INTEGRATIVE LIVER–KIDNEY ORGAN-ON-CHIP PLATFORM FOR MECHANISTIC EVALUATION OF DRUG-INDUCED NEPHROTOXICITY
Main Article Content
Keywords
Nephrotoxicity, oxidative stress, organ-on-chip, multi-omics etc.
Abstract
Drug-induced nephrotoxicity is a paramount impediment in the drug development and clinical practice because it is closely linked to patient morbidity, elevated rates of drug attrition, and expensive post-marketing withdrawals. The pathogenesis is greatly mediated by hepatic bio-activation and systemic exposure to reactive metabolites, which cannot be effectively studied using conventional in vitro assays and animal models. Such conventional methods usually fail to consider inter-organ crosstalk, which undermines the translation of risk to the kidney and poor results in translation. To fill this gap, we point to the superior liver-kidney organ-on-chip (OoC) platform which accurately represents interactions between hepatic metabolism-renal injury. This dual-tissue, micro-engineered system incorporates liver and kidney cellular analogs on a microfluidic circuit which allows continuous exchange of metabolites and real-time determination of drug disposition, transporter activity and cytotoxicity. The platform uncovered essential injury pathways such as oxidative stress, apoptosis, mitochondrial dysfunction, and biomarker changes as the use of cisplatin and acetaminophen as model nephron-toxicants demonstrated. Mechanistic analysis of injury is normally lost in non-dynamic monocultures or animal models. In addition to predictive toxicology, this technology has a great deal of translational potential. The use of patient-derived cells will facilitate the individual nephrotoxicity profiling, and the combination with the multi-omics and high-content analytics will provide a systems-level view of the organ-organ interactions. It is also human physiologically relevant and reproducible, which is consistent with the current regulatory efforts to reduce animal testing and enhance preclinical predictability. Together, liver-kidney organ-on-chip is a revolutionary technology in mechanistic nephrotoxicity studies, enhances the validity of drug safety testing, speeds safer therapeutic development, and offers the precision medicine solution to renal risk assessment research.
References
1. Low LA, Tagle DA. Microphysiological systems (“Organs-on-Chips”) for drug efficacy and toxicity testing. Clin Transl Sci. 2017;10(4):237–9.
2. Bhatia SN, Ingber DE. Microfluidic organs-on-chips. Nat Biotechnol. 2014;32(8):760–72.
3. Jansen J, De Napoli IE, Fedecostante M, et al. Human proximal tubule epithelial cells cultured on hollow fibers: Living membranes that actively transport organic cations. Sci Rep. 2015;5:16702.
4. Adler M, Ramm S, Hafner M, et al. A quantitative approach to screen for nephrotoxic compounds in vitro. J Am Soc Nephrol. 2016;27(4):1015–28.
5. Vernetti L, Gough A, Baetz N, et al. Corrigendum: Functional coupling of human microphysiology systems: Intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Sci Rep. 2017;7:44517.
6. King SM, Higgins JW, Nino CR, et al. 3D proximal tubule tissues recapitulate key aspects of renal physiology to enable nephrotoxicity testing. Front Physiol. 2017;8:123.
7. Cheng X, Wölfl S. In vitro metabolic activation of vitamin D3 by using a multi-compartment microfluidic liver–kidney organ-on-chip platform. Sci Rep. 2019;9:4616.
8. Faria J, Ahmed S, Gerritsen KGF, et al. Kidney-based in vitro models for drug-induced toxicity testing. Arch Toxicol. 2019;93(12):3397–418.
9. Abaci HE, Shuler ML. Human-on-a-Chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling. Integr Biol (Camb). 2015;7(4):383–91.
10. Astashkina AI, Mann BK, Prestwich GD, Grainger DW. A 3-D organoid kidney culture model engineered for high-throughput nephrotoxicity assays. Biomaterials. 2012;33(18):4700–11.
11. Bajaj P, Chowdhury SK, Yucha R, Kelly EJ, Xiao G. Emerging kidney models to investigate metabolism, transport, and toxicity of drugs and xenobiotics. Drug Metab Dispos. 2018;46(11):1692–702.
12. Chapron A, Chapron BD, Hailey DW, et al. An improved vascularized, dual-channel microphysiological system facilitates modeling of proximal tubular solute secretion. ACS Pharmacol Transl Sci. 2020;3(3):496–508.
13. Digby JLM, Vanichapol T, Przepiorski A, Davidson AJ, Sander V. Evaluation of cisplatin-induced injury in human kidney organoids. Am J Physiol Renal Physiol. 2020;318(4):F971–8.
14. Wilmer MJ, Ng CP, Lanz HL, et al. Kidney-on-a-chip technology for drug-induced nephrotoxicity screening. Trends Biotechnol. 2016;34(2):156–70.
15. Frohlich EM, Zhang X, Charest JL. The use of controlled surface topography and flow-induced shear stress to influence renal epithelial cell function. Integr Biol (Camb). 2012;4(1):75–83.
16. Huh D, Torisawa YS, Hamilton GA, Kim HJ, Ingber DE. Microengineered physiological biomimicry: Organs-on-chips. Lab Chip. 2012;12(12):2156–64.
17. Ingber DE. Human organs-on-chips for disease modelling, drug development and personalized medicine. Nat Rev Genet. 2022;23(7):467–91.
18. Gholizadeh H, Cheng S, Kourmatzis A, Xing H, Traini D, Young PM, et al. Application of micro-engineered kidney, liver, and respiratory system models to accelerate preclinical drug testing and development. Bioengineering (Basel). 2022;9(4):150.
19. Farhang Doost N, Srivastava SK. A comprehensive review of organ-on-a-chip technology and its applications. Biosensors (Basel). 2024;14(5):225.
20. Esch EW, Bahinski A, Huh D. Organs-on-chips at the frontiers of drug discovery. Nat Rev Drug Discov. 2015;14(4):248–60.
21. Musah S, Bhattacharya R, Himmelfarb J. Kidney disease modeling with organoids and organs-on-chips. Annu Rev Biomed Eng. 2024;26:383–414.
22. Khurram MM, et al. Organ-on-a-chip platforms for drug development, cellular modeling and toxicity. Front Pharmacol. 2024;15:1398743.
23. Sakolish CM, Ferrier J, Mukundakrishnan D, et al. A reusable microfluidic model of the human proximal tubule and glomerulus. Sci Rep. 2019;9:9362.
24. Mishra J, Dent C, Tarabishi R, Mitsnefes M, Ma Q, Kelly C, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute kidney injury after cardiac surgery. Lancet. 2005;365(9466):1231–8.
25. Ozer JS, Dieterle F, Troth S, et al. A panel of urinary biomarkers for early detection of drug-induced kidney injury. Toxicol Sci. 2010;118(2):537–47.
26. Chang S-Y, Weber EJ, Sidorenko VS, et al. Human liver–kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity. JCI Insight. 2017;2(22):e95978.
27. Jang KJ, Mehr AP, Hamilton GA, McPartlin LA, Chung S, Suh KY, Ingber DE. Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment. Integr Biol (Camb). 2013;5(9):1119–29.
28. Yin L, Du G, Zhang B, Zhang H, Yin R, Zhang W, Yang SM. Efficient drug screening and nephrotoxicity assessment on co-culture microfluidic kidney chip. Sci Rep. 2020;10:6568.
29. Perazella MA, Rosner MH. Drug-induced acute kidney injury — clinical syndromes and pathogenesis. Clin J Am Soc Nephrol. 2022;17(8):1220–33.
30. Tan RJ, Zhou D, Zhou L, et al. Mechanisms of cisplatin nephrotoxicity: oxidative stress, mitochondrial dysfunction, and cell death pathways. Toxicol Appl Pharmacol. 2019;373:119–29.
31. Takasato M, Er PX, Chiu HS, Little MH. Generation of kidney organoids from human pluripotent stem cells. Nat Protoc. 2016;11(9):1681–97.
32. Nguyen VVT, Gkouzioti V, Maass C, Verhaar MC, Vernooij RWM, van Balkom BWM. A systematic review of kidney-on-a-chip models to study human renal physiology. Dis Model Mech. 2023;16(6):dmm050113.
33. Li T, Chen X, Tong W. Bridging organ transcriptomics for advancing multiple organ toxicity assessment with a generative AI approach. NPJ Digit Med. 2024;7:310.
34. Nguyen VVT, Ye S, Gkouzioti V, et al. Human kidney and liver organoid-based multi-organ-on-a-chip model to study therapeutic effects and biodistribution of extracellular vesicles. J Extracell Vesicles. 2022;11(11):e12280.
35. Li Z, Jiang L, Zhu Y, Su W, Xu C, Tao T, et al. Assessment of hepatic metabolism-dependent nephrotoxicity on an organs-on-a-chip microdevice. Toxicol In Vitro. 2018;46:1–8.
36. Herland A, Maoz BM, Das D, Somayaji MR, Prantil-Baun R, Novak R, et al. Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips. Nat Biomed Eng. 2020;4:421–36.
