Annual Review of Biomedical Engineering - Volume 14, 2012

An understanding of the interactions between nanoparticles and biological systems is of significant interest. Studies aimed at correlating the properties of nanomaterials such as size, shape, chemical functionality, surface charge, and composition with biomolecular signaling, biological kinetics, transportation, and toxicity in both cell culture and animal experiments are under way. These fundamental studies will provide a foundation for engineering the next generation of nanoscale devices. Here, we provide rationales for these studies, review the current progress in studies of the interactions of nanomaterials with biological systems, and provide a perspective on the long-term implications of these findings.

Mucosal surfaces are a major portal of entry for many human pathogens that are the cause of infectious diseases worldwide. Vaccines capable of eliciting mucosal immune responses can fortify defenses at mucosal front lines and protect against infection. However, most licensed vaccines are administered parenterally and fail to elicit protective mucosal immunity. Immunization by mucosal routes may be more effective at inducing protective immunity against mucosal pathogens at their sites of entry. Recent advances in our understanding of mucosal immunity and identification of correlates of protective immunity against specific mucosal pathogens have renewed interest in the development of mucosal vaccines. Efforts have focused on efficient delivery of vaccine antigens to mucosal sites that facilitate uptake by local antigen-presenting cells to generate protective mucosal immune responses. Discovery of safe and effective mucosal adjuvants are also being sought to enhance the magnitude and quality of the protective immune response.

Injury and degeneration of tendon, the soft tissue that mechanically links muscle and bone, can cause substantial pain and loss of function. This review discusses the composition and function of healthy tendon and describes the structural, biological, and mechanical changes initiated during the process of tendon healing. Biochemical pathways activated during repair, experimental injury models, and parallels between tendon healing and tendon development are emphasized, and cutting-edge strategies for the enhancement of tendon healing are discussed.

A new set of manufacturing technologies has emerged in the past decades to address market requirements in a customized way and to provide support for research tasks that require prototypes. These new techniques and technologies are usually referred to as rapid prototyping and manufacturing technologies, and they allow prototypes to be produced in a wide range of materials with remarkable precision in a couple of hours. Although they have been rapidly incorporated into product development methodologies, they are still under development, and their applications in bioengineering are continuously evolving. Rapid prototyping and manufacturing technologies can be of assistance in every stage of the development process of novel biodevices, to address various problems that can arise in the devices' interactions with biological systems and the fact that the design decisions must be tested carefully. This review focuses on the main fields of application for rapid prototyping in biomedical engineering and health sciences, as well as on the most remarkable challenges and research trends.

Biological growth processes involve mass exchanges that increase, decrease, or replace material that constitutes cells, tissues, and organs. In most cases, such exchanges alter the structural makeup of the material and consequently affect associated mechanobiological responses to applied loads. Given that the type and extent of changes in structural integrity depend on the different constituents involved (e.g., particular cytoskeletal or extracellular matrix proteins), the continuum theory of mixtures is ideally suited to model the mechanics of growth and remodeling. The goal of this review is twofold: first, to highlight a few illustrative examples that show diverse applications of mixture theory to describe biological growth and/or remodeling; second, to identify some open problems in the fields of modeling soft-tissue growth and remodeling.

Advances in materials, mechanics, and manufacturing now allow construction of high-quality electronics and optoelectronics in forms that can readily integrate with the soft, curvilinear, and time-dynamic surfaces of the human body. The resulting capabilities create new opportunities for studying disease states, improving surgical procedures, monitoring health/wellness, establishing human-machine interfaces, and performing other functions. This review summarizes these technologies and illustrates their use in forms integrated with the brain, the heart, and the skin.

The ramified architectures of organs such as the mammary gland and lung are generated via branching morphogenesis, a developmental process through which individual cells bud and pinch off of pre-existing epithelial sheets. Although specified by signaling programs, organ development requires integration of all aspects of the microenvironment. We describe the essential role of endogenous cellular contractility in the formation of branching tubes. We also highlight the role of exogenous forces in normal and aberrant branching.

Over the past decade, synthetic biology has emerged as an engineering discipline for biological systems. Compared with other substrates, biology poses a unique set of engineering challenges resulting from an incomplete understanding of natural biological systems and tools for manipulating them. To address these challenges, synthetic biology is advancing from developing proof-of-concept designs to focusing on core platforms for rational and high-throughput biological engineering. These platforms span the entire biological design cycle, including DNA construction, parts libraries, computational design tools, and interfaces for manipulating and probing synthetic circuits. The development of these enabling technologies requires an engineering mindset to be applied to biology, with an emphasis on generalizable techniques in addition to application-specific designs. This review aims to discuss the progress and challenges in synthetic biology and to illustrate areas where synthetic biology may impact biomedical engineering and human health.

