Pulsed Electromagnetic Fields Reduce Postoperative Interleukin-1ß, Pain, and Inflammation: A Double-Blind, Placebo-Controlled Study in TRAM Flap Breast Reconstruction Patients.

BACKGROUND: Pulsed electromagnetic fields have been shown to reduce postoperative pain, inflammation, and narcotic requirements after breast reduction and augmentation surgical procedures. This study examined whether pulsed electromagnetic field therapy could produce similar results in patients undergoing unilateral transverse rectus abdominis myocutaneous (TRAM) flap breast reconstruction, a significantly more complex and painful surgical procedure. METHODS: In this double-blind, placebo-controlled, randomized study, 32 patients undergoing unilateral TRAM flap breast reconstruction received active or sham pulsed electromagnetic field therapy. Pain levels were measured by using a visual analogue scale; narcotic use and wound exudate volume were recorded starting 1 hour postoperatively. Wound exudates were analyzed for interleukin-1ß. RESULTS: Mean visual analogue scale pain scores were 2-fold higher in the sham cohort at 5 hours and 4-fold higher at 72 hours (p < 0.01), along with a concomitant 2-fold increase in narcotic use in sham patients (p < 0.01). Wound exudate volume was 2-fold higher in the sham cohort at 24 hours (p < 0.01), and mean interleukin-1ß concentration in wound exudates of sham patients was 5-fold higher at 24 hours (p < 0.001). CONCLUSIONS: Pulsed electromagnetic field therapy significantly reduced postoperative pain, inflammation, and narcotic use following TRAM flap breast reconstruction, paralleling its effect in breast reduction patients. Both studies also report a significant reduction of interleukin-1ß in the wound exudate, supporting a mechanism involving a pulsed electromagnetic field effect on nitric oxide/cyclic guanosine monophosphate signaling, which modulates the body's antiinflammatory pathways. Adjunctive pulsed electromagnetic field therapy could impact the speed and quality of wound repair in many surgical procedures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

Pulsed electromagnetic fields dosing impacts postoperative pain in breast reduction patients.

BACKGROUND: Pulsed electromagnetic fields (PEMF) reduce postoperative pain and narcotic requirements in breast augmentation, reduction, and reconstruction patients. PEMF enhances both calmodulin-dependent nitric oxide and/or cyclic guanosine monophosphate signaling and phosphodiesterase activity, which blocks cyclic guanosine monophosphate. The clinical effect of these competing responses on PEMF dosing is not known. METHODS: Two prospective, nonrandomized, active cohorts of breast reduction patients, with 15 min PEMF per 2 h; "Q2 (active)", and 5 min PEMF per 20 min; "5/20 (active)", dosing regimens were added to a previously reported double-blind clinical study wherein 20 min PEMF per 4 h, "Q4 (active)", dosing significantly accelerated postoperative pain reduction compared with Q4 shams. Postoperative visual analog scale pain scores and narcotic use were compared with results from the previous study. RESULTS: Visual analog scale scores at 24 h were 43% and 35% of pain at 1 h in the Q4 (active) and Q2 (active) cohorts, respectively (P < 0.01). Pain at 24 h in the 5/20 (active) cohort was 87% of pain at 1 h, compared with 74% in the Q4 (sham) cohort (P = 0.451). Concomitantly, narcotic usage in the 5/20 (active) and Q4 (sham) cohorts was not different (P = 0.478), and 2-fold higher than the Q4 (active) and Q2 (active) cohorts (P < 0.02). CONCLUSIONS: This prospective study shows Q4/Q2, but not 5/20 PEMF dosing, accelerated postoperative pain reduction compared with historical shams. The 5/20 (active) regimen increases NO 4-fold faster than the Q4 (active) regimen, possibly accelerating phosphodiesterase inhibition of cyclic guanosine monophosphate sufficiently to block the PEMF effect. This study helps define the dosing limits of clinically useful PEMF signals.

Pulsed electromagnetic fields potentiate neurite outgrowth in the dopaminergic MN9D cell line.

