Microfluidic Devices: A New Paradigm in Toxicity Studies

Year 2020, Volume: 48 Issue: 3, 245 - 263, 15.06.2020

İffet İpek Boşgelmez , Kutay İçöz , Fatma Esra Yiğit

https://doi.org/10.15671/hjbc.610448

Cited By: 1

Abstract

In recent
years, great emphasis has been placed on non-animal toxicological methods (e.g.in
vitro models,in silico or −omics data) as alternative strategies to reduce
animal-testing, in line with the 3R principle. These methods help in the rapid
and accurate estimation of preclinical efficacy and safety associated with discovery
of new drugs, and reduction of failure rates in clinical trials. Currently, the
in vitro studies have been in a transformation or replacement from
two-dimensional cell cultures to three-dimensional cell cultures that can mimic
the physiology of tissues, organs, and organism.

In this
context, organ-on-a-chip systems have been developed by integration of
three-dimensional culture models with emerging microfluidic technologies. The
organ-on-a-chip systems provide a good understanding of dose-response and
toxicity mechanisms in drug development process, since impact of xenobiotics on
human body can be predicted in a satisfactory level. Besides, these systems may
support assessment of pharmacokinetic-pharmacodynamic parameters as well as detection
of drug resistance. Models can be generated as “disease-models-on-a-chip” or
with healthy cells to evaluate response to xenobiotic under test.

In this study,
we will focus on microfluidic systems being used in organ-on-a-chip systems and
emphasize their potential for toxicity studies in which micro-environments of examples
including liver,kidney,brain,lung,heart,and intestines and their physiological
properties as reflected to organ-on-a-chip models.

