Advanced Microengineered Lung Models for Translational Drug Discovery

Lung diseases impose a significant socioeconomic burden and are a leading cause of morbidity and mortality worldwide. Moreover, respiratory medicine, unlike several other therapeutic areas, faces a disappointingly low number of new approved therapies. This is partly due to lack of reliable in vitro or in vivo models that can reproduce organ-level complexity and pathophysiological responses of human lung. Here, we examine new opportunities in application of recently emerged organ-on-chip technology to model human lung alveolus and small airway in preclinical drug development and biomarker discovery. We also discuss challenges that need to be addressed in coming years to further enhance the physiological and clinical relevance of these microsystems, enable their increased accessibility, and support their leap into personalized medicine.

[1]  M. Yarmush,et al.  Evaluation of a microfluidic based cell culture platform with primary human hepatocytes for the prediction of hepatic clearance in human. , 2009, Biochemical pharmacology.

[2]  Megan Logan,et al.  Biocompatibility of hydrogel-based scaffolds for tissue engineering applications. , 2017, Biotechnology advances.

[3]  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.

[4]  F. Martinez Early-Life Origins of Chronic Obstructive Pulmonary Disease. , 2016, The New England journal of medicine.

[5]  April M. Kloxin,et al.  Hydrogel scaffolds as in vitro models to study fibroblast activation in wound healing and disease , 2014, Biomaterials science.

[6]  M. Cosio,et al.  Animal models of chronic obstructive pulmonary disease. , 2008, American journal of physiology. Lung cellular and molecular physiology.

[7]  Deok‐Ho Kim,et al.  Printing three-dimensional tissue analogues with decellularized extracellular matrix bioink , 2014, Nature Communications.

[8]  Asher Mullard,et al.  Biotech R&D spend jumps by more than 15% , 2016, Nature Reviews Drug Discovery.

[9]  M. Yarmush,et al.  A microfluidic hepatic coculture platform for cell-based drug metabolism studies. , 2010, Biochemical pharmacology.

[10]  Donald E Ingber,et al.  Engineered in vitro disease models. , 2015, Annual review of pathology.

[11]  Eric Leclerc,et al.  Metabolic characterization of primary rat hepatocytes cultivated in parallel microfluidic biochips. , 2013, Journal of pharmaceutical sciences.

[12]  ZilberbergJenny,et al.  Patient-specific 3D microfluidic tissue model for multiple myeloma. , 2014 .

[13]  R. W. Hansen,et al.  Journal of Health Economics , 2016 .

[14]  Ali Khademhosseini,et al.  Organs-on-a-chip for drug discovery. , 2013, Current opinion in pharmacology.

[15]  Stephen B. McMahon,et al.  Probing Functional Properties of Nociceptive Axons Using a Microfluidic Culture System , 2013, PloS one.

[16]  J. Grimshaw,et al.  Threats to Validity in the Design and Conduct of Preclinical Efficacy Studies: A Systematic Review of Guidelines for In Vivo Animal Experiments , 2013, PLoS medicine.

[17]  Charles C. Persinger,et al.  How to improve R&D productivity: the pharmaceutical industry's grand challenge , 2010, Nature Reviews Drug Discovery.

[18]  L. Fabbri,et al.  Severity of airflow limitation is associated with severity of airway inflammation in smokers. , 1998, American journal of respiratory and critical care medicine.

[19]  Gordana Vunjak-Novakovic,et al.  Patterning osteogenesis by inducible gene expression in microfluidic culture systems. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[20]  J. Cuevas,et al.  A modular approach to create a neurovascular unit-on-a-chip. , 2013, Lab on a chip.

[21]  J. Lewis,et al.  3D Bioprinting of Vascularized, Heterogeneous Cell‐Laden Tissue Constructs , 2014, Advanced materials.

[22]  Q. Hamid,et al.  Anatomy, pathology, and physiology of the tracheobronchial tree: emphasis on the distal airways. , 2009, The Journal of allergy and clinical immunology.

[23]  J. Kelm,et al.  Development of an Innovative 3D Cell Culture System to Study Tumour - Stroma Interactions in Non-Small Cell Lung Cancer Cells , 2013, PloS one.

[24]  Nancy A. Monteiro-Riviere,et al.  Characterization of microfluidic human epidermal keratinocyte culture , 2008, Cytotechnology.

[25]  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.

[26]  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.

[27]  D. Mannino,et al.  Economic Burden of COPD in the Presence of Comorbidities , 2015, Chest.

[28]  B. Stripp,et al.  Lung Stem Cell Differentiation in Mice Directed by Endothelial Cells via a BMP4-NFATc1-Thrombospondin-1 Axis , 2014, Cell.