Pulsed electromagnetic fields (PEMF) exert biological effects and are in clinical use to facilitate bone repair and wound healing. Research has demonstrated that PEMF can induce signaling molecules and growth factors, molecules that play important roles in neuronal differentiation. Here, we tested the effects of a low-amplitude, nonthermal, pulsed radiofrequency signal on morphological neuronal differentiation in MN9D, a dopaminergic cell line. Cells were plated in medium with 10% fetal calf serum. After 1 day, medium was replaced with serum-containing medium, serum-free medium, or medium supplemented with dibutyryl cyclic adenosine monophosphate (Bt2 cAMP), a cAMP analog known to induce neurite outgrowth. Cultures were divided into groups and treated with PEMF signals for either 30 min per day or continuously for 15 min every hour for 3 days. Both serum withdrawal and Bt2 cAMP significantly increased neurite length. PEMF treatment similarly increased neurite length under both serum-free and serum-supplemented conditions, although to a lesser degree in the presence of serum, when continuous treatments had greater effects. PEMF signals also increased cell body width, indicating neuronal maturation, and decreased protein content, suggesting that this treatment was antimitotic, an effect reversed by the inhibitor of cAMP formation dideoxyadenosine. Bt2 cAMP and PEMF effects were not additive, suggesting that neurite elongation was achieved through a common pathway. PEMF signals increased cAMP levels from 3 to 5 hr after treatment, supporting this mechanism of action. Although neuritogenesis is considered a developmental process, it may also represent the plasticity required to form and maintain synaptic connections throughout life.

Nonthermal electromagnetic fields: from first messenger to therapeutic applications.

Nonthermal pulsed electromagnetic fields, from low frequency to pulse-modulated radio frequency, have been successfully employed as adjunctive therapy for the treatment of delayed and non-union fractures, fresh fractures and chronic wounds. Recent increased understanding of the mechanism of action of electromagnetic fields (EMF) has permitted technologic advances allowing the development of EMF devices which are portable and disposable, can be incorporated into dressings, supports and casts, and can be used over clothing. This broadens the use of non-pharmacological, non-invasive EMF therapy to the treatment of postoperative pain and edema to enhance surgical recovery. EMF therapy is rapidly becoming a standard part of surgical care, and new, more significant, clinical applications for osteoarthritis, brain and cardiac ischemia and traumatic brain injury are in the pipeline. This study reviews recent evidence which suggests that calmodulin (CaM)-dependent nitric oxide signaling is involved in cell and tissue response to weak nonthermal EMF signals. There is abundant evidence that EMF signals can be configured a priori to increase the rate of CaM activation, which, in turn, can modulate the biochemical cascades living cells and tissues employ in response to external insult. Successful applications in pilot clinical trials, coupled with evidence at the cellular and animal levels, provide support that EMF is a first messenger that can modulate the response of challenged biological systems.

Non-invasive electromagnetic field therapy produces rapid and substantial pain reduction in early knee osteoarthritis: a randomized double-blind pilot study.

This study examined whether a non-thermal, non-invasive, pulsed electromagnetic field (PEMF), known to modulate the calmodulin (CaM)-dependent nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway, could reduce pain in early knee OA. This randomized, placebo-controlled, double-blind pilot clinical study enrolled 34 patients. Patient selection required initial VAS ≥4, 2 h of standing activity per day, and no recent interventions such as cortisone injections or surgery. Results showed VAS pain score decreased in the active cohort by 50 ± 11% versus baseline starting at day 1 and persisting to day 42 (P < 0.001). There was no significant decrease in VAS versus baseline at any time point in the sham cohort (P = 0.227). The overall decrease in mean VAS score for the active cohort was nearly threefold that of the sham cohort (P < 0.001). The results suggest that non-thermal, non-invasive PEMF therapy can have a significant and rapid impact on pain from early knee OA and that larger clinical trials are warranted.

Electromagnetic fields instantaneously modulate nitric oxide signaling in challenged biological systems.

This study shows that a non-thermal pulse-modulated RF signal (PRF), configured to modulate calmodulin (CaM) activation via acceleration of Ca(2+) binding kinetics, produced an immediate nearly 3-fold increase in nitric oxide (NO) from dopaminergic MN9D cultures (P < 0.001). NO was measured electrochemically in real-time using a NO selective membrane electrode, which showed the PRF effect occurred within the first seconds after lipopolysaccharide (LPS) challenge. Further support that the site of action of PRF involves CaM is provided in human fibroblast cultures challenged with low serum and exposed for 15 min to the identical PRF signal. In this case a CaM antagonist W-7 could be added to the culture 3 h prior to PRF exposure. Those results showed the PRF signal produced nearly a two-fold increase in NO, which could be blocked by W-7 (P < 0.001). To the authors' knowledge this is the first report of a real-time effect of non-thermal electromagnetic fields (EMF) on NO release from challenged cells. The results provide mechanistic support for the many reported bioeffects of EMF in which NO plays a role. Thus, in a typical clinical application for acute post operative pain, or chronic pain from, e.g., osteoarthritis, EMF therapy could be employed to modulate the dynamics of NO via Ca/CaM-dependent constitutive nitric oxide synthase (cNOS) in the target tissue. This, in turn, would modulate the dynamics of the signaling pathways the body uses in response to the various phases of healing after physical or chemical insult or injury.

