Abstract
Organs-on-chips, also known as “tissue chips” or microphysiological systems (MPS), are bioengineered microsystems capable of recreating aspects of human organ physiology and function and are in vitro tools with multiple applications in drug discovery and development. The ability to recapitulate human and animal tissues in physiologically relevant three-dimensional, multi-cellular environments allows applications in the drug development field, including; (1) use in assessing the safety and toxicity testing of potential therapeutics during early-stage preclinical drug development; (2) confirmation of drug/therapeutic efficacy in vitro; and (3) disease modeling of human tissues to recapitulate pathophysiology within specific subpopulations and even individuals, thereby advancing precision medicine efforts. This chapter will discuss the development and evolution of three-dimensional organ models over the past decade, and some of the opportunities offered by MPS technology that are not available through current standard two-dimensional cell cultures, or three-dimensional organoid systems. This chapter will outline future avenues of research in the MPS field, how cutting-edge biotechnology advances are expanding the applications for these systems, and discuss the current and future potential and challenges remaining for the field to address.
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References
Abaci HE, Shuler ML (2015) Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling. Integr Biol 7(4):383–391
Abaci HE et al (2016) Human skin constructs with spatially controlled vasculature using primary and iPSC-derived endothelial cells. Adv Healthc Mater 5(14):1800–1807
Agarwal A et al (2013) Microfluidic heart on a chip for higher throughput pharmacological studies. Lab Chip 13(18):3599–3608
Amor S et al (2010) Inflammation in neurodegenerative diseases. Immunology 129(2):154–169
An F et al (2015) Organ-on-a-Chip: new platform for biological analysis. Anal Chem Insights 10:39–45
Arrowsmith J (2011a) Trial watch: phase II failures: 2008–2010. Nat Rev Drug Discov 10(5):328–329
Arrowsmith J (2011b) Trial watch: phase III and submission failures: 2007–2010. Nat Rev Drug Discov 10(2):87–87
Arslan SY et al (2015) Novel three dimensional human Endocervix cultures respond to 28-day hormone treatment. Endocrinology 156(4):1602–1609
Au SH et al (2014) Hepatic organoids for microfluidic drug screening. Lab Chip 14(17):3290–3299
Awan Z, Genest J (2014) Inflammation modulation and cardiovascular disease prevention. Eur J Prev Cardiol 22(6):719–733
Balls M (1995) Defining the role of ECVAM in the development, validation and acceptance of alternative tests and testing strategies. Toxicol In Vitro 9(6):863–869
Biondi-Zoccai GGL et al (2003) Atherothrombosis, inflammation, and diabetes. J Am Coll Cardiol 41(7):1071–1077
Brown JA et al (2015) Recreating blood-brain barrier physiology and structure on chip: a novel neurovascular microfluidic bioreactor. Biomicrofluidics 9(5):054124
Brown JA et al (2016) Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit. J Neuroinflammation 13(1):306
Caballero D et al (2017) Organ-on-chip models of cancer metastasis for future personalized medicine: from chip to the patient. Biomaterials 149(Supplement C):98–115
Casey W et al (2015) A new path forward: the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) and National Toxicology Program’s Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). J Am Assoc Lab Anim Sci 54(2):170–173
Chen T et al (2016) A drug-compatible and temperature-controlled microfluidic device for live-cell imaging. Open Biol 6(8):160156
Cheng CS et al (2016) Cell density and joint microRNA-133a and microRNA-696 inhibition enhance differentiation and contractile function of engineered human skeletal muscle tissues. Tissue Eng A 22(7–8):573–583
de Peppo GM et al (2013) Engineering bone tissue substitutes from human induced pluripotent stem cells. Proc Natl Acad Sci 110(21):8680–8685
Du G et al (2016) Microfluidics for cell-based high throughput screening platforms—a review. Anal Chim Acta 903(Supplement C):36–50
Dutta D et al (2017) Disease Modeling in stem cell-derived 3D organoid systems. Trends Mol Med 23(5):393–410
Esch EW et al (2015) Organs-on-chips at the frontiers of drug discovery. Nat Rev Drug Discov 14:248–260
