Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing

Marx, Uwe

doi:10.14573/altex.1603161

Cited by 2963D Printing in Biomedical ResearchAnimal testing and alternativesMicrofluidic and Capillary Electrophoresis Applications

Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing

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Marx, Uwe·2016·ALTEX

DOI 10.14573/altex.1603161PMC PMC5396467

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Abstract

The recent advent of microphysiological systems - microfluidic biomimetic devices that aspire to emulate the biology of human tissues, organs and circulation in vitro - is envisaged to enable a global paradigm shift in drug development. An extraordinary US governmental initiative and various dedicated research programs in Europe and Asia have led recently to the first cutting-edge achievements of human single-organ and multi-organ engineering based on microphysiological systems. The expectation is that test systems established on this basis would model various disease stages, and predict toxicity, immunogenicity, ADME profiles and treatment efficacy prior to clinical testing. Consequently, this technology could significantly affect the way drug substances are developed in the future. Furthermore, microphysiological system-based assays may revolutionize our current global programs of prioritization of hazard characterization for any new substances to be used, for example, in agriculture, food, ecosystems or cosmetics, thus, replacing laboratory animal models used currently. Thirty-six experts from academia, industry and regulatory bodies present here the results of an intensive workshop (held in June 2015, Berlin, Germany). They review the status quo of microphysiological systems available today against industry needs, and assess the broad variety of approaches with fit-for-purpose potential in the drug development cycle. Feasible technical solutions to reach the next levels of human biology in vitro are proposed. Furthermore, key organ-on-a-chip case studies, as well as various national and international programs are highlighted. Finally, a roadmap into the future is outlined, to allow for more predictive and regulatory-accepted substance testing on a global scale.

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At present, organs-on-chips are considered the most promising way to model human diseases in vitro.
“OoCs currently constitute the most promising approach to emulate human diseases in vitro55,61.”
From Human disease models in drug development (2023) · cites this paper as [61]
Section 4.6 describes organ-on-chip projects for human disease models, and Section 7 envisages Body-on-a-chip systems providing solutions for disease modeling. The paper does not establish that organs-on-chips are currently the most promising in vitro approach; it presents some of these capabilities as future developments. (LLM, conf=0.86)
Experimental — accuracy not yet measured
To date, human-based models have mainly served toxicity testing, with preclinical and clinical use still nascent.
“human-based models have so far been primarily used for toxicity testing61–64, and their application in preclinical and clinical research is still in its infancy.”
From Human disease models in drug development (2023) · cites this paper as [61]
Section 5.5 describes chemical safety testing as a major driver of human-based alternative methods. Section 3.1 presents wider pharmaceutical adoption of microphysiological systems, including use during clinical development, as prospective. The paper does not establish that human-based models have been used primarily for toxicity testing or that preclinical and clinical research applications as a whole remain in their infancy; it also describes existing disease-modeling and drug-development applications. Page numbers were not available in our copy. (LLM, conf=0.82)
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A micro cell culture analog (µCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugs
Sung, J. H., & Shuler, M. L. (2009) · Lab on a Chip · doi:10.1039/b901377f · Cited by 431 · see citing works
Induced pluripotent stem cells: the new patient?
Bellin, M., Marchetto, M. C., Gage, F. H., & Mummery, C. L. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3448 · Cited by 431 · see citing works
Cell Culture on Artificial Capillaries: an Approach to Tissue Growth In Vitro
Knazek, R. A., Gullino, P. M., Kohler, P. O., & Dedrick, R. L. (1972) · Science · doi:10.1126/science.178.4056.65 · Cited by 424 · see citing works
A microfluidic 3D hepatocyte chip for drug toxicity testing
Toh, Y., Lim, T. C., Tai, D., Xiao, G., van Noort, D., & Yu, H. (2009) · Lab on a Chip · doi:10.1039/b900912d · Cited by 422 · see citing works
Why Drugs Fail - A Study on Side Effects in New Chemical Entities
Schuster, D., Laggner, C., & Langer, T. (2005) · Current Pharmaceutical Design · doi:10.2174/138161205774414510 · Cited by 417 · cited 1× · see citing works
“Despite intense preclinical safety testing in a number of phase I trials, safety issues may arise which can lead to the termination of a program (Cook et al., 2014; Schuster et al., 2005).”
