Abstract
Skeletal muscle cannot regenerate after volumetric muscle loss (VML), a traumatic injury defined as the loss of > 20% of a muscle's mass. VML directly reduces the number of myofibers and causes axonal degeneration of nerves, resulting in reduced muscle function and impaired neuromuscular junctions (NMJs). Biosponge (BSG) scaffolds, composed of gelatin, collagen, and laminin-111, have been shown to improve muscle mass, cross-sectional area, and myofiber number following VML. However, improvements in NMJ quantity were not observed. Glial cell line-derived neurotrophic factor (GDNF) is a growth factor that enhances motor unit survival and neurite outgrowth. In this work, BSG scaffolds were electrostatically coupled with GDNF via gelatin nanoparticles (GNPs) to support myofiber regeneration and preserve NMJs post-VML in a rodent model. In vitro determination of release kinetics revealed an initial burst release of surface bound GDNF with almost an equivalent amount of electrostatically bound GDNF retained within the BSG post 1 week of incubation at 37°C in phosphate buffered saline (PBS). To create the VML injury in male Lewis rats (10-12 weeks old), ∼20% of the muscle mass was removed from the tibialis anterior (TA) muscle of both hindlimbs. Relative to BSG+GNP alone, treatment with BSG+GNP+GDNF showed a significant increase (∼25%) in peak isometric torque at 6 weeks post-injury. Qualitative and quantitative histological analysis of NMJs revealed an enhanced overlap between pre- and post-synaptic structures in the BSG+GNP+GDNF group. Additionally, the incorporation of GDNF slowed BSG remodeling and degradation. Overall, these results suggest that the BSG-mediated delivery of GDNF is an effective strategy for mitigating NMJ loss and enhancing muscle recovery following VML. ABSTRACT FIGURE: Graphical Abstract Tadiwala et al., 2025 Biosponges embedded with GDNF promote neuromuscular recovery following volumetric muscle loss.