Needle-Implantable, Wireless Multi-Sensor for Continuous Glucose Monitoring

用于连续血糖监测的针植入式无线多传感器

• 批准号: 7808166
• 负责人: Syed K. Islam
• 金额: $ 45.71万
• 依托单位: BIORASIS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808166
• 关键词: Acetaminophen; Address; Animal Experimentation; Animals; Anoxia; Area; Artificial Pancreas; Ascorbic Acid; Attention; Back; Be++ element; Beryllium; Biocompatible; Biosensor; Blood Glucose; Blood Vessels; Body Fluids; Caring; Catalase A; Catheters; Cells; Cellular Phone; Chemicals; Code; Communication; Connecticut; Corrosion; Detection; Development; Devices; Dexamethasone; Diabetes Mellitus; Diet; Diffusion; Electrodes; Electronics; Elements; Ensure; Enzymes; Event; Excision; Exercise; Exercise Physiology; Exhibits; Feedback; Fibrosis; Fingers; Foreign Bodies; Frequencies; Future; Generations; Glucose; Growth Factor; Health; Hydrogels; Hydrogen Peroxide; Hypoxia; Image; Immune; Immune response; Implant; In Vitro; Individual; Inflammation; Insulin; Intellectual Property; Kidney Failure; Knowledge; Lead; Legal patent; Licensing; Light; Lighting; Link; Liquid substance; Logic; Marketing; Measures; Membrane; Methods; Microdialysis; Microspheres; Miniaturization; Modeling; Molecular Weight; Monitor; Monosaccharides; Mus; Nature; Needles; Obesity; Operative Surgical Procedures; Optics; Oxidation-Reduction; Oxygen; Patients; Performance; Personal Computers; Personal Digital Assistant; Pharmaceutical Preparations; Phase; Physicians' Offices; Physiologic pulse; Physiological; Physiology; Power Sources; Process; Radiation; Rattus; Reaction; Reading; Research; Research Design; Rest; Sensory; Side; Signal Transduction; Site; Skin; Source; Specificity; Staging; Tensile Strength; Testing; Time; Tissues; Universities; Uric Acid; Variant; Water; Wireless Technology; Work; Wrist; analytical method; angiogenesis; base; catalase; commercialization; cost; crosslink; diabetes management; diabetic; diabetic patient; digital; dosage; drug development; glucose monitor; glucose oxidase; glucose sensor; hypodermic needle; implantable device; implantation; improved; in vivo; millimeter; miniaturize; novel; open wound; oxidation; pre-clinical; prevent; public health relevance; research and development; response; seal; sensor; subcutaneous; sugar; tool

DESCRIPTION (provided by applicant): Background: Over the past five years, the University of Connecticut together with its start-up spin-off corporation (Biorasis Inc.) has been developing a totally implantable biosensor platform (0.5 mm x 0.5 mm x 5 mm) capable of continuously monitoring glucose. The underlying principle in developing this miniaturized sensor hinges on extreme miniaturization utilizing light, both as a powering source and a communication link. Such implant size reduction results in minimal tissue damage during implantation. The localized release of various tissue response modifiers has also afforded effective inflammation control and fibrosis suppression along with neo-angiogenesis. While significant progress has been achieved in the electrochemical determination of D-glucose using the highly-specific glucose oxidase enzyme, changes in user physiology (i.e. exercise, irregular homeostatis, anoxia/hypoxia, diet etc.) contribute to interferences that lower sensor accuracy. Objective/Hypothesis: By outfitting our implantable glucose sensing platform with two additional sensing elements capable of independently assessing oxygen and various interfering agent levels, the accuracy and reliability of glucose detection can be significantly improved, which will take us, a step closer to developing a closed-loop artificial pancreas. Study Design: We propose to develop a low-bias glucose+O2 sensing element (which is devoid of interference from endogenous redox-active species) and integrate it with two other (already-developed) sensing elements to accurately determine subcutaneous glucose concentrations irrespective of user physiology. This will be accomplished by outfitting the implantable platform with two additional potentiostats and an optically-coded, sensor-select circuit to sequentially interrogate each of the three sensing elements. All sensing elements and associated electrical and optical components will be integrated in a compact unit (0.75 x 0.75 x 9 mm) that is hermetically sealed against body fluids to enable long-term in vivo operation. This will be augmented by the respective optimization of the biocompatible sensor coatings to address the slightly enlarged sensor size, and develop in vitro release testing methods necessary for future FDA filing. Phase-II will focus on: (i) reducing the size of the multi-sensor unit, (ii) optimizing device assembly, and (iii) conducting extensive preclinical animal studies along with developing appropriate analytical methods necessary for FDA filing. Relevance: In view of the growing number of diabetics worldwide, there is a tremendous need for devices that provide accurate detection of glucose levels. In lieu of the difficulties associated with glucose monitoring using non-invasive methods, extreme miniaturization of a totally implantable device together with assured accuracy and long-term operation, present a viable alternative. The proposed multi-sensor platform addresses miniaturization and accurate glucose readings. In addition, the wireless communication and prolonged lifetime render it an effective device for diabetic care as well as a powerful tool for testing new drugs in small animals. PUBLIC HEALTH RELEVANCE: The increasing occurrence of diabetes (ca. 23.6 and 189 million diabetic patients in US and rest of the world, respectively) poses a serious health problem, especially when associated with obesity, renal failure and other serious conditions. Continuous glucose monitoring will provide the necessary warning to prevent hypo- and hyper-glycemic events as well as to minimize fluctuations in glucose levels that would otherwise lead to many debilitating complications associated with diabetes. Currently, there is no totally implantable device for continuous glucose monitoring available on the market. Therefore, diabetics must rely on either finger pricking (approximately five times per day) or microprobe, skin-penetrating devices that need to be replaced every 3-7 days due to their open-wound nature and associated negative tissue responses. A reliable, long-term, continuous monitoring is expected to provide the necessary corrective feedback to the patient so that together with appropriate insulin delivery, an effective sugar-level management can be attained to prevent hypo- and hyper-glycemic events. The proposed research intends to realize the first generation of a low-cost, miniaturized, implantable sensor that can continuously and accurately monitor blood glucose levels over a period of one month. This implantable sensor will establish a wireless link to a wrist-watch-like communicator capable of interacting with various digital accessories (such as, personal digital assistants, cell phones and personal computers). The implanted device can be inserted under the skin and similarly removed via a needle, thus avoiding the need for surgical implantation and removal. Another important feature of this sensor is its ability to delineate interferences and accurately obtain glucose levels, independent of user physiology (exercise, irregular homeostatis, anoxia/hypoxia, diet etc.). The miniaturized size of this sensory platform has immediate applicability not only in diabetes management, but also to diabetes research, where the ability of obtaining continuous glucose monitoring of the smallest research animals (i.e. mice, rats) will provide an invaluable tool in diabetes drug development.

