Electrical Stimulation and Platelet-Rich Plasma as Complementary Approaches for Peripheral Nerve Regeneration

Abstract

Peripheral nerve injuries (PNIs) remain a major cause of long-term disability, with standard treatments such as microsurgical repair and autologous grafting often yielding incomplete recovery due to slow axonal regeneration, fibrotic scarring, and limited reinnervation. Emerging therapies, including electrical stimulation (ES) and platelet-rich plasma (PRP), have shown promise but remain insufficient as standalone interventions. ES enhances axonal elongation, remyelination, and neuroplasticity by upregulating regeneration-associated genes and neurotrophins, while PRP delivers autologous growth factors that promote angiogenesis, Schwann cell activation, immunomodulation, and antioxidant defense. Both therapies converge on shared pathways by reducing inflammation, oxidative stress, and scar formation, thereby remodeling the microenvironment into a pro-regenerative niche. Preclinical evidence indicates that combining ES and PRP provides complementary benefits, with ES priming the injury site and PRP sustaining trophic support, resulting in superior axonal density, myelination, and functional recovery compared to monotherapies. Future directions emphasize personalized protocols, optimized ES parameters, standardized PRP formulations, and integration with biomaterials and closed-loop stimulation systems. Translation to clinical practice, however, requires standardized guidelines and rigorous randomized controlled trials to validate these multimodal strategies and enable patient-specific regenerative therapies.

Graphical Abstract

A visual summary of the nerve regeneration process, showcasing how electrical stimulation and platelet-rich plasma target shared pathways through complementary mechanisms. The graphic also explores future innovations like biomaterial integration and personalized medicine approaches.

Peripheral nerve injury regeneration pathway

Highlights

Electrical stimulation and platelet-rich plasma enhance peripheral nerve regeneration.

Both reduce inflammation and oxidative stress.

Combined therapy offers enhanced recovery benefits beyond monotherapies.

Introduction

Peripheral nerve injuries (PNIs) remain a major source of long-term disability, with few therapeutic options capable of achieving complete functional recovery. These injuries typically result from trauma, surgical complications, or systemic diseases, and disproportionately affect individuals in their most productive years. Despite advances in microsurgical techniques and rehabilitation, PNIs continue to represent a significant unmet clinical challenge. The incidence of PNIs ranges between 1.5% and 3% among trauma admissions in major hospitals, rising to nearly 5% when plexus and root injuries are included (Peer and Gruber 2008; Ditty et al. 2015). Extremity trauma is the leading cause, with crush injuries showing the highest association with nerve damage, affecting nearly 1.9% of such cases (Taylor et al. 2008). Surgical injury is another important contributor, with iatrogenic damage occurring during orthopedic or maxillofacial procedures (Tayyab et al. 2022). Additional etiologies include stretch injuries, compression syndromes, and less frequent causes such as ischemia, radiation, and systemic disease–related neuropathies (Duan and Shen 2015). Despite promising preclinical evidence, there remains a critical gap in systematically evaluating the combined use of electrical stimulation and platelet-rich plasma for peripheral nerve injuries, particularly regarding optimized protocols, standardized formulations, and clinical validation.

The clinical consequences of PNIs are profound, often leading to partial or complete loss of motor, sensory, or autonomic function. The upper extremities are most commonly affected, particularly the radial, ulnar, and median nerves (Duan and Shen 2015). Delayed or inadequate treatment can result in irreversible deficits, chronic pain, and long-term disability, most often impacting young, working-age populations (Peer and Gruber 2008). Functional impairments arise from axonal discontinuity, loss of target innervation, and maladaptive central plasticity, spanning motor, sensory, and autonomic domains, all of which severely diminish quality of life.

Motor dysfunction is one of the most disabling consequences of PNIs. Depending on the severity and chronicity of the injury, patients may experience weakness, paralysis, or muscle atrophy (Navarro et al. 2007). Even when reinnervation occurs, imperfect reconnection and central reorganization often leave patients with persistent motor deficits (Rotterman et al. 2019). Sensory deficits present as numbness, paresthesia, hyperesthesia, or distorted tactile localization, driven by degeneration of sensory fibers and maladaptive reorganization of sensory maps (Adcock et al. 2021). Impaired sensory input can further compromise reflex arcs and motor recovery. Autonomic dysfunction, although less frequently reported, has significant consequences: patients may develop sweating abnormalities, vasomotor instability, trophic skin changes, and impaired thermoregulation (Shen and Zhu 1996). Many patients suffer from overlapping impairments, such as wrist drop, numbness, chronic pain, and cold intolerance following radial nerve injuries (Adcock et al. 2021). The extent of deficits is shaped by the type, location, timing of repair, and the patient’s regenerative capacity.

Standard treatment for PNIs involves microsurgical repair, nerve grafting, and structured rehabilitation. Primary neurorrhaphy, or direct end-to-end suturing, is the preferred method for clean injuries with minimal tissue loss, provided the nerve ends can be approximated without tension (Dahlin 2008). In cases with segmental nerve loss, autologous nerve grafting, typically using the sural nerve, serves as the gold standard (Grujicić et al. 2003). While functional recovery rates after grafting can exceed 80% depending on injury site and timing, grafts remain limited by donor site morbidity, restricted tissue availability, and inconsistent outcomes in long-gap (> 5 cm) injuries (Ayache et al. 2024). Rehabilitation, particularly physiotherapy, is critical to prevent muscle atrophy and joint contractures, yet even with intensive therapy, recovery is slow and frequently incomplete, especially in adults (Ryu et al., 2011; Kubiak et al. 2018). Standard therapies are constrained by delayed reinnervation, muscle atrophy, and poor outcomes in proximal lesions or older patients, with no standardized rehabilitation or outcome protocols available.

The slow biological pace of axonal regeneration is a fundamental limitation in PNI recovery. Axons typically regrow at only 1–2 mm per day under optimal conditions (Kanaya 2014). This slow rate becomes a critical barrier when the injury gap exceeds a certain threshold, typically greater than 3–4 cm in humans, beyond which the likelihood of successful spontaneous regeneration drops significantly. In cases of long-gap or proximal injuries, it may take several months for axons to reach their targets, a timeframe that exceeds the survival of the distal pathway, resulting in the progressive degeneration of Schwann cells and irreversible muscle atrophy (Höke 2011). Prolonged delays result in irreversible atrophy, fibrosis, and loss of neuromuscular junctions, contributing to poor recovery even when repair is attempted (Allodi et al. 2012). Compounding this, fibrotic scar formation creates mechanical and biochemical barriers that further obstruct regeneration. Excessive collagen deposition and perineural scarring restrict axonal growth and contribute to chronic pain (Atkins et al. 2006; Wang et al. 2019). These processes are mediated by fibroblast proliferation, extracellular matrix accumulation, and pro-fibrotic signaling, particularly via TGF-β, with Schwann cell senescence also playing a role (Liang et al. 2024). While therapeutic strategies such as fibrin glue and pharmacologic modulation of autophagy have shown promise in limiting fibrosis (Mayrhofer-Schmid et al. 2024; Ko et al. 2018), clinical success remains limited.

