Advances in sciatic nerve regeneration: A review of contemporary techniques

Abstract

Sciatic nerve injury, affecting the longest and thickest nerve in the human body, often leads to severe pain, weakness, and impaired motor function in the lower extremities. Despite the peripheral nervous system's inherent capacity for some degree of regeneration, complete recovery remains elusive, necessitating advanced therapeutic approaches. This review explores two promising modalities electrical stimulation (ES) and platelet-rich plasma (PRP) that have shown the potential to enhance nerve repair and functional recovery. ES, through techniques such as transcutaneous electrical nerve stimulation (TENS), neuromuscular electrical stimulation (NMES), and direct current stimulation (DCS), facilitates neuronal regeneration by guiding axonal growth, releasing neurotrophic factors, and promoting synaptic plasticity. PRP, derived from autologous blood, is rich in growth factors such as Platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and nerve growth factor (NGF), which are essential for nerve regeneration, angiogenesis, and reducing inflammation. Clinical evidence supports the efficacy of ES and PRP in promoting nerve regeneration and functional recovery (Figure 1). However, further research is needed to optimize their application and understand their long-term outcomes. This review highlights the potential of these therapies to capitalize on their actions, potentially creating a robust regenerative milieu. Further research is needed to optimize treatment procedures and validate their efficacy and safety in humans.

1. Introduction

The sciatic nerve, the human body's longest and thickest nerve, plays a crucial role in transmitting sensory and motor signals from the lower back, through the buttocks, and down each leg [1]. Despite its significance, the sciatic nerve is prone to injury and damage due to various factors, including trauma, herniated discs, spinal stenosis, and piriformis syndrome [2,3]. Such injuries can result in debilitating consequences, such as pain, weakness, numbness, and impaired motor function in the lower extremities [4]. Factors influencing the severity of the injury and the potential for nerve regeneration include the location of the injury, the extent of nerve damage, and the patient's age and overall health [5]. However, while the peripheral nervous system (PNS), including sciatic nerve regeneration capacity, may exist to some degree, its ability can often prove inadequate and lead to incomplete recovery or permanent neurological deficits [1]. Consequently, there is an urgent need to explore innovative therapeutic strategies to enhance neuronal regeneration and repair after sciatic nerve injury [5,6].

Neuronal regeneration and repair are crucial in neuroscience and clinical medicine, as the brain and spinal cord control motor function through peripheral nerves [7,8]. Nerve injuries, such as sciatic nerve injury, disrupt neural networks and result in debilitating symptoms, including muscle atrophy, decreased blood flow, and sensory deficits [9]. Restoring lost function through neuronal regeneration can alleviate pain and prevent long-term disability, highlighting its importance in promoting optimal healing [10,11]. Understanding the role neuroplasticity plays in recovery is of great significance this understanding highlights how therapies that promote this natural capacity for adaptability may accelerate functional recovery [12].

This review aims to elucidate the potential of contemporary approaches especially electrical stimulation (ES) and platelet-derived rich plasma (PRP), in promoting nerve regeneration and functional recovery following sciatic nerve injury. The review emphasizes ES and PRP because of their non-invasive nature, affordability, and recognized success in promoting nerve regeneration and functional recovery. These have shown higher efficiency and better outcomes, which makes them the most practical and promising options for enhancing nerve repair. ES is known for its ability to modulate cellular activity and guide nerve growth, while PRP harnesses the regenerative properties of growth factors and cytokines found in platelets. By examining the effects of these approaches on neuronal regeneration, this review aims to highlight their mechanisms of action, clinical evidence, and potential implementation for enhancing patient outcomes in sciatic nerve injury cases. Understanding these approaches could transform nerve injury management and facilitate successful nerve repair and functional recovery. Ultimately, this review lays the groundwork for further advancements in nerve injury management and regenerative medicine, offering valuable insights into the future of nerve regeneration and repair.

2. Approaches to promote PNS repair and recovery

Peripheral nerve injuries (PNI), particularly sciatic nerve traumas, present significant barriers to recovery and quality of life due to their impact on motor and sensory functions [[13], [14], [15]]. As these injuries often require multiple strategies for successful repair and recovery, these injuries require multifaceted approaches to treatment. From traditional surgical interventions and physical therapy to cutting-edge stem cell and gene therapies, each approach to nerve regeneration offers distinct advantages [16,17]. Advanced approaches like gene therapy and stem cell therapy are invasive, expensive, and time-consuming thus limiting their application in sciatic nerve injury. Traditional surgeries, neurotrophic factors, and physiotherapies play a significant role in healing and recovery from peripheral nerve injuries, providing essential components for successful management. Understanding these strategies offers the best chance at improving outcomes and regaining function following sciatic nerve injury [18].

