Pulsed Electromagnetic Field Therapy

Preprint: Submitted to “Electromagnetic Biology and Medicine” for publication
November ‘061
PULSED ELECTROMAGNETIC FIELD THERAPY
HISTORY, STATE OF THE ART AND FUTURE
Marko S. Markov
Research International, Williamsville, NY 14221

Abstract

Magnetic and electromagnetic fields are now recognized by the XXI century medicine as real physical entities that promise healing of various health problems, even when conventional medicine has failed. Today magnetotherapy provides a noninvasive, safe and easy method to directly treat the site of injury, the source of pain and inflammation, and other types of diseases and pathologies. Millions of people worldwide have received help in treatment of musculoskeletal system, as well as pain relief. Pulsed electromagnetic fields are one important modality in magnetotherapy and recent technological innovations, such as Curatron PEMF devices, offer excellent, state of the art computer controlled therapy system. In this paper the development, state of the art and future of pulsed electromagnetic field therapy are discussed.

Introduction

This paper was triggered by information found on Internet that a new, computerized system for pulsed electromagnetic field (PEMF) therapy has been introduced on the market. It appears that the Curatron system marks new era in the biomagnetic technology: use of computer during the planning and executing of the therapy (www.curatronic.com).

It is recognized that the use of magnetic fields for therapy has a long history. Physicians from ancient Greece, China, Japan and Europe successfully applied natural magnetic materials in their daily practice. The contemporary magnetotherapy has begun immediately after the World War II by introducing both magnetic and electromagnetic fields, generated by various waveshapes of the supplying currents. Starting in Japan, this modality quickly moved to Europe, first in Romania and the former Soviet Union. During the period 1960-1985 nearly all European countries designed and manufactured own magnetotherapeutic systems. Indeed, the first book on magnetotherapy, written by N. Todorov, was published in Bulgaria in 1982 and summarizes the experience of utilizing magnetic fields for treatment of 2700 patients, having 33 different pathologies. During the 1970’s, the team of Andrew Bassett introduced a new approach for treatment of delayed fractures, that employed a very specific biphasic low frequency signal (Bassett et al., 1974,1977). This signal was allowed by FDA for application in the USA only for non-union/delayed fractures. A decade later, FDA allowed the use of pulsed radiofrequency electromagnetic field (PRF) for treatment of pain and edema in superficial soft tissues. It is now commonly accepted that weak electromagnetic fields (EMF) are capable of initiating various healing processes including delayed fractures, pain relief, multiple sclerosis and Parkinson’s disease. (Rosch, Markov, 2004). This proven benefit could be obtained by using both static and time-varying magnetic fields.

This paper discusses only the modalities that utilize time varying low frequency EMF, known as pulsed electromagnetic fields. Therefore, a large body of research, including many clinical studies that report the successful application of static magnetic fields and high frequency EMF as well as electroporation and electrical stimulation will remain outside this paper. We suggest several excellent reviews concerning these stimulation modalities (Gardner et al., 1999; Rushton, 2002; Sluka and Walsh, 2003; Ojingwa and Isseroff, 2003; Rosch and Markov,
2004).

It should be noted, that, thus far, the medical communities’ approach to magnetotherapy is as to an adjuvant therapy, especially for treatment of a variety of musculoskeletal injuries. There is a large body of basic science and clinical evidence that time-varying magnetic fields can modulate molecular, cellular and tissue function in a physiologically and clinically significant manner. (Markov, 2002; Rosch and Markov, 2004).

The fundamental questions related to the biophysical conditions under which EMF signals could be recognized by cells in order to modulate cell and tissue functioning remain to be elucidated. The scientific and medical communities still lack the understanding that different magnetic fields applied to different tissues could cause different effects.

The medical part of the equation should identify the exact target and the “dose” of EMF that the target needs to receive. Then, physicists and engineers should design the exposure system in such way that the target tissue received the required magnetic flux density. One should not expect, for example, that the magnetic field which is beneficial for superficial wounds, might be as good for fracture healing. Particular attention must be paid to the biophysical dosimetry which should predict which EMF signals could be bioeffective and monitor this efficiency. This raises the question of using theoretical models and biophysical dosimetry in selection of the appropriate signals and in engineering and clinical application of new PEMF therapeutic devices.

Some examples for target populations

The largest populations of patients that have received, or could benefit frommagnetic field therapy are victims of musculoskeletal disorders, wounds and pain. Following is a summary of information for the number of people in the

USA

  • who needs help in above-mentioned areas.
  • Five million bone fractures occur annually in the United States alone.
  • About 5% of these became delayed or nonunion fractures (Ryaby, 1998).
  • According to National Osteoporosis Foundation about 10 million Americans have
  • osteoporosis and 34 million(s) of US citizens have low bone density, which put
  • them at risk for further musculoskeletal disorders.
  • Chronic wounds and their treatment are an enormous burden on the
  • healthcare system, both in terms of their cost ($5 billion to $9 billion annually)
  • and the intensity of care required. There is even more cost to society from human
  • suffering and reduced productivity. More than 2 million people suffer from pressure ulcers and as many as 600,000 to 2.5 million more have chronic leg and foot wounds (Wysocki,1996).
  • Diabetic foot ulcers are probably the most common chronic wounds inwestern industrialized countries. Of the millions who have diabetes mellitus, 15 per cent will suffer foot ulceration which often leads to amputation (100,000 per annum in the US alone). (Pilla, 2006)
  • The National Institutes of Health estimate that more than 48 million Americans suffer chronic pain that results in a 65 billion loss of productivity and over $100 billion spent on pain care (Markov, 2004c). Better part of this money is spent for pain-relief medications.
  • Recent advances in magnetotherapy suggest that carefully selected magnetic fields might be helpful in treatment of diseases as Parkinson’s, Alzheimer, as well as Reflex Sympathetic Disorders which have relatively small number of potential users.

