Applications of microphysiological systems to disease models in the biopharmaceutical industry: Opportunities and challenges

Main Article Content

Onyi Irrechukwu, Ronnie Yeager, Rhiannon David, Jason Ekert, Anitha Saravanakumar, Colin K. Choi
[show affiliations]


Disease models enable researchers to investigate, test, and identify therapeutic targets that would alter the patients’ disease condition and improve quality of life. Advances in genetic alteration and analytical techniques have enabled rapid devel­opment of disease models using preclinical animals and cell cultures. However, success rates of drug development remain low due to limited recapitulation of clinical pathophysiology by these models. To resolve this challenge, the pharmaceutical industry has explored microphysiological system (MPS) disease models, which are complex in vitro systems that include but are not limited to organ-on-a-chip, organoids, spheroids, and 3D bioengineered tissues (e.g., 3D printing, hydrogels). Capable of integrating key in vivo properties, such as disease-relevant human cells, multi-cellularity/dimensionality of organs, and/or well-controlled physical and molecular cues, MPS disease models are being developed for a variety of indications. With on-going qualifications or validations for wide adoption within the pharmaceutical industry, MPS disease models hold exciting potential to enable in-depth investigation of in vivo pathophysiology and enhance drug discovery and development processes. To introduce the present status of MPS disease models, this paper describes notable examples in six disease areas: cancer, liver/kidney diseases, respiratory diseases/COVID-19, neurodegenerative diseases, gastrointestinal diseases, and select rare diseases. Additionally, we describe current technical limitations and provide recommendations for future development that would expand application opportunities within the pharmaceutical industry.

Article Details

How to Cite
Irrechukwu, O. (2023) “Applications of microphysiological systems to disease models in the biopharmaceutical industry: Opportunities and challenges”, ALTEX - Alternatives to animal experimentation, 40(3), pp. 485–518. doi: 10.14573/altex.2204071.
Articles Special Issue

Agrawal, M., Ajazuddin, Tripathi, D. K. et al. (2017). Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer’s disease. J Control Release 260, 61-77. doi:10.1016/j.jconrel.2017.05.019

Ahn, S. I., Sei, Y. J., Park, H. J. et al. (2020). Microengineered human blood-brain barrier platform for understanding nanoparticle transport mechanisms. Nat Commun 11, 175. doi:10.1038/s41467-019-13896-7

Ainslie, G. R., Davis, M., Ewart, L. et al. (2019). Microphysiological lung models to evaluate the safety of new pharmaceutical modalities: A biopharmaceutical perspective. Lab Chip 19, 3152-3161. doi:10.1039/c9lc00492k

Ananthanarayanan, A., Nugraha, B., Triyatni, M. et al. (2014). Scalable spheroid model of human hepatocytes for hepatitis C infection and replication. Mol Pharm 11, 2106-2114. doi:10.1021/mp500063y

Anderson, R. M., Hadjichrysanthou, C., Evans, S. et al. (2017). Why do so many clinical trials of therapies for Alzheimer’s disease fail? Lancet 390, 2327-2329. doi:10.1016/s0140-6736(17)32399-1

Andorfer, C., Acker, C. M., Kress, Y. et al. (2005). Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 25, 5446-5454. doi:10.1523/JNEUROSCI.4637-04.2005

Arian, C. M., Imaoka, T., Yang, J. et al. (2022). Gutsy science: In vitro systems of the human intestine to model oral drug disposition. Pharmacol Ther 230, 107962. doi:10.1016/j.pharmthera.2021.107962

Arrowsmith, J. and Miller, P. (2013). Trial watch: Phase II and phase III attrition rates 2011-2012. Nat Rev Drug Discov 12, 569. doi:10.1038/nrd4090

Astashkina, A. I., Mann, B. K., Prestwich, G. D. et al. (2012). A 3-D organoid kidney culture model engineered for high-throughput nephrotoxicity assays. Biomaterials 33, 4700-4711. doi:10.1016/j.biomaterials.2012.02.063

Atchison, L., Zhang, H., Cao, K. et al. (2017). A tissue engineered blood vessel model of Hutchinson-Gilford progeria syndrome using human iPSC-derived smooth muscle cells. Sci Rep 7, 8168. doi:10.1038/s41598-017-08632-4

Ausems, M. G., Verbiest, J., Hermans, M. P. et al. (1999). Frequency of glycogen storage disease type II in the Netherlands: Implications for diagnosis and genetic counselling. Eur J Hum Genet 7, 713-716. doi:10.1038/sj.ejhg.5200367

Austin, C. P. (2010). NIH translational research for rare diseases and orphan products: NCGC and TRND. Presentation to the IOM Committee on Accelerating Rare Diseases Research and Orphan Product Development. Washington, DC.

Avila, A. M., Bebenek, I., Bonzo, J. A. et al. (2020). An FDA/CDER perspective on nonclinical testing strategies: Classical toxicology approaches and new approach methodologies (NAMs). Regul Toxicol Pharmacol 114, 104662. doi:10.1016/j.yrtph.2020.104662

Bai, H., Si, L., Jiang, A. et al. (2022). Mechanical control of innate immune responses against viral infection revealed in a human lung alveolus chip. Nat Commun 13, 1928. doi:10.1038/s41467-022-29562-4

Bailey, J., Thew, M. and Balls, M. (2015). Predicting human drug toxicity and safety via animal tests: Can any one species predict drug toxicity in any other, and do monkeys help? Altern Lab Anim 43, 393-403. doi:10.1177/026119291504300607

Baran, S. W., Brown, P. C., Baudy, A. R. et al. (2022). Perspectives on the evaluation and adoption of complex in vitro models in drug development: Workshop with the FDA and the pharmaceutical industry (IQ MPS affiliate). ALTEX 39, 297-314. doi:10.14573/altex.2112203

Barkal, L. J., Procknow, C. L., Alvarez-Garcia, Y. R. et al. (2017). Microbial volatile communication in human organotypic lung models. Nat Commun 8, 1770. doi:10.1038/s41467-017-01985-4

Baudy, A. R., Otieno, M. A., Hewitt, P. et al. (2020). Liver microphysiological systems development guidelines for safety risk assessment in the pharmaceutical industry. Lab Chip 20, 215-225. doi:10.1039/c9lc00768g

Beal, M. F. (2010). Parkinson’s disease: A model dilemma. Nature 466, S8-10. doi:10.1038/466S8a

Beck, J. N., Singh, A., Rothenberg, A. R. et al. (2013). The independent roles of mechanical, structural and adhesion characteristics of 3D hydrogels on the regulation of cancer invasion and dissemination. Biomaterials 34, 9486-9495. doi:10.1016/j.biomaterials.2013.08.077

Benam, K. H., Dauth, S., Hassell, B. et al. (2015). Engineered in vitro disease models. Annu Rev Pathol 10, 195-262. doi:10.1146/annurev-pathol-012414-040418

Benam, K. H., Villenave, R., Lucchesi, C. et al. (2016). Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro. Nat Methods 13, 151-157. doi:10.1038/nmeth.3697

Benam, K. H., Denney, L. and Ho, L. P. (2019). How the respiratory epithelium senses and reacts to influenza virus. Am J Respir Cell Mol Biol 60, 259-268. doi:10.1165/rcmb.2018-0247TR

Berg, H. F., Hjelmeland, M. E., Lien, H. et al. (2021). Patient-derived organoids reflect the genetic profile of endometrial tumors and predict patient prognosis. Commun Med (Lond) 1, 20. doi:10.1038/s43856-021-00019-x