A lung-on-a-chip array with an integrated bio-inspired respiration mechanism
Stucki, A., Stucki, J. D., Hall, S. R. R., Felder, M., Mermoud, Y., Schmid, R. A., Geiser, T., & Guenat, O. T. (2014) · Lab on a Chip · doi:10.1039/c4lc01252f · Cited by 415 · see citing works
A novel 3D mammalian cell perfusion-culture system in microfluidic channels
Toh, Y.-C., Zhang, C., Zhang, J., Khong, Y. M., Chang, S., Samper, V. D., van Noort, D., Hutmacher, D. W., & Yu, H. (2007) · Lab on a Chip · doi:10.1039/b614872g · Cited by 414 · see citing works
Computerized microfluidic cell culture using elastomeric channels and Braille displays
Gu, W., Zhu, X. A., Futai, N., Cho, B. S., & Takayama, S. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404353101 · Cited by 403 · see citing works
Quantification of Chemical Peptide Reactivity for Screening Contact Allergens: A Classification Tree Model Approach
Gerberick, G. F., Vassallo, J. D., Foertsch, L. M., Price, B. B., Chaney, J. G., & Lepoittevin, J. (2007) · Toxicological Sciences · doi:10.1093/toxsci/kfm064 · Cited by 399 · see citing works
Reconfigurable microfluidic hanging drop network for multi-tissue interaction and analysis
Frey, O., Misun, P. M., Fluri, D. A., Hengstler, J. G., & Hierlemann, A. R. (2014) · Nature Communications · doi:10.1038/ncomms5250 · Cited by 382 · see citing works
Applying Adverse Outcome Pathways (AOPs) to support Integrated Approaches to Testing and Assessment (IATA)
Tollefsen, K. E., Scholz, S., Cronin, M., Edwards, S. W., de Knecht, J. A., Crofton, K. M., García‐Reyero, N., Härtung, T., Worth, A. P., & Patlewicz, G. Y. (2014) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2014.09.009 · Cited by 380 · see citing works
Microelectrode arrays: A physiologically based neurotoxicity testing platform for the 21st century
Johnstone, A. F. M., Gross, G. W., Weiss, D. G., Schroeder, O. H.-U., Gramowski, A., & Shafer, T. J. (2010) · NeuroToxicology · doi:10.1016/j.neuro.2010.04.001 · Cited by 375 · see citing works
Guidance on Good Cell Culture Practice: A Report of the Second ECVAM Task Force on Good Cell Culture Practice
Coecke, S., Balls, M., Bowe, G., Davis, J., Gstraunthaler, G., Hartung, T., Hay, R., Merten, O.-W., Price, A., Schechtman, L., et al. (2005) · Alternatives to Laboratory Animals · doi:10.1177/026119290503300313 · Cited by 371 · see citing works
The Design and Fabrication of Three-Chamber Microscale Cell Culture Analog Devices with Integrated Dissolved Oxygen Sensors
Sin, A., Chin, K. C., Jamil, M. F., Kostov, Y. V., Rao, G., & Shuler, M. L. (2004) · Biotechnology Progress · doi:10.1021/bp034077d · Cited by 369 · see citing works
A dataset on 145 chemicals tested in alternative assays for skin sensitization undergoing prevalidation
Natsch, A., Ryan, C. A., Foertsch, L. M., Emter, R., Jaworska, J., Gerberick, F., & Kern, P. (2013) · Journal of Applied Toxicology · doi:10.1002/jat.2868 · Cited by 363 · see citing works
