Microfluidic systems: A new toolbox for pluripotent stem cells

Conventional culture systems are often limited in their ability to regulate the growth and differentiation of pluripotent stem cells. Microfluidic systems can overcome some of these limitations by providing defined growth conditions with user‐controlled spatiotemporal cues. Microfluidic systems allow researchers to modulate pluripotent stem cell renewal and differentiation through biochemical and mechanical stimulation, as well as through microscale patterning and organization of cells and extracellular materials. Essentially, microfluidic tools are reducing the gap between in vitro cell culture environments and the complex and dynamic features of the in vivo stem cell niche. These microfluidic culture systems can also be integrated with microanalytical tools to assess the health and molecular status of pluripotent stem cells. The ability to control biochemical and mechanical input to cells, as well as rapidly and efficiently analyze the biological output from cells, will further our understanding of stem cells and help translate them into clinical use. This review provides a comprehensive insignt into the implications of microfluidics on pluripotent stem cell research.

[1]  A. Khademhosseini,et al.  Controlling size, shape and homogeneity of embryoid bodies using poly(ethylene glycol) microwells. , 2007, Lab on a chip.

[2]  Shuichi Takayama,et al.  Microfluidic hydrodynamic cellular patterning for systematic formation of co-culture spheroids. , 2009, Integrative biology : quantitative biosciences from nano to macro.

[3]  Todd C McDevitt,et al.  Engineering the embryoid body microenvironment to direct embryonic stem cell differentiation , 2009, Biotechnology progress.

[4]  S. Yamanaka,et al.  The Use of Induced Pluripotent Stem Cells in Drug Development , 2011, Clinical pharmacology and therapeutics.

[5]  H. Kurosawa.  Methods for inducing embryoid body formation: in vitro differentiation system of embryonic stem cells. , 2007, Journal of bioscience and bioengineering.

[6]  G. Whitesides,et al.  Generation of Solution and Surface Gradients Using Microfluidic Systems , 2000 .

[7]  G. Martin,et al.  Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Y. Mishina,et al.  BMP signalling inhibits premature neural differentiation in the mouse embryo , 2007, Development.

[9]  Daniel G. Anderson,et al.  Nanoliter-scale synthesis of arrayed biomaterials and application to human embryonic stem cells , 2004, Nature Biotechnology.

[10]  Shuichi Takayama,et al.  High-throughput 3D spheroid culture and drug testing using a 384 hanging drop array. , 2011, The Analyst.

[11]  P. Andersson,et al.  Biogrid--a microfluidic device for large-scale enzyme-free dissociation of stem cell aggregates. , 2011, Lab on a chip.

[12]  A. Engler,et al.  Photopolymerization in Microfluidic Gradient Generators: Microscale Control of Substrate Compliance to Manipulate Cell Response , 2004 .

[13]  Gi Seok Jeong,et al.  Meniscus induced self organization of multiple deep concave wells in a microchannel for embryoid bodies generation. , 2012, Lab on a chip.

[14]  David J. Mooney,et al.  Growth Factors, Matrices, and Forces Combine and Control Stem Cells , 2009, Science.

[15]  A. Abbott.  Cell culture: Biology's new dimension , 2003, Nature.

[16]  Joachim P Spatz,et al.  Activation of integrin function by nanopatterned adhesive interfaces. , 2004, Chemphyschem : a European journal of chemical physics and physical chemistry.

[17]  Kahp Yang Suh,et al.  Cell research with physically modified microfluidic channels: a review. , 2008, Lab on a chip.

[18]  C. S. Chen,et al.  Geometric control of cell life and death. , 1997, Science.

[19]  C. Håkansson,et al.  Studies on Ciliated Epithelia of the Human Genital Tract. II. The Mucociliary Wave Pattern of Fallopian Tube Epithelium**Supported by Grant B75-16X-04509 from the Swedish Medical Research Council. , 1977 .

[20]  Farshid Guilak,et al.  Nanotopography-induced changes in focal adhesions, cytoskeletal organization, and mechanical properties of human mesenchymal stem cells. , 2010, Biomaterials.

[21]  Scott E Fraser,et al.  Vascular remodeling of the mouse yolk sac requires hemodynamic force , 2007, Development.

[22]  Weixiong Wang,et al.  Semicontinuous flow electroporation chip for high-throughput transfection on mammalian cells. , 2009, Analytical chemistry.

[23]  Ernst Wolvetang,et al.  Optimization of flowrate for expansion of human embryonic stem cells in perfusion microbioreactors , 2011, Biotechnology and bioengineering.

[24]  Chengpei Xu,et al.  A novel culture system shows that stem cells can be grown in 3D and under physiologic pulsatile conditions for tissue engineering of vascular grafts. , 2006, The Journal of surgical research.

[25]  Bong Geun Chung,et al.  Development of a multi-layer microfluidic array chip to culture and replate uniform-sized embryoid bodies without manual cell retrieval. , 2010, Lab on a chip.