Bersini, S., Jeon, J. S., Dubini, G. et al. (2014). A microfluidic 3D in vitro model for specificity of breast cancer metastasis to bone. Biomaterials 35, 2454-2461. doi:10.1016/j.biomaterials.2013.11.050

Birey, F., Andersen, J., Makinson, C. D. et al. (2017). Assembly of functionally integrated human forebrain spheroids. Nature 545, 54-59. doi:10.1038/nature22330

Birgersdotter, A., Sandberg, R. and Ernberg, I. (2005). Gene expression perturbation in vitro – A growing case for three-dimensional (3D) culture systems. Semin Cancer Biol 15, 405-412. doi:10.1016/j.semcancer.2005.06.009

Bleijs, M., Van de Wetering, M., Clevers, H. et al. (2019). Xenograft and organoid model systems in cancer research. EMBO J 38, e101654. doi:10.15252/embj.2019101654

Blesa, J. and Przedborski, S. (2014). Parkinson’s disease: Animal models and dopaminergic cell vulnerability. Front Neuroanat 8, 155. doi:10.3389/fnana.2014.00155

Blomme, E. A. and Will, Y. (2016). Toxicology strategies for drug discovery: Present and future. Chem Res Toxicol 29, 473-504. doi:10.1021/acs.chemrestox.5b00407

Blume, C., Reale, R., Held, M. et al. (2017). Cellular crosstalk between airway epithelial and endothelial cells regulates barrier functions during exposure to double-stranded RNA. Immun Inflamm Dis 5, 45-56. doi:10.1002/iid3.139

Blutt, S. E., Broughman, J. R., Zou, W. et al. (2017). Gastrointestinal microphysiological systems. Exp Biol Med (Maywood) 242, 1633-1642. doi:10.1177/1535370217710638

Bolognin, S., Fossepre, M., Qing, X. et al. (2019). 3D cultures of Parkinson’s disease-specific dopaminergic neurons for high content phenotyping and drug testing. Adv Sci (Weinh) 6, 1800927. doi:10.1002/advs.201800927

Bousquet, J. and Meunier, J. M. (1962). Organotypic culture, on natural and artificial media, of fragments of the adult rat hypophysis [Article in French]. C R Seances Soc Biol Fil 156, 65-67.

Bregenzer, M. E., Horst, E. N., Mehta, P. et al. (2019). Integrated cancer tissue engineering models for precision medicine. PLoS One 14, e0216564. doi:10.1371/journal.pone.0216564

Burniston, J. G., Clark, W. A., Tan, L. B. et al. (2006). Dose-dependent separation of the hypertrophic and myotoxic effects of the β2-adrenergic receptor agonist clenbuterol in rat striated muscles. Muscle Nerve 33, 655-663. doi:10.1002/mus.20504

Bussani, R., Schneider, E., Zentilin, L. et al. (2020). Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of advanced covid-19 pathology. EBioMedicine 61, 103104. doi:10.1016/j.ebiom.2020.103104

Carvalho, M. P., Costa, E. C., Miguel, S. P. et al. (2016). Tumor spheroid assembly on hyaluronic acid-based structures: A review. Carbohydr Polym 150, 139-148. doi:10.1016/j.carbpol.2016.05.005

Carvalho, M. R., Barata, D., Teixeira, L. M. et al. (2019). Colorectal tumor-on-a-chip system: A 3D tool for precision onco-nanomedicine. Sci Adv 5, eaaw1317. doi:10.1126/sciadv.aaw1317

Chang, S. S., Tu, S., Baek, K. I. et al. (2017). Optimal occlusion uniformly partitions red blood cells fluxes within a microvascular network. PLoS Comput Biol 13, e1005892. doi:10.1371/journal.pcbi.1005892

Chen, J., Deng, X., Liu, Y. et al. (2020). Kupffer cells in non-alcoholic fatty liver disease: Friend or foe? Int J Biol Sci 16, 2367-2378. doi:10.7150/ijbs.47143

Chen, Y. W., Huang, S. X., de Carvalho, A. et al. (2017). A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat Cell Biol 19, 542-549. doi:10.1038/ncb3510

Chlebanowska, P., Tejchman, A., Sulkowski, M. et al. (2020). Use of 3D organoids as a model to study idiopathic form of Parkinson’s disease. Int J Mol Sci 21, 694. doi:10.3390/ijms21030694

Cho, N. J., Elazar, M., Xiong, A. et al. (2009). Viral infection of human progenitor and liver-derived cells encapsulated in three-dimensional peg-based hydrogel. Biomed Mater 4, 011001. doi:10.1088/1748-6041/25/1/011001

Choi, S. H., Kim, Y. H., Hebisch, M. et al. (2014). A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515, 274-278. doi:10.1038/nature13800

Choi, Y. J., Chae, S., Kim, J. H. et al. (2013a). Neurotoxic amyloid beta oligomeric assemblies recreated in microfluidic platform with interstitial level of slow flow. Sci Rep 3, 1921. doi:10.1038/srep01921

Choi, Y. J., Park, J. and Lee, S. H. (2013b). Size-controllable networked neurospheres as a 3D neuronal tissue model for Alzheimer’s disease studies. Biomaterials 34, 2938-2946. doi:10.1016/j.biomaterials.2013.01.038

Choucha Snouber, L., Jacques, S., Monge, M. et al. (2012). Transcriptomic analysis of the effect of ifosfamide on MDCK cells cultivated in microfluidic biochips. Genomics 100, 27-34. doi:10.1016/j.ygeno.2012.05.001

Choucha-Snouber, L., Aninat, C., Grsicom, L. et al. (2013). Investigation of ifosfamide nephrotoxicity induced in a liver-kidney co-culture biochip. Biotechnol Bioeng 110, 597-608. doi:10.1002/bit.24707

Chowdury, M. A., Heileman, K. L., Moore, T. A. et al. (2019). Biomicrofluidic systems for hematologic cancer research and clinical applications. SLAS Technol 24, 457-476. doi:10.1177/2472630319846878

Chramiec, A., Teles, D., Yeager, K. et al. (2020). Integrated human organ-on-a-chip model for predictive studies of anti-tumor drug efficacy and cardiac safety. Lab Chip 20, 4357-4372. doi:10.1039/d0lc00424c

Clark, M. and Steger-Hartmann, T. (2018). A big data approach to the concordance of the toxicity of pharmaceuticals in animals and humans. Regul Toxicol Pharmacol 96, 94-105. doi:10.1016/j.yrtph.2018.04.018

Cleary, S. J., Pitchford, S. C., Amison, R. T. et al. (2020). Animal models of mechanisms of SARS-CoV-2 infection and COVID-19 pathology. Br J Pharmacol 177, 4851-4865. doi:10.1111/bph.15143

Compston, A. and Coles, A. (2008). Multiple sclerosis. Lancet 372, 1502-1517. doi:10.1016/S0140-6736(08)61620-7

Costa, J. and Ahluwalia, A. (2019). Advances and current challenges in intestinal in vitro model engineering: A digest. Front Bioeng Biotechnol 7, 144. doi:10.3389/fbioe.2019.00144

Croft, C. L., Futch, H. S., Moore, B. D. et al. (2019). Organotypic brain slice cultures to model neurodegenerative proteinopathies. Molecular Neurodegeneration 14, 45. doi:10.1186/s13024-019-0346-0

Cruz, N. M., Song, X., Czerniecki, S. M. et al. (2017). Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease. Nat Mater 16, 1112-1119. doi:10.1038/nmat4994