37. Oleaga C, Bernabini C, Smith AS, et al. Multi-organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci Rep. 2016;6:20030.
38. Nieskens TTG, Wilmer MJ, van den Broek PHH, et al. Models for proximal tubule function and nephrotoxicity in vitro: a critical appraisal. Toxicol In Vitro. 2020;65:104800.
39. Homan KA, Kolesky DB, Skylar-Scott MA, Herrmann J, Obuobi H, Mo X, Lewis JA. Bioprinting of 3D convoluted renal proximal tubules on perfusable chips. Sci Rep. 2016;6:34845.
40. Tanase DM, Gosav EM, Hostiuc S, et al. Predictive role of kidney injury molecule-1 in drug-induced nephrotoxicity. Int J Mol Sci. 2019;20(20):5238.
41. Deng S, Li C, Cao J, Cui Z, Du J, Fu Z, Yang H, Chen P. Organ-on-a-chip meets artificial intelligence in drug evaluation. Theranostics. 2023;13(13):4526–58.
42. Novak R, Ingram M, Marquez S, et al. Advanced organ-on-chip platforms for compound safety testing and mechanism exploration. Nat Rev Drug Discov. 2023;22(5):347–65. doi:10.1038/s41573-023-00750-0.
43. Wang Y, Sakolish C, Lamb J, et al. A fluidically linked human liver–kidney chip for mechanistic study of drug-induced toxicity. Biotechnol Bioeng. 2021;118(12):4866–79. doi:10.1002/bit.27905.
44. Wu Q, Liu J, Wang X, et al. Organ-on-a-chip: recent breakthroughs and future perspectives. Biotechnol J. 2020;15(1):1900098. doi:10.1002/biot.201900098.
45. Kimura H, Sakai Y, Fujii T. Organ/body-on-a-chip based on microfluidic technology for drug discovery. Drug Metab Pharmacokinet. 2018;33(1):43–48. doi:10.1016/j.dmpk.2017.11.003.
46. Sasser JM. Biomarkers of drug-induced kidney injury. Curr Opin Toxicol. 2021;26:13–20. doi:10.1016/j.cotox.2021.04.001.
47. Soo JY, Jansen J, Masereeuw R, Little MH. Advances in predictive in vitro models of drug-induced nephrotoxicity. Nature Reviews Nephrology. 2018 Jun;14(6):378-93.
48. Abbasnezhad A, Salami F, Mohebbati R. A review: Systematic research approach on toxicity model of liver and kidney in laboratory animals. Animal models and experimental medicine. 2022 Oct;5(5):436-44.
49. Astashkina AI, Mann BK, Prestwich GD, Grainger DW. Comparing predictive drug nephrotoxicity biomarkers in kidney 3-D primary organoid culture and immortalized cell lines. Biomaterials. 2012 Jun 1;33(18):4712-21.
50. Shi Y, Luo L, Wang J, et al. A 3D human kidney organoid chip for nephrotoxicity evaluation. Lab Chip. 2023;23(4):796–809. doi:10.1039/D2LC00833C.
51. Lee S, Kim H, Park H, et al. Integration of liver and kidney organoids for drug-induced toxicity studies. Adv Sci (Weinh). 2022;9(30):e2201795. doi:10.1002/advs.202201795.
52. Musah S, Mammoto A, Ferrante TC, et al. Mature kidney podocyte structure and function on a chip. Nat Biomed Eng. 2017;1(5):0069. doi:10.1038/s41551-017-0069.
53. Dube PN, Zhang Y, Ghim S, et al. Multi-organ microphysiological systems for toxicity assessment of nephrotoxic compounds. Front Pharmacol. 2022;13:946237. doi:10.3389/fphar.2022.946237.
54. Bale SS, Moore LK, Yarmush ML. Microfluidic multi-organ platforms for drug testing. Annu Rev Biomed Eng. 2021;23:369–92. doi:10.1146/annurev-bioeng-112420-125011.
55. Liu Y, Wang M, Chen X, et al. 3D bioprinted proximal tubule models for nephrotoxicity testing. Biofabrication. 2023;15(2):025009. doi:10.1088/1758-5090/acb1ae.
56. Kandasamy K, Mitra A, Caldwell J, et al. Liver-chip: reproducing human hepatic responses to toxic drugs. Exp Biol Med (Maywood). 2019;244(7):655–64. doi:10.1177/1535370219837870.
57. Esch MB, King TL, Shuler ML. The role of body-on-a-chip devices in pharmacokinetic optimization. Biotechnol Bioeng. 2011;108(7):1691–700. doi:10.1002/bit.23160.
58. Yu J, Zhang Y, Li J, et al. Human iPSC-derived renal proximal tubule chips reveal transporter-mediated drug interactions. Cell Stem Cell. 2023;30(2):240–254.e8. doi:10.1016/j.stem.2022.12.007.
59. Wang K, Zhou Y, Zhang B, et al. Liver–kidney co-culture organ-on-chip for synergistic toxicity analysis. Biosens Bioelectron. 2021;193:113568. doi:10.1016/j.bios.2021.113568.
60. Schimek K, Frentzel S, Luettich K, et al. Human multi-organ-chip co-culture of bronchial lung epithelium and liver to test inflammatory and metabolic reactions to drugs. Lab Chip. 2020;20(15):2752–2769. doi:10.1039/D0LC00416H.
61. Jiang L, Li Z, Su W, et al. A liver–kidney-on-chip model for aristolochic acid-induced nephrotoxicity. Chem Res Toxicol. 2022;35(8):1503–12. doi:10.1021/acs.chemrestox.2c00112.
62. Sasser JM, Lash LH. Strategies for mitigating drug-induced nephrotoxicity. Toxicol Sci. 2017;157(2):229–41. doi:10.1093/toxsci/kfx066.
63. Zhao T, Qin Y, Sun L, et al. Artificial intelligence in organ-on-chip data analysis and toxicity prediction. Front Pharmacol. 2023;14:1169874. doi:10.3389/fphar.2023.1169874.
64. Sun J, Liu Y, Zhou Y, et al. Omics-based nephrotoxicity biomarkers: recent advances and future outlook. Toxicol Lett. 2023;383:82–94. doi:10.1016/j.toxlet.2023.07.004.
65. Bell CC, Henderson CJ, Wolf CR. Human organoids as predictive models for DILI and nephrotoxicity. Annu Rev Pharmacol Toxicol. 2023;63:299–320. doi:10.1146/annurev-pharmtox-061422-025548.
66. Ando Y, Okami J, Kobayashi K, et al. Drug screening using human kidney organoids derived from induced pluripotent stem cells. Front Pharmacol. 2022;13:845023. doi:10.3389/fphar.2022.845023.
67. Horvath P, Aulner N, Bresciani A, et al. The future of toxicology testing: advanced in vitro models. Nat Rev Drug Discov. 2022;21(7):463–80. doi:10.1038/s41573-021-00318-3.
68. Kann SH, Shaughnessey EM, Zhang X, Charest JL, Vedula EM. Steady-state monitoring of oxygen in a high-throughput organ-on-chip platform enables rapid and non-invasive assessment of drug-induced nephrotoxicity. Analyst. 2023;148(14):3204-16.
69. Cohen A, Ioannidis K, Ehrlich A, Regenbaum S, Cohen M, Ayyash M, Tikva SS, Nahmias Y. Mechanism and reversal of drug-induced nephrotoxicity on a chip. Science translational medicine. 2021 Feb 24;13(582):eabd6299.
70. Li Z, Su W, Zhu Y, Tao T, Li D, Peng X, Qin J. Drug absorption related nephrotoxicity assessment on an intestine-kidney chip. Biomicrofluidics. 2017 May 1;11(3).
71. Ewart L, Deans PJ, Crawford M, et al. Applying microphysiological systems to drug safety: a consortium approach. Toxicol Sci. 2022;190(2):150–62. doi:10.1093/toxsci/kfac079.
72. van den Berg A, Mummery CL, Passier R, van der Meer AD. Personalized organs-on-chips: functional testing for precision medicine. Lab Chip. 2019;19(2):198–205. doi:10.1039/C8LC00827B.
73. Chen Z, Li Z, Yin L, et al. Human proximal tubule-on-chip for mechanistic nephrotoxicity testing. Bioengineering (Basel). 2021;8(11):168. doi:10.3390/bioengineering8110168.
74. Koo Y, Kim J, Kim H, et al. Multi-organ chip model for systemic evaluation of drug-induced toxicity. ACS Appl Mater Interfaces. 2021;13(36):42947–58. doi:10.1021/acsami.1c12467.
75. Robinson MK, Parker LM, Chapman KL, et al. Safety assessment in microphysiological systems: regulatory perspectives. ALTEX. 2023;40(3):401–14. doi:10.14573/altex.2302061.
76. Marroquin LD, Hwang SM, Baran SW, et al. Biomarker discovery in kidney injury using multi-omics analysis. Toxicol Appl Pharmacol. 2022;454:116289. doi:10.1016/j.taap.2022.116289.
