Role of Macrophages on Tissue Remodeling Following Cochlear Implantation

项目摘要 人工耳蜗(CI)电极阵列由铂丝和触点组成 聚二甲基硅氧烷(PDMS，有机硅)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，它们也会引起异物反应和纤维化。 会产生有害的影响。例如，最终包裹所有CI电极阵列的纤维性包膜 导致阻抗增加和信号展宽，从而降低设备的有效性。 此外，耳壳内纤维化与听力丧失有关，听力丧失可能在数月至数年后发生。 植入。由于CI的候选人数正在迅速扩大，包括许多有显著残留的患者 在听力方面，迫切需要了解导致绒毛间质纤维化的基本过程。 巨噬细胞被认为是异物对其他生物材料反应的关键和中枢调节细胞 组织和我们的初步数据显示，植入顺式细胞后，巨噬细胞大量募集。 我们假设CI生物材料激活巨噬细胞导致成纤维细胞和 生物材料的纤维化/包裹以及电刺激调节这种巨噬细胞的反应 取决于刺激水平和发病时间。在目标1中，使用体外培养模型来探索 PDMS和铂对耳蜗成纤维细胞巨噬细胞募集、激活和调节的不同作用 具有增殖和合成功能。目标1还调查了时间和空间的激活和招募 使用报告小鼠模型观察人工耳蜗术后巨噬细胞的变化。《目标2》考察了 巨噬细胞在人工耳蜗术后纤维化/新骨化中的作用首先，我们测试了 利用允许有条件和选择性的小鼠系治疗脑梗塞后脑内纤维化的巨噬细胞 巨噬细胞耗尽。接下来，植入的小鼠被用一种特定的CSF1R抑制剂治疗以耗尽 巨噬细胞作为临床前翻译模型。最后，使用CX3CR1空鼠标来确定 Fractalkine信号在脑梗塞后纤维化中的作用。目标3确定不同水平的电信号的影响 刺激和电刺激开始时间对巨噬细胞募集和卵泡内的影响 纤维化症。这项拟议的工作提供了对特定生物材料、植入 创伤和电刺激对大鼠巨噬细胞反应和纤维化的调节作用 耳蜗骨。这项工作的长期影响是确定具体、有效和持久的战略，以限制 脑梗塞或其他耳蜗伤后的纤维化。

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.