Skip to main content
SpringerLink
Log in

Hydrogel-integrated Microfluidic Systems for Advanced Stem Cell Engineering

  • Review Article
  • Published:
BioChip Journal Aims and scope Submit manuscript

Abstract

Previous culture techniques are often ineffective for providing appropriate conditions to cells grown in vitro for efficient growth and maturation. However, the advent of microfluidic chips allows us to manipulate various factors from co-culturing cells to inducing shear stress and biochemical gradient. The above have all been effectively applied to stem cell engineering, allowing dynamic interactions with other cells and, as a result, acquisition of a more mature state. The introduction of both synthetic and natural hydrogels into the chip provides more precise in vivo-like biophysical and biochemical cues to cells, enabling better recapitulation of the in vivo-like physiological behaviors and further maturation of stem cells even to the scale of organoids. This review addresses fundamental roles of microfluidic chips and hydrogels and how hydrogel-integrated chip systems provide breakthroughs in advanced stem cell engineering.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Luo, Y. Lou, C., Zhang, S., Zhu, Z., Xing, Q., Wang, P., Liu, T., Liu, H., Li, C. & Shi, W. Three-dimensional hydrogel culture conditions promote the differentiation of human induced pluripotent stem cells into hepatocytes. Cytotherapy20, 95–107 (2018).

    CAS  PubMed  Google Scholar 

  2. Takayama, K., Kawabata, K., Nagamoto, Y., Kishimoto, K., Tashiro, K., Sakurai, F., Tachibana, M., Kanda, K., Hayakawa, T. & Furue, M.K. 3D spheroid culture of hESC/hiPSC-derived hepatocyte-like cells for drug toxicity testing. Biomaterials34, 1781–1789 (2013).

    CAS  PubMed  Google Scholar 

  3. Lewis, K.J., Hall, J.K., Kiyotake, E.A., Christensen, T., Balasubramaniam, V. & Anseth, K.S. Epithelial-mesenchymal crosstalk influences cellular behavior in a 3D alveolus-fibroblast model system. Biomaterials155, 124–134 (2018).

    CAS  PubMed  Google Scholar 

  4. Estabridis, H.M., Jana, A., Nain, A. & Odde, D.J. Cell migration in 1D and 2D nanofiber microenvironments. Ann. Biomed. Eng.46, 392–403 (2018).

    PubMed  Google Scholar 

  5. Korkaya, H., Liu, S. & Wicha, M.S. Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J. Clin. Invest.121, 3804–3809 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Gong, Q., Ou, Q., Ye, S., Lee, W.P., Cornelius, J., Diehl, L., Lin, W.Y., Hu, Z., Lu, Y., Chen, Y., Wu, Y., Meng, Y.G., Gribling, P., Lin, Z., Nguyen, K., Tran, T., Zhang, Y., Rosen, H., Martin, F. & Chan, A.C. Importance of Cellular Microenvironment and Circulatory Dynamics in B Cell Immunotherapy. J. Immunol.174, 817–826 (2005).

    CAS  PubMed  Google Scholar 

  7. Baker, B.M. & Chen, C.S. Deconstructing the third dimension — how 3D culture microenvironments alter cellular cues. J. Cell Sci.125, 3015–3024 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Watt, F.M. & Hogan, B.L. Out of Eden: stem cells and their niches. Science287, 1427–1430 (2000).

    CAS  PubMed  Google Scholar 

  9. Jin, L. Hu, B., Li, Z., Li, J., Gao, Y., Wang, Z. & Hao, J. Synergistic Effects of Electrical Stimulation and Aligned Nanofibrous Microenvironment on Growth Behavior of Mesenchymal Stem Cells. ACS Appl. Mater. Interfaces10, 18543–18550 (2018).

    CAS  PubMed  Google Scholar 

  10. Patel, B.B. Sharifi, F., Stroud, D.P., Montazami, R., Hashemi, N.N. & Sakaguchi, D.S. 3D Microfibrous Scaffolds Selectively Promotes Proliferation and Glial Differentiation of Adult Neural Stem Cells: A Platform to Tune Cellular Behavior in Neural Tissue Engineering. Macromol. Biosci.19, 1800236 (2019).

