It is well-known that the nervous system possesses strong stability, and once damaged, spontaneous repair becomes extremely challenging (1). Peripheral nerve injuries are a common type of neurological damage in clinical practice, leading to varying degrees of autonomic dysfunction, sensory or motor impairments, localized paralysis, and chronic neuropathic pain, thereby diminishing patients’ quality of life (2). In the United States, the annual incidence rate of upper limb peripheral nerve injuries is 16.9 per 100,000 people, with an average emergency care cost of $5,779 per person. Calculated accordingly, the total annual medical expenses due to upper limb peripheral nerve injuries in the U.S. reach nearly $300 million (3). Therefore, peripheral nerve injuries represent a significant clinical and public health concern.

The causes of peripheral nerve injuries are complex, including cutting injuries, tearing injuries, traction injuries, compressive injuries, and iatrogenic injuries. Among these, traction-related peripheral nerve injuries are the most common, followed by tearing injuries and compressive injuries that can cause complete transverse damage to the affected nerves (4). Clinically, the Seddon or Sunderland classification methods are often employed. Seddon classifies the severity of nerve injuries into neurapraxia (temporary functional changes with preserved axonal continuity), axonotmesis (loss of axonal continuity with varying degrees of endoneurial disruption, temporary loss of function), and neurotmesis (complete loss of axonal and endoneurial continuity, incomplete nerve regeneration, and incomplete functional recovery) (5). Sunderland refines the Seddon classification into five degrees, corresponding to varying degrees of severity from concussion (first degree) to rupture (fifth degree), providing a more detailed assessment of overall injury severity and recovery difficulty (4).

Different nerve repair methods are adopted based on the varying degrees of nerve injury. Autologous nerve transplantation is the most widely used bridging technique for repairing peripheral nerve defects, currently considered the “gold standard” for treating long-distance peripheral nerve defects (6, 7). However, autologous nerve transplantation comes with numerous limitations and risk factors, such as denervation of the donor area, increased surgical complications, and diameter or nerve bundle mismatches. With the development of tissue engineering, tissue-engineered nerve grafts (TENG) have become an important potential alternative to autologous nerve grafts (8).

The ECM is a complex molecular network synthesized and released into the extracellular space by cells residing in tissues or organs (9). Its main components include collagen, proteoglycans/glycosaminoglycans, elastin, laminin, fibronectin, etc., providing structural support and attachment sites for cells (10). Schwann cells, as the primary glial cells in the peripheral nervous system, play various crucial roles and are considered the gold standard in cell therapy for peripheral nerve injuries (7, 11). Therefore, ECM derived from Schwann cells has become one of the most suitable biomaterials for peripheral nerve repair (7). To explore new approaches for peripheral nerve injury repair, this article provides a review of the key histological foundations of peripheral nerve regeneration - Schwann cells and ECM, as well as their interactions.

Although the peripheral nervous system possesses strong regenerative potential, spontaneous regeneration rarely occurs in cases of nerve transection, and the outcomes of treatment interventions are often unsatisfactory (12). Conservative treatment and surgical intervention are the two main approaches for peripheral nerve injury (2). Conservative treatment involves non-surgical methods to protect damaged neurons, promote nerve regeneration and maturation, thereby facilitating the recovery of nerve function (13). Surgical treatment, depending on the type and severity of peripheral nerve injury, may employ direct nerve anastomosis or bridging repair as two repair strategies (14). For injuries with a small nerve defect distance (5 mm), surgical suturing is generally considered the best repair method, while nerve transplantation is required for larger defects (≥5 mm) (15). Autologous nerve transplantation is the most widely used bridging technique in clinical practice for repairing long-distance peripheral nerve defects and is currently considered the “gold standard.” Autologous nerve transplantation has advantages such as good regeneration effects (higher vascularization, an elevated degree of anastomosis), minimal immune rejection impact, etc. However, it comes with inevitable drawbacks, including limited availability of autologous nerve grafts, denervation of the donor area, nerve tumor formation, increased infection risk, diameter mismatch, etc. Therefore, optimization and exploration of alternative solutions are crucial (16–21).

