Bioelectrodynamics in Living Organisms

Bioelectrodynamics in living organisms
Shu-Ang Zhou
a,b,
*
, Mitsuru Uesaka
a
a
University of Tokyo, Nuclear Professional School, Graduate School of Engineering, 2-22 Shirane Shirakata Tokai-mura Naka-gun,
Ibaraki 319-1188, Japan
b
National Institute of Radiological Sciences, Chiba, Japan
Available online 27 December 2005
Abstract
This article introduces an interdisciplinary subject of bioelectrodynamics in living organisms and its related research
challenges and opportunities. Bioelectrodynamics in living organisms is aimed to reveal critical roles of electromagnetism
and mechanics in biology, to correlate biophysical functions of living organisms with biochemical processes at the cellular
level, and to introduce theoretical basis and methodology, such as modeling and simulations, for stimulating technical
innovations and promoting technology development in biomedicine as well as for the study of human healthcare issues
related to environments among others in our modern society. The article reviews some important issues in bioelectrody-
namic modeling. This includes the modeling of living cells, blood, bones and soft tissues that may have unique properties,
such as active control, regulation and remodeling capabilities that are completely dierent from those of conventionally
man-made materials. Possible biological eects and potential biomedical usages of endogenous and exogenous electromag-
netic elds and mechanical stresses in living organisms are also reviewed, which indicate promising future of biomedical
imaging and therapeutic methods based on bioelectrodynamic techniques. The fact that living organisms may have
well-organized structures, actively controlled actions and responses, extremely sensitivity in electromagnetic elds and
mechanical actions, and amazing signal amplication functions may not only cause complexity and variety of the biolo-
gical world, but also create opportunities for technical innovations in biomedicine to improve future quality of human life.
2005 Elsevier Ltd. All rights reserved.
Keywords: Bioelectricity; Bioelectrodynamics; Biomechanics; Biology; Biomedicine
1. Introduction
Bioelectrodynamics in living organisms is an interdisciplinary subject, which studies electromagnetic,
mechanical and their coupling phenomena in biological media and their relations with physiological and path-
ophysiological behaviors of living organisms. It is aimed to reveal critical roles of electromagnetism and
mechanics in biology, to correlate biophysical functions of living organisms with biochemical processes at
0020-7225/$ - see front matter 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ijengsci.2005.11.001
*
Corresponding author. Address: University of Tokyo, Nuclear Professional School, Graduate School of Engineering, 2-22 Shirane
Shirakata Tokai-mura Naka-gun, Ibaraki 319-1188, Japan. Tel.: +81 29 287 8480; fax: +81 29 287 8488.
E-mail address: shu-ang.zhou@telia.com (S.-A. Zhou).
International Journal of Engineering Science 44 (2006) 6792
www.elsevier.com/locate/ijengsci
the cellular level, and to introduce theoretical basis and methodology, such as modeling and simulations, for
stimulating technical innovations and promoting technology development in biomedicine as well as for the
study of human healthcare issues related to environments among others in our modern society.
In living organisms, cells and tissues are constantly subject to forces and stresses. These forces and stres-
ses have various origins from pressure forces linked to gravity to motional forces, and from electromagnetic
forces arising from molecular interactions, environmental and externally applied electromagnetic (EM)
elds. These forces and EM elds are likely to modify cellular behaviors, the synergetic properties of which
may also aect physiological behaviors of the living organisms. One can imagine if there were no sunlight
and geomagnetic elds, there would be no high-level living organisms on the Earth. The biological eects of
electromagnetic elds are denitive and crucial to the formation of human beings. The fact that motion and
mechanical training of a human body can aect signicantly the physical performance and health status of
the human body is also well known. On the other hand, these forces and EM elds, including their energy
and power, may also be manipulated and utilized properly for therapeutic purposes in biomedicine, pro-
vided that one had proper understanding of the mechanisms involved in the interaction processes in any
specic application. This is indeed one of the main objectives of the bioelectrodynamics to discover, via both
theoretical and experimental eorts, those biophysical mechanisms of critical importance to the human life
and health.
The ideas of using electromagnetic means for therapeutic applications in medicine already existed since the
18th century when our knowledge about AC currents, transformers and related electrical machines were rap-
idly developed during that period. However, due partly to the premature of those devices and partly to the
widespread introduction of antibiotics, improved surgical techniques and other competing therapies after
World War II, those early ideas and techniques did not ourish. Today, with our increasing knowledge about
bioelectromagnetic phenomena in living organisms, especially at the cellular level, and the rapid development
of advanced technologies, such as microsystems and nano-technology, there is an increasing interest to explore
novel therapies based on bioelectrodynamic technologies with possible combination of other well-established
techniques in biomedicine. In this article, some of recent bioelectrodynamic imaging techniques and bioelec-
trodynamic therapies that could be of potential interest for further exploration will be reviewed. Some issues
and important research results on biological eects of electromagnetic radiations on living organisms and
related bioelectrodynamic modeling of living organisms will also be reviewed.
2. Bioelectrical phenomena in animals
Although our scientic understanding of phenomena of electricity has only a few hundreds years of history,
the electrical phenomena in living organisms was observed thousands of years ago probably rst by shermen
who found that some shes, such as the torpedo (or electric rays) existed in the Atlantic and Mediterranean,
were capable of administering a shock to persons and benumbing them. Systematical scientic studies of the
electric phenomena in living organisms, their origins and possible usages in medicine started later in the 18th
century.
2.1. Galvanis animal electricity
Luigi Galvani, a professor at Bologana, rst observed in 1786 that electricity caused a dissected frogs leg
muscle to twitch and claimed that he had demonstrated the existence of animal electricity. On the basis of his
ndings (and of the results of a multiplicity of studies in which experimental conditions were varied), Galvani
came to the conclusion that some form of intrinsic electricity was present in the animal, and that connective
nerve and muscle together, by means of conductive materials, induced contractions by allowing for the ow of
this internal electricity. Galvanis claim was however challenged by his country man, Alessandro Volta, a
physics professor at Pavia, who argued that the electricity was articial, arising from a potential dierence
when two dissimilar metals were in contact.
In the middle of 19th century, the successors of Galvani at Bologna, such as Carlo Matteucci, a physics
professor at the University of Pisa, had demonstrated that living organisms did indeed produce a small,
but denitive electric current [1,2]. Further studies found that, in contrast to animal experiments, plants, even
68 S.-A. Zhou, M. Uesaka / International Journal of Engineering Science 44 (2006) 6792
the touch-sensitive mimosa, could not be electrically stimulated. This fact had led to the conclusion of Von
Humboldt [3] that the ability to be excited by electricity is a general property of animals. Since then, eorts
began both to understand how these signals were produced and propagated along the neurons and to improve
instrumentation for detecting and recording these signals.
According to Galvani, animal electricity exists in a state of non-equilibrium, which is generated by a
particular machine. We now know that this machine corresponds to the cell membrane with its complex orga-
nization of ionic pumps and ion channels. This peculiar machine creates dissimilar Na
+
and K
+
concentra-
tions, and converts concentration gradients into an electric potential dierence between the intracellular and
extracellular medium. The later invention of the voltage-clamp technique [4,5] made possible to study exper-
imentally membrane events underlying the generation of action potentials. As we now know, although signal-
ing in nerve and muscle is a genuine electric process, it diers profoundly from the simple passive conduction
along electric cables, which would predicted a signal propagation speed close to the speed of light that was not
observed by experiments. On the contrary, it appears to be an active process, which depends on a particular
form of electrical energy, accumulated between the interior and the exterior of the nerve ber, as a conse-
quence of physiological processes clearly belonging to the domain of life, a true animal electricity with
characteristics corresponding to the fundamental intuition of Galvani. Today, it is fair to say that Galvanis
studies had laid down the foundation of electrophysiology, a science that in recent times has had a develop-
ment comparable to that of the physical study of electricity in the rst half of the 19th century. On the other
hand, Voltas experiments had led to the invention of the electrical battery, the famous Voltaic pile, which
opened a new path to the tremendous subsequent development of physical investigations of electricity, elec-
trochemistry, electromagnetism and related phenomena.
2.2. Electricity in shes and controllable discharge
According to modern physics, living organisms are composed of atoms and molecules, and the forces
between atoms and molecules are largely electrical, just like those in non-living natural or man-made materi-
als. The main dierence between living organisms and materials is that the electrical force in the living organ-
isms can be actively controlled. Proper understanding of such a dierence is crucial in our later discussion
about biological eects of electromagnetic elds on living organisms.
Living animals can use their internal electricity to monitor and control their own physiological processes.
Some aquatic animals can also inadvertently produce electrical elds in their vicinity, as a result of being ion-
ically dierent from the water and having electrogenic processes in the gills, mucous membranes and skin. For
instance, catshes and sharks have electrosensory (electroreceptor) organs, which can detect very low-fre-
quency signals with spectral frequency components between DC and 100 Hz. It was demonstrated that fresh-
water catsh is surrounded by stationary electrical DC elds upon which AC components related with
respiration are superimposed [6]. Such elds have been found in many aquatic species, and they reveal elec-
trically the presence of an individual to other electrosensitive species. For the catsh it has been demonstrated
that such elds can be used for the detection and recognition of prey. It has also been demonstrated that cat-
sh can feel each other electrically [79].
Electric shes generate electricity through their electric organs and membrane processes that are similar to
those involved in electrical phenomena of other animals, but, unlike them, these shes can produce large
potential dierences at their body surface, and thus aect other animals living in their habitat. Normally this
occurs because the individual cells in the stacks of electrocytes are asymmetrical, maintaining a constant rest-
ing potential across one face (normally not innervated), while a command from the central nervous system
(CNS) generates a brief electrical response in the other face, which receives a strong innervation (nervous
face). This was rst explained in experiments carried out on the electric eel, soon after intracellular recording
electrodes were available. In electric eels, this response is a normal Na
+
-dependent reversal of the membrane
potential, so that on open circuit, each electrocyte contributes about 150 mV at the peak of the spike. In some
shes, there can be several thousands of such electrocytes in series, which could be red synchronously (see
Fig. 1). An electric eel is such an example of having the capability of generating violent discharge at high volt-
ages up to several hundreds of volt. The phenomenon that controllable and synchronous action of living cells
may create unexpected physical consequences may remind us some extreme physical performance made by
S.-A. Zhou, M. Uesaka / International Journal of Engineering Science 44 (2006) 6792 69
well-trained athletes among others. Further studies will however be required to discover the intrinsic mecha-
nisms leading to those extreme physical performances by the human body.
2.3. Electrical stimulation and early medical usage
Today, Galvanis electrical stimulation and activation of frog legs with an electrical current is well known.