Cost and benefit of EMF therapy

Improvement in even in only a small percentage of above mentioned cases would be of great benefit: less suffering, reduced expenses, decreased duration of treatment should be considered in parallel with individual and social
welfare. Thus, the clinical effects of PEMF on musculoskeletal system repair are physiologically significant and often constitute the method of choice when the conventional standard of care has failed to produce adequate clinical results. PEMF modalities are usually applied directly on the targeted area of the body. Compared to regular pharmaceuticals, PEMF offers an alternative with fewer, if any, side effects. This is a tremendous advantage versus pharmaceutical treatment at which the administered medication spreads over the entire body, thereby causing adverse effects in different organs, which sometimes might be significant. One should not forget that in order to deliver the medication dose needed to treat the target tissue/organ, patients routinely receive medication dose hundreds time larger than the dose needed by the target.

However, regulatory and reimbursement issues have prevented more widespread use of PEMF modalities, especially in the USA. The FDA policy toward magnetotherapy is unnecessarily restrictive. In concert with this policy, the Center for Medicare Services (CMS) for a period of time refused to allow reimbursement even for modalities cleared by FDA. It took several years of court fighting until CMS reversed its position. This was a result of the pressure from general public and physical therapy communities. In fact, the CMS has now recognized that PEMF is a plausible therapeutic modality which produces sufficient clinical outcome to permit, and reimburse for, use in the off-label application of healing chronic wounds, such as pressure sores and diabetic leg and foot ulcers (Pilla, 2006).

PEMF Signals

Today magnetic-field-dependent modalities could be categorized in six groups,but this paper is discussing only the PEMF signals (for details see Markov,2004c). An excellent review of the physics and engineering of low frequencysignals was published by Liboff, 2004

The PEMF signals in clinical use have variety of designs, which in most cases is selected without any motivation for the choice of the particular waveform, field amplitude or other physical parameters.

Sinewave type signals

It seems reasonable that the first and widely used waveshape is the sine wave with frequency of 60 Hz in North America and 50 Hz in the rest of the world



Figure 1 Three types of sinewave signals with the same amplitude, but different frequencies. Even not a subject of this paper, it should be noted that the 27.12 MHz continuous sinewave have been used for deep tissue heating in fighting various form of cancer.

From the symmetrical sinewaves engineers moved to an asymmetrical waveform by means of rectification. These types of signals basically flip-flop the negative part of the sinewave into positive, thereby creating a pulsating sinewave. The textbooks usually show the rectified signal as a set of ideal semisinewaves. However, due to the impedance of the particular design such ideal waveshape is impossible to be achieved. As a result, the ideal form is distorted and in many cases a short DC-type component appears between two consecutive semi sine-waves.

Figure 2 Example of real bridge rectified signal: a small DC component occurs between two semi sine waves and a slight distortion of the front part of semi sine wave might be observed. This form of the signals has been tested for treatment of low back pain and Reflex sympathetic disorder. However, the most successful implementation of this signal is shown in animal experiments as causing anti-angiogenic effects (Williams et al., 2001). Investigating a range of amplitudes for 120 pulses per second signal, the authors demonstrated that the 15 mT prevents formation of the blood vessels in growing tumors, thereby depriving the tumor from expanding the blood vessel network and causing tumor starvation and death.

In the middle of 1980’s the Ion Cyclotron Theory was proposed by Liboff et al. (1985,1987) and shortly after that a clinical device was created based on the ICR model (Orthologics, Temple, AZ). This device is in current use for recalcitrant bone fractures. The alternating 40 ?T sinusoidal magnetic field is at 76.6 Hz (a combination of Ca2+ and Mg2+ resonance frequencies). This signal, shown in has oscillating character, but due to the DC magnetic field it oscillates only as a positive signal.

Fig.3
Figure 3 Adding a DC signal to sinusoidal signal might cause the positive only signal to originate Preprint: Submitted to “Electromagnetic Biology and Medicine” for publication
November ‘06 6

The other type of sinewave-like signals might be seen when a sinewave signal is modulated by another signal. This exploit the principle of amplitude modulation, used in radio-broadcasting.

Figure 4 Example of amplitude modulation of a high frequency sinusoidal signal Usually, the sinewave signal is at high frequency (in KHz and MHz range), while the modulating signal is a low frequency signal. There are also devices that apply two high frequency signals and the interference of both signal results in an interference magnetic field (Todorov, 1982).

Rectangular type of signals

In addition to sinewave type signals, a set of devices which utilize unipolar or bipolar rectangular signals is available at the market. Probably for those signals the most important is to know that due to the electrical characteristics (mostly the impedance) of the unit, these signals could never be rectangular. It should be a short delay both in raising the signal up and in its decay to zero. The rise-time of such signal could be of extreme importance because the large value of dB/dt could induce significant electric current into the target tissue. Some authors consider that neither frequency, nor the amplitude are so important for the biological response, but the dB/dt rate is the factor responsible for observed beneficial effects. There are recent suggestions that the rectangular signals should be replaced by more realistic trapezoid signals. (Kotnik and Miklavcic, 2006)

Figure 5 Trapezoid signal minimizes the problems with the rising time in case of rectangular signals

Pulsed signals

The first clinical signal approved by FDA for treatment of nonunion or delayed fractures (Bassett, 1974, 1977) exploited the pulse burst approach. Having repetition rate of 15 burst per second, this asymmetrical signal (with a long
positive and very short negative component) has more than 30 years of very successful clinical use for healing nonunion bones.