Keywords

microfluidics, organ-on-a-chip, toxicity testing

References

• [1] S.N. Bhatia, D.E. Ingber, Microfluidic organs-on-chips, Nat. Biotechnol. 32 (2014) 760–772.
• [2] M.B. Esch, A.S.T. Smith, J.-M. Prot, C. Oleaga, J.J. Hickman, M.L. Shuler, How multi-organ microdevices can help foster drug development, Adv. Drug Deliv. Rev. 69–70 (2014) 158–169.
• [3] C.M. Sakolish, M.B. Esch, J.J. Hickman, M.L. Shuler, G.J. Mahler, Modeling barrier tissues in vitro: Methods, Achievements, and Challenges, EBioMedicine. 5(2016) 30–39.
• [4] J.D. Caplin, N.G. Granados, M.R. James, R. Montazami, N. Hashemi, Microfluidic organ-on-a-chip technology for advancement of drug development and toxicology, Adv. Healthc. Mater. 4 (2015) 1426–1450.
• [5] R. Greek, A. Menache, Systematic Reviews of animal models: Methodology versus epistemology, Int. J. Med. Sci. 10 (2013) 206–221.
• [6] A. Skardal, T. Shupe, A. Atala, Organoid-on-a-chip and body-on-a-chip systems for drug screening and disease modeling, Drug Discov. Today. 21 (2016) 1399–1411.
• [7] L. Ewart, K. Fabre, A. Chakilam, Y. Dragan, D.B. Duignan, J. Eswaraka, J. Gan, P. Guzzie-Peck, M. Otieno, C.G. Jeong, D.A. Keller, S.M. de Morais, J.A. Phillips, W. Proctor, R. Sura, T. Van Vleet, D. Watson, Y. Will, D. Tagle, B. Berridge, Navigating tissue chips from development to dissemination: A pharmaceutical industry perspective, Exp. Biol. Med. 242 (2017) 1579–1585.
• [8] S. Ishida, Organs-on-a-chip: Current applications and consideration points for in vitro ADME-Tox studies, Drug Metab. Pharmacokinet. 33 (2018) 49–54.
• [9] H. Kimura, Y. Sakai, T. Fujii, Organ/body-on-a-chip based on microfluidic technology for drug discovery, Drug Metab. Pharmacokinet. 33 (2018) 43–48.
• [10] S. Lu, F. Cuzzucoli, J. Jiang, L.-G. Liang, Y. Wang, M. Kong, X. Zhao, W. Cui, J. Li, S. Wang, Development of a biomimetic liver tumor-on-a-chip model based on decellularized liver matrix for toxicity testing, Lab Chip. 18 (2018) 3379–3392.
• [11] J. Vriend, T.T.G. Nieskens, M.K. Vormann, B.T. van den Berge, A. van den Heuvel, F.G.M. Russel, L. Suter-Dick, H.L. Lanz, P. Vulto, R. Masereeuw, M.J. Wilmer, Screening of drug-transporter interactions in a 3D microfluidic renal proximal tubule on a chip, AAPS J. 20 (2018) 87.
• [12] M.K. Vormann, L. Gijzen, S. Hutter, L. Boot, A. Nicolas, A. van den Heuvel, J. Vriend, C.P. Ng, T.T.G. Nieskens, V. van Duinen, B. de Wagenaar, R. Masereeuw, L. Suter-Dick, S.J. Trietsch, M. Wilmer, J. Joore, P. Vulto, H.L. Lanz, Nephrotoxicity and kidney transport assessment on 3D perfused proximal tubules, AAPS J. 20 (2018) 90.
• [13] W. Wang, Y. Yan, C.W. Li, H.M. Xia, S.S. Chao, D.Y. Wang, Z.P. Wang, Live human nasal epithelial cells (hNECs) on chip for in vitro testing of gaseous formaldehyde toxicity via airway delivery, Lab Chip. 14(2014) 677-680.
• [14] L.M. Griep, F. Wolbers, B. de Wagenaar, P.M. ter Braak, B.B. Weksler, I.A. Romero, P.O. Couraud, I. Vermes, A.D. van der Meer, A. van den Berg, BBB ON CHIP: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function, Biomed. Microdevices. 15 (2013) 145–150.
• [15] A. Grosberg, P.W. Alford, M.L. McCain, K.K. Parker, Ensembles of engineered cardiac tissues for physiological and pharmacological study: Heart on a chip, Lab Chip. 11(2011) 4165–4173.
• [16] G. Khanal, K. Chung, X. Solis-Wever, B. Johnson, D. Pappas, Ischemia/reperfusion injury of primary porcine cardiomyocytes in a low-shear microfluidic culture and analysis device, Analyst. 136 (2011) 3519–3526.
• [17] I. Maschmeyer, A.K. Lorenz, K. Schimek, T. Hasenberg, A.P. Ramme, J. Hübner, M. Lindner, C. Drewell, S. Bauer, A. Thomas, N.S. Sambo, F. Sonntag, R. Lauster, U. Marx, A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents, Lab Chip. 15 (2015) 2688–2699.
