Introduction

The interaction between electric and magnetic forces generates electromagnetic fields (EMFs), dynamic phenomena characterized by variable signal frequencies, waveforms, and intensities, each capable of producing either positive or negative biological outcomes. In the medical field, EMFs have found application both diagnostically and therapeutically, with a growing body of evidence highlighting their ability to influence cellular behavior and promote tissue regeneration¹. By acting at the cell membrane level, EMFs can modulate cellular functions and disturb or restore homeostatic processes. Their dual nature, offering therapeutic promise while posing potential biological risks, necessitates continuous monitoring and sustained investigative efforts. Advancing the understanding of EMF-biological interactions is pivotal for maximizing therapeutic outcomes while minimizing potential adverse effects².

Within the broader family of EMFs, pulsed electromagnetic fields (PEMFs) have attracted particular attention as therapeutic tools. These noninvasive and economically accessible treatments have demonstrated efficacy across multiple pathological contexts^3,4. PEMFs are capable of modulating key cellular events, such as proliferation, differentiation, apoptosis, regulation of the cell cycle, and interactions with the extracellular matrix. Through these mechanisms, PEMFs can alter cell physiology and initiate extensive biological cascades⁵. Furthermore, PEMF exposure can influence cellular behavior indirectly by modulating signal transduction pathways, including A2A adenosine receptors and the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, while also restoring cellular homeostasis. Biological mediators such as calcium ion flux, nitric oxide signaling, and growth factor release have been implicated in the cellular responses elicited by PEMFs⁶. These mechanisms promote the upregulation of regenerative and tendon-related markers, including scleraxis, vascular endothelial growth factor (VEGF-A), and collagen type I, while also enhancing the release of interleukin (IL)-6, IL-10, and transforming growth factor-beta (TGF-β), together with increased elastin and fibronectin production in tendon cells.

The biological effectiveness of PEMFs depends critically on technical parameters including signal waveform, intensity, frequency, and exposure dose⁷. Preclinical research aimed at optimizing these variables is vital for translating PEMF therapy into reliable clinical interventions. Additionally, it is important to recognize that not all cell types respond uniformly to PEMF exposure, underscoring the need for careful dosimetry and a nuanced understanding of the complex interactions between physical stimuli and biological systems. As in the field of pharmacology, dose-response relationships constitute a fundamental aspect of developing safe and effective clinical applications of PEMFs⁸.

Biophysics serves as a bridge between physics and biology, applying physical principles and methodologies to explore the behavior of biological systems. It specifically focuses on how non-ionizing physical stimuli – such as electrical, magnetic, and mechanical forces – interact with biological tissues to alter their functional states, a process termed biophysical stimulation. In clinical applications, biophysical stimulation can function as a primary therapeutic strategy aimed at reinforcing reparative and anabolic activities within tissues⁹. Moreover, when used alongside pharmacological agents or growth factors, biophysical stimulation can enhance therapeutic outcomes while simultaneously reducing drug dosages and limiting adverse effects, thereby positioning itself as a powerful adjunct to traditional medical treatments.

The aim of this review is to delve into the role of PEMF-based biophysical stimulation in regenerative medicine, considering both preclinical and clinical evidence, with particular emphasis on its applications in promoting muscle and tendon repair in sports medicine and orthopedic contexts.

Methodology

Eligible studies included original experimental, preclinical, and clinical research evaluating PEMF interventions in skeletal muscle and tendon. Both in vitro and in vivo studies were considered when they explored biological mechanisms, cellular responses, tissue healing, angiogenesis, myogenesis, tenogenesis, osteogenesis, chondrogenesis, or functional outcomes associated with electromagnetic stimulation. Clinical studies involving human participants with musculoskeletal disorders, sports injuries, osteoarthritis, tendon pathology, postoperative rehabilitation, or muscle dysfunction were also included if PEMF therapy was used as a therapeutic intervention. Review articles, systematic reviews, and meta-analyses were retained for background synthesis and contextual.

Biophysical Stimulation in Regenerative Medicine for Muscular Lesions

As one of the largest organs in the human body, skeletal muscle plays a critical role in enabling both respiration and movement. Its intricate structural organization grants it an extraordinary capacity for regeneration, a function predominantly mediated by resident muscle stem cells¹⁰. Nevertheless, this innate reparative ability may become impaired in the context of severe injury. In response to such limitations, recent preclinical investigations have increasingly focused on applying biophysical stimulation techniques to promote muscle repair.

