生物活性骨修复材料的构建与生物学响应研究
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摘要
创伤、肿瘤、感染等因素造成骨组织缺损和破坏困扰和影响人类健康。研制具有调控骨组织相关细胞行为和组织再生过程的生物活性材料成为生物材料领域的热点。本研究从仿生人体骨组织结构与细胞外基质的机制出发,从材料组成、结构优化以及生物因子装载等角度构建新型具有高活性的骨修复材料,并从细胞生物学与体内动物实验等方面较系统地研究材料的组成、结构、生长因子及其之间的协同对细胞行为和组织形成过程的影响规律,并对过程的机理进行了初步的探索。
磷酸镁/磷酸钙骨水泥与成骨相关细胞的相互作用研究——镁是骨代谢过程中的重要微量元素。本研究以Ca(H2P04)2和MgO为反应物并掺入磷酸钙骨水泥,控制Mg/P摩尔比例在5、10和20%,分别称为5MCPC.10MCPC和20MCPC.以MG63成骨细胞为模型,体外培养实验结果表明,三种试样均具有良好的生物相容性。外源性的镁以及掺镁骨水泥浸提液的镁对成骨细胞的粘附效率无显著影响。但将细胞直接培养于掺镁骨水泥表面后其粘附效率得到了很大提高。随镁含量的升高掺镁骨水泥的表面粗糙度逐渐减低,细胞骨架却在5MCPC和10MCPC铺展最好。整合素Integrinα5表达在5MCPC和10MCPC表面明显上调,而Integrinα1、α2、β1的表达却没有正影响。溶液中的镁离子在粘附过程是次要的,而材料表面的镁直接参与细胞粘附整合素的信号通路。进一步选用5MCPC研究其对血管内皮细胞增殖与血管发生因子表达的影响发现:内皮细胞在5MCPC表面铺展更好,培养3天后增殖较CPC表面具有显著性差异。5MCPC表面的细胞的血管发生因子表达量有明显上调,其一氧化氮分泌量也有明显提高。这些结果表明较低剂量的镁元素掺入CPC是一种简单而有效的方法以提高成骨细胞粘附及成骨血管发生几率,有利于加速植入材料与新生组织之间生物稳定界面的快速形成以加快骨修复进程。
不同含钙量纳米介孔硅基干凝胶对成骨细胞的响应——制备了不同氧化钙含量的介孔硅基干凝胶(0、5、10、15%,命名为m-SXCO、m-SXC5、m-SXC10、m-SXC15)以MG63成骨细胞为模型,体外培养实验结果发现：干凝胶对成骨细胞形态无明显影响。细胞在m-SXC10增殖速率最高。细胞NO表达量随干凝胶中钙含量增高而增高。碱性磷酸酶活性和前列腺素2均在m-SXC5组表达最高。M-SXC5组胶原Ⅰ和骨钙素的基因表达得到了上调。培养7天的n-SXC10细胞外信号调节激酶的磷酸化程度最高。结果表明适量的钙在介孔硅基干凝胶中起到了对成骨细胞活性的重要的调节作用,可作为骨修复领域的更优异的药物控释载体。
不同比表面积纳米介孔硅基干凝胶与成骨细胞相互作用研究——比表面积是介孔硅基材料的重要参数,而迄今鲜有关于其对成骨细胞响应的报道。实验制备了3种不同比表面积的干凝胶,结果发现,随表面积的增高蛋白吸附量增加,而表面硅羟基含量却降低。表面磷灰石的生成速率随表面积增高而加快。大比表面积干凝胶有利于成骨细胞增殖。基因表达及流式细胞蛋白检测均表明细胞整合素Integrin a5在大比表面积干凝胶上得到了明显上调。这些结果表明增加干凝胶的比表面积能够通过吸附血清蛋白和加速磷灰石层形成速率从而提高其表面细胞亲和力。调节比表面积也成为一种有效的介孔硅基材料的设计手段,为骨修复和药物控释领域更优异的组织响应能力提供更多的选择。
壳聚糖磺酸化修饰及其与骨形态发生蛋白-2的作用机理研究——BMP-2作为有效的生长因子而广泛用于骨修复研究,大剂量使用的潜在副作用限制了其临床的广泛应用。肝素等具有调节BMP-2活性的功能。而磺化壳聚糖类对BMP-2的影响尚未见报道。我们制备了多种不同磺化壳聚糖,以C2C12细胞为模型,实验证明6-O磺化壳聚糖对促进BMP-2活性起到关键作用,而2-N位只起到辅助作用。低浓度的2-N,6-O磺化壳聚糖(26SCS)对BMP-2诱导的碱性磷酸酶活性、矿化形成以及成骨基因表达均有明显促进效果。增加链长和提高磺化度能够进一步提高其活性。26SCS表现出比肝素更好的促进BMP-2能力。体内动物异位成骨实验同样证明了这一现象。这些结果证明26SCS调节BMP-2的信号通路有望作为BMP-2的协同因子。
硅酸钙/磷酸钙骨水泥大孔支架与骨形态发生蛋白-2的成骨协同作用研究——将硅酸钙引入到磷酸钙骨水泥体系中制备了复合大孔支架并负载骨形态发生蛋白(BMP-2),考察二者之间的协同作用。复合支架的蛋白吸附量远高于CPC支架,其体外降解速率也远高于CPC支架。复合支架释放出大量的硅、钙、磷离子。以MG63为细胞模型,间接培养和直接培养实验均表明负载BMP-2的复合支架具有最佳的成骨分化效果。通过micro-CT和组织切片对体内动物实验结果进行分析也得到了同样的结论。本章的结果表明硅酸钙复合磷酸钙大孔骨水泥支架与BMP-2之间存在着明显的协同作用,有望成为优异的骨修复治疗材料。
