Bioelectrodynamics in living organisms - Thayer School...

International Journal of Engineering Science 44 (2006) 67–92

www.elsevier.com/locate/ijengsci

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, Japanb 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 researchchallenges and opportunities. Bioelectrodynamics in living organisms is aimed to reveal critical roles of electromagnetismand mechanics in biology, to correlate biophysical functions of living organisms with biochemical processes at the cellularlevel, and to introduce theoretical basis and methodology, such as modeling and simulations, for stimulating technicalinnovations and promoting technology development in biomedicine as well as for the study of human healthcare issuesrelated 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 different from those of conventionallyman-made materials. Possible biological effects and potential biomedical usages of endogenous and exogenous electromag-netic fields and mechanical stresses in living organisms are also reviewed, which indicate promising future of biomedicalimaging and therapeutic methods based on bioelectrodynamic techniques. The fact that living organisms may havewell-organized structures, actively controlled actions and responses, extremely sensitivity in electromagnetic fields andmechanical actions, and amazing signal amplification 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 andmechanics 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 ShiraneShirakata Tokai-mura Naka-gun, Ibaraki 319-1188, Japan. Tel.: +81 29 287 8480; fax: +81 29 287 8488.

E-mail address: [email protected] (S.-A. Zhou).

mailto:[email protected]

68 S.-A. Zhou, M. Uesaka / International Journal of Engineering Science 44 (2006) 67–92

the cellular level, and to introduce theoretical basis and methodology, such as modeling and simulations, forstimulating technical innovations and promoting technology development in biomedicine as well as for thestudy 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 electromagneticforces arising from molecular interactions, environmental and externally applied electromagnetic (EM)fields. These forces and EM fields are likely to modify cellular behaviors, the synergetic properties of whichmay also affect physiological behaviors of the living organisms. One can imagine if there were no sunlightand geomagnetic fields, there would be no high-level living organisms on the Earth. The biological effects ofelectromagnetic fields are definitive and crucial to the formation of human beings. The fact that motion andmechanical training of a human body can affect significantly the physical performance and health status ofthe human body is also well known. On the other hand, these forces and EM fields, including their energyand 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 anyspecific application. This is indeed one of the main objectives of the bioelectrodynamics to discover, via boththeoretical and experimental efforts, those biophysical mechanisms of critical importance to the human lifeand health.

The ideas of using electromagnetic means for therapeutic applications in medicine already existed since the18th 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 thewidespread introduction of antibiotics, improved surgical techniques and other competing therapies afterWorld War II, those early ideas and techniques did not flourish. Today, with our increasing knowledge aboutbioelectromagnetic phenomena in living organisms, especially at the cellular level, and the rapid developmentof advanced technologies, such as microsystems and nano-technology, there is an increasing interest to explorenovel therapies based on bioelectrodynamic technologies with possible combination of other well-establishedtechniques 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 issuesand important research results on biological effects of electromagnetic radiations on living organisms andrelated bioelectrodynamic modeling of living organisms will also be reviewed.

2. Bioelectrical phenomena in animals

Although our scientific 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 first by fishermenwho found that some fishes, 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 scientific studies of theelectric phenomena in living organisms, their origins and possible usages in medicine started later in the 18thcentury.

2.1. Galvani’s animal electricity

Luigi Galvani, a professor at Bologana, first observed in 1786 that electricity caused a dissected frog’s legmuscle to twitch and claimed that he had demonstrated the existence of animal electricity. On the basis of hisfindings (and of the results of a multiplicity of studies in which experimental conditions were varied), Galvanicame to the conclusion that some form of intrinsic electricity was present in the animal, and that connectivenerve and muscle together, by means of conductive materials, induced contractions by allowing for the flow ofthis internal electricity. Galvani’s claim was however challenged by his country man, Alessandro Volta, aphysics professor at Pavia, who argued that the electricity was artificial, arising from a potential differencewhen two dissimilar metals were in contact.

In the middle of 19th century, the successors of Galvani at Bologna, such as Carlo Matteucci, a physicsprofessor at the University of Pisa, had demonstrated that living organisms did indeed produce a small,but definitive electric current [1,2]. Further studies found that, in contrast to animal experiments, plants, even

S.-A. Zhou, M. Uesaka / International Journal of Engineering Science 44 (2006) 67–92 69

the touch-sensitive mimosa, could not be electrically stimulated. This fact had led to the conclusion of VonHumboldt [3] that the ability to be excited by electricity is a general property of animals. Since then, effortsbegan both to understand how these signals were produced and propagated along the neurons and to improveinstrumentation for detecting and recording these signals.

According to Galvani, animal electricity exists in a state of ‘non-equilibrium’, which is generated by aparticular 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 difference between the intracellular andextracellular 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 differs profoundly from the simple ‘passive’ conductionalong electric cables, which would predicted a signal propagation speed close to the speed of light that was notobserved by experiments. On the contrary, it appears to be an ‘active’ process, which depends on a particularform of electrical energy, accumulated between the interior and the exterior of the nerve fiber, as a conse-quence of physiological processes clearly ‘‘belonging to the domain of life,’’ a true ‘‘animal electricity’’ withcharacteristics corresponding to the fundamental intuition of Galvani. Today, it is fair to say that Galvani’sstudies 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 first half of the 19th century. On the otherhand, Volta’s experiments had led to the invention of the electrical battery, the famous Voltaic pile, whichopened a new path to the tremendous subsequent development of physical investigations of electricity, elec-trochemistry, electromagnetism and related phenomena.

2.2. Electricity in fishes and controllable discharge

According to modern physics, living organisms are composed of atoms and molecules, and the forcesbetween atoms and molecules are largely electrical, just like those in non-living natural or man-made materi-als. The main difference between living organisms and materials is that the electrical force in the living organ-isms can be actively controlled. Proper understanding of such a difference is crucial in our later discussionabout biological effects of electromagnetic fields 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 fields in their vicinity, as a result of being ion-ically different from the water and having electrogenic processes in the gills, mucous membranes and skin. Forinstance, catfishes 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 catfish is surrounded by stationary electrical DC fields upon which AC components related withrespiration are superimposed [6]. Such fields have been found in many aquatic species, and they reveal elec-trically the presence of an individual to other electrosensitive species. For the catfish it has been demonstratedthat such fields can be used for the detection and recognition of prey. It has also been demonstrated that cat-fish can feel each other electrically [7–9].

Electric fishes generate electricity through their electric organs and membrane processes that are similar tothose involved in electrical phenomena of other animals, but, unlike them, these fishes can produce largepotential differences at their body surface, and thus affect other animals living in their habitat. Normally thisoccurs 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 (nervousface). This was first explained in experiments carried out on the electric eel, soon after intracellular recordingelectrodes were available. In electric eels, this response is a normal Na+-dependent reversal of the membranepotential, so that on open circuit, each electrocyte contributes about 150 mV at the peak of the spike. In somefishes, there can be several thousands of such electrocytes in series, which could be fired synchronously (seeFig. 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 cellsmay create unexpected physical consequences may remind us some extreme physical performance made by

…+ − + − + − + −

electrocyte

firing state

0

-50

50

2 4 6

Time (ms)

V (

mV

)

Fig. 1. An electrical eel with its electrocytes responsible for the electrical shock firing.


