Organs-on-a-chip models for biological research

Vunjak-Novakovic, Gordana; Ronaldson-Bouchard, Kacey; Radisic, Milica

doi:10.1016/j.cell.2021.08.005

Cited by 2483D Printing in Biomedical ResearchTissue Engineering and Regenerative MedicineMicrofluidic and Capillary Electrophoresis Applications

Organs-on-a-chip models for biological research

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Vunjak-Novakovic, Gordana, Ronaldson-Bouchard, Kacey, Radisic, Milica·2021·Cell

DOI 10.1016/j.cell.2021.08.005PMC PMC8417425

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Abstract

We explore the utility of bioengineered human tissues-individually or connected into physiological units-for biological research. While much smaller and simpler than their native counterparts, these tissues are complex enough to approximate distinct tissue phenotypes: molecular, structural, and functional. Unlike organoids, which form spontaneously and recapitulate development, "organs-on-a-chip" are engineered to display some specific functions of whole organs. Looking back, we discuss the key developments of this emerging technology. Thinking forward, we focus on the challenges faced to fully establish, validate, and utilize the fidelity of these models for biological research.

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Organs-on-chips are perfused microfluidic devices with engineered or miniaturized tissues linked by 3D microchannels to mimic organ functions, biomechanics and pathophysiological responses.
“OoCs are perfused microfluidic platforms that contain bioengineered or miniaturized tissues or organs interconnected by 3D microchannels to simulate the in vivo functions, biomechanics and (patho)physiological responses of organs6,52–54.”
From Human disease models in drug development (2023) · cites this paper as [53]
The Introduction describes organs-on-chips as engineered tissue constructs that reproduce selected organ functions using physical signals and fabricated channels. But it says these constructs are not mini-organs, and the section on combining single-organ models describes several ways to connect them—not necessarily 3D microchannels. The claim therefore overstates what all organs-on-chips contain. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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BackgroundInfluential
Synergistic Engineering: Organoids Meet Organs-on-a-Chip
Takebe, T., Zhang, B., & Radisic, M. (2017) · Cell Stem Cell · doi:10.1016/j.stem.2017.08.016 · Cited by 258 · cited 2× · see citing works
“Clear distinction between OOC and organoids is also important (Takebe et al., 2017) (Figure 1).”
BackgroundSelf-citation
A microphysiological model of the human placental barrier
Blundell, C., Tess, E. R., Schanzer, A., Coutifaris, C., Su, E. J., Parry, S. I., & Huh, D. (2016) · Lab on a Chip · doi:10.1039/c6lc00259e · Cited by 253 · cited 4× · see citing works
“…including the use of medium flow to mimic blood perfusion and electrical and mechanical stimuli to drive the maturation of muscle, neural tissues or bone (Alimperti et al., 2017; Blundell et al., 2016; de Graaf et al., 2019; Ronaldson-Bouchard et al., 2018; Vatine et al., 2019; Zhao et al., 2019).”
BackgroundInfluential
Revolutionizing medicine in the 21st century through systems approaches
Hood, L., Balling, R., & Auffray, C. (2012) · Biotechnology Journal · doi:10.1002/biot.201100306 · Cited by 244 · see citing works
Colorectal tumor-on-a-chip system: a 3D tool for precision onco-nanomedicine
Carvalho, M. R., Barata, D., Teixeira, L. M., Giselbrecht, S., Reis, R. L., Oliveira, J. M., Truckenmüller, R., & Habibovic, P. (2019) · Science Advances · doi:10.1126/sciadv.aaw1317 · Cited by 230 · cited 2× · see citing works
“Suchmodels are becoming invaluable for assessing the efficacy of drug-loaded nanoparticles in emerging therapies (Figure 4D) (Carvalho et al., 2019a).”
Background
Electrical stimulation increases hypertrophy and metabolic flux in tissue-engineered human skeletal muscle
Khodabukus, A., Madden, L. R., Prabhu, N. K., Koves, T. R., Jackman, C. P., Muoio, D. M., & Bursac, N. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.08.058 · Cited by 227 · cited 1× · see citing works
“Similar to cardiac models, skeletal muscle models can also be matured using electrical stimulation (Khodabukus et al., 2019) and derived from human iPSCs (Rao et al.”
Background
Engineered heart tissue models from hiPSC-derived cardiomyocytes and cardiac ECM for disease modeling and drug testing applications
Goldfracht, I., Efraim, Y., Shinnawi, R., Kovalev, E., Huber, I., Gepstein, A., Arbel, G., Shaheen, N., Tiburcy, M., Zimmermann, W. H., et al. (2019) · Acta Biomaterialia · doi:10.1016/j.actbio.2019.05.016 · Cited by 222 · cited 1× · see citing works
“Likewise, calcium flux measurements are already well established for a number of tissue systems (Goldfracht et al., 2019).”
Background
Bioengineered human acellular vessels recellularize and evolve into living blood vessels after human implantation
Kirkton, R. D., Santiago-Maysonet, M., Lawson, J. H., Tente, W. E., Dahl, S. L. M., Niklason, L. E., & Prichard, H. L. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aau6934 · Cited by 210 · cited 1× · see citing works
“Tissue-engineered blood vessels will hopefully follow soon, as the clinical trials in atrioventricular shunt patients are being completed (Kirkton et al., 2019).”
Background
Bioengineered Human Organ-on-Chip Reveals Intestinal Microenvironment and Mechanical Forces Impacting Shigella Infection
Grassart, A., Malardé, V., Gobaa, S., Sartori-Rupp, A., Kerns, J., Karalis, K., Marteyn, B., Sansonetti, P., & Sauvonnet, N. (2019) · Cell Host & Microbe · doi:10.1016/j.chom.2019.08.007 · Cited by 206 · see citing works
Gut-Liver Physiomimetics Reveal Paradoxical Modulation of IBD-Related Inflammation by Short-Chain Fatty Acids
Trapecar, M., Communal, C., Velazquez, J., Maass, C. A., Huang, Y.-J., Schneider, K., Wright, C. W., Butty, V., Eng, G., Yilmaz, O., et al. (2020) · Cell Systems · doi:10.1016/j.cels.2020.02.008 · Cited by 204 · see citing works
Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics
McAleer, C. W., Long, C. J., Elbrecht, D., Sasserath, T., Bridges, L. R., Rumsey, J. W., Martin, C., Schnepper, M., Wang, Y., Schuler, F., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aav1386 · Cited by 199 · cited 1× · see citing works
“Models of human safety and efficacy (phase 2/3) Multi-OOCs have been able to accurately model both the ontarget effects of cancer therapies and off-target heart and liver toxicity for drugs involving liver metabolism (McAleer et al., 2019).”
Background
Correction: Corrigendum: Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle
Vernetti, L. A., Gough, A., Baetz, N. W., Blutt, S. E., Broughman, J. R., Brown, J. A., Foulke-Abel, J. D., Hasan, N. M., In, J., Kelly, E. J., et al. (2017) · Scientific Reports · doi:10.1038/srep44517 · Cited by 189 · see citing works
Microvasculature-on-a-chip for the long-term study of endothelial barrier dysfunction and microvascular obstruction in disease
Qiu, Y., Ahn, B., Sakurai, Y., Hansen, C. E., Tran, R., Mimche, P. N., Mannino, R. G., Ciciliano, J. C., Lamb, T. J., Joiner, C. H., et al. (2018) · Nature Biomedical Engineering · doi:10.1038/s41551-018-0224-z · Cited by 188 · cited 1× · see citing works
“recapitulating the blood vessel intima, to study the inflammatory mediators of barrier function and sickle cell occlusion (Qiu et al., 2018) (Figure 4C).”