Less well known is the fact that the frog leg muscle could also be stimulated at a distance by a spark produced
by a static generator. Actually, Galvani had already noticed the muscle contractions caused by the spark elic-
ited from an electrical machine separated from the frog [2]. Based on these results, in 1890s, Nikola Tesla had
started his study on possible use of RF energy for medical and health related purposes, while his most known
work was on the AC frequency based transfer of electrical power. In particular, Nikola Tesla noticed the heat
caused by high-frequency current, which may have impact on a living organism and led to the eld of dia-
thermy. The diathermy, treatment of internal tissue by heating without burning the skin, through means of
electromagnetic radiation, continued to develop through the 20th century, with various frequencies being
applied. Tumors were one illness treated locally in this way, and in the case of infection the whole body could
be heated. At about the same time, a French scientist, Arsene DArsonval made similar work on potential use
of electricity in medical cares, and made his mostly well-known remark in 1896: I am convinced that the ther-
apy of the future will employ heat, light, electricity and agents yet unknown. Toxic drugs shall cede their place
to physical agents, the employment of which at least has the advantage of not introducing any foreign body
into the organism.
As we know today, such a statement has not been realized. On the contrary, for instance, the popularity of
Teslas diathermy waned after World War II with the widespread introduction of antibiotics, improved sur-
gical techniques, and other competing therapies. A large drug industry based essentially on various types of
chemicals and their compounds has instead been developed. In spite of some controversy stories in the history
of drug industries, we are now seeing gradually the entrance of physical means used in medical cares with the
rapid progress and development of advanced technologies, such as the nano-technology, material science and
electromagnetic techniques among others. We may foresee the combined usage of traditionally chemical-based
drugs and modern techniques based on physical means, their related instrumentations and smart systems of
targeted drug delivery to reduce toxic side eects of chemicals in living organisms. In this respect, the theory
of bioelectrodynamics and its related techniques will play a role of increasing importance in future biomedi-
cine, as we shall discuss in the following sections.
3. Bioelectrical signals in human body
Since the discovery of electrical activities in animals, one has been interested in detecting bioelectrical sig-
nals not only in animals for understanding the intrinsic mechanisms of these electrical activities inside the liv-
ing organisms, but also in human bodies in order to nd correlations of these bioelectrical signals with disease
conditions in human bodies. After many years of scientic eorts, the relationship between muscle motion,
nerve cells, and electrical activity in human bodies gradually came to be understood.
+ + + +
electrocyte
firing state
0
-50
50
2 4 6
Time (ms)
V

(
m
V
)
Fig. 1. An electrical eel with its electrocytes responsible for the electrical shock ring.
3.1. Electrocardiogram and cardiac pacemaking
As early as 1875, the electrical activity of the brain in the absence of muscle motion was observed. The
heart, meanwhile, as an active muscle with somewhat stronger signals, was closely studied though initially with
animal experimentation. The instrumentation to measure these relatively weak signals non-invasively was
however developed rather slowly. In 1878, Theodore Wilhelm Engelmann in Utrecht produced the rst plot
of a primitive electrocardiogram (ECG), and 10 years later the Englishman A.D. Waller recorded the rst plot
of a human ECG from the body surface [10]. Potential signicance of the ECG to clinical applications was
noticed later by Willem Einthoven in 1900, who discovered the mechanism of the electrocardiogram, for which
he received the Nobel Prize in medicine in 1924 [11].
The ECG is undoubtedly a medical diagnostic device, which has received the earliest and most intensive
study. Considerable eort is devoted to the inverse problem of determining cardiac activity from the surface
ECG. Most of these eorts are devoted to reconstructing potentials on the epicardial surface of the heart.
These studies have resulted in a good picture of how body surface potentials are related to cellular activity
at the membrane for which models incorporating the kinetics of ion movement have also been developed
to aid our understanding of the electrical activity of the heart. As we know now, the heart is a blood pump.
The timing of the pump is determined by electrical events. Malfunction of the pumping action of the heart
may lead to morbidity and death. Sudden cardiac death accounts for almost 20% of all deaths from natural
causes in developed countries. Present evidence is that 8090% of these persons died because of an arrhythmia
culminating in cardiac arrest or ventricular brillation where electrical activity is uncoordinated and pumping
action is lost [12]. The therapy for brillation is to deliver a large pulse of current into the heart from a de-
brillator. Many victims of sudden cardiac death can now be resuscitated in the hospital. Nowadays, a com-
monly used therapeutic device is the articial pacemaker, which delivers electrical pulses to the heart to
correct situations where the hearts electrical system is malfunctioning.
3.2. Electroencephalogram and cell communications
Similar to ECG, electrical activity of neurons in the brain may give rise to the electro-encephalogram
(EEG) on the scalp, and the activity of skeletal muscle may give rise to the electromyogram (EMG), which
may be detected on the skin overlying the muscle. Compared with ECG, the EEG (or EMG) signals are much
weak, but detectable by modern electronic instruments. An EEG can show what state a person is in asleep,
awake or anaesthetized because the characteristic patterns of current dier for each of these states. Certain
brain abnormalities can also be detected by observing changes in the normal pattern of the brains electrical
activity. A major drawback of the EEG is that they cannot show us the structures and anatomy of the brain or
really tell us which specic regions of the brain do what.
Today, it is widely accepted that human body is made up of thousands of billions of cells that must act in
concert to allow us to perform our daily activities and to meet challenges. This cooperation is achieved partly
by cells communicating with each other through electrical and/or chemical signals. For instance, the heart
beats spontaneously and rhythmically, unlike skeletal muscle, whose contraction is triggered by motor neu-
rons. The cell-to-cell communication in the heart is electrical and does not involve chemical transmitters
[12]. As chemical signals, hormones and other signal molecules are released from glands, nerves and other tis-
sues. The chemical signals may attach to specic recognition molecules, receptors, on the cell surface. These
receptors then transmit the signals to the interior of the cell. The discovery of such mechanism of action of
hormones by Earl Sutherland at Vanderbilt University in USA was awarded the Nobel Prize in Physiology
or Medicine in 1971, who showed that the signal that is used to communicate between cells (the rst messen-
ger) is converted in the cell membrane to a signal that acts inside the cell (the second messenger). Since
then, one has been wondering if there were any more basic mechanisms behind the highly selective structural
binding between signaling molecules and the receptors, characterizing the specic features of the chemical sig-
nal communication. No clear answer has yet been obtained, although some studies on allergy patients have
revealed that there might exist an interchangeable relationship between chemical stimuli and electromagnetic
stimuli [13,14].
4. Biomagnetic signals in human body, MCG and MEG
Time-varying electrical potential elds on the body surface, caused by the heart (or brain) from small cur-
rents by electrically active cells of the heart muscle (or neurons) can be recorded as the ECG (or EEG) with the
aid of electrodes and ampliers. According to the theory of electrodynamics, it is known that time-varying
electric elds can induce magnetic elds. Thus, instead of measuring the time-varying electrical potential elds,
one could measure the time-varying magnetic elds to monitor the heart and brain activities. Although the
electromagnetic principle was known a long time ago, the rst successful recording of the biomagnetic signals
from heart activities, the magnetocardiogram (MCG), was made by Gerhard Baule and Richard McFee at
Syracuse University in 1963, using an induction coil magnetometer [15]. Later, in 1970, David Cohen et al.
at the Massachusetts Institute of Technology (MIT) rst used the superconducting quantum interference
device (SQUID) to record the magnetocardiogram [16]. As expected, the biomagnetic elds measured are
rather weak. The human heart is the strongest biomagnetic source but still the highest feature in the MCG
has the amplitude of less than 100 pT, about 10
6
of the geomagnetic eld. With the aid of the extremely sen-
sitive SQUID magnetometer, the measurement of biomagnetic elds of the brain was rst carried out at MIT
by David Cohen in 1972, who successfully recorded a human magnetic alpha rhythm with a satisfactory sig-
nal-to-noise ratio [17]. A few years later, magnetic signals associated with brain activity evoked by peripheral
sensory stimulation were also detected [18].
The magnetoencephalography (MEG) is methodologically closely related to MCG. Instead of the heart, the
brain is being examined. Although the detailed structure of the human head is quite complicated, the main
building blocks of the brain are neurons and glial cells. The brain active process is associated with a primary
current source related to the movement of ions due to their chemical concentration gradients across the neu-
ron cell membrane. In addition, passive ohmic currents are set up in the surrounding medium. This so-called
volume current completes the loop of ionic ow so that there is no build up of charge. The magnetic eld is
thus generated by both primary and volume currents. The biomagnetic signals created by neuron activities in
human brains are typically 50500 fT, which is about 1000 times smaller than that of the biomagnetic signals
from the heart.
Indeed, it has been a challenging task for developing proper measurement techniques and related systems
for detecting such weak biomagnetic signals in the brain. Actually, it was only in the second half of the 1990s
that systems able to simultaneously map magnetic elds over the whole scalp, namely whole-head systems,
became available. With the help of these systems, it is now possible to perform sophisticated studies on basic
functions of the brain, exploring both the primary and secondary sensory areas, and the cognitive functions,
such as those associated with memory, attention, language, etc. Additionally, the availability of large systems
has raised the interest of clinicians and today the MEG is used routinely in numerous hospital laboratories as
a methodology complementary to PET and fMRI to investigate brain diseases such as epilepsy, Parkinsons
disease, Alzheimers disease and stroke and, last but not least, to perform pre-surgical mapping [19].
Generally, there exit a number of biomagnetic signals originating from the human body (see Fig. 2). For
instance, ionic currents in the eye may give rise to a eld of about 10 pT, which may change during eye move-
ments and blinks. These biomagnetic elds are also very weak in the range from 100 fT to 100 pT. At present,
the superconducting quantum interference devices (SQUIDs) are still the choice for such ultra-weak magnetic
eld measurements, even though low-temperature environment is necessary for the operation of SQUIDs.
M
u
s
c
l
e
s
H
u
m
a
n

e
y
e
H
u
m
a
n

b
r
a
i
n
MEG
MMG
MOG
MCG
Urban noise
Earth field
SQUID
10
-13
10
-12
10
-11
10
-10
10
-9
10
-8
10
-7
10
-6
10
-5
10
-4
(Tesla)
10
-14
10
-15
fT pT nT T
H
u
m
a
n

h
e
a
r
t
Fig. 2. Range of biomagnetic elds.
5. Bioelectromagnetic signals in living organisms
The functioning of the heart, brain or other organs results in oscillations in the ELF range of the electro-
magnetic spectrum. The bioelectric and biomagnetic signals in the ECG, EEG, MCG and MEG discussed
above have frequency components of interest up to about a few kHz, which are all rather limited at the
low-frequency side of the electromagnetic spectrum. These bioelectric and biomagnetic phenomena are com-
monly modeled as quasi-static cases, in which the electric and magnetic elds can be studied separately. How-
ever, further study of living cells has revealed that under certain conditions, such as cell growth and mitosis,
living cells may also transmit ultra-weak high-frequency electromagnetic waves (photons) (e.g., a few hundred
photons per cm
2
per second at near infrared frequencies), the intensity of which depends on functional status
of the cells. Furthermore, it has been shown that cells in culture might transmit and receive signals carried by
EM radiation, which may control the orientation and migration of the cells [20]. However, the origin and
putative roles of this rudimentary cell vision are largely unknown. It is also not yet known whether these
biological EM phenomena exist in higher organized structures such as the brain and whether they may play
a role in intracellular communication under physiological or pathological conditions.
