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

描述（由申请人提供）：背景：在过去的五年里，康涅狄格大学连同其初创分拆公司（Biorasis Inc.）一直在开发一种完全可植入的生物传感器平台（0.5 mm x 0.5 mm x 5 mm），能够连续监测葡萄糖。开发这种微型传感器的基本原理在于利用光作为电源和通信链路的极端微型化。这种植入物尺寸减小导致植入期间的最小组织损伤。各种组织反应调节剂的局部释放也提供了有效的炎症控制和纤维化抑制沿着新血管生成。虽然在使用高度特异性的葡萄糖氧化酶的D-葡萄糖的电化学测定中已经取得了显著的进展，但是用户生理学的变化（即，运动、不规则的体内平衡、缺氧/低氧、饮食等）仍然存在。导致干扰，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额外传感元件，可以显着提高葡萄糖检测的准确性和可靠性，这将使我们更接近开发闭环人工胰腺。 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），并将其与其他两种（已经开发的）传感元件集成，以准确确定皮下葡萄糖浓度，而不考虑用户生理学。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实现，以依次询问三个传感元件中的每一个。所有传感元件和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，该单元对体液进行密封，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，以解决略微增大的传感器尺寸，并开发未来FDA备案所需的体外释放测试方法。第二阶段将侧重于：（i）减小多传感器单元的尺寸，（ii）优化装置组装，以及（iii）进行广泛的临床前动物研究，沿着开发FDA备案所需的适当分析方法。 相关性：鉴于全世界糖尿病患者数量的增长，对提供葡萄糖水平的准确检测的设备存在巨大的需求。代替与使用非侵入性方法的葡萄糖监测相关的困难，完全植入式设备的极端小型化以及有保证的准确性和长期操作，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准确的葡萄糖读数。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中测试新药的强大工具。 公共卫生相关性：糖尿病发病率的增加（约。23.6和1.89亿糖尿病患者）构成严重的健康问题，尤其是当与肥胖、肾衰竭和其它严重病症相关时。动态血糖监测将提供必要的警告，以防止低血糖和高血糖事件，并尽量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，市场上还没有完全可植入的连续葡萄糖监测设备。因此，糖尿病患者必须依靠手指针刺（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。预期可靠、长期、连续的监测将向患者提供必要的校正反馈，以便与适当的胰岛素输送一起，可以实现有效的糖水平管理以防止低血糖和高血糖事件。 这项研究旨在实现第一代低成本、小型化、可植入的传感器，该传感器可以在一个月内连续准确地监测血糖水平。这种可植入的传感器将建立与手表式通信器的无线链路，该通信器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肤下，并且类似地通过针移除，从而避免了手术植入和移除的需要。该传感器的另一个重要特征是能够描绘干扰并准确获得葡萄糖水平，与用户生理学（运动、不规则稳态、缺氧/低氧、饮食等）无关。这种传感平台的小型化尺寸不仅在糖尿病管理中具有直接的适用性，而且在糖尿病研究中也具有直接的适用性，其中获得最小研究动物（即小鼠、大鼠）的连续葡萄糖监测的能力将在糖尿病药物开发中提供无价的工具。

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.