Background
A multi-throughput multi-organ-on-a-chip system on a plate formatted pneumatic pressure-driven medium circulation platform
Satoh, T., Sugiura, S., Shin, K., Onuki-Nagasaki, R., Ishida, S., Kikuchi, K., Kakiki, M., & Kanamori, T. (2018) · Lab on a Chip · doi:10.1039/c7lc00952f · Cited by 181 · cited 1× · see citing works
“, 2017), recirculation using pneumatic pressure-driven actuation (Satoh et al., 2017), and peristaltic pumps (Chramiec et al.”
Background
Engineering a perfusable 3D human liver platform from iPS cells
Schepers, A. G., Li, C. Y., Chhabra, A., Tschudy-Seney, B., & Bhatia, S. N. (2016) · Lab on a Chip · doi:10.1039/c6lc00598e · Cited by 174 · cited 2× · see citing works
“, 2019; Tiburcy, 2017), liver ((Kostrzewski et al., 2019; Schepers et al., 2016) alveolar unit of the lung (Huh et al.”
Background
IFlowPlate—A Customized 384‐Well Plate for the Culture of Perfusable Vascularized Colon Organoids
Rajasekar, S., Lin, D. S. Y., Abdul, L., Liu, A. W. K., Sotra, A., Zhang, F., & Zhang, B. (2020) · Advanced Materials · doi:10.1002/adma.202002974 · Cited by 167 · cited 1× · see citing works
“Up to 128 independent vascularized colons-on-a-chip were formed in a 384-well-plate platform with gravity flow that supported modeling of colon inflammation with innate immune function (Rajasekar et al., 2020).”
Development of a Functional Glomerulus at the Organ Level on a Chip to Mimic Hypertensive Nephropathy
Zhou, M., Zhang, X., Wen, X., Wu, T., Wang, W., Yang, M., Wang, J., Fang, M., Lin, B., & Lin, H. (2016) · Scientific Reports · doi:10.1038/srep31771 · Cited by 162 · cited 2× · see citing works
“, 2019), kidney glomerulus and proximal tubule (Zhou et al., 2016; Homan et al., 2016), neuromuscular junction (Afshar Bakooshli et al.”
Background
Multiscale reverse engineering of the human ocular surface
Seo, J., Byun, W. Y., Alisafaei, F., Georgescu, A., Yi, Y., Massaro‐Giordano, M., Shenoy, V. B., Lee, V., Bunya, V. Y., & Huh, D. (2019) · Nature Medicine · doi:10.1038/s41591-019-0531-2 · Cited by 149 · cited 1× · see citing works
“The patterned cells are periodically lubricated by a hydrogel lid to create a blinking-eye-on-a-chip (Seo et al., 2019).”
Background
Engineering of human cardiac muscle electromechanically matured to an adult-like phenotype
Ronaldson-Bouchard, K., Yeager, K., Teles, D., Chen, T., Ma, S., Song, L., Morikawa, K., Wobma, H. M., Vasciaveo, A., Ruiz, E. C., et al. (2019) · Nature Protocols · doi:10.1038/s41596-019-0189-8 · Cited by 144 · cited 2× · see citing works
“An example is the engineered heart muscle matured by electromechanical conditioning with the force generation and conduction developing more slowly and to a lesser extent than structural features (Ronaldson-Bouchard et al., 2018; Ronaldson-Bouchard et al., 2019).”
BackgroundSelf-citation
Recapitulating Pancreatic Tumor Microenvironment through Synergistic Use of Patient Organoids and Organ‐on‐a‐Chip Vasculature
Lai, B. F. L., Lu, R. X. Z., Hu, Y., Davenport Huyer, L., Dou, W., Wang, E. Y., Radulovich, N., Tsao, M. S., Sun, Y., & Radisic, M. (2020) · Advanced Functional Materials · doi:10.1002/adfm.202000545 · Cited by 142 · cited 4× · see citing works
“…OOC devices are on the order of micrometers to millimeters in size, whereas regenerative engineering re-creates structures on the order of millimeters to centimeters. ll Review 2016), and tumors (Lai et al., 2020), all of which are being used to study tissue maturation, regeneration, and disease.”
BackgroundMethodInfluentialSelf-citation
A glass-based, continuously zonated and vascularized human liver acinus microphysiological system (vLAMPS) designed for experimental modeling of diseases and ADME/TOX
Li, X., George, S. M., Vernetti, L. A., Gough, A., & Taylor, D. L. (2018) · Lab on a Chip · doi:10.1039/c8lc00418h · Cited by 138 · cited 1× · see citing works
“Recent PDMS-free OOCs with separate hepatic and vascular channels (incorporating primary human hepatocytes and sinusoidal endothelial cells and stellate and Kupffer cell lines) recapitulated the liver acinus and oxygen zonation (Li et al., 2018).”
Background
Microfluidic vascularized bone tissue model with hydroxyapatite-incorporated extracellular matrix
Jusoh, N., Oh, S., Kim, S., Jangho, K., & Jeon, N. L. (2015) · Lab on a Chip · doi:10.1039/c5lc00698h · Cited by 136 · cited 2× · see citing works
“An OOC model of vascularized bone was also created by inducing microvascular flow into the mineralized ECM populated by bone-forming cells (Jusoh et al., 2015).”
Background
Current challenges in the evaluation of cardiac safety during drug development: Translational medicine meets the Critical Path Initiative
Piccini, J. P., Whellan, D. J., Berridge, B. R., Finkle, J. K., Pettit, S. D., Stockbridge, N., Valentin, J., Vargas, H. M., & Krucoff, M. W. (2009) · American Heart Journal · doi:10.1016/j.ahj.2009.06.007 · Cited by 125 · see citing works
Three-dimensional biomimetic vascular model reveals a RhoA, Rac1, and <i>N</i> -cadherin balance in mural cell–endothelial cell-regulated barrier function
Alimperti, S., Mirabella, T., Bajaj, V., Polacheck, W., Pirone, D. M., Duffield, J., Eyckmans, J., Assoian, R. K., & Chen, C. S. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1618333114 · Cited by 122 · cited 3× · see citing works
“A long-standing limitation of iPSCs, the immaturity of the resulting tissues, is being addressed by inclusion of supporting cells and metabolic and physical regulatory factors (Aleman et al., 2019; Alimperti et al., 2017; Bauer et al., 2017; Benam et al., 2016; Blundell et al., 2016; Keung et al., 2014; Kostrzewski et…”
Background
Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs
Lin, Z., Li, Z. A., Li, E. N., Li, X., Duke, C. D., Shen, H., Hao, T., O’Donnell, B. T., Bunnell, B. A., Goodman, S. B., et al. (2019) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2019.00411 · Cited by 122 · see citing works
SarcTrack
Toepfer, C. N., Sharma, A., Cicconet, M., Garfinkel, A. C., Mücke, M. B., Neyazi, M., Willcox, J. A. L., Agarwal, R., Schmid, M., Rao, J., et al. (2019) · Circulation Research · doi:10.1161/circresaha.118.314505 · Cited by 119 · see citing works
Integrated human organ-on-a-chip model for predictive studies of anti-tumor drug efficacy and cardiac safety
Chramiec, A. G., Teles, D., Yeager, K. J., Marturano-Kruik, A., Pak, J., Chen, T. F., Hao, L. Y., Wang, M. C., Lock, R. I., Tavakol, D. N., et al. (2020) · Lab on a Chip · doi:10.1039/d0lc00424c · Cited by 119 · cited 3× · see citing works
“Multi-organ model screening of the anti-cancer drug linsitinib recapitulated clinical findings, including limited efficacy of the drug in treating bone tumors and limited cardiac toxicity in the human setting (Chramiec et al., 2020).”
