Advances in peripheral and maxillofacial nerve reconstruction: a narrative review

Introduction

Peripheral nerve injury (PNI) imposes a substantial burden on people especially the young working part. In oral and maxillofacial surgery, the most common iatrogenic nerve injury is inferior alveolar nerve (IAN) paresthesia following dental extraction or tumor resection, while trigeminal neuralgia is also a frequent condition. Despite its frequency, a perplexing clinical reality remains: Aside from oral agents such as mecobalamin and basic fibroblast growth factor (bFGF), and injectable agents such as corticosteroids and lidocaine, few effective therapeutic options are frequently used to restore nerve function or alleviate persistent symptoms (1). This leads us to question whether the reason lies in the failure to translate basic research into clinical practice promptly. Although the repair of oral and maxillofacial nerve injuries may have higher requirements than that of other peripheral nerves, the basic principles are common. Therefore, instead of address the two domains as separate fields, we integrated them and aim to explore whether insights from peripheral nerve repair strategies can inform better guidance of maxillofacial nerve injuries. In the PNI section, we elaborated on both established and emerging clinical approaches, summarizing their respective advantages, disadvantages, and current clinical status, with conclusions supported by higher-level evidence including systematic reviews and clinical trials. Subsequently, we highlight several peripheral nerve repair strategies that are also commonly used in maxillofacial settings—for example, nerve transfer for facial nerve reconstruction and neurolysis for IAN repair. In contrast, steroid therapy is more frequently applied to maxillofacial nerves than to other peripheral nerves. By linking these two domains, we aim to provide a concise clinical reference. We present this article in accordance with the Narrative Review reporting checklist (available at https://fomm.amegroups.com/article/view/10.21037/fomm-2025-1-52/rc).

Methods

The literature search was performed on PubMed, Embase, and MEDLINE databases using a combined search strategy of MeSH terms and free-text keywords for both peripheral and maxillofacial nerve injuries, limited to studies published within the past 5 years (Table 1).

Discussion

Common repair strategies for peripheral nerve defects

Many studies have demonstrated that end-to-end neurorrhaphy, when the nerve gap is short(<1 cm) and the stumps can be approximated without tension, achieves better outcomes compared with nerve grafting, while autologous nerve grafting is recommended for gaps of 1–5 cm and autologous vascularized nerve grafts are preferred for defects exceeding 5 cm (2-5). However, in many cases of nerve injury, such as large defects caused by tumor resection, infection, trauma, the nerve stumps cannot be directly approximated and sutured. In such situations, other repair methods such as nerve transplantation are required (6).

Autologous nerve graft

Autologous nerve grafting has long been regarded as the “gold standard” for repairing long nerve defects. According to the differences in circulation, autologous grafts can be classified into three types: (I) free grafts with spontaneous vascularization; (II) grafts with original vascular pedicles retained; (III) microvascular anastomosis grafts. However, Lukas et al. mentioned that due to the long operation time and the extremely low vascular requirement of most grafts because of their thin diameter, the indications for nerve transplantation with microvascular anastomosis have been narrowed to ischemic beds, large defects, and large-diameter nerve transplantation. Therefore, free autologous nerve grafting remains the major technique for nerve defect reconstruction (6).

Common donor nerves include greater auricular nerve (GAN), sural nerve, etc. Among these, GAN is convenient to harvest and has a better diameter match (7), making it suitable for repair of facial nerve branches or IANs. The sural nerve can be harvested to a length of up to 40 cm, making it suitable for long-segment defects, but a second surgical site is inevitable.

However, autografting has several limitations: (I) sensory loss, pain, or neuroma formation at the donor site; (II) the graft produces two anastomotic ends, increasing the risk of axonal loss; (III) the effectiveness of long gap repair is limited, especially when the gap exceeds 5 cm.

To avoid tension and to mitigate the effects of the suture emerged, some new suture materials such as fibrin glue have emerged to replace sutures. Heterologous fibrin sealant (HFS) consists of a fibrinogen-rich cryoprecipitate extracted from Bubalus bubalis buffalo blood and a thrombin-like enzyme purified from Crotalus durissus terrificus snake venom (8). In a rat experiment, comparing the “suture + HFS” group with the simple suture group, not only can the suture sites be reduced, but also the values related to the area and diameter of axons and nerve fibers are optimized (9). Furthermore, Tissium Company has independently developed the Coaptium Connect nerve coaptation system and photopolymerization platform called Tissium Light. It was announced in June 2025 that the system has received market access approval from the U.S. Food and Drug Administration (FDA). Its average repair strength is statistically comparable to that of microsutures (P>0.05) (10).