    Google Scholar 

  11. Bao, M., Xie, J., Katoele, N., Hu, X., Wang, B., Piruska, A. & Huck, W.T. Cellular volume and matrix stiffness direct stem cell behavior in a 3D microniche. ACS Appl. Mater. Interfaces11, 1754–1759 (2018).

    PubMed Central  Google Scholar 

  12. Abgrall, P. & Gué, A.M. Lab-on-chip technologies: making a microfluidic network and coupling it into a complete microsystem—a review. J. Micromech. Microeng.17, R15–R49 (2007).

    Google Scholar 

  13. Whitesides, G.M. The origins and the future of microfluidics. Nature442, 368 (2006).

    CAS  PubMed  Google Scholar 

  14. Selimović, Š., Kaji, H., Bae, H. & Khademhosseini, A. Microfluidic systems for controlling stem cell microenvironments. in Microfluidic Cell Culture Systems 31–63 (Elsevier, 2019).

  15. Chung, B.G. Flanagan, L.A., Rhee, S.W., Schwartz, P.H., Lee, A.P., Monuki, E.S. & Jeon, N.L. Human neural stem cell growth and differentiation in a gradient-generating microfluidic device. Lab Chip5, 401–406 (2005).

    CAS  PubMed  Google Scholar 

  16. Kim, L., Vahey, M.D., Lee, H.-Y. & Voldman, J. Microfluidic arrays for logarithmically perfused embryonic stem cell culture. Lab Chip6, 394–406 (2006).

    CAS  PubMed  Google Scholar 

  17. Villa-Diaz, L.G. Torisawa, Y.-S., Uchida, T., Ding, J., Nogueira-de-Souza, N.C., O’Shea, K.S., Takayama, S. & Smith, G.D. Microfluidic culture of single human embryonic stem cell colonies. Lab Chip9, 1749–1755 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu, H., Wang, Y., Cui, K., Guo, Y., Zhang, X. & Qin, J. Advances in Hydrogels in Organoids and Organs-on-a-Chip. Adv. Mater.31, 1902042 (2019).

    CAS  Google Scholar 

  19. Li, Y. & Kumacheva, E. Hydrogel microenvironments for cancer spheroid growth and drug screening. Sci. Adv.4, eaas8998 (2018).

    PubMed  PubMed Central  Google Scholar 

  20. Theobald, J. Abu el Maaty, M.A., Kusterer, N., Wetterauer, B., Wink, M., Cheng, X. & Wölfl, S. In vitro metabolic activation of vitamin D3 by using a multi-compartment microfluidic liver-kidney organ on chip platform. Sci. Rep.9, 4616 (2019).

    PubMed  PubMed Central  Google Scholar 

  21. Sances, S. Ho, R., Vatine, G., West, D., Laperle, A., Meyer, A., Godoy, M., Kay, P.S., Mandefro, B., Hatata, S., Hinojosa, C., Wen, N., Sareen, D., Hamilton, G.A. & Svendsen, C.N. Human iPSC-Derived Endothelial Cells and Microengineered Organ-Chip Enhance Neuronal Development. Stem Cell Rep.10, 1222–1236 (2018).

    CAS  Google Scholar 

  22. Park, T.-E. Mustafaoglu, N., Herland, A., Hasselkus, R., Mannix, R., FitzGerald, E.A., Prantil-Baun, R., Watters, A., Henry, O., Benz, M., Sanchez, H., Mc Crea, H.J., Goumnerova, L.C., Song, H.W., Palecek, S.P., Shusta, E. & Ingber, D.E. Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies. Nat. Commun.10, 2621 (2019).

    PubMed  PubMed Central  Google Scholar 

  23. Humayun, M., Chow, C.-W. & Young, E.W.K. Microfluidic lung airway-on-a-chip with arrayable suspended gels for studying epithelial and smooth muscle cell interactions. Lab Chip18, 1298–1309 (2018).

    CAS  PubMed  Google Scholar 

  24. Joo, S., Lim, J. & Nam, Y. Design and Fabrication of Miniaturized Neuronal Circuits on Microelectrode Arrays Using Agarose Hydrogel Micro-molding Technique. Biochip J.12, 193–201 (2018).

    CAS  Google Scholar 

  25. Bitgood, M.J. & McMahon, A.P. Hedgehogand-BmpGenes Are Coexpressed at Many Diverse Sites of Cell-Cell Interaction in the Mouse Embryo. Dev. Biol.172, 126–138 (1995).

