Multi-Organ Toxicity Demonstration in a Functional Human in Vitro System Composed of Four Organs

Overview

Journal Sci Rep

Specialty Science

Date 2016 Feb 4

PMID 26837601

Citations 179

Authors

Carlota Oleaga

Catia Bernabini

Alec S T Smith

Balaji Srinivasan

Max Jackson

William McLamb

Vivien Platt

Richard Bridges

Yunqing Cai

Navaneetha Santhanam

Bonnie Berry

Sarah Najjar

Nesar Akanda

Xiufang Guo

Candace Martin

Gail Ekman

Mandy B Esch

Jessica Langer

Gladys Ouedraogo

Jose Cotovio

Lionel Breton

Michael L Shuler

James J Hickman

Affiliations

Soon will be listed here.

Abstract

We report on a functional human model to evaluate multi-organ toxicity in a 4-organ system under continuous flow conditions in a serum-free defined medium utilizing a pumpless platform for 14 days. Computer simulations of the platform established flow rates and resultant shear stress within accepted ranges. Viability of the system was demonstrated for 14 days as well as functional activity of cardiac, muscle, neuronal and liver modules. The pharmacological relevance of the integrated modules were evaluated for their response at 7 days to 5 drugs with known side effects after a 48 hour drug treatment regime. The results of all drug treatments were in general agreement with published toxicity results from human and animal data. The presented phenotypic culture model exhibits a multi-organ toxicity response, representing the next generation of in vitro systems, and constitutes a step towards an in vitro "human-on-a-chip" assay for systemic toxicity screening.

Citing Articles

Advanced In Vitro Models for Preclinical Drug Safety: Recent Progress and Prospects.

Nair D, Weiskirchen R Curr Issues Mol Biol. 2025; 47(1).

PMID: 39852122 PMC: 11763796. DOI: 10.3390/cimb47010007.

Microphysiological system to address the opioid crisis: A novel multi-organ model of acute opioid overdose and recovery.

Patel A, Poddar S, Nierenberg D, Lang S, Wang H, Pires DeMello C Curr Res Toxicol. 2025; 8():100209.

PMID: 39839141 PMC: 11745978. DOI: 10.1016/j.crtox.2024.100209.

Organ-on-a-Chip Models-New Possibilities in Experimental Science and Disease Modeling.

Wysoczanski B, Swiatek M, Wojcik-Gladysz A Biomolecules. 2025; 14(12.

PMID: 39766276 PMC: 11674024. DOI: 10.3390/biom14121569.

A 3D-printed multi-compartment organ-on-chip platform with a tubing-free pump models communication with the lymph node.

Cook S, Ball A, Mohammad A, Pompano R Lab Chip. 2024; 25(2):155-174.

PMID: 39661075 PMC: 11633827. DOI: 10.1039/d4lc00489b.

Increasing sustainability and reproducibility of toxicology applications: serum-free cultivation of HepG2 cells.

Pfeifer L, Sensbach J, Pipp F, Werkmann D, Hewitt P Front Toxicol. 2024; 6:1439031.

PMID: 39650261 PMC: 11621109. DOI: 10.3389/ftox.2024.1439031.

References

Szkolnicka D, Farnworth S, Lucendo-Villarin B, Storck C, Zhou W, Iredale J . Accurate prediction of drug-induced liver injury using stem cell-derived populations. Stem Cells Transl Med. 2013; 3(2):141-8. PMC: 3925059. DOI: 10.5966/sctm.2013-0146. View

Lee J, Maeng S, Kang S, Y Choi H, Oh T, Ju B . Valproic acid protects motor neuron death by inhibiting oxidative stress and endoplasmic reticulum stress-mediated cytochrome C release after spinal cord injury. J Neurotrauma. 2013; 31(6):582-94. PMC: 3949506. DOI: 10.1089/neu.2013.3146. View

Vozzi F, Heinrich J, Bader A, Ahluwalia A . Connected culture of murine hepatocytes and HUVEC in a multicompartmental bioreactor. Tissue Eng Part A. 2008; 15(6):1291-9. DOI: 10.1089/ten.tea.2008.0066. View

Carvalho C, Santos R, Cardoso S, Correia S, Oliveira P, Santos M . Doxorubicin: the good, the bad and the ugly effect. Curr Med Chem. 2009; 16(25):3267-85. DOI: 10.2174/092986709788803312. View

Zhang C, Zhao Z, Abdul Rahim N, van Noort D, Yu H . Towards a human-on-chip: culturing multiple cell types on a chip with compartmentalized microenvironments. Lab Chip. 2009; 9(22):3185-92. DOI: 10.1039/b915147h. View

