新型多孔生物活性骨水泥用于椎体成型术的动物实验研究
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摘要
研究背景:
骨质疏松症（Osteoporosis，OP）是我国老年人群的三大疾病之一。50岁以上人群中，OP总患病率女性为20.7%，男性为14.4%。随着年龄增加，OP的发病率急剧增加，80岁以上女性OP发病率甚至高达66%。脊柱是OP受累最为严重的部位，50岁以上女性的脊柱OP发病率为28%，远远高于股骨的15%。因此，骨质疏松性椎体压缩骨折的发生率远远高于其他部位骨折，我国每年新发椎体压缩骨折约l81万例，预计至2020年椎体骨折患者将高达3675万人。椎体压缩骨折会导致患者剧烈疼痛、出现神经功能障碍，同时，由于脊柱后凸畸形改变躯干力线，导致临近节段椎体骨折风险增加，形成骨折-畸形-再骨折的恶性循环。所以，如何重新恢复压缩骨折椎体的强度和高度，降低骨质疏松椎体压缩骨折发生率，使骨质疏松的患者不再出现驼背畸形具有重要的临床价值和深远的社会意义。
椎体成型术和球囊成型术是治疗骨质疏松椎体压缩性骨折的有效手段，目前使用的椎体填充材料绝大多数是聚甲基丙烯酸甲酯（Polymethyl Methacrylate，PMMA）。然而，该材料存在明显的缺陷：单纯的力学支撑，不具有骨传导、骨诱导作用；无法被自身组织吸收替代；弹性模量过高。因此，迫切需要一种新型的椎体成型填充材料，在对疏松椎体提供力学支撑的同时，还可通过骨传导和骨诱导作用促进骨折的愈合。
课题组前期将生物玻璃、壳聚糖与聚甲基丙烯酸甲酯复合，研发了一种新型可注射型多孔生物活性骨水泥，发现该材料具有适宜的生物力学强度和良好的体外生物活性，在体内部分可吸收。但能否将其作为椎体成型术的填充材料，以及其对骨质疏松椎体的作用及尚不明确。
研究目的:
通过兔骨质疏松模型评估新型可注射型多孔生物活性骨水泥作为椎体成型材料的有效性和可行性。
材料方法:
将生物玻璃、聚甲基丙烯酸甲酯和壳聚糖按照4:5:1的比例构建多孔生物活性骨水泥。骨水泥固/液比为1.5:1。首先，通过扫描电子显微镜观察材料表面形态，了解材料各组份分布情况。然后，将骨水泥样本浸泡于PBS磷酸缓冲液中降解4周，通过生物力学实验，检测骨水泥的体外最大抗压缩强度。同时，将骨水泥浸泡于模拟体液中，通过X线衍射分析，评价材料的体外生物活性。采用随机对照研究方案，将80只新西兰大白兔随机分为去势组（OVX, n=72）和假手术组（Sham，n=8）。通过双侧卵巢去势法，建立兔骨质疏松模型。采用随机对照研究方案，将去势组随机分为BBC组（BBC, n=24）、PMMA组（PMMA, n=24）和骨质疏松对照组（CON,n=24）。通过模拟椎体成形术，分别在BBC组和PMMA组兔子L4、L5椎体注射骨水泥材料，每组均于术后1周、4周、12周处死8只。采用组织学、MicroCT及生物力学实验评估新型多孔生物活性骨水泥对脊柱骨质疏松的治疗作用。
结果:
骨水泥材料固化后扫描电镜结果提示：生物玻璃颗粒和壳聚糖颗粒均匀的分布于PMMA基质当中。体外生物力学检测结果提示：在各时间点，新型材料的最大抗压缩强度均小于PMMA （P<0.05）。X线衍射结果显示：在模拟体液浸泡7天后，骨水泥表面有磷灰石层形成，并且随浸泡时间延长，磷灰石层增厚。组织形态学观察发现，椎体成形术后4周，BBC组可见骨连接形成；术后12周，可见新生骨小梁。显微CT结果显示：椎体成型术后4周至12周，BBC组的骨体积分数（BV/TV）从28.27±1.69%增至38.43±1.34%，而PMMA组的骨体积分数无明显变化。生物力学实验结果表明，在椎体成型术后1周、4周、12周，BBC组和PMMA组椎体的最大抗压缩强度均明显高于骨质疏松对照组（P<0.05）。术后1周、4周，BBC组椎体的最大抗压缩强度均低于PMMA组（P<0.05）。术后12周，两组椎体最大抗压缩强度无明显区别。
结论:
新型多孔生物活性骨水泥在体内可部分吸收，有一定的成骨活性，可以迅速有效地改善骨质疏松椎体骨小梁的三维构筑，提高椎体的力学强度。随着进一步的改性研究，有望成为新型的椎体成型材料。
Background: Osteoporosis (OP) is one of the three major diseases in elderly populationin China. By the age of50years,the prevalence of OP in women is nearly20.7%; in men,the corresponding figure is14.4%. The incidence of OP increases markedly with age,evenas high as66%in women after the age of80years. Vertebral compression fracture is themost common complication of osteoporosis. Spine is the most serious part for OPinvolvement. The prevalence of OP at spine is28%in women aged50years or older,which is much higher than the15%at femur. Therefore, vertebral fractures are the mostcommon of all osteoporotic fractures. In china, it is estimated that there are around1.81million osteoporotic fractures each year,and the number is predicted to36.75million by2020. Patients with vertebral compression fracture can present with severe back pain orneurological dysfunction, and kyphotic deformities that cause biomechanical changes inthe spinal segment and increase the incidence of adjacent vertebral fractures, forming avicious cycle of "fracture-deformity-re-fracture". Thus, it is important and significant to augment impaired bony structures in order to maintain or improve strength and stability ofthe spinal column, to reduce the prevalence of osteoporotic vertebral compressionfracture,and to correct the kyphotic deformities caused by OP.Vertebroplasty and kyphoplasty are two percutaneous minimally invasive techniques intreating symptomatic VCFs patients who do not have neurological impairment. The mostcommonly used cement in vertebroplasty is polymethyl methacrylate (PMMA). However,the limitations of PMMA could not be ignored, including un-absorbable, poorbiocompatibility, missing osteoconductivity and excessive stiffness.
