Showing papers in "Annual Review of Biomedical Engineering in 2013"

Multifunctional Nanoparticles for Drug Delivery and Molecular Imaging

Abstract: Recent advances in nanotechnology and growing needs in biomedical applications have driven the development of multifunctional nanoparticles. These nanoparticles, through nanocrystalline synthesis, advanced polymer processing, and coating and functionalization strategies, have the potential to integrate various functionalities, simultaneously providing (a) contrast for different imaging modalities, (b) targeted delivery of drug/gene, and (c) thermal therapies. Although still in its infancy, the field of multifunctional nanoparticles has shown great promise in emerging medical fields such as multimodal imaging, theranostics, and image-guided therapies. In this review, we summarize the techniques used in the synthesis of complex nanostructures, review the major forms of multifunctional nanoparticles that have emerged over the past few years, and provide a perceptual vision of this important field of nanomedicine.

Functional attachment of soft tissues to bone: development, healing, and tissue engineering.

Abstract: Connective tissues such as tendons or ligaments attach to bone across a multitissue interface with spatial gradients in composition, structure, and mechanical properties. These gradients minimize stress concentrations and mediate load transfer between the soft and hard tissues. Given the high incidence of tendon and ligament injuries and the lack of integrative solutions for their repair, interface regeneration remains a significant clinical challenge. This review begins with a description of the developmental processes and the resultant structure-function relationships that translate into the functional grading necessary for stress transfer between soft tissue and bone. It then discusses the interface healing response, with a focus on the influence of mechanical loading and the role of cell-cell interactions. The review continues with a description of current efforts in interface tissue engineering, highlighting key strategies for the regeneration of the soft tissue–to-bone interface, and concludes with a summary of challenges and future directions.

The Pivotal Role of Vascularization in Tissue Engineering

Abstract: Vascularization is one of the great challenges that tissue engineering faces in order to achieve sizeable tissue and organ substitutes that contain living cells. There are instances, such as skin replacement, in which a tissue-engineered substitute does not absolutely need a preexisting vascularization. However, tissue or organ substitutes in which any dimension, such as thickness, exceeds 400 μm need to be vascularized to ensure cellular survival. Consistent with the wide spectrum of approaches to tissue engineering itself, which vary from acellular synthetic biomaterials to purely biological living constructs, approaches to tissue-engineered vascularization cover numerous techniques. Those techniques range from micropatterns engineered in biomaterials to microvascular networks created by endothelial cells. In this review, we strive to provide a critical overview of the elements that must be considered in the pursuit of this goal and the major approaches that are investigated in hopes of achieving it.

Mechanics in neuronal development and repair.

Abstract: Biological cells are well known to respond to a multitude of chemical signals. In the nervous system, chemical signaling has been shown to be crucially involved in development, normal functioning, and disorders of neurons and glial cells. However, there are an increasing number of studies showing that these cells also respond to mechanical cues. Here, we summarize current knowledge about the mechanical properties of nervous tissue and its building blocks, review recent progress in methodology and understanding of cellular mechanosensitivity in the nervous system, and provide an outlook on the implications of neuromechanics for future developments in biomedical engineering to aid overcoming some of the most devastating and currently incurable CNS pathologies such as spinal cord injuries and multiple sclerosis.

Multiscale Computational Models of Complex Biological Systems

Abstract: Integration of data across spatial, temporal, and functional scales is a primary focus of biomedical engineering efforts. The advent of powerful computing platforms, coupled with quantitative data from high-throughput experimental methodologies, has allowed multiscale modeling to expand as a means to more comprehensively investigate biological phenomena in experimentally relevant ways. This review aims to highlight recently published multiscale models of biological systems, using their successes to propose the best practices for future model development. We demonstrate that coupling continuous and discrete systems best captures biological information across spatial scales by selecting modeling techniques that are suited to the task. Further, we suggest how to leverage these multiscale models to gain insight into biological systems using quantitative biomedical engineering methods to analyze data in nonintuitive ways. These topics are discussed with a focus on the future of the field, current challenges encountered, and opportunities yet to be realized.

