Bioelectrodynamics in living organisms

International Journal of Engineering Science 44 (2006) 67–92 www.elsevier.com/locate/ijengsci

Bioelectrodynamics in living organisms Shu-Ang Zhou a

a,b,*

, Mitsuru Uesaka

a

University of Tokyo, Nuclear Professional School, Graduate School of Engineering, 2-22 Shirane Shirakata Tokai-mura Naka-gun, Ibaraki 319-1188, Japan b National Institute of Radiological Sciences, Chiba, Japan Available online 27 December 2005

Abstract This article introduces an interdisciplinary subject of bioelectrodynamics in living organisms and its related research challenges and opportunities. Bioelectrodynamics in living organisms is aimed to reveal critical roles of electromagnetism and mechanics in biology, to correlate biophysical functions of living organisms with biochemical processes at the cellular level, and to introduce theoretical basis and methodology, such as modeling and simulations, for stimulating technical innovations and promoting technology development in biomedicine as well as for the study of human healthcare issues related to environments among others in our modern society. The article reviews some important issues in bioelectrodynamic 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 conventionally man-made materials. Possible biological effects and potential biomedical usages of endogenous and exogenous electromagnetic fields and mechanical stresses in living organisms are also reviewed, which indicate promising future of biomedical imaging and therapeutic methods based on bioelectrodynamic techniques. The fact that living organisms may have well-organized structures, actively controlled actions and responses, extremely sensitivity in electromagnetic fields and mechanical actions, and amazing signal amplification functions may not only cause complexity and variety of the biological world, but also create opportunities for technical innovations in biomedicine to improve future quality of human life.
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 pathophysiological behaviors of living organisms. It is aimed to reveal critical roles of electromagnetism and mechanics in biology, to correlate biophysical functions of living organisms with biochemical processes at

* Corresponding author. Address: University of Tokyo, Nuclear Professional School, Graduate School of Engineering, 2-22 Shirane Shirakata Tokai-mura Naka-gun, Ibaraki 319-1188, Japan. Tel.: +81 29 287 8480; fax: +81 29 287 8488. E-mail address: [email protected] (S.-A. Zhou).

0020-7225/$ - see front matter
2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ijengsci.2005.11.001

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the cellular level, and to introduce theoretical basis and methodology, such as modeling and simulations, for stimulating technical innovations and promoting technology development in biomedicine as well as for the study of human healthcare issues related to environments among others in our modern society. In living organisms, cells and tissues are constantly subject to forces and stresses. These forces and stresses have various origins from pressure forces linked to gravity to motional forces, and from electromagnetic forces arising from molecular interactions, environmental and externally applied electromagnetic (EM) fields. These forces and EM fields are likely to modify cellular behaviors, the synergetic properties of which may also affect physiological behaviors of the living organisms. One can imagine if there were no sunlight and geomagnetic fields, there would be no high-level living organisms on the Earth. The biological effects of electromagnetic fields are definitive and crucial to the formation of human beings. The fact that motion and mechanical training of a human body can affect significantly the physical performance and health status of the human body is also well known. On the other hand, these forces and EM fields, including their energy and power, may also be manipulated and utilized properly for therapeutic purposes in biomedicine, provided that one had proper understanding of the mechanisms involved in the interaction processes in any specific application. This is indeed one of the main objectives of the bioelectrodynamics to discover, via both theoretical and experimental efforts, those biophysical mechanisms of critical importance to the human life and health. The ideas of using electromagnetic means for therapeutic applications in medicine already existed since the 18th century when our knowledge about AC currents, transformers and related electrical machines were rapidly developed during that period. However, due partly to the premature of those devices and partly to the widespread introduction of antibiotics, improved surgical techniques and other competing therapies after World War II, those early ideas and techniques did not flourish. Today, with our increasing knowledge about bioelectromagnetic phenomena in living organisms, especially at the cellular level, and the rapid development of advanced technologies, such as microsystems and nano-technology, there is an increasing interest to explore novel therapies based on bioelectrodynamic technologies with possible combination of other well-established techniques in biomedicine. In this article, some of recent bioelectrodynamic imaging techniques and bioelectrodynamic therapies that could be of potential interest for further exploration will be reviewed. Some issues and important research results on biological effects of electromagnetic radiations on living organisms and related 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 fishermen who 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 the electric phenomena in living organisms, their origins and possible usages in medicine started later in the 18th century. 2.1. Galvani’s animal electricity Luigi Galvani, a professor at Bologana, first observed in 1786 that electricity caused a dissected frog’s leg muscle to twitch and claimed that he had demonstrated the existence of animal electricity. On the basis of his findings (and of the results of a multiplicity of studies in which experimental conditions were varied), Galvani came to the conclusion that some form of intrinsic electricity was present in the animal, and that connective nerve and muscle together, by means of conductive materials, induced contractions by allowing for the flow of this internal electricity. Galvani’s claim was however challenged by his country man, Alessandro Volta, a physics professor at Pavia, who argued that the electricity was artificial, arising from a potential difference when two dissimilar metals were in contact. In the middle of 19th century, the successors of Galvani at Bologna, such as Carlo Matteucci, a physics professor at the University of Pisa, had demonstrated that living organisms did indeed produce a small, but definitive electric current [1,2]. Further studies found that, in contrast to animal experiments, plants, even

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the touch-sensitive mimosa, could not be electrically stimulated. This fact had led to the conclusion of Von Humboldt [3] that the ability to be excited by electricity is a general property of animals. Since then, efforts began both to understand how these signals were produced and propagated along the neurons and to improve instrumentation for detecting and recording these signals. According to Galvani, animal electricity exists in a state of ‘non-equilibrium’, which is generated by a particular machine. We now know that this machine corresponds to the cell membrane with its complex organization of ionic pumps and ion channels. This peculiar ‘machine’ creates dissimilar Na+ and K+ concentrations, and converts concentration gradients into an electric potential difference between the intracellular and extracellular medium. The later invention of the voltage-clamp technique [4,5] made possible to study experimentally membrane events underlying the generation of action potentials. As we now know, although signaling in nerve and muscle is a genuine electric process, it differs profoundly from the simple ‘passive’ conduction along electric cables, which would predicted a signal propagation speed close to the speed of light that was not observed by experiments. On the contrary, it appears to be an ‘active’ process, which depends on a particular form of electrical energy, accumulated between the interior and the exterior of the nerve fiber, as a consequence of physiological processes clearly ‘‘belonging to the domain of life,’’ a true ‘‘animal electricity’’ with characteristics corresponding to the fundamental intuition of Galvani. Today, it is fair to say that Galvani’s studies had laid down the foundation of electrophysiology, a science that in recent times has had a development comparable to that of the physical study of electricity in the first half of the 19th century. On the other hand, Volta’s experiments had led to the invention of the electrical battery, the famous Voltaic pile, which opened a new path to the tremendous subsequent development of physical investigations of electricity, electrochemistry, 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 forces between atoms and molecules are largely electrical, just like those in non-living natural or man-made materials. The main difference between living organisms and materials is that the electrical force in the living organisms can be actively controlled. Proper understanding of such a difference is crucial in our later discussion about 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 ionically different from the water and having electrogenic processes in the gills, mucous membranes and skin. For instance, catfishes and sharks have electrosensory (electroreceptor) organs, which can detect very low-frequency signals with spectral frequency components between DC and 100 Hz. It was demonstrated that freshwater catfish is surrounded by stationary electrical DC fields upon which AC components related with respiration are superimposed [6]. Such fields have been found in many aquatic species, and they reveal electrically the presence of an individual to other electrosensitive species. For the catfish it has been demonstrated that such fields can be used for the detection and recognition of prey. It has also been demonstrated that catfish can feel each other electrically [7–9]. Electric fishes generate electricity through their electric organs and membrane processes that are similar to those involved in electrical phenomena of other animals, but, unlike them, these fishes can produce large potential differences at their body surface, and thus affect other animals living in their habitat. Normally this occurs because the individual cells in the stacks of electrocytes are asymmetrical, maintaining a constant resting potential across one face (normally not innervated), while a command from the central nervous system (CNS) generates a brief electrical response in the other face, which receives a strong innervation (nervous face). This was first explained in experiments carried out on the electric eel, soon after intracellular recording electrodes were available. In electric eels, this response is a normal Na+-dependent reversal of the membrane potential, so that on open circuit, each electrocyte contributes about 150 mV at the peak of the spike. In some fishes, there can be several thousands of such electrocytes in series, which could be fired synchronously (see Fig. 1). An electric eel is such an example of having the capability of generating violent discharge at high voltages up to several hundreds of volt. The phenomenon that controllable and synchronous action of living cells may create unexpected physical consequences may remind us some extreme physical performance made by

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firing state +−

…

+− +−

+−

V (mV)

50

electrocyte

0

2

4

6

-50 Time (ms)