Preclinical Evidence

The intricate anatomical organization of skeletal muscle enables the precise generation of contractile forces essential for both respiration and movement¹¹. This contractile function is attributed to the structural arrangement of myofibers, which are formed through the fusion of myoblasts into multinucleated myotubes. In addition to its mechanical capabilities, skeletal muscle is distinguished by a remarkable regenerative capacity, particularly following minor injuries¹². This regenerative potential largely depends on the activity of muscle stem cells, known as satellite cells, which reside in a quiescent state and become activated when repair is required, ensuring rapid recovery and the preservation of muscle function. However, in the presence of severe trauma or pathological conditions, this intrinsic self-repair mechanism can be significantly impaired¹³.
Beyond satellite cells and myoblasts, adult skeletal muscle also hosts a variety of progenitor cell populations with high myogenic potential. These include CD133+ progenitor cells, muscle-derived stem cells (MDSCs), multipotent perivascular progenitor cells, and muscle-derived side-population (SP) cells. Furthermore, multipotent cells capable of myogenic differentiation have been isolated from non-muscle tissues such as bone marrow, adipose tissue, and umbilical cord sources^12-14.
Efforts in tissue engineering and regenerative medicine have extensively explored strategies to enhance the muscle healing response following injury, such as cell therapy, tissue engineering, and acellular scaffold implantation¹⁴. Cell therapy is a therapeutic approach involving the direct injection of exogenous myogenic progenitor cells into damaged muscle tissue. Among the most studied cell sources is the stromal vascular fraction derived from adipose tissue, known for its capacity to differentiate into adipogenic, chondrogenic, osteogenic, and myogenic lineages¹⁵. This myogenic potential has been validated both through in vitro and in vivo studies¹⁶. Interestingly, after intramuscular administration, adipose-derived stem cells (ADSCs) have demonstrated the ability to suppress inflammation, promote angiogenesis, and restore dystrophin expression in a mouse model of muscular dystrophy¹⁷. Additionally, Kang et al¹⁸ reported that ADSC transplantation in a murine ischemic hindlimb model enhanced vascular density and reduced muscle atrophy at four weeks post-injury. Nevertheless, the clinical translation of cell therapy approaches has been challenged by issues such as poor cell survival, limited engraftment into host tissues, and complex regulatory hurdles¹⁹.
Emerging evidence^20-22 suggests that biophysical stimulation represents a promising adjunctive strategy to enhance muscle regeneration, leveraging the intrinsic contractile properties of skeletal muscle. Various modalities, including mechanical stimulation, electrical stimulation, and their combined application, have been studied for their capacity to activate and support the regenerative niche within muscle tissue²³. Although electrical stimulation and pharmacological interventions have historically dominated tissue regeneration research, both techniques are associated with notable limitations, prompting the search for alternative therapies. Within this context, PEMFs have garnered interest as a potential non-invasive method to stimulate skeletal muscle regeneration (Figure 1). The in vitro study from Maiullari et al²⁴, demonstrated that PEMF exposure can facilitate muscle cell repair by upregulating proteins associated with cellular stress responses and damage repair mechanisms. Specifically, skeletal muscle cells (SkMCs) exposed to a 1.5 mT PEMF stimulus for four hours across two consecutive days exhibited increased proliferation without signs of apoptosis or metabolic dysfunction. Remarkably, PEMF-treated cells showed accelerated wound closure and enhanced migratory activity in scratch assays, indicating a facilitated regenerative response.