Early study of the cell-to-cell communication by electromagnetic waves (signals) may be traced back to the
work of the Russian scientist Gurwitsch in 1920s. In his experiments, Gurwitsh could show the induction of
mitosis from the tip of an onion root to the shaft of a second onion root. He found that the induction worked
when the second root was in a quartz tube, which is transparent for ultraviolet (UV) light but not when it was
in a glass tube, which is opaque for UV light. From this result, he concluded that it was UV-light causing the
eect, which he called mitogenetic radiation. However, at that time, he could not directly measure the UV
photons emitted by the onion root, as he expected, due to the lack of proper instruments to detect such weak
UV photons. With the invention of photomultipliers (PM) in 1950s, it became then possible to detect ultra-
weak photon emissions in the visible region. In 1960s, Konev and coworkers were among the rst to report
the detection of UV photon emission from living organisms by using the UV-sensitive photomultiplier tube
[21,22]. Later detection of photon emissions in various types of living organisms by a number of scientists with
much improved version of PM detectors has been made for the detection of ultra-weak photon emissions in
the spectral region of 1801000 nm, covering the UV, visible and near infrared from living organisms.
With increasing amount of claims of positive detection of ultra-weak photons from living organisms, one
may wonder what the mechanism is for such generation of ultra-weak photons in living systems. By the end of
1930s, as a result of extensive studies with the participation of prominent physicists and chemists, it was con-
cluded that the emission of photons by living systems could be considered as a kind of chemiluminescence due
to the recombination of the free radicals, which appear in a number of chemical reactions [23]. Thus, one had
further wondered if such an ultra-weak photon emission could simply just be the waste of bioenergy, or con-
tain really some specic bioinformation that may play a regulatory role in living systems. At present, although
researches in the eld have not yet reached the state required for the ultimate verication or falsication of the
hypothesis on the biophotonic information in cell division and other cell physiological processes, as originally
investigated and suggested by Gurwitsch, the search for evidence of the informational character of ultra-
weak photon emission from biological systems continues. In particular, having stimulated by the thought
of bioinformative characteristics of the ultra-weak photon emissions in living organisms, the German scientist,
Fritz-Albert Popp introduced the concept of biophotons in 1976 [24].
Like bioluminescence, which species luminescence of biological systems, biophotons refer to the biological
system as a whole. From the view of the theory of living cells and their division in living organisms, on aver-
age, every human being consists of trillions of cells, which are generated by many successive rounds of cell
doublings for a human being to reach its adulthood. In every individual, every second, millions of cells
may die and must be replaced in a short period of time. It cannot be predicted where and when a cell will
die, but if the replacement rate were to be only slightly lower (or higher), the body would disintegrate quickly.
It has been argued that if the growth regulation of biological systems were based on information originating
from the death of cells, it would not be possible to explain this regulation by messenger molecules from indi-
vidual cells. Rather, electromagnetic interactions are suited for transferring the necessary messages and have
to take the role of regulators of a biological system in order to explain many, if not all regulatory functions
[25]. To understand and analyse the complex biological phenomena in living organisms, and their interaction
and communication, it is of both scientic importance and practical interest to study possible roles and
communication mechanisms of the bioelectromagnetic signals in living organisms.
6. Biological eects of electromagnetic elds on living organisms
Electromagnetic elds are ubiquitous in our environment. The existence of geomagnetic elds is well
known. Others like lightning, sunlight and cosmic radiations are also sources of environmental electromag-
netic elds. Nowadays, in our modern society, electromagnetic elds are constantly generated by man-made
devices, such as mobile phones, microwave ovens, TV apparatus, electrical heaters and electrical power trans-
mission lines among others. These electromagnetic elds external to living organisms cover a wide range of
frequency spectrum from extremely low frequencies to extremely high frequencies of c-photons.
6.1. Eects of non-ionizing electromagnetic elds
What are the possible biological eects of electromagnetic elds (EMF) on living organisms? It is well
known that high-energy photons, such as X-rays (keV) and c-rays (MeV), may cause ionization of atoms
or biomolecules, such as proteins and DNA, in living organisms. These ionizing radiations are biologically
harmful since they may destroy the capacity for cell reproduction or division or cause cell mutation. Some
delayed eects include cancer, leukemia, cataracts, life shortening from organ failure and abortion, etc.
[26]. On the other hand, ionizing radiation, such as X-rays, can be helpful, if used properly, for medical appli-
cations, such as biomedical imaging and radiation therapy for cancer treatments among others.
What are possible eects of non-ionizing radiation to living organisms then? The non-ionizing radiation
includes the spectrum of ultraviolet (UV), visible light, infrared (IR), microwave (MW), radio frequency
(RF), and extremely low frequency (ELF). A widespread belief is that non-ionizing radiation or electromag-
netic elds have essentially no eects (or no signicant biological eects) on living organisms as long as the
applied eld intensity (energy) is much less than the ionizing energy of biomolecules or the energy that
may heat signicantly the biological tissues. Such thresholds for weak EM eld eects in biological systems
have been studied based on the analyses of thermal uctuations, leading to the thermal noise limit in physical
theories and the molecular shot noise limit in biochemical processes according to currently known biophysical
mechanisms for coupling elds to ongoing, metabolically driven biochemical processes [27,28]. These research
results indicated that unless large, organized, and electrically amplifying multicellular systems such as the
ampullae of Lorenzini of elasmobranch sh are involved, possible eects of weak ELF electric and magnetic
elds (10
4
T) in human implicated by epidemiology could not be explained by the currently known bio-
physical mechanism of voltage-gated macromolecules in the membranes of cells [28].
The fact is that living organisms may have well-organized structures, extreme sensitivity in EM elds, and
amazing signal amplication functions, all of which may contribute to our knowledge about the fact that
non-ionizing radiation found in our environment can pose a considerable health risk to us if not properly con-
trolled. Great eorts have been made in studying potential biological eects of non-ionizing radiations on
human health. Recent epidemiological studies and other evidences have implicated long-term exposure to
non-ionizing EM elds, such as those emitted by power lines, in increased health hazards. These hazards
may include, for instance, an increased risk in children of developing leukemia [29]. Many regulations have
therefore been formulated in order to prevent potential risks. There are however still many unknown cases
due to the complexity of living organisms interacting with EM elds. Careful researches have demonstrated that
electromagnetic elds of very tiny energy could have profound biological signicance and biological eects of
EM elds do not follow simply the intuitive rule that its eects increase with increasing eld intensity [30,31].
6.2. Benecial eects of electromagnetic elds
Electromagnetic elds may have potential risk to human health if not properly controlled as often empha-
sized in public researches. On the other hand, if used properly, electromagnetic elds can be benecial to living
organisms. We are living in the world under constant exertion of electromagnetic elds. The evolution of
human beings as well as other living organisms on the Earth has a long history. One can imagine if there were
no sunlight and geomagnetic elds, there would be no high-level living organisms. The biological eects of
electromagnetic elds are denitive and crucial to the formation of human beings.
Besides, life on the Earth is not isolated from the universe, but is susceptible to the elds of the planet and
other celestial bodies. Sunspots and cycles of the Moon may cause changes in ionospheric currents and geo-
physical elds, which in turn inuence the elds within us. The geomagnetic eld (GMF) may also be dis-
turbed by magnetic storms, which may vary from 35 lT in the equatorial areas, where it is mainly
parallel to the terrestrial surface, to 70 lT in the vicinity of the magnetic poles of the earth, where it is
near-vertical. The GMF and its biological eects on living organisms have been most widely studied
[32,33]. Animals living constantly in the GMF have adapted to its action and have even learned to benet from
it [34]. The possible connection between the orientations of birds (e.g., pigeons and sea gulls) to the GMF is
widely known [3537].
The usefulness of the biological eects of EM elds and radiation may also be noticed from the well-known
function of the human eye, which gives us vision images of the colorful world through the detection of photons
of variety of frequencies in the visible range of EM spectrum. The human eye is just one of the sensory systems
that enable the living organisms to build up an accurate image and awareness of itself in relation to its sur-
roundings by detecting EM radiation signals. The traditional ve senses of a human are sight, hearing, smell,
taste and touch, the origin of which can be electromagnetic, chemical and/or mechanical. In addition to the
well-known ve senses, human beings may have counterparts to less familiar sensory systems characterized in
other living organisms. These sensory systems may respond to environmental factors other than visible light,
molecular shape and/or air motion. Further scientic investigations are however required to reveal these
mechanisms [38].
Obviously, during many years of evolution, living organisms have lived with natural EM elds and radia-
tions in harmony, and have made use of EM elds and radiations. One may wonder what could happen if such
a harmony would be disrupted by externally man-made EM elds. The consequence could be either positive or
negative to human health, as one may expect. For instance, recently there are reports indicating that external
EM excitation may aect functions of the brain, such as cellular signalling or permeability of the bloodbrain
barrier among others [3941]. Reported biological eects of low intensity non-ionizing EM elds on living sys-
tems have so far led to two application areas. One is related to therapeutic, diagnostic and biological appli-
cations. The second area concerns the updating of the database for EMF safety standards, eventually
going beyond the current mechanistic assumption that is based on the disruption of metabolism due to the
electromagnetic power deposition in biological tissues. In connection with the recently rapid progresses in
nano-technology, nano-electronics and micro-/nano-systems, the study may also lead to innovative bio-
mimetic devices and systems of practical interest.
7. On bioelectrodynamic modeling of living organisms
Theoretical modeling of living organisms at dierent scales is a very challenging and important task, requir-
ing interdisciplinary knowledge and insights into the complex biological world. Physicists have had good expe-
rience and knowledge to model natural or man-made materials, where mathematics plays an important role to
analyze and quantify scientic measures of material properties and behaviors under various conditions. To
model physiological behaviors and properties of living organisms, further interdisciplinary research eorts
across several scientic elds will however be required. In this article, we shall focus our attention to some
issues related to bioelectrodynamic modeling of living organisms. Here, the bioelectrodynamic modeling
implies not only the modeling of electromagnetic properties and behaviors but also the modeling of mechan-
ical properties and dynamic behaviors of the living organisms, including electromagneto-mechanical coupling
eects of importance. This is necessary because, in living organisms, cells and tissues are constantly subject to
forces and stresses. These forces and stresses may have various origins from pressure forces linked to gravity to
motional forces and from EM forces arising from molecular interactions, environmental and externally
applied EM elds. These forces and EM elds are likely to modify cellular behaviors by aecting metabolism,
paracrine or autocrine factor secretion and gene expression among others [42], the synergetic properties of
which may also aect physiological behaviors of the living organisms. The facts that motion and mechanical
training of a human body can aect signicantly the physical performance and health status of the human
body and that the sunlight from EM radiation has signicant inuence on the life of living organisms on the
Earth are well known. On the other hand, these forces, energies and powers may also be manipulated and uti-
lized properly for therapeutic purposes in biomedicine, provided that one had a good and deep understanding
of the mechanisms involved in the interaction processes in any specic application.