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 mechanisms 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 produced by a static generator. Actually, Galvani had already noticed the muscle contractions caused by the spark elicited from an electrical machine separated from the frog [2]. Based on these results, in 1890s, Nikola Tesla had started his study on possible use of RF energy for medical and health related purposes, while his most known work was on the AC frequency based transfer of electrical power. In particular, Nikola Tesla noticed the heat caused by high-frequency current, which may have impact on a living organism and led to the field of diathermy. The diathermy, treatment of internal tissue by heating without burning the skin, through means of electromagnetic radiation, continued to develop through the 20th century, with various frequencies being applied. Tumors were one illness treated locally in this way, and in the case of infection the whole body could be heated. At about the same time, a French scientist, Arsene D’Arsonval made similar work on potential use of electricity in medical cares, and made his mostly well-known remark in 1896: ‘‘I am convinced that the therapy of the future will employ heat, light, electricity and agents yet unknown. Toxic drugs shall cede their place to physical agents, the employment of which at least has the advantage of not introducing any foreign body into the organism.’’ As we know today, such a statement has not been realized. On the contrary, for instance, the popularity of Tesla’s diathermy waned after World War II with the widespread introduction of antibiotics, improved surgical techniques, and other competing therapies. A large drug industry based essentially on various types of chemicals and their compounds has instead been developed. In spite of some controversy stories in the history of drug industries, we are now seeing gradually the entrance of physical means used in medical cares with the rapid progress and development of advanced technologies, such as the nano-technology, material science and electromagnetic techniques among others. We may foresee the combined usage of traditionally chemical-based drugs and modern techniques based on physical means, their related instrumentations and smart systems of targeted drug delivery to reduce toxic side effects of chemicals in living organisms. In this respect, the theory of bioelectrodynamics and its related techniques will play a role of increasing importance in future biomedicine, 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 signals not only in animals for understanding the intrinsic mechanisms of these electrical activities inside the living organisms, but also in human bodies in order to find correlations of these bioelectrical signals with disease conditions 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.

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3.1. Electrocardiogram and cardiac pacemaking As early as 1875, the electrical activity of the brain in the absence of muscle motion was observed. The heart, meanwhile, as an active muscle with somewhat stronger signals, was closely studied though initially with animal experimentation. The instrumentation to measure these relatively weak signals non-invasively was however developed rather slowly. In 1878, Theodore Wilhelm Engelmann in Utrecht produced the first plot of a primitive electrocardiogram (ECG), and 10 years later the Englishman A.D. Waller recorded the first plot of a human ECG from the body surface [10]. Potential significance of the ECG to clinical applications was noticed later by Willem Einthoven in 1900, who discovered the mechanism of the electrocardiogram, for which he received the Nobel Prize in medicine in 1924 [11]. The ECG is undoubtedly a medical diagnostic device, which has received the earliest and most intensive study. Considerable effort is devoted to the inverse problem of determining cardiac activity from the surface ECG. 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 activity at the membrane for which models incorporating the kinetics of ion movement have also been developed to aid our understanding of the electrical activity of the heart. As we know now, the heart is a blood pump. The timing of the pump is determined by electrical events. Malfunction of the pumping action of the heart may lead to morbidity and death. Sudden cardiac death accounts for almost 20% of all deaths from natural causes in developed countries. Present evidence is that 80–90% of these persons died because of an arrhythmia culminating in cardiac arrest or ventricular fibrillation where electrical activity is uncoordinated and pumping action is lost [12]. The therapy for fibrillation is to deliver a large pulse of current into the heart from a defibrillator. Many victims of sudden cardiac death can now be resuscitated in the hospital. Nowadays, a commonly used therapeutic device is the artificial pacemaker, which delivers electrical pulses to the heart to correct 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), which may be detected on the skin overlying the muscle. Compared with ECG, the EEG (or EMG) signals are much weak, but detectable by modern electronic instruments. An EEG can show what state a person is in asleep, awake or anaesthetized because the characteristic patterns of current differ for each of these states. Certain brain abnormalities can also be detected by observing changes in the normal pattern of the brain’s electrical activity. A major drawback of the EEG is that they cannot show us the structures and anatomy of the brain or really tell us which 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 in concert to allow us to perform our daily activities and to meet challenges. This cooperation is achieved partly by cells communicating with each other through electrical and/or chemical signals. For instance, the heart beats spontaneously and rhythmically, unlike skeletal muscle, whose contraction is triggered by motor neurons. 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 tissues. The chemical signals may attach to specific recognition molecules, receptors, on the cell surface. These receptors then transmit the signals to the interior of the cell. The discovery of such mechanism of action of hormones by Earl Sutherland at Vanderbilt University in USA was awarded the Nobel Prize in Physiology or Medicine in 1971, who showed that the signal that is used to communicate between cells (‘‘the first messenger’’) is converted in the cell membrane to a signal that acts inside the cell (‘‘the second messenger’’). Since then, one has been wondering if there were any more basic mechanisms behind the highly selective structural binding between signaling molecules and the receptors, characterizing the specific features of the chemical signal communication. No clear answer has yet been obtained, although some studies on allergy patients have revealed that there might exist an interchangeable relationship between chemical stimuli and electromagnetic stimuli [13,14].

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4. Biomagnetic signals in human body, MCG and MEG

SQUID

10-15

fT

10-14

Human heart

Muscles

Human eye

Human brain

Time-varying electrical potential fields on the body surface, caused by the heart (or brain) from small currents by electrically active cells of the heart muscle (or neurons) can be recorded as the ECG (or EEG) with the aid of electrodes and amplifiers. According to the theory of electrodynamics, it is known that time-varying electric 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 the electromagnetic principle was known a long time ago, the first successful recording of the biomagnetic signals from heart activities, the magnetocardiogram (MCG), was made by Gerhard Baule and Richard McFee at Syracuse University in 1963, using an induction coil magnetometer [15]. Later, in 1970, David Cohen et al. at the Massachusetts Institute of Technology (MIT) first used the superconducting quantum interference device (SQUID) to record the magnetocardiogram [16]. As expected, the biomagnetic fields measured are rather weak. The human heart is the strongest biomagnetic source but still the highest feature in the MCG has the amplitude of less than 100 pT, about 10 6 of the geomagnetic field. With the aid of the extremely sensitive SQUID magnetometer, the measurement of biomagnetic fields of the brain was first carried out at MIT by David Cohen in 1972, who successfully recorded a human magnetic alpha rhythm with a satisfactory signal-to-noise ratio [17]. A few years later, magnetic signals associated with brain activity evoked by peripheral sensory stimulation were also detected [18]. The magnetoencephalography (MEG) is methodologically closely related to MCG. Instead of the heart, the brain is being examined. Although the detailed structure of the human head is quite complicated, the main building blocks of the brain are neurons and glial cells. The brain active process is associated with a primary current source related to the movement of ions due to their chemical concentration gradients across the neuron cell membrane. In addition, passive ohmic currents are set up in the surrounding medium. This so-called volume current completes the loop of ionic flow so that there is no build up of charge. The magnetic field is thus generated by both primary and volume currents. The biomagnetic signals created by neuron activities in human brains are typically 50–500 fT, which is about 1000 times smaller than that of the biomagnetic signals from the heart. Indeed, it has been a challenging task for developing proper measurement techniques and related systems for detecting such weak biomagnetic signals in the brain. Actually, it was only in the second half of the 1990s that systems able to simultaneously map magnetic 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 basic functions of the brain, exploring both the primary and secondary sensory areas, and the cognitive functions, such as those associated with memory, attention, language, etc. Additionally, the availability of large systems has raised the interest of clinicians and today the MEG is used routinely in numerous hospital laboratories as a methodology complementary to PET and fMRI to investigate brain diseases such as epilepsy, Parkinson’s disease, 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). For instance, ionic currents in the eye may give rise to a field of about 10 pT, which may change during eye movements 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 magnetic field measurements, even though low-temperature environment is necessary for the operation of SQUIDs.

MMG MCG MEG MOG 10-13

10-12

pT

10-11

10-10

Urban noise

10-9

10-8

10-7

nT

Fig. 2. Range of biomagnetic fields.