Figure 6 The original signal for treatment of non-union fractures proposed by Bassett et al.
It was supposed that the cell would ignore the short opposite polarity pulse and
respond only to the envelope of the burst which had a duration of 5 msec,
enough to induce sufficient amplitude in the kHz frequency range.
A series of modalities utilizes signals that consists of single narrow pulses
separated by a long “signal-off” intervals. This approach allows modification not
only of the amplitude of the signal, but duty cycle (time on/time off) as well.
The pulsed radiofrequency signal, originally proposed by Ginsburg in 1934
and later allowed by FDA for treatment of pain and edema in superficial soft
tissues (Diapulse) utilizes the 27.12 MHz in pulsed mode. Thus, having short 65
?sec burst and 1600 ?sec pause between pulse bursts, the signal does not
generate heat during 30 min use.

Clinical benefit

A large number of scientific and clinical studies have been reporting that PEMF
help in bone unification; reduce pain, edema and inflammation; increase blood
circulation; stimulate immune and endocrine systems. Most wound studies
involve arterial or venous skin ulcers, diabetic ulcers, pressure ulcers and
surgical and burn wounds. Since cells involved in wound repair are electrically
Preprint: Submitted to “Electromagnetic Biology and Medicine” for publication
November ‘06
8
charged, some endogenous EMF signals may facilitate cellular migration to the
wound area (Lee et al.,1993), thereby restoring normal electrostatic and
metabolic conditions. An important concept was proposed, that at any injury site
of the musculoskeletal system an injury current occur (Canaday and Lee, 1991).
Because the main goal of any therapy is to restore normal function to the
organism, electric, magnetic or electromagnetic modalities appear suitable to
compensate the injury currents. Of course, the optimal parameters to achieve
this goal would depend on the type and extent of the injury that cause the
specific injury current to originate.

PEMF have also been beneficial in treatment of chronic pain associated
with connective tissue (cartilage, tendon, ligaments and bone) injury and jointassociated
soft tissue injury (Rosch and Markov, 2004; Hazlewood and Markov,
2006).

Numerous cellular studies have addressed effects of EMF on signal
transduction pathways. It is well accepted now that the cellular membrane is a
primary target for magnetic field action. (Adey, 2004) Evidence is collected that
selected magnetic fields are capable of affecting the signal transaction pathways
via alteration of ion binding and transport. The calcium ion is recognized as a key
player in such alterations. In a series of studies of calcium-calmodulin dependent
myosin phosphorylation my group demonstrated that specific static magnetic
fields, PEMF and 27.12 MHz PRF could modulate Ca2+ binding to CaM to a
twofold enhancement in Ca+2 binding kinetics in a cell-free enzyme preparation.
(Markov et al., 1992, 1993, 1994; Markov and Pilla, 1993, 1994a,b; Markov
2004a,b) The ion binding target pathway has recently been confirmed in other
studies using static magnetic fields (Engstrom et al., 2002; Liboff et al., 2003).
A meta-analysis performed on randomized clinical trials using PEMF on
soft tissues and joints showed that both PEMF and PRF were effective in
accelerating healing of skin wounds (Ieran et al., 1990; Ito et al., 1991; Stiller et
al.,1992; Comorosan et al, 1993; Seaborne et al., 1996; Canedo-Dorantes et
al.,2002), soft tissue injury (Bental, 1986; Foley-Nolan et al., 1990; Vodovnik and
Karba,1992; Pennington, 1993; Pilla et al.,1996), as well as providing
symptomatic relief in patients with osteoarthritis and other joint conditions
(Fitzsimmons et al.,1994; Zizic, 1995; Ryaby, 1998).

We, as scientists, are guilty of making statements like this: “Today there is
abundance of in vitro and in vivo data obtained in the laboratory research as well
as clinical evidence that time-varying magnetic fields of various configurations
can generate beneficial effects for various conditions, such as chronic and acute
pain, chronic wounds and recalcitrant bone fractures. This has been achieved
with low intensity, non-thermal, non-invasive time-varying electromagnetic fields,
having various configurations within a broad frequency range.” (Pilla, 2006).
What is wrong with this statement? One only word is missing “some”. By not
saying that some or selected PEMF could initiate plausible therapeutic effects,
we simply say that all magnetic fields could achieve the goals.
Which signals and at which conditions could be effective? Are any signal
parameters better than others? It should be pointed out that many EMF signals
used in research and as therapeutic modalities have been chosen in some
Preprint: Submitted to “Electromagnetic Biology and Medicine” for publication
November ‘06
9
arbitrary manner. Very few studies assessed the biological and clinical
effectiveness of different signals by comparing the physical/biophysical dosimetry
and biological/clinical outcomes. With the exponential development of Internet it
is easy to find tens, if not hundreds of devices, which promised to cure each and
any medical problem. A careful look at these sites would show that no
engineering, biophysical and clinical evidence is given to substantiate the claims.
It has been three decades, since the concept of “biological windows” was
introduced. In fact, three groups, unknown to one another, published, almost
simultaneously that during evolution Mother Nature created preferable levels of
recognition of the signals from exogenous magnetic fields. The “biological
windows” could be identified by amplitude, frequency and their combinations.
The research in this direction requires assessment of the response in a range of
amplitudes and frequencies. It has been shown that at least 3 amplitude windows
exist: at 50-100 ?T (5-10 Gauss), 15-20 mT (150-200 Gauss) and 45-50 mT
(450-500 Gauss) (Markov, 2005). Using cell-free myosin phosphorylation to
study a variety of signals, my group has shown that the biological response
depends strongly on the parameters of applied signal, confirming the validity of
the last two “windows” (Markov, 2004a,b). Interestingly, a new PEMF system,
developed by Curatronic Ltd. generates electromagnetic signals within the range
of these amplitude windows and exploit amplitude signals already proven to be
biologically and clinically effective (www.curatronic.com)

