Imaging live cells at high spatiotemporal resolution for lab-on-a-chip applications.

Conventional optical imaging techniques are limited by the diffraction limit and difficult-to-image biomolecular and sub-cellular processes in living specimens. Novel optical imaging techniques are constantly evolving with the desire to innovate an imaging tool that is capable of seeing sub-cellular processes in a biological system, especially in three dimensions (3D) over time, i.e. 4D imaging. For fluorescence imaging on live cells, the trade-offs among imaging depth, spatial resolution, temporal resolution and photo-damage are constrained based on the limited photons of the emitters. The fundamental solution to solve this dilemma is to enlarge the photon bank such as the development of photostable and bright fluorophores, leading to the innovation in optical imaging techniques such as super-resolution microscopy and light sheet microscopy. With the synergy of microfluidic technology that is capable of manipulating biological cells and controlling their microenvironments to mimic in vivo physiological environments, studies of sub-cellular processes in various biological systems can be simplified and investigated systematically. In this review, we provide an overview of current state-of-the-art super-resolution and 3D live cell imaging techniques and their lab-on-a-chip applications, and finally discuss future research trends in new and breakthrough research areas of live specimen 4D imaging in controlled 3D microenvironments.

[1]  K. Suh,et al.  A multi-layer microfluidic device for efficient culture and analysis of renal tubular cells. , 2010, Lab on a chip.

[2]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[3]  Jean-Louis Viovy,et al.  Axon diodes for the reconstruction of oriented neuronal networks in microfluidic chambers. , 2011, Lab on a chip.

[4]  Walter Fontana,et al.  Lifespan-on-a-chip: microfluidic chambers for performing lifelong observation of C. elegans. , 2010, Lab on a chip.

[5]  Wesley R. Legant,et al.  Lattice light-sheet microscopy: Imaging molecules to embryos at high spatiotemporal resolution , 2014, Science.

[6]  R. Kamm,et al.  Cell migration into scaffolds under co-culture conditions in a microfluidic platform. , 2009, Lab on a chip.

[7]  Yoshikazu Hirai,et al.  Body on a Chip: Re-Creation of a Living System In Vitro , 2013, IEEE Nanotechnology Magazine.

[8]  A. Diaspro,et al.  Live-cell 3D super-resolution imaging in thick biological samples , 2011, Nature Methods.

[9]  Duc-Huy T Nguyen,et al.  Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro , 2013, Proceedings of the National Academy of Sciences.

[10]  Victoria J Allan,et al.  Light Microscopy Techniques for Live Cell Imaging , 2003, Science.

[11]  Catarina Brito,et al.  SPIM-fluid: open source light-sheet based platform for high-throughput imaging. , 2015, Biomedical optics express.

[12]  Bryant B. Chhun,et al.  Super-Resolution Video Microscopy of Live Cells by Structured Illumination , 2009, Nature Methods.

[13]  S. Hell,et al.  Fluorogenic probes for live-cell imaging of the cytoskeleton , 2014, Nature Methods.

[14]  M. Davidson,et al.  Noninvasive Imaging beyond the Diffraction Limit of 3D Dynamics in Thickly Fluorescent Specimens , 2012, Cell.

[15]  Guoan Zheng,et al.  Color-capable sub-pixel resolving optofluidic microscope for on-chip cell imaging , 2010, IEEE Winter Topicals 2011.

[16]  Hang Lu,et al.  Long-term high-resolution imaging and culture of C. elegans in chip-gel hybrid microfluidic device for developmental studies. , 2010, Lab on a chip.

[17]  Philipp J. Keller,et al.  Imaging Morphogenesis: Technological Advances and Biological Insights , 2013, Science.

[18]  J. Koenderink.  Q… , 2014, Les noms officiels des communes de Wallonie, de Bruxelles-Capitale et de la communaute germanophone.

[19]  L K Chin,et al.  Study of endothelial cell apoptosis using fluorescence resonance energy transfer (FRET) biosensor cell line with hemodynamic microfluidic chip system. , 2013, Lab on a chip.