Electrical stimulation (ES) and growth factor therapies, including platelet-rich plasma (PRP) or neurotrophic factor delivery, have shown encouraging results but remain insufficient as standalone treatments. ES enhances axon regrowth, remyelination, and functional recovery, yet its long-term effects in humans and large-gap injuries remain inconsistent (Ni et al. 2023; Zuo et al. 2020; Gordon 2024a). Growth factors, such as BDNF and NGF, promote axonal elongation and survival, but effects are transient, and delivery challenges hinder sustained efficacy (Gordon 2016). Similarly, PRP has demonstrated improvements in myelination and axon density, though functional recovery tends to plateau in severe injuries (Song et al. 2021). These findings highlight the limitations of monotherapy and the need for more comprehensive, integrative approaches.

Isolated interventions often have limited effects, leading to interest in multimodal strategies that combine surgical, biological, and electrical approaches. Evidence shows that combining central and peripheral nerve stimulation can enhance recovery compared to using either alone. For instance, a study found that combining these treatments led to faster motor recovery in a rat model of nerve injury, with the combined group reaching pre-injury function by the third week, much sooner than those receiving only one type of stimulation (Eftekari et al. 2025). Dual gene therapy using VEGF and G-CSF demonstrated superior improvements in axonal regeneration and functional recovery compared to either factor alone (Lopes et al. 2013). Likewise, biomaterial-based approaches, such as conductive silk fibroin hydrogels enhanced with exosomes, have shown concurrent improvements in axonal regeneration, myelination, and angiogenesis (Gao et al. 2024).

One of the most compelling integrative approaches is the combination of ES and PRP therapy. ES promotes axonal regrowth and upregulates endogenous neurotrophic factors such as BDNF and NGF (Haastert-Talini et al. 2011; Alrashdan et al. 2011), while PRP supplies a sustained source of autologous growth factors including PDGF, VEGF, and IGF-1, which support axonal regeneration, modulate inflammation, and foster a pro-regenerative extracellular environment (Zheng et al. 2014; Yadav et al. 2022). When used together, these therapies appear to enhance each other’s effects: ES primes the nerve environment to respond to growth factors, while PRP sustains regeneration through angiogenesis, Schwann cell activation, and reduction of oxidative stress (Dong et al. 2023; Zhang et al. 2024).This dual approach not only enhances structural regeneration, such as axonal density and myelin thickness, but also accelerates functional outcomes, including conduction velocity and muscle reinnervation.

The objective of this review is to critically evaluate the current evidence on ES and PRP as therapeutic strategies for peripheral nerve regeneration, with a particular focus on their shared mechanisms, complementary effects, and potential for combined application. By examining their roles in modulating axonal growth, Schwann cell activity, neuroinflammation, and oxidative stress, this paper aims to highlight how integrating bioelectric and biological therapies may overcome the limitations of traditional surgical repair. Furthermore, we outline emerging directions in personalization, biomaterial integration, and clinical translation, with the ultimate goal of defining a roadmap toward patient-specific, multimodal strategies that can enhance functional recovery in PNIs.

Electrical Stimulation in Nerve Regeneration

Overview of Electrical Modalities

Transcutaneous Electrical Nerve Stimulation (TENS) is a widely used, non-invasive neuromodulation technique that delivers electrical currents through the skin to influence peripheral nerve activity. Traditionally applied for pain relief in rehabilitation, TENS has more recently been explored for its regenerative potential in PNIs. Preclinical studies have shown encouraging results: in a rabbit model, repeated TENS sessions enhanced axonal sprouting and improved conduction velocity, suggesting structural and functional benefits over several weeks of application (Li-Xin 2003). Similarly, experimental evidence demonstrates that TENS can improve myelination and functional recovery after nerve coaptation surgeries, including side-to-side and end-to-side neurorrhaphy (Zhang 2006; Tong 2001). A 2022 systematic review further concluded that TENS accelerates motor recovery, increases axon diameter, and enhances axon density, though outcomes are highly dependent on stimulation frequency and duration (Alarcón et al. 2022). Notably, low-frequency TENS (typically ~ 1–10 Hz; e.g., 4 Hz) has been reported to support structural regeneration, whereas high-frequency stimulation (generally ≥ 50 Hz; e.g., 100 Hz) may promote disorganized axonal growth and impair recovery in sciatic crush models (Cavalcante et al. 2014; Baptista et al. 2008). Thus, while TENS is promising as an adjunctive tool, optimized protocols remain essential for clinical translation.

Neuromuscular Electrical Stimulation (NMES), another established modality, delivers electrical currents directly to motor nerves or muscle bellies to induce contractions. Initially developed to counteract disuse atrophy, NMES is increasingly applied in the context of peripheral nerve injury to promote muscle reinnervation, prevent degeneration, and accelerate recovery. Evidence from both animal and clinical studies indicates that NMES enhances axonal regeneration, improves voluntary motor function, and increases the amplitude of compound muscle action potentials (CMAPs) when applied with carefully adjusted parameters (Cun-Yi 2009). Reviews of NMES for PNIs emphasize that early application helps direct axonal growth, prevents atrophy, and facilitates reinnervation, though the precise pulse width, frequency, and intensity must be individualized for effectiveness (Liu et al. 2010). Beyond PNIs, NMES has shown benefits in post-stroke rehabilitation and diabetic neuropathy, improving conduction velocity and muscle strength (Rani and Nesamony 2021). More recently, invasive NMES applied after sciatic nerve repair significantly improved outcomes, including enhanced myelination, increased axonal counts, and greater functional recovery (Petriv et al. 2023).

Recent advancements in electrical stimulation therapies for nerve regeneration have highlighted the potential of Direct Current Stimulation (DCS) in enhancing peripheral nerve repair. DCS has been shown to promote axonal alignment, Schwann cell migration, and myelination, which are essential for effective nerve regeneration. A study demonstrated that immediate electrical stimulation in the distal segment of the sciatic nerve accelerated Wallerian degeneration, facilitating faster recovery without excessive sprouting of axons (Hamid et al. 2022). Additionally, research found that asymmetric charge-balanced waveforms, a variant of DCS, could direct axon growth in retinal ganglion cells, offering insights into how DCS can be optimized for different types of nerve injuries (Peng et al. 2023). Furthermore, the synergy between electrical stimulation and topological structures in guiding axonal growth suggests that DCS could be more effective when combined with biomaterials that provide directional cues (Lu et al. 2023).