In recent years, with the advancement of tissue engineering research, tissue-engineered nerve grafts are considered promising alternatives to autologous nerve grafts (22). Tissue-engineered nerve grafts encompass tissue-engineered neural biomaterial scaffolds, mainly including nerve conduits and their fillers, with diverse structural forms. They can be tailored to repair peripheral nerves of different diameters and defect lengths, making them a current hotspot in peripheral nerve repair and regeneration (23). Tissue-engineered nerves consist of three elements: scaffold, seed cells, and soluble regulatory factors. The core idea is to use living cells to combine with ECM or scaffold material in a certain way, and add factors that induce and promote growth to form neural tissue in vitro, replacing damaged tissue (24).The neural scaffold or conduit provides a foundational space for nerve regeneration, guiding axonal regeneration and preventing scar formation. However, seed cells and soluble regulatory factors face various limitations. Therefore, there is an urgent need to find an alternative biomaterial that can support cells and growth factors, leading to the construction of a novel tissue-engineered nerve graft (25). ECM possesses various characteristics, promoting axonal regeneration while avoiding the limitations of supporting cells and growth factors. Hence, it holds the potential to replace seed cells and growth factors, becoming a crucial biomaterial in the construction of innovative tissue-engineered nerves (26, 27).

Undoubtedly, Schwann cells play a dominant role in the regeneration and development following peripheral nerve injuries (16, 28–32). Derived from the neural crest, Schwann cell precursors (SCPs) can generate various polarized cells, including Schwann cell precursors (33, 34). These precursors proliferate rapidly, developing into immature SCs, which subsequently differentiate into two mature types of SCs: myelinating SCs and non-myelinating SCs (35). In recent years, scholars have discovered another subset of mature Schwann cells (SCs), termed repair Schwann cells, which are formed through adaptive cell reprogramming following nerve injury (36). Although non-myelinating SCs do not produce myelin, they still play important roles in the peripheral nervous system, such as maintaining axonal metabolism and preventing neuropathic pain. Non-myelinating SCs still possess the potential for myelination. After axonal or nerve injury, SCs trigger defense mechanisms involving inflammation and immune responses, activate Wallerian degeneration, and promote the survival of damaged neurons and axon regeneration (7). At this stage, both myelinating and non-myelinating SCs transition to repair Schwann cells to initiate the repair process (37). This phenotypic change requires adaptive cell reprogramming of SCs, including dedifferentiation of myelin and activation of axon repair and regeneration functions (36). These characteristics indicate that SCs are highly plastic and can undergo conversion between different subtypes in response to environmental signals.

Recent studies have found that Schwann cells have functions such as migration, adhesion, ECM production, secretion of various neurotrophic factors, and bioactive substances (38, 39). Neurotrophic factors include NGF, BDNF, CNTF, FGF, NT, GAP-43, etc. (40). Secreted ECM components include FN, LN, IV collagen, V collagen, heparin sulfate proteoglycan (HSPG), and entactin (38). These ECM components are deposited outside Schwann cells to form the basal lamina. Schwann cells also synthesize cell adhesion molecules (CAMs), which affect cell adhesion. CAMs include neural cell adhesion molecule (N-CAM), neural glial cell adhesion molecule (NG-CAM), MAG, peripheral myelin protein, etc. ECM and CAMs, in the early stages of nerve regeneration, regulate the initial extension of nerves, growth rate, and maturity, promote cell adhesion, maintain the stability of growth cone advancement, and accelerate axonal initiation and growth (41).

Myelinating Schwann cells, the focus of this discussion, exhibit radial and longitudinal polarization. As myelination progresses, Schwann cells organize into distinct domains, each with a unique protein array and a set of interconnected cytoplasmic compartments. Longitudinal polarity is prominently manifested in the overall organization of myelinating Schwann cells and axons, forming distinct nodal, paranodal, and internodal compartments. Radial polarity is evident on different inner and outer membrane surfaces, present at opposite ends of the cell; the compact myelin sheath inserts between these two domains (42). Myelinating Schwann cells express many typical genes in an immature state under normal physiological conditions and many newly expressed genes (such as EGFL8 gene, H3K27 gene, Oct6 gene, and Krox20 gene). These genes regulate and drive the process of neuron survival, damaged axon breakdown, and the regeneration process. The regeneration process involves myelin clearance, axon regeneration, guiding regenerated axons to their normal physiological locations, and ultimately remyelinating the regenerated axons (35, 43, 44). Therefore, elucidating the various biochemical mechanisms influencing Schwann cell growth, proliferation, function, and apoptosis is undeniably crucial for peripheral nerve regeneration research.