Clinical Evidence

Recent evidence suggests that PEMFs modulate mitochondrial function, thereby promoting regenerative processes and tissue repair²⁵. Such properties are particularly relevant in post-operative rehabilitation scenarios, including recovery following anterior cruciate ligament reconstruction (ACLR). A randomized controlled clinical trial²⁶ evaluated the impact of PEMFs during the post-operative phase of ACLR rehabilitation. Results demonstrated that patients receiving PEMF therapy exhibited superior improvements in quadriceps muscle strength compared to those undergoing standard rehabilitation alone. These functional gains were corroborated by imaging assessments, including ultrasound and magnetic resonance imaging (MRI), which confirmed increases in muscle volume. In a separate double-blind, placebo-controlled randomized trial²⁷, the efficacy of PEMF in alleviating delayed onset muscle soreness (DOMS) was investigated in 30 healthy male participants. Primary endpoints included assessments of muscle pain, peak torque, median frequency (MDF), and electromechanical delay (EMD) during isometric contractions at 24-, 48-, and 72-hours following DOMS induction. PEMF therapy was associated with significant improvements in muscle pain perception, MDF, and EMD, reflecting accelerated recovery from physiological impairments. However, no significant advantage was observed over placebo regarding improvements in peak isometric torque. Further research assessed the influence of PEMF on muscle activation and metabolism during exercise in semi-professional cyclists. In a randomized crossover study, Trofè et al²⁸ evaluated twenty athletes engaged in constant-load exercise sessions under active (ON) and inactive (OFF) PEMF stimulation conditions. During the load-free warm-up phase, active PEMFs significantly increased muscle activity. Additionally, higher blood lactate concentrations were recorded during PEMF exposure, suggesting an enhancement of glycolytic metabolic pathways. These findings indicate that PEMF stimulation can promote increased muscle fiber activation and metabolic responsiveness during low-intensity exercise.

The research works reviewed in this section are listed in Table 1.

Table 1. Muscle and PEMFs.

Figure 1. PEMF therapy for muscular lesions. PEMF therapy promotes mitochondrial function, induces stress response, proliferation, migration, and angiogenesis, and improves muscle fiber activation and metabolism.

Biophysical Stimulation in Regenerative Medicine for Tendon Lesions

While PEMFs have long been explored for therapeutic applications in several fields, their widespread clinical adoption for the treatment of tendinopathies and tendon injuries remains an unmet objective. Tendon tissue represents one of the most recent frontiers for biophysical stimulation strategies. Although modern in vitro investigations have yielded promising results, it is noteworthy that a substantial, yet relatively under-recognized, body of clinical and preclinical research originating from the 1980s already suggested a potential role for PEMF therapy as a conservative treatment option for tendon pathologies.

Preclinical Evidence

The earliest preclinical investigation into the effects of PEMFs on tendon healing dates back to the 1980s, when Watkins et al²⁹ created defects in the superficial digital flexor tendons of a horse model. Animals exposed to PEMF treatment for only two hours daily exhibited delayed maturation of the reparative tissue within the lesion. In the ensuing decades, research predominantly shifted toward small animal models, a transition likely driven by economic considerations and the enhanced reproducibility of experimental outcomes. In 1997, Lee et al³⁰ demonstrated the beneficial role of PEMFs in a rat model of experimental Achilles tendonitis, where treatment was associated with reduced inflammation and a more complete restoration of the tendon’s histological architecture. Further evidence was subsequently provided by Strauch et al³¹, who investigated PEMF application following Achilles tendon transection and repair in rats. Their findings indicated a substantial increase (up to 69%) in the tensile strength at the repair site after three weeks compared to unstimulated controls. These observations began to suggest that PEMFs might accelerate tendon healing, opening the possibility for early rehabilitation protocols incorporating PEMF exposure in clinical practice.