The dynamics of many cardiac arrhythmias, as well as the nature of transitions between different heart rhythms, have long been considered evidence of nonlinear phenomena playing a direct role in cardiac arrhythmogenesis. In most types of cardiac disease, the pathology develops slowly and gradually, often over many years. In contrast, arrhythmias often occur suddenly. In nonlinear systems, sudden changes in qualitative dynamics can, counterintuitively, result from a gradual change in a system parameter—this is known as a bifurcation. Here, we review how nonlinearities in cardiac electrophysiology influence normal and abnormal rhythms and how bifurcations change the dynamics. In particular, we focus on the many recent developments in computational modeling at the cellular level that are focused on intracellular calcium dynamics. We discuss two areas where recent experimental and modeling work has suggested the importance of nonlinearities in calcium dynamics: repolarization alternans and pacemaker cell automaticity.

In vitro studies of vascular physiology have traditionally relied on cultures of endothelial cells, smooth muscle cells, and pericytes grown on centimeter-scale plates, filters, and flow chambers. The introduction of microfluidic tools has revolutionized the study of vascular physiology by allowing researchers to create physiologically relevant culture models, at the same time greatly reducing the consumption of expensive reagents. By taking advantage of the small dimensions and laminar flow inherent in microfluidic systems, recent studies have created in vitro models that reproduce many features of the in vivo vascular microenvironment with fine spatial and temporal resolution. In this review, we highlight the advantages of microfluidics in four areas: the investigation of hemodynamics on a capillary length scale, the modulation of fluid streams over vascular cells, angiogenesis induced by the exposure of vascular cells to well-defined gradients in growth factors or pressure, and the growth of microvascular networks in biomaterials. Such unique capabilities at the microscale are rapidly advancing the understanding of microcirculatory dynamics, shear responses, and angiogenesis in health and disease as well as the ability to create in vivo–like blood vessels in vitro.

Recent advances in far-field microscopy have demonstrated that fluorescence imaging is possible at resolutions well below the long-standing diffraction limit. By exploiting photophysical properties of fluorescent probe molecules, this new class of methods yields a resolving power that is fundamentally diffraction unlimited. Although these methods are becoming more widely used in biological imaging, they must be complemented by suitable data analysis approaches if their potential is to be fully realized. Here we review the basic principles of diffraction-unlimited microscopy and how these principles influence the selection of available algorithms for data analysis. Furthermore, we provide an overview of existing analysis strategies and discuss their application.

The recent tremendous progress in understanding physical plasma phenomena, together with the development of new plasma sources, has put a growing focus on the application of nonthermal plasmas in the biomedical domain. Among several novel applications, the inactivation of bacteria by nonthermal plasmas (so-called plasma sterilization) is particularly interesting. This introductory review provides a summary of the current status of this emerging research field. In addition to the inactivation of bacteria on nonliving surfaces, this review also focuses on the sterilization of living surfaces, such as animal and human tissues. Clearly, nonthermal plasmas have undoubtedly great potential as a novel method for low-temperature sterilization.

Autism spectrum disorders are a group of lifelong disabilities that affect people's ability to communicate and to understand social cues. Research into applying robots as therapy tools has shown that robots seem to improve engagement and elicit novel social behaviors from people (particularly children and teenagers) with autism. Robot therapy for autism has been explored as one of the first application domains in the field of socially assistive robotics (SAR), which aims to develop robots that assist people with special needs through social interactions. In this review, we discuss the past decade's work in SAR systems designed for autism therapy by analyzing robot design decisions, human-robot interactions, and system evaluations. We conclude by discussing challenges and future trends for this young but rapidly developing research area.

