Theoretical Evaluation and Experimental Validation of Localized Therapeutic Hypothermia Application to Preserve Residual Hearing After Cochlear Implantation.

OBJECTIVES: Cochlear implantation surgery has been shown to result in trauma to inner ear sensory structures, resulting in loss of residual hearing. Localized therapeutic hypothermia has been shown in clinical care to be a neuroprotective intervention. Previously, we have shown in an experimental model that localized hypothermia protects cochlear hair cells and residual hearing function against surgical and cochlear implantation trauma. Using experimental temperature measurements carried out in human cadaver temporal bones and a finite element model of the inner ear, the present study examined the temperature distribution of a custom-designed hypothermia delivery system in the human inner ear organs. DESIGN: The efficacy of the hypothermia probe and resulting heat distribution across human cochlea and surrounding tissues were modeled in three-dimensional in COMSOL. The geometry and dimensions of inner ear and temporal bones were derived from computed tomographic and magnetic resonance imaging images. Model predictions were compared with experimental observations from five human temporal bones. RESULTS: In both the modeling and experimental studies, the cochlear temperature was lowered by 4 to 6 °C on the round window from a baseline of 37 °C within 16 to 18 minutes. The model simulations showed uniformly distributed cooling across the cochlea. This study provides insight for design, operation, and protocols for efficacious delivery of mild therapeutic hypothermia to the human cochlea that may significantly benefit patients undergoing surgical cochlear implantation by preserving residual hearing. CONCLUSION: There was a close correlation between the results of the numerical simulations and experimental observations in this study. Our custom-designed system is capable of effectively providing mild therapeutic hypothermia locally to the human cochlea. When combined with results from in vivo animal experiments, the present study suggests that the application of localized therapeutic hypothermia may hold potential for patients with an aim to preserve residual hearing after cochlear implantation.

Transcriptional response to mild therapeutic hypothermia in noise-induced cochlear injury.

Introduction: Prevention or treatment for acoustic injury has been met with many translational challenges, resulting in the absence of FDA-approved interventions. Localized hypothermia following noise exposure mitigates acute cochlear injury and may serve as a potential avenue for therapeutic approaches. However, the mechanisms by which hypothermia results in therapeutic improvements are poorly understood. Methods: This study performs the transcriptomic analysis of cochleae from juvenile rats that experienced noise-induced hearing loss (NIHL) followed by hypothermia or control normothermia treatment. Results: Differential gene expression results from RNA sequencing at 24 h post-exposure to noise suggest that NIHL alone results in increased inflammatory and immune defense responses, involving complement activation and cytokine-mediated signaling. Hypothermia treatment post-noise, in turn, may mitigate the acute inflammatory response. Discussion: This study provides a framework for future research to optimize hypothermic intervention for ameliorating hearing loss and suggests additional pathways that could be targeted for NIHL therapeutic intervention.

Mild therapeutic hypothermia protects against inflammatory and proapoptotic processes in the rat model of cochlear implant trauma.

OBJECTIVE: Mild therapeutic hypothermia (MTH) has been demonstrated to prevent residual hearing loss from surgical trauma associated with cochlear implant (CI) insertion. Here, we aimed to characterize the mechanisms of MTH-induced hearing preservation in CI in a well-established preclinical rodent model. APPROACH: Rats were divided into four experimental conditions: MTH-treated and implanted cochleae, cochleae implanted under normothermic conditions, MTH only cochleae and un-operated cochleae (controls). Auditory brainstem responses (ABRs) were recorded at different time points (up to 84 days) to confirm long-term protection and safety of MTH locally applied to the cochlea for 20 min before and after implantation. Transcriptome sequencing profiling was performed on cochleae harvested 24 h post CI and MTH treatment to investigate the potential beneficial effects and underlying active gene expression pathways targeted by the temperature management. RESULTS: MTH treatment preserved residual hearing up to 3 months following CI when compared to the normothermic CI group. In addition, MTH applied locally to the cochleae using our surgical approach was safe and did not affect hearing in the long-term. Results of RNA sequencing analysis highlight positive modulation of signaling pathways and gene expression associated with an activation of cellular inflammatory and immune responses against the mechanical damage caused by electrode insertion. SIGNIFICANCE: These data suggest that multiple and possibly independent molecular pathways play a role in the protection of residual hearing provided by MTH against the trauma of cochlear implantation.

Targeted therapeutic hypothermia protects against noise induced hearing loss.

