Neuromuscular Recovery Through Integrated Bioelectronic Interfaces

Volumetric muscle loss (VML) results from extensive neuromuscular trauma and leads to debilitating chronic functional impairment. Current treatment strategies such as physical therapy, autologous muscle transfer and cell-based therapies each have significant limitations, underscoring a need for novel approaches to address VML injury. Recently, the application of neuromuscular electrical stimulation (ES) during the mid-healing stage (2 to 6 weeks) post-injury in rodent VML models has shown promise by promoting muscle hypertrophy and motor neuron regeneration. However, the potentially enhanced impact of ES applied during the acute phase (0 to 2 weeks) post-injury, its underlying mechanisms of action, and its applicability to larger mammals remain unclear.

To facilitate these experiments, novel therapeutic platforms were developed, incorporating advanced electrode materials specifically designed to (a) safely deliver electrical current and (b) quantitatively monitor electrophysiological adaptations.

In the large-animal model, compliant 10 µm microelectrode arrays were applied directly to the VML wound bed to provide ES and to record evoked neuromuscular activity. Coating the flexible arrays electrodes with the conductive polymer PEDOT: PSS markedly improved their electrochemical performance, yielding low impedance, high charge injection capacity, and robust charge storage. With this platform, muscle recruitment curves and detailed three-dimensional evoked potential maps were generated, revealing neuromuscular activation patterns and identifying localized functional deficits in the injured tissue. Furthermore, ES applied during the acute phase post-VML led to marked transcriptional and proteomic changes, characterized by the upregulation of genes linked to muscle stem cell activation, cellular proliferation and fusion, neurogenic lineage commitment, and anti-inflammatory protein expression.

In the rodent model, implanted electrodes modified with nano-platinum (NanoPt) enabled safe, high efficiency charge delivery and spontaneous electromyographic (EMG) recording without the use of general anesthesia. Histological and impedance analyses indicated that ES-treated defects have enhanced myofiber preservation and less fibrotic tissue formation. Furthermore, spontaneous EMG recordings indicate that acute-phase ES preserved muscle fiber bursting activity that was otherwise lost in untreated defects. Importantly, the acute-phase ES treatment enhanced functional torque production. Animals receiving ES exhibited measurable strength improvements by two weeks post-injury, the earliest such enhancement reported in a VML model. The functional improvement persisted through at least eight weeks post-injury, accompanied by sustained reductions in fibrotic scar tissue. Muscle fiber cross sectional area analyses confirmed acute-phase ES, in addition to preserving neuromuscular integrity induced hypertrophy. Together, these findings strongly support the incorporation of acute-phase ES therapy into clinical protocols for patients with severe muscle injuries.