Implantation of a passive electrical neurostimulation device achieves inflammatory modulation in rodents

Vagus nerve stimulation (VNS) has been identified as a treatment for diseases ranging from depression to rheumatoid arthritis. Despite widespread interest, the modulation of both pro- and anti-inflammatory cytokines using a chronically implanted VNS device in rodents has not yet been demonstrated. Existing neuromodulation devices typically utilize application-specific integrated circuits for miniaturization. Here, we present a neuromodulation system comprising a passive, wirelessly driven, implantable neurostimulator capable of bipolar, multisite, and temporal interference stimulation. The device incorporates a bidirectional current-limiting circuit to protect tissue from excessive cathodal and anodal stimulation. System performance is validated through sciatic nerve stimulation to demonstrate functionality and versatility, and through VNS to demonstrate chronic reliability and inflammatory control in rats. After three weeks of implantation, VNS significantly modulates blood pressure and cytokine concentrations, increasing anti-inflammatory and decreasing pro-inflammatory cytokines following lipopolysaccharide injection. Passive, miniaturized neuromodulation systems may enable chronic VNS studies and facilitate clinical translation.