复合离子杂化仿生人工骨支架的3D打印构筑与骨缺损修复规律探究

Bones of human beings are composed of nano hydroxyapatite (HAp) and collagen. HAp can promote new bone ingrowth through osteoconduction mechanism. And the collagen, which gives the bone its elastic resistance, acts as a matrix for the deposition and growth of minerals. So how to realize the careful control over the physical and chemical properties of HAp is regarded as the key to the construction of artificial bones, based on which the collagens may be effectively co-assembled..Here, we simulate natural biological minerals in the structure characteristics, and utilize a series of multi-ion-doped nanoHAp as the inorganic phase and human-like collagen (HLC) with superior biocompatibility as the main organic phase, and prepare series of degradable artificial bones using an advanced 3D printing technology, liquid nitrogen cryogenic molding, post-crosslinking technology, and ultra-low temperature freeze-dry technology. The bone defect repair was dynamically monitored using the peripheral bone quantitative CT scan (pQCT) method. The bone defect reconstruction scaffold material constructed by 3D printing was evaluated and fed back from the development of the four-dimensional bone..This study will reveal the repair pattern of the target artificial bone to the bone defect, define the utility of multi-impurity ions in the target bone material, and obtain a new bone-forming stent with good biocompatibility and osteoinductive activity, and the rate of artificial bone degradation is well matched with the rate of new bone formation, which providing theoretical the basis for the accurate construction of the ideal hierarchical hole pattern biomimetic artificial bone.

人类骨骼已经被证实由纳米尺度的羟基磷灰石（HAp）及胶原蛋白构成，HAp通过骨传导机制可以促进新骨的生长，胶原蛋白则作为矿物沉积和生长的基质赋予骨弹力。如何在纳米尺度实现对HAp理化性质的控制，并以此为基础与胶原蛋白进行高效复合是获得性能优异的人工骨材料的关键。.本项目模拟天然生物矿物质的结构组成，利用系列多元离子杂化纳米磷灰石与类人胶原蛋白复合，采用3D打印、液氮冷冻成型、后交联和超低温冷冻干燥技术构筑复合离子杂化仿生人工骨支架，并采用外周骨定量CT扫描法（pQCT法）对骨缺损修复进行动态监控，从四维骨骼的发展变化规律评价和反馈优化骨修复支架材料。.本研究将揭示目标人工骨对骨缺损的修复规律，明确多元杂质离子在目标骨材料中的功效性，获得兼具良好生物相容性和骨诱导活性的促新骨形成支架材料，实现降解速率与新骨生成速率良好匹配，为层级孔型的理想仿生人工骨支架的精准构筑提供理论依据。

本项目通过可降解多孔支架材料的无机主相创新合成、3D打印成型工艺、可降解多孔支架材料的生物学功效等方面，研究了构筑性能优异的人工骨支架材料的关键技术，具体为：首先，不同杂质离子的半径大小特点，分别成功研制了钴、镍、锡离子掺杂的羟基磷灰石纳米晶、超长羟基磷灰石纳米线，富铈、硒型介孔生物活性玻璃、稀土Eu/Tb掺杂的富镁白磷钙石纳米晶等，并详细研究了各种材料的理化性质和生物学功效。其次，采用离子杂化型羟基磷灰石纳米棒为光固化树脂增材，并选用的具有良好生物相容性的PEG400DA和TMPTA，设计打印了牙齿的3D打印模型。以离子杂化的羟基磷灰石纳米线为无机主相，类人胶原蛋白为有机主相，采用谷氨酰胺转移酶溶液混入打印浆料中作为预交联剂增加打印浆料的粘性，通过3D打印和液氮瞬时冷冻成型法获得多孔支架材料，并通过EDAC) 和NHS的无水乙醇浸泡的二次交联，最终获得性能优异的3D仿生可降解人工骨支架。最后，研究了超长羟基磷灰石纳米线基可降解多孔水凝胶、可用于骨瘤术后组织修复的富铈和硒的微凝胶骨粉（粒径约为500-700μm）、可示踪缺损组织修复的Eu/Tb掺杂的富镁白磷钙石组织填充材料。动物学模型试验结果表明，以不同的材料设计可以实现不同类型的组织缺损修复，可为特异性骨组织缺损提供了高度针对性的可降解支架材料，并可以通过荧光示踪法可视化填充材料的降解过程和组织的修复过程，为理想仿生人工骨支架的精准构筑提供理论依据和新型材料。