scispace - formally typeset
Search or ask a question

Showing papers in "Annual Review of Biomedical Engineering in 2006"


Journal ArticleDOI
TL;DR: The molecular mechanisms by which bone adapts to loading and repairs damage are starting to become clear, and have implications for bone health, disease, and the feasibility of living in weightless environments (e.g., spaceflight).
Abstract: Bone is a dynamic tissue that is constantly renewed. The cell populations that participate in this process--the osteoblasts and osteoclasts--are derived from different progenitor pools that are under distinct molecular control mechanisms. Together, these cells form temporary anatomical structures, called basic multicellular units, that execute bone remodeling. A number of stimuli affect bone turnover, including hormones, cytokines, and mechanical stimuli. All of these factors affect the amount and quality of the tissue produced. Mechanical loading is a particularly potent stimulus for bone cells, which improves bone strength and inhibits bone loss with age. Like other materials, bone accumulates damage from loading, but, unlike engineering materials, bone is capable of self-repair. The molecular mechanisms by which bone adapts to loading and repairs damage are starting to become clear. Many of these processes have implications for bone health, disease, and the feasibility of living in weightless environments (e.g., spaceflight).

1,151 citations


Journal ArticleDOI
TL;DR: The forces and electrodes used to create electrophoretic and dielectrophoresis, and potential impacts on cell health, are examined, followed by examples of devices for both separating cells and handling them.
Abstract: Electrical forces for manipulating cells at the microscale include electrophoresis and dielectrophoresis. Electrophoretic forces arise from the interaction of a cell’s charge and an electric field, whereas dielectrophoresis arises from a cell’s polarizability. Both forces can be used to create microsystems that separate cell mixtures into its component cell types or act as electrical “handles” to transport cells or place them in specific locations. This review explores the use of these two forces for microscale cell manipulation. We first examine the forces and electrodes used to create them, then address potential impacts on cell health, followed by examples of devices for both separating cells and handling them.

857 citations


Journal ArticleDOI
TL;DR: The most pertinent technologies associated with in vivo noninvasive or minimally invasive fluorescence imaging of tissues are summarized and focus is given to small-animal imaging.
Abstract: There is a wealth of new fluorescent reporter technologies for tagging of many cellular and subcellular processes in vivo. This imposed contrast is now captured with an increasing number of available imaging methods that offer new ways to visualize and quantify fluorescent markers distributed in tissues. This is an evolving field of imaging sciences that has already achieved major advances but is also facing important challenges. It is nevertheless well poised to significantly impact the ways of biological research, drug discovery, and clinical practice in the years to come. Herein, the most pertinent technologies associated with in vivo noninvasive or minimally invasive fluorescence imaging of tissues are summarized. Focus is given to small-animal imaging. However, while a broad spectrum of fluorescence reporter technologies and imaging methods are outlined, as necessary for biomedical research, and clinical translation as well.

728 citations


Journal ArticleDOI
TL;DR: Comparing technical barriers involved in applying microfluidics for sensing and diagnostic use and applying such techniques to HTS explains why HTS products based on a CD fluidic platform are already commercially available, whereas the authors might have to wait longer to see commercial CD-based diagnostics.
Abstract: In this paper, centrifuge-based microfluidic platforms are reviewed and compared with other popular microfluidic propulsion methods. The underlying physical principles of centrifugal pumping in microfluidic systems are presented and the various centrifuge fluidic functions, such as valving, decanting, calibration, mixing, metering, heating, sample splitting, and separation, are introduced. Those fluidic functions have been combined with analytical measurement techniques, such as optical imaging, absorbance, and fluorescence spectroscopy and mass spectrometry, to make the centrifugal platform a powerful solution for medical and clinical diagnostics and high throughput screening (HTS) in drug discovery. Applications of a compact disc (CD)-based centrifuge platform analyzed in this review include two-point calibration of an optode-based ion sensor, an automated immunoassay platform, multiple parallel screening assays, and cellular-based assays. The use of modified commercial CD drives for high-resolution optical imaging is discussed as well. From a broader perspective, we compare technical barriers involved in applying microfluidics for sensing and diagnostic use and applying such techniques to HTS. The latter poses less challenges and explains why HTS products based on a CD fluidic platform are already commercially available, whereas we might have to wait longer to see commercial CD-based diagnostics.