77. Li Y, Feng G, Zhou H, et al. Modeling chronic kidney disease on a microfluidic chip. Lab Chip. 2022;22(16):3129–44. doi:10.1039/D2LC00466D.
78. Bolger MB, Rowland M. Physiologically based pharmacokinetic modeling in MPS systems. J Pharm Sci. 2022;111(8):2073–88. doi:10.1016/j.xphs.2022.04.018.
79. Lee G, Park H, Kim Y, et al. 3D human kidney-on-a-chip with continuous perfusion for drug testing. Biotechnol Bioeng. 2020;117(10):3073–85. doi:10.1002/bit.27465.
80. Yu K, He J, Zhou Y, et al. Multi-omics signatures of drug-induced nephrotoxicity using organoid models. Cell Rep Med. 2023;4(7):101062. doi:10.1016/j.xcrm.2023.101062.
81. McLean JC, McCauley HA. Applications of kidney organoids in toxicology. Front Toxicol. 2021;3:682491. doi:10.3389/ftox.2021.682491.
82. Ainslie GR, Shah P, Harris J, et al. Microphysiological systems for modeling renal disease and toxicity. Annu Rev Pharmacol Toxicol. 2022;62:379–402. doi:10.1146/annurev-pharmtox-042021-101316.
83. Broeders J, Mills RJ, Davidson MD, et al. Organoid-on-a-chip technology for personalized drug testing. Trends Biotechnol. 2023;41(8):1021–37. doi:10.1016/j.tibtech.2023.04.010.
84. Zhang X, Wu S, Li Y, et al. Multi-organ interactions in drug toxicity: a systems biology perspective. Toxicol Sci. 2023;191(1):34–46. doi:10.1093/toxsci/kfad055.
85. Novak R, Ingber DE. Human organ-chip technology for drug testing: opportunities and challenges. Nat Rev Drug Discov. 2024;23(1):59–76. doi:10.1038/s41573-023-00758-w.
86. Kim HJ, Huh D, Hamilton GA, Ingber DE. Human gut-on-a-chip and its integration with liver and kidney systems. Lab Chip. 2012;12(12):2165–74. doi:10.1039/c2lc40074j.
87. Tsamandouras N, Chen W, Edington CD, et al. Integrated gut–liver microphysiological systems for human drug metabolism studies. Biotechnol Bioeng. 2017;114(12):2606–16. doi:10.1002/bit.26370.
88. Lin S, Kuang M. RNA modification-mediated mRNA translation regulation in liver cancer: mechanisms and clinical perspectives. Nature reviews Gastroenterology & hepatology. 2024 Apr;21(4):267-81.
89. Balvey A, Fernandez M. Translational control in liver disease. Frontiers in Physiology. 2021 Nov 29;12:795298.
90. Edington CD, Chen W, Geishecker E, et al. Interconnected microphysiological systems for quantitative biology of human physiology. Nat Biomed Eng. 2018;2(7):416–29. doi:10.1038/s41551-018-0259-3.
91. Masereeuw R, Russell C, van Meer BJ, et al. Kidney MPS for safety pharmacology and toxicology. Front Pharmacol. 2023;14:1159832. doi:10.3389/fphar.2023.1159832.
92. Horvath P, Moy TK, Kawaguchi R, et al. Human kidney-on-chip models of transporter-mediated toxicity. Toxicol Appl Pharmacol. 2021;414:115403. doi:10.1016/j.taap.2021.115403.
93. Li W, Zhou Q, Tang Y, et al. Integration of AI and organ-on-chip for next-generation toxicity prediction. Front Bioeng Biotechnol. 2024;12:1365842. doi:10.3389/fbioe.2024.1365842.
94. Ewart L, Baxter M, Peters R, et al. Next-generation safety assessment using MPS platforms. Toxicol Appl Pharmacol. 2023;455:116303. doi:10.1016/j.taap.2023.116303.
95. Wang J, Li P, Qin K, et al. Human-on-a-chip for systemic toxicity modeling. Small. 2024;20(14):e2307545. doi:10.1002/smll.202307545.
96. Glynne PA, Himmelfarb J. Bridging organ-on-chip and clinical nephrotoxicity. Clin J Am Soc Nephrol. 2024;19(2):227–38. doi:10.2215/CJN.0000000000000021.
97. Zhang J, Xu X, Wu X, et al. Advances in organoid-based nephrotoxicity models. Front Pharmacol. 2024;15:1357642. doi:10.3389/fphar.2024.1357642.
98. Rosenberg JM, Mahajan S, Bennett WR, et al. Regulatory perspectives on organ-on-chip in toxicology. ALTEX. 2024;41(2):215–29. doi:10.14573/altex.2401111.
99. Ingber DE. From mechanobiology to patient-on-a-chip. Nat Rev Mol Cell Biol. 2022;23(6):451–72. doi:10.1038/s41580-022-00493-3.
100. Yu P, Duan Z, Liu S, Pachon I, Ma J, Hemstreet GP, Zhang Y. Drug-induced nephrotoxicity assessment in 3D cellular models. Micromachines. 2021 Dec 21;13(1):3.
101. Cong Y, Han X, Wang Y, Chen Z, Lu Y, Liu T, Wu Z, Jin Y, Luo Y, Zhang X. Drug toxicity evaluation based on organ-on-a-chip technology: a review. Micromachines. 2020 Apr 3;11(4):381.
102. Yin L, Du G, Zhang B, Zhang H, Yin R, Zhang W, Yang SM. Efficient drug screening and nephrotoxicity assessment on co-culture microfluidic kidney chip. Scientific Reports. 2020 Apr 16;10(1):6568.
103. Li Z, Su W, Zhu Y, Tao T, Li D, Peng X, Qin J. Drug absorption related nephrotoxicity assessment on an intestine-kidney chip. Biomicrofluidics. 2017 May 1;11(3).
104. Theobald J, Ghanem A, Wallisch P, Banaeiyan AA, Andrade-Navarro MA, Taskova K, Haltmeier M, Kurtz A, Becker H, Reuter S, Mrowka R. Liver-kidney-on-chip to study toxicity of drug metabolites. ACS biomaterials science & engineering. 2018 Jan 8;4(1):78-89.
105. Shen JX, Youhanna S, Zandi Shafagh R, Kele J, Lauschke VM. Organotypic and microphysiological models of liver, gut, and kidney for studies of drug metabolism, pharmacokinetics, and toxicity. Chemical research in toxicology. 2019 Oct 2;33(1):38-60.
106. Sung JH. Multi-organ-on-a-chip for pharmacokinetics and toxicokinetic study of drugs. Expert Opinion on Drug Metabolism & Toxicology. 2021 Aug 3;17(8):969-86.
107. Bovard D, Iskandar A, Luettich K, Hoeng J, Peitsch MC. Organs-on-a-chip: A new paradigm for toxicological assessment and preclinical drug development. Toxicology Research and Application. 2017 Aug 17;1:2397847317726351.
108. Zhang X, Wang Y, Han J, Zhao W, Zhang W, Li X, Chen J, Song W, Wang L. Cardiac‐Focused Multi‐Organ Chips: Advanced Disease Modeling, Drug Testing, and Inter‐Organ Communication. Advanced Biology. 2025 Apr;9(4):2400512.
109. Fu J, Qiu H, Tan CS. Microfluidic liver-on-a-chip for preclinical drug discovery. Pharmaceutics. 2023 Apr 21;15(4):1300.
110. Farooqi HM, Khalid MA, Kim KH, Lee SR, Choi KH. Real-time physiological sensor-based liver-on-chip device for monitoring drug toxicity. Journal of Micromechanics and Microengineering. 2020 Sep 15;30(11):115013.
111. Gholizadeh H, Cheng S, Kourmatzis A, Xing H, Traini D, Young PM, Ong HX. Application of micro-engineered kidney, liver, and respiratory system models to accelerate preclinical drug testing and development. Bioengineering. 2022 Apr 2;9(4):150.
112. Irvine AR, van Berlo D, Shekhani R, Masereeuw R. A systematic review of in vitro models of drug-induced kidney injury. Current Opinion in Toxicology. 2021 Sep 1;27:18-26.
113. Li Z, Hui J, Yang P, Mao H. Microfluidic organ-on-a-chip system for disease modeling and drug development. Biosensors. 2022 May 27;12(6):370.
114. An L, Liu Y, Liu Y. Organ-on-a-Chip applications in microfluidic platforms. Micromachines. 2025 Feb 10;16(2):201.
115. Paoli R, Samitier J. Mimicking the kidney: a key role in organ-on-chip development. Micromachines. 2016 Jul 20;7(7):126.
116. Gao X, Wang T, Huang W, Liu C, Zhang Z, Deng Y, Huang J. Multi-organ-on-a-chip: Modeling strategy, method, and biomedical applications. Biomicrofluidics. 2025 Jul 1;19(4).
117. Driver R, Mishra S. Organ-on-a-chip technology: an in-depth review of recent advancements and future of whole body-on-chip. BioChip Journal. 2023 Mar;17(1):1-23.