7.1. On modeling of cells
According to the theory of cells, all organisms are composed of the fundamental unit of life, the cell. From
the unicellular bacteria to multicellular animals, the cell is the organizational principle for biology. The deve-
lopment of organs from cells and its regulation are important subjects in themselves. Since the cell is the basic
building block of living organisms, physical modeling of cells is an important subject. At the cell level, many
theories and mathematical modeling approaches from classical physics could be utilized by consideration of
the fact that the size of a cell is typically 10100 lm, though the cell sizes may vary depending on the cell type
and circumstances. For instance, a human red blood cell is about 7.5 lm in diameter, while some neurons are
about 1 m long (from spinal cord to leg).
In physiology, it is known that properties and behaviors of ion channels located at cell membranes play a
critical role in regulating the life process of biological cells and therefore health status of the human body.
Most of medicines developed today are based on some ways of aecting the ion channel behaviors at the cel-
lular level. Studies have shown that living cells may have several dierent ways of regulating their ion channel
behaviors. These include the ligand-gated ion channels, whose permeability to ions is increased by the binding
of a specic ligand (e.g., a neurotransmitter at a synapse), the voltage-gated ion channels, whose permeability
to ions is extremely sensitive to the transmembrane potential dierence, and the mechanically gated ion chan-
nels, whose permeability to ions is sensitive to mechanical stretches and deformation of the cells.
The discovery of ligand-gated ion channels started from the work of Earl Sutherland in USA who discov-
ered the mechanism of action of hormones and showed that signals used to communicate between cells (the
rst messenger) is converted to a signal that acts inside the cell (the second messenger) and such a conversion
occurred in the cell membrane. In other words, the chemical signals (e.g., hormones as signal molecules) attach
rst to specic recognition molecules, receptors, on the cell surface, which then transmit the signals to the inte-
rior of the cell. For his discovery, Earl Sutherland was awarded the Nobel Prize in Physiology or Medicine in
1971. However, the transduction process of the signals in cells was unclear until Alfred G. Gilman and Martin
Rodbell made their discovery of the so-called G-proteins and their role in signal transduction in cells. In par-
ticular, Gilman and Rodbell found that G-proteins have the ability to activate dierent cellular amplier sys-
tems, which may receive multiple signals from the exterior, integrate them and thus control fundamental life
processes in the cells. A cascade of reactions enables a single molecular event at the cell surface to initiate,
accelerate, or inhibit biological processes. This is possible because of amplication. The signicance of the
amplication was recognized by the 1994 Nobel Prize in Physiology or Medicine, awarded to Gilman and
Rodbell.
Recently, there appear also some fresh thoughts about possible eects of electromagnetic interaction in
such signal transduction process. A tiny eld, far too weak to power any cellular activity, may trigger a change
at the regulatory level, which then leads to a substantial physiological response that is carried out using the
energy of cell metabolism [43]. Various components of the regulatory cascade, including receptors, calcium
channels, and enzymatic processes within the cell are sensitive to EM elds. The electromagnetic forces at
the membranes outer surface could modify ligandreceptor interactions (e.g., the binding of messenger mole-
cules such as hormones and growth factors to specialized cell membrane molecules called receptors), which in
turn would alter the state of large membrane molecules that play a role in controlling the cells internal pro-
cesses [44]. New research is revealing how free radicals, including nitric oxide, are involved in the coupling of
EM elds to chemical events in the signal cascade. Again, the medical importance of this research was recog-
nized by the 1998 Nobel Prize in Physiology or Medicine [45]. The other two types of the voltage-gated ion
channels and the mechanically gated channels are evidently related to electromechanical phenomena at the
cellular level. These evidences suggests that the cell membrane can be one of the primary locations where
applied EM elds and forces act upon, causing a variety of biological eects observed on the macroscopic
scales. Experiments to establish the full details of a mechanistic chain of events however are just beginning
with the aid of advanced measurement techniques available nowadays or to be developed in the near future. In
connection with experimental eorts, proper theoretical models are required to give a comprehensive explana-
tion for the experimental data. Eorts of bioelectrodynamic modeling of ion ow dynamics in dierent ion
channels at the cellular level are therefore necessary and required. While modeling of behaviors of individual
ion channels is of importance, the collective properties and behaviors of living cells may deserve special atten-
tion, in which interaction of cells and exogenous EM elds as well as thermal noise eects have to be taken
properly into consideration, especially when low eld intensities are involved [46].
7.2. On modeling of tissues
At a larger size-scale, one is interested in studying properties and behaviors of biological tissues and organs.
At such a scale, human body tissues could be modeled as a suspension of many cells in a deformable and con-
ducting medium. At these scales, it is convenient to model the tissue as a continuum since biological tissues
and organs are composed of many atoms, molecules and cells. Classical Newtonian mechanics and electrody-
namics may also be sucient to describe biophysical phenomena at these scales. Even at the cellular level,
eorts of using continuum models have been made to study ion channels [47,48]. For instance, to model rheo-
logical behaviors of living cells, which are important features of living cells [49], the viscoelastic model has
been used with a few characteristic relaxation time constants that could be determined experimentally [50].
Besides, thermodynamic approaches have also been used to model mechanosensitive ion channels, in which
possible eects of membrane stiness, thickness, spontaneous curvature or changes in channel shape, length
or stiness could all be taken into consideration [51].
Since 1960s, continuum biomechanics has been developed as a distinct eld of study and contributed to our
understanding of human health as well as to disease, injury and their treatment. According to Fung [52], bio-
mechanics is dened as the mechanics applied to biology. Fungs pioneering work on mechanical modeling of
blood ow and lungs soft tissues among others are very interesting [53]. Although biomechanical properties
and behaviors of biological media are important subjects to be studied, bioelectromagnetic behaviors and bio-
electrochemical properties of the living organisms are extremely important for us to understand, to manipulate
and to make use of the fascinating biological phenomena in living organisms, for which interdisciplinary
research eorts are greatly desired. This is because, unlike man-made materials, bioelectrical, biomechanical
and biochemical phenomena in living organisms are generally coupled and have to be studied synergetically,
though some simplication could be made in certain cases.
7.2.1. Blood
Blood is marvelous uid composed of red blood cells (erythrocytes), white blood cells (leucocytes) and
platelets (thrombocytes) mixed in the blood plasma. The blood plasma is found to behave like a Newtonian
viscous uid with a coecient of viscosity almost twice as high as that of water due to dissolved macromol-
ecules [53]. Unlike its plasma, the whole blood has characters of a non-Newtonian uid. Like any uid in the
continuum modeling, the viscosity of the blood is a major determinant of blood ow and tissue perfusion.
Interestingly, living organism may have means to control blood viscosity and prevent hyperviscosity. In other
words, negative feedback mechanisms may exist, which down regulate viscosity-related genes in the case of
elevated blood viscosity. Although knowledge about such mechanisms is scant, some evidence exists. Besides,
blood cells have some interesting physiological and physiochemical properties to keep them alive in the circu-
latory system for a long time. These include their surface characteristics (e.g., surface charge, membrane
phospholipid composition, surface antigens) as well as bulk properties (e.g., shape and their extent of defor-
mability). For instance, red blood cells may avoid macrophage surveillance. Their deformable nature also
allows them to bypass the human splenic ltration process among others.
Furthermore, the electrical properties of blood are of interest for the modeling of blood with respect to its
in vivo characteristics. Experimental measurements have shown that both the dielectric permittivity and elec-
tric conductivity of the blood are frequency-dependent. For instance, for cow and sheep blood with a haema-
tocrit level of about 40%, it was found that the relative permittivity of the blood has a value of about 1370 at
1 MHz and decreases to a value of 50 at 1 GHz frequency. The conductivity has a value of about 0.7 S/m at
1 MHz and increases to a value of about 1.3 S/m at 1 GHz [54].
7.2.2. Bone
Bone is perhaps the only tissue that can be considered as a solid material in the living organism due to its
strong and solid nature. Actually, a live bone is not a simple solid, but involves also a uid phase. Bone uid
has many functions. It transports nutrients to, and carries waste from the bone cells (osteocytes) buried in the
bony matrix. It is also involved in the transport of mineral ions to the bone tissue for storage and retrieval of
those mineral ions when which are needed by the body. Recently, the bone-uid ow has been suggested to have
a role in bones mechanosensory system, in which bone deformation causes the bone uid to ow over the bone
cell membrane, where the shear stress of the owing uid is sensed [55]. In general, bone is an anisotropic med-
ium containing several phases, such as the collagen, the mineral (e.g. hydroxyapatite), the pores, the interstitial
uid and blood. As a live bone, it can change, grow or be removed by resorption, and the bone-uid circulation
can transport materials to and from the bone. It has been estimated that the collagen occupies about 50% of the
volume in compact bone, the mineral 40% and the pores 10% [56]. Thus, macroscopically, the bone may be
modeled as an inorganicbiooganic composite material [53]. Poroelasticity theory has also been introduced
to model the interaction of deformation and uid ow in a uid-saturated porous bone medium [57].
During normal activities, such as walking, running and sitting, various parts of human skeleton and bone are
subjected to forces, which may be time varying. The bone motion consists physiologically not only of compres-
sion, tension and shear, but also a bending moment, which, for long compact bone, may produce a stress or
strain gradient. In the wet state of bone, the strain gradient can produce a combination of responses, involving
piezoelectricity, interfacial polarization, streaming potential and non-centrosymmetric charge displacement,
which may also be temperature- and/or frequency-dependent. The existence of piezoelectricity in dry and wet
bones has been known since 1950s [58]. The stream potential has also been considered to be a major electrome-
chanical eect arising from the ow of ion-interstitial (ion-containing) uid (electrolyte) through a ow channel
within the bone, which may be driven by, for instance, the deformation of the bone under external forces [59].
The electromechanical properties of bone play an important role in the development and growth remodel-
ing of the skeleton, a hypothesis made plausible by the observed role of electrical stimulation of bone healing
[60]. Besides, stress-related biochemical activity of calcium my also contribute to the remodeling process as it
was shown that the solubility of the hydroxyapatite crystals may change in response to stresses [61]. Although
the subject of electromechanical properties and behaviors of bone has been studied extensively for about half a
century, new research eorts are still made to study bone structures and properties at nano-scales and to
explore potential applications of nano-technology to create articial bone materials with potential uses as
implants and therapies [62].