In the previous study, we have showed the development and characteristic of a novelinjectable Porous Surface Modified Bioactive Bone Cement (PSMBBC), which had goodbioactivity in vitro, appropriate biomechanical strength, partial degradability, and wascomposed of bioglass, chitosan and PMMA. However, whether it can be use as a fillingmaterial for vertebroplasty or its effects on strengthening osteoporotic vertebrae stillremain unknown. Thus, the aim of this study is to determine the feasibility andeffectiveness of the PSMBBC for vertebroplasty of aiding osteoporotic vertebrae in anosteoporosis model.
Materials and Methods: The novel Porous Surface Modified Bioactive Bone Cementwas composed of bioglass,chitosan and PMMA as weight ratio4:5:1, and a solid: liquidmass ratio of1.5:1was used. Samples of cured cement were immersed in15ml phosphatebuffered saline (PBS) at37°C and kept for4weeks. In order to measure the mechanicalproperties of the novel bone cement in vitro, the compressive strength values wereexamined.by biomechanical tests. Meanwhile, the samples were soaked in SBF and the invitro bioactivity of the novel bine cement was assess by X-ray diffraction (XRD).80adultfemale New Zealand white rabbits were randomly divided into two groups. Theovariectomy group (n=72) received bilateral ovariectomy (OVX), and the sham group(n=8) only received the sham operation. Then, the rabbits of the OVX group wererandomly divided into three groups: PMMA group, Bioactive Bone Cement group (BBC)and control group (CON). PMMA and BBC were administrated to osteoporotic vertebraein Vertebroplasty, respectively. The animals were sacrificed at1w,4w,12w after the procedure. Micro-CT analysis, biomechanical tests and histological analysis wereperformed at each time point.
Results: The glass and CS particles were uniformly distributed in the polymeric matrix fordry cement samples by SEM analysis. A significantly lower compressive strength (P<0.05)was observed for the BBC compared to the PMMA bone cement at each degradation time.Newly formed apatites were confirmed by XRD at7day. From4to12weeks after bonecements implantation, the bone volume fraction (BV/TV,%) of the BBC group increasedfrom28.27±1.69%to38.43±1.34%. However, the BV/TV of the PMMA group showedno significant differences. At4weeks, direct contact between bone and bone cement wasobserved in the BBC group. At12weeks, it showed neo intact bone trabecular formed inPSMBBC group. Furthermore, the maximum compressive strength values of the BBCgroup were significantly higher than that of the control group at each time point afterimplantation. At1,4weeks, the maximum compressive strength values of the BBC groupwere lower than that of the PMMA group. At12weeks, it showed no difference betweenthe two groups.
Conclusion：This study suggests that the novel Porous Surface Modified Bioactive BoneCement has a certain osteogenicability, appropriate biomechanical strength, partialdegradability, making it an excellent material for vertebroplasty.