580 citations


Journal ArticleDOI
TL;DR: This review considers several current approaches for intracellular drug delivery: the use of pH-sensitive liposomes, theuse of cell-penetrating proteins and peptides, and theUse of immunoliposomes targeting intrace cellular antigens, including nuclei, mitochondria, and lysosomes.
Abstract: Intracellular delivery of various drugs, including DNA, and drug carriers can sharply increase the efficiency of various treatment protocols. However, the receptor-mediated endocytosis of drugs, drug carriers, and DNA results in their lysosomal delivery and significant degradation. The problem can be solved and therapy efficacy still further increased if the approaches for direct intracytoplasmic delivery that bypass the endocytic pathway are developed. This is especially important for many anticancer drugs (proapoptotic drugs whose primary action site is the mitochondrial membrane) and gene therapy (nuclear or mitochondrial genomes should be targeted). This review considers several current approaches for intracellular drug delivery: the use of pH-sensitive liposomes, the use of cell-penetrating proteins and peptides, and the use of immunoliposomes targeting intracellular antigens. Among intracellular targets, nuclei (gene therapy), mitochondria (proapoptotic cancer therapy and targeting of the mitochondrial genome), and lysosomes (lysosomal targeting of enzymes for the therapy of the lysosomal storage diseases) are considered. Examples of successful intracellular and organelle-specific delivery of biologically active molecules, including DNA, are presented; unanswered questions, challenges, and future trends are also discussed.

528 citations


Journal ArticleDOI
TL;DR: A review of the development of EIT and its clinical applications, examining hardware for the collection of data and reconstruction algorithms to generate images, and looking at future developments that are evolving from EIT.
Abstract: Electrical impedance tomography (EIT) is a relatively new imaging method that has evolved over the past 20 years. It has the potential to be of great value in clinical diagnosis; however, EIT is a technically difficult problem to solve in terms of developing hardware for data capture and the algorithms to reconstruct the images. This review looks at the development of EIT and how it has evolved. It focuses on its clinical applications, examining hardware for the collection of data and reconstruction algorithms to generate images. Finally, this review looks at future developments that are evolving from EIT. These new variations use mixed modalities that may produce interesting new clinical imaging tools.

400 citations


Journal ArticleDOI
Paul Sajda1
TL;DR: The review describes recent developments in machine learning, focusing on supervised and unsupervised linear methods and Bayesian inference, which have made significant impacts in the detection and diagnosis of disease in biomedicine.
Abstract: Machine learning offers a principled approach for developing sophisticated, automatic, and objective algorithms for analysis of high-dimensional and multimodal biomedical data. This review focuses on several advances in the state of the art that have shown promise in improving detection, diagnosis, and therapeutic monitoring of disease. Key in the advancement has been the development of a more in-depth understanding and theoretical analysis of critical issues related to algorithmic construction and learning theory. These include trade-offs for maximizing generalization performance, use of physically realistic constraints, and incorporation of prior knowledge and uncertainty. The review describes recent developments in machine learning, focusing on supervised and unsupervised linear methods and Bayesian inference, which have made significant impacts in the detection and diagnosis of disease in biomedicine. We describe the different methodologies and, for each, provide examples of their application to specific domains in biomedical diagnostics.