Earth field

10-6

µT

10-5

10-4 (Tesla)

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5. Bioelectromagnetic signals in living organisms The functioning of the heart, brain or other organs results in oscillations in the ELF range of the electromagnetic spectrum. The bioelectric and biomagnetic signals in the ECG, EEG, MCG and MEG discussed above have frequency components of interest up to about a few kHz, which are all rather limited at the low-frequency side of the electromagnetic spectrum. These bioelectric and biomagnetic phenomena are commonly modeled as quasi-static cases, in which the electric and magnetic fields can be studied separately. However, further study of living cells has revealed that under certain conditions, such as cell growth and mitosis, living cells may also transmit ultra-weak high-frequency electromagnetic waves (photons) (e.g., a few hundred photons per cm2 per second at near infrared frequencies), the intensity of which depends on functional status of the cells. Furthermore, it has been shown that cells in culture might transmit and receive signals carried by EM radiation, which may control the orientation and migration of the cells [20]. However, the origin and putative roles of this ‘‘rudimentary cell vision’’ are largely unknown. It is also not yet known whether these biological EM phenomena exist in higher organized structures such as the brain and whether they may play a role in intracellular communication under physiological or pathological conditions. Early study of the cell-to-cell communication by electromagnetic waves (signals) may be traced back to the work of the Russian scientist Gurwitsch in 1920s. In his experiments, Gurwitsh could show the induction of mitosis from the tip of an onion root to the shaft of a second onion root. He found that the induction worked when the second root was in a quartz tube, which is transparent for ultraviolet (UV) light but not when it was in a glass tube, which is opaque for UV light. From this result, he concluded that it was UV-light causing the effect, which he called ‘‘mitogenetic radiation’’. However, at that time, he could not directly measure the UV photons emitted by the onion root, as he expected, due to the lack of proper instruments to detect such weak UV photons. With the invention of photomultipliers (PM) in 1950s, it became then possible to detect ultraweak photon emissions in the visible region. In 1960s, Konev and coworkers were among the first to report the detection of UV photon emission from living organisms by using the UV-sensitive photomultiplier tube [21,22]. Later detection of photon emissions in various types of living organisms by a number of scientists with much improved version of PM detectors has been made for the detection of ultra-weak photon emissions in the spectral region of 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, one may wonder what the mechanism is for such generation of ultra-weak photons in living systems. By the end of 1930s, as a result of extensive studies with the participation of prominent physicists and chemists, it was concluded that the emission of photons by living systems could be considered as a kind of chemiluminescence due to the recombination of the free radicals, which appear in a number of chemical reactions [23]. Thus, one had further wondered if such an ultra-weak photon emission could simply just be the waste of bioenergy, or contain really some specific bioinformation that may play a regulatory role in living systems. At present, although researches in the field have not yet reached the state required for the ultimate verification or falsification of the hypothesis on the biophotonic information in cell division and other cell physiological processes, as originally investigated and suggested by Gurwitsch, the search for evidence of the ‘informational character’ of ultraweak photon emission from biological systems continues. In particular, having stimulated by the thought of bioinformative characteristics of the ultra-weak photon emissions in living organisms, the German scientist, Fritz-Albert Popp introduced the concept of biophotons in 1976 [24]. Like bioluminescence, which specifies luminescence of biological systems, biophotons refer to the biological system as a whole. From the view of the theory of living cells and their division in living organisms, on average, every human being consists of trillions of cells, which are generated by many successive rounds of cell doublings for a human being to reach its adulthood. In every individual, every second, millions of cells may die and must be replaced in a short period of time. It cannot be predicted where and when a cell will die, but if the replacement rate were to be only slightly lower (or higher), the body would disintegrate quickly. It has been argued that if the growth regulation of biological systems were based on information originating from the death of cells, it would not be possible to explain this regulation by messenger molecules from individual cells. Rather, electromagnetic interactions are suited for transferring the necessary messages and have to take the role of regulators of a biological system in order to explain many, if not all regulatory functions [25]. To understand and analyse the complex biological phenomena in living organisms, and their interaction

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and communication, it is of both scientific importance and practical interest to study possible roles and communication 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 well known. Others like lightning, sunlight and cosmic radiations are also sources of environmental electromagnetic fields. Nowadays, in our modern society, electromagnetic fields are constantly generated by man-made devices, such as mobile phones, microwave ovens, TV apparatus, electrical heaters and electrical power transmission lines among others. These electromagnetic fields external to living organisms cover a wide range of frequency 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 well known that high-energy photons, such as X-rays (keV) and c-rays (MeV), may cause ionization of atoms or biomolecules, such as proteins and DNA, in living organisms. These ionizing radiations are biologically harmful since they may destroy the capacity for cell reproduction or division or cause cell mutation. Some delayed 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 applications, 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 radiation includes the spectrum of ultraviolet (UV), visible light, infrared (IR), microwave (MW), radio frequency (RF), and extremely low frequency (ELF). A widespread belief is that non-ionizing radiation or electromagnetic fields have essentially no effects (or no significant biological effects) on living organisms as long as the applied field intensity (energy) is much less than the ionizing energy of biomolecules or the energy that may heat significantly the biological tissues. Such thresholds for weak EM field effects in biological systems have been studied based on the analyses of thermal fluctuations, leading to the thermal noise limit in physical theories and the molecular shot noise limit in biochemical processes according to currently known biophysical mechanisms for coupling fields to ongoing, metabolically driven biochemical processes [27,28]. These research results indicated that unless large, organized, and electrically amplifying multicellular systems such as the ampullae of Lorenzini of elasmobranch fish are involved, possible effects of weak ELF electric and magnetic fields (10 4 T) in human implicated by epidemiology could not be explained by the currently known biophysical 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, and amazing signal amplification functions, all of which may contribute to our knowledge about the fact that non-ionizing radiation found in our environment can pose a considerable health risk to us if not properly controlled. Great efforts have been made in studying potential biological effects of non-ionizing radiations on human health. Recent epidemiological studies and other evidences have implicated long-term exposure to non-ionizing EM fields, such as those emitted by power lines, in increased health hazards. These hazards may include, for instance, an increased risk in children of developing leukemia [29]. Many regulations have therefore been formulated in order to prevent potential risks. There are however still many unknown cases due to the complexity of living organisms interacting with EM fields. Careful researches have demonstrated that electromagnetic fields of very tiny energy could have profound biological significance and biological effects of EM 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 emphasized in public researches. On the other hand, if used properly, electromagnetic fields can be beneficial to living organisms. We are living in the world under constant exertion of electromagnetic fields. The evolution of human beings as well as other living organisms on the Earth has a long history. One can imagine if there were

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no sunlight and geomagnetic fields, there would be no high-level living organisms. The biological effects of electromagnetic 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 and other celestial bodies. Sunspots and cycles of the Moon may cause changes in ionospheric currents and geophysical fields, which in turn influence the fields within us. The geomagnetic field (GMF) may also be disturbed by magnetic storms, which may vary from 35 lT in the equatorial areas, where it is mainly parallel to the terrestrial surface, to 70 lT in the vicinity of the magnetic poles of the earth, where it is near-vertical. The GMF and its biological 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 from it [34]. The possible connection between the orientations of birds (e.g., pigeons and sea gulls) to the GMF is widely known [35–37]. The usefulness of the biological effects of EM fields and radiation may also be noticed from the well-known function of the human eye, which gives us vision images of the colorful world through the detection of photons of variety of frequencies in the visible range of EM spectrum. The human eye is just one of the sensory systems that enable the living organisms to build up an accurate image and awareness of itself in relation to its surroundings 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 the well-known five senses, human beings may have counterparts to less familiar sensory systems characterized in other living organisms. These sensory systems may respond to environmental factors other than visible light, molecular shape and/or air motion. Further scientific investigations are however required to reveal these mechanisms [38]. Obviously, during many years of evolution, living organisms have lived with natural EM fields and radiations in harmony, and have made use of EM fields and radiations. One may wonder what could happen if such a harmony would be disrupted by externally man-made EM fields. The consequence could be either positive or negative to human health, as one may expect. For instance, recently there are reports indicating that external EM excitation may affect functions of the brain, such as cellular signalling or permeability of the blood–brain barrier among others [39–41]. Reported biological effects of low intensity non-ionizing EM fields on living systems have so far led to two application areas. One is related to therapeutic, diagnostic and biological applications. The second area concerns the updating of the database for EMF safety standards, eventually going beyond the current mechanistic assumption that is based on the disruption of metabolism due to the electromagnetic power deposition in biological tissues. In connection with the recently rapid progresses in nano-technology, nano-electronics and micro-/nano-systems, the study may also lead to innovative biomimetic 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, requiring interdisciplinary knowledge and insights into the complex biological world. Physicists have had good experience and knowledge to model natural or man-made materials, where mathematics plays an important role to analyze and quantify scientific measures of material properties and behaviors under various conditions. To model physiological behaviors and properties of living organisms, further interdisciplinary research efforts across several scientific fields will however be required. In this article, we shall focus our attention to some issues related to bioelectrodynamic modeling of living organisms. Here, the bioelectrodynamic modeling implies not only the modeling of electromagnetic properties and behaviors but also the modeling of mechanical properties and dynamic behaviors of the living organisms, including electromagneto-mechanical coupling effects of importance. This is necessary because, in living organisms, cells and tissues are constantly subject to forces and stresses. These forces and stresses may have various origins from pressure forces linked to gravity to motional forces and from EM forces arising from molecular interactions, environmental and externally applied EM 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 of which may also affect physiological behaviors of the living organisms. The facts that motion and mechanical training of a human body can affect significantly the physical performance and health status of the human

