Engineering a Cell-Based Glucose Monitor

设计基于细胞的血糖监测仪

• 批准号: 8633822
• 负责人: RICHARD T LEE
• 金额: $ 125万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633822
• 关键词: Animals; Artificial Pancreas; Autologous; Biosensor; Blood Glucose; Blood capillaries; Cells; Data; Detection; Development; Device Designs; Devices; Engineering; Face; Fluorescence; Gene Transfer; Genes; Glucose; Goals; Human; Hypoglycemia; Individual; Insulin; Insulin Infusion Systems; Insulin-Dependent Diabetes Mellitus; Knock-in Mouse; Laboratories; Light; Measurement; Measures; Modality; Monitor; Nature; Noise; Normal Range; Patients; Price; Protein Engineering; Proteins; Reporter; Signal Transduction; Skin; Solutions; Spectrum Analysis; System; Technology; Tertiary Protein Structure; Testing; Time; Translations; Work; base; blood glucose regulation; capillary; cellular engineering; clinically significant; design; design and construction; diabetes control; diabetic patient; extracellular; genotoxicity; glucose monitor; glucose sensor; high risk; improved; in vivo; miniaturize; novel; prevent; prototype; public health relevance; research study; response; sensor; sugar; type I diabetic

Devices for Continuous Glucose Monitoring have advanced over the past decade, but there is not yet a glucose monitoring system that provides the precision necessary for automated control of insulin delivery in diabetic patients. In particular, protecting patients against hypoglycemia could allow more aggressive insulin therapy and a closed-loop glucose control system could be enabled. Here we describe a novel biosensor Continuous Glucose Monitoring concept based on fluorescent protein engineering and exploiting glucose- responsive protein domains that already exist in nature. The ultimate goal of this project is to develop a Continuous Glucose Monitoring cell-based biosensor that can wirelessly transmit to the patient's insulin pump and control insulin delivery all day. There are three critical components of this Continuous Glucose Monitoring concept, and thus this project requires an interdisciplinary team working in concert. The first Aim of this project is to generate a high signal-to-noise genetically encoded fluorescence intensity sensor for glucose that will be suitable for the in vivo monitoring technology. We also need a device that can interpret the fluorescent intensity change in the skin and transmit to the insulin pump. Thus, the second Aim of this project is to develop and optimize a fluorescence measurement device for detection of the fluorescence change. We have already initiated design of this device, which we predict could be manufactured for a low price. Finally, we need to introduce the protein into the patient's skin, so that the new device can record the fluorescence change. Thus, the third Aim is to explore both gene transfer and autologous cell transfer experiments in order to deliver the fluorescent biosensor protein in a safe and practical manner. This is a critical and challenging goal, as successful translation will require that the system be stable and devoid of genotoxicity. Although our Continuous Glucose Monitoring concept is high risk and faces major challenges, a solution to the Continuous Glucose Monitoring problem would be of great clinical significance. Redundant monitoring systems may be necessary for optimal glucose control, and independent technologies may reduce the noise inherent in all of these monitoring technologies. For example, a cell-based system as described here could interface with a non-biological spectroscopic system to provide redundant signals for preventing hypoglycemia. Ultimately, a combined modality Continuous Glucose Monitoring biosensor in conjunction with an insulin pump could allow reliable closed-loop glucose control.

用于连续葡萄糖监测的设备在过去的十年中已经发展，但是还没有一个 葡萄糖监测系统，可提供自动控制胰岛素输送所需的精确度 糖尿病患者特别是，保护患者免受低血糖可能会允许更积极的胰岛素 治疗和闭环葡萄糖控制系统。在这里，我们描述了一种新型的生物传感器 基于荧光蛋白工程和利用葡萄糖的连续葡萄糖监测概念- 已经存在于自然界中的响应蛋白结构域。该项目的最终目标是开发一个 持续葡萄糖监测基于细胞的生物传感器，可以无线传输到患者的胰岛素泵 并全天控制胰岛素输注。动态葡萄糖监测有三个关键组成部分 因此，这个项目需要一个跨学科的团队协同工作。 本项目的第一个目的是产生一个高信噪比的基因编码 荧光强度传感器的葡萄糖，将适用于在体内监测技术。 我们还需要一种设备，可以解释皮肤中的荧光强度变化，并将其传输到胰岛素 泵 因此，本项目的第二个目的是开发和优化荧光测量 用于检测荧光变化的装置。我们已经开始设计这个装置， 预测可以以低廉的价格制造。最后，我们需要将蛋白质引入病人的皮肤， 这样新的装置就可以记录荧光的变化。 因此，第三个目的是探索基因转移和自体细胞转移实验， 以便以安全和实用的方式递送荧光生物传感器蛋白。这是一个关键的， 这是一个具有挑战性的目标，因为成功的翻译需要系统稳定且无遗传毒性。 尽管我们的动态葡萄糖监测概念具有高风险且面临重大挑战， 持续葡萄糖监测问题的解决方案将具有重要的临床意义。冗余 监测系统对于最佳血糖控制可能是必要的，独立技术可能会减少 所有这些监测技术中固有的噪音。例如，这里描述的基于小区的系统 可以与非生物光谱系统接口，以提供冗余信号， 低血糖最终，一种组合模态连续葡萄糖监测生物传感器， 与胰岛素泵结合可以实现可靠的闭环葡萄糖控制。