Cell-Based Biosensors and Their Application in Biomedicine
Liu, Q., Wu, C., Cai, H., Hu, N., Zhou, J., & Wang, P. (2014) · Chemical Reviews · doi:10.1021/cr2003129 · Cited by 351 · see citing works
Development of an in vitro skin sensitization test using human cell lines: The human Cell Line Activation Test (h-CLAT)
Ashikaga, T., Yoshida, Y., Hirota, M., Yoneyama, K., Itagaki, H., Sakaguchi, H., Miyazawa, M., Ito, Y., Suzuki, H., & Toyoda, H. (2005) · Toxicology in Vitro · doi:10.1016/j.tiv.2005.10.012 · Cited by 342 · see citing works
Towards a human-on-chip: Culturing multiple cell types on a chip with compartmentalized microenvironments
Zhang, C., Zhao, Z., Abdul Rahim, N. A., van Noort, D., & Yu, H. (2009) · Lab on a Chip · doi:10.1039/b915147h · Cited by 340 · see citing works
Oral exposure to polystyrene nanoparticles affects iron absorption
Mahler, G. J., Esch, M. B., Tako, E., Southard, T. L., Archer, S. D., Glahn, R. P., & Shuler, M. L. (2012) · Nature Nanotechnology · doi:10.1038/nnano.2012.3 · Cited by 339 · see citing works
Performance of a novel keratinocyte-based reporter cell line to screen skin sensitizers in vitro
Emter, R., Ellis, G., & Natsch, A. (2010) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2010.03.009 · Cited by 337 · see citing works
Microscale 3-D hydrogel scaffold for biomimetic gastrointestinal (GI) tract model
Sung, J. H., Yu, J., Luo, D., Shuler, M. L., & March, J. C. (2010) · Lab on a Chip · doi:10.1039/c0lc00273a · Cited by 321 · see citing works
Directed differentiation of cholangiocytes from human pluripotent stem cells
Ogawa, M., Ogawa, S., Bear, C. E., Ahmadi, S., Chin, S., Li, B., Grompe, M., Keller, G. M., Kamath, B. M., & Ghanekar, A. (2015) · Nature Biotechnology · doi:10.1038/nbt.3294 · Cited by 318 · see citing works
"Cytokine Storm" in the Phase I Trial of Monoclonal Antibody TGN1412: Better Understanding the Causes to Improve PreClinical Testing of Immunotherapeutics
Stebbings, R., Findlay, L., Edwards, C., Eastwood, D., Bird, C., North, D., Mistry, Y., Dilger, P., Liefooghe, E., Cludts, I., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.5.3325 · Cited by 317 · cited 1× · see citing works
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Scaling and systems biology for integrating multiple organs-on-a-chip
Wikswo, J. P., Curtis, E. L., Eagleton, Z. E., Evans, B. C., Kole, A., Hofmeister, L. H., & Matloff, W. J. (2013) · Lab on a Chip · doi:10.1039/c3lc50243k · Cited by 310 · see citing works
Microfabrication and microfluidics for tissue engineering: state of the art and future opportunities
Andersson, H., & van den Berg, A. (2004) · Lab on a Chip · doi:10.1039/b314469k · Cited by 309 · see citing works
Development of a Microscale Cell Culture Analog To Probe Naphthalene Toxicity
Viravaidya‐Pasuwat, K., Sin, A., & Shuler, M. L. (2004) · Biotechnology Progress · doi:10.1021/bp0341996 · Cited by 306 · see citing works
Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner
