Application of Microphysiological Systems to Enhance Safety Assessment in Drug Discovery.

Enhancing the early detection of new therapies that are likely to carry a safety liability in the context of the intended patient population would provide a major advance in drug discovery. Microphysiological systems (MPS) technology offers an opportunity to support enhanced preclinical to clinical translation through the generation of higher-quality preclinical physiological data. In this review, we highlight this technological opportunity by focusing on key target organs associated with drug safety and metabolism. By focusing on MPS models that have been developed for these organs, alongside other relevant in vitro models, we review the current state of the art and the challenges that still need to be overcome to ensure application of this technology in enhancing drug discovery.

[1]  A. Pointon,et al.  From the Cover: High-Throughput Imaging of Cardiac Microtissues for the Assessment of Cardiac Contraction during Drug Discovery , 2017, Toxicological sciences : an official journal of the Society of Toxicology.

[2]  Lucas H. Hofmeister,et al.  Scaling and systems biology for integrating multiple organs-on-a-chip. , 2013, Lab on a chip.

[3]  William McLamb,et al.  Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs , 2016, Scientific Reports.

[4]  Xuetao Sun,et al.  Biowire platform for maturation of human pluripotent stem cell-derived cardiomyocytes. , 2016, Methods.

[5]  T. Pruett,et al.  Hemodynamic flow improves rat hepatocyte morphology, function, and metabolic activity in vitro. , 2013, American journal of physiology. Cell physiology.

[6]  D. Ingber,et al.  Reconstituting Organ-Level Lung Functions on a Chip , 2010, Science.

[7]  Jong Hwan Sung,et al.  A pumpless multi‐organ‐on‐a‐chip (MOC) combined with a pharmacokinetic–pharmacodynamic (PK–PD) model , 2017, Biotechnology and bioengineering.

[8]  Eva Wagner,et al.  Physiologic force-frequency response in engineered heart muscle by electromechanical stimulation. , 2015, Biomaterials.

[9]  Catarina Brito,et al.  Human liver cell spheroids in extended perfusion bioreactor culture for repeated‐dose drug testing , 2012, Hepatology.

[10]  Mandy B. Esch,et al.  Characterization of a gastrointestinal tract microscale cell culture analog used to predict drug toxicity , 2009, Biotechnology and bioengineering.

[11]  V. Weaver,et al.  Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha , 2016, Hepatology.

[12]  W. Zimmermann,et al.  Three-dimensional engineered heart tissue from neonatal rat cardiac myocytes. , 2000, Biotechnology and bioengineering.

[13]  K. BéruBé,et al.  Tissue-Specific stem cell differentiation in an in vitro airway model. , 2011, Macromolecular bioscience.

[14]  M. Ingelman-Sundberg,et al.  Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease , 2016, Scientific Reports.

[15]  Luke P. Lee,et al.  Human iPSC-based Cardiac Microphysiological System For Drug Screening Applications , 2015, Scientific Reports.

[16]  L. Griffith,et al.  Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System , 2017, The Journal of Pharmacology and Experimental Therapeutics.

[17]  Delilah F. G. Hendriks,et al.  Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability , 2016, Scientific Reports.

[18]  Uwe Marx,et al.  Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing. , 2016, ALTEX.

[19]  M. Goumans,et al.  Defined Engineered Human Myocardium With Advanced Maturation for Applications in Heart Failure Modeling and Repair , 2017, Circulation.

[20]  M. Ponec,et al.  Characterization and comparison of reconstructed skin models: morphological and immunohistochemical evaluation. , 2000, Acta dermato-venereologica.

[21]  D. Davies,et al.  Temporal Monitoring of Differentiated Human Airway Epithelial Cells Using Microfluidics , 2015, PloS one.

[22]  C. Kjellstrand,et al.  Iatrogenic renal disease. , 1991, Archives of internal medicine.

[23]  D. L. Taylor,et al.  Evolution of Experimental Models of the Liver to Predict Human Drug Hepatotoxicity and Efficacy. , 2017, Clinics in liver disease.