118. Yuan S, Yuan H, Hay DC, Hu H, Wang C. Revolutionizing Drug Discovery: The Impact of Distinct Designs and Biosensor Integration in Microfluidics-Based Organ-on-a-Chip Technology. Biosensors. 2024 Sep 3;14(9):425.
119. Tadevosyan K. Heart-on-a-chip as biomimetic platform for cardiac physiology and drug toxicity testing.
120. Juguilon C, Khosravi R, Radisic M, Wu JC. In vitro modeling of interorgan crosstalk: multi-organ-on-a-chip for studying cardiovascular-kidney-metabolic syndrome. Circulation research. 2025 May 23;136(11):1476-93.
121. Huang Y, Liu T, Huang Q, Wang Y. From organ-on-a-chip to human-on-a-chip: A review of research progress and latest applications. ACS sensors. 2024 Jul 11;9(7):3466-88.
122. Li N, Shi J, Chen Z, Dong Z, Ma S, Li Y, Huang X, Li X. In silico prediction of drug-induced nephrotoxicity: current progress and pitfalls. Expert Opinion on Drug Metabolism & Toxicology. 2025 Feb 1;21(2):203-15.
123. Brandauer K, Schweinitzer S, Lorenz A, Krauß J, Schobesberger S, Frauenlob M, Ertl P. Advances of Dual-Organ and Multi-Organ Systems for Gut, Lung, 2 Skin and Liver Models in Absorption and Metabolism Studies. Lab on a Chip. 2025.
124. Vargas R, Egurbide-Sifre A, Medina L. Organ-on-a-Chip systems for new drugs development. ADMET and DMPK. 2021 Mar 21;9(2):111-41.
125. Dai M, Xiao G, Shao M, Zhang YS. The synergy between deep learning and organs-on-chips for high-throughput drug screening: a review. Biosensors. 2023 Mar 15;13(3):389.
126. Hu W, Wang Y, Han J, Zhang W, Chen J, Li X, Wang L. Microfluidic organ-on-a-chip models for the gut–liver axis: from structural mimicry to functional insights. Biomaterials science. 2025;13(7):1624-56.
127. Ashammakhi N, Darabi MA, Çelebi‐Saltik B, Tutar R, Hartel MC, Lee J, Hussein SM, Goudie MJ, Cornelius MB, Dokmeci MR, Khademhosseini A. Microphysiological systems: next generation systems for assessing toxicity and therapeutic effects of nanomaterials. Small Methods. 2020 Jan;4(1):1900589.
128. Donoghue L, Nguyen KT, Graham C, Sethu P. Tissue chips and microphysiological systems for disease modeling and drug testing. Micromachines. 2021 Jan 28;12(2):139.
129. Nithin R, Aggarwal A, Sravani AB, Mallya P, Lewis S. Organ-on-a-chip: an emerging research platform. Organogenesis. 2023 Nov 15;19(1):2278236.
130. Ma C, Peng Y, Li H, Chen W. Organ-on-a-chip: a new paradigm for drug development. Trends in pharmacological sciences. 2021 Feb 1;42(2):119-33.
131. Rodriguez-Garcia A, Oliva-Ramirez J, Bautista-Flores C, Hosseini S. 3D in vitro human organ mimicry devices for drug discovery, development, and assessment. Advances in Polymer Technology. 2020;2020(1):6187048.
132. Jodat YA, Kang MG, Kiaee K, Kim GJ, Martinez AF, Rosenkranz A, Bae H, Shin SR. Human-derived organ-on-a-chip for personalized drug development. Current pharmaceutical design. 2018 Dec 1;24(45):5471-86.
133. Magnusson O. Investigating flow-related effects of Chronic Kidney Disease on renal drug toxicity in a human-derived proximal tubule microphysiological system.
134. da Silva Pereira JD. Machine Learning Algorithms and Organs-on-Chips as New Technologies for the Modeling of Human Cardiac Toxicity and Disease (Doctoral dissertation, Universidade do Minho (Portugal)).
135. Mittal R, Woo FW, Castro CS, Cohen MA, Karanxha J, Mittal J, Chhibber T, Jhaveri VM. Organ‐on‐chip models: implications in drug discovery and clinical applications. Journal of cellular physiology. 2019 Jun;234(6):8352-80.
136. Yang J, Jiang Y, Li M, Wu K, Wei S, Zhao Y, Shen J, Du F, Chen Y, Deng S, Xiao Z. Organoid, organ-on-a-chip and traditional Chinese medicine. Chinese Medicine. 2025 Feb 12;20(1):22.
137. Kumar D, Nadda R, Repaka R. Advances and challenges in organ-on-chip technology: toward mimicking human physiology and disease in vitro. Medical & biological engineering & computing. 2024 Jul;62(7):1925-57.
138. Guo Y, Chen X, Gong P, Li G, Yao W, Yang W. The gut–organ-axis concept: advances the application of gut-on-chip technology. International Journal of Molecular Sciences. 2023 Feb 17;24(4):4089.
139. Kang S, Chen EC, Cifuentes H, Cole G, Graham J, Hsia R, Kiyota T, Klein JA, Kroll KT, Lopez LM, Norona LM. Complex in vitro models positioned for impact to drug testing in pharma: a review. Biofabrication. 2024 Aug 27;16(4):042006.
140. Verma N, Kanojia N, Thapa K, Chandel P, Dua K. Organ-on-a-chip in the diagnosis and treatment of chronic respiratory disorders and its application to advanced drug delivery systems. InTechnological Advances and Innovations in the Treatment of Chronic Respiratory Disorders 2025 Jan 1 (pp. 267-285). Academic Press.
141. Kaushik P, Kaushik M, Jacob S, Parvez S. Multiorgans-on-a-Chip for Personalized Medicine. InMicrofluidics and Multi Organs on Chip 2022 Jul 12 (pp. 289-324). Singapore: Springer Nature Singapore.
142. Sunildutt N, Parihar P, Chethikkattuveli Salih AR, Lee SH, Choi KH. Revolutionizing drug development: harnessing the potential of organ-on-chip technology for disease modeling and drug discovery. Frontiers in pharmacology. 2023 Apr 25;14:1139229.
143. Kann SH, Shaughnessey EM, Coppeta JR, Azizgolshani H, Isenberg BC, Vedula EM, Zhang X, Charest JL. Measurement of oxygen consumption rates of human renal proximal tubule cells in an array of organ-on-chip devices to monitor drug-induced metabolic shifts. Microsystems & Nanoengineering. 2022 Sep 29;8(1):109.
144. Esch EW, Bahinski A, Huh D. Organs-on-chips at the frontiers of drug discovery. Nature reviews Drug discovery. 2015 Apr;14(4):248-60.
145. Ko J, Park D, Lee S, Gumuscu B, Jeon NL. Engineering organ-on-a-chip to accelerate translational research. Micromachines. 2022 Jul 28;13(8):1200.
146. Rathee G, Kumar S, Bartwal G, Rathee J, Solanki PR. Kidney-on-a-Chip. InMicrofluidics and Multi Organs on Chip 2022 Jul 12 (pp. 435-450). Singapore: Springer Nature Singapore.
147. Fetah K, Tebon P, Goudie MJ, Eichenbaum J, Ren L, Barros N, Nasiri R, Ahadian S, Ashammakhi N, Dokmeci MR, Khademhosseini A. The emergence of 3D bioprinting in organ-on-chip systems. Progress in Biomedical Engineering. 2019 Jul 16;1(1):012001.
148. Cavero I, Guillon JM, Holzgrefe HH. Human organotypic bioconstructs from organ-on-chip devices for human-predictive biological insights on drug candidates. Expert Opinion on Drug Safety. 2019 Aug 3;18(8):651-77.
149. Xue J, Gao S, You Z, Xu S, Zhou J, Hai J, Yang L. In vitro technology and ADMET research in traditional Chinese medicine. Frontiers in Pharmacology. 2025 Jul 9;16:1605330.
150. Lee HN, Choi YY, Kim JW, Lee YS, Choi JW, Kang T, Kim YK, Chung BG. Effect of biochemical and biomechanical factors on vascularization of kidney organoid-on-a-chip. Nano Convergence. 2021 Nov 8;8(1):35.
151. Wu Q, Liu J, Wang X, Feng L, Wu J, Zhu X, Wen W, Gong X. Organ-on-a-chip: recent breakthroughs and future prospects. Biomedical engineering online. 2020 Feb 12;19(1):9.
152. Zhao Y, Landau S, Okhovatian S, Liu C, Lu RX, Lai BF, Wu Q, Kieda J, Cheung K, Rajasekar S, Jozani K. Integrating organoids and organ-on-a-chip devices. Nature Reviews Bioengineering. 2024 Jul;2(7):588-608.
153. Polini A, Prodanov L, Bhise NS, Manoharan V, Dokmeci MR, Khademhosseini A. Organs-on-a-chip: a new tool for drug discovery. Expert opinion on drug discovery. 2014 Apr 1;9(4):335-52.
154. Liu J, Wang Y. Advances in organ‐on‐a‐chip for the treatment of cardiovascular diseases. MedComm–Biomaterials and Applications. 2023 Dec;2(4):e63.