Iori E, Vinci B, Murphy E, Marescotti M, Avogaro A, Ahluwalia A . Glucose and fatty acid metabolism in a 3 tissue in-vitro model challenged with normo- and hyperglycaemia. PLoS One. 2012; 7(4):e34704. PMC: 3324505. DOI: 10.1371/journal.pone.0034704. View

Rumack B, MATTHEW H . Acetaminophen poisoning and toxicity. Pediatrics. 1975; 55(6):871-6. View

Horner S, Robinson S, Lees D, Callander R, Roberts R . Target organ profiles in toxicity studies supporting human dosing: an assessment of recovery and chronic dosing. Regul Toxicol Pharmacol. 2014; 70(1):270-85. DOI: 10.1016/j.yrtph.2014.07.008. View

Guo X, Johe K, Molnar P, Davis H, Hickman J . Characterization of a human fetal spinal cord stem cell line, NSI-566RSC, and its induction to functional motoneurons. J Tissue Eng Regen Med. 2009; 4(3):181-93. PMC: 2908506. DOI: 10.1002/term.223. View

10.

Lau Y, Chen Y, Liu T, Li C, Cui X, White R . Evaluation of a novel in vitro Caco-2 hepatocyte hybrid system for predicting in vivo oral bioavailability. Drug Metab Dispos. 2004; 32(9):937-42. View

11.

Hadzimichalis N, Baliga S, Golfetti R, Jaques K, Firestein B, Merrill G . Acetaminophen-mediated cardioprotection via inhibition of the mitochondrial permeability transition pore-induced apoptotic pathway. Am J Physiol Heart Circ Physiol. 2007; 293(6):H3348-55. DOI: 10.1152/ajpheart.00947.2007. View

12.

Wood W, Eckert G, Igbavboa U, Muller W . Statins and neuroprotection: a prescription to move the field forward. Ann N Y Acad Sci. 2010; 1199:69-76. PMC: 2909025. DOI: 10.1111/j.1749-6632.2009.05359.x. View

13.

Sung J, Kam C, Shuler M . A microfluidic device for a pharmacokinetic-pharmacodynamic (PK-PD) model on a chip. Lab Chip. 2010; 10(4):446-55. DOI: 10.1039/b917763a. View

14.

Esch M, Smith A, Prot J, Oleaga C, Hickman J, Shuler M . How multi-organ microdevices can help foster drug development. Adv Drug Deliv Rev. 2014; 69-70:158-69. PMC: 4095890. DOI: 10.1016/j.addr.2013.12.003. View

15.

Loscher W . Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs. 2002; 16(10):669-94. DOI: 10.2165/00023210-200216100-00003. View

16.

Holme J, Hongslo J, Bjorge C, Nelson S . Comparative cytotoxic effects of acetaminophen (N-acetyl-p-aminophenol), a non-hepatotoxic regioisomer acetyl-m-aminophenol and their postulated reactive hydroquinone and quinone metabolites in monolayer cultures of mouse hepatocytes. Biochem Pharmacol. 1991; 42(5):1137-42. DOI: 10.1016/0006-2952(91)90299-k. View

17.

Guo X, Gonzalez M, Stancescu M, Vandenburgh H, Hickman J . Neuromuscular junction formation between human stem cell-derived motoneurons and human skeletal muscle in a defined system. Biomaterials. 2011; 32(36):9602-11. PMC: 3200565. DOI: 10.1016/j.biomaterials.2011.09.014. View

18.

Raschi E, Ceccarini L, De Ponti F, Recanatini M . hERG-related drug toxicity and models for predicting hERG liability and QT prolongation. Expert Opin Drug Metab Toxicol. 2009; 5(9):1005-21. DOI: 10.1517/17425250903055070. View

19.

Lins R, Matthys K, Verpooten G, Peeters P, Dratwa M, Stolear J . Pharmacokinetics of atorvastatin and its metabolites after single and multiple dosing in hypercholesterolaemic haemodialysis patients. Nephrol Dial Transplant. 2003; 18(5):967-76. DOI: 10.1093/ndt/gfg048. View

20.

Cusack B, Young S, Driskell J, Olson R . Doxorubicin and doxorubicinol pharmacokinetics and tissue concentrations following bolus injection and continuous infusion of doxorubicin in the rabbit. Cancer Chemother Pharmacol. 1993; 32(1):53-8. DOI: 10.1007/BF00685876. View