Prelude

Our bodies appear, from the outside, to be solid masses that are slow to change but, just beneath the surface, the body's fluids are in constant motion. Blood moves at high velocity throughout the body within an interconnected and highly branched network of vessels (Figure 8.1). The human circulatory system is responsible for the movement of fluid, and therefore the vital nutrients contained in the fluid, throughout the body.

The purpose of the circulatory system is a familiar one to engineers and bakers; it provides mixing, and good mixing is an essential element of many successful enterprises. Cakes are made from flour, eggs, sugar, and milk (among other things); your birthday will be ruined (or at least a bit tarnished) if the chef does not mix these ingredients well. But why must humans be mixed? Mixing exposes cells throughout the body to oxygen and other nutrients, while simultaneously providing a pathway for removal of waste products. It is the circulatory system that enables us to grow large, so that we have inner regions that are separated from the atmospheric oxygen that all cells need for energy (Figure 8.2).

Circulation of fluids is the function of the cardiovascular system. The human cardiovascular system is composed of three separate organs: The heart serves as a pump, the vasculature serves as the plumbing, and the blood is the circulated fluid. Failure in any of these organs can result in failure of the system, so diseases of the cardiovascular system have grave consequences.

Biomedical engineers have made contributions to almost every area of cardiovascular health, including construction of artificial hearts and heart valves (see Chapter 15), understanding of the flow properties of blood, and mathematical modeling of the microcirculation. In fact, some of the most important work in understanding the special blood vessels that develop in tumors has been done by biomedical engineers (Figure 8.3).

Prelude

Humans eat, drink, and breathe to bring into their bodies the raw materials for growth, repair, and generation of the energy necessary for life and the actions that bring pleasure to life. This chapter provides an overview of human nutrition and respiration from the perspective of biomedical engineering (BME). The human body is an elegant machine that requires inputs for sustained operation. What are the processes responsible for input of nutrients and raw materials? How are molecular nutrients extracted from inhaled and ingested materials? How are these processes controlled?

The human machine requires food and water for continued operation, but the relationship between food intake and human health is complex and poorly understood. Some things are clear: Whole foods that we ingest get broken down into components such as amino acids and sugars, which the body uses to synthesize new proteins and to generate or store energy. Some elements of these metabolic processes are presented in Chapter 2. Protein synthesis, energy generation, and metabolic processes occur in cells throughout the body; hence all of these processes are related to the circulation of molecules in the body, which is discussed in Chapter 8. This chapter will look at overall events and establish some general descriptions of the quantity and composition of what enters our bodies.

The issues of food intake, nutrition, and human health are becoming increasingly important in the United States. The Centers for Disease Control and Prevention (CDC) report a dramatic increase in obesity in the United States during the period from 1985 through 2005 (Figure 7.1). In addition, diseases related to environmental exposure to toxins and pollutants are widespread and the numbers are still increasing. Asthma among children has increased to epidemic proportions, accounting for 1 in 6 of all visits to pediatric emergency departments in the United States (Figure 7.2).

How can biomedical engineers help address public health problems such as obesity and asthma? One of the central themes of engineering is the analysis and interpretation of mechanisms, often from complex systems in which all of the internal workings of the system are not known.

Prelude

Each person ingests a large number of molecules per day with meals and snacks (Figure 9.1). A similarly large number of molecules enters the body through respiration (Figure 9.2). Body processes—such as building proteins, producing energy, and replenishing lost nutritional stores—use many of these molecules (recall Table 7.1). But a sizeable number of ingested chemicals are either not usable or not needed by the body, and therefore must be eliminated. In addition, metabolic processes generate waste products that are toxic if they accumulate in body tissues. These molecules must also be eliminated.

The problem of elimination of molecules is staggeringly complex, because the diversity of molecules that can be ingested is enormous (recall Table 7.3). In addition to molecules gained in our diet, each person—in the course of sleeping, walking, or bicycling through his or her normal day—will inhale diverse molecules that float freely in the atmosphere. The systems of elimination in the body must be capable of responding to this onslaught; they must safely manage both the number of molecules and the diversity of molecules to ensure the chemical balance that is necessary for life.