Westein, E., van der Meer, A. D., Kuijpers, M. J. E., Frimat, J., van den Berg, A., & Heemskerk, J. W. M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1209905110 · Cited by 305 · see citing works
An integrated microfluidic system for long-term perfusion culture and on-line monitoring of intestinal tissue models
Kimura, H., Yamamoto, T., Sakai, H., Sakai, Y., & Fujii, T. (2008) · Lab on a Chip · doi:10.1039/b717091b · Cited by 293 · see citing works
Inhibition of Angiogenesis by Thalidomide Requires Metabolic Activation, Which Is Species-dependent
Bauer, K. S., Dixon, S. C., & Figg, W. D. (1998) · Biochemical Pharmacology · doi:10.1016/s0006-2952(98)00046-x · Cited by 291 · see citing works
Characterization of Caco-2 and HT29-MTX cocultures in an in vitro digestion/cell culture model used to predict iron bioavailability
Mahler, G. J., Shuler, M. L., & Glahn, R. P. (2008) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2008.05.006 · Cited by 289 · see citing works
Patterned cell culture inside microfluidic devices
Rhee, S. W., Taylor, A. M., Tu, C. H., Cribbs, D. H., Cotman, C. W., & Jeon, N. L. (2004) · Lab on a Chip · doi:10.1039/b403091e · Cited by 283 · see citing works
Rapid heterogeneous liver-cell on-chip patterning via the enhanced field-induced dielectrophoresis trap
Ho, C.-T., Lin, R., Chang, W.-Y., Chang, H., & Liu, C. (2006) · Lab on a Chip · doi:10.1039/b602036d · Cited by 283 · see citing works
Comparison of the local lymph node assay with the guinea-pig maximization test for the detection of a range of contact allergens
Basketter, D. A., & Scholes, E. W. (1992) · Food and Chemical Toxicology · doi:10.1016/0278-6915(92)90138-b · Cited by 282 · see citing works
Body-on-a-chip simulation with gastrointestinal tract and liver tissues suggests that ingested nanoparticles have the potential to cause liver injury
Esch, M. B., Mahler, G. J., Stokol, T., & Shuler, M. L. (2014) · Lab Chip · doi:10.1039/c4lc00371c · Cited by 281 · cited 1× · see citing works
“ALTEX 33(3), 2016 285 A µCCA platform-based two-organ chip mimicking the gastrointestinal tract by a co-culture of CaCo-2 cells and the mucin producing cell line TH29-MTX, and the liver by a HepG2/C3A cell line culture has recently been described by Shuler’s team (Esch et al., 2014).”
Skin and hair on-a-chip: in vitro skin models versus ex vivo tissue maintenance with dynamic perfusion
Ataç, B., Wagner, I. P., Horland, R., Lauster, R., Marx, U., Tonevitsky, A., Azar, R. P., & Lindner, G. (2013) · Lab on a Chip · doi:10.1039/c3lc50227a · Cited by 273 · see citing works
Self-citation
Microfluidic platforms for mechanobiology
Polacheck, W. J., Li, R., Uzel, S. G. M., & Kamm, R. D. (2013) · Lab on a Chip · doi:10.1039/c3lc41393d · Cited by 272 · cited 1× · see citing works
“For more details on how microfluidic tools can be used to study mechanobiology we refer to a comprehensive review (Polacheck et al., 2013).”