• [18] T.M. Marin, N. de Carvalho Indolfo, S.A. Rocco, F.L. Basei, M. de Carvalho, K. de Almeida Gonçalves, E. Pagani, Acetaminophen absorption and metabolism in an intestine/liver microphysiological system, Chem. Biol. Interact. 299 (2019) 59–76.
• [19] D. Huh, D.C. Leslie, B.D. Matthews, J.P. Fraser, S. Jurek, G.A. Hamilton, K.S. Thorneloe, M.A. McAlexander, D.E. Ingber, A human disease model of drug toxicity–induced pulmonary edema in a lung-on-a-chip microdevice, Sci. Transl. Med. 4 (2012) 159ra147.
• [20] G.M. Whitesides, The origins and the future of microfluidics, Nature. 442 (2006) 368–373.
• [21] D. Mark, S. Haeberle, G. Roth, F. Von Stetten, R. Zengerle, Microfluidic lab-on-a-chip platforms: Requirements, characteristics and applications, Chem Soc Rev. 39(3) (2010) 1153–1182.
• [22] K. İçöz, O. Mzava, Detection of proteins using nano magnetic particle accumulation-based signal amplification, Appl. Sci. 6 (2016) 394.
• [23] K. İçöz, T. Gerçek, A. Murat, S. Özcan, E. Ünal, Capturing B type acute lymphoblastic leukemia cells using two types of antibodies, Biotechnol. Prog. 35(2019) e2737.
• [24] D. Pekin, Y. Skhiri, J.C. Baret, D. Le Corre, L. Mazutis, C. Ben Salem, F. Millot, A. El Harrak, J.B. Hutchison, J.W. Larson, D.R. Link, P. Laurent-Puig, A.D. Griffiths, V. Taly, Quantitative and sensitive detection of rare mutations using droplet-based microfluidics, Lab Chip. 11(2011) 2156-2166.
• [25] Y. Li, S. Wang, R. Huang, Z. Huang, B. Hu, W. Zheng, G. Yang, X. Jiang, Evaluation of the effect of the structure of bacterial cellulose on full thickness skin wound repair on a microfluidic chip, Biomacromolecules. 16 (2015) 780–789.
• [26] R.R.G. Soares, D. Ramadas, V. Chu, M.R. Aires-Barros, J.P. Conde, A.S. Viana, A.C. Cascalheira, An ultrarapid and regenerable microfluidic immunoassay coupled with integrated photosensors for point-of-use detection of ochratoxin A, Sensors Actuators B Chem. 235 (2016) 554–562.
• [27] F.E. Yigit, İ.İ.Bosgelmez, Emerging potential of microfluidic chips in the field of forensics. 3rd Regional TIAFT Meeting in Turkey, 18-20 October 2018, pp.175-176.
• [28] W. Zhou, J. Le, Y. Chen, Y. Cai, Z. Hong, Y. Chai, Recent advances in microfluidic devices for bacteria and fungus research, TrAC Trends Anal. Chem. 112 (2019) 175–195.
• [29] X. Zhang, S.J. Haswell, Materials matter in microfluidic devices, MRS Bull. 31 (2006) 95–99.
• [30] X. Hou, Y.S. Zhang, G.T. Santiago, M.M. Alvarez, J. Ribas, S.J. Jonas, P.S. Weiss, A.M. Andrews, J. Aizenberg, A. Khademhosseini, Interplay between materials and microfluidics, Nat. Rev. Mater. 2 (2017) 17016.
• [31] K. Ren, J. Zhou, H. Wu, Materials for microfluidic chip fabrication, Acc. Chem. Res. 46 (2013) 2396–2406.
• [32] X. Liu, B. Lin, Materials Used in Microfluidic Devices, in: Encycl. Microfluid. Nanofluidics, Springer US, Boston, MA, 2014: pp. 1–5.
• [33] H. Becker, L.E. Locascio Polymer microfluidic devices, Talanta. 56 (2002) 267–287.
• [34] S.A. Soper, A.C. Henry, B. Vaidya, M. Galloway, M. Wabuyele, R.L. McCarley, Surface modification of polymer-based microfluidic devices, Anal. Chim. Acta. 470 (2002) 87–99.
• [35] I. Wong, C.-M. Ho, Surface molecular property modifications for poly(dimethylsiloxane) (PDMS) based microfluidic devices, Microfluid. Nanofluidics. 7 (2009) 291–306.
• [36] K.R. King, C.C.J. Wang, M.R. Kaazempur-Mofrad, J.P. Vacanti, J.T. Borenstein, Biodegradable microfluidics. Adv. Mater 16(2004) 2007-2012.
• [37] G.M. Whitesides, E. Ostuni, S. Takayama, X. Jiang, D.E. Ingber, Soft lithography in biology and biochemistry, Annu. Rev. Biomed. Eng. 3 (2001) 335–373.
• [38] T. Thorsen, S.J. Maerkl, S.R. Quake, Microfluidic large-scale integration, Science 298(2002) 580–584.
