンを固溶したリン酸三カルシウムの構造安定性は、Ca(5)サイトの酸化物イオンとの配位状態(6配位)に依存する。すなわち、β-TCPのCa(5)サイトの6配位の結晶化学的な安定性は熱的安定性に一致し、さらにリン酸三カルシウムの溶解性および固体の拡散(焼結性)にも依存する。すなわち、Ca(5)サイトの安定化によるブロッキング効果の増大によって物質移動は抑制され、バルクを構成する粒子成長を抑制することに寄与する。一方、α-TCPに三価金属イオンを固溶させると、3Ca2+イオン=2M3+イオン+□で置換固溶する。生じた空孔濃度は物質移動に寄与する。このように三価金属イオンを固溶させることによってリン酸三カルシウム構造の安定性と空孔濃度を制御することができ、それによってリン酸三カルシウムの溶解性や固体反応を制御するものである。 Unlike the previous reports, the present invention has clarified that when trivalent metal ions are dissolved in β-TCP, only Ca (5) sites are substituted. In addition, trivalent metal ions were dissolved in 2Ca (5) + Ca (4) + □ = 2M III + 2 □, and the solid solution limit was found to be 9.09 mol% with respect to the total Ca site. . However, the structural stability of tricalcium phosphate in which a trivalent metal ion is dissolved depends on the coordination state (6-coordinate) with the oxide ion at the Ca (5) site. That is, the 6-coordination crystal chemical stability of the Ca (5) site of β-TCP matches the thermal stability, and also the solubility of tricalcium phosphate and the diffusion of solids (sinterability). Dependent. That is, mass transfer is suppressed by an increase in the blocking effect due to stabilization of the Ca (5) site, which contributes to suppressing growth of particles constituting the bulk. On the other hand, when trivalent metal ions are dissolved in α-TCP, they are replaced by 3Ca 2+ ions = 2M 3+ ions + □. The generated vacancy concentration contributes to mass transfer. Thus, by dissolving the trivalent metal ions, the stability of the tricalcium phosphate structure and the vacancy concentration can be controlled, thereby controlling the solubility and solid reaction of the tricalcium phosphate. .
Claims (3)
逆に前記固溶量を減少することでＣａ（５）サイトの安定性を減少して前記溶解性を増加させ、体積収縮率及びかさ密度を上昇させるとともに気孔率を低下させることを指す焼結性の上昇をもたらす、
リン酸三カルシウムからなる生体材料セラミックスの溶解性及び焼結性の制御方法。 By increasing the solid solution amount of trivalent metal ions classified as biological essential elements or biological trace essential elements, biomaterial ceramics consisting of crystals consisting of tricalcium phosphate and β-TCP type crystal structure to the living body Solubility is decreased by stabilization of the Ca (5) site, resulting in a decrease in volume shrinkage and bulk density and a decrease in sinterability, which refers to increasing porosity.
Conversely, by reducing the amount of the solid solution, the stability of the Ca (5) site is decreased, the solubility is increased, the volume shrinkage rate and the bulk density are increased, and the porosity is decreased. Bring about an increase in sex,
A method for controlling solubility and sinterability of biomaterial ceramics made of tricalcium phosphate.
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