The damage and defect on bone tissue resulting from traumas, tumours and infections has been an important medical project affecting human health. Nowadays, it's a hot topic to develop novel biomaterials with the capabilities modulating cell behaviors and tissue regeneration. Considering the structure and extracellular matrix of the natural bone, several materials with high bioactivity for bone repair were fabricated, and the interactions between the materials and cells/tissues, the potential mechanism and applications were investigated.
Magnesium phosphate/calcium phosphate cement and interactions with osteo-related cells——Trace element magnesium is reported to be essential in bone biological process. In the present study, the influences of magnesium in calcium phosphate cement (CPC) on osteoblast initial adhesion and vasculation were explored. Incorporation of magnesium into CPC was performed using Ca(H2PCO4)2 and MgO as reactants. Magnesium-calcium phosphate cement (MCPC) was developed by controlling Mg/P ratio (5,10, and 20%) and denoted as 5MCPC,10MCPC and 20MCPC, respectively. Using MG63 as in vitro model, these cements showed excellent biocompatibility. The exogenous magnesium in culture medium or ionic dissolution from cement had negligibly positive impacts on the initial cellular adhesion. However, adhesion efficiency was significantly enhanced when osteoblasts were cultured on MCPCs surface directly, especially on 5MCPC. Despite surface roughness of MCPCs decreased as compared with CPC, cell attachments were evidently enhanced on 5MCPC and 10MCPC as proved by phalloidin-cytoskeleton staining. Gene expression of integrin a5 was significantly up-regulated on 5MCPC and 10MCPC, while integrin al, a2 andβ1 expressions were not positively influenced. Magnesium existing forms seem to play different roles on osteoblast adhesion:ionic Mg2+ is subsidiary in osteoblast adhesion process. But magnesium on cement surface was directly involved as a cell-inducing factor via integrinα5 signaling pathway. The present study indicated that low amount of magnesium incorporation into calcium phosphate cement was a feasible and effective way to improve osteoblast adhesion and to accelerate stable bio-interface formation for enhancing bone regeneration in orthopaedic and trauma surgery.