The concept of accelerated tendon healing was further reinforced by Tucker et al³², who utilized a rat model of acute rotator cuff detachment and repair. Their work highlighted the capacity of PEMFs to enhance tendon-to-bone healing, evidenced by improved mechanical and histological tendon properties. Specifically, they observed an early increase in the elastic modulus (notably at 4-8 weeks post-injury), alongside cellular changes such as more rounded tenocyte morphology, suggestive of heightened metabolic activity, and better-organized collagen fibers within the tendon substance. This study represents a pivotal milestone in preclinical PEMF research. Similar trends were noted in the study conducted by Huegel et al³³ which evidenced that in a bilateral rat supraspinatus injury model, enhanced tendon mechanical properties, including modulus and stiffness, and improved collagen organization were reported following PEMF exposure for up to six hours daily. Consistent findings were later confirmed by Dolkart et al³⁴ using the same model, reinforcing the positive impact of PEMFs during the early stages of tendon healing. Mechanistic insights were further advanced by Huegel et al³⁵, who identified that PEMF exposure promoted upregulation of bone morphogenetic protein 2 (BMP2) signaling, increased the expression of pro-osteogenic genes at the tendon-bone interface, downregulated genes associated with fibrotic healing, and induced anti-inflammatory shifts, such as the transition of macrophages from an M1 to an M2 phenotype. However, not all findings were uniformly positive. In a subsequent study, the same group³⁶ reported that PEMFs failed to enhance healing in a rat Achilles tendon tear model (both complete tears with surgical repair and partial tears without repair) following up to three hours of daily stimulation. Differences in the anatomical and biomechanical nature of the lesions (Achilles tendon injuries being purely soft tissue, whereas supraspinatus injuries involve a tendon-bone interface) likely account for the observed discrepancies. These results highlight the necessity of more nuanced preclinical evaluations to clarify the contexts in which PEMF therapy is most effective. Interestingly, even in this model, partial-width Achilles tears exhibited early positive responses to PEMF exposure, suggesting that the timing and extent of injury may influence therapeutic outcomes. Moreover, the rapid intrinsic healing capacity of rodent models may underestimate the potential clinical impact of PEMF therapy in humans.

Recent studies have renewed interest in PEMF application for Achilles tendinopathy. Perucca Orfei et al³⁷ demonstrated an anabolic effect of PEMFs administered for eight hours daily. Using a type I collagenase-induced tendinopathy model, they found that PEMF exposure during the mid-acute phase (7-14 days post-induction) significantly improved collagen fiber architecture, restored normal cell morphology, and reduced inflammatory infiltrates. Supporting these findings, Uzun et al³⁸ conducted a rabbit model study involving Achilles tendon tear and repair, applying PEMFs for 21 days post-surgery. Their results indicated effective tendon recovery, reinforcing the regenerative potential of PEMFs even though the precise molecular mechanisms remain incompletely understood. The effects of PEMFs on tendons are summarized in Figure 2.

In Vitro Modern Evidence

Despite the pre-clinical evidence supporting the use of PEMF, a detailed understanding of PEMF’s specific effects on tendon metabolism remains relatively limited³⁹. In vitro studies have thus become a critical avenue for elucidating the cellular and molecular changes triggered by PEMF exposure, particularly concerning receptor activation and gene expression profiles. Rosso et al⁴⁰ have highlighted several key mechanistic pathways (Figure 2):

• Adenosine receptors A2A and A3 activation:

In an experimental model involving tendon cells exposed to PEMFs for 48 hours alongside IL-1β stimulation, Colombini et al⁴¹ observed increased surface expression and ligand affinity of the A2A receptor. This upregulation was associated with a pronounced anabolic and reparative cellular response, characteristic of the early inflammatory phase of tendon healing, including elevated secretion of IL-6 and prostaglandin E2 (PGE2) and enhanced expression of the tenogenic markers scleraxis (SCX) and collagen type III alpha 1 (COL3A1). Complementary studies by de Girolamo et al^42,43 further reported an upregulation of anti-inflammatory and pro-regenerative factors such as IL-10, vascular endothelial growth factor (VEGF-A), and transforming growth factor-beta (TGF-β) under PEMF stimulation.

• Upregulation of anti-inflammatory genes via the mitogen-activated protein kinase/extracellular signal-regulated kinase-1/2 (MAPK/ERK1/2) pathway:

Vinhas et al^44,45 explored the anti-inflammatory potential of PEMFs using magnetically assisted cell sheets composed of human tendon-derived cells and magnetic nanoparticles exposed to IL-1β. Their findings demonstrated that brief PEMF treatment suppressed the expression of pro-inflammatory cytokines [IL-6, tumor necrosis factor-alpha (TNF-α), IL-8] and enzymes [cyclooxygenase-2 (COX-2), matrix metallopeptidase-1, -2, -3 (MMP-1, MMP-2, MMP-3)], while simultaneously enhancing the expression of anti-inflammatory mediators such as IL-4, IL-10, and tissue inhibitor of metalloproteinases-1 (TIMP-1)⁴⁶. Supporting these observations, Gehwolf et al⁴⁷ identified increased expression of IL-1 receptor type 2 (IL-1R2), a decoy receptor that modulates IL-1β signaling, following PEMF exposure, suggesting a significant immunomodulatory role.

