超临界流体技术制备多孔组织工程支架的应用基础研究

Supercritical carbon dioxide (SCCO2) foaming is a process useful for fabricating porous tissue engineering scaffolds, in which the interactions between SCCO2 and polymers play the key role. The absence of organic solvents, mild operation temperature and easy/flexible control of product properties make this process very attractive. Combining SCCO2 foaming with supercritical fluid assisted atomization introduced by a hydrodynamic cavitation mixer (SAA-HCM) technique, this work will focus on the preparation of porous composite scaffolds for tissue engineering with incorporated active protein growth factors, in which biodegradable polyesters like poly(lactic acid), poly(lactic acid-co-glycolic acid) and poly(ε-caprolactone) are used as polymer matrices and bioceramics as solid filler, together with micro- and submicro- sized solid porogens. The influences of operation conditions on scaffold properties will be investigated and the characterization of scaffolds including physicochemical properties, biocompatibility and in vivo performance will be carried out. Especially, the emphasis will lay on the study of controlling inner pore structure, filler and protein distribution inside the scaffold and protein release behavior. Furthermore, we also will study thermodynamics and dynamic processes about the SCCO2 foaming technology. The solubilization of SCCO2 in the biodegradable polymers, the swelling and plasticizing effect of SCCO2 on these polymers will be determined. Meanwhile, the mechanisms of foaming, matrix cooling and hardening will be discussed. Finally, mathematics model of gas nucleation and pore growth will be established. This multidisciplinary work will serve to expand the research of SCCO2 foaming on processing biodegradable polymers, deepening the theoretical study, and will be meaningful to further improvement and scaling up of this process.

超临界二氧化碳发泡法是一种利用超临界流体与聚合物相互作用制备多孔组织工程支架的有效手段，具有不使用有机溶剂、操作条件温和、产品性能易于控制等优点。本研究将超临界二氧化碳发泡法和新型超临界微粒化技术SAA-HCM相结合，以生物可降解聚酯为基质材料，活性生物陶瓷为固相添加剂，使用微米级/亚微米级拓孔剂，得到能够负载活性蛋白生长因子的多孔复合支架。考察工艺参数对支架性能的影响，对支架进行表征包括支架的理化性质、生物活性和体内作用；深入研究支架内部孔结构、物质分布和活性因子释放行为的调控；测定二氧化碳在生物可降解聚合物中的溶解、对聚合物的溶胀和塑化等相关热力学数据；探讨生物可降解聚合物的发泡和支架成型机理。本项目涉及多个学科的研究范畴，研究成果将有助于推动超临界发泡技术在生物可降解材料中的应用，对组织工程支架的超临界二氧化碳发泡工艺设计和理论的深化具有重要意义。

按照计划书的研究内容，首先建立了高压CO2发泡工艺流程，以聚酯类化合物如聚(乳酸-乙醇酸)共聚物、聚己内酯等为基质，利用超临界压CO2发泡法制备多孔组织工程支架。采用简单发泡法制备单模式孔支架，考察了聚合物分子量、保压时间、发泡温度、发泡压力和泄压速率对泡孔结构、孔隙率和机械强度等性能的影响；采用两步泄压发泡法制备具有双模式孔组织工程支架，探究了不同的操作策略与能否形成双模式孔的关系，并讨论了泡孔生长的机理；进一步，采用超临界压CO2发泡/颗粒滤沥法以及添加异相成核剂如羟基磷灰石等制备了单/双/多模式孔多孔支架。其次，选择布洛芬、地塞米松和人血清白蛋白为生物活性物质，将小分子药物和蛋白类药物/生长因子载入聚合物支架，研究生物活性物质在支架中的分布以及释放行为，考察药物、聚合物和水体系之间的相互作用。最后，研究了多孔支架的体外降解行为及生物相容性，为多孔支架应用于骨/软骨组织的修复和再生奠定了基础。