[24]  Kevin Kit Parker,et al.  Human airway musculature on a chip: an in vitro model of allergic asthmatic bronchoconstriction and bronchodilation. , 2014, Lab on a chip.

[25]  C. Laggner,et al.  Why drugs fail--a study on side effects in new chemical entities. , 2005, Current pharmaceutical design.

[26]  Chitra Kanchagar,et al.  Establishment of a Hepatocyte-Kupffer Cell Coculture Model for Assessment of Proinflammatory Cytokine Effects on Metabolizing Enzymes and Drug Transporters , 2015, Drug Metabolism and Disposition.

[27]  R. Bhowmick,et al.  Cells and Culture Systems Used to Model the Small Airway Epithelium , 2016, Lung.

[28]  J R Coppeta,et al.  A portable and reconfigurable multi-organ platform for drug development with onboard microfluidic flow control. , 2016, Lab on a chip.

[29]  Frank Stahl,et al.  Comparison of primary human hepatocytes and hepatoma cell line Hepg2 with regard to their biotransformation properties. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[30]  Danny D Shen,et al.  Development of a microphysiological model of human kidney proximal tubule function. , 2016, Kidney international.

[31]  S. Hogan,et al.  Intestinal barrier function: molecular regulation and disease pathogenesis. , 2009, The Journal of allergy and clinical immunology.

[32]  Johan U. Lind,et al.  Instrumented cardiac microphysiological devices via multimaterial three-dimensional printing , 2016 .

[33]  Gordana Vunjak-Novakovic,et al.  Autonomous beating rate adaptation in human stem cell-derived cardiomyocytes , 2016, Nature Communications.

[34]  Kelly Bérubé,et al.  Human primary bronchial lung cell constructs: the new respiratory models. , 2010, Toxicology.

[35]  Yvonne Will,et al.  Use of micropatterned cocultures to detect compounds that cause drug-induced liver injury in humans. , 2013, Toxicological sciences : an official journal of the Society of Toxicology.

[36]  Michael L Shuler,et al.  Design and demonstration of a pumpless 14 compartment microphysiological system , 2016, Biotechnology and bioengineering.

[37]  L. Tolosa,et al.  Competency of different cell models to predict human hepatotoxic drugs , 2014, Expert opinion on drug metabolism & toxicology.

[38]  Manjunath Hegde,et al.  Towards a three-dimensional microfluidic liver platform for predicting drug efficacy and toxicity in humans , 2013, Stem Cell Research & Therapy.

[39]  Cécile Legallais,et al.  Metabolomics-on-a-chip and predictive systems toxicology in microfluidic bioartificial organs. , 2012, Analytical chemistry.

[40]  F. Mach,et al.  Role of cytokines and chemokines in non-alcoholic fatty liver disease. , 2012, World journal of gastroenterology.

[41]  Richard Novak,et al.  Matched-Comparative Modeling of Normal and Diseased Human Airway Responses Using a Microengineered Breathing Lung Chip. , 2016, Cell systems.

[42]  Wolfram-Hubertus Zimmermann,et al.  Optimizing Engineered Heart Tissue for Therapeutic Applications as Surrogate Heart Muscle , 2006, Circulation.

[43]  Jorrit J Hornberg,et al.  Exploratory toxicology as an integrated part of drug discovery. Part II: Screening strategies. , 2014, Drug discovery today.

[44]  Olof Beck,et al.  Endogenous and xenobiotic metabolic stability of primary human hepatocytes in long-term 3D spheroid cultures revealed by a combination of targeted and untargeted metabolomics , 2017, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[45]  Amy Pointon,et al.  Cardiac Non-myocyte Cells Show Enhanced Pharmacological Function Suggestive of Contractile Maturity in Stem Cell Derived Cardiomyocyte Microtissues , 2016, Toxicological sciences : an official journal of the Society of Toxicology.

[46]  Uwe Marx,et al.  Integrating biological vasculature into a multi-organ-chip microsystem. , 2013, Lab on a chip.

[47]  Jong Hwan Sung,et al.  Using physiologically-based pharmacokinetic-guided “body-on-a-chip” systems to predict mammalian response to drug and chemical exposure , 2014, Experimental biology and medicine.