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, Galvani’s 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 producedby 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 hadstarted his study on possible use of RF energy for medical and health related purposes, while his most knownwork was on the AC frequency based transfer of electrical power. In particular, Nikola Tesla noticed the heatcaused by high-frequency current, which may have impact on a living organism and led to the field of dia-thermy. The diathermy, treatment of internal tissue by heating without burning the skin, through means ofelectromagnetic radiation, continued to develop through the 20th century, with various frequencies beingapplied. Tumors were one illness treated locally in this way, and in the case of infection the whole body couldbe heated. At about the same time, a French scientist, Arsene D’Arsonval made similar work on potential useof 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 placeto physical agents, the employment of which at least has the advantage of not introducing any foreign bodyinto the organism.’’

As we know today, such a statement has not been realized. On the contrary, for instance, the popularity ofTesla’s 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 ofchemicals and their compounds has instead been developed. In spite of some controversy stories in the historyof drug industries, we are now seeing gradually the entrance of physical means used in medical cares with therapid progress and development of advanced technologies, such as the nano-technology, material science andelectromagnetic techniques among others. We may foresee the combined usage of traditionally chemical-baseddrugs and modern techniques based on physical means, their related instrumentations and smart systems oftargeted drug delivery to reduce toxic side effects of chemicals in living organisms. In this respect, the theoryof 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 find correlations of these bioelectrical signals with diseaseconditions in human bodies. After many years of scientific efforts, the relationship between muscle motion,nerve cells, and electrical activity in human bodies gradually came to be understood.


3.1. Electrocardiogram and cardiac pacemaking

As early as 1875, the electrical activity of the brain in the absence of muscle motion was observed. Theheart, meanwhile, as an active muscle with somewhat stronger signals, was closely studied though initially withanimal experimentation. The instrumentation to measure these relatively weak signals non-invasively washowever developed rather slowly. In 1878, Theodore Wilhelm Engelmann in Utrecht produced the first plotof a primitive electrocardiogram (ECG), and 10 years later the Englishman A.D. Waller recorded the first plotof a human ECG from the body surface [10]. Potential significance of the ECG to clinical applications wasnoticed later by Willem Einthoven in 1900, who discovered the mechanism of the electrocardiogram, for whichhe received the Nobel Prize in medicine in 1924 [11].

The ECG is undoubtedly a medical diagnostic device, which has received the earliest and most intensivestudy. Considerable effort is devoted to the inverse problem of determining cardiac activity from the surfaceECG. Most of these efforts 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 activityat the membrane for which models incorporating the kinetics of ion movement have also been developedto 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 heartmay lead to morbidity and death. Sudden cardiac death accounts for almost 20% of all deaths from naturalcauses in developed countries. Present evidence is that 80–90% of these persons died because of an arrhythmiaculminating in cardiac arrest or ventricular fibrillation where electrical activity is uncoordinated and pumpingaction is lost [12]. The therapy for fibrillation is to deliver a large pulse of current into the heart from a defi-brillator. Many victims of sudden cardiac death can now be resuscitated in the hospital. Nowadays, a com-monly used therapeutic device is the artificial pacemaker, which delivers electrical pulses to the heart tocorrect situations where the heart’s 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), whichmay be detected on the skin overlying the muscle. Compared with ECG, the EEG (or EMG) signals are muchweak, 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 differ for each of these states. Certainbrain abnormalities can also be detected by observing changes in the normal pattern of the brain’s electricalactivity. A major drawback of the EEG is that they cannot show us the structures and anatomy of the brain orreally tell us which specific 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 inconcert to allow us to perform our daily activities and to meet challenges. This cooperation is achieved partlyby cells communicating with each other through electrical and/or chemical signals. For instance, the heartbeats 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 specific recognition molecules, receptors, on the cell surface. Thesereceptors then transmit the signals to the interior of the cell. The discovery of such mechanism of action ofhormones by Earl Sutherland at Vanderbilt University in USA was awarded the Nobel Prize in Physiologyor Medicine in 1971, who showed that the signal that is used to communicate between cells (‘‘the first messen-ger’’) is converted in the cell membrane to a signal that acts inside the cell (‘‘the second messenger’’). Sincethen, one has been wondering if there were any more basic mechanisms behind the highly selective structuralbinding between signaling molecules and the receptors, characterizing the specific features of the chemical sig-nal communication. No clear answer has yet been obtained, although some studies on allergy patients haverevealed that there might exist an interchangeable relationship between chemical stimuli and electromagneticstimuli [13,14].


4. Biomagnetic signals in human body, MCG and MEG

Time-varying electrical potential fields 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 theaid of electrodes and amplifiers. According to the theory of electrodynamics, it is known that time-varyingelectric fields can induce magnetic fields. Thus, instead of measuring the time-varying electrical potential fields,one could measure the time-varying magnetic fields to monitor the heart and brain activities. Although theelectromagnetic principle was known a long time ago, the first successful recording of the biomagnetic signalsfrom heart activities, the magnetocardiogram (MCG), was made by Gerhard Baule and Richard McFee atSyracuse University in 1963, using an induction coil magnetometer [15]. Later, in 1970, David Cohen et al.at the Massachusetts Institute of Technology (MIT) first used the superconducting quantum interferencedevice (SQUID) to record the magnetocardiogram [16]. As expected, the biomagnetic fields measured arerather weak. The human heart is the strongest biomagnetic source but still the highest feature in the MCGhas the amplitude of less than 100 pT, about 10�6 of the geomagnetic field. With the aid of the extremely sen-sitive SQUID magnetometer, the measurement of biomagnetic fields of the brain was first carried out at MITby 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 peripheralsensory stimulation were also detected [18].

The magnetoencephalography (MEG) is methodologically closely related to MCG. Instead of the heart, thebrain is being examined. Although the detailed structure of the human head is quite complicated, the mainbuilding blocks of the brain are neurons and glial cells. The brain active process is associated with a primarycurrent 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-calledvolume current completes the loop of ionic flow so that there is no build up of charge. The magnetic field isthus generated by both primary and volume currents. The biomagnetic signals created by neuron activities inhuman brains are typically 50–500 fT, which is about 1000 times smaller than that of the biomagnetic signalsfrom the heart.

Indeed, it has been a challenging task for developing proper measurement techniques and related systemsfor detecting such weak biomagnetic signals in the brain. Actually, it was only in the second half of the 1990sthat systems able to simultaneously map magnetic fields 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 basicfunctions 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 systemshas raised the interest of clinicians and today the MEG is used routinely in numerous hospital laboratories asa methodology complementary to PET and fMRI to investigate brain diseases such as epilepsy, Parkinson’sdisease, Alzheimer’s 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). Forinstance, ionic currents in the eye may give rise to a field of about 10 pT, which may change during eye move-ments and blinks. These biomagnetic fields 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 magneticfield measurements, even though low-temperature environment is necessary for the operation of SQUIDs.