A Human Breathing Lung-on-a-Chip
Huh, D. (2015) · Annals of the American Thoracic Society · doi:10.1513/annalsats.201410-442mg · Cited by 270 · see citing works
Tubeless microfluidic angiogenesis assay with three-dimensional endothelial-lined microvessels
Bischel, L. L., Young, E. W. K., Mader, B. R., & Beebe, D. J. (2012) · Biomaterials · doi:10.1016/j.biomaterials.2012.11.005 · Cited by 266 · see citing works
Liver-Specific Functional Studies in a Microfluidic Array of Primary Mammalian Hepatocytes
Kane, B. J., Zinner, M. J., Yarmush, M. L., & Toner, M. (2006) · Analytical Chemistry · doi:10.1021/ac051856v · Cited by 265 · see citing works
Re-evaluation of animal numbers and costs for in vivo tests to accomplish REACH legislation requirements for chemicals - a report by the Transatlantic Think Tank for Toxicology (t4)
Rovida, C. (2009) · ALTEX · doi:10.14573/altex.2009.3.187 · Cited by 262 · see citing works
Experimental rat models to study the metabolic syndrome
Aleixandre, A., & Miguel, M. (2009) · British Journal Of Nutrition · doi:10.1017/s0007114509990729 · Cited by 261 · see citing works
A novel high aspect ratio microfluidic design to provide a stable and uniform microenvironment for cell growth in a high throughput mammalian cell culture array
Hung, P. J., Lee, P. J., Sabounchi, P., Aghdam, N., Lin, R., & Lee, L. P. (2004) · Lab on a Chip · doi:10.1039/b410743h · Cited by 259 · see citing works
Chemical regulators have overreached
Härtung, T., & Rovida, C. (2009) · Nature · doi:10.1038/4601080a · Cited by 258 · see citing works
Generation of 3D Skin Equivalents Fully Reconstituted from Human Induced Pluripotent Stem Cells (iPSCs)
Itoh, M., Umegaki-Arao, N., Guo, Z., Liu, L., Higgins, C. A., & Christiano, A. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077673 · Cited by 239 · see citing works
The Myeloid U937 Skin Sensitization Test (U-SENS) addresses the activation of dendritic cell event in the adverse outcome pathway for skin sensitization
Piroird, C., Ovigne, J.-M., Rousset, F., Martinozzi, S., Gomes, C., Cotovio, J., & Alépée, N. (2015) · Toxicology in Vitro · doi:10.1016/j.tiv.2015.03.009 · Cited by 238 · see citing works
Microfluidic PDMS (Polydimethylsiloxane) Bioreactor for Large-Scale Culture of Hepatocytes
Leclerc, É., Sakai, Y., & Fujii, T. (2004) · Biotechnology Progress · doi:10.1021/bp0300568 · Cited by 236 · see citing works
In vitro model of tumor cell extravasation
Jeon, J. S., Zervantonakis, I. K., Chung, S., Kamm, R. D., & Charest, J. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056910 · Cited by 233 · see citing works
Human iPS cell–derived alveolar epithelium repopulates lung extracellular matrix
Ghaedi, M., Calle, E. A., Mendez, J. J., Gard, A. L., Balestrini, J. L., Booth, A., Bove, P. F., Gui, L., White, E. S., & Niklason, L. E. (2013) · Journal of Clinical Investigation · doi:10.1172/jci68793 · Cited by 230 · see citing works
A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing
Basketter, D. (2012) · ALTEX · doi:10.14573/altex.2012.1.003 · Cited by 226 · see citing works
Putting the parts together: Combining in vitro methods to test for skin sensitizing potentials
Bauch, C., Kolle, S. N., Ramı́rez, T., Eltze, T., Fabian, E. J., Mehling, A., Teubner, W., van Ravenzwaay, B., & Landsiedel, R. (2012) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2012.05.013 · Cited by 226 · see citing works
An improved 3D tetraculture system mimicking the cellular organisation at the alveolar barrier to study the potential toxic effects of particles on the lung
Klein, S. G., Serchi, T., Hoffmann, L., Blömeke, B., & Gutleb, A. C. (2013) · Particle and Fibre Toxicology · doi:10.1186/1743-8977-10-31 · Cited by 224 · see citing works
State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology
Alépée, N. (2014) · ALTEX · doi:10.14573/altex1406111 · Cited by 221 · see citing works
Characterization of a gastrointestinal tract microscale cell culture analog used to predict drug toxicity
Mahler, G. J., Esch, M. B., Glahn, R. P., & Shuler, M. L. (2009) · Biotechnology and Bioengineering · doi:10.1002/bit.22366 · Cited by 220 · see citing works
Chip-based human liver–intestine and liver–skin co-cultures – A first step toward systemic repeated dose substance testing in vitro
Maschmeyer, I., Hasenberg, T., Jaenicke, A., Lindner, M., Lorenz, A., Zech, J., Garbe, L., Sonntag, F., Hayden, P. J., Ayehunie, S., et al. (2015) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2015.03.002 · Cited by 220 · see citing works
Self-citation
Macro- and microscale fluid flow systems for endothelial cell biology
Young, E. W. K., & Simmons, C. A. (2009) · Lab on a Chip · doi:10.1039/b913390a · Cited by 216 · see citing works
In vitromodels of the human epithelial airway barrier to study the toxic potential of particulate matter
Rothen‐Rutishauser, B., Blank, F., Mühlfeld, C., & Gehr, P. (2008) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.4.8.1075 · Cited by 214 · see citing works
Evaluation of Cryopreserved Human Hepatocytes as an Alternative in Vitro System to Microsomes for the Prediction of Metabolic Clearance
Brown, H. S., Griffin, M., & Houston, J. B. (2006) · Drug Metabolism and Disposition · doi:10.1124/dmd.106.011569 · Cited by 212 · see citing works
Luminescence Lifetime Imaging of Oxygen, pH, and Carbon Dioxide Distribution Using Optical Sensors
Liebsch, G., Klimant, I., Frank, B., Holst, G., & Wolfbeis, O. S. (2000) · Applied Spectroscopy · doi:10.1366/0003702001949726 · Cited by 211 · see citing works
Evaluation of Differentiated Human Bronchial Epithelial Cell Culture Systems for Asthma Research
Stewart, C. E., Torr, E., Jamili, N. H. M., Bosquillon, C., & Sayers, I. (2012) · Journal of Allergy · doi:10.1155/2012/943982 · Cited by 211 · see citing works
The Directed Differentiation of Human iPS Cells into Kidney Podocytes
Song, B., Smink, A. M., Jones, C. V., Callaghan, J. M., Firth, S. D., Bernard, C. C. A., Laslett, A. L., Kerr, P. G., & Ricardo, S. D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046453 · Cited by 207 · see citing works
Look back in anger – what clinical studies tell us about preclinical work
Härtung, T. (2013) · ALTEX · doi:10.14573/altex.2013.3.275 · Cited by 203 · see citing works
A microfluidic approach for in vitro assessment of interorgan interactions in drug metabolism using intestinal and liver slices
van Midwoud, P. M., Merema, M. T., Verpoorte, E., & Groothuis, G. M. M. (2010) · Lab on a Chip · doi:10.1039/c0lc00043d · Cited by 203 · see citing works
Alternative Approaches Can Reduce the Use of Test Animals under REACH.
Katinka, V. D. J., j., M. S., Tørsløv, J., & de Bruijn, J. H. M. (2004) · Joint Research Centre (European Commission) · Cited by 202 · see citing works
Effects and uptake of gold nanoparticles deposited at the air–liquid interface of a human epithelial airway model
Brandenberger, C., Rothen‐Rutishauser, B., Mühlfeld, C., Schmid, O., FERRON, G. A., Maier, K., Gehr, P., & Lenz, A. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.09.014 · Cited by 195 · see citing works
Development of a Hybrid Liver Support System: A Review
Gerlach, J. (1996) · The International Journal of Artificial Organs · doi:10.1177/039139889601901105 · Cited by 191 · see citing works
Microfluidic titer plate for stratified 3D cell culture
Trietsch, S. J., Israëls, G. D., Joore, J., Hankemeier, T., & Vulto, P. (2013) · Lab on a Chip · doi:10.1039/c3lc50210d · Cited by 189 · see citing works
Translational research: 4 ways to fix the clinical trial
