Opportunities and challenges for human microphysiological systems in drug development

Articles

Abi-Gerges, N., Indersmitten, T., Truong, K., et al. (2020). Multiparametric mechanistic profiling of inotropic drugs in adult human primary cardiomyocytes. Sci Rep 10, 7692. doi:10.1038/s41598-020-64657-2

Adriaanse, M. P., Tack, G. J., Passos, V. L. et al. (2013). Serum I-FABP as marker for enterocyte damage in coeliac disease and its relation to villous atrophy and circulating autoantibodies. Aliment Pharmacol Ther 37, 482-490. doi:10.1111/apt.12194

Afonso, M. B., Marques, V., van Mil, S. W. C. et al. (2024). Human liver organoids: From generation to applications. Hepatology 79, 1432-1451. doi:10.1097/Hep.0000000000000343

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

Alqahtani, M. S., Kazi, M., Alsenaidy, M. A. et al. (2021). Advances in oral drug delivery. Front Pharmacol 12, 618411. doi:10.3389/fphar.2021.618411

Amirabadi, H. E, Donkers, J. M., Wierenga, E. et al. (2022). Intestinal explant barrier chip: long-term intestinal absorption screening in a novel microphysiological system using tissue explants. Lab Chip 22, 326-342. doi:10.1039/d1lc00669j

Andrade, E. L., Bento, A. F., Cavalli, J. et al. (2016). Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies. Braz J Med Biol Res 49, e5646. doi:10.1590/1414-431X20165646

Antfolk, M. and Jensen, K. B. (2020). A bioengineering perspective on modelling the intestinal epithelial physiology in vitro. Nat Commun 11, 6244. doi:10.1038/s41467-020-20052-z

Antoine, D. J., Dear, J. W., Lewis, P. S. et al. (2013). Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Hepatology 58, 777-787. doi:10.1002/hep.26294

Arakawa, H., Nakazono, Y., Matsuoka, N. et al. (2023). Induction of open-form bile canaliculus formation by hepatocytes for evaluation of biliary drug excretion. Communications Biology 6, 866. doi:10.1038/s42003-023-05216-z

Arefin, A., Mendoza, M., Dame, K., Garcia, M. I. et al. (2023). Reproducibility of drug-induced effects on the contractility of an engineered heart tissue derived from human pluripotent stem cells. Front Pharmacol 14, 1212092. doi:10.3389/fphar.2023.1212092

Arhontoulis, D. C., Kerr, C. M., Richards, D. et al. (2022). Human cardiac organoids to model COVID-19 cytokine storm induced cardiac injuries. J Tissue Eng Regen Med 16, 799-811. doi:10.1002/term.3327

Ashammakhi, N., Nasiri, R., Barros, N. R. et al. (2020). Gut-on-a-chip: Current progress and future opportunities. Biomaterials 255, 120196. do: 10.1016/j.biomaterials.2020.120196

Aubrecht, J. and Schomaker, S. (2013). Serum glutamate dehydrogenase as a potential biomarker of mitochondrial dysfunction. Toxicol Sci 134, 223-223. doi:10.1093/toxsci/kft088

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

Avila, A. M., Bebenek, I., Mendrick, D. L. et al. (2023). Gaps and challenges in nonclinical assessments of pharmaceuticals: An FDA/CDER perspective on considerations for development of new approach methodologies. Regul Toxicol Pharmacol 139, 105345. doi:10.1016/j.yrtph.2023.105345

Bai, B. J., Yang, X. L., Li, Y. Z. et al. (2023). Deep learning-enabled virtual histological staining of biological samples. Light Sci Appl 12, 57. doi:10.1038/s41377-023-01104-7

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

Baker, T. K., van Vleet, T. R., Mahalingaiah, P. K. et al. (2023). The current status and use of microphysiological systems by the pharmaceutical industry: the IQ microphysiological systems affiliate survey and commentary. Drug Metab Dispos 52, 198-209. doi:10.1124/dmd.123.001510

Balijepalli, A. and Sivaramakrishan, V. (2017). Organs-on-chips: research and commercial perspectives. Drug Discov Today, 22, 397-403. doi:10.1016/j.drudis.2016.11.009

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

Barndt, R. J., Ma, N., Tang, Y. et al. (2021). Modeling of dilated cardiomyopathy by establishment of isogenic human iPSC lines carrying phospholamban C25T (R9C) mutation (UPITTi002-A-1) using CRISPR/Cas9 editing. Stem Cell Res 56, 102544. doi:10.1016/j.scr.2021.102544

Barnes, P. J., Bonini, S., Seeger, W. et al. (2015). Barriers to new drug development in respiratory disease. Eur Respir J 45, 1197-1207. doi:10.1183/09031936.00007915

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

Beaurivage, C., Kanapeckaite, A., Loomans, C. et al. (2020). Development of a human primary gut-on-a-chip to model inflammatory processes. Sci Rep 10, 21475. doi:10.1038/s41598-020-78359-2

Beaurivage, C., Naumovska, E., Chang, Y. X. et al. (2019). Development of a gut-on-a-chip model for high throughput disease modeling and drug discovery. Int J of Mol Sci 20, 5661. doi:10.3390/ijms20225661

Bedard, P., Gauvin, S., Ferland, K. et al. (2020). Innovative human three-dimensional tissue-engineered models as an alternative to animal testing. Bioengineering (Basel) 7, 115. doi:10.3390/bioengineering7030115

Bein, A., Shin, W., Jalili-Firoozinezhad, S. et al. (2018). Microfluidic organ-on-a-chip models of human intestine. Cell Mol Gastroenterol Hepatol 5, 659-668. doi:10.1016/j.jcmgh.2017.12.010

Bell, C. C., Dankers, A. C. A., Lauschke, V. M., et al. (2018). Comparison of hepatic 2D sandwich cultures and 3D spheroids for long-term toxicity applications: a multicenter study. Toxicol Sci 162, 655-666. doi:10.1093/toxsci/kfx289

Ben-Moshe, S., Shapira, Y., Moor, A. E. et al. (2019). Spatial sorting enables comprehensive characterization of liver zonation. Nat Metab 1, 899-911. doi:10.1038/s42255-019-0109-9

Benam, K. H., Villenave, R., Lucchesi, C. et al. (2016a). 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., Novak, R., Nawroth, J. et al. (2016b). Matched-comparative modeling of normal and diseased human airway responses using a microengineered breathing lung chip. Cell Systems 3, 454-466.e454. doi:10.1016/j.cels.2016.10.003

Bennet, T. J., Randhawa, A., Hua, J. et al. (2021). Airway-on-a-chip: designs and applications for lung repair and disease. Cells 10, 1602. doi:10.3390/cells10071602

Bircsak, K. M., DeBiasio, R., Miedel, M. et al. (2021). A 3D microfluidic liver model for high throughput compound toxicity screening in the OrganoPlate(R). Toxicology 450, 152667. doi:10.1016/j.tox.2020.152667

Blinova, K., Dang, Q., Millard, D., et al. (2018). International multisite study of human-induced pluripotent stem cell-derived cardiomyocytes for drug proarrhythmic potential assessment. Cell Rep 24, 3582-3592. doi:10.1016/j.celrep.2018.08.079

Blinova, K., Schocken, D., Patel, D. et al. (2019). Clinical trial in a dish: personalized stem cell-derived cardiomyocyte assay compared with clinical trial results for two QT-prolonging drugs. Clin Transl Sci 12, 687-697. doi:10.1111/cts.12674

Blumenrath, S. H., Lee, B. Y., Low, L. et al. (2020). Tackling rare diseases: Clinical trials on chips. Exp Biol Med (Maywood) 245, 1155-1162. doi:10.1177/1535370220924743

Bonanini, F., Dinkelberg, R., Torregrosa, M. C. et al. (2024). A microvascularized in vitro liver model for disease modeling and drug discovery. Biofabrication 17. doi:10.1088/1758-5090/ad818a

Boonekamp, K. E., Dayton, T. L. and Clevers, H. (2020). Intestinal organoids as tools for enriching and studying specific and rare cell types: advances and future directions. J Mol Cell Biol 12, 562-568. doi:10.1093/jmcb/mjaa034

Borghardt, J. M., Kloft, C. and Sharma, A. (2018). Inhaled therapy in respiratory disease: the complex interplay of pulmonary kinetic processes. Can Respir J 2018, 2732017. doi:10.1155/2018/2732017

Boyer, J. L. (2013). Bile formation and secretion. Compr Physiol 3, 1035-1078. doi:10.1002/cphy.c120027

Brodehl, A., Pour Hakimi, S. A., Stanasiuk, C. et al. (2019). Restrictive cardiomyopathy is caused by a novel homozygous desmin (DES) mutation p.Y122H leading to a severe filament assembly defect. Genes (Basel) 10, 918. doi:10.3390/genes10110918

Brovold, M., Keller, D., Devarasetty, M. et al. (2021). Biofabricated 3D in vitro model of fibrosis-induced abnormal hepatoblast/biliary progenitors' expansion of the developing liver. Bioeng Transl Med 6, e10207. doi:10.1002/btm2.10207

Browne, S., Gill, E. L., Schultheiss, P. et al. (2021). Stem cell-based vascularization of microphysiological systems. Stem Cell Reports 16, 2058-2075. doi:10.1016/j.stemcr.2021.03.015

Buderus, S., Boone, J. H. and Lentze, M. J. (2015). Fecal lactoferrin: reliable biomarker for intestinal inflammation in pediatric IBD. Gastroenterol Res Pract 2015, 578527. doi:10.1155/2015/578527

Bushby, K., Finkel, R., Birnkrant, D. J. et al. (2010). Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol 9, 77-93. doi:10.1016/S1474-4422(09)70271-6

Caetano-Pinto, P. and Stahl, S. H. (2018). Perspective on the application of microphysiological systems to drug transporter studies. Drug Metab Dispos 46, 1647-1657. doi:10.1124/dmd.118.082750

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

Carvalho, M. R., Yan, L. P., Li, B. et al. (2023). Gastrointestinal organs and organoids-on-a-chip: advances and translation into the clinics. Biofabrication 15. doi:10.1088/1758-5090/acf8fb

Chang, Y. S., Edeen, K., Lu, X. J. et al. (2006). Keratinocyte growth factor induces lipogenesis in alveolar type II cells through a sterol regulatory element binding protein-1c-dependent pathway. Am J Respir Cell Mol Biol 35, 268-274. doi:10.1165/rcmb.2006-0037OC

Charrez, B., Charwat, V., Siemons, B. et al. (2021). In vitro safety "clinical trial" of the cardiac liability of drug polytherapy. Clin Transl Sci 14, 1155-1165. doi:10.1111/cts.13038

