可注射生物玻璃—磷酸钙骨水泥复合生物材料的实验研究
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摘要
我国50岁以上人群中有骨质疏松(Osteoporosis, OP)患者近7000万，每年新发脊柱压缩骨折约181万例。微创椎体成形术(Vertebroplasty, VP)或球囊扩张椎体后凸成形术(Balloon kphoplasty, BKP)是脊柱压缩骨折(Vertebral compression fractures, VCF)的主要外科治疗手段。VP或BKP中所采用的材料大多数为聚甲基丙烯酸甲酯（Polymethylmethacrylate, PMMA）。该材料存在明显缺陷：不可吸收、无生物活性（骨传导、诱导作用等），固化过程中发热明显等。因此，寻找一种能够具有良好流动性、骨传导、骨诱导作用，兼具良好的力学支撑性能及一定降解率的骨修复材料已经成为骨科亟待解决的难题。
磷酸钙骨水泥（Calcium phosphate cement, CPC）因其自固化，无类似PMMA的产热效应，可任意塑形，良好的生物相容性、骨传导性及可降解被新生骨替代等特点，具有广阔的临床应用价值。然而，CPC在体内降解缓慢。另外，在一些供血不足区域及伴代谢紊乱的老年病患中，CPC的骨传导作用并不足以达到完全的骨修复效果，因此赋予CPC更高的传导性或诱导性可进一步改善其生物学性能。
生物玻璃（Bioactive glass, BG）由于其良好的生物活性和生物相容性倍受关注，生物玻璃与软组织或骨之间存在密切的离子交换，可直接参与人体骨组织的代谢和修复过程，最终可在材料表面形成与人体骨相同的无机矿物成分——碳酸羟基磷灰石，诱导新生骨组织的生长。将其作为可注射型材料组成成分与CPC复合应用于椎体成形或球囊成形术及不规则骨缺损如口腔及颅面部等处的骨缺损填充修复的研究鲜见文献报道。
目的：
优选最佳的CPC与BG材料复合比，研发出一种体内可吸收、具有良好生物相容性及成骨活性的新型可注射生物复合材料。
方法：
1.将CPC与BG以不同质量比混合后，比较其固化时间及可注射性能，筛选出合适的材料复合比；
2.将CPC与BG以选定的材料复合比及固液比混合后，分析其组成成分，微观结构，固化时间，可注射性能，力学强度及体外生物活性特性和降解性等材料学特性；
3.将大鼠成骨细胞(osteoblasts, OB)接种于材料试件表面，观察OB在试件表面粘附、增殖和分化能力；
4.将CPC-BG复合生物材料植入新西兰白兔体内4，12周后，行大体、显微CT（Micro-computed tomography，Micro-CT）分析和组织学观察。
结果：
1.随着BG加入的比例增加（10%,20%,30%,40%），CPC-BG复合生物材料的固化时间延长，可注射性能提高。较单纯CPC，CPC-BG组固化时间延长（21min到44min），同时可注射性能显著提高（P <0.05）；
2. CPC-BG复合生物材料的材料学研究中，X射线衍射分析（X-ray diffraction，XRD）结果显示CPC及CPC-BG复合生物材料组主要的衍射峰为沉积的羟基磷灰石（Hydroxyapatite, HAp），随着BG含量从10%升至20%，可出现Ca2SiO4及Ca3SiO5衍射峰，电镜观察发现加入BG后，材料结构更紧密。力学性能方面，固化1天及7天后的材料CPC+20%BG组明显高于单纯CPC组（P <0.05）。体外生物活性实验结果发现，浸泡模拟体液（Simulated body fluid, SBF）后，CPC-BG组表面HA沉积量明显多于CPC。能谱结果（Energy dispersive spectroscopy, EDS）表明，CPC-BG复合材料表面沉积的HA主要由Ca, P及Si组成，而CPC仅含Ca及P元素。体外降解实验发现，加入BG后可提高材料降解性；
3.细胞学实验结果表明，加入BG后，可提高成骨细胞的粘附，增殖及分化。MTT结果显示，8h后，CPC-BG复合材料组与单纯CPC组有统计学差异（P<0.05）。随着时间的延长，细胞进一步增殖，在1d，4d及7d时MTT结果显示，CPC-BG组优于CPC组，其中在4d及7d时，CPC-BG组与CPC组有统计学差异（P <0.05）。碱性磷酸酶活性（Alkaline phosphatase, ALP）检测发现，7d时，CPC-BG组与CPC组有统计学差异（P <0.05）；
4.新西兰白兔体内植入实验中，大体，Micro-CT和组织学检测显示，在4周和12周，所有材料组的体内降解率和新生骨生成量随着时间的延长而增加，其中CPC-BG组材料的体内降解率和新生骨生成量均明显高于CPC组（P <0.05）。
结论：
1．CPC-BG（10%,20%）复合生物材料的固化时间及可注射性符合外科手术要求，随着BG的增加，复合生物材料的成分、微观结构发生了改变，可注射性，力学性能进一步提高，同时，体外生物活性及降解率也有了明显的改善；
2．将BG引入CPC中，有利于成骨细胞的粘附、增殖和分化；
3．CPC-BG复合生物材料具有优秀的生物相容性，更高的生物活性、体内降解率和骨生成率，更有利于骨缺损的修复。
In China, there are70million people over the age of50suffering from osteoporosis(OP) and1.81million cases of vertebral compression fractures (VCF) occurred annually.Currently, percutaneous vertebroplasty (VP) and balloon kyphoplasty (BKP) have becomethe main surgical treatment of VCF. Polymethylmethacrylate (PMMA) is the mostcommonly used cement in VP and KP. However, there are several disadvantages ofPMMA: nonbiodegradable, no osteoconductive, osteoinductive and osteogenic activityand the high-polymerization isotherm leading to thermal necrosis of the soft tissues at theaugmentation site. Therefore, to design a novel biomaterial with good flowability,osteoconductive, osteoinductive and osteogenic activity as well as good mechanicalproperty and certain degradation rate for bone regeneration has become the urgentproblem in the field of orthopedics.
