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Biological fundamental concepts
Biological cells
All living organisms are made of cells. The smallest living unit of structure and function of all the organisms in the human body is the cell. Each human being contain about 100 trillion (1014) cells. [1] These cells grouping together have certain characteristics which are important for the proper, essential, and basic functioning of tissues, organs, and human body systems. Cells, which are commonly several microns in diameter, are distinguished by their sizes and shapes which can be related to their specific functions. For example, the length of the muscle cells may be a few millimeters and that of the nerve cells (axons) may be over a meter.
The entire characteristics of a cell mainly include: a thin membrane or plasma which contains or holds the cell together called cytoplasm which is like a gel material within the membrane and usually a nucleus. In fact, not all cells have a nucleus, but some muscle cells have several nucleus and red blood cells have no nucleus. Within the cytoplasm, there are several types of specialized subunits called organelles which perform certain specific metabolic functions.
The cell membrane separates biological cells into two parts: a highly specific intracellular chemical content and nonspecific extracellular solution. The membrane selectively controls the transport of chemical species into and out of the cell. [4]
The human’s cells have complex structures which are rich with complicated charged surfaces. When they are exposed to force, they can change their orientation and movement because of being stuffed with high charged atoms and molecules. The cell nucleus controls the cell activities and contains most of the human body’s hereditary information in the chromosomes. Genetic materials are stored in strands along the chromosomes. Genes are usually composed of double stranded DNA (Deoxyribonucleic acid) which controls the most cellular activities in the form of twisted helix. A cell reproduces itself by using a blueprint stored in genetic materials in its nucleus.
Cells grow, change, and reproduce in a continuous cycle process which is referred to mitosis. Chromosomes in a cell nucleus are duplicated into two identical sets of chromosomes with its own nucleus. While the cells which do not have the nuclei like human red blood cells cannot divide.
Biological tissues
Similar cells from the same origin are grouped together and combined with their intercellular materials to form biological tissues. Organs are then formed by the functional grouping together of multiple tissues. There are four basic types of biological tissues: epithelial, connective, muscular, and nervous.
• Epithelial tissues such as the surface of the skin, the airways, and the reproductive tract are made up of cells in single or multilayered membranes. They serve as protective layers to perform function of protection and regulation of secretion and absorption of material in body organs and systems.
• Connective tissues consist of dispersed cells which typically lack intercellular contact and nonliving materials which are called an extracellular matrix such as fibers and gelatinous substances. It gives shape to human organs and holds them in place. Typical examples of connective tissue are blood and bone.
• Muscular tissues have several functions such as production of force and motion (either movement within internal organs); propulsion of blood through vessels, movement of food or body secretions through tracts and thermoregulation. Muscular tissue has three distinct categories: skeletal muscle (controlled voluntarily) found attached to skeletal elements and cartilage providing for important movement; visceral or smooth muscle (controlled involuntarily) found in the inner linings of organ; and cardiac muscle (controlled involuntarily) found in myocardium of the heart, allowing it to contract and pump blood throughout an organism. [7] [8]
• Nervous tissue is the main component of the two parts of the nervous system; the brain and spinal cord of the central nervous system (CNS), and the branching peripheral nerves of the peripheral nervous system (PNS). [9] Nervous tissues are composed of two main types of cells: nerve cells and glial cells which provide communication with other types of tissues in order to sense, control and govern human body activities. Nerve cells receive and transmit impulses. Glial cells surround neurons to support, protect, separate and nourish them.
Neoplasm, tumor and cancer
Neoplasm is an abnormal growth of tissue having four groups of: benign, in situ, malignant, and neoplasm of uncertain or unknown behavior.[10][11][12] When the abnormal growth of tissue forms a mass or appears enlarged in size, it is commonly referred to as a tumor (figure 1.5). Some neoplasms do not form a tumor. Cancer, also known as a malignant tumor or malignant neoplasm is a group of diseases involving uncontrolled abnormal cell growth with the potential to invade nearby parts of the body or spread to other parts of the body. [13][14] Not every change in the body’s tissues will lead to a cancer except the pathological tissues which are not cured.