Attenuation of interleukin-1beta by pulsed electromagnetic fields after traumatic brain injury.

Traumatic Brain Injury (TBI) is a major cause of morbidity and mortality in civilian and military populations. Interleukin-1beta (IL-1ß) is a pro-inflammatory cytokine with a key role in the inflammatory response following TBI and studies indicate that attenuation of this cytokine improves behavioral outcomes. Pulsed electromagnetic fields (PEMF) can reduce inflammation after soft tissue injuries in animals and humans. Therefore, we explored whether PEMF signals could alter the course of IL-1ß production in rats subjected to closed-head contusive weight-drop injuries (Marmarou method) and penetrating needle-stick brain injuries. Protein levels, measured by the Biorad assay, were not altered by injuries or PEMF treatment. In addition, we verified that IL-1ß levels in cerebrospinal fluid (CSF) were proportional to injury severity in the contusion model. Results demonstrate that PEMF treatment attenuated IL-1ß levels up to 10-fold in CSF within 6h after contusive injury and also significantly suppressed IL-1ß within 17-24h after penetrating injury. In contrast, no differences in IL-1ß were seen between PEMF-treated and control groups in brain homogenates. To the authors' knowledge, this is the first report of the use of PEMF to modulate an inflammatory cytokine after TBI. These results warrant further studies to assess the effects of PEMF on other inflammatory markers and functional outcomes.

Effects of pulsed electromagnetic fields on interleukin-1 beta and postoperative pain: a double-blind, placebo-controlled, pilot study in breast reduction patients.

BACKGROUND: Surgeons seek new methods of pain control to reduce side effects and speed postoperative recovery. Pulsed electromagnetic fields are effective for bone and wound repair and pain and edema reduction. This study examined whether the effect of pulsed electromagnetic fields on postoperative pain was associated with differences in levels of cytokines and angiogenic factors in the wound bed. METHODS: In this double-blind, placebo-controlled, randomized study, 24 patients, undergoing breast reduction for symptomatic macromastia received pulsed electromagnetic field therapy configured to modulate the calmodulin-dependent nitric oxide signaling pathway. Pain levels were measured by a visual analogue scale, and narcotic use was recorded. Wound exudates were analyzed for interleukin (IL)-1 beta, tumor necrosis factor-alpha, vascular endothelial growth factor, and fibroblast growth factor-2. RESULTS: Pulsed electromagnetic fields produced a 57 percent decrease in mean pain scores at 1 hour (p < 0.01) and a 300 percent decrease at 5 hours (p < 0.001), persisting to 48 hours postoperatively in the active versus the control group, along with a concomitant 2.2-fold reduction in narcotic use in active patients (p = 0.002). Mean IL-1 beta concentration in the wound exudates of treated patients was 275 percent lower (p < 0.001). There were no significant differences found for tumor necrosis factor-alpha, vascular endothelial growth factor, or fibroblast growth factor-2 concentrations. CONCLUSIONS: Pulsed electromagnetic field therapy significantly reduced postoperative pain and narcotic use in the immediate postoperative period. The reduction of IL-1 beta in the wound exudate supports a mechanism that may involve manipulation of the dynamics of endogenous IL-1 beta in the wound bed by means of a pulsed electromagnetic field effect on nitric oxide signaling, which could impact the speed and quality of wound repair.

A Lorentz model for weak magnetic field bioeffects: part II--secondary transduction mechanisms and measures of reactivity.