Mus

cles

Hum

an e

ye

Hum

an b

rain

MEGMMG

MOGMCG 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)10-1410-15

fT pT nT µT

Hum

an h

eart

Fig. 2. Range of biomagnetic fields.


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 discussedabove have frequency components of interest up to about a few kHz, which are all rather limited at thelow-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 fields 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 hundredphotons per cm2 per second at near infrared frequencies), the intensity of which depends on functional statusof the cells. Furthermore, it has been shown that cells in culture might transmit and receive signals carried byEM radiation, which may control the orientation and migration of the cells [20]. However, the origin andputative roles of this ‘‘rudimentary cell vision’’ are largely unknown. It is also not yet known whether thesebiological EM phenomena exist in higher organized structures such as the brain and whether they may playa 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 thework of the Russian scientist Gurwitsch in 1920s. In his experiments, Gurwitsh could show the induction ofmitosis from the tip of an onion root to the shaft of a second onion root. He found that the induction workedwhen the second root was in a quartz tube, which is transparent for ultraviolet (UV) light but not when it wasin a glass tube, which is opaque for UV light. From this result, he concluded that it was UV-light causing theeffect, which he called ‘‘mitogenetic radiation’’. However, at that time, he could not directly measure the UVphotons emitted by the onion root, as he expected, due to the lack of proper instruments to detect such weakUV 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 first to reportthe 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 withmuch improved version of PM detectors has been made for the detection of ultra-weak photon emissions inthe spectral region of 180–1000 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, onemay wonder what the mechanism is for such generation of ultra-weak photons in living systems. By the end of1930s, 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 dueto the recombination of the free radicals, which appear in a number of chemical reactions [23]. Thus, one hadfurther wondered if such an ultra-weak photon emission could simply just be the waste of bioenergy, or con-tain really some specific bioinformation that may play a regulatory role in living systems. At present, althoughresearches in the field have not yet reached the state required for the ultimate verification or falsification of thehypothesis on the biophotonic information in cell division and other cell physiological processes, as originallyinvestigated 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 thoughtof 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 specifies luminescence of biological systems, biophotons refer to the biologicalsystem 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 celldoublings for a human being to reach its adulthood. In every individual, every second, millions of cellsmay die and must be replaced in a short period of time. It cannot be predicted where and when a cell willdie, 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 originatingfrom 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 haveto 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 scientific importance and practical interest to study possible roles andcommunication mechanisms of the bioelectromagnetic signals in living organisms.

6. Biological effects of electromagnetic fields on living organisms

Electromagnetic fields are ubiquitous in our environment. The existence of geomagnetic fields is wellknown. Others like lightning, sunlight and cosmic radiations are also sources of environmental electromag-netic fields. Nowadays, in our modern society, electromagnetic fields are constantly generated by man-madedevices, such as mobile phones, microwave ovens, TV apparatus, electrical heaters and electrical power trans-mission lines among others. These electromagnetic fields external to living organisms cover a wide range offrequency spectrum from extremely low frequencies to extremely high frequencies of c-photons.

6.1. Effects of non-ionizing electromagnetic fields

What are the possible biological effects of electromagnetic fields (EMF) on living organisms? It is wellknown that high-energy photons, such as X-rays (keV) and c-rays (MeV), may cause ionization of atomsor biomolecules, such as proteins and DNA, in living organisms. These ionizing radiations are biologicallyharmful since they may destroy the capacity for cell reproduction or division or cause cell mutation. Somedelayed effects 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 effects of non-ionizing radiation to living organisms then? The non-ionizing radiationincludes 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 fields have essentially no effects (or no significant biological effects) on living organisms as long as theapplied field intensity (energy) is much less than the ionizing energy of biomolecules or the energy thatmay heat significantly the biological tissues. Such thresholds for weak EM field effects in biological systemshave been studied based on the analyses of thermal fluctuations, leading to the thermal noise limit in physicaltheories and the molecular shot noise limit in biochemical processes according to currently known biophysicalmechanisms for coupling fields to ongoing, metabolically driven biochemical processes [27,28]. These researchresults indicated that unless large, organized, and electrically amplifying multicellular systems such as theampullae of Lorenzini of elasmobranch fish are involved, possible effects of weak ELF electric and magneticfields (�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 fields, andamazing signal amplification functions, all of which may contribute to our knowledge about the fact thatnon-ionizing radiation found in our environment can pose a considerable health risk to us if not properly con-trolled. Great efforts have been made in studying potential biological effects of non-ionizing radiations onhuman health. Recent epidemiological studies and other evidences have implicated long-term exposure tonon-ionizing EM fields, such as those emitted by power lines, in increased health hazards. These hazardsmay include, for instance, an increased risk in children of developing leukemia [29]. Many regulations havetherefore been formulated in order to prevent potential risks. There are however still many unknown casesdue to the complexity of living organisms interacting with EM fields. Careful researches have demonstrated thatelectromagnetic fields of very tiny energy could have profound biological significance and biological effects ofEM fields do not follow simply the intuitive rule that its effects increase with increasing field intensity [30,31].

6.2. Beneficial effects of electromagnetic fields

Electromagnetic fields 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 fields can be beneficial to livingorganisms. We are living in the world under constant exertion of electromagnetic fields. The evolution ofhuman beings as well as other living organisms on the Earth has a long history. One can imagine if there were


no sunlight and geomagnetic fields, there would be no high-level living organisms. The biological effects ofelectromagnetic fields are definitive and crucial to the formation of human beings.

Besides, life on the Earth is not isolated from the universe, but is susceptible to the fields of the planet andother celestial bodies. Sunspots and cycles of the Moon may cause changes in ionospheric currents and geo-physical fields, which in turn influence the fields within us. The geomagnetic field (GMF) may also be dis-turbed by magnetic storms, which may vary from �35 lT in the equatorial areas, where it is mainlyparallel to the terrestrial surface, to �70 lT in the vicinity of the magnetic poles of the earth, where it isnear-vertical. The GMF and its biological effects 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 benefit fromit [34]. The possible connection between the orientations of birds (e.g., pigeons and sea gulls) to the GMF iswidely known [35–37].

The usefulness of the biological effects of EM fields and radiation may also be noticed from the well-knownfunction of the human eye, which gives us vision images of the colorful world through the detection of photonsof variety of frequencies in the visible range of EM spectrum. The human eye is just one of the sensory systemsthat 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 five 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 thewell-known five senses, human beings may have counterparts to less familiar sensory systems characterized inother living organisms. These sensory systems may respond to environmental factors other than visible light,molecular shape and/or air motion. Further scientific investigations are however required to reveal thesemechanisms [38].