Mechanisms of action

The biophysical mechanism(s) of interaction of weak electric and magnetic fields
with biological systems as well as the biological transductive mechanism(s) have
been vigorously studied by the bioelectromagnetics community. Both
experimental and theoretical data have been collected worldwide in search of
potential mechanisms of interactions. As of today, a number of mechanisms have
been proposed, such as ion cyclotron resonance, ion parametric resonance, free
radical concept, heat shock proteins, etc. One of the first proposed models uses
a linear physicochemical approach (Pilla 1972,1974) in which an electrochemical
model of the cell membrane was employed in order to assess the EMF
parameters for which bioeffects might be expected. It was assumed that nonthermal
EMF may directly affect ion binding and/or transport and possibly alter
the cascade of biological processes related to tissue growth and repair.
This electrochemical information transfer hypothesis postulated that one
plausible way for interactions between the cell membrane and the
electromagnetic fields could modulate the rate of ion binding to receptor sites.
Several distinct types of electrochemical interactions can occur at cell surfaces,
but two deserve special attention: non-specific electrostatic interactions involving
water dipoles and hydrated (or partially hydrated) ions at the lipid
bilayer/aqueous interface of a cell membrane as well as voltage dependent
ion/ligand binding (Pilla et al., 1997)

It should be noted the significant contribution of late Ross Adey in studying
biophysical mechanisms of interactions of EMF with biological membranes which
has both fundamental and clinical importance. (Adey, 1986; Adey, 2004)
Ion cyclotron resonance (ICR) proposed during the mid-1980’s by Liboff
(1985,1987), described specific combinations of DC and AC magnetic fields
which can increase the mobility of specific ions near receptor sites and/or
through ion channels.

Any discussion of the possibility for MF to cause biological/clinical effects
must involve a discussion of the problem of thermal noise (“kT”). Physicists and
physical chemists, for example, have rejected the possibility that static and low
frequency magnetic fields may cause biological effects because of “thermal
noise”. Indeed, thermal noise has been cited as the main objection to the ICR
model (Muesham and Pilla, 1996; Pilla et al., 1999; Zhadin, 1998). Bianco and
Chiabrera (1992) have provided an elegant explanation of the inclusion of
thermal noise in the Lorentz-Langevin model which clearly shows the force
applied by a magnetic field on a charge moving outside the binding site is
negligible compared to background Brownian motion and therefore has no
significant effect on binding or transport at a cell membrane.
To resolve the thermal noise problems in the ICR model, Lednev (1991)
formulated an ion parametric resonance (IPR) model which was further
developed during the 1990’s (Blanchar and Blackman, 1994; Blackman and
Blanchar, 1995; Engstrom, 1996). In this quantum approach, an ion in the
binding site of a macromolecule (e.g., Calmodulin) is considered to be a charged
harmonic oscillator. It was proposed that the presence of a static magnetic field
could split the energy level of the bound ion into two sublevels with amplitudes
corresponding to electromagnetic frequencies in the infrared band. The
difference between these two energy levels is the Larmor frequency.
For me, the most important contribution of Lednev is the experiment he
designed to estimate the validity of his ICR model: myosin phosphorylation in a
cell-free mode (Shouvalova et al., 1991). The calmodulin molecule provides ideal
model for investigating ion binding without and with the presence of exogenous
magnetic field. This molecule has 4 molecular clefts ready to bind Calcium ion.
Moreover, calmodulin undergoes conformational changes at each filling of the
binding sites. The experiment proposed by Lednev, and further elaborated by my
group (Markov, 2004a,b), allows the Pilla’s group to propose a model that over
comes the problem of thermal noise. In addition, evidence showing both low
frequency sinusoidal magnetic fields, which induce electric fields well below the
thermal noise threshold, and weak static magnetic fields, for which there is no
induced electric field, can have biologically and clinically significant effects
(Shouvalova et al., 1991; Markov et al., 1992, 1993, 1994; Markov and Pilla,
1993, 1994a,b; Liburdy and Yost, 1993; Engstrom et al., 2002; Liboff et al., 2003)
have been collected.

Larmor precession, which describes the effects of exogenous magnetic
fields on the dynamics of ion binding, when the ion is already bound, has been
suggested as a possible mechanism for observed bioeffects due to weak static
and alternating magnetic field exposures (Zhadin and Fesenko, 1990; Edmonds,
1993; Muesham and Pilla, 1994a,b,1996; Pilla et al., 1997a,b).
A bound ionic oscillator in a static magnetic field will precess at the Larmor
frequency in the plane perpendicular to the applied field. This motion will persist
in superposition with thermal forces, until thermal forces eventually eject the
oscillator from a binding site. The threshold for Larmor precession model is
determined only by the bound lifetime of the charged oscillator, allowing
extremely weak magnetic fields to affect its dynamics. It should be taken into
account, that when an ion is approaching the binding site, the molecular cleft is
already occupied with water molecules. Therefore, the ion must compete with the
water molecules. The geometry of the binding site can create a locally
hydrophobic region, from which water molecules could be repelled. Weak static
magnetic fields have been reported to accelerate Ca/CaM dependent myosin
light chain kinase (MLCK) and protein kinase C (PKC) dependent processes up
to twofold (Markov and Pilla, 1994).