Chen, M. B., Srigunapalan, S., Wheeler, A. R. et al. (2013). A 3D microfluidic platform incorporating methacrylated gelatin hydrogels to study physiological cardiovascular cell-cell interactions. Lab Chip 13, 2591-2598. doi:10.1039/c3lc00051f

Chen, W., Wang, J. B., Abnet, C. C. et al. (2015). Association between C-reactive protein, incident liver cancer, and chronic liver disease mortality in the linxian nutrition intervention trials: a nested case-control study. Cancer Epidemiol Biomarkers Prev 24, 386-392. doi:10.1158/1055-9965.Epi-14-1038

Chhabra, R. S. (1979). Intestinal absorption and metabolism of xenobiotics. Environ Health Perspect 33, 61-69. doi:10.1289/ehp.793361

Chunduri, V., Maddi, M. (2023). Role of in vitro two-dimensional (2D) and three-dimensional (3D) cell culture systems for ADME-Tox screening in drug discovery and development: a comprehensive review. ADMET DMPK 11, 1-32. doi:10.5599/admet.1513

Church, R. J. and Watkins, P. B. (2017). The transformation in biomarker detection and management of drug-induced liver injury. Liver Int 37, 1582-1590. doi:10.1111/liv.13441

Clevers, H. (2013). The intestinal crypt, a prototype stem cell compartment. Cell 154, 274-284. doi:10.1016/j.cell.2013.07.004

Cong Y., Han, X., Wang, Y. et al. (2020). Drug Toxicity evaluation based on organ-on-a-chip technology: a review. Micromachines 11, 381. doi:10.3390/mi11040381

Cooper, B. L., Salameh, S. and Posnack, N. G. (2024). Comparative cardiotoxicity assessment of bisphenol chemicals and estradiol using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci 198, 273-287. doi:10.1093/toxsci/kfae015

Cox, B., Barton, P., Class, R., et al. (2022). Setup of human liver-chips integrating 3D models, microwells and a standardized microfluidic platform as proof-of-concept study to support drug evaluation. Biomater Biosyst 7, 100054. doi:10.1016/j.bbiosy.2022.100054

Cox, C. R., Lynch, S., Goldring, C. et al. (2020). Current perspective: 3D spheroid models utilizing human-based cells for investigating metabolism-dependent drug-induced liver injury. Front Med Technol 2, 611913. doi:10.3389/fmedt.2020.611913

Crenn, P., Messing, B. and Cynober, L. (2008). Citrulline as a biomarker of intestinal failure due to enterocyte mass reduction. Clin Nutr 27, 328-339. doi:10.1016/j.clnu.2008.02.005

Crenn, P., Vahedi, K., Lavergne-Slove, A. et al. (2003). Plasma citrulline: A marker of enterocyte mass in villous atrophy-associated small bowel disease. Gastroenterology 124, 1210-1219. doi:10.1016/s0016-5085(03)00170-7

Cunningham, R. P. and Porat-Shliom, N. (2021). Liver zonation - revisiting old questions with new technologies. Frontiers in Physiology 12, 732929. doi:10.3389/fphys.2021.732929

D'Agostino, L., Daniele, B., Pignata, S. et al. (1988). Postheparin plasma diamine oxidase in subjects with small bowel disease. Diagnostic efficiency of a simplified test. Digestion 41, 46-54. doi:10.1159/000199731

Dalsbecker, P., Adiels, C.B. and Goksor, M. (2022). Liver-on-a-chip devices: the pros and cons of complexity. Am J Physiol Gastrointest Liver Physiol 323, G188-G204. doi:10.1152/ajpgi.00346.2021

Dame, K. and Ribeiro, A. J. S. (2021). Microengineered systems with iPSC-derived cardiac and hepatic cells to evaluate drug adverse effects. Exp Biol Med 246, 317-331. doi:10.1177/1535370220959598

Deguchi, S. and Takayama, K. (2022). State-of-the-art liver disease research using liver-on-a-chip. Inflamm Regen 42, 62. doi:10.1186/s41232-022-00248-0

Deng, J., Wei, W., Chen, Z. et al. (2019). Engineered liver-on-a-chip platform to mimic liver functions and its biomedical applications: a review. Micromachines (Basel) 10, 676. doi:10.3390/mi10100676

Di, L. (2019). The impact of carboxylesterases in drug metabolism and pharmacokinetics. Curr Drug Metab 20, 91-102. doi:10.2174/1389200219666180821094502

Di, L. and Kerns, E. H. (2009). Stability challenges in drug discovery. Chem Biodivers 6, 1875-1886. doi:10.1002/cbdv.200900061

Donkers, J. M., van der Vaart, J. I. and van de Steeg, E. (2023). Gut-on-a-chip research for drug development: implications of chip design on preclinical oral bioavailability or intestinal disease studies. Biomimetics (Basel), 8, 226. doi:10.3390/biomimetics8020226

Dou, W. K., Malhi, M., Zhao, Q. L. et al. (2022). Microengineered platforms for characterizing the contractile function of in vitro cardiac models. Microsyt Nanoeng 8, 26. doi:10.1038/s41378-021-00344-0

Du, Y., Khandekar, G., Llewellyn, J. et al. (2020). A bile duct-on-a-chip with organ-level functions. Hepatology 71, 1350-1363. doi:10.1002/hep.30918

Du, Y., Li, N., Yang, H. et al. (2017). Mimicking liver sinusoidal structures and functions using a 3D-configured microfluidic chip. Lab Chip 17, 782-794. doi:10.1039/c6lc01374k

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

Ehrlich, A., Duche, D., Ouedraogo, G. and Nahmias, Y. (2019). Challenges and opportunities in the design of liver-on-chip microdevices. Annu Rev Biomed Eng 21, 219-239. doi:10.1146/annurev-bioeng-060418-052305

Eichenbaum, G., Yang, K., Gebremichael, Y., et al. (2020). Application of the DILIsym(R) Quantitative Systems Toxicology drug-induced liver injury model to evaluate the carcinogenic hazard potential of acetaminophen. Regul Toxicol Pharmacol 118, 104788. doi:10.1016/j.yrtph.2020.104788

Eisner, D. A., Caldwell, J. L., Kistamas, K. et al. (2017). Calcium and excitation-contraction coupling in the heart. Circ Res 121, 181-195. doi:10.1161/CIRCRESAHA.117.310230

Ekert, J. E., Deakyne, J., Pribul-Allen, P. et al. (2020). Recommended guidelines for developing, qualifying, and implementing complex in vitro models (CIVMs) for drug discovery. SLAS Discov 25, 1174-1190. doi:10.1177/2472555220923332

Enlo-Scott, Z., Backstrom, E., Mudway et al. (2021). Drug metabolism in the lungs: opportunities for optimising inhaled medicines. Expert Opin Drug Metab Toxicol 17, 611-625. doi:10.1080/17425255.2021.1908262

Esch, M. B., Mahler, G. J., Stokor, T. et al. (2014). Body-on-a-chip simulation with gastrointestinal tract and liver tissues suggests that ingested nanoparticles have the potential to cause liver injury. Lab Chip 14, 3081-3092. doi:10.1039/c4lc00371c

Ewart, L., Apostolou, A., Briggs, S. A. et al. (2022). Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology. Commun Med (Lond) 2, 154. doi:10.1038/s43856-022-00209-1

Ewart, L. and Roth, A. (2021). Opportunities and challenges with microphysiological systems: a pharma end-user perspective. Nat Rev Drug Discov 20, 327-328. doi:10.1038/d41573-020-00030-2

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

Fahrner, R., Groger, M., Settmacher, U. et al. (2023). Functional integration of natural killer cells in a microfluidically perfused liver on-a-chip model. BMC Res Notes 16, 285. doi:10.1186/s13104-023-06575-w

Fang, G., Chen, Y. C., Lu, H. et al. (2023). Advances in spheroids and organoids on a chip. Adv Funct Mater 33, 2215043. doi:10.1002/adfm.202215043

Feaster, T. K., Feric, N., Pallotta, I. et al. (2022). Acute effects of cardiac contractility modulation stimulation in conventional 2D and 3D human induced pluripotent stem cell-derived cardiomyocyte models. Front Physiol 13, 1023563. doi:10.3389/fphys.2022.1023563

Fedi, A., Vitale, C., Ponschin, G. et al. (2021). In vitro models replicating the human intestinal epithelium for absorption and metabolism studies: A systematic review. J Control Release 335, 247-268. doi:10.1016/j.jconrel.2021.05.028

Feldstein, A. E., Wieckowska, A., Lopez, A. R. et al. (2009). Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 50, 1072-1078. doi:10.1002/hep.23050

Ferdowsian, H. R. and Beck, N. (2011). Ethical and scientific considerations regarding animal testing and research. PLoS One 6, e24059. doi:10.1371/journal.pone.0024059

Ferreira, G. S., Veening-Griffioen, D. H., Boon, W. P. C. et al. (2019). A standardised framework to identify optimal animal models for efficacy assessment in drug development. Plos One 14, e0218014. doi:10.1371/journal.pone.0218014

Fonoudi, H., Lyra-Leite, D. M., Javed, H. A. et al. (2020). Generating a cost-effective, weekend-free chemically defined human induced pluripotent stem cell (hiPSC) culture medium. Curr Protoc Stem Cell Biol 53, e110. doi:10.1002/cpsc.110

Fowler, S., Chen, W. L. K., Duignan, D. B. et al. (2020). Microphysiological systems for ADME-related applications: current status and recommendations for system development and characterization. Lab Chip 20, 446-467. doi:10.1039/c9lc00857h

Fragkos, K. C. and Forbes, A. (2018). Citrulline as a marker of intestinal function and absorption in clinical settings: A systematic review and meta-analysis. United European Gastroenterol J 6, 181-191. doi:10.1177/2050640617737632

Francis, I., Shrestha, J., Paudel, K. R. et al. (2022). Recent advances in lung-on-a-chip models. Drug Discovery Today 27, 2593-2602. doi:10.1016/j.drudis.2022.06.004

Freag, M. S., Namgung, B., Reyna Fernandez, M. E. et al. (2021). Human nonalcoholic steatohepatitis on a chip. Hepatol Commun 5, 217-233. doi:10.1002/hep4.1647

Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. et al. (2018). Mechanisms of NAFLD development and therapeutic strategies. Nat Med 24, 908-922. doi:10.1038/s41591-018-0104-9

Fu, S., Wu, D., Jiang, W. et al. (2019). Molecular biomarkers in drug-induced liver injury: challenges and future perspectives. Front Pharmacol 10, 1667. doi:10.3389/fphar.2019.01667

Fukudome, I., Kobayashi, M., Dabanaka, K. et al. (2014). Diamine oxidase as a marker of intestinal mucosal injury and the effect of soluble dietary fiber on gastrointestinal tract toxicity after intravenous 5-fluorouracil treatment in rats. Med Mol Morphol, 47, 100-107. doi:10.1007/s00795-013-0055-7

