2022
Lor Huai Chong, Terry Ching, Hui Jia Farm, Gianluca Grenci, Keng-Hwee Chiam, Yi-Chin Toh*, Integration of a microfluidic multicellular array with machine learning analysis to predict adverse cutaneous drug reactions, 2022, Lab on a Chip, 22, 1890 – 1904
Here, we report a novel in vitro drug screening platform, which comprises a microfluidic multicellular coculture array (MCA) to model different mechanisms-of-action using a collection of simplistic cellular assays. The resultant readouts are then integrated with a machine-learning algorithm to predict the skin sensitizing potential of systemic drugs. The MCA consists of 4 cell culture compartments connected by diffusion microchannels to enable crosstalk between hepatocytes that generate drug metabolites, antigen-presenting cells (APCs) that detect the immunogenicity of the drug metabolites, and keratinocytes and dermal fibroblasts, which collectively determine drug metabolite-induced FasL-mediated apoptosis.
Chak Ming Leung, Pim de Haan, Kacey Ronaldson-Bouchard, Ge-Ah Kim, Jihoon Ko, Hoon Suk Rho, Zhu Chen7, Pamela Habibovic*, Noo Li Jeon*, Shuichi Takayama*, Michael L. Shuler*, Gordana Vunjak-Novakovic*, Olivier Frey*, Elisabeth Verpoorte*, Yi-Chin Toh*, A Guide to the Organ-on-a-Chip, 2022, Nature Reviews Methods Primer, 2, 33. https://doi.org/10.1038/s43586-022-00118-6
This Primer is intended to give an introduction to the aspects of OoC that need to be considered when developing an application-specific OoC. The Primer covers guiding principles and considerations to design, fabricate and operate an OoC, as well as subsequent assaying techniques to extract biological information from OoC devices. Alongside this is a discussion of current and future applications of OoC technology, to inform design and operational decisions during the implementation of OoC systems.
Chak Ming Leung, Louis Jun Ye Ong, Sangho Kim & Yi-Chin Toh*, A Physiological Adipose-on-Chip Disease Model to Mimic Adipocyte Hypertrophy and Inflammation, 2022, Organs-on-a-Chip, 4: 100021 https://doi.org/10.1016/j.ooc.2022.100021
The adipose tissue is a metabolically active endocrine organ with a dynamic secretome that is known to be implicated in metabolic disorders. This study reports for the first time, the establishment of a physiologically-relevant in vitro ‘Adipose-on-Chip’ (AOC) disease model using a microfluidic device that can support 3D culture of adipocytes derived from human bone marrow mesenchymal stem cells (BMMSCs). The model mimics adipose tissue pathophysiology in obesity via excessive free fatty acids (FFA) loading which drove adipocyte inflammation and formation of hypertrophic lipid droplets.
2021
Terry Ching, Yi-Chin Toh, Michinao Hashimoto, Yu Shrike Zhang, Bridging the academia-to-industry gap: organ-on-a-chip platforms for safety and toxicology assessment, 2021, Trends in Pharmacological Science, 42(9): 715-728
Organ-on-a-chip (OoC) systems have been shown to recapitulate human physiology and pathology, and have demonstrated similar or better predictive ability for drug evaluation than static cellular cultures and animal models. In this publication, we describe the needs and potential of OoC developments, the current existing state of systems, and recommendations for the future of these technologies.
Terry Ching, Jyothsna Vasudevan, Hsih Yin Tan, Chwee Teck Lim, Javier Fernandez, Yi-Chin Toh*, Michinao Hashimoto, Highly-customizable 3D-printed peristaltic pump kit, 2021, Hardware X, e00202
Here, we designed a 3D printable micro-peristaltic pump kit as a cost-effective (~50 USD) alternative to current commercial pumps (>1000 USD). In this paper, we detail the fabrication and operation of two variations of pumps with different flow rates using the developed kit. Using a modular design, the kit is easily customizable, easy to replace, and has exceptional forward compatibility. The peristaltic pump kit exhibited good repeatability in flow rates and functioned for 7 days without any noticeable issues in performance.
Geetika Sahni, Shu-Yung Chang1, Jeremy Teo Choon Meng, Jerome Zu Yao Tan, Jean Jacques Clement Fatien, Carine Bonnard, Kagistia Hana Utami, Puck Wee Chan, Thong Teck Tan, Umut Altunoglu, Hülya Kayserili, Mahmoud Pouladi, Bruno Reversade, Yi-Chin Toh*, A micropatterned human-specific neuroepithelial tissue for modeling gene and drug-induced neurodevelopmental defects, 2021, Advanced Science, https://doi.org/10.1002/advs.202001100
In this paper, we combine hPSC micropatterning and a temporally‐sequenced induction protocol to specify neuroepithelial (NE) cells in spatial juxtaposition to mesoendoderm cells. This resulted in the formation of a reproducible and highly‐organized NE tissue. By evaluating NE tissue structural dysmorphia in the micropatterned NE model, we can successfully model gene- and drug-induced neurodevelopmental defects.