[48]  K. Suh,et al.  A multi-layer microfluidic device for efficient culture and analysis of renal tubular cells. , 2010, Lab on a chip.

[49]  L. Bergers,et al.  Immune-competent human skin disease models. , 2016, Drug discovery today.

[50]  Iain S Haslam,et al.  Characterisation of human tubular cell monolayers as a model of proximal tubular xenobiotic handling. , 2008, Toxicology and applied pharmacology.

[51]  D. Ingber,et al.  Microfluidic organs-on-chips , 2014, Nature Biotechnology.

[52]  S. S. Syed Sulaiman,et al.  Development of an Adverse Drug Reaction Risk Assessment Score among Hospitalized Patients with Chronic Kidney Disease , 2014, PloS one.

[53]  DA Lauffenburger,et al.  Physiome-on-a-Chip: The Challenge of “Scaling” in Design, Operation, and Translation of Microphysiological Systems , 2015, CPT: pharmacometrics & systems pharmacology.

[54]  K. Tilmant,et al.  Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins , 2012, Cell Biology and Toxicology.

[55]  Dave T. Gerrard,et al.  Proteome-wide analyses of human hepatocytes during differentiation and dedifferentiation , 2013, Hepatology.

[56]  BeauchampPhilippe,et al.  Development and Characterization of a Scaffold-Free 3D Spheroid Model of Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes , 2015 .

[57]  M. Schäfer-Korting,et al.  The Phenion® Full-Thickness Skin Model for Percutaneous Absorption Testing , 2009, Skin Pharmacology and Physiology.

[58]  Albert Gough,et al.  A human liver microphysiology platform for investigating physiology, drug safety, and disease models , 2016, Experimental biology and medicine.

[59]  C. Reijnders,et al.  Development of a Full-Thickness Human Skin Equivalent In Vitro Model Derived from TERT-Immortalized Keratinocytes and Fibroblasts , 2015, Tissue engineering. Part A.

[60]  William McLamb,et al.  A phenotypic in vitro model for the main determinants of human whole heart function. , 2015, Biomaterials.

[61]  N J Izzo,et al.  HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[62]  S. Hoffmann,et al.  Catch-up validation study of an in vitro skin irritation test method based on an open source reconstructed epidermis (phase II). , 2016, Toxicology in vitro : an international journal published in association with BIBRA.

[63]  Steven C George,et al.  Engineering anastomosis between living capillary networks and endothelial cell-lined microfluidic channels. , 2016, Lab on a chip.

[64]  N. S. Bakar,et al.  The limitations of renal epithelial cell line HK-2 as a model of drug transporter expression and function in the proximal tubule , 2012, Pflügers Archiv - European Journal of Physiology.

[65]  DA Lauffenburger,et al.  Quantitative Systems Pharmacology Approaches Applied to Microphysiological Systems (MPS): Data Interpretation and Multi-MPS Integration , 2015, CPT: pharmacometrics & systems pharmacology.

[66]  K. Brouwer,et al.  Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity , 2010, Drug metabolism reviews.

[67]  J. Collins,et al.  Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip , 2015, Proceedings of the National Academy of Sciences.

[68]  J. Kelm,et al.  Multi-cell type human liver microtissues for hepatotoxicity testing , 2012, Archives of Toxicology.

[69]  Liang Guo,et al.  Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

[70]  Rene Spijker,et al.  Differentiation of Human Embryonic Stem Cells to Cardiomyocytes: Role of Coculture With Visceral Endoderm-Like Cells , 2003, Circulation.

[71]  H. Clevers,et al.  Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche , 2009, Nature.

[72]  F. Noor,et al.  Novel human hepatic organoid model enables testing of drug-induced liver fibrosis in vitro. , 2016, Biomaterials.

[73]  T. Andersson,et al.  In Vitro Evaluation of Major In Vivo Drug Metabolic Pathways Using Primary Human Hepatocytes and HepaRG Cells in Suspension and a Dynamic Three-Dimensional Bioreactor System , 2012, Journal of Pharmacology and Experimental Therapeutics.