Mechanisms of Action

The regenerative effects of ES are mediated through multiple molecular and neuroplastic mechanisms. One of the key processes involves the upregulation of regeneration-associated genes and neurotrophic factors. For example, ES significantly increases the expression of Growth-Associated Protein-43 (GAP-43), which is essential for axonal sprouting and elongation. Brief stimulation has been shown to accelerate GAP-43 transcription in regenerating motoneurons, directly correlating with faster axonal outgrowth (Al-Majed et al. 2004). GAP-43 also works in conjunction with adhesion molecules such as L1 to enhance regeneration (Zhang et al. 2005). In addition, direct electrical stimulation of the injured nerve stimulates the expression of brain-derived neurotrophic factor (BDNF) and its receptor trkB, promoting downstream transcription of GAP-43 and Tα1-tubulin to enhance regenerative signaling (Gordon et al. 2009). Another critical pathway involves cyclic AMP (cAMP), as this specific ES paradigm elevates intracellular cAMP, thereby reprogramming injured neurons into a regenerative state. Pharmacological activation of this pathway using rolipram mimics this effect (Gordon 2009).

Beyond molecular activation, ES also influences neuroplasticity at spinal and cortical levels, which facilitates functional recovery. Pulsed ES has demonstrated neuroprotective effects in the spinal cord and dorsal root ganglia, preserving neurons and improving conduction velocity after sciatic nerve injury (Pei et al. 2015). At a transcriptional level, ES increases phosphorylated CREB (p-CREB) and BDNF expression within central nervous system regions, thereby enhancing synaptic plasticity and remodeling (Huang 2015). Cortical reorganization has also been observed. Clinical rehabilitation studies confirm that electrical stimulation (ES) accelerates sensorimotor recovery, a process that involves the remapping of sensory inputs and the strengthening of alternative motor pathways (Ni et al. 2023). When combined with physical exercise, ES further amplifies spinal and cortical plasticity; one study found that pairing early ES with treadmill running improved muscle reinnervation and spinal excitability modulation (Asensio-Pinilla et al. 2009).

Functionally, ES has been shown to accelerate sensorimotor recovery, improve tactile discrimination, and reduce deficits following peripheral nerve injury (Ni et al. 2023; ElAbd et al., 2022; Senger et al. 2019). Electrophysiological measures, such as increased CMAP amplitudes and faster nerve conduction velocities, confirm that ES enhances remyelination and axonal regrowth (Zhang et al. 2013; Huang et al. 2013; Pion et al. 2023). Furthermore, ES prevents denervation-induced muscle atrophy and restores muscle strength, with studies reporting improvements in mass, force generation, and contractile recovery in both animals and humans (Gabira et al. 2019; Gordon 2024b; Koopman et al. 2025). Importantly, when ES is combined with cell therapies or biomaterial scaffolds, the outcomes are even more pronounced, yielding faster reinnervation, thicker myelination, and enhanced locomotor recovery in preclinical models (Song et al. 2021; Huang et al. 2010).

Limitations and Challenges

Despite its therapeutic promise, the clinical translation of ES in nerve regeneration is hindered by several limitations. The most prominent issue is the absence of standardized protocols for stimulation parameters. Frequency, duration, and intensity vary widely across studies, making it difficult to establish universally effective regimens. Low-frequency stimulation (1–20 Hz) is generally associated with better axonal regeneration, while high-frequency protocols (> 100 Hz) may cause maladaptive effects, such as disorganized axonal growth (Cavalcante et al. 2014; Baptista et al. 2008). Similarly, timing and duration are critical: a single, brief period of stimulation applied immediately after surgery can accelerate regeneration, whereas prolonged or delayed application is less effective (Gordon 2009). Optimal current amplitudes and waveforms also remain undefined, with sub-threshold intensities minimizing tissue damage but higher intensities sometimes required for motor recruitment. Safety thresholds are not well established, and excessive stimulation risks nerve fatigue or injury.

Long-term safety is another concern. Overstimulation can cause neuronal fatigue, desensitization, or axonal degeneration, while continuous application risks promoting fibrosis around electrodes, obstructing conductivity and axonal extension (Hughes et al. 1981). Chronic stimulation may also alter neuronal excitability, producing hyperalgesia, dysesthesia, or reduced responsiveness due to maladaptive plasticity in central and peripheral circuits. In invasive applications, electrodes present additional risks of infection, scarring, and impedance changes, further compromising efficacy over time.

Perhaps most importantly, patient outcomes vary considerably depending on injury type, severity, and biological factors. Long-gap and proximal injuries, for instance, respond less favorably to ES compared with distal or crush injuries (Ransom et al. 2020). Systematic reviews of clinical studies emphasize the wide variability in stimulation protocols, frequencies ranging from 3 to 30 Hz and pulse widths from 0.1 to 1.0 ms, along with inconsistent electrode placements (Costello et al. 2023). Genetic differences also influence responsiveness: carriers of the BDNF Val66Met polymorphism, for example, exhibit impaired regeneration and reduced therapeutic response to ES, highlighting the need for personalized treatment strategies (Walters et al. 2025). Additionally, comorbidities such as diabetes further impair nerve plasticity, although carefully optimized ES still shows benefits even in these populations (Singh et al. 2015).

Biological Therapies with Growth Factors

Platelet-Rich Plasma (PRP) Composition

Platelet-rich plasma (PRP) has garnered significant attention as a promising biological therapy for peripheral nerve regeneration due to its rich content of growth factors, which are crucial for tissue repair, angiogenesis, and neurogenesis. The therapeutic potential of PRP lies in its ability to promote nerve regeneration by releasing factors such as nerve growth factor (NGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and transforming growth factor-beta (TGF-β) (Maulina and Sofia 2024). Studies have highlighted its positive impact on peripheral nerve injuries, where PRP has been shown to reduce neuronal apoptosis, stimulate vascular growth, and improve functional recovery in both animal models and clinical settings (Bastami et al. 2017). Furthermore, PRP’s ability to regulate the inflammatory microenvironment and its favorable safety profile have made it an appealing therapeutic option in regenerative medicine (Shamkin et al. 2023). These molecules are essential for angiogenesis, neurogenesis, cell proliferation, and tissue repair. For example, Beitia et al. (2023) reported that PRP preparations contained significantly elevated PDGF, TGF-β, and VEGF levels, which correlated with enhanced cell proliferation, particularly when IGF-1 was present. Similarly, reviews have confirmed the consistent presence of growth factors such as IGF-1, PDGF, VEGF, TGF-β, and FGF across different PRP preparations, all of which are critical for regenerative processes in various tissues, including nerves (Cecerska-Heryć et al. 2022; Kabiri et al. 2014).