Cui, X., Morales, R. T., Qian, W. et al. (2018). Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis. Biomaterials 161, 164-178. doi:10.1016/j.biomaterials.2018.01.053

Dagogo-Jack, I. and Shaw, A. T. (2018). Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol 15, 81-94. doi:10.1038/nrclinonc.2017.166

Davidson, M. D., Lehrer, M. and Khetani, S. R. (2015). Hormone and drug-mediated modulation of glucose metabolism in a microscale model of the human liver. Tissue Eng Part C Methods 21, 716-725. doi:10.1089/ten.TEC.2014.0512

Dawson, T. M., Golde, T. E. and Lagier-Tourenne, C. (2018). Animal models of neurodegenerative diseases. Nat Neurosci 21, 1370-1379. doi:10.1038/s41593-018-0236-8

DesRochers, T. M., Suter, L., Roth, A. et al. (2013). Bioengineered 3D human kidney tissue, a platform for the determination of nephrotoxicity. PLoS One 8, e59219. doi:10.1371/journal.pone.0059219

Dixon, E. E. and Woodward, O. M. (2018). Three-dimensional in vitro models answer the right questions in ADPKD cystogenesis. Am J Physiol Renal Physiol 315, F332-F335. doi:10.1152/ajprenal.00126.2018

Dorsey, E. R., Constantinescu, R., Thompson, J. P. et al. (2007). Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68, 384-386. doi:10.1212/01.wnl.0000247740.47667.03

Douvaras, P., Wang, J., Zimmer, M. et al. (2014). Efficient generation of myelinating oligodendrocytes from primary progressive multiple sclerosis patients by induced pluripotent stem cells. Stem Cell Reports 3, 250-259. doi:10.1016/j.stemcr.2014.06.012

Edington, C. D., Chen, W. L. K., Geishecker, E. et al. (2018). Interconnected microphysiological systems for quantitative biology and pharmacology studies. Sci Rep 8, 4530. doi:10.1038/s41598-018-22749-0

Edwards, S. J., Carannante, V., Kuhnigk, K. et al. (2020). High-resolution imaging of tumor spheroids and organoids enabled by expansion microscopy. Front Mol Biosci 7, 208. doi:10.3389/fmolb.2020.00208

Ekert, J. E., Johnson, K., Strake, B. et al. (2014). Three-dimensional lung tumor microenvironment modulates therapeutic compound responsiveness in vitro – Implication for drug development. PLoS One 9, e92248. doi:10.1371/journal.pone.0092248

Fabre, K., Berridge, B., Proctor, W. R. et al. (2020). Introduction to a manuscript series on the characterization and use of microphysiological systems (MPS) in pharmaceutical safety and ADME applications. Lab Chip 20, 1049-1057. doi:10.1039/c9lc01168d

Fan, H., Demirci, U. and Chen, P. (2019). Emerging organoid models: Leaping forward in cancer research. J Hematol Oncol 12, 142. doi:10.1186/s13045-019-0832-4

Feigin, V. L., Nichols, E., Alam, T. et al. (2019). Global, regional, and national burden of neurological disorders, 1990-2016: A systematic analysis for the global burden of disease study 2016. Lancet Neurol 18, 459-480. doi:10.1016/s1474-4422(18)30499-x

Fidler, I. J. and Kripke, M. L. (2015). The challenge of targeting metastasis. Cancer Metastasis Rev 34, 635-641. doi:10.1007/s10555-015-9586-9

Foo, M. A., You, M., Chan, S. L. et al. (2022). Clinical translation of patient-derived tumour organoids- bottlenecks and strategies. Biomark Res 10, 10. doi:10.1186/s40364-022-00356-6

Freundt, E. C., Maynard, N., Clancy, E. K. et al. (2012). Neuron-to-neuron transmission of alpha-synuclein fibrils through axonal transport. Ann Neurol 72, 517-524. doi:10.1002/ana.23747

Fujii, M., Clevers, H. and Sato, T. (2019). Modeling human digestive diseases with CRISPR-Cas9-modified organoids. Gastroenterology 156, 562-576. doi:10.1053/j.gastro.2018.11.048

Gard, A. L., Luu, R. J., Miller, C. R. et al. (2021). High-throughput human primary cell-based airway model for evaluating influenza, coronavirus, or other respiratory viruses in vitro. Sci Rep 11, 14961. doi:10.1038/s41598-021-94095-7

Gitler, A. D., Dhillon, P. and Shorter, J. (2017). Neurodegenerative disease: Models, mechanisms, and a new hope. Dis Model Mech 10, 499-502. doi:10.1242/dmm.030205

Goedert, M., Eisenberg, D. S. and Crowther, R. A. (2017). Propagation of tau aggregates and neurodegeneration. Annu Rev Neurosci 40, 189-210. doi:10.1146/annurev-neuro-072116-031153

Goris, K., Uhlenbruck, S., Schwegmann-Wessels, C. et al. (2009). Differential sensitivity of differentiated epithelial cells to respiratory viruses reveals different viral strategies of host infection. J Virol 83, 1962-1968. doi:10.1128/JVI.01271-08

Gould, S. E., Junttila, M. R. and de Sauvage, F. J. (2015). Translational value of mouse models in oncology drug development. Nat Med 21, 431-439. doi:10.1038/nm.3853

Grantham, J. J., Uchic, M., Cragoe, E. J., Jr. et al. (1989). Chemical modification of cell proliferation and fluid secretion in renal cysts. Kidney Int 35, 1379-1389. doi:10.1038/ki.1989.137

Grigoryan, B., Paulsen, S. J., Corbett, D. C. et al. (2019). Multivascular networks and functional intravascular topologies within biocompatible hydrogels. Science 364, 458-464. doi:10.1126/science.aav9750

Gural, N., Mancio-Silva, L., He, J. et al. (2018). Engineered livers for infectious diseases. Cell Mol Gastroenterol Hepatol 5, 131-144. doi:10.1016/j.jcmgh.2017.11.005

Han, J., Jun, Y., Kim, S. H. et al. (2016). Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology. Proc Natl Acad Sci U S A 113, 14283-14288. doi:10.1073/pnas.1614898113

Han, Y., Duan, X., Yang, L. et al. (2020). Identification of SARS-CoV-2 inhibitors using lung and colonic organoids. Nature 589, 270-275. doi:10.1038/s41586-020-2901-9

Hargrove-Grimes, P., Low, L. A. and Tagle, D. A. (2022). Microphysiological systems: Stakeholder challenges to adoption in drug development. Cells Tissues Organs 211, 269-281. doi:10.1159/000517422

Herrscher, C., Roingeard, P. and Blanchard, E. (2020). Hepatitis B virus entry into cells. Cells 9, 1486. doi:10.3390/cells9061486

Hesla, A. C., Papakonstantinou, A. and Tsagkozis, P. (2021). Current status of management and outcome for patients with Ewing sarcoma. Cancers (Basel) 13, 1202. doi:10.3390/cancers13061202

Higuita-Castro, N., Mihai, C., Hansford, D. J. et al. (2014). Influence of airway wall compliance on epithelial cell injury and adhesion during interfacial flows. J Appl Physiol (1985) 117, 1231-1242. doi:10.1152/japplphysiol.00752.2013

Hild, M. and Jaffe, A. B. (2016). Production of 3-D airway organoids from primary human airway basal cells and their use in high-throughput screening. Curr Protoc Stem Cell Biol 37, IE 9 1-IE 9 15. doi:10.1002/cpsc.1

