Showing papers by "Marlan R. Hansen published in 2022"

Comparative Analysis of Robotics-Assisted and Manual Insertions of Cochlear Implant Electrode Arrays

Abstract: Hypothesis Robotics-assisted cochlear implant (CI) insertions will result in reduced intracochlear trauma when compared with manual, across multiple users. Background Whether intracochlear trauma and translocations are two factors that may contribute to significant variability in CI outcomes remains to be seen. To address this issue, we have developed a robotics-assisted insertion system designed to aid the surgeon in inserting electrode arrays with consistent speeds and reduced variability. This study evaluated the effect of robotics-assisted insertions on the intracochlear trauma as compared with manual insertions in cadaveric cochleae in a simulated operative environment. Methods Twelve neurotologists performed bilateral electrode insertions into cochleae of full cadaveric heads using both the robotics-assisted system and manual hand insertion. Lateral wall electrodes from three different manufacturers (n = 24) were used and randomized between surgeons. Insertion angle of the electrode and trauma scoring were evaluated using high-resolution three-dimensional x-ray microscopy and compared between robotics-assisted and manual insertions. Results Three-dimensional x-ray microscopy provided excellent resolution to characterize the in situ trauma and insertion angle. Robotics-assisted insertions significantly decreased insertional intracochlear trauma as measured by reduced trauma scores compared with manual insertions (average: 1.3 versus 2.2, device versus manual, respectively; p < 0.05). There was no significant difference between insertion angles observed for manual and robotics-assisted techniques (311 ± 131° versus 307 ± 96°, device versus manual, respectively). Conclusions Robotics-assisted insertion systems enable standardized electrode insertions across individual surgeons and experience levels. Clinical trials are necessary to investigate whether insertion techniques that reduce insertional variability and the likelihood of intracochlear trauma also improve CI auditory outcomes.

Longitudinal Electrocochleography as an Objective Measure of Serial Behavioral Audiometry in Electro-Acoustic Stimulation Patients

Abstract: Minimally traumatic surgical techniques and advances in cochlear implant (CI) electrode array designs have allowed acoustic hearing present in a CI candidate prior to surgery to be preserved post-operatively. As a result, these patients benefit from combined electric-acoustic stimulation (EAS) post-operatively. However, 30-40% of EAS CI users experience a partial loss of hearing up to 30 dB after surgery. In the present study, electrocochleography (ECoG) was used to study cochlear microphonic (hair cell response) and auditory nerve neurophonic (neural response) in patients with preserved hearing and patients with loss of hearing. These measures were obtained longitudinally over the course of CI use. At each test session, ECoG amplitude growth functions for several low-frequency stimuli were obtained. The threshold, slope, and suprathreshold amplitude at a fixed stimulation level was obtained from each growth function at each time point. Subjects were categorized as having stable hearing or loss of hearing. Longitudinal linear mixed effects models were used study trends in ECoG thresholds, slopes, and amplitudes for these two categories of subjects. Results showed that CM and ANN thresholds and amplitudes were stable in CI users with preserved residual hearing. CM and ANN thresholds increased (worsened) while CM and ANN amplitudes decreased (worsened) for those with delayed hearing loss. The slope did not distinguish between subjects with stable hearing and subjects with delayed loss of hearing. These results provide a new application of post-operative ECoG as an objective tool to monitor residual hearing and understand the pathophysiology of delayed hearing loss.

Neural correlates of speech in noise perception differences between combined electric-acoustic stimulation and standard cochlear implants

Abstract: Cochlear implants have evolved to utilize residual acoustic hearing that combines to electric stimulation, known as electric-acoustic stimulation (EAS). However, there are mixed expectations about the benefits of EAS. A positive perspective expects that contributions from residual hearing provide better access to acoustic cues that is helpful for speech-in-noise perception. An opposing view concerns potentially poorer spectral resolution of EAS electrodes’ stimulation as those electrodes are often inserted close to lateral wall, which may cause poorer speech-in-noise perception. This study aimed to directly compare neural processes of speech-in-noise perception between EAS and standard CI users to provide an answer to the above alternative expectations. We used 64-channel EEG to measure cortical evoked responses to (1) background noise and (2) target word while listeners perform a word-in-noise task. Then, we compared the amplitude ratio of evoked responses to the target word and background noise, referred to as “internal SNR,” which reflects how well target sound is unmasked from the mixture of speech and noise. Based on the comparison of 55 EAS and 22 standard CI users, internal SNR was significantly larger in EAS CI users. This result indicates that EAS provides enhanced neural processes for speech unmasking.