骨质疏松症（Osteoporosis，OP）是我国老年人群的三大疾病之一。50岁以上人群中，OP总患病率女性为20.7%，男性为14.4%。随着年龄增加，OP的发病率急剧增加，80岁以上女性OP发病率甚至高达66%。脊柱是OP受累最为严重的部位，50岁以上女性的脊柱OP发病率为28%，远远高于股骨的15%。因此，骨质疏松性椎体压缩骨折的发生率远远高于其他部位骨折，我国每年新发椎体压缩骨折约l81万例，预计至2020年椎体骨折患者将高达3675万人。椎体压缩骨折会导致患者剧烈疼痛、出现神经功能障碍，同时，由于脊柱后凸畸形改变躯干力线，导致临近节段椎体骨折风险增加，形成骨折-畸形-再骨折的恶性循环。所以，如何重新恢复压缩骨折椎体的强度和高度，降低骨质疏松椎体压缩骨折发生率，使骨质疏松的患者不再出现驼背畸形具有重要的临床价值和深远的社会意义。
椎体成型术和球囊成型术是治疗骨质疏松椎体压缩性骨折的有效手段，目前使用的椎体填充材料绝大多数是聚甲基丙烯酸甲酯（Polymethyl Methacrylate，PMMA）。然而，该材料存在明显的缺陷：单纯的力学支撑，不具有骨传导、骨诱导作用；无法被自身组织吸收替代；弹性模量过高。因此，迫切需要一种新型的椎体成型填充材料，在对疏松椎体提供力学支撑的同时，还可通过骨传导和骨诱导作用促进骨折的愈合。
课题组前期将生物玻璃、壳聚糖与聚甲基丙烯酸甲酯复合，研发了一种新型可注射型多孔生物活性骨水泥，发现该材料具有适宜的生物力学强度和良好的体外生物活性，在体内部分可吸收。但能否将其作为椎体成型术的填充材料，以及其对骨质疏松椎体的作用及尚不明确。
研究目的:
通过兔骨质疏松模型评估新型可注射型多孔生物活性骨水泥作为椎体成型材料的有效性和可行性。
材料方法:
将生物玻璃、聚甲基丙烯酸甲酯和壳聚糖按照4:5:1的比例构建多孔生物活性骨水泥。骨水泥固/液比为1.5:1。首先，通过扫描电子显微镜观察材料表面形态，了解材料各组份分布情况。然后，将骨水泥样本浸泡于PBS磷酸缓冲液中降解4周，通过生物力学实验，检测骨水泥的体外最大抗压缩强度。同时，将骨水泥浸泡于模拟体液中，通过X线衍射分析，评价材料的体外生物活性。采用随机对照研究方案，将80只新西兰大白兔随机分为去势组（OVX, n=72）和假手术组（Sham，n=8）。通过双侧卵巢去势法，建立兔骨质疏松模型。采用随机对照研究方案，将去势组随机分为BBC组（BBC, n=24）、PMMA组（PMMA, n=24）和骨质疏松对照组（CON,n=24）。通过模拟椎体成形术，分别在BBC组和PMMA组兔子L4、L5椎体注射骨水泥材料，每组均于术后1周、4周、12周处死8只。采用组织学、MicroCT及生物力学实验评估新型多孔生物活性骨水泥对脊柱骨质疏松的治疗作用。
结果:
骨水泥材料固化后扫描电镜结果提示：生物玻璃颗粒和壳聚糖颗粒均匀的分布于PMMA基质当中。体外生物力学检测结果提示：在各时间点，新型材料的最大抗压缩强度均小于PMMA （P<0.05）。X线衍射结果显示：在模拟体液浸泡7天后，骨水泥表面有磷灰石层形成，并且随浸泡时间延长，磷灰石层增厚。组织形态学观察发现，椎体成形术后4周，BBC组可见骨连接形成；术后12周，可见新生骨小梁。显微CT结果显示：椎体成型术后4周至12周，BBC组的骨体积分数（BV/TV）从28.27±1.69%增至38.43±1.34%，而PMMA组的骨体积分数无明显变化。生物力学实验结果表明，在椎体成型术后1周、4周、12周，BBC组和PMMA组椎体的最大抗压缩强度均明显高于骨质疏松对照组（P<0.05）。术后1周、4周，BBC组椎体的最大抗压缩强度均低于PMMA组（P<0.05）。术后12周，两组椎体最大抗压缩强度无明显区别。
结论:
新型多孔生物活性骨水泥在体内可部分吸收，有一定的成骨活性，可以迅速有效地改善骨质疏松椎体骨小梁的三维构筑，提高椎体的力学强度。随着进一步的改性研究，有望成为新型的椎体成型材料。
Background: Osteoporosis (OP) is one of the three major diseases in elderly populationin China. By the age of50years,the prevalence of OP in women is nearly20.7%; in men,the corresponding figure is14.4%. The incidence of OP increases markedly with age,evenas high as66%in women after the age of80years. Vertebral compression fracture is themost common complication of osteoporosis. Spine is the most serious part for OPinvolvement. The prevalence of OP at spine is28%in women aged50years or older,which is much higher than the15%at femur. Therefore, vertebral fractures are the mostcommon of all osteoporotic fractures. In china, it is estimated that there are around1.81million osteoporotic fractures each year,and the number is predicted to36.75million by2020. Patients with vertebral compression fracture can present with severe back pain orneurological dysfunction, and kyphotic deformities that cause biomechanical changes inthe spinal segment and increase the incidence of adjacent vertebral fractures, forming avicious cycle of "fracture-deformity-re-fracture". Thus, it is important and significant to augment impaired bony structures in order to maintain or improve strength and stability ofthe spinal column, to reduce the prevalence of osteoporotic vertebral compressionfracture,and to correct the kyphotic deformities caused by OP.Vertebroplasty and kyphoplasty are two percutaneous minimally invasive techniques intreating symptomatic VCFs patients who do not have neurological impairment. The mostcommonly used cement in vertebroplasty is polymethyl methacrylate (PMMA). However,the limitations of PMMA could not be ignored, including un-absorbable, poorbiocompatibility, missing osteoconductivity and excessive stiffness.