BackgroundSelf-citation
COVID-19 can affect the heart
Topol, E. J. (2020) · Science · doi:10.1126/science.abe2813 · Cited by 117 · cited 2× · see citing works
“, 2016), and precision medicine app side effects in asymptomatic and recovering coronavirus disease 2019 (COVID-19)-infected individuals (Topol, 2020).”
BackgroundResult
Human Organs-on-Chips for Virology
Tang, H., Abouleila, Y., Si, L., Ortega‐Prieto, A. M., Mummery, C. L., Ingber, D. E., & Mashaghi, A. (2020) · Trends in Microbiology · doi:10.1016/j.tim.2020.06.005 · Cited by 114 · cited 1× · see citing works
“OOCs have been invaluable for the studies of SARS-CoV-2 and other viral infections associated with organ dysfunction (Tang et al., 2020).”
Background
A 96-well culture platform enables longitudinal analyses of engineered human skeletal muscle microtissue strength
Afshar, M. E., Abraha, H. Y., Bakooshli, M. A., Davoudi, S., Thavandiran, N., Tung, K., Ahn, H., Ginsberg, H. J., Zandstra, P. W., & Gilbert, P. M. (2020) · Scientific Reports · doi:10.1038/s41598-020-62837-8 · Cited by 113 · see citing works
SARS-CoV-2 Infects Human Pluripotent Stem Cell-Derived Cardiomyocytes, Impairing Electrical and Mechanical Function
Marchianò, S., Hsiang, T.-Y., Khanna, A., Higashi, T., Whitmore, L. S., Bargehr, J., Davaapil, H., Chang, J., Smith, E. A., Ong, L. P., et al. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.02.008 · Cited by 110 · cited 1× · see citing works
“The heart OOC demonstrated profound contractile dysfunction (Marchiano et al., 2020), consistent with the recent reports of cardiac”
Result
The intercell dynamics of T cells and dendritic cells in a lymph node-on-a-chip flow device
Rosa, P. M., Gopalakrishnan, N. V., Ibrahim, H., Haug, M., & Halaas, Ø. (2016) · Lab on a Chip · doi:10.1039/c6lc00702c · Cited by 107 · cited 1× · see citing works
“Lymph-node-on-a-chip was modeled using a PDMS channel with two inlets and two outlets, supporting a monolayer of dendritic cells to which T cells can be bound during flow in an antigen-specific manner (Moura Rosa et al., 2016).”
Method
A 96-well format microvascularized human lung-on-a-chip platform for microphysiological modeling of fibrotic diseases
Mejías, J. C., Nelson, M. R., Liseth, O. Y., & Roy, K. (2020) · Lab on a Chip · doi:10.1039/d0lc00644k · Cited by 103 · cited 1× · see citing works
“A multi-layered lungon-a-chip with patterned vasculature and lung channels was used to form cystic-fibrosis-like epithelium and study neutrophil migration (Mejı́as et al., 2020).”
Method
InVADE: integrated vasculature for assessing dynamic events
Lai, B. F. L., Huyer, L. D., Lu, R. X. Z., Drecun, S., Radisic, M., & Zhang, B. (2017) · Advanced Functional Materials · doi:10.1002/adfm.201703524 · Cited by 97 · cited 1× · see citing works
“This platform can be scaled down to a footprint of a 96-well plate (Figure 4G) using the InVADE system, requiring only 100,000 cells per tissue and enabling facile connections of tumor and liver tissues (Lai et al., 2017; Lai et al., 2020).”
MethodSelf-citation
Engineering a 3D functional human peripheral nerve in vitro using the Nerve-on-a-Chip platform
Sharma, A. D., McCoy, L., Jacobs, E. H., Willey, H., Behn, J. Q., Nguyen, H. T., Bolon, B. N., Curley, J. L., & Moore, M. J. (2019) · Scientific Reports · doi:10.1038/s41598-019-45407-5 · Cited by 96 · cited 3× · see citing works
“Reproduced with permission from (Sharma et al., 2019a).”
BackgroundInfluential
Microphysiological heart–liver body-on-a-chip system with a skin mimic for evaluating topical drug delivery
de Mello, C. P. P., Carmona‐Moran, C. A., McAleer, C. W., Perez, J., Coln, E. A., Long, C. J., Oleaga, C., Riu, A., Note, R., Teissier, S., et al. (2020) · Lab on a Chip · doi:10.1039/c9lc00861f · Cited by 94 · see citing works
h-FIBER: Microfluidic Topographical Hollow Fiber for Studies of Glomerular Filtration Barrier
Xie, R., Korolj, A., Liu, C., Song, X., Lu, R. X. Z., Zhang, B., Ramachandran, A., Liang, Q., & Radisic, M. (2020) · ACS Central Science · doi:10.1021/acscentsci.9b01097 · Cited by 93 · cited 1× · see citing works
“, 2016), microfluidic spinning of glomerulus-on-a-chip (Xie et al., 2020), and stereolithographic printing of microvasculature and lung alveoli in photopolymerizable hydrogels using food colors as photoabsorbers (Grigoryan et al.”
BackgroundSelf-citation
Differential Monocyte Actuation in a Three‐Organ Functional Innate Immune System‐on‐a‐Chip
Sasserath, T., Rumsey, J. W., McAleer, C. W., Bridges, L. R., Long, C. J., Elbrecht, D. H., Schuler, F., Roth, A. B., Bertinetti‐LaPatki, C., Shuler, M. L., et al. (2020) · Advanced Science · doi:10.1002/advs.202000323 · Cited by 93 · see citing works
Concerns about the widespread use of rodent models for human risk assessments of endocrine disruptors
Habert, R., Muczynski, V., Grisin, T., Moison, D., Messiaen, S., Frydman, R., Benachi, A., Delbès, G., Lambrot, R., Lehraiki, A., et al. (2014) · Reproduction · doi:10.1530/rep-13-0497 · Cited by 88 · cited 1× · see citing works
“The immune and endocrine systems are particularly important, as they interact with all organ systems in the body and are poorly modeled in animals (Habert et al., 2014).”
Background
Modeling alcohol-associated liver disease in a human Liver-Chip
Nawroth, J. C., Petropolis, D. B., Manatakis, D. V., Maulana, T. I., Burchett, G., Schlünder, K., Witt, A., Shukla, A., Kodella, K., Ronxhi, J., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109393 · Cited by 88 · see citing works
Developmental cues for the maturation of metabolic, electrophysiological and calcium handling properties of human pluripotent stem cell-derived cardiomyocytes
Keung, W., Boheler, K. R., & Li, R. A. (2014) · Stem Cell Research & Therapy · doi:10.1186/scrt406 · Cited by 87 · cited 2× · see citing works
“A long-standing limitation of iPSCs, the immaturity of the resulting tissues, is being addressed by inclusion of supporting cells and metabolic and physical regulatory factors (Aleman et al., 2019; Alimperti et al., 2017; Bauer et al., 2017; Benam et al., 2016; Blundell et al., 2016; Keung et al., 2014; Kostrzewski et…”
Background
Deconstructed Microfluidic Bone Marrow On‐A‐Chip to Study Normal and Malignant Hemopoietic Cell–Niche Interactions
Aleman, J., George, S. K., Herberg, S., Devarasetty, M., Porada, C. D., Skardal, A., & Almeida-Porada, G. D. (2019) · Small · doi:10.1002/smll.201902971 · Cited by 86 · cited 3× · see citing works
“A long-standing limitation of iPSCs, the immaturity of the resulting tissues, is being addressed by inclusion of supporting cells and metabolic and physical regulatory factors (Aleman et al., 2019; Alimperti et al., 2017; Bauer et al., 2017; Benam et al., 2016; Blundell et al., 2016; Keung et al., 2014; Kostrzewski et…”
Background
Monitoring tissue-level remodelling during inflammatory arthritis using a three-dimensional synovium-on-a-chip with non-invasive light scattering biosensing
Rothbauer, M., Höll, G., Eilenberger, C., Kratz, S. R. A., Farooq, B., Schuller, P., Calvo, I. O., Byrne, R. A., Meyer, B., Niederreiter, B., et al. (2020) · Lab on a Chip · doi:10.1039/c9lc01097a · Cited by 85 · cited 1× · see citing works
“Patient-derived primary synovial organoids were cultivated in the absence and presence of tumor necrosis factor by noninvasive detection of changes in tissue architecture via light scattering (Rothbauer et al., 2020).”