Allogeneic nerve graft

To avoid the donor site morbidity associated with autografts, decellularized human nerve allografts have been introduced into clinical practice. A typical product is Axogen’s Avance Nerve Graft, which was approved by the FDA in 2007. This graft is manufactured from donated human peripheral nerve tissue through rigorous tissue preparation processes, including sterilization, preconditioning, and decellularization. These steps remove residual axonal fragments within the endoneurial tubes while preserving the extracellular matrix (ECM) and laminin (LN) that promote axonal growth. Enzymatic treatment inactivates chondroitin sulfate proteoglycans (CSPGs) that inhibit axon regeneration simultaneously. Since 2007, there have been over 50,000 successful grafting cases with no reported adverse reactions related to implantation. In a multicenter study involving 385 subjects and 624 nerve repairs, Avance achieved a meaningful recovery rate of 82% for sensory, mixed, and motor nerve repairs (with gaps up to 70 mm), including 6 cases of head and neck nerve reconstruction with a 100% success rate (11).

The 2023 study by Raizman et al. found no significant difference in total procedure costs between allograft and autograft nerve repair in either inpatient or outpatient settings, with higher operating room costs for autograft offset by higher implant costs for allograft, while the cost of allografts is significantly higher than that of autografts in the inpatient setting ($25,751 and $29,560, respectively) (12). Another comparative research demonstrated allografts resulted cost savings compared with autograft and the benefits of reduced hospital stay and no donor site morbidity are evident (13). The use of allograft with the Avance clearly has the potential to be a cost-effective alternative to autograft for the surgical treatment of PNI.

Nerve transfer

Increasingly, nerve transfers are becoming the standard of care for selected PNI cause they shorten the time and distance to reinnervate muscles and they confer greater specificity in directing motor and sensory axons toward their respective targets (14).

Despite the shorter distance for reinnervation, distal nerve transfers are not always associated with a markedly speedier recovery. Bertelli et al. indicates muscle contraction is practically never noticed before 3 months, and useful function is not recognized before 12 months after surgery (15). Additionally, surgical timing is a critical factor influencing the speed of functional recovery. Dengler et al., in a multicenter retrospective cohort study of 268 patients with cervical spinal cord injury, demonstrated that surgical intervention should be performed within 6 months (16). Texakalidis et al., in a systematic review, confirmed that most successful nerve transfers for hand function are performed within the 6–12 months window, achieving finger extension recovery in 86.5% of cases (17).

Another key determinant of successful nerve transfer is the histological compatibility between donor and recipient nerves—specifically, the axon count ratio. Schreiber et al. conducted a histomorphometric analysis on 10 cadaveric specimens to quantify the axon counts of donor nerves (ulnar and median nerve fascicles) and recipient nerves (biceps and brachialis branches of the musculocutaneous nerve) commonly used in brachial plexus nerve transfers. Their findings demonstrated that a donor-to-recipient axon count ratio below 0.7:1 correlates with significantly lower rates of successful functional recovery (18). This axon count principle has since been validated in a 2023 study on gender-affirming phalloplasty, similarly applied the 0.7:1 threshold to guide donor nerve selection, confirming its generalizability across different anatomical regions (19).

Successful functional recovery after nerve transfer depends not only on effective surgery but also on central neuroplasticity—the brain’s ability to reorganize its motor programs in response to altered peripheral pathways, this process can be quantified by the Plasticity Grading Scale (PGS). Socolovsky et al. demonstrated that after facial nerve transfers, mean PGS scores were only 1.64 (hypoglossal) and 1.63 (masseter), indicating that complete cortical adaptation is rarely achieved (20). Key determinants of plasticity include age at surgery, time from injury to intervention, and quality of rehabilitation, with younger age and shorter delays predicting better outcomes (20,21).

Neural tissue engineering: nerve guidance conduits (NGCs)

In clinical applications, NGCs are generally used to repair thin diameter nerves with gaps less than 3 cm. Early NGCs were mostly hollow silicone tubes or autologous veins. In recent years, these conduits that passively provide nerve growth scaffolds gradually drop out of sight and replaced by the booming bioengineered conduits. Selim et al. classified nerve conduits into three categories in order of increasing manufacturing complexity: biomaterials-based, conventional TE-based, and AM (Additive manufacturing)-based conduits (22). Among these, the former two remain the most widely used in clinical practice because of the high cost and manufacturing complexity of the third one. The most common materials for scaffolds are listed in Table 2. Different physicochemical properties of these materials have respective effects on the behaviors of different nerve regeneration-related cells. For example, some scholars have proposed that Electrospun PCL is more suitable for the growth and migration of Schwann cells, while PLLA Nanofibers are more suitable for neural stem cells (23). Considering pure natural or synthetic materials have limited functional restoration, many scholar have been dedicated to integrate conductive materials (e.g., piezoelectric polymers, carbon nanotubes, graphene) and stem cells, exosomes, growth factors to further enhance efficacy and additive manufacturing is ideally suited for this purpose (24). To overcome the limitations of a single growth factor, some scholars try to add fillers such as platelet, which can secrete different types of growth factors such as TGF-β, FGF-2, platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) into the duct. The catheter is made by rapid 3D printing of live platelets mixed with gelatin methacrylate (GelMA) and poly(ethylene) glycol diacrylate (PEGDA). Hydrogels can significantly extend the survival time of platelets they contain (25). VEGF can promote both angiogenesis and the neural differentiation of stem cells (26).