Calcium phosphate cements (CPC) have been widely used as bone substitutematerials in clinic applications because of their self-setting properties, no thermogeniceffect, high biocompatibility and osteoconduction as well as bone replacement capability.However, the currently used CPC has some limitations due to its poor mechanicalproperties and low biodegradation rate. Furthermore, the osteoconductive properties ofCPC are not sufficient to achieve complete bone repairment under critical conditions, suchas poorly vascularized sites and elderly patients with metabolic disorders. Consequently,the enrichment of CPC with osteopromotive or osteoinductive factors is necessary toimprove its biological performance.
As a surface active bone substitute, bioactive glass (BG) has recently attracted moreattention due to their good biocompatibility and bioactivity both in bone and in soft tissues.Studies have shown that close ion exchange between BG and soft issue or bone can bedirectly involved in the metabolism of human bone tissue and repair process. Bioactiveglass such as45S5BG bonds strongly to bone and promotes bone growth with formationof a hydroxycarbonate apatite (HCA) layer and the release of Ca, P and Si ions. As far aswe know, it is not until recently, there were a few relevant literatures available regardingCPC-BG applicably in minimally invasive injectable graft.
Objective:
The aim of this study is to develop a new injectable biocomposite with excellentbiocompatibility, improved bioactivity and biodegradability by adding BG into CPC.
Methods:
1. Prepare the CPC-BG composite by adding different proportions of BG45S5powder(10wt%,20wt%,30wt%,40wt%) into CPC powder and mixed with potassiumphosphate buffers (pH7.0) at a given P/L ratio of2.0g/ml. Optimize the compositionratio by comparing setting time and injectability among different groups;
2. Fabricate the CPC-BG composite with the selected composition ratio and P/L ratio andinvestigate the composition, morphology/microstructure, setting time, injectability,compressive strength, surface reaction layer formation and degradation of CPC-BG;
3. The osteoblasts (OB) were seeded onto the CPC-BG composite disks and the adhesion,proliferation, morphology and differentiation abilities of the OB were observed;
4. The CPC-BG and CPC specimens were implanted into femoral condyle defects ofrabbits. After4and12weeks implantation, macroscopic evaluation, histologicalevaluation, and micro-CT analysis were performed.