    CAS  PubMed  Google Scholar 

  26. Wilson, S.E., Mohan, R.R., Mohan, R.R., Ambrósio, R., Hong, J. & Lee, J. The Corneal Wound Healing Response: Cytokine-mediated Interaction of the Epithelium, Stroma, and Inflammatory Cells. Prog. Retin. Eye Res.20, 625–637 (2001).

    CAS  PubMed  Google Scholar 

  27. Werner, S., Krieg, T. & Smola, H. Keratinocyte-Fibroblast Interactions in Wound Healing. J. Invest. Dermatol.127, 998–1008 (2007).

    CAS  PubMed  Google Scholar 

  28. Jessell, T.M. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat. Rev. Genet.1, 20 (2000).

    CAS  PubMed  Google Scholar 

  29. Wälchli, T., Wacker, A., Frei, K., Regli, L., Schwab, M.E., Hoerstrup, S.P., Gerhardt, H. & Engelhardt, B. Wiring the vascular network with neural cues: a CNS perspective. Neuron87, 271–296 (2015).

    PubMed  Google Scholar 

  30. Huh, D. Matthews, B.D., Mammoto, A., Montoya-Zavala, M., Hsin, H.Y. & Ingber, D.E. Reconstituting Organ-Level Lung Functions on a Chip. Science328, 1662 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Huh, D. Leslie, D.C., Matthews, B.D., Fraser, J.P., Jurek, S., Hamilton, G.A., Thorneloe, K.S., Mc Alexander, M.A. & Ingber, D.E. A Human Disease Model of Drug Toxicity-Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice. Sci. Transl. Med.4, 159ra147 (2012).

    PubMed  PubMed Central  Google Scholar 

  32. Jain, A. Barrile, R., van der Meer, A., Mammoto, A., Mammoto, T., De Ceunynck, K., Aisiku, O., Otieno, M., Louden, C., Hamilton, G., Flaumenhaft, R. & Ingber, D. Primary Human Lung Alveolus-on-a-chip Model of Intravascular Thrombosis for Assessment of Therapeutics. Clin. Pharmacol. Ther.103, 332–340 (2018).

    CAS  PubMed  Google Scholar 

  33. Campisi, M. Shin, Y., Osaki, T., Hajal, C., Chiono, V. & Kamm, R.D. 3D self-organized microvascular model of the human blood-brain barrier with endothelial cells, pericytes and astrocytes. Biomaterials180, 117–129 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Jalili-Firoozinezhad, S. Gazzaniga, F.S., Calamari, E.L., Camacho, D.M., Fadel, C.W., Bein, A., Swenor, B., Nestor, B., Cronce, M.J., Tovaglieri, A., Levy, O., Gregory, K. E., Breault, D.T., Cabral, J.M.S., Kasper, D.L., Novak, R. & Ingber, D.E. A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip. Nat. Biomed. Eng.3, 520–531 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Seo, J., Byun, W. Y., Alisafaei, F., Georgescu, A., Yi, Y.-S., Massaro-Giordano, M., Shenoy, V.B., Lee, V., Bunya, V.Y. & Huh, D Multiscale reverse engineering of the human ocular surface. Nat. Med.25, 1310–1318 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kim, T.H., Lee, J.M., Ahrberg, C.D. & Chung, B.G. Development of the Microfluidic Device to Regulate Shear Stress Gradients. Biochip J.12, 294–303 (2018).

    CAS  Google Scholar 

  37. Kappings, V. Grün, C., Ivannikov, D., Hebeiss, I., Kattge, S., Wendland, I., Rapp, B. E., Hettel, M., Deutschmann, O. & Schepers, U. vasQchip: A Novel Microfluidic, Artificial Blood Vessel Scaffold for Vascularized 3D Tissues. Adv. Mater. Technol.3, 1700246 (2018).

    Google Scholar 

  38. Ong, L.J.Y. Islam, A., DasGupta, R., Iyer, N.G., Leo, H.L. & Toh, Y.C. A 3D printed microfluidic perfusion device for multicellular spheroid cultures. Biofabrication9, 045005 (2017).

    PubMed  Google Scholar 

  39. Agarwal, T., Narayana, G.H. & Banerjee, I. Keratinocytes are mechanoresponsive to the microflow-induced shear stress. Cytoskeleton (Hoboken)76, 209–218 (2019).

