Annual Review of Biomedical Engineering - Volume 2, 2000

Hydrogels are cross-linked hydrophilic polymers that can imbibe water or biological fluids. Their biomedical and pharmaceutical applications include a very wide range of systems and processes that utilize several molecular design characteristics. This review discusses the molecular structure, dynamic behavior, and structural modifications of hydrogels as well as the various applications of these biohydrogels.

Recent advances in the preparation of three-dimensional structures with exact chain conformations, as well as tethering of functional groups, allow for the preparation of promising new hydrogels. Meanwhile, intelligent biohydrogels with pH- or temperature-sensitivity continue to be important materials in medical applications.

Strategies for rationally manipulating cell behavior in cell-based technologies and molecular therapeutics and understanding effects of environmental agents on physiological systems may be derived from a mechanistic understanding of underlying signaling mechanisms that regulate cell functions. Three crucial attributes of signal transduction necessitate modeling approaches for analyzing these systems: an ever-expanding plethora of signaling molecules and interactions, a highly interconnected biochemical scheme, and concurrent biophysical regulation. Because signal flow is tightly regulated with positive and negative feedbacks and is bidirectional with commands traveling both from outside-in and inside-out, dynamic models that couple biophysical and biochemical elements are required to consider information processing both during transient and steady-state conditions. Unique mathematical frameworks will be needed to obtain an integrated perspective on these complex systems, which operate over wide length and time scales. These may involve a two-level hierarchical approach wherein the overall signaling network is modeled in terms of effective “circuit” or “algorithm” modules, and then each module is correspondingly modeled with more detailed incorporation of its actual underlying biochemical/biophysical molecular interactions.

This is the first of two chapters dealing with some 60 years of accumulated knowledge in the field of impact biomechanics. The regions covered in this first chapter are the head, neck, and thorax. The next chapter will discuss the abdomen, pelvis, and the lower extremities. Although the principal thrust of the research has been toward the mitigation of injuries sustained by automotive crash victims, the results of this research have applications in aircraft safety, contact sports, and protection of military personnel and civilians from intentional injury, such as in the use of nonlethal weapons. The reader should be keenly aware of the wide variation in human response and tolerance data in the cited results. This is due primarily to the large biological variation among humans and to the effects of aging. Average values are useful in design but cannot be applied to individuals.

In this chapter, biomechanical methods used to analyze healing and repair of ligaments and tendons are initially described such that the tensile properties of these soft tissues as well as their contribution to joint motion can be determined. The focus then turns to the important mechanical and biological factors that improve the healing process of ligaments. The biomechanics of surgical reconstruction of the anterior cruciate ligament and the key surgical parameters that affect the performance of the replacement grafts are subsequently reviewed. Finally, injury mechanisms and the biomechanical analysis of various treatment techniques for various types of tendon injuries are described.

Three topics of importance to modeling the integrative function of the heart are reviewed. The first is modeling of the ventricular myocyte. Emphasis is placed on excitation-contraction coupling and intracellular Ca²⁺ handling, and the interpretation of experimental data regarding interval-force relationships. Second, data on use of diffusion tensor magnetic resonance (DTMR) imaging for measuring the anatomical structure of the cardiac ventricles are presented. A method for the semi-automated reconstruction of the ventricles using a combination of gradient recalled acquisition in the steady state (GRASS) and DTMR images is described. Third, we describe how these anatomically and biophysically based models of the cardiac ventricles can be implemented on parallel computers.

Cryosurgery is a surgical technique that employs freezing to destroy undesirable tissue. Developed first in the middle of the nineteenth century it has recently incorporated new imaging technologies and is a fast growing minimally invasive surgical technique. A historical review of the field of cryosurgery is presented, showing how technological advances have affected the development of the field. This is followed by a more in-depth survey of two important topics in cryosurgery: (a) the biochemical and biophysical mechanisms of tissue destruction during cryosurgery and (b) monitoring and imaging techniques for cryosurgery.