Introduction: Exposure to occupational or recreational loud noise activates multiple biological regulatory circuits and damages the cochlea, causing permanent changes in hearing sensitivity. Currently, no effective clinical therapy is available for the treatment or mitigation of noise-induced hearing loss (NIHL). Here, we describe an application of localized and non-invasive therapeutic hypothermia and targeted temperature management of the inner ear to prevent NIHL. Methods: We developed a custom-designed cooling neck collar to reduce the temperature of the inner ear by 3-4°C post-injury to deliver mild therapeutic hypothermia. Results: This localized and non-invasive therapeutic hypothermia successfully mitigated NIHL in rats. Our results show that mild hypothermia can be applied quickly and safely to the inner ear following noise exposure. We show that localized hypothermia after NIHL preserves residual hearing and rescues noise-induced synaptopathy over a period of months. Discussion: This study establishes a minimally-invasive therapeutic paradigm with a high potential for rapid translation to the clinic for long-term preservation of hearing health.

Therapeutic hypothermia reduces cortical inflammation associated with utah array implants.

OBJECTIVE: Neuroprosthetics hold tremendous promise to restore function through brain-computer interfaced devices. However, clinical applications of implantable microelectrodes remain limited given the challenges of maintaining neuronal signals for extended periods of time and with multiple biological mechanisms negatively affecting electrode performance. Acute and chronic inflammation, oxidative stress, and blood brain barrier disruption contribute to inconsistent electrode performance. We hypothesized that therapeutic hypothermia (TH) applied at the microelectrode insertion site will positively modulate both inflammatory and apoptotic pathways, promoting neuroprotection and improved performance in the long-term. APPROACH: A custom device and thermoelectric system were designed to deliver controlled TH locally to the cortical implant site at the time of microelectrode array insertion and immediately following surgery. The TH paradigm was derived from in vivo cortical temperature measurements and finite element modeling of temperature distribution profiles in the cortex. Male Sprague-Dawley rats were implanted with non-functional Utah microelectrodes arrays (UMEA) consisting of 4 × 4 grid of 1.5 mm long parylene-coated silicon shanks. In one group, TH was applied to the implant site for two hours following the UMEA implantation, while the other group was implanted under normothermic conditions without treatment. At 48 h, 72 h, 7 d and 14 d post-implantation, mRNA expression levels for genes associated with inflammation and apoptosis were compared between normothermic and hypothermia-treated groups. MAIN RESULTS: The custom system delivered controlled TH to the cortical implant site and the numerical models confirmed that the temperature decrease was confined locally. Furthermore, a one-time application of TH post UMEA insertion significantly reduced the acute inflammatory response with a reduction in the expression of inflammatory regulating cytokines and chemokines. SIGNIFICANCE: This work provides evidence that acutely applied hypothermia is effective in significantly reducing acute inflammation post intracortical electrode implantation.

Anatomical Correlates and Surgical Considerations for Localized Therapeutic Hypothermia Application in Cochlear Implantation Surgery.

HYPOTHESIS: Application of localized, mild therapeutic hypothermia during cochlear implantation (CI) surgery is feasible for residual hearing preservation. BACKGROUND: CI surgery often results in a loss of residual hearing. In preclinical studies, local application of controlled, mild therapeutic hypothermia has shown promising results as a hearing preservation strategy. This study investigated a suitable surgical approach to deliver local hypothermia in patients utilizing anatomical and radiologic measurements and experimental measurements from cadaveric human temporal bones. METHODS: Ten human cadaveric temporal bones were scanned with micro-computed tomography and anatomical features and measurements predicting round window (RW) visibility were characterized. For each bone, the standard facial recess and myringotomy approaches for delivery of hypothermia were developed. The St. Thomas Hospital (STH) classification was used to record degree of RW visibility with and without placement of custom hypothermia probe. Therapeutic hypothermia was delivered through both approaches and temperatures recorded at the RW, RW niche, over the lateral semicircular canal and the supero-lateral mastoid edge. RESULTS: The average facial recess area was 13.87 ±â€Š5.52 mm. The introduction of the cooling probe through either approach did not impede visualization of the RW or cochleostomy as determined by STH grading. The average temperatures at RW using the FR approach reduced by 4.57 ±â€Š1.68 °C for RW, while using the myringotomy approach reduced by 4.11 ±â€Š0.98 °C for RW. CONCLUSION: Local application of therapeutic hypothermia is clinically feasible both through the facial recess and myringotomy approaches without limiting optimal surgical visualization.