7.2.3. Soft tissues
Soft tissues are composed of cells and extracellular matrix, which may exist in many dierent forms, each
specialized to perform a specic function and each having a unique microstructure. Since the human body is
mainly made up of soft tissues, the medical consequence of soft tissue modeling is important for applications,
such as the surgery planning, including neurosurgery, plastic surgery, musculoskeletal surgery, heart surgery,
abdominal surgery and minimally invasive surgery, as well as tissue engineering for the construction, repair or
replacement of damaged or missing tissue in the human body [63]. Biological tissues are by essence highly
complex systems that host chemical, cellular, electrical and mechanical processes. Today, powerful computers
are readily available to simulate very complex systems so that diculties in costly experimental studies could
be avoided for a variety of applications. However, numerical models require the knowledge of accurate con-
stitutive equations for modeling biological materials. Because of the inherent complexities of microstructure
and biomechanical behavior of biological cells and tissues, soft tissue mechanics is a still a vast area for the
development of constitutive theories.
Mechanically, the main characteristics of biological soft tissues are that they sustain large deformations and
displacements, have a highly non-linear behavior and possess strongly anisotropic mechanical properties [53].
At present, the mechanical properties of the softest tissues in the body are not well characterized. While much
is known about the mechanics of bone, cartilage, tendons and various types of muscle, data on the mechanical
properties of very soft tissues with Youngs moduli less than about 10
4
Pa, such as brain, liver, glandular tis-
sues, and tumors, are sparse. Information on the mechanics of very soft tissues has many applications, includ-
ing detection of disease through palpation of tissue or low-frequency ultrasound (e.g., breast tumors),
estimation of tissue deformation under external mechanical loads and design of medical implants. The
mechanical properties of tissues also inuence the movement of water through extracellular spaces, which
is relevant to formation of edema, and to convective movement of solutes through tissues, including the deliv-
ery of chemotherapeutic drugs. Some theoretical models have been developed to predict elastic properties of
very soft tissues, such as glands, tumors and brain [64].
Macroscopic properties and behaviors of biological tissues are closely related to the properties and behav-
iors of their constitutive cells. Researches have shown that many types of cells may change their structures and
functions in response to even subtle changes in their mechanical environment [65], and in many respects, it is
the extracellular matrix that regulates cell shape, orientation, movement and overall function [66]. Study of
soft tissues at the cellular level is therefore very important. In particular, the modeling of eects of interaction
between electromagnetics and mechanics in living biological tissues at the cellular level is very challenging.
Electromagnetic properties of biological tissues are very special for living soft tissues. For instance, heart tissue
and skeletal muscle are electrically active. Other thoracic tissues, as well as inactive regions of the heart, are pas-
sive. In general, biological tissues are electrically heterogeneous, while their magnetic permeability is very close to
that of free space. Application of an electric eld pulse may result in rapid polarization changes that can deform
mechanically unconstrained cell membranes, followed by ionic charge redistribution governed by electrolyte con-
ductance and distributed capacitance. The cellular nature of tissues also establishes a vast number of dielectric
partitions that separate strongly conducting intracellular and extracellular compartments. For instance, cells
are enclosed by poorly conducting membranes with a typical resistance of 5000 X/cm
2
and lie within an extracel-
lular space with a specic resistance as lowas 4 X/cm[67]. It has been found that the dielectric properties of tissues
are highly dispersive [68], the mechanisms of which come mainly from the dielectric relaxation of free water (fre-
quency near 20 GHz and dielectric constant 1050), the MaxwellWagner type of relaxation resulting from the
charging of cell membranes (frequency near 1 MHz and dielectric constant 1001000), and the frequency-depen-
dence of membrane capacitance of the cells (frequency near 100 Hz and dielectric constant around 10
5
).
At lower frequencies, the electrical properties of tissues are mainly characterized by their electrical resistiv-
ities, which are also frequency-dependent. According to a recent study of electrical resistivities of human tis-
sues in the frequency range from 100 Hz to 10 MHz [69], the experimental data reported in literature are quite
scatted. It is shown that dierences between the mean values of resistivities of most tissues from muscle and
internal organs are statistically insignicant. For instance, the reported mean resistivity is 171 X cm for skel-
etal muscle, 175 X cm for cardiac muscle, 211 X cm for kidney, 342 X cm for liver, 157 X cm for lung,
339 X cm for breast, 329 X cm for skin, and 151 X cm for blood. Only bone (124 10
6
X cm) and fat
(3850 X cm) have signicant higher resistivities. A linear relation was found between the resistivity and the
water content of some tissues. The low water content of bone and fat explains their high resistivities, while
the high water content of other tissues explains their low resistivities. Besides, the anisotropic structures of
biological tissues may also contribute signicantly to the measured electrical properties. Skeletal muscle is
probably the best example of this variation, in which the resistivity can be up to 10 times lower along the
length of the muscle bres compared to the perpendicular orientation.
Many living tissues exhibit also temporal changes in their electrical properties due to variations in structure.
For instance, the electrical properties of lung tissue are highly dependent on the condition of the tissue and
that both conductivity and relative permittivity decrease with increased air content. The conductivity of blood
can also alter by up to 20% as a function of ow. This is due to variations in the erythrocyte orientation, axial
accumulation (where the concentration of erythrocytes is uneven due to the velocity prole), and elongation of
the erythrocyte in the direction of the ow [70]. Obviously, to model electrical properties of blood, both
mechanical ow behaviors and electrical properties of the blood have to be taken into consideration. The cou-
pled electrical and mechanical models are also required for studying physical properties of, for instance, living
bones and heart among others. While great eorts have been made in cardiac electrophysiology to understand
and model the human heart, little is known about electrodynamic properties of other organs. Some eorts
have been made recently in modeling, for instance, the gastrointestinal system, which is also an electrically
and mechanically active organ with propagating electrical activation and mechanical contraction [71].
Because of the inherent complexities of the microstructures and bioelectromechanical behaviors of biolog-
ical cells and tissues, there is still a need for new theoretical frameworks to guide the design and interpretation
of new classes of experiments. New mathematical models and computational methods to solve the complex
boundary and initial-value problems of clinical, industrial and academic importance are also needed due to the
complex geometries, interface conditions and loading conditions. Nowadays, with the increasing amount of
computational power available, there appear interest and eorts to develop human simulators for a variety
of purposes, including biomedical research, education and clinical applications.
8. Bioelectrodynamic imaging
Bioelectrodynamic imaging is the method for non-invasively obtaining anatomic and physiologic informa-
tion about the human body through the use of electromagnetic means as well as their interaction with dynamic
properties of the human body. Over the past century, imaging has experienced a quantum leap in technology
and clinical applications, which includes X-ray computed tomography (CT); emission computed tomography
(SPECT and PET); magnetic-resonance imaging (MRI) and spectroscopy (MRS), including functional MRI
(fMRI), among others. Since there exist a vast number of literatures on these subjects, in this review, we shall
focus on some recent progress and development in the X-ray imaging technique, which is one of the oldest and
most widely used imaging techniques nowadays.
8.1. Tunable quasi-monochromatic X-rays
During those early days, X-rays are generated by rather simple devices with inductors, vacuum tubes and
high voltage sources. Today, X-rays can be generated by modern accelerators (synchrotron) or by high-power
laser interacting with electron beams among others. Recent advancement in high-power laser technology has
led to the development of a new type of X-ray source with compact size (the so-called table-top X-ray
source). In 1998, a research group led by Frank Carroll at Vanderbilt University was successful in producing
pulsed, tunable (quasi-) monochromatic X-rays using the free electron laser as a source of both high-energy
electrons and intense infrared (IR) laser light although the properties of the X-rays were not satisfactory
for clinical applications. In April 2001, after 2 years of re-design and engineering, a new prototype device
was completed and commissioned at the MFEL Center at the Vanderbilt University but used a conguration
that was not that of an FEL. This machine uses a linear accelerator operating in what they call the single-
pulse mode and a tabletop terawatt IR laser to provide the counter propagated beams. It delivers 10
10
X-ray
photons/8 ps pulse throughout its tunable 1250 keV range at anywhere from a 110% bandwidth in a cone-
beam area geometry [72]. Today new eorts have been made to develop the small-sized tunable (quasi-) mono-
chromatic X-ray sources in Japan, especially at the University of Tokyo [73] (see Fig. 3).
These tunable and pulsed (quasi-) monochromatic X-rays have some special features particularly useful for
their applications in biomedicine. These include:
Softer X-rays are absent from incident beam (avoid beam hardening), lowering entrance dose to the patient.
Higher energy photons could be eliminated, reducing the amount of scatter and improving the contrast, the
image quality, and lowering the dose to the patient.
Tunability makes possible to use optimal X-ray energies to improve contrast among others. (The choice of
the optimum energy depends on the size and composition of the object.)
Novel imaging techniques based on the X-ray phase information.
Among the anticipated uses of the tunable monochromatic X-ray beams in medicine are markedly
improved mammography, K-edge imaging, phase-contrast imaging, time-of-ight imaging, small-animal
imaging and protein crystallography among others [74].
8.2. K-edge imaging and improved mammography
For the K-edge imaging, the monochromatic X-ray that takes advantage of its tunability could lead to
improved diagnostic techniques. Iodine, for example, attenuates X-rays much more eectively at 33.2 keV
than at any other energy, because the binding energy of the k-shell electron is 33.2 keV. When hit by a photon
at that energy, the K-shell electron is ejected from its orbit, extinguishing the incident photon. Because mono-
chromatic beams of a narrow bandwidth can be tuned to that energy, they can be used to decrease the amount
of contrast material needed for X-ray imaging and/or be used to signicantly reduce radiation dose to the
patient. Iodine is not the only atom that is useful for such imaging tasks. Gadolinium, for example, has a
K-shell binding energy of 50 keV. If used in place of iodine, gadolinium agents could further decrease the radi-
ation dose to the patient. By tuning the energy of the monochromatic beam and increasing it from 33.2 to
50 keV, the beam becomes more penetrating, and the body becomes more transparent to the X-rays, with a
lower radiation dose. However, the gadolinium will then act more eciently in stopping the beam wherever
it is placed. Besides, the dual-energy monochromatic X-ray computed tomography may also be developed
to obtain information about electron densities for materials and/or biological media, which is important,
for instance, for medical treatment planning for proton and heavier-ion radiotherapy [75].
Today, breast cancer is one of the leading causes of death of women in industrialized countries. Mammog-
raphy screening is therefore an important public health issue where the prospect of developing new imaging
methods plays a central role. In conventional X-ray imaging, as we know, the structures of the object are
mapped by an incident X-ray beam and detector of sucient spatial resolution. The relative variation of
the mapping property of the object is the contrast that depicts dierences in X-ray absorption among various
tissue constituents in the path of the X-ray beam. These images may provide excellent visualization of tissues
with signicantly dierent absorption characteristics resulting from dierences in physical density and atomic
number Z. When these dierences are slight, such as for soft tissues, conventional X-ray imaging methods are
however limited. Mammography is one example where conventional X-ray imaging methods are challenged.