Ledford, H. K. (2011) · Nature · doi:10.1038/477526a · Cited by 188 · see citing works
Consensus report on the future of animal-free systemic toxicity testing
Leist, M. (2014) · ALTEX · doi:10.14573/altex.1406091 · Cited by 182 · see citing works
On chip porous polymer membranes for integration of gastrointestinal tract epithelium with microfluidic ‘body-on-a-chip’ devices
Esch, M. B., Sung, J. H., Yang, J. H., Yu, C., Yu, J., March, J. C., & Shuler, M. L. (2012) · Biomedical Microdevices · doi:10.1007/s10544-012-9669-0 · Cited by 180 · see citing works
Microfluidics embedded within extracellular matrix to define vascular architectures and pattern diffusive gradients
Baker, B. M., Trappmann, B., Stapleton, S. C., Toro, E., & Chen, C. S. (2013) · Lab on a Chip · doi:10.1039/c3lc50493j · Cited by 180 · see citing works
Integrating biological vasculature into a multi-organ-chip microsystem
Schimek, K. M. S., Busek, M., Brincker, S., Groth, B., Hoffmann, S., Lauster, R., Lindner, G., Lorenz, A., Menzel, U., Sonntag, F., et al. (2013) · Lab on a Chip · doi:10.1039/c3lc50217a · Cited by 177 · see citing works
Self-citation
Muscle on a chip: In vitro contractility assays for smooth and striated muscle
Grosberg, A., Nesmith, A. P., Goss, J. A., Brigham, M. D., McCain, M. L., & Parker, K. K. (2012) · Journal of Pharmacological and Toxicological Methods · doi:10.1016/j.vascn.2012.04.001 · Cited by 177 · see citing works
Migration dynamics of breast cancer cells in a tunable 3D interstitial flow chamber
Haessler, U., Teo, J. C. M., Foretay, D., Renaud, P., & Swartz, M. A. (2012) · Integrative Biology · doi:10.1039/c1ib00128k · Cited by 176 · see citing works
Engineering Challenges for Instrumenting and Controlling Integrated Organ-on-Chip Systems
Wikswo, J. P., Block, F. E., Cliffel, D. E., Goodwin, C. R., Marasco, C. C., Markov, D. A., McLean, D. L., MCLEAN, J. A. J., McKenzie, J. R., Reiserer, R. S., et al. (2013) · IEEE Transactions on Biomedical Engineering · doi:10.1109/tbme.2013.2244891 · Cited by 176 · see citing works
Integrated testing strategies (ITS) for safety assessment
Rovida, C. (2014) · ALTEX · doi:10.14573/altex.1411011 · Cited by 175 · see citing works
Intestinal Subepithelial Myofibroblasts Support in vitro and in vivo Growth of Human Small Intestinal Epithelium
Lahar, N., Lei, N., Wang, J., Jabaji, Z. B., Tung, S. C., Joshi, V. S., Lewis, M. S., Stelzner, M. G., Martı́n, M. G., & Dunn, J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026898 · Cited by 175 · see citing works
‘Human-on-a-chip’ Developments: A Translational Cutting-edge Alternative to Systemic Safety Assessment and Efficiency Evaluation of Substances in Laboratory Animals and Man?
Marx, U., Walles, H., Hoffmann, S., Lindner, G., Horland, R., Sonntag, F., Klotzbach, U., Sakharov, D. A., Tonevitsky, A., & Lauster, R. (2012) · Alternatives to Laboratory Animals · doi:10.1177/026119291204000504 · Cited by 174 · see citing works
Self-citation
Automated cell culture in high density tubeless microfluidic device arrays
Meyvantsson, I., Warrick, J. W., Hayes, S. A., Skoien, A., & Beebe, D. J. (2008) · Lab on a Chip · doi:10.1039/b715375a · Cited by 172 · see citing works
Micro Total Bioassay System for Ingested Substances: Assessment of Intestinal Absorption, Hepatic Metabolism, and Bioactivity
Imura, Y., Sato, K., & Yoshimura, E. (2010) · Analytical Chemistry · doi:10.1021/ac100806x · Cited by 172 · see citing works
Generation of Functional Mesenchymal Stem Cells from Different Induced Pluripotent Stem Cell Lines
Hynes, K., Menicanin, D., Mrozik, K. M., Gronthos, S., & Bartold, P. M. (2013) · Stem Cells and Development · doi:10.1089/scd.2013.0111 · Cited by 171 · see citing works
SnapShot: Growing Organoids from Stem Cells
