New generation approaches in neural tissue engineering: Exosome-loaded 3D systems in peripheral nerve therapy

Central and peripheral nerve injuries can lead to permanent paralysis and organ dysfunction. With current methods, the return to previous quality of life after treatment of nerve damage is quite low. Complete recovery is not observed, and patients' mobility may continue to deteriorate even after treatment. Peripheral nerve injuries create a significant economic burden for patients and society by leading to disability and neuropathic pain. This comprehensive review critically evaluates the latest advances in next-generation 3D tissue engineered constructs for repairing peripheral nerve injuries (PNI). With a focus on the rational integration of electroactive biomaterials with emerging strategies from exosome biology, our analysis delves into how stem cell-derived exosomes-harvested using standardized protocols-modulate the neuroregenerative microenvironment. We dissect key molecular pathways governed by the contents of these exosomes-ranging from microRNAs (e.g., miRNA-21, miR-122-5p) to growth factors like NGF-as well as the comparative efficacy of cell-free versus cell-loaded hybrid matrices. Our discussion further explores the bioelectrical properties that allow conductive 3D matrices (i.e., containing components like rGO or PEDOT:PSS) to propagate action potential currents and synchronize with electrical stimulation to forestall nerve-damage-related muscle atrophy. Finally, through an exploration of pivotal translational challenges, including the non-biodegradability of rGO, the propensity of in vivo fluids to shunt out bioactives, and discrepancies between acute rodent models and human neural spaces, we provide a definitive roadmap towards the clinical implementation of future neuroengineering applications. We conclude with insights into scaling up EV production under Good Manufacturing Practice (GMP) conditions.