• [39] M.-C. Bélanger, Y. Marois, Hemocompatibility, biocompatibility, inflammatory and in vivo studies of primary reference materials low-density polyethylene and polydimethylsiloxane: A review, J. Biomed. Mater. Res. 58 (2001) 467–477.
• [40] D. Bovard, A. Iskandar, K. Luettich, J. Hoeng, M.C. Peitsch, Organs-on-a-chip: New in vitro tools multi-organ-on-a-chip challenges, limitations, and future prospects for fluidic devices, Toxicology Research and Application. 1(2017) 1-16.
• [41] M.W. Toepke, D.J. Beebe, PDMS absorption of small molecules and consequences in microfluidic applications, Lab Chip. 6 (2006) 1484–1486.
• [42] J.D. Wang, N.J. Douville, S. Takayama, M. ElSayed, Quantitative analysis of molecular absorption into PDMS microfluidic channels, Ann. Biomed. Eng. 40 (2012) 1862–1873.
• [43] A. Alrifaiy, O.A. Lindahl, K. Ramser, Polymer-based microfluidic devices for pharmacy, biology and tissue engineering, Polymers (Basel). 4 (2012) 1349–1398.
• [44] B.J. van Meer, H. de Vries, K.S.A. Firth, J. van Weerd, L.G.J. Tertoolen, H.B.J. Karperien, P. Jonkheijm, C. Denning, A.P. IJzerman, C.L. Mummery, Small molecule absorption by PDMS in the context of drug response bioassays, Biochem. Biophys. Res. Commun. 482 (2017) 323–328.
• [45] S. Halldorsson, E. Lucumi, R. Gómez-Sjöberg, R.M.T. Fleming, Advantages and challenges of microfluidic cell culture in polydimethylsiloxane devices, Biosens. Bioelectron. 63 (2015) 218–231.
• [46] H. Hirama, T. Satoh, S. Sugiura, K. Shin, R. Onuki-Nagasaki, T. Kanamori, T. Inoue, Glass-based organ-on-a-chip device for restricting small molecular absorption, J. Biosci. Bioeng. 127 (2019) 641–646.
• [47] A. Naderi, N. Bhattacharjee, A. Folch, Digital manufacturing for microfluidics, Annu. Rev. Biomed. Eng. 21 (2019) 325–364.
• [48] J.U. Lind, T.A. Busbee, A.D. Valentine, F.S. Pasqualini, H. Yuan, M. Yadid, S.-J. Park, A. Kotikian, A.P. Nesmith, P.H. Campbell, J.J. Vlassak, J.A. Lewis, K.K. Parker, Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing, Nat. Mater. 16 (2017) 303–308.
• [49] H.-G. Yi, H. Lee, D.-W. Cho, 3D Printing of organs-on-chips, Bioengineering. 4 (2017) 10.
• [50] F. Kotz, P. Risch, K. Arnold, S. Sevim, J. Puigmartí-Luis, A. Quick, M. Thiel, A. Hrynevich, P.D. Dalton, D. Helmer, B.E. Rapp, Fabrication of arbitrary three-dimensional suspended hollow microstructures in transparent fused silica glass, Nat. Commun. 10 (2019) 1439.
• [51] Y. Alapan, K. Icoz, U.A. Gurkan, Micro- and nanodevices integrated with biomolecular probes, Biotechnol. Adv. 33 (2015) 1727–1743.
• [52] H. Liu, Y. Wang, K. Cui, Y. Guo, X. Zhang, J. Qin, Advances in hydrogels in organoids and organs‐on‐a‐chip, Adv. Mater. (2019) e1902042.
• [53] M. Kaljurand, Paper microzones as a route to greener analytical chemistry, Curr. Opin. Green Sustain. Chem. 19 (2019) 15–18.
• [54] Y. Ai, F. Zhang, C. Wang, R. Xie, Q. Liang, Recent progress in lab-on-a-chip for pharmaceutical analysis and pharmacological/toxicological test, TrAC - Trends Anal. Chem. 117(2019) 215-230.
• [55] J. Park, I. Wetzel, D. Dréau, H. Cho, 3D Miniaturization of human organs for drug discovery, Adv. Healthc. Mater. 7 (2018) 1700551.
• [56] S. Loiodice, A. Nogueira da Costa, F. Atienzar, Current trends in in silico , in vitro toxicology, and safety biomarkers in early drug development, Drug Chem. Toxicol. 42 (2019) 113–121.
• [57] A. Balijepalli, V. Sivaramakrishan, Organs-on-chips: research and commercial perspectives, Drug Discov. Today. 22 (2017) 397–403.
• [58] C.H. Beckwitt, A.M. Clark, S. Wheeler, D.L. Taylor, D.B. Stolz, L. Griffith, A. Wells, Liver ‘organ on a chip,’ Exp. Cell Res. 363 (2018) 15–25.