2.1. Neurotrophic factors

Neurotrophic factors (NF), which include nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF) play an essential role in nerve regeneration [19]. They enhance neuron survival, guide axonal regrowth, and increase synaptic plasticity, resulting in nerve repair and regeneration [20]. They specifically bind receptors on nerve cells, activate intracellular signaling pathways that protect cells from death, and encourage their growth and differentiation [21]. Administering NGF has been investigated to speed nerve regeneration following injuries to sciatic nerves. In connection with this, the administration of purified NGF in rats has been reported to enhance motor and sensory functions and improve muscle action potential, and motor distal latency in rats with sciatic nerve injury [22]. In another study, rats with sciatic nerve injuries were treated with NGF and GDNF, both individually and in combination, using a delivery system. The treatment resulted in increased fibre density, neural tissues, and myelinated area [23]. Similarly, mineral-coated NGF and GDNF were administered to rats with sciatic nerve injuries that significantly increased axonal growth and function, starting from the 7th week and continuing until the 12th week of administration [24]. A similar outcome has been reported with the use of concentrated growth factors. It has been reported that administration of concentrated NGF and GDNF to rats resulted in increased Schwann cell proliferation and improved functions [25]. Studies in rats have also reported positive outcomes of BDNF. It has been reported that mimicked BDNF peptides used in hydrogel promoted Schwann cell activity and vascular penetration in rats [26]. Similarly, Polylactic-co-glycolic acid microspheres impregnated with BDNF effectively promoted sciatic nerve repair after injury in rats [27]. The research indicates that NF significantly promotes sciatic nerve repair and recovery. However, challenges are also associated with NF delivery for sciatic nerve repair. Simple administration of NFs is insufficient due to their short half-life and rapid deactivation in body fluids [15]. Delivery systems like nerve conduits are needed for controlled release [15]. High doses of NFs are required, raising concerns about duration, dosage, and immune response [28]. A combination of multiple NFs is often needed for optimal effects rather than a single factor [29]. Endogenous production of NFs may be limited after injury and not sufficient for repair [20]. Further research is needed to overcome these limitations.

2.2. Surgical interventions

Surgery is often needed after major accidents that have resulted in nerve damage or discontinuity in function [30]. Surgical interventions include neurolysis, sutures, grafting, tandem transfer, and angiogenesis. Studies have reported different outcomes of the aforementioned interventions. A retrospective study reported that patients with sciatic nerve injuries in which positive intraoperative nerve action potentials underwent neurolysis and suture interventions. In both cases, at least Grade 3 functional outcomes were obtained in 87 % of patients with neurolysis and 73 % of patients with sutures, respectively [31]. Nerve Grafting/Repair involves transplanting healthy nerve segments from another part of the body into injured ones to bridge gaps caused by injury and provide scaffolds through which new regenerating axons may grow [32]. In a study on patients with peroneal nerve injuries, nerve grafting was performed, and functional recovery was observed [33]. A systematic review has reported that graft lengths of less than 4 cm within the intermediate region yielded more successful outcomes [34]. Tendon transfer, which involves rerouting a functional tendon from its original attachment to a new site to replace the function of a damaged nerve, has been reported to enhance functions in patients with sciatic nerve injuries [33]. Surgical angiogenesis applied to nerve grafts in a sciatic nerve injury rat model has been reported to enhance nerve regeneration. It increased vascularity in the nerve graft, with subsequent improvement of early muscle force recovery in the model [35]. Surgical interventions for sciatic nerve repair show inconsistent outcomes. Insufficient graft material, the nature of the injury site where some areas recover early while others recover late, and a lack of standardized outcome measures are limitations of the surgical interventions that hinder the practical implementation of these interventions [36]. Further research is needed to address these challenges and improve the efficacy of the procedures.

2.3. Physical therapy and rehabilitation

Physical therapy and rehabilitation play an integral part in recovery after experiencing peripheral nerve injury such as sciatic nerve damage. These programs aim to restore muscle strength, enhance coordination skills, and maximize nerve health through targeted exercises and training programs [37]. Physical exercise, electrical stimulation, and the use of biomaterials have been studied for their role in sciatic nerve repair [38]. A systematic review has reported that active exercise and electrical stimulation, both alone and in combination, promote axonal regeneration and improve function. Outcomes have been measured through electrophysiological recordings, the Sciatic Functional Index (SFI), and Compound Muscle Action Potentials (CMAPs) [39]. The authors argue that for humans, too little research has been conducted on this topic to reach a definitive conclusion. Future studies are needed to test the validity of these methods as potential rehabilitation treatments in humans [39]. In a study, the impact of biomaterial cues combined with physical therapy has been evaluated for functional recovery in a rat sciatic nerve injury model. Nerve growth conduits were filled with hyaluronic acid fibers and growth factors that resulted in improved recovery and functionalities [40]. Combining different physical therapies with biomaterials may further boost these outcomes, though their timing and dosage must be carefully managed to prevent potential negative side effects [41,42]. Further research is necessary to optimize rehabilitation strategies in human clinical environments and prove their efficacy.

