Peripheral nerve injury (PNI) is a complex and protracted process, and existing therapeutic approaches struggle to achieve effective nerve regeneration. Recent studies have shown that mesenchymal stem cells (MSCs) may be a pivotal choice for treating peripheral nerve injury. MSCs possess robust paracrine capabilities, and exosomes, as the primary secretome of MSCs, are considered crucial regulatory mediators involved in peripheral nerve regeneration. Exosomes, as nanocarriers, can transport various endogenous or exogenous bioactive substances to recipient cells, thereby promoting vascular and axonal regeneration while suppressing inflammation and pain. In this review, we summarize the mechanistic roles of exosomes derived from MSCs in peripheral nerve regeneration, discuss the engineering strategies for MSC-derived exosomes to improve therapeutic potential, and explore the combined effects of MSC-derived exosomes with biomaterials (nerve conduits, hydrogels) in peripheral nerve regeneration.

Neuroma, a pathological response to peripheral nerve injury, refers to the abnormal growth of nerve tissue characterized by disorganized axonal proliferation. Commonly occurring after nerve injuries, surgeries, or amputations, this condition leads to the formation of painful nodular structures. Traditional treatment options include surgical excision and pharmacological management, aiming to alleviate symptoms. However, these approaches often offer temporary relief without addressing the underlying regenerative challenges, necessitating the exploration of advanced strategies such as tissue-engineered materials for more comprehensive and effective solutions. In this study, we discussed the etiology, molecular mechanisms, and histological morphology of traumatic neuromas after peripheral nerve injury. Subsequently, we summarized and analyzed current nonsurgical and surgical treatment options, along with their advantages and disadvantages. Additionally, we emphasized recent advancements in treating traumatic neuromas with tissue-engineered material strategies. By integrating biomaterials, growth factors, cell-based approaches, and electrical stimulation, tissue engineering offers a comprehensive solution surpassing mere symptomatic relief, striving for the structural and functional restoration of damaged nerves. In conclusion, the utilization of tissue-engineered materials has the potential to significantly reduce the risk of neuroma recurrence after surgical treatment.

Severe peripheral nerve injuries, such as deficits over long distances or proximal nerve trunk injuries, pose complex reconstruction challenges that often result in unfavorable outcomes. Innovative techniques, such as nerve transposition repair with conduit suturing, can be employed to successfully treat severe peripheral nerve damage. However, cylindrical nerve guides are typically unsuitable for nerve transposition repair. Furthermore, angiogenic and neurotrophic factors are necessary to stimulate the emergence of axonal lateral sprouts, proximal growth, and the rehabilitation of neuron structures and functions. In the current study, we used chitosan to make chitin conduits with different inner diameters at both ends, combined with gelatin methacrylate hydrogels that can continuously release dual growth factors, namely, the vascular endothelial growth factor (VEGF) and the nerve growth factor (NGF), and evaluated its impact on nerve transposition repair in rats. At 16 weeks after the operation, our findings showed that the conduit combined with the dual growth factor hydrogel significantly improved the restoration of both motor and conduction functions of the nerve. In addition, histological analysis showed significant recovery of nerve fibers, target muscles, and neurons. In conclusion, the combination of chitin conduits with different inner diameters and dual growth factor hydrogels can significantly improve the effect of nerve transposition repair, which has important potential clinical value.

Background/Objectives: Peripheral neuropathy (PN) triggers early oxidative stress, disrupting Schwann cell homeostasis. In this context, mitochondria serve as a primary source and vulnerable target of reactive oxygen species (ROS). Here, we investigated whether methylcobalamin (MeCbl) mitigates oxidative stress-induced mitochondrial dysfunction. Methods: RSC96 cells were exposed to H₂O₂ to model oxidative injury, then treated with MeCbl. Mitochondrial network integrity was evaluated using super-resolution imaging coupled with quantitative morphometric analysis. RNA-sequencing was performed to identify differentially expressed genes (DEGs) and enriched biological pathways. Additionally, a network-pharmacology approach was employed to intersect the predicted MeCbl targets with the transcriptomic signature. Results: MeCbl treatment alleviated H₂O₂-induced mitochondrial fragmentation, restoring the interconnected reticulum characterized by increased branch number, total area, and a reduction in punctate mitochondria. Transcriptome analyses revealed the reprogramming of stress-response pathways. The DEGs were significantly enriched in processes including mitochondrial organization and dynamics, redox homeostasis, protein quality control, and pro-survival signaling. Network pharmacology demonstrated convergence between the MeCbl targets and DEGs at core nodes governing mitochondrial quality control and antioxidant defense, thereby providing a mechanistic basis for the imaging phenotypes. Conclusions: MeCbl improved the mitochondrial structure and remodeled the stress-response pathways in Schwann cells under oxidative stress. By linking high-resolution organelle phenotypes to molecular networks, these findings support MeCbl as a rational adjunct to mitigate oxidative stress-driven peripheral neuropathy and identify an intervenable regulatory axis for future targeted therapies.

Artificial nerve guidance conduits (NGCs) have gained significant attention in the field of peripheral nerve regeneration for the treatment of critically sized nerve defects. Nanotechnology-based NGCs are being explored as potential solutions for repairing and reconstructing peripheral nerve injuries due to their unique structure and topography. In this study, we present a novel core–sheath GelMA/PCL nanofiber construct fabricated through electrospinning and phase separation methods. The core–sheath GelMA/PCL nanofibers replicate the topological morphology of the native extracellular matrix (ECM). The outer layer, composed of GelMA, serves as an “adhesion domain” facilitating direct interaction with surrounding cells and tissues while improving wettability, integrin-mediated cell adhesion/attachment, and degradation. PCL, acting as the “elastic domain” within the nanofibers, enhances mechanical properties, maintains long-term stability of the NGCs, and enables controlled release of GelMA. Histomorphometric analysis along with electrophysiological and behavioral assessments demonstrate that these core–sheath GelMA/PCL nanofiber-based NGCs can activate endogenous mechanisms for peripheral nerve repair while promoting sensory/motor nerve regeneration and functional recovery. Overall, our findings demonstrate that GelMA/PCL nanofibers within the nuclear sheath can effectively remodel the nerve regeneration microenvironment by integrating “mechanical- biochemical” signals, thereby offering a novel strategy for addressing critical-size nerve defects.

Bone mesenchymal stem cells (BMSCs) are multipotent progenitors with significant potential for bone tissue engineering and regenerative medicine. This study compared the mitochondrial imaging and transcriptome of BMSCs under two-dimensional (2D) and three-dimensional (3D) culture conditions during osteogenesis. 2D BMSCs were induced toward osteogenesis for 7, 14, and 21 days, while 3D BMSCs were induced for 21 days. Osteogenic mineralization was assessed by Alizarin Red S (ARS) staining, and whole-transcriptome sequencing (RNA-Seq) was performed to elucidate gene expression profiles. Furthermore, mitochondrial morphology in live cells was monitored at 0, 7, 14, and 21 days of 2D osteogenic differentiation to observe the mitochondrial changes. High-Sensitivity Structured Illumination Microscopy (HIS-SIM) imaging showed that mitochondrial morphology in BMSCs underwent a shift toward elongated and interconnected networks over time. The transcriptional profile showed that genes associated with skeletal morphogenesis, bone development, and extracellular matrix organization were significantly upregulated in 3D culture systems. These findings indicate that 3D culture is associated with a transcriptional profile enriched in pathways commonly observed during in vivo osteogenesis, which can inform scaffold-based bone-regeneration strategies.