[26]  Ali Khademhosseini,et al.  Microwell-mediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11 , 2009, Proceedings of the National Academy of Sciences.

[27]  J. Thomson,et al.  Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells , 2005, Nature Methods.

[28]  M. Bennett,et al.  Metabolic gene regulation in a dynamically changing environment , 2008, Nature.

[29]  A. Russo,et al.  Retinoic acid is enriched in Hensen's node and is developmentally regulated in the early chicken embryo. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Noo Li Jeon,et al.  Patterned cell culture inside microfluidic devices. , 2005, Lab on a chip.

[31]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[32]  Gwo-Bin Lee,et al.  Stem cells in microfluidics. , 2011, Biomicrofluidics.

[33]  Morag H. Stewart,et al.  Human embryonic stem cells: lessons from stem cell niches in vivo. , 2008, Regenerative medicine.

[34]  Lu Wang,et al.  Engineering of a microfluidic cell culture platform embedded with nanoscale features. , 2011, Lab on a chip.

[35]  S. Bhatia,et al.  An extracellular matrix microarray for probing cellular differentiation , 2005, Nature Methods.

[36]  D. Beebe,et al.  Physics and applications of microfluidics in biology. , 2002, Annual review of biomedical engineering.

[37]  Samuel Aparicio,et al.  High-throughput microfluidic single-cell RT-qPCR , 2011, Proceedings of the National Academy of Sciences.

[38]  Peter W. Zandstra,et al.  Derivation, expansion and differentiation of induced pluripotent stem cells in continuous suspension cultures , 2012, Nature Methods.

[39]  J. Lahann,et al.  Synthetic substrates for long-term stem cell culture , 2012 .

[40]  D. Solter,et al.  From teratocarcinomas to embryonic stem cells and beyond: a history of embryonic stem cell research , 2006, Nature Reviews Genetics.

[41]  Shuichi Takayama,et al.  Microfluidic culture of single human embryonic stem cell colonies. , 2009, Lab on a chip.

[42]  Christopher S. Chen,et al.  Mechanotransduction in development: a growing role for contractility , 2009, Nature Reviews Molecular Cell Biology.

[43]  Shengnian Wang,et al.  Micronozzle array enhanced sandwich electroporation of embryonic stem cells. , 2010, Analytical chemistry.

[44]  Feng Xu,et al.  Embryonic stem cell bioprinting for uniform and controlled size embryoid body formation. , 2011, Biomicrofluidics.

[45]  Shuichi Takayama,et al.  Polymeric Aqueous Biphasic Systems for Non‐Contact Cell Printing on Cells: Engineering Heterocellular Embryonic Stem Cell Niches , 2010, Advanced materials.

[46]  M. Sheetz,et al.  Local force and geometry sensing regulate cell functions , 2006, Nature Reviews Molecular Cell Biology.

[47]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2007, Cell.

[48]  Maya Schuldiner,et al.  Induced neuronal differentiation of human embryonic stem cells , 2001, Brain Research.

[49]  Ratmir Derda,et al.  Defined substrates for human embryonic stem cell growth identified from surface arrays. , 2007, ACS chemical biology.

[50]  Shuichi Takayama,et al.  Efficient formation of uniform-sized embryoid bodies using a compartmentalized microchannel device. , 2007, Lab on a chip.

[51]  B. Chung,et al.  Human neural stem cell growth and differentiation in a gradient-generating microfluidic device. , 2005, Lab on a chip.

[52]  I. Drummond.  Cilia functions in development. , 2012, Current opinion in cell biology.

[53]  H. Van de Velde,et al.  The roles of FGF and MAP kinase signaling in the segregation of the epiblast and hypoblast cell lineages in bovine and human embryos , 2012, Development.

[54]  Joel Voldman,et al.  Fluid shear stress primes mouse embryonic stem cells for differentiation in a self‐renewing environment via heparan sulfate proteoglycans transduction , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[55]  Bong Geun Chung,et al.  An integrated microfluidic culture device to regulate endothelial cell differentiation from embryonic stem cells , 2011, Electrophoresis.

[56]  S. Sen,et al.  Matrix Elasticity Directs Stem Cell Lineage Specification , 2006, Cell.

[57]  J. Ando,et al.  Differentiation from embryonic stem cells to vascular wall cells under in vitro pulsatile flow loading , 2005, Journal of Artificial Organs.

[58]  Elizabeth J. Robertson,et al.  Role of insulin-like growth factors in embryonic and postnatal growth , 1993, Cell.

[59]  M. Evans,et al.  Differentiation of clonal lines of teratocarcinoma cells: formation of embryoid bodies in vitro. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[60]  Robert T Kennedy,et al.  Dynamic monitoring of glucagon secretion from living cells on a microfluidic chip , 2012, Analytical and Bioanalytical Chemistry.

[61]  M M Newhouse,et al.  Analysis of the vestigial tail mutation demonstrates that Wnt-3a gene dosage regulates mouse axial development. , 1996, Genes & development.

