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Microtechnology Projects

Cellular Micropatterns

 

Tissue function is modulated by the spatial organization of cells on a sub-millimeter scale. For this reason, artificial replication of cellular microstructures is important in understanding, measuring, and simulating their in vivo functions in the laboratory. We are continuously developing techniques that allow us to selectively attach cells on a variety of substrates, including biocompatible polymers, hydrogels, and porous substrates.

​References:

Ellen Tenstad, Anna Tourovskaia, A. Folch, Ola Myklebost, and Edith Rian, “Extensive adipogenic and osteogenic differentiation of patterned human mesenchymal stem cells in a microfluidic device”, Lab Chip 10: 1401 (2010).

Rettig, J. R. and Folch, A. “Large-Scale Single-Cell Trapping and Imaging Using Microwell Arrays”, Analytical Chemistry 77: 5628-5634 (2005).

Tourovskaia, A., Figueroa-Masot, X. and Folch, A., “Differentiation-on-a-chip: A Microfluidic Platform for Long-Term Cell Culture Studies”, Lab on a Chip 5:14 (2005).

Li, N., Tourovskaia, A., and Folch, A. “Biology on a Chip: Microfabrication in Cell Culture Studies”, Critical Reviews in Biomedical Engineering 31:68 (2003).

Tourovskaia, A., Barber, T., Wickes, B., Hirdes, D., Grin, B., Castner, D. G., Healy, K. E., and Folch, A. “Micropatterns of Chemisorbed Cell Adhesion-Repellent Films Using Oxygen Plasma Etching and Elastomeric Masks”, Langmuir 19:4754 (2002).

Folch, A. and Toner, M.  “Microengineering of Cellular Interactions”, Annual Rev. of Biomedical Engineering 2: 227 (2000).

Microfluidic automation

With a few exceptions, microfluidic devices are notoriously difficult to use. At best, they are based on non-intuitive user interfaces and complex tubing setups that are prone to bubble nucleation and human error. We believe that, in order to become a standard technology in clinical devices, microfluidic automation should draw some inspiration from car automation standards, whereby the user operates an intuitive user interface that commands a computer (hidden from the user), which in turns drives a car -- the user no longer drives the car. We are developing microfluidic systems where all the layers of automation (microvalves and micropumps) are hidden from the user, they can be programmed via a battery-operated mini-processor, and the user can introduce all the fluids into the device via intuitive interfaces such as a multi-well plate and standardized connectors.

References:

Adina Scott, Anthony  K. Au, Elise Vinckenbosch, and Albert Folch, “A microfluidic D-subminiature connector”, accepted to Lab on a Chip (2013).

A. K. Au, H. Lai, B. R. Utela, and A. Folch, “Microvalves and Micropumps for BioMEMS”, Micromachines 2, 179 (2011).

H. Lai and A. Folch, "Design and characterization of "single-stroke" peristaltic PDMS micropumps", Lab Chip 11, 336 (2011).

J. M. Hoffman, M. Ebara, J. J. Lai, A. S. Hoffman, A. Folch, and P. Stayton, "A helical flow, circular microreactor for separating and enriching smart polymer-antibody capture reagents", Lab Chip 10, 3130 (2010).

Lam, E.W., Cooksey, G.A., Finlayson, B.A., and Folch, A. “Microfluidic Circuits with Tunable Flow Resistances”, Appl. Phys. Lett. 89: 164105 (2006).

Hsu, C.-H. and Folch, A. “Spatiotemporally-Complex Concentration Profiles Using a Tunable Chaotic Micromixer”, Appl. Phys. Lett. 89: 144102 (2006).

Frevert, C.W., Boggy, G., Keenan, T.M., and Folch, A. “Measurement of cell migration in response to an evolving radial chemokine gradient triggered by a microvalve”, Lab on a Chip 6: 849 (2006).

Li, N., Hsu, C.-H., and Folch, A. “Parallel mixing of Photolithographically-Defined Nanoliter Volumes Using Elastomeric Microvalve Arrays”, Electrophoresis 26: 3758-3764 (2005).

Hsu, C.-H. and Folch, A. “Microfluidic Devices with Tunable Microtopographies”, Applied Physics Letters 86, 023508 (2005).

Hoffman, J., Shao, J., Hsu, C.-H., and Folch, A. “Elastomeric Molds with Tunable Microtopographies”, Advanced Materials 16:2201 (2004).