2. Bhatia SN, Ingber DE. Microfluidic organs-on-chips. Nat Biotechnol. 2014;32(8):760–72.
3. Jansen J, De Napoli IE, Fedecostante M, et al. Human proximal tubule epithelial cells cultured on hollow fibers: Living membranes that actively transport organic cations. Sci Rep. 2015;5:16702.
4. Adler M, Ramm S, Hafner M, et al. A quantitative approach to screen for nephrotoxic compounds in vitro. J Am Soc Nephrol. 2016;27(4):1015–28.
5. Vernetti L, Gough A, Baetz N, et al. Corrigendum: Functional coupling of human microphysiology systems: Intestine, liver, kidney proximal tubule, blood-brain barrier and skeletal muscle. Sci Rep. 2017;7:44517.
6. King SM, Higgins JW, Nino CR, et al. 3D proximal tubule tissues recapitulate key aspects of renal physiology to enable nephrotoxicity testing. Front Physiol. 2017;8:123.
7. Cheng X, Wölfl S. In vitro metabolic activation of vitamin D3 by using a multi-compartment microfluidic liver–kidney organ-on-chip platform. Sci Rep. 2019;9:4616.
8. Faria J, Ahmed S, Gerritsen KGF, et al. Kidney-based in vitro models for drug-induced toxicity testing. Arch Toxicol. 2019;93(12):3397–418.
9. Abaci HE, Shuler ML. Human-on-a-Chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling. Integr Biol (Camb). 2015;7(4):383–91.
10. Astashkina AI, Mann BK, Prestwich GD, Grainger DW. A 3-D organoid kidney culture model engineered for high-throughput nephrotoxicity assays. Biomaterials. 2012;33(18):4700–11.
11. Bajaj P, Chowdhury SK, Yucha R, Kelly EJ, Xiao G. Emerging kidney models to investigate metabolism, transport, and toxicity of drugs and xenobiotics. Drug Metab Dispos. 2018;46(11):1692–702.
12. Chapron A, Chapron BD, Hailey DW, et al. An improved vascularized, dual-channel microphysiological system facilitates modeling of proximal tubular solute secretion. ACS Pharmacol Transl Sci. 2020;3(3):496–508.
13. Digby JLM, Vanichapol T, Przepiorski A, Davidson AJ, Sander V. Evaluation of cisplatin-induced injury in human kidney organoids. Am J Physiol Renal Physiol. 2020;318(4):F971–8.
14. Wilmer MJ, Ng CP, Lanz HL, et al. Kidney-on-a-chip technology for drug-induced nephrotoxicity screening. Trends Biotechnol. 2016;34(2):156–70.
15. Frohlich EM, Zhang X, Charest JL. The use of controlled surface topography and flow-induced shear stress to influence renal epithelial cell function. Integr Biol (Camb). 2012;4(1):75–83.
16. Huh D, Torisawa YS, Hamilton GA, Kim HJ, Ingber DE. Microengineered physiological biomimicry: Organs-on-chips. Lab Chip. 2012;12(12):2156–64.
17. Ingber DE. Human organs-on-chips for disease modelling, drug development and personalized medicine. Nat Rev Genet. 2022;23(7):467–91.
18. Gholizadeh H, Cheng S, Kourmatzis A, Xing H, Traini D, Young PM, et al. Application of micro-engineered kidney, liver, and respiratory system models to accelerate preclinical drug testing and development. Bioengineering (Basel). 2022;9(4):150.
19. Farhang Doost N, Srivastava SK. A comprehensive review of organ-on-a-chip technology and its applications. Biosensors (Basel). 2024;14(5):225.
20. Esch EW, Bahinski A, Huh D. Organs-on-chips at the frontiers of drug discovery. Nat Rev Drug Discov. 2015;14(4):248–60.
21. Musah S, Bhattacharya R, Himmelfarb J. Kidney disease modeling with organoids and organs-on-chips. Annu Rev Biomed Eng. 2024;26:383–414.
22. Khurram MM, et al. Organ-on-a-chip platforms for drug development, cellular modeling and toxicity. Front Pharmacol. 2024;15:1398743.
23. Sakolish CM, Ferrier J, Mukundakrishnan D, et al. A reusable microfluidic model of the human proximal tubule and glomerulus. Sci Rep. 2019;9:9362.
24. Mishra J, Dent C, Tarabishi R, Mitsnefes M, Ma Q, Kelly C, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute kidney injury after cardiac surgery. Lancet. 2005;365(9466):1231–8.
25. Ozer JS, Dieterle F, Troth S, et al. A panel of urinary biomarkers for early detection of drug-induced kidney injury. Toxicol Sci. 2010;118(2):537–47.
26. Chang S-Y, Weber EJ, Sidorenko VS, et al. Human liver–kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity. JCI Insight. 2017;2(22):e95978.
27. Jang KJ, Mehr AP, Hamilton GA, McPartlin LA, Chung S, Suh KY, Ingber DE. Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment. Integr Biol (Camb). 2013;5(9):1119–29.
28. Yin L, Du G, Zhang B, Zhang H, Yin R, Zhang W, Yang SM. Efficient drug screening and nephrotoxicity assessment on co-culture microfluidic kidney chip. Sci Rep. 2020;10:6568.
29. Perazella MA, Rosner MH. Drug-induced acute kidney injury — clinical syndromes and pathogenesis. Clin J Am Soc Nephrol. 2022;17(8):1220–33.
30. Tan RJ, Zhou D, Zhou L, et al. Mechanisms of cisplatin nephrotoxicity: oxidative stress, mitochondrial dysfunction, and cell death pathways. Toxicol Appl Pharmacol. 2019;373:119–29.
31. Takasato M, Er PX, Chiu HS, Little MH. Generation of kidney organoids from human pluripotent stem cells. Nat Protoc. 2016;11(9):1681–97.
32. Nguyen VVT, Gkouzioti V, Maass C, Verhaar MC, Vernooij RWM, van Balkom BWM. A systematic review of kidney-on-a-chip models to study human renal physiology. Dis Model Mech. 2023;16(6):dmm050113.
33. Li T, Chen X, Tong W. Bridging organ transcriptomics for advancing multiple organ toxicity assessment with a generative AI approach. NPJ Digit Med. 2024;7:310.
34. Nguyen VVT, Ye S, Gkouzioti V, et al. Human kidney and liver organoid-based multi-organ-on-a-chip model to study therapeutic effects and biodistribution of extracellular vesicles. J Extracell Vesicles. 2022;11(11):e12280.
35. Li Z, Jiang L, Zhu Y, Su W, Xu C, Tao T, et al. Assessment of hepatic metabolism-dependent nephrotoxicity on an organs-on-a-chip microdevice. Toxicol In Vitro. 2018;46:1–8.
36. Herland A, Maoz BM, Das D, Somayaji MR, Prantil-Baun R, Novak R, et al. Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips. Nat Biomed Eng. 2020;4:421–36.
37. Oleaga C, Bernabini C, Smith AS, et al. Multi-organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci Rep. 2016;6:20030.
38. Nieskens TTG, Wilmer MJ, van den Broek PHH, et al. Models for proximal tubule function and nephrotoxicity in vitro: a critical appraisal. Toxicol In Vitro. 2020;65:104800.
39. Homan KA, Kolesky DB, Skylar-Scott MA, Herrmann J, Obuobi H, Mo X, Lewis JA. Bioprinting of 3D convoluted renal proximal tubules on perfusable chips. Sci Rep. 2016;6:34845.
40. Tanase DM, Gosav EM, Hostiuc S, et al. Predictive role of kidney injury molecule-1 in drug-induced nephrotoxicity. Int J Mol Sci. 2019;20(20):5238.
41. Deng S, Li C, Cao J, Cui Z, Du J, Fu Z, Yang H, Chen P. Organ-on-a-chip meets artificial intelligence in drug evaluation. Theranostics. 2023;13(13):4526–58.
42. Novak R, Ingram M, Marquez S, et al. Advanced organ-on-chip platforms for compound safety testing and mechanism exploration. Nat Rev Drug Discov. 2023;22(5):347–65. doi:10.1038/s41573-023-00750-0.
43. Wang Y, Sakolish C, Lamb J, et al. A fluidically linked human liver–kidney chip for mechanistic study of drug-induced toxicity. Biotechnol Bioeng. 2021;118(12):4866–79. doi:10.1002/bit.27905.
44. Wu Q, Liu J, Wang X, et al. Organ-on-a-chip: recent breakthroughs and future perspectives. Biotechnol J. 2020;15(1):1900098. doi:10.1002/biot.201900098.
45. Kimura H, Sakai Y, Fujii T. Organ/body-on-a-chip based on microfluidic technology for drug discovery. Drug Metab Pharmacokinet. 2018;33(1):43–48. doi:10.1016/j.dmpk.2017.11.003.
46. Sasser JM. Biomarkers of drug-induced kidney injury. Curr Opin Toxicol. 2021;26:13–20. doi:10.1016/j.cotox.2021.04.001.
