Applications of Microwaves in Medicine and Biology

Abstract

This chapter deals with the description of recent research activities oriented on the perspective of microwave technologies in medicine and biology. It brings new ideas about the possibilities of using microwaves in thermotherapy—above all toward hyperthermia in cancer treatment. Development of new types of hyperthermia applicators (based, e.g., on technologies such as metamaterials, evanescent modes in waveguides, and other types of transmission structures) will be discussed here. Furthermore, we would like to underline in this chapter perspectives of microwaves in medical diagnostics. It is possible to expect that, e.g., microwave differential tomography, UWB radar, and microwave radiometers (all three can be used both for medical diagnostic and for noninvasive temperature measurement) will soon play an important role in it. Finally, experimental equipment necessary for research on the biological effects of EM fields is presented.

1. Introduction

Wide utilization of microwave thermotherapy can be observed in the countries of the European Union, the United States, Russia, China, Japan, and many others, including the Czech Republic. Interactions of the electromagnetic (EM) field with the human body have been utilized in medicine (e.g., cardiology, oncology, physiotherapy, and urology) since the late seventieth of the twentieth century. A very important role in this process plays scientific societies, e.g., the European Society for Hyperthermia Oncology (ESHO), which cooperates with STM (Society for Thermal Medicine), and ASHO (Asian Society of Hyperthermia Oncology).

Currently, EM fields are frequently used in a few well-established medical procedures already. Good examples in the area of medical diagnostics are, e.g., computer tomography (CT) and magnetic resonance imaging (MRI). In the area of therapy, we can mention, e.g., electrosurgery and radiofrequency (RF) heating in physiotherapy. Then microwave (MW) hyperthermia and RF + MW ablation in clinical therapy are being used for the treatment of cancer and other diseases.

According to the purpose of how microwaves are used, we can divide the medical applications of microwaves into the following three main groups [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17]:

• Therapy (mostly so-called thermal effects are being used; so-called nonthermal effects are still under discussion).

• Diagnostics (based on permittivity measurements, very prospective can be, e.g., an MW differential tomography, UWB radar technology, and MW radiometers).

• MW is only a part of the medical system (e.g., microwave technology as the basis of the linear accelerator).

As told above, treatment applications of MW are represented mainly by those based on thermal effects. Thus, we can speak about the MW thermotherapy, which can be generally divided into several basic modalities with respect to the goal temperature level or interval:

• Diathermia: which means mild heating up to 41°C at maximum (clinically can be used, e.g., in physiotherapy).

• Hyperthermia: this means increasing the temperature in the tumor area up to the interval of 41–45°C (clinically mostly used in oncology).

• Thermoablation: this means to increase the temperature over 45°C (clinically can be used, e.g., in urology for BPH treatment and in cardiology for treatments of fibrillation and/or arrhythmia).

For the abovementioned methods of thermotherapy treatments, frequency interval from 1 up to 5600 MHz is mostly used.

As for diagnostics based on the EM field—significant importance for the near future can be identified for the following methods mainly:

• MRI and CT (both these diagnostics methods have been largely used since the 80th of the last century already; they both represent the highest possible level of medical diagnostics).

• Microwave differential tomography (very prospective as a diagnostics method for the near future, to be used mainly as diagnostics of cancer or for noninvasive temperature measurements).

• Microwave UWB diagnostic radar (can be used for the same purposes as microwave differential tomography, but as well for other purposes, such as monitoring of breathing).

• Microwave radiometry (can be used for the same purposes as microwave differential tomography, but it works on different physical principles).

As for the frequency spectrum of the EM field (Figure 1), then it is possible to see that MRI is working in the frequency band from 64 to 299 MHz (i.e., the upper part of the RF band); instead, CT then is working in hard X-ray band. The MW frequency band is frequencies from 300 MHz to 300 GHz. The lower part of this frequency band, from 300 MHz to 6 GHz, is very prospective for MW medical imaging. Frequency band above approx. 100 GHz is very prospective for imaging with Terahertz waves. In Figure 1, there is a picture of the frequency spectrum of the EM field.

Figure 1.

Frequency spectrum of EM fields.

In this chapter, we will not describe the MRI and CT technology, as it is a well-known and broadly used application of the EM field in medical diagnostics. We will describe and discuss here other methods based on microwave technology mentioned above. The idea of MWs for medical diagnostics is a relatively new area but rapidly developing. The main advantages of MW technology with respect to CT and/or MRI are as follows:

• MWs belong to EM nonionizing radiation (such as MRI); instead, CT works in the ionizing part of the EM frequency spectrum.

• The system for MW diagnostics is very small and lightweight in comparison with MRI and CT (its dimension and weight are comparable to a notebook, so it will be possible to have it in an ambulance).

• MW diagnostic systems have the potential to be at least one order less expensive than either MRI or CT (since the MW technology is being massively used in mobile telecommunications).

And it is important to underline that for MW diagnostics, low power levels (1–20 mW) are used only.

2. Microwave thermotherapy

The first four of the following list of thermotherapeutical applications are just largely used in many countries around the world; the last three instead are at this moment in the phase of very promising projects:

• Oncology (cancer treatment)

  Biological principle utilizes the fact that certain tumor cells are very sensitive to a temperature higher than 41°C, while normal cells generally survive elevated temperatures up to 45°C. And so heating of the tumor region at temperatures of 41–45°C can selectively destroy tumor cells.

• Physiotherapy (treatment of rheumatic and skeletal diseases)

  Like in hyperthermia, therapeutic effect is caused by the principle of heating biological tissue, but to lower temperatures—usually only up to 41°C. It is used for treating pain in certain rheumatic and degenerative diseases and the treatment of chronic inflammations resistant to antibiotics, often used in rehabilitation and physical therapy.