Life processes require a rather stringent set of chemical conditions. As examples, Chapter 2 described the importance of pH, which must be maintained within narrow limits for proper function of cells and proteins, and Chapter 5 described the importance of sodium and potassium concentrations in the normal function of neurons. The function of communication systems within the body, such as the nervous system and the endocrine system, depends on the release, movement, and recognition of specific chemical messengers. These systems cannot function well if stray molecules compete with normal recognition processes. This is one of the reasons that chemical composition within the brain is tightly regulated by the blood–brain barrier. Most organs and tissues do not have individual protective mechanisms like that of the brain; instead they rely on organs that are specialized for molecular exchange and excretion to maintain an overall homeostasis in the body.

Prelude

Most cells are fully independent living entities, capable of consuming nutrients, growing, and functioning autonomously (see Chapter 5). The human body is a collection of trillions of cells and, amazingly, these units act in a coordinated fashion, so that people can walk (usually without bumping into walls), breathe (without consciously motivating each breath), and kill invading pathogens (without knowing that they are there). How is the operation of all of these cells coordinated? This chapter reviews how cells communicate with each other directly and through signaling molecules to relay signals from outside and inside the cell (Figure 6.1).

Cells communicate with each other directly or indirectly via molecules called ligands. In direct cell–cell communication, the ligands are bound to the surface of the cell providing the signal. Soluble, diffusible ligands are released by cells for indirect communication with target cells to which they are not physically connected; these soluble ligands may communicate with nearby targets or targets that are long distances away. The target cell has specialized proteins called receptors, which are often located on the target cell surface, but anchored in the membrane. Some receptors, such as steroid hormone receptors, are located inside the target cell, so the ligand must be able to cross the cell membrane to bind to them. All receptors have two properties: 1) they bind specifically to their ligand, and 2) they initiate signals inside the cell. The binding of ligand to its receptor is similar to the “lock-and-key” fit between an enzyme and its substrate (see Chapter 4). The difference is that the binding site does not have catalytic activity, so the ligand is not chemically altered after binding. Some receptors do have intrinsic, or built-in, catalytic activity located in other parts of their structure that can be activated upon ligand binding. How tightly a ligand binds to its receptor is called its affinity and can be determined as described in Box 6.1.

Prelude

The previous chapter introduced three of the major subjects of interest in bio-molecular engineering: drug delivery, nano-biotechnology, and tissue engineering. This chapter focuses on additional applications of biomolecular engineering, particularly approaches for enhancing the function of the immune system. The most familiar application of biomedical engineering (BME) in immunology is the development of vaccines.

The development of vaccines that are both safe and effective has been one of the great achievements of modern medicine. Because of an effective vaccine, smallpox—a frequently fatal disease that claimed thousands of lives in previous centuries—has been eradicated, or eliminated as a natural infectious agent. Other severe infectious diseases, such as polio and influenza, are now in control in most countries of the world. There are, however, many diseases that have proven to be difficult for vaccine makers. Acquired immune deficiency syndrome (AIDS), which is caused by infection with human immunodeficiency virus (HIV), has killed millions of people worldwide and there is still no effective vaccine available. In some parts of the world, deaths from HIV/AIDS have a substantial impact on overall life expectancy (Figure 14.1). Most residents of developed nations, such as the United States, receive a spectrum of vaccines during child hood, but there are no vaccines for other diseases (such as malaria, schistosomia sis, and diarrheal disease) that are major causes of death in the developing world (Table 14.1). According to the World Health Organization (WHO), vaccines and clean water are the two public health interventions that have had the most substantial impact on world health. Both of these interventions represent the work of engineers: civil and environmental engineers, who developed water sanitation systems, and bio-medical and chemical engineers, who developed methods for the mass production of safe vaccines. Vaccines prolong the lives of millions of people each year by preventing infectious diseases. Because of the development of an effective and portable vaccine, smallpox—a disease that took the lives of millions and likely caused the fall of Aztec civilizations—has been eradicated from the world.