The medical terms tumor and cancer are sometimes mentioned interchangeably which can make people misunderstand. In fact, a tumor is not necessarily a cancer. A cancer is a particularly threatening type of tumor. The tumor generally refers to a mass. The term cancer specifically refers to a new growth which is able to invade surrounding tissues, metastasize (spread to other organs) and which may eventually make unsuccessfully cured patient die. It is important to explain clearly the difference between tumor and cancer to the patients. Distinctions among the different neoplasms are listed in the table 1.1.
There are more than 100 different known cancers which affect various parts of the body. Each type of cancer is unique with its own causes, symptoms, and methods of treatment. The most common 6 types of cancer which make human die are: lung, liver, stomach, colorectal, breast and oesophageal cancer. In 2012, World Health Organization (WHO) estimated that 14 million people were diagnosed with cancer across the world and 8.2 million people died from the disease. Annual cancer cases are expected to rise from 14 million in 2012 to 22 million within the next 2 decades. [13] Human cancer is the result of the accumulation of various genetic and epigenetic changes of normal cells almost anywhere in the human body. Normally, human cells grow and divide to form new cells as the body needs them, but if the cells in a part of the body grow out of control, cancer will appear. Normal cells become cancer cells because of changes and damages to their DNA.
Normal cells constantly communicate with each other to keep human body healthy. Communications are carried on by using chemical signals produced in the body. The chemical signals are accepted by the receptors either on the surface or inside the cell. This triggers a flow of signals inside the cell sending messages to its nucleus. Finally, the messages get through to tell the cell properly switches certain genes on and off or to do something correct such as division and death.
For cancer cell, the signaling often goes wrong. For examples, the messages accepted by the nucleus might be sent too many times; the messages might not get through at all or be sent even though no chemical singling has not attached to receptors. Cancer cells might have extra receptors boosting the effects of the signals. Cancer cells grow much faster than the human body’s own healthy cells. They can become detached from their neighbors (figure 1.6). That can explain why they are able to spread so quickly to other parts of the body once it has gained a foothold. Cancer cells grow out of control and become invasive. Different characteristics between normal cells and cancer cells are compared in the table 1.2 and what is especially mentioned is that the polarizations between cancerous and normal cells are opposite (figure 1.7).
Electromagnetic hyperthermia
Electromagnetic therapy
In recent years, medical applications based on various sources of electromagnetic energy have been more and more widely investigated. Research and development of medical devices with various diagnostic and therapeutic applications have been also driven and carried out because of the advances in electronic and electromagnetic domains. Therapies using electromagnetic sources at radio frequencies and microwave frequencies can be classified in thermal therapy methods. Thermal therapy includes all therapeutic treatments based on transferring thermal energy into or out of human body. The major objective of thermal therapy is to efficiently treat pathological tissues without damaging normal tissues. It is considered as a minimally invasive alternative technique comparing with traditional surgery in the treatment of tumor and cancer. Figure 1.8 shows the schematic view of thermal therapy methods.
The cryotherapy is a treatment mainly with liquid nitrogen to reduce the tissue temperature below –50°C for more than 10 minutes. This allows the freezing and the disruption of the cell membrane leading to the physical cell destruction. For other heating methods above 40°C, according to the attained temperature level and treatment time duration, thermal therapy is generally categorized into three different modalities:
• Diathermia is to produce local heat in body tissues by electric currents for therapeutic purposes. Heating up to 41°C with applications in physiotherapy for the treatment of rheumatic diseases.
• Hyperthermia makes temperature of a part of the body or of the whole body be raised to a higher than normal level (41–45°C), which may allow other types of cancer treatments such as radiation therapy or chemotherapy to work better.
• Thermal ablation produces very high temperature (above 45°C) and can be used to destroy cells within a localized section of a tumor. This is commonly used in oncology for cancer treatment, in urology for benign prostatic hyperplasia (BPH) treatment, and in cardiology for heart stimulations and other areas. [21]
Effect of heat injury on biological tissues
Injury of the tissue by thermal energy has two distinct phases. The initial phase is direct heat injury which predominantly depends on the total energy applied to the tissue. Some studies demonstrate that tumor or cancer cells can be destroyed at lower temperatures than normal cells. The second phase is indirect injury after focal hyperthermia application which produces a progression of damage in the tissue.