Esch MB et al (2016) Modular, pumpless body-on-a-chip platform for the co-culture of GI tract epithelium and 3D primary liver tissue. Lab Chip 16(14):2719–2729
Fashe MM et al (2015) Species-specific differences in the in vitro metabolism of Lasiocarpine. Chem Res Toxicol 28(10):2034–2044
Fernandez CE et al (2016) Human vascular microphysiological system for in vitro drug screening. Sci Rep 6:21579
Foulke-Abel, J., et al. (2016). Human enteroids as a model of upper small intestinal ion transport physiology and pathophysiology. Gastroenterology 150(3): 638–649.e638
Gan W et al (2004) Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 59(7):574–580
Groll J et al (2016) Biofabrication: reappraising the definition of an evolving field. Biofabrication 8(1):013001
Guillouzo A (1998) Liver cell models in in vitro toxicology. Environ Health Perspect 106(Suppl 2):511–532
Hanahan D, Weinberg RA (2011) Hallmarks of Cancer: the next generation. Cell 144(5):646–674
He Y et al (2016) Developments of 3D printing microfluidics and applications in chemistry and biology: a review. Electroanalysis 28(8):1658–1678
Henry OYF et al (2017) Organs-on-chips with integrated electrodes for trans-epithelial electrical resistance (TEER) measurements of human epithelial barrier function. Lab Chip 17(13):2264–2271
Herland A et al (2016) Distinct contributions of astrocytes and Pericytes to Neuroinflammation identified in a 3D human blood-brain barrier on a Chip. PLoS One 11(3):e0150360
Huh D et al (2010) Reconstituting organ-level lung functions on a Chip. Science 328(5986):1662–1668
Huh D et al (2012) A human disease model of drug toxicity–induced pulmonary Edema in a lung-on-a-Chip microdevice. Sci Trans Med 4(159):159ra147–159ra147
Jackson EL, Lu H (2016) Three-dimensional models for studying development and disease: moving on from organisms to organs-on-a-chip and organoids. Integr Biol Quant Biosci Nano Macro 8(6):672–683
Jang K-J et al (2013) Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment. Integr Biol 5(9):1119–1129
Jiang, Y., et al. (2018). Maturation of cardiomyocytes derived from human pluripotent stem cells: current strategies and limitations. Mol Cells 41(7):613–621
Junaid A et al (2017) An end-user perspective on organ-on-a-chip: assays and usability aspects. Curr Opin Biomed Eng 1:15–22
Kanamori T et al (2018) Technical aspects of microphysiological systems (MPS) as a promising wet human-in-vivo simulator. Drug Metab Pharmacokinet 33(1):40–42
Kawabori M, Yenari MA (2015) Inflammatory responses in brain ischemia. Curr Med Chem 22(10):1258–1277
Kim HJ et al (2012) Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. Lab Chip 12(12):2165–2174
Kniazeva T et al (2011) A microfluidic respiratory assist device with high gas permeance for artificial lung applications. Biomed Microdevices 13(2):315–323
Kolesky DB et al (2014) 3D bioprinting of vascularized, heterogeneous cell-laden tissue constructs. Adv Mater 26(19):3124–3130
Koutsouras DA et al (2017) Simultaneous monitoring of single cell and of micro-organ activity by PEDOT:PSS covered multi-electrode arrays. Mater Sci Eng C 81:84–89
Lancaster MA et al (2013) Cerebral organoids model human brain development and microcephaly. Nature 501:373–379
Laronda MM et al (2013) Recreating the female reproductive tract in vitro using iPSC technology in a linked microfluidics environment. Stem Cell Res Ther 4(Suppl 1):S13–S13
Lee-Montiel FT et al (2017) Control of oxygen tension recapitulates zone-specific functions in human liver microphysiology systems. Exp Biol Med 242(16):1617–1632
Li AP et al (2012) Definition of metabolism-dependent xenobiotic toxicity with co-cultures of human hepatocytes and mouse 3T3 fibroblasts in the novel integrated discrete multiple organ co-culture (IdMOC) experimental system: results with model toxicants aflatoxin B1, cyclophosphamide and tamoxifen. Chem Biol Interact 199(1):1–8
Li J et al (2016) Recent advances in bioprinting techniques: approaches, applications and future prospects. J Trans Med 14(1):271
Liu C et al (2018) Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond. Development 145(5):dev156166
Lopes FM et al (2017) Mimicking Parkinson’s disease in a dish: merits and pitfalls of the most commonly used dopaminergic in vitro models. NeuroMolecular Med 19(2):241–255
Lou Y-R, Leung AW (2018) Next generation organoids for biomedical research and applications. Biotechnol Adv 36(1):132–149