Obviously, during many years of evolution, living organisms have lived with natural EM fields and radia-tions in harmony, and have made use of EM fields and radiations. One may wonder what could happen if sucha harmony would be disrupted by externally man-made EM fields. The consequence could be either positive ornegative to human health, as one may expect. For instance, recently there are reports indicating that externalEM excitation may affect functions of the brain, such as cellular signalling or permeability of the blood–brainbarrier among others [39–41]. Reported biological effects of low intensity non-ionizing EM fields 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, eventuallygoing beyond the current mechanistic assumption that is based on the disruption of metabolism due to theelectromagnetic power deposition in biological tissues. In connection with the recently rapid progresses innano-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 different 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 toanalyze and quantify scientific measures of material properties and behaviors under various conditions. Tomodel physiological behaviors and properties of living organisms, further interdisciplinary research effortsacross several scientific fields will however be required. In this article, we shall focus our attention to someissues related to bioelectrodynamic modeling of living organisms. Here, the bioelectrodynamic modelingimplies 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 couplingeffects of importance. This is necessary because, in living organisms, cells and tissues are constantly subject toforces and stresses. These forces and stresses may have various origins from pressure forces linked to gravity tomotional forces and from EM forces arising from molecular interactions, environmental and externallyapplied EM fields. These forces and EM fields are likely to modify cellular behaviors by affecting metabolism,paracrine or autocrine factor secretion and gene expression among others [42], the synergetic properties ofwhich may also affect physiological behaviors of the living organisms. The facts that motion and mechanicaltraining of a human body can affect significantly the physical performance and health status of the human


body and that the sunlight from EM radiation has significant influence on the life of living organisms on theEarth 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 understandingof the mechanisms involved in the interaction processes in any specific 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. Fromthe 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 basicbuilding block of living organisms, physical modeling of cells is an important subject. At the cell level, manytheories and mathematical modeling approaches from classical physics could be utilized by consideration ofthe fact that the size of a cell is typically 10–100 lm, though the cell sizes may vary depending on the cell typeand circumstances. For instance, a human red blood cell is about 7.5 lm in diameter, while some neurons areabout 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 acritical 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 affecting the ion channel behaviors at the cel-lular level. Studies have shown that living cells may have several different ways of regulating their ion channelbehaviors. These include the ligand-gated ion channels, whose permeability to ions is increased by the bindingof a specific ligand (e.g., a neurotransmitter at a synapse), the voltage-gated ion channels, whose permeabilityto ions is extremely sensitive to the transmembrane potential difference, 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 (thefirst messenger) is converted to a signal that acts inside the cell (the second messenger) and such a conversionoccurred in the cell membrane. In other words, the chemical signals (e.g., hormones as signal molecules) attachfirst to specific 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 in1971. However, the transduction process of the signals in cells was unclear until Alfred G. Gilman and MartinRodbell 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 different cellular amplifier sys-tems, which may receive multiple signals from the exterior, integrate them and thus control fundamental lifeprocesses 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 amplification. The significance of theamplification was recognized by the 1994 Nobel Prize in Physiology or Medicine, awarded to Gilman andRodbell.

Recently, there appear also some fresh thoughts about possible effects of electromagnetic interaction insuch signal transduction process. A tiny field, far too weak to power any cellular activity, may trigger a changeat the regulatory level, which then leads to a substantial physiological response that is carried out using theenergy of cell metabolism [43]. Various components of the regulatory cascade, including receptors, calciumchannels, and enzymatic processes within the cell are sensitive to EM fields. The electromagnetic forces atthe membrane’s outer surface could modify ligand–receptor interactions (e.g., the binding of messenger mole-cules such as hormones and growth factors to specialized cell membrane molecules called receptors), which inturn would alter the state of large membrane molecules that play a role in controlling the cell’s internal pro-cesses [44]. New research is revealing how free radicals, including nitric oxide, are involved in the coupling ofEM fields 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 ionchannels and the mechanically gated channels are evidently related to electromechanical phenomena at thecellular level. These evidences suggests that the cell membrane can be one of the primary locations whereapplied EM fields and forces act upon, causing a variety of biological effects observed on the macroscopicscales. 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. Inconnection with experimental efforts, proper theoretical models are required to give a comprehensive explana-tion for the experimental data. Efforts of bioelectrodynamic modeling of ion flow dynamics in different ionchannels at the cellular level are therefore necessary and required. While modeling of behaviors of individualion 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 fields as well as thermal noise effects have to be takenproperly into consideration, especially when low field 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 tissuesand organs are composed of many atoms, molecules and cells. Classical Newtonian mechanics and electrody-namics may also be sufficient to describe biophysical phenomena at these scales. Even at the cellular level,efforts 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 hasbeen 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 whichpossible effects of membrane stiffness, thickness, spontaneous curvature or changes in channel shape, lengthor stiffness could all be taken into consideration [51].

Since 1960s, continuum biomechanics has been developed as a distinct field of study and contributed to ourunderstanding of human health as well as to disease, injury and their treatment. According to Fung [52], bio-mechanics is defined as the mechanics applied to biology. Fung’s pioneering work on mechanical modeling ofblood flow and lung’s soft tissues among others are very interesting [53]. Although biomechanical propertiesand 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 manipulateand to make use of the fascinating biological phenomena in living organisms, for which interdisciplinaryresearch efforts are greatly desired. This is because, unlike man-made materials, bioelectrical, biomechanicaland biochemical phenomena in living organisms are generally coupled and have to be studied synergetically,though some simplification could be made in certain cases.

7.2.1. Blood

Blood is marvelous fluid composed of red blood cells (erythrocytes), white blood cells (leucocytes) andplatelets (thrombocytes) mixed in the blood plasma. The blood plasma is found to behave like a Newtonianviscous fluid with a coefficient 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 fluid. Like any fluid in thecontinuum modeling, the viscosity of the blood is a major determinant of blood flow and tissue perfusion.Interestingly, living organism may have means to control blood viscosity and prevent hyperviscosity. In otherwords, negative feedback mechanisms may exist, which down regulate viscosity-related genes in the case ofelevated 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, membranephospholipid 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 alsoallows them to bypass the human splenic filtration process among others.

Furthermore, the electrical properties of blood are of interest for the modeling of blood with respect to itsin 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 at1 MHz and decreases to a value of 50 at 1 GHz frequency. The conductivity has a value of about 0.7 S/m at1 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 itsstrong and solid nature. Actually, a live bone is not a simple solid, but involves also a fluid phase. Bone fluidhas many functions. It transports nutrients to, and carries waste from the bone cells (osteocytes) buried in thebony matrix. It is also involved in the transport of mineral ions to the bone tissue for storage and retrieval ofthose mineral ions when which are needed by the body. Recently, the bone-fluid flow has been suggested to havea role in bone’s mechanosensory system, in which bone deformation causes the bone fluid to flow over the bonecell membrane, where the shear stress of the flowing fluid 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 interstitialfluid and blood. As a live bone, it can change, grow or be removed by resorption, and the bone-fluid circulationcan transport materials to and from the bone. It has been estimated that the collagen occupies about 50% of thevolume in compact bone, the mineral 40% and the pores 10% [56]. Thus, macroscopically, the bone may bemodeled as an inorganic–biooganic composite material [53]. Poroelasticity theory has also been introducedto model the interaction of deformation and fluid flow in a fluid-saturated porous bone medium [57].

