Modulating and Monitoring the Foreign Body Response to Implants

项目总结/摘要 临床意义所有植入的材料都会引发免疫反应， 异物反应这种异物反应通常会导致植入物周围的纤维化。为 植入物，如葡萄糖传感器，纤维化是限制电流的主要原因之一 FDA批准的植入式葡萄糖传感器的临床决策时间为5至7天（例如，注入 胰岛素或消耗碳水化合物）。据信大分子提供了 引导导致植入物纤维化的异物反应的生物活性分子线索。 我们的假设是，将巨噬细胞的极化导向伤口愈合M2c， 表型将促进愈合和组织整合，而没有过度的纤维化或炎症。 这项工作的完成将提供重要的体内生物活性剂途径信息， 创建和快速评估新的和改进的生物工程方法，以减少或消除 与异物反应有关的纤维化此外，这些研究将提供 关于细胞因子途径的重要定量分子信息在 改变巨噬细胞表型的有效方法。 实验方法。微透析取样探头将用作葡萄糖传感器 模拟物可同时递送旨在改变巨噬细胞表型的介质， 对大鼠中植入物/组织界面处产生的生物活性细胞因子进行取样。这种方法 将允许快速测试不同的药物或细胞因子，目的是指导巨噬细胞， 伤口愈合M2c表型。本研究中将用于指导 巨噬细胞极化包括白细胞介素-10（IL-10），一种抗炎细胞因子; 地塞米松，一种抗炎皮质类固醇;伊洛前列素（PGI2），一种有前途的抗纤维化药物 药物;和PGE2，一种已知可减少纤维化的内源性前列腺素。微透析 探针将用于收集极化改变期间产生的细胞因子，以预测 成功转换为M2c偏振态。微透析探针也将用于 评估不同治疗期间器械校准和寿命的变化。真实的- 整个动物细胞成像将被用来成像细胞运动到 植入器械。这些方法的组合将提供体外快速翻译的 动物模型研究，并进行疗效验证。

Project Summary/Abstract CLINICAL SIGNIFICANCE. All implanted materials elicit an immune response that leads to the foreign body reaction. This foreign body reaction often causes fibrosis around the implant. For implants such as glucose sensors, the fibrosis is one of the primary causes for limiting current FDA-approved implanted glucose sensors to 5 to 7 days for clinical decisions (e.g., to inject insulin or to consume carbohydrate). Macrophages are believed to provide the complex bioactive molecular cues that direct the foreign body reaction leading to fibrosis of the implant. Our hypothesis is that directing the polarization of macrophages to a wound healing M2c phenotype will promote healing and tissue integration without excessive fibrosis or inflammation. Completion of this work will provide significant in vivo bioactive agent pathway information to create and rapidly assess new and improved bioengineering approaches to reduce or eliminate the fibrosis associated with the foreign body reaction. Additionally, these studies will provide important quantitative molecular information with respect to cytokine pathways altered during efficacious methods that alter macrophage phenotype. EXPERIMENTAL APPROACH. Microdialysis sampling probes will be used as glucose sensor mimics that can concomitantly deliver mediators aimed to alter macrophage phenotype while sampling the bioactive cytokines produced at the implant/tissue interface in rats. This approach will allow rapid testing of different drugs or cytokines with the aim of directing macrophages to the wound healing M2c phenotype. The compounds that will be used in this study to direct macrophage polarization include interleukin-10 (IL-10), an anti-inflammatory cytokine; dexamethasone, an anti-inflammatory corticosteroid; iloprost (PGI2), a promising anti-fibrotic agent; and PGE2, an endogenous prostaglandin known to reduce fibrosis. The microdialysis probe will be used to collect the cytokines produced during polarization alteration to predict successful conversion to the M2c polarization state. The microdialysis probe will also be used to assess how device calibration and longevity is altered during the different treatments. Real- time whole animal cellular imaging will be employed to image cellular movement to the implanted device. The combination of these approaches will provide rapid translation of in vitro studies to animal models with efficacy verification.