In the last section we saw how chemical engineers apply principles of biology, biochemistry, and microbiology to synthesize compounds that can be used in medical diagnostics, vaccines, drugs, food technology, agriculture, and specialty chemicals. That breed of chemical engineer is often referred to as the biochemical engineer, and their focus is at the cellular level: how can we manipulate the genetics of a cell or microorganism to produce a chemical compound of importance to humanity, or how can we isolate, concentrate, and nurture an existing cell or microorganism so that it can produce sufficiently large quantities of the important compound?
Another biological branch of chemical engineering is called biomedical engineering. As one would guess from the name, biomedical engineering is the application of chemical engineering knowledge to the fields of medicine and biology. The biomedical engineer must be well grounded in biology and physiology and have engineering knowledge that is broad, drawing upon some aspects of electrical and mechanical engineering, in addition to the core areas of chemical engineering. The biomedical engineer may work in any of a large range of areas. One of these is the provision of artificial means to assist defective body functionssuch as hearing aids, artificial limbs, and supportive or substitute organs. In another direction, closely related to biochemical engineering, the biomedical engineer may use recombinant DNA techniques in an effort to help the body combat disease or build a defense against potential disease.
Before World War II the field of biomedical engineering was essentially unknown, and little communication or interaction existed between the engineer and the life scientist. Today there are many more examples of interaction between biology and engineering, particularly in the medical and life-support fields. In addition to an increased awareness of the need for communication between the engineer and the associate in the life sciences, there is an increasing recognition of the role the engineer can play in several of the biological fields, including human medicine, and, likewise, an awareness of the contributions biological science can make toward the solution of engineering problems.
Interestingly, much of the increase in biomedical engineering activity can be credited to electrical engineers. In the 1950s biomedical engineering meetings were dominated by sessions devoted to medical electronics. Medical instrumentation and medical electronics continue to be major areas of interest, but biological modeling, blood-flow dynamics, prosthetics, biomechanics (dynamics of body motion and strength of materials), biological heat transfer, biomaterials, and other areas are now included in conference programs. Biomedical engineering developed out of specific desires or needs: the desire of surgeons to bypass the heart, the need for replacement organs, the requirement for life support in space, and many more. In most cases the early interaction and education were a result of personal contacts between physician, or physiologist, and chemical engineer. Communication between the chemical engineer and the life scientist was immediately recognized as a problem. Most chemical engineers who wandered into the field in its early days probably had an exposure to biology through a high-school course and no further work. To overcome this problem, engineers began to study not only the subject matter but also the methods and techniques of their counterparts in medicine, physiology, psychology, and biology. Much of the information was self-taught or obtained through personal association and discussions. Finally, recognizing a need to assist in overcoming the communication barrier as well as to prepare engineers for the future, engineering schools developed courses and curricula in biomedical engineering.
Chemical engineers play an active role in a number of broad areas within biomedical engineering, including
Within the medical engineering specialty, chemical engineers continue to make important contributions to the development of artificial organs, artificial tissues, and protheses (artificial implants, joints, and limbs). The first successful artificial organthe artificial kidneywas the result of an innovative government program in the early 1960s that brought together an interdisciplinary team of chemical engineers, materials scientists, and physicians. Chemical engineers supplied the fundamental concepts of fluid mechanics, membrane transport theory, mass transfer, and interfacial physical chemistry to systems design. These chemical engineers developed predictive correlations relating the blood-cleaning performance of dialyzer to operating parameters such as total membrane area, channel dimensions, blow and dialysate flow rates, pressure drop across the device, and temperature. Within five years, several sound engineering prototype systems, using disposable membrane cartridges and sophisticated monitoring and control equipment, were in advanced stages of development. By the 1970s hemodialysis had graduated from an experimental procedure to a well-established, reliable, and safe means of sustaining patients suffering from acute and chronic renal failure. Today, hemodialysis and its companion process, hemofiltration, are standard hospital and clinical procedures and are responsible for major reductions in mortality and morbidity due to kidney failure.
Some of the targets for future artificial organs, such as the pancreas and the liver, are much more complex systems than the kidney, in which large numbers of chemical reactions are carried out. In these cases, attempts at organ replacement have focused on the use of hybrid artificial organs containing living and functional cells in an artificial matrix. Developments of these hybrid systems are critically dependent on the contributions of chemical engineers to interdisciplinary teams.