Results:
1. The setting times of CPC-BG were prolonged as the content of BG increased,increased from21min to44min, with the weight ratio of BG varied from10%to40%at P/L ratio of2.0g/ml. The injectability of CPC-BG composite paste was significantlyimproved compared with injectability of CPC paste (p <0.05);
2. XRD showed that main peaks for HA of hardened CPC-BG composite, were notobviously altered and peaks for Ca2SiO4and Ca3SiO5could be seen in the XRDpatterns of CPC-BG composite with10%and20%BG. The SEM micrographs for thecross section of the CPC and CPC-BG composite specimens (10%,20%) showed thatthe CPC-BG composite specimens closely combined with each other which showedmore compact microstructure than CPC. The compressive strength of CPC-BGcomposites rose with an increase in the weight ratio of BG and there were significantdifferences between CPC and CPC-20%BG composite specimens at day1and day7(p<0.05). After immersing in simulated body fluid (SBF) for7and14days, the amountof apatite aggregates on CPC-BG composite surface were larger and apatite layersgrew more densely on CPC-BG composite surface than amount on CPC surface. EDSindicated that the surface of CPC-BG composite (10%,20%) consisted of a calciumphosphate with a Ca/P ratio of about1.56and1.53and contained Si, while the surfaceof CPC consisted of a calcium phosphate with a Ca/P ratio of about1.67, contained noSi. The degradation rates of all CPC-BG composite specimens were significantlyhigher than degradation rates of CPC specimens (p <0.05);
3. The degree of cell attachment, proliferation and differentiation was increased byadding BG into CPC. The MTT assay showed that the OD values of CPC-BG composite specimens (20%) were significantly higher than OD values of CPCspecimens (p <0.05) in a period of8h. OD values of CPC-BG composite specimens(20%) were significantly higher than OD values of CPC specimens at4and7days (p<0.05), indicating that CPC-BG composite specimens promoted cell growth andfacilitated proliferation with no cytotoxic effect on cells compared with CPCspecimens. The ALP activity of cells cultured on CPC-BG composite (20%) wassignificantly higher than ALP activity on CPC and TCPS control (p <0.05) at4and7days;
4. With the prolonged implantation period from4to12weeks, the in vivo degradationrate and the amount of newly formed bone of CPC-BG composites and CPC wereincreased. Moreover, the in vivo degradation rate and the amount of newly formedbone of CPC-BG composites were significantly higher that of CPC specimens (p <0.05).
Conclusions:
1. The setting time and injectablity of CPC-BG composite (10%,20%) conform to thesurgical requirement. CPC-BG（10%，20%） possessed a retarded setting time andmarkedly better injectability and mechanical properties than CPC. Meanwhile,CPC-BG samples showed significantly improved in vitro degradability and bioactivitycompared to CPC in SBF.
2. Adding BG into CPC is benefit for OB to adhere, proliferate and differentiate.
3. CPC-BG with excellent biocompatibility, improved bioactivity and in vivodegradability enhanced the efficiency of new bone formation in comparison with CPC,which exhibits promising prospects for bone regeneration.
磷酸钙骨水泥（Calcium phosphate cement, CPC）因其自固化，无类似PMMA的产热效应，可任意塑形，良好的生物相容性、骨传导性及可降解被新生骨替代等特点，具有广阔的临床应用价值。然而，CPC在体内降解缓慢。另外，在一些供血不足区域及伴代谢紊乱的老年病患中，CPC的骨传导作用并不足以达到完全的骨修复效果，因此赋予CPC更高的传导性或诱导性可进一步改善其生物学性能。
生物玻璃（Bioactive glass, BG）由于其良好的生物活性和生物相容性倍受关注，生物玻璃与软组织或骨之间存在密切的离子交换，可直接参与人体骨组织的代谢和修复过程，最终可在材料表面形成与人体骨相同的无机矿物成分——碳酸羟基磷灰石，诱导新生骨组织的生长。将其作为可注射型材料组成成分与CPC复合应用于椎体成形或球囊成形术及不规则骨缺损如口腔及颅面部等处的骨缺损填充修复的研究鲜见文献报道。
目的：