Mesoporous silica xerogels with different calcium contents and responses on osteoblasts——Mesoporous silica xerogels with various amount of calcium oxide (0,5,10 and 15%, named m-SXCO, m-SXC5, m-SXC10 and m-SXC15, respectively) were synthesized by template sol-gel methods. Cell morphology was not affected by m-SXCs indicating good biocompatibility. Furthermore, cell proliferation ratio on the m-SXCs increased over time, among which m-SXC10 was highest. NO production obviously rose with the increase of Ca content in m-SXCs. ALP activity and PGE2 level on m-SXC5 significantly improved compared with m-SXCO while decreased with the increase of Ca content for m-SXC10 and m-SXC15. The collagen I and osteocalcin mRNA expression on m-SXC5 were up-regulated, while decreased on m-SXC15 evidently. The phosphorylation level of ERK 1/2 for the m-SXC10 was highest after 7 days. In conclusion, calcium in m-SXCs plays an important role in osteoblast activity, which indicates mesoporous silica xeroel containing appropriate calcium could stimulate osteoblast proliferation, differentiation, gene expression via the activation of ERK 1/2 signaling pathway, and shows great prospects in bone regeneration field using as a drug controlled release filler.
Mesoporous silica xerogerl with different specific surface area and responses on osteoblasts——Specific surface area is a critical parameter of mesoporous silica-based biomaterials, however, little is known about its effects on osteoblast responses in vitro. In the present study, mesoporous silica xerogels (MSXs) with different surface area (401,647 and 810 m2/g, respectively) were synthesized by a sol-gel process. Surface silanol contents decreased with the increase of surface area with which protein adsorption capability positively correlated. And the apatite-like surface seemed to form faster on MSXs with higher surface area determined by XRD analysis. Using MG63 osteoblast-like cells as models, it was found that cell proliferations were promoted on MSXs with higher surface area, based on the premise that the effects of Si released from materials on osteoblast viability were excluded by real-time Transwell(?) assay. RT-PCR results indicated cell adhesion-related integrin subunits a5 were up-regulated by higher surface area at day 1, which was further confirmed by flow cytometry analysis. The data suggest that increasing SSA of MSXs could promote surface cellular affinity by adsorbing serum proteins and accelerating apatite-like layer formation, which results in promoted osteoblastic proliferation via integrin subunit a5 at initial adhesion stage. Regulating SSA, an effective approach in designing mesoporous silica-based materials, provides an alternative method to obtain desirable tissue-response in bone regeneration and drug delivery system.
Modifying chitosan with sulfate group and its interaction with bone morphogenetic protein-2——Bone morphogenetic protein-2 (BMP-2) has been widely used as an effective growth factor in bone tissue engineering. However, large amounts of BMP-2 required to induce new bone formation would result in potential side-effects, which limits its clinical application. Sulfated polysaccharides, such as native heparin have been found to modulate BMP-2 bioactivity. Whereas the direct role of chitosan modified with sulfate group on BMP-2 signaling has not been reported till now. Several sulfated chitosans with different positions were synthesized by regioselective reactions firstly. Using C2C12 myoblast cells as in vitro models, the enhanced bioactivity of BMP-2 was attributed primarily to the stimulation from 6-O-sulfated chitosan (6SCS), while 2-N-sulfate was subsidiary group with less activation. Low dose of 2-N,6-O-sulfated chitosan (26SCS) showed significant enhancement on the alkaline phosphatase (ALP) activity and the mineralization formation induced by BMP-2, as well as the expression of ALP and Osteocalcin mRNA. Moreover, increased chain-length and further sulfation on 26SCS also resulted in a higher ALP activity. Dose-dependent effects on BMP-2 bioactivity were observed in both sulfated chitosan and heparin. Compared with native heparin,26SCS showed much stronger simultaneous effects on the BMP-2 bioactivity at low dose. Furthermore, simultaneous administration of BMP-2 and 26SCS in vivo dose-dependently induced larger amounts of ectopic bone formation compared with BMP-2 alone. These findings clearly indicate that 26SCS is a more potent enhancer for BMP-2 bioactivity to induce osteoblastic differentiation in vitro and in vivo by promoting BMP-2 signaling pathway, suggesting that 26SCS could be used as the synergistic factor of BMP-2 for bone regeneration.
The synergistic effects of calcium silicate/calcium phosphate cement scaffolds and bone morphogenetic protein-2——Calcium silicate was incorporated into calcium phosphate cement to fabricate marcoporous scaffolds and load bone morphogenetic protein-2 (BMP-2), the possible synergistic effects were investigated. The protein absorption capability of composite scaffolds was much higher than that of CPC. Faster degradation rate was observed in composite scaffolds, which also released larger amounts of silicon, calcium and phosphate ions. Using MG63 cells as model, the indirect and direct cluture experiments demonstrated composite scaffolds in the presence of BMP-2 induced highest alkaline phosphatase activity. Same conclusion was also brought by Micro-CT and histological sections analysis on in vivo studies. These results showed that calcium silicate incorporated macroporous scaffolds have synergistic enhancing effects with BMP-2 on bone regeneration, which could be potential therapy in future.