The further development of this approach leads to the dynamical systems
model which assumes the ion binding as a dynamical process wherein the
particle has two energetically stable points separated by a few kT (double
potential well), either bound in the molecular cleft, or unbound in the plane of
closest approach to the hydrated surface (Helmholtz plane) at the electrified
interface between the molecular cleft and its aqueous environment. Ion
binding/dissociation is treated as the process of hopping between these two
states driven by thermal noise and EMF effects are measured by modulation of
the ratio of time bound (in the molecular cleft) to time unbound (in the Helmholtz
plane). (Pilla et al., 1997)

This dynamical system uses the thermal noise as the driving force for ion
binding and dissociation. The external force could modulate the relative depth of
the wells thereby affecting the ratio of time bound to time unbound and thus the
kinetics of the binding process. A weak magnetic field can indirectly affect the
double well, which, in turn, modulates the ratio of time bound to time unbound
and therefore reaction rate. (Pilla et al.,1997)

The biophysical dogma prevailing until the late 1980’s and lingering to this
day is that, unless the amplitude and frequencies of an applied electric field were
sufficient to trigger membrane alterations, to produce tissue heating or to move
an ion along a field gradient, there could be no effect. This was a serious
obstacle in the search for biological mechanisms and therapeutic applications of
weak EMF signals.

The underlying problem for any model of biophysical mechanism of weak
EMF bioeffects relates to the signal detection at the molecular/cellular/tissue
target in the presence of thermal noise, i.e., signal to thermal noise ratio (SNR).
Clinical experience, as well as numerous animal and in vitro studies,
suggest the initial conditions of the EMF-sensitive target pathway determine
whether a physiologically meaningful bioeffect could be achieved. For example,
when broken bone received treatment with PEMF, the surrounding soft tissues
receive the same dose as the fracture site, but physiologically important
Preprint: Submitted to “Electromagnetic Biology and Medicine” for publication
November ‘06 12 response occurs only in the injured bone tissue, while changes in the soft tissue
have not been observed.

This is crucially important behavior, indicating that magnetic fields are
more effective when the tissue is out of equilibrium. Therefore, the experiments
with healthy volunteers are not always indicative for the potential response of
patients who are victims of injury or disease. The healthy organism has much
larger compensational ability than the diseased organism, which in turn would
reduce the manifestation of the response.

Support for this notion comes from a study of Jurkat cells in which the
state of the cell was found to be important in regard to the response of tissues to
magnet fields: normal T-lymphocytes neglect the applied PEMF, while being
stimulated by other factors. Furthermore, the response of lymphocytes to
magnetic fields clearly shows a dependence on the stimulation with other factors.
In other words, it might be approximated with pendulum effect – the larger is the
deviation from equilibrium, the stronger is the response (Nindl et al., 2002;
Markov et al., 2006). For example, Nindl has demonstrated, in an in vitro study,
that the initial conditions of lymphocytes are important in terms of the biological
effects of those cells to magnetic fields.

The future

Even with the large variety of devices and signals in use for PEMF therapy, some
general categories have been identified as more promising for the future
development of the magnetic field therapy. It appears that semi sinewaves are
more effective compared to continuous sine waves. This approach is based on
rectification of the continuous sinusoidal signal, described earlier.
It is too preliminary to generalize, but the future research should clarify the
importance of the short DC component between the consecutive semi sinewaves.
In an unpublished study, we have found that the duration of this DC
component is associated with different biological response in several outcomes.
There are at least two different approaches for utilization of these signals.
One relies on constructing an elliptical or spherical coil which could be moved
around the patient body (Williams et al, 2001) and the other, applies the
magnetic field on the upper or lower limbs, assuming that the results appear
following systemic effects when the benefit is obtained at site distant from the site
of application (Erickson et al., 2004).
Living in the era of computers, we should expect that the advantages of
powerful computer technologies should be implemented in designing new
magnetotherapeutical devices. At first, it should be the computerized control of
the signal and maintenance of the parameters of the signal during the whole
treatment session. Next, inclusion of user-friendly software packages with
prerecorded programs, as well as with the ability to modify programs depending
the patient needs. With appropriate sensors, the feedback information could be
recorded and used during the course of therapy. Last, but not least, is the
possibility to store the data for the treatment of individuals in a large database
and further analyze the cohort of data for particular study or disease.
Preprint: Submitted to “Electromagnetic Biology and Medicine” for publication
November ‘06 13

One of the most promising PEMF units available now worldwide is the
Curatron system, designed and distributed by Curatronic Ltd. The Curatron
system generates a sinusoidal dual rectified waveform, subjected to Fast Fourier
Transformation. This way the signal contains at a given time only one frequency
component, resulting in a single peak at the frequency of the wave. Gating of the
above waveform with a precise time window creates the pulsing frequency. The
process of creating the pulse waveform, pulsing frequency, zero crossing, timing
and impulse intensity is completely software controlled by the built-in computer
(www.curatronic.com)

By utilizing the precise computer-controlled timing for gating of the time
window, responsible for the actual pulse frequency, the maximum utilization of
the energy contents of the modulated sinusoidal signal is obtained. Very fast
pulse rise time guarantees maximum electromagnetic energy transfer deep
inside the tissue and cells, explaining the high efficacy for the Curatron. The
strength of the PEMF generated by the coil applicators is monitored and
controlled by a laser-calibrated Hall-effect sensor.


Figure 8 Schematic representation of the computerized system for magnetic field therapy employed by

Curatron system

By connecting the Curatron unit to a standard Personal Computer a large
database with readily pre-programmed therapy protocols becomes available.
Thus, the specially designed software package takes full control of the Curatron
unit and all therapy parameters are under direct command and control of the PC
program.

Therapy setting can be selected from a database, which contains an
extensive list of preprogrammed treatment protocols, applicable for various
diseases. Besides the pre-programmed protocols the therapist can very easily
compile his own therapy protocols and save it in the database for future use. The
complete program runs fully automatic in sequence, according to the
corresponding frequencies and intensities for each stage, during the total
treatment time of each session. The inventors of Curatron assume that the
automatic parameters change is important to avoid adaptation of the body to
repeated stimulus. As an example, the therapy program developed for
osteoporosis monitors the bone density and the bone densitometry values and
Preprint: Submitted to “Electromagnetic Biology and Medicine” for publication
November ‘06 14 scores are used for calculating automatically the optimal therapy parameters for
each individual patient.