Platelet-rich plasma’s autologous nature confers significant clinical advantages. Being derived from the patient’s own blood, PRP avoids risks of immune rejection, disease transmission, or major adverse reactions, making it highly biocompatible for regenerative applications (Mariani and Pulsatelli 2020). Its preparation is minimally invasive, typically involving venipuncture followed by centrifugation to concentrate platelets. This process can be performed quickly, cost-effectively, and without extensive processing or additives, making PRP broadly accessible for clinical use (Zollino et al. 2014; Dugrillon et al. 2002). Platelet-rich plasma (PRP) has gained significant attention in regenerative medicine due to its ability to accelerate tissue healing and promote nerve regeneration. The therapeutic effects of PRP are primarily attributed to the growth factors it contains, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-1), and brain-derived neurotrophic factor (BDNF). These factors play a crucial role in various cellular processes, including angiogenesis, Schwann cell activation, macrophage polarization, and the maintenance of redox balance (Shamkin et al. 2023; Liang et al. 2022). VEGF contributes to blood vessel formation, ensuring adequate perfusion to injured tissues, while PDGF promotes Schwann cell activation, which is vital for nerve guidance and repair. Additionally, PRP aids in creating a conducive repair environment by influencing the polarization of M2 macrophages, which support tissue regeneration (Hosseini et al. 2023; Liang et al. 2022). These coordinated processes converge at the injury site to create a pro-regenerative microenvironment that enhances tissue recovery (Fig. 1).

Fig. 1.

Mechanistic pathways of platelet-rich plasma (PRP) in neural repair

Mechanisms in Nerve Repair

Platelet-rich plasma supports peripheral nerve regeneration through a combination of vascular, cellular, and immunomodulatory mechanisms. One of the key processes involves VEGF-driven angiogenesis, which provides the vascular supply required for regenerating nerves. Nishida et al. (2018) demonstrated that VEGF-VEGFR signaling peaks within three days of injury, with VEGF-A and VEGF-B upregulation directly supporting axonal elongation. Blocking VEGF-A not only impaired angiogenesis but also inhibited neural repair, establishing a causal relationship between vascular growth and nerve regeneration. Similarly, Huang et al. (2024) showed that VEGF-A-transfected Schwann cells embedded in a biomaterial conduit significantly enhanced angiogenesis, axonal growth, and functional recovery, achieving outcomes comparable to autografts. Muratori et al. (2018) further confirmed that VEGF165 facilitates Schwann cell migration, a prerequisite for forming regenerative pathways.

Schwann cells play a pivotal role in nerve repair and respond directly to PRP-mediated signaling. Following injury, Schwann cells dedifferentiate into a repair phenotype, suppressing myelin proteins while upregulating trophic factors and adhesion molecules (Manole et al. 2022; Namgung 2015). These cells then align longitudinally to form Bands of Büngner, which physically and chemically guide regenerating axons (Bryan et al. 1999; Webber et al. 2011). Schwann cells also secrete BDNF, NGF, and VEGF, while expressing adhesion molecules such as L1-CAM and NCAM, providing critical chemotactic and haptotactic cues (Grabovyi et al. 2024; Zhang et al. 2025). Once axons reach their targets, Schwann cells redifferentiate and remyelinate the fibers, restoring conduction velocity and functional performance, processes regulated by signaling cascades such as c-Jun and Erk1/2 (Namgung 2015; Han et al. 2007). Moreover, Schwann cells are highly responsive to various forms of stimulation, which can significantly enhance their pro-regenerative functions. For instance, recent studies demonstrate that a Nanosecond Pulse Electric Field (nsPEF) can directly promote Schwann cell proliferation, migration, and the synthesis of key neurotrophic factors (Han et al. 2024a). Complementing this, research into chiral biomaterials shows that specific molecular architectures (e.g., L-phenylalanine-based hydrogels) can maintain the stem-like “repair Schwann cell” phenotype by activating critical pathways like c-Jun, thereby enhancing their capacity to support nerve regeneration (Han et al. 2024b). These findings underscore that targeted stimulation via electrical fields or engineered biomaterials can powerfully augment Schwann cell activity, further optimizing the axon-Schwann cell interactions essential for successful repair.

Platelet-rich plasma also modulates immune responses, which are critical to creating a pro-regenerative microenvironment. Yadav et al. (2022) demonstrated that PRGF (a PRP derivative) reduces pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) while promoting M2 macrophage polarization, thereby reducing inflammation and supporting axonal growth, Schwann cell activation, and remyelination. Long-term studies confirmed that PRP reduces macrophage infiltration and fibrosis, correlating with improved sciatic functional recovery and preserved muscle tissue (Pejkova et al. 2025). These effects appear to enhance the outcomes of physical modalities: for instance, Zhu et al. (2020) showed that combining PRP with ultrashort wave therapy further reduced inflammation, enhanced axonal regeneration, and improved myelination. Likewise, low-frequency ES has been reported to reduce inflammation in chemically impaired nerves, reinforcing the idea that PRP may function best as part of a multimodal regenerative approach (Liao et al. 2020).

Evidence from Preclinical and Clinical Models

Preclinical studies consistently support the regenerative potential of PRP in PNIs. In sciatic nerve transection models, PRP treatment increased axonal density, myelin sheath thickness, and nerve fiber diameter, with histological analyses showing normalized S100 protein expression, which is indicative of Schwann cell activation and remyelination (Zhu et al. 2020). Functional assessments have demonstrated earlier and stronger electrophysiological recovery, including greater CMAP amplitudes and faster nerve conduction velocities. Pejkova et al. (2025) reported that PRP-treated animals achieved 66–72% improvement in sciatic functional index (SFI) scores, alongside reduced inflammation and fibrosis. PRGF has further been shown to promote macrophage M2 polarization and enhance the expression of axonal, Schwann cell, and myelin markers, confirming both structural and immunological benefits (Yadav et al. 2022).