2.4. Nutritional support

Nutrition can play an essential part in supporting nerve repair and overall health, particularly following peripheral nerve injuries such as sciatic nerve damage. Proper nutrition - including an intake of essential vitamins, minerals, and antioxidants - provides essential support for natural healing processes within the body as well as creating the conditions needed for nerve regeneration [43]. Vitamins such as B-complex (B1, B6, and B12) play an integral part in nerve health by aiding with neurotransmitter production and supporting myelin sheath protection for nerve fibers [44]. It has been reported that admonition of vitamin B12 and α lipoic acid enhances nerve regeneration in rats. However, their human impact is yet to be confirmed [45]. Similarly, vitamin K supplementation in a rabbit with sciatic nerve injury resulted in enhanced functional recovery [46]. Antioxidants help combat oxidative stress that impedes nerve repair while certain amino acids and fatty acids provide structural integrity of nerve cells [47]. Supplementing and eating foods rich in these nerve-supportive nutrients may improve their efficacy as part of therapy interventions used to recover nerve function.

2.5. Innovative techniques

Advanced technologies such as ES, PRP, stem cell therapy, and gene therapy represent cutting-edge peripheral nerve repair strategies with great promise to accelerate nerve regeneration and healing. Stem cell therapy entails using mesenchymal stem cells (MSCs) or neural stem cells (NSCs) to facilitate tissue regeneration, reduce inflammation, and support new neuron growth [48,49]. These cells can then develop into various cell types such as neurons and Schwann cells that aid the healing of damaged nerves. Gene therapy involves administering specific genes directly into nerve cells to promote regeneration or protect against cell death [50]. Stem cell and gene therapies offer great potential in treating complex nerve injuries like sciatic nerve damage by upregulating the production of neurotrophic factors or proteins essential for repair [51]. However, stem cell and gene therapy are in their early stages of exploration. These are invasive, expensive, and time-consuming. Such limitations hinder their application in sciatic nerve injury. ES and PRP on the other hand are the best choices for successful treatment of the sciatic nerve injury. PRP provides indigenous growth factors required for the natural healing process while ES enhances the healing process by providing a continuous stimulus to the affected area. Both approaches hold immense promise as ways to manage such injuries in the future effectively.

3. Therapies for PNS regeneration

3.1. Electrical stimulation

ES, a therapeutic technique involving controlled electrical currents applied to biological tissues or cells, holds promise for promoting neuronal regeneration and repair following peripheral nerve injuries, such as sciatic nerve injuries [52,53]. This non-invasive or minimally invasive approach can be implemented through various methods with unique characteristics and applications. Transcutaneous Electrical Nerve Stimulation (TENS) is one such method where electrodes are placed on the skin surface over the affected area and is commonly used for pain relief. It may indirectly influence nerve regeneration by modulating pain perception and the release of endogenous opioids [54]. TENS therapy employs specific parameters, with High-frequency (HF) TENS (50–100 Hz) for acute pain management and Low-frequency (LF) TENS (1–10 Hz) for chronic pain conditions [55]. The pulse width, representing the duration of each electrical pulse, is crucial in TENS therapy, with short pulse widths (50–80 μs) targeting superficial nerves and long pulse widths (200–400 μs) penetrating deeper [54,55].

Another method, neuromuscular electrical stimulation (NMES), involves stimulating motor nerves to induce muscle contractions, aiding in preventing muscle atrophy and improving muscle function in cases of denervation or disuse, thereby supporting the regenerative process [56]. Direct Current Stimulation (DCS) applies a constant electrical current to tissues or nerves, influencing cell membrane polarization, and is investigated for its potential to promote axonal growth and regeneration [57]. Pulsed Electromagnetic Field (PEMF) utilizes magnetic fields to generate electrical currents within tissues, studied for its effects on cellular activity, including promoting nerve regeneration [58]. These methods represent the diverse applications of ES in promoting nerve regeneration and repair, highlighting its potential in advancing therapeutic approaches for peripheral nerve injuries.