优选最佳的CPC与BG材料复合比，研发出一种体内可吸收、具有良好生物相容性及成骨活性的新型可注射生物复合材料。
方法：
1.将CPC与BG以不同质量比混合后，比较其固化时间及可注射性能，筛选出合适的材料复合比；
2.将CPC与BG以选定的材料复合比及固液比混合后，分析其组成成分，微观结构，固化时间，可注射性能，力学强度及体外生物活性特性和降解性等材料学特性；
3.将大鼠成骨细胞(osteoblasts, OB)接种于材料试件表面，观察OB在试件表面粘附、增殖和分化能力；
4.将CPC-BG复合生物材料植入新西兰白兔体内4，12周后，行大体、显微CT（Micro-computed tomography，Micro-CT）分析和组织学观察。
结果：
1.随着BG加入的比例增加（10%,20%,30%,40%），CPC-BG复合生物材料的固化时间延长，可注射性能提高。较单纯CPC，CPC-BG组固化时间延长（21min到44min），同时可注射性能显著提高（P <0.05）；
2. CPC-BG复合生物材料的材料学研究中，X射线衍射分析（X-ray diffraction，XRD）结果显示CPC及CPC-BG复合生物材料组主要的衍射峰为沉积的羟基磷灰石（Hydroxyapatite, HAp），随着BG含量从10%升至20%，可出现Ca2SiO4及Ca3SiO5衍射峰，电镜观察发现加入BG后，材料结构更紧密。力学性能方面，固化1天及7天后的材料CPC+20%BG组明显高于单纯CPC组（P <0.05）。体外生物活性实验结果发现，浸泡模拟体液（Simulated body fluid, SBF）后，CPC-BG组表面HA沉积量明显多于CPC。能谱结果（Energy dispersive spectroscopy, EDS）表明，CPC-BG复合材料表面沉积的HA主要由Ca, P及Si组成，而CPC仅含Ca及P元素。体外降解实验发现，加入BG后可提高材料降解性；
3.细胞学实验结果表明，加入BG后，可提高成骨细胞的粘附，增殖及分化。MTT结果显示，8h后，CPC-BG复合材料组与单纯CPC组有统计学差异（P<0.05）。随着时间的延长，细胞进一步增殖，在1d，4d及7d时MTT结果显示，CPC-BG组优于CPC组，其中在4d及7d时，CPC-BG组与CPC组有统计学差异（P <0.05）。碱性磷酸酶活性（Alkaline phosphatase, ALP）检测发现，7d时，CPC-BG组与CPC组有统计学差异（P <0.05）；
4.新西兰白兔体内植入实验中，大体，Micro-CT和组织学检测显示，在4周和12周，所有材料组的体内降解率和新生骨生成量随着时间的延长而增加，其中CPC-BG组材料的体内降解率和新生骨生成量均明显高于CPC组（P <0.05）。
结论：
1．CPC-BG（10%,20%）复合生物材料的固化时间及可注射性符合外科手术要求，随着BG的增加，复合生物材料的成分、微观结构发生了改变，可注射性，力学性能进一步提高，同时，体外生物活性及降解率也有了明显的改善；
2．将BG引入CPC中，有利于成骨细胞的粘附、增殖和分化；
3．CPC-BG复合生物材料具有优秀的生物相容性，更高的生物活性、体内降解率和骨生成率，更有利于骨缺损的修复。
In China, there are70million people over the age of50suffering from osteoporosis(OP) and1.81million cases of vertebral compression fractures (VCF) occurred annually.Currently, percutaneous vertebroplasty (VP) and balloon kyphoplasty (BKP) have becomethe main surgical treatment of VCF. Polymethylmethacrylate (PMMA) is the mostcommonly used cement in VP and KP. However, there are several disadvantages ofPMMA: nonbiodegradable, no osteoconductive, osteoinductive and osteogenic activityand the high-polymerization isotherm leading to thermal necrosis of the soft tissues at theaugmentation site. Therefore, to design a novel biomaterial with good flowability,osteoconductive, osteoinductive and osteogenic activity as well as good mechanicalproperty and certain degradation rate for bone regeneration has become the urgentproblem in the field of orthopedics.
Calcium phosphate cements (CPC) have been widely used as bone substitutematerials in clinic applications because of their self-setting properties, no thermogeniceffect, high biocompatibility and osteoconduction as well as bone replacement capability.However, the currently used CPC has some limitations due to its poor mechanicalproperties and low biodegradation rate. Furthermore, the osteoconductive properties ofCPC are not sufficient to achieve complete bone repairment under critical conditions, suchas poorly vascularized sites and elderly patients with metabolic disorders. Consequently,the enrichment of CPC with osteopromotive or osteoinductive factors is necessary toimprove its biological performance.
As a surface active bone substitute, bioactive glass (BG) has recently attracted moreattention due to their good biocompatibility and bioactivity both in bone and in soft tissues.Studies have shown that close ion exchange between BG and soft issue or bone can bedirectly involved in the metabolism of human bone tissue and repair process. Bioactiveglass such as45S5BG bonds strongly to bone and promotes bone growth with formationof a hydroxycarbonate apatite (HCA) layer and the release of Ca, P and Si ions. As far aswe know, it is not until recently, there were a few relevant literatures available regardingCPC-BG applicably in minimally invasive injectable graft.