Emerging clinical studies suggest that PRP may translate these preclinical benefits into functional outcomes for patients. Pilot trials in compression neuropathies and entrapment syndromes, particularly carpal tunnel syndrome (CTS) and ulnar nerve entrapment, report consistent improvements in pain, function, and conduction velocity. Galán et al. (2022) observed significant gains in pain (VAS), function (QuickDASH), and symptoms (Boston CTS scale) at 12-month follow-up after PRP-assisted nerve release surgery, with no adverse events. Randomized controlled trials comparing PRP with corticosteroid injections for CTS demonstrate that PRP provides equal or superior improvements in pain and function, with benefits persisting up to six months (Wu et al. 2017; Benny et al. 2022). Other studies report improvements across electrophysiological measures and symptom scores at 1, 3, and 6 months post-injection, reinforcing the reproducibility of clinical benefits (Atwa et al. 2019; Wang et al. 2023a). Importantly, PRP appears safe, minimally invasive, and well-tolerated, with no major adverse events reported across trials (Hong et al. 2022).

Despite these encouraging results, challenges remain. The lack of standardized preparation protocols results in substantial variability in platelet concentration, growth factor content, and leukocyte presence, making it difficult to compare outcomes across studies (Wang et al. 2023a). Leukocyte-rich PRP may exacerbate inflammation, while leukocyte-poor PRP appears to favor anti-inflammatory and regenerative responses, yet no consensus exists on which formulation is optimal (Hong et al. 2022). Similarly, there is little agreement on dosage, injection frequency, or centrifugation protocols, with differences in spin speed, duration, and single- versus double-spin methods influencing the final composition and efficacy of PRP (Benny et al. 2022; Galán et al. 2022). These inconsistencies underscore the urgent need for standardized protocols to maximize PRP’s therapeutic potential in clinical nerve repair.

Intersection of Electrical Stimulation and Growth Factor Therapies

Cross-Talk Between Bioelectric Signaling and Trophic Support

Electrical stimulation (ES) and growth factor signaling share a dynamic, bidirectional relationship that underlies their potential in nerve repair. ES has consistently been shown to upregulate key neurotrophic factors, thereby conditioning both the local and central environments for regeneration. For example, ES increases expression of BDNF, NGF, NT-4/5, VEGF, and cAMP, all of which accelerate axonal elongation, enhance neuronal survival, and support functional regeneration across injury sites (Thomas et al. 2024). In rat models using conductive scaffolds, ES significantly boosted endogenous BDNF expression, enhancing Schwann cell proliferation and myelination, as evidenced by increased myelin basic protein levels (Wu et al. 2020). These effects extend beyond the peripheral injury site: ES also upregulates BDNF mRNA and phosphorylated CREB (pCREB) in the spinal cord and dorsal root ganglia, demonstrating trophic cross-talk between peripheral and central nervous system structures (Huang 2015). Mechanistically, ES-induced BDNF expression depends on calcium influx and Erk signaling; blocking either pathway abrogates the trophic effect (Wenjin et al. 2011). Similarly, ES enhances NGF expression, which has been correlated with improved locomotor recovery in spinal cord injury models (Hong et al. 2012).

The interplay works in reverse as well, with growth factors modulating neuronal excitability and responsiveness to electrical input. NGF in particular is known to enhance electrical activity in neurons. Tomioka et al. (2012) showed that NGF increased spontaneous field potential amplitude by nearly 20-fold in bone marrow-derived neurons, while Zhang et al. (2012) reported that NGF enhances action potential firing via PKMζ activation, suppressing potassium currents and boosting sodium currents to increase excitability. Earlier studies demonstrated that NGF strengthened afferent connectivity and enhanced responsiveness of dorsal horn neurons to peripheral input (Lewin et al. 1992), while classic work in PC12 cells confirmed that NGF promotes excitability and acetylcholine sensitivity (Dichter et al. 1977). When combined with ES, NGF enhances neurite outgrowth through complementary activation of ERK1/2 signaling pathways (Chang et al. 2013). Together, these findings illustrate how trophic support enhances bioelectric responsiveness, while ES simultaneously augments trophic expression, establishing a feedback loop that promotes robust nerve repair.

Complementary Mechanisms of Action

Electrical stimulation (ES) and PRP act through complementary mechanisms, including growth factor upregulation, improved vascularization, immune modulation, and cellular priming, which together enhance nerve repair and functional recovery (Table 1; Fig. 2).

Table 1.

Complementary mechanisms of electrical stimulation (ES) and platelet-rich plasma (PRP) in nerve regeneration

Treatment/Approach	Multiple models	Growth factor upregulation	Prepares the microenvironment	References
ES ↑ BDNF, NGF, VEGF, cAMP	Rat sciatic nerve	Schwann cell proliferation and myelination	Enhances glial receptivity	Thomas et al. (2024)
ES ↑ BDNF	Rat sciatic nerve	Macrophage recruitment and faster Wallerian degeneration	Supports PRP-driven angiogenesis	Wu et al. (2020)
ES ↑ Vascularization & clearance	Human progenitor cells (hNPCs)	Increased neurotrophic factors and myelination	Outperforms either treatment alone	Li et al. (2023)
ES + hNPCs	Multiple models/not model-specific	Early application is more effective than delayed application	Optimizes the response to PRP and stem cell therapies	Song et al. (2021)
ES priming (timing critical)	Rabbit sciatic nerve, SCI	Upregulation of VEGF, integrin β−8, and PI3K/AKT/mTOR signaling	Sustains ES-related vascular benefits	Zuo et al. (2020)
PRP ↑ Angiogenesis	Rodent models, scaffold studies	M2 macrophage shift with reduced TNF-α, IL-1β, and IL-6, and increased ZnSOD and GPX4	Complements ES-induced trophic signaling	Wang et al. (2022a); Yun et al. (2025)
PRP ↓ Inflammation & oxidative stress	Rat models	Increased axonal regeneration and angiogenesis with reduced muscle atrophy	Potentiates ES-induced repair	Yadav et al. (2022); Qiu et al. (2014)
PRP + bioelectric modality	Multiple models	Growth factor upregulation	Prepares the microenvironment	Zhu et al. (2020)

Fig. 2.

Mechanism of Action of ES and PRP

Preclinical and Emerging Clinical Evidence

Evidence from preclinical studies strongly supports the superior efficacy of combined ES and PRP over single modalities, demonstrating a powerful additive effect. In a rabbit sciatic nerve crush model, the combination of PRP with low-dose ultrashort wave therapy produced the greatest improvements in axon density, myelin thickness, nerve conduction, and muscle reinnervation, outperforming either treatment alone (Zhu et al. 2020). Similarly, conductive nerve conduits delivering both ES and BDNF significantly improved Schwann cell proliferation, myelination, and conduction velocity in rats (Wu et al. 2020). These combinatorial benefits are believed to arise from concurrent angiogenesis, neurotrophin upregulation, and sustained anti-inflammatory signaling (Liu and Fox 2024).