Fullenkamp, D. E., Willis, A. B., Curtin, J. L. et al. (2024). Physiological stress improves stem cell modeling of dystrophic cardiomyopathy. Dis Model Mech 17. doi:10.1242/dmm.050487

Gaffar, S. and Aathirah, A. S. (2023). Fatty-acid-binding proteins: from lipid transporters to disease biomarkers. Biomolecules 13, 1753. doi:10.3390/biom13121753

Gall, L., Jardi, F., Lammens, L. et al. (2023). A dynamic model of the intestinal epithelium integrates multiple sources of preclinical data and enables clinical translation of drug-induced toxicity. CPT Pharmacometrics Syst Pharmacol 12, 1511-1528. doi:10.1002/psp4.13029

Gao, G., Park, J. Y., Kim, B. S. et al. (2018). Coaxial cell printing of freestanding, perfusable, and functional in vitro vascular models for recapitulation of native vascular endothelium pathophysiology. Adv Healthc Mater 7, e1801102. doi:10.1002/adhm.201801102

Gao, L., Kupfer, M. E., Jung, J. P. et al. (2017). Myocardial tissue engineering with cells derived from human-induced pluripotent stem cells and a native-like, high-resolution, 3-dimensionally printed scaffold. Circ Res 120, 1318-1325. doi:10.1161/CIRCRESAHA.116.310277

Garcia-Gutierrez, E. and Cotter, P. D. (2022). Relevance of organ(s)-on-a-chip systems to the investigation of food-gut microbiota-host interactions. Crit Rev Microbiol 48, 463-488. doi:10.1080/1040841X.2021.1979933

Gardiner, B., Dougherty, J. A., Ponnalagu, D. et al. (2020). Measurement of oxidative stress markers in vitro using commercially available kits. In L. J. Berliner & N. L. Parinandi (Eds.), Measuring Oxidants and Oxidative Stress in Biological Systems (pp. 39-60). doi:10.1007/978-3-030-47318-1_4

Garg, P., Oikonomopoulos, A., Chen, H. et al. (2018). Genome editing of induced pluripotent stem cells to decipher cardiac channelopathy variant. J Am Coll Cardiol 72, 62-75. doi:10.1016/j.jacc.2018.04.041

Giannini, E. G., Testa, R. and Savarino, V. (2005). Liver enzyme alteration: a guide for clinicians. CMAJ 172, 367-379. doi:10.1503/cmaj.1040752

Gissen, P. and Arias, I. M. (2015). Structural and functional hepatocyte polarity and liver disease. J Hepatol 63, 1023-1037. doi:10.1016/j.jhep.2015.06.015

Godier-Furnemont, A. F. G., Tiburcy, M., Wagner, E. et al. (2015). Physiologic force-frequency response in engineered heart muscle by electromechanical stimulation. Biomaterials 60, 82-91. doi:10.1016/j.biomaterials.2015.03.055

Gough, A., Soto-Gutierrez, A., Vernetti, L. et al. (2021). Human biomimetic liver microphysiology systems in drug development and precision medicine. Nat Rev Gastroenterol Hepatol 18, 252-268. doi:10.1038/s41575-020-00386-1

Graham, M. L. and Prescott, M. J. (2015). The multifactorial role of the 3Rs in shifting the harm-benefit analysis in animal models of disease. Eur J of Pharmacol 15, 19-29. doi:10.1016/j.ejphar.2015.03.040

Greenhalgh, K., Ramiro-Garcia, J., Heinken, A. et al. (2019). Integrated and modeling delineates the molecular effects of a synbiotic regimen on colorectal-cancer-derived cells. Cell Reports 27, 1621-1632. doi:10.1016/j.celrep.2019.04.001

Gronbaek, H., Vestergaard, E. M., Hey, H. et al. (2006). Serum trefoil factors in patients with inflammatory bowel disease. Digestion 74, 33-39. doi:10.1159/000096591

Guo, Y., Chen, X., Gong, P. et al. (2023). The gut-organ-axis concept: advances the application of gut-on-chip technology. Int J Mol Sci 24, 4089. doi:10.3390/ijms24044089

Guo, Y., Chu, X., Parrott, N. J. et al. (2018a). Advancing Predictions of tissue and intracellular drug concentrations using in vitro, imaging and physiologically based pharmacokinetic modeling approaches. Clin Pharmacol Ther 104, 865-889. doi:10.1002/cpt.1183

Guo, Y., Li, Z., Su, W., Wang, L., Zhu, Y., & Qin, J. (2018b). A biomimetic human gut-on-a-chip for modeling drug metabolism in intestine. Artif Organs 42, 1196-1205. doi:10.1111/aor.13163

Gupta, P., Garcia, E., Sarkar, A. et al. (2019). Nanoparticle based treatment for cardiovascular diseases. Cardiovasc Hematol Disord Drug Targets 19, 33-44. doi:10.2174/1871529X18666180508113253

Gurvinder Kaur, J. M. D. (2012). Cell lines: valuable tools or useless artifacts. Spermatogenesis 2, 1-5. doi:10.4161/spmg.19885

Hachey, S. J., Movsesyan, S., Nguyen, Q. H. et al. (2021). An in vitro vascularized micro-tumor model of human colorectal cancer recapitulates in vivo responses to standard-of-care therapy. Lab Chip 21, 1333-1351. doi:10.1039/d0lc01216e

Haddrick, M. and Simpson, P. B. (2019). Organ-on-a-chip technology: turning its potential for clinical benefit into reality. Drug Discov Today 24, 1217-1223. doi:10.1016/j.drudis.2019.03.011

Han, L. Q., Wang, S., Ma, J. L. et al. (2023). Expression and significance of serum KL-6 in patients with acute respiratory distress syndrome. J Thorac Dis 15, 6988-6995. doi:10.21037/jtd-23-1787

Han, J.J. (2023). FDA modernization act 2.0 allows for alternatives to animal testing. Artif Organs 47, 449-450. doi:10.1111/aor.14503

Hargrove-Grimes, P., Low, L. A. and Tagle, D. A. (2021). Microphysiological systems: What it takes for community adoption. Exp Biol Medicine 246, 1435-1446. doi:10.1177/15353702211008872

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

Harrison, S. P., Baumgarten, S. F., Verma, R. et al. (2021). Liver organoids: recent developments, limitations and potential. Front Med (Lausanne) 8, 574047. doi:10.3389/fmed.2021.574047

Henry, O. Y. F., Villenave, R., Cronce, M. J. et al. (2017). Organs-on-chips with integrated electrodes for trans-epithelial electrical resistance (TEER) measurements of human epithelial barrier function. Lab Chip 17, 2264-2271. doi:10.1039/c7lc00155j

Hidalgo, I. J., Raub, T. J. and Borchardt, R. T. (1989). Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. Gastroenterology 96, 736-749. https://www.ncbi.nlm.nih.gov/pubmed/2914637

Hornberg, J. J., Laursen, M., Brenden, N. et al. (2014). Exploratory toxicology as an integrated part of drug discovery. Part II: Screening strategies. Drug Discov Today 19, 1137-1144. doi:10.1016/j.drudis.2013.12.009

Howell, B. A., Yang, Y., Kumar, R. et al. (2012). In vitro to in vivo extrapolation and species response comparisons for drug-induced liver injury (DILI) using DILIsym: a mechanistic, mathematical model of DILI. J Pharmacokinet Pharmacodyn 39, 527-541. doi:10.1007/s10928-012-9266-0

Huang, P., Xia, L., Guo, Q. et al. (2022). Genome-wide association studies identify miRNA-194 as a prognostic biomarker for gastrointestinal cancer by targeting ATP6V1F, PPP1R14B, BTF3L4 and SLC7A5. Front Oncol 12, 1025594. doi:10.3389/fonc.2022.1025594

Huh, D., B. D. M., Matthews, B.D., Mammoto, A. et al. (2010). Reconstituting organ-level lung functions on a chip. Science 328, 1662-1668. doi:10.1126/science.1188302

Huggins, D.J., Sherman, W. and Tidor, B. (2012). Rational approaches to improving selectivity in drug design. J Med Chem 55, 1424-1444. doi:10.1021/jm2010332

Iluz-Freundlich, D., Zhang, M., Uhanova, J. et al. (2020). The relative expression of hepatocellular and cholestatic liver enzymes in adult patients with liver disease. Ann Hepatol 19, 204-208. doi:10.1016/j.aohep.2019.08.004

Imai, T., Imoto, M., Sakamoto, H. et al. (2005). Identification of esterases expressed in Caco-2 cells and effects of their hydrolyzing activity in predicting human intestinal absorption. Drug Metab Dispos 33, 1185-1190. doi:10.1124/dmd.105.004226

Ingber, D. E. (2020). Is it time for reviewer 3 to request human organ chip experiments instead of animal validation studies? Adv Sci (Weinh) 7, 2002030. doi:10.1002/advs.202002030

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

Ishida, S. (2021). Research and development of microphysiological systems in japan supported by the AMED-MPS project. Front Toxicol 3, 657765. doi:10.3389/ftox.2021.657765

Jackel, S., Pipp, F. C., Emde, B. et al. (2021). L-citrulline: A preclinical safety biomarker for the small intestine in rats and dogs in repeat dose toxicity studies. J Pharmacol Toxicol Methods 111, 107110. doi:10.1016/j.vascn.2021.107110

Jackson, E. L. and Lu, H. (2016). Three-dimensional models for studying development and disease: moving on from organisms to organs-on-a-chip and organoids. Integr Biol (Camb) 8, 672-683. doi:10.1039/c6ib00039h

Jagdish, R. K., Maras, J. S. and Sarin, S. K. (2021). Albumin in advanced liver diseases: the good and bad of a drug! Hepatology 74, 2848-2862. doi:10.1002/hep.31836

Jalili-Firoozinezhad, S., Gazzaniga, F. S., Calamari, E. L., et al. (2019). A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip. Nat Biomed Eng 3, 520-531. doi:10.1038/s41551-019-0397-0

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

Jang, M., Neuzil, P., Volk, T. et al. (2015). On-chip three-dimensional cell culture in phaseguides improves hepatocyte functions in vitro. Biomicrofluidics 9, 034113. doi:10.1063/1.4922863

Jardim, D. L., Groves, E. S., Breitfeld, P. P. et al. (2017). Factors associated with failure of oncology drugs in late-stage clinical development: A systematic review. Cancer Treat Rev 52, 12-21. doi:10.1016/j.ctrv.2016.10.009

Jensen, C. and Teng, Y. (2020). Is it time to start transitioning from 2D to 3D cell culture? Front Mol Biosci 7, 33. doi:10.3389/fmolb.2020.00033