• Urology (BPH treatment)

  Microwave thermocoagulation—heating up to temperatures much higher than 45°C, usually around 70°C. An example can be given the microwave treatment of Benign Prostate Hyperplasia, which can replace a complicated surgery.

• Cardiology (arrhythmia and fibrillation treatment, microwave angioplasties)

  Cardiac catheter thermal ablation is now the standard of care for various cardiac arrhythmia types (irregular heartbeat rhythm). The method uses a catheter terminated with a microwave antenna, which is introduced into either heart of the patient or into partially or totally blocked blood vessels. Heat gained by microwave energy either safely removes the cells inside the human heart causing arrhythmia and/or fibrillation or removes sclerotic plaques deposited on the walls of blood vessels.

• Surgery (microwave scalpel, growing implants)

• Ophthalmology (retina corrections)

• Neurology (stroke identification, brain stimulation)

For here mentioned thermotherapy treatments, it is important to mention that frequencies from the frequency band started approximately at 1 MHz and going up to 10 GHz are mostly used. This frequency range is given by the optimal depth of penetration of EM waves into biological tissue. Thus, this frequency band can achieve the needed depth of effective treatment.

2.1 Clinical applications of microwave hyperthermia

In Prague, the clinical applications of microwave hyperthermia for cancer treatment started in 1981, in cooperation with the Medical Faculty (the Charles University in Prague), the Radiotherapy Institute in Prague, and the Dept. of EM Field (the Czech Technical University in Prague). Since then, microwave hyperthermia has been clinically applied to more than 1000 cancer patients. Mostly added to radiotherapy (RT), a clinical study has been approved as a significantly positive contribution to RT treatment. Recently, a combination of hyperthermia added to proton therapy has been clinically applied in Prague.

Treatment of malignant tumors comprises several techniques usually. In some cases, tumors can be resected by surgery. Radiotherapy and/or chemotherapy can be applied when surgery is not possible or as part of a multidisciplinary approach. A less widely known treatment modality is hyperthermia. It is a therapeutic application of heat in which tumor temperatures are elevated in the range of 41–45°C. The heating of tumor tissue has a cell killing (cytotoxic) effect. However, the cytotoxic effect is small at temperatures below 45°C. Therefore, hyperthermia is always clinically combined with either radiotherapy or chemotherapy. The application of hyperthermia has been proven to increase the therapeutic effect of both radiotherapy and chemotherapy.

The effect of hyperthermia is strongly dependent on the achieved tumor temperatures and heating time. Preclinical research has shown that the cell-killing effect doubles every centigrade, e.g., 1 hour at 42°C is equivalent to half an hour at 43°C. Hypoxic tumors, i.e., tumors with a low level of oxygen, are more resistant to ionizing radiation than well-oxygenated tumors, while hyperthermia is particularly effective in hypoxic tumors.

Large solid tumors often contain hypoxic areas due to heterogeneous vascularization, making hyperthermia a useful addition to radiotherapy. The complementary effect of hyperthermia and radiotherapy is also because cells in the S-phase of the cell cycle are more sensitive to hyperthermia than the G1-phase, whereas cells are more resistant to radiotherapy in the S-phase.

Repair of DNA damage caused by radiotherapy is inhibited by hyperthermia. Hyperthermia also induces radiosensitization and chemosensitization. Furthermore, blood flow increases during hyperthermia improving tumor oxygenation and probably enhancing radiosensitivity. The increased blood flow also improves the uptake of cytostatics in tumor cells. Thus, the increased blood flow during hyperthermia is favorable for improving radiotherapy and chemotherapy effectiveness.

In clinical practice, we need to increase the temperature in a more or less circumscribed body region with tumor load. Treated volume ranges from a few cubic centimeters in case of thermoablation in lesions up to heating the whole body. Because of this, we need different types of applicators for each of the below-mentioned special cases. Thus, we can speak about different clinical modes of microwave hyperthermia.

First of all, we would like to offer an overview of the technical equipment needed for clinical applications of microwave thermotherapy in this chapter. Further, the main basic principles of EM field behavior inside the living biological system, selected from the point of view of physics related to microwave thermotherapy, will be mentioned. Moreover, we will provide the reader with references in literature, where detailed information on both physical and technical aspects of microwave thermotherapy (especially microwave hyperthermia) can be found.

2.2 Classification of clinical modes of microwave thermotherapy

According to ESHO guidelines following classification of different clinical modes of microwave hyperthermia (or thermotherapy in general) can be made:

• Local hyperthermia – Medical indications for local hyperthermia include chest wall recurrences, superficial malignant melanoma lesions, and lymph node metastases of head and neck tumors—all of which are validated in prospective randomized studies. The basic physical and technical descriptions will be given in the following text.

• Regional hyperthermia – Medical indications for regional hyperthermia include locally advanced and/or recurrent pelvis tumors, i.e., rectal carcinoma, cervical carcinoma, bladder carcinoma, prostate carcinoma, or soft tissue sarcoma. Some of these indications were validated in prospective studies. Basic physical and technical descriptions will be given in the following text.

• Part-body hyperthermia – Heated volume of a body region such as the whole pelvis, the whole abdomen, or (if clinically desirable) the upper abdomen or lower thorax or others. Basic physical and technical descriptions will be given in the following text.

• Whole-body hyperthermia (WBHT) –means to heat the whole body either up to 42°C for 60 minutes (so-called “Extreme WBHT”) or only 39.5–41°C for a longer time, e.g., 3 hours (so-called “Moderate WBHT” or “Fever-like WBHT”).