327 citations


Journal ArticleDOI
TL;DR: This review highlights the important aspects of GAGs and summarizes these aspects in the context of taking a glycomics approach that integrates the different technologies to define structure-function relationships of G AGs.
Abstract: Extracellular modulation of phenotype is an emerging paradigm in this current postgenomics age of molecular and cell biology. Glycosaminoglycans (GAGs) are primary components of the cell surface and the cell-extracellular matrix (ECM) interface. Advances in the technology to analyze GAGs and in whole-organism genetics have led to a dramatic increase in the known important biological role of these complex polysaccharides. Owing to their ubiquitous distribution at the cell-ECM interface, GAGs interact with numerous proteins and modulate their activity, thus impinging on fundamental biological processes such as cell growth and development. Many recent reviews have captured important aspects of GAG structure and biosynthesis, GAG-protein interactions, and GAG biology. GAG research is currently at a stage where there is a need for an integrated systems or glycomics approach, which involves an integration of all of the above concepts to define their structure-function relationships. Focusing on heparin/heparan (HSGAGs) and chondroitin/dermatan sulfate (CSGAGs), this review highlights the important aspects of GAGs and summarizes these aspects in the context of taking a glycomics approach that integrates the different technologies to define structure-function relationships of GAGs.

275 citations


Journal ArticleDOI
TL;DR: How recent developments in flow models are providing insight into antiangiogenic and chemotherapeutic drug treatment of solid tumors is indicated.
Abstract: Angiogenesis, the growth of a network of blood vessels, is a crucial component of solid tumor growth, linking the relatively harmless avascular and the potentially fatal vascular growth phases of the tumor. As a process, angiogenesis is a well-orchestrated sequence of events involving endothelial cell migration and proliferation; degradation of tissue; new capillary vessel formation; loop formation (anastomosis) and, crucially, blood flow through the network. Once there is flow associated with the nascent network, subsequent growth evolves both temporally and spatially in response to the combined effects of angiogenic factors, migratory cues via the extracellular matrix, and perfusion-related hemodynamic forces in a manner that may be described as both adaptive and dynamic. In this article, we first present a review of previous theoretical and computational models of angiogenesis and then indicate how recent developments in flow models are providing insight into antiangiogenic and chemotherapeutic drug treatment of solid tumors.

248 citations


Journal ArticleDOI
TL;DR: Force measurements quantified both kinetic and strength differences between different classical cadherins that may underlie cell sorting behavior and showed that differential cadherin-mediated adhesion, rather than exclusive homophilic binding between identical caderins, direct cell segregation and the organization of tissue interfaces during morphogenesis is shown.
Abstract: Cadherins are essential cell adhesion molecules involved in tissue morphogenesis and the maintenance of tissue architecture in adults. The adhesion and selectivity functions of cadherins are located in their extracellular regions. Biophysical studies show that the adhesive activity is not confined to a single interface. Instead, multiple cadherin domains contribute to binding. By contrast, the specificity-determining site maps to the N-terminal domains, which adhere by the reciprocal binding of Trp2 residues from opposing proteins. Structural cooperativity can transmit the effects of subtle structural changes or ligand binding over large distances in the protein. Increasingly, studies show that differential cadherin-mediated adhesion, rather than exclusive homophilic binding between identical cadherins, direct cell segregation and the organization of tissue interfaces during morphogenesis. Force measurements quantified both kinetic and strength differences between different classical cadherins that may underlie cell sorting behavior. Despite the complex adhesion mechanisms and differences in binding properties, cadherin-mediated cell adhesion is also regulated by many other biochemical processes. Elucidating the mechanisms by which cadherins organize cell junctions and tissue architecture requires not only quantitative, mechanistic investigations of cadherin function but also investigations of the biochemical and cellular processes that can modulate those functions.

205 citations


Journal ArticleDOI
TL;DR: This review discusses the advantages and challenges in developing multimodality imaging systems for in vivo use, highlights some successful combinations that are now routinely used in the clinic and in research, and discusses recent advances in multi-modality instrumentation that may offer new opportunities for imaging.
Abstract: Many different types of radiation have been exploited to provide images of the structure and function of tissues inside a living subject. Each imaging modality is characterized by differing resolutions on the spatial and temporal scales, and by a different sensitivity for measuring properties related to morphology or function. Combinations of imaging modalities that integrate the strengths of two modalities, and at the same time eliminate one or more weaknesses of an individual modality, thus offer the prospect of improved diagnostics, therapeutic monitoring, and preclinical research using imaging approaches. This review discusses the advantages and challenges in developing multimodality imaging systems for in vivo use, highlights some successful combinations that are now routinely used in the clinic and in research, and discusses recent advances in multimodality instrumentation that may offer new opportunities for imaging.