During normal activities, such as walking, running and sitting, various parts of human skeleton and bone aresubjected 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 orstrain gradient. In the wet state of bone, the strain gradient can produce a combination of responses, involvingpiezoelectricity, 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 wetbones has been known since 1950s [58]. The stream potential has also been considered to be a major electrome-chanical effect arising from the flow of ion-interstitial (ion-containing) fluid (electrolyte) through a flow channelwithin 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 itwas shown that the solubility of the hydroxyapatite crystals may change in response to stresses [61]. Althoughthe subject of electromechanical properties and behaviors of bone has been studied extensively for about half acentury, new research efforts are still made to study bone structures and properties at nano-scales and toexplore potential applications of nano-technology to create artificial bone materials with potential uses asimplants and therapies [62].

7.2.3. Soft tissues

Soft tissues are composed of cells and extracellular matrix, which may exist in many different forms, eachspecialized to perform a specific function and each having a unique microstructure. Since the human body ismainly 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 orreplacement of damaged or missing tissue in the human body [63]. Biological tissues are by essence highlycomplex systems that host chemical, cellular, electrical and mechanical processes. Today, powerful computersare readily available to simulate very complex systems so that difficulties in costly experimental studies couldbe 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 microstructureand biomechanical behavior of biological cells and tissues, soft tissue mechanics is a still a vast area for thedevelopment of constitutive theories.

Mechanically, the main characteristics of biological soft tissues are that they sustain large deformations anddisplacements, 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 muchis known about the mechanics of bone, cartilage, tendons and various types of muscle, data on the mechanicalproperties of very soft tissues with Young’s moduli less than about 104 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. Themechanical properties of tissues also influence the movement of water through extracellular spaces, whichis 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 ofvery 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 andfunctions in response to even subtle changes in their mechanical environment [65], and in many respects, it isthe extracellular matrix that regulates cell shape, orientation, movement and overall function [66]. Study ofsoft tissues at the cellular level is therefore very important. In particular, the modeling of effects of interactionbetween 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 tissueand 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 tothat of free space. Application of an electric field pulse may result in rapid polarization changes that can deformmechanically 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 dielectricpartitions that separate strongly conducting intracellular and extracellular compartments. For instance, cellsare enclosed by poorly conducting membranes with a typical resistance of 5000 X/cm2 and lie within an extracel-lular space with a specific resistance as low as 4 X/cm [67]. It has been found that the dielectric properties of tissuesare highly dispersive [68], the mechanisms of which come mainly from the dielectric relaxation of free water (fre-quency near 20 GHz and dielectric constant 10–50), the Maxwell–Wagner type of relaxation resulting from thecharging of cell membranes (frequency near 1 MHz and dielectric constant 100–1000), and the frequency-depen-dence of membrane capacitance of the cells (frequency near 100 Hz and dielectric constant around 105).

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 quitescatted. It is shown that differences between the mean values of resistivities of most tissues from muscle andinternal organs are statistically insignificant. 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 · 106 X cm) and fat(3850 X cm) have significant higher resistivities. A linear relation was found between the resistivity and thewater content of some tissues. The low water content of bone and fat explains their high resistivities, whilethe high water content of other tissues explains their low resistivities. Besides, the anisotropic structures ofbiological tissues may also contribute significantly to the measured electrical properties. Skeletal muscle isprobably the best example of this variation, in which the resistivity can be up to 10 times lower along thelength of the muscle fibres 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 andthat both conductivity and relative permittivity decrease with increased air content. The conductivity of bloodcan also alter by up to 20% as a function of flow. This is due to variations in the erythrocyte orientation, axialaccumulation (where the concentration of erythrocytes is uneven due to the velocity profile), and elongation ofthe erythrocyte in the direction of the flow [70]. Obviously, to model electrical properties of blood, bothmechanical flow 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, livingbones and heart among others. While great efforts have been made in cardiac electrophysiology to understandand model the human heart, little is known about electrodynamic properties of other organs. Some effortshave been made recently in modeling, for instance, the gastrointestinal system, which is also an electricallyand 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 interpretationof 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 thecomplex geometries, interface conditions and loading conditions. Nowadays, with the increasing amount ofcomputational power available, there appear interest and efforts to develop human simulators for a varietyof 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 dynamicproperties of the human body. Over the past century, imaging has experienced a quantum leap in technologyand 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 shallfocus on some recent progress and development in the X-ray imaging technique, which is one of the oldest andmost 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 andhigh voltage sources. Today, X-rays can be generated by modern accelerators (synchrotron) or by high-powerlaser interacting with electron beams among others. Recent advancement in high-power laser technology hasled to the development of a new type of X-ray source with compact size (the so-called ‘‘table-top’’ X-raysource). In 1998, a research group led by Frank Carroll at Vanderbilt University was successful in producingpulsed, tunable (quasi-) monochromatic X-rays using the free electron laser as a source of both high-energyelectrons and intense infrared (IR) laser light although the properties of the X-rays were not satisfactoryfor clinical applications. In April 2001, after 2 years of re-design and engineering, a new prototype devicewas completed and commissioned at the MFEL Center at the Vanderbilt University but used a configurationthat 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 1010 X-rayphotons/8 ps pulse throughout its tunable 12–50 keV range at anywhere from a 1–10% bandwidth in a cone-beam area geometry [72]. Today new efforts 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 fortheir 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, theimage quality, and lowering the dose to the patient.

• Tunability makes possible to use optimal X-ray energies to improve contrast among others. (The choice ofthe 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 markedlyimproved mammography, K-edge imaging, phase-contrast imaging, time-of-flight imaging, small-animalimaging 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 toimproved diagnostic techniques. Iodine, for example, attenuates X-rays much more effectively at 33.2 keVthan at any other energy, because the binding energy of the k-shell electron is 33.2 keV. When hit by a photonat that energy, the K-shell electron is ejected from its orbit, extinguishing the incident photon. Because mono-

Fig. 3. Scheme of the compact X-ray systems for medical applications.


chromatic beams of a narrow bandwidth can be tuned to that energy, they can be used to decrease the amountof contrast material needed for X-ray imaging and/or be used to significantly reduce radiation dose to thepatient. Iodine is not the only atom that is useful for such imaging tasks. Gadolinium, for example, has aK-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 to50 keV, the beam becomes more penetrating, and the body becomes more transparent to the X-rays, with alower radiation dose. However, the gadolinium will then act more efficiently in stopping the beam whereverit is placed. Besides, the dual-energy monochromatic X-ray computed tomography may also be developedto 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 imagingmethods plays a central role. In conventional X-ray imaging, as we know, the structures of the object aremapped by an incident X-ray beam and detector of sufficient spatial resolution. The relative variation ofthe mapping property of the object is the contrast that depicts differences in X-ray absorption among varioustissue constituents in the path of the X-ray beam. These images may provide excellent visualization of tissueswith significantly different absorption characteristics resulting from differences in physical density and atomicnumber Z. When these differences are slight, such as for soft tissues, conventional X-ray imaging methods arehowever 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 beneficial.When cancerous and normal breast tissues are trans-illuminated by different energies of monochromatic X-rays, cancers act as if they have a higher effective atomic number and hence a higher linear attenuation.Use of these monochromatic X-ray beams could therefore highlight contrast differences 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, bycombining images at different energies, it is possible to produce hybrid images in which the contrast of relevantstructures 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-resolutionimages of the coronary arteries. In conventional coronary angiography, a catheter is inserted into the iliac