The concept of the artificial pancreas illustrates how chemical engineers can develop new artificial or semiartificial organs, particularly if they are grounded in whole-organ physiology and biochemistry and capable of communicating fluently with endocrinologists and physiologists. A chemical engineer working alone might conceive of an implantable power-driven insulin pump, for instance, controlled by feedback from an electronic glucose sensor. In talking with an endocrinologist, the engineer might devise an implantable device containing viable pancreatic islet cells that functions as a normal pancreas. Working with a subcellular physiologist and enzymologist, the chemical engineer might come up with what is, in effect, an artificial islet cella "smart membrane" device that senses blood glucose levels and in response releases insulin from a reservoir encapsulated by the membrane. Each of these design concepts is potentially useful; the one that ultimately succeeds in practice will be the one that is easiest to make, most reliable, and most durable under the actual conditions of use. The wide choice of options and alternatives makes this field of research particularly exciting and rewarding for chemical engineers.
Artificial organs that perform the physical and biochemical functions of the heart, liver, pancreas, or lung are one class of organ replacements. A rather different target of opportunity is the development of biological materials that play a more passive role in the body; for example,
Chemical engineers have already applied their knowledge of polymer science and biocompatible materials to seeming mundane, yet vitally important aspects of medicine. One example of this is platelet storage. (A platelet, also called a thrombocyte, is a small, colorless, nonnucleated, usually round body that is very important in the formation of blood clots and is found only in the blood of mammals. Platelets are produced in the bone marrow and stored in the spleen.) Trauma, leukemia, and hemophilia patients commonly require infusions of platelets to control bleeding. These platelets are obtained from separation from donated whole blood and are stored in special plastic bags. Ten years ago, the platelets would only survive 3 days in the bags, and this resulted in a chronic shortage of platelets, particularly during periods where blood donations declined. Chemical engineers looked at this problem by first analyzing the biochemistry of platelet metabolism. Like may cells, platelets consume glucose (dextrose) by two pathways, and oxidative pathway and an anaerobic pathway. The oxidative pathway produces carbon dioxide, which makes the solution containing the platelets more acidic. (The carbon dioxide dissolved in the liquid can react with water to form carbonic acid.) The second pathway produces large amounts of lactic acid, further increasing the acidity of the mixture. The engineers found that, after several days of platelet cell metabolism, the increase in liquid acidity from both pathways killed the platelets. The chemical engineers used polymer synthesis techniques to design a new material for the storage bag that was capable of "breathing", that is, of allowing carbon dioxide to diffuse out and oxygen to diffuse in, preventing the increase in acidity. Platelets stored in these bags can now survive more than 10 days.
In general, a prothesis is an artificial substitute for a missing part of the body. The artificial parts that are most commonly thought of as prostheses are those that replace lost arms and legs, but bone, artery, and heart valve replacements are common, and artificial eyes and teeth are also termed prostheses. The term is sometimes extended to cover such things as eyeglasses and hearing aids, which improve the functioning of a part. The origin of prosthetics as a science is attributed to the 16th-century French surgeon Ambroise Paré. Later workers developed upper-extremity replacements, including metal hands made either in one piece or with movable parts. The solid metal hand of the 16th and 17th centuries later gave way in great measure to a single hook or a leather-covered, nonfunctioning hand attached to the forearm by a leather or wooden shell. Improvement in the design of prostheses and increased acceptance of their use have accompanied major wars. New lightweight materials and better mechanical joints were introduced after World Wars I and II. The introduction of the new materials was due, in large part, to the expertise of chemical engineers in designing, synthesizing, and producing biocompatible polymeric materials. These new materials are often called "biomaterials", and are discussed in the next section. Sometimes in the case of prosthetic replacement, the new device is constructed out of the same material as the original. But, with increasing frequency, bone, artery, and heart valve replacements are synthetic ceramic and polymeric materials, respectively. For example, when surgeons need to graft bonefor, say, reconstructing someone's face after an accident they dig it out of another part of the patient's body, usually the pelvis. This is a painful operation, and because the patient must undergo essentially two operations, he has to stay on the operating table for a longer time. The result is higher cost and longer recovery time.
Within the past year, biomedical engineers have found a way to avoid that first, bone-harvesting operation. They've developed a polymer scaffold that mimics the structure of real bone. In particular, it's designed to work like trabecular bonethe spongy bone beneath the skeleton's hard outer shell. Like trabecular bone, the matrix has countless interconnected pores, each about a millimeter in size. Nestled within those pores are both osteoclasts (bone-eating cells) and osteoblasts (bone-making cells). When the synthetic bone is transplanted, those cells spread and grow new bone, healing the injury. Researchers have tried to seed bones onto a scaffold before, but with little luck. Some groups tried a matrix of calcium phosphatethe mineral that makes up coral. This appears to work very well when it comes to growing cells, but when it's put in the body it's not absorbed. It just stays there. Another approach is to use biodegradable foams, but the pores in the foam are so small that bone cells can't penetrate them. In the newest approach, by tinkering with two manufacturing processes commonly used to make biodegradable foams, the engineers have made a foam with much larger poresabout the same size as the pores in real spongy bone. This results in cell growth down into the matrix of the foam.