Breast Image Analysis for Risk Assessment, Detection, Diagnosis, and Treatment of Cancer

Abstract: The role of breast image analysis in radiologists' interpretation tasks in cancer risk assessment, detection, diagnosis, and treatment continues to expand. Breast image analysis methods include segmentation, feature extraction techniques, classifier design, biomechanical modeling, image registration, motion correction, and rigorous methods of evaluation. We present a review of the current status of these task-based image analysis methods, which are being developed for the various image acquisition modalities of mammography, tomosynthesis, computed tomography, ultrasound, and magnetic resonance imaging. Depending on the task, image-based biomarkers from such quantitative image analysis may include morphological, textural, and kinetic characteristics and may depend on accurate modeling and registration of the breast images. We conclude with a discussion of future directions.

Self-Organization and the Self-Assembling Process in Tissue Engineering

Abstract: In recent years, the tissue engineering paradigm has shifted to include a new and growing subfield of scaffoldless techniques that generate self-organizing and self-assembling tissues. This review aims to cogently describe this rel- atively new research area, with special focus on applications toward clinical use and research models. Particular emphasis is placed on providing clear definitions of self-organization and the self-assembling process, as delin- eated from other scaffoldless techniques in tissue engineering and regen- erative medicine. Significantly, during formation, self-organizing and self- assembling tissues display biological processes similar to those that occur in vivo. These processes help lead to the recapitulation of native tissue morpho- logical structure and organization. Notably, functional properties of these engineered tissues, some of which are already in clinical trials, also approach native tissue values. This review endeavors to provide a cohesive summary of work in this field and to highlight the potential of self-organization and the self-assembling process for providing cogent solutions to currently in- tractable problems in tissue engineering.

Engineered culture models for studies of tumor-microenvironment interactions.

Abstract: Heterogeneous microenvironmental conditions play critical roles in cancer pathogenesis and therapy resistance and arise from changes in tissue dimensionality, cell-extracellular matrix (ECM) interactions, soluble factor signaling, oxygen as well as metabolic gradients, and exogeneous biomechanical cues. Traditional cell culture approaches are restricted in their ability to mimic this complexity with physiological relevance, offering only partial explanation as to why novel therapeutic compounds are frequently efficacious in vitro but disappoint in preclinical and clinical studies. In an effort to overcome these limitations, physical sciences–based strategies have been employed to model specific aspects of the cancer microenvironment. Although these strategies offer promise to reveal the contributions of microenvironmental parameters on tumor initiation, progression, and therapy resistance, they, too, frequently suffer from limitations. This review highlights physicochemical and biological key features of ...

Microfluidics and coagulation biology.

Abstract: The study of blood ex vivo can occur in closed or open systems, with or without flow. Microfluidic devices, which constrain fluids to a small (typically submillimeter) scale, facilitate analysis of platelet function, coagulation biology, cellular biorheology, adhesion dynamics, and pharmacology and, as a result, can be an invaluable tool for clinical diagnostics. An experimental session can accommodate hundreds to thousands of unique clotting, or thrombotic, events. Using microfluidics, thrombotic events can be studied on defined surfaces of biopolymers, matrix proteins, and tissue factor, under constant flow rate or constant pressure drop conditions. Distinct shear rates can be generated on a device using a single perfusion pump. Microfluidics facilitated both the determination of intraluminal thrombus permeability and the discovery that platelet contractility can be activated by a sudden decrease in flow. Microfluidic devices are ideal for multicolor imaging of platelets, fibrin, and phosphatidylserine and provide a human blood analog to mouse injury models. Overall, microfluidic advances offer many opportunities for research, drug testing under relevant hemodynamic conditions, and clinical diagnostics.

