摘要
每年有大量病人因骨产品的缺口而忍受着骨相关疾病困扰。自然骨有自我愈合的能力,但是骨缺损过大时不能自我愈合就需要进行手术移植,现在临床治疗手段包括主要自体骨和异体骨移植,但自体骨会造成新的创伤及感染,而异体骨存在着免疫排斥及疾病感染的风险,因此人工骨支架得到了科研者的关注。理想的人工骨支架需要一定的孔隙率、力学性能和细胞附着性能,并且可以提供力学性能稳定性确保骨移植后在缺损部位完成骨修复过程。本课题选择磷钙基材料制备骨支架,因为自然骨中的无机成分主要为类骨磷酸钙,此外磷酸钙具有良好的成骨作用。首先对多相磷酸钙合成和相形成条件进行了系统研究,选择合适制备方法制备出具有良好力学性能和生物学性能的多孔磷钙基支架,并对支架的物化性能和生物学性能进行了系统表征,最后对支架的成骨性能进行了评估,其主要研究内容和结果如下：
1.通过湿化学方法合成的羟基磷灰石(HA)主要为针状,而合成的磷酸三钙(TCP)为无规则颗粒。常温下主要为无定形态,在800℃温度以上煅烧后变为p-TCP。湿化学方法可以制备多相磷酸钙,可通过pH值、钙磷比和煅烧温度控制多相磷酸钙的相组成。煅烧温度在600-800℃主要为缺钙性磷灰石(CDA)相,在1200℃为多相。多相磷酸钙在pH为6.5和10.5时,随钙磷比的增加结晶度呈增加趋势,主要为HA和p-TCP两相。pH在7.5-9.5之间,钙磷比在1.55时,多相磷酸钙除了HA和β-TCP相的存在外有CDA相存在；钙磷比在1.60和1.75时,多相磷酸钙具有较好的结晶度,存在三种以上的相成分；钙磷比在1.65和1.70时,多相磷酸钙主要有HA和CDA相。多相磷酸钙在未煅烧条件下主要针状形貌,随煅烧温度增加,颗粒形貌发生变化,在600℃为棒状,在800℃下为类椭圆状,在120℃下变为无规则相貌。
2.双相磷酸钙中HA/(HA+β-TCP)比值主要受反应条件中pH值和钙磷比影响。随着pH值的增加,双相磷酸钙中的HA含量增加,反之,β-TCP含量降低。在相同pH值的条件下,钙磷比为1.65时,双相磷酸钙中的HA含量最高；钙磷比接近1.65时,双相磷酸钙中的HA含量越高；偏离1.65时,双相磷酸钙中的HA含量越低。
3.采用乳化发泡法结合循环冷冻解冻方法制备BCP/PVA支架,可以通过PVA含量调节控制支架的孔径尺寸(50-700μm)、孔隙率(73-87%)、力学性能(0.19-0.26MPa)、降解速率以及生物学性能。随着PVA含量增加,BCP/PVA支架的孔隙率、力学性能、降解速率及细胞相容性呈现降低趋势。当PVA含量为30%,BCP/PVA支架的孔径尺寸在300-500μm之间,且压缩强度最大。此外,BCP/PVA支架在模拟体液中pH变化幅度较小,保持在7.18-7.36之间。BCP/PVA支架对成骨细胞的繁殖没有抑制作用,随着PVA含量的降低,成骨细胞在支架表面的繁殖呈增加趋势,且间充质干细胞可以在PVA含量为30%的BCP/PVA支架上附着和繁殖。综上所述,制备出的BCP/PVA支架可以满足松质骨组织工程的要求。
4.采用PU泡沫复制法可以制备孔径尺寸在300-700μm的孔连通结构BCP支架,可通过选择不同ppi的PU泡沫控制BCP支架的孔径尺寸。采用HA/PLLA纳米复合物对多孔BCP支架进行涂层,未改变支架的孔径尺寸和孔连通结构,可以填补BCP支架孔壁的断裂裂纹并在孔壁上形成高分子基纤维,以提高支架的力学性能。对BCP支架进行涂层后,孔隙率有所降低,仍保持在93%以上,但压缩强度从0.31MPa提高到3.35-3.95MPa之间,可以满足松质骨压缩强度(0.02-4MPa)的要求。此外,对BCP支架涂层后,降低了支架在模拟体液中的降解速率,模拟体液的pH也没有较大幅度变化,保持在6.8-7.4之间,在30天后保持在7.4左右。采用HA/PLLA纳米复合物对多孔BCP支架进行多次涂层后减低了支架的孔隙率,但压缩强度进一步得到了提高,随涂层次数的增加,孔隙率呈降低趋势,压缩强度呈增加趋势。通过MTT实验表明,随着涂层次数的增加,支架的细胞相容性呈增加后降低趋势,其中HA/PLLA纳米复合物三次涂层的BCP多孔支架细胞相容性最好,对此组的支架进行肌肉植入实验,通过HE染色分析,发现在前期出现炎症细胞,随着时间的增加,炎症细胞消失,并出现了类骨磷灰石层和纤维组织层,表明支架具有良好的生物相容性。
5.在单倍模拟体液环境下,随着仿生沉积时间增加,HA/PLLA纳米复合物涂层BCP支架的失重比呈降低后又增加的趋势,前期以支架降解为主,后期以磷酸钙矿化物沉积为主。支架孔壁上首先有氯化钠晶体出现,后氯化钠在SBF溶液中溶解,支架孔壁表面形成纳米级磷酸钙矿化物颗粒,并伴随有针状矿化物的出现；在沉积后期,在支架表面形成均匀的沉积物涂层。在过饱和模拟体液环境下,支架的仿生沉积速度得到了提高,磷酸钙矿化物很快沉积在支架孔壁表面,随着沉积时间的增加,在支架孔壁上的沉积物形貌变得均匀,和单倍SBF环境下较为相似。对仿生沉积改性后的支架经过低温冷冻处理,在-20℃下,支架在孔壁上形成了尺寸为3-5μm大小的微孔,磷酸钙中的钙离子被镁和钾离子置换,形成生物活性类骨磷灰石。
6.通过双乳液法制备出的线性PLGA-mPEG共聚物载药微球尺寸在5-10μm,尺寸大小分布比较均匀。通过紫外分光光度计检测分析,可以确定BSA和万古霉素的标准曲线,对于BSA含量低于200mg/L时在221.6nm的拟合度较好,含量高于100mg/L时在278nm的拟合度较好；对于万古霉素,在280nm吸光度有较好的拟合度。可以通过控制共聚物的LA/GA摩尔比控制共聚物降解速率,并进一步控制共聚物载药微球的释放速率,并通过不同LA/GA摩尔比的共聚物载两种药物实现两种药物在不同阶段的控制释放。此外,制备出的载药微球可以良好地附着在HA/PLLA纳米复合物涂层BCP多孔支架上。
7.对制备出的HA/PLLA纳米复合物涂层BCP支架进行毒理性试验分析,此类支架在毒性测试中未表现出明显毒性性质,在急性毒性分级标准中为无毒性,符合国家医疗器械生物学评价标准。通过肌肉植入实验,实验动物在术后未出现活动异常,且支架在动物体内随着时间增加会形成类骨磷灰石层和纤维组织层,而对周围的肌肉组织表现出生物惰性,可知支架具有良好的生物相容性。通过骨缺损修复实验,支架植入后,在缺损部位新骨逐级形成,支架被吸收降解,在密质骨的中心区域,成熟的骨组织附近有大量的骨单位形成,新骨和周围骨组织在后期紧密连接在一块难以区分,说明制备的支架具有良好的成骨性能和骨修复效果。