Following nerve injury, a series of molecular mechanisms are activated to promote axonal growth and repair. Electrical stimulation has been shown to enhance these processes by upregulating key signaling pathways. One of the central players in this response is Brain-Derived Neurotrophic Factor (BDNF), a growth factor that supports neuronal survival and growth. BDNF activates several downstream pathways, including the cAMP-PKA pathway. In this pathway, adenyl cyclase converts ATP into cyclic AMP (cAMP), which then activates Protein Kinase A (PKA). PKA, in turn, phosphorylates the transcription factor CREB (cAMP Response Element-Binding Protein), leading to the transcription of genes involved in neuronal growth and repair [56] (see Fig. 1).

Fig. 1.

Graphical abstract.

BDNF also activates the Ras-MAPK pathway, which involves a cascade of kinases including Ras, Raf, Mek 1/2, and ERK. This pathway regulates cell proliferation, differentiation, and survival, further supporting axonal growth. Another critical pathway activated by BDNF is the PI3K-AKT pathway. PI3K phosphorylates and activates AKT, which promotes cell survival and growth by inhibiting apoptosis and enhancing protein synthesis. The p38 MAPK pathway also plays a role in axonal regeneration by modulating cytoskeletal dynamics and gene expression in response to stress [58]. These pathways collectively regulate the expression of growth factors and cytoskeletal proteins, such as Growth-Associated Protein 43 (GAP-43) and actin, which are essential for the formation of growth cones and axonal elongation (Fig. 2).

Fig. 2.

Mechanistic pathways of electrical stimulation (ES) in treating peripheral nerve injuries (PNI). Key factors involved include brain-derived neurotrophic factor (BDNF) and its receptor Trk, MEK 1/2, P38 MAPK, PI3K, AKT, ATP, cAMP, PKA, CREB, glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and growth-associated protein-43 (GAP-43).

The integration of these signaling pathways leads to enhanced transcription, translation, and cytoskeletal reorganization, ultimately promoting axonal growth and repair. Electrical stimulation amplifies these molecular mechanisms, making it a promising therapeutic approach for nerve injury recovery. This comprehensive understanding of the molecular processes involved in axonal regeneration highlights the potential for targeted interventions to improve outcomes following nerve injury.

3.1.1. Mechanisms of action

ES's regenerative effects on neuronal tissue result from a complex interplay of cellular and molecular mechanisms [59]. The application of controlled electrical currents to injured nerves or surrounding tissues initiates a series of events that facilitate neuronal regeneration and repair [60]. This interplay involves guiding axonal regeneration, the extensions of nerve cells that transmit electrical signals, by altering their direction and orientation through the application of electric fields [54,56]. This guidance helps axons return to their intended destinations, promoting appropriate reinnervation of muscles and sensory pathways [61]. Moreover, ES enhances the release of neurotrophic factors such as nerve Growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF), enhancing neuronal survival, development, and differentiation [53,62]. These factors promote nerve cell proliferation, axonal elongation, and synapse formation, crucial for nerve healing and functional recovery (Fig. 2) [63]. ES also increases neuronal excitability, aiding in the restoration of motor and sensory function along injured nerves [64,65]. It reduces pro-inflammatory cytokines and fosters an environment conducive to nerve regeneration, axonal development, and remyelination at the lesion site [60,66,67].

ES also induces synaptic plasticity, the ability of synapses to adapt and strengthen in response to neural activity, facilitating the establishment of new connections and neural circuit reorganization critical for functional recovery [68,69]. It promotes Schwann cells, necessary for nerve regeneration, by supporting axonal development and providing structural support during the healing process [7]. This complex interaction makes ES a viable therapeutic intervention for neuronal regeneration and repair [70,71]. Understanding these mechanisms can help improve stimulation procedures and treatment regimens, leading to enhanced nerve healing and functional outcomes. Subsequent sections will delve deeper into clinical evidence, underscoring its promise as a valuable therapeutic strategy.

3.1.2. Clinical applications and evidence

Electrophysiological measurements are crucial in clinical practice for assessing the effectiveness of ES in promoting neuronal renewal and operational recovery [72]. These evaluations involve monitoring and assessing electrical signals generated by nerve and muscle activity [73]. For instance, Moschos et al. conducted a study utilizing various tests, including electroretinograms, visual evoked potentials, electrooculograms, multifocal electroretinograms, and multifocal visual evoked potentials, to aid in the diagnosis, monitoring, and evaluation of treatment efficacy, particularly in uveitis [74]. Chen and Chen provided an overview of electrophysiological examinations for movement disorders, emphasizing the utility of techniques such as surface electromyography (sEMG), electroencephalography (EEG), and accelerometry in diagnosing hyperkinetic movement disorders, particularly tremors, and myoclonus [75].