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body and that the sunlight from EM radiation has significant influence on the life of living organisms on the Earth are well known. On the other hand, these forces, energies and powers may also be manipulated and utilized properly for therapeutic purposes in biomedicine, provided that one had a good and deep understanding of the mechanisms involved in the interaction processes in any 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. From the unicellular bacteria to multicellular animals, the cell is the organizational principle for biology. The development of organs from cells and its regulation are important subjects in themselves. Since the cell is the basic building block of living organisms, physical modeling of cells is an important subject. At the cell level, many theories and mathematical modeling approaches from classical physics could be utilized by consideration of the fact that the size of a cell is typically 10–100 lm, though the cell sizes may vary depending on the cell type and circumstances. For instance, a human red blood cell is about 7.5 lm in diameter, while some neurons are about 1 m long (from spinal cord to leg). In physiology, it is known that properties and behaviors of ion channels located at cell membranes play a critical role in regulating the life process of biological cells and therefore health status of the human body. Most of medicines developed today are based on some ways of affecting the ion channel behaviors at the cellular level. Studies have shown that living cells may have several different ways of regulating their ion channel behaviors. These include the ligand-gated ion channels, whose permeability to ions is increased by the binding of a specific ligand (e.g., a neurotransmitter at a synapse), the voltage-gated ion channels, whose permeability to ions is extremely sensitive to the transmembrane potential difference, and the mechanically gated ion channels, 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 discovered the mechanism of action of hormones and showed that signals used to communicate between cells (the first messenger) is converted to a signal that acts inside the cell (the second messenger) and such a conversion occurred in the cell membrane. In other words, the chemical signals (e.g., hormones as signal molecules) attach first to specific recognition molecules, receptors, on the cell surface, which then transmit the signals to the interior of the cell. For his discovery, Earl Sutherland was awarded the Nobel Prize in Physiology or Medicine in 1971. However, the transduction process of the signals in cells was unclear until Alfred G. Gilman and Martin Rodbell made their discovery of the so-called G-proteins and their role in signal transduction in cells. In particular, Gilman and Rodbell found that G-proteins have the ability to activate different cellular amplifier systems, which may receive multiple signals from the exterior, integrate them and thus control fundamental life processes in the cells. A cascade of reactions enables a single molecular event at the cell surface to initiate, accelerate, or inhibit biological processes. This is possible because of amplification. The significance of the amplification was recognized by the 1994 Nobel Prize in Physiology or Medicine, awarded to Gilman and Rodbell. Recently, there appear also some fresh thoughts about possible effects of electromagnetic interaction in such signal transduction process. A tiny field, far too weak to power any cellular activity, may trigger a change at the regulatory level, which then leads to a substantial physiological response that is carried out using the energy of cell metabolism [43]. Various components of the regulatory cascade, including receptors, calcium channels, and enzymatic processes within the cell are sensitive to EM fields. The electromagnetic forces at the membrane’s outer surface could modify ligand–receptor interactions (e.g., the binding of messenger molecules such as hormones and growth factors to specialized cell membrane molecules called receptors), which in turn would alter the state of large membrane molecules that play a role in controlling the cell’s internal processes [44]. New research is revealing how free radicals, including nitric oxide, are involved in the coupling of EM fields to chemical events in the signal cascade. Again, the medical importance of this research was recognized by the 1998 Nobel Prize in Physiology or Medicine [45]. The other two types of the voltage-gated ion channels and the mechanically gated channels are evidently related to electromechanical phenomena at the cellular level. These evidences suggests that the cell membrane can be one of the primary locations where applied EM fields and forces act upon, causing a variety of biological effects observed on the macroscopic scales. Experiments to establish the full details of a mechanistic chain of events however are just beginning

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with the aid of advanced measurement techniques available nowadays or to be developed in the near future. In connection with experimental efforts, proper theoretical models are required to give a comprehensive explanation for the experimental data. Efforts of bioelectrodynamic modeling of ion flow dynamics in different ion channels at the cellular level are therefore necessary and required. While modeling of behaviors of individual ion channels is of importance, the collective properties and behaviors of living cells may deserve special attention, in which interaction of cells and exogenous EM fields as well as thermal noise effects have to be taken properly 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 conducting medium. At these scales, it is convenient to model the tissue as a continuum since biological tissues and organs are composed of many atoms, molecules and cells. Classical Newtonian mechanics and electrodynamics 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 rheological behaviors of living cells, which are important features of living cells [49], the viscoelastic model has been used with a few characteristic relaxation time constants that could be determined experimentally [50]. Besides, thermodynamic approaches have also been used to model mechanosensitive ion channels, in which possible effects of membrane stiffness, thickness, spontaneous curvature or changes in channel shape, length or stiffness could all be taken into consideration [51]. Since 1960s, continuum biomechanics has been developed as a distinct field of study and contributed to our understanding of human health as well as to disease, injury and their treatment. According to Fung [52], biomechanics is defined as the mechanics applied to biology. Fung’s pioneering work on mechanical modeling of blood flow and lung’s soft tissues among others are very interesting [53]. Although biomechanical properties and behaviors of biological media are important subjects to be studied, bioelectromagnetic behaviors and bioelectrochemical properties of the living organisms are extremely important for us to understand, to manipulate and to make use of the fascinating biological phenomena in living organisms, for which interdisciplinary research efforts are greatly desired. This is because, unlike man-made materials, bioelectrical, biomechanical and biochemical phenomena in living organisms are generally coupled and have to be studied synergetically, though some 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) and platelets (thrombocytes) mixed in the blood plasma. The blood plasma is found to behave like a Newtonian viscous fluid with a coefficient of viscosity almost twice as high as that of water due to dissolved macromolecules [53]. Unlike its plasma, the whole blood has characters of a non-Newtonian fluid. Like any fluid in the continuum 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 other words, negative feedback mechanisms may exist, which down regulate viscosity-related genes in the case of elevated blood viscosity. Although knowledge about such mechanisms is scant, some evidence exists. Besides, blood cells have some interesting physiological and physiochemical properties to keep them alive in the circulatory system for a long time. These include their surface characteristics (e.g., surface charge, membrane phospholipid composition, surface antigens) as well as bulk properties (e.g., shape and their extent of deformability). For instance, red blood cells may avoid macrophage surveillance. Their deformable nature also allows 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 its in vivo characteristics. Experimental measurements have shown that both the dielectric permittivity and electric conductivity of the blood are frequency-dependent. For instance, for cow and sheep blood with a haematocrit level of about 40%, it was found that the relative permittivity of the blood has a value of about 1370 at 1 MHz and decreases to a value of 50 at 1 GHz frequency. The conductivity has a value of about 0.7 S/m at 1 MHz and increases to a value of about 1.3 S/m at 1 GHz [54].

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7.2.2. Bone Bone is perhaps the only tissue that can be considered as a solid material in the living organism due to its strong and solid nature. Actually, a live bone is not a simple solid, but involves also a fluid phase. Bone fluid has many functions. It transports nutrients to, and carries waste from the bone cells (osteocytes) buried in the bony matrix. It is also involved in the transport of mineral ions to the bone tissue for storage and retrieval of those mineral ions when which are needed by the body. Recently, the bone-fluid flow has been suggested to have a role in bone’s mechanosensory system, in which bone deformation causes the bone fluid to flow over the bone cell membrane, where the shear stress of the flowing fluid is sensed [55]. In general, bone is an anisotropic medium containing several phases, such as the collagen, the mineral (e.g. hydroxyapatite), the pores, the interstitial fluid and blood. As a live bone, it can change, grow or be removed by resorption, and the bone-fluid circulation can transport materials to and from the bone. It has been estimated that the collagen occupies about 50% of the volume in compact bone, the mineral 40% and the pores 10% [56]. Thus, macroscopically, the bone may be modeled as an inorganic–biooganic composite material [53]. Poroelasticity theory has also been introduced to 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 are subjected to forces, which may be time varying. The bone motion consists physiologically not only of compression, tension and shear, but also a bending moment, which, for long compact bone, may produce a stress or strain gradient. In the wet state of bone, the strain gradient can produce a combination of responses, involving piezoelectricity, interfacial polarization, streaming potential and non-centrosymmetric charge displacement, which may also be temperature- and/or frequency-dependent. The existence of piezoelectricity in dry and wet bones has been known since 1950s [58]. The stream potential has also been considered to be a major electromechanical effect arising from the flow of ion-interstitial (ion-containing) fluid (electrolyte) through a flow channel within the bone, which may be driven by, for instance, the deformation of the bone under external forces [59]. The electromechanical properties of bone play an important role in the development and growth remodeling of the skeleton, a hypothesis made plausible by the observed role of electrical stimulation of bone healing [60]. Besides, stress-related biochemical activity of calcium my also contribute to the remodeling process as it was shown that the solubility of the hydroxyapatite crystals may change in response to stresses [61]. Although the subject of electromechanical properties and behaviors of bone has been studied extensively for about half a century, new research efforts are still made to study bone structures and properties at nano-scales and to explore potential applications of nano-technology to create artificial bone materials with potential uses as implants and therapies [62]. 7.2.3. Soft tissues Soft tissues are composed of cells and extracellular matrix, which may exist in many different forms, each specialized to perform a specific function and each having a unique microstructure. Since the human body is mainly made up of soft tissues, the medical consequence of soft tissue modeling is important for applications, such as the surgery planning, including neurosurgery, plastic surgery, musculoskeletal surgery, heart surgery, abdominal surgery and minimally invasive surgery, as well as tissue engineering for the construction, repair or replacement of damaged or missing tissue in the human body [63]. Biological tissues are by essence highly complex systems that host chemical, cellular, electrical and mechanical processes. Today, powerful computers are readily available to simulate very complex systems so that difficulties in costly experimental studies could be avoided for a variety of applications. However, numerical models require the knowledge of accurate constitutive equations for modeling biological materials. Because of the inherent complexities of microstructure and biomechanical behavior of biological cells and tissues, soft tissue mechanics is a still a vast area for the development of constitutive theories. Mechanically, the main characteristics of biological soft tissues are that they sustain large deformations and displacements, have a highly non-linear behavior and possess strongly anisotropic mechanical properties [53]. At present, the mechanical properties of the softest tissues in the body are not well characterized. While much is known about the mechanics of bone, cartilage, tendons and various types of muscle, data on the mechanical properties of very soft tissues with Young’s moduli less than about 104 Pa, such as brain, liver, glandular tissues, and tumors, are sparse. Information on the mechanics of very soft tissues has many applications, including detection of disease through palpation of tissue or low-frequency ultrasound (e.g., breast tumors),

