Invasive electrical stimulation (IES) is a promising bioelectronic medicine with therapeutic potential for various nervous system diseases, including peripheral nerve injury (PNI), Parkinson's syndrome, and hysterical paralysis. However, conventional IES often leads to excessive charge accumulation on cell membranes, causing neural stimulus-inertia. This phenomenon induces complications like inflammation, immune rejection, pain, and even inhibits nerve growth. Endogenous electrical-neural signals, however, do not trigger stimulus-inertia due to their inherent biological self-adjustment. These signals mediate communication between excitable cells and promote neuronal network maturation. Therefore, mimicking the self-adjusting nature of endogenous nerve responses in external electrostimulation could potentially eliminate neural stimulus-inertia, allowing for long-lasting nerve regeneration activation. Recent advancements in electromechanically coupled nanogenerator (NG) technology offer the possibility of converting biomechanical deformations into pulsed electrical signals, correlating physiological behaviors with electrostimulation. This research introduces a neural IES system incorporating a triboelectric/piezoelectric hybrid NG (TP-hNG)-based elastic bioelectrical bandage and an implantable polyethylene dioxythiophene (PEDOT) biodegradable multi-functional nerve guide conduit (MF-NGC). This system aims to harness the body's natural rhythms to provide a more effective and biocompatible form of stimulation.

The existing literature highlights the challenges associated with conventional invasive electrical stimulation (IES) in treating neurological disorders. Studies have extensively documented the phenomenon of neural stimulus-inertia, where excessive charge accumulation on cell membranes hinders effective stimulation and promotes adverse effects. Research has explored alternative approaches, including the use of nanogenerators to convert biomechanical energy into electrical signals for targeted stimulation. However, the development of a truly biomimetic and self-regulating system that eliminates stimulus-inertia and promotes long-term nerve regeneration remains a significant challenge. This paper builds upon the existing body of work by introducing a novel system that integrates both biomechanical energy harvesting and biofeedback mechanisms to address these limitations.

This study involved the design, fabrication, and testing of a wearable neural IES system. The system consisted of two main components: a wearable bioelectronic bandage and an implantable MF-NGC. The bioelectronic bandage incorporated a TP-hNG, which converted respiratory motion into pulsed electrical signals. The TP-hNG was optimized using electrospun polyvinylidene fluoride piezoelectric nanofibers (NFs) and polypropylene electret (PP) NFs as friction layers. The design incorporated mechanical asymmetry (hard PET outer layer and flexible PDMS inner layer) to enhance contact and separation of friction layers. The MF-NGC was fabricated by integrating aligned core-shell chitosan/PEDOT NFs as the conductive layer and porous poly(ε-caprolactone) (PCL) as the outer supporting layer. The system's ability to generate synchronized pulsed electrical signals that correlated with respiratory patterns (frequency and amplitude) was validated in vivo using Sprague-Dawley (SD) rats. The impact of the biofeedback IES (Bio-iES) signals on neural stimulus-inertia was investigated both in vitro using cultured motor neurons and in vivo using a long-segmental PNI model in SD rats. In vitro studies evaluated the effect on motor neuron activity, intracellular calcium levels, and neurite growth. In vivo studies assessed nerve regeneration, myelination, angiogenesis, and motor function recovery using various techniques, including immunohistochemistry, histology, electron microscopy, and functional assessments like gait analysis and electromyography (EMG). The control groups included conventional square-wave (Sw-iES) and triangular-wave (Tw-iES) stimulation.

The results demonstrated that the wearable bioelectronic bandage successfully generated Bio-iES signals synchronized with respiratory movements. The frequency and amplitude of the Bio-iES signals closely correlated with vagus and phrenic nerve impulses. In vitro studies revealed that Bio-iES effectively eliminated neural stimulus-inertia, maintaining motor neuron activity and promoting neurite growth compared to Sw-iES and Tw-iES. In vivo experiments using a 15 mm sciatic nerve defect model showed that Bio-iES significantly accelerated nerve regeneration and functional recovery. The regenerated nerves in the Bio-iES group exhibited significantly greater diameter, higher density of Schwann cells, more extensive myelination, and increased expression of myelin-specific proteins (MBP and S100) and axon-specific proteins (NF200 and Tuj1) compared to the control groups (Sw-iES and Tw-iES). Bio-iES also promoted angiogenesis, as evidenced by increased VEGF, CD34, and CD31 expression and higher microvessel density. Functional recovery, assessed by gait analysis, CMAP, NCV, and gastrocnemius muscle weight, was significantly better in the Bio-iES group, approaching or exceeding that of the autograft group. Furthermore, Bio-iES stimulated the expression of C-fos and BDNF, key markers of neuronal activity and neurotrophic signaling, which were significantly lower in the control groups. These findings suggest that Bio-iES consistently induced calcium influx and activated the TrkB/BDNF pathway, leading to sustained nerve regeneration and functional improvement.

The findings demonstrate that the novel wearable neural IES system effectively eliminates neural stimulus-inertia, leading to significantly improved nerve regeneration and functional recovery. The biofeedback mechanism inherent in the Bio-iES signals allows for dynamic modulation of voltage-gated calcium channels, preventing the excessive charge accumulation that contributes to stimulus-inertia. The results support the hypothesis that biomimetic stimulation, synchronized with physiological rhythms, is superior to conventional constant-amplitude stimulation. The comparable outcomes to autograft in the long-segmental PNI model suggest a clinically relevant therapeutic potential for this technology. The study also highlights the importance of a well-designed nerve guide conduit (MF-NGC) in delivering the Bio-iES signals effectively and promoting nerve regeneration. The superior performance of Bio-iES compared to both Sw-iES and Tw-iES underscores the significance of the biofeedback and self-adjusting nature of the stimulation.

This study introduces a novel wearable neural IES system that utilizes biofeedback-driven electrostimulation to overcome the limitations of conventional IES. The system's ability to eliminate neural stimulus-inertia, promote nerve regeneration, and enhance functional recovery was demonstrated in both in vitro and in vivo models. The results suggest significant potential for personalized IES therapy in treating nerve injuries and neurodegenerative diseases. Future research could focus on refining the system's design, investigating its efficacy in other neurological conditions, and conducting larger-scale clinical trials to evaluate its translational potential.

The study primarily focused on a rat model of sciatic nerve injury, and the results may not be directly generalizable to humans. The long-term effects of the Bio-iES system, beyond the three-month study period, need further investigation. The use of percutaneous leads for signal delivery in the in vivo experiments might introduce potential complications, requiring further optimization for clinical translation. Additionally, while the study provides strong evidence of the effectiveness of the Bio-iES system, the precise underlying mechanisms of action may require further investigation.