F. Ciotti; A. Cimolato; N. Gozzi; P. Palopoli; L. Brugnoli; N.K. Secerovic; R. Gallivan; A. Shokurov; C. Menon; J. Weichart; I. Delgado-Martinez
Advanced Functional Materials (2025) e22367
Vagus nerve stimulation shows promise for treating heart failure, epilepsy,
diabetes, psychiatric disorders, but its clinical use is yet limited, possibly due to
the poor spatial selectivity ofcuffelectrodes presently used. Existing intraneural
electrodes offer higher selectivity but are invasive and complex to implant.
An electrode with a unique feature ofcombining epineural and intraneural
contacts was developed and optimized via in silico modeling for selective
stimulation, rapid implantation, and minimal invasiveness. A tridimentional
fabrication process integrating photolithography techniques with 2-photon
polymerization was engineered to create penetrating, narrow spikes on a
flexible polyimide substrate. In vitro tests demonstrate mechanical robustness
and enhance electrochemical properties thanks to customized titanium
nitride coating. In vivo trials in rats and pigs showcase that the optimized
design enables lower-threshold stimulation with precise function targeting
and fewer off-target effects. This framework, including model-driven design
and novel fabrication process, enables precise tailoring ofneural interfaces to
diverse clinical targets, overcoming the selectivity–invasiveness trade-offand
advancing bioelectronic therapies toward closed-loop control and chronic use.