Achieving control over cell behavior and pattern formation requires molecular-level understanding of regulatory mechanisms. Alongside transcriptional networks and biochemical gradients, there functions an important system of cellular communication and control: transmembrane voltage gradients (Vmem). Bioelectrical signals encoded in spatiotemporal changes of Vmem control cell proliferation, migration, and differentiation. Moreover, endogenous bioelectrical gradients serve as instructive cues mediating anatomical polarity and other organ-level aspects of morphogenesis. In the past decade, significant advances in molecular physiology have enabled the development of new genetic and biophysical tools for the investigation and functional manipulation of bioelectric cues. Recent data implicate Vmem as a crucial epigenetic regulator of patterning events in embryogenesis, regeneration, and cancer. We review new conceptual and methodological developments in this fascinating field. Bioelectricity offers a novel way of quantitatively understanding regulation of growth and form in vivo, and it reveals tractable, powerful control points that will enable truly transformative applications in bioengineering, regenerative medicine, and synthetic biology.

Stem cells hold significant promise for regeneration of tissue defects and disease-modifying therapies. Although numerous promising stem cell approaches are advancing in clinical trials, intraoperative stem cell therapies offer more immediate hope by integrating an autologous cell source with a well-established surgical intervention in a single procedure. Herein, the major developments in intraoperative stem cell approaches, from in vivo models to clinical studies, are reviewed, and the potential regenerative mechanisms and the roles of different cell populations in the regeneration process are discussed. Although intraoperative stem cell therapies have been shown to be safe and effective for several indications, there are still critical challenges to be tackled prior to adoption into the standard surgical armamentarium.

Optical microscopic imaging offers opportunities to perform noninvasive assessments of numerous parameters associated with the biochemistry, morphology, and functional state of biological samples. For example, it is possible to detect the endogenous fluorescence from a small number of important biomolecules, including NADH and FAD, which are two coenzymes involved in key metabolic pathways such as glycolysis, the Krebs cycle, and oxidative phosphorylation. Here, we review different imaging approaches to isolate the fluorescence from these chromophores in two- and three-dimensional samples and discuss the origins and potential interpretation of the observed signals in terms of cell metabolic status. Finally, we discuss the challenges and limitations of these approaches, as well as important research directions that we expect will evolve in the near future.

Rapid deformation of brain tissue in response to head impact or acceleration can lead to numerous pathological changes, both immediate and delayed. Modeling and simulation hold promise for illuminating the mechanisms of traumatic brain injury (TBI) and for developing preventive devices and strategies. However, mathematical models have predictive value only if they satisfy two conditions. First, they must capture the biomechanics of the brain as both a material and a structure, including the mechanics of brain tissue and its interactions with the skull. Second, they must be validated by direct comparison with experimental data. Emerging imaging technologies and recent imaging studies provide important data for these purposes. This review describes these techniques and data, with an emphasis on magnetic resonance imaging approaches. In combination, these imaging tools promise to extend our understanding of brain biomechanics and improve our ability to study TBI in silico.

The gastrointestinal tract is home to some of the most deadly human diseases. Exacerbating the problem is the difficulty of accessing it for diagnosis or intervention and the concomitant patient discomfort. Flexible endoscopy has established itself as the method of choice and its diagnostic accuracy is high, but there remain technical limitations in modern scopes, and the procedure is poorly tolerated by patients, leading to low rates of compliance with screening guidelines. Although advancement in clinical endoscope design has been slow in recent years, a critical mass of enabling technologies is now paving the way for the next generation of gastrointestinal endoscopes. This review describes current endoscopes and provides an overview of innovative flexible scopes and wireless capsules that can enable painless endoscopy and/or enhanced diagnostic and therapeutic capabilities. We provide a perspective on the potential of these new technologies to address the limitations of current endoscopes in mass cancer screening and other contexts and thus to save many lives.

Mechanical loading induces both nuclear distortion and alterations in gene expression in a variety of cell types. Mechanotransduction is the process by which extracellular mechanical forces can activate a number of well-studied cytoplasmic signaling cascades. Inevitably, such signals are transduced to the nucleus and induce transcription factor–mediated changes in gene expression. However, gene expression also can be regulated through alterations in nuclear architecture, providing direct control of genome function. One putative transduction mechanism for this phenomenon involves alterations in nuclear architecture that result from the mechanical perturbation of the cell. This perturbation is associated with direct mechanical strain or osmotic stress, which is transferred to the nucleus. This review describes the current state of knowledge relating the nuclear architecture and the transfer of mechanical forces to the nucleus mediated by the cytoskeleton, the nucleoskeleton, and the LINC (linker of the nucleoskeleton and cytoskeleton) complex. Moreover, remodeling of the nucleus induces alterations in nuclear stiffness, which may be associated with cell differentiation. These phenomena are discussed in relation to the potential influence of nuclear architecture-mediated mechanoregulation of transcription and cell fate.