Nanostructured coatings on soft-polymer based neural probes for addressing neuroinflammation

Intracortical microelectrodes (IMEs) record neural activity with single- and multi-unit resolution and interface with brain-machine interfaces (BMIs) to control assistive devices. Long-term performance, however, remains limited by neuroinflammatory responses that progressively degrade signal quality. Multiple strategies have been explored to improve tissue-device integration, including mechanically compliant substrates to reduce strain, surface coatings to modulate cell-material interactions, and local delivery of anti-inflammatory therapeutics. Here, we combined approaches by transferring dexamethasone-loaded titania nanotube arrays (TNAs) onto a mechanically adaptive polymer nanocomposite (NC) substrate. To isolate the effects of mechanical compliance, nanostructured surfaces, and sustained local dexamethasone delivery, four implant types-silicon, NC, TNA-NC Empty, and TNA-NC DEX-were evaluated in a mouse model (n = 10 per group) at 2- and 4-week time points using a targeted 154-gene neuroinflammatory panel. At 2 weeks post-implantation, gene expression profiles were broadly similar across all implant types, reflecting a conserved acute injury response at early time points. By 4 weeks, expression patterns diverged, indicating a material-dependent tissue response over time. At this later time point, NC-based implants (NC, TNA-NC Empty, and TNA-NC DEX) exhibited fewer differentially expressed neuroinflammatory genes relative to rigid silicon implants. Notably, TNA-NC Empty implants demonstrated further improvements compared to both NC and TNA-NC DEX groups. The lack of improvement in the DEX group suggests that TNA-mediated dexamethasone delivery requires optimization. Nevertheless, the findings indicate the addition of the TNA layer to a soft, compliant material produces synergistic effects that promote the resolution of the neuroinflammatory response at 4 weeks. STATEMENT OF SIGNIFICANCE: Intracortical neural interfaces fail over time due to persistent neuroinflammation driven by mechanical mismatch, cell-material interactions, and immune activation. Prior studies have shown that mechanically compliant materials reduce strain at the tissue-device interface but do not fully resolve inflammation. We addressed this limitation by integrating anti-inflammatory and antimicrobial titania nanotube arrays (TNAs) onto a mechanically adaptive polymer nanocomposite substrate and evaluating the biological response using transcriptomic analysis. Comparisons across stiff silicon, a compliant control, and unloaded and drug-loaded TNA coatings demonstrate that combining mechanical compliance with nanoscale surface bioactivity reduces inflammation-related gene expression while increasing enrichment of tissue repair and developmental pathways. Our findings reveal the synergistic effects of materials and support the development of multi-material implant architectures.