A great advance in fabrication of functional upper-extremity prostheses followed World War II. Arm prostheses came to be made of plastic, frequently reinforced with glass fibers. The below-elbow prosthesis consists of a single plastic shell and a metal wrist joint to which is attached a terminal device, either a hook or a hand. The person wears a shoulder harness made of webbing, from which a steel cable extends to the terminal device. When the person shrugs the shoulder, thus tightening the cable, the terminal device opens and closes. In certain cases the biceps muscle may be attached to the prosthesis by a surgical operation known as cineplasty. This procedure makes it possible to dispense with the shoulder harness and allows finer control of the terminal device. The above-elbow prosthesis has, in addition to the forearm shell, an upper-arm plastic shell and a mechanical, locking elbow joint. This complicates its use, inasmuch as there must be one cable control for the terminal device and another control to lock and unlock the elbow. After World War II the APRL hand (from U.S. Army Prosthetic Research Laboratory) was developed. This is a metal mechanical hand covered by a rubber glove of a color similar to that of the patient's remaining hand. Many attempts have been made to use electrical energy as the source of hook or hand control. This is done primarily by building into the arm prosthesis electrodes that are activated by the patient's own muscle contractions. The electric current generated by these muscle contractions is then amplified by means of electrical components and batteries to control the terminal device. Such an arrangement is referred to as a myoelectrical control system.
Breast prostheses are used after mastectomy. External prostheses may be worn, but surgical reconstruction of the breast, involving implantation of a prosthesis, became increasingly common from the 1970s. This happened because chemical engineers were able to design a material that had the resiliency of tissue, and equally important, biocompatibility so that it was safe to leave in the body without the possibility of rejection.
The treatment of many human disease conditions requires surgical intervention in order to assist, augment, sustain, or replace a diseased organ, and such procedures involve the use of materials foreign to the body. These materials, known as biomaterials, include synthetic polymers and, to a lesser extent, biological polymers, metals, and ceramics. Specific applications of biomaterials range from high-volume products such as blood bags, syringes, and needles to more challenging implantable devices designed to augment or replace a diseased human organ. The latter devices are used in cardiovascular, orthopedic, and dental applications as well as in a wide range of invasive treatment and diagnostic systems. Many of these devices have made possible notable clinical successes. For example, in cardiovascular applications, thousands of lives have been saved by heart valves, heart pacemakers, and large-diameter vascular grafts, and orthopedic hip-joint replacements have shown great long-term success in the treatment of patients suffering from debilitating joint diseases. With such a tremendous increase in medical applications, demand for a wide range of biomaterials grows by 5 to 15 percent each year. In the United States the annual market for surgical implants exceeds $10 billion, approximately 10 percent of world demand.
Nevertheless, applications of biomaterials are limited by biocompatibility, the problem of adverse interactions arising at the junction between the biomaterial and the host tissue. Optimizing the interactions that occur at the surface of implanted biomaterials represents the most significant key to further advances, and an excellent basis for these advances can be found in the growing understanding of complex biological materials and in the development of novel biomaterials custom-designed at the molecular level for specific medical applications.
Research on developing new biomaterials is an interdisciplinary effort, often involving collaboration among materials scientists, chemical engineers, pathologists, and clinicians to solve clinical problems. The design or selection of a specific biomaterial depends on the relative importance of the various properties that are required for the intended medical application. Physical properties that are generally considered include hardness, tensile strength, modulus, and elongation; fatigue strength, which is determined by a material's response to cyclic loads or strains; impact properties; resistance to abrasion and wear; long-term dimensional stability, which is described by a material's viscoelastic properties; swelling in aqueous media; and permeability to gases, water, and small biomolecules. In addition, biomaterials are exposed to human tissues and fluids, so that predicting the results of possible interactions between host and material is an important and unique consideration in using synthetic materials in medicine. Two particularly important issues in biocompatibility are thrombosis, which involves blood coagulation and the adhesion of blood platelets to biomaterial surfaces, and the fibrous-tissue encapsulation of biomaterials that are implanted in soft tissues.