    CAS  Google Scholar 

  40. van der Meer, A.D., Poot, A.A., Feijen, J. & Vermes, I. Analyzing shear stress-induced alignment of actin filaments in endothelial cells with a microfluidic assay. Biomicrofluidics4, 011103 (2010).

    CAS  PubMed Central  Google Scholar 

  41. Wang, J., Heo, J. & Hua, S.Z. Spatially resolved shear distribution in microfluidic chip for studying force transduction mechanisms in cells. Lab Chip10, 235–239 (2010).

    PubMed  Google Scholar 

  42. Naskar, S., Panda, A.K., Kumaran, V., Mehta, B. & Basu, B. Controlled Shear Flow Directs Osteogenesis on UHMWPE-Based Hybrid Nanobiocomposites in a Custom-Designed PMMA Microfluidic Device. ACS Appl. Bio Mater.1, 414–435 (2018).

    CAS  PubMed  Google Scholar 

  43. Donà, E., Barry, J.D., Valentin, G., Quirin, C., Khmelinskii, A., Kunze, A., Durdu, S., Newton, L.R., Fernandez-Minan, A., Huber, W., Knop, M. & Gilmour, D. Directional tissue migration through a self-generated chemokine gradient. Nature503, 285–289 (2013).

    PubMed  Google Scholar 

  44. Moore, K.A. & Lemischka, I.R. Stem Cells and Their Niches. Science311, 1880–1885 (2006).

    CAS  PubMed  Google Scholar 

  45. Kim, S., Kim, H.J. & Jeon, N.L. Biological applications of microfluidic gradient devices. Integr. Biol.2, 584–603 (2010).

    CAS  Google Scholar 

  46. Park, J.Y. Kim, S.-K., Woo, D.-H., Lee, E.-J., Kim, J.-H. & Lee, S.-H. Differentiation of Neural Progenitor Cells in a Microfluidic Chip-Generated Cytokine Gradient. Stem Cells27, 2646–2654 (2009).

    CAS  PubMed  Google Scholar 

  47. Zhang, F. Tian, C., Liu, W., Wang, K., Wei, Y., Wang, H., Wang, J. & Liu, S. Determination of Benzopyrene-Induced Lung Inflammatory and Cytotoxic Injury in a Chemical Gradient-Integrated Microfluidic Bronchial Epithelium System. ACS Sens.3, 2716–2725 (2018).

    CAS  PubMed  Google Scholar 

  48. Schwarz, J., Bierbaum, V., Merrin, J., Frank, T., Hauschild, R., Bollenbach, T., Tay, S., Sixt, M. & Mehling, M. A microfluidic device for measuring cell migration towards substrate-bound and soluble chemokine gradients. Sci. Rep.6, 36440 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Ghiaseddin, A. Pouri, H., Soleimani, M., Vasheghani-Farahani, E., Ahmadi Tafti, H. & Hashemi-Najafabadi, S. Cell laden hydrogel construct on-a-chip for mimicry of cardiac tissue in-vitro study. Biochem. Biophys. Res. Commun.484, 225–230 (2017).

    CAS  PubMed  Google Scholar 

  50. Kenny, P.A. Lee, G.Y., Myers, C.A., Neve, R.M., Semeiks, J.R., Spellman, P.T., Lorenz, K., Lee, E.H., Barcellos-Hoff, M.H., Petersen, O.W., Gray, J.W. & Bissell, M. J. The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Mol. Oncol.1, 84–96 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Johansson, U. Widhe, M., Shalaly, N.D., Arregui, I.L., Nilebäck, L., Tasiopoulos, C. P., Åstrand, C., Berggren, P.-O., Gasser, C. & Hedhammar, M. Assembly of functionalized silk together with cells to obtain proliferative 3D cultures integrated in a network of ECM-like microfibers. Sci. Rep.9, 6291 (2019).

    PubMed  PubMed Central  Google Scholar 

  52. Ghosh, S. Spagnoli, G.C., Martin, I., Ploegert, S., Demougin, P., Heberer, M. & Reschner, A. Three-dimensional culture of melanoma cells profoundly affects gene expression profile: A high density oli-gonucleotide array study. J. Cell. Physiol.204, 522–531 (2005).