磷酸镁/磷酸钙骨水泥与成骨相关细胞的相互作用研究——镁是骨代谢过程中的重要微量元素。本研究以Ca(H2P04)2和MgO为反应物并掺入磷酸钙骨水泥,控制Mg/P摩尔比例在5、10和20%,分别称为5MCPC.10MCPC和20MCPC.以MG63成骨细胞为模型,体外培养实验结果表明,三种试样均具有良好的生物相容性。外源性的镁以及掺镁骨水泥浸提液的镁对成骨细胞的粘附效率无显著影响。但将细胞直接培养于掺镁骨水泥表面后其粘附效率得到了很大提高。随镁含量的升高掺镁骨水泥的表面粗糙度逐渐减低,细胞骨架却在5MCPC和10MCPC铺展最好。整合素Integrinα5表达在5MCPC和10MCPC表面明显上调,而Integrinα1、α2、β1的表达却没有正影响。溶液中的镁离子在粘附过程是次要的,而材料表面的镁直接参与细胞粘附整合素的信号通路。进一步选用5MCPC研究其对血管内皮细胞增殖与血管发生因子表达的影响发现:内皮细胞在5MCPC表面铺展更好,培养3天后增殖较CPC表面具有显著性差异。5MCPC表面的细胞的血管发生因子表达量有明显上调,其一氧化氮分泌量也有明显提高。这些结果表明较低剂量的镁元素掺入CPC是一种简单而有效的方法以提高成骨细胞粘附及成骨血管发生几率,有利于加速植入材料与新生组织之间生物稳定界面的快速形成以加快骨修复进程。
不同含钙量纳米介孔硅基干凝胶对成骨细胞的响应——制备了不同氧化钙含量的介孔硅基干凝胶(0、5、10、15%,命名为m-SXCO、m-SXC5、m-SXC10、m-SXC15)以MG63成骨细胞为模型,体外培养实验结果发现：干凝胶对成骨细胞形态无明显影响。细胞在m-SXC10增殖速率最高。细胞NO表达量随干凝胶中钙含量增高而增高。碱性磷酸酶活性和前列腺素2均在m-SXC5组表达最高。M-SXC5组胶原Ⅰ和骨钙素的基因表达得到了上调。培养7天的n-SXC10细胞外信号调节激酶的磷酸化程度最高。结果表明适量的钙在介孔硅基干凝胶中起到了对成骨细胞活性的重要的调节作用,可作为骨修复领域的更优异的药物控释载体。
不同比表面积纳米介孔硅基干凝胶与成骨细胞相互作用研究——比表面积是介孔硅基材料的重要参数,而迄今鲜有关于其对成骨细胞响应的报道。实验制备了3种不同比表面积的干凝胶,结果发现,随表面积的增高蛋白吸附量增加,而表面硅羟基含量却降低。表面磷灰石的生成速率随表面积增高而加快。大比表面积干凝胶有利于成骨细胞增殖。基因表达及流式细胞蛋白检测均表明细胞整合素Integrin a5在大比表面积干凝胶上得到了明显上调。这些结果表明增加干凝胶的比表面积能够通过吸附血清蛋白和加速磷灰石层形成速率从而提高其表面细胞亲和力。调节比表面积也成为一种有效的介孔硅基材料的设计手段,为骨修复和药物控释领域更优异的组织响应能力提供更多的选择。
壳聚糖磺酸化修饰及其与骨形态发生蛋白-2的作用机理研究——BMP-2作为有效的生长因子而广泛用于骨修复研究,大剂量使用的潜在副作用限制了其临床的广泛应用。肝素等具有调节BMP-2活性的功能。而磺化壳聚糖类对BMP-2的影响尚未见报道。我们制备了多种不同磺化壳聚糖,以C2C12细胞为模型,实验证明6-O磺化壳聚糖对促进BMP-2活性起到关键作用,而2-N位只起到辅助作用。低浓度的2-N,6-O磺化壳聚糖(26SCS)对BMP-2诱导的碱性磷酸酶活性、矿化形成以及成骨基因表达均有明显促进效果。增加链长和提高磺化度能够进一步提高其活性。26SCS表现出比肝素更好的促进BMP-2能力。体内动物异位成骨实验同样证明了这一现象。这些结果证明26SCS调节BMP-2的信号通路有望作为BMP-2的协同因子。
硅酸钙/磷酸钙骨水泥大孔支架与骨形态发生蛋白-2的成骨协同作用研究——将硅酸钙引入到磷酸钙骨水泥体系中制备了复合大孔支架并负载骨形态发生蛋白(BMP-2),考察二者之间的协同作用。复合支架的蛋白吸附量远高于CPC支架,其体外降解速率也远高于CPC支架。复合支架释放出大量的硅、钙、磷离子。以MG63为细胞模型,间接培养和直接培养实验均表明负载BMP-2的复合支架具有最佳的成骨分化效果。通过micro-CT和组织切片对体内动物实验结果进行分析也得到了同样的结论。本章的结果表明硅酸钙复合磷酸钙大孔骨水泥支架与BMP-2之间存在着明显的协同作用,有望成为优异的骨修复治疗材料。
The damage and defect on bone tissue resulting from traumas, tumours and infections has been an important medical project affecting human health. Nowadays, it's a hot topic to develop novel biomaterials with the capabilities modulating cell behaviors and tissue regeneration. Considering the structure and extracellular matrix of the natural bone, several materials with high bioactivity for bone repair were fabricated, and the interactions between the materials and cells/tissues, the potential mechanism and applications were investigated.