Poor selection of materials can lead to clinical problems. One example of this situation was the choice of silicone rubber as a poppet in an early heart valve design. The silicone absorbed lipid from plasma and swelled sufficiently to become trapped between the metal struts of the valve. Another unfortunate choice as a biomaterial was Teflon, which is noted for its low coefficient of friction and its chemical inertness but which has relatively poor abrasion resistance. Thus, as an occluder in a heart valve or as an acetabular cup in a hip-joint prosthesis, Teflon may eventually wear to such an extent that the device would fail. In addition, degradable polyester urethane foam was abandoned as a fixation patch for breast prostheses, because it offered a distinct possibility for the release of carcinogenic byproducts as it degraded.
Besides their constituent polymer molecules, synthetic biomaterials may contain several additives, such as unreacted monomers and catalysts, inorganic fillers or organic plasticizers, antioxidants and stabilizers, and processing lubricants or mold-release agents on the material's surface. In addition, several degradation products may result from the processing, sterilization, storage, and ultimately implantation of a device. Many additives are beneficialfor example, the silica filler that is indispensable in silicone rubber for good mechanical performance or the antioxidants and stabilizers that prevent premature oxidative degradation of polyetherurethanes. Other additives, such as pigments, can be eliminated from biomedical products. Indeed, a "medical-grade" biomaterial is one that has had nonessential additives and potential contaminants excluded or eliminated from the polymer. In order to achieve this grade, the polymer may need to be solvent-extracted before use, thereby eliminating low-molecular-weight materials. Generally, additives in polymers are regarded with extreme suspicion, because it is often the additives rather than the constituent polymer molecules that are the source of adverse biocompatibility.
Since the properties of each material are dependent on the chemical structure and macromolecular organization of its polymer chains, an understanding of some common structural features of various polymers provides considerable insight into their properties. Compared with complex biological molecules, synthetic polymers are relatively simple; often they comprise only one type of repeating subunit, analogous to a polypeptide consisting of just one repeating amino acid. On the basis of common structures and properties, synthetic polymers are classified into one of three categories: elastomers, which include natural and synthetic rubbers; thermoplastics; and thermosets. The properties that provide the basis for this classification include molecular weight, crosslink density, percent crystallinity, thermal transition temperature, and bulk mechanical properties.
Elastomers are typically amorphous with low crosslink density (although linear polyurethane block copolymers are an important exception). This gives them low to moderate modulus and tensile properties as well as high elasticity. For example, elastomeric devices can be extended by 100 to 1,000% of their initial dimensions without causing any permanent deformation to the material. Silicone rubbers such as Silastic, produced by Dow Corning, Inc., are crosslinked, so that they cannot be melted or dissolvedalthough swelling may occur in the presence of a good solvent. Such properties contrast with those of the linear polyurethane elastomers, which consist of soft polyether amorphous segments and hard urethane-containing glassy or crystalline segments. The two segments are incompatible at room temperature and undergo microphase separation, forming hard domains dispersed in an amorphous matrix. A key feature of this macromolecular organization is that the hard domains serve as physical crosslinks and reinforcing filler. This results in elastomeric materials that possess relatively high modulus and extraordinary long-term stability under sustained cyclic loading. In addition, they can be processed by methods common to thermoplastics.
Some thermoplastic biomaterials, such as polylactic acid and polyglycolic acid, are polymers based on a repeating amino acid subunit. These polypeptides are biodegradable, and, along with biodegradable polyesters and polyorthoesters, they have applications in absorbable sutures and drug-release systems. The rate of biodegradation in the body can be adjusted by using copolymers. These are polymers that link two different monomer subunits into a single polymer chain. The resultant biomaterial exhibits properties, including biodegradation, that are intermediate between the two homopolymers.
Applications of biomaterials
While the possibility of thrombosis can be minimized in blood-contacting biomaterials, it cannot be eliminated entirely. For this reason, patients who receive artificial heart valves or other blood-contacting devices also receive anticoagulation therapy. This is needed because all foreign surfaces initiate blood coagulation and platelet adhesion to some extent. Platelets are circulating cellular components of blood, two to four micrometers in size, that attach to foreign surfaces and actively participate in blood coagulation and thrombus formation. Research on new biomaterials for cardiovascular applications is largely devoted to understanding thrombus formation and to developing novel surfaces for biomaterials that will provide improved blood compatibility.
Synthetic vascular graft materials are used to patch injured or diseased areas of arteries, for replacement of whole segments of larger arteries such as the aorta, and for use as sewing cuffs (as with the heart valve mentioned above). Such materials need to be flexible to allow for the difficulties of implantation and to avoid irritating adjacent tissues; also, the internal diameter of the graft should remain constant under a wide range of flexing and bending conditions, and the modulus or compliance of the vessel should be similar to that of the natural vessel. These aims are largely achieved by crimped woven Dacron and expanded polytetrafluoroethylene (ePTFE). Crimping of Dacron in processing results in a porous vascular graft that may be bent 180º or twisted without collapsing the internal diameter.
