Annual Review of Biomedical Engineering - Volume 1, 1999

Because of an aging population and increased occurrence of sports-related injuries, musculoskeletal disorders have become one of the major health concerns in the United States. Current treatments, although fairly successful, do not provide the optimum therapy. These treatments typically rely on donor tissues obtained either from the patient or from another source. The former raises the issue of supply, whereas the latter poses the risk of rejection and disease transfer. This has prompted orthopedic surgeons and scientists to look for viable alternatives. In recent years, tissue engineering has gained increasing support as a method to treat orthopedic disorders. Because it uses principles of engineering, biology, and chemistry, tissue engineering may provide a more effective approach to the treatment of musculoskeletal disorders than traditional methods. This chapter presents a review of current methods and new tissue-engineering techniques for the treatment of disorders affecting bone, ligament, and cartilage.

The dimensions, composition, and stiffness of the airway wall are important determinants of airway cross-sectional area during dynamic collapse in a forced expiration or when airway smooth muscle is constricted. Under these circumstances, airway caliber is determined by an interaction between the forces acting to open the airway (parenchymal tension and wall stiffness) and those acting to close it (smooth-muscle force and surface tension at the inner gas-liquid interface). Experimental measurements and theoretical models of the airway tube law (relationship between cross-sectional area and transmural pressure) are presented. Data are presented for the elastic properties of the wall tissue. Simulations of airway constriction in normal and asthmatic airways are discussed. To the extent possible, comparisons are presented between the various models and existing experimental data.

The microcirculation represents a region of the circulation in which blood vessels are directly surrounded by the tissue and cells to which they supply nutrients and from which they collect metabolites. The cellular elements that make up the microcirculation have now been identified, and a large body of evidence has become available that provides molecular definitions of these elements. The blood flow is in a domain in which viscous stresses dominate, but the viscoelastic and active properties of cells lead to nonlinear problems. The ability of cells to actively control cytoplasmic mechanical properties and shape, as well as their membrane adhesion, leads to unique cell behavior in microvessels that has a direct influence on organ transport and function. There is also increasing evidence that the properties of the cells are in turn influenced by fluid shear stresses. These issues have greatly expanded the scope of microvascular analysis. The microcirculation is one of the sites in which diseases manifest themselves at an early stage. The application of biomechanical analysis of the microcirculation is starting to focus on diseases. The field is rich with problems of high significance.

The successful application and optimization of cell transplantation will require quantitative engineering design and analysis of cells and materials in which relevant biological processes remain complex and incompletely defined. This report primarily reviews the engineering and material considerations in islet cell transplantation, including established biological constraints and biohybrid devices for cell delivery, as well as available barrier materials and the associated processing strategies directed at the control of solute transport, barrier permeability, and host responses at the biological–material interface. Also described are current areas of investigation with particular promise as enabling technologies for accelerating the clinical effectiveness of islet cell transplantation.

Hematopoietic cell culture, or ex vivo expansion of hematopoietic cells, is an enabling technology with many potential applications in bone-marrow transplantation, immunotherapy, gene therapy, and the production of blood products. Hematopoietic cultures are complex, with many different cell types at different stages of development present at any given point in time and never in steady state. Moreover, these cells interact strongly with each other and the environment through cytokines (growth factors) and adhesion molecules, as well as through their metabolism. Despite these significant challenges, cell products produced in bioreactors have shown promise in recent phase 1 clinical trials.

By maintaining a near normal (70–120 mg/dL) glucose concentration, diabetic patients can drastically reduce the likelihood of the occurrence of diabetes complications. In the near future, subcutaneously implanted electrochemical glucose sensors will be available to provide frequent or continuous information on which timely treatment decisions, such as insulin injection or glucose source intake, can be based, as well as timely alarm signals. The currently engineered devices are of three types: (a) innocuous microsensors, with actively mass-transporting areas <10⁻³ cm², replaced twice a week by the patient; (b) self-contained, surgeon-implanted, transmitter-containing packages of >1 cm² area, operating for >100 days; and (c) devices transporting subcutaneous fluid to an external sensor, based on implanted microfiltration or microdialysis fibers or on iontophoretic transport of the subcutaneous fluid through the skin.