• Promotion of extracellular matrix (ECM) anabolism:

Recent work by Marmotti et al^48,49 revealed that prolonged PEMF stimulation (21 days) exerted strong anabolic effects on tenocytes⁴⁸ or tendon explants⁴⁹ derived from hamstring grafts used in anterior cruciate ligament reconstruction. Their study highlighted not only enhanced tenogenic differentiation but also upregulation of collagen type VI, a key ECM component with mechano-sensing functions. Similar anabolic responses were reported after exposing umbilical cord-derived mesenchymal stem cells to PEMFs⁵⁰, supporting the hypothesis proposed by Viganò et al⁵¹ that mesenchymal precursor cells are important therapeutic targets of biophysical stimulation strategies. Furthermore, Liu et al⁵² demonstrated that PEMF exposure induced a marked anabolic gene expression profile in human rotator cuff tenocytes, but only under inflammatory conditions induced by IL-1β stimulation. Specifically, PEMF treatment led to significant upregulation of collagen I, TGF-β1, platelet-derived growth factor subunit B (PDGFb), BMP12, and TIMP4, highlighting its potential to enhance tendon repair processes within an inflammatory microenvironment, such as that present in the early postoperative period following rotator cuff repair.

Clinical Evidence

Since 1984, PEMFs have demonstrated promising therapeutic effects in the management of tendinopathies. In a pivotal pilot study, Binder et al⁵³ conducted a double-blind randomized controlled trial focusing on persistent rotator cuff tendinitis, where they reported favorable outcomes following PEMF treatment. Building upon these early findings, subsequent clinical investigations explored the utility of PEMFs across various tendinopathies. In 1985, Devereaux et al⁵⁴ evaluated the effects of PEMFs in patients with chronic lateral humeral epicondylitis; however, no significant clinical improvements were detected in their cohort. Conversely, in 2007, Uzunca et al⁵⁵ demonstrated that PEMF therapy, when compared to corticosteroid injections and sham PEMF, significantly reduced pain during rest, activity, and nighttime in patients with lateral epicondylitis (“tennis elbow”), thereby providing stronger clinical evidence for the analgesic benefits of PEMF application in tendinous disorders. Further support for the therapeutic potential of PEMFs was later provided by Osti et al⁵⁶, who showed that PEMF treatment in the early postoperative period following rotator cuff repair significantly reduced pain, decreased analgesic consumption, and improved joint stiffness. Although these benefits were apparent in the short term, no significant differences in outcomes between treated and untreated groups were observed at the two-year follow-up, suggesting that PEMFs may primarily exert an early acceleration of the healing process rather than affecting long-term outcomes. Additional confirmation of PEMF efficacy was obtained through a study conducted by Klüter et al⁵⁷, who combined high-energy PEMF therapy with extracorporeal shock wave therapy (ESWT) in the conservative management of rotator cuff tendinopathy. Their results demonstrated significantly greater improvements in pain and functional outcomes after 24 weeks in patients receiving the combined treatment compared to those receiving ESWT alone, reinforcing the notion that PEMFs may provide clinical benefit even without surgical intervention. Nevertheless, some inconsistency remains in the literature. A more recent study⁵⁸ failed to demonstrate a significant additional benefit of PEMF therapy when combined with diathermy [ultrasound (US)] and transcutaneous electrical nerve stimulation (TENS) compared to US and TENS alone, a result that may be attributed to the limited PEMF exposure time (25 minutes per session, five sessions per week for two weeks) used in that protocol. Emerging research continues to explore the broader potential of PEMFs in tendinopathy management. A 2023 investigation conducted by researchers at the Chinese University of Hong Kong proposed the use of PEMFs as an adjunctive therapy to eccentric exercise for the treatment of Achilles tendinopathy⁵⁹. This ongoing prospective, randomized, double-blinded, placebo-controlled trial suggests that PEMF exposure may improve pain relief and enhance tendon mechanical properties, potentially augmenting the therapeutic response to standard eccentric exercise protocols. Should these findings be confirmed, PEMF therapy could represent a safe and effective conservative strategy for managing Achilles tendinopathy.