Background
Bioprinted liver provides early insight into the role of Kupffer cells in TGF-β1 and methotrexate-induced fibrogenesis
Norona, L. M., Nguyen, D. G., Gerber, D. A., Presnell, S. C., Mosedale, M., & Watkins, P. B. (2019) · PLoS ONE · doi:10.1371/journal.pone.0208958 · Cited by 79 · cited 1× · see citing works
“Sensing of drug injury was demonstrated through incorporation of Kupffer cells into Organovo’s 3D-printed liver spheroids (Norona et al., 2019).”
Background
3D curvature-instructed endothelial flow response and tissue vascularization
Mandrycky, C., Hadland, B., & Zheng, Y. Y. (2020) · Science Advances · doi:10.1126/sciadv.abb3629 · Cited by 79 · cited 1× · see citing works
“vasculature in collagen hydrogel (Mandrycky et al., 2020), an important consideration for epithelial/endothelial barriers.”
Background
A Microphysiological System for Studying Nonalcoholic Steatohepatitis
Kostrzewski, T., Maraver, P., Ouro‐Gnao, L., Levi, A., Snow, S., Miedzik, A., Rombouts, K., & Hughes, D. (2020) · Hepatology Communications · doi:10.1002/hep4.1450 · Cited by 77 · cited 2× · see citing works
“A long-standing limitation of iPSCs, the immaturity of the resulting tissues, is being addressed by inclusion of supporting cells and metabolic and physical regulatory factors (Aleman et al., 2019; Alimperti et al., 2017; Bauer et al., 2017; Benam et al., 2016; Blundell et al., 2016; Keung et al., 2014; Kostrzewski et…”
Background
Scalable microphysiological system to model three-dimensional blood vessels
de Graaf, M. N. S., Cochrane, A., van den Hil, F. E., Buijsman, W., van der Meer, A. D., van den Berg, A., Mummery, C. L., & Orlova, V. V. (2019) · APL Bioengineering · doi:10.1063/1.5090986 · Cited by 71 · see citing works
Toward Brain-on-a-Chip: Human Induced Pluripotent Stem Cell-Derived Guided Neuronal Networks in Tailor-Made 3D Nanoprinted Microscaffolds
Harberts, J. I., Fendler, C., Teuber, J., Siegmund, M., Trenkle, A. D. S., Rieck, N., Wolpert, M., Zierold, R., & Blick, R. H. (2020) · ACS Nano · doi:10.1021/acsnano.0c04640 · Cited by 68 · cited 2× · see citing works
“…Zhao et al., 2019; Tiburcy, 2017), liver ((Kostrzewski et al., 2019; Schepers et al., 2016) alveolar unit of the lung (Huh et al., 2010), brain (Harberts et al., 2020) and blood-brain barrier (Vatine et al., 2019), kidney glomerulus and proximal tubule (Zhou et al., 2016; Homan et al., 2016),…”
Background
Quantification of human neuromuscular function through optogenetics
Vila, O. F., Uzel, S. G. M., Ma, S. P., Williams, D. J., Pak, J., Kamm, R. D., & Vunjak‐Novakovic, G. (2019) · Theranostics · doi:10.7150/thno.25735 · Cited by 62 · cited 1× · see citing works
“In another study, the first patient-specific model of NMJ was established using muscle cells and optogenetically edited motoneurons to model myasthenia gravis, an autoimmune disease resulting in NMJ dysfunction (Vila et al., 2019).”
BackgroundSelf-citation
Tissue engineered autologous cartilage-bone grafts for temporomandibular joint regeneration
Chen, D., Wu, J. Y., Kennedy, K. M., Yeager, K. J., Bernhard, J., Ng, J., Zimmerman, B., Robinson, S. T., Durney, K. M., Shaeffer, C., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.abb6683 · Cited by 58 · see citing works
Self-citation
Organotypic primary blood vessel models of clear cell renal cell carcinoma for single-patient clinical trials
Virumbrales-Muñoz, M., Chen, J., Ayuso, J., Lee, M., Abel, E. J., & Beebe, D. J. (2020) · Lab on a Chip · doi:10.1039/d0lc00252f · Cited by 39 · cited 1× · see citing works
“RNAsequencingofbloodvessels allowed selection of candidate drugs, ultimately leading to the testing of sirolimus and nintedanib (Virumbrales-Munoz et al., 2020).”
Background
Organs-on-a-Chip
Low, L. A., Sutherland, M. L., Lumelsky, N. L., Selimović, Š., Lundberg, M. S., & Tagle, D. A. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-36588-2_3 · Cited by 33 · cited 1× · see citing works
“More detail can be found in several excellent reviews (Low et al., 2020; Marx et al., 2016; Takebe et al., 2017).”
Background
Organ-on-a-Chip Systems for Modeling Pathological Tissue Morphogenesis Associated with Fibrosis and Cancer
Hayward, K. L., Kouthouridis, S., & Zhang, B. (2020) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.0c01089 · Cited by 31 · cited 1× · see citing works
“As fibrosis affects essentially all organs as the end stage of various diseases and injuries, recent OOC studies have focused on recapitulating fibrosis (Hayward et al., 2021).”
Background
SARS-CoV-2 infects human pluripotent stem cell-derived cardiomyocytes, impairing electrical and mechanical functionPreprint
Marchianò, S., Hsiang, T.-Y., Higashi, T., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.30.274464 · Cited by 19 · see citing works
Modeling Alcoholic Liver Disease in a Human Liver-ChipPreprint
Nawroth, J. C., Petrópolis, D. B., Manatakis, D. V., Maulana, T. I., Burchett, G., Schlünder, K., Witt, A., Shukla, A., Hamilton, G. A., Seki, E., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.07.14.203166 · Cited by 6 · see citing works
2D vs 3D – Triple negative breast cancer spheroid formation induces quantitative heterogeneity of VEGF and PDGF receptor profiles and modulates cytosolic phosphorylation
Oyirifi, A., Joyce, K. M., Helferich, W. G., & Imoukhuede, P. I. (2019) · The FASEB Journal · doi:10.1096/fasebj.2019.33.1_supplement.647.30 · Cited by 2 · cited 2× · see citing works
“By coupling multiple OOCs together through vascular perfusion of a shared blood substitute or supernatant exchange, one can study organ-organ interactions and systemic diseases such as cancer (Jeon et al., 2015; Oyirifi et al., 2019; Xu et al., 2016), inflammation (Lin et al.”
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[76]Si L, Bai H, Rodas M, Cao W, Oh CY, Jiang A, Nurani A, Zhu DY, Goyal G, Gilpin SE, (2020). Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics. bioRxiv, 2020.2004.2013.039917.