    CAS  PubMed  Google Scholar 

  53. Weigelt, B., Lo, A.T., Park, C.C., Gray, J.W. & Bissell, M.J. HER2 signaling pathway activation and response of breast cancer cells to HER2-targeting agents is dependent strongly on the 3D microenvironment. Breast Cancer Res. Treat.122, 35–43 (2010).

    CAS  PubMed  Google Scholar 

  54. Koh, I. & Kim, P. In Vitro Reconstruction of Brain Tumor Microenvironment. Biochip J.13, 1–7 (2019).

    CAS  Google Scholar 

  55. Rosso, F., Giordano, A., Barbarisi, M. & Barbarisi, A. From cell-ECM interactions to tissue engineering. J. Cell. Physiol.199, 174–180 (2004).

    CAS  PubMed  Google Scholar 

  56. Howard, C.M. & Baudino, T.A. Dynamic cell-cell and cell-ECM interactions in the heart. J. Mol. Cell. Cardiol.70, 19–26 (2014).

    CAS  PubMed  Google Scholar 

  57. McMillen, P. & Holley, S.A. Integration of cell-cell and cell-ECM adhesion in vertebrate morphogenesis. Curr. Opin. Cell Biol.36, 48–53 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Ugolini, G.S., Visone, R., Redaelli, A., Moretti, M. & Rasponi, M. Generating Multicompartmental 3D Biological Constructs Interfaced through Sequential Injections in Microfluidic Devices. Adv. Healthc. Mater.6, 1601170 (2017).

    Google Scholar 

  59. Bang, S., Na, S., Jang, J.M., Kim, J. & Jeon, N.L. Engineering-Aligned 3D Neural Circuit in Microfluidic Device. Adv. Healthcare Mater.5, 159–166 (2016).

    CAS  Google Scholar 

  60. Han, S. Yang, K., Shin, Y., Lee, J. S., Kamm, R.D., Chung, S. & Cho, S.-W. Three-dimensional extra-cellular matrix-mediated neural stem cell differentiation in a microfluidic device. Lab Chip12, 2305–2308 (2012).

    CAS  PubMed  Google Scholar 

  61. Tse, J.R. & Engler, A.J. Stiffness Gradients Mimicking In Vivo Tissue Variation Regulate Mesenchymal Stem Cell Fate. PLoS One6, e15978 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Kim, H.N. & Choi, N. Consideration of the Mechanical Properties of Hydrogels for Brain Tissue Engineering and Brain-on-a-chip. Biochip J.13, 8–19 (2019).

    CAS  Google Scholar 

  63. Wang, Z., Volinsky, A.A. & Gallant, N.D. Cross-linking effect on polydimethylsiloxane elastic modulus measured by custom-built compression instrument. J. Appl. Polym. Sci.131, 41050 (2014).

    Google Scholar 

  64. Bandyopadhyay, A., Valavala, P.K., Clancy, T.C., Wise, K.E. & Odegard, G.M. Molecular modeling of crosslinked epoxy polymers: The effect of crosslink density on thermomechanical properties. Polymer52, 2445–2452 (2011).

    CAS  Google Scholar 

  65. Coutinho, D.F. Sant, S.V., Shin, H., Oliveira, J.T., Gomes, M.E., Neves, N.M., Khademhosseini, A. & Reis, R.L. Modified Gellan Gum hydrogels with tunable physical and mechanical properties. Biomaterials31, 7494–7502 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. García, S. Sunyer, R., Olivares, A., Noailly, J., Atencia, J. & Trepat, X. Generation of stable orthogonal gradients of chemical concentration and substrate stiffness in a microfluidic device. Lab Chip15, 2606–2614 (2015).

    PubMed  Google Scholar 

  67. Wang, W., Li, L., Ding, M., Luo, G. & Liang, Q. A Microfluidic Hydrogel Chip with Orthogonal Dual Gradients of Matrix Stiffness and Oxygen for Cytotoxicity Test. Biochip J.12, 93–101 (2018).

    CAS  Google Scholar 

  68. Pedron, S., Becka, E. & Harley, B.A. Spatially Gradated Hydrogel Platform as a 3D Engineered Tumor Microenvironment. Adv. Mater.27, 1567–1572 (2015).