[20]  K. Cheung,et al.  Droplet-based microfluidic system for multicellular tumor spheroid formation and anticancer drug testing. , 2010, Lab on a chip.

[21]  Ashwin Seshia,et al.  A microfluidic device for the hydrodynamic immobilisation of living fission yeast cells for super-resolution imaging , 2014, Sensors and actuators. B, Chemical.

[22]  D. P. Fromm,et al.  Methods of single-molecule fluorescence spectroscopy and microscopy , 2003 .

[23]  Michael J Rust,et al.  Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM) , 2006, Nature Methods.

[24]  E. Boyden,et al.  Simultaneous whole-animal 3D-imaging of neuronal activity using light-field microscopy , 2014, Nature Methods.

[25]  D. Ingber,et al.  Reconstituting Organ-Level Lung Functions on a Chip , 2010, Science.

[27]  Meng-Hua Yen,et al.  Label-free quantification of asymmetric cancer-cell filopodium activities in a multi-gradient chip. , 2009, Lab on a chip.

[28]  Hanry Yu,et al.  Fish and Chips: a microfluidic perfusion platform for monitoring zebrafish development. , 2012, Lab on a chip.

[29]  C. Johnson,et al.  A Microfluidic-Enabled Mechanical Microcompressor for the Immobilization of Live Single- and Multi-Cellular Specimens , 2014, Microscopy and Microanalysis.

[30]  P ? ? ? ? ? ? ? % ? ? ? ? , 1991 .

[31]  X. Zhuang,et al.  Fast three-dimensional super-resolution imaging of live cells , 2011, Nature Methods.

[32]  J. Lippincott-Schwartz,et al.  Imaging Intracellular Fluorescent Proteins at Nanometer Resolution , 2006, Science.

[33]  J. Pawley,et al.  Handbook of Biological Confocal Microscopy , 1990, Springer US.

[34]  Kristin Decker,et al.  Fundamentals Of Light Microscopy And Electronic Imaging , 2016 .

[35]  L K Chin,et al.  Production of reactive oxygen species in endothelial cells under different pulsatile shear stresses and glucose concentrations. , 2011, Lab on a chip.

[36]  Chien-Chung Peng,et al.  Migration and vascular lumen formation of endothelial cells in cancer cell spheroids of various sizes. , 2014, Biomicrofluidics.

[37]  Hanry Yu,et al.  Towards a human-on-chip: culturing multiple cell types on a chip with compartmentalized microenvironments. , 2009, Lab on a chip.

[38]  Tarik Bourouina,et al.  Nuclear deformation during breast cancer cell transmigration. , 2012, Lab on a chip.

[39]  X. Zhuang,et al.  Actin, Spectrin, and Associated Proteins Form a Periodic Cytoskeletal Structure in Axons , 2013, Science.

[40]  B. J. Kane,et al.  Liver-specific functional studies in a microfluidic array of primary mammalian hepatocytes. , 2006, Analytical chemistry.

[41]  Jerry Westerweel,et al.  Zebrafish embryo development in a microfluidic flow-through system. , 2011, Lab on a chip.

[42]  X. Zhuang,et al.  Superresolution Imaging of Chemical Synapses in the Brain , 2010, Neuron.

[43]  E. Betzig,et al.  Live-cell photoactivated localization microscopy of nanoscale adhesion dynamics , 2008, Nature Methods.

[44]  Alessandro Valeri,et al.  Super-Resolution Imaging of Bacteria in a Microfluidics Device , 2013, PloS one.

[45]  B. Giepmans,et al.  Immunolabeling artifacts and the need for live-cell imaging , 2012, Nature Methods.

[46]  M. Davidson,et al.  Extended-resolution structured illumination imaging of endocytic and cytoskeletal dynamics , 2015, Science.

[47]  Fei Wang,et al.  High-throughput mapping of brain-wide activity in awake and drug-responsive vertebrates. , 2015, Lab on a chip.