Nerve conduction studies (NCS), which assess nerve impulse speed and amplitude in the sciatic nerve pathway, offer insights into nerve fiber integrity and axonal regeneration [76]. Najafi et al. demonstrated the accuracy and reliability of NCS in measuring peripheral nerve function in diabetic neuropathy when conventional protocols are followed, through electrophysiological measurements [77]. In a clinical scenario involving rats with induced diabetes and sciatic nerve transection, the application of intermittent ES using needle electrodes for 15 min at 2 Hz over a 2-week period following 1–15 days of repair led to notable improvements. These include improved operation restoration, increased vascular functionality, and improved macrophage aggregation at the injury spot [78]. EMG evaluates muscle innervation and contractile performance in response to nerve stimulation, facilitating assessments of motor recovery [72] (Table 1).

Table 1.

Summary of clinical studies of electrical stimulation (ES) used in peripheral nerve regeneration.

Study type	Model	Assessment methods/Model	Regeneration outcomes/Intervention	Key findings	Reference
Clinical	Rats	Functional recovery	Enhanced motor and sensory function	ES is accelerating the recovery of peripheral nerve regeneration,	Willand et al. [64]; Fang et al. [121]
Clinical	(Rats)	Sciatic nerve section restored with 10 mm PPY/SF∗ NGC‡	ES through wire electrode on conductive NGC (1 h at 20 Hz each 2nd day − 7 times) (ES 1 h at 100 mV on 1, 3, 5, & 7 days)	Improved axonal growth, with recovery comparable to an autograft.	Sun et al. [122]
Clinical	Animal model (Rats)	The rat sciatic nerve repair was prolonged for 2, 4, 12, and 24 weeks. For the rat common peroneal and tibial nerve transection, the repair was prolonged for 3 months.	ES through wire electrode after reparation – 1 h at 20 Hz later 3 months of damage ES 20 min at 20 Hz after prolonged repair	Enhanced axon extension analogous to abrupt repair resulted in enhanced operational recovery, which gradually fell from a 2 to 24-week delay.	Huang et al. [71]; Elzinga et al. [123]
Clinical	Rats	Sciatic nerve	Low electrical stimulation enhances nerve regeneration, lowers Wallerian degeneration, and boosts TNF and IL-10 expression	Electrical stimulation increases neurotrophic factors required for cell survival, proliferation, and axonal elongation.	Yanez et al. [124]
Clinical	Sprague-Dawley Rats	Histological evaluation	Increased axonal growth and myelination	Electrical stimulation promotes nerve fiber regeneration in animal models.	Kim et al. [67]
Clinical	Rats	Electrophysiological assessment such as nerve conduction studies (NCS) and electromyography (EMG)	Improved nerve conduction velocity	ES promotes nerve conduction velocity and detects axonal damage through compound motor action potential (CMAP) and sensory nerve action potential (SNAPs).	Kong et al.[125]
Clinical	Rats	Induced diabetes in rats with sciatic nerve transection.	Intermittent ES through needle electrodes 15 min at 2 Hz for 2 weeks later 1–15 days of reparation	Improved operation recovery, improved vascular, and enhanced macrophage aggregation at the injury spot.	Lin et al. [78]
Clinical	Human	Carpal tunnel syndrome.	ES through wire electrode – 1 h at 20 Hz after Carpal tunnel release	Augmented motor unit number estimation (MUNE) with full reinnervation of thenar muscles.	Gordon [12].
Clinical	Rats	Transection of the digital nerve.	Electrical stimulation through wire electrode for 1 h at 20 Hz following digital nerve repairtion.	Accelerated recovery of all sensory modalities.	Song et al. [126]

Tumor Necrosis Factor (TNF), Polypyrrole/Silk Fibroin (PPY/SF), Nerve Guidance Conduit (NGC), Nerve conduction studies (NCS), electromyography (EMG), Compound Motor Action Potential (CMAP), Sensory Nerve Action Potential (SNAPs) and Motor Unit Number Estimation (MUNE).