Sorted by citations

A guide to the organ-on-a-chip
Leung, C. M., de Haan, P., Ronaldson-Bouchard, K., Kim, G.-A., Ko, J., Rho, H. S., Chen, Z., Habibovic, P., Jeon, N. L., Takayama, S., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-022-00118-6 · Cited by 1,116 · see citing works
Self-citation
The role of goblet cells and mucus in intestinal homeostasis
Gustafsson, J. K., & Johansson, M. (2022) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-022-00675-x · Cited by 698 · see citing works
Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications
Cerneckis, J., Cai, H., & Shi, Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01809-0 · Cited by 452 · see citing works
“187 188 – 194 OoCs have separate compartments and are constantly perfused, enabling controlled tissue assembly, exposure to shear ﬂ uid forces, and separation of culture medium reservoirs.”
Background
Hepatic fibrosis 2022: Unmet needs and a blueprint for the future
Friedman, S. L., & Pinzani, M. (2022) · Hepatology · doi:10.1002/hep.32285 · Cited by 430 · see citing works
Phenotypic drug discovery: recent successes, lessons learned and new directions
Vincent, F., Nueda, A., Lee, J. L. C., Schenone, M., Prunotto, M., & Mercola, M. A. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00472-w · Cited by 372 · see citing works
Human disease models in drug development
Loewa, A., Feng, J. J., & Hedtrich, S. (2023) · Nature Reviews Bioengineering · doi:10.1038/s44222-023-00063-3 · Cited by 331 · see citing works
Organ-on-a-chip meets artificial intelligence in drug evaluation
Deng, S., Li, C., Cao, J., Cui, Z., Du, J., Fu, Z. H., Yang, H., & Chen, P. (2023) · Theranostics · doi:10.7150/thno.87266 · Cited by 272 · see citing works
“OoCs are now starting to attract AI, especially the machine learning (ML) and deep learning (DL) approaches to experimental design and data interpretation [57].”
Background
Integrating organoids and organ-on-a-chip devices
Zhao, Y., Landau, S., Okhovatian, S., Liu, C., Lu, R. X. Z., Lai, B. F. L., Wu, Q., Kieda, J., Cheung, K., Rajasekar, S., et al. (2024) · Nature Reviews Bioengineering · doi:10.1038/s44222-024-00207-z · Cited by 206 · see citing works
“Other biofabrication approaches have demonstrated vascular lumens with cell infiltration 173,174,178 , including those from commercial sources, such as Nortis, Emulate, Aracari, AIM Biotech or Mimetas 8,180 .”
InfluentialSelf-citation
Challenges and opportunities for the next generation of cardiovascular tissue engineering
Cho, S., Discher, D. E., Leong, K. W., Vunjak-Novakovic, G., & Wu, J. C. (2022) · Nature Methods · doi:10.1038/s41592-022-01591-3 · Cited by 176 · see citing works
Self-citation
Polymer-based responsive structural color materials
Wang, H., Zhang, H., Chen, Z., Zhao, Y., Gu, Z., & Shang, L. (2023) · Progress in Materials Science · doi:10.1016/j.pmatsci.2023.101091 · Cited by 139 · see citing works
The Discovery of Extracellular Vesicles and Their Emergence as a Next-Generation Therapy
Rai, A., Claridge, B., Lozano, J., & Greening, D. W. (2024) · Circulation Research · doi:10.1161/circresaha.123.323054 · Cited by 135 · see citing works
The neurovascular unit and systemic biology in stroke — implications for translation and treatment
Tiedt, S., Buchan, A. M., Dichgans, M., Lizasoaín, I., Moro, M. Á., & Lo, E. H. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00703-z · Cited by 132 · see citing works
3D bioprinting of collagen-based high-resolution internally perfusable scaffolds for engineering fully biologic tissue systems
Shiwarski, D. J., Hudson, A. R., Tashman, J. W., Bakırcı, E., Moss, S., Coffin, B. D., & Feinberg, A. W. (2025) · Science Advances · doi:10.1126/sciadv.adu5905 · Cited by 120 · see citing works
“These microphysiological systems have proved to be useful platforms for studying vasculogenesis and angiogenesis, as well as modeling human diseases and pharmaceutical responses that cannot be studied in patients ( 7 ).”
Microfluidic high-throughput 3D cell culture
Ko, J., Park, D., Lee, J., Jung, S., Baek, K., Sung, K. E., Lee, J., & Jeon, N. L. (2024) · Nature Reviews Bioengineering · doi:10.1038/s44222-024-00163-8 · Cited by 88 · see citing works
Organoids and organs-on-chips: insights into predicting the efficacy of systemic treatment in colorectal cancer
Zhu, J., Ji, L., Chen, Y., Li, H., Huang, M., Dai, Z., Wang, J., Xiang, D., Fu, G., Lei, Z., et al. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01354-9 · Cited by 87 · see citing works
“The dynamic study of microenvironment, the reduction of using animal models, novel drug development, drug efficacy, and toxicity assessment are all areas of applied research in organ chips technology that are currently in full swing [63].”
Background
Stem cell-derived intestinal organoids: a novel modality for IBD
Tian, C., Yang, M., Xu, H., Zhu, M., Yue, N.-N., Zhang, Y., Shi, R., Yao, J., Wang, L., Liang, Y.-J., et al. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01556-1 · Cited by 85 · see citing works
Synovial joint-on-a-chip for modeling arthritis: progress, pitfalls, and potential
Li, Z. A., Sant, S., Cho, S. K., Goodman, S. B., Bunnell, B. A., Tuan, R. S., Gold, M. S., & Lin, H. (2022) · Trends in biotechnology · doi:10.1016/j.tibtech.2022.07.011 · Cited by 78 · see citing works
Modeling early pathophysiological phenotypes of diabetic retinopathy in a human inner blood-retinal barrier-on-a-chip
Maurissen, T. L., Spielmann, A. J., Schellenberg, G., Bickle, M., Vieira, J. R., Lai, S. Y., Pavlou, G., Fauser, S., Westenskow, P. D., Kamm, R. D., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45456-z · Cited by 73 · see citing works
“Bioengineered human model systems closely mimic the physiological organization and function of native tissues, enabling researchers to investigate disease mechanisms and response to treatments 3 .”
Microfluidics meets 3D cancer cell migration
Mehta, P., Rahman, Z., ten Dijke, P., & Boukany, P. E. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.03.006 · Cited by 72 · see citing works
Electroconductive and Anisotropic Structural Color Hydrogels for Visual Heart‐on‐a‐Chip Construction
Sun, L., Chen, Z., Xu, D., & Zhao, Y. (2022) · Advanced Science · doi:10.1002/advs.202105777 · Cited by 68 · see citing works
Advances in organ-on-a-chip systems for modelling joint tissue and osteoarthritic diseases
Banh, L., Cheung, K. K., Chan, M. W. Y., Young, E. W. K., & Viswanathan, S. (2022) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2022.03.012 · Cited by 69 · see citing works
Patient‐derived cancer organoids for drug screening: Basic technology and clinical application
Ren, X., Chen, W., Yang, Q., Li, X., & Xu, L. (2022) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.15930 · Cited by 69 · see citing works
Roadblocks confronting widespread dissemination and deployment of Organs on Chips
Alver, C. G., Drabbe, E., Ishahak, M., & Agarwal, A. (2024) · Nature Communications · doi:10.1038/s41467-024-48864-3 · Cited by 74 · see citing works
“While traditional 2D culture methods have served the scienti ﬁ c community well over the past century, the development of Organ on Chip devices has improved the ability to culture more complex 3D engineered and ex-vivo tissues 1 – 6 .”