Johnson, S. A., Rupp, A. B., Rupp, K. L. et al. (2021). Clinical outcomes and costs associated with procalcitonin utilization in hospitalized patients with pneumonia, heart failure, viral respiratory infection, or chronic obstructive pulmonary disease. Intern Emerg Med 16, 677-686. doi:10.1007/s11739-020-02618-3

Jopling, C. L., Yi, M., Lancaster, A. M. et al. (2005). Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 309, 1577-1581. doi:10.1126/science.1113329

Jukic, A., Bakiri, L., Wagner, E. F. et al. (2021). Calprotectin: from biomarker to biological function. Gut 70, 1978-1988. doi:10.1136/gutjnl-2021-324855

Kalra, A., Yetiskul, E., Wehrle, C. J. et al. (2024). Physiology, Liver. In StatPearls. https://www.ncbi.nlm.nih.gov/pubmed/30571059

Kanabekova, P., Kadyrova, A. and Kulsharova, G. (2022). Microfluidic organ-on-a-chip devices for liver disease modeling in vitro. Micromachines (Basel), 13. doi:10.3390/mi13030428

Kane, S. V., Sandborn, W. J., Rufo, P. A. et al. (2003). Fecal lactoferrin is a sensitive and specific marker in identifying intestinal inflammation. Am J Gastroenterol 98, 1309-1314. doi:10.1111/j.1572-0241.2003.07458.x

Kang, Y. B., Rawat, S., Duchemin, N. et al. (2017). Human liver sinusoid on a chip for hepatitis b virus replication study. Micromachines 8. doi:10.3390/mi8010027

Kang, Y. B., Eo, J., Bulutoglu, B. et al. (2020). Progressive hypoxia-on-a-chip: An in vitro oxygen gradient model for capturing the effects of hypoxia on primary hepatocytes in health and disease. Biotechnol Bioeng 117, 763-775. doi:10.1002/bit.27225

Kang, Y. B. A., Eo, J., Mert, S. et al. (2018). Metabolic patterning on a chip: towards in vitro liver zonation of primary rat and human hepatocytes. Sci Rep 8, 8951. doi:10.1038/s41598-018-27179-6

Kanno, T., Sudo, K., Maekawa, M. et al. (1988). Lactate dehydrogenase M-subunit deficiency: a new type of hereditary exertional myopathy. Clin Chim Acta 173, 89-98. doi:10.1016/0009-8981(88)90359-2

Kapalczynska, M., Kolenda, T., Przybyla, W. et al. (2018). 2D and 3D cell cultures - a comparison of different types of cancer cell cultures. Arch Med Sci 14, 910-919. doi:10.5114/aoms.2016.63743

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

Katsura, H., Kobayashi, Y., Tata, P. R. et al. (2019). IL-1 and TNFα contribute to the inflammatory niche to enhance alveolar regeneration. Stem Cell Reports 12, 657-666. doi:10.1016/j.stemcr.2019.02.013

Kenna, J. G. and Uetrecht, J. (2018). Do in vitro assays predict drug candidate idiosyncratic drug-induced liver injury risk? DMD 46, 1658-1669. doi:10.1124/dmd.118.082719

Kerns, S.J., Belgur, C., Petropolis, D. et al. (2021). Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies. Elife 10, e67106. doi:10.7554/eLife.67106

Kia, R., Kelly, L., Sison-Young, R. L. et al. (2015). MicroRNA-122: a novel hepatocyte-enriched in vitro marker of drug-induced cellular toxicity. Toxicol Sci 144, 173-185. doi:10.1093/toxsci/kfu269

Kilic, O., Yoon, A, Shah, S. R. et al. (2019). A microphysiological model of the bronchial airways reveals the interplay of mechanical and biochemical signals in bronchospasm. Nat Biomed Eng 3, 532-544. doi:10.1038/s41551-019-0366-7

Kim, H. J., Huh, D., Hamilton, G. et al. (2012). Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. Lab Chip 12, 2165-2174. doi:10.1039/c2lc40074j

Kim, H. J. and Ingber, D. E. (2013). Gut-on-a-chip microenvironment induces human intestinal cells to undergo villus differentiation. Integr Biol 5, 1130-1140. doi:10.1039/C3IB40126J

Kim, H. J., Li, H., Collins, J. J. et al. (2016). Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip. Proc Natl Acad Sci U S A 113, E7-15. doi:10.1073/pnas.1522193112

Konikoff, M. R. and Denson, L. A. (2006). Role of fecal calprotectin as a biomarker of intestinal inflammation in inflammatory bowel disease. Inflamm Bowel Dis 12, 524-534. doi:10.1097/00054725-200606000-00013

Korver, S., Bowen, J., Pearson, K. et al. (2021). The application of cytokeratin-18 as a biomarker for drug-induced liver injury. Arch Toxicol 95, 3435-3448. doi:10.1007/s00204-021-03121-0

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

Kostrzewski, T., Maraver, P., Ouro-Gnao, L. et al. (2020). A Microphysiological system for studying nonalcoholic steatohepatitis. Hepatol Commun 4, 77-91. doi:10.1002/hep4.1450

Kostrzewski, T., Snow, S., Battle, A. L. et al. (2021). Modelling human liver fibrosis in the context of non-alcoholic steatohepatitis using a microphysiological system. Commun Biol 4, 1080. doi:10.1038/s42003-021-02616-x

Kubinyi, H. (2003). Drug research: myths, hype and reality. Nat Rev Drug Discov 2, 665-668. doi:10.1038/nrd1156

Kulsharova, G. and Kurmangaliyeva, A. (2021). Liver microphysiological platforms for drug metabolism applications. Cell Prolif, 54, e13099. doi:10.1111/cpr.13099

Kulthong, K., Duivenvoorde, L., Sun, H. et al. (2020). Microfluidic chip for culturing intestinal epithelial cell layers: Characterization and comparison of drug transport between dynamic and static models. Toxicol In Vitro 65, 104815. doi:10.1016/j.tiv.2020.104815

Kulthong, K., Hooiveld, G., Duivenvoorde, L. et al. (2021). Transcriptome comparisons of in vitro intestinal epithelia grown under static and microfluidic gut-on-chip conditions with in vivo human epithelia. Sci Rep 11, 3234. doi:10.1038/s41598-021-82853-6

Kurokawa, Y. K. and George, S. C. (2016). Tissue engineering the cardiac microenvironment: Multicellular microphysiological systems for drug screening. Adv Drug Deliv Rev 96, 225-233. doi:10.1016/j.addr.2015.07.004

Langhorst, J., Elsenbruch, S., Koelzer, J. et al. (2008). Noninvasive markers in the assessment of intestinal inflammation in inflammatory bowel diseases: performance of fecal lactoferrin, calprotectin, and PMN-elastase, CRP, and clinical indices. Am J Gastroenterol 103, 162-169. doi:10.1111/j.1572-0241.2007.01556.x

Larregieu, C. A. and Benet, L. Z. (2013). Drug discovery and regulatory considerations for improving in silico and in vitro predictions that use Caco-2 as a surrogate for human intestinal permeability measurements. AAPS J 15, 483-497. doi:10.1208/s12248-013-9456-8

Lau, E., Marques, C., Pestana, D. et al. (2016). The role of I-FABP as a biomarker of intestinal barrier dysfunction driven by gut microbiota changes in obesity. Nutr Metab 13, 31. doi:10.1186/s12986-016-0089-7

Laurino, A., Franceschini, A., Pesce, L. et al. (2023). A guide to perform 3D histology of biological tissues with fluorescence microscopy. Int J Mol Sci 24, 6747. doi:10.3390/ijms24076747

Lea, T. (2015). Caco-2 Cell Line. In K. Verhoeckx, P. Cotter, I. Lopez-Exposito, C. Kleiveland, T. Lea, A. Mackie, T. Requena, D. Swiatecka, and H. Wichers (Eds.), The Impact of Food Bioactives on Health: in vitro and ex vivo models (pp. 103-111). doi:10.1007/978-3-319-16104-4_10

Leach, T, Gandhi, U., Reeves, K. D., et al. (2023). Development of a novel air–liquid interface airway tissue equivalent model for in vitro respiratory modeling studies. Sci Rep 13, 10137. doi:10.1038/s41598-023-36863-1

Lee, H., Chae, S., Kim, J. Y. et al. (2019). Cell-printed 3D liver-on-a-chip possessing a liver microenvironment and biliary system. Biofabrication 11, 025001. doi:10.1088/1758-5090/aaf9fa

Lee, S. W. L., Adriani, G., Ceccarello, E. et al. (2018). Characterizing the Role of Monocytes in T Cell Cancer Immunotherapy Using a 3D Microfluidic Model. Front Immunol 9, 416. doi:10.3389/fimmu.2018.00416

Leise, M. D., Poterucha, J. J. and Talwalkar, J. A. (2014). Drug-induced liver injury. Mayo Clin Proc 89, 95-106. doi:10.1016/j.mayocp.2013.09.016

Lennernas, H., Ahrenstedt, O., Hallgren, R. et al. (1992). Regional jejunal perfusion, a new in vivo approach to study oral drug absorption in man. Pharm Res 9, 1243-1251. doi:10.1023/a:1015888813741

Leri, A., Rota, M., Pasqualini, F. S. et al. (2015). Origin of cardiomyocytes in the adult heart. Circ Res 116, 150-166. doi:10.1161/CIRCRESAHA.116.303595

Leung, C.M, Haan, P.D., Ronaldson-Bouchard, K. et al., (2022). A guide to the organ-on-a-chip. Nat Rev Methods Primers 2, 33. doi:10.1038/s43586-022-00118-6

Levner, D. and Ewart, L. (2023). Integrating liver-chip data into pharmaceutical decision-making processes. Expert Opin Drug Discov 18, 1313-1320. doi:10.1080/17460441.2023.2255127

Li, X., George, S. M., Vernetti, L. et al. (2018). A glass-based, continuously zonated and vascularized human liver acinus microphysiological system (vLAMPS) designed for experimental modeling of diseases and ADME/TOX. Lab Chip 18, 2614-2631. doi:10.1039/c8lc00418h

Li, K., Yang, X., Xue, C. et al. (2019). Biomimetic human lung-on-a-chip for modeling disease investigation. Biomicrofluidics 13, 031501. doi:10.1063/1.5100070

Liang, P., Lan, F., Lee, A. S. et al. (2013). Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation 127, 1677-1691. doi:10.1161/circulationaha.113.001883

Lim, A. Y., Kato, Y., Sakolish, C. et al. (2023). Reproducibility and robustness of a liver microphysiological system physiomimix lc12 under varying culture conditions and cell type combinations. Bioengineering 10, 1195. doi:10.3390/bioengineering10101195