Hunderfund et al. developed and validated an EMG direct observation instrument (EMG-DOT) for measuring electrodiagnostic skills in medical trainees. Somatosensory evoked potentials (SSEPs) measure electrical responses in sensory pathways to assess sensory nerve function and signal transmission from the sciatic nerve to the CNS [56,79]. Kane and Oware explored the value of SSEPs in predicting neurological outcomes in patients with hypoxic-ischemic brain injury, highlighting the relevance of SSEP timing and methodology [80]. Wu et al. found that long-latency SSEP (LL-SSEP) within 30–100 msec plays a unique role in monitoring brain impairment caused by cardiac arrest and predicting long-term recovery [81]. In a clinical study involving humans with Cubital Tunnel Syndrome, ES administered through a wire electrode for 1 h at 20 Hz following Cubital tunnel release resulted in notable improvements, including elevated motor unit number estimation (MUNE) and increased grip and pinch strengths [82].

These examinations offer objective and quantitative data, enabling clinicians to monitor the progress of nerve regeneration over time. Improvements in nerve conduction velocities, muscle activation patterns, and sensory responses indicate positive responses to ES and may correlate with better functional outcomes [56,83]. However, factors such as age, gender, type, and duration of disease must also be kept in consideration while applying ES.

3.2. Platelet rich plasma (PR)

PRP is an autologous biological product derived from the patient's own blood, prized for its regenerative properties and broad medical applications, including nerve regeneration [84]. PRP is acquired through a straightforward and minimally invasive procedure, rendering it an appealing option for therapy [85]. Within the realm of nerve regeneration, PRP has garnered considerable interest as a potential treatment to enhance nerve repair and facilitate functional recovery following sciatic nerve injury [86].

3.2.1. Composition and preparation of PRP

PRP is a blood component crucial for blood clotting and wound healing [87], separated through centrifugation to yield a concentrated platelet solution in plasma [88]. The composition of PRP varies based on an individual's health, age, and preparation technique, primarily comprising platelets containing essential growth factors and cytokines for tissue repair and regeneration [89]. Platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), and insulin-like growth factor (IGF) are among the key factors within platelets, critical for nerve regeneration due to their roles in cell proliferation, differentiation, and extracellular matrix production [90]. PRP also harbors immunomodulatory and anti-inflammatory cytokines, fostering a conducive environment for nerve healing [87]. Proteins aid in extracellular matrix formation, offering structural support for cells and guiding axonal growth during nerve regeneration [89]. The presence of lipids and soluble proteins further contributes to regenerative properties [84]. The content and concentration of growth factors in PRP are influenced by centrifugation speed, duration, and the use of anticoagulants [89]. PRP, with its high concentration of growth factors and bioactive compounds, stands as a promising option for promoting nerve regeneration after sciatic nerve injury [91]. Understanding PRP's composition and regenerative capabilities is crucial to unlocking its potential as an effective therapeutic intervention for peripheral nerve injuries, including sciatic nerve regeneration and repair.

3.2.2. Mechanism of action

When injected into the injured nerve environment, growth factors present in PRP modulate cellular processes to enhance nerve regeneration [69]. PDGF and FGF stimulate the proliferation and migration of key cell types, including Schwann cells, which guide axonal growth, offer structural support, and promote remyelination [92]. Local administration of growth factors, potentially in conjunction with nerve conduits, is indicated for more effective and safer treatment outcomes [93]. PRP also contains nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), crucial for sensory and motor neuron persistence and proliferation [94]. Vascular endothelial growth factor (VEGF) in PRP induces angiogenesis, restoring blood flow to the injured nerve site [84,95]. Transforming growth factor (TGF) and interleukin-1 receptor antagonist (IL-1ra) are anti-inflammatory factors in PRP, fostering a conducive environment for nerve repair and [96,97].

Molecular mechanisms regulating neuronal growth and Schwann cell function shows various growth factors like FGF2, BDNF, NT-3, FGF10, and Nrg1 binding to their respective receptors on the cell membrane [93]. These interactions activate signaling pathways such as PLCγ and Syk, leading to increased intracellular calcium (Ca²⁺) levels, which drive cellular responses. The downstream activation of Stat3 and AJK supports neuronal growth and remodeling, while also promoting axonal sorting and cellular migration. Along with this, Nrg1 activates ErB signaling, which stimulates Schwann cell proliferation and remyelination, crucial for peripheral nerve repair (Fig. 3).

Fig. 3.

Platelet-rich plasma (PRP) enriched with growth factors (FGF10, BDNF, NT-3, FGF-2) activates the Nrg1/ErbB and JAK/STAT3 pathways, promoting neuronal development, axonal remodeling, Schwann cell differentiation, and remyelination.

Numerous trials have demonstrated PRP's ability to endorse nerve renewal and operational recovery following sciatic nerve injury [98,99]. Subsequent sections will delve into clinical research to elucidate PRP's impact on neuronal cell proliferation, angiogenesis, inflammation, and functional recovery.