Here, the application of tunable monochromatic X-rays to mammography could prove particularly benecial.
When cancerous and normal breast tissues are trans-illuminated by dierent energies of monochromatic X-
rays, cancers act as if they have a higher eective atomic number and hence a higher linear attenuation.
Use of these monochromatic X-ray beams could therefore highlight contrast dierences between these malig-
nant and normal tissues. Studies of these tissues have shown that in the energy range of approximately 20
30 keV, cancerous breast tissues exhibit a higher attenuation than do normal tissues [76]. In particular, by
combining images at dierent energies, it is possible to produce hybrid images in which the contrast of relevant
structures is preserved while unwanted masking contrast (structural noise) can be largely removed.
8.3. Intravenous coronary angiography
Clinical coronary angiography is an important diagnostic method, which provides detailed high-resolution
images of the coronary arteries. In conventional coronary angiography, a catheter is inserted into the iliac
Fig. 3. Scheme of the compact X-ray systems for medical applications.
artery and guided to the aorta and to the beginning of a coronary artery. An iodine-containing contrast agent
is injected into the artery and radiographs are taken at short intervals. If the stenosis is not too severe, cor-
onary angiography is followed by balloon-tipped angioplasty. The method is well developed, but still compli-
cations and even mortality are too frequent to allow conventional coronary angiography to be used as a
routine diagnostic method for screening or follow-up studies. The attempts to avoid the risks by intravenous
injection of the contrast agent failed because, by the time the bolus reaches the coronary arteries, it is diluted
to a few percent of the initial concentration. Recently, K-edge subtraction (KES) angiography with synchro-
tron radiation has demonstrated its capability of providing images of clinical quality even when intravenous
injection is used. In the intravenous coronary angiography, for each scan, two monochromatic X-ray images
below and above the K-edge of the contrast agent, such as the iodine, are recorded simultaneously. The two
images can then be subtracted to produce a maximal contrast enhancement of the iodine. Since the KES
method is used following the injection of the iodine contrast agent into a peripheral vein, the risks associated
with arterial catheterization are avoided. Even when diluted on its way through the heart and lungs before
reaching the aorta, where the heart arteries branch o, the concentration of iodine is sucient to provide
clinical quality subtraction images [77].
8.4. Phase-contrast imaging and diraction enhanced imaging
An X-ray beam traversing a patient picks up absorption information that is traditionally used in diagnostic
imaging. Because soft biological tissues are made up predominantly of light elements such as carbon, hydro-
gen, oxygen and nitrogen, X-ray absorption coecients for these elements in the body may approach zero.
However, even these light elements may cause X-ray phase shifts that are large enough to be detected. Density
changes, either from dierences in specic gravity of adjacent tissues or the interfaces of dierent tissue types
in the breast, can produce inhomogeneity in the refractive index of breast tissues, which may aect propaga-
tion behaviors of the X-rays. Thus, it is possible to explore imaging properties of the X-ray beam that may
acquire phase information from dierences in tissue composition. In fact, the X-ray phase shift cross-section
for light elements is found to be 1001000 times larger than the corresponding X-ray absorption cross-section
[78]. This implies that remarkable improvement in sensitivity can be achieved by using X-ray phase informa-
tion in the imaging of soft tissues. In addition, the high sensitivity contributes to the reduction of X-ray radi-
ation damage, which is important in biological X-ray imaging. However, the imaging techniques using X-ray
phase information require new detectors and analyzers to cull this information from the transmitted beam.
Recently, a diraction enhanced imaging technique has been introduced, which utilizes a silicon crystal,
positioned between the tissue sample, and the detector to separate refracted X-rays from transmitted and scat-
tered radiation by the Bragg diraction [79]. This allows pure absorption images and pure refraction images to
be produced, rather than a mixture of the two. A synchrotron source is used to provide a quasi-parallel mono-
chromatic X-ray beam of sucient brightness. The contrast in the images produced is related to the changes in
the X-ray refractive index of the biological tissues, resulting in remarkable clarity compared with conventional
X-ray images based on absorption eects. These changes are greatest at the boundaries between dierent tis-
sues, giving a marked edge enhancement eect and three-dimensional appearance to the images. For investi-
gating the diraction enhanced imaging, the synchrotron radiation source is ideal. While it is feasible to use
such a source for developing new techniques and undertaking a certain amount of clinical research, it would
not be suitable for large-scale clinical applications, owing to a variety of factors such as limited availability and
geographical considerations. It is probable that in future such limitations can be overcome through the deve-
lopment of compact, intense monochromatic X-ray sources, which would be suitable for medical imaging.
Even now it is possible to observe limited phase contrast eects by some conventional X-ray equipments.
8.5. Targeted cell imaging
Recently rapid developments in both molecular/cellular biology and non-invasive imaging techniques have
led to the emergence of a relatively new discipline, the molecular imaging [80]. The molecular imaging has
its roots in both molecular and cell biology as well as in imaging technology. At present, non-invasive in vivo
molecular imaging techniques are mainly based on the magnetic resonance, the nuclear (positron emission
tomography; gamma camera) and the in vivo optical imaging systems. These disciplines have now converged
to provide a well-established foundation for exciting new research opportunities and for translation into clin-
ical applications. It is however possible that future generation X-ray imaging systems may also make use of the
molecular imaging strategies. Practical realization of such systems may be related to the development of
advanced high-spatial resolution x-detectors. It is expected that biocompatible nano-particles or micelles,
encapsulated with specic nano-materials and/or molecules, can be used as contrast agents in biomedical
X-ray imaging for detecting tiny early-stage cancer cells. We may foresee a paradigm shift in cancer imaging
and therapy in the 21st century. This implies the shift from anatomical imaging to molecular/cell signature
probing and from non-specic systematic cytotoxic agents (poisons) to tumor-specic targeted therapies.
New X-ray techniques for image acquisition and methods for cancer imaging and image-guided interventions
and molecular-radiation cancer therapy will be developed along these lines.
9. Bioelectrodynamic therapy
It has been shown that not only living organisms have their own endogenous EM elds for cell communi-
cations, tissue activities and their senses with environments, but also their physiological behaviors and health
states can be inuenced by exogenous EM elds and/or their energy or power. Besides, mechanical energy
expended in biological structures may also produce electrical potentials of sucient magnitude to exert a wide
range of eects in living systems. These may include control of cell nutrition, local pH, control and enzyme
activation or suppression, orientation of intra- and extra-cellular macromolecules, migratory and proliferative
activity of cells, synthetic capability and specialized function of cells, contractility and permeability of cell
membranes and energy transfer. If the EM elds and mechanical energy could be properly controlled and
designed for their applications to human body according to proper guidelines, it is possible to perform ther-
apeutic treatments to certain diseases or to improve the health status of the human body. The questions are
then how one could nd those proper guidelines and what types of diseases or health functions for the human
body could be treated with the use of applied EM elds, mechanical forces and/or their energy or power. Here,
we shall review some of the most important therapies using bioelectrodynamic means that could be of poten-
tial interest for further development.
9.1. Bone remodeling
The phenomenon of bone remodeling by mechanical stresses is well known since the early work of J. Wol,
a German anatomist in 1892, who postulated that the trajectories of the trabecular bone align with the prin-
cipal stress trajectories and bones may change their shape in response to stresses. Wols discovery raised a
profound question: what is the mechanism that enables a bone (or any other tissue) to adjust its structure
in relation to the way it is used? It is obvious that such adjustments take place otherwise training for an ath-
letic or artistic performance would not stimulate the body to change its structure in the most appropriate way
to accommodate the desired performance. Although the basic concepts of Wols law are generally accepted
based largely on phenomenological observations, the basic mechanisms and mathematical laws relating bone
remodeling to the stress/strain relations are still not well understood and deserve further investigation.
According to the observations, the bone remodeling appears to be governed by a feedback system in which
the bone cells sense the state of strain in the bone matrix around them and either add or remove bone as
needed to maintain the strain within normal limits. What is then the process by which the bone cells are able
to sense the strain? One hypothesis is that the piezoelectric eect in bone is the part of the feedback loop by
which the bone cells sense the strain eld. This hypothesis obtained support from observations of osteogenesis
in response to externally applied electric elds of the same order of magnitude as those generated naturally by
stress via the piezoelectric eect [60]. Besides, the electrokinetic phenomenon of bone-uid ow (streaming)
potential may also contribute to the bone remodeling process. Such an electromechanical stimulation mech-
anism has stimulated the invention of medical devices for therapeutic purposes for bones, specically in the
hands of the orthopedic surgeon: it is able to restore and augment osteogenetic activity in bone repair tissue.
For instance, Becker [81,82] demonstrated that the bone cell function could be altered with implanted elec-
trodes providing a current of 10050 lA/cm
2
. Thus, by passing a current through a bone fracture, one could
stimulate the bone repair process. A key breakthrough was the later realization that magnetic elds applied
from the outside of the body could induce electric currents within cells and tissues. In relation to bone healing,
this would mean that it is no longer necessary to insert electrodes into the bone itself, in order to pass a current
through a fracture site. A comparable current could be magnetically induced to ow through the fracture site
using coils placed outside of the skin. That magnetic elds in the environment can induce currents deep within
the body has now been well documented by medical researchers using pulsing magnetic eld therapy to induce
current ows through bone fractures that fail to heal.
9.2. Transcranial magnetic stimulation
The transcranial magnetic stimulation (TMS) is a technique that makes use of the principle of electromag-
netic induction through the application of a time-varying magnetic eld, driven by an electrical current pulse,
to generate non-invasively electrical elds suitable for neural stimulation inside the brain. Such an externally
applied electrical eld may deviate cells membrane potential, i.e., depolarize the cell membrane and hence
activate excitable tissues among others. The early documents on magnetic stimulation may be traced back
to the work of Jacques dArsonval in 1896 and Silvanus P. Thompson in 1910, describing the magnetic stim-
ulation of the retina [83], which is known to be very sensitive to stimulation by induced currents and eld
strengths. In 1985, researchers at the University of Sheeld in UK achieved successfully the transcranial mag-
netic stimulation and made the rst clinical examinations [84]. Now, there are essentially two types of the mag-
netic stimulators commercially available: the single-pulse devices and the repetitive TMS (rTMS) devices that
may generate trains of stimuli at 160 Hz. Since TMS can exert both excitatory and inhibitory eects on
human cerebral cortex, it is possible to use TMS either as a therapeutic tool or as a diagnostic tool for deter-
mination of the interaction between excitatory and inhibitory circuits within and between specic cortical
areas of the brain. TMS and repetitive TMS (rTMS) have been used for more than 20 years to non-invasively
study the human brain. In particular, it allows the evaluation of motor conduction in the CNS, which may
provide specic information in neurological conditions characterized by clinical and sub-clinical upper motor
neuron involvement. TMS has also proved useful in monitoring motor abnormalities and the recovery of
motor function. TMS can also give information on the pathophysiology of the processes underlying the var-
ious clinical conditions. More complex TMS applications allow investigation into the mechanisms of diseases
causing changes in the excitability of cortical motor areas. They are also useful in monitoring the eects of
neurotrophic drugs on cortical activity [85]. Today, TMS is an established investigative tool in the cognitive
neurosciences, and is being explored for the study of perception, attention, learning, plasticity and awareness
among others [86]. TMS or rTMS has also been considered recently as a therapeutic tool for depression,
Parkinsons disease, and other neurological conditions [87,88].
