基于金纳米簇和MEMS微针贴片的无痛响应型血糖调节体系研究

Diabetes is a critical medical challenge affecting all of the world. The insulin injection according to the glucose level is a key issue for the treatment of type 1 and advanced type 2 diabetes. In this study, based on gold nanoclusters (GNCs) and MEMS microneedle patches, we aim to develop a smart insulin releasing system responding to the surrounding glucose level. We choose GNCs as a novel carrier due to their high loading capacity of drugs. Then we decorate the GNCs with phenylboronic acid (PBA) or its derivatives, which serve as key switch factor for glucose-responsive insulin release. By optimizing the PBA molecules and reaction condition, we are able to develop glucose-responsive insulin releasing GNCs ,with strong specificity and high sensitivity to glucose. Moreover, using MEMS technology, we develop a microneedle patch containing the above responsive GNCs, which enables the painless puncture of skins and the in vivo drug release. In both in vitro condition and in vivo in the mouse model of type 1 diabetes, our system can effectively release insulin and regulate the glucose level according to the surrounding environment. This painless and responsive system can help the diagnosis and treatment of diabetes.

糖尿病是严重危害人类健康的重大慢性疾病。实时监测体内血糖水平、并适时注射胰岛素是有效控制1型糖尿病和中晚期2型糖尿病的关键。本项目拟研究一种对环境葡萄糖浓度响应并智能释放胰岛素的金纳米簇颗粒和MEMS微针贴片体系，用于无痛响应型血糖调节。我们拟选择具有高载药率的金纳米簇颗粒作为载体，并在其上修饰苯硼酸及其衍生物分子作为葡萄糖响应释放胰岛素的敏感开关因子。通过苯硼酸分子及反应条件优化，制备出对葡萄糖特异性反应灵敏度高、根据葡萄糖浓度快速响应释放胰岛素的金纳米簇颗粒。基于MEMS技术，进一步制备包载上述响应型金纳米簇颗粒的微针贴片，实现皮肤的无痛穿刺和体内智能响应释药。在体外和1型糖尿病模型小鼠中，实现体系根据环境葡萄糖浓度智能调节胰岛素释放、智能调节血糖水平。通过本项目的实施，发展一种无痛无创的智能血糖调节体系，并指导糖尿病的诊疗。

糖尿病是严重危害人类健康的重大慢性疾病，实时监测体内血糖、按需输注胰岛素是糖尿病治疗和管理的关键。本项目设计和开发了一系列葡萄糖响应性胰岛素释放的金纳米簇药物颗粒，用于体内血糖调节。进一步，基于MEMS模板翻模法或生物3D打印技术，制备了包载上述响应性金纳米簇药物颗粒的微针贴片。微针贴片实现了皮肤表面的微创穿刺，实现了体内响应性胰岛素释放和智能血糖调节。同时，我们设计和构建了葡萄糖响应性水凝胶和可穿戴传感器件，实现了微创、快速、可视化的葡萄糖传感和检测，并展示了葡萄糖响应性水凝胶在促进糖尿病伤口愈合方面的效果。通过本项目的实施，我们发展了微创、快速、可视化的葡萄糖传感技术，并实现了无痛响应性体内血糖调节，为糖尿病的临床检测和治疗提供了实验依据和理论参考，具有潜在的临床应用价值。基于本项目的研究，我们在Small Methods、Biosensors and Bioelectronics等高水平国际学术期刊发表论文11篇，撰写专著2章节；申请中国发明专利8项，其中授权5项，转让2项；参加国内外学术会议6次；培养博士研究生1名、硕士研究生9名。