用于长期可植入式葡萄糖传感器材料的生物相容性改性研究

Diabetes mellitus becomes the third threat to public health worldwide. Continuous glucose monitoring systems (CGMS) provide real-time information of glucose changes and thus improve the life quality of diabetic patients. However, up till now, there is a tremendous lack of long-term, implanted glucose sensors for CGMS, mainly due to the poor biocompatibility of implanted sensors which further hampers the long-term sensor performance. Thus, it is critical to develop biocompatible materials for glucose sensors for future development of CGMS. Here in this work, we focus on the surface modification and biocompatibility of key sensing area of implanted glucose sensors. We modify the outer membrane (polyurethane, polyvinyl alcohol) by doping anti-inflammatory dexamethasone, angiogenic SVVYGLR peptide and NO-releasing materials, by applying the concept of “active release materials”, as well as by conjugation with nanoparticulate system which enable controlled drug releases. We aim to understanding the effects of different surface modifications onto the biocompatibility of glucose sensors from both in vitro and in vivo evaluation, thus to develop a long-term biocompatible glucose sensor with miniaturized foreign body responses and improved tissue integration, and thus to improve the in vivo glucose sensor performance for extended periods (from days to at least weeks). This project will lead to the development and application of biocompatible materials for CGMS.

糖尿病是目前世界范围内危害人类健康的第三大疾病，动态血糖监测系统(CGMS)能极大改善糖尿病患者的生活质量。然而，到目前为止，用于CGMS的长期植入式葡萄糖传感器仍然缺乏，其关键原因是植入后传感器的生物相容性不佳而导致传感器性能下降造成的。因此，提高葡萄糖传感器表面的生物相容性，对动态血糖监测系统的发展和应用至关重要。本项目中，我们拟针对传感器的关键传感区进行材料表面修饰和改性。在外膜材料（聚氨酯，聚乙烯醇等）中掺杂修饰抗炎药物地塞米松、促血管生成肽SVVYGLR和NO释放材料，采用“主动释放药物”的概念，并结合现代纳米技术实现药物控释和缓释，通过体外、体内实验研究不同改性对传感器/组织界面的影响，减少传感器表面的异物反应、增加传感器生物相容性，从而提高葡萄糖传感器在体内的传感性能和长期使用寿命(数天至数周)。为发展长期动态血糖监测系统提供理论和技术的创新性支持。

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糖尿病的关键。动态血糖监测系统(CGMS)能实时提供体内的血糖数据，但由于CGMS传感器生物相容性不佳，导致传感器长期功能下降。我们对传感器表面进行改性来提高其生物相容性。我们在外膜材料（聚乙烯醇水凝胶）中添加铁蛋白纳米载药颗粒，并在纳米颗粒中包载抗炎药物地塞米松、促血管生成肽SVVYGLR等。纳米载药颗粒根据传感器植入后的炎症反应智能释放药物。改性涂层提高了葡萄糖传感器的体内生物相容性，减少其表面的异物反应；并提高了葡萄糖传感器的体内传感性能和长期使用寿命。然后，我们构建了响应型血糖调节的金纳米簇颗粒体系。我们制备了具有高载药率的金纳米簇颗粒，并在其上修饰苯硼酸分子作为葡萄糖响应的敏感开关因子，制备根据葡萄糖浓度快速、响应释放胰岛素的金纳米簇颗粒体系。在体外和1型糖尿病小鼠中，该体系能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，我们实现了血糖的长期动态监测与血糖的智能调节，可用于指导糖尿病诊疗。