The effects of heat injury are determined by the applied total thermal energy, attained temperature, rate of heat removal, and specific thermal sensitivity of tissue. The temperature elevation in a biological tissue generates multiple complex influences on cellular, sub–cellular and molecular levels. The main mechanism for cell death is probably protein denaturation, beyond 40°C, which leads to alterations in multi– molecular structures (e.g., membranes) and synthesis and repair of DNA. One of the most important influences is an increase in blood perfusion. It means that the physiological process guarantees the oxygen and chemical components of cells. An increase of blood flow is responsible for removing the heat excess via the blood vessels through the body.
Table 1.3: Effect of temperature on biological tissues [22]
Changes of physical and biological properties of tissue at different temperature levels with associated expose time are shown in the table 1.3. Classical hyperthermia cause irreversible cellular damage with temperature 42-45°C. Beyond 50°C, apoptosis, the phenomenon of protein denaturation can cause immediate death of tumor cell. Beyond 100°C, vaporization phenomenon happens, because of the amount of water in the tissue decrease sharply. Beyond 300°C carbonization, charring and generation of smoke will happen.
Hyperthermia
Hyperthermia is a type of tumor or cancer treatment where body tissue is exposed to high temperatures (45°C). Research has shown that high temperatures can damage proteins and structures within tumor or cancer cells and kill them, usually with minimal injury to normal tissues. [23] It might be defined more precisely as raising the temperature above normal for a decided period of time in a part of or the whole human body. Hyperthermia is always implemented as part of a multimodal, oncological treatment strategy, i.e., in combination with radiotherapy or chemotherapy. The effectiveness of hyperthermia treatment is related to the temperature achieved during the treatment, the length of treatment, and cell and tissue characteristics. [24] To ensure that the desired temperature is reached, but not exceeded, the temperature of the tumor and surrounding tissues is monitored throughout the procedure. There are several types of hyperthermia such as: local hyperthermia, regional hyperthermia, external hyperthermia, whole–body hyperthermia and extracellular hyperthermia depending on the type of pathological tissue and its position.
• Local hyperthermia is to be used for increasing mainly the tumor temperature while sparing surrounding normal tissue with either external or interstitial techniques. Energy is delivered to a small area to heat the tumor. Local hyperthermia treatment is a well–established cancer treatment method. If a rise in temperature to 42°C can be obtained for one hour within a cancer tumor, the cancer cells will be destroyed. [25] Primary malignant tumors have poor blood circulation, which makes them more sensitive to changes in temperature. Local hyperthermia is used to heat a small area. It involves creating very high temperatures that destroy the heated cells. The heat may be applied using three different methods: external approaches; intraluminal or endocavitary methods and interstitial techniques.
• Regional hyperthermia is indicated for patients with locally advanced deep-seated tumors such as those in the pelvis or abdomen. The application of regional hyperthermia is, however, more complex than local heating, particularly because of the wide variation in physical and physiological properties of body tissues. It requires more sophisticated planning, thermometry, and quality assurance. Since regional heating techniques apply energy to the adjacent deep-seated tumors in a focused manner, energy will be delivered to the adjacent normal tissues. [26] Under such conditions, selective heating of tumors is only possible when heat dissipation by blood flow in normal tissue is greater than that in tumor tissue.
• Whole–body hyperthermia is used to treat metastatic cancer that has spread throughout the body. To ensure that the desired temperature is reached, but not exceeded, the temperature of the tumor and surrounding tissue is monitored throughout hyperthermia treatment. Whole-body hyperthermia (to a limit of 42°C) is a distinctive and complex pathophysiological condition which has tremendous impact on tissue metabolism, blood flow, organ function, and tissue repair. [25]
• Extracellular hyperthermia is to heat up the targeted tissue by means of electric field, keeping the energy absorption within the extracellular liquid. It is based on a capacitively coupled energy transfer applied at a frequency that is primarily absorbed in the extracellular matrix due to its inability to penetrate the cell membrane. [27] Since the energy absorption for these effects is more significant than the temperature, it is also important to characterize the hyperthermia by thermal dose but not only by temperature.