A biomaterial used for blood vessel replacement will be in contact not only with blood but also with adjacent soft tissues. Experience with different materials has shown that tissue growth into the interstices of the biomaterials aids healing and integration of the material with host tissue after implantation. In order for the tissue, which consists mostly of collagen, to grow in the graft, the vascular graft must have an open structure with pores at least 10 micrometers in diameter. These pores allow new blood capillaries that develop during healing to grow into the graft, and the blood then provides oxygen and other nutrients for fibroblasts and other cells to survive in the biomaterial matrix. Fibroblasts synthesize the structural protein tropocollagen, which is needed in the development of new fibrous tissue as part of the healing response to a surgical wound.
Occasionally, excessive tissue growth may be observed at the anastomosis, which is where the graft is sewn to the native artery. This is referred to as internal hyperplasia and is thought to result from differences in compliance between the graft and the host vessels. In addition, in order to optimize compatibility of the biomaterial with the blood, the synthetic graft eventually should be coated with a confluent layer of host endothelial cells, but this does not occur with current materials. Therefore, most proposed modifications to existing graft materials involve potential improvements in blood compatibility.
Artificial heart valves and vascular grafts, while not ideal, have been used successfully and have saved many thousands of lives. However, the risk of thrombosis has limited the success of existing cardiovascular devices and has restricted potential application of the biomaterials to other devices. For example, there is an urgent clinical need for blood-compatible, synthetic vascular grafts of small diameter in peripheral vascular surgerye.g., in the legsbut this is currently impracticable with existing biomaterials because of the high risk of thrombotic occlusion. Similarly, progress with implantable miniature sensors, designed to measure a wide range of blood conditions continuously, has been impeded because of problems directly attributable to the failure of existing biomaterials. With such biocompatibility problems resolved, biomedical sensors would provide a very important contribution to medical diagnosis and monitoring. Considerable advances have been made in the ability to manipulate molecular architecture at the surfaces of materials by using chemisorbed or physisorbed monolayer films. Such progress in surface modification, combined with the development of nanoscale probes that permit examination at the molecular and submolecular level, provide a strong basis for optimism in the development of specialty biomaterials with improved blood compatibility.
Hip-joint replacements are principally used for structural support. Consequently, they are dominated by materials that possess high strength, such as metals, tough plastics, and reinforced polymer-matrix composites. In addition, biomaterials used for orthopedic applications must have high modulus, long-term dimensional stability, high fatigue resistance, long-term biostability, excellent abrasion resistance, and biocompatibility (i.e., there should be no adverse tissue response to the implanted device). Early developments in this field used readily available materials such as stainless steels, but evidence of corrosion after implantation led to their replacement by more stable materials, particularly titanium alloys, cobalt-chromium-molybdenum alloys, and carbon fiber-reinforced polymer composites. A typical modern artificial hip consists of a nitrided and highly polished cobalt-chromium ball connected to a titanium alloy stem that is inserted into the femur and cemented into place by in situ polymerization of polymethylmethacrylate. The articulating component of the joint consists of an acetabular cup made of tough, creep-resistant, ultrahigh-molecular-weight polyethylene. Abrasion at the ball-and-cup interface can lead to the production of wear particles, which in turn can lead to significant inflammatory reaction by the host. Consequently, much research on the development of hip-joint materials has been devoted to optimizing the properties of the articulating components in order to eliminate surface wear. Other modifications include porous coatings made by sintering the metal surface or coatings of wire mesh or hydroxyapatite; these promote bone growth and integration between the implant and the host, eliminating the need for an acrylic bone cement.
While the strength of the biomaterials is important, another goal is to match the mechanical properties of the implant materials with those of the bone in order to provide a uniform distribution of stresses (load sharing). If a bone is loaded insufficiently, the stress distribution will be made asymmetric, and this will lead to adaptive remodeling with cortical thinning and increased porosity of the bone. Such lessons in structure hierarchy and in the structure-property relationships of materials have been obtained from studies on biologic composite materials, and they are being translated into new classes of synthetic biomaterials. One development is carbon fiber-reinforced polymer-matrix composites. Typical matrix polymers include polysulfone and polyetheretherketones. The strength of these composites is lower than that of metals, but it more closely approximates that of bone.
