新型生物衍生骨骼肌再生支架的免疫原性、修复机制和生物安全性研究

The use of regenerative medicine technology to achieve functional repair of skeletal muscle is the reaearch trend in muscle defect treatment.Currently, the U.S. Army is using the " non-tissue-specific extracellular matrix " scaffolds to achieve muscle induced regeneration and applying this technology to the clinical. In this aspect, our research group has developed a new type of skeletal muscle "tissue-specific" scaffolds- - skeletal muscle whole organ skeletal muscle acellular matrix(SMWOACM) previously, and confirmed it ofthorough decellularization, together with the complex three-dimensional microstructure of hierarchical and parallel arrayed basal lamina, muscle-tendinous connection, internal capillary network, and the bioactive contents including growth factors, glycosaminoglycans, and basement membrane structural proteins.The in vitro evaluation also confirmed SMWOACM promote muscle-derived stem cells migration, proliferation and differentiation better compared to non-tissue-specific extracellular matrix.In this project,we will make it clear the impact of SMWOACM on the host immune system, the short- and long-term effect on the local and systemic muscle-derived stem cells,the inflence on stem cell reservoir in the body when combined with chemokines, as well as the metabolic pathways and biological safety of SMWOACM. The findings will lay the foundation for the clinical application of SMWOACM and help to improve the technology. Preliminary work has been announced in the top international surgical congress-American College of Surgeons Clinical Congress and accepted by SCI journals.The applicant and participants grasp the related techniques associated with acellular matrix and muscle stem cells, which will make the research objective can definitely be achieved.

再生医学技术实现骨骼肌的功能性修复是肌肉缺损治疗的研究趋势，美军方利用"非组织特异性细胞外基质"支架材料已实现肌组织诱导再生并临床应用。这方面课题组前期制备出新型的骨骼肌"组织特异性"再生支架- - 骨骼肌全器官脱细胞基质（SMWOACM），并证实其脱细胞彻底，具有平行排列的基底膜管、功能性血管网络、肌肉-肌腱接头等三维超微结构和生长因子、糖胺聚糖等生物活性成分，体外较非组织特异性细胞外基质更好的促进肌源性干细胞的增殖、迁移和分化。本课题拟明确SMWOACM对宿主免疫系统的影响，对修复区局部和全身肌源性干细胞的短期、长期效应，以及联合趋化因子对全身干细胞储备的作用并确认其代谢途径和生物安全性。研究结果将为其临床应用奠定基础。前期工作已申请发明专利、在外科顶级国际会议-美国外科年会做大会报告并被SCI期刊收录。申请者和课题合作方熟悉脱细胞基质、肌肉干细胞相关操作技术，研究目标均能实现。

再生医学技术实现骨骼肌的功能性修复是肌肉缺损治疗的研究趋势，美军方利用"非组织特异性细胞外基质"支架材料已实现肌组织诱导再生并临床应用。这方面课题组前期制备出新型的骨骼肌"组织特异性"再生支架- - 骨骼肌全器官脱细胞基质（SMWOACM），并证实其脱细胞彻底，具有平行排列的基底膜管、功能性血管网络、肌肉-肌腱接头等三维超微结构和生长因子、糖胺聚糖等生物活性成分，体外较非组织特异性细胞外基质更好的促进肌源性干细胞的增殖、迁移和分化。基于上述研究，本课题发现①SMWOACM的免疫原性极低，体外对免疫细胞的结构和功能无影响；②SMWOACM植入体内修复肌肉缺损，修复区无剧烈免疫反应，组织再生和修复疗效显著优于平行材料；③SMWOACM的植入对临近肌肉干细胞具备一定的调动作用，趋化因子可以进一步增强调动作用；④SMWOACM体内代谢途径为修复区和肾脏；⑤SMWOACM生物安全性良好。本课题研究成果已在材料学顶级期刊《Biomaterials》（IF 8.557）上发表论著1篇和方法学论著1篇，另发表中文核心期刊综述1篇，尚有SCI高分值论文2篇修回中，1篇中文论著已接收。授权国家发明专利1项、实用新型1项，申请PCT国际专利1项，申请国家发明专利2项。主办1场国内学术会议，参加多次国际、国内学术会议交流，项目组负责人和成员获批国家自然科学基金面上项目2项、上海市科委启明星计划1项，培养博士生2名，硕士生2名。