Journal ArticleDOI
TL;DR: A new hypothesis for the generation of inflammatory mediators in plasma that are derived from the digestive pancreatic enzymes responsible for digestion is presented, offering a large number of opportunities for development of quantitative models that describe various aspects of human diseases.
Abstract: In the past, inflammation has been associated with infections and with the immune system. But more recent evidence suggests that a much broader range of diseases have telltale markers for inflammation. Inflammation is the basic mechanism available for repair of tissue after an injury and consists of a cascade of cellular and microvascular reactions that serve to remove damaged and generate new tissue. The cascade includes elevated permeability in microvessels, attachment of circulating cells to the vessels in the vicinity of the injury site, migration of several cell types, cell apoptosis, and growth of new tissue and blood vessels. This review provides a summary of the major microvascular, cellular, and molecular mechanisms that regulate elements of the inflammatory cascade. The analysis is largely focused on the identification of the major participants, notably signaling and adhesion molecules, and their mode of action in the inflammatory cascade. We present a new hypothesis for the generation of inflammatory mediators in plasma that are derived from the digestive pancreatic enzymes responsible for digestion. The inflammatory cascade offers a large number of opportunities for development of quantitative models that describe various aspects of human diseases.

Journal ArticleDOI
TL;DR: Recent progress and obstacles to using siRNAs as small molecule drugs are discussed, including pilot siRNA clinical studies began just three years after the discovery that RNAi works in mammalian cells.
Abstract: RNA interference (RNAi) is a well-conserved, ubiquitous, endogenous mechanism that uses small noncoding RNAs to silence gene expression. The endogenous small RNAs, called microRNAs, are processed from hairpin precursors and regulate important genes involved in cell death, differentiation, and development. RNAi also protects the genome from invading genetic elements, encoded by transposons and viruses. When small double-stranded RNAs, called small interfering (si)RNAs, are introduced into cells, they bind to the endogenous RNAi machinery to disrupt the expression of mRNAs containing complementary sequences with high specificity. Any disease-causing gene and any cell type or tissue can potentially be targeted. This technique has been rapidly utilized for gene-function analysis and drug-target discovery and validation. Harnessing RNAi also holds great promise for therapy, although introducing siRNAs into cells in vivo remains an important obstacle. Pilot siRNA clinical studies began just three years after the discovery that RNAi works in mammalian cells. This review discusses recent progress and obstacles to using siRNAs as small molecule drugs.

Journal ArticleDOI
TL;DR: Recent advances in bioresorbable stents are described, focusing on drug-eluting bioresolved stents for various applications, to enhance healing of the surrounding tissues, and increase the implant's biocompatibility.
Abstract: A stent is a medical device designed to serve as a temporary or permanent internal scaffold to maintain or increase the lumen of a body conduit. Metallic coronary stents were first introduced to prevent arterial dissections and to eliminate vessel recoil and intimal hyperplasia associated with percutaneous transluminal coronary angioplasty. The stent application range has expanded as more experience was gained, and encouraging results have been obtained in the treatment of vascular diseases. Stents are currently used for support of additional body conduits, including the urethra, trachea, and esophagus. The rationale for bioresorbable stents is the support of a body conduit only during its healing process. The stent mass and strength decrease with time, and the mechanical load is gradually transferred to the surrounding tissue. Bioresorbable stents also enable longer term delivery of drugs to the conduit wall from an internal reservoir and abolish the need for a second surgery to remove the device. The present review describes recent advances in bioresorbable stents, focusing on drug-eluting bioresorbable stents for various applications. Controlled release of an active agent from a stent can be used to enhance healing of the surrounding tissues, to increase the implant's biocompatibility, as well as to help cure certain diseases. Because a lot of research in this field has been done by us, examples for these functions are described based mainly on developments in our laboratories.