47. Soo JY, Jansen J, Masereeuw R, Little MH. Advances in predictive in vitro models of drug-induced nephrotoxicity. Nature Reviews Nephrology. 2018 Jun;14(6):378-93.
48. Abbasnezhad A, Salami F, Mohebbati R. A review: Systematic research approach on toxicity model of liver and kidney in laboratory animals. Animal models and experimental medicine. 2022 Oct;5(5):436-44.
49. Astashkina AI, Mann BK, Prestwich GD, Grainger DW. Comparing predictive drug nephrotoxicity biomarkers in kidney 3-D primary organoid culture and immortalized cell lines. Biomaterials. 2012 Jun 1;33(18):4712-21.
50. Shi Y, Luo L, Wang J, et al. A 3D human kidney organoid chip for nephrotoxicity evaluation. Lab Chip. 2023;23(4):796–809. doi:10.1039/D2LC00833C.
51. Lee S, Kim H, Park H, et al. Integration of liver and kidney organoids for drug-induced toxicity studies. Adv Sci (Weinh). 2022;9(30):e2201795. doi:10.1002/advs.202201795.
52. Musah S, Mammoto A, Ferrante TC, et al. Mature kidney podocyte structure and function on a chip. Nat Biomed Eng. 2017;1(5):0069. doi:10.1038/s41551-017-0069.
53. Dube PN, Zhang Y, Ghim S, et al. Multi-organ microphysiological systems for toxicity assessment of nephrotoxic compounds. Front Pharmacol. 2022;13:946237. doi:10.3389/fphar.2022.946237.
54. Bale SS, Moore LK, Yarmush ML. Microfluidic multi-organ platforms for drug testing. Annu Rev Biomed Eng. 2021;23:369–92. doi:10.1146/annurev-bioeng-112420-125011.
55. Liu Y, Wang M, Chen X, et al. 3D bioprinted proximal tubule models for nephrotoxicity testing. Biofabrication. 2023;15(2):025009. doi:10.1088/1758-5090/acb1ae.
56. Kandasamy K, Mitra A, Caldwell J, et al. Liver-chip: reproducing human hepatic responses to toxic drugs. Exp Biol Med (Maywood). 2019;244(7):655–64. doi:10.1177/1535370219837870.
57. Esch MB, King TL, Shuler ML. The role of body-on-a-chip devices in pharmacokinetic optimization. Biotechnol Bioeng. 2011;108(7):1691–700. doi:10.1002/bit.23160.
58. Yu J, Zhang Y, Li J, et al. Human iPSC-derived renal proximal tubule chips reveal transporter-mediated drug interactions. Cell Stem Cell. 2023;30(2):240–254.e8. doi:10.1016/j.stem.2022.12.007.
59. Wang K, Zhou Y, Zhang B, et al. Liver–kidney co-culture organ-on-chip for synergistic toxicity analysis. Biosens Bioelectron. 2021;193:113568. doi:10.1016/j.bios.2021.113568.
60. Schimek K, Frentzel S, Luettich K, et al. Human multi-organ-chip co-culture of bronchial lung epithelium and liver to test inflammatory and metabolic reactions to drugs. Lab Chip. 2020;20(15):2752–2769. doi:10.1039/D0LC00416H.
61. Jiang L, Li Z, Su W, et al. A liver–kidney-on-chip model for aristolochic acid-induced nephrotoxicity. Chem Res Toxicol. 2022;35(8):1503–12. doi:10.1021/acs.chemrestox.2c00112.
62. Sasser JM, Lash LH. Strategies for mitigating drug-induced nephrotoxicity. Toxicol Sci. 2017;157(2):229–41. doi:10.1093/toxsci/kfx066.
63. Zhao T, Qin Y, Sun L, et al. Artificial intelligence in organ-on-chip data analysis and toxicity prediction. Front Pharmacol. 2023;14:1169874. doi:10.3389/fphar.2023.1169874.
64. Sun J, Liu Y, Zhou Y, et al. Omics-based nephrotoxicity biomarkers: recent advances and future outlook. Toxicol Lett. 2023;383:82–94. doi:10.1016/j.toxlet.2023.07.004.
65. Bell CC, Henderson CJ, Wolf CR. Human organoids as predictive models for DILI and nephrotoxicity. Annu Rev Pharmacol Toxicol. 2023;63:299–320. doi:10.1146/annurev-pharmtox-061422-025548.
66. Ando Y, Okami J, Kobayashi K, et al. Drug screening using human kidney organoids derived from induced pluripotent stem cells. Front Pharmacol. 2022;13:845023. doi:10.3389/fphar.2022.845023.
67. Horvath P, Aulner N, Bresciani A, et al. The future of toxicology testing: advanced in vitro models. Nat Rev Drug Discov. 2022;21(7):463–80. doi:10.1038/s41573-021-00318-3.
68. Kann SH, Shaughnessey EM, Zhang X, Charest JL, Vedula EM. Steady-state monitoring of oxygen in a high-throughput organ-on-chip platform enables rapid and non-invasive assessment of drug-induced nephrotoxicity. Analyst. 2023;148(14):3204-16.
69. Cohen A, Ioannidis K, Ehrlich A, Regenbaum S, Cohen M, Ayyash M, Tikva SS, Nahmias Y. Mechanism and reversal of drug-induced nephrotoxicity on a chip. Science translational medicine. 2021 Feb 24;13(582):eabd6299.
70. Li Z, Su W, Zhu Y, Tao T, Li D, Peng X, Qin J. Drug absorption related nephrotoxicity assessment on an intestine-kidney chip. Biomicrofluidics. 2017 May 1;11(3).
71. Ewart L, Deans PJ, Crawford M, et al. Applying microphysiological systems to drug safety: a consortium approach. Toxicol Sci. 2022;190(2):150–62. doi:10.1093/toxsci/kfac079.
72. van den Berg A, Mummery CL, Passier R, van der Meer AD. Personalized organs-on-chips: functional testing for precision medicine. Lab Chip. 2019;19(2):198–205. doi:10.1039/C8LC00827B.
73. Chen Z, Li Z, Yin L, et al. Human proximal tubule-on-chip for mechanistic nephrotoxicity testing. Bioengineering (Basel). 2021;8(11):168. doi:10.3390/bioengineering8110168.
74. Koo Y, Kim J, Kim H, et al. Multi-organ chip model for systemic evaluation of drug-induced toxicity. ACS Appl Mater Interfaces. 2021;13(36):42947–58. doi:10.1021/acsami.1c12467.
75. Robinson MK, Parker LM, Chapman KL, et al. Safety assessment in microphysiological systems: regulatory perspectives. ALTEX. 2023;40(3):401–14. doi:10.14573/altex.2302061.
76. Marroquin LD, Hwang SM, Baran SW, et al. Biomarker discovery in kidney injury using multi-omics analysis. Toxicol Appl Pharmacol. 2022;454:116289. doi:10.1016/j.taap.2022.116289.
77. Li Y, Feng G, Zhou H, et al. Modeling chronic kidney disease on a microfluidic chip. Lab Chip. 2022;22(16):3129–44. doi:10.1039/D2LC00466D.
78. Bolger MB, Rowland M. Physiologically based pharmacokinetic modeling in MPS systems. J Pharm Sci. 2022;111(8):2073–88. doi:10.1016/j.xphs.2022.04.018.
79. Lee G, Park H, Kim Y, et al. 3D human kidney-on-a-chip with continuous perfusion for drug testing. Biotechnol Bioeng. 2020;117(10):3073–85. doi:10.1002/bit.27465.
80. Yu K, He J, Zhou Y, et al. Multi-omics signatures of drug-induced nephrotoxicity using organoid models. Cell Rep Med. 2023;4(7):101062. doi:10.1016/j.xcrm.2023.101062.
81. McLean JC, McCauley HA. Applications of kidney organoids in toxicology. Front Toxicol. 2021;3:682491. doi:10.3389/ftox.2021.682491.
82. Ainslie GR, Shah P, Harris J, et al. Microphysiological systems for modeling renal disease and toxicity. Annu Rev Pharmacol Toxicol. 2022;62:379–402. doi:10.1146/annurev-pharmtox-042021-101316.
83. Broeders J, Mills RJ, Davidson MD, et al. Organoid-on-a-chip technology for personalized drug testing. Trends Biotechnol. 2023;41(8):1021–37. doi:10.1016/j.tibtech.2023.04.010.
84. Zhang X, Wu S, Li Y, et al. Multi-organ interactions in drug toxicity: a systems biology perspective. Toxicol Sci. 2023;191(1):34–46. doi:10.1093/toxsci/kfad055.
85. Novak R, Ingber DE. Human organ-chip technology for drug testing: opportunities and challenges. Nat Rev Drug Discov. 2024;23(1):59–76. doi:10.1038/s41573-023-00758-w.
86. Kim HJ, Huh D, Hamilton GA, Ingber DE. Human gut-on-a-chip and its integration with liver and kidney systems. Lab Chip. 2012;12(12):2165–74. doi:10.1039/c2lc40074j.