    CAS  PubMed  Google Scholar 

  69. Gattazzo, F., Urciuolo, A. & Bonaldo, P. Extracellular matrix: a dynamic microenvironment for stem cell niche. Biochim. Biophys. Acta- Gen. Subj.1840, 2506–2519 (2014).

    CAS  Google Scholar 

  70. Flaim, C.J., Teng, D., Chien, S. & Bhatia, S.N. Combinatorial signaling microenvironments for studying stem cell fate. Stem Cells Dev.17, 29–40 (2008).

    CAS  PubMed  Google Scholar 

  71. Birbrair, A. Stem cell microenvironments and beyond. in Stem Cell Microenvironments and Beyond 1–3 (Springer, 2017).

  72. Xie, Q.-P. Huang, H., Xu, B., Dong, X., Gao, S.-L., Zhang, B., Wu, Y.-L., Human bone marrow mesenchymal stem cells differentiate into insulin-producing cells upon microenvironmental manipulation in vitro. Differentiation77, 483–491 (2009).

    CAS  PubMed  Google Scholar 

  73. Wang, B. Jakus, A.E., Baptista, P.M., Soker, S., Soto-Gutierrez, A., Abecassis, M.M., Shah, R.N. & Wertheim, J.A. Functional maturation of induced pluripotent stem cell hepatocytes in extracellular matrix—a comparative analysis of bioartificial liver microenvironments. Stem Cells Transl. Med.5, 1257–1267 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Yang, K. Park, H.-J., Han, S., Lee, J., Ko, E., Kim, J., Lee, J.S., Yu, J.H., Song, K.Y. & Cheong, E. Recapitulation of in vivo-like paracrine signals of human mesenchymal stem cells for functional neuronal differentiation of human neural stem cells in a 3D microfluidic system. Biomaterials63, 177–188 (2015).

    CAS  PubMed  Google Scholar 

  75. Cho, H., Kim, D. & Kim, K. Engineered Co-culture Strategies Using Stem Cells for Facilitated Chondrogenic Differentiation and Cartilage Repair. Biotechnol. Bioprocess Eng.23, 261–270 (2018).

    CAS  Google Scholar 

  76. Tabata, Y. & Lutolf, M.P. Multiscale microenvironmental perturbation of pluripotent stem cell fate and self-organization. Sci. Rep.7, 44711 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Shi, X., Zhou, J., Zhao, Y., Li, L. & Wu, H. GradientRegulated Hydrogel for Interface Tissue Engineering: Steering Simultaneous Osteo/Chondrogenesis of Stem Cells on a Chip. Adv. Healthc. Mater.2, 846–853 (2013).

    CAS  PubMed  Google Scholar 

  78. Uzel, S.G. Platt, R.J., Subramanian, V., Pearl, T.M., Rowlands, C.J., Chan, V., Boyer, L.A., So, P.T. & Kamm, R.D. Microfluidic device for the formation of optically excitable, three-dimensional, compartmentalized motor units. Sci. Adv.2, e1501429 (2016).

    PubMed  PubMed Central  Google Scholar 

  79. Jin, Y., Seo, J., Lee, J.S., Shin, S., Park, H.J., Min, S., Cheong, E., Lee, T. & Cho, S.W., Triboelectric nanogenerator accelerates highly efficient nonviral direct conversion and in vivo reprogramming of fibroblasts to functional neuronal cells. Adv. Mater.28, 7365–7374 (2016).

    CAS  PubMed  Google Scholar 

  80. Solozobova, V., Wyvekens, N. & Pruszak, J. Lessons from the embryonic neural stem cell niche for neural lineage differentiation of pluripotent stem cells. Stem Cell Rev. Rep.8, 813–829 (2012).

    PubMed  Google Scholar 

  81. Sun, Y. Yong, K.M., Villa-Diaz, L.G., Zhang, X., Chen, W., Philson, R., Weng, S., Xu, H., Krebsbach, P.H. & Fu, J. Hippo/YAP-mediated rigidity-dependent motor neuron differentiation of human pluripotent stem cells. Nat. Mater.13, 599–604 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Jin, Y. Lee, J.S., Kim, J., Min, S., Wi, S., Yu, J. H., Chang, G.-E., Cho, A.-N., Choi, Y. & Ahn, D.-H. Three-dimensional brain-like microenvironments facilitate the direct reprogramming of fibroblasts into therapeutic neurons. Nat. Biomed. Eng.2, 522 (2018).

