连续血糖监测用微纳传感器的构建及其失效机理研究

Traditional glucometer can not meet the medical need for continuous glucose monitoring (CGM), and the life-time of current products, which proved by FDA, in the market for CGM are less than one week. It has great social and economical impact to develop long-term minimally-invasive implantable glucose sensor, as the rapid increment of diabetic patients in China. Based on the micro-/nano- electrodes developed in my group, this project plans to improve electrochemical activity of electrodes by in-situ coating with noble metal nano- particles. It leads to a direct electron transfer between electrodes and glucose oxidase. A new biocompatible multi-layer membrane, including semi-permeable membrane, polyelectrolyte membrane and hydrogel with interpenetrating polymer network (IPN), were firstly suggested in this project. Transportation mechanism for glucose in each porous membrane, and the trend between molecular diffusion and membrane microstructure will be thoroughly discussed. Moreover, this project aims to evaluate the body response for implanted sensors, discuss the effect of IPN structure, functional groups etc., on the formation of fibrous capsule and biofouling, establish the difussion model between microstuture of fibrous capsule and glucose molecular. It thus clarifies failure mechanism for implanted sensor, and is able to evaluate the lift-time of an implanted sensor. Furthermore, the project plans to develop an integrated sensing system, which includes a tiny potentiostat, wirless data collecting system and hand-held receiver. Finally, a minimally-invasive implantable biosensor and integrated system will be developed, which is able to continuous monitor glucose for two months.

传统掌上血糖仪不能满足血糖动态监测的医疗需求，经FDA认证的几款植入传感器工作寿命低于1周，在中国糖尿病患者急速增加的今天，开发长效微创型植入式葡萄糖传感器有着重大的社会意义和经济效应。本项目将在课题组已有微纳电极的基础上，通过原位担载贵金属活性位点来促使电极与葡萄糖氧化酶之间产生直接电子传递。采用多层结构保护膜，包括半透膜、聚电解质复合膜和水凝胶层，探讨葡萄糖分子在各层膜材料中的输运机制，揭示分子扩散与膜材料微结构之间关联规律。通过动物实验评价器件植入后的机体反应，考察网络互穿结构、亲水官能团等参数对纤维包膜和蛋白质淤积的影响，建立纤维包膜厚度及形貌与葡萄糖分子输运之间扩散模型，阐明传感器植入后的失效机理从而能够预测传感器寿命。开发并集成传感器系统，包括微型电化学工作站、无线数据采集系统以及手持式接收处理盒等模块。通过本项目，有望制备出可持续监测2个月的微创型植入式葡萄糖传感器及其系统。

糖尿病作为健康的一个隐形杀手，是目前世界上患者最多的疾病之一，研究重症糖尿病患者用血糖传感器相关材料与器件有非常重要的应用价值。本项目首先制备出3种无酶/拟酶传感器：(1) 铜-钯双金属无酶传感器；(2) Pd修饰石墨烯纸基柔性传感器；(3) Pt修饰r-GO/Fe3O4传感器；重点考察还原石墨烯及其柔性石墨烯纸改性后的传感器性能，其中贵金属纳米粒子在还原石墨烯表面及石墨烯层间的沉积对传感性能的提升起到关键作用。研究同时表明Cu、Pd双金属的协同效应可减小Cu在电催化过程中的反应中间体引起的中毒效应。其次，用聚乙烯醇物理凝胶包封结构均匀的光子晶体，并用4-醛基苯硼酸(4-BBA)修饰形成具有葡萄糖响应的凝胶光子晶体，并创新性地嵌入亲水性角膜接触镜，用于糖尿病性视网膜病变的泪糖无创检测。研究结果表明该光子晶体传感器可以在葡萄糖STF溶液内线性检测0.1-0.6 mM，其检测灵敏度为41.83 nm/mM，检测极限为0.01 mM。第三，在植入器件研究中，我们选取螺旋型铂铱合金电极设计，旨在提高植入式器件的葡萄糖氧化酶担载量，并因此减少过氧化氢的聚集对氧化酶的毒害作用；研究表明调节酶配方、涂覆厚度及PVA与PEG的比例，可以有效调控膜尺寸，对于葡萄糖分子的输运起到重要作用，从而将灵敏度控制在10 - 30 nA/mM之间。选用半壁针植入方式可有效降低传感器植入后感染及血液对器件性能的影响，植入涂覆2 μL半透膜的传感器可以稳定工作2周，灵敏度增幅为31.3%。此外，利用微电流检测技术，结合低功耗和低电源电压设计，制备出一套小型化，可长期随身携带与使用的无线血糖监测系统。项目研究按照计划顺利进行，圆满完成了各项研究任务，全面达到指标要求。研究成果发表学术论文28篇，其中SCI收录22篇，授权发明专利5项。本项目研究不同类型传感器材料与器件，重点用于糖尿病监测用植入传感及泪糖传感器，同时也考察新型的核酸适配体传感器、低功耗气体传感器，为我国功能纳米电子器件及新型传感器的研制和发展提供有力的支撑。