[74]  Michael L Shuler,et al.  Pumpless microfluidic platform for drug testing on human skin equivalents. , 2015, Lab on a chip.

[75]  R. Chang,et al.  Numerical investigation of dynamic microorgan devices as drug screening platforms. Part II: Microscale modeling approach and validation , 2016, Biotechnology and bioengineering.

[76]  Ying Zheng,et al.  Innovations in preclinical biology: ex vivo engineering of a human kidney tissue microperfusion system , 2013, Stem Cell Research & Therapy.

[77]  Volker M Lauschke,et al.  Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates. , 2016, Chemical research in toxicology.

[78]  B. Schnabl,et al.  Methods to determine intestinal permeability and bacterial translocation during liver disease. , 2015, Journal of immunological methods.

[79]  Volker M. Lauschke,et al.  Transcriptional, Functional, and Mechanistic Comparisons of Stem Cell–Derived Hepatocytes, HepaRG Cells, and Three-Dimensional Human Hepatocyte Spheroids as Predictive In Vitro Systems for Drug-Induced Liver Injury , 2017, Drug Metabolism and Disposition.

[80]  B W Kimes,et al.  Properties of a clonal muscle cell line from rat heart. , 1976, Experimental cell research.

[81]  Shuichi Takayama,et al.  Pharmacokinetic profile that reduces nephrotoxicity of gentamicin in a perfused kidney-on-a-chip , 2016, Biofabrication.

[82]  Ying Mei,et al.  Cell number per spheroid and electrical conductivity of nanowires influence the function of silicon nanowired human cardiac spheroids. , 2017, Acta biomaterialia.

[83]  F. Sonntag,et al.  A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents. , 2015, Lab on a chip.

[84]  F. Sonntag,et al.  A dynamic multi-organ-chip for long-term cultivation and substance testing proven by 3D human liver and skin tissue co-culture. , 2013, Lab on a chip.

[85]  David B Duignan,et al.  Navigating tissue chips from development to dissemination: A pharmaceutical industry perspective , 2017, Experimental biology and medicine.

[86]  K. Giacomini,et al.  Renal transporters in drug development. , 2013, Annual review of pharmacology and toxicology.

[87]  Aaron Sin,et al.  Development of a Microscale Cell Culture Analog To Probe Naphthalene Toxicity , 2008, Biotechnology progress.

[88]  Clay W Scott,et al.  Human induced pluripotent stem cells and their use in drug discovery for toxicity testing. , 2013, Toxicology letters.

[89]  P. Annaert,et al.  Sandwich-cultured hepatocytes: utility for in vitro exploration of hepatobiliary drug disposition and drug-induced hepatotoxicity , 2013, Expert opinion on drug metabolism & toxicology.

[90]  M. Ingelman-Sundberg,et al.  A multicenter assessment of single-cell models aligned to standard measures of cell health for prediction of acute hepatotoxicity , 2016, Archives of Toxicology.

[91]  Uwe Marx,et al.  Validation of Bioreactor and Human-on-a-Chip Devices for Chemical Safety Assessment. , 2016, Advances in experimental medicine and biology.

[92]  Uwe Marx,et al.  Skin and hair on-a-chip: in vitro skin models versus ex vivo tissue maintenance with dynamic perfusion. , 2013, Lab on a chip.

[93]  Jong Hwan Sung,et al.  A microfluidic device for a pharmacokinetic-pharmacodynamic (PK-PD) model on a chip. , 2010, Lab on a chip.

[94]  Uwe Marx,et al.  Emulating human microcapillaries in a multi-organ-chip platform. , 2015, Journal of biotechnology.

[95]  Andreas Hess,et al.  Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts , 2006, Nature Medicine.

[96]  Kevin E. Healy,et al.  Miniaturized iPS-Cell-Derived Cardiac Muscles for Physiologically Relevant Drug Response Analyses , 2016, Scientific Reports.

[97]  Hyunjae Lee,et al.  Engineering of functional, perfusable 3D microvascular networks on a chip. , 2013, Lab on a chip.