Reduction of sporadic and neurofibromatosis type 2-associated vestibular schwannoma growth in vitro and in vivo after treatment with the c-Jun N-terminal kinase inhibitor AS602801.

Abstract: OBJECTIVE Vestibular schwannomas (VSs) are benign nerve sheath tumors that result from mutation in the tumor suppressor gene NF2, with functional loss of the protein merlin. The authors have previously shown that c-Jun N-terminal kinase (JNK) is constitutively active in human VS cells and plays a central role in their survival by suppressing accumulation of mitochondrial superoxides, implicating JNK inhibitors as a potential systemic treatment for VS. Thus, the authors hypothesized that the adenosine 5'-triphosphate-competitive JNK inhibitor AS602801 would demonstrate antitumor activity in multiple VS models. METHODS Treatment with AS602801 was tested in primary human VS cultures, human VS xenografts, and a genetic mouse model of schwannoma (Postn-Cre;Nf2flox/flox). Primary human VS cell cultures were established from freshly obtained surgical tumor specimens; treatment group media was enriched with AS602801. VS xenograft tumors were established in male athymic nude mice from freshly collected human tumor. Four weeks postimplantation, a pretreatment MRI scan was obtained, followed by 65 days of AS602801 (n = 18) or vehicle control (n = 19) treatment. Posttreatment MRI scans were used to measure final tumor volume. Tumors were then harvested. Finally, Postn-Cre;Nf2flox/flox mice were treated with AS602801 (n = 10) or a vehicle (n = 13) for 65 days. Posttreatment auditory brainstem responses were obtained. Dorsal root ganglia from Postn-Cre;Nf2flox/flox mice were then harvested. In all models, schwannoma identity was confirmed with anti-S100 staining, cell proliferation was measured with the EdU assay, and cell death was measured with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. All protocols were approved by the local institutional review board and Institutional Animal Care and Use Committees. RESULTS Treatment with AS602801 decreased cell proliferation and increased apoptosis in primary human VS cultures. The systemic administration of AS602801 in mice with human VS xenografts reduced tumor volume and cell proliferation. Last, the AS602801-treated Postn-Cre;Nf2flox/flox mice demonstrated decreased cell proliferation in glial cells in the dorsal root ganglia. However, AS602801 did not significantly delay hearing loss in Postn-Cre;Nf2flox/flox mice up to 3 months posttreatment. CONCLUSIONS The data suggest that JNK inhibition with AS602801 suppresses growth of sporadic and neurofibromatosis type 2-associated VSs. As such, AS602801 is a potential systemic therapy for VS and warrants further investigation.

Tmet-34. radiation metabolomics in primary human meningioma and schwannoma: early experience and initial results

