Bridging the electrode-neuron gap: finite element modeling of in vitro neurotrophin gradients to optimize neuroelectronic interfaces in the inner ear

Although cochlear implant (CI) technology has allowed for the partial restoration of hearing over the last few decades, persistent challenges (e.g., poor performance in noisy environments and limited ability to decode intonation and music) remain. The electrode-neuron gap is inherent to these challenges and poses the most significant obstacle to advancing past the current plateau in CI performance. We propose the development of a neuro-regenerative nexus-a biological interface that doubly preserves native spi-ral ganglion neurons (SGNs) while precisely directing the growth of neurites arising from transplanted human pluripotent stem cell (hPSC)-derived otic neuronal progenitors (ONPs) toward the native SGN population. We hypothesized that the Polyhedrin Delivery System (PODS (R)-recombinant human brain-derived neurotrophic factor [rhBDNF]) could stably provide the adequate BDNF concentration gradient to hPSC-derived late-stage ONPs to facilitate otic neuronal differentiation and directional neurite outgrowth. To test this hypothesis, a finite element model (FEM) was constructed to simulate BDNF concentration profiles generated by PODS (R)-rhBDNF based on initial concentration and culture device geometry. For bi-ological validation of the FEM, cell culture experiments assessing survival, differentiation, neurite growth direction, and synaptic connections were conducted using a multi-chamber microfluidic device. We were able to successfully generate the optimal BDNF concentration gradient to enable survival, neuronal dif-ferentiation toward SGNs, directed neurite extension of hPSC-derived SGNs, and synaptogenesis between two hPSC-derived SGN populations. This proof-of-concept study provides a step toward the next genera-tion of CI technology.

Automated summary

This study proposes a neuro-regenerative nexus to address the challenges in cochlear implant technology. By guiding the differentiation and directional growth of stem cells, it aims to improve the performance of cochlear implants in noisy environments and music decoding. The feasibility of the proposed concept was demonstrated through finite element modeling and cell culture experiments.