Holton, A. B., Sinatra, F. L., Kreahling, J. et al. (2017). Microfluidic biopsy trapping device for the real-time monitoring of tumor microenvironment. PLoS One 12, e0169797. doi:10.1371/journal.pone.0169797

Horvath, L., Umehara, Y., Jud, C. et al. (2015). Engineering an in vitro air-blood barrier by 3D bioprinting. Sci Rep 5, 7974. doi:10.1038/srep07974

Huh, D., Fujioka, H., Tung, Y. C. et al. (2007). Acoustically detectable cellular-level lung injury induced by fluid mechanical stresses in microfluidic airway systems. Proc Natl Acad Sci U S A 104, 18886-18891. doi:10.1073/pnas.0610868104

Hui, K. P. Y., Ching, R. H. H., Chan, S. K. H. et al. (2018). Tropism, replication competence, and innate immune responses of influenza virus: An analysis of human airway organoids and ex-vivo bronchus cultures. Lancet Respir Med 6, 846-854. doi:10.1016/S2213-2600(18)30236-4

Hwang, T. J., Carpenter, D., Lauffenburger, J. C. et al. (2016). Failure of investigational drugs in late-stage clinical development and publication of trial results. JAMA Intern Med 176, 1826-1833. doi:10.1001/jamainternmed.2016.6008

Ibrahim, S. H., Kohli, R. and Gores, G. J. (2011). Mechanisms of lipotoxicity in NAFLD and clinical implications. J Pediatr Gastroenterol Nutr 53, 131-140. doi:10.1097/MPG.0b013e31822578db

In, J., Foulke-Abel, J., Zachos, N. C. et al. (2016a). Enterohemorrhagic Escherichia coli reduce mucus and intermicrovillar bridges in human stem cell-derived colonoids. Cell Mol Gastroenterol Hepatol 2, 48-62.e43. doi:10.1016/j.jcmgh.2015.10.001

In, J. G., Foulke-Abel, J., Estes, M. K. et al. (2016b). Human mini-guts: New insights into intestinal physiology and host-pathogen interactions. Nat Rev Gastroenterol Hepatol 13, 633-642. doi:10.1038/nrgastro.2016.142

Ingber, D. E. (2022). Human organs-on-chips for disease modelling, drug development and personalized medicine. Nat Rev Genet 23, 467-491. doi:10.1038/s41576-022-00466-9

Jacob, A., Morley, M., Hawkins, F. et al. (2017). Differentiation of human pluripotent stem cells into functional lung alveolar epithelial cells. Cell Stem Cell 21, 472-488.e410. doi:10.1016/j.stem.2017.08.014

Jalili-Firoozinezhad, S., Prantil-Baun, R., Jiang, A. et al. (2018). Modeling radiation injury-induced cell death and countermeasure drug responses in a human gut-on-a-chip. Cell Death Dis 9, 223. doi:10.1038/s41419-018-0304-8

Jang, K. J., Mehr, A. P., Hamilton, G. A. et al. (2013). Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment. Integr Biol (Camb) 5, 1119-1129. doi:10.1039/c3ib40049b

Jang, K. J., Otieno, M. A., Ronxhi, J. et al. (2019). Reproducing human and cross-species drug toxicities using a liver-chip. Sci Transl Med 11, eaax5516. doi:10.1126/scitranslmed.aax5516

Jucker, M. (2010). The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nat Med 16, 1210-1214. doi:10.1038/nm.2224

Kang, Y. B., Cai, Y. and Zhang, H. (2017). Gut microbiota and allergy/asthma: From pathogenesis to new therapeutic strategies. Allergol Immunopathol (Madr) 45, 305-309. doi:10.1016/j.aller.2016.08.004

Kasendra, M., Tovaglieri, A., Sontheimer-Phelps, A. et al. (2018). Development of a primary human small intestine-on-a-chip using biopsy-derived organoids. Sci Rep 8, 2871. doi:10.1038/s41598-018-21201-7

Kasendra, M., Luc, R., Yin, J. et al. (2020). Duodenum intestine-chip for preclinical drug assessment in a human relevant model. Elife 9, e50135. doi:10.7554/eLife.50135

Katt, M. E., Placone, A. L., Wong, A. D. et al. (2016). In vitro tumor models: Advantages, disadvantages, variables, and selecting the right platform. Front Bioeng Biotechnol 4, 12. doi:10.3389/fbioe.2016.00012

Kaushik, G., Seshacharyulu, P., Rauth, S. et al. (2021). Selective inhibition of stemness through EGFR/FOXA2/SOX9 axis reduces pancreatic cancer metastasis. Oncogene 40, 848-862. doi:10.1038/s41388-020-01564-w

Khalid, M. A. U., Kim, Y. S., Ali, M. et al. (2020). A lung cancer-on-chip platform with integrated biosensors for physiological monitoring and toxicity assessment. Biochem Eng J 155, 107469. doi:10.1016/j.bej.2019.107469

Kim, H. N., Habbit, N. L., Su, C.-Y. et al. (2019). Microphysiological systems as enabling tools for modeling complexity in the tumor microenvironment and accelerating cancer drug development. Adv Funct Mater 29, 1807553. doi:10.1002/adfm.201807553

Kim, J., Koo, B. K. and Knoblich, J. A. (2020). Human organoids: Model systems for human biology and medicine. Nat Rev Mol Cell Biol 21, 571-584. doi:10.1038/s41580-020-0259-3

Kobelt, G., Thompson, A., Berg, J. et al. (2017). New insights into the burden and costs of multiple sclerosis in Europe. Mult Scler 23, 1123-1136. doi:10.1177/1352458517694432

Konishi, S., Gotoh, S., Tateishi, K. et al. (2016). Directed induction of functional multi-ciliated cells in proximal airway epithelial spheroids from human pluripotent stem cells. Stem Cell Reports 6, 18-25. doi:10.1016/j.stemcr.2015.11.010

Kostrzewski, T., Cornforth, T., Snow, S. A. et al. (2017). Three-dimensional perfused human in vitro model of non-alcoholic fatty liver disease. World J Gastroenterol 23, 204-215. doi:10.3748/wjg.v23.i2.204

Kozyra, M., Johansson, I., Nordling, A. et al. (2018). Human hepatic 3D spheroids as a model for steatosis and insulin resistance. Sci Rep 8, 14297. doi:10.1038/s41598-018-32722-6

Kratochwil, N. A., Triyatni, M., Mueller, M. B. et al. (2018). Simultaneous assessment of clearance, metabolism, induction, and drug-drug interaction potential using a long-term in vitro liver model for a novel hepatitis B virus inhibitor. J Pharmacol Exp Ther 365, 237-248. doi:10.1124/jpet.117.245712

Kuo, I. Y., DesRochers, T. M., Kimmerling, E. P. et al. (2014). Cyst formation following disruption of intracellular calcium signaling. Proc Natl Acad Sci U S A 111, 14283-14288. doi:10.1073/pnas.1412323111

Kwak, B., Ozcelikkale, A., Shin, C. S. et al. (2014). Simulation of complex transport of nanoparticles around a tumor using tumor-microenvironment-on-chip. J Control Release 194, 157-167. doi:10.1016/j.jconrel.2014.08.027

Lanz, H. L., Saleh, A., Kramer, B. et al. (2017). Therapy response testing of breast cancer in a 3D high-throughput perfused microfluidic platform. BMC Cancer 17, 709. doi:10.1186/s12885-017-3709-3

Larsen, B. M., Kannan, M., Langer, L. F. et al. (2021). A pan-cancer organoid platform for precision medicine. Cell Rep 36, 109429. doi:10.1016/j.celrep.2021.109429