Akshaya Srinivasan, Nelson Teo, Poon Kei Jun, Priya Tiwari, Akhilandeshwari Ravichandran, Wen Feng, Swee Hin Teoh, Thiam Chye Lim, Yi-Chin Toh*, Comparative Craniofacial Bone Regeneration Capacities of Mesenchymal Stem Cells Derived from Human Neural Crest Stem Cells and Bone Marrow, 2021, ACS Biomaterial Science and Research, 7, 1, 207–221
Most craniofacial bones are derived from the ectodermal germ layer via neural crest stem cells, which are distinct from mesoderm-derived long bones. This paper investigates the potential of neural crest derived human ecto-mesenchymal stem cells (eMSCs) for future clinical use in craniofacial regeneration applications and indicates the importance of considering MSC origin when selecting an MSC source for regenerative applications.
Dibakar Mondal, Akshaya Srinivasan, Patricia Comeau, Yi-Chin Toh*, Thomas L Willett, Acrylated Epoxidized Soybean Oil / Hydroxyapatite-Based Nanocomposite Scaffolds Prepared by Additive Manufacturing for Bone Tissue Engineering, 2021, Materials Science & Engineering C, 118:111400
This is a collaborative effort with Dr Thomas Willett @ Waterloo University demonstrating the utility of 3D printed soybean-based scaffolds for bone tissue engineering application.
2020
Hsih Yin Tan and Yi-Chin Toh*, What can microfluidics do for microbiome research? Biomicrofluidics, 2020, 14, (5), DOI: 10.1063/5.0012185
Dysregulation of the human microbiome has been linked to various disease states, which has galvanized the efforts to modulate human health through microbiomes. This paper discusses how microfluidic technologies can value add to the different phases of human microbiome research as well as the unique challenges that microfluidics must overcome when working with microbiome-relevant biological materials.
Louis Jun Ye Ong, Liang Zhu, Gabriel Jenn Sern Tan, Yi-Chin Toh*, Quantitative Image-Based Cell Viability (QuantICV) Assay for Microfluidic 3D Tissue Culture Applications, 2020, Micromachines, 11 (7): 10.3390/mi11070669
Fluorescence-based assays have long being used to assess cell viability in microfluidic devices. However, quantification of cell viability in dense 3D tissue constructs is not straightforward. This paper reports a double nuclear-staining technique in combination with confocal image processing to visualize and quantify cell viability in microfluidic 3D tissue constructs.
Seep Arora, Akshaya Srinivasan, Chak Ming Leung, Yi-Chin Toh*, Bio-mimicking shear stress environments for enhancing mesenchymal stem cell differentiation, 2020, Current Stem Cell Research & Therapy, 15(5):414-427
This article reviews and discusses the application of fluid shear stress for modulating the in vitro differentiation of MSCs into various lineages.
Seep Arora, Christine Cheung, Evelyn Yim*, Yi-Chin Toh*, Topography elicits distinct phenotypes and functions in human primary and stem cell derived endothelial cells, 2020, Biomaterials, 234, 119747
Different endothelial cell subtypes often exhibit similar morphological response to topographical cues, however, they can demonstrate different phenotypic and functional responses. This study is a comprehensive evaluation of the effects of various topographical cues on arterial- or venous-specific EC phenotype and function.
Xianzhu Zhang, Dandan Cai, Feifei Zhou, Jie Yu, Xinyu Wu, Dongsheng Yu, Yiwei Zou, Yi Hong, Chunhui Yuan, Yishan Chen, Zongyou Pan, Varitsara Bunpetch, Heng Sun, Chengrui An, Yi-Chin Toh, Hongwei Ouyang, Shufang Zhang, Targeting downstream subcellular YAP activity as a function of matrix stiffness with Verteporfin-encapsulated chitosan microsphere attenuates osteoarthritis, 2020, Biomaterials, 232: 119724
2019
Terry Ching, Yi-Chin Toh, Michinao Hashimoto, Fabrication of Complex 3D Fluidic Networks via Modularized Stereolithography, 2019, Advanced Engineering Materials, 1901109, https://doi.org/10.1002/adem.201901109
This paper describes the fabrication of complex networks of microchannel via modularized stereolithography 3D printing. By applying the modularized approach, 2D and 3D networks of microchannels with high complexity (i.e., multiple branching networks) and small cross‐sectional dimensions (w = 75 μm and h = 100 μm) are fabricated in photoresins and hydrogels.
