功能性可降解骨植入材料的示踪性能和生物性能研究

The current biodegradable polymer materials and their inorganic-organic composites, as orthopedic implants, can not be traced timely by using the existing medical imaging techniques due to lack of relaxed hydrogen proton ability and the low density. In order to solve this problem, the project is based on the unique magnetic properties of gadolinium (Gd)-containing compounds and the particularity of micro-nano materials. Controls the synthesis of inorganic gadolinium micro/nano particles with regular morphology and uniform size. And the composites with biodegradable polymers are investigated systematically. Many factors affecting the in vitro/in vivo imaging signals of magnetic resonance imaging (MRI) and X-ray computed tomography (CT) are studied, including different types of Gd-containing compounds, morphology, size and incorporation concentrations in bone-implanted composites. The types and concentrations of materials for tracing degradable bone implants were screened by in vitro cell experiments and in vivo animal experiments. Then, Gd-containing nano-and micro-materials were modified by polyglutamic acid with good biocompatibility. The effects of different modification processes on the imaging signal and biological effects of MRI were studied to improve the dispersion, biocompatibility and biological activity of inorganic-organic composites. This project aims at tracing biodegradable polymer bone implant materials, ensuring the biocompatibility of materials, improving the biological activity of materials, promoting the induction of bone formation, and facilitating the cross-fusion of disciplines. It has important scientific significance and application prospects.

目前，作为骨科植入材料的生物降解高分子材料及其无机－有机复合材料，由于缺乏驰豫氢质子能力和密度低等缺陷，无法利用现有的医学影像手段进行植入后的跟踪观察。为解决这一问题，本项目基于含钆材料所具有的独特磁学特性以及微纳米材料的特殊性，控制合成形貌规则、尺寸均一的无机含钆微纳米粒子及其与可降解高分子材料复合体系，研究不同含钆化合物种类、形貌、尺寸和掺入浓度对骨植入复合材料MRI和CT体外/体内成像信号的影响。利用体外细胞实验和体内动物实验，筛选用于示踪可降解骨植入材料的种类和浓度。通过聚谷氨酸对其进行表面修饰，研究不同修饰产物对成像信号和生物学效应的影响，提高含钆微纳米材料在可降解骨植入材料中的分散性、生物相容性和生物活性。本项目的实施，以示踪可降解高分子骨植入材料为目标，以材料生物相容性为保障，提升材料的生物学活性，促进诱导骨生成，有利于学科的交叉融合，具有重要的科学意义和应用前景。

目前，作为骨科植入器械的可降解高分子材料，由于密度低，缺乏驰豫氢质子能力等缺陷，无法利用现有的医学成像技术进行实时追踪。含钆（Gd）稀土无机微纳米材料，因Gd3+特有的电子构型使其具有顺磁性，结合其表面效应、量子尺寸等效应可作为多功能材料，在骨科植入器械及骨组织工程领域具有潜在的应用价值。本项目围绕可降解高分子骨植入材料不可示踪的问题，探索不同含钆微纳米粒子种类、形貌、尺寸、掺入浓度以及表面修饰程度，对骨植入复合材料MRI成像和成/软骨效应的影响及其影响机制，获得以下结论：（1）不同形貌、晶体结构对MRI T1相加权成像效果具有明显的影响，制备七种形貌（方形、抱枕形、星形、杨桃形、空心圆柱、鼓形和枣形）的GdPO4:5%Eu3+微/纳米材料中，杨桃形GdPO4:5%Eu3+微/纳米粒子具有较高弛豫率0.7709 mM-1 s-1；（2）与可生物降解的聚（乳酸-乙醇酸）PLGA复合后，氧化钆（Gd2O3）微球的MRI T1相加权成像（r1=0.0023 mM-1 s-1）强于硫氧化钆（Gd2O2S）微球（r1=0.0008 mM-1 s-1），都可显著促进COL I和COL II在mRNA和蛋白中的表达；（3）通过SiO2表面封装GdPO4‧H2O，氨基丙基三甲氧基硅烷（APS）预修饰和聚（g-苄基-L-谷氨酸）（PBLG）修饰，随着改性过程的进行，MRI T1成像信号依次减弱，GdPO4‧H2O@SiO2/PLGA培养的MC3T3-E1前成骨细胞COL I和COL II的表达量至少为对照组PLGA的3倍。本项目的研究成果为含钆微纳米材料在无损示踪可降解骨植入材料的研究与应用提供了可靠的实验数据。基于含钆微纳米材料对MRI示踪性和成/软骨诱导及矿化活性的影响研究，阐明MRI成像及生物活性影响机制，为骨植入材料的多功能性应用开发研究提供了有益探索。