Annual Review of Biomedical Engineering - Volume 9, 2007

Forces are increasingly recognized as major regulators of cell structure and function, and the mechanical properties of cells are essential to the mechanisms by which cells sense forces, transmit them to the cell interior or to other cells, and transduce them into chemical signals that impact a spectrum of cellular responses. Comparison of the mechanical properties of intact cells with those of the purified cytoskeletal biopolymers that are thought to dominate their elasticity reveal the extent to which the studies of purified systems can account for the mechanical properties of the much more heterogeneous and complex cell. This review summarizes selected aspects of current work on cell mechanics with an emphasis on the structures that are activated in cell-cell contacts, that regulate ion flow across the plasma membrane, and that may sense fluid flow that produces low levels of shear stress.

This article presents a review on the existing techniques for manipulating biological cells. Because biomanipulation involves a wide range of disciplines, from biology to engineering, we concentrate on some of the key methodologies that would result in an efficient biomanipulation system. Some of the key methodologies discussed in this article for cell manipulation relate to the use of magnetics, microelectromechanical systems (MEMS)-based approaches, optics, electric field, and mechanical techniques. Recent advances in engineering have allowed researchers worldwide to address the problems arising from conventional manipulation techniques. This paper assimilates significance and limitations of biomanipulation techniques described in the literature.

Forensic injury biomechanics is the science that relates mechanical forces to disruption of anatomical regions of the human body. In this review, we introduce (a) how scaling techniques can be used to describe injury severity and probability of death; (b) how a simple ratio, the factor of risk, and more sophisticated injury risk functions can be used to determine the probability of injury; and (c) how injury criteria (also known as tolerance limits) are defined for the head and neck. Methods for establishing injury causation are then illustrated by real-world examples drawn from litigation involving motor vehicle collisions and slips, trips and falls. Those factors that distinguish litigation from basic and applied research are also discussed, including the criteria for admissibility of expert opinions and the level of certainty used as the basis for these opinions. The criteria that must be met to support opinions on causation at both epidemiological and individual levels are also noted. If the expert appreciates the difference between the demands of ligation and those of basic and applied research, expert opinion can play a crucial role in the decision-making process that characterizes litigation. Because forensic injury biomechanics is central to opinions on injury causation, and because causation is often the key to determinations of who is at fault, forensic injury biomechanics can be the deciding factor in many personal injury, products and premises liability, wrongful death, and criminal cases.

The clinical challenges of skeletal regenerative medicine have motivated significant advances in cellular and tissue engineering in recent years. In particular, advances in molecular biology have provided the tools necessary for the design of gene-based strategies for skeletal tissue repair. Consequently, genetic engineering has emerged as a promising method to address the need for sustained and robust cellular differentiation and extracellular matrix production. As a result, gene therapy has been established as a conventional approach to enhance cellular activities for skeletal tissue repair. Recent literature clearly demonstrates that genetic engineering is a principal factor in constructing effective methods for tissue engineering approaches to bone, cartilage, and connective tissue regeneration. This review highlights this literature, including advances in the development of efficacious gene carriers, novel cell sources, successful delivery strategies, and optimal target genes. The current status of the field and the challenges impeding the clinical realization of these approaches are also discussed.

Over the past decade, since it was first observed in vivo, there has been an explosion in interest in the thin (∼500 nm), gel-like endothelial glycocalyx layer (EGL) that coats the luminal surface of blood vessels. In this review, we examine the mechanical and biochemical properties of the EGL and the latest studies on the interactions of this layer with red and white blood cells. This includes its deformation owing to fluid shear stress, its penetration by leukocyte microvilli, and its restorative response after the passage of a white cell in a tightly fitting capillary. We also examine recently discovered functions of the EGL in modulating the oncotic forces that regulate the exchange of water in microvessels and the role of the EGL in transducing fluid shear stress into the intracellular cytoskeleton of endothelial cells, in the initiation of intracellular signaling, and in the inflammatory response.

Rupture of abdominal aortic aneurysms (AAAs) alone is the thirteenth leading cause of death in the United States. Thus, reliable AAA-rupture risk prediction is an important advancement. If repair becomes necessary, the minimally invasive technique of inserting a stent-graft (SG), commonly referred to as endovascular aneurysm repair (EVAR), is a viable option in many cases. However, postoperative complications, such as endoleaks and/or SG migration, may occur. Computational fluid-structure interaction simulations provide physical insight into the hemodynamics coupled with multi-wall mechanics’ function as an assessment tool for optimal SG placement and improved device design.

Monitoring the change in expression patterns over time provides the distinct possibility of unraveling the mechanistic drivers characterizing cellular responses. Gene arrays measuring the level of mRNA expression of thousands of genes simultaneously provide a method of high-throughput data collection necessary for obtaining the scope of data required for understanding the complexities of living organisms. Unraveling the coherent complex structures of transcriptional dynamics is the goal of a large family of computational methods aiming at upgrading the information content of time-course gene expression data. In this review, we summarize the qualitative characteristics of these approaches, discuss the main challenges that this type of complex data present, and, finally, explore the opportunities in the context of developing mechanistic models of cellular response.