• Thermoablation – is performed with thin laser applicators or radiofrequency electrodes of a few millimeters. It is a minimally invasive procedure in every case, i.e., the applicators must be implanted in the lesions under CT or MR guidance. Achieved temperatures are high (up to 90°C), but the thermal gradients are pretty steep, and the effective range is 1–2 cm (i.e., lesions with diameters of 3–4 cm are the limit using standard techniques). Liver metastases (numbers up to 4) are the most frequent indication. The procedures are typically performed under MR control.

• Interstitial hyperthermia – an array of interstitial antennas or electrodes is implanted in inaccessible tumors, which might be located in deep or superficial tissues. The distance between the antennas must not exceed 1–2 cm, and therefore, lesions with diameters below 5 cm are suitable (in order to limit the number of puncturing tracks). From a physical point of view, we mostly want to create the best possible approximation through outward propagating spherical EM waves irradiated from each applicator. Thus, we can get the best approximation of the tumor dimensions and shape by dimensions and shape of the SAR distribution and thus, the best approximation of temperature distribution. Interstitial hyperthermia is an invasive procedure. Temperature measurements must be performed at the antennas and between them. In most systems, every single antenna is controlled by its generator. Dedicated systems have two or more segments per antenna or electrode controlled in phase and/or amplitude. Clinically interstitial hyperthermia has been applied for prostate carcinoma, recurrent breast cancer, and malignant brain tumors.

• Endoluminal hyperthermia – uses natural orifices to position various kinds of endocavitary applicators (microwave, radiowave, ultrasound, etc.) in direct contact with a tumor. From the physical point of view, we mostly want to create the best possible approximation with the aid of an outward propagating cylindrical EM wave irradiated from the applicator. For physical reasons, the penetration depth around those endoluminal applicators is limited and of the order of the applicator’s diameter (in the centimeter range). Accessible tumors include esophageal carcinoma, prostate carcinoma, rectal and cervical carcinoma.

2.3 Local hyperthermia

The term “Local hyperthermia” means superficial treatment, and typically the clinical range is up to 3–4 cm. It can be performed with so-called superficial applicators, e.g., based on EM waves in the lower part of the microwave frequency band (usually 434, 915, and 2450 MHz), ultrasound, and IR power. The technological base of EM wave applicators can be of different kinds: waveguides (water filled or with evanescent mode), microwave planar technology (e.g., patches and spirals), and according to results of this habilitation thesis, MTM applicators are very perspective as well.

From a physical point of view, we mostly want the superficial applicators to create the best possible approximation of a plane EM wave, which is the case of the deepest penetration of EM power into the area to be treated (at a given working frequency) and the best homogeneity of SAR distribution and thus, the best homogeneity of temperature distribution as well.

A system for local hyperthermia consists of a microwave (MW) power generator, an MW applicator for transfer of EM power into the treated area, see eq. (7) (tumor), a multichannel thermometer with several probes for temperature measurements in the tumor and its surroundings, and the main computer. See the schematics in Figure 2.

Figure 2.

MW hyperthermia system schematics.

Invasive sensors then measure temperature, and according to it, MW power is being controlled in order to keep the temperature on a predetermined level.

The applicator is positioned upon the area to be treated and coupled to the tissue by a water bolus. The temperature and pressure of the water in the water bolus are possible to control, so it is possible to modify the temperature profile in the area to be treated.

In our discussion, it is essential to distinguish the following two important terms: “Depth of EM wave penetration” and “Depth of efficient treatment.” The second one can have different definitions for different clinical applications of thermotherapy treatments (i.e., hyperthermia, physiotherapy, and ablations). Here, we will work with the definition for hyperthermia only.

2.4 Depth of EM wave penetration and depth of efficient treatment

For the initial estimation of EM wave penetration into biological tissue, we can take a model for the behavior of amplitude of the plane wave in a lossy media.

$$E\left(z\right)=E_0{e}^{-\mathrm{\alpha z}}$$E1

where E is electrical field intensity, E₀ is its value at the surface of biological tissue, z is the depth under the surface, and α means the attenuation constant of EM wave in lossy media.

The depth of the EM wave penetration d then has its definition in EM field theory based on the decrease of the amplitude of electrical field intensity to value E_o/e (where e is a basis of natural logarithm) when a plane EM wave enters into a lossy media; see the following equation.

$$d=\frac{1}{\sqrt{\mathit{\pi \sigma }{\mathrm{\mu }}_{0}f}}.$$E2

It can be seen that d is inversely proportional to the square root of σ and ${\mu }_0$ of a given tissue and to the frequency f of the EM field. For the usual operating frequencies of the applicators 27, 70, 434, 915, and 2450 MHz (all of them except 70 MHz belong to ISM frequency bands reserved for industrial, scientific, and medical applications), it can be concluded that the lower the operating frequency, the deeper will be the penetration depth. The same conclusion can be made for the value of conductivity.

In the case of microwave hyperthermia, the depth of the efficient treatment is given by the distribution of temperature in the treated area—it is formulated as a 25% decrease of the SAR value with respect to the maximum value of SAR inside the treated area. That guarantees quick and quality heating of the treated area from 37°C to at least 41°C. Suppose the maximum temperature in the tumor will be at the level of 45°C, then the depth of the efficient treatment depends on the following factors:

1. Depth of EM wave penetration – At a given working frequency and a given type of biological tissue.

2. EM field distribution in the aperture of the applicator – Usually, we are trying to create in the aperture of the applicator the distribution of EM field very similar to plane wave—thus, it is possible to accomplish the deepest penetration depth for the particular frequency and aperture dimensions.