In Part I it was shown that the thermal component of the motion of a charged particle in an oscillator potential, that is, within a molecular binding site, rotates at the Larmor frequency in an applied magnetic field. It was also shown that the Larmor angular frequency is independent of the thermal noise strength and thus offers a mechanism for the biological detection of weak (microT-range) magnetic fields. Part II addresses the question of how the Larmor trajectory could affect biological reactivity. The projection of the motion onto a Cartesian axis measures the nonuniformity of the Larmor trajectory in AC and combined AC/DC magnetic fields, suggesting a means of assessing resonances. A physically meaningful measure of reactivity based upon the classical oscillator trajectory is suggested, and the problem of initial conditions is addressed through averaging over AC phases. AC resonance frequencies occur at the Larmor frequency and at other frequencies, and are dependent upon the ratio of AC/DC amplitudes and target kinetics via binding lifetime. The model is compared with experimental data reported for a test of the ion parametric resonance (IPR) model on data from Ca2+ flux in membrane vesicles, neurite outgrowth from PC-12 cells and a cell-free calmodulin-dependent myosin phosphorylation system, and suggests Mg2+ is the target for these systems. The results do not require multiple-ion targets, selection of isotopes, or additional curve fitting. The sole fitting parameter is the binding lifetime of the target system and the results shown are consistent with the literature on binding kinetics.

A Lorentz model for weak magnetic field bioeffects: part I--thermal noise is an essential component of AC/DC effects on bound ion trajectory.

We have previously employed the Lorentz-Langevin model to describe the effects of weak exogenous magnetic fields via the classical Lorentz force on a charged ion bound in a harmonic oscillator potential, in the presence of thermal noise forces. Previous analyses predicted that microT-range fields give rise to a rotation of the oscillator orientation at the Larmor frequency and bioeffects were based upon the assumption that the classical trajectory of the bound charge itself could modulate a biochemical process. Here, it is shown that the thermal component of the motion follows the Larmor trajectory. The results show that the Larmor frequency is independent of the thermal noise strength, and the motion retains the form of a coherent oscillator throughout the binding lifetime, rather than devolving into a random walk. Thermal equilibration results in a continual increase in the vibrational amplitude of the rotating oscillator towards the steady-state amplitude, but does not affect the Larmor orbit. Thus, thermal noise contributes to, rather than inhibits, the effect of the magnetic field upon reactivity. Expressions are derived for the ensemble average of position and the velocity of the thermal component of the oscillator motion. The projection of position and velocity onto a Cartesian axis measures the nonuniformity of the Larmor trajectory and is illustrated for AC and combined AC/DC magnetic fields, suggesting a means of interpreting resonance phenomena. It is noted that the specific location and height of resonances are dependent upon binding lifetime and initial AC phase.

Evidence-based use of pulsed electromagnetic field therapy in clinical plastic surgery.

BACKGROUND: The initial development of pulsed electromagnetic field (PEMF) therapy and its evolution over the last century for use in clinical surgery has been slow, primarily because of lack of scientifically-derived, evidence-based knowledge of the mechanism of action. OBJECTIVE: Our objective was to review the major scientific breakthroughs and current understanding of the mechanism of action of PEMF therapy, providing clinicians with a sound basis for optimal use. METHODS: A literature review was conducted, including mechanism of action and biologic and clinical studies of PEMF. Using case illustrations, a holistic exposition on the clinical use of PEMF in plastic surgery was performed. RESULTS: PEMF therapy has been used successfully in the management of postsurgical pain and edema, the treatment of chronic wounds, and in facilitating vasodilatation and angiogenesis. Using scientific support, the authors present the currently accepted mechanism of action of PEMF therapy. CONCLUSIONS: This review shows that plastic surgeons have at hand a powerful tool with no known side effects for the adjunctive, noninvasive, nonpharmacologic management of postoperative pain and edema. Given the recent rapid advances in development of portable and economical PEMF devices, what has been of most significance to the plastic surgeon is the laboratory and clinical confirmation of decreased pain and swelling following injury or surgery.

Effects of pulsed electromagnetic fields on postoperative pain: a double-blind randomized pilot study in breast augmentation patients.

