钙磷玻璃体系药物缓释材料制备及体外模拟研究
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摘要
骨组织的取代,药物的控制释放载体作为一种新的生物材料成为了现今的研究热点。本文对掺入锶的钙磷生物微晶玻璃作为药物缓释材料的制备、性能和生物降解进行了研究。以CaO-P_2O_5-Na_2O为基础玻璃,钙磷摩尔比为1.25,通过掺入SrO制得CPSN微晶玻璃;并与传统熔融法制备的CaO-P_2O_5-Na_2O生物微晶玻璃体系进行了对比研究。CPSN生物微晶玻璃分别采用传统熔融法和溶胶凝胶法制得。
采用XRD测定不同条件下制备的玻璃、微晶玻璃和降解产物的相组成,利用SEM观察生物玻璃的晶化情况以及降解不同天数后样品表面的形貌。通过三点弯曲法测定生物玻璃的弯曲强度。玻璃体系的生物降解性表征试验在pH值为7.4的PBS缓冲液中,恒温37oC进行。而溶解于PBS溶液中不同天数的Ca2+浓度由原子吸收分光光度计来测得。
实验结果表明采用传统熔融法制得的CPSN生物微晶玻璃的主晶相为具有生物相容性的β-Ca2P2O7 (β-DCP)和少量的Ca3(PO4)以及易溶性的Na2CaP2O7。样品致密,仅有极少的微孔,其弯曲强度为40~50MPa。将样品浸渍于PBS溶液中后,溶液中的钙离子浓度在3~7天呈现上升趋势,之后开始降低。样品在降解一段时间后表面产生了新的物质,经XRD分析为类羟基磷灰石和锶羟基磷灰石。在降解26天后的样品表面可观察到一层由细晶的类羟基磷灰石相和锶羟基磷灰石相所组成的致密的矿化层。
用溶胶凝胶法制得的CPSN生物微晶玻璃的主晶相为β-Ca_2P_2O_7 (β-DCP)和NaCaPO_4。与传统熔融法制得的玻璃相比,溶胶凝胶法所制得的样品晶粒比较小,比表面积大,这有利于微晶玻璃的生物降解。将样品浸渍于PBS溶液中3天后,溶液中的钙离子浓度达到峰值,紧接着出现了一个剧烈的降低,在浸渍11天时达到最低。随着时间的继续推移,离子浓度曲线再次出现起伏,这表明此法制得的生物玻璃具有可持续降解的特性。从SEM照片中可观察到降解一段时间后,样品表面沉积了一层锶羟基磷灰石矿化层。此法制得的微晶玻璃的弯曲强度较低,只有19~24MPa。
Replacements of biological tissues, controlled drug delivery represents new development of biomaterials research. The purpose of this study was to investigate that the Sr containing calcium phosphate glass-ceramic as a potential biomaterial for drug delivery. The glass-ceramic system was selected based on CaO-P_2O_5-Na_2O and an inert metal oxide SrO, with CaO/P_2O_5 molar ratio=1.25. Also, CaO-P_2O_5-Na_2O glass-ceramic system prepared by melting-sintering method was investigated as comparable system. The CPSN (CaO-P_2O_5-SrO-Na_2O) glass-ceramic was prepared by melting-sintering way and sol-gel way, respectively. In order to evaluate the degradation of the glass-ceramic prepared, degradation studies were carried out after dipped in in PBS-HCl solution for 26 days at 37℃, pH 7.4, which was close to that found in human. Concentration of Ca~(2+) in the PBS-HCl solution was tested by Atomic Absorption Spectrometer with different days.
Using XRD analysis, biocompatibleβ-Ca2P2O7 (β-DCP) phase and small amount of Ca3(PO4) and Na2CaP2O7 were clearly identified from the CPSN glass-ceramic prepared by melting-sintering method. The compact is densified successfully with few closed pores. By soaking in PBS solution, the concentration of calcium ion increased from 3 days to 7 days and then a decrease was observed until 16 days. Some new phases—hydroxyapatite-like (HA-like) and Sr-hydroxyapatite (Sr-HA) as dominant phases detected by XRD—were formed on the surface of the glass-ceramic samples during degradation. At the meantime, formation of mineralized layer with high density which consisted of HA-like and Sr-HA containing random oriented fine crystals was observed by SEM. The average strength of CPSN glass-ceramic sample determined by 3-point bending method was 40～50MPa.
Biocompatibleβ-Ca2P2O7 (β-DCP) and NaCaPO4 phase were clearly identified from the CPSN glass-ceramics prepared by sol-gel method, using XRD analysis. The size of the granules was smaller in this glass-ceramic, which is different from one prepared by melting-sintering way. By soaking 3 days in PBS solution, the concentration of calcium ion reached peak value and then a severe decrease was observed until 11 days. With time increased, fluctuation of ion concentration curve was observed. It demonstrated that persistent degradation occurred on this glass-ceramic. And the Sr-HA mineralized layer was formed on the surface of the glass-ceramic samples during degradation. The bending strength of this CPSN glass-ceramic sample appeared a decrease, was about 19～24MPa.