At all levels of biology, fluid flow is an essential feature of life. In marine organisms control of fluid flows provides the means of locomotion and feeding. In higher organisms, maintenance of a controlled internal environment depends on the proper functioning of the cardiovascular system which provides the fluid link between various organ systems and allows for gas, nutrient, and waste transport to and from tissues and cells. It therefore of central importance to understand the properties of fluid flow and how cells and organisms respond and interact with flow. The term "fluid mechanics" is an expression describing the general studyexperimental and theoreticalof how fluids flow, and it is one of the oldest areas of study within chemical engineering. Biofluid mechanics focuses this discipline further to the flow of biological fluids, for example, blood, air, tissue fluid and synovial fluid; this attention to biological systems is a much more recent endeavor. An understanding of biofluid dynamics is particularly important for the design of artificial organs such as total heart, heart-valves, vascular grafts, knee joints etc. It is also essential in the design of medical devices like heart-lung machine, lung-ventilators, hemodialysis machines and ventricular-assist devices. In these applications, good flow characteristics must be designed to reduce fluid friction losses and minimize flow-related damage to tissues and cells. Some examples of ongoing research into biofluid mechanics include
Research on blood flow vastly outweighs investigations into other aspects of biofluid mechanics, probably because of the continued widespread incidence of cardiovascular diseases, especially coronary infarctions and atherosclerosis. While theoretical and experimental studies for these purposes have become increasingly rigorous and detailed, the clinical connection or relevance is often not clear or direct. In most pathological conditions, other biochemical, immunological, or cellular aspects are also important and intertwined with the fluid-mechanical effects.
The next-most studied aspect of physiological fluid flow is concerned with airflow in and out of the lungs. Some of these investigations deal with purely fluid mechanical aspects or behavior, but the interaction with the elasticity of the wall and with diffusion mechanisms (that is, oxygen absorption and diffusion through the lung wall) must still be investigated. The elasticity and collapsibility of the blood vessels in the lung is particularly important, and the subject of ongoing investigation.
Another important physiological system, but one that has received comparatively little attention from the fluid mechanics research community is the entire urinary system. In the ureter, which delivers urine from the kidney to the bladder, there is a bolus flow that is relatively well understood. From the bladder through the urethra the system is highly flexible and is subject to various elastic and muscular contractions. The study of flow through collapsible tubes has shed some light onto the behavior of this system, but the interaction of theory and practice is not as well developed as for the cardiovascular system.
Other systems of fluid flow in the body are lymph flow, which is a low volume and low pressure flow system with its own intricacies. The lymph is fed by flow from the capillary vessels through the tissue of the body to the lymph system. The transport of fluids, oxygen, and nutrients through the tissue is a considerable field of physiology by itself, one in which there is some fluid mechanics involved, particularly the study of flow through a porous media. The nature of the interstitial media and cell junctions is important to this flow and involves many considerations besides just the fluid mechanics aspects.
There are a number of small systems in the body involving minute flows of considerable physiological importance. For example, in the ear and eye there are important regions in which carefully controlled fluids are maintained. Certain pathologies arise when the flow of these fluids is blocked and the pressure rises inordinately. This may lead to tinnitus of the ear or glaucoma of the eye; we'll look more at modeling fluid flow in the eye in the next section. In the ear the process of hearing involves the transduction of the acoustic energy to a neural impulse that goes through a fluid elastic system of great complexity and small size.
There are a number of very slow, viscous flows in the body, including the development and movement of cerebral-spinal fluid. The biochemical osmotic and pressure balances in the cerebral-spinal fluid system are controlling factors, although problems of drainage may be clinically very important and lead to hydrocephalus and other pathologies in the case of blockage.
As one specific example consider the fluid mechanics of blood flow in mammalian systems. In a general sense, it is well known that fluid flow properties in the mammalian cardiovascular system affects changes at the cellular and tissue level. For example, high blood pressure which increases stresses in the vessel wall and changes flow patterns in unknown ways is thought to cause arteriosclerotic disease, the fibrosis and stiffening of the arterial wall. It is also known that atherosclerosisthe focal formation of plaque in blood vesselshas a tendency to occur at certain sites in the vascular system. For example, it is more likely to develop in areas which are subject to stretching (areas of tensile stress), at areas around orifices or bifurcations, at areas where bending occurs frequently (the coronary arteries), and at areas where flow is rapid or pulsatile or is variable in flow rates. It has been hypothesized that variability in shear stress may be important in the pathogenesis of arterial plaques. Yet despite the fact that arteriosclerosis and atherosclerosis are the main causes of morbidity and mortality in the elderly, remarkably little is known about exactly how fluid flow characteristics contribute to these changes.