A Multilayer MEMS Platform for Single-Cell Electric Impedance Spectroscopy and Electrochemical Analysis.

The fabrication and characterization of a microchamber electrode array for electrical and electrochemical studies of individual biological cells are presented. The geometry was tailored specifically for measurements from sensory hair cells isolated from the cochlea of the mammalian inner ear. Conventional microelectromechanical system (MEMS) fabrication techniques were combined with a heat-sealing technique and polydimethylsiloxane micromolding to achieve a multilayered microfluidic system that facilitates cell manipulation and selection. The system allowed for electrical stimulation of individual living cells and interrogation of excitable cell membrane dielectric properties as a function of space and time. A three-electrode impedimetric system was incorporated to provide the additional ability to record the time-dependent concentrations of specific biochemicals in microdomain volumes near identified regions of the cell membrane. The design and fabrication of a robust fluidic and electrical interface are also described. The interface provided the flexibility and simplicity of a "cartridge-based" approach in connecting to the MEMS devices. Cytometric measurement capabilities were characterized by using electric impedance spectroscopy (1 kHz-10 MHz) of isolated outer hair cells. Chemical sensing capability within the microchannel recording chamber was characterized by using cyclic voltammetry with varying concentrations of potassium ferricyanide (K(3)Fe(CN)(6)). Chronoamperometric recordings of electrically stimulated PC12 cells highlight the ability of the platform to resolve exocytosis events from individual cells.

A cool approach to reducing electrode-induced trauma: Localized therapeutic hypothermia conserves residual hearing in cochlear implantation.

OBJECTIVE: The trauma caused during cochlear implant insertion can lead to cell death and a loss of residual hair cells in the cochlea. Various therapeutic approaches have been studied to prevent cochlear implant-induced residual hearing loss with limited success. In the present study, we show the efficacy of mild to moderate therapeutic hypothermia of 4 to 6 °C applied to the cochlea in reducing residual hearing loss associated with the electrode insertion trauma. APPROACH: Rats were randomly distributed in three groups: control contralateral cochleae, normothermic implanted cochleae and hypothermic implanted cochleae. Localized hypothermia was delivered to the middle turn of the cochlea for 20 min before and after implantation using a custom-designed probe perfused with cooled fluorocarbon. Auditory brainstem responses (ABRs) were recorded to assess the hearing function prior to and post-cochlear implantation at various time points up to 30 days. At the conclusion of the trials, inner ears were harvested for histology and cell count. The approach was extended to cadaver temporal bones to study the potential surgical approach and efficacy of our device. In this case, the hypothermia probe was placed next to the round window niche via the facial recess or a myringotomy. MAIN RESULTS: A significant loss of residual hearing was observed in the normothermic implant group. Comparatively, the residual hearing in the cochleae receiving therapeutic hypothermia was significantly conserved. Histology confirmed a significant loss of outer hair cells in normothermic cochleae receiving the surgical trauma when compared to the hypothermia treated group. In human temporal bones, a controlled and effective cooling of the cochlea was achieved using our approach. SIGNIFICANCE: Collectively, these results suggest that therapeutic hypothermia during cochlear implantation may reduce traumatic effects of electrode insertion and improve conservation of residual hearing.

Dynamic displacement of normal and detached semicircular canal cupula.

The dynamic displacement of the semicircular canal cupula and modulation of afferent nerve discharge were measured simultaneously in response to physiological stimuli in vivo. The adaptation time constant(s) of normal cupulae in response to step stimuli averaged 36 s, corresponding to a mechanical lower corner frequency for sinusoidal stimuli of 0.0044 Hz. For stimuli equivalent to 40-200 deg/s of angular head velocity, the displacement gain of the central region of the cupula averaged 53 nm per deg/s. Afferents adapted more rapidly than the cupula, demonstrating the presence of a relaxation process that contributes significantly to the neural representation of angular head motions by the discharge patterns of canal afferent neurons. We also investigated changes in time constants of the cupula and afferents following detachment of the cupula at its apex-mechanical detachment that occurs in response to excessive transcupular endolymph pressure. Detached cupulae exhibited sharply reduced adaptation time constants (300 ms-3 s, n = 3) and can be explained by endolymph flowing rapidly over the apex of the cupula. Partially detached cupulae reattached and normal afferent discharge patterns were recovered 5-7 h following detachment. This regeneration process may have relevance to the recovery of semicircular canal function following head trauma.