The research works reviewed in this section are listed in Table 2.

Table 2. Tendon and PEMFs.

Scleraxis (SCX); vascular endothelial growth factor (VEGF-A); transforming growth factor-beta (TGF-β); interleukin (IL); tumor necrosis factor-alpha (TNF-α); cyclooxygenase-2 (COX-2); matrix metallopeptidase-1, -2, -3 (MMP-1, MMP-2, MMP-3); tissue inhibitor of metalloproteinases-1 (TIMP-1); mammalian target of rapamycin (mTOR); collagen type III alpha 1 (COL3A1); collagen type I alpha 1 (COL1A1); A2A adenosine receptor (A2AAR).

Figure 2. PEMF therapy for tendon lesions. PEMF therapy reduces inflammation and pain and promotes tensile strength, elastic modulus and collagen organization. PEMFs act through activation of Adenosine A2A and A3 receptors, upregulating anti-inflammatory genes via the MAPK/ERK1/2 pathway and promoting extracellular matrix anabolism. Created in https://BioRender.com

Discussion

Experimental evidence indicates that PEMFs can influence key cellular processes involved in muscle repair, including proliferation, migration, oxidative stress responses, and mitochondrial metabolism. Maiullari et al²⁴ demonstrated that PEMF exposure promoted skeletal muscle cell proliferation and accelerated wound closure without inducing apoptosis or metabolic dysfunction, suggesting a favorable regenerative microenvironment. Similarly, clinical investigations in postoperative rehabilitation and sports medicine demonstrated improvements in quadriceps strength, muscle activation, and recovery from delayed-onset muscle soreness. These findings support the concept that PEMFs may enhance muscle performance and recovery not only through structural regeneration but also through metabolic and neuromuscular adaptations. Despite these encouraging observations, the current evidence regarding PEMF therapy for muscular lesions remains limited by substantial heterogeneity in stimulation protocols, exposure duration, field intensity, treatment timing, and outcome measures. Furthermore, many available studies involve relatively small cohorts or experimental models, limiting the generalizability of their findings. The exact molecular mechanisms underlying PEMF-mediated muscle regeneration also remain incompletely understood. Nonetheless, emerging evidence^{6,25,42,43,52} suggests that PEMFs may regulate intracellular signaling pathways associated with calcium flux, nitric oxide release, mitochondrial dynamics, and growth factor expression, ultimately contributing to restoration of cellular homeostasis and tissue repair.

The evidence supporting PEMF application in tendon healing appears comparatively more extensive and mechanistically characterized. Preclinical animal studies^29-38,47 consistently demonstrated improvements in tendon mechanical properties, collagen organization, and tendon-to-bone healing following PEMF exposure. Importantly, several investigations^{35,37,41-45,52} identified anti-inflammatory and anabolic effects mediated through modulation of adenosine receptors, MAPK/ERK signaling, and cytokine expression. PEMFs were shown to promote tenogenic differentiation, increase expression of collagen-related genes, and suppress pro-inflammatory mediators such as IL-1β, TNF-α, and matrix metalloproteinases. These biological effects are particularly relevant considering the limited vascularity and slow intrinsic healing capacity of tendon tissue. Nevertheless, tendon-related studies^36,54,58 also revealed inconsistencies that warrant careful interpretation. While beneficial effects were frequently observed in rotator cuff and tendon-to-bone healing models, some studies failed to demonstrate significant improvements in Achilles tendon injuries³⁶, lateral humeral epicondylitis⁵⁴ and supraspinatus tendon tear⁵⁸. Such discrepancies likely reflect differences in tendon biology, biomechanical loading, injury chronicity, and the presence or absence of a tendon-bone interface. Moreover, the timing and dosage of PEMF exposure appear to critically influence therapeutic efficacy, emphasizing the need for standardized stimulation parameters. Clinical evidence remains promising but still insufficient to support definitive recommendations for routine practice. Early randomized controlled trials^53,55,56,59 demonstrated reductions in pain, stiffness, and analgesic consumption in rotator cuff tendinopathy and postoperative rehabilitation settings. More recent studies have suggested potential synergistic effects when PEMFs are combined with established conservative approaches such as extracorporeal shockwave therapy⁵⁷ or eccentric exercise⁵⁹. However, long-term superiority over standard treatments has not been consistently demonstrated, and several studies remain limited by small sample sizes, short follow-up periods, and variability in treatment protocols.