Gradient Generators

Biomolecule gradients have been shown to play roles in a wide range of biological processes including development, inflammation, wound healing, and cancer metastasis.  Elucidation of these phenomena requires the ability to expose cells to biomolecule gradients that are quantifiable, controllable, and mimic those that are present in vivo.  Microfluidic gradient generators offer greater levels of precision, quantitation, and spatiotemporal gradient control than traditional methods, and may greatly enhance our understanding of many biological phenomena.

References:

​C. G. Sip, N. Bhattacharjee, and A. Folch, “A Modular Cell Culture Device for Generating Arrays of Gradients Using Stacked Microfluidic Flows”, Biomicrofluidics 5, 022210 (2011).

D. M. Cate, C. G. Sip, and A. Folch, "A microfluidic platform for generation of sharp gradients in open-access culture", Biomicrofluidics 4, 044105 (2010).

Keenan, T.M., Frevert, C.W., Wu, A., Wong, V., and Folch, A. “A New Method for Studying Gradient-Induced Neutrophil Desensitization Based on an Open Microfluidic Chamber”, Lab Chip 10: 116 (2010).

Bhattacharjee, N., Li, N., Keenan, T.M., and Folch, A. “A Neuron-Benign Microfluidic Gradient Generator for Studying the Growth of Mammalian Neurons towards Axon Guidance Factors”, Integrative Biology 2, 669 (2010).

Keenan, T.M. and Folch, A. “Biomolecular gradients in cell culture systems”, Lab Chip 8, 34 (2008).

Hsu, C.-H. and Folch, A. “Spatiotemporally-Complex Concentration Profiles Using a Tunable Chaotic Micromixer”, Appl. Phys. Lett. 89: 144102 (2006).

Neils, C. M., Tyree, Z., Finlayson, B., and Folch, A. “Combinatorial Mixing of Microfluidic Streams”, Lab on a Chip 4:342 (2004).

Chen, C., Hirdes, D., and Folch, A. “Gray-Scale Photolithography Using Microfluidic Photomasks”, Proceedings of National Academy of Sciences 100:1499 (2003).

Micro-bioreactors

Biologists and doctors have attempted to recreate "organ-like" conditions in petri dishes. In these conditions, cells dissociated from the organ are seeded on a homogeneous plastic surface (usually coated with protein) and homogeneously batheed in cell culture medium. These conditions do not reproduce the microscale gradients and substrate heterogeneity present in vivo, which can affect critical cellular functions negatively and irreversibly. They also require considerable human labor, so they produce results at very low throughput. Hence, we use microfluidic technology for mimicking the physiological conditions on a cellular scale and for automating high-throughput cell culture experiments that can provide low-cost alternatives to animal and clinical studies.  

References:

​Ellen Tenstad, Anna Tourovskaia, A. Folch, Ola Myklebost, and Edith Rian, “Extensive adipogenic and osteogenic differentiation of patterned human mesenchymal stem cells in a microfluidic device”, Lab Chip 10: 1401 (2010).

​Keenan, T.M., Frevert, C.W., Wu, A., Wong, V., and Folch, A. “A New Method for Studying Gradient-Induced Neutrophil Desensitization Based on an Open Microfluidic Chamber”, Lab Chip 10: 116 (2010).

​Bhattacharjee, N., Li, N., Keenan, T.M., and Folch, A. “A Neuron-Benign Microfluidic Gradient Generator for Studying the Growth of Mammalian Neurons towards Axon Guidance Factors”, Integrative Biology 2, 669 (2010).

​​​Tourovskaia, A., Li, N., and Folch, A., “Localized acetylcholine receptor clustering dynamics in response to microfluidic focal stimulation with agrin”, Biophys. J. 95: 3009 (2008).

​Chen, H.-H., Shen, H., Heimfeld, S., Tran, K.K., Reems, J., Folch, A., and Gao, D. “A microfluidic study of mouse dendritic cell membrane transport properties of water and cryoprotectants”, Int. J. Heat and Mass Transfer 51: 5687 (2008).

​Chen, H.-H., Purtteman, J.J.P., Heimfeld, S., Folch, A., and Gao, D. “Development of a Microfluidic Device for Determination of Cell Osmotic Behavior and Membrane Transport Properties”, Cryobiol. 55: 200 (2007).

​Tourovskaia, A., Figueroa-Masot, X., and Folch, A. “Long-term Microfluidic Cultures of Myotube Microarrays for High-Throughput Focal Stimulation”, Nature Protocols 1: 1092 (2006).

​Tourovskaia, A., T.F. Kosar, and Folch, A. “Local Induction of Acetylcholine Receptor Clustering in Myotube Cultures Using Microfluidic Application of Agrin”, Biophys. J. 90: 2192-2198 (2006).

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