Low LA, Tagle DA (2017a) Organs-on-chips: Progress, challenges, and future directions. Exp Biol Med (Maywood, NJ) 242(16):1573–1578
Low LA, Tagle DA (2017b) Tissue chips - innovative tools for drug development and disease modeling. Lab Chip 17(18):3026–3036
Luan Q et al (2017) A microfluidic in-line ELISA for measuring secreted protein under perfusion. Biomed Microdevices 19(4):101
Madden L et al (2015) Bioengineered human myobundles mimic clinical responses of skeletal muscle to drugs. elife 4:e04885
Maoz BM et al (2017) Organs-on-chips with combined multi-electrode array and transepithelial electrical resistance measurement capabilities. Lab Chip 17(13):2294–2302
Martin L et al (2017) How much do clinical trials cost? Nat Rev Drug Discov 16:381–382
Marturano-Kruik A et al (2018) Biomechanical regulation of drug sensitivity in an engineered model of human tumor. Biomaterials 150:150–161
Maschmeyer I et al (2015) A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. Lab Chip 15(12):2688–2699
Materne E-M et al (2015) The multi-organ Chip - a microfluidic platform for long-term multi-tissue Coculture. J Vis Exp: JoVE 98:52526
Mathur A et al (2015) Human iPSC-based cardiac microphysiological system for drug screening applications. Sci Rep 5:8883
Merkel TC et al (2000) Gas sorption, diffusion, and permeation in poly(dimethylsiloxane). J Polym Sci B Polym Phys 38(3):415–434
Morgan S et al (2011) The cost of drug development: a systematic review. Health Policy 100(1):4–17
Moya ML et al (2013) In vitro perfused human capillary networks. Tissue Eng Part C Methods 19(9):730–737
Niu N, Wang L (2015) In vitro human cell line models to predict clinical response to anticancer drugs. Pharmacogenomics 16(3):273–285
Nunes SS et al (2013) Biowire: a platform for maturation of human pluripotent stem cell–derived cardiomyocytes. Nat Methods 10:781–787
Oleaga C et al (2016) Multi-organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci Rep 6:20030
Pournasr B, Duncan SA (2017) Modeling inborn errors of hepatic metabolism using induced pluripotent stem cells. Arterioscler Thromb Vasc Biol 37(11):1994–1999
Probst C et al (2018) High-throughput organ-on-a-chip systems: current status and remaining challenges. Curr Opin Biomed Eng 6:33–41
Profile Toolkit (2018) The Dynamic U.S. Research and Development Ecosystem. from https://http://www.phrma.org/industryprofile/2018/
Rebelo SP et al (2016) Validation of bioreactor and human-on-a-Chip devices for chemical safety assessment. Validation of alternative methods for toxicity testing. C. Eskes and M. Whelan. Springer, Cham, pp 299–316
Riahi R et al (2016) Automated microfluidic platform of bead-based electrochemical immunosensor integrated with bioreactor for continual monitoring of cell secreted biomarkers. Sci Rep 6:24598
Roberts RA et al (2014) Reducing attrition in drug development: smart loading preclinical safety assessment. Drug Discov Today 19(3):341–347
Ronaldson-Bouchard K et al (2018) Advanced maturation of human cardiac tissue grown from pluripotent stem cells. Nature 556(7700):239–243
Sakolish C et al (2018) Technology transfer of the microphysiological systems: a case study of the human proximal tubule tissue Chip. Sci Rep 8(1):14882–14882
Sances S et al (2018) Human iPSC-derived endothelial cells and microengineered organ-Chip enhance neuronal development. Stem Cell Reports 10(4):1222–1236
Sasahara K et al (2015) Pharmacokinetics and metabolism of Delamanid, a novel anti-tuberculosis drug, in animals and humans: importance of albumin metabolism in vivo. Drug Metab Dispos 43(8):1267–1276
Schimek K et al (2018) Bioengineering of a full-thickness skin equivalent in a 96-well insert format for substance permeation studies and organ-on-a-chip applications. Bioengineering 5(2)
Shah P et al (2016) A microfluidics-based in vitro model of the gastrointestinal human–microbe interface. Nat Commun 7:11535
Shirure VS, George SC (2017) Design considerations to minimize the impact of drug absorption in polymer-based organ-on-a-chip platforms. Lab Chip 17:681–690
Sin A et al (2004) The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors. Biotechnol Prog 20(1):338–345
Singh Dolt K et al (2017) Modeling Parkinson’s disease with induced pluripotent stem cells harboring α-synuclein mutations. Brain Pathol 27(4):545–551
Skardal A et al (2017) Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform. Sci Rep 7(1):8837
