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: 10645188
• 负责人: Marlan R Hansen
• 金额: $ 39.91万
• 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/10645188
• 关键词: 3-Dimensional; Ablation; 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; Macrophage; Macrophage Activation; Measures; Mechanics; Modeling; Mus; Operative Surgical Procedures; Oral Administration; Osteogenesis; Outcome; Patients; Performance; Persons; 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; battery life; capsule; chemokine; confocal imaging; density; electric impedance; experimental study; flexibility; implantation; improved; inhibitor; 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.

项目摘要 耳蜗植入物（CI）电极阵列由铂（PT）电线和触点制成 聚二甲基硅氧烷（PDMS，硅酮）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。但是，它们也引起异物反应和纤维化 具有不利影响。例如，最终包围所有CI电极阵列的纤维化胶囊 导致阻抗和信号扩展增加，从而降低了设备的有效性。 此外，应验证内纤维化与可能发生在几个月至几年之后的声学听力的丧失有关 植入。由于CI的候选资格正在迅速扩展，其中包括许多具有显着残留的患者 听力，迫切需要了解导致对等方内纤维化的基本过程。 巨噬细胞被认为是关键，是外国体内对生物材料的反应的中心调节剂 组织和我们的初步数据表明，植入顺式后，巨噬细胞募集剧烈。 我们假设CI生物材料激活巨噬细胞，导致成纤维细胞募集和 生物材料的纤维化/封装，并且电刺激调节了这种巨噬细胞反应 取决于刺激水平和发作时间。在AIM 1中，使用体外培养模型来探索 PDM和PT对人工耳蜗成纤维细胞的巨噬细胞募集，激活和调节的差异作用 增殖和合成功能。 AIM 1还研究了时间和空间激活和募集 使用记者小鼠模型人工耳蜗植入后的巨噬细胞。 AIM 2检查了 人工耳蜗植入后纤维化/新化解的巨噬细胞。首先，我们测试了 CI后使用小鼠系的巨噬细胞进行巨噬细胞，该线条允许有条件和选择性 巨噬细胞的消耗。接下来，用特定的CSF1R抑制剂处理植入的小鼠以耗尽 巨噬细胞作为临床前翻译模型。最后，使用CX3CR1 null鼠标来确定 分子信号传导对CI后纤维化的影响。 AIM 3确定电气水平的影响 电刺激发作对巨噬细胞募集和菌道刺激的刺激和影响 纤维化。拟议的工作对特定生物材料，插入的影响进行了严格的研究 创伤和对巨噬细胞反应的电刺激以及对纤维化的调节 耳蜗。这项工作的长期影响是确定限制特定，有效且持久的策略 CI或耳蜗受伤后的纤维化。