Role of Macrophages on Tissue Remodeling Following Cochlear Implantation

巨噬细胞在人工耳蜗植入后组织重塑中的作用

• 批准号: 10208852
• 负责人: Marlan R Hansen
• 金额: $ 41.54万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-03 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10208852
• 关键词: 3-Dimensional; Acoustics; Action Potentials; Adhesions; Affect; Architecture; Auditory Brainstem Responses; Biocompatible Materials; Biological; CSF1R gene; Cells; Charge; Cicatrix; Clinical; Cochlea; Cochlear Implants; Cochlear implant procedure; Collagen; Data; Devices; Ear; Effectiveness; Electric Stimulation; Electrodes; Electrophysiology (science); Encapsulated; Environment; Equipment Malfunction; Evaluation; Fibroblasts; Fibrosis; Foreign Bodies; Foreign-Body Reaction; Fractalkine; Frequencies; Future; Genetic; Goals; Health; Hearing; Housing; Implant; Implanted Electrodes; In Vitro; Inflammation; Inflammatory; Injury; Intervention; Investigation; Knockout Mice; Lead; Life; Macrophage Activation; Measures; Mechanics; Modeling; Mus; Operative Surgical Procedures; Oral; Osteogenesis; Outcome; Patients; Performance; Physiologic Ossification; Platinum; Play; Process; Property; Reaction; Regulation; Reporter; Residual state; Role; Scala Tympani; Signal Transduction; Silicones; Stimulus; Surface; Surface Properties; System; Testing; Therapeutic Studies; Time; Tissues; Trauma; Work; X ray microscopy; base; capsule; chemokine; confocal imaging; density; electric impedance; experimental study; flexibility; implantation; improved; inhibitor/antagonist; macrophage; microscopic imaging; mouse model; negative affect; otoacoustic emission; platinum electrode; polydimethylsiloxane; pre-clinical; preservation; recruit; response; translational model

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.

项目概要 人工耳蜗 (CI) 电极阵列由铂 (Pt) 线和封装在其中的触点制成 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，它们也会诱发异物反应和纤维化 会产生有害影响。例如，最终包裹所有 CI 电极阵列的纤维化胶囊 导致阻抗增加和信号展宽，从而降低设备的有效性。 此外，耳蜗内纤维化与听力损失有关，这种损失可能在术后数月至数年发生。 植入。随着 CI 候选者的迅速扩大，包括许多具有显着残留的患者 听力方面，迫切需要了解导致耳蜗内纤维化的基本过程。 巨噬细胞被认为是其他领域生物材料异物反应的关键、中央调节者 组织和我们的初步数据表明植入 CI 后巨噬细胞大量募集。 我们假设 CI 生物材料激活巨噬细胞，导致成纤维细胞的募集和 生物材料的纤维化/封装以及电刺激调节巨噬细胞的反应 取决于刺激水平和开始时间。在目标 1 中，使用体外培养模型来探索 PDMS 和 Pt 对巨噬细胞募集、激活和耳蜗成纤维细胞调节的不同影响 增殖和合成功能。目标 1 还研究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植入后的巨噬细胞。目标 2 检查的作用 人工耳蜗植入后纤维化/新骨化中的巨噬细胞。首先我们测试一下需求 使用允许有条件和选择性的小鼠系，巨噬细胞用于 CI 后耳蜗内纤维化 巨噬细胞耗竭。接下来，植入的小鼠接受特定的 CSF1R 抑制剂治疗，以消除 巨噬细胞作为临床前转化模型。最后，使用 CX3CR1 空鼠来确定 fractalkine 信号传导对 CI 后纤维化的影响。目标 3 确定不同电气水平的影响 刺激以及电刺激开始时间对巨噬细胞募集和耳蜗内的影响 纤维化。拟议的工作对特定生物材料、插入物的影响进行了严格的研究 创伤和电刺激对巨噬细胞反应和纤维化的调节作用 耳蜗。这项工作的长期影响是确定具体、有效和持久的策略来限制 CI 或其他耳蜗损伤后的纤维化。