Approaching Two Decades: Biomolecular Coronas and Bio–Nano Interactions
Li, S., Cortez‐Jugo, C., Ju, Y., & Caruso, F. (2024) · ACS Nano · doi:10.1021/acsnano.4c13214 · Cited by 64 · see citing works
Standardizing designed and emergent quantitative features in microphysiological systems
Nahon, D. M., Moerkens, R., Aydoğmuş, H., Lendemeijer, B., Martínez-Silgado, A., Stein, J. M., Dostanić, M., Frimat, J., Gontan, C., de Graaf, M. N. S., et al. (2024) · Nature Biomedical Engineering · doi:10.1038/s41551-024-01236-0 · Cited by 62 · see citing works
“The first examples of how these advanced model systems can impact toxicological, pharmaceutical and biomedical science are beginning to emerge 1,2 .”
Modeling Heart Diseases on a Chip: Advantages and Future Opportunities
Mourad, O., Yee, R., Li, M., & Nunes, S. S. (2023) · Circulation Research · doi:10.1161/circresaha.122.321670 · Cited by 60 · see citing works
Glioblastoma-on-a-chip construction and therapeutic applications
Xie, Z., Chen, M., Lian, J., Wang, H., & Ma, J. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1183059 · Cited by 59 · see citing works
The tendon microenvironment: Engineered in vitro models to study cellular crosstalk
Gómez‐Florit, M., Labrador‐Rached, C. J., Domingues, R. M. A., & Gomes, M. E. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114299 · Cited by 52 · see citing works
A photonic biosensor-integrated tissue chip platform for real-time sensing of lung epithelial inflammatory markers
Cognetti, J. S., Moen, M. T., Brewer, M. G., Bryan, M. R., Tice, J. D., McGrath, J. L., & Miller, B. L. (2022) · Lab on a Chip · doi:10.1039/d2lc00864e · Cited by 52 · see citing works
From organoids to organoids-on-a-chip: Current applications and challenges in biomedical research
Liu, K., Chen, X., Fan, Z., Ren, F., Liu, J., & Hu, B. (2025) · Chinese Medical Journal · doi:10.1097/cm9.0000000000003535 · Cited by 56 · see citing works
“[3,54] [71,135,136] Modeling development of specific brain regions, cortical layering, early neurogenesis, synapse formation, and spontaneous electrical activity Size limit due to oxygen and nutrient diffusion constraints; lack of microvascular differentiation; absence of microglial cells; can not…”
Magnetically driven formation of 3D freestanding soft bioscaffolds
Xie, R., Cao, Y., Sun, R., Wang, R., Morgan, A., Kim, J., Callens, S. J. P., Xie, K., Zou, J., Lin, J., et al. (2024) · Science Advances · doi:10.1126/sciadv.adl1549 · Cited by 46 · see citing works
Recent Advances in Generation of In Vitro Cardiac Organoids
Sahara, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076244 · Cited by 47 · see citing works
“In regards to topics of other in vitro 3D culture models, including various EHT models [16,26], a microfluidics/heart-on-a-chip [27,28], bioprinting [29,30], and electrospinning [31,32], the author asks readers to refer to the suggested reviews, respectively.”
Background
ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription
Gorodetska, I., Offermann, A., Püschel, J., Lukiyanchuk, V., Gaete, D., Kurzyukova, A., Freytag, V., Haider, M., Fjeldbo, C. S., Gaetano, S. D., et al. (2024) · Theranostics · doi:10.7150/thno.88057 · Cited by 46 · see citing works
“Employing patient-derived ex vivo models such as organs-on-a-chip providing physiologically relevant microenvironment [92] could be an alternative approach to further validate these findings.”
Result
Harnessing the power of artificial intelligence for human living organoid research
Wang, H., Li, X., You, X., & Zhao, G. (2024) · Bioactive Materials · doi:10.1016/j.bioactmat.2024.08.027 · Cited by 43 · see citing works
“It can in vitro partially replicate organ-specific structures (e.g., villi, gas-liquid interface, blood vessel, and neural networks, etc) and realize key functions (e. g., blood-brain barrier, rhythmic respiration, peristalsis, and angiogenesis, etc) [72 – 74].”
Background
Engineering complexity in human tissue models of cancer
Ronaldson-Bouchard, K., Baldassarri, I., Tavakol, D. N., Graney, P. L., Samaritano, M., Cimetta, E., & Vunjak‐Novakovic, G. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114181 · Cited by 41 · see citing works
“and OOC models is to provide biological complexity while keeping the models user-friendly [59,75].”
BackgroundSelf-citation
Strengthening cardiac therapy pipelines using human pluripotent stem cell-derived cardiomyocytes
Raniga, K., Nasir, A., Vo, N. T. N., Vaidyanathan, R., Dickerson, S., Hilcove, S. A., Mosqueira, D., Mirams, G. R., Clements, P., Hicks, R., et al. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.01.007 · Cited by 38 · see citing works
What Can an Organ-on-a-Chip Teach Us About Human Lung Pathophysiology?
Bai, H., & Ingber, D. E. (2022) · Physiology · doi:10.1152/physiol.00012.2022 · Cited by 39 · see citing works
Analysis of drug efficacy for inflammatory skin on an organ-chip system
Quan, Q., Weng, D., Li, X., An, Q., Yang, Y., Yu, B., Ma, Y., & Wang, J. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.939629 · Cited by 37 · see citing works
“In recent years, with the help of organ-on-chip technologies, researchers can design amicroenvironment close to physiological conditions to obtain more complete organ structure and mature tissue function in vitro (Trietsch et al., 2017; Vunjak-Novakovic et al., 2021).”
Background
Innate immune cell response to host-parasite interaction in a human intestinal tissue microphysiological system
Humayun, M., Ayuso, J. M., Park, K. Y., Genova, B. M. D., Skala, M. C., Kerr, S. C., Knoll, L. J., & Beebe, D. J. (2022) · Science Advances · doi:10.1126/sciadv.abm8012 · Cited by 34 · see citing works
Perspectives on organ-on-a-chip technology for natural products evaluation
Wang, X., Miao, Y., Zhao, X.-M., Liu, X., Hu, Y.-W., & Deng, D. (2024) · Food & medicine homology. · doi:10.26599/fmh.2024.9420013 · Cited by 36 · see citing works
Generative AI: driving productivity and scientific breakthroughs in pharmaceutical R&D
Doron, G., Genway, S., Roberts, M., & Jasti, S. (2024) · Drug Discovery Today · doi:10.1016/j.drudis.2024.104272 · Cited by 36 · see citing works
Heart-on-a-chip using human iPSC-derived cardiomyocytes with an integrated vascular endothelial layer based on a culture patch as a potential platform for drug evaluation
Tang, Y., Tian, F., Miao, X., Wu, D., Wang, Y., Wang, H., You, K., Li, Q., Zhao, S., & Wang, W. (2022) · Biofabrication · doi:10.1088/1758-5090/ac975d · Cited by 35 · see citing works
“Recent advancements in the development of stem-cell technology, especially the flourishing human-induced pluripotent stem cell (hiPSC), enable us to overcome species differences and allow human cardiomyocytes (CMs) to be abundantly available via the differentiation of hiPSCs for the construction of in vitro human card…”
Advancing Intelligent Organ‐on‐a‐Chip Systems with Comprehensive In Situ Bioanalysis
Li, X., Zhu, H. J., Gu, B., Yao, C., Gu, Y., Xu, W., Zhang, J., He, J., Liu, X., & Li, D. (2023) · Advanced Materials · doi:10.1002/adma.202305268 · Cited by 37 · see citing works
Emerging microfluidics-enabled platforms for osteoarthritis management: from benchtop to bedside
Zou, Z., Luo, X., Chen, Z., Zhang, Y. S., & Wen, C. (2021) · Theranostics · doi:10.7150/thno.62685 · Cited by 33 · see citing works
“An OOC device is a microfluidics-based 3D cell culture platform that mimics the essential functional aspects of specific organs or tissues [40-44].”