Lin, C., Li, Y., McGlotten, J. et al. (1977). Isolation and identification of the major metabolite of albuterol in human urine. DMD 5, 234-238. https://dmd.aspetjournals.org/content/dmd/5/3/234.full.pdf

Lind, J. U., Yadid, M., Perkins, I. et al. (2017). Cardiac microphysiological devices with flexible thin-film sensors for higher-throughput drug screening. Lab Chip 17, 3692-3703. doi:10.1039/c7lc00740j

Liu, D., Saikam, V., Skrada, K. A. et al. (2022). Inflammatory bowel disease biomarkers. Med Res Rev 42, 1856-1887. doi:10.1002/med.21893

Liu, Y., Wang, S. and Wang, Y. (2016). Patterned fibers embedded microfluidic chips based on pla and pdms for ag nanoparticle safety testing. Polymers (Basel) 8, 402. doi:10.3390/polym8110402

Lohasz, C., Bonanini, F., Hoelting, L. et al. (2020). Predicting metabolism-related drug-drug interactions using a microphysiological multitissue system. Adv Biosyst 4, e2000079. doi:10.1002/adbi.202000079

Long, G. Y., Gong, R., Wang, Q. et al. (2022). Role of released mitochondrial DNA in acute lung injury. Frontiers in Immunology 13, 973089. doi:10.3389/fimmu.2022.973089

Low, L. A., Mummery, C., Berridge, B. R. et al. (2021). Organs-on-chips: into the next decade. Nat Rev Drug Discov 20, 345-361. doi:10.1038/s41573-020-0079-3

Lowe, D., et al. (2024). Alkaline Phosphatase, in StatPearls. Treasure Island (FL).

Maass, C., Stokes, C. L., Griffith, L. G. et al. (2017). Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS). Integr Biol 9, 290-302. doi:10.1039/c6ib00243a

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

Magri, D., Gallo, G., Piepoli, M. et al. (2024). What about chronotropic incompetence in heart failure with mildly reduced ejection fraction? Clinical and prognostic implications from the metabolic exercise combined with cardiac and kidney indexes score dataset. Eur J Prev Cardiol 31, 263-271. doi:10.1093/eurjpc/zwad338

Maji, S., Lee, M., Lee, J. et al. (2023). Development of lumen-based perfusable 3D liver in vitro model using single-step bioprinting with composite bioinks. Mater Today Bio 21, 100723. doi:10.1016/j.mtbio.2023.100723

Malik, M., Yang, Y., Fathi, P. et al. (2021). Critical considerations for the design of multi-organ microphysiological systems (MPS). Front Cell Dev Biol 9, 721338. doi:10.3389/fcell.2021.721338

Maric, S., Restin, T., Muff, J. L. et al. (2021). Citrulline, biomarker of enterocyte functional mass and dietary supplement. metabolism, transport, and current evidence for clinical use. Nutrients 13, 2794. doi:10.3390/nu13082794

Martignoni, M., Groothuis, G. M. and de Kanter, R. (2006). Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol 2, 875-894. doi:10.1517/17425255.2.6.875

Marx, U., Anderson, T. B., Baker, E. 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

Marx, U., Anderson, T. B., Bahinski, A. et al. (2016). Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing. ALTEX 33, 272-321. doi:10.14573/altex.1603161

Mathur, A., Loskill, P., Shao, K. et al. (2015). Human iPSC-based cardiac microphysiological system for drug screening applications. Sci Rep 5, 8883. doi:10.1038/srep08883

Mittal, E., Cupp, G. and Kang, Y. A. (2023). Simulating the effect of gut microbiome on cancer cell growth using a microfluidic device. Sensors (Basel), 23, 1265. doi:10.3390/s23031265

Miyoshi, J., Miyamoto, H., Goji, T. et al. (2015). Serum diamine oxidase activity as a predictor of gastrointestinal toxicity and malnutrition due to anticancer drugs. J Gastroenterol Hepatol 30, 1582-1590. doi:10.1111/jgh.13004

Mofrad, P., Contos, M. J., Haque, M. et al. (2003). Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 37, 1286-1292. doi:10.1053/jhep.2003.50229

Moman, R. N., Gupta, N. and Varacallo, M. (2024). Physiology, Albumin, in StatPearls. Treasure Island (FL).

Moradi, E., Jalili-Firoozinezhad, S. and Solati-Hashjin, M. (2020). Microfluidic organ-on-a-chip models of human liver tissue. Acta Biomaterialia 116, 67-83. doi:10.1016/j.actbio.2020.08.041

Morelli, M., Kurek, D., Ng, C. P. et al. (2023). Gut-on-a-chip models: current and future perspectives for host-microbial interactions research. Biomedicines 11, 619. doi:10.3390/biomedicines11020619

Moretti, A., Bellin, M., Welling, A. et al. (2010). Patient-specific induced pluripotent stem-cell models for long-QT syndrome. N Engl J Med 363, 1397-1409. doi:10.1056/NEJMoa0908679

Morgan, S. J., Elangbam, C. S., Berens, S. et al. (2013). Use of animal models of human disease for nonclinical safety assessment of novel pharmaceuticals. Toxicol Pathol 41, 508-518. doi:10.1177/0192623312457273

Murray, D. D., Itenov, T. S., Sivapalan, P. et al. (2019). Biomarkers of acute lung injury the individualized approach: for phenotyping, risk stratification and treatment surveillance. J Clin Med 8, 1163. doi:10.3390/jcm8081163

Nagy, P., Thorgeirsson, S. S. and Grisham, J. W. (2020). Organizational principles of the liver. In The Liver (pp. 1-13). doi:10.1002/9781119436812.ch1

Najjar, A., Kramer, N., Gardner, I. et al. (2023). Editorial: Advances in and applications of predictive toxicology: 2022. Front Pharmacol 14, 1257423. doi:10.3389/fphar.2023.1257423

Nakao, Y., Kimura, H., Sakai, Y. et al. (2011). Bile canaliculi formation by aligning rat primary hepatocytes in a microfluidic device. Biomicrofluidics 5, 22212. doi:10.1063/1.3580753

Namikawa, T., Fukudome, I., Kitagawa, H. et al. (2012). Plasma diamine oxidase activity is a useful biomarker for evaluating gastrointestinal tract toxicities during chemotherapy with oral fluorouracil anti-cancer drugs in patients with gastric cancer. Oncology 82, 147-152. doi:10.1159/000336799

Natarajan, V., Simoneau, C. R., Erickson, A. L. et al. (2022). Modelling T-cell immunity against hepatitis C virus with liver organoids in a microfluidic coculture system. Open Biol 12, 210320. doi:10.1098/rsob.210320

Naumovska, E., Aalderink, G., Valencia, C. et al. (2020). Direct on-chip differentiation of intestinal tubules from induced pluripotent stem cells. Int J Mol Sci 21. doi:10.3390/ijms21144964

Nawroth, J. C., Barrile, R., Conegliano, D. et al. (2019). Stem cell-based lung-on-chips: The best of both worlds? Adv Drug Deliv Rev 140, 12-32. doi:10.1016/j.addr.2018.07.005

Nawroth, J. C., Petropolis, D. B., Manatakis, D. V. et al. (2021). Modeling alcohol-associated liver disease in a human Liver-Chip. Cell Rep 36, 109393. doi:10.1016/j.celrep.2021.109393

Nawroth, J. C., Roth, D., van Schadewijk, A. et al. (2023). Breathing on chip: Dynamic flow and stretch accelerate mucociliary maturation of airway epithelium in vitro. Mater Today Bio 21, 100713. doi:10.1016/j.mtbio.2023.100713

Nelson, M. T., Charbonneau, M. R., Coia, H. G. et al. (2021). Characterization of an engineered live bacterial therapeutic for the treatment of phenylketonuria in a human gut-on-a-chip. Nat Commun 12, 2805. doi:10.1038/s41467-021-23072-5

Nesmith, A. P., Agarwal, A., McCain, M.L., et al. (2014). Human airway musculature on a chip: an in vitro model of allergic asthmatic bronchoconstriction and bronchodilation. Lab Chip 14, 3925-3936. doi:10.1039/c4lc00688g

Nguyen, N., Nguyen, W., Nguyenton, B. et al. (2017). Adult human primary cardiomyocyte-based model for the simultaneous prediction of drug-induced inotropic and pro-arrhythmia risk. Front Physiol 8, 1073. doi:10.3389/fphys.2017.01073

Norman, B. H. (2020). Drug induced liver injury (DILI). Mechanisms and medicinal chemistry avoidance/mitigation strategies. J Med Chem 63, 11397-11419. doi:10.1021/acs.jmedchem.0c00524

Novac, O., Silva, R., Young, L. M. et al. (2022). Human liver microphysiological system for assessing drug-induced liver toxicity in vitro. J Vis Exp (179), e63389. doi:10.3791/63389

Okada, K., Sekino, M., Funaoka, H. et al. (2018). Intestinal fatty acid-binding protein levels in patients with chronic renal failure. J Surg Res 230, 94-100. doi:10.1016/j.jss.2018.04.057

Oleaga, C., Bernabini, C., Smith, A. S. et al. (2016). Multi-organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci Rep 6, 20030. doi:10.1038/srep20030

Ong, L. J. Y., Ching, T., Chong, L. H. et al. (2019). Self-aligning tetris-like (TILE) modular microfluidic platform for mimicking multi-organ interactions. Lab Chip 19, 2178-2191. doi:10.1039/c9lc00160c

Ortega-Prieto, A. M., Skelton, J. K., Cherry, C. et al. (2019). "Liver-on-a-chip" cultures of primary hepatocytes and kupffer cells for hepatitis B virus infection. J Vis Exp (144), e58333. doi:10.3791/58333

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

Otumala, A. E., Hellen, D. J., Luna, C. A. et al. (2023). Opportunities and considerations for studying liver disease with microphysiological systems on a chip. Lab Chip 23, 2877-2898. doi:10.1039/d2lc00940d

Pamies, D., Ekert, J., Zurich, M. G. et al. (2024). Recommendations on fit-for-purpose criteria to establish quality management for microphysiological systems and for monitoring their reproducibility. Stem Cell Rep 19, 1041-1041. doi:10.1016/j.stemcr.2024.06.007

Paone, P. and Cani, P. D. (2020). Mucus barrier, mucins and gut microbiota: the expected slimy partners? Gut 69, 2232-2243. doi:10.1136/gutjnl-2020-322260

Papadia, C., Sherwood, R. A., Kalantzis, C. et al. (2007). Plasma citrulline concentration: a reliable marker of small bowel absorptive capacity independent of intestinal inflammation. Am J Gastroenterol 102, 1474-1482. doi:10.1111/j.1572-0241.2007.01239.x