Lawlor, E. R., Scheel, C., Irving, J. et al. (2002). Anchorage-independent multi-cellular spheroids as an in vitro model of growth signaling in Ewing tumors. Oncogene 21, 307-318. doi:10.1038/sj.onc.1205053

Lewin, T. D., Avignon, B., Tovaglieri, A. et al. (2022). An in silico model of T cell infiltration dynamics based on an advanced in vitro system to enhance preclinical decision making in cancer immunotherapy. Front Pharmacol 13, 837261. doi:10.3389/fphar.2022.837261

Li, Y. and Kumacheva, E. (2018). Hydrogel microenvironments for cancer spheroid growth and drug screening. Sci Adv 4, eaas8998. doi:10.1126/sciadv.aas8998

Liu, G., Betts, C., Cunoosamy, D. M. et al. (2019). Use of precision cut lung slices as a translational model for the study of lung biology. Respir Res 20, 162. doi:10.1186/s12931-019-1131-x

Low, L. A. and Tagle, D. A. (2016). Tissue chips to aid drug development and modeling for rare diseases. Expert Opin Orphan Drugs 4, 1113-1121. doi:10.1080/21678707.2016.1244479

Lyons, S. K., Plenker, D. and Trotman, L. C. (2021). Advances in preclinical evaluation of experimental antibody-drug conjugates. Cancer Drug Resist 4, 745-754. doi:10.20517/cdr.2021.37

Ma, C., Peng, Y., Li, H. et al. (2021). Organ-on-a-chip: A new paradigm for drug development. Trends Pharmacol Sci 42, 119-133. doi:10.1016/

Madden, L., Juhas, M., Kraus, W. E. et al. (2015). Bioengineered human myobundles mimic clinical responses of skeletal muscle to drugs. Elife 4, e04885. doi:10.7554/eLife.04885

Madden, L. R., Nguyen, T. V., Garcia-Mojica, S. et al. (2018). Bioprinted 3D primary human intestinal tissues model aspects of native physiology and ADME/Tox functions. iScience 2, 156-167. doi:10.1016/j.isci.2018.03.015

Mak, I. W., Evaniew, N. and Ghert, M. (2014). Lost in translation: Animal models and clinical trials in cancer treatment. Am J Transl Res 6, 114-118.

Makale, M. (2007). Cellular mechanobiology and cancer metastasis. Birth Defects Res C Embryo Today 81, 329-343. doi:10.1002/bdrc.20110

Marx, U., Akabane, T., Andersson, T. B. et al. (2020). Biology-inspired microphysiological systems to advance patient benefit and animal welfare in drug development. ALTEX 37, 365-394. doi:10.14573/altex.2001241

Masiello, T., Dhall, A., Hemachandra, L. P. M. et al. (2018). A dynamic culture method to produce ovarian cancer spheroids under physiologically-relevant shear stress. Cells 7, 277. doi:10.3390/cells7120277

McCauley, K. B., Hawkins, F., Serra, M. et al. (2017). Efficient derivation of functional human airway epithelium from pluripotent stem cells via temporal regulation of Wnt signaling. Cell Stem Cell 20, 844-857 e846. doi:10.1016/j.stem.2017.03.001

McColgan, P. and Tabrizi, S. J. (2018). Huntington’s disease: A clinical review. Eur J Neurol 25, 24-34. doi:10.1111/ene.13413

McDonald, J., Bayrak-Toydemir, P. and Pyeritz, R. E. (2011). Hereditary hemorrhagic telangiectasia: An overview of diagnosis, management, and pathogenesis. Genet Med 13, 607-616. doi:10.1097/GIM.0b013e3182136d32

McGowan, E., Eriksen, J. and Hutton, M. (2006). A decade of modeling Alzheimer’s disease in transgenic mice. Trends Genet 22, 281-289. doi:10.1016/j.tig.2006.03.007

Miller, C. P., Tsuchida, C., Zheng, Y. et al. (2018). A 3D human renal cell carcinoma-on-a-chip for the study of tumor angiogenesis. Neoplasia 20, 610-620. doi:10.1016/j.neo.2018.02.011

Miller, J. S., Stevens, K. R., Yang, M. T. et al. (2012). Rapid casting of patterned vascular networks for perfusable engineered three-dimensional tissues. Nat Mater 11, 768-774. doi:10.1038/nmat3357

Molina-Jimenez, F., Benedicto, I., Dao Thi, V. L. et al. (2012). Matrigel-embedded 3D culture of Huh-7 cells as a hepatocyte-like polarized system to study hepatitis C virus cycle. Virology 425, 31-39. doi:10.1016/j.virol.2011.12.021

Moll, S., Ebeling, M., Weibel, F. et al. (2013). Epithelial cells as active player in fibrosis: Findings from an in vitro model. PLoS One 8, e56575. doi:10.1371/journal.pone.0056575

Mollaki, V. (2021). Ethical challenges in organoid use. BioTech (Basel) 10, 12. doi:10.3390/biotech10030012

Montesano, R., Ghzili, H., Carrozzino, F. et al. (2009). cAMP-dependent chloride secretion mediates tubule enlargement and cyst formation by cultured mammalian collecting duct cells. Am J Physiol Renal Physiol 296, F446-457. doi:10.1152/ajprenal.90415.2008

Monticello, T. M., Jones, T. W., Dambach, D. M. et al. (2017). Current nonclinical testing paradigm enables safe entry to first-in-human clinical trials: The IQ consortium nonclinical to clinical translational database. Toxicol Appl Pharmacol 334, 100-109. doi:10.1016/j.taap.2017.09.006

Moreno, E. L., Hachi, S., Hemmer, K. et al. (2015). Differentiation of neuroepithelial stem cells into functional dopaminergic neurons in 3D microfluidic cell culture. Lab Chip 15, 2419-2428. doi:10.1039/c5lc00180c

Mosaad, E. O., Chambers, K. F., Futrega, K. et al. (2018). The microwell-mesh: A high-throughput 3D prostate cancer spheroid and drug-testing platform. Sci Rep 8, 253. doi:10.1038/s41598-017-18050-1

Mulay, A., Konda, B., Garcia, G. et al. (2020). SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery. bioRxiv doi:10.1101/2020.06.29.174623

Müller, F. A. and Sturla, S. J. (2019). Human in vitro models of nonalcoholic fatty liver disease. Curr Opin Toxicol 16, 9-16. doi:10.1016/j.cotox.2019.03.001

Munos, B. (2009). Lessons from 60 years of pharmaceutical innovation. Nat Rev Drug Discov 8, 959-968. doi:10.1038/nrd2961

Nagle, P. W., Plukker, J. T. M., Muijs, C. T. et al. (2018). Patient-derived tumor organoids for prediction of cancer treatment response. Semin Cancer Biol 53, 258-264. doi:10.1016/j.semcancer.2018.06.005

Nawroth, J. C., Lucchesi, C., Cheng, D. et al. (2020). A microengineered airway lung chip models key features of viral-induced exacerbation of asthma. Am J Respir Cell Mol Biol 63, 591-600. doi:10.1165/rcmb.2020-0010MA

Ng, C. P., Hinz, B. and Swartz, M. A. (2005). Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro. J Cell Sci 118, 4731-4739. doi:10.1242/jcs.02605

Nikolakopoulou, P., Rauti, R., Voulgaris, D. et al. (2020). Recent progress in translational engineered in vitro models of the central nervous system. Brain 143, 3181-3213. doi:10.1093/brain/awaa268