Lor Huai Chong, Celine Ng, Huan Li, Edmund Feng Tian, Abhishek Ananthanarayanan, Michael McMillian, Yi-Chin Toh, Hepatic Bioactivation of Skin-Sensitizing Drugs to Immunogenic Reactive Metabolites, 2019, ACS Omega, 4, 9, 13902-13912
This paper demonstrates the generation and quantification of immunogenic metabolite species of paradigm skin sensitising drugs using a human progenitor cell (HepaRG)-derived hepatocyte model and highly sensitive liquid chromatography-mass spectrometry analytical assays.
Louis Jun Ye Ong, Terry Tsz Him Ching, Lor Huai Chong, Seep Arora, Huan Li, Ramanuj DasGupta, Po Ki Yuen, Yi-Chin Toh*, Self-Aligning Tetris-Like (TILE) Modular Microfluidic Platform for Mimicking Multi-Organ Interactions, 2019, Lab on a Chip,19, 2178-2191, 10.1039/C9LC00160C
This paper describes a modular microfluidic platform that enables a user-intuitive and flexible way to configure multi-organ perfusion culture systems.
Terry Ching, Yingying Li, Rahul Karyappa, Akihiro Ohno, Yi-Chin Toh, Michinao Hashimoto, Fabrication of Integrated Microfluidic Devices by Direct Ink Write (DIW) 3D Printing, 2019, Sensors & Actuators B: Chemical https://doi.org/10.1016/j.snb.2019.05.086
This paper reports a rapid and simple method of fabricating integrated microfluidic devices with direct ink write (DIW) 3D printer. This is achieved by dispensing a fast-curing flexible silicone resin on various substrates to form microchannels.
Seep, Evelyn Yim, Yi-Chin Toh*, Environmental specification of pluripotent stem cell derived endothelial cells towards arterial and venous subtypes, 2019, Frontiers in Bioengineering and Biotechnology https://doi.org/10.3389/fbioe.2019.00143
This review aims to provide a framework as well as highlight opportunities to advance pluripotent stem cell endothelial cell differentiation protocols from EC lineage commitment to arterial-venous specification.
Akshaya Srinivasan, Yi-Chin Toh*, Human Pluripotent Stem Cell-derived Neural Crest Cells for Tissue Regeneration and Disease Modeling, 2019, Frontiers in Molecular Neuroscience, 12, https://doi.org/10.3389/fnmol.2019.00039
This paper reviews the various in vitro strategies that have been used to derive NCCs from hPSCs and specify NCCs into cranial, trunk and vagal subpopulations and their derivatives. We also discuss the potential applications of these human specific NCC platforms, including the use of iPSCs for disease modeling and the potential of NCCs for future regenerative applications
Seep Arora, Jing Ying Adele Lam, Christine Cheung, Evelyn KF Yim, Yi-Chin Toh*, Determination of critical shear stress for maturation of human pluripotent stem cell derived endothelial cells towards an arterial subtype, 2019, Biotechnology and Bioengineering, 116 (5), 1164-1175, https://doi.org/10.1002/bit.26910
A multiplex microfluidic platform to systematically investigate the dose‐time shear responses on hPSC‐EC morphology and arterial‐venous phenotypes over a range of magnitudes coincidental with physiological levels of embryonic and adult vasculatures.
2018
Lor Huai Chong, Huan Li, Isaac Wetzel, Hansang Cho, Yi-Chin Toh*, A liver-immune coculture array for predicting systemic drug-induced skin sensitization, 2018, Lab on a Chip 18: 3239
This paper reports a liver-immune coculture array that can mimic liver-mediated bioactivation of parent drugs into reactive metabolites and their subsequent activation of immune cells.
Yi-Chin Toh, Anju Raja, Hanry Yu, Danny van Noort, A 3D Microfluidic Model to Recapitulate Cancer Cell Migration and Invasion, 2018, Bioengineering, 5(2): 29
Live visualisation and tracking of breast cancer cells migrating across an ECM barrier in a microfluidic 3D tumor model
Srinivasan, A., Chang, S.Y., Zhang, S., Toh, W.S., Toh, Y.C.*, Substrate stiffness modulates the multipotency of neural crest derived human ectomesenchymal stem cells via CD44 mediated PDGFR signaling, 2018, Biomaterials 167:153-167
This paper demonstrated that substrate stiffness mediated mechanical cues can directly modulate the development of ectodermal MSCs (eMSCs) from a precursor human neural crest stem cell (NCSC) population. We also discovered that substrate stiffness modulated the differentiation of NCSCs to eMSCs via a Rho-ROCK dependent pathway involving CD44-mediated inhibition of PDGFRβ signaling.
