Perineural Co-Administration of Bone Marrow-Derived Extracellular Vesicle Fractions and Mononuclear Cells via a Collagen Vehicle in a Rat Neuropathic Pain Model: An Exploratory Proof-of-Concept Study.

BACKGROUND: Neuropathic pain involves chronic neuroinflammation and resists conventional analgesics. Combining bone marrow-derived extracellular vesicles (EVs) and mononuclear cells (BMMNCs) may provide complementary therapeutic benefits. We evaluated localized perineural co-delivery using a collagen hydrogel vehicle in rats. NEW METHOD: Rats with chronic constriction injury received perineural collagen hydrogels loaded with EV fractions, BMMNCs, or both. Mechanical hypersensitivity was tracked using von Frey filaments over 4 weeks. Nerve preservation and inflammatory markers were evaluated using descriptive histology and exploratory molecular assays (n = 1 per group). RESULTS: Co-administration of EV fractions and BMMNCs significantly attenuated mechanical hypersensitivity compared with vehicle (P < 0.001), reaching Sham levels by week 4 while remaining comparable to EV monotherapy. Descriptive histology showed preserved axonal bundle alignment in representative combination samples. Exploratory molecular analyses suggested qualitative reductions in GFAP and TNF-alpha. COMPARISON WITH EXISTING METHODS: Unlike rapid-clearance liquid injections, this approach provides localized perineural placement using a biocompatible collagen vehicle. However, direct efficacy comparisons against free suspensions were not evaluated and warrant future study. CONCLUSIONS: Perineural co-administration of EV fractions and BMMNCs via a collagen vehicle attenuated mechanical allodynia and preserved nerve morphology. Although functional recovery was comparable to EV monotherapy and molecular findings remain exploratory (n = 1), these preliminary proof-of-concept observations support the feasibility of localized combinatorial interventions for neuropathic pain.