3. Aperture size of the applicator – Bigger aperture size helps to approach better the EM field distribution inside the applicator aperture to the case of a plane wave. Very good results are expected if the aperture dimension size is comparable or bigger than a half wavelength at the operating frequency.

4. 3D configuration of biological tissues in front of applicator aperture – Biological tissues can roughly be sorted into two categories: high or low water content. Tissues with high water content have higher attenuation than tissues with low water content. So, e.g., in the fat layer, there is EM wave less attenuated than in muscle tissue, and thus it penetrates deeper in fat than into muscle tissue.

5. Temperature of water in water bolus – This water can cool the surface of the area to be treated and thus improve the temperature profile inside this area.

There is a general rule for hyperthermia applicators optimization if we need to reach the maximal depth of efficient treatment and the best possible homogeneity of the temperature distribution inside the treated area. At least in the central part of their aperture, the distribution of the EM field should be very similar to plane wave; thus, it is possible to accomplish the deepest penetration depth for the particular frequency and aperture dimensions.

2.5 Regional hyperthermia

The term “Regional hyperthermia” means treating deep-seated tumors of the pelvis or lower extremities, etc. The so-called regional applicators can perform treatment, i.e., usually, an array of phase-controlled radiating elements typically working in the frequency range of 50–150 MHz. As radiating elements again, waveguides or dipoles are mostly being used. They surround the whole circumference; all possible directions are employed to deliver EM energy into the treated volume. The higher number of antennas and higher the frequency have the potential to control the heating 3D pattern. Several rings of antennas directed to the patient axis can be used to enable flexibility with respect to the anatomical structures for optimization.

A system for regional hyperthermia consists of a microwave (MW) or radiofrequency (RF) multichannel power generator (multiple power generators), an array of MW applicators for focusing EM power into the area to be treated (tumor), a multichannel thermometer with several probes for measurements of temperature in the tumor and its surroundings, and the main computer; see the schematics in Figure 3.

Figure 3.

Schematics of microwave system for regional or part-body hyperthermia.

Applicators are positioned upon the area to be treated and coupled to the tissue by a water bolus. The water temperature in the water bolus is possible to control, so it is possible to modify the temperature profile in the area to be treated, like in the case of local hyperthermia. In the case of regional hyperthermia, the water temperature in the water bolus is usually below 10°C.

From a physical point of view, we mostly want to create the best possible approximation of a cylindrical or spherical EM wave irradiated from several (typically from 4 up to 12) single applicators situated around the patient. Superposition of the waves from these single applicators then creates inward propagating cylindrical or spherical waves, enabling the focus EM power in the area to be treated. Thus we can get the best approximation of the tumor dimensions and shape by dimensions and shape of the SAR distribution and thus, the best approximation of temperature distribution.

In discussed case, when we have a cylindrical phantom surrounded by several above mentioned applicators, then for the thermotherapy, the most important component of the EM field will be longitudinal component Ez, which in the discussed case can be expressed by equation.

$${\mathbf{E}}_z\left(r\right)=K{\mathrm{H}}_0^{\left(2\right)}\left(\mathit{\gamma }r\right),$$E3

where ${\mathrm{H}}_0^{\left(2\right)}$ is the Hankel function of zero order and second kind, K is a constant, r is a radius vector, γ is a complex propagation constant. Hankel function ${\mathrm{H}}_0^{\left(2\right)}$ can be calculated as a linear combination of the Bessel function ${\mathrm{J}}_0$ and the Neumann function ${\mathrm{N}}_0$:

$${\mathrm{H}}_0^{\left(2\right)}\left(\mathit{\gamma }r\right)={\mathrm{J}}_0\left(\mathit{\gamma }r\right)–\mathrm{j}{\mathrm{N}}_0\left(\mathit{\gamma }r\right),$$E4

As cylindrical agar phantom is mimicking muscle tissue, i.e., lossy medium, then the argument of Hankel function is a complex number. In Figure 3, there are three basic cases of temperature distribution inside an area treated by regional hyperthermia, which follows from the behavior of the Hankel function (see the narrow colored strips signed by letters a, b, and c):

• If the frequency is very low (from 27 to 80 MHz) and thus the depth of the penetration at this frequency is comparable to or bigger than the radius of the phantom D/2, then the shape of the temperature distribution may be approaching the case a, which corresponds to part-body treatment.

• If the frequency is increased to 100 MHz or higher (i.e., attenuation constant is increasing), then we expect to approach the shape of the temperature distribution given by case b of a very significant focus of temperature on the tumor. This case corresponds to regional treatment.

• Case c then corresponds to the situation when the depth of penetration of the studied EM wave is much less than the radius of the area to be treated. This typically happens for frequencies of, e.g., 434 MHz and higher. This case corresponds to deep local or superficial local treatment.

Given examples of frequency bands are valid either for the human body of average dimensions or for agar phantom with similar dimensions and dielectric parameters with values near to values valid for muscle tissue.

2.6 Part-body hyperthermia

Part-body hyperthermia is a technique derived from the regional approach and developed to heat a selected anatomical region in an extended manner up to 41–42°C under careful MR monitoring. From a physical point of view, we want mostly to create the best possible approximation of a spherical EM wave irradiated from several (typically from 12 up to 24) single applicators situated around the patient.

Superposition of the waves from these single applicators then creates inward propagating spherical waves enabling the focus EM power in the area to be treated. Thus, we can get the best approximation of the tumor dimensions and shape by dimensions and shape of the SAR distribution and thus, the best approximation of temperature distribution.

Due to safety reasons, the use of MR monitoring (to measure online temperature and perfusion) and a planning system is required at these higher power levels. Systems for part-body hyperthermia are called “hybrid systems” because they are based on the MR-compatible integration of a multiantenna applicator into an MR tomograph.