2017 and earlier
Ong, L.J.Y., Islam, A.B., DasGupta, R., Iyer, N.G., Leo., H.L., Toh, Y.C.*, A 3D Printed Microfluidic Perfusion Device for Multicellular Spheroid Cultures, 2017, Biofabrication
Ong, L.J.Y., Chong, L.H., Jin, L., Singh, P.K., Lee, P.S., Yu, H., Ananthanarayanan, A., Leo, H.L., Toh, Y.C.*, A pump-free microfluidic 3D perfusion platform for the efficient differentiation of human hepatocyte-like cells, 2017, Bioengineering & Biotechnology
Choudhury, Y.#, Toh, Y.C.#, Xing, J., Qu, Y., Poh, J., Huan, L., Tan, H.S., Kanesvaran, R., Yu, H. and Tan, M.H., 2017. Patient-specific hepatocyte-like cells derived from induced pluripotent stem cells model pazopanib-mediated hepatotoxicity. Scientific Reports, 7.
Tasnim, F., Toh, Y.C., Qu, Y., Li, H., Phan, D., Narmada, B.C., Ananthanarayanan, A., Mittal, N., Meng, R.Q. and Yu, H., 2016. Functionally enhanced human stem cell derived hepatocytes in galactosylated cellulosic sponges for hepatotoxicity testing. 2016, Molecular Pharmaceutics, 13(6), pp.1947-1957.
Sahni, G., Yuan, J. and Toh, Y.C.*, 2016. Stencil Micropatterning of Human Pluripotent Stem Cells for Probing Spatial Organization of Differentiation Fates. 2016, JoVE (Journal of Visualized Experiments), 112: pp.e54097-e54097.
Tasnim, F., Phan, D., Toh, Y.C. and Yu, H., 2015. Cost-effective differentiation of hepatocyte-like cells from human pluripotent stem cells using small molecules. 2015, Biomaterials, 70, pp.115-125.
Xing, J., Toh, Y.C., Xu, S. and Yu, H., 2015. A method for human teratogen detection by geometrically confined cell differentiation and migration. 2015, Scientific Reports
Toh, Y.C., Xing, J. and Yu, H., 2015. Modulation of integrin and E-cadherin-mediated adhesions to spatially control heterogeneity in human pluripotent stem cell differentiation, 2015, Biomaterials, 50 (0): 87-97.
Anene-Nzelu, C.G., Peh, K.Y., Fraiszudeen, A., Kuan, Y.H., Ng, S.H., Toh, Y.C.*, Leo, H.L. and Yu, H., 2013. A scalable method for aligning 3D micro-tissues in microfluidic chips, 2013, Lab on a Chip, 13(20): 4124 – 4133
Anene-Nzelu, C.G., Choudhury, D., Li, H., Fraiszudeen, A., Peh, K.Y., Toh, Y.C., Ng, S.H., Leo, H.L. and Yu, H., 2013. Scalable cell alignment on optical media substrates, 2013, Biomaterials, 34(21): 5078-5087
Wang, Y., Toh, Y.C., Li, Q., Nugraha, B., Zheng, B., Lu, T.B., Gao, Y., Ng, M.M.L. and Yu, H., 2013. Mechanical compaction directly modulates the dynamics of bile canaliculi formation, 2013, Integrative Biology, 5 (2): 390 – 400. Featured in Global Medical Discovery (ISSN 1929-8536),
Featured in Global Medical Discovery (ISSN 1929-8536), Jan 2013
Toh, Y.C., Blagovic, K., Yu, H. and Voldman, J., 2011. Spatially organized in vitro models instruct asymmetric stem cell differentiation, 2011, Integrative Biology, 3: 1179-1187
Toh, Y.C., Kang, T.G., van Noort, D., Burkholder, B. and Zhang, J.B., 2011. Leveraging on being small—Singapore’s strategy to catalyze integrative innovations, 2011, Lab on a Chip, 11: 1853-1855
(Invited article)
Toh, Y.C. and Voldman, J., 2011. Fluid shear stress primes mouse embryonic stem cells for differentiation in a self-renewing environment via heparan sulfate proteoglycans transduction, 2011, FASEB Journal, 25: 1208-1217