In conclusion,
The author strongly believes that a lot of work remains to be done in designing
both technology and methodology of application of magnetotherapeutic devices.
One of the very important issues that engineers and biophysicists neglect, is the
frequency spectrum of the signal. At any pulsed electromagnetic field, a large
spectrum of harmonics, up to 3 kHz exists with the first harmonic usually having
the amplitude close to 20% of the amplitude of basic signal. In that aspect, the
computerized system, offered and already in use, by Curatron is of great
importance. The computer technology allows a collection of feedback
information, analysis and monitoring of the signal during the entire treatment
session and opportunities for Furrier analysis of the signal during the use.
Shortly, computer link to PEMF is the future of the therapy with PEMF.
Acknowledgment: The author express his deep gratitude to Dr. A.R. Liboff for
his kind permission to use figures from his excellent paper published in
“Bioelectromagnetic Medicine”
Disclamer: The author does not have any commercial interest linked to
Curatronic Ltd.

References

Adey, W.R. (1986) The sequence and energetics of cell membrane transducing coupling to intracellular
enzyme systems. Bioelectrochem. Bioenergetics. 15:447-456.
Adey, W.R. (2004) Potential therapeutic application of nonthermal electromagnetic fields: Ensemble
organization of cells in tissue as a factor in biological tissue sensing. In Rosch, P.J. and Markov,
M.S., eds. Bioelectromagnetic Medicine. New York, Marcel Dekker. 1-15
Bassett, C.A.L., Pawluk, R.J., Pilla, A.A. (1974) Acceleration of Fracture Repair by Electromagnetic
Fields. Ann NY Acad Sci. 238:242-262.
Bassett, C.A.L., Pilla, A.A., Pawluk, R. (1977) A non-surgical salvage of surgically-resistant
pseudoarthroses and non-unions by pulsing electromagnetic fields. Clin Orthop 124:117-131.
Bental, R.H.C. (1986) Low-level pulsed radiofrequency fields and the treatment of soft-tissue injuries.
Bioelectrochem. Bioenergetics 16:531-548.
Blackman, C.F., Blanchard, J.P., Benane, S.G., House, D.E. (1995) The ion parametric resonance model
predicts magnetic field parameters that affect nerve cells. FASEB J. 9:547-51.
Blanchard, J.P., Blackman, C.F. (1994) Clarification and application of an ion parametric resonance model
for magnetic field interactions with biological systems. Bioelectromagnetics 15:217–238.
Bianco, B., Chiabrera, A. (1992) From the Langevin-Lorentz to the Zeeman model of electromagnetic
effects on ligand-receptor binding. Bioelectrochem Bioenergetics. 28:355-365.
Canaday, D.J., Lee, R.C. (1991) Scientific basis for clinical applications of electric fields in soft-tissue
Repair. In: Brighton, C.T., Pollack, S.R., eds. Electromagnetics in Biology and Medicine, San
Francisco Press Inc., 1991: 275-291
Canedo-Dorantes, L., Garcia-Cantu, R., Barrera, R., Mendez-Ramirez, I., Navarro, V.H., Serrano, G.
(2002) Healing of chronic arterial and venous leg ulcers with systemic electromagnetic fields.
Arch Med Res 33:281-289.
Comorosan, S., Vasilco, R., Arghiropol, M., Paslaru, L., Jieanu, V., Stelea, S. (1993) The effect of Diapulse
therapy on the healing of decubitus ulcer. Rom J Physiol 30:41-45.
Edmonds, D.T. (1993) Larmor precession as a mechanism for the detection of static and alternating
magnetic fields. Bioelectrochem Bioenerg. 30: 3-12.
Preprint: Submitted to “Electromagnetic Biology and Medicine” for publication
November ‘06
15
Engstrom, S. (1996) Dynamic properties of Lednev’s parametric resonance mechanism.
Bioelectromagnetics 17:58-70.
Engstrom, S., Markov, M.S., McLean, M.J., Holcomb, R.R., Markov, J.M. (20020 Effects of non-uniform
static magnetic fields on the rate of myosin phosphorylation. Bioelectromagnetics 23:475-479.
Ericsson, A.D., Hazlewood, C.F., Markov, M.S., Crawford, F. (2004d) Specific Biochemical changes in
circulating lymphocytes following acute ablation of symptoms in Reflex Sympathetic Dystrophy
(RSD): A pilot study, In: Kostarakis, P., ed. Proceedings of 3rd International Workshop on
Biological Effects of EMF – Kos, Greece, October 4-8, 2004, ISBN 960-233-151-8. p.683-688.
Fitzsimmons, R.J., Ryaby, J.T., Magee, F.P., Baylink, D.J. (1994) Combined magnetic fields increase net
calcium flux in bone cells. Calcif Tiss Intl.55: 376-380.
Foley-Nolan, D,, Barry, C., Coughlan, R.J., O’Connor, P., Roden, D. (1990) Pulsed high frequency
(27MHz) Electromagnetic therapy for persistent neck pain: a double blind placebo-controlled
study of 20 patients. Orthopedics 13:445-451.
Gardner, S.E., Frantz, R.A., Schmidt, F.L. (1999) Effect of electrical stimulation on chronic wound healing:
a meta-analysis. Wound Rep Regen 7:495-503.
Ginsburg, A.J. (1934) Ultrashort radio waves as a therapeutic agent. Med Record 19: 1-8.
Hazlewood, C.F., Markov, M.S. (2006) Magnetic fields for relief of myofascial and/or low back pain