Hyperthermia techniques
There are three main significantly developed hyperthermia techniques: ultrasound hyperthermia, radiofrequency hyperthermia, and microwave hyperthermia.
• Ultrasound hyperthermia: Ultrasound waves propagate at a frequency of 2–20 MHz through soft tissues. Absorption of ultrasound energy results in heating of the biological tissues. Theoretically, ultrasound has the best combination of small wavelengths and corresponding attenuation coefficient allowing penetration to deep sites with the ability to focus power into small size regions. The primary limitation of such systems is their inability to penetrate air and the difficulty in penetrating bone. Over the years, ultrasound devices capable of improved heating uniformity and controlled depth of penetration, mostly by using multiple applicators with phasing and power steering, have been designed. [28-34]
• Radiofrequency hyperthermia (RF): the initial investigation of the use of radiofrequency waves in the body is in 1891 [35], which showed that RF waves which pass through living tissue cause a temperature increase in the tissue without causing neuromuscular excitation. For heating large tumors at depth, RF waves in the range of 10–120 MHz are generally used with wavelengths that are long compared to body dimensions. [36] A closed-loop circuit is created by placing a generator, a large dispersive electrode (ground pad), a patient acting as a resistor, and a needle electrode in series. An alternating electric field is created within the tissue of the patient. Ionic agitation in the tumor tissue creates frictional heating within the body, which can be tightly controlled through depositing the amount of RF energy. Studies have shown that RF hyperthermia induced lesions increase rapidly in size at the beginning of RF power application, and then the rate of increase diminishes rapidly as the resistance rises at the interface between electrode and tissue.
• Microwave hyperthermia: Microwave hyperthermia energy is used to destroy cancerous tumors. Microwave hyperthermia was evaluated in the 80s for the treatment of cancer and has been used for the medical treatment of prostate or breast cancer. Microwave hyperthermia has generally utilized antennas working at 915 MHz and 2450 MHz. Microwave hyperthermia is also frequently used in conjunction with other cancer therapies, such as radiation therapy where it can increase tumor blood flow helping to oxygenate poorly oxygenated malignant cells. Table 1.4 shows the types of hyperthermia for different pathological tissues. Table 1.5 shows a comparison among the different hyperthermia approaches.
Thermal ablation
Ablation may be performed by surgery, hormones, drugs, radiofrequency, heat, or other methods. There are mainly two available ablation methods: thermal ablation and chemical ablation. In medicine, high temperature hyperthermia is considered as thermal ablation, which means the removal or destruction of a body part or tissue or its function. Thermal ablation methods include radiofrequency ablation, microwave ablation, laser ablation, and high density focus ultrasound (HIFU) by creating the thermal injury, and cryoablation which achieve cellular death through freezing. Chemical ablation methods include ethanol ablation, which cause diseased cellular death through direct toxicity, and acetic acid ablation. The applicators for thermal ablation techniques are different: electrodes for radio frequency ablation, antennas for microwave ablation, and fiber for laser ablation.
Based on realistic limitations of each thermal approach, any form of thermal therapy is unlikely to replace the others. Thermal ablation can be used to treat a tumor with a defined volume where surgery is difficult to be carried out (e.g., liver) or where organ function is needed to be preserved (e.g., prostate or uterus). However, thermal ablation for treatments of large bulky tumors such as bone, colorectal cancer primaries, soft tissue sarcomas, head and neck nodules and superficial disease (e.g., skin) is not quite helpful. In order to preserve surrounding critical normal tissue structures, more subtle moderate temperature hyperthermia is preferred.
All the mentioned thermal therapies above belong to the minimally invasive therapy techniques for the treatment of different diseases, which are being researched and developed continuously. Minimally invasive techniques could make patients suffer less pain and reduce the risks of the surgical operation. With the developing minimally invasive technologies, they will become better choices for the patients in the future.