    CAS  PubMed  Google Scholar 

  83. Lu, S. Cuzzucoli, F., Jiang, J., Liang, L.-G., Wang, Y., Kong, M., Zhao, X., Cui, W., Li, J. & Wang, S. Development of a biomimetic liver tumor-on-a-chip model based on decellularized liver matrix for toxicity testing. Lab Chip18, 3379–3392 (2018).

    CAS  PubMed  Google Scholar 

  84. Marturano-Kruik, A. Nava, M.M., Yeager, K., Chramiec, A., Hao, L., Robinson, S., Guo, E., Raimondi, M.T. & Vunjak-Novakovic, G. Human bone perivascular niche-on-a-chip for studying metastatic colonization. Proc. Natl. Acad. Sci. U.S.A.115, 1256–1261 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Lee, J.S. Cho, A.-N., Jin, Y., Kim, J., Kim, S. & Cho, S.-W., Bio-artificial tongue with tongue extracellular matrix and primary taste cells. Biomaterials151, 24–37 (2018).

    CAS  PubMed  Google Scholar 

  86. Lee, J.S. Roh, Y.H., Choi, Y.S., Jin, Y., Jeon, E.J., Bong, K.W. & Cho, S.W. Tissue Beads: Tissue-Specific Extracellular Matrix Microbeads to Potentiate Reprogrammed Cell-Based Therapy. Adv. Funct. Mater.29, 1807803 (2019).

    Google Scholar 

  87. Lee, J.S., Choi, Y.S. & Cho, S.-W. Decellularized Tissue Matrix for Stem Cell and Tissue Engineering. Adv. Exp. Med. Biol.1064, 161–180 (2018).

    CAS  PubMed  Google Scholar 

  88. Rozario, T. & DeSimone, D.W. The extracellular matrix in development and morphogenesis: a dynamic view. Dev. Biol.341, 126–140 (2010).

    CAS  PubMed  Google Scholar 

  89. Wang, H., Luo, X. & Leighton, J. Extracellular matrix and integrins in embryonic stem cell differentiation. Biochem. Insights8, S30377 (2015).

    Google Scholar 

  90. Maul, T.M., Chew, D.W., Nieponice, A. & Vorp, D.A. Mechanical stimuli differentially control stem cell behavior: morphology, proliferation, and differentiation. Biomech. Model. Mechanobiol.10, 939–953 (2011).

    PubMed  PubMed Central  Google Scholar 

  91. Jin, Y. Kim, J., Lee, J.S., Min, S., Kim, S., Ahn, D.H., Kim, Y.G. & Cho, S. W Vascularized liver organoids generated using induced hepatic tissue and dynamic liver-specific microenvironment as a drug testing platform. Adv. Funct. Mater.28, 1801954 (2018).

    Google Scholar 

  92. Holle, A.W. Tang, X., Vijayraghavan, D., Vincent, L.G., Fuhrmann, A., Choi, Y.S., del Álamo, J.C. & Engler, A.J. In situ mechanotransduction via vinculin regulates stem cell differentiation. Stem Cells31, 2467–2477 (2013).

    CAS  PubMed  Google Scholar 

  93. Fischer, M., Rikeit, P., Knaus, P. & Coirault, C. YAP-mediated mechanotransduction in skeletal muscle. Front. Physiol.7, 41 (2016).

    PubMed  PubMed Central  Google Scholar 

  94. Hao, J. Zhang, Y., Jing, D., Shen, Y., Tang, G., Huang, S. & Zhao, Z. Mechanobiology of mesenchymal stem cells: perspective into mechanical induction of MSC fate. Acta Biomater.20, 1–9 (2015).

    PubMed  Google Scholar 

  95. Wozniak, M.A. & Chen, C.S. Mechanotransduction in development: a growing role for contractility. Nat. Rev. Mol. Cell Biol.10, 34–43 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Seo, J. Shin, J.-Y., Leijten, J., Jeon, O., Bal Öztürk, A., Rouwkema, J., Li, Y., Shin, S. R., Hajiali, H., Alsberg, E. & Khademhosseini, A. Interconnectable dynamic compression bioreactors for combinatorial screening of cell mechanobiology in three dimensions. ACS Appl. Mater. Interfaces10, 13293–13303 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Clevers, H. Modeling development and disease with organoids. Cell165, 1586–1597 (2016).