2.7 EM waves in biological tissue

The most important effect from the point of view of microwave thermotherapy is the propagation of EM waves through the biological tissue to be treated. It can be classified as lossy dielectrics. So the power (energy) of propagating EM wave will be changed into thermal power (energy). For more details, see [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20].

EM energy turns to heat, particularly due to the following mechanism: When the alternate field takes effect, vibrating electric particles lag behind the exciting intensity of the electric field; the current is not entirely in phase with electric field intensity. It is possible to describe this phase mathematically in a way that we virtually split up the movement of electrons into:

• Component that follows electric field intensity.

• Component that is in phase with the difference of potentials on electrodes.

The first component mentioned above determines the real part of permittivity ${\epsilon }^{\prime }$. The other one is the cause of loss of current heating up the dielectric and determining the imaginary (conductive) part of permittivity ${\epsilon }^{\prime \prime }$. From this, relative permittivity depends on the polarization charge value of the dipole, and alternate losses depend on the weight and volume of moving particles. The dielectric quality is thus given by the ratio of particle charge and particle mass.

When the electromagnetic energy goes through the biological tissue, it is absorbed and turned into heat, resulting in a temperature increase of biological tissue within the irradiated area. Spatial distribution of temperature induced the way mentioned above (with respect to depth of EM wave penetration and depth of efficient treatment) depends on various factors.

The interaction of the EM field with biological tissue studied from a physical point of view is well described in several references, e.g. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20], so we do not need to go into the details here. When studying these interactions to be used in clinical applications of thermotherapy, then usually it is necessary to determine by calculations or measurements following 3D or 4D distributions:

• The 3D spatial distribution of the values of the EM field main quantities (e.g., vector of electric field strength E(x,y,z), vector of magnetic field strength H(x,y,z), etc.) in a certain area of the biological tissue—area to be treated.

• The 3D spatial distribution of power P_a absorbed in a given biological object can be for a single point or elementary volume (voxel) calculated as

$$P_a\left(x,y,z\right)=\frac{\sigma }{2}{\left|\mathbf{E}\left(x,y,z\right)\right|}^2.$$E5

The 3D spatial distribution of specific absorption rate—the SAR [W/kg] indicates the EM energy absorbed in the biological tissue and, as shown by the unit, it is the power absorbed per 1 kg of tissue

$$\mathit{SAR}=\frac{\delta }{\mathit{\delta t}}\left(\frac{\mathit{\delta W}}{\mathit{\delta m}}\right)=\frac{\delta }{\mathit{\delta t}}\left(\frac{\mathit{\delta W}}{\mathit{\rho \delta V}}\right)=\frac{\mathit{\delta P}}{\mathit{\delta m}}=\frac{\mathit{\delta P}}{\mathit{\rho \delta V}},$$E6

where W is the electromagnetic energy absorbed in the biological tissue, t is the time, and m denotes mass. P is the power of the electromagnetic wave that spreads the biological tissue, ρ is the density of the tissue, and V is the volume. By introducing the spatial distribution of the intensity of the electric field E (x, y, z), the relationship is as follows:

$$\mathit{SAR}=\frac{\sigma }{\rho }\frac{{\left|E\left(x,y,z\right)\right|}^2}{2}$$E7

Which can be further modified as SAR = P_a/ρ. In case of experimental evaluation of the SAR, we can measure the temperature increase ΔT after heating by EM-power in time interval Δt.

$$\mathit{SAR}=c\frac{\mathit{\delta T}\left(x,y,z,t\right)}{\mathit{\delta t}}=c\frac{∆T\left(x,y,z,t\right)}{∆t},$$E8

where c is the specific heat of the biological tissue or its phantom and SAR very well defines the level of exposure of the biological tissue.

• The 4D—i.e., spatial and time-dependent distribution of temperature T (x,y,z,t) in a given biological object, which can be calculated from the so-called Penne’s Bioheat Equation, see in part 2.9 of this chapter.

High-frequency electromagnetic fields can penetrate the human body and propagate through. During the propagation of EM waves through biological tissues, their energy is gradually absorbed and converted into heat, thereby increasing the temperature of the irradiated area. To such a wave, biological tissues behave as a lossy dielectric. In such a case, permittivity and permeability become to be complex numbers. The spatial distribution of temperature depends on many factors, the most important of which are:

• The type of the EM wave (i.e., whether it is planar, cylindrical, or spherical).

• Operating frequency determines the EM wavelength (i.e., penetration depth).

• Spatial distribution of the biological tissue in the irradiated volume.

• Dielectric and thermal characteristics of each tissue type in a certain area.

• Blood flowing into the treated area.

2.8 Treatment planning of clinical application of thermotherapy

The term treatment planning for clinical application of the thermotherapy means mathematical and experimental modeling of the effective treatment timing to determine the four-dimensional (4D) distribution of temperature (i.e., 3D in space + temperature behavior with respect to time) during the scheduled treatment (both within the treatment area and in its surroundings).

When preparing a particular type of clinical application, it is necessary to perform a series of experiments and model calculations to create a specific idea about the actual distribution of temperature (with respect to SAR) in the treated area. It is a highly complex problem that is not yet fully resolved. This is due to several factors, of which the most important may be considered:

• highly inhomogeneous nature of the biological object—i.e., mainly irregular and complex definable spatial distribution of different types of biological tissues in the human body,

• in practice, the usually unavailable precise description of the topology of the bloodstream, and particularly its response to external stimuli—i.e., mainly at an increasing temperature in the treatment area,

• very “complicated” nature called near electromagnetic field emitted from the aperture thermotherapy applicators.