Conclusions

The present review highlights the growing interest in PEMFs as a regenerative strategy for muscular and tendon lesions. Their non-invasive nature and favorable safety profile make PEMFs a promising adjunctive therapy in regenerative medicine.

Despite encouraging preclinical and early clinical findings, the evidence remains limited by methodological heterogeneity, small sample sizes, and inconsistent treatment protocols. Further high-quality translational and clinical studies are needed to standardize stimulation parameters, clarify optimal indications, and determine long-term clinical efficacy. Moreover, future research must differentiate among tendon types to better define the specific clinical contexts in which PEMF therapy may be most effective.

An emerging area of interest is the combination of PEMFs with regenerative cellular therapies, such as mesenchymal stem cells, to enhance cell survival, differentiation, and tissue repair. In parallel, recent research suggests that the early anabolic response to PEMF exposure is associated with the upregulation of early differentiation genes like c-fos⁴⁹, indicating that PEMFs may act as upstream modulators directing progenitor cells toward osteogenic, chondrogenic, or tenogenic pathways depending on the local environment. Recent studies^60-62 on mechanosensitive ion channels, particularly the PIEZO-type components (PIEZO)-1 and -2, which were awarded the 2021 Nobel Prize in Physiology or Medicine, offer further insights. Matsushima et al⁶³ identified PIEZO-1 as a key sensor of mechanical stimuli in tenocytes, suggesting that PEMFs may exert some of their effects via activation of these channels, transducing mechanical cues into biological signals. Elucidating these pathways represents a critical frontier in PEMF research and may enable the development of more effective biophysical therapies.

Overall, PEMFs represent a biologically plausible and promising tool in musculoskeletal regenerative medicine, although further mechanistic and clinical research is required to fully define their therapeutic role.

Informed Consent:

Not applicable.

Ethics Approval:

Ethics approval was not required due to the nature of the study.

Conflict of Interest:

The authors declare no conflict of interest.

Authors’ Contributions:

Marmotti A. and Coco M. conceived the review and supervised the overall project. De Girolamo L., Di Matteo B., Vadalà G. and Mangiavini L. contributed to the design and coordination of the work and provided critical intellectual input. De Luca P., De Giorgi S., Carnevale A., Veronesi F., Berton A., Menon A., Ragni E., Anzillotti G., Giorgino R., Nannini A., Cucchi D., Rossi N., and Cavallo C. performed the literature search, organized the evidence, and drafted sections of the manuscript. Marmotti A., De Luca P., Coco M. and Setti S. critically revised the manuscript. All authors contributed to the writing process, approved the final version of the manuscript, and agreed to be accountable for its content.

ORCID ID:

A. Marmotti: 0000-0002-1683-6094
M. Coco: 0009-0002-8095-9862
P. De Luca: 0000-0001-9810-8818
S. De Giorgi: 0000-0002-0635-4964
A. Carnevale: 0000-0003-4543-1149
B. Di Matteo: 0000-0002-9807-0271
F. Veronesi: 0000-0002-6750-9376
A. Berton: 0000-0001-9767-7824
L. Mangiavini: 0000-0003-1892-1249
A. Menon: 0000-0003-2786-8099
L. de Girolamo: 0000-0002-9979-3092
E. Ragni: 0000-0003-0272-7417
G. Anzillotti: 0000-0001-9327-5350
R. Giorgino: 0000-0002-1067-7424
A. Nannini: 0000-0001-6742-2273
D. Cucchi: 0000-0001-6284-7977
N. Rossi: 0000-0003-4895-4789
C. Cavallo: 0000-0002-2913-856X
G. Vadalà: 0000-0001-7142-1660
S. Setti: 0000-0001-8990-5452

Funding:

None.

AI Disclosure:

AI tools were used during the preparation of this manuscript to assist with language refinement and editing. All scientific content, interpretation of the literature, critical analysis, and final approval of the manuscript were performed by the authors, who take full responsibility for the accuracy and integrity of the work.

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