Peripheral nerve injury (PNI) is a major clinical problem that may lead to different levels of sensory and motor dysfunction including paralysis. Due to the high disability rate and unsatisfactory prognosis, the exploration and revealment of the mechanisms involved in the PNI are urgently required. Ferroptosis, a recently identified novel form of cell death, is an iron‐dependent process. It is a unique modality of cell death, closely associated with iron concentrations, generation of reactive oxygen species, and accumulation of the lipid reactive oxygen species. These processes are regulated by multiple cellular metabolic pathways, including iron overloading, lipid peroxidation, and the glutathione/glutathione peroxidase 4 pathway. Furthermore, ferroptosis is accompanied by morphological changes in the mitochondria, such as increased membrane density and shrunken mitochondria; this association between ferroptosis and mitochondrial damage has been detected in various diseases, including spinal cord injury and PNI. The inhibition of ferroptosis can promote the repair of damaged peripheral nerves, reduce mitochondrial damage, and promote the recovery of neurological function. In this review, we intend to discuss the detailed mechanisms of ferroptosis and summarize the current researches on ferroptosis with respect to nerve injury. This review also aims at providing new insights on targeting ferroptosis for PNI treatment.

Biomaterials are widely used for bone regeneration and fracture repair. The migration of bone marrow mesenchymal stem cells (BMSCs) into bone defect sites or material implantation sites, and their differentiation into osteoblasts, is central to the fracture healing process, and the directional migration of BMSCs depends on cytokines or chemokines at the defect site. BMP-2 can stimulate the migration of a variety of cells, but it remains unclear whether BMSC migration can be induced. To provide evidence for BMP-2-induced BMSC migration, we tested the cytoskeletal changes and migration ability of BMSCs after treatment with recombinant human BMP-2 (rhBMP-2). We also explored the recruitment of BMSCs from the circulatory system using a collagen sponge incorporating rhBMP-2 that was implanted in vivo. Furthermore, to understand the mechanism underlying this migration, we investigated the effect of rhBMP-2 on migration-related signal pathways. Here, we found that, rhBMP-2 treatment significantly increased the migration of BMSCs in vitro via activation of the CDC42/PAK1/LIMK1 pathway, and that this migration could be blocked by silencing CDC42. In vivo, collagen sponge material loaded with rhBMP-2 could recruit BMSCs injected into the circulatory system. Moreover, inhibition using the small interfering RNA for CDC42 led to a significant decrease in the number of BMSCs within the material. In conclusion, our data prove that rhBMP-2 can accelerate BMSC migration via the CDC42/PAK1/LIMK1 pathway both in vivo and in vitro, and therefore provides a foundation for further understanding and application of rhBMP-2-incorporated materials by enhancing BMSC recruitment.

The treatment of osteoporotic bone defect remains a big clinical challenge because osteoporosis (OP) is associated with oxidative stress and high levels of reactive oxygen species (ROS), a condition detrimental for bone formation. Anti-oxidative nanomaterials such as selenium nanoparticles (SeNPs) have positive effect on osteogenesis owing to their pleiotropic pharmacological activity which can exert anti-oxidative stress functions to prevent bone loss and facilitate bone regeneration in OP. In the current study a strategy of one-pot method by introducing Poly (lactic acid-carbonate) (PDT) and β-Tricalcium Phosphate (β-TCP) with SeNPs, is developed to prepare an injectable, anti-collapse, shape-adaptive and adhesive bone graft substitute material (PDT-TCP-SE). The PDT-TCP-SE bone graft substitute exhibits sufficient adhesion in biological microenvironments and osteoinductive activity, angiogenic effect and anti-inflammatory as well as anti-oxidative effect in vitro and in vivo. Moreover, the PDT-TCP-SE can protect BMSCs from erastin-induced ferroptosis through the Sirt1/Nrf2/GPX4 antioxidant pathway, which, in together, demonstrated the bone graft substitute material as an emerging biomaterial with potential clinical application for the future treatment of osteoporotic bone defects. STATEMENT OF SIGNIFICANCE: Injectable, anti-collapse, adhesive, plastic and bioactive bone graft substitute was successfully synthesized. Incorporation of SeNPs with PDT into β-TCP regenerated new bone in-situ by moderating oxidative stress in osteoporotic bone defects area. The PDT-TCP-SE bone graft substitute reduced high ROS levels in osteoporotic bone defect microenvironment. The bone graft substitute could also moderate oxidative stress and inhibit ferroptosis via Sirt1/Nrf2/GPX4 pathway in vitro. Moreover, the PDT-TCP-SE bone graft substitute could alleviate the inflammatory environment and promote bone regeneration in osteoporotic bone defect in vivo. This biomaterial has the advantages of simple synthesis, biocompatibility, anti-collapse, injectable, and regulation of oxidative stress level, which has potential application value in bone tissue engineering.

Peripheral nerve injury (PNI) remains a challenging area in regenerative medicine. Nerve guide conduit (NGC) transplantation is a common treatment for PNI, but the prognosis of NGC treatment is unsatisfactory due to 1) neuromechanical unmatching and 2) the intra‐conduit inflammatory microenvironment (IME) resulting from Schwann cell pyroptosis and inflammatory‐polarized macrophages. A neuromechanically matched NGC composed of regenerated silk fibroin (RSF) loaded with poly(3,4‐ethylenedioxythiophene): poly(styrene sulfonate) (P:P) and dimethyl fumarate (DMF) are designed, which exhibits a matched elastic modulus (25.1 ± 3.5 MPa) for the peripheral nerve and the highest 80% elongation at break, better than most protein‐based conduits. Moreover, the NGC can gradually regulate the intra‐conduit IME by releasing DMF and monitoring sciatic nerve movements via piezoresistive sensing. The combination of NGC and electrical stimulation modulates the IME to support PNI regeneration by synergistically inhibiting Schwann cell pyroptosis and reducing inflammatory factor release, shifting macrophage polarization from the inflammatory M1 phenotype to the tissue regenerative M2 phenotype and resulting in functional recovery of neurons. In a rat sciatic nerve crush model, NGC promoted remyelination and functional and structural regeneration. Generally, the DMF/RSF/P:P conduit provides a new potential therapeutic approach to promote nerve repair in future clinical treatments.