Parasrampuria, D. A., Benet, L. Z. and Sharma, A. (2018). Why drugs fail in late stages of development: case study analyses from the last decade and recommendations. AAPS J 20, 46. doi:10.1208/s12248-018-0204-y

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

Penarete-Acosta, D., Stading, R., Emerson, L. et al. (2023). A microfluidic model of colonocyte-microbiota interaction mimicking the colorectal cancer microenvironment. bioRxiv. doi:10.1101/2023.08.29.555442

Penarete-Acosta, D., Stading, R,, Emerson, L. et al. (2024). A microfluidic co-culture model for investigating colonocytes–microbiota interactions in colorectal cancer. Lab Chip 24, 3690-3703. doi:10.1039/D4LC00013G

Peters, M. F., Choy, A. L., Pin, C. et al. (2020). Developing in vitro assays to transform gastrointestinal safety assessment: potential for microphysiological systems. Lab Chip 20, 1177-1190. doi:10.1039/c9lc01107b

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

Picollet-D'hahan, N., Zuchowska, A., Lemeunier, I. et al. (2021). Multiorgan-on-a-chip: a systemic approach to model and decipher inter-organ communication. Trends Biotechnol 39, 788-810. doi:10.1016/j.tibtech.2020.11.014

Picot, D., Garin, L., Trivin, F. et al. (2010). Plasma citrulline is a marker of absorptive small bowel length in patients with transient enterostomy and acute intestinal failure. Clin Nutr 29, 235-242. doi:10.1016/j.clnu.2009.08.010

Pimenta, J., Ribeiro, R., Almeida, R. et al. (2022). Organ-on-chip approaches for intestinal 3D in vitro modeling. CMGH 13, 351-367. doi:10.1016/j.jcmgh.2021.08.015

Plebani, R., Potla, R., Soong, M. et al. (2022). Modeling pulmonary cystic fibrosis in a human lung airway-on-a-chip. J Cyst Fibros 21, 606-615. doi:10.1016/j.jcf.2021.10.004

Pocock, K., Delon, L., Bala, V. et al. (2017). Intestine-on-a-chip microfluidic model for efficient in vitro screening of oral chemotherapeutic uptake. ACS Biomater Sci Eng 3, 951-959. doi:10.1021/acsbiomaterials.7b00023

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

Purdie, J. L., Kowle, R. L., Langland, A. L. et al. (2016). Cell culture media impact on drug product solution stability. Biotechnol Prog 32, 998-1008. doi:10.1002/btpr.2289

Rajan, S.A.P., Aleman, J., Wan, M. et al. (2020). Probing prodrug metabolism and reciprocal toxicity with an integrated and humanized multi-tissue organ-on-a-chip platform. Acta Biomaterialia 106, 124-135. doi:10.1016/j.actbio.2020.02.015

Rebs, S., Sedaghat-Hamedani, F., Kayvanpour, E. et al. (2020). Generation of pluripotent stem cell lines and CRISPR/Cas9 modified isogenic controls from a patient with dilated cardiomyopathy harboring a RBM20 p.R634W mutation. Stem Cell Res 47, 101901. doi:10.1016/j.scr.2020.101901

Regev, A. (2014). Drug-induced liver injury and drug development: industry perspective. Semin Liver Dis 34, 227-239. doi:10.1055/s-0034-1375962

Ren, L., Liu, W., Wang, Y. et al. (2013). Investigation of hypoxia-induced myocardial injury dynamics in a tissue interface mimicking microfluidic device. Anal Chem 85, 235-244. doi:10.1021/ac3025812

Reyes, D. R., Esch, M. B., Ewart, L. et al. (2024). From animal testing to systems: advancing standardization in microphysiological systems. Lab Chip 24, 1076-1087. doi:10.1039/d3lc00994g

Ribeiro, A. J. S., Yang, X., Patel, V. et al. (2019). Liver microphysiological systems for predicting and evaluating drug effects. Clin Pharmacol Ther 106, 139-147. doi:10.1002/cpt.1458

Rizki-Safitri, A., Tokito, F. and Nishikawa, M. (2021). Prospect of in vitro bile fluids collection in improving cell-based assay of liver function. Front Toxicol 3, 657432. doi:10.3389/ftox.2021.657432

Roderburg, C., Benz, F., Cardenas, D. et al. (2015). Elevated miR-122 serum levels are an independent marker of liver injury in inflammatory diseases. Liver Int 35, 1172-1184. doi:10.1111/liv.12627

Ronaldson-Bouchard, K., Ma, S. P., Yeager, K. (2019). Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature 572, E16-E17. doi:10.1038/s41586-019-1415-9

Ronaldson-Bouchard, K. and Vunjak-Novakovic, G. (2018). Organs-on-a-chip: a fast track for engineered human tissues in drug development. Cell Stem Cell 22, 310-324. doi:10.1016/j.stem.2018.02.011

Rose, K. A., Holman, N. S., Green, A. M. et al. (2016). Co-culture of hepatocytes and kupffer cells as an in vitro model of inflammation and drug-induced hepatotoxicity. J Pharm Sci 105, 950-964. doi:10.1016/S0022-3549(15)00192-6

Ross, Y. and Ballou, S. (2023). Reliability of C-reactive protein as an inflammatory marker in patients with immune-mediated inflammatory diseases and liver dysfunction. Rheumatol Adv Pract 7, rkad045. doi:10.1093/rap/rkad045

Rowe, C., Gerrard, D. T., Jenkins, R. et al. (2013). Proteome-wide analyses of human hepatocytes during differentiation and dedifferentiation. Hepatology 58, 799-809. doi:10.1002/hep.26414

Rowe, C., Shaeri, M., Large, E. et al. (2018). Perfused human hepatocyte microtissues identify reactive metabolite-forming and mitochondria-perturbing hepatotoxins. Toxicol In Vitro 46, 29-38. doi:10.1016/j.tiv.2017.09.012

Rubiano, A., Indapurkar, A., Yokosawa, R. et al. (2021). Characterizing the reproducibility in using a liver microphysiological system for assaying drug toxicity, metabolism, and accumulation. Clin Transl Sci 14, 1049-1061. doi:10.1111/cts.12969

Salameh, H., Raff, E., Erwin, A. et al. (2015). PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease. Am J Gastroenterol 110, 846-856. doi:10.1038/ajg.2015.137

Sandoval, Y., Januzzi, J. L. and Jaffe, A. S. (2020). Cardiac troponin for assessment of myocardial injury in COVID-19: jacc review topic of the week. J Am Coll Cardiol 76, 1244-1258. doi:10.1016/j.jacc.2020.06.068

Santana, P. T., Rosas, S. L. B., Ribeiro, B. E. et al. (2022). Dysbiosis in inflammatory bowel disease: pathogenic role and potential therapeutic targets. Int J Mol Sci 23. doi:10.3390/ijms23073464

Santbergen, M. J. C., van der Zande, M., Gerssen, A. et al. (2020). Dynamic in vitro intestinal barrier model coupled to chip-based liquid chromatography mass spectrometry for oral bioavailability studies. Anal Bioanal Chem 412, 1111-1122. doi:10.1007/s00216-019-02336-6

Sasaki, Y., Tatsuoka, H., Tsuda, M. (2022). Intestinal permeability of drugs in caco-2 cells cultured in microfluidic devices. Biol Pharm Bull 45, 1246-1253. doi:10.1248/bpb.b22-00092

Savoji, H., Mohammadi, M. H., Rafatian, N., et al. (2019). Cardiovascular disease models: A game changing paradigm in drug discovery and screening. Biomaterials 198, 3-26. doi:10.1016/j.biomaterials.2018.09.036

Schmidt, E. S. and Schmidt, F. W. (1988). Glutamate dehydrogenase: biochemical and clinical aspects of an interesting enzyme. Clin Chim Acta 173, 43-55. doi:10.1016/0009-8981(88)90356-7

Schofield, C. A., Walker, T. M., Taylor, M. A. et al. (2021). Evaluation of a three-dimensional primary human hepatocyte spheroid model: adoption and industrialization for the enhanced detection of drug-induced liver injury. Chem Res Toxicol 34, 2485-2499. doi:10.1021/acs.chemrestox.1c00227

Schomaker, S., Potter, D., Warner, R. et al. (2020). Serum glutamate dehydrogenase activity enables early detection of liver injury in subjects with underlying muscle impairments. Plos One 15, e0229753. doi:10.1371/journal.pone.0229753

Schulze, R. J., Schott, M. B., Casey, C. A. et al. (2019). The cell biology of the hepatocyte: A membrane trafficking machine. J Cell Biol 218, 2096-2112. doi:10.1083/jcb.201903090

Schurink, M., Kooi, E. M., Hulzebos, C. V. et al. (2015). Intestinal fatty acid-binding protein as a diagnostic marker for complicated and uncomplicated necrotizing enterocolitis: a prospective cohort study. PLoS One 10, e0121336. doi:10.1371/journal.pone.0121336

Seirup, M., Sengupta, S., Swanson, S. et al. (2022). Rapid changes in chromatin structure during dedifferentiation of primary hepatocytes in vitro. Genomics 114, 110330. doi:10.1016/j.ygeno.2022.110330

Serras, A. S., Rodrigues, J. S., Cipriano, M. et al. (2021). A critical perspective on 3D liver models for drug metabolism and toxicology studies. Front Cell Dev Biol 9, 626805. doi:10.3389/fcell.2021.626805

Shan, J., Schwartz, R. E., Ross, N. T. et al. (2013). Identification of small molecules for human hepatocyte expansion and iPS differentiation. Nat Chem Biol 9, 514-520. doi:10.1038/nchembio.1270

Shin, S. R., Zhang, Y. S., Kim, D. J. et al. (2016). Aptamer-based microfluidic electrochemical biosensor for monitoring cell-secreted trace cardiac biomarkers. Anal Chem 88, 10019-10027. doi:10.1021/acs.analchem.6b02028

Shin, W. and Kim, H. J. (2022). 3D in vitro morphogenesis of human intestinal epithelium in a gut-on-a-chip or a hybrid chip with a cell culture insert. Nat Protoc 17, 910-939. doi:10.1038/s41596-021-00674-3

Shin, W., Su, Z., Yi, S. S. et al. (2022). Single-cell transcriptomic mapping of intestinal epithelium that undergoes 3D morphogenesis and mechanodynamic stimulation in a gut-on-a-chip. iScience 25, 105521. doi:10.1016/j.isci.2022.105521

Shoemaker, J. T., Zhang, W., Atlas, S. I. et al. (2020). A 3D cell culture organ-on-a-chip platform with a breathable hemoglobin analogue augments and extends primary human hepatocyte functions in vitro. Front Mol Biosci 7, 568777. doi:10.3389/fmolb.2020.568777

