【摘要】：背景：在關(guān)節(jié)置換術(shù)中,骨水泥通過(guò)與周?chē)墙M織形成穩(wěn)定的機(jī)械性結(jié)合,可以實(shí)現(xiàn)相對(duì)長(zhǎng)期固定,但隨著時(shí)間延長(zhǎng),骨-骨水泥界面會(huì)出現(xiàn)松動(dòng),因此研發(fā)具有生物活性的骨水泥具有顯著臨床意義。本課題組之前研究發(fā)現(xiàn),在聚甲基丙烯酸甲酯中添加15%的礦化骨膠原(Mineralized collagen, MC),可以提高骨水泥的生物活性。目的：為了進(jìn)一步提高生物活性,本文主要是通過(guò)混合磷酸氫鍶(SrHPO4)、礦化骨膠原及聚甲基丙烯酸甲酯(Polymethylmethacrylate, PMMA)制備了一種新型生物活性骨水泥(SR-MC-PMMA),研究新型生物活性骨水泥的生物力學(xué)特性及骨組織相容性。方法：將SrHPO4按不同比例(1%、2%、5%、10%)添加到含有礦化骨膠原MC 15%的聚甲基丙烯酸甲酯PMMA復(fù)合骨水泥中,按照外科植入物丙烯酸類(lèi)樹(shù)脂骨水泥國(guó)家標(biāo)準(zhǔn)ISO 5833,檢測(cè)生物力學(xué)性能,包括凝固時(shí)間、抗壓強(qiáng)度及抗彎曲強(qiáng)度。在SrHPO4、MC與PMMA比例分別為5%、15%的條件下,制取SR-MC-PMMA生物活性骨水泥,試驗(yàn)選用的是GB/T 16886.5-2013/ISO 10993-5:1999推薦的L-929小鼠成纖維細(xì)胞對(duì)含5%的SrHPO4的SR-MC-PMMA骨水泥、MC-PMMA骨水泥、C-PMMA骨水泥的浸提液進(jìn)行細(xì)胞毒性檢查.按照國(guó)家標(biāo)準(zhǔn)GB/T 16886-2003/ISO 10993-5:1999規(guī)定的體外細(xì)胞毒性分級(jí)法標(biāo)準(zhǔn),檢測(cè)生物活性骨水泥的體外細(xì)胞毒性。將SR-MC-PMMA在無(wú)菌條件下,包埋于成熟的新西蘭家兔股骨內(nèi)側(cè)髁,分別于術(shù)后4周、8周、12周取出家兔的股骨,經(jīng)固定液固定后,行Micro-CT和硬組織切片,觀察指定區(qū)域骨CT密度及骨組織相容性。通過(guò)Image-Pro18.0軟件,測(cè)量分析新生骨組織在植入骨水泥材料中的面積比,進(jìn)行分析。結(jié)果：在含有15%礦化骨膠原的聚甲基丙烯酸甲酯骨水泥中,添加5%的SrHPO4,抗壓強(qiáng)度為(73.77±6.33MPa),壓縮模量為(1.74±0.11GPa),符合骨水泥國(guó)家標(biāo)準(zhǔn)(ISO5833和ASTM F451標(biāo)準(zhǔn))抗壓強(qiáng)度不低于70MPa。凝固特性表明添加了5% SrHPO4的之后的,改性骨水泥操作性能變化不大,具有較好的操作性能。按照GB/T 16886／ISO10993檢測(cè)SR-MC-PMMA骨水泥的生物安全性,包括體外細(xì)胞毒性,急性全身毒性反應(yīng),慢性肝腎毒性實(shí)驗(yàn),試驗(yàn)中均無(wú)毒性反應(yīng)。在兔股骨標(biāo)本組織切片觀察發(fā)現(xiàn),在試驗(yàn)第4周、8周、12周,SR-MC-PMMA組均表現(xiàn)出較好的骨組織長(zhǎng)入,在第12周,SR-MC-PMMA組為(15.99±0.41%)與MC-PMMA組(9.85±0.72%)相比具有差異。在PMMA組中,第4周、8周、12周,骨組織長(zhǎng)入比例無(wú)明顯差異。MC-PMMA、 SR-MC-PMMA組中,相比于第4周,第8周和第12周,均有新生骨組織長(zhǎng)入,具有統(tǒng)計(jì)學(xué)差異。結(jié)論：在含有15%礦化骨膠原的聚甲基丙烯酸甲酯骨水泥基礎(chǔ)上,添加5%的SrHPO4后抗壓強(qiáng)度,抗彎曲強(qiáng)度及凝固性能,均符合ISO 5833生物材料標(biāo)準(zhǔn)。SR-MC-PMMA骨水泥在體外細(xì)胞實(shí)驗(yàn)和體內(nèi)急性全身反應(yīng)、慢性肝腎毒性試驗(yàn)中,表現(xiàn)較好的生物安全性。在兔骨組織包埋中,相比于C-PMMA、MC-PMMA骨水泥,SR-MC-PMMA骨水泥表現(xiàn)出有更多新生骨組織長(zhǎng)入,具有較好的生物活性。
[Abstract]:Background: during joint replacement, bone cement can be fixed relatively for a long time by forming a stable mechanical combination with the surrounding bone tissue. However, as time goes on, the interface between bone and bone cement will be loosened. Therefore, it is of great clinical significance to develop bone cement with biological activity. Our previous study found that adding 15% mineralized collagen (Mineralized collagen, MC), to polymethyl methacrylate can improve the biological activity of bone cement. Objective: to further improve biological activity, a new bioactive bone cement (SR-MC-PMMA) was prepared by mixing strontium hydrogen phosphate (SrHPO4), mineralized bone collagen and polymethyl methacrylate (Polymethylmethacrylate, PMMA). The biomechanical properties and bone histocompatibility of new bioactive bone cement were studied. Methods: SrHPO4 was added to polymethyl