9.3. Electro-acupuncture
As a complementary medical modality, acupuncture is commonly used in many countries. The acupunc-
ture involves the stimulation of specic points on the skin, usually by the insertion of needles. Acupuncture
was based on the principles of traditional Chinese medicine to understand human health in terms of a vital
force or energy called Qi, which circulates between the organs along channels called meridians. Qi energy
must ow in the correct strength and quality through each of these meridians and organs for health to be
maintained. Disturbance of such energy ow may cause symptoms of certain sicknesses. The acupuncture
points are located along the meridians and provide one means of altering the ow of Qi by proper stimula-
tions. According to current knowledge of medicine, the acupuncture points are considered to correspond to
physiological and anatomical features such as peripheral nerve junctions. This might explain the eectiveness
of the acupuncture for releasing pains of patients from various origins, and its limitation of general use in
medicine.
Along the line of the electrical stimulation discussed above, electrical stimulations via acupuncture needles
as well as micro currents have also been explored to release pains of certain patients. Clinical benets have
been reported for the uses of the electro-acupuncture and the micro current therapy [8991]. Studies indicated
that clinically tested results depend on the frequency of the applied electrical currents, which shows character-
istic of the patient and the aected tissues to be treated. It was then hypothesized that precise frequencies
appear to interact through resonance with biological tissues and biochemical regulators in such a way as to
neutralize specic conditions, and address specic tissues, possibly by altering membrane conguration [91].
Further eorts are however required to identify the mechanisms involved in such therapies.
9.4. Photodynamic therapy
The therapeutic properties of light have been known for thousands of years since ancient Egyptian, Indian
and Chinese civilizations had used light to treat various diseases. Modern photodynamic therapy was however
developed in the last century, starting from the pioneering work of Niels Ryberg Finsen, a professor at the
University of Copenhagen in Demark, on the treatment of diseases, and in particular the treatment of lupus
vulgaris by means of concentrated light rays. Finsens method has proved of use in the treatment of a number
of other skin diseases, but it has been particularly successful in the treatment of lupus vulgaris. None of the
methods previously used for the treatment of this disease had produced results, which can in any way be com-
pared to those obtained with the phototherapy according to the presentation speech in connection with the
Nobel Prize in Physiology or Medicine awarded to N.R. Finsen in 1903 for his discovery.
At the beginning of the last century, researchers, such as Oscar Raab in 1900 and H. van Tappeiner and
A. Jesionek in 1903, also observed that a combination of light and certain chemicals could induce cell death.
Experiments to test various combinations of reagents and light had then led to the emergence of modern
photodynamic therapy (PDT), which is used mainly for anticancer therapy [92]. The PDT is a novel treat-
ment based essentially on three components: a photosensitizer, light that is absorbed by the photosensitizer,
and molecular oxygen. All three components are thought necessary for best long-term response, but their
relative roles vary considerably depending on the photosensitizing drug, its sub-cellular and tissue distribu-
tion, the tumor type and its microvasculature and the type and duration of inammatory and immune
responses elicited in the host [93]. In the PDT treatment, photosensitizer is pre-administrated like a drug into
the patient and is stored selectively in diseased tissue, such as the tumorous tissue. Upon activation by
absorption of light photons, the photosensitizers generate reactive oxygen species (singlet oxygen and free
radicals), which are able to damage membranes, DNA and other cellular structures of the tumor. This
implies that PDT could be a particularly useful alternative treatment for drug-resistant tumors. Recently,
some studies have also been made to introduce externally applied pulsating electromagnetic elds to inu-
ence, for instance, the permeability of cell membranes for photosensitizers and therefore to enhance the pho-
todynamic ecacy in the PDT for treating some cancer cells [94]. PDT has also been explored for the
treatment of cardiovascular diseases [95].
Although photodynamic therapy oers certain advantages over other therapies, such as conventional
chemotherapy, it does have several limitations since the success of the technique is dependent upon the simul-
taneous presence of light, oxygen and photosensitizer. Tumors are however relatively anoxic and the light pen-
etration through tissue at currently used therapeutic wavelengths is limited to a few millimeters. Besides, the
absorption coecients of the photosensitizer at these wavelengths are low. In addition to the problems of
light, oxygen and photosensitizer presence, the ratio of the photosensitizer uptake between tumor and normal
tissue is only marginally in favor of tumor in many cases. As a result, a considerable amount localizes in the
skin causing acute photosensitivity, which can persist for several weeks. Further eorts and innovative ideas
are required in this eld.
9.5. Electroporation therapy
Electrical pulses can transiently disrupt cell membranes and create primary membrane pores of a few nano-
meters, and thereby permits transmembrane transport or intracellular delivery of molecules. The phenomenon
of the cell electroporation was studied extensively and used as a research tool to facilitate cellular uptake of
genetic material in vitro in 1980s. Recently, tissue electroporation is under investigation for therapeutic pur-
poses aimed at cancer treatment, gene therapy and transdermal drug delivery [9698]. Though the exact mech-
anism for the cell electroporation has not yet been known, plausible models exist to explain majority of
experimental results. Considering that biological systems are electrically heterogeneous, application of an
electrical eld pulse may result in rapid polarization changes that can deform mechanically unconstrained cell
membranes (e.g., suspended vesicles and cells) followed by ionic charge redistribution governed by electrolyte
conductivity and distributed capacitance. As primary pores appear in the membrane, its resistance drops, and
the voltages within the system redistribute on a time scale governed by the instantaneous values of the various
conductivities and capacitance. Once the membrane resistance has dropped, a membrane tends to rapidly dis-
charge, but pores are metastable, disappearing on a much longer time scale (often >1 s) than their creation
time (ls). The membrane recovery (resealing) is slow and generally is temperature dependent. Thus, some
pores remain open for long times, during which ions and molecules can continue to cross the cell membrane
by diusion and electrically driven transport associated with diusion potentials and metabolically driven
membrane pumps [96]. Generally, the most important parameters for eective electroporation are the electri-
cal eld strength and the length of time the eld is applied (pulse length). For tissue electroporation in which
cells are in multicellular environments, it is suggested that the required electric eld strength should be larger
than that used for cells in dilute suspensions [98]. Besides, tissue electroporation could be enhanced by apply-
ing short pulses at relatively large eld strengths, delaying application of pulses until some time after injection
of solutes, and possibly applying multiple pulses with long interpulse delays. A large variety of other param-
eters may also inuence the ecacy of the electroporation, and the uptake of molecules depends on their
molecular size, charge and other physicochemical properties [97].
As a therapeutic tool, the electroporation has been found to be an eective technique for molecular ther-
apies, which require drug delivery systems to deliver eective drugs to enter the targeted cells in many cases.
The combined treatment consisting of a chemotherapeutic agent and pulsed electrical elds has been termed
electrochemotherapy. This relatively new treatment modality relies on the physical eects of locally applied
electrical elds to destabilize cell membranes in the presence of a drug. In 1987, Okino and Mohri [99] pub-
lished the rst in vivo electroporation results attained in an animal tumor model. It was shown that the use of
the anticancer drug bleomycin in combination with pulsed electrical elds killed tumors far more eectively
than the use of bleomycin or electroporation alone. Since that the publication by Okino and Mohri, the eld
of electroporation has progressed continuously, and a large number of publications have appeared on in vitro
and in vivo studies, as well as clinical trials. Currently, electroporation therapy devices for a number of bio-
medical applications are also under development by a number of companies.
9.6. Iontophoretic drug delivery
Iontophoretic drug delivery is a technique based mainly on three mechanisms that may enhance transder-
mal drug delivery: (a) the ion-electrical eld interaction provides an additional force which drives ions through
the skin; (b) the ow of electrical current increases permeability of skin; and (c) the electroosmosis produces
bulk motion of the solvent itself that carries ions or neutral species with the solvent stream [100]. For charged
drug molecules (ions), the electrical eld imposes a force on the ions, which adds to and may dominate the
diusion force or concentration gradient. This electrical force drives the charged drug molecules through
the membrane far more eciently than in the case of pure diusion or passive transdermal drug delivery.
In the case of uncharged drug molecules, the bulk solvent ow caused by electroosmosis was suggested as
a possible mechanism for enhanced transport of neutral drug molecules, in which the electroosmotic ow is
caused by the electrical volume force acting on mobile counterions. By varying the applied current density
and area of application, the iontophoretic transport of drugs can be regulated. Normally, the higher the cur-
rent amplitude, the greater is the ux enhancement for the charged permeant agents. A current density that is
too high may however be unpleasant for the patient.
In clinical practice, iontophoretic therapy is used primarily for the treatment of inammatory conditions in
skin, muscles, tendons and joints, such as temporomandibular joint dysfunctions. Attention has been drawn to
the possibility that sensation (pain and burning) may be felt and that burns may occur in the iontophoretic
therapy. These side eects may occur after treatments, which are short (10 or 20 min is the recommended time)
but of relatively high current densities (up to 1.3 mA/cm
2
) [101]. Recently, study of future pharmacologic
treatment for psychiatric disorders based on non-oral drug delivery systems such as implantable and transder-
mal delivery systems has indicated that iontophoresis might appear to be a promising and perhaps the most
ecient assisted-delivery technique for future antidepressant transdermal delivery [102].
9.7. Sonophoretic drug delivery
Sonophoretic drug delivery is a technique making use of ultrasound to enhance transdermal drug delivery
for a variety of molecules and drug substances. Study of the phenomenon of increased skin permeability
(sonophoresis) by application of ultrasound started in 1950s and received a major boost from the identica-
tion of low-frequency sonophoresis in the frequency range from 20 kHz to 100 kHz, which enabled the appli-
cation of sonophoresis to the delivery of macromolecules through the skin. To date, both in vitro and in vivo
experimental data exist for the sonophoretic transdermal delivery of insulin, mannitol, heparin, glucose,
caeine and the tetanus toxoid vaccine etc. Recent attention has been paid for potential applications of the
technique for vaccination and gene therapy [103].