Si, L., Bai, H., Rodas, M. et al. (2021a). 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

Si, L., Bai, H., Oh, C. Y. et al. (2021b). Clinically relevant influenza virus evolution reconstituted in a human lung airway-on-a-chip. Microbiol Spectr 9, e0025721. doi:10.1128/Spectrum.00257-21

Signore, M. A., De Pascali, C., Giampetruzzi, L. et al. (2021). Gut-on-chip microphysiological systems: latest advances in the integration of sensing strategies and adoption of mature detection mechanisms. Sens Bio-Sens Res 33, 100443. doi:10.1016/j.sbsr.2021.100443

Singh, K. P., Jaffe, A. S. and Liang, B. T. (2011). The clinical impact of circulating caspase-3 p17 level: a potential new biomarker for myocardial injury and cardiovascular disease. Future Cardiol 7, 443-445. doi:10.2217/fca.11.29

Sivapalan, P. and Jensen, J. U. (2021). Biomarkers in chronic obstructive pulmonary disease: emerging roles of eosinophils and procalcitonin. J Innate Immun 14, 89-97. doi:10.1159/000517161

Siwczak, F., Loffet, E., Kaminska, M. et al. (2021). Intestinal stem cell-on-chip to study human host-microbiota interaction. Front Immunol 12, 798552. doi:10.3389/fimmu.2021.798552

Smagris, E., BasuRay, S., Li, J. et al. (2015). Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 61, 108-118. doi:10.1002/hep.27242

Snow, S. and Kodavanti, U. P. (2019). Respiratory Toxicity Biomarkers. Biomarkers in Toxicology, Second Edition. doi:10.1016/B978-0-12-814655-2.00013-X

Soares, I., Belote, B. L., Santin, E. et al. (2022). Morphological assessment and biomarkers of low-grade, chronic intestinal inflammation in production animals. Animals 12, 3036. doi:10.3390/ani12213036

Sobrino, A., Phan, D. T., Datta, R. et al. (2016). 3D microtumors in vitro supported by perfused vascular networks. Sci Rep 6, 31589. doi:10.1038/srep31589

Sodero, G., Gentili, C., Mariani, F. et al. (2024). Procalcitonin and presepsin as markers of infectious respiratory diseases in children: a scoping review of the literature. Children, 11, 350. doi:10.3390/children11030350

Somers, G. I., Lindsay, N., Lowdon, B. M. et al. (2007). A comparison of the expression and metabolizing activities of phase I and II enzymes in freshly isolated human lung parenchymal cells and cryopreserved human hepatocytes. Drug Metab Dispos 35, 1797-1805. doi:10.1124/dmd.107.015966

Srivastava, S., Kedia, S., Kumar, S. et al. (2015). Serum human trefoil factor 3 is a biomarker for mucosal healing in ulcerative colitis patients with minimal disease activity. J Crohns Colitis 9, 575-579. doi:10.1093/ecco-jcc/jjv075

Stern, S., Wang, H. and Sadrieh, N. (2023). Microphysiological models for mechanistic-based prediction of idiosyncratic dili. Cells 12. doi:10.3390/cells12111476

Strelez, C., Chilakala, S., Ghaffarian, K. et al. (2021). Human colorectal cancer-on-chip model to study the microenvironmental influence on early metastatic spread. iScience 24, 102509. doi:10.1016/j.isci.2021.102509

Strimbu, K. and Tavel, J. A. (2010). What are biomarkers? Curr Opin HIV AIDS 5, 463-466. doi:10.1097/COH.0b013e32833ed177

Strobel, S., Kostadinova, R., Fiaschetti-Egli, K. et al. (2021). A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates. Sci Rep 11, 22765. doi:10.1038/s41598-021-01951-7

Strong, P., Ito, K., Murray, J. et al. (2018). Current approaches to the discovery of novel inhaled medicines. Drug Discovery Today 23, 1705-1717. doi:10.1016/j.drudis.2018.05.017

Sumigray, K. D., Terwilliger, M. and Lechler, T. (2018). Morphogenesis and compartmentalization of the intestinal crypt. Dev Cell 45, 183-197 e185. doi:10.1016/j.devcel.2018.03.024

Sun, D., Gao, W., Hu, H. et al. (2022). Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B 12, 3049-3062. doi:10.1016/j.apsb.2022.02.002

Sung, J. H., Wang, Y. I., Sriram, N. N. et al. (2019). Recent advances in body-on-a-chip systems. Anal Chem 91, 330-351. doi:10.1021/acs.analchem.8b05293

Swaters, D., van Veen, A., van Meurs, W. et al. (2022). a history of regulatory animal testing: what can we learn? Altern Lab Anim 50, 322-329. doi:10.1177/02611929221118001

Swift, B., Pfeifer, N. D. and Brouwer, K. L. (2010). Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity. Drug Metab Rev 42, 446-471. doi:10.3109/03602530903491881

Tacke, F. and Weiskirchen, R. (2012). Update on hepatic stellate cells: pathogenic role in liver fibrosis and novel isolation techniques. Expert Rev Gastroenterol Hepatol 6, 67-80. doi:10.1586/egh.11.92

Tagle, D. A. (2019). The NIH microphysiological systems program: developing in vitro tools for safety and efficacy in drug development. Curr Opin Pharmacol 48, 146-154. doi:10.1016/j.coph.2019.09.007

Takahashi, K. and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676. doi:10.1016/j.cell.2006.07.024

Takeda, M., Miyagawa, S., Fukushima, S. et al. (2018). Development of in vitro drug-induced cardiotoxicity assay by using three-dimensional cardiac tissues derived from human induced pluripotent stem cells. Tissue Eng Part C Methods 24, 56-67. doi:10.1089/ten.TEC.2017.0247

Tan, K., Coppeta, J., Azizgolshani, H. et al. (2020). A high-throughput microfluidic microphysiological system (PREDICT-96) to recapitulate hepatocyte function in dynamic, re-circulating flow conditions. Lab Chip 20, 3653-3653. doi:10.1039/d0lc90069a

Tan, Y., Zhan, X. J., Cui, H. B. et al. (2021). The application of procalcitonin in respiratory diseases: an evaluation of the current research literature. Ann Palliat Med 10, 5329-5340. doi:10.21037/apm-21-840

Tasnim, F., Huang, X., Lee, C. Z. W. et al. (2021). Recent advances in models of immune-mediated drug-induced liver injury. Front Toxicol 3, 605392. doi:10.3389/ftox.2021.605392

Tatrai, P. and Krajcsi, P. (2020). Prediction of drug-induced hyperbilirubinemia by in vitro testing. Pharmaceutics 12, 755. doi:10.3390/pharmaceutics12080755

Taylor, D. L., Gough, A., Schurdak, M. E. et al. (2019). Harnessing human microphysiology systems as key experimental models for quantitative systems pharmacology. Handb Exp Pharmacol 260, 327-367. doi:10.1007/164_2019_239

Temple, R. (2006). Hy's Law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 15, 241-243. doi:10.1002/pds.1211

Ternes, D., Karta, J., Tsenkova, M. et al. (2020). Microbiome in colorectal cancer: how to get from meta-omics to mechanism? Trends Microbiol 28, 698-698. doi:10.1016/j.tim.2020.05.013

Ternes, D., Tsenkova, M., Pozdeev, V. I. et al. (2022). The gut microbial metabolite formate exacerbates colorectal cancer progression. Nat Metab 4, 458-475. doi:10.1038/s42255-022-00558-0

Teufel, A., Itzel, T., Erhart, W. et al. (2016). Comparison of gene expression patterns between mouse models of nonalcoholic fatty liver disease and liver tissues from patients. Gastroenterology 151, 513-525 e510. doi:10.1053/j.gastro.2016.05.051

Thelen, K. and Dressman, J. B. (2009). Cytochrome P450-mediated metabolism in the human gut wall. J Pharm Pharmacol 61, 541-558. doi:10.1211/jpp/61.05.0002

Theobald, J., Maaty, M. A., Kusterer, N. et al. (2019). In vitro metabolic activation of vitamin D3 by using a multi-compartment microfluidic liver-kidney organ on chip platform. Sci Rep 9, 4616. doi:10.1038/s41598-019-40851-9

Thummel, K. E. (2007). Gut instincts: CYP3A4 and intestinal drug metabolism. J Clin Invest 117, 3173-3176. doi:10.1172/JCI34007

Tonon, F., Giobbe, G. G., Zambon, A. et al. (2019). In vitro metabolic zonation through oxygen gradient on a chip. Sci Rep 9, 13557. doi:10.1038/s41598-019-49412-6

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. doi:10.1126/sciadv.abd1707

Travaglini, K. J., Nabhan, A. N., Penland, L. et al. (2020). A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature 587, 619-625. doi:10.1038/s41586-020-2922-4

Treyer, A. and Musch, A. (2013). Hepatocyte polarity. Compr Physiol 3, 243-287. doi:10.1002/cphy.c120009

Tsao, C. W., Aday, A. W., Almarzooq, Z. I. et al. (2023). Heart disease and stroke statistics-2023 update: a report from the american heart association. Circulation 147, E93-E621. doi:10.1161/Cir.0000000000001123

Tu, C. Y., Chao, B. S. and Wu, J. C. (2018). Strategies for improving the maturity of human induced pluripotent stem cell-derived cardiomyocytes. Circ Res 123, 512-514. doi:10.1161/Circresaha.118.313472

Tutty, M. A., Movia, D. and Prina-Mello, A. (2022). Three-dimensional (3D) liver cell models - a tool for bridging the gap between animal studies and clinical trials when screening liver accumulation and toxicity of nanobiomaterials. Drug Deliv Transl Res 12, 2048-2074. doi:10.1007/s13346-022-01147-0

Vaduganathan, M., Mensah, G. A., Turco, J. V. et al. (2022). The global burden of cardiovascular diseases and risk: a compass for future health. J Am Coll Cardiol 80, 2361-2371. doi:10.1016/j.jacc.2022.11.005

Valiei, A., Aminian-Dehkordi, J. and Mofrad, M. R. K. (2023). Gut-on-a-chip models for dissecting the gut microbiology and physiology. APL Bioeng 7, 011502. doi:10.1063/5.0126541

van den Berg, A., Mummery, C. L., Passier, R. et al. (2019). Personalised organs-on-chips: functional testing for precision medicine. Lab Chip 19, 198-205. doi:10.1039/c8lc00827b

van Grunsven, L. A. (2017). 3D in vitro models of liver fibrosis. Adv Drug Deliv Rev 121, 133-146. doi:10.1016/j.addr.2017.07.004

van Meer, B. J., de Vries, H., Firth, K. S. A. et al. (2017). Small molecule absorption by PDMS in the context of drug response bioassays. Biochem Biophys Res Commun 482, 323-328. doi:10.1016/j.bbrc.2016.11.062

van Ness, K. P., Cesar, F., Yeung, C. K. et al. (2022). Microphysiological systems in absorption, distribution, metabolism, and elimination sciences. Clin Transl Sci 15, 9-42. doi:10.1111/cts.13132

van Spreeuwel, A. C. C., Bax, N. A. M., van Nierop, B. J. et al. (2017). Mimicking cardiac fibrosis in a dish: fibroblast density rather than collagen density weakens cardiomyocyte function. J Cardiovasc Transl Res 10, 116-127. doi:10.1007/s12265-017-9737-1