3.2.3. Clinical applications and evidence

A study in rats with sciatic nerve injuries has demonstrated that the introduction of PRP at the defected site significantly (p < 0.05) enhances the repair process as compared to the control group [100]. In a similar rat model with sciatic nerve defects, platelet-rich fibrin (PRP, 0.1 ml), and adipose-based stem cells (ASC, 10⁶ cells/0.1 ml) were inoculated in the defective region, proving to be an effective technique for addressing sciatic nerve impairment in vivo. The collective approach of ASC with PRF demonstrates a superior impact on nerve repair [101]. An increase in axonal density and length suggests nerve regeneration and reinnervation, where Schwann cell proliferation and migration are essential for axonal development and remyelination [102,103]. Histological examination also revealed the presence of extracellular matrix proteins such as fibronectin and collagen, which are essential for tissue remodeling [104,105]. In rats with facial nerve injuries, Mourad et al. applied PRF infiltration combined with topical tacrolimus at the defect site, with the combined approach leading to the most favourable outcomes in terms of nerve regeneration following a facial nerve crush injury compared to PRF alone [106]. These studies ' positive histological and functional results support using PRP as a viable therapeutic technique for individuals suffering from sciatic nerve injury [107,108] (Table 2). However, more clinical evidence is required to validate PRP's efficacy in nerve renewal and operational restoration in sciatic nerve injuries.

Table 2.

Summary of clinical studies of platelets rich plasma (PRP) used in peripheral nerve regeneration.

Study type	Treatment protocol	Model	Assessment methods/Model	Regeneration outcomes/Intervention	Key findings	References
Clinical	PRP	Rats	Histological evaluation of cavernous nerve injury	Injected chitosan-activated platelet-rich plasma (cPRP) intracavernosally (IC).	This concurrently promotes the renewal of myelinated axons in the cavernous nerve, diminishes apoptosis, and accelerates the propagation of corporal smooth muscle cells at a former phase	Wu et al. [86]
Clinical	PRP	Rats	Sciatic nerves injury	Introduction of PRP into the site of the defect.	PRP demonstrated a noteworthy impact (p < 0.05) on the repair of the sciatic nerve in comparison to the control group.	Kokkalas et al. [100]
Clinical	PRP	Rats	Sciatic nerve crush damage and transection injury	Faster gait recovery and enhanced compound muscle action potential at lower labelled motor neurons	In the crush injury group, gait recovery was faster at 14 days, with improved compound muscle action potential and lower labelled motor neurons at 21 days. As well as higher numbers of new myelin sheaths and a favourable g-ratio.	Wang et al. [91]
Clinical	PRP	Rats	Sciatic nerve lesion model	Composite nerve conduit reveals that it can facilitate axonal regeneration	PRP in a composite nerve conduit demonstrated potential in facilitating axonal rejuvenation and promoting operational restoration in a rat sciatic nerve lesion model.	Dong et al. [127]
Clinical	PRP	Rats	Bilateral cavernous nerve injury	Examined samples utilizing a cytokine antibody array and conducted ELISA.	The study offers support for the involvement of CXCL5 and CXCR2 as agents mediating the effects of PRP in maintaining erectile function following cavernous nerve injury.	Deabes et al. [128]
Clinical	PRF	Rabbits	Facial nerve regeneration	A platelet-rich fibrin membrane prepared with titanium was encased in a tube around the incapacitated area.	The use of T-PRF membrane enhances facial movement recovery after nerve injury, accelerating electrophysiological warning threshold recovery. Extended studies with improved protocols are crucial for a comprehensive understanding of PRF effects on nerve healing.	Işik et al. [129]
Clinical	PRF and ADSC	Rats	Sciatic nerve defect	PRFr (0.1 ml) and adipose-derived stem cells (106 cells/0.1 ml) were administered to the site of the defect	This injection method demonstrates an effective technique for addressing sciatic nerve defects in vivo. The combined approach of ADSCs with PRF yields a superior impact on nerve repair.	Chuang et al. [130]
Clinical	PRF	Rats	Facial nerve damage	PRF penetration combined with the contemporary application of tacrolimus at the defect site.	In comparison to PRF alone, the application of PRF with topical tacrolimus resulted in the most favourable regeneration outcome following a facial nerve crush injury.	Mourad et al. [106]

