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1.  [No title available] 
PMCID: PMC3912461  PMID: 24484881
2.  [No title available] 
PMCID: PMC3912463  PMID: 24484875
3.  [No title available] 
PMCID: PMC3912466  PMID: 24484889
4.  [No title available] 
PMCID: PMC3912467  PMID: 24484877
5.  Vaccine Design: Emerging Concepts and Renewed Optimism 
Current opinion in biotechnology  2013;24(6):10.1016/j.copbio.2013.02.015.
Arguably, vaccination represents the single most effective medical intervention ever developed. Yet, vaccines have failed to provide any or adequate protection against some of the most significant global diseases. The pathogens responsible for these vaccine-recalcitrant diseases have properties that allow them to evade immune surveillance and misdirect or eliminate the immune response. However, genomic and systems biology tools, novel adjuvants and delivery systems, and refined molecular insight into protective immunity have started to redefine the landscape, and results from recent efficacy trials of HIV and malaria vaccines have instilled hope that another golden age of vaccines may be on the horizon.
doi:10.1016/j.copbio.2013.02.015
PMCID: PMC3696422  PMID: 23474232
6.  Molecular tools for chemical biotechnology 
Current opinion in biotechnology  2013;24(6):10.1016/j.copbio.2013.03.001.
Biotechnological production of high value chemical products increasingly involves engineering in vivo multi-enzyme pathways and host metabolism. Recent approaches to these engineering objectives have made use of molecular tools to advance de novo pathway identification, tunable enzyme expression, and rapid pathway construction. Molecular tools also enable optimization of single enzymes and entire genomes through diversity generation and screening, whole cell analytics, and synthetic metabolic control networks. In this review, we focus on advanced molecular tools and their applications to engineered pathways in host organisms, highlighting the degree to which each tool is generalizable.
doi:10.1016/j.copbio.2013.03.001
PMCID: PMC3740197  PMID: 23528237
7.  Metabolic flux rewiring in mammalian cell cultures 
Current opinion in biotechnology  2013;24(6):10.1016/j.copbio.2013.04.016.
Continuous cell lines (CCLs) engage in “wasteful” glucose and glutamine metabolism that leads to accumulation of inhibitory byproducts, primarily lactate and ammonium. Advances in techniques for mapping intracellular carbon fluxes and profiling global changes in enzyme expression have led to a deeper understanding of the molecular drivers underlying these metabolic alterations. However, recent studies have revealed that CCLs are not necessarily entrenched in a glycolytic or glutaminolytic phenotype, but instead can shift their metabolism toward increased oxidative metabolism as nutrients become depleted and/or growth rate slows. Progress to understand dynamic flux regulation in CCLs has enabled the development of novel strategies to force cultures into desirable metabolic phenotypes, by combining fed-batch feeding strategies with direct metabolic engineering of host cells.
doi:10.1016/j.copbio.2013.04.016
PMCID: PMC3775942  PMID: 23726154
Metabolic flux analysis; continuous cell lines; lactate shift; aerobic glycolysis; oxidative phosphorylation; fed-batch culture; metabolic engineering
8.  Meta-omic characterization of prokaryotic gene clusters for natural product biosynthesis 
Current opinion in biotechnology  2013;24(6):10.1016/j.copbio.2013.05.001.
Microorganisms produce a remarkable selection of bioactive small molecules. The study and exploitation of these secondary metabolites has traditionally been restricted to the cultivable minority of bacteria. Rapid advances in meta-omics challenge this paradigm. Breakthroughs in metagenomic library methodologies, direct sequencing, single cell genomics, and natural product-specific bioinformatic tools now facilitate the retrieval of previously inaccessible biosynthetic gene clusters. Similarly, metaproteomic developments enable the direct study of biosynthetic enzymes from complex microbial communities. Additional methods within and beyond meta-omics are also in development. This review discusses recent reports in these arenas and how they can be utilized to characterize natural product biosynthetic gene clusters and pathways.
doi:10.1016/j.copbio.2013.05.001
PMCID: PMC3797859  PMID: 23731715
9.  Matrix-based gene delivery for tissue repair 
Current opinion in biotechnology  2013;24(5):855-863.
Scaffolds for tissue repair must provide structural and biochemical cues to initiate the complex cascade of events that lead to proper tissue formation. Incorporating genes into these scaffolds is an attractive alternative to protein delivery since gene delivery can be tunable to any DNA sequence and genes utilize the cells’ machinery to continuously produce therapeutic proteins, leading to longer lasting transgene expression and activation of autocrine and paracrine signaling that are not activated with bulk protein delivery. In this review, we discuss the importance of scaffold design and the impact of its design parameters (e.g. material, architecture, vector incorporation, biochemical cue presentation) on transgene expression and tissue repair.
doi:10.1016/j.copbio.2013.04.007
PMCID: PMC3770770  PMID: 23680305
10.  Extracellular Matrix Signaling in Morphogenesis and Repair 
Current opinion in biotechnology  2013;24(5):830-833.