artery and guided to the aorta and to the beginning of a coronary artery. An iodine-containing contrast agentis 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 aroutine diagnostic method for screening or follow-up studies. The attempts to avoid the risks by intravenousinjection of the contrast agent failed because, by the time the bolus reaches the coronary arteries, it is dilutedto 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 intravenousinjection is used. In the intravenous coronary angiography, for each scan, two monochromatic X-ray imagesbelow and above the K-edge of the contrast agent, such as the iodine, are recorded simultaneously. The twoimages can then be subtracted to produce a maximal contrast enhancement of the iodine. Since the KESmethod is used following the injection of the iodine contrast agent into a peripheral vein, the risks associatedwith arterial catheterization are avoided. Even when diluted on its way through the heart and lungs beforereaching the aorta, where the heart arteries branch off, the concentration of iodine is sufficient to provideclinical quality subtraction images [77].

8.4. Phase-contrast imaging and diffraction enhanced imaging

An X-ray beam traversing a patient picks up absorption information that is traditionally used in diagnosticimaging. Because soft biological tissues are made up predominantly of light elements such as carbon, hydro-gen, oxygen and nitrogen, X-ray absorption coefficients 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. Densitychanges, either from differences in specific gravity of adjacent tissues or the interfaces of different tissue typesin the breast, can produce inhomogeneity in the refractive index of breast tissues, which may affect propaga-tion behaviors of the X-rays. Thus, it is possible to explore imaging properties of the X-ray beam that mayacquire phase information from differences in tissue composition. In fact, the X-ray phase shift cross-sectionfor light elements is found to be 100–1000 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-rayphase information require new detectors and analyzers to cull this information from the transmitted beam.

Recently, a diffraction 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 diffraction [79]. This allows pure absorption images and pure refraction images tobe produced, rather than a mixture of the two. A synchrotron source is used to provide a quasi-parallel mono-chromatic X-ray beam of sufficient brightness. The contrast in the images produced is related to the changes inthe X-ray refractive index of the biological tissues, resulting in remarkable clarity compared with conventionalX-ray images based on absorption effects. These changes are greatest at the boundaries between different tis-sues, giving a marked edge enhancement effect and three-dimensional appearance to the images. For investi-gating the diffraction enhanced imaging, the synchrotron radiation source is ideal. While it is feasible to usesuch a source for developing new techniques and undertaking a certain amount of clinical research, it wouldnot be suitable for large-scale clinical applications, owing to a variety of factors such as limited availability andgeographical 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 effects by some conventional X-ray equipments.

8.5. Targeted cell imaging

Recently rapid developments in both molecular/cellular biology and non-invasive imaging techniques haveled to the emergence of a relatively new discipline, the ‘‘molecular imaging’’ [80]. The molecular imaging hasits roots in both molecular and cell biology as well as in imaging technology. At present, non-invasive in vivomolecular 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 convergedto 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 themolecular imaging strategies. Practical realization of such systems may be related to the development ofadvanced high-spatial resolution x-detectors. It is expected that biocompatible nano-particles or micelles,encapsulated with specific nano-materials and/or molecules, can be used as contrast agents in biomedicalX-ray imaging for detecting tiny early-stage cancer cells. We may foresee a paradigm shift in cancer imagingand therapy in the 21st century. This implies the shift from anatomical imaging to molecular/cell signatureprobing and from non-specific systematic cytotoxic agents (poisons) to tumor-specific targeted therapies.New X-ray techniques for image acquisition and methods for cancer imaging and image-guided interventionsand 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 fields for cell communi-cations, tissue activities and their senses with environments, but also their physiological behaviors and healthstates can be influenced by exogenous EM fields and/or their energy or power. Besides, mechanical energyexpended in biological structures may also produce electrical potentials of sufficient magnitude to exert a widerange of effects in living systems. These may include control of cell nutrition, local pH, control and enzymeactivation or suppression, orientation of intra- and extra-cellular macromolecules, migratory and proliferativeactivity of cells, synthetic capability and specialized function of cells, contractility and permeability of cellmembranes and energy transfer. If the EM fields and mechanical energy could be properly controlled anddesigned 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 arethen how one could find those proper guidelines and what types of diseases or health functions for the humanbody could be treated with the use of applied EM fields, 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. Wolff,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. Wolff’s discovery raised aprofound question: what is the mechanism that enables a bone (or any other tissue) to adjust its structurein 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 wayto accommodate the desired performance. Although the basic concepts of Wolff’s law are generally acceptedbased largely on phenomenological observations, the basic mechanisms and mathematical laws relating boneremodeling 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 whichthe bone cells sense the state of strain in the bone matrix around them and either add or remove bone asneeded to maintain the strain within normal limits. What is then the process by which the bone cells are ableto sense the strain? One hypothesis is that the piezoelectric effect in bone is the part of the feedback loop bywhich the bone cells sense the strain field. This hypothesis obtained support from observations of osteogenesisin response to externally applied electric fields of the same order of magnitude as those generated naturally bystress via the piezoelectric effect [60]. Besides, the electrokinetic phenomenon of bone-fluid flow (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, specifically in thehands 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 100–50 lA/cm2. 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 fields appliedfrom 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 currentthrough a fracture site. A comparable current could be magnetically induced to flow through the fracture siteusing coils placed outside of the skin. That magnetic fields in the environment can induce currents deep withinthe body has now been well documented by medical researchers using pulsing magnetic field therapy to inducecurrent flows 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 field, driven by an electrical current pulse,to generate non-invasively electrical fields suitable for neural stimulation inside the brain. Such an externallyapplied electrical field may deviate cell’s membrane potential, i.e., depolarize the cell membrane and henceactivate excitable tissues among others. The early documents on magnetic stimulation may be traced backto the work of Jacques d’Arsonval 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 fieldstrengths. In 1985, researchers at the University of Sheffield in UK achieved successfully the transcranial mag-netic stimulation and made the first 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 thatmay generate trains of stimuli at 1–60 Hz. Since TMS can exert both excitatory and inhibitory effects onhuman 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 specific corticalareas of the brain. TMS and repetitive TMS (rTMS) have been used for more than 20 years to non-invasivelystudy the human brain. In particular, it allows the evaluation of motor conduction in the CNS, which mayprovide specific information in neurological conditions characterized by clinical and sub-clinical upper motorneuron involvement. TMS has also proved useful in monitoring motor abnormalities and the recovery ofmotor 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 diseasescausing changes in the excitability of cortical motor areas. They are also useful in monitoring the effects ofneurotrophic drugs on cortical activity [85]. Today, TMS is an established investigative tool in the cognitiveneurosciences, and is being explored for the study of perception, attention, learning, plasticity and awarenessamong others [86]. TMS or rTMS has also been considered recently as a therapeutic tool for depression,Parkinson’s 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 specific points on the skin, usually by the insertion of needles. Acupuncturewas based on the principles of traditional Chinese medicine to understand human health in terms of a vitalforce or energy called ‘‘Qi’’, which circulates between the organs along channels called meridians. Qi energymust flow in the correct strength and quality through each of these meridians and organs for health to bemaintained. Disturbance of such energy flow may cause symptoms of certain sicknesses. The acupuncturepoints are located along the meridians and provide one means of altering the flow of Qi by proper stimula-tions. According to current knowledge of medicine, the acupuncture points are considered to correspond tophysiological and anatomical features such as peripheral nerve junctions. This might explain the effectivenessof the acupuncture for releasing pains of patients from various origins, and its limitation of general use inmedicine.