The modeling of blood flow is complicated by several factors. The first complexity involves the rheological properties of the blood itself (see box below). Blood is actually a suspension of red cells (erythrocytes), white blood cells (leukocytes), and platelets in plasma. Whole blood behaves as a viscoelastic liquid as it flows, that is, its responsee.g., its flow rate or apparent viscosityto a constant force (such as when it's pumped at constant speed) will vary with time. This viscoelastic behavior is associated with the elastic properties of the red cell membrane and the viscosity of internal (hemoglobin solution) and external (plasma) fluids. The blood plasma by itself is Newtonian, which means that the response of this material to a constant force is constant and independent of time. Red cells, which are biconcave disks, constitute more than 99% of the particulate matter in blood and 40 to 45% of the blood by total volume. The material properties of the red blood cell membrane, its relatively large surface area compared to its volume, and the fluidity of its internal contents make it easy for the cell to deform under the action of external forces such as those occurring as blood is pumped through arteries. The reason that blood's viscoelastic behavior complicates analysis is the lack of rigorous models relating its rate of deformation (i.e., flow) to the force applied to make it deform.
A second factor complicating analysis is the flexibility and elasticity of the "tubes" the blood passes through. Some of the deformation of these boundaries is due to muscle contraction, and this physiological response is readily accounted for. However, some of the deformation is due to the movement of the blood through the flexible tube(s), and it is the fact that the details of the flow depend on the tube geometry while at the same time the details of the tube geometry depend on the details of the flow, that makes this something of a Catch 22. A third, somewhat less stupefying complication, is that the flow is pulsatile. In other words, the pressure exerted on the blood by the pump (the heart) varies with time, and as a result, so does the flow rate. The complication in this case is that it's necessary to have a detailed understanding of the heart's behavior to be able to determine a time-varying pressure in the blood. None of these difficulties have seriously daunted biomedical engineers interested in the cardiovascular system, and there have been a large number of modeling studies aimed at understanding the pathology of heart disease.
Unraveling the mechanisms which underlie the development of arteriosclerosis and atherosclerosis is a daunting task, as it requires detailed knowledge of the properties of fluid flow and mechanical stress, as well as methods of assessing changes in cell function and structure that occur with changes in fluid flow. Current research in this area utilizes recent advances in numerical techniques and computer technology to create a detailed map of flow in the cardiovascular system, including a detailed map of shear stress, and in parallel, develops techniques to measure the response of cells to changes in flow.
In our efforts to understand and predict the body's response to different environmental factors and pathologies, we often develop models that focus on a very specific aspect of the system of interest. As shown in the example above, to try to understand the link between blood flow and arteriosclerosis, researchers have modeled blood flow in a single, 90º bifurcation. Mathematical physiological models continue to become increasingly complex, but we are still in an era where the complexity of the model is often inversely proportional to the scale or the complexity of the system. So, while it's now possible to predict in minute detail the flow of blood through simple branched tube geometries, we can not yet obtain this same level of detail for the actual arterial system. Nevertheless, it is still desirable to be able to predict the function of systems in the body, ranging from simple to complex organs, up to the entire body.
One example of relatively simple system is the human eye. When functioning properly, the mammalian eye captures and transmits visual information efficiently over a wide range of length scales and lighting conditions. Unfortunately, injury and disease can damage the eye, leading to impaired function. Using structural data on the eye and measuring mechanical properties of its components, investigators are constructing a computer model to elucidate the mechanisms of eye damage. As mentioned in the previous section, approximately two million Americans suffer from glaucoma, which is damage to the optic nerve head gene rally associated with increased intraocular pressure (IOP). Although the correlation between IOP and nerve damage is well established, a number of unanswered questions exist, notable among them why some people have high IOP without optic nerve damage, and others experience glaucomatous damage with relatively low IOP. The computer model is used to explore how the interaction between IOP and other factors (such as eye geometry) affects the stress and strain experienced by the optic nerve. This model is a relatively straightforward (conceptually) study of fluid mechanics in a novel geometry, that is, the eye. It is anticipated that the capability to predict in significant detail the stress experienced by the optic nerve due to the flow of liquid (tears) across the eye will resolve at least some of these issues. Additionally, numerical tools are being developed to examine and predict the effects of various mechanical and pharmacological treatments.
Another biofluid mechanics issue of interest, in a more complicated geometry, concerns the presence of closed loops in both the arteriolar and venous portions of most microvascular networks. These networks, often referred to as arcades, are present in skeletal muscle, mesentery, heart, and connective tissues, and connect vessels of 30200 microns in diameter. From these arcade vessels blood is fed to the capillaries via treelike arterioles. The hemodynamic function of the closed loops in these arcades is not yet known. The significance may be that the pressure drop from an inflow to the organ to any site in the arcade network is relatively constant and can be maintained at a constant level even if flow to one or more arcade vessels is interrupted. This provides the regulatory vessels, that is, the small arterioles that feed the capillaries, with a constant pressure head (driving force for blood flow). However, this is only speculation, since it's very difficult to measure pressure drop in tubes as small as those in the arcades outside the body, let alone inside a living organism. Instead, biomedical engineers have turned to computational fluid mechanics techniques to try to understand the function of these networks.