    CAS  PubMed  Google Scholar 

  98. Lancaster, M.A. & Knoblich, J.A. Organogenesis in a dish: modeling development and disease using organoid technologies. Science345, 1247125 (2014).

    PubMed  Google Scholar 

  99. Kim, S., Cho, A.N., Min, S., Kim, S. & Cho, S.W. Organoids for Advanced Therapeutics and Disease Models. Advanced Therapeutics2, 1800087 (2019).

    Google Scholar 

  100. Rossi, G., Manfrin, A. & Lutolf, M.P. Progress and potential in organoid research. Nat. Rev. Genet.19, 671–687 (2018).

    CAS  PubMed  Google Scholar 

  101. Yoon, S.-J. Elahi, L.S., Paṣca, A.M., Marton, R.M., Gordon, A., Revah, O., Miura, Y., Walczak, E.M., Holdgate, G.M. & Fan, H.C. Reliability of human cortical organoid generation. Nat. Methods16, 75–78 (2019).

    CAS  PubMed  Google Scholar 

  102. Kim, Y.K., Nam, S.A. & Yang, C.W. Applications of kidney organoids derived from human pluripotent stem cells. Korean J. Intern. Med.33, 649–659 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Takasato, M. Pei, X.E., Chiu, H.S., Maier, B., Baillie, G.J., Ferguson, C., Parton, R. G., Wolvetang, E.J., Roost, M.S. & de Sousa Lopes, S.M.C. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature526, 564–568 (2015).

    CAS  PubMed  Google Scholar 

  104. van den Berg, C.W. Ritsma, L., Avramut, M.C., Wiersma, L.E., van den Berg, B.M., Leuning, D.G., Lievers, E., Koning, M., Vanslambrouck, J.M. & Koster, A.J. Renal subcapsular transplantation of PSC-derived kidney organoids induces neo-vasculogenesis and significant glomerular and tubular maturation in vivo. Stem Cell Rep.10, 751–765 (2018).

    Google Scholar 

  105. Homan, K.A. Gupta, N., Kroll, K.T., Kolesky, D.B., Skylar-Scott, M., Miyoshi, T., Mau, D., Valerius, M.T., Ferrante, T. & Bonventre, J.V. Flow-enhanced vascularization and maturation of kidney organoids in vitro. Nat. Methods16, 255–262 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Berger, E. Magliaro, C., Paczia, N., Monzel, A.S., Antony, P., Linster, C.L., Bolognin, S., Ahluwalia, A. & Schwamborn, J.C. Millifluidic culture improves human midbrain organoid vitality and differentiation. Lab Chip18, 3172–3183 (2018).

    CAS  PubMed  Google Scholar 

  107. Lee, K.K., McCauley, H.A., Broda, T.R., Kofron, M.J., Wells, J.M. & Hong, C. I. Human stomach-on-a-chip with luminal flow and peristaltic-like motility. Lab Chip18, 3079–3085 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Sidar, B. Jenkins, B.R., Huang, S., Spence, J.R., Walk, S.T. & Wilking, J.N. Long-term flow through human intestinal organoids with the gut organoid flow chip (GOFlowChip). Lab Chip19, 3552–3562 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhang, Y.S., Aleman, J., Shin, S.R., Kilic, T., Kim, D., Shaegh, S.A.M., Massa, S., Riahi, R., Chae, S. & Hu, N. Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors. Proc. Natl. Acad. Sci. U.S.A.114, E2293–E2302 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants (2017M3C7A1047659 and 2017R1A2B3005 994) from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT), Korea.

Author information

Authors and Affiliations

  1. Department of Biotechnology, Yonsei University, Seoul, 03722, Korea

    Soohwan An, Seung Yeop Han & Seung-Woo Cho

Authors
  1. Soohwan An
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Seung Yeop Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seung-Woo Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seung-Woo Cho.

Additional information

Conflict of Interests The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

An, S., Han, S.Y. & Cho, SW. Hydrogel-integrated Microfluidic Systems for Advanced Stem Cell Engineering. BioChip J 13, 306–322 (2019). https://doi.org/10.1007/s13206-019-3402-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13206-019-3402-5

Keywords

Search

Navigation