Integrated Nano-Biomechanics

Takami Yamaguchi, Takuji Ishikawa, Yohsuke Imai

• Publisher: Elsevier
• Year: 2018
• Print ISBN: 9780323389440
• eBook ISBN: 9780323389594
• Topic: Medicine
• Subtopic: Medical Microbiology & Parasitology

Integrated Nano-Biomechanics provides an integrated look into the rapidly evolving field of nanobiomechanics. The book demystifies the processes in living organisms at the micro- and nano-scale through mechanics, using theoretical, computational and experimental means. The book develops the concept of integrating different technologies along the hierarchical structure of biological systems and clarifies biomechanical interactions among different levels for the analysis of multi-scale pathophysiological phenomena. With a focus on nano-scale processes and biomedical applications, it is shown how knowledge obtained can be utilized in a range of areas, including diagnosis and treatment of various human diseases and alternative energy production.This book is based on collaboration of researchers from a unique combination of fields, including biomechanics, computational mechanics, GPU application, electron microscopy, biology of motile micro-organisms, entomological mechanics and clinical medicine. The book will be of great interest to scientists and researchers involved in disciplines, such as micro- and nano-engineering, bionanotechnology, biomedical engineering, micro- and nano-scale fluid-mechanics (such as in MEMS devices), nanomedicine and microbiology, as well as industries such as optical devices, computer simulation, plant based energy sources and clinical diagnosis of the gastric diseases.- Provides knowledge of integrated biomechanics, focusing on nano-scale, in this rapidly growing research field- Explains how the different technologies can be integrated and applied in a variety of biomedical application fields, as well as for alternative energy sources- Uses a collaborative, multidisciplinary approach to provide a comprehensive coverage of nano-biomechanics

1

Introduction

Takami Yamaguchi Biomedical Engineering, Tohoku University, Sendai, Japan

Biomechanics contains a wide variety of research fields related to biology and mechanics. It was conventionally regarded to deal with rather mechanical aspects of biology such as motion, deformation, and flow of biological existence. However, nowadays, biomechanics extends its realm to almost all essential parts of studies of life. Embryology is a good example of the extension of biomechanics to the deepest secret of life. The very first most important event in the embryonic development of the fetus, the gastrulation, is now one of the most actively studied phenomena of cellular biomechanics. Through gastrulation, we were transformed from two-dimensional object to truly three-dimensional existence. Biomechanics of solid structure is mandatory to understand the process. Moreover, the determination of the laterality of the body is now known as being governed by the flow produced by the flagella motion in the fetus.

Migration, attachment, and invasion of white blood cells (WBCs) are the key phenomenon in the inflammatory response of the living system against infection. To construct a comprehensive view of the recruit, compilation, and immune activity of the WBCs, we find the biomechanics mandatory. Some key phenomena should be clarified by mechanics, such as how the WBCs come close to the vascular inner wall in the blood flow streamline, how it is attached to the endothelium, and how it goes across the intraendothelial junction to work in the extracellular inflammatory region. These questions can never be fully answered without the consideration of blood flow and cellular mechanics. Chemical attraction, which is commonly recalled by biologists, cannot explain the phenomena because the blood flow and the concentration boundary layer produced by the flow interfere the transmission of chemical substances between the vascular wall and flowing cells.

Above all, the discovery of the mechanical transduction of the cell opened a wide gate to a new discipline of mechanobiology that can help in the understanding of integrated biological problem. Living system lives in the mechanical environment from its first stage of germs to the senescent degradation. It is now widely recognized that there is no complete nor fruitful study on the living system without considering its mechanical condition and the response and adaptation to it.

Needless to say, progress of biology in the 20th and 21st century was remarkable. Led by the development of molecular biology, understanding of function and structure of living system has been incredibly advanced in these centuries. To be noteworthy, from the late 20th century, mechanical responses of living system drew strong attention of biologists who had never been interested in or even neglected mechanical environment of living cells. First, it was recognized by the biomechanists that endothelial cells of relatively large vessels have a capability of sensing fluid mechanical stress and adapt to the shear stress exerted by the blood flow. Before that time, these mechanical responses were interesting to a limited group of biomechanists and were estimated as rather a peripheral phenomenon to the mainstream of biology. Most of biologists tend to regard the mechanical phenomena as a toy of mechanists who do not understand the mainstream of biology. However, studies have revealed that many biological processes that seem to be purely biological not mechanical are caused and governed by the mechanical events and conditions. If we include, for example, the diffusion that is naturally a physical phenomenon, all the signal transduction in the living system can be said to be mechanically driven.

