Development of an Implantable Optical Glucose Sensor

糖尿病是一种慢性疾病，如果不加以控制，会引起血糖水平的大幅波动。为了维持正常的血糖水平，必须全天频繁监测血糖。在这项提议中，提出了一项计划，设计和开发新型植入式、荧光掺杂的皮内聚合物换能器，这种换能器将与光学探头相结合来量化血糖水平。目前，商业上只有有创的血糖监测仪，每一次读数都需要一根手指。在这项研究中，荧光标记的聚合物微球将以相当于纹身的方式注射到表皮下0.15 mm处。这项研究中使用的聚合物将由聚乙二醇(PEG)的交联水凝胶制成，该团队和其他团队已经在体内证明了这种水凝胶是稳定、无毒和无抗原性的。聚合物水凝胶微球的荧光强度与周围介质中的葡萄糖成正比，将由包含刀豆蛋白A(一种葡萄糖结合蛋白，简称ConA)荧光团和葡聚糖-荧光团的光聚合聚乙二醇制成。ConA和葡聚糖都将被绑在凝胶骨架上，以防止因淋失而导致的不稳定。在没有葡萄糖的情况下，ConA和葡聚糖是非共价结合的，导致葡聚糖荧光团的猝灭。在葡萄糖存在下，葡聚糖从ConA结合部位(与葡萄糖浓度成比例)置换，导致葡聚糖荧光团的荧光增强。当葡萄糖特异性荧光微球被注射到皮肤下150 mm处后，当被照亮时，它将扮演一个智能纹身的角色，并将以与微球周围组织液中葡萄糖浓度成正比的强度发光。为了获得通过皮肤的发射光，将在分析光在混浊介质中的传播的基础上设计、构造和优化光学传感器。该系统(由微球和光学传感器组成)最初将在测试单元中使用简单的葡萄糖溶液进行研究。然后，这些微球将在复杂的多种化学溶液中进行测试，然后在包裹着0.15毫米猪表皮的测试单元中进行多种化学溶液的测试，以努力在活体实验之前优化设计。最后，在非糖尿病动物和糖尿病动物身上的初步体内研究将使用无毛大鼠动物模型进行。将开发使用波长选择和偏最小二乘等技术的后处理算法，以提高测量的精度和灵敏度。与文献中报道的近红外光谱等其他非侵入性和非特异性的光学方法不同，由于微球荧光对葡萄糖的化学敏感性，该技术有望对葡萄糖浓度具有高度特异性。

9908439CoteDiabetes mellitus is a chronic disease that, if unregulated, can give rise to large fluctuations in blood glucose levels. In order to maintain normal glucose levels, blood glucose must be monitored frequently throughout the day. In this proposal a plan is forwarded to design and develop novel implantable, fluorescent-doped, intradermal polymer transducers that will be combined with an optical probe to quantify blood glucose levels.Currently, only invasive blood glucose monitors are commercially available, which require a finger stick for each reading. In this research, fluorescence-tagged polymer microspheres will be injected 0.15 mm below the epidermis in a manner equivalent to a tattoo. The polymers used in this research will be made from crosslinked hydrogels of poly(ethylene glycol) (PEG) which have been shown by this team and others to be stable, nontoxic, and non-antigenic in vivo. Polymer hydrogel microspheres that exhibit fluorescence intensity proportional to glucose in the surrounding media will be fabricated from photopolymerized PEG containing a concanavalin A (a glucose binding protein abbreviated ConA) fluorophore conjugate and a dextran-fluorophore conjugate. Both ConA and dextran will be tethered to the gel backbone to prevent instability due to leaching. In the absence of glucose, ConA and dextran are non-covalently bound, resulting in the quenching of the dextran fluorophore. In the presence of glucose, dextran is displaced from ConA binding sites (in proportion to the glucose concentration), resulting in an increase in the fluorescence of the dextran fluorophore. After implantation by injection 150 mm below the skin, the glucose specific fluorescent microspheres, when illuminated, will act as a "smart tattoo" and will emit light at an intensity proportional to the glucose concentration in the interstitial fluid surrounding the microspheres. To acquire the emitted light through the skin, an optical sensor will be designed, constructed and optimized based on analysis of light propagation through the turbid medium. The system (consisting of the microspheres and optical sensor) will initially be studied using simply glucose solution in a test cell. The microspheres will then be tested in a complex multi-chemical solution followed by a multi-chemical solution in a test cell wrapped in 0.15 mm of pig epidermis in an effort to optimize the design prior to in vivo experiments. Lastly preliminary in vivo studies in both non-diabetic and diabetic animals will be performed using a hairless rat animal model. Post-processing algorithms using techniques such as wavelength selection and PLS will be developed to improve accuracy and sensitivity of the measurement. Unlike other noninvasive and non-specific optical approaches such as near-infrared spectroscopy reported in the literature, this technique promises to be highly specific to the concentration of glucose because of the chemical sensitivity of microsphere fluorescence to glucose.