Electrical stimulation also enhances outcomes in graft-based repair strategies. Conditioning electrical stimulation (CES) has been shown to improve axonal regeneration, reinnervation, and functional recovery more effectively than postoperative stimulation or no stimulation in autograft models (Senger et al. 2020). In tibial nerve isografts, intraoperative ES improved early axonal regeneration and recovery over 21 weeks, highlighting its translational promise for graft repair (Keane et al. 2022). Likewise, PRP has demonstrated benefits in vein graft models, improving axon diameter, myelin thickness, and fascicle organization (Roque et al. 2017).

Early clinical data also provide encouraging signs. Brief postoperative ES has been used in patients with compressive neuropathies and digital nerve lacerations, leading to accelerated axonal outgrowth and functional recovery (Chan et al. 2016). Pilot studies and reviews suggest that intraoperative ES enhances axon regeneration even in delayed or long-gap injuries, primarily through cAMP and BDNF-mediated pathways (Gordon 2016; Ransom et al. 2020). However, translation of combined ES and PRP approaches to human trials remains limited.

Research Gaps and Limitations

Despite promising evidence, significant challenges remain. ES protocols vary widely in frequency, duration, and delivery method, limiting reproducibility and meta-analysis (ElAbd et al., 2022). Only a handful of randomized controlled trials (RCTs) exist for ES in peripheral nerve repair, underscoring the urgent need for larger, high-quality trials (de Mattos et al. 2021). PRP suffers from similar limitations, as preparation methods, platelet concentrations, and leukocyte content vary substantially, complicating comparisons across studies (Firat et al. 2016). Standardization of PRP composition, dosing, and delivery remains a critical barrier. While preclinical studies show strong combined effects of ES and PRP, no clinical protocols currently define optimal timing, sequencing, or dosage for integrated therapies (Zhu et al. 2020). Addressing these gaps will be essential for moving from experimental promise to standardized clinical practice.

Neuroinflammation and Oxidative Stress as Targets

Shared Pathways Modulated by ES and PRP

Neuroinflammation and oxidative stress are two critical barriers to effective peripheral nerve regeneration, and both ES and PRP have been shown to modulate these pathways. ES exerts potent immunomodulatory effects, enhancing anti-inflammatory cytokines while suppressing damaging pro-inflammatory signals. For instance, immediate ES applied to injured sciatic nerves significantly increased IL-10 levels, shifting the immune response toward a regenerative phenotype (Hamid et al. 2022). In parallel, ES consistently reduces TNF-α and IL-1β levels across multiple preclinical models, including vagus nerve stimulation and pulsed electromagnetic fields (PEMF), highlighting its ability to suppress inflammatory mediators linked to neural damage (Fontana et al. 2024; Zhou et al. 2014). These cytokine shifts reflect a balanced immune modulation, dampening harmful inflammation while maintaining regenerative responses (Taskinen et al. 2000; Tsaava et al. 2020), and are strongly correlated with improved axonal regeneration, reduced scarring, and enhanced motor recovery (Nadeau et al. 2011).

Platelet-rich plasma complements these effects by mitigating oxidative stress and bolstering endogenous antioxidant defenses. In diabetic rat models, PRP treatment reduced malondialdehyde (MDA), a marker of lipid peroxidation, while simultaneously elevating superoxide dismutase (SOD) and catalase activity (Zarin et al. 2019). In paclitaxel-induced neuropathy, PRP outperformed carvedilol in preserving nerve structure, reducing oxidative markers, and restoring antioxidant enzyme activity (Fekry et al. 2025). Reviews consistently confirm PRP’s ability to enhance antioxidant defenses and support neuroregeneration by reducing reactive oxygen species–mediated injury (Wang et al. 2022b). Together, ES and PRP converge on shared pathways of inflammation and oxidative stress, creating conditions more favorable for nerve repair.

Microenvironmental Remodeling

Plasma rich in growth factors (PRGF), a derivative of PRP, has been shown to reduce pro-inflammatory macrophages and cytokine expression, shifting the response toward regenerative macrophages that support nerve repair (Yadav et al. 2022). Moreover, ES has been demonstrated to enhance nerve regeneration by promoting cellular proliferation and guiding axon growth, particularly in conjunction with nerve guide conduits (Rahman et al. 2023). Comparative studies demonstrate that PRP outperforms hyaluronic acid in limiting scar tissue formation and promoting functional recovery in vascular conduit models (Firat et al. 2016). ES contributes indirectly by enhancing Schwann cell function and suppressing reactive gliosis, which minimizes inhibitory scar formation and facilitates axonal growth (Gu et al. 2015).

Extracellular matrix (ECM) remodeling also plays a pivotal role in regeneration. Matrix metalloproteinases (MMPs), which regulate ECM turnover, are modulated by both trophic factor release and PRP application, restoring neuroglial balance and improving regenerative potential (De Luca et al. 2022). When combined with low-dose ultrashort wave therapy, PRP not only promoted ECM remodeling but also increased myelinated fiber density, leading to better reinnervation and functional recovery compared to PRP alone (Zhu et al. 2020).

At the cellular level, PRP and ES enhance axonal elongation and synaptic reconnection. In rabbit sciatic nerve crush models, PRP combined with ultrashort wave therapy promoted early axonal regrowth, improved myelination, and increased compound muscle action potentials (CMAPs), indicating superior synaptic recovery (Zhu et al. 2020). ES itself boosts axonal extension by upregulating neurotrophins such as BDNF and activating downstream receptors like TrkB, which drive synaptic plasticity (Al-Majed et al. 2000; English et al. 2007). These effects are reinforced by the induction of regeneration-associated genes such as GAP-43 and Tα1-tubulin, which sustain axonal sprouting and elongation (Al-Majed et al. 2004; Sharma et al. 2010).

Potential for Combinatorial Therapy

The dual capacity of PRP and ES to regulate inflammation, oxidative stress, and microenvironmental remodeling suggests strong potential for combined application. PRP downregulates pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), promotes M2 macrophage polarization, reduces fibrosis, and enhances antioxidant defenses such as SOD and catalase (Yadav et al. 2022; Pejkova et al. 2025). At the same time, PRP stimulates angiogenesis and increases regenerative markers in Schwann cells and axons (e.g., S100β, MBP, PGP9.5), creating a supportive milieu for repair (Yadav et al. 2022). When combined with ES, which primes the microenvironment through neurotrophin upregulation, angiogenesis, and accelerated debris clearance, the result may be superior axonal density, enhanced remyelination, and more complete functional recovery (Zhang et al. 2024).