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estimation of tissue deformation under external mechanical loads and design of medical implants. The mechanical properties of tissues also influence the movement of water through extracellular spaces, which is relevant to formation of edema, and to convective movement of solutes through tissues, including the delivery of chemotherapeutic drugs. Some theoretical models have been developed to predict elastic properties of very soft tissues, such as glands, tumors and brain [64]. Macroscopic properties and behaviors of biological tissues are closely related to the properties and behaviors of their constitutive cells. Researches have shown that many types of cells may change their structures and functions in response to even subtle changes in their mechanical environment [65], and in many respects, it is the extracellular matrix that regulates cell shape, orientation, movement and overall function [66]. Study of soft tissues at the cellular level is therefore very important. In particular, the modeling of effects of interaction between electromagnetics and mechanics in living biological tissues at the cellular level is very challenging. Electromagnetic properties of biological tissues are very special for living soft tissues. For instance, heart tissue and skeletal muscle are electrically active. Other thoracic tissues, as well as inactive regions of the heart, are passive. In general, biological tissues are electrically heterogeneous, while their magnetic permeability is very close to that of free space. Application of an electric field pulse may result in rapid polarization changes that can deform mechanically unconstrained cell membranes, followed by ionic charge redistribution governed by electrolyte conductance and distributed capacitance. The cellular nature of tissues also establishes a vast number of dielectric partitions that separate strongly conducting intracellular and extracellular compartments. For instance, cells are enclosed by poorly conducting membranes with a typical resistance of 5000 X/cm2 and lie within an extracellular space with a specific resistance as low as 4 X/cm [67]. It has been found that the dielectric properties of tissues are highly dispersive [68], the mechanisms of which come mainly from the dielectric relaxation of free water (frequency near 20 GHz and dielectric constant 10–50), the Maxwell–Wagner type of relaxation resulting from the charging of cell membranes (frequency near 1 MHz and dielectric constant 100–1000), and the frequency-dependence 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 resistivities, which are also frequency-dependent. According to a recent study of electrical resistivities of human tissues in the frequency range from 100 Hz to 10 MHz [69], the experimental data reported in literature are quite scatted. It is shown that differences between the mean values of resistivities of most tissues from muscle and internal organs are statistically insignificant. For instance, the reported mean resistivity is 171 X cm for skeletal 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 the water content of some tissues. The low water content of bone and fat explains their high resistivities, while the high water content of other tissues explains their low resistivities. Besides, the anisotropic structures of biological tissues may also contribute significantly to the measured electrical properties. Skeletal muscle is probably the best example of this variation, in which the resistivity can be up to 10 times lower along the length of the muscle 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 and that both conductivity and relative permittivity decrease with increased air content. The conductivity of blood can also alter by up to 20% as a function of flow. This is due to variations in the erythrocyte orientation, axial accumulation (where the concentration of erythrocytes is uneven due to the velocity profile), and elongation of the erythrocyte in the direction of the flow [70]. Obviously, to model electrical properties of blood, both mechanical flow behaviors and electrical properties of the blood have to be taken into consideration. The coupled electrical and mechanical models are also required for studying physical properties of, for instance, living bones and heart among others. While great efforts have been made in cardiac electrophysiology to understand and model the human heart, little is known about electrodynamic properties of other organs. Some efforts have been made recently in modeling, for instance, the gastrointestinal system, which is also an electrically and mechanically active organ with propagating electrical activation and mechanical contraction [71]. Because of the inherent complexities of the microstructures and bioelectromechanical behaviors of biological cells and tissues, there is still a need for new theoretical frameworks to guide the design and interpretation of new classes of experiments. New mathematical models and computational methods to solve the complex

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boundary and initial-value problems of clinical, industrial and academic importance are also needed due to the complex geometries, interface conditions and loading conditions. Nowadays, with the increasing amount of computational power available, there appear interest and efforts to develop human simulators for a variety of purposes, including biomedical research, education and clinical applications. 8. Bioelectrodynamic imaging Bioelectrodynamic imaging is the method for non-invasively obtaining anatomic and physiologic information about the human body through the use of electromagnetic means as well as their interaction with dynamic properties of the human body. Over the past century, imaging has experienced a quantum leap in technology and clinical applications, which includes X-ray computed tomography (CT); emission computed tomography (SPECT and PET); magnetic-resonance imaging (MRI) and spectroscopy (MRS), including functional MRI (fMRI), among others. Since there exist a vast number of literatures on these subjects, in this review, we shall focus on some recent progress and development in the X-ray imaging technique, which is one of the oldest and most widely used imaging techniques nowadays. 8.1. Tunable quasi-monochromatic X-rays During those early days, X-rays are generated by rather simple devices with inductors, vacuum tubes and high voltage sources. Today, X-rays can be generated by modern accelerators (synchrotron) or by high-power laser interacting with electron beams among others. Recent advancement in high-power laser technology has led to the development of a new type of X-ray source with compact size (the so-called ‘‘table-top’’ X-ray source). In 1998, a research group led by Frank Carroll at Vanderbilt University was successful in producing pulsed, tunable (quasi-) monochromatic X-rays using the free electron laser as a source of both high-energy electrons and intense infrared (IR) laser light although the properties of the X-rays were not satisfactory for clinical applications. In April 2001, after 2 years of re-design and engineering, a new prototype device was completed and commissioned at the MFEL Center at the Vanderbilt University but used a configuration that was not that of an FEL. This machine uses a linear accelerator operating in what they call the ‘‘singlepulse’’ mode and a tabletop terawatt IR laser to provide the counter propagated beams. It delivers 1010 X-ray photons/8 ps pulse throughout its tunable 12–50 keV range at anywhere from a 1–10% bandwidth in a conebeam area geometry [72]. Today new efforts have been made to develop the small-sized tunable (quasi-) monochromatic X-ray sources in Japan, especially at the University of Tokyo [73] (see Fig. 3). These tunable and pulsed (quasi-) monochromatic X-rays have some special features particularly useful for their applications in biomedicine. These include: • Softer X-rays are absent from incident beam (avoid beam hardening), lowering entrance dose to the patient. • Higher energy photons could be eliminated, reducing the amount of scatter and improving the contrast, the image quality, and lowering the dose to the patient. • Tunability makes possible to use optimal X-ray energies to improve contrast among others. (The choice of the optimum energy depends on the size and composition of the object.) • Novel imaging techniques based on the X-ray phase information. Among the anticipated uses of the tunable monochromatic X-ray beams in medicine are markedly improved mammography, K-edge imaging, phase-contrast imaging, time-of-flight imaging, small-animal imaging and protein crystallography among others [74]. 8.2. K-edge imaging and improved mammography For the K-edge imaging, the monochromatic X-ray that takes advantage of its tunability could lead to improved diagnostic techniques. Iodine, for example, attenuates X-rays much more effectively at 33.2 keV than at any other energy, because the binding energy of the k-shell electron is 33.2 keV. When hit by a photon at that energy, the K-shell electron is ejected from its orbit, extinguishing the incident photon. Because mono-

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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 amount of contrast material needed for X-ray imaging and/or be used to significantly reduce radiation dose to the patient. Iodine is not the only atom that is useful for such imaging tasks. Gadolinium, for example, has a K-shell binding energy of 50 keV. If used in place of iodine, gadolinium agents could further decrease the radiation dose to the patient. By tuning the energy of the monochromatic beam and increasing it from 33.2 to 50 keV, the beam becomes more penetrating, and the body becomes more transparent to the X-rays, with a lower radiation dose. However, the gadolinium will then act more efficiently in stopping the beam wherever it is placed. Besides, the dual-energy monochromatic X-ray computed tomography may also be developed to obtain information about electron densities for materials and/or biological media, which is important, for instance, for medical treatment planning for proton and heavier-ion radiotherapy [75]. Today, breast cancer is one of the leading causes of death of women in industrialized countries. Mammography screening is therefore an important public health issue where the prospect of developing new imaging methods plays a central role. In conventional X-ray imaging, as we know, the structures of the object are mapped by an incident X-ray beam and detector of sufficient spatial resolution. The relative variation of the mapping property of the object is the contrast that depicts differences in X-ray absorption among various tissue constituents in the path of the X-ray beam. These images may provide excellent visualization of tissues with significantly different absorption characteristics resulting from differences in physical density and atomic number Z. When these differences are slight, such as for soft tissues, conventional X-ray imaging methods are however limited. Mammography is one example where conventional X-ray imaging methods are challenged. Here, the application of tunable monochromatic X-rays to mammography could prove particularly beneficial. When cancerous and normal breast tissues are trans-illuminated by different energies of monochromatic Xrays, 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 malignant and normal tissues. Studies of these tissues have shown that in the energy range of approximately 20– 30 keV, cancerous breast tissues exhibit a higher attenuation than do normal tissues [76]. In particular, by combining images at different energies, it is possible to produce hybrid images in which the contrast of relevant structures is preserved while unwanted masking contrast (structural noise) can be largely removed. 8.3. Intravenous coronary angiography Clinical coronary angiography is an important diagnostic method, which provides detailed high-resolution images of the coronary arteries. In conventional coronary angiography, a catheter is inserted into the iliac