The reason why we are particularly concerned in the nanoscale study is that the nanometer-scale interactions of the component of the living organism should be regarded as the site of life itself. Apparently, most fundamental substances comprising life, for example, protein, nucleic acids, lipids, and carbohydrate molecules, are not living. They are just chemical substances. Life lies under the interactions of these components, that is, chemical and physical reactions, of the nanometer scale. If we proceed more into picometer- or femtometer-scale phenomena, we see how those molecules are composed but not the life phenomenon as it is clearly distinguished from merely chemical reactions. Though we do not want to revive the archaic vitalism, needless to say, nanoscale interactions among components of the cell, if they are fully understood, would answer our most fundamental question, what is life.

Life emerged in the cosmos of purely inorganic materials under physical or mechanical conditions and evolved in the terrestrial environment. It forged itself a distinguished existence that lives. Throughout its evolution, it was immersed in the gravitational influences whence its structure and function were developed inevitably under mechanical constraints. It is natural, therefore, that mechanical construction and behavior are crucial to understand and comprehend its secret. It is obvious that our most fundamental question, that is, “what is life?,” will never be solved without the wide and profound use of mechanics of the utmost wide, from molecular to ecological length and timescales. Living organisms are extremely complex system, of which multiple levels of interactions take place and regulated by the physicochemical control system. It is now widely accepted even by traditional biologists that mechanical behavior is the key to elucidate the mechanism of life even when it seems to be pure chemical or biological. Mechanics always play important roles in the living beings and the contribution of mechanical structures and the functions of living organisms. Of many levels of mechanical interactions that govern life, cellular and subcellular mechanical interactions are most significant.

So far, we have mainly concentrated into healthy or normal life phenomena. However, boundaries of normal condition are delineated by abnormal or disease phenomena. Those boundaries must be carefully determined by studying various pathological degradations by diseases. It is noteworthy that the boundary between healthy and diseased condition is not usually clearly divided. They are in a sense continuous. Therefore, we now have to study the transition and difference between normal healthy mechanical condition and disease pathological escape, as well as the purely normal healthy conditions. By this study, we will more deeply understand life. Research of the pathological state is of course potentially useful to find measures of diagnosis and treatment of diseases. Though our principal purpose of the current series of studies is to understand the mechanics and mechanism of life, we believe that we will be able to contribute to medicine through such approaches.

As earlier discussed, it is certain that the cell is the entity that is alive. Because there is no concise definition available, we usually use some descriptive definition of life. Though there are some variations of the descriptions, metabolism, reactivity, compartment, and reproduction are major necessities by which we distinguish the living and nonliving system. Cell undoubtedly fulfills the requirement. However, none of subcellular components do. Mitochondrion is an exception, but it cannot survive when it is taken out from the cell after a very long cohabitation with eukaryotic cells. It is also undoubtedly clear that any molecules, even very large and complex protein, are not alive. If we accept the fact, we will be obliged to consider that the relationship or interactions between these components of the cell are life, and this is the reason why the nanoscale biomechanics is necessary. After the establishment of molecular biology, particularly so-called omics studies, complex nature of the biological existence is exceedingly pronounced. However, not the appreciation of complex nature nor its massive statistical analysis without guiding principle leads to truly comprehensive understanding of life. In this sense, nanoscale interactions between subnanoscale substances in the cell, which our nanoscale study is aimed, are the key issue of the biology.

Biology of the cell revealed that every cell has an ability to sense and quantitate the mechanical environments surrounding it. This understanding is now widely possessed by researchers, and thus, the field of the study is called mechanobiology. Not only mechanics is important in the analysis of mechanical response of special cells such as endothelium of the vascular wall, but also the study of many different kinds of cells should be carried out. Mechanical receptor proteins or mechanoreceptor channels are widely studied in sensing cells. These receptor-mediated mechanisms may be a part of mechanobiological processes. However, we need to consider the whole structure of the cell that responds to mechanical stimuli and detailed mechanism. Again, this is the level of nanobiomechanics, and further study, not merely molecular research, is now necessary.