Ortega-Prieto, A. M., Skelton, J. K., Wai, S. N. et al. (2018). 3D microfluidic liver cultures as a physiological preclinical tool for hepatitis B virus infection. Nat Commun 9, 682. doi:10.1038/s41467-018-02969-8

Osaki, T., Uzel, S. G. M. and Kamm, R. D. (2018). Microphysiological 3D model of amyotrophic lateral sclerosis (ALS) from human iPS-derived muscle cells and optogenetic motor neurons. Sci Adv 4, eaat5847. doi:10.1126/sciadv.aat5847

Pacitti, D., Privolizzi, R. and Bax, B. E. (2019). Organs to cells and cells to organoids: The evolution of in vitro central nervous system modelling. Front Cell Neurosci 13, 129. doi:10.3389/fncel.2019.00129

Park, J., Lee, B. K., Jeong, G. S. et al. (2015). Three-dimensional brain-on-a-chip with an interstitial level of flow and its application as an in vitro model of Alzheimer’s disease. Lab Chip 15, 141-150. doi:10.1039/c4lc00962b

Park, J., Wetzel, I., Marriott, I. et al. (2018a). A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat Neurosci 21, 941-951. doi:10.1038/s41593-018-0175-4

Park, J. Y., Ryu, H., Lee, B. et al. (2018b). Development of a functional airway-on-a-chip by 3D cell printing. Biofabrication 11, 015002. doi:10.1088/1758-5090/aae545

Park, K. M. and Gerecht, S. (2014). Hypoxia-inducible hydrogels. Nat Commun 5, 4075. doi:10.1038/ncomms5075

Park, T. E., Mustafaoglu, N., Herland, A. et al. (2019). Hypoxia-enhanced blood-brain barrier chip recapitulates human barrier function and shuttling of drugs and antibodies. Nat Commun 10, 2621. doi:10.1038/s41467-019-10588-0

Persson, B. D., Jaffe, A. B., Fearns, R. et al. (2014). Respiratory syncytial virus can infect basal cells and alter human airway epithelial differentiation. PLoS One 9, e102368. doi:10.1371/journal.pone.0102368

Peters, M. F., Landry, T., Pin, C. et al. (2019). Human 3D gastrointestinal microtissue barrier function as a predictor of drug-induced diarrhea. Toxicol Sci 168, 3-17. doi:10.1093/toxsci/kfy268

Petropolis, D. B., Faust, D. M., Tolle, M. et al. (2016). Human liver infection in a dish: Easy-to-build 3D liver models for studying microbial infection. PLoS One 11, e0148667. doi:10.1371/journal.pone.0148667

Phan, N., Hong, J. J., Tofig, B. et al. (2019). A simple high-throughput approach identifies actionable drug sensitivities in patient-derived tumor organoids. Commun Biol 2, 78. doi:10.1038/s42003-019-0305-x

Philips, T. and Rothstein, J. D. (2015). Rodent models of amyotrophic lateral sclerosis. Curr Protoc Pharmacol 69, 5.67.1-5.67.21. doi:10.1002/0471141755.ph0567s69

Phillips, J. A., Grandhi, T. S. P., Davis, M. et al. (2020). A pharmaceutical industry perspective on microphysiological kidney systems for evaluation of safety for new therapies. Lab Chip 20, 468-476. doi:10.1039/c9lc00925f

Picher-Martel, V., Valdmanis, P. N., Gould, P. V. et al. (2016). From animal models to human disease: A genetic approach for personalized medicine in ALS. Acta Neuropathol Commun 4, 70. doi:10.1186/s40478-016-0340-5

Pickl, M. and Ries, C. H. (2009). Comparison of 3D and 2D tumor models reveals enhanced HER2 activation in 3D associated with an increased response to trastuzumab. Oncogene 28, 461-468. doi:10.1038/onc.2008.394

Pitrez, P. R., Estronca, L., Monteiro, L. M. et al. (2020). Vulnerability of progeroid smooth muscle cells to biomechanical forces is mediated by MMP13. Nat Commun 11, 4110. doi:10.1038/s41467-020-17901-2

Placone, J. K., Mahadik, B. and Fisher, J. P. (2020). Addressing present pitfalls in 3D printing for tissue engineering to enhance future potential. APL Bioeng 4, 010901. doi:10.1063/1.5127860

Plummer, S., Wallace, S., Ball, G. et al. (2019). A human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine. Sci Rep 9, 1407. doi:10.1038/s41598-018-38130-0

Poewe, W., Seppi, K., Tanner, C. M. et al. (2017). Parkinson disease. Nat Rev Dis Primers 3, 17013. doi:10.1038/nrdp.2017.13

Polacheck, W. J., German, A. E., Mammoto, A. et al. (2014). Mechanotransduction of fluid stresses governs 3D cell migration. Proc Natl Acad Sci U S A 111, 2447-2452. doi:10.1073/pnas.1316848111

Pradhan, S., Hassani, I., Seeto, W. J. et al. (2017). PEG-fibrinogen hydrogels for three-dimensional breast cancer cell culture. J Biomed Mater Res A 105, 236-252. doi:10.1002/jbm.a.35899

Proctor, W. R., Foster, A. J., Vogt, J. et al. (2017). Utility of spherical human liver microtissues for prediction of clinical drug-induced liver injury. Arch Toxicol 91, 2849-2863. doi:10.1007/s00204-017-2002-1

Puls, T. J., Tan, X., Husain, M. et al. (2018). Development of a novel 3D tumor-tissue invasion model for high-throughput, high-content phenotypic drug screening. Sci Rep 8, 13039. doi:10.1038/s41598-018-31138-6

Rae, C., Amato, F. and Braconi, C. (2021). Patient-derived organoids as a model for cancer drug discovery. Int J Mol Sci 22, doi:10.3390/ijms22073483

Ramsden, D., Belair, D. G., Agarwal, S. et al. (2022). Leveraging microphysiological systems to address challenges encountered during development of oligonucleotide therapeutics. ALTEX 39, 273-296. doi:10.14573/altex.2108241

Ransohoff, R. M. (2018). All (animal) models (of neurodegeneration) are wrong. Are they also useful? J Exp Med 215, 2955-2958. doi:10.1084/jem.20182042

Rao, L., Qian, Y., Khodabukus, A. et al. (2018). Engineering human pluripotent stem cells into a functional skeletal muscle tissue. Nat Commun 9, 126. doi:10.1038/s41467-017-02636-4

Rauth, S., Karmakar, S., Batra, S. K. et al. (2021). Recent advances in organoid development and applications in disease modeling. Biochim Biophys Acta Rev Cancer 1875, 188527. doi:10.1016/j.bbcan.2021.188527

Ribas, J., Zhang, Y. S., Pitrez, P. R. et al. (2017). Biomechanical strain exacerbates inflammation on a progeria-on-a-chip model. Small 13, 1603737. doi:10.1002/smll.201603737

Rock, J. R., Onaitis, M. W., Rawlins, E. L. et al. (2009). Basal cells as stem cells of the mouse trachea and human airway epithelium. Proc Natl Acad Sci U S A 106, 12771-12775. doi:10.1073/pnas.0906850106

Rogal, J., Zbinden, A., Schenke-Layland, K. et al. (2019). Stem-cell based organ-on-a-chip models for diabetes research. Adv Drug Deliv Rev 140, 101-128. doi:10.1016/j.addr.2018.10.010

Russell, W. M. S. and Burch, R. L. (1959). The Principles of Humane Experimental Technique. London, UK: Methuen.