The precise mechanism by which the ultrasound wave helps to enhance permeability through the skin has
not been fully understood yet. It is hypothesized that the micro-cavitation in the skin caused by the ultrasound
plays the dominant role in sonophoresis, which helps drug molecules to diuse into and through the skin. Fur-
ther eorts are needed to enhance knowledge of the mechanism of sonophoresis. Specically, detailed charac-
terization of cavitation events on the skin surface may prove useful in designing strategies for controlling
cavitation with a view to achieving greater enhancement in drug delivery without compromising safety.
Although transdermal drug delivery techniques discussed above can individually enhance transdermal drug
transport, which may oer several advantages over traditional drug delivery systems, such as oral delivery and
injection to minimize pain and possible sustained release of drug, the transdermal transport of macromole-
cules is generally a slow process due to low permeability of stratum corneum, the uppermost layer of the skin.
It has been expected that the combination of above techniques is more eective compared to each of them
alone. For instance, the sonophoresis can operate in synergy with other enhancers of transdermal drug trans-
port, including chemicals, electroporation and iontophoresis. Recent researches have shown results supporting
such expectation [104]. Again, synergetic use of our knowledge and techniques may play important roles for
future development of ecient transdermal drug delivery systems.
9.8. Electromagnetic radiation therapy
Electromagnetic radiation therapy has existed for almost 100 years. Not long after the discoveries of X-rays
and of radium, ionizing radiation had begun to be applied by pioneers for the treatment of tumors. Dierent
forms of ionizing radiation are used for cancer therapy. All the techniques have the same goal of concentrating
the absorbed dose at the tumor. Ideally, radiation should be transported to the tumor with minimum damage
to the surrounding tissue, and radiation should cause secondary processes that stop the tumor growth and
eliminate the tumor. Past advances in quantitative dosimetry, the development of computing techniques,
and the design of linear accelerators had provided the science-based (in practice the physics-based) innova-
tions in radiation cancer therapy in the latter part of the 20th century. This series of developments has culmi-
nated in the advent of conformal radiation therapy, allowing radiation elds to be contoured to permit the
treatment of precisely dened but arbitrarily shaped treatment volumes [105]. Furthermore, the conformal
radiation therapy could be developed to converge the CT imaging and the X-ray therapy into a single gantry,
so that tomographic images could be used to monitor treatment alignment and dose distribution continually
as the treatment progresses. In general, the conformal radiation therapy provides the ultimate in the physical
targeting of radiation to tumors, where the targeting depends on the anatomical and geometrical location of
macroscopic tumors, but does not require in-depth knowledge of their biological or radiation-biological
properties.
Although the radiation cancer therapy has many advantages, such as the soundly physics-based approach
allowing for quantitative and precise planning of the individual treatment, its easy access to tumor cells that
may be protected from cytotoxic drugs, and less frequently developed resistance of tumor cells to the radiation
than those to drugs, the conventional radiation therapy has some disadvantages such as the fact that high-dose
radiation therapy (e.g., 1060 Gy or more) is only tolerable when delivered to limited volumes within the
body. Besides, radiation therapy is usually only applied radically in the treatment of tumors large enough
to be imaged (typically >1 cm diameter) which limits the usefulness of the radiation in dealing with dissemi-
nated disease. More importantly, the biological dierences in the response of normal and tumor cells are
generally rather smallslight dierences in intrinsic cellular radio-sensitivity and in repair capacities. Conse-
quently, the therapeutic dierential between normal tissues and tumors is quite narrow, and there exist too
many tumors, which cannot be cured by tolerable doses of radiation. Much research work is now directed
to ameliorate the disadvantages of radiation therapy without losing the advantages.
9.9. Targeted radiation therapy
Recently, targeted radiation therapy has been developed as a novel and possibly advantageous approach to
radiation therapy. The basic idea is to deliver higher radiation doses to tumor than normal cells by means of
radioisotopes chemically conjugated to tumor-seeking targeting agents. The targeted radiation therapy
requires a targeting agent capable of seeking out tumor cells and delivering to them a radioisotope which
provides the irradiation. The selectivity of the treatment depends on the ability of the targeting agent to
discriminate malignant from normal cells. The cell killing eectiveness depends on the ability of the agent
to penetrate tumor masses and the absolute amounts of radio-nuclide, which can be delivered to those cells
that are successfully targeted.
In 1975, the prospects for targeted radiation therapy received a boost with the advent of monoclonal anti-
body technology [106], which oered the possibility that targeting molecules (monoclonal antibodies) could be
obtained which would recognize small dierences between molecular groups on the surface of normal and can-
cer cells. More than two decades of extensive international scientic eorts have proved rather disappointing.
The major diculties have been: less than perfect discrimination between cancer and normal cells, poor uptake
of absolute amounts of antibody in tumors, heterogeneous intra-tumor distribution of antibody and poor
penetration of antibodies within solid tumors.
During the past few years, a new strategy of genetic radiation therapy has appeared on the horizon. This
strategy builds upon growing knowledge of the genetics of cancer cells and how they dier from the cells of
normal tissues, as well as new technologies of genetic engineering, which allows individual genes to be trans-
ferred to cells or cell populations. The goal is to exploit the biological features of tumors to allow more radi-
ation to be delivered to the tumor, or, for a given dose of radiation to improve the therapeutic dierential by
increasing the radiation sensitivity of tumors or by reducing the radiation sensitivity of normal tissues. There
are several approaches by which genetic manipulation could enhance the therapeutic ecacy of radiation
therapy [107].
With the availability of monochromatic radiation sources, the photon activation therapy has recently been
introduced, in which a cascade of Auger and photoelectrons is created in the tumor during irradiation by a
monochromatic radiation beam (e.g. X-rays). The targets in the tumor cell are the strands of DNA, which
are broken leading to lethal damage to the tumor cell. This is a two-step therapy, where a sucient concen-
tration of a high-Z containing compound is physiologically directed to the tumor. Monochromatic radiation
with energy slightly above the K-absorption edge is then targeted on the tumor, and the Auger electrons
deposit their energy near the atom where photo-absorption takes place. This combined treatment takes advan-
tage of the selective electron excitation and ionization of the high-Z compound introduced in the DNA of the
tumor cell produced by the monochromatic X-ray beam. The physical explanation of the mechanism involves
the release of high-LET Auger electrons. The Auger electrons release a large amount of energy in the imme-
diate vicinity of their emission, in an average radius of some tens of nanometers. Several in vitro experiments
with cell cultures have been carried out and small-animal studies are beginning. In one early experiment,
iodine atoms were transported to the target by iodo-deoxyuridine [108]. It was observed that the eective radi-
ation dose was enhanced by a factor of 2 that was attributable to Auger electron emission. In recent experi-
ments at the ESRF, platinum has been used instead of iodine, which has the advantage that the X-ray energy
is higher (about 80 keV), and the number of Auger electrons is larger. The basic diculty of the method is that
the range of the Auger electrons is very small, a few tens of nanometers only, so that the heavy absorbing atom
should be incorporated into the DNA itself or to a location very close to it.
Despite its intuitive appeal and some successes, targeted radiation therapy has not yet become a main-
stream form of cancer treatment. Limited selectivity of uptake of targeting agents, limited absolute uptake
and limited penetration of most agents in solid tumors result in targeted radiation therapy having only a
few successful clinical applications at the present time. Recent progresses in biotechnology and in the
molecular genetics of tumors have however begun to open up new ways of using radiation in cancer treat-
ments, which exploit the known biology of particular tumors. Furthermore, recent technology development
in nano-technology, nano-materials, such as polymeric micelles, and possible use of tunable pulsed monochro-
matic radiation sources have provided us with new opportunities of developing novel solutions to these pro-
blems. Examples of such solutions may involve the development of promising imaging enhancers (contrast
agents or molecular probes) as well as smart drugs (target-specic poisons and/or biomedical bombs) at
nanometer scales and their translation from laboratory synthesis to clinical applications in novel X-ray imag-
ing and molecular-radiation therapy.
10. Summary
An interdisciplinary subject of bioelectrodynamics in living organisms has been introduced, which is of
increasing interest in recent years. It is shown that electromagnetic elds are intrinsic in living organisms
due to biophysical and biochemical processes that happen constantly in the living organisms and can be reg-
ulated partly by the CNS inside the living organisms. These endogenous EM elds are closely related to phys-
iological and pathophysiological behaviors of the living organisms, and their signal levels, though quite weak
in general, are strong enough to be detected by modern detectors. Thus, these endogenous EM signals in living
organisms can be monitored for diagnosis among other possible applications in biomedicine, such as the ECG,
EEG, MCG and MEG. It is also shown that in living organisms, cells and tissues are constantly subject to
forces and stresses, which may be originated from pressure forces linked to gravity to motional forces and
from electromagnetic forces arising from molecular interactions, environmental and externally applied EM
elds. These forces and EM elds are likely to modify cellular behaviors and aect physiological behaviors
of the living organisms. It is therefore of both scientic and practical interest and importance to study theo-
retically and experimentally the bioelectromagnetic, mechanical and their coupling phenomena in living
organisms, including their correlations with biochemical processes that may be initiated and/or activated
by these forces and/or EM elds.
Some issues related to bioelectrodynamic modeling of living organisms are reviewed. It is emphasized that
bioelectrodynamic modeling of ion-channel ow dynamics at the cellular level are important and the collective
properties and behaviors of living cells may deserve special attention, in which interaction of cells and exo-
genous EM elds as well as thermal noise eects may have to be taken properly into consideration, especially
when low eld intensities are involved. Some electromagnetic and mechanical properties of biological tissues,
such as blood, bones and soft tissues are also reviewed. The unique properties, such as actively control, reg-
ulation and remodeling capabilities of living tissues that are completely dierent from those of conventionally
man-made materials deserve also special attention in the modeling of living tissues.
Since mechanical forces and exogenous EM elds may aect physiological properties and behaviors of liv-
ing organisms, if used properly, these forces and EM elds can be utilized for biomedical applications, such as
biomedical imaging and therapy. Some recent biomedical imaging and therapeutic methods with the aid of
bioelectrodynamic techniques are also reviewed, indicating their promising future. The fact that living organ-
isms may have well-organized structures, actively controlled actions and responses, extremely sensitivity in
EM elds and mechanical actions, and amazing signal amplication functions may not only cause complexity
and variety of the biological world, but also create opportunities for technical innovations in biomedicine to
improve future quality of human life. Bioelectrodynamics in living organisms is indeed a very challenging and
promising research eld in the 21st century.
Acknowledgements
The author, S.-A. Zhou would like to thank the National Institute of Radiological Sciences and the Uni-
versity of Tokyo for their kind nancial support to his research activities in Japan. Thanks also to Prof. K.
Miya at Keio University, Prof. M. Uesaka at University of Tokyo and Prof. T. Takagi at Tohoku University
for their kind support and hospitality. He would like also to thank Dr. K. Dobashi for discussion on the sub-
ject of the Compton backscattering X-ray source. Helpful suggestion from anonymous referees for the paper is
greatly acknowledged.
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