In the case of treatment planning, first, we need to do the calculation of SAR 3D distribution and after to do the calculation of the temperature 3D distribution. This distribution inside the treated area (heated by microwave energy q) can be expressed from the well-known Pennes Bioheat Eq. (1948):

$$\rho C_p\frac{\partial T}{\partial t}=\nabla \bullet \left(k\nabla T\right)+{\omega }_b{C}_{p,b}\left(T_a-T\right)+q_m+\mathit{\text{ρSAR.}}$$E9

where T is tissue temperature (K), t is time (s), ρ tissue density (kg/m³), C_p specific heat capacity of tissue (J/kg/K), C_p,b specific heat capacity of blood (J/kg/K), k thermal conductivity (W/m/K), ω_b volumetric blood flow rate (kg/s/m³) of the specific tissue, T_a arterial blood temperature (usually 37°C), and q_m metabolic heat source rate (W/m³).

The possibilities of an analytical solution to this equation are limited to a few cases—e.g., the “one-dimensional” case of plane wave penetrating homogeneous phantom. Therefore, computers are to be used to solve this equation to obtain the temperature $T\left(x,y,z,t\right)$ time dependence and 3D space distribution. For the treatment planning of microwave thermotherapy, it is possible to use commercially available SW products, e.g., SEMCAD X, Sim4Life, Comsol Multiphysics, and CST Microwave Studio.

In general, it is necessary to solve the time dependence of the temperature $T\left(x,y,z,t\right)$ at different points in complex three-dimensional space with the inhomogeneous structure of the biological tissue whose blood supply changes depending on heating. This is not analytically solvable in general, only partially in the case of simplified geometric models.

The versatile option is to apply numerical methods using very powerful computers. The numerical solution then typically uses differential methods or finite element methods. The biggest problem then acts precisely, defining and modeling the bloodstream and its responses to cool or heat certain areas of the human body. The situation is further complicated dramatically by the topology of the heated area. The topology can be a good guess for subsurface treatment in clinical applications. However, the more complicated is the situation for deep regional heating when mapping the treated area requires a CT and/or MRI.

3. Noninvasive temperature monitoring

Noninvasive temperature monitoring of hyperthermia cancer treatment is one of the crucial points for its successful clinical applications. MRI is often discussed to be a prospective solution to this problem. However, it is a costly way (commercially available hyperthermia system controlled by MRI has a price above 1 million EUR). Because of that, cheaper solutions-based on, e.g., microwave or ultrasound technology, could be a convenient alternative to MRI temperature monitoring. Till now, microwave radiometers have been discussed for this purpose. Radiometers can measure the absolute value of temperature, but their spatial resolution is not sufficient. They integrate thermal noise from certain volumes, and thus, they indicate approximately average temperature inside this volume, so it may happen that the microwave radiometer will not identify existing hot spots or cold spots.

Our theoretical and experimental research work is focused now on microwave differential tomography (MDT). The Department of Biomedical Technology (the Czech Technical University in Prague) developed its own MDT system (see photo in Figure 4) in cooperation with Prof. Andrea Massa from Eledia Research Center (Trento, Italy). It seems realistic that the MDT methods can be used for 3D noninvasive temperature monitoring of the treated volume during thermotherapy in oncology. Existing suitable reconstruction algorithms, which allow quasi-real-time monitoring of changes of dielectric properties due to changes of temperature, were implemented. Reconstruction algorithms were tested on different 2D and 3D models. The obtained results using the Distorted Born Algorithm (DBA) and Born Algorithm (BA) were compared in terms of the algorithms’ ability to reconstruct the shape and position of the target and flatness of the obtained object function in regions without change in dielectric properties.

Figure 4.

Photograph of an experimental system for research of MDT.

4. Microwave applicators

Our research work is oriented toward studies and developments of local external applicators working at 27, 70, 434, and 2450 MHz (see Figure 2). These applicators were used to treat deep-seated and/or superficial tumors (treatment depth from 2 up to 8 cm).

Now, following new trends in this field, we continue our research in the important directions of regional applicators (see Figure 3). Moreover, we are trying to implement new microwave technologies in the design of new hyperthermia applicators, e.g., applicators based on metamaterial technology. Our BioEM team with Prof. Paul Stauffer from Thomas Jefferson University Hospital in Philadelphia has developed such applicators. Research of MW thermotherapy systems and MW medical diagnostics is in Prague done in cooperation with Dept. of EM Field (Faculty of Electrical Engineering) and Dept. of Biomedical Technique (Faculty of Biomedical Engineering), both are part of the Czech Technical University in Prague. The most important technical activities in this field can be specified as:

• Design of the applicators based on new MW technologies, i.e., development of new type applicators for more effective local, intracavitary, and regional treatment;

• Development of treatment planning, i.e., mathematical and experimental modeling of the effective treatment;

• Feasibility study of noninvasive temperature monitoring, e.g., microwave differential tomography or UWB radar technology;

• MW medical diagnostics (e.g., MW differential tomography).

In Figure 5, there is an example of the calculated distribution temperature obtained by a matrix of a 3x2 MTM elements array. The highest temperature level is displayed here in red color, and the yellow color denotes the threshold therapeutic temperature of 41°C.

Figure 5.

Calculation of the temperature distribution at 3.5 cm depth under the 3 × 2 MTM elements array. The yellow color denotes the threshold of the treated area.

In actual clinics, we need the treatment planning to create so-called phantoms of the patient body or at least phantoms of the area to be treated, see Figure 6a and b. In Figure 6a, there is an example of a homogeneous phantom; in Figure 6b then, there is an example of the anatomical phantom. The first one is suitable for verifying the fundamental behavior of the applicator; the second one then is needed for the 3D SAR and 3D temperature distribution during the treatment of the actual patient.