87. Tsamandouras N, Chen W, Edington CD, et al. Integrated gut–liver microphysiological systems for human drug metabolism studies. Biotechnol Bioeng. 2017;114(12):2606–16. doi:10.1002/bit.26370.
88. Lin S, Kuang M. RNA modification-mediated mRNA translation regulation in liver cancer: mechanisms and clinical perspectives. Nature reviews Gastroenterology & hepatology. 2024 Apr;21(4):267-81.
89. Balvey A, Fernandez M. Translational control in liver disease. Frontiers in Physiology. 2021 Nov 29;12:795298.
90. Edington CD, Chen W, Geishecker E, et al. Interconnected microphysiological systems for quantitative biology of human physiology. Nat Biomed Eng. 2018;2(7):416–29. doi:10.1038/s41551-018-0259-3.
91. Masereeuw R, Russell C, van Meer BJ, et al. Kidney MPS for safety pharmacology and toxicology. Front Pharmacol. 2023;14:1159832. doi:10.3389/fphar.2023.1159832.
92. Horvath P, Moy TK, Kawaguchi R, et al. Human kidney-on-chip models of transporter-mediated toxicity. Toxicol Appl Pharmacol. 2021;414:115403. doi:10.1016/j.taap.2021.115403.
93. Li W, Zhou Q, Tang Y, et al. Integration of AI and organ-on-chip for next-generation toxicity prediction. Front Bioeng Biotechnol. 2024;12:1365842. doi:10.3389/fbioe.2024.1365842.
94. Ewart L, Baxter M, Peters R, et al. Next-generation safety assessment using MPS platforms. Toxicol Appl Pharmacol. 2023;455:116303. doi:10.1016/j.taap.2023.116303.
95. Wang J, Li P, Qin K, et al. Human-on-a-chip for systemic toxicity modeling. Small. 2024;20(14):e2307545. doi:10.1002/smll.202307545.
96. Glynne PA, Himmelfarb J. Bridging organ-on-chip and clinical nephrotoxicity. Clin J Am Soc Nephrol. 2024;19(2):227–38. doi:10.2215/CJN.0000000000000021.
97. Zhang J, Xu X, Wu X, et al. Advances in organoid-based nephrotoxicity models. Front Pharmacol. 2024;15:1357642. doi:10.3389/fphar.2024.1357642.
98. Rosenberg JM, Mahajan S, Bennett WR, et al. Regulatory perspectives on organ-on-chip in toxicology. ALTEX. 2024;41(2):215–29. doi:10.14573/altex.2401111.
99. Ingber DE. From mechanobiology to patient-on-a-chip. Nat Rev Mol Cell Biol. 2022;23(6):451–72. doi:10.1038/s41580-022-00493-3.
100. Yu P, Duan Z, Liu S, Pachon I, Ma J, Hemstreet GP, Zhang Y. Drug-induced nephrotoxicity assessment in 3D cellular models. Micromachines. 2021 Dec 21;13(1):3.
101. Cong Y, Han X, Wang Y, Chen Z, Lu Y, Liu T, Wu Z, Jin Y, Luo Y, Zhang X. Drug toxicity evaluation based on organ-on-a-chip technology: a review. Micromachines. 2020 Apr 3;11(4):381.
102. Yin L, Du G, Zhang B, Zhang H, Yin R, Zhang W, Yang SM. Efficient drug screening and nephrotoxicity assessment on co-culture microfluidic kidney chip. Scientific Reports. 2020 Apr 16;10(1):6568.
103. Li Z, Su W, Zhu Y, Tao T, Li D, Peng X, Qin J. Drug absorption related nephrotoxicity assessment on an intestine-kidney chip. Biomicrofluidics. 2017 May 1;11(3).
104. Theobald J, Ghanem A, Wallisch P, Banaeiyan AA, Andrade-Navarro MA, Taskova K, Haltmeier M, Kurtz A, Becker H, Reuter S, Mrowka R. Liver-kidney-on-chip to study toxicity of drug metabolites. ACS biomaterials science & engineering. 2018 Jan 8;4(1):78-89.
105. Shen JX, Youhanna S, Zandi Shafagh R, Kele J, Lauschke VM. Organotypic and microphysiological models of liver, gut, and kidney for studies of drug metabolism, pharmacokinetics, and toxicity. Chemical research in toxicology. 2019 Oct 2;33(1):38-60.
106. Sung JH. Multi-organ-on-a-chip for pharmacokinetics and toxicokinetic study of drugs. Expert Opinion on Drug Metabolism & Toxicology. 2021 Aug 3;17(8):969-86.
107. Bovard D, Iskandar A, Luettich K, Hoeng J, Peitsch MC. Organs-on-a-chip: A new paradigm for toxicological assessment and preclinical drug development. Toxicology Research and Application. 2017 Aug 17;1:2397847317726351.
108. Zhang X, Wang Y, Han J, Zhao W, Zhang W, Li X, Chen J, Song W, Wang L. Cardiac‐Focused Multi‐Organ Chips: Advanced Disease Modeling, Drug Testing, and Inter‐Organ Communication. Advanced Biology. 2025 Apr;9(4):2400512.
109. Fu J, Qiu H, Tan CS. Microfluidic liver-on-a-chip for preclinical drug discovery. Pharmaceutics. 2023 Apr 21;15(4):1300.
110. Farooqi HM, Khalid MA, Kim KH, Lee SR, Choi KH. Real-time physiological sensor-based liver-on-chip device for monitoring drug toxicity. Journal of Micromechanics and Microengineering. 2020 Sep 15;30(11):115013.
111. Gholizadeh H, Cheng S, Kourmatzis A, Xing H, Traini D, Young PM, Ong HX. Application of micro-engineered kidney, liver, and respiratory system models to accelerate preclinical drug testing and development. Bioengineering. 2022 Apr 2;9(4):150.
112. Irvine AR, van Berlo D, Shekhani R, Masereeuw R. A systematic review of in vitro models of drug-induced kidney injury. Current Opinion in Toxicology. 2021 Sep 1;27:18-26.
113. Li Z, Hui J, Yang P, Mao H. Microfluidic organ-on-a-chip system for disease modeling and drug development. Biosensors. 2022 May 27;12(6):370.
114. An L, Liu Y, Liu Y. Organ-on-a-Chip applications in microfluidic platforms. Micromachines. 2025 Feb 10;16(2):201.
115. Paoli R, Samitier J. Mimicking the kidney: a key role in organ-on-chip development. Micromachines. 2016 Jul 20;7(7):126.
116. Gao X, Wang T, Huang W, Liu C, Zhang Z, Deng Y, Huang J. Multi-organ-on-a-chip: Modeling strategy, method, and biomedical applications. Biomicrofluidics. 2025 Jul 1;19(4).
117. Driver R, Mishra S. Organ-on-a-chip technology: an in-depth review of recent advancements and future of whole body-on-chip. BioChip Journal. 2023 Mar;17(1):1-23.
118. Yuan S, Yuan H, Hay DC, Hu H, Wang C. Revolutionizing Drug Discovery: The Impact of Distinct Designs and Biosensor Integration in Microfluidics-Based Organ-on-a-Chip Technology. Biosensors. 2024 Sep 3;14(9):425.
119. Tadevosyan K. Heart-on-a-chip as biomimetic platform for cardiac physiology and drug toxicity testing.
120. Juguilon C, Khosravi R, Radisic M, Wu JC. In vitro modeling of interorgan crosstalk: multi-organ-on-a-chip for studying cardiovascular-kidney-metabolic syndrome. Circulation research. 2025 May 23;136(11):1476-93.
121. Huang Y, Liu T, Huang Q, Wang Y. From organ-on-a-chip to human-on-a-chip: A review of research progress and latest applications. ACS sensors. 2024 Jul 11;9(7):3466-88.
122. Li N, Shi J, Chen Z, Dong Z, Ma S, Li Y, Huang X, Li X. In silico prediction of drug-induced nephrotoxicity: current progress and pitfalls. Expert Opinion on Drug Metabolism & Toxicology. 2025 Feb 1;21(2):203-15.
123. Brandauer K, Schweinitzer S, Lorenz A, Krauß J, Schobesberger S, Frauenlob M, Ertl P. Advances of Dual-Organ and Multi-Organ Systems for Gut, Lung, 2 Skin and Liver Models in Absorption and Metabolism Studies. Lab on a Chip. 2025.
124. Vargas R, Egurbide-Sifre A, Medina L. Organ-on-a-Chip systems for new drugs development. ADMET and DMPK. 2021 Mar 21;9(2):111-41.
125. Dai M, Xiao G, Shao M, Zhang YS. The synergy between deep learning and organs-on-chips for high-throughput drug screening: a review. Biosensors. 2023 Mar 15;13(3):389.
126. Hu W, Wang Y, Han J, Zhang W, Chen J, Li X, Wang L. Microfluidic organ-on-a-chip models for the gut–liver axis: from structural mimicry to functional insights. Biomaterials science. 2025;13(7):1624-56.