Journal ArticleDOI
TL;DR: The successful realization of this potential requires an understanding of the kinetics of the HSP expression process in response to sublethal stress regimens along with the ability to model the governing events in the process to design practical protocols that could be applied in therapeutic settings.
Abstract: In all organisms there is an elevated synthesis of a select family of “stress proteins” in response to a broad array of environmentally driven stress vectors including elevated or depressed temperature, changes in pH, treatment with many classes of chemicals, ischemia, desiccation, and UV irradiation. The presence of stress proteins, often termed heat shock proteins (HSPs), has been recognized for more than four decades, and there is an extensive literature that addresses the structure and properties of HSPs, their function in normal and injured cells and tissues, and the molecular mechanisms of HSP expression in response to stress. Owing to this substantial aggregate of research, there is a growing appreciation of the potential for manipulating the magnitude and timing of elevated HSP expression to achieve targeted therapeutic objectives. The successful realization of this potential requires an understanding of the kinetics of the HSP expression process in response to sublethal stress regimens along with the ability to model the governing events in the process to design practical protocols that could be applied in therapeutic settings. Significant progress has been made in recent years in defining and developing capabilities in these two areas.

Journal ArticleDOI
TL;DR: This article presents a brief review of the statistical methodology, multiple logistic regression, which underlies most of the models currently used in critical care, and emphasizes the importance of model calibration in this domain.
Abstract: Prognostic risk prediction models have been employed in the intensive care unit (ICU) setting since the 1980s and provide health care providers with important information to help inform decisions related to treatment and prognosis, as well as to compare outcomes across institutions. Prognostic models for critical care are among the most widely utilized and tested predictive models in healthcare. In this article, we review and compare mortality prediction models, including the APACHE (1981), SAPS (1984), APACHE-II (1985), MPM (1987), APACHE-III (1991), SAPS-II (1993), and MPM-II (1993). We emphasize the importance of model calibration in this domain. In addition, we present a brief review of the statistical methodology, multiple logistic regression, which underlies most of the models currently used in critical care.

Journal ArticleDOI
TL;DR: The principles of engineering design and biofluid and biosolid mechanics principles that may have the greatest bearing on mechanical homeostasis and the long-term outcome of CABG are outlined.
Abstract: Since its inception in the 1960s, coronary artery bypass graft (CABG) evolved as one of the most common, best documented, and most effective of all major surgical treatments for ischemic heart disease. Despite its widespread use, however, the outcome is not always completely satisfactory. The objective of this review is to highlight the physical determinants of biomechanical design of CABG so that future procedures would have prolonged patency and better outcome. Our central axiom postulates the existence of a mechanical homeostatic state of the blood vessel, i.e., the variation in vessel wall stresses and strains are relatively small under physiological conditions. Any perturbation of mechanical homeostasis leads to growth and remodeling. In this sense, stenosis and failure of a graft may be viewed as an adaptation process gone awry. We outline the principles of engineering design and discuss the biofluid and biosolid mechanics principles that may have the greatest bearing on mechanical homeostasis and the long-term outcome of CABG.

Journal ArticleDOI
TL;DR: The development of an alternative to natural blood has evolved from the initial goal of replicating blood properties to the current objective of formulating a fluid that can be used to replace blood while preserving microvascular function and delivering oxygen.
Abstract: The development of an alternative to natural blood has evolved from the initial goal of replicating blood properties to the current objective of formulating a fluid that can be used to replace blood while preserving microvascular function and delivering oxygen. The properties of this fluid are counterintuitive and different from blood because it has high viscosity, oxygen affinity, and a low oxygen carrier concentration when compared with blood. The optimal oxygen carrier devised presently is poly-ethylene-conjugated human hemoglobin, a material demonstrated to be vasoinactive and void of the toxicities present in previous hemoglobin formulations. A feature of this material is that it is effective in small quantities, and therefore amplifies the equivalent supply of blood derived from blood donations.