Figure 6.

Example of a homogeneous (a) and the anatomical phantom (b).

In Figure 7, an example of SAR distribution is calculated for the case of the anatomical phantom. A very strong focus of MW power on a big tumor can be observed here.

Figure 7.

Example of SAR distribution calculated for the case of anatomical phantom given in Figure 6.

5. Microwave medical diagnostics

As mentioned above, recently, there have been strong trends in research to apply microwave technology in medical diagnostics. Significant importance for the future can be identified for above all the following methods: microwave differential tomography, microwave diagnostic UWB radar, and microwave radiometry.

5.1 Microwave differential tomography (MDT)

In Prague, the MDT is developed by a research group from the Dept. of Biomedical Technology in cooperation with Prof. Andrea Massa and his group from ELEDIA Research Center (University of Trento, Italy). Theoretical works are focused on a theory of differential microwave imaging (DMI) in quasi-real-time. Existing suitable reconstruction algorithms, namely Distorted Born Algorithm (DBA) and Born Algorithm (BA), which allow quasi-real-time monitoring of changes of dielectric properties due to changes of temperature, were implemented. They were applied and tested both numerically and experimentally within the feasibility studies.

These reconstruction algorithms were tested on numerical data from numerical 2D and 3D simulations; see Figure 8.

Figure 8.

Numerical models for testing of reconstruction algorithms.

The below described results based on DBA and BA were compared in terms of the ability to reconstruct the shape and position of the target and flatness of the obtained object function in regions without change in dielectric properties. Influences of varying TSVD threshold values, number of voxels, calibration, and normalization were tested. BA with a low TSVD-threshold value leads to clear pictures of the difference in relative permittivity, but we lose information about the difference in conductivity. The described algorithms were tested with a sphere that was virtually homogeneously heated. The resulting pictures were not of the clear boundary of the so-called objective function: the predicted changes of object function are smooth, see Figures 9 and 10. Even if the implemented algorithms show several deficits, they represent state of the art and are therefore a suitable starting point in developing the combined MW system. Here described, the principle of noninvasive temperature monitoring, once it is commercially available, would mean a very significant improvement in quality assurance for hyperthermia treatment of oncological patients in actual clinics and for the comfort of their treatment as well.

Figure 9.

Results of reconstruction on a 2D model.

Figure 10.

Results of reconstruction on a 3D model.

In Figure 4, there is a photograph of the laboratory MDT system built at the Dept. of Biomedical Technique. In this case, it consists of eight bow-tie antennas, but we can go up to 24 antennas in total. Necessary MATLAB scripts for measurements automatization, data acquisition, and image reconstruction were implemented by us. We created numerical models for solving the forward problem, which is necessary for the reconstruction algorithms. A preliminary evaluation of the system based on measurement results was performed at the same time. It seems realistic that the DMI methods can be used for 3D noninvasive temperature monitoring of the treated volume during thermotherapy in oncology.

Currently, we study (by means of numerical simulations) the suitability of different types of antennas, e.g., their EM principle, dimensions, number, and geometrical configuration. We know that the main resolution limit of the described system is a low number of radiating elements. We plan to extend the system to the maximum possible number of antenna elements (i.e., up to 24). We believe there will be considerable improvement in the resolution.

Another prospective possibility of using the principle and technology of DMI is the rapid detection, identification, and classification of strokes (SDI), which would be essential for the quick, qualified decision of what kind of treatment is necessary to give to the stroke patient already in the ambulance when he/she is being transferred to the hospital. The Pioneer research group in this area is a team of Prof. Mikael Persson from Chalmers University in Goeteborg, Sweden.

5.2 UWB radar

Dr. Marko Helbig and Dr. Juergen Sachs from TU Ilmenau in Germany came up with the idea to use microwave UWB radar technology for noninvasive microwave imaging and/or noninvasive temperature monitoring. In Prague, they are followed by people from the Dept. of EM Field.

The detection of temperature change via UWB radar signal is based on the fact that the complex permittivity changes with temperature. We have shown that it is possible to detect these changes by UWB microwave radar. In our case, the antenna array comprises eight dipole antennas (21 x 11 mm). These antennas are excited by the UWB pulse in the frequency band 1–8 GHz. The values of relative permittivity and specific conductivity of all considered tissue temperatures (at starting temperature of 37°C) can be taken, e.g., from the IT’IS Foundation database.

We worked with an experimental antenna setup for UWB temperature change detection to be used in microwave hyperthermia treatment. Our numerical and laboratory models with implemented frequency and temperature dispersive parameters of biological tissues were used for a series of simulation purposes. The results from our numerical simulations show that it is possible to identify even very low changes in tumor permittivity caused by temperature change.

Our experiments with the homogeneous and nonhomogeneous phantoms have shown that we can detect even different temperature layers. From the reconstructed image, we can partially reconstruct the shape and position of the simulated inhomogeneity. The way to improve the chance for more accurate differential temperature reconstruction is in the higher number of antennas closer to the heated area utilization and in the attenuation correction improvement.

6. Biological effect of microwave power

Research studies on the interactions between the EM field and biological systems have been the subject of high interest during the last decades. Here, we would like to give more details about such kind of research and obtained technical and biological results (i.e., basic description of implemented exposure systems). Two of our recent projects were oriented on the research of thermal effects of EM field (using either waveguide or array applicators). And the third one then on the research of nonthermal effects. Whole-body exposure chamber, operating at 900 MHz, was developed for small animals in the frame of this research project. The setup was designed with respect to homogeneity of induced EM field, elimination of external radiation, and exact determination of absorbed power. Further sufficient space for mice movement was taken into account. The whole-body exposure chamber with an anatomical mouse model was simulated by two different numerical methods, e.g., finite-difference-time-domain method (FDTD) and finite integration technique (FIT), and compared computed SAR values and its dosimetry results.