Sobrino A et al (2016) 3D microtumors in vitro supported by perfused vascular networks. Sci Rep 6:31589
Soto-Gutierrez A et al (2017) Pre-clinical and clinical investigations of metabolic zonation in liver diseases: the potential of microphysiology systems. Exp Biol Med 242(16):1605–1616
Stephenson J et al (2018) Inflammation in CNS neurodegenerative diseases. Immunology 154(2):204–219
Sun X, Nunes SS (2016) Biowire platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Methods 101:21–26
Sutherland ML et al (2013) The national institutes of health microphysiological systems program focuses on a critical challenge in the drug discovery pipeline. Stem Cell Res Ther 4(1):1–5
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676
Takebe T et al (2015) Vascularized and complex organ buds from diverse tissues via mesenchymal cell-driven condensation. Cell Stem Cell 16(5):556–565
Takebe T et al (2017) Synergistic engineering: organoids meet organs-on-a-chip. Cell Stem Cell 21(3):297–300
Tan W, Desai TA (2004) Layer-by-layer microfluidics for biomimetic three-dimensional structures. Biomaterials 25(7–8):1355–1364
Tanataweethum N et al (2018) Establishment and characterization of a primary murine adipose tissue-chip. Biotechnol Bioeng 0(0)
van der Helm MW et al (2017) Fabrication and validation of an organ-on-chip system with integrated electrodes to directly quantify transendothelial electrical resistance. JoVE 127:e56334
Vernetti LA et al (2016) A human liver microphysiology platform for investigating physiology, drug safety, and disease models. Exp Biol Med 241(1):101–114
Vunjak-Novakovic G et al (2013) HeLiVa platform: integrated heart-liver-vascular systems for drug testing in human health and disease. Stem Cell Res Ther 4(1):1–6
Wagner J et al (2017a) A dynamic map for learning, communicating, navigating and improving therapeutic development. Nat Rev Drug Discov 17:150
Wagner JA et al (2017b) Application of a dynamic map for learning, communicating, navigating, and improving therapeutic development. Clin Transl Sci 11(2):166–174
Wallet MA et al (2017) Isogenic cellular systems model the impact of genetic risk variants in the pathogenesis of type 1 diabetes. Front Endocrinol 8(276)
Wang Y et al (2012) Systematic prevention of bubble formation and accumulation for long-term culture of pancreatic islet cells in microfluidic device. Biomed Microdevices 14(2):419–426
Wang G et al (2014) Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat Med 20(6):616–623
Wang YI et al (2017) Microfluidic blood–brain barrier model provides in vivo-like barrier properties for drug permeability screening. Biotechnol Bioeng 114(1):184–194
Waring MJ et al (2015) An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat Rev Drug Discov 14:475–486
Weber EJ et al (2016) Development of a microphysiological model of human kidney proximal tubule function. Kidney Int 90(3):627–637
Wikswo JP et al (2013) Engineering challenges for instrumenting and controlling integrated organ-on-Chip Systems. IEEE Trans Biomed Eng 60(3):682–690
Workman MJ et al (2016) Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat Med 23:49
Xiao S et al (2017) A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nat Commun 8:14584
Yoon No D et al (2015) 3D liver models on a microplatform: well-defined culture, engineering of liver tissue and liver-on-a-chip. Lab Chip 15(19):3822–3837
Yu J et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920
Zhang B, Radisic M (2017) Organ-on-a-chip devices advance to market. Lab Chip 17(14):2395–2420
Zhang YS et al (2016) Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. Biomaterials 110:45–59
Zhang YS et al (2017) Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors. Proc Natl Acad Sci 114(12):E2293–E2302
Zheng Z, Zheng F (2016) Immune cells and inflammation in diabetic nephropathy. J Diabetes Res 2016:10
Zhu J et al (2016) Human fallopian tube epithelium co-culture with murine ovarian follicles reveals crosstalk in the reproductive cycle. Mol Hum Reprod 22:756–767
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Low, L.A., Sutherland, M., Lumelsky, N., Selimovic, S., Lundberg, M.S., Tagle, D.A. (2020). Organs-on-a-Chip. In: Oliveira, J., Reis, R. (eds) Biomaterials- and Microfluidics-Based Tissue Engineered 3D Models. Advances in Experimental Medicine and Biology, vol 1230. Springer, Cham. https://doi.org/10.1007/978-3-030-36588-2_3
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