Prelude

The search for artificial replacements for failing human organs is long and filled with great successes. Today, hemodialysis is routinely used to replace kidney function, artificial hip prostheses allow millions of people to walk, and artificial lenses provide cataract sufferers with clear vision. There are many disappointments as well; despite decades of serious effort, there is still no proven artificial heart or liver.

This chapter describes the success of several artificial organs, including hemodialysis for treating kidney failure and artificial hips. It also describes the efforts to build artificial hearts, livers, and pancreases, and the challenges that remain for these artificial organs. Because all artificial organs depend on the use of materials, usually manmade materials, the chapter begins with a review of biomaterials science, and the body's response to implanted biomaterials.

Biomaterials

A biomaterial is often defined as “a nonviable material used in a medical device, intended to interact with biological systems” (1). Notice that, in this definition, biomaterials are “nonviable,” or not living: They are nonliving materials that are introduced, for some purpose, into a living body. To be most useful, these materials should be biocompatible, or not harmful to the living body in which they are placed.

Over the years, some materials have been demonstrated to be biocompatible after implantation, although the degree of compatibility can vary significantly depending on the site of implantation and the function of the material at that site. Biomaterials are now used routinely in diverse medical applications—from contact lenses to artificial hearts. Frequently, the materials used in biomedical applications are polymers (Table 15.1) or metals (Table 15.2).

The concept of biocompatibility is essential for understanding how biomaterials are used in humans. Unfortunately, biocompatibility in materials is difficult to define precisely. A useful definition, which is accepted by most experts, is “the ability of a material to perform with an appropriate host response in a specific application” (2).

Prelude

The cell is the basic functional unit in the body. The human body is composed of more than 200 different types of cells (Figure 5.1). Each cell of an individual is genetically the same: They all share the same genetic information, but cell types within an individual differ with respect to size, shape, and constituent molecules (Figure 5.2); therefore, they have different properties. For example, liver cells have abundant enzymes for detoxification of chemicals whereas red blood cells have abundant hemoglobin for oxygen transport. These differences are important to the function of the cell in the context of the organ in which it resides.

The human body contains trillions of cells: most estimates range from 10 to 200 trillion cells in an average person, but a research group examining all of the estimates suggests that 37 trillion is the best number (1). Despite a great diversity of cell composition and function, the trillions of cells in each person share common properties. In addition to their identical genetic material, most cells in the body have the same structural organization. Cells in humans are all surrounded by a lipid bilayer membrane and contain many of the same structural features. For that reason, biologists can discuss general principles of the operation of the cell. Of course, specific types of cells exhibit behaviors and properties that are specific to that cell type.

Much of what is known about cells has been learned from the study of cells in culture (Figure 5.1). Cell culture, or the maintenance and growth of cells outside of the body, was first discovered in the early 1900s and is now routine. The ability to maintain and study cells in a controlled and reproducible fashion has enabled scientists to dissect and classify many of the functions of human cells. Experiments in cell culture are often called in vitro experiments—from the Latin phrase meaning “in glass”—because they occur in an artificial environment, outside of the living organism.

Prelude

One of the most fascinating and well-known stories in science is that of the discovery of the structure of DNA, which was accomplished by James Watson and Francis Crick in 1953, when both were young men working at Cavendish Laboratory in Cambridge, England. Watson's autobiographical book, The Double Helix, describes that period of accomplishment, but it retains its popularity because it deals directly with a more general theme. It might be the best description for modern readers of the magical quality of science and its appeal for young people seeking adventure, mystery, and fame. In this way, the story of DNA, beginning with its unveiling, has been linked to romance, celebrity, and power.