采用XRD测定不同条件下制备的玻璃、微晶玻璃和降解产物的相组成,利用SEM观察生物玻璃的晶化情况以及降解不同天数后样品表面的形貌。通过三点弯曲法测定生物玻璃的弯曲强度。玻璃体系的生物降解性表征试验在pH值为7.4的PBS缓冲液中,恒温37oC进行。而溶解于PBS溶液中不同天数的Ca2+浓度由原子吸收分光光度计来测得。
实验结果表明采用传统熔融法制得的CPSN生物微晶玻璃的主晶相为具有生物相容性的β-Ca2P2O7 (β-DCP)和少量的Ca3(PO4)以及易溶性的Na2CaP2O7。样品致密,仅有极少的微孔,其弯曲强度为40~50MPa。将样品浸渍于PBS溶液中后,溶液中的钙离子浓度在3~7天呈现上升趋势,之后开始降低。样品在降解一段时间后表面产生了新的物质,经XRD分析为类羟基磷灰石和锶羟基磷灰石。在降解26天后的样品表面可观察到一层由细晶的类羟基磷灰石相和锶羟基磷灰石相所组成的致密的矿化层。
用溶胶凝胶法制得的CPSN生物微晶玻璃的主晶相为β-Ca_2P_2O_7 (β-DCP)和NaCaPO_4。与传统熔融法制得的玻璃相比,溶胶凝胶法所制得的样品晶粒比较小,比表面积大,这有利于微晶玻璃的生物降解。将样品浸渍于PBS溶液中3天后,溶液中的钙离子浓度达到峰值,紧接着出现了一个剧烈的降低,在浸渍11天时达到最低。随着时间的继续推移,离子浓度曲线再次出现起伏,这表明此法制得的生物玻璃具有可持续降解的特性。从SEM照片中可观察到降解一段时间后,样品表面沉积了一层锶羟基磷灰石矿化层。此法制得的微晶玻璃的弯曲强度较低,只有19~24MPa。
Replacements of biological tissues, controlled drug delivery represents new development of biomaterials research. The purpose of this study was to investigate that the Sr containing calcium phosphate glass-ceramic as a potential biomaterial for drug delivery. The glass-ceramic system was selected based on CaO-P_2O_5-Na_2O and an inert metal oxide SrO, with CaO/P_2O_5 molar ratio=1.25. Also, CaO-P_2O_5-Na_2O glass-ceramic system prepared by melting-sintering method was investigated as comparable system. The CPSN (CaO-P_2O_5-SrO-Na_2O) glass-ceramic was prepared by melting-sintering way and sol-gel way, respectively. In order to evaluate the degradation of the glass-ceramic prepared, degradation studies were carried out after dipped in in PBS-HCl solution for 26 days at 37℃, pH 7.4, which was close to that found in human. Concentration of Ca~(2+) in the PBS-HCl solution was tested by Atomic Absorption Spectrometer with different days.
Using XRD analysis, biocompatibleβ-Ca2P2O7 (β-DCP) phase and small amount of Ca3(PO4) and Na2CaP2O7 were clearly identified from the CPSN glass-ceramic prepared by melting-sintering method. The compact is densified successfully with few closed pores. By soaking in PBS solution, the concentration of calcium ion increased from 3 days to 7 days and then a decrease was observed until 16 days. Some new phases—hydroxyapatite-like (HA-like) and Sr-hydroxyapatite (Sr-HA) as dominant phases detected by XRD—were formed on the surface of the glass-ceramic samples during degradation. At the meantime, formation of mineralized layer with high density which consisted of HA-like and Sr-HA containing random oriented fine crystals was observed by SEM. The average strength of CPSN glass-ceramic sample determined by 3-point bending method was 40～50MPa.
Biocompatibleβ-Ca2P2O7 (β-DCP) and NaCaPO4 phase were clearly identified from the CPSN glass-ceramics prepared by sol-gel method, using XRD analysis. The size of the granules was smaller in this glass-ceramic, which is different from one prepared by melting-sintering way. By soaking 3 days in PBS solution, the concentration of calcium ion reached peak value and then a severe decrease was observed until 11 days. With time increased, fluctuation of ion concentration curve was observed. It demonstrated that persistent degradation occurred on this glass-ceramic. And the Sr-HA mineralized layer was formed on the surface of the glass-ceramic samples during degradation. The bending strength of this CPSN glass-ceramic sample appeared a decrease, was about 19～24MPa.
引文
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[2] Klemm K W, Antibiotic bead chains, Clin Orthop, 1993, 295: 63~76
[3] Henry S L, Galloway K P, Local antibacterial therapy for the management of orthopaedic infections, Pharmacokinetic considerations, Clin Pharmacokinet, 1995, 29: 36~45
[4] Neut D, Belt H, Stokroos I, et al, Biomaterial-associated infection of gentamicin-loaded PMMA beads in orthopaedic revision surgery, Antimicrob Chemother, 2001, 47: 885~891
[5]俞玮,周勇,植入式药物缓释系统在骨缺损修复中的研究进展,现代康复, 2001,5(9):56~57
[6]杨莽,张彩霞,陈德敏,磷酸钙骨水泥药物缓释载体研究进展,国外医学生物医学工程分册,2002,25(1):8~11
[7]王德平,周萘,多孔微晶玻璃作为缓释药物载体的体外实验研究,中国修复重建外科杂志,2002,16(5):322~324
[8]陈希德,杨连甲,杨维东,组织工程与基因工程联合应用于骨缺损修复的研究,现代康复,2001,5(5):59~60
[9]孙明林,胡蕴玉,张瑞萍,磷酸钙骨水泥/骨形态发生蛋白复合人工骨修复骨缺损的实验研究,现代康复,2001,5(5):32
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