Biophysical Cues and Cell Behavior: The Big Impact of Little Things

Abstract: The extracellular matrix is composed of a variety of proteins, polysaccharides, and glycosaminoglycans that self-assemble into a hierarchical order of nanometer- to micrometer-scale fibrils and fibers. The shapes, sizes, and elasticity present within this highly ordered meshwork regulate behaviors in most cell types. It has been well documented that cellular migration, proliferation, differentiation, and tissue development are all influenced by matrix geometries and compliance, but how these external biophysical cues are translated into activated intracellular signaling cascades remains poorly understood. Fortunately, technological improvements in artificial substrate fabrication have provided biologists with tools to test cellular interactions within controlled three-dimensional environments. Here, we review cellular responses to biophysical cues and discuss their clinical relevancy and application. We focus especially on integrative approaches that aim to first characterize the properties of specific ex...

Sensors and Decoding for Intracortical Brain Computer Interfaces

Abstract: Intracortical brain computer interfaces (iBCIs) are being developed to enable people to drive an output device, such as a computer cursor, directly from their neural activity. One goal of the technology is to help people with severe paralysis or limb loss. Key elements of an iBCI are the implanted sensor that records the neural signals and the software that decodes the user's intended movement from those signals. Here, we focus on recent advances in these two areas, placing special attention on contributions that are or may soon be adopted by the iBCI research community. We discuss how these innovations increase the technology's capability, accuracy, and longevity, all important steps that are expanding the range of possible future clinical applications.

eHealth: Extending, Enhancing, and Evolving Health Care

Abstract: eHealth holds the promise of revolutionizing health care by improving its efficiency; extending and enhancing its reach; energizing and engaging its practitioners and their patients; and in the process, democratizing, decentralizing, and even partially demystifying the practice of medicine. In emerging and developing countries, the use of eHealth and smart health-care planning has the potential to expand access to necessary treatments and prevention services that can serve as underpinnings of rapid economic development. In developed countries, the application of eHealth promises to restructure the business model of health-care delivery, while at the same time improving and personalizing the quality of care received. This article reviews the past, present, and future of eHealth in an effort to illuminate the potential of its impact.

Replacing Antibodies: Engineering New Binding Proteins

Abstract: Nature's reliance on proteins to carry out nearly all biological processes has led to the evolution of biomolecules that exhibit a seemingly endless range of functions. Much research has been devoted toward advancing this process in the laboratory in order to create new proteins with improved or unique capabilities. The protein-engineering field has rapidly evolved from pioneering studies in engineering protein stability and activity to an application-driven powerhouse on the forefront of emerging technologies in biomedical engineering and biotechnology. A classic protein-engineering technique in the medical field has focused on manipulating antibodies and antibody fragments for various applications. New classes of alternative scaffolds have recently challenged this paradigm, and these structures have been successfully engineered for applications including targeted cancer therapy, regulated drug delivery, in vivo imaging, and a host of others. This review aims to capture recent advances in the engineering of nonimmunoglobulin scaffolds as well as some of the applications for these molecular recognition elements in the biomedical field.

Exploring neural cell dynamics with digital holographic microscopy.

Abstract: In this review, we summarize how the new concept of digital optics applied to the field of holographic microscopy has allowed the development of a reliable and flexible digital holographic quantitative phase microscopy (DH-QPM) technique at the nanoscale particularly suitable for cell imaging. Particular emphasis is placed on the original biological information provided by the quantitative phase signal. We present the most relevant DH-QPM applications in the field of cell biology, including automated cell counts, recognition, classification, three-dimensional tracking, discrimination between physiological and pathophysiological states, and the study of cell membrane fluctuations at the nanoscale. In the last part, original results show how DH-QPM can address two important issues in the field of neurobiology, namely, multiple-site optical recording of neuronal activity and noninvasive visualization of dendritic spine dynamics resulting from a full digital holographic microscopy tomographic approach.