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artery and guided to the aorta and to the beginning of a coronary artery. An iodine-containing contrast agent is injected into the artery and radiographs are taken at short intervals. If the stenosis is not too severe, coronary angiography is followed by balloon-tipped angioplasty. The method is well developed, but still complications and even mortality are too frequent to allow conventional coronary angiography to be used as a routine diagnostic method for screening or follow-up studies. The attempts to avoid the risks by intravenous injection of the contrast agent failed because, by the time the bolus reaches the coronary arteries, it is diluted to a few percent of the initial concentration. Recently, K-edge subtraction (KES) angiography with synchrotron radiation has demonstrated its capability of providing images of clinical quality even when intravenous injection is used. In the intravenous coronary angiography, for each scan, two monochromatic X-ray images below and above the K-edge of the contrast agent, such as the iodine, are recorded simultaneously. The two images can then be subtracted to produce a maximal contrast enhancement of the iodine. Since the KES method is used following the injection of the iodine contrast agent into a peripheral vein, the risks associated with arterial catheterization are avoided. Even when diluted on its way through the heart and lungs before reaching the aorta, where the heart arteries branch off, the concentration of iodine is sufficient to provide clinical 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 diagnostic imaging. Because soft biological tissues are made up predominantly of light elements such as carbon, hydrogen, 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. Density changes, either from differences in specific gravity of adjacent tissues or the interfaces of different tissue types in the breast, can produce inhomogeneity in the refractive index of breast tissues, which may affect propagation behaviors of the X-rays. Thus, it is possible to explore imaging properties of the X-ray beam that may acquire phase information from differences in tissue composition. In fact, the X-ray phase shift cross-section for 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 information in the imaging of soft tissues. In addition, the high sensitivity contributes to the reduction of X-ray radiation damage, which is important in biological X-ray imaging. However, the imaging techniques using X-ray phase information require new detectors and analyzers to cull this information from the transmitted beam. Recently, a 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 scattered radiation by the Bragg diffraction [79]. This allows pure absorption images and pure refraction images to be produced, rather than a mixture of the two. A synchrotron source is used to provide a quasi-parallel monochromatic X-ray beam of sufficient brightness. The contrast in the images produced is related to the changes in the X-ray refractive index of the biological tissues, resulting in remarkable clarity compared with conventional X-ray images based on absorption effects. These changes are greatest at the boundaries between different tissues, giving a marked edge enhancement effect and three-dimensional appearance to the images. For investigating the diffraction enhanced imaging, the synchrotron radiation source is ideal. While it is feasible to use such a source for developing new techniques and undertaking a certain amount of clinical research, it would not be suitable for large-scale clinical applications, owing to a variety of factors such as limited availability and geographical considerations. It is probable that in future such limitations can be overcome through the development 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 have led to the emergence of a relatively new discipline, the ‘‘molecular imaging’’ [80]. The molecular imaging has its roots in both molecular and cell biology as well as in imaging technology. At present, non-invasive in vivo molecular imaging techniques are mainly based on the magnetic resonance, the nuclear (positron emission

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tomography; gamma camera) and the in vivo optical imaging systems. These disciplines have now converged to provide a well-established foundation for exciting new research opportunities and for translation into clinical applications. It is however possible that future generation X-ray imaging systems may also make use of the molecular imaging strategies. Practical realization of such systems may be related to the development of advanced high-spatial resolution x-detectors. It is expected that biocompatible nano-particles or micelles, encapsulated with specific nano-materials and/or molecules, can be used as contrast agents in biomedical X-ray imaging for detecting tiny early-stage cancer cells. We may foresee a paradigm shift in cancer imaging and therapy in the 21st century. This implies the shift from anatomical imaging to molecular/cell signature probing and from non-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 interventions and molecular-radiation cancer therapy will be developed along these lines. 9. Bioelectrodynamic therapy It has been shown that not only living organisms have their own endogenous EM fields for cell communications, tissue activities and their senses with environments, but also their physiological behaviors and health states can be influenced by exogenous EM fields and/or their energy or power. Besides, mechanical energy expended in biological structures may also produce electrical potentials of sufficient magnitude to exert a wide range of effects in living systems. These may include control of cell nutrition, local pH, control and enzyme activation or suppression, orientation of intra- and extra-cellular macromolecules, migratory and proliferative activity of cells, synthetic capability and specialized function of cells, contractility and permeability of cell membranes and energy transfer. If the EM fields and mechanical energy could be properly controlled and designed for their applications to human body according to proper guidelines, it is possible to perform therapeutic treatments to certain diseases or to improve the health status of the human body. The questions are then how one could find those proper guidelines and what types of diseases or health functions for the human body 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 potential 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 principal stress trajectories and bones may change their shape in response to stresses. Wolff’s discovery raised a profound question: what is the mechanism that enables a bone (or any other tissue) to adjust its structure in relation to the way it is used? It is obvious that such adjustments take place otherwise training for an athletic or artistic performance would not stimulate the body to change its structure in the most appropriate way to accommodate the desired performance. Although the basic concepts of Wolff’s law are generally accepted based largely on phenomenological observations, the basic mechanisms and mathematical laws relating bone remodeling to the stress/strain relations are still not well understood and deserve further investigation. According to the observations, the bone remodeling appears to be governed by a feedback system in which the bone cells sense the state of strain in the bone matrix around them and either add or remove bone as needed to maintain the strain within normal limits. What is then the process by which the bone cells are able to sense the strain? One hypothesis is that the piezoelectric effect in bone is the part of the feedback loop by which the bone cells sense the strain field. This hypothesis obtained support from observations of osteogenesis in response to externally applied electric fields of the same order of magnitude as those generated naturally by stress 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 mechanism has stimulated the invention of medical devices for therapeutic purposes for bones, specifically in the hands of the orthopedic surgeon: it is able to restore and augment osteogenetic activity in bone repair tissue. For instance, Becker [81,82] demonstrated that the bone cell function could be altered with implanted electrodes providing a current of 100–50 lA/cm2. Thus, by passing a current through a bone fracture, one could

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stimulate the bone repair process. A key breakthrough was the later realization that magnetic fields applied from the outside of the body could induce electric currents within cells and tissues. In relation to bone healing, this would mean that it is no longer necessary to insert electrodes into the bone itself, in order to pass a current through a fracture site. A comparable current could be magnetically induced to flow through the fracture site using coils placed outside of the skin. That magnetic fields in the environment can induce currents deep within the body has now been well documented by medical researchers using pulsing magnetic field therapy to induce current 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 electromagnetic 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 externally applied electrical field may deviate cell’s membrane potential, i.e., depolarize the cell membrane and hence activate excitable tissues among others. The early documents on magnetic stimulation may be traced back to the work of Jacques d’Arsonval in 1896 and Silvanus P. Thompson in 1910, describing the magnetic stimulation of the retina [83], which is known to be very sensitive to stimulation by induced currents and field strengths. In 1985, researchers at the University of Sheffield in UK achieved successfully the transcranial magnetic stimulation and made the first clinical examinations [84]. Now, there are essentially two types of the magnetic stimulators commercially available: the single-pulse devices and the repetitive TMS (rTMS) devices that may generate trains of stimuli at 1–60 Hz. Since TMS can exert both excitatory and inhibitory effects on human cerebral cortex, it is possible to use TMS either as a therapeutic tool or as a diagnostic tool for determination of the interaction between excitatory and inhibitory circuits within and between specific cortical areas of the brain. TMS and repetitive TMS (rTMS) have been used for more than 20 years to non-invasively study the human brain. In particular, it allows the evaluation of motor conduction in the CNS, which may provide specific information in neurological conditions characterized by clinical and sub-clinical upper motor neuron involvement. TMS has also proved useful in monitoring motor abnormalities and the recovery of motor function. TMS can also give information on the pathophysiology of the processes underlying the various clinical conditions. More complex TMS applications allow investigation into the mechanisms of diseases causing changes in the excitability of cortical motor areas. They are also useful in monitoring the effects of neurotrophic drugs on cortical activity [85]. Today, TMS is an established investigative tool in the cognitive neurosciences, and is being explored for the study of perception, attention, learning, plasticity and awareness among others [86]. TMS or rTMS has also been considered recently as a therapeutic tool for depression, 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 acupuncture involves the stimulation of specific points on the skin, usually by the insertion of needles. Acupuncture was based on the principles of traditional Chinese medicine to understand human health in terms of a vital force or energy called ‘‘Qi’’, which circulates between the organs along channels called meridians. Qi energy must flow in the correct strength and quality through each of these meridians and organs for health to be maintained. Disturbance of such energy flow may cause symptoms of certain sicknesses. The acupuncture points are located along the meridians and provide one means of altering the flow of Qi by proper stimulations. According to current knowledge of medicine, the acupuncture points are considered to correspond to physiological and anatomical features such as peripheral nerve junctions. This might explain the effectiveness of the acupuncture for releasing pains of patients from various origins, and its limitation of general use in medicine. Along the line of the electrical stimulation discussed above, electrical stimulations via acupuncture needles as well as micro currents have also been explored to release pains of certain patients. Clinical benefits have been reported for the uses of the electro-acupuncture and the micro current therapy [89–91]. Studies indicated that clinically tested results depend on the frequency of the applied electrical currents, which shows character-