Magnesium phosphate/calcium phosphate cement and interactions with osteo-related cells——Trace element magnesium is reported to be essential in bone biological process. In the present study, the influences of magnesium in calcium phosphate cement (CPC) on osteoblast initial adhesion and vasculation were explored. Incorporation of magnesium into CPC was performed using Ca(H2PCO4)2 and MgO as reactants. Magnesium-calcium phosphate cement (MCPC) was developed by controlling Mg/P ratio (5,10, and 20%) and denoted as 5MCPC,10MCPC and 20MCPC, respectively. Using MG63 as in vitro model, these cements showed excellent biocompatibility. The exogenous magnesium in culture medium or ionic dissolution from cement had negligibly positive impacts on the initial cellular adhesion. However, adhesion efficiency was significantly enhanced when osteoblasts were cultured on MCPCs surface directly, especially on 5MCPC. Despite surface roughness of MCPCs decreased as compared with CPC, cell attachments were evidently enhanced on 5MCPC and 10MCPC as proved by phalloidin-cytoskeleton staining. Gene expression of integrin a5 was significantly up-regulated on 5MCPC and 10MCPC, while integrin al, a2 andβ1 expressions were not positively influenced. Magnesium existing forms seem to play different roles on osteoblast adhesion:ionic Mg2+ is subsidiary in osteoblast adhesion process. But magnesium on cement surface was directly involved as a cell-inducing factor via integrinα5 signaling pathway. The present study indicated that low amount of magnesium incorporation into calcium phosphate cement was a feasible and effective way to improve osteoblast adhesion and to accelerate stable bio-interface formation for enhancing bone regeneration in orthopaedic and trauma surgery.
Mesoporous silica xerogels with different calcium contents and responses on osteoblasts——Mesoporous silica xerogels with various amount of calcium oxide (0,5,10 and 15%, named m-SXCO, m-SXC5, m-SXC10 and m-SXC15, respectively) were synthesized by template sol-gel methods. Cell morphology was not affected by m-SXCs indicating good biocompatibility. Furthermore, cell proliferation ratio on the m-SXCs increased over time, among which m-SXC10 was highest. NO production obviously rose with the increase of Ca content in m-SXCs. ALP activity and PGE2 level on m-SXC5 significantly improved compared with m-SXCO while decreased with the increase of Ca content for m-SXC10 and m-SXC15. The collagen I and osteocalcin mRNA expression on m-SXC5 were up-regulated, while decreased on m-SXC15 evidently. The phosphorylation level of ERK 1/2 for the m-SXC10 was highest after 7 days. In conclusion, calcium in m-SXCs plays an important role in osteoblast activity, which indicates mesoporous silica xeroel containing appropriate calcium could stimulate osteoblast proliferation, differentiation, gene expression via the activation of ERK 1/2 signaling pathway, and shows great prospects in bone regeneration field using as a drug controlled release filler.
