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

用于人工胰腺的长期非酶葡萄糖传感器

• 批准号: 8931206
• 负责人: Natalie Ann Wisniewski
• 金额: $ 2.68万
• 依托单位: PROFUSA, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8931206
• 关键词: Adoption; Affect; Aging; Antioxidants; Area; Artificial Pancreas; Blood capillaries; Boronic Acids; Cells; Characteristics; Chemistry; Chronic Disease; Clinical; Detection; Development; Devices; Diabetes Mellitus; Dyes; Educational workshop; Electronics; Expenditure; Failure; Family suidae; Fibrosis; Film; Fluorescence; Foreign Bodies; Fright; Glucose; Goals; Hand; Health; Healthcare; Healthcare Systems; Hydrogels; Hydrogen Peroxide; Immune; Immune response; Implant; Inflammation; Injectable; Insulin Infusion Systems; Life; Longevity; Marketing; Methods; Modality; Modeling; Monitor; Nanosphere; Nanotechnology; Nature; Optical Readers; Optics; Oxygen; Performance; Phase; Physiological; Plastics; Platinum; Polymers; Proteins; Pump; Reporter; Research; Signal Transduction; Simulate; Skin; Small Business Innovation Research Grant; Solid; Solutions; Stabilizing Agents; Surface; Syringes; System; Technology; Testing; Time; Tissues; United States National Institutes of Health; Variant; Vertebral column; Water; Work; base; burden of illness; capillary; capsule; catalase; commercial application; cost; design; diabetes management; diabetic patient; glucose monitor; glucose sensor; hard metal; implantable device; improved; in vivo; interstitial; luminescence; minimally invasive; nanoparticle; nanosized; novel; optical sensor; oxidation; porous hydrogel; pre-clinical; prototype; response; scaffold; sensor; skin patch; technological innovation

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.

描述（由申请人提供）：尽管经过多年的开发，目前可用的连续葡萄糖监测仪（CGMs）仍然缺乏良好的准确性和可靠性，无法在糖尿病管理中短期使用，特别是长期使用。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CGM的主要障碍是传感化学和身体对传感器的免疫反应的不稳定性-特别是异物反应（FBR）-导致生物淤积、炎症、无血管纤维化和传感化学降解。此外，目前市场上和开发中的CGM系统要么是笨重的经皮探头，要么是包裹在硬金属或塑料中的可植入装置，随着时间的推移，这些硬金属或塑料会被无血管组织囊包围或被免疫细胞吸收（如果是纳米尺寸）。在这个I期SBIR中，我们建议证明使用我们的新型组织整合“智能”水凝胶生产的微创，长期，非酶葡萄糖传感器的可行性，这些水凝胶成为它们感测的组织的一部分，以克服FBR。“智能”水凝胶的近红外（NIR）荧光基于葡萄糖浓度调节，并且通过皮肤非侵入性地检测。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性质提供了超过1000倍的传感器表面积的精密毛细管接近性，从而克服了FBR并提高了葡萄糖检测的准确性和寿命。申报的CGM系统在体内不包含植入式电子设备或硬件。外部光学读取器基于NIR光学信号的变化经皮监测间质葡萄糖。光学阅读器采用薄膜微光学皮肤贴片或手持棒的形式。PROFUSA的长期目标是开发一种自校准、可注射、软水凝胶CGM，其最短使用寿命为3个月，长期目标为12个月，具有足够的准确性，以实现人工胰腺。此外，由于该技术的平台性质，还可以将对其他分析物（例如氧、乳酸盐）具有特异性的感测纳米球并入水凝胶基质中。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，并提供优于固体，非组织集成传感器的传感性能。本提案的总体重点是延长荧光传感化学的寿命，以匹配体内水凝胶平台的观察寿命。将采用多种基于纳米技术的稳定剂。我们将评估葡萄糖传感器的性能与和没有铂纳米球，过氧化氢酶和其他抗氧化剂随着时间的推移。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H2 O2暴露条件下，1个月内灵敏度最多损失5%。荧光组织整合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。

项目成果

Design and biofabrication of dermal regeneration scaffolds: role of oligomeric collagen fibril density and architecture.

• DOI: 10.2217/rme-2019-0084
• 发表时间: 2020-02
• 期刊: Regenerative medicine
• 影响因子: 2.7
• 作者: David O. Sohutskay;Kevin P Buno;S. Tholpady;Samantha J Nier;S. Voytik-Harbin