Historically, electronic devices such as pacemakers and neuromuscular stimulators have been surgically implanted into animals and humans. A new class of implants made possible by advances in monolithic electronic design and implant packaging is small enough to be implanted by percutaneous injection through large-gauge hypodermic needles and does not require surgical implantation. Among these, commercially available implants, known as radio frequency identification (RFID) tags, are used for livestock, pet, laboratory animal, and endangered-species identification. The RFID tag is a subminiature glass capsule containing a solenoidal coil and an integrated circuit. Acting as the implanted half of a transcutaneous magnetic link, the RFID tag is powered by and communicates with an extracorporeal magnetic reader. The tag transmits a unique identification code that serves the function of identifying the animal. Millions of RFID tags have been sold since the early 1980s. Based on the success of the RFID tags, research laboratories have developed injectable medical implants, known as micromodules. One type of micromodule, the microstimulator, is designed for use in functional-neuromuscular stimulation. Each microstimulator is uniquely addressable and could comprise one channel of a multichannel functional-neuromuscular stimulation system. Using bidirectional telemetry and commands, from a single extracorporeal transmitter, as many as 256 microstimulators could form the hardware basis for a complex functional-neuromuscular stimulation feedback-control system. Uses include stimulation of paralyzed muscle, therapeutic functional-neuromuscular stimulation, and neuromodulatory functions such as laryngeal stimulation and sleep apnea.

Robotic technology is enhancing surgery through improved precision, stability, and dexterity. In image-guided procedures, robots use magnetic resonance and computed tomography image data to guide instruments to the treatment site. This requires new algorithms and user interfaces for planning procedures; it also requires sensors for registering the patient’s anatomy with the preoperative image data. Minimally invasive procedures use remotely controlled robots that allow the surgeon to work inside the patient’s body without making large incisions. Specialized mechanical designs and sensing technologies are needed to maximize dexterity under these access constraints. Robots have applications in many surgical specialties. In neurosurgery, image-guided robots can biopsy brain lesions with minimal damage to adjacent tissue. In orthopedic surgery, robots are routinely used to shape the femur to precisely fit prosthetic hip joint replacements. Robotic systems are also under development for closed-chest heart bypass, for microsurgical procedures in ophthalmology, and for surgical training and simulation. Although results from initial clinical experience is positive, issues of clinician acceptance, high capital costs, performance validation, and safety remain to be addressed.

Extraordinary advances in molecular biology and biotechnology have led to the development of a vast number of therapeutic anti-cancer agents. To reach cancer cells in a tumor, a blood-borne therapeutic molecule, particle, or cell must make its way into the blood vessels of the tumor and across the vessel wall into the interstitium, which it then must migrate through. Unfortunately, tumors often develop in ways that hinder these steps. The goal of research in this area is to analyze each of these steps experimentally and theoretically and integrate the resulting information into a unified theoretical framework. This paradigm of analysis and synthesis has fostered a better understanding of physiological barriers in solid tumors and aided in the development of novel strategies to exploit and/or overcome these barriers for improved cancer detection and treatment.

Driven by advances in the acquisition of genetic sequence information and the ability to manipulate small quantities of nucleic acid, a number of technologies are emerging that exploit nucleic acids for research, diagnostic, and therapeutic utility. In this review, we cover three technologies based on nucleic acids—DNA microarrays, antisense technology, and gene therapy—that are especially promising and may make a substantial impact in the laboratory and in the clinic during the coming years. For each of these areas, an overview of the current status and applications is provided, followed by a discussion of critical issues and challenges to be faced for further advancement of the technology; an emphasis is placed on quantitative and engineering aspects.

The cardiovascular system is an internal flow loop with multiple branches circulating a complex liquid. The hallmarks of blood flow in arteries are pulsatility and branches, which cause wall stresses to be cyclical and nonuniform. Normal arterial flow is laminar, with secondary flows generated at curves and branches. Arteries can adapt to and modify hemodynamic conditions, and unusual hemodynamic conditions may cause an abnormal biological response. Velocity profile skewing can create pockets in which the wall shear stress is low and oscillates in direction. Atherosclerosis tends to localize to these sites and creates a narrowing of the artery lumen—a stenosis. Plaque rupture or endothelial injury can stimulate thrombosis, which can block blood flow to heart or brain tissues, causing a heart attack or stroke. The small lumen and elevated shear rate in a stenosis create conditions that accelerate platelet accumulation and occlusion. The relationship between thrombosis and fluid mechanics is complex, especially in the post-stenotic flow field. New convection models have been developed to predict clinical occlusion from platelet thrombosis in diseased arteries. Future hemodynamic studies should address the complex mechanics of flow-induced, large-scale wall motion and convection of semisolid particles and cells in flowing blood.

Ventricular fibrillation, a loss of synchronus electrical activity in the heart which leads to hemodynamic collapse, is a leading cause of death. Because of the devastating personal and societal effects of this phenomenon, the automatic cardioverter-defibrillator has been developed for automatic detection and termination of the arrhythmia and is in widespread clinical use. Advances in circuits, leads, waveforms, and signal processing along with increased knowledge of the mechanisms of fibrillation have led to continuing improvements in this device, extending its use to many patients. A device has also been developed for the automatic or semiautomatic treatment of atrial fibrillation, an arrhythmia less life-threatening than ventricular fibrillation, but still a serious health problem. Continued improvement of these devices and the development of qualitatively new approaches hold great promise for exciting therapeutic advances in this area.

