Department of Otolaryngology Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, United States; Department of Otolaryngology Head and Neck Surgery, University of California San Diego, San Diego, CA 92103, United States.
Department of Otolaryngology Head and Neck Surgery, University of Iowa, Iowa City, IA 52242, United States; Department of Biomedical Sciences, Creighton University, Omaha, NE 68178, United States.
Hear Res. 2022 Dec;426:108510. doi: 10.1016/j.heares.2022.108510. Epub 2022 Apr 26.
Cochlear implantation is an effective auditory rehabilitation strategy for those with profound hearing loss, including those with residual low frequency hearing through use of hybrid cochlear implantation techniques. Post-mortem studies demonstrate the nearly ubiquitous presence of intracochlear fibrosis and neo-ossification following cochlear implantation. Current evidence suggests post-implantation intracochlear fibrosis is associated with delayed loss of residual acoustic hearing in hybrid cochlear implant (CI) recipients and may also negatively influence outcomes in traditional CI recipients. This study examined the contributions of surgical trauma, foreign body response and electric stimulation to intracochlear fibrosis and the innate immune response to cochlear implantation and the hierarchy of these contributions.
Normal hearing CX3CR1 mice underwent either round window opening (sham), acute CI insertion or chronic CI insertion with no, low- or high-level electric stimulation. Electric stimulation levels were based on neural response telemetry (NRT), beginning post-operative day 7 for 5 h per day. Subjects (n=3 per timepoint) were sacrificed at 4 h, 1,4,7,8,11,14 and 21 days. An unoperated group (n=3) served as controls. Cochleae were harvested at each time-point and prepared for immunohistochemistry with confocal imaging. The images were analyzed to obtain CX3CR1+ macrophage cell number and density in the lateral wall (LW), scala tympani (ST) and Rosenthal's canal (RC).
A ST peri-implant cellular infiltrate and fibrosis occurred exclusively in the chronically implanted groups starting on day 7 with a concurrent infiltration of CX3CR1+ macrophages not seen in the other groups. CX3CR1+ macrophage infiltration was seen in the LW and RC in all experimental groups within the first week, being most prominent in the 3 chronically implanted groups during the second and third week.
The cochlear immune response was most prominent in the presence of chronic cochlear implantation, regardless of electric stimulation level. Further, the development of intracochlear ST fibrosis was dependent on the presence of the indwelling CI foreign body. An innate immune response was evoked by surgical trauma alone (sham and acute CI groups) to a lesser degree. These data suggest that cochlear inflammation and intrascalar fibrosis after cochlear implantation are largely dependent on the presence of a chronic indwelling foreign body and are not critically dependent on electrical stimulation. Also, these data support a role for surgical trauma in inciting the initial innate immune response.
人工耳蜗植入是一种有效的听觉康复策略，适用于重度听力损失患者，包括使用混合人工耳蜗植入技术保留低频听力的患者。尸检研究表明，人工耳蜗植入后几乎普遍存在耳蜗内纤维化和新生骨化。目前的证据表明，植入后耳蜗内纤维化与混合人工耳蜗植入（CI）受者残余听觉的延迟丧失有关，并且可能对传统 CI 受者的结果产生负面影响。本研究探讨了手术创伤、异物反应和电刺激对耳蜗内纤维化和对耳蜗植入的固有免疫反应的影响，并探讨了这些因素的层次结构。
正常听力的 CX3CR1 小鼠接受圆窗开窗术（假手术）、急性 CI 插入术或慢性 CI 插入术，同时给予低水平或高水平电刺激。电刺激水平基于神经反应遥测术（NRT），术后第 7 天开始每天 5 小时。在 4 小时、1、4、7、8、11、14 和 21 天时处死每组 3 只动物。未手术组（n=3）作为对照。在每个时间点收获耳蜗，并进行免疫组织化学染色和共聚焦成像。对图像进行分析，以获得外侧壁（LW）、鼓阶（ST）和 Rosenthal 管（RC）中 CX3CR1+巨噬细胞的数量和密度。
在慢性植入组中，从第 7 天开始，仅在慢性植入组中出现 ST 周围植入细胞浸润和纤维化，同时伴有 CX3CR1+巨噬细胞浸润，而其他组未见这种情况。在所有实验组中，CX3CR1+巨噬细胞浸润在第 1 周内出现在 LW 和 RC 中，在第 2 和第 3 周时在 3 个慢性植入组中最为明显。
无论电刺激水平如何，慢性耳蜗植入都会引起最显著的耳蜗免疫反应。此外，内植入物的存在是导致 ST 纤维化的关键因素。单独的手术创伤（假手术和急性 CI 组）也会引起较弱程度的固有免疫反应。这些数据表明，人工耳蜗植入后的耳蜗炎症和内骨化在很大程度上取决于慢性植入物的存在，而不是对电刺激的严重依赖。此外，这些数据支持手术创伤在引发初始固有免疫反应中的作用。
