Targeting extracellular collagen assembly to enhance functional recovery in composite neuromuscular trauma

PURPOSE: Composite neuromuscular injuries involving damage to peripheral nerves and skeletal muscles result in poor functional recovery due to excessive scarring. Current therapies lack specificity or carry significant side effects. We investigated the efficacy of a recombinant anti-collagen antibody (ACA) designed to inhibit extracellular collagen fibril formation, thereby reducing scar formation without disrupting intracellular reparative pathways. MATERIALS AND METHODS: In a rabbit model of composite injury involving a peroneal nerve crush and volumetric muscle loss of the tibialis anterior muscle, animals received local injections of an ACA-loaded or control thermoresponsive hydrogel. We measured neuromuscular functional recovery after composite injury using biomechanical and electrophysiological assays. Tissue was analyzed using histology, immunohistochemistry, and Fourier transform infrared (FTIR) spectroscopy. RESULTS: While electrophysiological parameters of injured nerves declined in all injured groups, ACA treatment markedly improved biomechanical properties of the injured limbs at 4 weeks post-injury compared to controls. This functional benefit was sexually dimorphic; females, who exhibited a more robust fibrotic response and severe muscle atrophy compared to males, demonstrated the most pronounced therapeutic recovery with ACA treatment. FTIR spectroscopy and polarized light microscopy confirmed that ACA treatment modulated the scar architecture, showing a trend toward reduced collagen content and cross-link maturity. Notably, the uninjured contralateral limbs likely exhibited compensatory hypertrophy and electrophysiological changes, highlighting their active role in systemic adaptation. CONCLUSIONS: Together, these findings suggest that targeting extracellular collagen fibrillogenesis may modestly enhance early functional recovery in composite neuromuscular trauma, particularly in biological contexts prone to excessive fibrosis.