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WIREs Nanomed Nanobiotechnol
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Microengineered synthetic cellular microenvironment for stem cells

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Abstract Stem cells possess the ability of self‐renewal and differentiation into specific cell types. Therefore, stem cells have great potentials in fundamental biology studies and clinical applications. The most urgent desire for stem cell research is to generate appropriate artificial stem cell culture system, which can mimic the dynamic complexity and precise regulation of the in vivo biochemical and biomechanical signals, to regulate and direct stem cell behaviors. Precise control and regulation of the biochemical and biomechanical stimuli to stem cells have been successfully achieved using emerging micro/nanoengineering techniques. This review provides insights into how these micro/nanoengineering approaches, particularly microcontact printing and elastomeric micropost array, are applied to create dynamic and complex environment for stem cells culture. WIREs Nanomed Nanobiotechnol 2012, 4:414–427. doi: 10.1002/wnan.1175 This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement

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Schematic showing the stem cell niche where interactions between stem cells and their local microenvironment regulate stem cell fate. The stem cell niche is a complex, dynamically regulated three‐dimensional (3D) microenvironment comprising of soluble biochemical and insoluble biomechanical cues, adhesive signals as well as signals arising from direct cell–cell contacts. Soluble biochemical cues include small ions, growth factors, and cytokines, etc. Insoluble biophysical signals consist of matrix rigidity and topology, fluid shear stress, and other mechanical forces exerted by adjacent cells or owing to tissue growth and loading. Stem cells sense and respond to these biophysical stimuli through different mechanosensory components including heterodimeric integrins, mechanosensitive ion channels, cytoskeleton structures (actin microfilaments, microtubules, and intermediate filaments), and cell–cell contacts.

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Integrated microfluidic devices to control soluble biochemical cues and fluid shear stress to regulate stem cell function. (a) Design of a microfluidic chip for long‐term stem cell culture. This fully automated cell culture screening microfluidic system could create arbitrary culture media formulations in 96 independent culture chambers and maintain stem cell viability for weeks. (Reprinted with permission from Ref 45. Copyright 2007 American Chemical Society) (b) A microfluidic chemical gradient generator. (Reprinted with permission from Ref 62. Copyright 2005 John Wiley & Sons Ltd.) (c) Growth and differentiation of human neural stem cells (hNSCs) in a gradient‐generating microfluidic device. hNSCs cultured in the gradient chamber for 7 days exhibited higher percentage of astrocyte differentiation (stained by an antibody against glial fibrillary acidic protein, an astrocyte marker; green) in the low growth factor region. (Reprinted with permission from Ref 63. Copyright 2005 Royal Society of Chemistry) (d) Microfluidic arrays for logarithmically perfused mouse embryonic stem cell (mESC) culture. The top photograph shows a microfluidic device fabricated using soft lithography with multiple chambers for long‐term culture of mESCs. The bottom two Brightfield images show colonies of mESCs after 4 days of perfusion at different culture flow rates. (Reprinted with permission from Ref 47. Copyright 2006 Royal Society of Chemistry)

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Elastomeric poly(dimethylsiloxane) (PDMS) micropost array to control adhesive extracellular matrix (ECM) patterns, cell–cell contacts, substrate rigidity, cell stretching forces, and subcellular mechanical forces. (a) Modulating the PDMS micropost diameter and center‐to‐center spacing to regulate adhesive ECM patterns. (Reprinted with permission from Ref 59. Copyright 2011 Elsevier) (b) Cells constrained to a bowtie ECM pattern on the PDMS microposts using microcontact printing to regulate cell‐cell contacts. Cells were costained for nuclei (DAPI; red) and AJs (green). (Reprinted with permission from Ref 35. Copyright 2010 National Academy of Sciences USA) (c) Scanning electron microscopy images showing single human mesenchymal stem cells (hMSCs) plated on PDMS micropost arrays of the same surface geometry but different post heights to control substrate rigidity independently of effects on adhesive and other material surface properties. (Reprinted with permission from Ref 44. Copyright 2010 Nature Publishing Group) (d) A stretchable micropost array membrane (mPAM) that could apply cell stretching forces to adherent cells attached on the micropost tops. (Reprinted with permission from Ref 60. Copyright 2012 Royal Society of Chemistry) (e) Magnetic PDMS microposts to apply local mechanical forces to adherent cells through individual focal adhesions. (Reprinted with permission from Ref 61. Copyright 2007 National Academy of Sciences USA)

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Microcontact printing to pattern adhesive protein islands. (a) Schematic drawing of standard procedures for stamp‐on (left) and stamp‐off (right) methods. (b) Deformations of poly(dimethylsiloxane) (PDMS) stamp during microcontact printing. Such deformations include lateral collapse (top) and sagging (bottom) of the PDMS stamp. (Reprinted with permission from Ref 55. Copyright 2007 Royal Society of Chemistry) (c) Representative fluorescence images of arrays of adhesive islands patterned using stamp‐on (top) or stamp‐off (bottom) methods. The squared‐shaped arrays of 20 µm adhesive islands are spaced 20 (left), 110 (middle), and 200 µm (right) apart (edge‐to‐edge). (Reprinted with permission from Ref 56. Copyright 2011 Royal Society of Chemistry) (d) Left: Immunofluorescence image showing a single hMSC cultured on a flower‐shaped adhesive island. The cell was costained for F‐actin (green), vinculin (red) and nuclei (DAPI; blue). (Reprinted with permission from Ref 57. Copyright 2010 National Academy of Sciences USA) Right: Brightfield micrograph of a squared‐shaped hMSC colony costained for alkaline phosphatase activity (ALP, blue) and lipid droplet accumulation (Lip, red) after 14 days of culture in a bipotential differentiation medium supportive for both osteogenic and adipogenic differentiation of hMSCs. (Reprinted with permission from Ref 58. Copyright 2008 John Wiley & Sons Ltd.)

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