Veldhuizen, J., Migrino, R. Q. and Nikkhah, M. (2019). Three-dimensional microengineered models of human cardiac diseases. J Biol Eng 13, 29. doi:10.1186/s13036-019-0155-6

Venturelli, O. S., Carr, A. C., Fisher, G. et al. (2018). Deciphering microbial interactions in synthetic human gut microbiome communities. Mol Syst Biol 14, e8157. doi:10.15252/msb.20178157

Vilstrup, H. (1980). Synthesis of urea after stimulation with amino-acids - relation to liver-function. Gut 21, 990-995. doi:10.1136/gut.21.11.990

Vivares, A., Salle-Lefort, S., Arabeyre-Fabre, C. et al. (2015). Morphological behaviour and metabolic capacity of cryopreserved human primary hepatocytes cultivated in a perfused multiwell device. Xenobiotica 45, 29-44. doi:10.3109/00498254.2014.944612

Volpe, D. A. (2010). Application of method suitability for drug permeability classification. AAPS J 12, 670-678. doi:10.1208/s12248-010-9227-8

Volpe, D. A. (2011). Drug-permeability and transporter assays in Caco-2 and MDCK cell lines. Future Med Chem 3, 2063-2077. doi:10.4155/fmc.11.149

Vreugdenhil, A. C., Wolters, V. M., Adriaanse, M. P. et al. (2011). Additional value of serum I-FABP levels for evaluating celiac disease activity in children. Scand J Gastroenterol 46, 1435-1441. doi:10.3109/00365521.2011.627447

Vuorenpaa, H., Bjorninen, M., Valimaki, H. et al. (2023). Building blocks of microphysiological system to model physiology and pathophysiology of human heart. Front Physiol 14, 1213959. doi:10.3389/fphys.2023.1213959

Walker, E. G., Baker, A. F. and Sauer, J. M. (2016). Promoting adoption of the 3Rs through regulatory qualification. Ilar Journal 57(2), 221-225. doi:10.1093/ilar/ilw032

Walker, T. R., Land, M. L., Kartashov, A. et al. (2007). Fecal lactoferrin is a sensitive and specific marker of disease activity in children and young adults with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 44, 414-422. doi:10.1097/MPG.0b013e3180308d8e

Wang, B. Z., Nash, T. R., Zhang, X. et al. (2023). Engineered cardiac tissue model of restrictive cardiomyopathy for drug discovery. Cell Rep Med 4, 100976. doi:10.1016/j.xcrm.2023.100976

Wang, H., Wen, T. Q., Zhu, W. et al. (2024). Microfluidic strategies for biomimetic lung chip establishment and SARS-CoV2 study. Mater Today Bio 24, 100905. doi:10.1016/j.mtbio.2023.100905

Wang, Y., Kim, R., Gunasekara, D. B. et al. (2018a). Formation of human colonic crypt array by application of chemical gradients across a shaped epithelial monolayer. Cell Mol Gastroenterol Hepatol 5, 113-130. doi:10.1016/j.jcmgh.2017.10.007

Wang, Y., Wang, H., Deng, P. et al. (2018b). In situ differentiation and generation of functional liver organoids from human iPSCs in a 3D perfusable chip system. Lab Chip 18, 3606-3616. doi:10.1039/c8lc00869h

Wange, R. L., Brown, P. C. and Davis-Bruno, K. L. (2021). Implementation of the principles of the 3Rs of animal testing at CDER: Past, present and future. Regul Toxicol Pharmacol 123, 104953. doi:10.1016/j.yrtph.2021.104953

Wesseler, M. F., Taebnia, N., Harrison, S. et al. (2023). 3D microperfusion of mesoscale human microphysiological liver models improves functionality and recapitulates hepatic zonation. Acta Biomaterialia 171, 336-349. doi:10.1016/j.actbio.2023.09.022

Wieckowska, A., Zein, N. N., Yerian, L. M. et al. (2006). In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease. Hepatology 44, 27-33. doi:10.1002/hep.21223

Woodcock, J. and Woosley, R. (2008). The FDA critical path initiative and its influence on new drug development. Annu Rev Med 59, 1-12. doi:10.1146/annurev.med.59.090506.155819

Wright, N. A., Poulsom, R., Stamp, G. et al. (1993). Trefoil peptide gene expression in gastrointestinal epithelial cells in inflammatory bowel disease. Gastroenterology 104, 12-20. doi:10.1016/0016-5085(93)90830-6

Wu, P., Deng, G., Sai, X. et al. (2021). Maturation strategies and limitations of induced pluripotent stem cell-derived cardiomyocytes. Biosci Rep 41. doi:10.1042/BSR20200833

Wu, Q., Zhang, P., O'Leary, G. et al. (2023). Flexible 3D printed microwires and 3D microelectrodes for heart-on-a-chip engineering. Biofabrication 15, 035023. doi:10.1088/1758-5090/acd8f4

Xian, C., Zhang, J., Zhao, S. et al. (2023). Gut-on-a-chip for disease models. J Tissue Eng 14, 20417314221149882. doi:10.1177/20417314221149882

Xiao, Y., Zhang, B., Liu, H. et al. (2014). Microfabricated perfusable cardiac biowire: a platform that mimics native cardiac bundle. Lab Chip 14, 869-882. doi:10.1039/c3lc51123e

Xu, H., Wali, R., Cheruiyot, C. et al. (2021). Non-negative blind deconvolution for signal processing in a CRISPR-edited iPSC-cardiomyocyte model of dilated cardiomyopathy. FEBS Lett 595, 2544-2557. doi:10.1002/1873-3468.14189

Xu, Q. (2021). Human three-dimensional hepatic models: cell type variety and corresponding applications. Front Bioeng Biotechnol 9, 730008. doi:10.3389/fbioe.2021.730008

Yamazaki, D. (2023). Toward regulatory acceptance of MPS-cardiac safety assessment as an example. Yakugaku Zasshi 143, 55-63. doi:10.1248/yakushi.22-00161-3

Yang, L., Price, E. T., Chang, C. W. et al. (2013). Gene expression variability in human hepatic drug metabolizing enzymes and transporters. Plos One 8, e60368. doi:10.1371/journal.pone.0060368

Yang, S., Zhang, T., Ge, Y. et al. (2023). Sentinel supervised lung-on-a-chip: A new environmental toxicology platform for nanoplastic-induced lung injury. J Hazard Mater 15, 131962. doi:10.1016/j.jhazmat.2023.131962

Yang, S., Ooka, M., Margolis, R. J. et al. (2023). Liver three-dimensional cellular models for high-throughput chemical testing. Cell Rep Methods 3, 100432. doi:10.1016/j.crmeth.2023.100432

Yeon, J. H. and Park, J. K. (2009). Drug permeability assay using microhole-trapped cells in a microfluidic device. Anal Chem 81, 1944-1951. doi:10.1021/ac802351w

Yilmaz, Y., Williams, G., Walles, M. et al. (2019). Comparison of rat and human pulmonary metabolism using precision-cut lung slices (PCLS). Drug Metab Lett 13, 53-63. doi:10.2174/1872312812666181022114622

Yimu Zhao, S. L., Okhovatian, S., Liu, C. et al. (2024). Integrating organoids and organ-on-a-chip devices. Nat Rev Bioeng 2, 588–608. doi:10.1038/s44222-024-00207-z

Yoon, H. J., Lee, S., Kim, T. Y. et al. (2022). Sprayable nanomicelle hydrogels and inflammatory bowel disease patient cell chips for development of intestinal lesion-specific therapy. Bioact Mater 18, 433-445. doi:10.1016/j.bioactmat.2022.03.031

Zhang, C. J., Meyer, S. R., O'Meara, M. J. et al. (2023). A human liver organoid screening platform for DILI risk prediction. J Hepatol 78, 998-1006. doi:10.1016/j.jhep.2023.01.019

Zhang, D. and Qiao, L. (2023). Intestine-on-a-chip for intestinal disease study and pharmacological research. VIEW 4(1), 20220037. doi:10.1002/VIW.20220037

Zhang, Y., Xu, D., Bai, L. et al. (2022). A review of non-invasive drug delivery through respiratory routes. Pharmaceutics 14, 1974. doi:10.3390/pharmaceutics14091974

Zhang, S. Y., Ong, W. S. Y., Subelzu, N. et al. (2024). Validation of a Caco-2 microfluidic Chip model for predicting intestinal absorption of BCS Class I-IV drugs. Int J Pharm 656, 124089. doi:10.1016/j.ijpharm.2024.124089

Zhang, X., Jiang, T., Chen, D. et al. (2020). Three-dimensional liver models: state of the art and their application for hepatotoxicity evaluation. Crit Rev Toxicol 50, 279-309. doi:10.1080/10408444.2020.1756219

Zhang, Y., Jia, Y., Zheng, R. (2010). Plasma microRNA-122 as a biomarker for viral-, alcohol-, and chemical-related hepatic diseases. Clin Chem 56, 1830-1838. doi:10.1373/clinchem.2010.147850

Zheng, D., Liwinski, T. and Elinav, E. (2020). Interaction between microbiota and immunity in health and disease. Cell Res 30, 492-506. doi:10.1038/s41422-020-0332-7

Zhou, B., Shi, X., Tang, X. et al. (2022). Functional isolation, culture and cryopreservation of adult human primary cardiomyocytes. Signal Transduct Target Ther 7, 254. doi:10.1038/s41392-022-01044-5

Zhou, Y., Shen, J. X. and Lauschke, V. M. (2019). Comprehensive evaluation of organotypic and microphysiological liver models for prediction of drug-induced liver injury. Front Pharmacol 10, 1093. doi:10.3389/fphar.2019.01093

Zucco, F., Batto, A. F., Bises, G. et al. (2005). An inter-laboratory study to evaluate the effects of medium composition on the differentiation and barrier function of Caco-2 cell lines. Altern Lab Anim 33, 603-618. doi:10.1177/026119290503300618

Zushin, P. J. H., Mukherjee, S., and Wu, J. C. (2023). FDA modernization act 2.0: transitioning beyond animal models with human cells, organoids, and AI/ML-based approaches. J Clin Invest 133, e175824. doi:10.1172/JCI175824