Based on these advances, an ideal NGC should possess the following characteristics (22):

• Good biocompatibility and controllable biodegradability;
• Neuroconductivity;
• Good elasticity but with a certain mechanical robustness;
• Simulating the microstructure of the ECM;
• Porosity should allow for vascular infiltration and tissue remodeling.

Electrical stimulation——adjunctive methods

Electrical stimulation is being incorporated into nerve regeneration strategies. Instead of being used as a standalone regenerative method, it is often combined with surgery or nerve conduits, etc. In vivo studies using an 8‐mm sciatic nerve defect rat model demonstrated that the APNF‐NGC——fabricated from PEG blended with PLLA that provide wireless ultrasound-driven electrical stimulation——achieved nerve reinnervation comparable to that of autografts, as comprehensively validated by behavioral, motor function, and histological evaluations (27). In a randomized controlled trial involving 182 patients with carpal tunnel syndrome, the electrical stimulation group received alternating high- and low-frequency electrical stimulation (100 mA, 2 Hz/15 Hz, 15 minutes) intraoperatively. Follow-up assessments at 1 month and 6 months showed significantly improved sensory and motor function, muscle strength, motor conduction velocity, and maximum compound muscle action potential compared to the control group. Multiple randomized controlled trials have shown that applying postoperative electrical stimulation (PES) (typically 20 Hz, 1 hour) can significantly accelerate axonal regeneration speed and improve distal muscle reinnervation (28). Recently, conditioning electrical stimulation (CES), applied before nerve injury, has been introduced as a candidate for clinical translation. A 2025 review clarified that while both CES and PES share common downstream pathways (PI3K/MAPK activation, upregulation of BDNF and GAP43), the inflammatory environment may be a key factor contributing to the effects of PES, representing a fundamental difference from CES (29).

The mechanisms by which electrical stimulation promotes nerve regeneration may include (29):

• Enhance glucose uptake, glycolysis, and oxidative phosphorylation;
• Promote Schwann cell proliferation and polarization;
• Upregulate the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) by activating voltage-gated calcium channels (VGCC);
• Inhibit muscle atrophy and maintain endplate sensitivity.

In Table 3, we summarize the common repair strategies for PNI.

Typical methods of oral and maxillofacial nerve reconstruction

The repair strategies for PNIs reviewed above offer a valuable reference for maxillofacial nerve repair. For instance, nerve transfer techniques such as hypoglossal-facial anastomosis and masseteric nerve transfer have already been successfully adapted for facial reanimation. Likewise, Ramsay Hunt syndrome can benefit from surgical decompression, analogous to carpal tunnel syndrome (39,40). However, steroid therapy, while being the first line for Bell’s palsy, have limited clinical application in other PNIs, where they are primarily used for compression neuropathies and postoperative pain control (41,42). Moreover, several regenerative approaches—including stem cell-loaded conduits and exosome-based therapies—remain largely experimental in both fields, highlighting shared translational challenges. Based on this framework, we then focus on the management of the most common maxillofacial nerve injuries——the facial nerve and the IAN.

Selection of facial nerve repair methods

Facial palsy is classified by onset as recent (<12–18 months, with viable mimic muscles) or permanent (>18–24 months, with atrophied muscles). Etiologically, Bell’s palsy is the most common form (accounting for approximately 51–70% of cases), characterized by acute unilateral weakness with no identifiable cause. It is believed to result from viral reactivation (especially herpes simplex virus), inflammation, or ischemia of the facial nerve. First-line treatment for Bell’s palsy is oral steroids (e.g., prednisone 50mg/day for 10 days, ideally initiated within 72 hours of symptom onset), intratympanic steroid injections were also mentioned as a potential treatment option (41). Antiviral agents (Valacyclovir or Acyclovir) may be added in severe cases or when viral involvement is suspected, but antiviral monotherapy is ineffective and not recommended.

For cases of facial nerve defects caused by trauma or tumor resection, surgical intervention is required. The GAN remains the most commonly used donor for reconstructing facial nerve defects due to its proximity to the facial nerve, although sensory nerves such as GAN or sural nerve have significantly lower axonal counts per unit area compared to motor nerves including the hypoglossal and facial nerves (43). This efficacy may be attributed to the substantial functional reserve of the facial nerve, which contains far more axons than necessary for effective muscle contraction. To further optimize axonal supply, the technique of “doubling over” the GAN has been introduced clinically. Masseteric nerve transfer, hypoglossal nerve transfer, and other donor nerve techniques are also commonly used in facial reanimation surgery. However, no evidence currently supports the superiority of any single technique. Each approach has its optimal indications, and clinical decision-making should be based on patient-specific factors and preferences, including the location of the nerve defect, the viability of distal musculature, patient age, and functional expectations. A summary of these techniques is provided in Table 4.