• [59] G.J. Mahler, M.B. Esch, R.P. Glahn, M.L. Shuler, Characterization of a gastrointestinal tract microscale cell culture analog used to predict drug toxicity, Biotechnol. Bioeng. 104 (2009) 193–205.
• [60] V.M. Lauschke, D.F.G. Hendriks, C.C. Bell, T.B. Andersson, M. Ingelman-Sundberg, Novel 3D culture systems for studies of human liver function and assessments of the hepatotoxicity of drugs and drug candidates. Chem Res Toxicol, 29(2016) 1936-1955.
• [61] J. Dai, M. Hamon, S. Jambovane, Microfluidics for antibiotic susceptibility and toxicity testing, Bioengineering. 3 (2016) 25.
• [62] C.Y. Li, K.R. Stevens, R.E. Schwartz, B.S. Alejandro, J.H. Huang, S.N. Bhatia, Micropatterned cell–cell interactions enable functional encapsulation of primary hepatocytes in hydrogel microtissues, Tissue Eng. Part A. 20 (2014) 2200–2212.
• [63] L. Shintu, R. Baudoin, V. Navratil, J.-M. Prot, C. Pontoizeau, M. Defernez, B.J. Blaise, C. Domange, A.R. Péry, P. Toulhoat, C. Legallais, C. Brochot, E. Leclerc, M.-E. Dumas, Metabolomics-on-a-chip and predictive systems toxicology in microfluidic bioartificial organs, Anal. Chem. 84 (2012) 1840–1848.
• [64] S.M. Hattersley, J. Greenman, S.J. Haswell, Study of ethanol induced toxicity in liver explants using microfluidic devices, Biomed. Microdevices. 13 (2011) 1005–1014.
• [65] P.M. van Midwoud, M.T. Merema, E. Verpoorte, G.M.M. Groothuis, A microfluidic approach for in vitro assessment of interorgan interactions in drug metabolism using intestinal and liver slices, Lab Chip. 10 (2010) 2778–2786.
• [66] Y.-C. Toh, T.C. Lim, D. Tai, G. Xiao, D. van Noort, H. Yu, A microfluidic 3D hepatocyte chip for drug toxicity testing, Lab Chip. 9 (2009) 2026–2035.
• [67] K.-J. Jang, A.P. Mehr, G.A. Hamilton, L.A. McPartlin, S. Chung, K.-Y. Suh, D.E. Ingber, Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment, Integr. Biol. 5 (2013) 1119–1129.
• [68] R. Baudoin, L. Griscom, M. Monge, C. Legallais, E. Leclerc, Development of a renal microchip for in vitro distal tubule models, Biotechnol. Prog. 23(2007) 1245-1253.
• [69] J.H. Yeon, D. Na, K. Choi, S.-W. Ryu, C. Choi, J.-K. Park, Reliable permeability assay system in a microfluidic device mimicking cerebral vasculatures, Biomed. Microdevices. 14 (2012) 1141–1148.
• [70] G. Shayan, Y.S. Choi, E. V. Shusta, M.L. Shuler, K.H. Lee, Murine in vitro model of the blood–brain barrier for evaluating drug transport, Eur. J. Pharm. Sci. 42 (2011) 148–155.
• [71] A. Agarwal, J.A. Goss, A. Cho, M.L. McCain, K.K. Parker, Microfluidic heart on a chip for higher throughput pharmacological studies, Lab Chip. 13 (2013) 3599–3608.
• [72] W. Siyan, Y. Feng, Z. Lichuan, W. Jiarui, W. Yingyan, J. Li, L. Bingcheng, W. Qi, Application of microfluidic gradient chip in the analysis of lung cancer chemotherapy resistance, J. Pharm. Biomed. Anal. 49 (2009) 806–810.
• [73] J.H. Yeon, J.-K. Park, Drug permeability assay using microhole-trapped cells in a microfluidic device, Anal. Chem. 81 (2009) 1944–1951.
• [74] D. Bovard, A. Sandoz, K. Luettich, S. Frentzel, A. Iskandar, D. Marescotti, K. Trivedi, E. Guedj, Q. Dutertre, M.C. Peitsch, J. Hoeng, A lung/liver-on-a-chip platform for acute and chronic toxicity studies, Lab Chip. 18 (2018) 3814–3829.
• [75] J.H. Sung, Y.I. Wang, N. Narasimhan Sriram, M. Jackson, C. Long, J.J. Hickman, M.L. Shuler, Recent advances in body-on-a-chip systems, Anal. Chem. 91 (2019) 330–351.
• [76] C. Oleaga, C. Bernabini, A.S.T. Smith, B. Srinivasan, M. Jackson, W. McLamb, V. Platt, R. Bridges, Y. Cai, N. Santhanam, B. Berry, S. Najjar, N. Akanda, X. Guo, C. Martin, G. Ekman, M.B. Esch, J. Langer, G. Ouedraogo, J. Cotovio, L. Breton, M.L. Shuler, J.J. Hickman, Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs, Sci. Rep. 6 (2016) 20030.
