生醫鈣磷酸鹽骨水泥結構穩定度之研究

Structural stability of Calcium Phosphate Bone Cement

許秀菁(Hsiu-Ching Hsu)

指導教授 ： 段維新

國立臺灣大學/工學院/材料科學與工程學研究所/博士(2008年)

https://doi.org/10.6342/NTU.2008.10606

摘要

本論文是探討室溫下製備自硬化型的鈣磷酸鹽骨水泥(CPC)經生物礦化後產生具相同組成的氫氧基磷灰石(Hydroxyapatite, Ca10(PO4)6(OH)2, HAp)，也因此理解CPC合成出HAp的溶液化學生成機制，乃對於開發硬骨組織替代物則將有深刻的理解認識。本研究由CaHPO4 (DCPA)與Ca(OH)2粉體顆粒組合成的CPC混合粉體與磷酸氫鈉溶液反應固化生成HAp之反應化學可利用in-situ與long-term (超過150天或3600小時)浸泡時效來觀察。另外，反應物種及其粒子大小、溶液pH變化、無機物質的添加、具生物活性金屬的存在都將對CPC固化及所生成HAp的微結構及機械性質有莫大的影響。因此，我們利用以下分析技術進行以上性質分析：pH、粒子大小分析、磷酸氫鈉鹽溶液之濃度、固化時間之測定、差式掃瞄熱卡計(DSC)、原子吸收光譜儀(AAS)、電子微探針分析(EPMA)、X光繞射、X光吸收光譜、電子顯微鏡(SEM/TEM)、機械強度(DTS及CS))。
對室溫下DCPA/Ca(OH)2/Na2HPO4骨水泥系統而言，固化反應的時間及產物HAp的顯微形貌則強烈的受到Na2HPO4溶液濃度的影響。溶液濃度愈高固化時間較短，殘留反應物較少以及機械強度較高。pH分析則顯示出當CPC固化反應開始，溶液的pH呈現出下降的趨勢，導致有更多的固體粒子在溶液中發生溶解，並於溶液化學中趨近一不變點以求介穩平衡。至於37℃下生成奈米尺寸級HAp的微結構則多以糾結纏繞的棒狀晶體顯微呈現，也因此CPC的固化及硬化則歸功於HAp棒狀晶體在微結構上糾結程度的貢獻。並藉由XRD及FTIR對浸泡已達3600小時的CPC生成產物進行定性與結構分析，則幾乎完全轉換生成HAp，且無其他相組成存在。
根據溶液化學理論，我們發現CPC中固體顆粒不斷地進行溶解並有新的結晶顆粒生成與析出是掌握整個固化反應的進行與否，因此HAp可在37℃下生成。In-situ觀察固化期間，固化反應會首先發生在DCPA與Ca(OH)2固體顆粒的表面區域(液體與固體顆粒間的接觸表面積)，因此控制了其初始溶解，同時，亦傾向析出結晶。在起始固體顆粒溶解階段期間，因為DCPA的溶解度高於HAp，所以初始HAp晶體會傾向生成於DCPA的表面，而HAp晶體的進一步成長則由未反應的DCPA不斷地進行，如此好似自然骨生物礦化的過程一樣。對照引用文獻中的發現，在CPC固化反應早期階段，HAp晶種的存在可促進固化反應，減少內部過渡組成成核；同時，增加DCPA顆粒固化反應的表面區域則對於固體初步的溶解則更具有主導控制反應的效果。
另外在此，將介紹為了改善骨水泥機械強度而提出CPC/Ti複合材料的製備方法。此複合材料是將Ti顆粒加入至DCPA及Ca(OH)2粒子中，利用物理機械混合的方式製備，並將1.0 M的磷酸氫鈉溶液加入，以便合成CPC/Ti骨水泥。由於DCPA, Ca(OH)2及 Ti顆粒可提供給予進行固化反應的表面積增加，因此固化反應就比CPC來的更迅速。XRD證實此此複合材料在符合生理條件環境下經固化3600小時後的產物為具低結晶度的HAp及些許殘留的起始原料於CPC/Ti骨水泥中，而且沒有中間相的存在。因為DCPA具有較高的溶解度，所以認為此創新的骨水泥，相較於磷灰石骨水泥，將可呈現出具較高的體內吸收能力。另外，藉由AAS分析浸泡3600小時的CPC/Ti複合骨水泥，則發現Ca與Ti元素並不存在其所浸泡的溶液中。如此則說明具非常低溶解度的HAp晶體生成於起始原料組成的表面區域，也因此導致CPC/Ti的固化反應逐漸降低，並且DCPA與Ti則隱藏在骨水泥內部。最終CPC/Ti複合骨水泥的機械強度則仰賴轉換生成的HAp晶體及其所建立起的微結構發展，即骨水泥的機械強度取決於生成HAp棒狀晶體其微結構糾結的程度而定。
結論為CPC與CPC/Ti骨水泥的長時效浸泡(研究最長時間的浸泡為10944小時的CPC，及5760小時的CPC/Ti試樣)下其顯微結構穩定度取決於HAp晶體的生成，並強化其顯微架構增加機械性質強度。如此骨水泥應用於整型外科及牙科方面，則應具臨床上的生物可吸收與生物相容性之性質。

