Modulating and Monitoring the Foreign Body Response to Implants

项目摘要/摘要 临床意义。所有植入的材料都会引发免疫反应，从而导致 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 植入葡萄糖传感器等，纤维化是限制电流的主要原因之一 FDA批准的植入葡萄糖传感器的时间为5至7天，用于临床决策(例如，注射 胰岛素或消耗碳水化合物)。巨噬细胞被认为提供了这种复合体 引导异物反应导致植入物纤维化的生物活性分子线索。 我们的假设是，将巨噬细胞的极化引导到伤口愈合的M2c 表型将促进愈合和组织整合，而不会出现过度的纤维化或炎症。 这项工作的完成将为体内生物活性物质途径提供重要的信息 创建并快速评估新的和改进的生物工程方法，以减少或消除 与异物反应相关的纤维化。此外，这些研究将提供 与细胞因子途径改变有关的重要定量分子信息 改变巨噬细胞表型的有效方法。 实验方法。微渗析采样探头将被用作葡萄糖传感器 可同时提供旨在改变巨噬细胞表型的介体的模拟物 采集大鼠种植体/组织界面产生的生物活性细胞因子。这种方法 将允许快速测试不同的药物或细胞因子，目的是引导巨噬细胞 创面愈合M2c表型。这项研究中将使用的化合物将指导 巨噬细胞极化包括白介素10(IL-10)，抗炎细胞因子； 地塞米松，一种抗炎的皮质类固醇；伊洛前列素(PGI2)，一种有前途的抗纤维化药物 PGE2，一种已知可以减少纤维化的内源性前列腺素。微透析法 将使用探针收集极化变化过程中产生的细胞因子来预测 成功地转换到M2c偏振态。微透析探头也将被使用 评估设备校准和寿命在不同治疗过程中的变化。真正的- 时间将使用全动物细胞成像来成像细胞运动到 植入的装置。这些方法的结合将提供体外快速翻译 对动物模型进行有效性验证的研究。

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.