Interstitial flow plays important roles in the morphogenesis, function, and pathogenesis of tissues. To investigate these roles and exploit them for tissue engineering or to overcome barriers to drug delivery, a comprehensive consideration of the interstitial space and how it controls and affects such processes is critical. Here we attempt to review the many physical and mathematical correlations that describe fluid and mass transport in the tissue interstitium; the factors that control and affect them; and the importance of interstitial transport on cell biology, tissue morphogenesis, and tissue engineering. Finally, we end with some discussion of interstitial transport issues in drug delivery, cell mechanobiology, and cell homing toward draining lymphatics.

Cancer nanotechnology is an interdisciplinary area of research in science, engineering, and medicine with broad applications for molecular imaging, molecular diagnosis, and targeted therapy. The basic rationale is that nanometer-sized particles, such as semiconductor quantum dots and iron oxide nanocrystals, have optical, magnetic, or structural properties that are not available from molecules or bulk solids. When linked with tumor targeting ligands such as monoclonal antibodies, peptides, or small molecules, these nanoparticles can be used to target tumor antigens (biomarkers) as well as tumor vasculatures with high affinity and specificity. In the mesoscopic size range of 5–100 nm diameter, nanoparticles also have large surface areas and functional groups for conjugating to multiple diagnostic (e.g., optical, radioisotopic, or magnetic) and therapeutic (e.g., anticancer) agents. Recent advances have led to bioaffinity nanoparticle probes for molecular and cellular imaging, targeted nanoparticle drugs for cancer therapy, and integrated nanodevices for early cancer detection and screening. These developments raise exciting opportunities for personalized oncology in which genetic and protein biomarkers are used to diagnose and treat cancer based on the molecular profiles of individual patients.

Single nucleotide polymorphisms (SNPs) are the most frequently occurring genetic variation in the human genome, with the total number of SNPs reported in public SNP databases currently exceeding 9 million. SNPs are important markers in many studies that link sequence variations to phenotypic changes; such studies are expected to advance the understanding of human physiology and elucidate the molecular bases of diseases. For this reason, over the past several years a great deal of effort has been devoted to developing accurate, rapid, and cost-effective technologies for SNP analysis, yielding a large number of distinct approaches. This article presents a review of SNP genotyping techniques and examines their principles of genotype determination in terms of allele differentiation strategies and detection methods. Further, several current biomedical applications of SNP genotyping are discussed.

Signaling pathways regulating proliferation, differentiation, and inflammation are commonly mediated through protein-protein interactions as well as reversible modification (e.g., phosphorylation) of proteins. To facilitate the study of regulated protein-protein interactions in cells and living animals, new imaging tools, many based on optical signals and capable of quantifying protein interactions in vivo, have advanced the study of induced protein interactions and their modification, as well as accelerated the rate of acquisition of these data. In particular, use of protein fragment complementation as a reporter strategy can accurately and rapidly dissect protein interactions with a variety of readouts, including absorbance, fluorescence, and bioluminescence. This review focuses on the development and validation of bioluminescent protein fragment complementation reporters that use either Renilla luciferase or firefly luciferase in vivo. Enhanced luciferase complementation provides a platform for near real-time detection and characterization of regulated and small-molecule-induced protein-protein interactions in intact cells and living animals and enables a wide range of novel applications in drug discovery, chemical genetics, and proteomics research.

The continuous technological progress of magnetic resonance imaging (MRI), as well as its widespread clinical use as a highly sensitive tool in diagnostics and advanced brain research, has brought a high demand for the development of magnetic resonance (MR)-compatible robotic/mechatronic systems. Revolutionary robots guided by real-time three-dimensional (3-D)-MRI allow reliable and precise minimally invasive interventions with relatively short recovery times. Dedicated robotic interfaces used in conjunction with fMRI allow neuroscientists to investigate the brain mechanisms of manipulation and motor learning, as well as to improve rehabilitation therapies. This paper gives an overview of the motivation, advantages, technical challenges, and existing prototypes for MR-compatible robotic/mechatronic devices.

The use of very low noise magnetometers based on Superconducting QUantum Interference Devices (SQUIDs) enables nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) in microtesla magnetic fields. An untuned superconducting flux transformer coupled to a SQUID achieves a magnetic field noise of 10⁻¹⁵ T Hz^−1/2. The frequency-independent response of this magnetometer combined with prepolarization of the nuclear spins yields an NMR signal that is independent of the Larmor frequency ω0. An MRI system operating in a field of 132 μT, corresponding to a proton frequency of 5.6 kHz, achieves an in-plane resolution of 0.7 × 0.7 mm² in phantoms. Measurements of the longitudinal relaxation time T1 in different concentrations of agarose gel over five decades of frequency reveal much greater T1-differentiation at fields below a few millitesla. Microtesla MRI has the potential to image tumors with substantially greater T1-weighted contrast than is achievable in high fields in the absence of a contrast agent.