In the multicellular organism including us, no cells move and work independently, except blood cells and germ cells, such as sperm and egg. Of those exceptions, egg is literally single, and others are collective. In order to analyze and understand the collective motion of those cells, single-cell motion should be examined first. Of those cells of collective motion, erythrocyte or red blood cells (RBCs) and platelets are thought of as purely passive because they have no motive element. Leucocytes or WBCs and sperms are active in their motion. However, their motility has quite different timescale. The timescale of spermatic motion is an order of 1–10^{− 3} s, while motion of leucocytes is almost passive when they are in the blood flow and become motile after they stick to the vascular wall. Its motion on and through the vascular wall could be an order of 1–10^{− 3} s or longer. In the case of sperm, their interaction to each other may not be important. However, it is shown that sperms move collectively. Interaction is very important in the case of blood cells. RBCs, particularly due its concentration in the blood, must be eventually analyzed through their multiple-body interactions. WBC motion must be analyzed with their interactions not with each other but with their interactions with the erythrocytes in the blood flow and with endothelial cells when they reside adjacent to the wall. Platelets are smaller than those blood cells, and their motion is strongly influenced by the RBC. Formation of thrombosis and hemostasis should be understood under this condition. Consequently, motion and characteristics of the multicellular fluid such as the blood must be examined through the single-cell mechanics, and their collective nature should be reconstructed by the collective motion of the unit component. This is an attempt to reorganize the rheology of the physiological fluids and is now possible to discuss this thanks to huge-scale computation.

Traditionally, particularly in the field of engineering, mechanics studies are divided into some subfields, typically fluid mechanics, solid mechanics, thermodynamics and transport phenomena, mechanical dynamics, and electromagnetics. However, we have to place a stress on the fact that none of the biological phenomenon can be analyzed by only one of those subspecific measures. For example, production, transmission, and transduction of biological signals are governed by the interaction of the electric field and electromagnetic transformation of ion channel protein molecules and the diffusion of molecules in the synaptic gap. This typically ends up in the contraction of muscle to produce macroscopic motion of the body. Conventionally, this process is not studied from the mechanical viewpoint. However, whole process is based on mechanics. Electric excitement and transmission of the pulse are sequential processes of the electromagnetic deformation of the channel protein, and final transmission of the excitement is based on the axonal transport of the material from the neuronal cell body to the synapse. Nanoscale biomechanics should be involved in the study of whole physiology of the living system as such.

Fluid-solid interaction is another problem of intermechanics or combined studies. As shown later in this book, a number of biological systems are composed of solid components and fluid components. Simplest cell in the whole body, the RBC, is a good example. It has no intracellular solid components such as the nucleus and the mitochondria, but just a thick solution of hemoglobin occupies the cell. Our analysis revealed, nevertheless, that the stiffness of the cell membrane and the viscosity of the intracellular fluid relative to that of surrounding fluid, which is the plasma, greatly affect the deformation and motion of the RBC and therefore total blood flow in the smaller vasculature. This is a typical example showing the necessity of the fluid-solid interaction studies, though the theoretical difficulty and the computational load are incredibly high. Existence of the cell-free layer in the vasculature is another example of the study that needs the extensive and rigorous fluid-solid interactions analysis of very large number of RBCs.

Diffusion of gases such as oxygen and carbon dioxide generated from metabolic processes, nutrients of a wide range of molecular weight, and messenger molecules from small-molecular-weight gas to large-molecular-weight polypeptides and proteins play very important roles in physiology. Particularly, the diffusion of these particles in the thick solution of cells, such as RBC, should be carefully analyzed because the interactions of the large (i.e., cellular)-scale motion of the medium strongly affect the diffusion and distribution of the smaller solutes in the blood.

Solid mechanics is now not only for the analysis of hard tissue such as bones and cartilages. The smaller the scale of biological motion analysis is analyzed, the smaller the source of force generation should be considered. In the fetal development, earlier mentioned, the flow of fluid produced by flagella motion is now focused in the study of the origin of laterality. This is another fluid-solid interaction problem, and the solid components actively contribute. In the utmost large scale, in terms of biological process, cardiac muscle contraction and the macroscopic blood flow are also such kind of complex fluid-solid interaction problem, although this is out of our scope of nanobiomechanics.