The extracellular matrix (ECM) is critically important for many cellular processes including growth, differentiation, survival, and morphogenesis. Cells remodel and reshape the ECM by degrading and reassembling it, playing an active role in sculpting their surrounding environment and directing their own phenotypes. Both mechanical and biochemical molecules influence ECM dynamics in multiple ways; by releasing small bioactive signaling molecules, releasing growth factors stored within the ECM, eliciting structural changes to matrix proteins which expose cryptic sites and by degrading matrix proteins directly. The dynamic reciprocal communication between cells and the ECM plays a fundamental roll in tissue development, homeostasis, and wound healing.
doi:10.1016/j.copbio.2013.04.011
PMCID: PMC3773047  PMID: 23726156
11.  Animal Models for Vascular Tissue-Engineering 
Current opinion in biotechnology  2013;24(5):916-925.
Due to rise in cardiovascular disease throughout the world, there is increasing demand for small diameter blood vessels as replacement grafts. The present review focuses on the animal models that have been used to test small-diameter TEVs with emphasis on the attributes of each model. Small animal models are used to test short-term patency and address mechanistic hypotheses; and large, pre-clinical animal models are employed to test long-term patency, remodeling and function in an environment mimicking human physiology. We also discuss recent clinical trials that employed laboratory fabricated TEVs and showed very promising results. Ultimately, animal models provide a testing platform for optimizing vascular grafts before clinical use in patients without suitable autologous vessels.
doi:10.1016/j.copbio.2013.05.005
PMCID: PMC3783521  PMID: 23769861
Vascular grafts; tissue engineering; regenerative medicine; animal models; cardiovascular physiology
12.  Engineering a Local Microenvironment for Pancreatic Islet Replacement 
Current opinion in biotechnology  2013;24(5):900-908.
Intraportal islet transplantation has emerged as a promising treatment for type 1 diabetes mellitus (T1DM). Nevertheless, long-term efficacy has been limited to a marginal number of patients. Outcomes have been restricted, in part, by challenges associated with the transplant site, poor vascularization, and disruption of the native islet architecture during the isolation process. Engineering a biomaterial platform that recapitulates critical components of the pancreatic environment can serve to address these hurdles. This review highlights the challenges and opportunities in engineering 3-D niches for islets, specifically: the importance of site selection; the application of scaffold functionalization to present bioactive motifs; and the development of technologies for enhancing implant nutritional profiles. The potential of these novel approaches to improve islet engraftment and duration of function is discussed.
doi:10.1016/j.copbio.2013.05.004
PMCID: PMC3783544  PMID: 23769320
13.  Towards High Resolution Analysis of Metabolic Flux in Cells and Tissues 
Current opinion in biotechnology  2013;24(5):933-939.
Metabolism extracts chemical energy from nutrients, uses this energy to form building blocks for biosynthesis, and interconverts between various small molecules that coordinate the activities of cellular pathways. The metabolic state of a cell is increasingly recognized to determine the phenotype of not only metabolically active cell types such as liver, muscle, and adipose, but also other specialized cell types such as neurons and immune cells. This review focuses on methods to quantify intracellular reaction flux as a measure of cellular metabolic activity, with emphasis on studies involving cells of mammalian tissue. Two key areas are highlighted for future development, single cell metabolomics and noninvasive imaging, which could enable spatiotemporally resolved analysis and thereby overcome issues of heterogeneity, a distinctive feature of tissue metabolism.
doi:10.1016/j.copbio.2013.07.001
PMCID: PMC3783555  PMID: 23906926
14.  Engineering Peripheral Nerve Repair 
Current opinion in biotechnology  2013;24(5):887-892.
Current approaches for treating peripheral nerve injury have resulted in promising, yet insufficient functional recovery compared to the clinical standard of care, autologous nerve grafts. In order to design a construct that can match the regenerative potential of the autograft, all facets of nerve tissue must be incorporated in a combinatorial therapy. Engineered biomaterial scaffolds in the future will have to promote enhanced regeneration and appropriate reinnervation by targeting the highly sensitive response of regenerating nerves to their surrounding microenvironment.
doi:10.1016/j.copbio.2013.05.006
PMCID: PMC3783565  PMID: 23790730
15.  Engineered Liver for Transplantation 
Current opinion in biotechnology  2013;24(5):893-899.