Mesoporous silica xerogerl with different specific surface area and responses on osteoblasts——Specific surface area is a critical parameter of mesoporous silica-based biomaterials, however, little is known about its effects on osteoblast responses in vitro. In the present study, mesoporous silica xerogels (MSXs) with different surface area (401,647 and 810 m2/g, respectively) were synthesized by a sol-gel process. Surface silanol contents decreased with the increase of surface area with which protein adsorption capability positively correlated. And the apatite-like surface seemed to form faster on MSXs with higher surface area determined by XRD analysis. Using MG63 osteoblast-like cells as models, it was found that cell proliferations were promoted on MSXs with higher surface area, based on the premise that the effects of Si released from materials on osteoblast viability were excluded by real-time Transwell(?) assay. RT-PCR results indicated cell adhesion-related integrin subunits a5 were up-regulated by higher surface area at day 1, which was further confirmed by flow cytometry analysis. The data suggest that increasing SSA of MSXs could promote surface cellular affinity by adsorbing serum proteins and accelerating apatite-like layer formation, which results in promoted osteoblastic proliferation via integrin subunit a5 at initial adhesion stage. Regulating SSA, an effective approach in designing mesoporous silica-based materials, provides an alternative method to obtain desirable tissue-response in bone regeneration and drug delivery system.
Modifying chitosan with sulfate group and its interaction with bone morphogenetic protein-2——Bone morphogenetic protein-2 (BMP-2) has been widely used as an effective growth factor in bone tissue engineering. However, large amounts of BMP-2 required to induce new bone formation would result in potential side-effects, which limits its clinical application. Sulfated polysaccharides, such as native heparin have been found to modulate BMP-2 bioactivity. Whereas the direct role of chitosan modified with sulfate group on BMP-2 signaling has not been reported till now. Several sulfated chitosans with different positions were synthesized by regioselective reactions firstly. Using C2C12 myoblast cells as in vitro models, the enhanced bioactivity of BMP-2 was attributed primarily to the stimulation from 6-O-sulfated chitosan (6SCS), while 2-N-sulfate was subsidiary group with less activation. Low dose of 2-N,6-O-sulfated chitosan (26SCS) showed significant enhancement on the alkaline phosphatase (ALP) activity and the mineralization formation induced by BMP-2, as well as the expression of ALP and Osteocalcin mRNA. Moreover, increased chain-length and further sulfation on 26SCS also resulted in a higher ALP activity. Dose-dependent effects on BMP-2 bioactivity were observed in both sulfated chitosan and heparin. Compared with native heparin,26SCS showed much stronger simultaneous effects on the BMP-2 bioactivity at low dose. Furthermore, simultaneous administration of BMP-2 and 26SCS in vivo dose-dependently induced larger amounts of ectopic bone formation compared with BMP-2 alone. These findings clearly indicate that 26SCS is a more potent enhancer for BMP-2 bioactivity to induce osteoblastic differentiation in vitro and in vivo by promoting BMP-2 signaling pathway, suggesting that 26SCS could be used as the synergistic factor of BMP-2 for bone regeneration.
The synergistic effects of calcium silicate/calcium phosphate cement scaffolds and bone morphogenetic protein-2——Calcium silicate was incorporated into calcium phosphate cement to fabricate marcoporous scaffolds and load bone morphogenetic protein-2 (BMP-2), the possible synergistic effects were investigated. The protein absorption capability of composite scaffolds was much higher than that of CPC. Faster degradation rate was observed in composite scaffolds, which also released larger amounts of silicon, calcium and phosphate ions. Using MG63 cells as model, the indirect and direct cluture experiments demonstrated composite scaffolds in the presence of BMP-2 induced highest alkaline phosphatase activity. Same conclusion was also brought by Micro-CT and histological sections analysis on in vivo studies. These results showed that calcium silicate incorporated macroporous scaffolds have synergistic enhancing effects with BMP-2 on bone regeneration, which could be potential therapy in future.
引文
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