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The promise of cellular therapy lies in the repair of damaged organs and tissues in vivo as well as generating tissue constructs in vitro for subsequent transplantation. Unfortunately, the lack of available donor cell sources limits its ultimate clinical applicability. Stem cells are a natural choice for cell therapy due to their pluripotent nature and self-renewal capacity. Creating reserves of undifferentiated stem cells and subsequently driving their differentiation to a lineage of choice in an efficient and scalable manner is critical for the ultimate clinical success of cellular therapeutics. In recent years, a variety of biomaterials have been incorporated in stem cell cultures, primarily to provide a conducive microenvironment for their growth and differentiation and to ultimately mimic the stem cell niche. In this review, we examine applications of natural and synthetic materials, their modifications as well as various culture conditions for maintenance and lineage-specific differentiation of embryonic and adult stem cells.
Eileen Dawsona Gazell Mapilia Kathryn Ericksona Sabia Taqvia Krishnendu RoyaEmail:kroy@mail.utexas.edu
[a]Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA
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Drug delivery has been greatly improved over the years by means of chemical and physical agents that increase bioavailability, improve pharmacokinetic and reduce toxicities. At the same time, cell based delivery systems have also been developed. These possesses a number of advantages including prolonged delivery times, targeting of drugs to specialized cell compartments and biocompatibility. Here we’ll focus on erythrocyte-based drug delivery. These systems are especially efficient in releasing drugs in circulations for weeks, have a large capacity, can be easily processed and could accommodate traditional and biologic drugs. These carriers have also been used for delivering antigens and/or contrasting agents. Carrier erythrocytes have been evaluated in thousands of drug administration in humans proving safety and efficacy of the treatments. Erythrocyte-based delivery of new and conventional drugs is thus experiencing increasing interests in drug delivery and in managing complex pathologies especially when side effects could become serious issues.
F. Pierigèa S. Serafinia L. Rossia M. MagnaniaEmail:mauro.magnani@uniurb.it
[a]Institute of Biological Chemistry “Giorgio Fornaini”, University of Urbino “Carlo Bo”, Urbino, Italy
Recently, myocardial tissue engineering has emerged as one of the most promising therapies for patients suffering from severe heart failure. Nevertheless, conventional methods in tissue engineering involving the seeding of cells into biodegradable scaffolds have intrinsic shortcomings, such as inflammatory reactions and fibrous tissue formation caused by scaffold degradation. On the other hand, we have developed cell sheet engineering as scaffoldless tissue engineering, and applied it for myocardial tissue engineering. Using temperature-responsive culture surfaces, cells can be harvested as intact sheets and cell-dense thick tissues are constructed by layering these cell sheets. Myocardial cell sheets non-invasively harvested from temperature-responsive culture surfaces are successfully layered, resulting in electrically communicative 3-dimensional (3-D) cardiac constructs. Transplantation of cell sheets onto damaged hearts improved heart function in several animal models. In this review, we summarize the development of myocardial tissue engineering using cell sheets harvested from temperature-responsive culture surfaces and discuss about future views.
Shinako Masudaa Tatsuya Shimizua Masayuki Yamatoa Teruo OkanoaEmail:tokano@abmes.twmu.ac.jp
[a]Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo 162-8666, Japan
This review presents a summary of the various types of cellular therapy used to treat spinal cord injury. The inhibitory environment and loss of axonal connections after spinal cord injury pose many obstacles to regenerating the lost tissue. Cellular therapy provides a means of restoring the cells lost to the injury and could potentially promote functional recovery after such injuries. A wide range of cell types have been investigated for such uses and the advantages and disadvantages of each cell type are discussed along with the research studying each cell type. Additionally, methods of delivering cells to the injury site are evaluated. Based on the current research, suggestions are given for future investigation of cellular therapies for spinal cord regeneration.
Stephanie M. Willertha Shelly E. Sakiyama-ElbertaEmail:sakiyama@wustl.edu
[a]Department of Biomedical Engineering, Washington University in St. Louis, USA;[b]Center for Materials Innovation, Washington University in St. Louis, USA
Cartilage tissue engineering is emerging as a technique for the regeneration of cartilage tissue damaged due to disease or trauma. Since cartilage lacks regenerative capabilities, it is essential to develop approaches that deliver the appropriate cells, biomaterials, and signaling factors to the defect site. The objective of this review is to discuss the approaches that have been taken in this area, with an emphasis on various cell sources, including chondrocytes, fibroblasts, and stem cells. Additionally, biomaterials and their interaction with cells and the importance of signaling factors on cellular behavior and cartilage formation will be addressed. Ultimately, the goal of investigators working on cartilage regeneration is to develop a system that promotes the production of cartilage tissue that mimics native tissue properties, accelerates restoration of tissue function, and is clinically translatable. Although this is an ambitious goal, significant progress and important advances have been made in recent years.