Along the line of the electrical stimulation discussed above, electrical stimulations via acupuncture needlesas well as micro currents have also been explored to release pains of certain patients. Clinical benefits havebeen reported for the uses of the electro-acupuncture and the micro current therapy [89–91]. Studies indicatedthat clinically tested results depend on the frequency of the applied electrical currents, which shows character-


istic of the patient and the affected tissues to be treated. It was then hypothesized that precise frequenciesappear to interact through resonance with biological tissues and biochemical regulators in such a way as toneutralize specific conditions, and address specific tissues, possibly by altering membrane configuration [91].Further efforts 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, Indianand Chinese civilizations had used light to treat various diseases. Modern photodynamic therapy was howeverdeveloped in the last century, starting from the pioneering work of Niels Ryberg Finsen, a professor at theUniversity of Copenhagen in Demark, on the treatment of diseases, and in particular the treatment of lupusvulgaris by means of concentrated light rays. Finsen’s method has proved of use in the treatment of a numberof other skin diseases, but it has been particularly successful in the treatment of lupus vulgaris. None of themethods 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 theNobel 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 andA. 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 modernphotodynamic 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 theirrelative 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 inflammatory and immuneresponses elicited in the host [93]. In the PDT treatment, photosensitizer is pre-administrated like a drug intothe patient and is stored selectively in diseased tissue, such as the tumorous tissue. Upon activation byabsorption of light photons, the photosensitizers generate reactive oxygen species (singlet oxygen and freeradicals), which are able to damage membranes, DNA and other cellular structures of the tumor. Thisimplies 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 fields to influ-ence, for instance, the permeability of cell membranes for photosensitizers and therefore to enhance the pho-todynamic efficacy in the PDT for treating some cancer cells [94]. PDT has also been explored for thetreatment of cardiovascular diseases [95].

Although photodynamic therapy offers certain advantages over other therapies, such as conventionalchemotherapy, 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, theabsorption coefficients of the photosensitizer at these wavelengths are low. In addition to the problems oflight, oxygen and photosensitizer presence, the ratio of the photosensitizer uptake between tumor and normaltissue is only marginally in favor of tumor in many cases. As a result, a considerable amount localizes in theskin causing acute photosensitivity, which can persist for several weeks. Further efforts and innovative ideasare required in this field.

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 phenomenonof the cell electroporation was studied extensively and used as a research tool to facilitate cellular uptake ofgenetic 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 [96–98]. Though the exact mech-anism for the cell electroporation has not yet been known, plausible models exist to explain majority ofexperimental results. Considering that biological systems are electrically heterogeneous, application of an


electrical field pulse may result in rapid polarization changes that can deform mechanically unconstrained cellmembranes (e.g., suspended vesicles and cells) followed by ionic charge redistribution governed by electrolyteconductivity and distributed capacitance. As primary pores appear in the membrane, its resistance drops, andthe voltages within the system redistribute on a time scale governed by the instantaneous values of the variousconductivities 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 creationtime (�ls). The membrane recovery (resealing) is slow and generally is temperature dependent. Thus, somepores remain open for long times, during which ions and molecules can continue to cross the cell membraneby diffusion and electrically driven transport associated with diffusion potentials and metabolically drivenmembrane pumps [96]. Generally, the most important parameters for effective electroporation are the electri-cal field strength and the length of time the field is applied (pulse length). For tissue electroporation in whichcells are in multicellular environments, it is suggested that the required electric field strength should be largerthan that used for cells in dilute suspensions [98]. Besides, tissue electroporation could be enhanced by apply-ing short pulses at relatively large field strengths, delaying application of pulses until some time after injectionof solutes, and possibly applying multiple pulses with long interpulse delays. A large variety of other param-eters may also influence the efficacy of the electroporation, and the uptake of molecules depends on theirmolecular size, charge and other physicochemical properties [97].

As a therapeutic tool, the electroporation has been found to be an effective technique for molecular ther-apies, which require drug delivery systems to deliver effective drugs to enter the targeted cells in many cases.The combined treatment consisting of a chemotherapeutic agent and pulsed electrical fields has been termedelectrochemotherapy. This relatively new treatment modality relies on the physical effects of locally appliedelectrical fields to destabilize cell membranes in the presence of a drug. In 1987, Okino and Mohri [99] pub-lished the first in vivo electroporation results attained in an animal tumor model. It was shown that the use ofthe anticancer drug bleomycin in combination with pulsed electrical fields killed tumors far more effectivelythan the use of bleomycin or electroporation alone. Since that the publication by Okino and Mohri, the fieldof electroporation has progressed continuously, and a large number of publications have appeared on in vitroand 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 field interaction provides an additional force which drives ions throughthe skin; (b) the flow of electrical current increases permeability of skin; and (c) the electroosmosis producesbulk motion of the solvent itself that carries ions or neutral species with the solvent stream [100]. For chargeddrug molecules (ions), the electrical field imposes a force on the ions, which adds to and may dominate thediffusion force or concentration gradient. This electrical force drives the charged drug molecules throughthe membrane far more efficiently than in the case of pure diffusion or passive transdermal drug delivery.In the case of uncharged drug molecules, the bulk solvent flow caused by electroosmosis was suggested asa possible mechanism for enhanced transport of neutral drug molecules, in which the electroosmotic flow iscaused by the electrical volume force acting on mobile counterions. By varying the applied current densityand area of application, the iontophoretic transport of drugs can be regulated. Normally, the higher the cur-rent amplitude, the greater is the flux enhancement for the charged permeant agents. A current density that istoo high may however be unpleasant for the patient.

In clinical practice, iontophoretic therapy is used primarily for the treatment of inflammatory conditions inskin, muscles, tendons and joints, such as temporomandibular joint dysfunctions. Attention has been drawn tothe possibility that sensation (pain and burning) may be felt and that burns may occur in the iontophoretictherapy. These side effects 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/cm2) [101]. Recently, study of future pharmacologictreatment 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 mostefficient 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 deliveryfor 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 identifica-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 vivoexperimental data exist for the sonophoretic transdermal delivery of insulin, mannitol, heparin, glucose,caffeine and the tetanus toxoid vaccine etc. Recent attention has been paid for potential applications of thetechnique for vaccination and gene therapy [103].