Sato, T., & Clevers, H. (2015) · Cell · doi:10.1016/j.cell.2015.06.028 · Cited by 168 · see citing works
In vitro analysis of a hepatic device with intrinsic microvascular-based channels
Carraro, A., Hsu, W.-M., Kulig, K. M., Cheung, W. S., Miller, M. L., Weinberg, E. J., Swart, E. F., Kaazempur-Mofrad, M., Borenstein, J. T., Vacanti, J. P., et al. (2008) · Biomedical Microdevices · doi:10.1007/s10544-008-9194-3 · Cited by 168 · see citing works
Engineering interconnected 3D vascular networks in hydrogels using molded sodium alginate lattice as the sacrificial template
Wang, X., Jin, Z., Gan, B.-W., Lv, S., Xie, M., & Huang, W. (2014) · Lab on a Chip · doi:10.1039/c4lc00069b · Cited by 165 · see citing works
Bayesian integrated testing strategy (ITS) for skin sensitization potency assessment: a decision support system for quantitative weight of evidence and adaptive testing strategy
Jaworska, J. S., Natsch, A., Ryan, C. A., Strickland, J. A., Ashikaga, T., & Miyazawa, M. (2015) · Archives of Toxicology · doi:10.1007/s00204-015-1634-2 · Cited by 165 · see citing works
Integrated testing strategies for safety assessments
Härtung, T. (2013) · ALTEX · doi:10.14573/altex.2013.1.003 · Cited by 164 · see citing works
Inflammatory findings on species extrapolations: humans are definitely no 70-kg mice
Leist, M., & Härtung, T. (2013) · Archives of Toxicology · doi:10.1007/s00204-013-1038-0 · Cited by 164 · see citing works
Investigation of Peptide Reactivity of Pro-hapten Skin Sensitizers Using a Peroxidase-Peroxide Oxidation System
Gerberick, G. F., Troutman, J. A., Foertsch, L. M., Vassallo, J. D., Quijano, M., Dobson, R. L. M., Goebel, C., & Lepoittevin, J. (2009) · Toxicological Sciences · doi:10.1093/toxsci/kfp192 · Cited by 162 · see citing works
Polymer-Based Microfluidic Devices for Pharmacy, Biology and Tissue Engineering
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Local lymph node assay (LLNA) for detection of sensitization capacity of chemicals
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Authors: Marx, U.
Corresponding author: Marx, Uwe
ORCID: Marx, Uwe
Venue: ALTEX
Publisher: ALTEX Edition
Published: 2016
Volume: 33
Issue: 3
Pages: 272-321
ISSN: 0946-7785 (ISSN-L)
1868-596X
DOI: 10.14573/altex.1603161
PMC: PMC5396467
OpenAlex: W2373100661
Cited by: 295
References: 373
Citations by year: 2026: 12 · 2025: 11 · 2024: 15 · 2023: 22 · 2022: 17 · 2021: 33 · 2020: 46 · 2019: 48 · 2018: 52 · 2017: 28 · 2016: 9
FWCI: 3.26
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: ALTEX (publishedVersion, cc-by)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
KOPS (University of Konstanz) (submittedVersion, cc-by)
Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
Rivm (National Institute for Public Health and the Environment) (submittedVersion)
OpenAgrar (submittedVersion, cc-by)
Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
ETH Zürich Research Collection (cc-by)
Funders: National Institutes of Health (Z99 TR999999)
U.S. Food and Drug Administration
National Human Genome Research Institute (Z01HG200319)
Topics: Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Physical Sciences › Engineering › Biomedical Engineering › Microfluidic and Capillary Electrophoresis Applications
Keywords: microphysiological systems, organ-on-a-chip, toxicity prediction, hazard characterization, alternatives to animal testing, drug development, in vitro disease model, ADME prediction, regulatory acceptance, microfluidics
MeSH terms: Animals, Animal Testing Alternatives, Cell Line, Stem Cells, Hazardous Substances, Toxicity Tests, Lab-On-A-Chip Devices

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Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing

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