Rusyn, I., Sakolish, C., Kato, Y. et al. (2022). Microphysiological systems evaluation: Experience of TEX-VAL tissue chip testing consortium. Toxicol Sci 188, 143-152. doi:10.1093/toxsci/kfac061

Sachs, N., de Ligt, J., Kopper, O. et al. (2018). A living biobank of breast cancer organoids captures disease heterogeneity. Cell 172, 373-386.e310. doi:10.1016/j.cell.2017.11.010

Sachs, N., Papaspyropoulos, A., Zomer-van Ommen, D. D. et al. (2019). Long-term expanding human airway organoids for disease modeling. EMBO J 38, e.100300. doi:10.15252/embj.2018100300

Saha, B., Mathur, T., Handley, K. F. et al. (2020). OvCa-chip microsystem recreates vascular endothelium-mediated platelet extravasation in ovarian cancer. Blood Adv 4, 3329-3342. doi:10.1182/bloodadvances.2020001632

Sasserath, T., Rumsey, J. W., McAleer, C. W. et al. (2020). Differential monocyte actuation in a three-organ functional innate immune system-on-a-chip. Adv Sci (Weinh) 7, 2000323. doi:10.1002/advs.202000323

Schetz, M., Dasta, J., Goldstein, S. et al. (2005). Drug-induced acute kidney injury. Curr Opin Crit Care 11, 555-565. doi:10.1097/01.ccx.0000184300.68383.95

Seok, J., Warren, H. S., Cuenca, A. G. et al. (2013). Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 110, 3507-3512. doi:10.1073/pnas.1222878110

Shaffiey, S. A., Jia, H., Keane, T. et al. (2016). Intestinal stem cell growth and differentiation on a tubular scaffold with evaluation in small and large animals. Regen Med 11, 45-61. doi:10.2217/rme.15.70

Shang, M., Soon, R. H., Lim, C. T. et al. (2019). Microfluidic modelling of the tumor microenvironment for anti-cancer drug development. Lab Chip 19, 369-386. doi:10.1039/c8lc00970h

Shanks, N., Greek, R. and Greek, J. (2009). Are animal models predictive for humans? Philos Ethics Humanit Med 4, 2. doi:10.1186/1747-5341-4-2

Shin, Y., Choi, S. H., Kim, E. et al. (2019). Blood-brain barrier dysfunction in a 3D in vitro model of Alzheimer’s disease. Adv Sci (Weinh) 6, 1900962. doi:10.1002/advs.201900962

Shlomai, A., Schwartz, R. E., Ramanan, V. et al. (2014). Modeling host interactions with hepatitis b virus using primary and induced pluripotent stem cell-derived hepatocellular systems. Proc Natl Acad Sci U S A 111, 12193-12198. doi:10.1073/pnas.1412631111

Si, L., Bai, H., Rodas, M. et al. (2021). A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics. Nat Biomed Eng 5, 815-829. doi:10.1038/s41551-021-00718-9

Skardal, A., Devarasetty, M., Forsythe, S. et al. (2016). A reductionist metastasis-on-a-chip platform for in vitro tumor progression modeling and drug screening. Biotechnol Bioeng 113, 2020-2032. doi:10.1002/bit.25950

Slanzi, A., Iannoto, G., Rossi, B. et al. (2020). In vitro models of neurodegenerative diseases. Front Cell Dev Biol 8, 328. doi:10.3389/fcell.2020.00328

Smits, L. M., Reinhardt, L., Reinhardt, P. et al. (2019). Modeling Parkinson’s disease in midbrain-like organoids. NPJ Parkinsons Dis 5, 5. doi:10.1038/s41531-019-0078-4

Song, B., Sun, G., Herszfeld, D. et al. (2012). Neural differentiation of patient specific iPS cells as a novel approach to study the pathophysiology of multiple sclerosis. Stem Cell Res 8, 259-273. doi:10.1016/j.scr.2011.12.001

Soucy, J. R., Bindas, A. J., Koppes, A. N. et al. (2019). Instrumented microphysiological systems for real-time measurement and manipulation of cellular electrochemical processes. iScience 21, 521-548. doi:10.1016/j.isci.2019.10.052

Spencer, J. I., Bell, J. S. and DeLuca, G. C. (2018). Vascular pathology in multiple sclerosis: Reframing pathogenesis around the blood-brain barrier. J Neurol Neurosurg Psychiatry 89, 42-52. doi:10.1136/jnnp-2017-316011

Spill, F., Reynolds, D. S., Kamm, R. D. et al. (2016). Impact of the physical microenvironment on tumor progression and metastasis. Curr Opin Biotechnol 40, 41-48. doi:10.1016/j.copbio.2016.02.007

Splawski, I., Timothy, K. W., Sharpe, L. M. et al. (2004). Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19-31. doi:10.1016/j.cell.2004.09.011

Stucki, J. D., Hobi, N., Galimov, A. et al. (2018). Medium throughput breathing human primary cell alveolus-on-chip model. Sci Rep 8, 14359. doi:10.1038/s41598-018-32523-x

Stys, P. K. and Tsutsui, S. (2019). Recent advances in understanding multiple sclerosis. F1000Res 8, 2100. doi:10.12688/f1000research.20906.1

Sung, K. E., Yang, N., Pehlke, C. et al. (2011). Transition to invasion in breast cancer: A microfluidic in vitro model enables examination of spatial and temporal effects. Integr Biol (Camb) 3, 439-450. doi:10.1039/c0ib00063a

Suzuki, T., Itoh, Y., Sakai, Y. et al. (2022). Generation of human bronchial organoids for SARS-CoV-2 research. Communications Biology 5, 516. doi:10.1101/2020.05.25.115600

Szot, C. S., Buchanan, C. F., Freeman, J. W. et al. (2011). 3D in vitro bioengineered tumors based on collagen I hydrogels. Biomaterials 32, 7905-7912. doi:10.1016/j.biomaterials.2011.07.001

Tan, G. A., Furber, K. L., Thangaraj, M. P. et al. (2018). Organotypic cultures from the adult CNS: A novel model to study demyelination and remyelination ex vivo. Cell Mol Neurobiol 38, 317-328. doi:10.1007/s10571-017-0529-6

Tan, Q., Choi, K. M., Sicard, D. et al. (2017). Human airway organoid engineering as a step toward lung regeneration and disease modeling. Biomaterials 113, 118-132. doi:10.1016/j.biomaterials.2016.10.046

Tong, S., Kim, K. H., Chante, C. et al. (2005). Hepatitis B virus e antigen variants. Int J Med Sci 2, 2-7. doi:10.7150/ijms.2.2

Trapecar, M., Wogram, E., Svoboda, D. et al. (2021). Human physiomimetic model integrating microphysiological systems of the gut, liver, and brain for studies of neurodegenerative diseases. Sci Adv 7, eabd1707. doi:10.1126/sciadv.abd1707

Trujillo-de Santiago, G., Flores-Garza, B. G., Tavares-Negrete, J. A. et al. (2019). The tumor-on-chip: Recent advances in the development of microfluidic systems to recapitulate the physiology of solid tumors. Materials (Basel) 12, 2945. doi:10.3390/ma12182945

Tsamandouras, N., Chen, W. L. K., Edington, C. D. et al. (2017). Integrated gut and liver microphysiological systems for quantitative in vitro pharmacokinetic studies. AAPS J 19, 1499-1512. doi:10.1208/s12248-017-0122-4

Tung, Y. C., Hsiao, A. Y., Allen, S. G. et al. (2011). High-throughput 3D spheroid culture and drug testing using a 384 hanging drop array. Analyst 136, 473-478. doi:10.1039/c0an00609b

