Biosensor Biocompatibility

描述(申请人提供)：今天有1800多万美国人患有胰岛素依赖型II型糖尿病。据估计，一半的II型糖尿病患者不能或不愿意使用标准的手指棒疗法来适当地调节自己的血糖。这些人中的许多人将从留置、闭合环路胰岛素输送装置中受益匪浅，例如使用传感器持续监测血液或间质液体中的血糖水平的人工胰腺。尽管有几个小组报告了生物传感器在体内成功工作了几周到几个月，但似乎没有一种葡萄糖传感器能够可靠和可预测地在长期植入后存活下来。因此，所有FDA批准的葡萄糖传感器都被认为只适用于急性应用。假设：我们的总体假设是，应用长期留置葡萄糖传感器的最后一个障碍是伤口愈合引起的传感器故障。我们通过设计和表征膜修饰和局部释放策略来解决这一假设，这些策略(1)抵抗生物污染，(2)减轻炎症，(3)减少纤维组织，(4)促进周围伤口愈合组织的血管形成，将葡萄糖通过感应膜的障碍降至最低。这种竞争更新分为转化性目标和试验性目标。翻译目标是将前一个资金周期中开发的地塞米松、血管内皮生长因子和质构策略应用于FDA批准的美敦力糖尿病SOF-SENSORTM血糖传感器。这将包括植入完整的组织，以及首次使用背部经皮窗口大鼠模型来直接观察皮下植入传感器附近的组织结构的演变。实验目标还检查了使用种子脂肪来源干细胞(ASC)在植入传感器周围的组织中中介炎症和促进血管形成的仿生策略。在每种情况下，来自窗口腔图像和实时传感器响应的实验结果将使用传感器表面与血液中携带的葡萄糖的灌流的传输模型进行基准测试。一个更精确的模型将被用来预测微血管密度、纤维包裹和生物污垢对观察到的传感器响应的预期影响。与公共健康相关：该项目解决了长期留置葡萄糖传感器应用的最后一个障碍--传感器无法可靠和可预测地在长期植入后存活。

DESCRIPTION (provided by applicant): More than 18 million Americans suffer today from insulin-dependent, type II diabetes. It is estimated that half of type II diabetics are unable or unwilling to properly gluco-regulate themselves using the standard finger stick regimen. Many of these people would benefit greatly from an indwelling, closed loop insulin delivery device, e.g. the artificial pancreas that employs a sensor to continuously monitor glucose levels in either blood or interstitial fluid. Although several groups have reported biosensors that have successfully functioned for weeks to months in vivo, no glucose sensor appears capable of reliably and predictably surviving long-term implantation. Consequently, all FDA-approved glucose sensors are deemed suitable for acute applications only. Hypothesis: Our global hypothesis is that the last remaining barrier to the application long-term indwelling of glucose sensors is surviving wound-healing mediated sensor failure. We address this hypothesis by devising and characterizing membrane modifications and local release strategies that (1) resist biofouling, (2) attenuate inflammation, (3) reduce the fibrosity and (4) promote vascularity of the surrounding wound healing tissue will minimize impediments to glucose transport across the sensor membrane. This competitive renewal is divided into translational and experimental objectives. The translational objective is the application of dexamethasone, VEGF and texturing strategies developed in the previous funding cycle to FDA-approved Medtronic Diabetes SOF-SENSORTM glucose sensors. This will include implantation in intact tissue, as well as the first-time use of a dorsal transcutaneous window chamber rat model to directly observe the evolution of tissue architecture in the vicinity immediately adjacent to a subcutaneously implanted sensor. The experimental objectives also examine biomimetic strategies that employ seeded adipose-derived stems cells (ASC) for mediating inflammation and promoting vessel formation in the tissue surrounding implanted sensors. In each case, the experimental results from the window chamber images and the live senor responses will be benchmarked using transport modeling of perfusion of the sensor surface with blood borne glucose. A more precise model will be used to predict the anticipated affects of microvessel density, fibrous encapsulation, and biofouling on the observed sensor response. PUBLIC HEALTH RELEVANCE: This project addresses the last remaining barrier to the application long-term indwelling of glucose sensors - the inability of sensors to reliably and predictably survive long- term implantation.