In the previous study, we have showed the development and characteristic of a novelinjectable Porous Surface Modified Bioactive Bone Cement (PSMBBC), which had goodbioactivity in vitro, appropriate biomechanical strength, partial degradability, and wascomposed of bioglass, chitosan and PMMA. However, whether it can be use as a fillingmaterial for vertebroplasty or its effects on strengthening osteoporotic vertebrae stillremain unknown. Thus, the aim of this study is to determine the feasibility andeffectiveness of the PSMBBC for vertebroplasty of aiding osteoporotic vertebrae in anosteoporosis model.
Materials and Methods: The novel Porous Surface Modified Bioactive Bone Cementwas composed of bioglass,chitosan and PMMA as weight ratio4:5:1, and a solid: liquidmass ratio of1.5:1was used. Samples of cured cement were immersed in15ml phosphatebuffered saline (PBS) at37°C and kept for4weeks. In order to measure the mechanicalproperties of the novel bone cement in vitro, the compressive strength values wereexamined.by biomechanical tests. Meanwhile, the samples were soaked in SBF and the invitro bioactivity of the novel bine cement was assess by X-ray diffraction (XRD).80adultfemale New Zealand white rabbits were randomly divided into two groups. Theovariectomy group (n=72) received bilateral ovariectomy (OVX), and the sham group(n=8) only received the sham operation. Then, the rabbits of the OVX group wererandomly divided into three groups: PMMA group, Bioactive Bone Cement group (BBC)and control group (CON). PMMA and BBC were administrated to osteoporotic vertebraein Vertebroplasty, respectively. The animals were sacrificed at1w,4w,12w after the procedure. Micro-CT analysis, biomechanical tests and histological analysis wereperformed at each time point.
Results: The glass and CS particles were uniformly distributed in the polymeric matrix fordry cement samples by SEM analysis. A significantly lower compressive strength (P<0.05)was observed for the BBC compared to the PMMA bone cement at each degradation time.Newly formed apatites were confirmed by XRD at7day. From4to12weeks after bonecements implantation, the bone volume fraction (BV/TV,%) of the BBC group increasedfrom28.27±1.69%to38.43±1.34%. However, the BV/TV of the PMMA group showedno significant differences. At4weeks, direct contact between bone and bone cement wasobserved in the BBC group. At12weeks, it showed neo intact bone trabecular formed inPSMBBC group. Furthermore, the maximum compressive strength values of the BBCgroup were significantly higher than that of the control group at each time point afterimplantation. At1,4weeks, the maximum compressive strength values of the BBC groupwere lower than that of the PMMA group. At12weeks, it showed no difference betweenthe two groups.
Conclusion：This study suggests that the novel Porous Surface Modified Bioactive BoneCement has a certain osteogenicability, appropriate biomechanical strength, partialdegradability, making it an excellent material for vertebroplasty.
引文
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