Every year, millions of people are suffering from bone defects arising from trauma, tumor or bone related diseases and of course several are dying due to insufficiency of ideal bone tissue. Biologically produced bone structures are known for self healing. However, large bone defects do not heal spontaneously and require surgical intervention for restoration, and the current therapies include autografts, allografts. Nonetheless, autografts maybe associated with donor shortage and donor site morbidity whereas allografts may have the risk of disease transmission and immune response. The aforesaid limitations and the expected shortage of bone grafts for surgical procedures, motivated materials scientists to find suitable bioactive materials, such as three-dimensional (3D) porous scaffold designed with the required porosity, mechanical strength and a favorable environment for bone cell attachment, to provide mechanical stability in the defect region and launch tissue regeneration with specific living cells. With the rapid development of bone biomaterials, great progress has been made in the last decade. However, as advancements are made, new challenges also emerge, which comes from the bone defect clinical requirements on the bone substitutes, In this paper, the multiphasic calcium phosphate was systematic studied, then the porous scaffold with good mechanical strength and biological properties based on calcium phosphate matrix was prepared with suitable preparation method, the properties of scaffold in vitro and in vivo were studied last, the main achievements were summarized as follows:
1. The HA paricles was needle-like prepared by wet chemistry, and the TCP paricle was irregular shapes, furthermore, TCP was amorphous state at room temperature, and transform to P-TCP after800℃sintering. The multiphasic calcium phosphate could be prepared by wet chemistry with controlling of pH, Ca/P, and sintering temperature. The sintering temperature was at600-800℃, the calcium-deficient apatite (CDA) powder was obtained, and the multiphasic calcium phosphate powder was obtained at1200℃. While the pH at6.5and10.5, the crystallinity degree of calcium phosphate was increased with the increase of Ca/P ratio, basically composed of HA and β-TCP phase. While the pH at7.5-9.5, the CDA phase was existed except for HA and β-TCP at1.55of Ca/P ratio, furthermore, the more three calcium phosphate phase was found while the Ca/P ratio was at1.60and1.75with good crystallinity, and the calcium phosphate was composed of HA and CDA phase while the Ca/P ratio was at1.65and1.70. The multiphasci calcium phosphate particle was needle-like, and the paricles morphology was changed with the increase of sintering temperature, rodlike at600℃, elliptical at800℃, and irregular at1200.