4. Discussion

It is important to differentiate between nerve repair, recovery, and regeneration in the context of therapeutic strategies. Repair refers to restoring nerve structure following injury, often involving surgical interventions. Recovery encompasses the return of function, including motor and sensory abilities, which may occur even without full anatomical repair. Regeneration, however, involves the complete physiological process of re-growing nerve tissues, axons, and myelin sheaths to restore full nerve functionality. Each process plays a role in treatment strategies and outcomes for peripheral nerve injuries. The application of ES and PRP in nerve repair presents a compelling rationale grounded in their distinct mechanisms of action and regenerative properties [109]. ES is a commonly used treatment, as low-frequency electric stimulus positively affects nerve regeneration [13,110,111]. Combining ES with physical activity, like treadmill exercise, also has fruitful impacts [110]. Selecting the correct frequency range is crucial, as higher frequencies can exacerbate muscle atrophy [13]. Standardizing ES parameters duration, frequency, and the nature of the nerve injury is essential to maximize therapeutic efficacy while mitigating potential harm to surrounding tissues [111]. To accelerate nerve regeneration, ES can be synergistically combined with steroids or surgical interventions [35]. One study applied weekly ES by a rooted wireless device to excite rat sciatic nerve renewal, resulting in accelerated regaining [112,113]. Administering ES under local anesthesia and using wireless implanted devices would be a promising technological advance and a new approach to common treatments [113].

Another non-surgical method is magnetic stimulation, which activates peripheral nerve regeneration by increasing the number and diameter of regenerated axons to promote functional recovery [114]. This technique's positive effects likely result from stimulating NGF movement and reducing cytokine movement. The therapeutic impacts of this technique depend on amplitude (0.3–300 mT), exposure time (10 min/day to 24 h/day), and frequency (2 Hz–2000 Hz). Furthermore, when combined with MSC, it encourages differentiation into neuron-like cells, affecting the cell cycle [13,69]. ES has been shown to promote neuronal survival and growth by upregulating the transcription of neurotrophic factors such as NGF and BDNF [115]. ES induces the release of growth factors, such as NGF, from nerve cells and surrounding tissues, and enhances their transport to the injured nerve location. This increased supply of growth factors promotes cell proliferation, axonal development, and angiogenesis, resulting in robust nerve regeneration [107,116]. ES also alters cellular responses, guides axonal development, and modifies neuronal excitability further leading to enhanced nerve regeneration [117].

PRP can stimulate nerve regeneration, promote axonal regeneration, regulate the inflammatory response, and alleviate nerve collateral muscle atrophy [90]. The practical usage of PRP in peripheral nerve regeneration is growing, with indications of its efficacy. PRP provides an enriched source of growth factors that promote cell proliferation, differentiation, and tissue repair [107]. PRP has anti-inflammatory properties that reduce inflammation in the injured region, creating favourable conditions for nerve healing [118]. PRP may increase axonal growth speed and direction while delivering critical growth factors and promoting tissue remodeling [64,119].

Moreover, these therapies are non-invasive and safe, reducing the risk of adverse reactions or immunological responses [120]. However, it is important to note that more research is needed to optimize treatment procedures, timing, and duration of these therapies. Clinical trials and comparative research will provide insights into the efficacy and safety of these approaches in promoting neuronal regeneration and functional recovery following sciatic nerve injury. More clinical trials in this context are needed to determine the efficacy and to refine treatment protocols.

5. Conclusion

This review underscores the importance of innovative therapeutic approaches for managing sciatic nerve injuries. ES and PRP present promising strategies to enhance nerve regeneration and functional recovery, targeting key biological processes such as cell proliferation, axonal growth, angiogenesis, and inflammation modulation. Clinical trials have shown safety and potential efficacy in improving outcomes in both animal models and early human trials. However further research is required to optimize treatment protocols and assess long-term outcomes. Research gaps persist, necessitating larger randomized trials with extended follow-ups to establish safety and effectiveness. Future investigations should refine therapy parameters, explore optimal timing and duration, validate their efficacy in diverse patient populations, and conduct comparative studies against conventional treatments. Extensive clinical trials are needed to validate efficacy, establish standardized protocols, and evaluate long-term outcomes, including quality of life. Future studies should focus on refining these techniques, understanding patient-specific responses, and exploring novel regenerative therapies to maximize recovery and improve the quality of life for individuals suffering from sciatic nerve injuries.

Consent to participate

Not Applicable.

Author contributions

Literature search: SA, MS, MNK; manuscript writing: SA; manuscript revision and review: SA, MS, MNK, FQ. All authors approved the final version of the manuscript.

Ethical considerations

Not Applicable.

Funding

This work was supported by the Li Ka Shing Foundation Cross Disciplinary Research Grant awarded to Qiang Fang (Grant No. 2020LKSFG01C).

Declaration of competing interest

The authors declared no potential conflicts of interest concerning this article's research, authorship, and publication.