關鍵字

骨水泥, 固化時間, 鈣磷酸鹽, 氫氧基磷灰石, 氫氧化鈣, 單鈣磷酸鹽

並列摘要

Self-setting or self-hardening calcium phosphate cement (CPC) has value in terms of developing synthetic hydroxyapatite [Ca10(PO4)6(OH)2 or HAp], similar in compositions formed by natural mineralization of bone. Understanding the in vitro solution chemistry mechanism of formation of the synthetic composition could produce insights into developing hard tissue analogs. The chemistry of CPC, composed of particulate CaHPO4 (DCPA) and Ca(OH)2, set with sodium hydrogen phosphate solution for formation of HAp were examined by in-situ and long-term aging (over 150 days or 3600 h) observation. In particular, the effects of particle size, pH, reactant species, inorganic salt additives and presence of bioactive metal on the CPC setting and microstructure/mechanical properties of HAp were determined by using the following analytical techniques: pH and setting time measurement, particle size, differential scanning catorimeter (DSC), atomic absorption spectrometer (AAS), electron probe micro-analyzer (EPMA), x-ray diffractometer, x-ray absorption spectrometer, electron microscopy (SEM/TEM), fourier transform infrared spectroscopy (FTIR), solution chemistry, diametrical test strength (DTS) and compressive strength test (CS).
For the DCPA/Ca(OH)2/Na2HPO4 system at room temperature, the setting reaction times and morphologies of the resultant HAp were found to be strongly dependent on the concentration of aqueous solution. Higher concentration of aqueous solution could be diminished the setting time, remnant reactants less, and better mechanical strength. The results revealed the pH of solution has presented drop-down trace when setting reaction happened, leading to more solids dissolved in the solution and approaching to a invariant point for meatstable equilibrium. The microstructure of the resultant HAp typically had entangled, rod-like morphology at 37°C having a nano scale crystalline size. The cement setting/hardening contributed to entanglement at the microstructural level. In the case, t the product set for 3600 h was hydroxyapatite [Ca10(PO4)6(OH)2] determined by XRD and FTIR, and no other intermediates or by-product were formed through the complete transformation.
According to solution chemistry theory, the continually solid dissolution and new crystal precipitation mechanism of CPC was found to control the overall setting reaction and thereby HAp formation at 37°C. During the in-situ observation, the setting reaction was first resulted within the surface area of the DCPA and Ca(OH)2 particulates hence controlling their initial dissolution, and simultaneously preformed to precipitate crystals. During the initial solids dissolution stage, HAp formation initiates preferentially on DCPA surfaces. Further growth of HAp continues progressively by dissolution and precipitation of unreacted DCPA, analogous to natural biomineralization events. Compare to literature cited findings, the presence of HAp seeds increase the setting reaction, eliminating the intrinsic nucleation step; while increasing in the surface area of the DCPA had a more predominant effect on the initial dissolution during the early stage of setting reaction.
CPC/Ti composite approach for improving the mechanical properties of the cement product was introduced. The Composites were prepared by physically incorporating Ti particles with DCPA and Ca(OH)2 particulates. 1.0 M sodium hydrogen phosphate solution, setting modifier, would be added into composite for set to cement block. Because the surface area provided by DCPA, Ca(OH)2 and Ti particles for setting reaction was increase, the reaction occurred faster than CPC. XRD demonstrated that setting product was involved HAp phase, which was low crystalline and remnant starting materials in CPC/Ti cement, no other intermediate phase found until incubation for 3600 h in physiological condition. Due to DCPA with higher solubility, the new cement was considered to exhibit a higher in vivo resorbability in comparison to the apatitic cements. In addition, Ca and Ti elements of composite set for 3600 h did not find in soaking solution by AAS analysis. It was elucidated the very low solubility of the initial HAp crystal layer was formed on the surface area of components, so as the setting reaction of CPC/Ti was getting slow, and then DCPA and Ti were hindering within cement. The mechanical properties of the final composite structure were related to the conversion of calcium phosphate to HAp and porous size.
Summary, The microstructural stability of CPC and/or CPC/Ti could be arrived in the long-term aging for HAp crystallites formation and improved the mechanical strength. Use these cement samples in orthpaedics and dental would be considered as bioresorble and biocompatible with in vivo.

並列關鍵字

bone cement, calcium phosphate cement, hydroxyapatite, DCPA

參考文獻

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