Cindy Chunga Jason A. BurdickaEmail:burdick2@seas.upenn.edu
[a]Department of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 S. 33rd Street, Philadelphia, PA 19104, USA
The concept of tissue and cell guidance is rapidly evolving as more information regarding the effect of the microenvironment on cellular function and tissue morphogenesis become available. These disclosures have lead to a tremendous advancement in the design of a new generation of multifunctional biomaterials able to mimic the molecular regulatory characteristics and the three-dimensional architecture of the native extracellular matrix. Micro- and nano-structured scaffolds able to sequester and deliver in a highly specific manner biomolecular moieties have already been proved to be effective in bone repairing, in guiding functional angiogenesis and in controlling stem cell differentiation. Although these platforms represent a first attempt to mimic the complex temporal and spatial microenvironment presented in vivo, an increased symbiosis of material engineering, drug delivery technology and cell and molecular biology may ultimately lead to biomaterials that encode the necessary signals to guide and control developmental process in tissue- and organ-specific differentiation and morphogenesis. Abbreviation list: bFGF; basic fibroblast growth factor; BMP; bone morphogenetic protein; BSA; bovine serum albumin; CASD; computer-aided scaffold design; DS; delivery systems; ECM; extracellular matrix; EGF; epidermal growth factor; EVAc; ethylene-vinyl acetate copolymers; GF; growth factor; HBDS; heparin-based delivery systems; NT-3; neurotrophin-3; PA; peptide amphiphile; PCL; poly(-caprolactone); PDGF; platelet derived growth factor; PEG; poly(ethylene glycol); PEO; poly(ethylene oxide); PLA; poly(lactide); PLGA; poly(lactide-co-glycolide); POE; poly(ortho esters); PTH; parathyroid hormone; SFF; solid free-form fabrication; TE; tissue engineering; TGF-β1; transforming growth factor-beta1; VEGF; vascular endothelial growth factor
Marco Biondia Francesca Ungaroa Fabiana Quagliaa Paolo Antonio NettiaEmail:nettipa@unina.it
[a]Interdisciplinary Research Centre on Biomaterials (CRIB), University of Naples Federico II, Naples, Italy
The extracellular microenvironment plays a significant role in controlling cellular behavior. Identification of appropriate biomaterials that support cellular attachment, proliferation and, most importantly in the case of human embryonic stem cells, lineage-specific differentiation is critical for tissue engineering and cellular therapy. In addition to growth factors and morphogenetic factors known to induce lineage commitment of stem cells, a number of scaffolding materials, including synthetic and naturally-derived biomaterials, have been utilized in tissue engineering approaches to direct differentiation. This review focuses on recent emerging findings and well-characterized differentiation models of human embryonic stem cells. Additionally, we also discuss about various strategies that have been used in stem cell expansion.
Nathaniel S. Hwanga Shyni Varghesea Jennifer ElisseeffaEmail:jhe@jhu.edu
[a]Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, USA
Tissue engineering and regenerative medicine is an exciting research area that aims at regenerative alternatives to harvested tissues for transplantation. Biomaterials play a pivotal role as scaffolds to provide three-dimensional templates and synthetic extracellular matrix environments for tissue regeneration. It is often beneficial for the scaffolds to mimic certain advantageous characteristics of the natural extracellular matrix, or developmental or wound healing programs. This article reviews current biomimetic materials approaches in tissue engineering. These include synthesis to achieve certain compositions or properties similar to those of the extracellular matrix, novel processing technologies to achieve structural features mimicking the extracellular matrix on various levels, approaches to emulate cell–extracellular matrix interactions, and biologic delivery strategies to recapitulate a signaling cascade or developmental/wound healing program. The article also provides examples of enhanced cellular/tissue functions and regenerative outcomes, demonstrating the excitement and significance of the biomimetic materials for tissue engineering and regeneration.
Peter X. MaaEmail:mapx@umich.edu
[a]Department of Biologic and Materials Sciences, The University of Michigan, Ann Arbor, MI 48109-1078, USA;[b]Department of Biomedical Engineering, The University of Michigan, Ann Arbor, MI 48109-1078, USA;[c]Macromolecular Science and Engineering Center, The University of Michigan, Ann Arbor, MI 48109-1078, USA
Dendritic cells are professional antigen-presenting cells with a key role in both immunity induction and tolerance maintenance. Dendritic cells are highly specialized in antigen capture, processing and presentation, and express co-stimulation signals which activate T lymphocytes and NK cells. Dendritic cells generated in culture and loaded with an antigen efficiently induce antigen-specific immunity after injection. More recently, methods have been developed that target antigens to dendritic cells in vivo, bypassing the need for ex vivo cell manipulations. Numerous ongoing studies aim to evaluate the effectiveness of dendritic cell vaccines in preventing tumor relapses and extending patients’ survival. Further implementation of this form of immunotherapy is expected following the identification of the mechanisms controlling dendritic cell immunogenicity, and from a better understanding of the cell dynamics whereby immune responses are orchestrated. Here, we discuss these new insights together with an overview of the dendritic cell-based clinical studies carried out to date.
Alberto Ballestreroa Davide Boya Eva Morana Gabriella Cirmenaa Peter Brossartb Alessio NencioniaEmail:A.Nencioni@gmx.net
[a]Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy;[b]Department of Hematology, Oncology and Immunology, University of Tübingen, D-72076 Tübingen, Germany
Gene modification of cells prior to their transplantation, especially stem cells, enhances their survival and increases their function in cell therapy. Like the Trojan horse, the gene-modified cell has to gain entrance inside the host’s walls and survive and deliver its transgene products Using cellular, molecular and gene manipulation techniques the transplanted cell can be protected in a hostile environment from immune rejection, inflammation, hypoxia and apoptosis. Genetic engineering to modify cells involves constructing modules of functional gene sequences. They can be simple reporter genes or complex cassettes with gene switches, cell specific promoters and multiple transgenes. We discuss methods to deliver and construct gene cassettes with viral and non-viral delivery, siRNA, and conditional Cre/Lox P. We review the current uses of gene-modified stem cells in cardiovascular disease, diabetes, neurological diseases, (including Parkinson’s, Alzheimer’s and spinal cord injury repair), bone defects, hemophilia, and cancer.
M. Ian PhillipsaEmail:ian_phillips@kgi.edu Yao Liang Tanga
[a]Keck Graduate Institute, Claremont, Ca 91711, USA