127. Ashammakhi N, Darabi MA, Çelebi‐Saltik B, Tutar R, Hartel MC, Lee J, Hussein SM, Goudie MJ, Cornelius MB, Dokmeci MR, Khademhosseini A. Microphysiological systems: next generation systems for assessing toxicity and therapeutic effects of nanomaterials. Small Methods. 2020 Jan;4(1):1900589.
128. Donoghue L, Nguyen KT, Graham C, Sethu P. Tissue chips and microphysiological systems for disease modeling and drug testing. Micromachines. 2021 Jan 28;12(2):139.
129. Nithin R, Aggarwal A, Sravani AB, Mallya P, Lewis S. Organ-on-a-chip: an emerging research platform. Organogenesis. 2023 Nov 15;19(1):2278236.
130. Ma C, Peng Y, Li H, Chen W. Organ-on-a-chip: a new paradigm for drug development. Trends in pharmacological sciences. 2021 Feb 1;42(2):119-33.
131. Rodriguez-Garcia A, Oliva-Ramirez J, Bautista-Flores C, Hosseini S. 3D in vitro human organ mimicry devices for drug discovery, development, and assessment. Advances in Polymer Technology. 2020;2020(1):6187048.
132. Jodat YA, Kang MG, Kiaee K, Kim GJ, Martinez AF, Rosenkranz A, Bae H, Shin SR. Human-derived organ-on-a-chip for personalized drug development. Current pharmaceutical design. 2018 Dec 1;24(45):5471-86.
133. Magnusson O. Investigating flow-related effects of Chronic Kidney Disease on renal drug toxicity in a human-derived proximal tubule microphysiological system.
134. da Silva Pereira JD. Machine Learning Algorithms and Organs-on-Chips as New Technologies for the Modeling of Human Cardiac Toxicity and Disease (Doctoral dissertation, Universidade do Minho (Portugal)).
135. Mittal R, Woo FW, Castro CS, Cohen MA, Karanxha J, Mittal J, Chhibber T, Jhaveri VM. Organ‐on‐chip models: implications in drug discovery and clinical applications. Journal of cellular physiology. 2019 Jun;234(6):8352-80.
136. Yang J, Jiang Y, Li M, Wu K, Wei S, Zhao Y, Shen J, Du F, Chen Y, Deng S, Xiao Z. Organoid, organ-on-a-chip and traditional Chinese medicine. Chinese Medicine. 2025 Feb 12;20(1):22.
137. Kumar D, Nadda R, Repaka R. Advances and challenges in organ-on-chip technology: toward mimicking human physiology and disease in vitro. Medical & biological engineering & computing. 2024 Jul;62(7):1925-57.
138. Guo Y, Chen X, Gong P, Li G, Yao W, Yang W. The gut–organ-axis concept: advances the application of gut-on-chip technology. International Journal of Molecular Sciences. 2023 Feb 17;24(4):4089.
139. Kang S, Chen EC, Cifuentes H, Cole G, Graham J, Hsia R, Kiyota T, Klein JA, Kroll KT, Lopez LM, Norona LM. Complex in vitro models positioned for impact to drug testing in pharma: a review. Biofabrication. 2024 Aug 27;16(4):042006.
140. Verma N, Kanojia N, Thapa K, Chandel P, Dua K. Organ-on-a-chip in the diagnosis and treatment of chronic respiratory disorders and its application to advanced drug delivery systems. InTechnological Advances and Innovations in the Treatment of Chronic Respiratory Disorders 2025 Jan 1 (pp. 267-285). Academic Press.
141. Kaushik P, Kaushik M, Jacob S, Parvez S. Multiorgans-on-a-Chip for Personalized Medicine. InMicrofluidics and Multi Organs on Chip 2022 Jul 12 (pp. 289-324). Singapore: Springer Nature Singapore.
142. Sunildutt N, Parihar P, Chethikkattuveli Salih AR, Lee SH, Choi KH. Revolutionizing drug development: harnessing the potential of organ-on-chip technology for disease modeling and drug discovery. Frontiers in pharmacology. 2023 Apr 25;14:1139229.
143. Kann SH, Shaughnessey EM, Coppeta JR, Azizgolshani H, Isenberg BC, Vedula EM, Zhang X, Charest JL. Measurement of oxygen consumption rates of human renal proximal tubule cells in an array of organ-on-chip devices to monitor drug-induced metabolic shifts. Microsystems & Nanoengineering. 2022 Sep 29;8(1):109.
144. Esch EW, Bahinski A, Huh D. Organs-on-chips at the frontiers of drug discovery. Nature reviews Drug discovery. 2015 Apr;14(4):248-60.
145. Ko J, Park D, Lee S, Gumuscu B, Jeon NL. Engineering organ-on-a-chip to accelerate translational research. Micromachines. 2022 Jul 28;13(8):1200.
146. Rathee G, Kumar S, Bartwal G, Rathee J, Solanki PR. Kidney-on-a-Chip. InMicrofluidics and Multi Organs on Chip 2022 Jul 12 (pp. 435-450). Singapore: Springer Nature Singapore.
147. Fetah K, Tebon P, Goudie MJ, Eichenbaum J, Ren L, Barros N, Nasiri R, Ahadian S, Ashammakhi N, Dokmeci MR, Khademhosseini A. The emergence of 3D bioprinting in organ-on-chip systems. Progress in Biomedical Engineering. 2019 Jul 16;1(1):012001.
148. Cavero I, Guillon JM, Holzgrefe HH. Human organotypic bioconstructs from organ-on-chip devices for human-predictive biological insights on drug candidates. Expert Opinion on Drug Safety. 2019 Aug 3;18(8):651-77.
149. Xue J, Gao S, You Z, Xu S, Zhou J, Hai J, Yang L. In vitro technology and ADMET research in traditional Chinese medicine. Frontiers in Pharmacology. 2025 Jul 9;16:1605330.
150. Lee HN, Choi YY, Kim JW, Lee YS, Choi JW, Kang T, Kim YK, Chung BG. Effect of biochemical and biomechanical factors on vascularization of kidney organoid-on-a-chip. Nano Convergence. 2021 Nov 8;8(1):35.
151. Wu Q, Liu J, Wang X, Feng L, Wu J, Zhu X, Wen W, Gong X. Organ-on-a-chip: recent breakthroughs and future prospects. Biomedical engineering online. 2020 Feb 12;19(1):9.
152. Zhao Y, Landau S, Okhovatian S, Liu C, Lu RX, Lai BF, Wu Q, Kieda J, Cheung K, Rajasekar S, Jozani K. Integrating organoids and organ-on-a-chip devices. Nature Reviews Bioengineering. 2024 Jul;2(7):588-608.
153. Polini A, Prodanov L, Bhise NS, Manoharan V, Dokmeci MR, Khademhosseini A. Organs-on-a-chip: a new tool for drug discovery. Expert opinion on drug discovery. 2014 Apr 1;9(4):335-52.
154. Liu J, Wang Y. Advances in organ‐on‐a‐chip for the treatment of cardiovascular diseases. MedComm–Biomaterials and Applications. 2023 Dec;2(4):e63.
Article Sidebar
Published
Sep 30, 2026
Article Details
How to Cite
Anuj Kumar Srivastava, Pardeep Kumar, Dev Prakash Dahiya, Sonali Thalur, Darpan Kaushik, Vineet Kapoor, Meena Devi, & Yamini. (2026). INTEGRATIVE LIVER–KIDNEY ORGAN-ON-CHIP PLATFORM FOR MECHANISTIC EVALUATION OF DRUG-INDUCED NEPHROTOXICITY. Journal of Population Therapeutics and Clinical Pharmacology, 32(11), 1409-1432. https://doi.org/10.53555/e5amvd96
Section
Articles
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.
Author Biographies
Anuj Kumar Srivastava
Sardar Patel College of Pharmacy, Gorakhpur, U.P.-273013, India
Pardeep Kumar
School of Pharmacy, Abhilashi University, Mandi, H.P.- 175028, India
Dev Prakash Dahiya
School of Pharmacy, Abhilashi University, Mandi, H.P.- 175028, India
Sonali Thalur
Maharishi Markandeshwar University, Mullana University Road, Mullana, Ambala, Haryana – 133207, India.
Darpan Kaushik
School of Pharmacy, Shri Venkateshwara University, Gajraula, Uttar Pradesh 244236
Vineet Kapoor
School of Pharmacy, Abhilashi University, Mandi, H.P.- 175028, India
Meena Devi
School of Pharmacy, Abhilashi University, Mandi, H.P.- 175028, India
Yamini
School of Pharmacy, Abhilashi University, Mandi, H.P.- 175028, India
How to Cite
Anuj Kumar Srivastava, Pardeep Kumar, Dev Prakash Dahiya, Sonali Thalur, Darpan Kaushik, Vineet Kapoor, Meena Devi, & Yamini. (2026). INTEGRATIVE LIVER–KIDNEY ORGAN-ON-CHIP PLATFORM FOR MECHANISTIC EVALUATION OF DRUG-INDUCED NEPHROTOXICITY. Journal of Population Therapeutics and Clinical Pharmacology, 32(11), 1409-1432. https://doi.org/10.53555/e5amvd96