The precise mechanism by which the ultrasound wave helps to enhance permeability through the skin hasnot been fully understood yet. It is hypothesized that the micro-cavitation in the skin caused by the ultrasoundplays the dominant role in sonophoresis, which helps drug molecules to diffuse into and through the skin. Fur-ther efforts are needed to enhance knowledge of the mechanism of sonophoresis. Specifically, detailed charac-terization of cavitation events on the skin surface may prove useful in designing strategies for controllingcavitation with a view to achieving greater enhancement in drug delivery without compromising safety.

Although transdermal drug delivery techniques discussed above can individually enhance transdermal drugtransport, which may offer several advantages over traditional drug delivery systems, such as oral delivery andinjection 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 effective compared to each of themalone. 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 supportingsuch expectation [104]. Again, synergetic use of our knowledge and techniques may play important roles forfuture development of efficient 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-raysand of radium, ionizing radiation had begun to be applied by pioneers for the treatment of tumors. Differentforms of ionizing radiation are used for cancer therapy. All the techniques have the same goal of concentratingthe absorbed dose at the tumor. Ideally, radiation should be transported to the tumor with minimum damageto the surrounding tissue, and radiation should cause secondary processes that stop the tumor growth andeliminate 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 fields to be contoured to permit thetreatment of precisely defined but arbitrarily shaped treatment volumes [105]. Furthermore, the conformalradiation 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 continuallyas the treatment progresses. In general, the conformal radiation therapy provides the ultimate in the physicaltargeting of radiation to tumors, where the targeting depends on the anatomical and geometrical location ofmacroscopic tumors, but does not require in-depth knowledge of their biological or radiation-biologicalproperties.

Although the radiation cancer therapy has many advantages, such as the soundly physics-based approachallowing for quantitative and precise planning of the individual treatment, its easy access to tumor cells thatmay be protected from cytotoxic drugs, and less frequently developed resistance of tumor cells to the radiationthan those to drugs, the conventional radiation therapy has some disadvantages such as the fact that high-doseradiation therapy (e.g., 10–60 Gy or more) is only tolerable when delivered to limited volumes within thebody. Besides, radiation therapy is usually only applied radically in the treatment of tumors large enoughto be imaged (typically >1 cm diameter) which limits the usefulness of the radiation in dealing with dissemi-nated disease. More importantly, the biological differences in the response of normal and tumor cells are


generally rather small—slight differences in intrinsic cellular radio-sensitivity and in repair capacities. Conse-quently, the therapeutic differential between normal tissues and tumors is quite narrow, and there exist toomany tumors, which cannot be cured by tolerable doses of radiation. Much research work is now directedto 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 toradiation therapy. The basic idea is to deliver higher radiation doses to tumor than normal cells by means ofradioisotopes chemically conjugated to tumor-seeking targeting agents. The targeted radiation therapyrequires a ‘targeting agent’ capable of seeking out tumor cells and delivering to them a radioisotope whichprovides the irradiation. The selectivity of the treatment depends on the ability of the targeting agent todiscriminate malignant from normal cells. The cell killing effectiveness depends on the ability of the agentto penetrate tumor masses and the absolute amounts of radio-nuclide, which can be delivered to those cellsthat are successfully targeted.

In 1975, the prospects for targeted radiation therapy received a boost with the advent of monoclonal anti-body technology [106], which offered the possibility that targeting molecules (monoclonal antibodies) could beobtained which would recognize small differences between molecular groups on the surface of normal and can-cer cells. More than two decades of extensive international scientific efforts have proved rather disappointing.The major difficulties have been: less than perfect discrimination between cancer and normal cells, poor uptakeof absolute amounts of antibody in tumors, heterogeneous intra-tumor distribution of antibody and poorpenetration of antibodies within solid tumors.

During the past few years, a new strategy of genetic radiation therapy has appeared on the horizon. Thisstrategy builds upon growing knowledge of the genetics of cancer cells and how they differ from the cells ofnormal 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 differential byincreasing the radiation sensitivity of tumors or by reducing the radiation sensitivity of normal tissues. Thereare several approaches by which genetic manipulation could enhance the therapeutic efficacy of radiationtherapy [107].

With the availability of monochromatic radiation sources, the photon activation therapy has recently beenintroduced, in which a cascade of Auger and photoelectrons is created in the tumor during irradiation by amonochromatic radiation beam (e.g. X-rays). The targets in the tumor cell are the strands of DNA, whichare broken leading to lethal damage to the tumor cell. This is a two-step therapy, where a sufficient concen-tration of a high-Z containing compound is physiologically directed to the tumor. Monochromatic radiationwith energy slightly above the K-absorption edge is then targeted on the tumor, and the Auger electronsdeposit 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 thetumor cell produced by the monochromatic X-ray beam. The physical explanation of the mechanism involvesthe 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 experimentswith 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 effective 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 energyis higher (about 80 keV), and the number of Auger electrons is larger. The basic difficulty of the method is thatthe range of the Auger electrons is very small, a few tens of nanometers only, so that the heavy absorbing atomshould 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 uptakeand limited penetration of most agents in solid tumors result in targeted radiation therapy having only afew 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 developmentin 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 (contrastagents or molecular probes) as well as ‘smart’ drugs (target-specific ‘poisons’ and/or biomedical ‘bombs’) atnanometer 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 ofincreasing interest in recent years. It is shown that electromagnetic fields are intrinsic in living organismsdue 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 fields are closely related to phys-iological and pathophysiological behaviors of the living organisms, and their signal levels, though quite weakin general, are strong enough to be detected by modern detectors. Thus, these endogenous EM signals in livingorganisms 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 toforces and stresses, which may be originated from pressure forces linked to gravity to motional forces andfrom electromagnetic forces arising from molecular interactions, environmental and externally applied EMfields. These forces and EM fields are likely to modify cellular behaviors and affect physiological behaviorsof the living organisms. It is therefore of both scientific and practical interest and importance to study theo-retically and experimentally the bioelectromagnetic, mechanical and their coupling phenomena in livingorganisms, including their correlations with biochemical processes that may be initiated and/or activatedby these forces and/or EM fields.

Some issues related to bioelectrodynamic modeling of living organisms are reviewed. It is emphasized thatbioelectrodynamic modeling of ion-channel flow dynamics at the cellular level are important and the collectiveproperties and behaviors of living cells may deserve special attention, in which interaction of cells and exo-genous EM fields as well as thermal noise effects may have to be taken properly into consideration, especiallywhen low field 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 different from those of conventionallyman-made materials deserve also special attention in the modeling of living tissues.

Since mechanical forces and exogenous EM fields may affect physiological properties and behaviors of liv-ing organisms, if used properly, these forces and EM fields can be utilized for biomedical applications, such asbiomedical imaging and therapy. Some recent biomedical imaging and therapeutic methods with the aid ofbioelectrodynamic 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 inEM fields and mechanical actions, and amazing signal amplification functions may not only cause complexityand variety of the biological world, but also create opportunities for technical innovations in biomedicine toimprove future quality of human life. Bioelectrodynamics in living organisms is indeed a very challenging andpromising research field 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 financial 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 Universityfor 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 isgreatly acknowledged.


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