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istic of the patient and the affected tissues to be treated. It was then hypothesized that precise frequencies appear to interact through resonance with biological tissues and biochemical regulators in such a way as to neutralize 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, Indian and Chinese civilizations had used light to treat various diseases. Modern photodynamic therapy was however developed in the last century, starting from the pioneering work of Niels Ryberg Finsen, a professor at the University of Copenhagen in Demark, on the treatment of diseases, and in particular the treatment of lupus vulgaris by means of concentrated light rays. Finsen’s method has proved of use in the treatment of a number of other skin diseases, but it has been particularly successful in the treatment of lupus vulgaris. None of the methods previously used for the treatment of this disease had produced results, which can in any way be compared to those obtained with the phototherapy according to the presentation speech in connection with the Nobel Prize in Physiology or Medicine awarded to N.R. Finsen in 1903 for his discovery. At the beginning of the last century, researchers, such as Oscar Raab in 1900 and H. van Tappeiner and A. Jesionek in 1903, also observed that a combination of light and certain chemicals could induce cell death. Experiments to test various combinations of reagents and light had then led to the emergence of modern photodynamic therapy (PDT), which is used mainly for anticancer therapy [92]. The PDT is a novel treatment based essentially on three components: a photosensitizer, light that is absorbed by the photosensitizer, and molecular oxygen. All three components are thought necessary for best long-term response, but their relative roles vary considerably depending on the photosensitizing drug, its sub-cellular and tissue distribution, the tumor type and its microvasculature and the type and duration of inflammatory and immune responses elicited in the host [93]. In the PDT treatment, photosensitizer is pre-administrated like a drug into the patient and is stored selectively in diseased tissue, such as the tumorous tissue. Upon activation by absorption of light photons, the photosensitizers generate reactive oxygen species (singlet oxygen and free radicals), which are able to damage membranes, DNA and other cellular structures of the tumor. This implies that PDT could be a particularly useful alternative treatment for drug-resistant tumors. Recently, some studies have also been made to introduce externally applied pulsating electromagnetic fields to influence, for instance, the permeability of cell membranes for photosensitizers and therefore to enhance the photodynamic efficacy in the PDT for treating some cancer cells [94]. PDT has also been explored for the treatment of cardiovascular diseases [95]. Although photodynamic therapy offers certain advantages over other therapies, such as conventional chemotherapy, it does have several limitations since the success of the technique is dependent upon the simultaneous presence of light, oxygen and photosensitizer. Tumors are however relatively anoxic and the light penetration through tissue at currently used therapeutic wavelengths is limited to a few millimeters. Besides, the absorption coefficients of the photosensitizer at these wavelengths are low. In addition to the problems of light, oxygen and photosensitizer presence, the ratio of the photosensitizer uptake between tumor and normal tissue is only marginally in favor of tumor in many cases. As a result, a considerable amount localizes in the skin causing acute photosensitivity, which can persist for several weeks. Further efforts and innovative ideas are required in this field. 9.5. Electroporation therapy Electrical pulses can transiently disrupt cell membranes and create primary membrane pores of a few nanometers, and thereby permits transmembrane transport or intracellular delivery of molecules. The phenomenon of the cell electroporation was studied extensively and used as a research tool to facilitate cellular uptake of genetic material in vitro in 1980s. Recently, tissue electroporation is under investigation for therapeutic purposes aimed at cancer treatment, gene therapy and transdermal drug delivery [96–98]. Though the exact mechanism for the cell electroporation has not yet been known, plausible models exist to explain majority of experimental results. Considering that biological systems are electrically heterogeneous, application of an

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electrical field pulse may result in rapid polarization changes that can deform mechanically unconstrained cell membranes (e.g., suspended vesicles and cells) followed by ionic charge redistribution governed by electrolyte conductivity and distributed capacitance. As primary pores appear in the membrane, its resistance drops, and the voltages within the system redistribute on a time scale governed by the instantaneous values of the various conductivities and capacitance. Once the membrane resistance has dropped, a membrane tends to rapidly discharge, but pores are metastable, disappearing on a much longer time scale (often >1 s) than their creation time (ls). The membrane recovery (resealing) is slow and generally is temperature dependent. Thus, some pores remain open for long times, during which ions and molecules can continue to cross the cell membrane by diffusion and electrically driven transport associated with diffusion potentials and metabolically driven membrane pumps [96]. Generally, the most important parameters for effective electroporation are the electrical field strength and the length of time the field is applied (pulse length). For tissue electroporation in which cells are in multicellular environments, it is suggested that the required electric field strength should be larger than that used for cells in dilute suspensions [98]. Besides, tissue electroporation could be enhanced by applying short pulses at relatively large field strengths, delaying application of pulses until some time after injection of solutes, and possibly applying multiple pulses with long interpulse delays. A large variety of other parameters may also influence the efficacy of the electroporation, and the uptake of molecules depends on their molecular size, charge and other physicochemical properties [97]. As a therapeutic tool, the electroporation has been found to be an effective technique for molecular therapies, 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 termed electrochemotherapy. This relatively new treatment modality relies on the physical effects of locally applied electrical fields to destabilize cell membranes in the presence of a drug. In 1987, Okino and Mohri [99] published the first in vivo electroporation results attained in an animal tumor model. It was shown that the use of the anticancer drug bleomycin in combination with pulsed electrical fields killed tumors far more effectively than the use of bleomycin or electroporation alone. Since that the publication by Okino and Mohri, the field of electroporation has progressed continuously, and a large number of publications have appeared on in vitro and in vivo studies, as well as clinical trials. Currently, electroporation therapy devices for a number of biomedical 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 transdermal drug delivery: (a) the ion-electrical field interaction provides an additional force which drives ions through the skin; (b) the flow of electrical current increases permeability of skin; and (c) the electroosmosis produces bulk motion of the solvent itself that carries ions or neutral species with the solvent stream [100]. For charged drug molecules (ions), the electrical field imposes a force on the ions, which adds to and may dominate the diffusion force or concentration gradient. This electrical force drives the charged drug molecules through the 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 as a possible mechanism for enhanced transport of neutral drug molecules, in which the electroosmotic flow is caused by the electrical volume force acting on mobile counterions. By varying the applied current density and area of application, the iontophoretic transport of drugs can be regulated. Normally, the higher the current amplitude, the greater is the flux enhancement for the charged permeant agents. A current density that is too high may however be unpleasant for the patient. In clinical practice, iontophoretic therapy is used primarily for the treatment of inflammatory conditions in skin, muscles, tendons and joints, such as temporomandibular joint dysfunctions. Attention has been drawn to the possibility that sensation (pain and burning) may be felt and that burns may occur in the iontophoretic therapy. These side 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 pharmacologic treatment for psychiatric disorders based on non-oral drug delivery systems such as implantable and transdermal delivery systems has indicated that iontophoresis might appear to be a promising and perhaps the most efficient assisted-delivery technique for future antidepressant transdermal delivery [102].