2. The HA/(HA+β-TCP) ratio in biphasic calcium phosphate was mainly controlled by pH and Ca/P ratio. With the increase of pH, the HA concentration of BCP was increased with the decrease of β-TCP concentration. At the same pH conditions, the BCP possess the highest HA concentration while the Ca/P ratio at1.65, furthermore, while the Ca/P ratio was close to1.65, the BCP powder with high HA concentration could be obtained.
3. A well-developed BCP/PVA scaffold with interconnectivity, porosity, and moderate compressive strength as well as good biocompatibility was fabricated by emulsion foam freeze-drying method for bone tissue engineering. The pore size (50-700μm), porosity (73-87%), and compressive strength (0.19-0.26MPa) could be controlled by weight ratio of BCP/PVA. Furthermore, the prepared scaffolds showed the lower variation of pH values (approximately7.18-7.36) in SBF solution, and an increase of porosity led to the increase of the biodegradation rate for BCP/PVA scaffolds. In addition, the BCP/PVA porous scaffold has good cytocompatibility, showing no negative effects on cells growth and proliferation. The porous structure, hydrophilicity, and mechanical strength of the BCP/PVA porous scaffold can meet essential requirements for bone tissue engineering and regeneration.
4. The3-D porous HA/PLLA nanocomposites coated BCP scaffolds with interconnectivity, high compressive strength and improved bioactivity has been fabricated and tested for repairing the large necrotic lesions in the loading-bearing region of rabbit femoral head using tissue-engineering technology. The compressive strength of BCP scaffold was increased to3.35-3.95MPa by HA/PLLA nanocomposites coating. Furthermore, based on unchanging interwork porous structure, the microstructure of pore wall on coated scaffold was formed, which lead to promote cell adhesion and proliferation. In addition, the developed scaffolds showed the capacity of bone regeneration combined with hBMSCs for large necrotic lesions in the rabbit femoral head. This study suggests a new strategy for use of nanocomposites coated scaffolds combined with hBMSCs, which can support cell adhesion and bone regeneration effectively and constantly for load-bearing bone tissue engineering application.
5. A well-developed BCP scaffolds coated with multi-layer of HA/PLLA nanocomposites with interconnectivity, high porosity, and moderate compressive strength as well as good biocompatibility were fabricated for bone tissue engineering. After coated with HA/PLLA nanocomposites, the scaffolds maintained the BCP framework structure, and the porous network structure of scaffolds remained unchanged, however, the compressive strength was increased with the increase coating layer number of HA/PLLA nanocomposites. The prepared scaffolds showed the lower variation of pH values in SBF solution, and an increase of coating layer number led to the decrease of the biodegradation rate at different days. Moreover, the multi-layer coating scaffolds had good cytocompatibility, showing no negative effects on cells growth and proliferation. Furthermore, the bone-like apatite layer was built obviously in the interface of scaffold after21days post-implantation in SD-rat muscle. In conclusion, the BCP scaffold coated with multi-layer of HA/PLLA nanocomposites could be a candidate as an excellent substitute for damaged or defect bone in bone tissue engineering.
6. Bioactive BCP scaffold coated with HA/PLLA nanomposites were prepared and modified by immersing in simulated body fluid to obtain the biomineralized materials for bone tissue engineering. The formation of mineralites was observed by SEM analysis, however, differ from literature, the NaCl apatite was identified by surface analyses at first stage and then Ca-P apatite with colloidal HA nanoparticles appeared and growed after increasing immersion time in SBF, subsequently, the bone-like apatite was detected until28days. At supersaturated SBF conditions, the deposition rate of scaffold was improved, and the deposition morphology of scaffold was similar to1×SBF fluid. The scaffold modified by biomimetic method was treated by low temperature freeze at-20℃, the micropore was formed on the pore wall, the micropore size was about3-5μm, furthermore, the calcium ion was substituted by magnesium and potassium ion in calcium phosphate to form the biological bone-like apatite.
7. The linear PLGA-mPEG microspheres loaded with different drugs was prepared by multiple emulsion method. Through UV spectrophotometer, the standard curves of BSA and vancomycin was comfirmed. The copolymer degradation rate could be controlled by controlling of LA/GA molar ratio, to the control the release rate of drugs loaded on the kind of compolymer microspheres. Furthermore, the types of drugs could be loaded on the PLGA-mPEG microspheres, and the sequential control release of two drugs could be achieved.
8. Through the toxicology test analysis, the BCP scaffold coated with HA/PLLA nanocomposites possess nontoxic properties, accord with medical apparatus and instruments standards. While the scaffolds were implanted in muscle, the experiments animal have not showed any abnormal activities, and the bone-like apatite layer was built obviously in the interface of scaffold. After the bone defect repair experiments, the new bone was formed gradually in the interface of scaffold while the scaffold was implanted in the bone defect part, at the same time, part of scaffold was degraded. There were still a few of unabsorbed scaffolds observed at some areas after2months postsurgery. They were mainly on the sides of newly formed radius and some of them were wrapped with new bone callus. The scaffolds were destroyed into small separated pieces and wrapped with invaded fibrous tissues. Most of them were hard to be distinguished except some areas. The coated scaffolds appeared to be osteoconductive and supported osteointegration and bone deposition, and also showed the osteophilicity, thus promoting medullary bone formation along the implants.
引文
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