Orthotopic liver transplantation is the only definitive treatment for end stage liver failure and the shortage of donor organs severely limits the number of patients receiving transplants. Liver tissue engineering aims to address the donor liver shortage by creating functional tissue constructs to replace a damaged or failing liver. Despite decades of work, various bottoms-up, synthetic biomaterials approaches have failed to produce a functional construct suitable for transplantation. Recently, a new strategy has emerged using whole organ scaffolds as a vehicle for tissue engineering. This technique involves preparation of these organ scaffolds via perfusion decellularization with the resulting scaffold retaining the circulatory network of the native organ. This important phenomenon allows for the construct to be repopulated with cells and to be connected to the blood torrent upon transplantation. This opinion paper presents the current advances and discusses the challenges of creating fully functional transplantable liver grafts with this whole liver engineering approach.
doi:10.1016/j.copbio.2013.05.008
PMCID: PMC3783566  PMID: 23791465
16.  Engineering synthetic hydrogel microenvironments to instruct stem cells 
Current opinion in biotechnology  2013;24(5):841-846.
Advances in our understanding and ability to manipulate stem cell behavior are helping to move stem cell-based therapies toward the clinic. However, much of our knowledge has been gained from standard 2-dimensional culture systems, which often misrepresent many of the signals that stem cells receive in their native 3-dimensional environments. Fortunately, the field of synthetic hydrogels is developing to better recapitulate many of these signals to guide stem cell behavior, both as in vitro models and as delivery vehicles for in vivo implantation. These include a multitude of structural and biochemical cues that can be presented on the cellular scale, such as degradation, adhesion, mechanical signals, topography, and the presentation of growth factors, often with precise spatiotemporal control.
doi:10.1016/j.copbio.2013.03.009
PMCID: PMC3783596  PMID: 23545441
17.  Bioengineering heart tissue for in vitro testing 
Current opinion in biotechnology  2013;24(5):926-932.
A classical paradigm of tissue engineering is to grow tissues for implantation by using human stem cells in conjunction with biomaterial scaffolds (templates for tissue formation) and bioreactors (culture systems providing environmental control). A reverse paradigm is now emerging through microphysiological platforms for preclinical testing of drugs and modeling of disease that contain large numbers of very small human tissues. We discuss the biomimetic approach as a common underlying principle and some of the specifics related to the design and utilization of platforms with heart micro-tissues for high-throughput screening in vitro.
doi:10.1016/j.copbio.2013.07.002
PMCID: PMC3783612  PMID: 23932513
18.  Mechanical factors in embryonic tendon development: Potential cues for stem cell tenogenesis 
Current opinion in biotechnology  2013;24(5):10.1016/j.copbio.2013.07.003.
Tendons are connective tissues required for motion and are frequently injured. Poor healing and inadequate return to normal tissue structure and mechanical function make tendon a prime candidate for tissue engineering, however functional tendons have yet to be engineered. The physical environment, from substrate stiffness to dynamic mechanical loading, may regulate tenogenic stem cell differentiation. Tissue stiffness and loading parameters derived from embryonic development may enhance tenogenic stem cell differentiation and tendon tissue formation. We highlight current understanding of the mechanical environment experienced by embryonic tendons and how progenitor cells may sense and respond to physical inputs. We further discuss how mechanical factors have only recently been used to induce tenogenic fate in stem cells.
doi:10.1016/j.copbio.2013.07.003
PMCID: PMC3813901  PMID: 23916867
19.  Engineering Cell-Cell Signaling 
Current opinion in biotechnology  2013;24(5):940-947.
Juxtacrine cell-cell signaling mediated by the direct interaction of adjoining mammalian cells is arguably the mode of cell communication that is most recalcitrant to engineering. Overcoming this challenge is crucial for progress in biomedical applications, such as tissue engineering, regenerative medicine, immune system engineering and therapeutic design. Here, we describe the significant advances that have been made in developing synthetic platforms (materials and devices) and synthetic cells (cell surface engineering and synthetic gene circuits) to modulate juxtacrine cell-cell signaling. In addition, significant progress has been made in elucidating design rules and strategies to modulate juxtacrine signaling based on quantitative, engineering analysis of the mechanical and regulatory role of juxtacrine signals in the context of other cues and physical constraints in the microenvironment. These advances in engineering juxtacrine signaling lay a strong foundation for an integrative approach to utilizing synthetic cells, advanced ‘chassis’ and predictive modeling to engineer the form and function of living tissues.
doi:10.1016/j.copbio.2013.05.007
PMCID: PMC3962617  PMID: 23856592
20.  How cells sense extracellular matrix stiffness: a material’s perspective 
Current opinion in biotechnology  2013;24(5):948-953.