Atlas-based neuroinformatics via MRI: harnessing information from past clinical cases and quantitative image analysis for patient care.

Abstract: With the ever-increasing amount of anatomical information radiologists have to evaluate for routine diagnoses, computational support that facilitates more efficient education and clinical decision making is highly desired. Despite the rapid progress of image analysis technologies for magnetic resonance imaging of the human brain, these methods have not been widely adopted for clinical diagnoses. To bring computational support into the clinical arena, we need to understand the decision-making process employed by well-trained clinicians and develop tools to simulate that process. In this review, we discuss the potential of atlas-based clinical neuroinformatics, which consists of annotated databases of anatomical measurements grouped according to their morphometric phenotypes and coupled with the clinical informatics upon which their diagnostic groupings are based. As these are indexed via parametric representations, we can use image retrieval tools to search for phenotypes along with their clinical metadata. The review covers the current technology, preliminary data, and future directions of this field.

Micro- and nanoscale engineering of cell signaling.

Abstract: It is increasingly recognized that cell signaling, as a chemical process, must be considered at the local, micrometer scale. Micro- and nanofabrication techniques provide access to these dimensions, with the potential to capture and manipulate the spatial complexity of intracellular signaling in experimental models. This review focuses on recent advances in adapting surface engineering for use with biomolecular systems that interface with cell signaling, particularly with respect to surfaces that interact with multiple receptor systems on individual cells. The utility of this conceptual and experimental approach is demonstrated in the context of epithelial cells and T lymphocytes, two systems whose ability to perform their physiological function is dramatically impacted by the convergence and balance of multiple signaling pathways.

Topology and Dynamics of Signaling Networks: In Search of Transcriptional Control of the Inflammatory Response

Abstract: Over the past several decades, to develop a fundamental understanding of inflammation's progression, research has focused on extracellular mediators, such as cytokines, as characteristic components of inflammatory response. These efforts have recently been complemented by advances in proteomics that allow analysis of multiple signaling proteins in parallel, to provide more complete mechanistic models of inflammation. In this review, we discuss various techniques for assessing protein activity, as well as computational techniques that are well suited for interpreting large amounts of proteomic data to generate signaling networks or for modeling the dynamics of known network interactions. We also discuss examples that explore these experimental and computational techniques in tandem to generate signaling networks under various conditions and that link those networks to transcriptional activity. Further advancements in this field will likely provide an explicit description of inflammatory response, paving th...

Systems Biology Characterization of Engineered Tissues

Abstract: Tissue engineering and molecular systems biology are inherently interdisciplinary fields that have been developed independently so far. In this review, we first provide a brief introduction to tissue engineering and to molecular systems biology. Next, we highlight some prominent applications of systems biology techniques in tissue engineering. Finally, we outline research directions that can successfully blend these two fields. Through these examples, we propose that experimental and computational advances in molecular systems biology can lead to predictive models of bioengineered tissues that enhance our understanding of bioengineered systems. In turn, the unique challenges posed by tissue engineering will usher in new experimental techniques and computational advances in systems biology.

Cardiovascular Magnetic Resonance: Deeper Insights Through Bioengineering

Abstract: Heart disease is the main cause of morbidity and mortality worldwide, with coronary artery disease, diabetes, and obesity being major contributing factors. Cardiovascular magnetic resonance (CMR) can provide a wealth of quantitative information on the performance of the heart, without risk to the patient. Quantitative analyses of these data can substantially augment the diagnostic quality of CMR examinations and can lead to more effective characterization of disease and quantification of treatment benefit. This review provides an overview of the current state of the art in CMR with particular regard to the quantification of motion, both microscopic and macroscopic, and the application of bioengineering analysis for the evaluation of cardiac mechanics. We discuss the current clinical practice and the likely advances in the next 5–10 years, as well as the ways in which clinical examinations can be augmented by bioengineering analysis of strain, compliance, and stress.