Macrophages secrete interleukin (IL)-1 after injury, inducing Schwann cells to release neurotrophic factors and transforming them into a regenerative phenotype. The jun gene transcription product c-jun plays a crucial role in this process, regulating the expression of 172 genes in Schwann cells. Prolonged denervation after injury leads to a decrease in the expression of this key factor, affecting Schwann cell phenotypic differentiation. Therefore, one potential direction is to add chemical stimulants to scaffolds to upregulate c-jun expression, thereby activating more Schwann cells with the Remak Schwann cell (RSC) phenotype (30, 45). Research has shown that the guidance receptor Plexin-B2 also plays a crucial role in this process. The expression of this receptor is significantly upregulated in infiltrating macrophages of damaged nerves, and it can guide the alignment of macrophages and Schwann cells, thereby preventing collisions with axons. Conditional deletion of Plexin-B2 in the myeloid lineage not only leads to misplacement of macrophages but also results in matrix disarray and Schwann cell disintegration, consequently causing axonal misguidance and delayed functional recovery (46). Additionally, another critical cellular factor, Exendin-4, has been found to promote Schwann cell proliferation and migration by activating the Jak–STAT pathway, thereby effectively promoting the repair process after nerve injury (31).

Research has focused on improving the efficiency of basic fibroblast growth factor (bFGF) transmission in the process of nerve regeneration. bFGF is a crucial growth factor for nerve injury repair, promoting Schwann cell proliferation. In one study, a specific collagen-binding domain (CBD) was fused to the N-terminus of bFGF. This fusion complex was then combined with a linearly ordered collagen fiber scaffold. The modified scaffold was transplanted into the cut end of the rat sciatic nerve, effectively enhancing bFGF factor transmission efficiency and regeneration outcomes (30). Tomokazu Fukuda and colleagues combined a controlled release system of basic fibroblast growth factor (bFGF) with biodegradable nerve conduits. They used enzyme-linked immunosorbent assay (ELISA) to measure the release of bFGF and investigated its effects on neurovascularization and Schwann cell proliferation in a mouse sciatic nerve model. The results indicated that compared to the control group, the experimental group with the addition of the controlled release system exhibited slow release of bFGF, leading to improvements in neurovascularization and Schwann cell proliferation (47).

It has been found that beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) weakens Schwann cell-mediated peripheral nerve regeneration. Inhibiting its activity can promote muscle nerve redenervation (48). MicroRNA (miRNA) is a short endogenous RNA with the potential to regulate and silence the expression of any RNA. Injecting miRNA into ECM during the regeneration process to silence the mRNA encoding BACE1 in Schwann cells might promote nerve regeneration and muscle nerve redenervation.

Osteopontin (OPN) is a glycoprotein containing the RGD (arginine-glycine-aspartic acid) sequence, exhibiting cytokine-like, chemotactic, and pro-adhesive properties. It is expressed in Schwann cells in the degenerated distal nerve stump and is regulated by axon-derived signals, significantly reducing severe axonal multifocal neuropathy (49). OPN is crucial for the secretion of type I collagen during dentin repair, improving the microenvironment for dental nerve regeneration (50). Application of OPN in the healing of replanted mouse teeth resulted in reduced inflammation and better reinnervation of blood vessels and nerves compared to the control group (51).

The main challenge in Schwann cell research is the inability to determine to what extent in vitro cultures of human Schwann cells reflect the changes and development of Schwann cell phenotypes in the actual human peripheral nerve environment after injury. This awaits the emergence of new research methods.

This review has outlined one of the key focuses in the field of peripheral nerve regeneration: Schwann cells, ECM, and their intricate interactions. It is evident that the quality of the ECM environment directly determines the proliferation and developmental processes of Schwann cells, thereby influencing the prognosis of peripheral nerve regeneration after injury. By improving the materials and manufacturing processes of nerve conduits to alter the physicochemical properties of the ECM, and by supplementing with exogenous growth factors or modulating the expression of specific genes, we can enhance Schwann cell growth, proliferation, and directionality. This approach aims to achieve nerve structures that closely resemble normal states, maximizing functional recovery and overcoming the inconveniences associated with autologous nerve transplantation.

However, the effectiveness of tissue-engineered nerve conduits relying on the interplay between the ECM and Schwann cells for repairing peripheral nerve injuries is not consistently uniform. From the literature covered in this review, future prospects involve the use of collagen-SiO2-chitosan composite materials, employing electrospinning and 3D printing to mimic the intricate internal structures of natural peripheral nerves. Additionally, the injection of exogenous growth factors such as bFGF, along with the use of gene editing techniques to introduce enhancers, miRNA, and other methods to activate/silence specific genes necessary for maintaining the complex interaction between Schwann cells and the ECM, holds promise. This approach is expected to establish a comprehensive and precise medical industry chain for peripheral nerve injuries – one of the most common and challenging surgical injuries. This development could bring significant economic benefits and health improvements, profoundly impacting the fundamental research in neuroscience.

MJ: Conceptualization, Funding acquisition, Project administration, Supervision, Validation, Writing – original draft, Writing – review & editing. MC: Writing – original draft, Writing – review & editing. NL: Writing – original draft, Writing – review & editing.