The continuing accrual of positive results in clinical cancer trials of adjunctive, synergistic hyperthermia therapy remains a strong motivation for the development of improved hyperthermia equipment and software. Indeed, the lack of needed engineering tools can be viewed as the major stumbling block to hyperthermia’s effective clinical implementation. Developing clinically effective systems will be difficult, however, because (a) it requires solving several complex engineering problems, for which (b) setting appropriate design and evaluation goals is currently difficult owing to a lack of critical biological, physiological, and clinical knowledge, two tasks which must (c) be accomplished within a complicated social/political structure.

Visualizable objects in biology and medicine extend across a vast range of scale, from individual molecules and cells through the varieties of tissue and interstitial interfaces to complete organs, organ systems, and body parts. These objects include functional attributes of these systems, such as biophysical, biomechanical, and physiological properties. Visualization in three dimensions of such objects and their functions is now possible with the advent of high-resolution tomographic scanners and imaging systems. Medical applications include accurate anatomy and function mapping, enhanced diagnosis, accurate treatment planning and rehearsal, and education/training. Biologic applications include study and analysis of structure-to-function relationships in individual cells and organelles. The potential for revolutionary innovation in the practice of medicine and in biologic investigations lies in direct, fully immersive, real-time multisensory fusion of real and virtual information data streams into online, real-time visualizations available during actual clinical procedures or biological experiments. Current high-performance computing, advanced image processing, and high-fidelity rendering capabilities have facilitated major progress toward realization of these goals. With these advances in hand, there are several important applications of three-dimensional visualization that will have a significant impact on the practice of medicine and on biological research.

Microfabrication uses integrated-circuit manufacturing technology supplemented by its own processes to create objects with dimensions in the range of micrometers to millimeters. These objects can have miniature moving parts, stationary structures, or both. Microfabrication has been used for many applications in biology and medicine. These applications fall into four domains: tools for molecular biology and biochemistry, tools for cell biology, medical devices, and biosensors. Microfabricated device structures may provide significantly enhanced function with respect to a conventional device. Sometimes microfabrication can enable devices with novel capabilities. These enhancing and enabling qualities are conferred when microfabrication is used appropriately to address the right types of problems.

Herein, we describe microfabrication technology and its application to biology and medicine. We detail several classes of advantages conferred by microfabrication and how these advantages have been used to date.

Blood clots form under hemodynamic conditions and can obstruct flow during angina, acute myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism, peripheral thrombosis, or dialysis access graft thrombosis. Therapies to remove these clots through enzymatic and/or mechanical approaches require consideration of the biochemistry and structure of blood clots in conjunction with local transport phenomena. Because blood clots are porous objects exposed to local hemodynamic forces, pressure-driven interstitial permeation often controls drug penetration and the overall lysis rate of an occlusive thrombus. Reaction engineering and transport phenomena provide a framework to relate dosage of a given agent to potential outcomes. The design and testing of thrombolytic agents and the design of therapies must account for (a) the binding, catalytic, and systemic clearance properties of the therapeutic enzyme; (b) the dose and delivery regimen; (c) the biochemical and structural aspects of the thrombotic occlusion; (d) the prevailing hemodynamics and anatomical location of the thrombus; and (e) therapeutic constraints and risks of side effects. These principles also impact the design and analysis of local delivery devices.

Ionic and molecular transfer among cells occurs by a variety of transport processes operative at different length scales. Cell membrane permeability and electrical conductance derive from channel proteins producing pores at the molecular (ultrastructural) scale. Intracellular mobility involves the dynamics of motion through the complex ultrastructure of the cytoplasm. These phenomena unite in the larger-scale (microscopic) process of gross intercellular transfer. When such movement occurs among sufficiently many cells, it in turn begins to reflect their average collective (macroscopic) behavior as bulk tissue. This article surveys selected aspects of intercellular and intracellular transport, with emphasis on detailed mechanistic theory, experimental probes of cellular permeability, and systematic transcendence from small to large length scales.

Protein crystallization is the most difficult and time-consuming step in the determination of a protein’s atomic structure. As X-ray diffraction becomes a commonly available tool in structural biology, the necessity for rational methodologies and protocols to produce single, high-quality protein crystals has come to the forefront. The basics of protein crystallization conform to the classical understanding of crystallization of small molecules. Understanding the effect of solution variables such as pH, temperature, pressure, and ionicity on protein solubility allows the proper evaluation of the degree of supersaturation present in protein crystallization experiments. Physicochemical measurements such as laser light scattering, X-ray scattering, X-ray diffraction, and atomic force microscopy provide a clearer picture of protein crystal nucleation and growth. This ever deepening knowledge base is generating rational methods to produce protein crystals as well as means to improve the diffraction quality of such protein crystals. Yet, much remains unclear, and the protein crystallization research community will be quite active for many years to come.