[48]  Johnny Tam,et al.  A Microfluidic Platform for Correlative Live-Cell and Super-Resolution Microscopy , 2014, PloS one.

[49]  Mehmet Fatih Yanik,et al.  Sub-cellular precision on-chip small-animal immobilization, multi-photon imaging and femtosecond-laser manipulation. , 2008, Lab on a chip.

[50]  Mehmet Fatih Yanik,et al.  Large-scale in vivo femtosecond laser neurosurgery screen reveals small-molecule enhancer of regeneration , 2010, Proceedings of the National Academy of Sciences.

[51]  Ulrich Berge,et al.  Tissue-culture light sheet fluorescence microscopy (TC-LSFM) allows long-term imaging of three-dimensional cell cultures under controlled conditions. , 2014, Integrative biology : quantitative biosciences from nano to macro.

[52]  Mark A. Scott,et al.  Identification of small molecules that Enhance Synaptogenesis using Synapse Microarrays , 2011, Nature communications.

[53]  Demetri Psaltis,et al.  Lensless high-resolution on-chip optofluidic microscopes for Caenorhabditis elegans and cell imaging , 2008, Proceedings of the National Academy of Sciences.

[54]  X. Zhuang,et al.  Whole cell 3D STORM reveals interactions between cellular structures with nanometer-scale resolution , 2008, Nature Methods.

[55]  Chien-Chung Peng,et al.  A microfluidic device for uniform-sized cell spheroids formation, culture, harvesting and flow cytometry analysis. , 2013, Biomicrofluidics.

[56]  Eli J. Weinberg,et al.  In vitro analysis of a hepatic device with intrinsic microvascular-based channels , 2008, Biomedical microdevices.

[57]  Chia-Fu Chou,et al.  Asymmetric cancer-cell filopodium growth induced by electric-fields in a microfluidic culture chip. , 2011, Lab on a chip.

[58]  Kung-Bin Sung,et al.  Substrate Stiffness Regulates Filopodial Activities in Lung Cancer Cells , 2014, PloS one.

[59]  S. Hell,et al.  Breaking the diffraction resolution limit by stimulated emission: stimulated-emission-depletion fluorescence microscopy. , 1994, Optics letters.

[60]  Fan Yang,et al.  An integrated microfluidic array system for evaluating toxicity and teratogenicity of drugs on embryonic zebrafish developmental dynamics. , 2011, Biomicrofluidics.

[61]  Raquel Perez-Castillejos,et al.  Partitioning microfluidic channels with hydrogel to construct tunable 3-D cellular microenvironments. , 2008, Biomaterials.

[62]  Stefan W. Hell,et al.  Supporting Online Material Materials and Methods Figs. S1 to S9 Tables S1 and S2 References Video-rate Far-field Optical Nanoscopy Dissects Synaptic Vesicle Movement , 2022 .

[63]  Vincent Studer,et al.  3D high- and super-resolution imaging using single-objective SPIM , 2015, Nature Methods.

[64]  Hongwei Zhou,et al.  Fish in chips: an automated microfluidic device to study drug dynamics in vivo using zebrafish embryos. , 2014, Chemical communications.

[65]  Hanry Yu,et al.  A novel 3D mammalian cell perfusion-culture system in microfluidic channels. , 2007, Lab on a chip.

[66]  D. Milkie,et al.  Rapid Adaptive Optical Recovery of Optimal Resolution over LargeVolumes , 2014, Nature Methods.

[67]  J. Lichtman,et al.  3D Multicolor Super-Resolution Imaging Offers Improved Accuracy in Neuron Tracing , 2012, PloS one.

[68]  M. Gustafsson,et al.  Super-resolution 3D microscopy of live whole cells using structured illumination , 2011, Nature Methods.

[69]  Andrew G. Glen,et al.  APPL , 2001 .

[70]  Nicolas C. Pégard,et al.  Flow-based structured illumination , 2013 .