This review offers a critical analysis of the state of the art of medical microbubbles and their application in therapeutic delivery and monitoring. When driven by an ultrasonic pulse, these small gas bubbles oscillate with a wall velocity on the order of tens to hundreds of meters per second and can be deflected to a vessel wall or fragmented into particles on the order of nanometers. While single-session molecular imaging of multiple targets is difficult with affinity-based strategies employed in some other imaging modalities, microbubble fragmentation facilitates such studies. Similarly, a focused ultrasound beam can be used to disrupt delivery vehicles and blood vessel walls, offering the opportunity to locally deliver a drug or gene. Clinical translation of these vehicles will require that current challenges be overcome, where these challenges include rapid clearance and low payload. The technology, early successes with drug and gene delivery, and potential clinical applications are reviewed.

Coronary artery disease (CAD) occurs when the arteries to the heart (the coronary arteries) become blocked by deposition of plaque, depriving the heart of oxygen-bearing blood. This disease is arguably the most important fatal disease in industrialized countries, causing one-third to one-half of all deaths in persons between the ages of 35 and 64 in the United States. Despite the fact that early detection of CAD allows for successful and cost-effective treatment of the disease, only 20% of CAD cases are diagnosed prior to a heart attack. The development of a definitive, noninvasive test for detection of coronary blockages is one of the holy grails of diagnostic cardiology. One promising approach to detecting coronary blockages noninvasively is based on identifying acoustic signatures generated by turbulent blood flow through partially occluded coronary arteries. In fact, no other approach to the detection of CAD promises to be as inexpensive, simple to perform, and risk free as the acoustic-based approach. Although sounds associated with partially blocked arteries are easy to identify in more superficial vessels such as the carotids, sounds from coronary arteries are very faint and surrounded by noise such as the very loud valve sounds. To detect these very weak signals requires sophisticated signal processing techniques. This review describes the work that has been done in this area since the 1980s and discusses future directions that may fulfill the promise of the acoustic approach to detecting coronary artery disease.

The widespread availability of high-performance computing and popularity of simulations stimulated the development of computational anthropomorphic models of the human anatomy for medical imaging modalities and dosimetry calculations. The widespread interest in molecular imaging spurred the development of more realistic three- to five-dimensional computational models based on the actual anatomy and physiology of individual humans and small animals. These can be defined by either mathematical (analytical) functions or digital (voxel-based) volume arrays (or a combination of both), thus allowing the simulation of medical imaging data that are ever closer to actual patient data. The paradigm shift away from the stylized human models is imminent with the development of more than 30 voxel-based tomographic models in recent years based on anatomical medical images. We review the fundamental and technical challenges of designing computational models of the human anatomy, and focus particularly on the latest developments and future directions of their application in the simulation of radiological imaging systems and dosimetry calculations.

Breast cancer is a serious disease that accounts for approximately 40,000 deaths per year in the United States. Unfortunately, there is no known cause of breast cancer, and therefore the best way to prevent mortality is early detection. In the past 15 years, breast cancer mortality has been reduced significantly, which is in part due to screening with film-screen mammography. Nonetheless, conventional mammography lacks sensitivity, especially for certain subgroups of women such as those with dense breast tissue, those under 50 years old, and pre- or perimenopausal women. In addition, mammography has a very poor positive predictive value for biopsy, with 70%–90% of biopsies performed turning out negative. By improving visualization of breast tissue, X-ray computerized tomography (CT) of the breast can potentially provide improvements in diagnostic accuracy over conventional mammography. Owing to recent technological developments in digital detector technology, flat-panel CT imagers dedicated to imaging of the breast are now feasible. A number of academic groups are currently researching dedicated breast CT and prototype systems are currently being evaluated in the clinical setting.

Noninvasive brain stimulation with transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) is valuable in research and has potential therapeutic applications in cognitive neuroscience, neurophysiology, psychiatry, and neurology. TMS allows neurostimulation and neuromodulation, while tDCS is a purely neuromodulatory application. TMS and tDCS allow diagnostic and interventional neurophysiology applications, and focal neuropharmacology delivery. However, the physics and basic mechanisms of action remain incompletely explored. Following an overview of the history and current applications of noninvasive brain stimulation, we review stimulation device design principles, the electromagnetic and physical foundations of the techniques, and the current knowledge about the electrophysiologic basis of the effects. Finally, we discuss potential biomedical and electrical engineering developments that could lead to more effective stimulation devices, better suited for the specific applications.

Approximately 20 years ago, the international community embarked on a project to bring health care to everyone by the year 2000 featuring, among other things, technologies that were known to be effective and economical. It was largely a failure. In fact, health care deteriorated in many of the target nations. Problems such as public mistrust, lack of spare parts, lack of required consumables, lack of reliable power and water, lack of public infrastructure such as roads, lack of technical expertise, and other problems plague health care technology in the developing world. Biomedical engineers are just beginning to quantify and address the barriers to technology unique to the developing world. This article reviews the barriers, both real and perceived, to the introduction of health care technology with a main focus on health care technology in hospitals.