Abstract: Meningiomas and schwannomas account for 45% of primary CNS tumors. Yet when surgery and radiation fail, no further treatments exist. Metabolomics has been used to discover new cancer therapies; however, to date few have used metabolomics to study meningiomas and schwannomas. Here we present initial results and lessons learned from this novel endeavor. Primary tumors were obtained from patients during surgery and immediately taken for culturing or xenograft implantation. Upon reaching >90% confluence, cultures were treated with 0gy, 3gy, 10gy, or 20gy gamma radiation, then flash frozen 6 or 72 hours post-treatment. Xenograft tumors were implanted in nude mice. MRI 4 weeks post-implantation confirmed tumor viability. Mice were then given 10gy, 20gy, or sham radiation treatment. Xenografts were harvested 72 hours post-treatment. Metabolites were measured with a ThermoISQ gas chromatography-mass spectrometer. Eleven meningiomas and nine schwannomas were successfully cultured. Unsupervised hierarchical clustering of cultures demonstrated greater influence from tumor of origin than from radiation. Univariate analysis of schwannoma xenografts demonstrated elevated ornithine following radiation (fold change 1.62; P = 0.008). However, principal component analysis did not show significant between-group differentiation. Orthotopic meningioma xenografts did not produce sufficient tissue for metabolomics; however, subsequent subcutaneous implants have been successful (data forthcoming). Standard cell cultures did not reveal significant metabolic changes following radiation; it is unclear whether this was due to culture technique or inter-tumor heterogeneity. In radiated schwannoma xenografts, elevated ornithine may implicate related pathways such as ornithine decarboxylase-mediated polyamide synthesis for DNA double-strand break repair. Compared to other ‘-omics’ studies, metabolomics requires more tissue per sample ( >10mg) and is more sensitive to environmental conditions. Thus, large sample sizes are needed to detect significant changes, and xenografts are likely superior to cell culture. Future plans include increased xenograft sample size and stable isotope tracing for pathway analysis.

A Steadier Hand: The First Human Clinical Trial of a Single-Use Robotic-Assisted Surgical Device for Cochlear Implant Electrode Array Insertion

Abstract: Objective To evaluate the safety and utility of an investigational robotic-assisted cochlear implant insertion system. Study Design Prospective, single-arm, open-label study under abbreviated Investigational Device Exemption requirements. Setting All procedures were performed, and all data were collected, at a single tertiary referral center. Patients Twenty-one postlingually deafened adult subjects that met Food and Drug Administration indication criteria for cochlear implantation. Intervention All patients underwent standard-of-care surgery for unilateral cochlear implantation with the addition of a single-use robotic-assisted insertion device during cochlear electrode insertion. Main Outcome Measures Successful insertion of cochlear implant electrode array, electrode array insertion time, postoperative implant function. Results Successful robotic-assisted insertion of lateral wall cochlear implant electrode arrays was achieved in 20 (95.2%) of 21 patients. One insertion was unable to be achieved by either robotic-assisted or manual insertion methods, and the patient was retrospectively found to have a preexisting cochlear fracture. Mean intracochlear electrode array insertion time was 3 minutes 15 seconds. All implants with successful robotic-assisted electrode array insertion (n = 20) had normal impedance and neural response telemetry measures for up to 6 months after surgery. Conclusions Here we report the first human trial of a single-use robotic-assisted surgical device for cochlear implant electrode array insertion. This device successfully and safely inserted lateral wall cochlear implant electrode arrays from the three device manufacturers with devices approved but he Food and Drug Administration.

Reducing the foreign body response on human cochlear implants and their materials in vivo with photografted zwitterionic hydrogel coatings

Abstract: The foreign body response to implanted materials often complicates the functionality of sensitive biomedical devices. For cochlear implants, this response can reduce device performance, battery life and preservation of residual acoustic hearing. As a permanent and passive solution to the foreign body response, this work investigates ultra-low-fouling poly(carboxybetaine methacrylate) (pCBMA) thin film hydrogels that are simultaneously photo-grafted and photo-polymerized onto polydimethylsiloxane (PDMS). The cellular anti-fouling properties of these coatings are robustly maintained even after six-months subcutaneous incubation and over a broad range of cross-linker compositions. On pCBMA-coated PDMS sheets implanted subcutaneously, capsule thickness and inflammation are reduced significantly in comparison to uncoated PDMS or coatings of polymerized poly(ethylene glycol dimethacrylate) (pPEGDMA) or poly(hydroxyethyl methacrylate) (pHEMA). Further, capsule thickness is reduced over a wide range of pCBMA cross-linker compositions. On cochlear implant electrode arrays implanted subcutaneously for one year, the coating bridges over the exposed platinum electrodes and dramatically reduces the capsule thickness over the entire implant. Coated cochlear implant electrode arrays could therefore lead to persistent improved performance and reduced risk of residual hearing loss. More generally, the in vivo anti-fibrotic properties of pCBMA coatings also demonstrate potential to mitigate the fibrotic response on a variety of sensing/stimulating implants. Graphical Abstract