[62]  A. Folch,et al.  Biomolecular gradients in cell culture systems. , 2008, Lab on a chip.

[63]  N. Barkai,et al.  Robust generation and decoding of morphogen gradients. , 2009, Cold Spring Harbor perspectives in biology.

[64]  David Tweedie,et al.  Differentiation of Pluripotent Embryonic Stem Cells Into Cardiomyocytes , 2002, Circulation research.

[65]  Krishanu Saha,et al.  Technical challenges in using human induced pluripotent stem cells to model disease. , 2009, Cell stem cell.

[66]  Á. Raya,et al.  Left–right asymmetry in the vertebrate embryo: from early information to higher-level integration , 2006, Nature Reviews Genetics.

[67]  Donald E Ingber,et al.  Mechanical control of tissue and organ development , 2010, Development.

[68]  R. Stewart,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[69]  S. Thorslund,et al.  A fluidic device to study directional angiogenesis in complex tissue and organ culture models. , 2009, Lab on a chip.

[70]  Ali Khademhosseini,et al.  A hollow sphere soft lithography approach for long-term hanging drop methods. , 2010, Tissue engineering. Part C, Methods.

[71]  Morriss Gm,et al.  Retinoids and mammalian development. , 1999 .

[72]  J. Lebkowski,et al.  Basic Fibroblast Growth Factor Supports Undifferentiated Human Embryonic Stem Cell Growth Without Conditioned Medium , 2005, Stem cells.

[73]  Nam-Trung Nguyen,et al.  Microfluidic platform for controlling the differentiation of embryoid bodies. , 2009, Lab on a chip.

[74]  D. Beebe,et al.  Cell culture models in microfluidic systems. , 2008, Annual review of analytical chemistry.

[75]  Vladimir Mironov,et al.  Review: bioprinting: a beginning. , 2006, Tissue engineering.

[76]  Ali Khademhosseini,et al.  A soft lithographic approach to fabricate patterned microfluidic channels. , 2004, Analytical chemistry.

[77]  Axel Scherer,et al.  A microfluidic processor for gene expression profiling of single human embryonic stem cells. , 2008, Lab on a chip.

[78]  K. Jensen,et al.  Cells on chips , 2006, Nature.

[79]  Hanry Yu,et al.  Stem cells in microfluidics , 2009, Biotechnology progress.

[80]  Kimiko Yamamoto,et al.  Fluid shear stress induces differentiation of Flk-1-positive embryonic stem cells into vascular endothelial cells in vitro. , 2005, American journal of physiology. Heart and circulatory physiology.

[81]  B. Ratner,et al.  VEGF Induces Differentiation of Functional Endothelium From Human Embryonic Stem Cells: Implications for Tissue Engineering , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[82]  M. Kaufman,et al.  Establishment in culture of pluripotential cells from mouse embryos , 1981, Nature.

[83]  N. Hirokawa,et al.  FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left–right determination , 2005, Nature.

[84]  George Q. Daley,et al.  Biomechanical forces promote embryonic haematopoiesis , 2009, Nature.

[85]  Avishay Bransky,et al.  A microfluidic traps system supporting prolonged culture of human embryonic stem cells aggregates , 2010, Biomedical microdevices.

[86]  V. Papaioannou,et al.  Paracrine action of FGF4 during periimplantation development maintains trophectoderm and primitive endoderm , 2003, Genesis.

[87]  Aaron R Wheeler,et al.  Microfluidic device for single-cell analysis. , 2003, Analytical chemistry.

[88]  M. Schmidt,et al.  Microfabrication in biology and medicine. , 1999, Annual review of biomedical engineering.

[89]  G. Whitesides,et al.  Patterning proteins and cells using soft lithography. , 1999, Biomaterials.

[90]  Gordana Vunjak-Novakovic,et al.  The effect of actin disrupting agents on contact guidance of human embryonic stem cells. , 2007, Biomaterials.

[91]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[92]  E. Amaya,et al.  FGF signalling: diverse roles during early vertebrate embryogenesis , 2010, Development.

[93]  R. Jaenisch,et al.  Microfluidic Control of Cell Pairing and Fusion , 2009, Nature Methods.

[94]  Shyni Varghese,et al.  Controlled differentiation of stem cells. , 2008, Advanced drug delivery reviews.

[95]  B. Mosadegh,et al.  Microprinted feeder cells guide embryonic stem cell fate. , 2011, Biotechnology and bioengineering.

[96]  Uri Dinnar,et al.  Periodic “flow-stop” perfusion microchannel bioreactors for mammalian and human embryonic stem cell long-term culture , 2009, Biomedical microdevices.

[97]  K. Oh,et al.  3-Dimensional cell culture for on-chip differentiation of stem cells in embryoid body. , 2011, Lab on a chip.

[98]  Joel Voldman,et al.  Advancing stem cell research with microtechnologies: opportunities and challenges. , 2010, Integrative biology : quantitative biosciences from nano to macro.

[99]  A. Nagy,et al.  Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression. , 2000, Development.