BACKGROUND: Postoperative pain may be experienced after breast augmentation surgery despite advances in surgical techniques which minimize trauma. The use of pharmacologic analgesics and narcotics may have undesirable side effects that can add to patient morbidity. This study reports the use of a portable and disposable noninvasive pulsed electromagnetic field (PEMF) device in a double-blind, randomized, placebo-controlled pilot study. This study was undertaken to determine if PEMF could provide pain control after breast augmentation. METHODS: Forty-two healthy females undergoing breast augmentation for aesthetic reasons entered the study. They were separated into three cohorts, one group (n = 14) received bilateral PEMF treatment, the second group (n = 14) received bilateral sham devices, and in the third group (n = 14) one of the breasts had an active device and the other a sham device. A total of 80 breasts were available for final analysis. Postoperative pain data were obtained using a visual analog scale (VAS) and pain recordings were obtained twice daily through postoperative day (POD) 7. Postoperative analgesic medication use was also followed. RESULTS: VAS data showed that pain had decreased in the active cohort by nearly a factor of three times that for the sham cohort by POD 3 (p < 0.001), and persisted at this level to POD 7. Patient use of postoperative pain medication correspondingly also decreased nearly three times faster in the active versus the sham cohorts by POD 3 (p < 0.001). CONCLUSION: Pulsed electromagnetic field therapy, adjunctive to standard of care, can provide pain control with a noninvasive modality and reduce morbidity due to pain medication after breast augmentation surgery.

A pulsing electric field (PEF) increases human chondrocyte proliferation through a transduction pathway involving nitric oxide signaling.

A potential treatment modality for joint pain due to cartilage degradation is electromagnetic fields (EMF) that can be delivered, noninvasively, to chondrocytes buried within cartilage. A pulsed EMF in clinical use for recalcitrant bone fracture healing has been modified to be delivered as a pulsed electric field (PEF) through capacitive coupling. It was the objective of this study to determine whether the PEF signal could have a direct effect on chondrocytes in vitro. This study shows that a 30-min PEF treatment can increase DNA content of chondrocyte monolayer by approximately 150% at 72 h poststimulus. Studies intended to explore the biological mechanism showed this PEF signal increased nitric oxide measured in culture medium and cGMP measured in cell extract within the 30-min exposure period. Increasing calcium in the culture media or adding the calcium ionophore A23187, without PEF treatment, also significantly increased short-term nitric oxide production. The inhibitor W7, which blocks calcium/calmodulin, prevented the PEF-stimulated increase in both nitric oxide and cGMP. The inhibitor L-NAME, which blocks nitric oxide synthase, prevented the PEF-stimulated increase in nitric oxide, cGMP, and DNA content. An inhibitor of guanylate cyclase (LY83583) blocked the PEF-stimulated increase in cGMP and DNA content. A nitric oxide donor, when present for only 30 min, increased DNA content 72 h later. Taken together, these results suggest the transduction pathway for PEF-stimulated chondrocyte proliferation involves nitric oxide and the production of nitric oxide may be the result of a cascade that involves calcium, calmodulin, and cGMP production.

Low intensity permanent magnets in the treatment of chronic lumbar radicular pain.

We assessed the pain-relieving efficacy of static magnetic fields produced by 200 Gauss (G) magnets compared with 50G magnets in a double-blind, randomized, two-phase crossover study in patients with chronic lumbar radicular pain. The surface field strengths of the magnets were 200 and 50G. Phase I included four random periods of two-week duration: two periods with 200G, one period with 50G, and one period of "no treatment." The magnets were positioned either vertically or horizontally in standard lumbosacral elastic corsets. Phase II consisted of two five-week periods with the most effective magnet from Phase I and its corresponding 50 or 200G device. The primary outcome was average daily leg pain score (0-10 scale) in each period of Phase II. Thirty-eight of 40 randomized patients completed Phase I, and 28 of 31 Phase II participants completed the study. In Phase I, pain scores did not differ significantly between 200 and 50G magnets. Phase II average leg pain scores tended to be lower with 200 vs. 50G magnets (3.2+/-2.1 for 200G vs. 3.9+/-2.2 for 50G magnets [P=0.08]) after excluding one unblinded patient. The relative treatment effect of the 200G magnets appeared to increase throughout the five-week period. Although these data cannot rule out a chance effect, the positive trends suggest that larger, longer-duration, sham-controlled trials with 200G magnets be considered in patients with chronic lumbar radicular pain.

Pulsed magnetic fields accelerate cutaneous wound healing in rats.