Van Den Eeden, S. K., Tanner, C. M., Bernstein, A. L. et al. (2003). Incidence of Parkinson’s disease: Variation by age, gender, and race/ethnicity. Am J Epidemiol 157, 1015-1022. doi:10.1093/aje/kwg068

Van der Meer, A. D., Orlova, V. V., ten Dijke, P. et al. (2013). Three-dimensional co-cultures of human endothelial cells and embryonic stem cell-derived pericytes inside a microfluidic device. Lab Chip 13, 3562-3568. doi:10.1039/c3lc50435b

Van der Sanden, S. M. G., Sachs, N., Koekkoek, S. M. et al. (2018). Enterovirus 71 infection of human airway organoids reveals VP1-145 as a viral infectivity determinant. Emerg Microbes Infect 7, 84. doi:10.1038/s41426-018-0077-2

Van Ness, K. P., Chang, S. Y., Weber, E. J. et al. (2017). Microphysiological systems to assess nonclinical toxicity. Curr Protoc Toxicol 73, 14.18.11-14.18.28. doi:10.1002/cptx.27

VanDussen, K. L., Marinshaw, J. M., Shaikh, N. et al. (2015). Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut 64, 911-920. doi:10.1136/gutjnl-2013-306651

Vatine, G. D., Barrile, R., Workman, M. J. et al. (2019). Human iPSC-derived blood-brain barrier chips enable disease modeling and personalized medicine applications. Cell Stem Cell 24, 995-1005.e6. doi:10.1016/j.stem.2019.05.011

Veeranki, O. L., Tong, Z., Mejia, A. et al. (2019). A novel patient-derived orthotopic xenograft model of esophageal adenocarcinoma provides a platform for translational discoveries. Dis Model Mech 12, dmm.041004. doi:10.1242/dmm.041004

Villasante, A., Marturano-Kruik, A. and Vunjak-Novakovic, G. (2014). Bioengineered human tumor within a bone niche. Biomaterials 35, 5785-5794. doi:10.1016/j.biomaterials.2014.03.081

Vitek, M. P., Araujo, J. A., Fossel, M. et al. (2020). Translational animal models for Alzheimer’s disease: An Alzheimer’s association business consortium think tank. Alzheimers Dement (N Y) 6, e12114. doi:10.1002/trc2.12114

Vlachogiannis, G., Hedayat, S., Vatsiou, A. et al. (2018). Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 359, 920-926. doi:10.1126/science.aao2774

Wallace, D. P., Grantham, J. J. and Sullivan, L. P. (1996). Chloride and fluid secretion by cultured human polycystic kidney cells. Kidney Int 50, 1327-1336. doi:10.1038/ki.1996.445

Walsh, K., Megyesi, J. and Hammond, R. (2005). Human central nervous system tissue culture: A historical review and examination of recent advances. Neurobiol Dis 18, 2-18. doi:10.1016/j.nbd.2004.09.002

Wang, G., McCain, M. L., Yang, L. et al. (2014). Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat Med 20, 616-623. doi:10.1038/nm.3545

Wang, J., Zhou, C. J., Khodabukus, A. et al. (2021). Three-dimensional tissue-engineered human skeletal muscle model of Pompe disease. Commun Biol 4, 524. doi:10.1038/s42003-021-02059-4

Wang, Q., Cohen, J. D., Yukawa, T. et al. (2022). Assessment of a 3D neural spheroid model to detect pharmaceutical-induced neurotoxicity. ALTEX 39, 560-582. doi:10.14573/altex.2112221

Watson, D. E., Hunziker, R. and Wikswo, J. P. (2017). Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology. Exp Biol Med (Maywood) 242, 1559-1572. doi:10.1177/1535370217732765

Weiswald, L. B., Bellet, D. and Dangles-Marie, V. (2015). Spherical cancer models in tumor biology. Neoplasia 17, 1-15. doi:10.1016/j.neo.2014.12.004

Wevers, N. R., Kasi, D. G., Gray, T. et al. (2018). A perfused human blood-brain barrier on-a-chip for high-throughput assessment of barrier function and antibody transport. Fluids Barriers CNS 15, 23. doi:10.1186/s12987-018-0108-3

Winer, J. P., Oake, S. and Janmey, P. A. (2009). Non-linear elasticity of extracellular matrices enables contractile cells to communicate local position and orientation. PLoS One 4, e6382. doi:10.1371/journal.pone.0006382

Witt-Kehati, D., Bitton Alaluf, M. and Shlomai, A. (2016). Advances and challenges in studying hepatitis B virus in vitro. Viruses 8, 21. doi:10.3390/v8010021

Wong, C. H., Siah, K. W. and Lo, A. W. (2019). Estimation of clinical trial success rates and related parameters. Biostatistics 20, 273-286. doi:10.1093/biostatistics/kxx069

Wu, G. F. and Alvarez, E. (2011). The immunopathophysiology of multiple sclerosis. Neurol Clin 29, 257-278. doi:10.1016/j.ncl.2010.12.009

Xicoy, H., Wieringa, B. and Martens, G. J. (2017). The SH-SY5Y cell line in Parkinson’s disease research: A systematic review. Mol Neurodegener 12, 10. doi:10.1186/s13024-017-0149-0

Xu, X., Sabanayagam, C. R., Harrington, D. A. et al. (2014). A hydrogel-based tumor model for the evaluation of nanoparticle-based cancer therapeutics. Biomaterials 35, 3319-3330. doi:10.1016/j.biomaterials.2013.12.080

Yan, H. H. N., Siu, H. C., Ho, S. L. et al. (2020). Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles. Gut 69, 2165-2179. doi:10.1136/gutjnl-2019-320019

Yazawa, M. and Dolmetsch, R. E. (2013). Modeling Timothy syndrome with iPS cells. J Cardiovasc Transl Res 6, 1-9. doi:10.1007/s12265-012-9444-x

Youk, J., Kim, T., Evans, K. V. et al. (2020). Three-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2. Cell Stem Cell 27, 905-919.e10. doi:10.1016/j.stem.2020.10.004

Zacharias, W. J., Frank, D. B., Zepp, J. A. et al. (2018). Regeneration of the lung alveolus by an evolutionarily conserved epithelial progenitor. Nature 555, 251-255. doi:10.1038/nature25786

Zager, R. A. (1997). Pathogenetic mechanisms in nephrotoxic acute renal failure. Semin Nephrol 17, 3-14.

Zhang, B. and Radisic, M. (2017). Organ-on-a-chip devices advance to market. Lab Chip 17, 2395-2420. doi:10.1039/c6lc01554a

Zhang, H., Jarjour, A. A., Boyd, A. et al. (2011). Central nervous system remyelination in culture – A tool for multiple sclerosis research. Exp Neurol 230, 138-148. doi:10.1016/j.expneurol.2011.04.009

Zhang, M., Wang, P., Luo, R. et al. (2020). Biomimetic human disease model of SARS-CoV-2 induced lung injury and immune responses on organ chip system. Adv Sci (Weinh) 8, 2002928. doi:10.1002/advs.202002928

Zhao, Y., Kankala, R. K., Wang, S. B. et al. (2019). Multi-organs-on-chips: Towards long-term biomedical investigations. Molecules 24, 675. doi:10.3390/molecules24040675

Zhu, W., Castro, N. J., Cui, H. et al. (2016). A 3D printed nano bone matrix for characterization of breast cancer cell and osteoblast interactions. Nanotechnology 27, 315103. doi:10.1088/0957-4484/27/31/315103

Most read articles by the same author(s)