Role of Macrophages on Tissue Remodeling Following Cochlear Implantation

项目摘要 钴植入物（CI）电极阵列由包裹在钛合金中的铂（Pt）线和触点制成。 聚二甲基硅氧烷（PDMS，硅胶）外壳。这些材料提供机械稳定性和灵活性 对设备的长期功能至关重要。然而，它们也诱导异物反应和纤维化 会产生有害影响。例如，最终包裹所有CI电极阵列的纤维化囊 导致阻抗增加和信号变宽，这降低了装置的有效性。 此外，耳蜗内纤维化与听觉丧失有关，听觉丧失可能发生在脑梗死后数月至数年。 置入由于CI的候选资格正在迅速扩大，包括许多具有显著残留的患者， 听力，迫切需要了解导致耳蜗内纤维化的基本过程。 巨噬细胞被认为是异物对其他生物材料反应的关键，中央调节器。 组织和我们的初步数据表明，植入CI后巨噬细胞募集活跃。 我们假设CI生物材料激活巨噬细胞，导致成纤维细胞的募集， 并且电刺激调节这种巨噬细胞反应 取决于刺激水平和发作时间。在目的1中，使用体外培养模型来探索 PDMS和Pt对巨噬细胞募集、活化和耳蜗成纤维细胞调节的不同作用 增殖和合成功能。目的1还研究了时间和空间的激活和募集 巨噬细胞的耳蜗植入后，使用报告小鼠模型。目标2审查了 巨噬细胞在耳蜗植入后纤维化/新骨化中的作用。首先，我们测试 巨噬细胞用于CI后的脑内纤维化，使用允许条件性和选择性 吞噬巨噬细胞。接下来，用特异性CSF 1 R抑制剂处理植入小鼠， 巨噬细胞作为临床前转化模型。最后，使用CX 3CR 1敲除小鼠来确定CX 3CR 1基因的表达。 Fractalkine信号传导对CI后纤维化的影响。目标3确定了不同水平的电 刺激和电刺激开始时间对巨噬细胞募集和脑内巨噬细胞的影响 纤维化拟议的工作提供了一个严格的调查的影响，具体的生物材料，插入 创伤和电刺激对巨噬细胞反应和纤维化的调节产生影响。 耳蜗这项工作的长期影响是确定具体、有效和持久的战略， CI或耳蜗的其他损伤后纤维化。

Project Summary Cochlear implant (CI) electrode arrays are made of platinum (Pt) wires and contacts encased in polydimethylsiloxane (PDMS, silicone) housing. These materials provide mechanical stability and flexibility critical to the long-term function of the device. However, they also induce a foreign body response and fibrosis that have detrimental effects. For example, the fibrotic capsule that eventually encases all CI electrode arrays leads to increased impedances and signal broadening which decreases the effectiveness of the device. Further, intracochlear fibrosis is implicated in the loss of acoustic hearing that can occur months to years after implantation. As candidacy for CI is rapidly expanding, including many patients with significant residual hearing, there is an urgent need to understand the fundamental processes that lead to intracochlear fibrosis. Macrophages are recognized as key, central regulators of the foreign body response to biomaterials in other tissues and our preliminary data demonstrate vigorous macrophage recruitment following implantation of CIs. We hypothesize CI biomaterials activate macrophages leading to the recruitment of fibroblasts and fibrosis/encapsulation of the biomaterials and that electrical stimulation modulates this macrophage response dependent on the stimulus level and timing of onset. In Aim 1, in vitro culture models are used to explore the differential effect of PDMS and Pt on macrophage recruitment, activation, and regulation of cochlear fibroblast proliferative and synthetic functions. Aim 1 also investigates the temporal and spatial activation and recruitment of macrophages following cochlear implantation using a reporter mouse model. Aim 2 examines the role of macrophages in fibrosis/neo-ossification following cochlear implantation. First, we test the requirement of macrophages for intracochlear fibrosis following CI using a mouse line that allows conditional and selective depletion of macrophages. Next, implanted mice are treated with a specific CSF1R inhibitor to deplete macrophages as a preclinical translational model. Finally, a CX3CR1 null mouse is used to determine the effect of fractalkine signaling on post-CI fibrosis. Aim 3 determines the effects of varying levels of electrical stimulation and effects of timing of electrical stimulation onset on macrophage recruitment and intracochlear fibrosis. The proposed work provides a rigorous investigation of the effects that specific biomaterials, insertion trauma, and electrical stimulation exert on macrophage responses and the regulation of the fibrosis in the cochlea. The long-term impact of the work is to identify specific, effective, and durable strategies to limit fibrosis following CI or other injuries to the cochlea.