The mechanical properties of the extracellular matrix (ECM) in which cells reside have emerged as an important regulator of cell fate. While materials based on natural ECM have been used to implicate the role of substrate stiffness for cell fate decisions, it is difficult in these matrices to isolate mechanics from other structural parameters. In contrast, fully synthetic hydrogels offer independent control over physical and adhesive properties. New synthetic materials that also recreate the fibrous structural hierarchy of natural matrices are now being designed to study substrate mechanics in more complex ECMs. This perspective examines the ways in which new materials are being used to advance our understanding of how extracellular matrix stiffness impacts cell function.
doi:10.1016/j.copbio.2013.03.020
PMCID: PMC4037408  PMID: 23611564
21.  Tissue engineering and regenerative medicine as applied to the gastrointestinal tract 
Current opinion in biotechnology  2013;24(5):909-915.
The gastrointestinal (GI) tract is a complex system characterized by multiple cell types with a determined architectural arrangement. Tissue engineering of the GI tract aims to reinstate the architecture and function of all structural layers. The key point for successful tissue regeneration includes the use of cells/biomaterials that elucidate minimal immune response after implantation. Different biomaterial choices and cell sources have been proposed to engineer the GI tract. This review summarizes the recent advances in bioengineering the GI tract with emphasis on cell sources and scaffolding biomaterials.
doi:10.1016/j.copbio.2013.03.021
PMCID: PMC3723710  PMID: 23583170
22.  Quantitative approaches to uncover physical mechanisms of tissue morphogenesis 
Current opinion in biotechnology  2013;24(5):954-961.
Morphogenesis, the creation of tissue and organ architecture, is a series of complex and dynamic processes driven by genetic programs, microenvironmental cues, and intercellular interactions. Elucidating the physical mechanisms that generate tissue form is key to understanding development, disease, and the strategies needed for regenerative therapies. Advancements in imaging technologies, genetic recombination techniques, laser ablation, and microfabricated tissue models have enabled quantitative descriptions of the cellular motions and tissue deformations and stresses with unprecedented temporal and spatial resolution. Using these data synergistically with increasingly more sophisticated physical, mathematical, and computational models will unveil the physical mechanisms that drive morphogenesis.
doi:10.1016/j.copbio.2013.04.006
PMCID: PMC3762917  PMID: 23647971
morphodynamics; mechanotransduction; mechanical stress; traction force microscopy
23.  Engineering the matrix microenvironment for cell delivery and engraftment for tissue repair 
Current opinion in biotechnology  2013;24(5):864-871.
Cell-based therapies represent promising strategies for tissue repair, particularly in cases in which host cells, due to disease, age, or excessive trauma, are unable to repair the defect or deficiency alone, even with additional delivered therapeutics. Current cell therapies fail to address long term engraftment or delivery timing and location and result in modest improvements with long term engraftment rates of less than 1%. In many cell therapy applications, an appropriate carrier must be used to deliver transplanted cells and promote cell engraftment and function for a successful outcome by providing the appropriate microenvironment for the interactions between transplanted and host cells. This review highlights important considerations for engineering the microenvironment for cell delivery and engraftment in tissue repair.
doi:10.1016/j.copbio.2013.04.005
PMCID: PMC3762938  PMID: 23647972
24.  Engineering Skeletal Muscle Repair 
Current opinion in biotechnology  2013;24(5):880-886.
Healthy skeletal muscle has a remarkable capacity for regeneration. Even at a mature age, muscle tissue can undergo a robust rebuilding process that involves the formation of new muscle cells and extracellular matrix and the re-establishment of vascular and neural networks. Understanding and reverse-engineering components of this process is essential for our ability to restore loss of muscle mass and function in cases where the natural ability of muscle for self-repair is exhausted or impaired. In this article, we will describe current approaches to restore the function of diseased or injured muscle through combined use of myogenic stem cells, biomaterials, and functional tissue-engineered muscle. Furthermore, we will discuss possibilities for expanding the future use of human cell sources towards the development of cell-based clinical therapies and in vitro models of human muscle disease.
doi:10.1016/j.copbio.2013.04.013
PMCID: PMC3766474  PMID: 23711735
25.  Reporter gene imaging of protein–protein interactions in living subjects 
In the past few years there has been a veritable explosion in the field of reporter gene imaging, with the aim of determining the location, duration and extent of gene expression within living subjects. An important application of this approach is the molecular imaging of interacting protein partners, which could pave the way to functional proteomics in living animals and might provide a tool for the whole-body evaluation of new pharmaceuticals targeted to modulate protein–protein interactions. Three general methods are currently available for imaging protein–protein interactions in living subjects using reporter genes: a modified mammalian two-hybrid system, a bioluminescence resonance energy transfer (BRET) system, and split reporter protein complementation and reconstitution strategies. In the future, these innovative approaches are likely to enhance our appreciation of entire biological pathway systems and their pharmacological regulation.
doi:10.1016/j.copbio.2007.01.007
PMCID: PMC4141564  PMID: 17254764

Results 1-25 (135)