Neural stem cell-loaded biohybrid hydrogel improves cochlear implants by electrode-neural coupling and neural regeneration

<b>Background:</b> Contemporary cochlear implants (CIs) face unresolved dual challenges: biomechanical-electrochemical mismatch at the electrode-tissue interface and progressive spiral ganglion neuron (SGN) degeneration, severely limiting long-term auditory restoration. Integrating regenerative medicine with bioelectronic engineering offers promise to overcome these bottlenecks. <b>Methods:</b> A biohybrid neural interface was developed by embedding neural stem cells (NSCs) in photopolymerized poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)/collagen hydrogel. Physicochemical properties were characterized via rheometry, electron microscopy, and electrochemical impedance spectroscopy. <i>In vitro</i> NSC responses (proliferation/differentiation) were quantified with EdU/Tuj1 assays. Therapeutic efficacy was evaluated in guinea pigs with ouabain-induced auditory neuropathy using auditory brainstem response (ABR) thresholds and immunohistochemical SGN quantification, comparing CI-alone versus NSC-hydrogel-CI groups. <b>Results:</b> The photopolymerized PEDOT:PSS/collagen hydrogel demonstrated cochlear tissue-matched viscoelastic properties (storage modulus: 8.7-12.4 kPa) with injectable sol-gel transition capability, while exhibiting enhanced bioelectronic coupling through high electrical conductivity (1.3 ± 0.1 S/m) and 97.7% reduction in charge transfer resistance. This electroactive microenvironment significantly promoted NSC proliferation (+51.6%) and neuronal differentiation (+76.4%) <i>in vitro</i>, effects further amplified by CI stimulation to achieve +71.5% proliferation and +23.4% neuronal differentiation. <i>In vivo</i> evaluation using ouabain-induced auditory neuropathy guinea pigs revealed substantial functional recovery, with ABR threshold improvements of 18.8-28.8 dB across 4-12 kHz frequencies by post-operative day 14, correlating with significant SGN regeneration in the apical turn (+11.14 cells/0.01 mm²), whereas CI-alone controls exhibited negligible recovery. <b>Conclusions:</b> This NSC-laden conductive hydrogel establishes a self-reinforcing therapeutic paradigm that simultaneously resolves electrode-tissue mismatch through optimized bioelectronic interfacing and reverses neurodegeneration via stem cell-mediated SGN regeneration. The dual-function platform pioneers active neural repair for next-generation neuroprosthetics.