6.1 Exposure chamber

The major advantage of the system we will describe here is the capability of direct measurement of the whole-body averaged SAR, which is performed by analysis of measured scattering parameters. As the basic idea and principle of the discussed exposure chamber, a circular waveguide was chosen. The advantage of the waveguide structure is a perfect shielding of EM field generated either inside (in order to protect the operators) or generated outside the system (in order to eliminate interference caused by external EM fields). The circularly polarized wave TE₁₁ is excited inside the exposure chamber with the aid of two monopoles that have mutually orthogonal orientations, and the distance between them is equal to one-fourth of the wavelength. Such circularly polarized wave provides relatively constant field coupling to each mouse regardless of its position, posture, or movement. The discussed exposure chamber is displayed in Figure 11.

Figure 11.

Waveguide-type exposure chamber for animal experiments.

EM field distribution and impedance matching of the discussed exposure chamber were optimized and verified by 3D EM field simulators SEMCAD X resp. Sim4Life. Dimensions of the exposure chamber were calculated to use the desired frequency of operation and the volume needed to expose mice. The exposure chamber is made of a copper cylinder with dimensions of 1650 mm in length and 240 mm in diameter. It is terminated by matched loads at both ends (conical shape, 500 mm long, and made of RF absorbers). The reflection loss of the matched load is more than −20 dB at 900 MHz.

The exposed mice are kept in a cylindrical box that is made of Styrofoam. Styrofoam has a dielectric constant of 1.03, i.e., very close to that of air, and thus, the disturbance of exposure and measurements is negligible. The box provides space for two separated mice. Punctured slit-like holes are set on the cover and side of the box for air ventilation. In the study, the mice were held in the chamber only during RF exposures, and therefore, no food or drinking water was necessary.

For the survival of experimental animals inside the exposure chamber, it is important to create efficient ventilation, which will maintain a constant temperature and good air quality in the chamber. The air comes toward mice through the ventilation hole placed below the styrofoam box and flows toward the second opposite ventilation hole placed above the box.

To be able to evaluate the results of experiments with small animals (mice in our case), we need to specify appropriate dosimetry. It is the quantification of the magnitude and distribution of absorbed EM energy within biological objects that are exposed to EM fields. In the case of radiofrequency and microwave frequency bands, there is the dosimetric quantity, which is called SAR (i.e., specific absorption rate). It is defined as the rate at which energy is absorbed per unit mass. The SAR is determined and influenced not only by the incident EM waves but also by the electrical and geometric characteristics of the irradiated subject and objects nearby it. It is strongly related to the internal electric field strength E as well as to the electric conductivity σ and the density of tissues ρ as discussed above and as can be seen, reminded by the following equation.

$$\mathrm{SAR}=\mathrm{\sigma }.{\mathrm{E}}^2/\text{2ρ}\left(\mathrm{W}/\mathrm{kg}\right)$$E10

Therefore, SAR is a suitable dosimetric parameter, even when a studied mechanism is determined to be “athermal.” SAR distributions are usually determined from measurements in animal tissues or from numerical calculations. It generally is difficult to measure the SAR directly in a living biological body, and therefore, dosimetry efforts are forced to rely on computer simulations mainly.

An anatomically based dielectric model of an experimental animal is essential for numerical dosimetry. It can be developed commonly from MRI or CT scans. In order to develop it, original gray-scale data must be interpreted into tissue types known as a process of segmentation. In our studies, the CT scans for mouse model development were obtained from the website: http://neuroimage.usc.edu/Digimouse_download.html. The mouse model has the resolution 0.1 mm, meaning voxel size 0.1 x 0.1 x 0.1 mm. Each voxel was assigned to one of 14 different tissue types, such as bone, muscle, brain, etc.

For dosimetry with the numerical voxel models, proper permittivity and conductivity values must be assigned to each tissue. The data from 10 MHz to 6 GHz, derived from 4-Cole-Cole extrapolation based on measurements for small animals, constitute the most widely accepted database for this information. The data are recommended by various international standardization organizations and can be accessed, e.g., from the website http://www.fcc.gov/fcc-bin/dielec.sh.

6.2 Result of biological experiment

In order to verify and rely on numerical dosimetry results, the simulations of the exposure chamber were done in two different EM field simulators (based on two different numerical methods). Our choice was SEMCAD X, which uses the finite difference time domain (FDTD) method, and CST Microwave Studio, which uses the finite integration technique (FIT) method. We used these simulations to the determination of SAR distribution inside the mice during experiments.

Researchers from Medical Faculty in Pilsen, Charles University (Prof. František Vožeh, MD., Jan Barcal, MD.), did biological experiments with the aid of this exposure chamber. With the aim of whether EM exposure can increase the content of free radicals in the exposed tissue, a series of EM exposures to small animals (mice) was done. SAR level was at the level of 0.8 W/kg in the case of these experiments. Evaluation of preliminary results is displayed in Figure 12. It can be interpreted as a significantly increased content of free radicals being found.

Figure 12.

Results of an animal experiment: in all four studied organ specimens (brain, heart, kidney, and liver), significantly increased content of free radicals was found.

Acknowledgments

This research was funded by Ministry of Education, Youth and Sports of the Czech Republic under Grant LTC19031, and the Student Grant Competition of the CTU, grant number SQS20/203/OHK4/3T/17.