Not all fundamental studies of organ function are theoretical, however, and often involve chemical engineering principles other than just fluid mechanics. One example of this is the kidney. It has long been known that the kidneys play a critical role in regulating the composition and volume of blood and other body fluids. In doing so they help ensure a healthy internal environment in the body. The first step in urine formation is the filtration of blood across the walls of certain microscopic blood vessels in the kidney. This filtration process allows some of the water and low-molecular-weight substances dissolved in blood plasma to enter the renal tubules, while retaining blood cells and essentially all plasma proteins within the bloodstream. The blood vessels involved, called glomerular capillaries, are arranged in spherical tufts a fraction of a millimeter (mm) in diameter, called glomeruli. Injury to many of the million or so glomeruli present in each kidney is a frequent feature of renal disease.
During the early 1970s, technical innovations by renal physiologists permitted the first direct measurements of the pressures responsible for glomerular filtration in mammals. This created the opportunity to use chemical engineering principles in analyzing kidney function. The resulting collaboration between physiologists and chemical engineers led to several major new insights.
Hydraulic permeabilitythe rate of filtration per unit of applied pressurewas one of the physical properties that were studied. It was discovered that the hydraulic permeability of the glomerular capillary wall was twice that of capillaries in other organs. This surprising finding implied that the limiting factor in kidney function was not hydraulic permeability, as had been assumed, but rather the rate of plasma flow to the kidney. It was further discovered that the design of the glomerulus ingeniously avoided one of the classic problems of man-made filtration devices: concentration polarization, that is, the buildup at the surface of a filter of substances too large to pass through.
The glomeruli normally produce large volumes of filtrate without significant leakage of plasma proteins into the urine. The amount of fluid that is filtered by the glomeruli each days is some 50 times the volume of blood plasma. Because the body cannot rapidly replace plasma proteins, even small defects in the glomerular barrier are potentially disastrous. Prior to the involvement of chemical engineers in kidney studies, it was thought that protein leakage was prevented because the holes in the glomerular membrane were smaller than the major protein molecules, so that the capillary wall acted as a sieve. While sieving is one important part of glomerular function, further collaborative studies by physiologists and chemical engineers revealed another, unexpected phenomenon. The glomerulus was found to discriminate among circulating proteins on the basis of their electrical charge, in addition to their molecular size. Negatively charged molecules were repelled by negatively charged components in the capillary wall, and there were retained in the bloodstream more effectively than uncharged molecules of the same size. The negatively charged molecules attached to the capillary walls of the glomeruli had been identified previously, but their functional significance was not appreciated.
These studies led to the realization that proteinuriathe abnormal appearance of protein in the urinecould result not only from the enlargement of submicroscopic holes in the glomerular capillary wall, but also from the loss or neutralization of its negatively charged components. This finding provided a new direction for research on the molecular basis for the nephrotic syndrome, a group of kidney diseases all characterized by massive proteinuria.
Finally, consider the most complicated mammalian system possible: the entire human body. Since it's very difficult to model the detailed function of even moderately complicated organs, it is no surprise that it is impossible to model the interactions of these organs with one another and how these collections of organs fit into the cardiovascular, pulminary, and other body systems. Given this limitation, it is nevertheless desirable, even necessary, in certain situations to have some sort of overall physiological model. Such situations arise when attempting to design a system in which the presence of human beings can affect the behavior of the system, and further, when it's not possible to straightforwardly measure that effect.
An example? The International Space Station (ISS). A habitat intended for long-term occupation by humans in near-vacuum has to be almost completely self-contained. When designing terrestrially well-understood components such as heating, cooling, ventilation, or humidification for use in such a vastly different environment, it's essential to take into account their loads. These loads depend not only on the number of people, but also their sizes, levels of activity, and gender. By treating the human as the "black box" shown below, it is, at least in principle, possible to develop an empirical model that predicts the level of the "outputs" for a given set of "inputs."
In this situation the questions are fairly simple compared to, for example, what causes proteinuria in the kidney or glaucoma in the eye, and as a result it's possible to construct a comparably simple model designed to answer those questions. What's hidden in this simple model is our basic chemical engineering knowledge of chemical kinetics, fluid mechanics, and heat and mass transfer, and how we can apply these to model gross bodily functions.