methacrylate (PMMA) composite bone cement containing 15% MC of mineralized bone collagen according to the national standard of acrylic resin bone cement (ISO 5833). Test biomechanical properties, including solidification time, compressive strength and bending strength. Under the condition that the ratio of SrHPO4,MC to PMMA is 5% and 15% respectively, the bioactive SR-MC-PMMA bone cement was prepared. In the experiment, L-929 mouse fibroblasts recommended by GB/T 16886.5-2013/ISO 10993-5: 1999 were used to test the cytotoxicity of SR-MC-PMMA bone cement, MC-PMMA bone cement and C-PMMA bone cement extract containing 5% SrHPO4. The in vitro cytotoxicity of bioactive bone cement was detected according to the standard of in vitro cytotoxicity classification set by GB/T 16886-2003/ISO 10993-5: 1999. SR-MC-PMMA was embedded in the medial femoral condyle of mature New Zealand rabbits in aseptic condition. The femur was removed at 4 weeks, 8 weeks and 12 weeks after operation. After fixed with fixed solution, Micro-CT and hard tissue sections were performed. Bone CT density and bone histocompatibility were observed. The area ratio of new bone tissue in bone cement implant was measured and analyzed by Image-Pro18.0 software. Results: the compressive strength and compression modulus of SrHPO4, were (73.77 鹵6.33MPa) and (1.74 鹵0.11GPa), respectively. Meet the national standards of bone cement (ISO5833 and ASTM F451) compressive strength is not less than 70 MPA. The solidification characteristics showed that the modified bone cement with 5% SrHPO4 had little change in operating performance and had better performance. The biological safety of SR-MC-PMMA bone cement was detected according to GB/T 16886/ISO10993, including in vitro cytotoxicity, acute systemic toxicity, chronic hepatorenal toxicity test, and no toxic reaction in the test. At the 4th week, 8th week, 12th week, the SR-MC-PMMA group showed good bone tissue growth, and at the 12th week. There was significant difference between SR-MC-PMMA group (15.99 鹵0.41%) and MC-PMMA group (9.85 鹵0.72%). In the PMMA group, there was no significant difference in the proportion of bone tissue growth in the 4th, 8th, 12th week, but in the MC-PMMA, SR-MC-PMMA group, there was significant difference between the 4th, 8th and 12th week. Conclusion: on the basis of polymethyl methacrylate bone cement containing 15% mineralized bone collagen, the compressive strength, bending strength and solidification property of 5% SrHPO4 were added. SR-MC-PMMA bone cement showed good biological safety in vitro cell test, acute systemic reaction in vivo and chronic hepatorenal toxicity test. Compared with C-PMMA-MC-PMMA bone cement, SR-MC-PMMA bone cement showed more new bone tissue growth and better biological activity.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：R687;R318.08

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