Toh, Y.C., Blagović, K. and Voldman, J., 2010. Advancing Stem Cell Research with microtechnologies: opportunities and challenges, 2010, Integrative Biology, 2: 305-325
Toh, Y.C., Lim, T.C., Tai, D., Xiao, G., van Noort, D. and Yu, H., 2009. A microfluidic 3D hepatocyte chip for drug toxicity testing, 2009, Lab on a Chip, 9(14): 2026-2035
Zhang, C., Chia, S.M., Ong, S.M., Zhang, S., Toh, Y.C., van Noort, D. and Yu, H., 2009. The controlled presentation of TGF-b1 to hepatocytes in a 3D microfludic cell culture system, 2009, Biomaterials, 2009, 30: 3847-3853
Zhang, S., Xia, L., Kang, C.H., Xiao, G., Ong, S.M., Toh, Y.C., Leo, H.L., van Noort, D., Kan, S.H., Tang, H.H. and Yu, H., 2008. Microfabricated silicon nitride membranes for hepatocyte sandwich culture, 2008, Biomaterials, 29 (29): 3993-4002
Zhao, D., Ong, S.M., Yue, Z., Jiang, Z., Toh, Y.C., Khan, M., Shi, J., Tan, C.H., Chen, J.P. and Yu, H., 2008. Dendrimer hydrazides as multivalent transient inter cellular linkers, Biomaterials, 2008, 29 (27): 3693-3702
Ong, S.M., Zhang, C., Toh, Y.C., Kim, S.H., Foo, H.L., Tan, C.H., van Noort, D., Park, S. and Yu, H., 2008. A gel-free 3D microfluidic cell culture system, 2008, Biomaterials, 29(22): 3237-3244
Toh, Y.C., Zhang, J., Khong, Y.M., Du, Y., Sun, W. and Yu, H., 2008. Integrating sensitive quantification of hepatic metabolic functions by capillary electrophoresis with laser-induced fluorescence detection, 2008, Analyst, 133: 326-330
Wen, F., Chang, S., Toh, Y.C., Arooz, T., Zhuo, L., Teoh, S.H. and Yu, H., 2008. Development of dual-compartment perfusion bioreactor for serial coculture of hepatocytes and stellate cells in poly (lactic-co-glycolic acid)-collagen scaffolds, Journal of Biomedical Materials Research Part B: Applied Biomaterials, 2008, 87(1): 154-162
Kim, L., Toh, Y.C., Voldman, J. and Yu, H., 2007. A Practical Guide to Microfluidic Perfusion Culture of Adherent Mammalian Cells. 2007, Lab on a Chip, 2007, 7: 681-694.
Y.C. Toh, C. Zhang, J. Zhang, Y.M. Khong, S. Chang, V.D. Samper, D. van Noort, D.W. Hutmacher and H.Yu. A novel 3D mammalian cell perfusion-culture system in microfluidic channels. 2007, Lab on a Chip, 7(3): 302-309. Featured in RSC’s Chemical Biology, 2007, Issue 4
Featured in RSC’s Chemical Biology, 2007, Issue 4
Wen, F., Chang, S., Toh, Y.C., Teoh, S.H. and Yu, H., 2007. Development of poly (lactic-co-glycolic acid)-collagen scaffolds for tissue engineering. 2007, Materials Science and Engineering: C, 27(2): 285–292.
Toh, Y.C., Ng, S., Khong, Y.M., Zhang, X., Zhu, Y., Lin, P.C., Te, C.M., Sun, W. and Yu, H., 2006. Cellular responses to a nanofibrous environment, 2006, NanoToday, 1(3): 34-43.
Toh, Y.C., Ng, S., Khong, Y.M., Samper, V. and Yu, H., 2005. A Configurable 3D Microenvironment in a Micro-fluidic Channel for Primary Hepatocytes Culture. 2005, Assay and Drug Development Technologies, 3(2): 169-176.
Toh, Y.C., Ho, S.T., Zhou, Y., Hutmacher, D.W. and Yu, H., 2005. Application of polyelectrolyte complex coacervation to improve the seeding efficiency of bone marrow stromal cells in 3D scaffolds. 2005, Biomaterials, 26(19): 4149–4160.
Toh, Y.C., Yen, J.J.L., Obbard, J.P. and Ting, Y.P., 2003. Decolourisation of azo dyes by white-rot fungi (WRF) isolated in Singapore. Enzyme and Microbial Technology, 2003, 33(5): 569-575.