Traditionally, two measures have been recognized in the field of mechanics research; they are experimental and theoretical studies. The third category, computational studies, became feasible after the late 20th century, and it occupies almost equal part as other two measures nowadays. Because we have been involved in computational studies for a long period, let us first depict the advancement of computational studies.

It is not very long ago when the third way of study, the computation, was recognized and accepted as the potentially important measure. When we started to construct the computational biomechanics, some 40 years ago, there were many controversies against it. At that moment, power of computer was so poor that it could not allow us to deal with complicated phenomena, such as fluid-solid interactions. It is well known that the first supercomputer, the Cray-1, whose number of installation was very limited in the world, had an ability of peak floating point operations of 10⁸ FLOPS (~ 100 MFLOPS) that is now much slower than that of the portable telephones. In the highest range of scientific computing, as is well known, computational power is discussed by an order of 10¹⁶ FLOPS. In early days, available computer power to ordinary research was much less than that of the highest level at that time, and we had to conduct studies under such restriction. However, owing to very rapid development of computer technology, we can now utilize incredibly higher (than that were available then) computer power and extend studies on what was thought to be impossible at that time. Of particular interest is the intervention of so-called graphics processing unit (GPU) microchips. Though this is an offspring of popular microcomputer technology, especially that of game machines, its speedup of floating point multiply-accumulate operations drastically affects the scientific computing. If we carefully choose the computing algorithm, we can now build a laboratory level supercomputer with affordable price as is discussed in the later part of this book.

This amazing increase of computer power actualized two important aspects of computational studies. First, it became possible to apply computation to problems of very large scale. In this book, the reader will find some examples of the advancement such as the flow analysis of RBCs in even small arterioles of the radius of an order 10^{− 4} m and number of cellular components involved approaches to the order of 10^{− 4}–10^{− 6}. Second, advancement is the refinement of methods and accuracy of computation. Orders of accuracy have been steadily improved for about 10^{− 3}–10^{− 6} or even smaller. Thus, we can now try to challenge every complex problem with extremely large scale in terms of numbers of elements in the computational domain with very high accuracy, so that we can now discuss the computational results with high confidence as theoretical and experimental results in many field of interest. We will see number of our results of complex computational studies in the following sections of this book.

Experimental studies are also advanced by the introduction of many sophisticated instruments and powerful experimental tools. From the mechanical viewpoints, development of various kinds of microscope significantly improved our understandings of nanoscale biomechanical phenomena. Of many microscopic instruments currently available, we find that the cryoelectron microscopy, particularly its tomographic extension applied to motor proteins in the cell, is of great significance. As later discussed in this book, it can help our understanding of the mechanism of intracellular transport phenomena. So, many transport mechanisms contribute to the cellular functions. Forces also emerged through the transport mechanism. The cryoelectron microscopy visualizes the molecular mechanism of those transport phenomena in a form that computational studies can be used to quantitatively follow the course of reactions. Another example of newly introduced microscopic method is the confocal laser scanning microscope. When it is applied to relatively large-scale RBC flows, it proves to be a powerful tool to analyze various types of diffusion processes in the cellular motion, again which is shown in a form that modern ultralarge-scale computational analysis results can be combined to build truly integrated nanobiomechanics.

Nanobiomechanics so far discussed should be said a comprehensive endeavor to understand life itself. It also bridges the molecular biology and mesoscale, that is, cellular and tissue level, biology. As previously discussed, molecule itself does not live, but interactions of molecules are where the life phenomenon rises up. Consequently, all the macroscopic biological phenomena, however complex its appearance seems, can be understood on the basis of nanobiomechanics. For example, our studies on the fluid-solid interactions between RBC and plasma fluid, started from analyses of single-cell motion, now reached to the level that the macroscopic rheological properties are reproduced by massive computation. Though, needless to say, the living organism is extremely complex and studies of biology are explosively advancing, we believe that the nanobiomechanics approach is one of most important keys to understand the whole life phenomena and to develop methods to cope with dis...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• 1: Introduction
• 2: Biomechanics of Microcirculation
• 3: Biomechanics of the Digestive System
• 4: Biomechanics for Pathology and Treatment
• 5: Ciliary Motion
• 6: Swimming Microorganisms
• 7: Microfluidic Devices Based on Biomechanics
• 8: Biomimetics
• Index