Background
Engineering Cardiac Tissue for Advanced Heart‐On‐A‐Chip Platforms
Chen, X., Liu, S., Han, M., Long, M., Li, T., Hu, L., Wang, L., Huang, W., & Wu, Y. (2023) · Advanced Healthcare Materials · doi:10.1002/adhm.202301338 · Cited by 35 · see citing works
In situ biosensing technologies for an organ-on-a-chip
Kim, J., Kim, J., Jin, Y., & Cho, S. (2023) · Biofabrication · doi:10.1088/1758-5090/aceaae · Cited by 34 · see citing works
“Multi-organs-on-chips allow the monitoring of the potential interaction between organs, as well as the systemic modeling of diseases, by availing cross-organ communication [7, 26, 27].”
Rapid Prototyping of Organ-on-a-Chip Devices Using Maskless Photolithography
Kasi, D. G., de Graaf, M. N. S., Motreuil-Ragot, P., Frimat, J., Ferrari, M. D., Sarro, P. M., Mastrangeli, M., van den Maagdenberg, A. M. J. M., Mummery, C. L., & Orlova, V. V. (2021) · Micromachines · doi:10.3390/mi13010049 · Cited by 32 · see citing works
Progress in Bioengineering Strategies for Heart Regenerative Medicine
Häneke, T., & Sahara, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073482 · Cited by 32 · see citing works
The Modular µSiM: A Mass Produced, Rapidly Assembled, and Reconfigurable Platform for the Study of Barrier Tissue Models In Vitro
McCloskey, M. C., Kasap, P., Ahmad, S. D., Su, S., Chen, K., Mansouri, M., Ramesh, N., Nishihara, H., Belyaev, Y., Abhyankar, V. V., et al. (2022) · Advanced Healthcare Materials · doi:10.1002/adhm.202200804 · Cited by 35 · see citing works
Modeling the Effects of Protracted Cosmic Radiation in a Human Organ‐on‐Chip Platform
Tavakol, D. N., Nash, T. R., Kim, Y., Graney, P. L., Liberman, M., Fleischer, S., Lock, R. I., O'Donnell, A., Andrews, L., Ning, D., et al. (2024) · Advanced Science · doi:10.1002/advs.202401415 · Cited by 30 · see citing works
Self-citation
An update on microfluidic multi-organ-on-a-chip systems for reproducing drug pharmacokinetics: the current state-of-the-art
Martinez, M. G. V., Frauenlob, M., & Rothbauer, M. (2024) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2024.2362183 · Cited by 31 · see citing works
“Notably, as a variety of reviews have already focused on general developments of the last decade in the field [35–39] we only included reports from the last three years of biochip advances that in our opinion noteworthy instances due to their chip manufacturing and perfusion approaches, in order to…”
Background
Fabrication of organ-on-a-chip using microfluidics
Ying-Jin, S., Yuste, I., González‐Burgos, E., & Serrano, D. R. (2025) · Bioprinting · doi:10.1016/j.bprint.2025.e00394 · Cited by 28 · see citing works
Organoids as models of immune-organ interaction
Harter, M. F., Recaldin, T., & Gjorevski, N. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116214 · Cited by 31 · see citing works
Alternative experimental approaches to reduce animal use in biomedical studies
Lee, S. Y., Lee, D. Y., Kang, J. H., Jeong, J. W., Kim, J. H., Kim, H. W., Oh, D. H., Kim, J., Rhim, S., Kim, G., et al. (2022) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2022.103131 · Cited by 30 · see citing works
Engineered Human Organoids for Biomedical Applications
Zhu, Y., Sun, L., Wu, X., Gu, Z., & Zhao, Y. (2023) · Advanced Functional Materials · doi:10.1002/adfm.202310961 · Cited by 27 · see citing works
Mimicking Tumor Metastasis Using a Transwell‐Integrated Organoids‐On‐a‐Chip Platform
Chen, M., Han, S., Tao, Q., Hu, R., Sun, Q., Zheng, M., Chen, Z., Lin, Q., Yin, M., Zhao, S., et al. (2024) · Small · doi:10.1002/smll.202308525 · Cited by 25 · see citing works
Challenges in validation of combination treatment strategies for CRC using patient-derived organoids
Benboubker, V., Ramzy, G. M., Jacobs, S., & Nowak-Sliwinska, P. M. (2024) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-024-03173-x · Cited by 28 · see citing works
“The engineering behind organoid on-chip models is challenging and still need improvement for standardization of the method for robust reproducibility but it unlocks new avenues of research by using models that are closer to in vivo [96].”
Method
Advances in humanoid organoid-based research on inter-organ communications during cardiac organogenesis and cardiovascular diseases
Ni, B., Ye, L., Zhang, Y., Hu, S., & Lei, W. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06381-x · Cited by 25 · see citing works
“Humanoid organoid models facilitate macroscopic and microscopic analyses of intercellular crosstalk, resulting in multi-organ models that effectively simulate complex tissue-tissue and inter-organ communications, making them suitable for organ development, toxicity, and efficacy [41].”
Microfluidic-based human prostate-cancer-on-chip
Jiang, L., Khawaja, H., Tahsin, S., Clarkson, T. A., Miranti, C. K., & Zohar, Y. (2024) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2024.1302223 · Cited by 26 · see citing works
A generic pump‐free organ‐on‐a‐chip platform for assessment of intestinal drug absorption
Guo, Y., Xie, Y., & Qin, J. (2024) · Biotechnology Journal · doi:10.1002/biot.202300390 · Cited by 23 · see citing works
Membrane-based microfluidic systems for medical and biological applications
Calzuola, S. T., Newman, G., Feaugas, T., Perrault, C. M., Blondé, J.-B., Roy, E., Porrini, C., Stojanović, G. M., & Vidić, J. (2024) · Lab on a Chip · doi:10.1039/d4lc00251b · Cited by 22 · see citing works
An engineered model of metastatic colonization of human bone marrow reveals breast cancer cell remodeling of the hematopoietic niche
Baldassarri, I., Tavakol, D. N., Graney, P. L., Chramiec, A. G., Hibshoosh, H. H., & Vunjak‐Novakovic, G. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2405257121 · Cited by 23 · see citing works
“The complexity of an OOC is dictated by the proposed research question, with flexibility to enable the deconstruction of microenvironmental and cellular contributions to cancer progression ( 16 , 17 , 20 , 21 , 27 ).”
Self-citation
Artificial intelligence-, organoid-, and organ-on-chip-powered models to improve pre-clinical animal testing of vaccines and immunotherapeutics: potential, progress, and challenges
Elfatimi, E., Lekbach, Y., Prakash, S., Karan, S., Dorotta, J. C., Garcia, A., Suoth, B. S., Maurya, C., Omorogieva, E., Ng, S. X. L., et al. (2025) · Frontiers in Artificial Intelligence · doi:10.3389/frai.2025.1681106 · Cited by 25 · see citing works
Three-Dimensional Human Bone Marrow Organoids for the Study and Application of Normal and Abnormal Hematoimmunopoiesis
de Janon, A., Mantalaris, A., & Panoskaltsis, N. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2200836 · Cited by 25 · see citing works
Boosting the Clinical Translation of Organ-on-a-Chip Technology
Caballero, D., Reis, R. L., & Kundu, S. C. (2022) · Bioengineering · doi:10.3390/bioengineering9100549 · Cited by 23 · see citing works
“To promote its adoption by the clinic as a regular screening tool, academic and industrial developers must adapt this technology to clinical practitioners to perform more efficient, simpler, reliable, robust and rapid diagnostic/screening tests, enhancing their compatibility with current medical technologies [66].”