描述（由申请人提供）： 背景：在过去五年中，康涅狄格大学及其初创分拆公司（Biorasis Inc.）一直在开发一种完全植入式生物传感器平台（0.5 mm x 0.5 mm x 5 mm) 能够连续监测血糖。开发这种小型化传感器的基本原理取决于利用光作为电源和通信链路的极端小型化。这种植入物尺寸的减小导致植入期间最小的组织损伤。各种组织反应调节剂的局部释放还提供了有效的炎症控制和纤维化抑制以及新血管生成。虽然使用高特异性葡萄糖氧化酶电化学测定 D-葡萄糖方面已经取得了重大进展，但用户生理的变化（即运动、不规则体内平衡、缺氧/缺氧、饮食等）会造成干扰，从而降低传感器精度。 目的/假设：通过为我们的植入式葡萄糖传感平台配备两个能够独立评估氧气和各种干扰剂水平的附加传感元件，可以显着提高葡萄糖检测的准确性和可靠性，这将使我们向开发闭环人工胰腺。 研究设计：我们建议开发一种低偏置葡萄糖+O2 传感元件（不受内源性氧化还原活性物质的干扰），并将其与其他两个（已开发的）传感元件集成，以准确确定皮下葡萄糖浓度，而不受内源性氧化还原活性物质的干扰。用户生理学。这将通过为植入式平台配备两个额外的恒电位仪和一个光学编码的传感器选择电路来顺序询问三个传感元件中的每一个来实现。所有传感元件以及相关的电气和光学组件将集成在一个紧凑的单元（0.75 x 0.75 x 9 mm）中，该单元密封地防止体液接触，以实现长期体内操作。这将通过生物相容性传感器涂层的相应优化来增强，以解决传感器尺寸略有增大的问题，并开发未来 FDA 备案所需的体外释放测试方法。第二阶段将重点关注：(i) 减小多传感器单元的尺寸，(ii) 优化设备组装，以及 (iii) 进行广泛的临床前动物研究，并开发 FDA 备案所需的适当分析方法。 相关性：鉴于全球糖尿病患者数量不断增加，对能够准确检测血糖水平的设备有着巨大的需求。为了解决使用非侵入性方法监测血糖的困难，完全植入式设备的极度小型化以及有保证的准确性和长期运行，提供了一种可行的替代方案。所提出的多传感器平台解决了小型化和精确葡萄糖读数的问题。此外，无线通信和延长的使用寿命使其成为糖尿病护理的有效设备以及在小动物身上测试新药的强大工具。 公共健康相关性：糖尿病发病率的增加（美国和世界其他地区分别有约 23.6 名和 1.89 亿糖尿病患者）带来了严重的健康问题，特别是与肥胖、肾衰竭和其他严重疾病相关时。连续血糖监测将提供必要的警告，以防止低血糖和高血糖事件，并最大限度地减少血糖水平的波动，否则会导致许多与糖尿病相关的衰弱并发症。目前，市场上还没有完全植入式的连续血糖监测设备。因此，糖尿病患者必须依靠手指刺扎（每天大约五次）或微探针、皮肤穿透装置，由于其开放性伤口性质和相关的负面组织反应，需要每 3-7 天更换一次。可靠、长期、连续的监测有望为患者提供必要的纠正反馈，以便与适当的胰岛素输送一起，实现有效的血糖水平管理，以预防低血糖和高血糖事件。 拟议的研究旨在实现第一代低成本、小型化、植入式传感器，可以在一个月内连续、准确地监测血糖水平。这种植入式传感器将与类似手表的通信器建立无线链接，能够与各种数字配件（例如个人数字助理、手机和个人电脑）进行交互。植入的装置可以插入皮下并类似地通过针取出，从而避免了手术植入和取出的需要。该传感器的另一个重要特征是它能够描绘干扰并准确获取血糖水平，而不受用户生理状况（运动、不规则体内平衡、缺氧/缺氧、饮食等）的影响。该传感平台的小型化尺寸不仅可立即应用于糖尿病管理，而且还可用于糖尿病研究，其中对最小研究动物（即小鼠、大鼠）进行连续血糖监测的能力将为糖尿病药物开发提供宝贵的工具。