• [77] Z. Li, L. Jiang, Y. Zhu, W. Su, C. Xu, T. Tao, Y. Shi, J. Qin, Assessment of hepatic metabolism-dependent nephrotoxicity on an organs-on-a-chip microdevice, Toxicol. Vitr. 46(2018) 1-8.
• [78] R. Jellali, P. Zeller, F. Gilard, A. Legendre, M.J. Fleury, S. Jacques, G. Tcherkez, E. Leclerc, Effects of DDT and permethrin on rat hepatocytes cultivated in microfluidic biochips: Metabolomics and gene expression study, Environ. Toxicol. Pharmacol. 59 (2018) 1–12.
• [79] J. Zhang, Z. Yang, Q. Liu, H. Liang, Electrochemical biotoxicity detection on a microfluidic paper-based analytical device via cellular respiratory inhibition, Talanta. 202 (2019) 384–391.
• [80] J. Slagboom, R.A. Otvos, F.C. Cardoso, J. Iyer, J.C. Visser, B.R. van Doodewaerd, R.J.R. McCleary, W.M.A. Niessen, G.W. Somsen, R.J. Lewis, R.M. Kini, A.B. Smit, N.R. Casewell, J. Kool, Neurotoxicity fingerprinting of venoms using on-line microfluidic AChBP profiling, Toxicon. 148 (2018) 213–222.
• [81] S.K. Mahto, T.H. Yoon, S.W. Rhee, Cytotoxic effects of surface-modified quantum dots on neuron-like PC12 cells cultured inside microfluidic devices, BioChip J. 4 (2010) 82–88.
• [82] C.W. McAleer, A. Pointon, C.J. Long, R.L. Brighton, B.D. Wilkin, L.R. Bridges, N. Narasimhan Sriram, K. Fabre, R. McDougall, V.P. Muse, J.T. Mettetal, A. Srivastava, D. Williams, M.T. Schnepper, J.L. Roles, M.L. Shuler, J.J. Hickman, L. Ewart, On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships, Sci. Rep. 9 (2019) 9619.
• [83] I. Wagner, E.-M. Materne, S. Brincker, U. Süßbier, C. Frädrich, M. Busek, F. Sonntag, D.A. Sakharov, E. V. Trushkin, A.G. Tonevitsky, R. Lauster, U. Marx, A dynamic multi-organ-chip for long-term cultivation and substance testing proven by 3D human liver and skin tissue co-culture, Lab Chip. 13 (2013) 3538-3547.
• [84] Y. Imura, E. Yoshimura, K. Sato, Micro total bioassay system for oral drugs: Evaluation of gastrointestinal degradation, intestinal absorption, hepatic metabolism, and bioactivity, Anal. Sci. 28 (2012) 197.
• [85] L. Ma, J. Barker, C. Zhou, W. Li, J. Zhang, B. Lin, G. Foltz, J. Küblbeck, P. Honkakoski, Towards personalized medicine with a three-dimensional micro-scale perfusion-based two-chamber tissue model system, Biomaterials. 33 (2012) 4353–4361.
• [86] J.H. Sung, C. Kam, M.L. Shuler, A microfluidic device for a pharmacokinetic–pharmacodynamic (PK–PD) model on a chip, Lab Chip. 10 (2010) 446-455.
• [87] J.H. Sung, M.L. Shuler, A micro cell culture analog (µCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugs, Lab Chip. 9 (2009) 1385-1394.
• [88] A. Perestrelo, A. Águas, A. Rainer, G. Forte, Microfluidic organ/body-on-a-chip devices at the convergence of biology and microengineering, Sensors. 15 (2015) 31142–31170.
• [89] P.N. Nge, C.I. Rogers, A.T. Woolley, Advances in microfluidic materials, functions, integration, and applications, Chem. Rev. 113 (2013) 2550–2583.
• [90] F. Zheng, F. Fu, Y. Cheng, C. Wang, Y. Zhao, Z. Gu, Organ-on-a-chip systems: Microengineering to biomimic living systems, Small. 12 (2016) 2253–2282.
• [91] L.H.M. van de Burgwal, P. van Dorst, H. Viëtor, R. Luttge, E. Claassen, Hybrid business models for ‘Organ-on-a-Chip’ technology: The best of both worlds, PharmaNutrition. 6 (2018) 55–63.
• [92] T. Kanamori, S. Sugiura, Y. Sakai, Technical aspects of microphysiological systems (MPS) as a promising wet human- in-vivo simulator, Drug Metab. Pharmacokinet. 33 (2018) 40–42.
• [93] G.J. Mahler, M.B. Esch, T. Stokol, J.J. Hickman, M.L. Shuler, Body-on-a-chip systems for animal-free toxicity testing, Altern. to Lab. Anim. 44 (2016) 469–478.
• [94] A. van den Berg, C.L. Mummery, R. Passier, A.D. van der Meer, Personalised organs-on-chips: functional testing for precision medicine, Lab Chip. 19 (2019) 198–205.