Beyond structural recovery, combinatorial therapy may also reduce the risk of chronic neuropathic pain. PRP has been shown to eliminate pain by resolving inflammation and completing the repair cascade, including axon regeneration (Kuffler 2013). Both preclinical and clinical studies report that PRP improves motor and sensory function while reducing neuropathic pain when used as an adjunct in nerve repair (Sánchez et al. 2017a; Bastami et al. 2017). When coupled with ES-induced neuroplasticity, PRP’s trophic and anti-inflammatory effects could prevent maladaptive circuit remodeling, thereby lowering the likelihood of persistent pain syndromes (Pejkova et al. 2025; Sánchez et al. 2017b). Taken together, the evidence suggests that targeting neuroinflammation and oxidative stress through integrated PRP and ES therapy offers a powerful, multimodal strategy to enhance structural regeneration, accelerate functional recovery, and reduce chronic pain in PNIs.

Future Directions

Reproducibility and Protocol Heterogeneity

A major barrier to clinical translation of emerging peripheral nerve regeneration therapies is poor reproducibility driven by wide variation in experimental and clinical protocols. Differences in injury models, anatomical sites, gap lengths, timing of intervention, and outcome measures lead to substantial variability in reported efficacy across studies (Dowaidar 2021; Choo et al. 2024; Li et al. 2014). As a result, even when similar therapies are tested, outcomes often diverge between research groups, underscoring the need for more standardized study designs and reporting frameworks.

This issue is especially evident in electrical stimulation research, where frequency, amplitude, waveform, duration, and timing vary markedly among studies. While several reports associate low-frequency stimulation with enhanced regeneration, others report neutral or adverse effects under different parameter sets, making cross-study comparisons difficult (Lu et al. 2008; Juckett et al. 2022; Zuo et al. 2020). Amplitude selection further contributes to inconsistency, as higher currents may improve efficacy in some contexts but increase the risk of neural damage if applied outside safe limits (McCreery et al. 1995). Recent reviews highlight that lack of uniform ES protocols and incomplete parameter reporting remain central reasons for conflicting findings in the literature (Ni et al. 2023; Costello et al. 2023).

Similar reproducibility challenges exist for platelet-rich plasma therapy because PRP products differ significantly across studies. Variations in leukocyte content, platelet concentration, activation methods, centrifugation speed, spin duration, and fraction selection produce biologically distinct preparations that are often grouped under a single label (Jayaram et al. 2023; Kobayashi et al. 2016; De Oliveira et al. 2020). These differences likely explain why some groups report strong regenerative benefits while others observe limited or inconsistent effects (Noh et al. 2018; Zheng et al. 2014). Overall, the field would benefit from consensus standards for PRP classification and preparation, as well as complete reporting of compositional metrics, to enable reliable replication and clearer interpretation of outcomes (Corsini et al. 2025).

Integration with Biomaterials and Scaffolds

A rapidly advancing frontier in nerve regeneration lies in the integration of ES and growth factors with biomaterials and scaffolds. Conductive hydrogels, nanocomposites, and electrotherapeutic scaffolds provide structural guidance while enabling localized, sustained, and even wireless electrical delivery. For example, silk–gelatin hydrogels incorporating graphene-Fe₃O₄ nanoparticles enhanced neuronal adhesion, differentiation, and neurite outgrowth, with ES further amplifying elongation by 1.5-fold over seven days (Lin et al. 2020). Similarly, wirelessly powered hydrogel platforms using capacitive coupling have restored remyelination and axonal regeneration in spinal cord injury models (Wu et al. 2024). Composite scaffolds combining silk fibroin, graphene oxide, and exosomes have demonstrated simultaneous axonal, myelin, and vascular regeneration via VEGF/NOTCH signaling (Gao et al. 2024). Injectable conductive fillers placed within nerve guidance conduits have shown autograft-comparable outcomes in rodent models, including myelination and functional recovery (Park et al. 2025).

Electrotherapeutic scaffolds (ACESs) composed of alginate and poly-acrylamide have produced robust axonal growth, muscle mass recovery, and sensory improvements, with the added advantage of minimally invasive electrode delivery (Srinivasan et al. 2023). Silk-based conductive scaffolds have further shown superior myelination and functional recovery compared to both non-ES controls and even autografts, highlighting their transformative potential (Soltani Khaboushan et al. 2024).

Beyond electrical conduction, scaffolds are being engineered for controlled delivery of growth factors. Multilayered degradable fibers releasing NT-3, BDNF, and PDGF sequentially have significantly enhanced sciatic nerve repair and locomotor recovery (Hong et al. 2018). Alginate scaffolds loaded with melatonin provided sustained antioxidant and anti-inflammatory support, improving axonal growth and conduction in long-gap injuries (Wang et al. 2023b). Core–shell nanofibers designed for dual NGF and GDNF release promoted neurite outgrowth through complementary mechanisms (Liu et al. 2021), while decellularized nerve hydrogels with NGF microchannels mimicked native structure and function (Rao et al. 2021). Silk fibroin scaffolds incorporating BDNF and VEGF achieved concurrent nerve regeneration and angiogenesis with minimal immune reaction (Liu et al. 2016).

An especially promising avenue is closed-loop stimulation systems, which adjust electrical delivery in real time based on neural activity. Triboelectric nanogenerator implants have been developed to deliver biphasic ES in response to limb motion, promoting sciatic nerve repair in rats (Zhou et al. 2022). Closed-loop peripheral nerve stimulation targeting wide-dynamic-range neurons normalized aberrant firing and alleviated pain in injury models (Beauchene et al. 2023). Active microstimulator probes and brain–computer interface systems are also under development to synchronize stimulation with motor intention, representing a leap toward adaptive and personalized neuromodulation (ElAnsary et al. 2021; Schildt 2016).

Roadmap Toward Clinical Adoption

The clinical adoption of nerve regeneration therapies is hindered by protocol heterogeneity and limited standardization. The diverse therapeutic landscape and evidence gaps, highlighting the urgent need for personalized, validated treatment protocols discussed in this roadmap (Table 2).

Table 2.

