Macrophages and Biosensor Function in Vivo

描述(申请人提供)：糖尿病确实是一个“沉默的杀手”，它给美国和世界带来的人力和经济代价被大大低估。糖尿病的主要并发症包括心脏病、中风、高血压、肾病、失明、神经系统损伤和截肢。因此，糖尿病是美国第五大致死性疾病。仅在2007年，糖尿病就给美国造成了1,740亿美元的损失。预防或至少将糖尿病并发症降至最低的关键是血糖控制。植入式血糖传感器，包括基于传感器的闭环系统，在预防糖尿病的破坏性并发症和经济成本方面具有最大的希望。不幸的是，长期植入式葡萄糖传感器的发展在很大程度上受到植入式传感器生物污垢的阻碍，这些生物污垢是与传感器引发的异物反应相关的组织反应，包括炎症、纤维化和血管退化。包括巨噬细胞(MQS)、树突状细胞(DC)和多核巨细胞(GC)在内的单核细胞相关细胞(MRCs)在控制炎症、血管生成、纤维化和血管退行性变中的关键作用在各种疾病和植入性生物材料中得到了充分的证实。虽然已知在传感器植入部位存在MRCs，但这些细胞在直接控制传感器功能(传感器的生物污垢)和/或通过控制组织、反应(炎症、血管生成和纤维化)间接控制传感器功能中的作用仍有待剖析。本研究的目的不仅是确定巨噬细胞及其产物在体内传感器功能丧失中的作用，而且还旨在开发通过靶向传感器植入部位的巨噬细胞及其产物来延长体内葡萄糖传感器寿命的策略和工具。与公共健康相关：葡萄糖传感器被认为是糖尿病患者长期血糖管理的最大希望。不幸的是，目前的植入式葡萄糖传感器在传感器功能丧失之前只能持续几天，这在很大程度上是由于组织炎症。我们目前的建议集中在确定巨噬细胞在体内传感器功能丧失中的作用，巨噬细胞是一种关键的炎症细胞。这些研究结果不仅可能对巨噬细胞在体内葡萄糖传感中的作用提供新的理解，而且可能为在体内控制巨噬细胞和延长体内可植入传感器的寿命提供新的工具。

DESCRIPTION (provided by applicant): Diabetes is truly a "silent killer", whose human and economic costs to the U.S., and the world is vastly under-appreciated. Major complications of diabetes include heart disease, stroke, high blood pressure, kidney disease, blindness, nervous system damage, and amputations. As such, diabetes represents the fifth-deadliest disease in the United States. In 2007 alone, diabetes was estimated to cost the U.S. $174 billion dollars. The key to preventing or at least minimizing the complications of diabetes is glycemic control. Implantable glucose sensors, including sensor based closed loop systems, hold the greatest promise for preventing the devastating complications and economic costs of diabetes. Unfortunately, the development of long-term implantable glucose sensors has been hampered in large part by bio-fouling of the implanted sensor by the tissue reactions associated with sensor-induced "foreign body reactions", including inflammation, fibrosis and vessel regression. The key role of Monocyte Related Cells (MRCs) including macrophages (MQs), dendritic cells (DCs), and multi-nucleated giant cells (GCs) in controlling inflammation, angiogenesis, fibrosis and vessel regression in "foreign body reactions" is well established in a variety of diseases and implantable biomaterials. Although MRCs are known to be present at sites of sensor implantation, the roles of these cells in controlling sensor function directly (biofouling of sensor) and/or indirectly by controlling tissue, reactions (inflammation, angiogenesis and fibrosis) remain to be dissected. The goal of this research is not only to determine the contribution of MRCs and their products to the in vivo loss of sensor function, but also to develop strategies and tools that can extend glucose sensor lifespan in vivo by targeting macrophages and their products at sites of sensor implantation. PUBLIC HEALTH RELEVANCE: Glucose sensors are considered the greatest hope for long-term glucose management for patients with diabetes. Unfortunately, current implantable glucose sensors last for only a few days before sensor function is lost due in large part to tissue inflammation. Our present proposal is focused on determining the role of macrophages, a key inflammatory cell, in this lost of sensor function in vivo. The results of these studies will likely not only provide a new understanding of the role of macrophages in glucose sensing in vivo, but will likely give new tools to control macrophages in vivo and prolong implantable sensor lifespan in vivo.