through trigger points. In: Kostarakis, P., ed. Proceedings of Forth International Workshop
Biological effects of electromagnetic fields., Crete 16-20 October 2006, ISBN# 960-233-172-0, p.
475-483.
Ieran, M., Zaffuto, S., Bagnacani, M., Annovi, M., Moratti, A., Cadossi, R. (1990) Effect of low frequency
electromagnetic fields on skin ulcers of venous origin in humans: a double blind study. J Orthop
Res. 8:276-282.
Itoh, M., Montemayor, J.S., Jr., Matsumoto, E., Eason, A., Lee, M.H., Folk, F.S. (1991) Accelerated wound
healing of pressure ulcers by pulsed high peak power electromagnetic energy (Diapulse).
Decubitus 4:24-25, 29-34.
Kotnik, T. Miklavcic, D. (2006) Theoretical analysis of voltage inducement on organic molecules. In:
Kostarakis, P., ed. Proceedings of Forth International Workshop Biological effects of
electromagnetic fields., Crete 16-20 October 2006, ISBN# 960-233-172-0, p. 217-226
Lee, R.C., Canaday, D.J/, Doong, H. (1993) A review of the biophysical basis for the clinical application of
electric fields in soft-tissue repair. J Burn Care Rehabil 14:319-335.
Lednev, V.V. (1991) Possible mechanism for the influence of weak magnetic fields on biological systems.
Bioelectromagnetics 12:71-75.
Liboff, A.R. (1985) Cyclotron resonance in membrane transport. In: Chiabrera, A., Nicolini, C., Schwan,
H.P., eds. Interactions between in Interactions Between Electromagnetic Fields and Cells. Plenum
Press, New York. 281-396.
Liboff, A.F., Fozek, R.J., Sherman, M.L., McLeod. B.R., Smith, S.D. (1987) Ca2+-45 cyclotron resonance
in human lymphocytes. J Bioelectricity 6:13–22.
Liboff, A.R., Cherng, S., Jenrow, K.A., Bull, A. (2003) Calmodulin-dependent cyclic nucleotide
phosphodiesterase activity is altered by 20 mT magnetostatic fields. Bioelectromagnetics 24:32-
38.
Liburdy, R.P., Yost, M.G. (1993) Tme-varying and static magnetic fields act in combination to alter
calcium signal transduction in the lymphocyte. In: Blank, M., ed. Electricity and Magnetism in
Biology and Medicine. San Francisco Press 331-334.
Markov, M.S., Pilla, A.A. (1993) Ambient range sinusoidal and DC magnetic fields affect myosin
phosphorylation in a cell-free preparation. In: Blank, M., ed. Electricity and Magnetism in Biology
and Medicine. San Francisco Press. 323-327.
Markov, M.S., Ryaby, J.T., Kaufman, J.J., Pilla, A.A. (1992) Extremely weak AC and DC magnetic field
significantly affect myosin phosphorylation. In: Allen, M.J., Cleary, S.F., Sowers, A.E., Shillady
D.D., eds. Charge and Field Effects in Biosystems-3, Birkhauser, Boston 1992; 225-230
Markov, M.S., Wang, S., Pilla, A.A. (1993) Effects of weak low frequency sinusoidal and DC magnetic
fields on myosin phosphorylation in a cell-free preparation. Bioelectrochem Bioenergetics 30:
119-125.
Markov, M.S., Muehsam, D.J., Pilla, A.A. (1994) Modulation of Cell-Free Myosin Phosphorylation with
Pulsed Radio Frequency Electromagnetic Fields. In Allen, M.J., Cleary, S.F, Sowers, A.E., eds.
Charge and Field Effects in Biosystems 4. World Scientific, New Jersey. 274-288.
Preprint: Submitted to “Electromagnetic Biology and Medicine” for publication
November ‘06
16
Markov, M.S., Pilla, A.A. (1994) Static magnetic field modulation of myosin phosphorylation: Calcium
dependence in two enzyme preparations. Bioelectrochem. Bioenergetics. 35:57-61.
Markov, M.S., Pilla, A.A. (1994) Modulation of Cell-Free Myosin Light Chain Phosphorylation with Weak
Low Frequency and Static Magnetic Fields. In: Frey, A., ed. On the Nature of Electromagnetic
Field Interactions with Biological Systems. R.G. Landes Co., Austin. 127-141.
Markov, M.S. (2002) How to go to magnetic field therapy? In: Kostarakis P., ed. Proceedings of Second
International Workshop of Biological effects of Electromagnetic fields, Rhodes, Greece, 7-11
October 2002, ISBN #960-86733-3-X. 5-15
Markov, M..S. (2004) Magnetic and electromagnetic field therapy: basic principles of application for pain
relief. In: Rosch, P.J., Markov, M.S., eds. Bioelectromagnetic Medicine, Marcel Dekker, NY, 251-
264.
Markov, M.S. (2004a) Myosin light chain phosphorylation modification depending on magnetic fields I.
Theoretical. Electromagnetic Biology and Medicine 23: 55-74.
Markov, M.S. (2004b) Myosin phosphorylation – a plausible tool for studying biological windows. Ross
Adey Memorial Lecture. In: Kostarakis, P. Proceedings of Third International Workshop on
Biological Effects of EMF. Kos, Greece, October 4-8, ISBN 960-233-151-8. 1-9
Markov, M.S., Hazlewood, C.F., Ericsson, A.D. (2004c) Systemic effect – a plausible explanation of the
benefit of magnetic field therapy: A hypothesis – In: Kostarakis, P., ed. Proceedings of 3rd
International Workshop on Biological Effects of EMF – Kos, Greece, October 4-8, 2004,
ISBN 960-233-151-8. p.673-682