Objective:
The aim of this study is to develop a new injectable biocomposite with excellentbiocompatibility, improved bioactivity and biodegradability by adding BG into CPC.
Methods:
1. Prepare the CPC-BG composite by adding different proportions of BG45S5powder(10wt%,20wt%,30wt%,40wt%) into CPC powder and mixed with potassiumphosphate buffers (pH7.0) at a given P/L ratio of2.0g/ml. Optimize the compositionratio by comparing setting time and injectability among different groups;
2. Fabricate the CPC-BG composite with the selected composition ratio and P/L ratio andinvestigate the composition, morphology/microstructure, setting time, injectability,compressive strength, surface reaction layer formation and degradation of CPC-BG;
3. The osteoblasts (OB) were seeded onto the CPC-BG composite disks and the adhesion,proliferation, morphology and differentiation abilities of the OB were observed;
4. The CPC-BG and CPC specimens were implanted into femoral condyle defects ofrabbits. After4and12weeks implantation, macroscopic evaluation, histologicalevaluation, and micro-CT analysis were performed.
Results:
1. The setting times of CPC-BG were prolonged as the content of BG increased,increased from21min to44min, with the weight ratio of BG varied from10%to40%at P/L ratio of2.0g/ml. The injectability of CPC-BG composite paste was significantlyimproved compared with injectability of CPC paste (p <0.05);
2. XRD showed that main peaks for HA of hardened CPC-BG composite, were notobviously altered and peaks for Ca2SiO4and Ca3SiO5could be seen in the XRDpatterns of CPC-BG composite with10%and20%BG. The SEM micrographs for thecross section of the CPC and CPC-BG composite specimens (10%,20%) showed thatthe CPC-BG composite specimens closely combined with each other which showedmore compact microstructure than CPC. The compressive strength of CPC-BGcomposites rose with an increase in the weight ratio of BG and there were significantdifferences between CPC and CPC-20%BG composite specimens at day1and day7(p<0.05). After immersing in simulated body fluid (SBF) for7and14days, the amountof apatite aggregates on CPC-BG composite surface were larger and apatite layersgrew more densely on CPC-BG composite surface than amount on CPC surface. EDSindicated that the surface of CPC-BG composite (10%,20%) consisted of a calciumphosphate with a Ca/P ratio of about1.56and1.53and contained Si, while the surfaceof CPC consisted of a calcium phosphate with a Ca/P ratio of about1.67, contained noSi. The degradation rates of all CPC-BG composite specimens were significantlyhigher than degradation rates of CPC specimens (p <0.05);
3. The degree of cell attachment, proliferation and differentiation was increased byadding BG into CPC. The MTT assay showed that the OD values of CPC-BG composite specimens (20%) were significantly higher than OD values of CPCspecimens (p <0.05) in a period of8h. OD values of CPC-BG composite specimens(20%) were significantly higher than OD values of CPC specimens at4and7days (p<0.05), indicating that CPC-BG composite specimens promoted cell growth andfacilitated proliferation with no cytotoxic effect on cells compared with CPCspecimens. The ALP activity of cells cultured on CPC-BG composite (20%) wassignificantly higher than ALP activity on CPC and TCPS control (p <0.05) at4and7days;
4. With the prolonged implantation period from4to12weeks, the in vivo degradationrate and the amount of newly formed bone of CPC-BG composites and CPC wereincreased. Moreover, the in vivo degradation rate and the amount of newly formedbone of CPC-BG composites were significantly higher that of CPC specimens (p <0.05).
Conclusions:
1. The setting time and injectablity of CPC-BG composite (10%,20%) conform to thesurgical requirement. CPC-BG（10%，20%） possessed a retarded setting time andmarkedly better injectability and mechanical properties than CPC. Meanwhile,CPC-BG samples showed significantly improved in vitro degradability and bioactivitycompared to CPC in SBF.
2. Adding BG into CPC is benefit for OB to adhere, proliferate and differentiate.
3. CPC-BG with excellent biocompatibility, improved bioactivity and in vivodegradability enhanced the efficiency of new bone formation in comparison with CPC,which exhibits promising prospects for bone regeneration.
引文
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