Method
Modeling and countering the effects of cosmic radiation using bioengineered human tissues
Tavakol, D. N., Nash, T. R., Kim, Y., He, S., Fleischer, S., Graney, P. L., Brown, J. A., Liberman, M., Tamargo, M. A., Harken, A. D., et al. (2023) · Biomaterials · doi:10.1016/j.biomaterials.2023.122267 · Cited by 23 · see citing works
Self-citation
Developing 3D bioprinting for organs-on-chips
Wu, Z., Liu, R., Shao, N., & Zhao, Y. (2025) · Lab on a Chip · doi:10.1039/d4lc00769g · Cited by 23 · see citing works
Toward continuous monitoring systems: emerging trends of on-chip sensors in organ-on-a-chip
Ling, S., Xu, C., Jiang, Y., Xu, F., Jin, H., Chen, H. H., Chen, S., Ding, Z., & Sun, D. (2026) · Microsystems & Nanoengineering · doi:10.1038/s41378-025-01142-8 · Cited by 24 · see citing works
“Its emergence represents a transformative advancement in biomedical research, with profound signi ﬁ cance for multiple domains, spanning basic life science, preclinical drug development, and personalized medicine 2 .”
Endodontic Tissue Regeneration: A Review for Tissue Engineers and Dentists
Astudillo-Ortiz, E., Babo, P., Sunde, P. T., Galler, K., Gómez-Florit, M., & Gomes, M. (2023) · Tissue engineering. Part B, Reviews · doi:10.1089/ten.teb.2022.0211 · Cited by 15 · see citing works
“209 Among these, the dentin–pulp interface has been recreated with a design comprising two microﬂuidic channels separated by a dentin fragment.”
Progress of organoid platform in cardiovascular research
Du, X., Jia, H., Chang, Y., Zhao, Y., & Song, J. (2024) · Bioactive Materials · doi:10.1016/j.bioactmat.2024.05.043 · Cited by 21 · see citing works
“…through vascular perfusion to influence each tissue (increasing its fidelity by cell continuation in a tissue-like environment in the body) as well as the entire multi-organ model (by providing system components such as metabolism, immunity, and clearing needed for physiological studies) [194].”
Background
Multiorgan microphysiological systems as tools to interrogate interorgan crosstalk and complex diseases
Trapečar, M. (2021) · FEBS Letters · doi:10.1002/1873-3468.14260 · Cited by 21 · see citing works
Using Microphysiological System for the Development of Treatments for Joint Inflammation and Associated Cartilage Loss—A Pilot Study
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Method
Trends in organ-on-a-chip for pharmacological analysis
Xu, X., Cheung, S., Jia, X., Fan, G., Ai, Y., Zhang, Y., & Liang, Q. (2024) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2024.117905 · Cited by 20 · see citing works
From “organs on a chip” to “patient on a chip”
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Background
Reagent‐Free Covalent Immobilization of Biomolecules in a Microfluidic Organ‐On‐A‐Chip
Ashok, D., Singh, J., Jiang, S., Waterhouse, A., & Bilek, M. (2024) · Advanced Functional Materials · doi:10.1002/adfm.202313664 · Cited by 19 · see citing works
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Microphysiological Neurovascular Barriers to Model the Inner Retinal Microvasculature
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Background
The Modular µSiM Reconfigured: Integration of Microfluidic Capabilities to Study In Vitro Barrier Tissue Models under Flow
Mansouri, M., Ahmed, A., Ahmad, S. D., McCloskey, M. C., Joshi, I. M., Gaborski, T. R., Waugh, R. E., McGrath, J. L., Day, S. W., & Abhyankar, V. V. (2022) · Advanced Healthcare Materials · doi:10.1002/adhm.202200802 · Cited by 19 · see citing works
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A biomimetic renal fibrosis progression model on-chip evaluates anti-fibrotic effects longitudinally in a dynamic fibrogenic niche
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The Endothelium as a Hub for Cellular Communication in Atherogenesis: Is There Directionality to the Message?
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“In this way, we may need to move to organon-a-chip methods (143) to better elucidate the ideal endothelial communication strategy we wish to either boost or interrupt.”
Method
Biomimetic cell culture for cell adhesive propagation for tissue engineering strategies
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Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer
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Looking on the horizon; potential and unique approaches to developing radiation countermeasures for deep space travel
Bokhari, R. S., Beheshti, A., Blutt, S. E., Bowles, D. E., Brenner, D., Britton, R. A., Bronk, L. F., Cao, X., Chatterjee, A., Clay, D. E., et al. (2022) · Life Sciences in Space Research · doi:10.1016/j.lssr.2022.08.003 · Cited by 15 · see citing works
Self-citation
Advancement of organ-on-chip towards next generation medical technology
Singh, G., Mishra, A., Mathur, A. K., Shastri, S., Nizam, A., Rizwan, A., Dadial, A. S., Firdous, A., & Hassan, H. (2024) · Biosensors and Bioelectronics X · doi:10.1016/j.biosx.2024.100480 · Cited by 16 · see citing works
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Human induced pluripotent stem cell-derived cardiomyocytes and their use in a cardiac organ-on-a-chip to assay electrophysiology, calcium and contractility
Garcia, M. I., Dame, K., Charwat, V., Siemons, B. A., Finsberg, H. N. T., Bhardwaj, B., Yokosawa, R., Goswami, I., Bruckner, D., Wall, S., et al. (2025) · Nature Protocols · doi:10.1038/s41596-025-01166-4 · Cited by 14 · see citing works
Building Blood Vessel Chips with Enhanced Physiological Relevance
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Innovative engineering approaches to model host-microbiome interactions in vitro
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Background
A synoptic examination of commercially viable nanofiber-based products
Chaudhari, D. R., Vinod, R., Shah, D. P., Vaishnav, D. J., & Kapoor, D. U. (2024) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2024.106323 · Cited by 13 · see citing works
Rapid Prototyping of Thermoplastic Microfluidic 3D Cell Culture Devices by Creating Regional Hydrophilicity Discrepancy
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Organs-on-a-Chip
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Authors: Vunjak-Novakovic, G., Ronaldson-Bouchard, K., & Radisic, M.
Affiliations: Columbia University (US)
University of Toronto (CA)
ORCID: Ronaldson-Bouchard, Kacey
Radisic, Milica
Venue: Cell
Publisher: Elsevier BV
Published: 2021-09
Volume: 184
Issue: 18
Pages: 4597-4611
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2021.08.005
PMC: PMC8417425
OpenAlex: W3197954209
Cited by: 248
References: 110
Citations by year: 2026: 45 · 2025: 54 · 2024: 64 · 2023: 41 · 2022: 39 · 2021: 5
FWCI: 3.14
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 366 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Natural Sciences and Engineering Research Council of Canada (RGPIN 326982-10)
Canadian Institutes of Health Research (FDN-167274)
National Institutes of Health (UH3 EB025765, CA249799, P41 EB027062, 3R01 HL076485)
National Aeronautics and Space Administration (NNX16AO69A, CHRP 493737-16)
National Science Foundation (NSF16478)
Canada Research Chairs
NSF
Topics: Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Physical Sciences › Engineering › Biomedical Engineering › Microfluidic and Capillary Electrophoresis Applications
Keywords: organ-on-a-chip, organoids, tissue engineering, model validation
MeSH terms: Animals, Humans, Models, Biological, Research, Tissue Engineering, Lab-On-A-Chip Devices, Cellular Microenvironment, Cell Engineering

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