Mir, L.M. (2001) Therapeutic perspectives of in vivo cell electropermeabilization. Bioelectrochemistry.
53:1-10.
`Muehsam, D.J., Pilla, A.A. (1994) Weak magnetic field modulation of ion dynamics in a potential well:
mechanistic and thermal noise considerations. Bioelectrochem Bioenerg. 35:71-79.
Muehsam, D.J., Pilla, A.A. (1994) Weak magnetic field modulation of ion dynamics in a potential well:
mechanistic and thermal noise considerations. Bioelectrochem. Bioenergetics 35:71-79.
Muehsam, D.S., Pilla. A.A. (1996) Lorentz approach to static magnetic field effects on bound ion dynamics
and binding kinetics: thermal noise considerations. Bioelectromagnetics 17:89-99.
Ojingwa, J.C., Isseroff, R.R. (2003) Electrical stimulation of wound healing. J Invest Derm 121:1-12.
Pennington, G.M., Danley, D.L., Sumko, M.H., et al. (1993) Pulsed, non-thermal, high frequency
electromagnetic energy (Diapulse) in the treatment of grade I and grade II ankle sprains. Military
Med. 158:101-104.
Pilla, A.A. (1972) Electrochemical information and energy transfer in vivo. Proc. 7th IECEC, Washington,
D.C., American Chemical Society. 761-64.
Pilla, A.A. (1974) Electrochemical Information Transfer at Living Cell Membranes. Ann NY Acad Sci,
238:149-170.
Pilla, A.A., Martin, D.E., Schuett, A.M., et al. (1996) Effect of pulsed radiofrequency therapy on edema
from grades I and II ankle sprains: a placebo controlled, randomized, multi-site, double-blind
clinical study. J Athl Train.S31:53.
Pilla, A.A., Muehsam, D.J., Markov, M.S. (1997) A dynamical systems/Larmor precession model for weak
magnetic field bioeffects: Ion-binding and orientation of bound water molecules. Bioelectrochem
Bioenergetics 43:239-249.
Rushton DN, Electrical stimulation in the treatment of pain. (2002) Disability Rehab 24:407-415.
Ryaby, J.T. (1998) Clinical effects of electromagnetic and electric fields on fracture healing. Clin Orthop.
355(suppl): 205–215.
Seaborne, D., Quirion-DeGirardi, C., Rousseau, M. (1996) The treatment of pressure sores using pulsed
electromagnetic energy (PEME). Physiotherapy Canada 48:131-137.
Shuvalova, L.A., Ostrovskaya, M.V., Sosunov, E.A., Lednev, V.V. (1991) Weak magnetic field influence
of the speed of calmodulin dependent phosphorylation of myosin in solution. Dokladi Acad Nauk
USSR 217: 227.
Sluka, K.A., Walsh, D. (2003) Transcutaneous electrical nerve stimulation: Basic science mechanisms and
clinical effectiveness. J Pain 4:109-121.
Stiller, M.J., Pak, G.H.,pack JL, Thaler, S., Kenny, C., Jondreau, L. (1992) A portable pulsed
electromagnetic field (PEMF) device to enhance healing of recalcitrant venous ulcers: a doubleblind,
placebo- controlled clinical trial. Br J Dermatol. 127:147-154.
Todorov, N. (1982) Magnetotherapy. Sofia: Meditzina i Physcultura Publishing House. 106 p.
Preprint: Submitted to “Electromagnetic Biology and Medicine” for publication
November ‘06
17
Vodovnik, L., Karba, R. (1992) Treatment of chronic wounds by means of electric and electromagnetic
fields. Med & Biol Engin & Comput 30: 257-266
Wysocki, A.B. (1996) Wound fluids and the pathogenesis of chronic wounds. J Wound Ostomy Care Nurs.
23:283–290.
www.curatronic.com
Zhadin, M.N. (1998) Combined action of static and alternating magnetic fields on ion motion in a
macromolecule: Theoretical aspects. Bioelectromagnetics 19:279-292.
Zhadin, M.N., Fesenko, E.E. (1990) Ionic cyclotron resonance in biomolecules. Biomed Sci 1:245–250.
Zizic, T., Hoffman, P., Holt, D., Hungerford , J., O’Dell, J., Jacobs, M, et al. (1995) The treatment of
osteoarthritis of the knee with pulsed electrical stimulation. J Rheumatol.22:1757-61.
Marko Markov Ph.D.
Dr. Markov received his B.S. and M.S. degrees in Physics in 1964 and 1967 and
his Ph.D. in Biophysics in 1980 from Sofia University. He completed his postdoctoral
training as Research Fellow at Moscow University in 1980.
Dr. Markov’s appointments included Adjunct Professor, Erie Community College,
Buffalo NY, Visiting Professor Mount Sinai Medical Center, NY and Oakland
Universities MI, Associated Dean and Chair of Department of Biophysics and
Radiobiology at Sofia University, Research Associate department of
Spectroscopy, Institute of Physics, Bulgarian Academy of Sciences.
Dr. Markov has published over 140 papers, has 7 registered magnetic field
patents to his name in the US and is co-editor of the following books:
“Electromagnetic Fields and Biomembranes”, co-edited with Prof. Martin
Blank Plenum Press, New York 1988.
“Bioelectromagnetic Medicine” co-edited with Prof. Paul Rosch, Marcel
Dekker, New York 2004
“Biological effects of Electromagnetic Fields” – A triple issue of the journal
THE ENVIRONMENTALIST – co-edited with Prof. Panos Kostarakis – Springer,
Dordrecht, The Netherlands, 2005
“BIOELECTROMAGNETICS: Current concepts” – co-edited with Prof. Sinerik
Ayrapetyan – Springer, Dordrecht, The Netherlands, 2006