DNA, the most famous of the family of biological polymers called nucleic acids, is worthy of this glamour. Nucleic acids are the key information storage molecules of life. Genetic information is encoded within the nucleic acids of almost every cell in our body, where it is capable of being inherited from one cell to the next, generation after generation. The study of nucleic acids is multifaceted: It involves examination of the structure and function of nucleic acid polymers, the capacity of these molecules to hold information, the changes in information content that happen upon modifications of nucleic acids, the diverse roles of nucleic acids in the life of a cell, and the characteristics that make them useful tools in biomedical engineering. In fact, as in many other areas of science and technology, the use of the nucleic acids DNA and RNA is becoming central to the work of biomedical engineers. The biological polymers called nucleic acids were introduced in Chapter 2; this chapter will expand on that introduction, showing how nucleic acids work to store genetic information and perform other essential biochemical functions.

DNA is intimately involved in human health. Many diseases result from failures at the DNA level.

The field of biomedical engineering has expanded markedly in the past 15 years. This growth is supported by advances in biological science, which have created new opportunities for development of tools for diagnosis of and therapy for human disease. This book is designed as a textbook for an introductory course in biomedical engineering. The text was written to be accessible for most entering college students. In short, the book presents some of the basic science knowledge used by biomedical engineers and illustrates the first steps in applying this knowledge to solve problems in human medicine.

Biomedical engineering now encompasses a range of fields of specialization including bioinstrumentation, bioimaging, biomechanics, biomaterials, and biomolecular engineering. Most undergraduate students majoring in biomedical engineering are faced with a decision, early in their program of study, regarding the subfield in which they would like to specialize. Each subfield has a set of course requirements, which can be supplemented by wise selection of elective and supporting coursework. Also, many young students of biomedical engineering use independent research projects as a source of inspiration and preparation but have difficulty identifying research areas that are right for them. Therefore, a second goal of this book is to link knowledge of basic science and engineering to current research, and the accompanying opportunities to create new medical products, in each subfield.

As a general introduction, this textbook assembles foundational resources from molecular and cellular biology and physiology and relates this science to various subspecialties of biomedical engineering. The first two parts of the book present basic information in molecular/cellular biology and human physiology; quantitative concepts are stressed in these sections. Comprehension of these basic life science principles provides the context in which biomedical engineers interact and innovate. The third part of the book introduces the subspecialties in biomedical engineering and emphasizes – through examples and profiles of people in the field – the types of problems biomedical engineers solve.

Time to harvest …

In Chapter 9, the tools allowing us to optimize and to rationally design chromatographic processes have been presented. Rules of thumb like “continuous processes must be preferred at large scale” are dangerous, and only a rigorous approach based on a detailed definition of tuning parameters, constrained parameters, objective function and algorithms guarantees the best option among those considered. The rigorous approach makes extensive use of numerical simulations and of the more or less detailed models presented in the first nine chapters of this book. We are, however, aware that a complete numerical design approach does not say a lot about the key drivers for performance. This chapter is therefore a series of situations designed as pedagogical examples, to be solved using the framework presented in the previous chapters. Our objective is not to make the reader an expert in specific processes, some of which have benefited from 40 years of continuous improvement, nor to give recipes for ready-to-cook meals, but to illustrate a methodology, to give decent orders of magnitude and, it is hoped, ideas to help the reader solve his own problems. Instead of proposing detailed process design, we will therefore favor shortcuts to better highlight features that we consider essential. We will keep the mathematics and detailed modeling to a minimum, in order to focus on a few messages that we consider key. With the essence of the problem well in mind, the previous chapters give the reader the methodologies and techniques for addressing specific topics requiring further detail and precision.

For confidentiality reasons, while the problems are real, the laboratory results and design parameters are not exact industrial data; they are, however, reasonable and precise enough for our conclusions to be realistic. Having orders of magnitude and references in mind is very important for performing an engineer's work; that is why typical characteristics of chromatographic processes are given in Appendix J.