[98]  Souren Mkrtchian,et al.  Massive rearrangements of cellular MicroRNA signatures are key drivers of hepatocyte dedifferentiation , 2016, Hepatology.

[99]  F. Bäckhed,et al.  The gut microbiota — masters of host development and physiology , 2013, Nature Reviews Microbiology.

[100]  Donald E Ingber,et al.  Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[101]  Milica Radisic,et al.  Functional assembly of engineered myocardium by electrical stimulation of cardiac myocytes cultured on scaffolds , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[102]  Adam S. Hayward,et al.  Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME , 2013, Archives of Toxicology.

[103]  Shoji Takeuchi,et al.  Skin integrated with perfusable vascular channels on a chip. , 2017, Biomaterials.

[104]  Daniel C Leslie,et al.  A Human Disease Model of Drug Toxicity–Induced Pulmonary Edema in a Lung-on-a-Chip Microdevice , 2012, Science Translational Medicine.

[105]  D. Ingber,et al.  Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[106]  Andreas Hierlemann,et al.  96-Well Format-Based Microfluidic Platform for Parallel Interconnection of Multiple Multicellular Spheroids , 2015, Journal of laboratory automation.

[107]  João Barroso,et al.  Two novel prediction models improve predictions of skin corrosive sub-categories by test methods of OECD Test Guideline No. 431. , 2015, Toxicology in vitro : an international journal published in association with BIBRA.

[108]  M. D. Davidson,et al.  Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes , 2016, Scientific Reports.

[109]  D. Ingber,et al.  From 3D cell culture to organs-on-chips. , 2011, Trends in cell biology.

[110]  M. Pirmohamed,et al.  Parsing interindividual drug variability: an emerging role for systems pharmacology , 2015, Wiley interdisciplinary reviews. Systems biology and medicine.

[111]  D. Basile,et al.  Pathophysiology of acute kidney injury. , 2012, Comprehensive Physiology.

[112]  Paul Wilmes,et al.  A microfluidics-based in vitro model of the gastrointestinal human–microbe interface , 2016, Nature Communications.

[113]  Thomas Rau,et al.  Human Engineered Heart Tissue as a Versatile Tool in Basic Research and Preclinical Toxicology , 2011, PloS one.

[114]  W Suter,et al.  How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines? , 2011, British journal of pharmacology.

[115]  Thomas Schreiter,et al.  Scaling down of a clinical three-dimensional perfusion multicompartment hollow fiber liver bioreactor developed for extracorporeal liver support to an analytical scale device useful for hepatic pharmacological in vitro studies. , 2011, Tissue engineering. Part C, Methods.

[116]  Frederic Yves Bois,et al.  Investigation of ifosfamide and chloroacetaldehyde renal toxicity through integration of in vitro liver–kidney microfluidic data and pharmacokinetic‐system biology models , 2016, Journal of applied toxicology : JAT.

[117]  M Liebsch,et al.  Catch-up validation study of an in vitro skin irritation test method based on an open source reconstructed epidermis (phase I). , 2016, Toxicology in vitro : an international journal published in association with BIBRA.

[118]  I. Kola,et al.  Can the pharmaceutical industry reduce attrition rates? , 2004, Nature Reviews Drug Discovery.

[119]  M. Ingelman-Sundberg,et al.  International Journal of Molecular Sciences the Importance of Patient-specific Factors for Hepatic Drug Response and Toxicity , 2022 .

[120]  Wolfgang Moritz,et al.  Development and Characterization of a Scaffold-Free 3 D Spheroid Model of Induced Pluripotent Stem Cell-Derived Human Cardiomyocytes , 2015 .

[121]  Paul Vulto,et al.  Kidney-on-a-Chip Technology for Drug-Induced Nephrotoxicity Screening. , 2016, Trends in biotechnology.

[122]  Amy E. Chadwick,et al.  Mechanistic evaluation of primary human hepatocyte culture using global proteomic analysis reveals a selective dedifferentiation profile , 2016, Archives of Toxicology.

[123]  Thomas Geiser,et al.  A lung-on-a-chip array with an integrated bio-inspired respiration mechanism. , 2015, Lab on a chip.