Physical characteristics of microwave hyperthermia
With microwave hyperthermia medical therapy, an electromagnetic source (antenna) is directly positioned in the target biological tissue and a proper microwave power is injected to destroy the pathological tissue. The concept of using microwave hyperthermia might come from the microwave oven. The microwave hyperthermia and microwave oven have the similar basic principle.
Figure 1.9: Different types of electromagnetic radiation [38]
Microwave hyperthermia refers to the region of the electromagnetic spectrum with frequencies from 0.9GHz to 2.450 GHz, which is between common infrared and radio frequencies (figure 1.9). Microwave hyperthermia works in the form of non-ionizing microwave radiation at the frequency of 2.45GHz, which heats a dielectric biological tissue. Water of the tissue absorbs energy from the microwave in a process of dielectric heating which is caused by water dipole rotation. The generated power density per volume by dielectric heating could be calculated by the formula:
where ω is the angular frequency, εr » is the imaginary part of the complex relative permittivity, ε0 is the permittivity of free space and E the electric field strength.
Water molecules (H2O) are polar. The electric charges on the water molecules are not symmetric. The alignment and the charges on the atoms of the water are that: the hydrogen side of the molecule has a positive charge, and the oxygen side has a negative charge. Microwave radiation has electric charges too. The representation of the microwave can be considered as the electric charges on the wave flipping between positive and negative. When the oscillating electric charges from microwave radiation interact maximally with water molecules, it causes them flip (figure 1.10). Because of the microwave radiations of different frequencies, the electrical charges on the water molecules could flip forth and back 2 to 5 billion times per second.
Table of contents :
Chapter 1 Biological fundamental concepts and electromagnetic hyperthermia
1.1 Biological fundamental concepts
1.1.1 Biological cells
1.1.2 Biological tissues
1.1.3 Neoplasm, tumor and cancer
1.2 Electromagnetic hyperthermia
1.2.1 Electromagnetic therapy
1.2.2 Effect of heat injury on biological tissues
1.2.3 Hyperthermia
1.2.4 Hyperthermia techniques
1.2.5 Thermal ablation
1.2.6 Physical characteristics of microwave hyperthermia
1.2.7 Current development of microwave hyperthermia
Chapter 2 Dielectric characterizations of biological tissues in microwave frequencies
2.1 Introduction
2.2 Permittivity
2.3 Dielectric mechanisms
2.4 Relaxation time
2.5 Debye relation
2.6 Cole–Cole diagram
2.7 Measurement techniques of dielectric characterizations
2.8 Models of the Open–Ended Coaxial Probe
2.9 Dielectric characterization measurement system
2.10 Dielectric characterization measurement by 1st method: coaxial probe
2.10.1 Electromagnetic therapy
2.10.2 Electromagnetic therapy
2.11 Dielectric characterization measurement by 2nd method: coaxial cable
2.11.1 Electromagnetic therapy
2.11.2 Electromagnetic therapy
2.12 Comparisons
2.13 Experimental tolerance
2.14 Conclusion
Chapter 3 Microwave hyperthermia instrumentation and ex vivo experiments on the biological tissues
3.1 Introduction
3.2 Microwave hyperthermia instrumentation system
3.3 Microwave hyperthermia experiment procedure
3.4 Experimental results 1st method: coaxial cable RG393
3.5 Experimental results 2nd method: Warrior cable
3.6 Comparisons
3.7 Conclusion
Chapter 4 COMSOL Multiphysics simulation of ex vivo microwave hyperthermia instrumentation on the biological tissues
4.1 Introduction
4.2 Introduction of COMSOL Multiphysics
4.3 Heating model for ex vivo microwave hyperthermia simulation
4.4 Design of microwave hyperthermia system
4.5 Microwave hyperthermia simulation protocol
4.6 Ex vivo microwave hyperthermia simulation results
4.7 Parameters’ Influences on the simulation
4.8 Discussions
4.9 Comparisons between experimental results and simulations
4.10 Conclusion