IAN repair methods

The IAN is often injured due to tumors, inflammation and iatrogenic factors such as bilateral sagittal split osteotomy (BSSO), dental implantation, tooth extraction and root canal therapy. The incidence of IAN injury resulting from tooth extraction is relatively low and most cases heal spontaneously. For more invasive procedures like BSSO or dental implantation, the management ranges from conservative clinical follow-up to pharmacological and surgical interventions. Pharmacological options have included steroids, non-steroidal anti-inflammatory drugs (NSAIDs), mecobalamin, pregabalin, antiepileptics, antidepressants, various vitamin complexes, etc. (54). Oral selegiline hydrochloride has been proved effective to facilitate recovery, despite these benefits were confined to specific parameters and time points (55). Surgical interventions include decompression, neurolysis, grafting, and neurorrhaphy, with decompression and neurolysis showing 85% and 75% success rates, respectively, for minor injuries. In comparison, grafts and neurorrhaphy achieved 87.3% and 88.9% success rates for severe cases (56). For nerve grafting, the IAN can be repaired either as an isolated nerve graft or as part of a vascularized osteomyocutaneous flap. Another special scenario warrants consideration. In patients requiring segmental mandibular reconstruction, innervated vascularized bone flaps (e.g., iliac flap with ilioinguinal nerve or fibular flap with posterior tibial nerve) can simultaneously restore bone continuity and IAN function, with preliminary studies showing favorable sensory recovery and reduced graft bone resorption (57,58).

Preventive surgical maneuvers are equally important in minimizing trauma at the source. The implantation of dental implants in severe atrophic mandibles is restricted by the proximity of the IAN. Techniques such as IAN lateralization (displacement of the IAN without cutting the mental nerve) and transposition (repositioning of the IAN involving the transection and relocation of the mental foramen) enable implant placement but are associated with neurosensory disturbances (NSDs). The majority of nerve sensory disorders caused by lateralization typically recovers within 6 months, regardless of interposed bone graft materials or collagen membranes are placed between IAN and the implant (59-61). A systematic review distinguished between IAN lateralization and transposition, highlight that while both techniques are effective, transposition tends to carry a higher burden of transient sensory complications and slower recovery. And lateralization combined with piezo-surgery and platelet-rich fibrin (PRF) shows favorable outcomes in minimizing nerve injury and optimizing implant success (62).

As this is a narrative review, we did not systematically assess the quality of included randomized controlled trials, such as the adequacy of randomization or blinding. A few studies overly rely on subjective outcomes, such as patient satisfaction. In addition, a few systematic reviews pooled studies with different designs in their meta-analyses, which we suspect may increase the heterogeneity of the outcomes. These factors should be considered when interpreting the findings.

Conclusions

In recent years, many new breakthroughs have been made in the field of peripheral nerve repair, such as the shift from traditional hollow conduits to the current nerve tissue engineering conduits containing various neuroregenerative contents, and the transition from traditional tensioned end-to-end anastomosis to various tension-free nerve connection systems. Emerging technologies such as brain-computer interfaces (BCIs) represent future frontier. Companies like Neuralink have developed implantable devices capable of decoding cortical signals to control external devices, while Merge Labs is exploring non-invasive ultrasound-based BCIs. Although these technologies remain in early experimental stages and are not yet applicable for direct nerve repair, they may eventually offer novel strategies for bypassing proximal nerve injuries or enhancing cortical plasticity in patients with chronic paralysis. Future research hotspots should focus on: (I) determining the optimal parameters for electrical stimulation; (II) accelerating the translation of stem cell- or exosome-loaded conduits from preclinical studies to clinical practice; (III) developing personalized treatment strategies (e.g., 3D-printed conduits) based on patient-specific factors and preferences.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://fomm.amegroups.com/article/view/10.21037/fomm-2025-1-52/rc

Peer Review File: Available at https://fomm.amegroups.com/article/view/10.21037/fomm-2025-1-52/prf

Funding: This work was supported by the Shanghai Municipal Health Commission (No. 202340135) and Special Fund for RCT of Shanghai Ninth People’s Hospital (No. 2025RCTB04).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://fomm.amegroups.com/article/view/10.21037/fomm-2025-1-52/coif). L.W. serves as an unpaid Managing Editor of Frontiers of Oral and Maxillofacial Medicine from May 2019 to April 2029. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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