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9.7. Sonophoretic drug delivery Sonophoretic drug delivery is a technique making use of ultrasound to enhance transdermal drug delivery for a variety of molecules and drug substances. Study of the phenomenon of increased skin permeability (sonophoresis) by application of ultrasound started in 1950s and received a major boost from the identification of low-frequency sonophoresis in the frequency range from 20 kHz to 100 kHz, which enabled the application of sonophoresis to the delivery of macromolecules through the skin. To date, both in vitro and in vivo experimental data exist for the sonophoretic transdermal delivery of insulin, mannitol, heparin, glucose, caffeine and the tetanus toxoid vaccine etc. Recent attention has been paid for potential applications of the technique for vaccination and gene therapy [103]. The precise mechanism by which the ultrasound wave helps to enhance permeability through the skin has not been fully understood yet. It is hypothesized that the micro-cavitation in the skin caused by the ultrasound plays the dominant role in sonophoresis, which helps drug molecules to diffuse into and through the skin. Further efforts are needed to enhance knowledge of the mechanism of sonophoresis. Specifically, detailed characterization of cavitation events on the skin surface may prove useful in designing strategies for controlling cavitation with a view to achieving greater enhancement in drug delivery without compromising safety. Although transdermal drug delivery techniques discussed above can individually enhance transdermal drug transport, which may offer several advantages over traditional drug delivery systems, such as oral delivery and injection to minimize pain and possible sustained release of drug, the transdermal transport of macromolecules 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 them alone. For instance, the sonophoresis can operate in synergy with other enhancers of transdermal drug transport, including chemicals, electroporation and iontophoresis. Recent researches have shown results supporting such expectation [104]. Again, synergetic use of our knowledge and techniques may play important roles for future development of 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-rays and of radium, ionizing radiation had begun to be applied by pioneers for the treatment of tumors. Different forms of ionizing radiation are used for cancer therapy. All the techniques have the same goal of concentrating the absorbed dose at the tumor. Ideally, radiation should be transported to the tumor with minimum damage to the surrounding tissue, and radiation should cause secondary processes that stop the tumor growth and eliminate the tumor. Past advances in quantitative dosimetry, the development of computing techniques, and the design of linear accelerators had provided the science-based (in practice the physics-based) innovations in radiation cancer therapy in the latter part of the 20th century. This series of developments has culminated in the advent of conformal radiation therapy, allowing radiation fields to be contoured to permit the treatment of precisely defined but arbitrarily shaped treatment volumes [105]. Furthermore, the conformal radiation therapy could be developed to converge the CT imaging and the X-ray therapy into a single gantry, so that tomographic images could be used to monitor treatment alignment and dose distribution continually as the treatment progresses. In general, the conformal radiation therapy provides the ultimate in the physical targeting of radiation to tumors, where the targeting depends on the anatomical and geometrical location of macroscopic tumors, but does not require in-depth knowledge of their biological or radiation-biological properties. Although the radiation cancer therapy has many advantages, such as the soundly physics-based approach allowing for quantitative and precise planning of the individual treatment, its easy access to tumor cells that may be protected from cytotoxic drugs, and less frequently developed resistance of tumor cells to the radiation than those to drugs, the conventional radiation therapy has some disadvantages such as the fact that high-dose radiation therapy (e.g., 10–60 Gy or more) is only tolerable when delivered to limited volumes within the body. Besides, radiation therapy is usually only applied radically in the treatment of tumors large enough to be imaged (typically >1 cm diameter) which limits the usefulness of the radiation in dealing with disseminated disease. More importantly, the biological differences in the response of normal and tumor cells are

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generally rather small—slight differences in intrinsic cellular radio-sensitivity and in repair capacities. Consequently, the therapeutic differential between normal tissues and tumors is quite narrow, and there exist too many tumors, which cannot be cured by tolerable doses of radiation. Much research work is now directed to ameliorate the disadvantages of radiation therapy without losing the advantages. 9.9. Targeted radiation therapy Recently, targeted radiation therapy has been developed as a novel and possibly advantageous approach to radiation therapy. The basic idea is to deliver higher radiation doses to tumor than normal cells by means of radioisotopes chemically conjugated to tumor-seeking targeting agents. The targeted radiation therapy requires a ‘targeting agent’ capable of seeking out tumor cells and delivering to them a radioisotope which provides the irradiation. The selectivity of the treatment depends on the ability of the targeting agent to discriminate malignant from normal cells. The cell killing effectiveness depends on the ability of the agent to penetrate tumor masses and the absolute amounts of radio-nuclide, which can be delivered to those cells that are successfully targeted. In 1975, the prospects for targeted radiation therapy received a boost with the advent of monoclonal antibody technology [106], which offered the possibility that targeting molecules (monoclonal antibodies) could be obtained which would recognize small differences between molecular groups on the surface of normal and cancer 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 uptake of absolute amounts of antibody in tumors, heterogeneous intra-tumor distribution of antibody and poor penetration of antibodies within solid tumors. During the past few years, a new strategy of genetic radiation therapy has appeared on the horizon. This strategy builds upon growing knowledge of the genetics of cancer cells and how they differ from the cells of normal tissues, as well as new technologies of genetic engineering, which allows individual genes to be transferred to cells or cell populations. The goal is to exploit the biological features of tumors to allow more radiation to be delivered to the tumor, or, for a given dose of radiation to improve the therapeutic differential by increasing the radiation sensitivity of tumors or by reducing the radiation sensitivity of normal tissues. There are several approaches by which genetic manipulation could enhance the therapeutic efficacy of radiation therapy [107]. With the availability of monochromatic radiation sources, the photon activation therapy has recently been introduced, in which a cascade of Auger and photoelectrons is created in the tumor during irradiation by a monochromatic radiation beam (e.g. X-rays). The targets in the tumor cell are the strands of DNA, which are broken leading to lethal damage to the tumor cell. This is a two-step therapy, where a sufficient concentration of a high-Z containing compound is physiologically directed to the tumor. Monochromatic radiation with energy slightly above the K-absorption edge is then targeted on the tumor, and the Auger electrons deposit their energy near the atom where photo-absorption takes place. This combined treatment takes advantage of the selective electron excitation and ionization of the high-Z compound introduced in the DNA of the tumor cell produced by the monochromatic X-ray beam. The physical explanation of the mechanism involves the release of high-LET Auger electrons. The Auger electrons release a large amount of energy in the immediate vicinity of their emission, in an average radius of some tens of nanometers. Several in vitro experiments with cell cultures have been carried out and small-animal studies are beginning. In one early experiment, iodine atoms were transported to the target by iodo-deoxyuridine [108]. It was observed that the effective radiation dose was enhanced by a factor of 2 that was attributable to Auger electron emission. In recent experiments at the ESRF, platinum has been used instead of iodine, which has the advantage that the X-ray energy is higher (about 80 keV), and the number of Auger electrons is larger. The basic difficulty of the method is that the range of the Auger electrons is very small, a few tens of nanometers only, so that the heavy absorbing atom should be incorporated into the DNA itself or to a location very close to it. Despite its intuitive appeal and some successes, targeted radiation therapy has not yet become a mainstream form of cancer treatment. Limited selectivity of uptake of targeting agents, limited absolute uptake and limited penetration of most agents in solid tumors result in targeted radiation therapy having only a few successful clinical applications at the present time. Recent progresses in biotechnology and in the

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molecular genetics of tumors have however begun to open up new ways of using radiation in cancer treatments, which exploit the known biology of particular tumors. Furthermore, recent technology development in nano-technology, nano-materials, such as polymeric micelles, and possible use of tunable pulsed monochromatic radiation sources have provided us with new opportunities of developing novel solutions to these problems. Examples of such solutions may involve the development of promising imaging enhancers (contrast agents or molecular probes) as well as ‘smart’ drugs (target-specific ‘poisons’ and/or biomedical ‘bombs’) at nanometer scales and their translation from laboratory synthesis to clinical applications in novel X-ray imaging and molecular-radiation therapy. 10. Summary An interdisciplinary subject of bioelectrodynamics in living organisms has been introduced, which is of increasing interest in recent years. It is shown that electromagnetic fields are intrinsic in living organisms due to biophysical and biochemical processes that happen constantly in the living organisms and can be regulated partly by the CNS inside the living organisms. These endogenous EM fields are closely related to physiological and pathophysiological behaviors of the living organisms, and their signal levels, though quite weak in general, are strong enough to be detected by modern detectors. Thus, these endogenous EM signals in living organisms can be monitored for diagnosis among other possible applications in biomedicine, such as the ECG, EEG, MCG and MEG. It is also shown that in living organisms, cells and tissues are constantly subject to forces and stresses, which may be originated from pressure forces linked to gravity to motional forces and from electromagnetic forces arising from molecular interactions, environmental and externally applied EM fields. These forces and EM fields are likely to modify cellular behaviors and affect physiological behaviors of the living organisms. It is therefore of both scientific and practical interest and importance to study theoretically and experimentally the bioelectromagnetic, mechanical and their coupling phenomena in living organisms, including their correlations with biochemical processes that may be initiated and/or activated by these forces and/or EM fields. Some issues related to bioelectrodynamic modeling of living organisms are reviewed. It is emphasized that bioelectrodynamic modeling of ion-channel flow dynamics at the cellular level are important and the collective properties and behaviors of living cells may deserve special attention, in which interaction of cells and exogenous EM fields as well as thermal noise effects may have to be taken properly into consideration, especially when 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, regulation and remodeling capabilities of living tissues that are completely different from those of conventionally man-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 living organisms, if used properly, these forces and EM fields can be utilized for biomedical applications, such as biomedical imaging and therapy. Some recent biomedical imaging and therapeutic methods with the aid of bioelectrodynamic techniques are also reviewed, indicating their promising future. The fact that living organisms may have well-organized structures, actively controlled actions and responses, extremely sensitivity in EM fields and mechanical actions, and amazing signal amplification functions may not only cause complexity and variety of the biological world, but also create opportunities for technical innovations in biomedicine to improve future quality of human life. Bioelectrodynamics in living organisms is indeed a very challenging and promising research field in the 21st century. Acknowledgements The author, S.-A. Zhou would like to thank the National Institute of Radiological Sciences and the University 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 University for their kind support and hospitality. He would like also to thank Dr. K. Dobashi for discussion on the subject of the Compton backscattering X-ray source. Helpful suggestion from anonymous referees for the paper is greatly acknowledged.

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