BACKGROUND: Previous studies of pulsed magnetic fields have reported enhanced fracture and chronic wound healing, endothelial cell growth, and angiogenesis. This study characterizes the biomechanical changes that occur when standard cutaneous wounds are exposed to radiofrequency pulsed magnetic fields with specific dosage parameters, in an attempt to determine whether return to functional tensile strength could be accelerated in wound healing. METHODS: There were two study phases and a total of 100 rats. In phase 1, wounds were exposed to a 1.0-G pulsed magnetic field signal in clinical use for wound repair for 30 minutes twice daily for 21 or 60 days. Phase 2 was a prospective, placebo-controlled, double-blind trial in which rats were treated for 30 minutes twice daily with three different low-amplitude signals (0.02 to 0.05 G), configured assuming a Ca binding transduction pathway, for 21 days. A midline, 8-cm, linear skin incision was made on the rat dorsum. Tensile strength was determined by measuring the point of rupture of the wound on a standard tensiometer loaded at 0.45 mm/second. RESULTS: The mean tensile strength of treated groups in phase 1 was 48 percent (p < 0.001) greater than that of controls at 21 days; there was no significant difference at 60 days. In phase 2, the treated groups showed 18 percent (not significant), 44 percent, and 59 percent (p < 0.001) increases in tensile strength over controls at 21 days. CONCLUSION: The authors successfully demonstrated that exposing wounds to pulsed magnetic fields of very specific configurations accelerated early wound healing in this animal model, as evidenced by significantly increased wound tensile strength at 21 days after wounding.

Pulsed magnetic field therapy increases tensile strength in a rat Achilles' tendon repair model.

PURPOSE: To examine the effect of pulsing electromagnetic fields on the biomechanic strength of rat Achilles' tendons at 3 weeks after transection and repair. METHODS: This noninvasive modality was tested in a prospective, randomized, double-blinded, placebo-controlled study to evaluate the effect of a specific noninvasive radiofrequency pulsed electromagnetic field signal on tendon tensile strength at 21 days post transection in a rat model. RESULTS: In the animals receiving PMF exposure, an increase in tensile strength of up to 69% was noted at the repair site of the rat Achilles' tendon at 3 weeks after transection and repair compared with nonstimulated control animals. CONCLUSIONS: The application of electromagnetic fields, configured to enhance Ca(2+) binding in the growth factor cascades involved in tissue healing, achieved a marked increase of tensile strength at the repair site in this animal model. If similar effects occur in humans, rehabilitation could begin earlier and the risk of developing adhesions or rupturing the tendon in the early postoperative period could be reduced.

Efficacy of static magnetic field therapy in chronic pelvic pain: a double-blind pilot study.

OBJECTIVE: The aim of the study was to determine the efficacy of static magnetic field therapy for the treatment of chronic pelvic pain (CPP) by measuring changes in pain relief and disability. STUDY DESIGN: Thirty-two patients with CPP completed 2 weeks and 19 patients completed 4 weeks of randomized double-blind placebo-controlled treatment at a gynecology clinic. Active (500 G) or placebo magnets were applied to abdominal trigger points for 24 hour per day. The McGill Pain Questionnaire, Pain Disability Index, and Clinical Global Impressions Scale were outcome measures. RESULTS: Patients receiving active magnets who completed 4 weeks of double-blind treatment had significantly lower Pain Disability Index (P <.05), Clinical Global Impressions-Severity (P <.05), and Clinical Global Impressions-Improvement (P <.01) scores than those receiving placebo magnets, but were more likely to correctly identify their treatment (P <.05). CONCLUSION: SMF therapy significantly improves disability and may reduce pain when active magnets are worn continuously for 4 weeks in patients with CPP, but blinding efficacy is compromised.

Low-intensity electromagnetic and mechanical modulation of bone growth and repair: are they equivalent?

Signals from both electromagnetic fields (EMF) and ultrasound (US) have a clinically significant effect upon bone repair. Both modalities are now a common part of the orthopedist's armamentarium for the care of delayed union, nonunion, and fresh fractures. Dynamization or controlled weight bearing also enhances bone repair. Consideration of the dosimetry of both EMF and US modalities suggests a possible unifying mechanism for the bioeffects from EMF, US, and strain-generated potentials (SGP) signals based on the time-varying electric field, E(t), associated with each type of stimulus. The E(t) field is directly induced with EMF devices and indirectly induced via the streaming potentials associated with the mechanical movement of ionic fluids within bone caniculi or directly past cell surfaces from US and SGP signals. It is shown that both electrically and mechanically induced E(t) have common waveform characteristics at the treatment site and thus can deliver similar doses of electrical stimulation. It is proposed that the time-varying endogenous electric field, E(t), from a time-varying change in the mechanical environment of healing or remodeling bone, can act as a dose-dependent growth stimulus. Thus, the primary messenger affecting cellular activity is E(t), suggesting that bone repair or remodeling may be interchangeably modulated using mechanical (including US) or electromagnetic signals.