Therapeutic approaches for PNI: current status and standardization gaps

Therapy	Type	Key mechanism of action	Advantage	Limitation	Evidence level	Synergy w/ES	Synergy w/PRP	References
Primary Neurorrhaphy	Surgical	Direct end-to-end suture	Tension-free repair	Limited to clean injuries	Clinical standard	Not studied	Not studied	Dahlin (2008)
Nerve Autograft	Surgical	Biological scaffold	Gold standard for gaps	Donor site morbidity	Clinical standard	Enhanced axon growth	Not studied	Grujicić et al. (2003)
TENS	Electrical	Non-invasive neuromodulation	Easy application	Parameter-dependent	Preclinical/Clinical	N/A (is ES)	Potential	Alarcón et al. (2022)
NMES	Electrical	Muscle contraction guidance	Prevents atrophy	Requires optimization	Preclinical/Clinical	N/A (is ES)	Potential	Petriv et al. (2023)
Direct Current Stimulation	Electrical	Directional axon guidance	Cathodal targeting	Safety concerns	Preclinical	N/A (is ES)	Potential	Shen and Zhu (1995)
PRP	Biological	Multi-growth factor release	Autologous, anti-inflammatory	Composition variability	Preclinical/Clinical	High	N/A (is PRP)	Yadav et al. (2022)
Fibrin Glue	Adjunct	Limits scar formation	Reduces fibrosis	Adjunctive only	Preclinical	Not studied	Compatible	Mayrhofer-Schmid et al. (2024)
Conductive Hydrogels	Biomaterial	Scaffold + electrical cues	Combined physical/electrical support	Manufacturing complexity	Preclinical	High	High	Gao et al. (2024)
Gene Therapy (VEGF + G-CSF)	Biological	Dual factor delivery	Synergistic myelination	Technical complexity	Preclinical	Not studied	Not studied	Lopes et al. (2013)
Closed-Loop Systems	Advanced ES	Real-time adaptive stimulation	Personalized therapy	Early development	Preclinical	High (enhances ES)	Potential	Zhou et al. (2022)

Despite encouraging progress, clinical adoption of ES and PRP for nerve repair remains limited due to lack of standardization and robust trial evidence. Multiple randomized controlled trials (RCTs) demonstrate that perioperative ES improves axon outgrowth, reinnervation, and functional recovery, yet variability in frequency, amplitude, and delivery methods prevents definitive consensus (Juckett et al. 2022; Wong et al. 2015; Hardy et al. 2024). A recent meta-analysis confirmed that ES enhances functional index, muscle mass, myelin thickness, and electrophysiological outcomes, but also underscored the need for standardized protocols and real-world validation (Koopman et al. 2025; Zuo et al. 2020; Ransom et al. 2020).

Platelet-rich plasma faces even greater translational challenges. While preclinical data consistently support its ability to promote axonal regeneration, remyelination, and angiogenesis, clinical evidence remains sparse and largely restricted to small pilot studies in compression neuropathies. Comparative studies suggest PRP may outperform hyaluronic acid and other adjuncts, but heterogeneity in leukocyte content, platelet concentration, and activation protocols prevents establishment of clear recommendations (Firat et al. 2016).

Regulatory and ethical considerations further complicate clinical translation. Therapies that combine autologous biologics such as PRP with medical devices like ES may be classified as “combination products,” requiring oversight from multiple regulatory bodies and complicating approval pathways (Carpenter and Couture 2010). Biological variability in autologous products raises further challenges for standardization and quality control (Sebbagh et al. 2023). Gaps in oversight are particularly concerning in private practice settings, where premature commercialization of unproven autologous therapies has previously resulted in patient exploitation (Lysaght and Sugarman 2018). Ethical frameworks must emphasize transparency in informed consent, equitable access to therapies, and long-term monitoring for delayed adverse effects (Jonlin 2021; Lysaght et al. 2018).

Looking ahead, the field of peripheral nerve regeneration is shifting toward multimodal, integrative strategies that combine biological, electrical, and material-based interventions. Stem cell therapies, exosomes, and PRP can modulate inflammation and promote regeneration via paracrine signaling (Widodo et al. 2025). ES can dynamically enhance neuronal excitability and trophic release, particularly when integrated with smart scaffolds and closed-loop systems (Sarhane et al. 2022). Biomaterials provide structural and biochemical guidance, with conductive or drug-releasing scaffolds offering personalized regenerative cues (López-Cebral et al. 2017). Ultimately, individualized treatment strategies, tailored by injury type, patient-specific factors, and real-time biofeedback, will likely define the next generation of peripheral nerve therapies.

Conclusion

Peripheral nerve injuries remain an area of significant unmet clinical need, with current surgical and rehabilitative strategies often falling short of restoring full function. The limitations of standard therapies arise from the inherently slow rate of axonal regeneration, susceptibility to fibrosis and oxidative damage, and incomplete reinnervation of target muscles and sensory organs. Adjunctive therapies such as ES and PRP have each demonstrated regenerative potential through distinct yet complementary mechanisms. ES enhances axonal elongation, remyelination, and central neuroplasticity, while PRP delivers autologous growth factors that promote angiogenesis, Schwann cell activation, and immune modulation. Importantly, both modalities converge on shared pathways by reducing inflammation, oxidative stress, and scarring, thereby creating a permissive microenvironment for nerve repair. Emerging preclinical and early clinical evidence suggests that combining ES with PRP produces additive outcomes, offering superior structural regeneration and functional recovery compared with either approach alone. Advances in biomaterials, including conductive hydrogels, nerve guidance conduits, and closed-loop stimulation systems, further expand the potential of these therapies by enabling localized, adaptive, and sustained delivery. Nonetheless, translation into routine clinical practice remains limited by variability in ES protocols, heterogeneity in PRP formulations, and a scarcity of large-scale randomized controlled trials. Looking forward, the path to clinical adoption will require rigorous standardization of treatment parameters, personalized therapy design tailored to injury type and patient-specific factors, and integrative approaches that combine biological, electrical, and material-based modalities. With continued innovation and careful clinical validation, ES and PRP, alone and in combination, hold the promise of transforming peripheral nerve repair from partial to truly restorative outcomes.

Author Contributions

SA: writing—original draft, review and editing, conceptualization, supervision. MM: formal analysis, conceptualization, writing, and editing. MNK: formal analysis, writing. MI: conceptualization, writing—review and editing, formal analysis. MK: writing—review and editing, SM review and editing, formal analysis.

Funding

This study was supported by "Methotrexate Induced Folic Acid Deficiency Exacerbates Neuronal Necroptosis Followed by Neuroinflammation and Cognitive Dysfunction in Mice in-vivo and in-silico approaches"—project Number: SDXHQD2025083, School of Medicine, Shandong Xiehe University.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Competing Interests

The authors declare no competing interests.

Consent for Publication

The authors declare that the research was conducted without any commercial or financial relationships that could potentially create a conflict of interest.