Modulating and Monitoring the Foreign Body Response to Implants

描述(申请人提供)：临床意义：所有植入材料都会引起免疫反应，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。对于葡萄糖传感器等植入物，纤维化是目前FDA批准的植入性葡萄糖传感器临床决策(例如注射胰岛素或消耗碳水化合物)限制在5至7天内的主要原因之一。巨噬细胞被认为提供了复杂的生物活性分子线索，指导异物反应导致植入物纤维化。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。这项工作的完成将提供重要的体内生物活性物质途径信息，以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相关的纤维化。此外，这些研究将提供关于在改变巨噬细胞表型的有效方法中改变的细胞因子途径的重要的定量分子信息。实验方法。微透析采样探针将被用作葡萄糖传感器的模拟物，可以同时输送旨在改变巨噬细胞表型的介体，同时采样在种植体/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适应伤口愈合的M2c表型。本研究中将用于引导巨噬细胞极化的化合物包括：抗炎细胞因子白介素10(IL-10)；抗炎皮质类固醇激素地塞米松；前景看好的抗纤维化药物伊洛前列素(PGI2)；以及已知可减少纤维化的内源性前列腺素PGE2。微透析探头将被用来收集极化转换过程中产生的细胞因子，以预测成功地转换到M2c极化状态。微透析探头也将被用来评估设备校准和寿命在不同治疗期间是如何改变的。将使用实时全动物细胞成像来成像植入设备的细胞运动。这些方法的结合将提供从体外研究到动物模型的快速转换，并进行有效性验证。 与公共健康相关：许多植入的医疗设备，包括葡萄糖传感器，都会产生免疫反应，最终导致胶原蛋白胶囊(纤维化)的形成，从而限制它们的寿命。将化合物直接输送到组织/设备界面，将免疫细胞引导到伤口愈合状态，将增加设备寿命。测量伤口愈合过程中产生的复杂化学信号将为降低对任何植入物的免疫反应提供重要信息。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Many implanted medical devices including glucose sensors generate an immune response that ultimately leads to the formation of a collagen capsule (fibrosis) that limits their longevity. Direct delivery of compounds to the tissue/device interface to direct immune cells to a wound healing state would increase device longevity. Measuring the complex chemical signals produced during wound healing will provide important information for reducing the immune response to any implant.