As the basic unit of life, the cell is a biologically complex system, the understanding of which requires a combination of various approaches including biomechanics. With recent progress in cell and molecular biology, the field of cell mechanics has grown rapidly over the last few years. This review synthesizes some of these recent developments to foster new concepts and approaches, and it emphasizes molecular-level understanding. The focuses are on the common themes and interconnections in three related areas: (a) the responses of cells to mechanical forces, (b) the mechanics and kinetics of cell adhesion, and (c) the deformation of biomolecules. Specific examples are also given to illustrate the quantitative modeling used in analyzing biological processes and physiological functions.

Tissue function is modulated by an intricate architecture of cells and biomolecules on a micrometer scale. Until now, in vitro cellular interactions were mainly studied by random seeding over homogeneous substrates. Although this strategy has led to important discoveries, it is clearly a nonoptimal analog of the in vivo scenario. With the incorporation—and adaptation—of microfabrication technology into biology, it is now possible to design surfaces that reproduce some of the aspects of that architecture. This article reviews past research on the engineering of cell-substrate, cell-cell, and cell-medium interactions on the micrometer scale.

Cryopreservation and cryosurgery are important biomedical applications used to selectively preserve or destroy cellular systems through freezing. Studies using cryomicroscopy techniques, which allow the visualization of the freezing process in single cells, have shown that a drop in viability correlates with the extent of two biophysical events during the freezing process: (a) intracellular ice formation and (b) cellular dehydration. These same biophysical events operate in tissue systems; however, the inability to visualize and quantify the dynamics of the freezing process in tissues has hampered direct correlation of these events with freezing-induced changes in viability. This review highlights two new techniques that use freeze substitution and differential scanning calorimetry to provide dynamic freezing data in tissue. Characteristic dimensions and parameters extracted from these new data are then used in a predictive model of biophysical freezing response in several tissues, including liver and tumor. This approach promises to help guide improved design of both cryopreservation and cryosurgical applications of tissue freezing.

By incorporating techniques adapted from the microelectronics industry, the field of microfabrication has allowed the creation of microneedles, which have the potential to improve existing biological-laboratory and medical devices and to enable novel devices for gene and drug delivery. Dense arrays of microneedles have been used to deliver DNA into cells. Many cells are treated at once, which is much more efficient than current microinjection techniques. Microneedles have also been used to deliver drugs into local regions of tissue. Microfabricated neural probes have delivered drugs into neural tissue while simultaneously stimulating and recording neuronal activity, and microneedles have been inserted into arterial vessel walls to deliver antirestenosis drugs. Finally, microhypodermic needles and microneedles for transdermal drug delivery have been developed to reduce needle insertion pain and tissue trauma and to provide controlled delivery across the skin. These needles have been shown to be robust enough to penetrate skin and dramatically increase skin permeability to macromolecules.

Image segmentation plays a crucial role in many medical-imaging applications, by automating or facilitating the delineation of anatomical structures and other regions of interest. We present a critical appraisal of the current status of semiautomated and automated methods for the segmentation of anatomical medical images. Terminology and important issues in image segmentation are first presented. Current segmentation approaches are then reviewed with an emphasis on the advantages and disadvantages of these methods for medical imaging applications. We conclude with a discussion on the future of image segmentation methods in biomedical research.

Antibodies are unique in their high affinity and specificity for a binding partner, a quality that has made them one of the most useful molecules for biotechnology and biomedical applications. The field of antibody engineering has changed rapidly in the past 10 years, fueled by novel technologies for the in vitro isolation of antibodies from combinatorial libraries and their functional expression in bacteria. This review presents an overview of the methods available for the de novo generation of human antibodies, for engineering antibodies with increased antigen affinity, and for the production of antibody fragments. Select applications of recombinant antibodies are also presented.

Electric fields can stimulate excitable tissue by a number of mechanisms. A uniform long, straight peripheral axon is activated by the gradient of the electric field that is oriented parallel to the fiber axis. Cortical neurons in the brain are excited when the electric field, which is applied along the axon-dendrite axis, reaches a particular threshold value. Cardiac tissue is thought to be depolarized in a uniform electric field by the curved trajectories of its fiber tracts. The bidomain model provides a coherent conceptual framework for analyzing and understanding these apparently disparate phenomena. Concepts such as the activating function and virtual anode and cathode, as well as anode and cathode break and make stimulation, are presented to help explain these excitation events in a unified manner. This modeling approach can also be used to describe the response of excitable tissues to electric fields that arise from charge redistribution (electrical stimulation) and from time-varying magnetic fields (magnetic stimulation) in a self-consistent manner. It has also proved useful to predict the behavior of excitable tissues, to test hypotheses about possible excitation mechanisms, to design novel electrophysiological experiments, and to interpret their findings.

