Safety assessment of a soft metal-free silicone peripheral nerve cuff implanted in rat models of neuropathic and inflammatory pain.

Abstract

Peripheral nerve stimulation offers a promising alternative to pharmacological treatments for chronic pain, and recent advances in direct current stimulation enable selective inhibition of nociceptive activity. However, the safety of direct current delivery systems, particularly soft, metal-free nerve cuffs, remains poorly characterized under pathological conditions. This study evaluated the safety and biocompatibility of a silicone tripolar cuff for ionic direct current delivery in naïve rats and rodent models of neuropathic (spared nerve injury) and inflammatory (complete Freund's adjuvant) pain. The cuff was implanted around the sciatic nerve and evaluated through behavioral testing (von Frey and Hargreaves), magnetic resonance imaging, and immunohistochemistry of the sciatic nerve, dorsal root ganglia, and spinal cord. In naïve cohorts, both short- and long-term implantation did not alter behavior outcomes, and neither disease model showed worsening of pain sensitivity. Across implanted groups, markers associated with immune activation and fibrotic encapsulation were upregulated. Notably, only the implanted spared nerve injury cohort exhibited additional pathological changes, including T cell infiltration in the sciatic nerve and dorsal root ganglia, elevated satellite glial and astrocytic responses, and significant interaction between injury and implantation. Demyelination and C-fiber loss were observed in spared nerve injury cohort irrespective of cuff placement, consistent with baseline injury-driven pathology. These findings indicate that the soft, metal-free cuff is well tolerated in healthy and inflammatory pain conditions but may exacerbate local inflammation and tissue changes when implanted near nerve injury. This supports its potential use in chronic pain management when implantation is distal to local injury site. PERSPECTIVE: This study provides the first comprehensive safety assessment of a soft, metal-free nerve cuff for iDC delivery in healthy and pathological pain models. This work advances iDC as a potential treatment for chronic pain, and helps identify pathological conditions in which invasive cuff implantation could exacerbate existing nerve injury.