Long-Term Non-Enzymatic Glucose Sensors for an Artificial Pancreas

描述（由申请人提供）：尽管多年的发展，目前可用的连续血糖监测仪（cgm）仍然缺乏良好的准确性和可靠性，短期，特别是长期用于糖尿病管理。虽然胰岛素泵工作良好，但CGM仍然是关闭人工胰腺循环的最大障碍。实现长期、准确的CGM的主要障碍是传感化学的不稳定性和人体对传感器的免疫反应-特别是异物反应(FBR) -导致生物污垢、炎症、无血管纤维化和传感化学降解。此外，目前市场上和正在开发的CGM系统要么是体积庞大的经皮探针，要么是包裹在硬金属或塑料中的植入式装置，随着时间的推移，它们被无血管组织胶囊包围，要么被免疫细胞吸收（如果是纳米级的）。在第一阶段的SBIR中，我们将展示一种微创的、长期的、无酶的葡萄糖传感器的可行性，该传感器使用我们的新型、组织集成的“智能”水凝胶生产，这种水凝胶成为它们所感知组织的一部分，以克服FBR。“智能”水凝胶的近红外（NIR）荧光根据葡萄糖浓度进行调节，并且可以通过皮肤进行非侵入性检测。与传统电化学传感器相比，这些水凝胶传感器的长期血管化特性提供了精致的毛细管接近性，其传感器表面积超过1000倍，从而克服了FBR，提高了葡萄糖检测的准确性和寿命。提出的CGM系统不包含植入体内的电子设备或硬件。外部光学读取器根据近红外光信号的变化透皮监测间质葡萄糖。光学读取器采用薄膜微光学皮肤贴片或手持魔杖的形式。PROFUSA的长期目标是开发一种自校准、可注射的软水凝胶CGM，其最低使用寿命为3个月，长期目标为12个月，具有足够的精度，可用于人工胰腺。此外，由于该技术的平台性质，对其他分析物（如氧气、乳酸盐）特定的传感纳米球也可以掺入水凝胶基质中。PROFUSA的组织集成传感器平台已被证明在体内稳定数月至数年，并且与固体非组织集成传感器相比，具有优越的传感性能。本提案的总体重点是延长荧光传感化学的寿命，以匹配观察到的体内水凝胶平台的寿命。多种基于纳米技术的稳定剂将被使用。随着时间的推移，我们将评估有无铂纳米球、过氧化氢酶和其他抗氧化剂的葡萄糖传感器的性能。最终目标是在3个月内实现稳定的传感器响应，在加速老化条件和H2O2暴露下，1个月内灵敏度损失最大5%。荧光组织集成传感器的改进有望为糖尿病管理和健康监测开辟一种全新的传感模式。

DESCRIPTION (provided by applicant): Despite years of development, currently available continuous glucose monitors (CGMs) still lack good accuracy and reliability for short-term and particularly, long-term use in diabetes management. While insulin pumps work well, CGM remains the single largest hurdle to closing the loop of an artificial pancreas. The main obstacles to achieving a long-term, accurate CGM are instabilities in the sensing chemistry and the body's immune response against the sensor - specifically the foreign body response (FBR) - leading to biofouling, inflammation, avascular fibrosis and sensing chemistry degradation. Additionally, current CGM systems in the market and under development are either bulky percutaneous probes or implantable devices encased in hard metals or plastics that become surrounded by an avascular tissue capsule over time or are taken up by immune cells (if nano-sized). In this Phase I SBIR, we propose to demonstrate the feasibility of a minimally invasive, long-term, non-enzymatic glucose sensor produced using our novel, tissue-integrating "smart" hydrogels that become part of the tissue they are sensing to overcome the FBR. The near infra-red (NIR) fluorescence of the "smart" hydrogel modulates based on the glucose concentration and is detected non- invasively through the skin. The long-term, vascularizing nature of these hydrogel sensors provides exquisite capillary proximity to more than 1000 times greater sensor surface area compared to traditional electrochemical sensors, thereby overcoming the FBR and enhancing accuracy and longevity of glucose detection. The proposed CGM system contains no implanted electronics or hardware in the body. An external optical reader monitors interstitial glucose transdermally based on changes in the NIR optical signal. The optical reader takes the form of a thin-film micro-optical skin patch or a hand-held wand. PROFUSA's long- term goal is to develop a self-calibrating, injectable, soft hydrogel CGM with a minimum operational life of 3 months and a longer-term goal of 12 months with sufficient accuracy to enable an artificial pancreas. Moreover, because of the platform-nature of this technology, sensing nanospheres specific to other analytes (e.g. oxygen, lactate) can also be incorporated within the hydrogel matrix. PROFUSA's tissue-integrating sensor platform has been demonstrated to be stable in the body for months to years and to provide superior sensing performance compared to solid, non-tissue integrating sensors. The overall focus in this proposal is to extend the longevity of fluorescent sensing chemistry to match the observed longevity of the in vivo hydrogel platform. Multiple nanotechnology-based stabilizing agents will be employed. We will evaluate the glucose sensor performance with and without platinum nanospheres, catalase and other antioxidants over time. The ultimate objective is to achieve stable sensor response over 3 months with a maximum 5% loss in sensitivity over 1 month in accelerated aging conditions and H2O2 exposure. Refinement of fluorescent tissue-intergrating sensors promises to open a whole new sensing modality for diabetes management and health monitoring.