Two-photon fluorescence microscopy is one of the most important recent inventions in biological imaging. This technology enables noninvasive study of biological specimens in three dimensions with submicrometer resolution. Two-photon excitation of fluorophores results from the simultaneous absorption of two photons. This excitation process has a number of unique advantages, such as reduced specimen photodamage and enhanced penetration depth. It also produces higher-contrast images and is a novel method to trigger localized photochemical reactions. Two-photon microscopy continues to find an increasing number of applications in biology and medicine.

The three-dimensional (3-D) nature of myocardial deformations is dependent on ventricular geometry, muscle fiber architecture, wall stresses, and myocardial-material properties. The imaging modalities of X-ray angiography, echocardiography, computed tomography, and magnetic resonance (MR) imaging (MRI) are described in the context of visualizing and quantifying cardiac mechanical function. The quantification of ventricular anatomy and cavity volumes is then reviewed, and surface reconstructions in three dimensions are demonstrated. The imaging of myocardial wall motion is discussed, with an emphasis on current MRI and tissue Doppler imaging techniques and their potential clinical applications. Calculation of 3-D regional strains from motion maps is reviewed and illustrated with clinical MRI tagging results. We conclude by presenting a promising technique to assess myocardial-fiber architecture, and we outline its potential applications, in conjunction with quantification of anatomy and regional strains, for the determination of myocardial stress and work distributions. The quantification of multiple components of 3-D cardiac function has potential for both fundamental-science and clinical applications.

Two-dimensional viewing of three-dimensional anatomy by conventional ultrasound limits our ability to quantify and visualize a number of diseases and is partly responsible for the reported variability in diagnosis. Over the past two decades, many investigators have addressed this limitation by developing three-dimensional imaging techniques, including three-dimensional ultrasound imaging. In this paper we describe the development of a number of three-dimensional ultrasound imaging systems that make use of B mode, color Doppler, and power Doppler. In these systems, the conventional ultrasound transducer is scanned mechanically or by a freehand technique. The ultrasound images are digitized and then reconstructed into a three-dimensional volume, which can be viewed and manipulated interactively by the diagnostician with a variety of image-rendering techniques. These developments as well as future trends are discussed with regard to their applications and limitations.

Electrical shock trauma tends to produce a very complex pattern of injury, mainly because of the multiple modes of frequency-dependent tissue-field interactions. Historically, Joule heating was thought to be the only cause of electrical injuries to tissue by commercial-frequency electrical shocks. In the last 15 years, biomedical engineering research has improved the understanding of the underlying biophysical injury mechanisms. Besides thermal burns secondary to Joule heating, permeabilization of cell membranes and direct electroconformational denaturation of macromolecules such as proteins have also been identified as tissue-damage mechanisms. This review summarizes the physics of tissue injury caused by contact with commercial-frequency power lines, as well as exposure to lightning and radio frequency (RF), microwave, and ionizing radiation. In addition, we describe the anatomic patterns of the resultant tissue injury from these modes of electromagnetic exposures.

We review some of the most recent advances in the area of wavelet applications in medical imaging. We first review key concepts in the processing of medical images with wavelet transforms and multiscale analysis, including time-frequency tiling, overcomplete representations, higher dimensional bases, symmetry, boundary effects, translational invariance, orientation selectivity, and best-basis selection. We next describe some applications in magnetic resonance imaging, including activation detection and denoising of functional magnetic resonance imaging and encoding schemes. We then present an overview in the area of ultrasound, including computational anatomy with three-dimensional cardiac ultrasound. Next, wavelets in tomography are reviewed, including their relationship to the radon transform and applications in position emission tomography imaging. Finally, wavelet applications in digital mammography are reviewed, including computer-assisted diagnostic systems that support the detection and classification of small masses and methods of contrast enhancement.