基于微流控的三维可灌注功能化血管网络构建及其在血管化肿瘤芯片中的应用研究

The development of organ-on-a-chip will speed up the pace of drug development, while the three-dimensional perfused microvascular network with specific microphysiological functions plays a key prerequisite and important part in developing all the functional and metabolic organ-chips. Especially on the development of anticancer drugs, it is essential to establish the novel organ chip-based vascularized tumor model to improve the reliability and accuracy of drug screening. With the combination of BioMEMS, biomechanics and tissue engineering technologies, this project will first study the early vasculogenesis and later vascular remodeling under the multiple well-controlled microenvironments comprehensively and systematically, and the key parameters are then extracted. The aim is to construct the vascularized organ-chips with metabolic functions and microphysiological properties of specific organs. Based on these results we further establish a three-dimensional tumor angiogenesis model with its own microcirculation system by mimicking in vivo tumor microenvironment on the vascularized tumor-chips. Moreover, the anti-angiogenic cancer drug screening will be performed to verify its effectiveness. The research results will provide important theoretical foundations and technical supports for the development of vascularized organ-chips, especially for the vascularized tumor-chips. Furthermore, it can also facilitate the study on pathophysiology of various vascular diseases, mechanism of tumor angiogenesis, as well as anticancer drug development and its clinical applications.

器官芯片的发展将加快药物研发，而具备特定微生理功能的三维可灌注式血管网络是发展一切具有新陈代谢功能器官芯片的前提条件和重要环节。尤其是在抗肿瘤药物研发方面，亟需建立基于器官芯片的新型血管化肿瘤模型来提高药物筛选的可靠性及准确性。本项目将结合生物微机电系统、生物力学以及组织工程学等首先对三维可灌注式血管网络在多重可控微环境下的前期生成机制及后期重建机制展开全面系统的研究并提取关键参数，构建出具有特定器官微生理特性及新陈代谢功能的血管化器官芯片；在此基础上，进一步在血管化肿瘤芯片上通过模拟人体内肿瘤生长微环境来构建具有自身微循环系统的三维肿瘤血管新生模型，并进行抗肿瘤血管生成药物筛选试验以验证其有效性。项目的研究成果将会对血管化器官芯片尤其是新型血管化肿瘤芯片的发展提供重要的理论依据与技术支持，并可被用于血管疾病的病理研究、肿瘤血管生成机制研究以及抗肿瘤药物研发与临床应用中。

仿人体器官芯片作为一种有效的临床前药物筛选手段，对于加速药物研发周期及降低研发费用具有重要意义。面对抗肿瘤新药研发的巨大需求，亟需一种新型的体外肿瘤器官芯片模型来提高药物筛选的可靠性及准确性。本项目基于微流控和组织工程技术，首先实现了微流控器官芯片的制备及片上多重微环境的调控；然后开展并实现了最优微环境下的具有新陈代谢功能的三维血管化器官芯片构建、可灌注性测试及重建；进一步通过与肿瘤小球共培养实现了具有自身微循环系统的三维可灌注血管化肿瘤器官芯片；通过构建高通量药物筛选平台实现了FDA认证的抗肿瘤药物筛选的单盲测试，初步验证了该模型用于新型抗肿瘤药物筛选的可行性及有效性；最后为了进一步优化片上微环境调控及多器官芯片联用技术，分别实现了基于可恢复导流器的水凝胶空间分布、新型生物反应器以及基于通用标准化接口技术的模块化器官芯片。相关研究成果将为血管化器官芯片在药物研发和个性化/精准医疗应用提供重要的理论和技术支持。本项目的研究内容和预期目标均已实现，共发表SCI论文6篇（其中2篇发表在微流控领域TOP期刊Lab on a Chip），申报美国专利1项，开展国内外学术交流活动7次（其中2篇微流控领域顶级会议MicroTAS），培养硕士研究生5名。

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