[29]  N. Krug,et al.  Ex vivo testing of immune responses in precision-cut lung slices. , 2008, Toxicology and applied pharmacology.

[30]  N. Schork Personalized medicine: Time for one-person trials , 2015, Nature.

[31]  T. Miyakawa,et al.  Genomic responses in mouse models poorly mimic human inflammatory diseases , 2013 .

[32]  J. Collins,et al.  Bone marrow–on–a–chip replicates hematopoietic niche physiology in vitro , 2014, Nature Methods.

[33]  M. Nikolić,et al.  Lung Organoids and Their Use To Study Cell-Cell Interaction , 2017, Current Pathobiology Reports.

[34]  Jiajie Yu,et al.  On chip porous polymer membranes for integration of gastrointestinal tract epithelium with microfluidic ‘body-on-a-chip’ devices , 2012, Biomedical microdevices.

[35]  A. van den Berg,et al.  Three-dimensional co-cultures of human endothelial cells and embryonic stem cell-derived pericytes inside a microfluidic device. , 2013, Lab on a chip.

[36]  Thomas C. Ferrante,et al.  Small airway-on-a-chip enables analysis of human lung inflammation and drug responses in vitro , 2015, Nature Methods.

[37]  Cécile Legallais,et al.  Analysis of transcriptomic and proteomic profiles demonstrates improved Madin–Darby canine kidney cell function in a renal microfluidic biochip , 2012, Biotechnology progress.

[38]  N. Wilson,et al.  Severe childhood asthma: a common international approach? , 2008, The Lancet.

[39]  Richard Novak,et al.  Human Lung Small Airway-on-a-Chip Protocol. , 2017, Methods in molecular biology.

[40]  E. Ingenito,et al.  Design and testing of biological scaffolds for delivering reparative cells to target sites in the lung , 2009, Journal of tissue engineering and regenerative medicine.

[41]  Kurt R Stenmark,et al.  Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. , 2009, American journal of physiology. Lung cellular and molecular physiology.

[42]  P. Kubes,et al.  Neutrophil recruitment and function in health and inflammation , 2013, Nature Reviews Immunology.

[43]  J. Draper,et al.  Organoids as a model system for studying human lung development and disease. , 2016, Biochemical and biophysical research communications.

[44]  M. Guenounou,et al.  Bronchial epithelial spheroids: an alternative culture model to investigate epithelium inflammation-mediated COPD , 2007, Respiratory research.

[45]  J. Arrowsmith,et al.  Trial Watch: Phase II and Phase III attrition rates 2011–2012 , 2013, Nature Reviews Drug Discovery.

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

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

[48]  L. Edwards,et al.  COPD association and repeatability of blood biomarkers in the ECLIPSE cohort , 2011, Respiratory research.

[49]  J. Wedzicha,et al.  Serum IP-10 as a biomarker of human rhinovirus infection at exacerbation of COPD. , 2010, Chest.

[50]  Yasmín R Álvarez-García,et al.  Microbial volatile communication in human organotypic lung models , 2017, Nature Communications.

[51]  D. Ingber,et al.  Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. , 2012, Lab on a chip.

[52]  Michael L Shuler,et al.  Murine in vitro model of the blood-brain barrier for evaluating drug transport. , 2011, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[53]  D. Ingber,et al.  TRPV4 Channels Mediate Cyclic Strain–Induced Endothelial Cell Reorientation Through Integrin-to-Integrin Signaling , 2009, Circulation research.

[54]  Magdi H. Yacoub,et al.  Hydrogel scaffolds for tissue engineering: Progress and challenges , 2013, Global cardiology science & practice.

[55]  P. Paré,et al.  The nature of small-airway obstruction in chronic obstructive pulmonary disease. , 2004, The New England journal of medicine.

[56]  Bryson M. Brewer,et al.  Glia co-culture with neurons in microfluidic platforms promotes the formation and stabilization of synaptic contacts. , 2013, Lab on a chip.

[57]  N. Yamamoto,et al.  Induction of blood–brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors , 1999, Neuroscience Research.

[58]  R. Libby,et al.  Molecular regulation of cigarette smoke induced-oxidative stress in human retinal pigment epithelial cells: implications for age-related macular degeneration. , 2009, American journal of physiology. Cell physiology.

[59]  M. Sakagami,et al.  Development and characterization of a naturally derived lung extracellular matrix hydrogel. , 2016, Journal of biomedical materials research. Part A.

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

[61]  D. Kohane,et al.  HYDROGELS IN DRUG DELIVERY: PROGRESS AND CHALLENGES , 2008 .

[62]  Scott H. Donaldson,et al.  Cystic fibrosis lung disease starts in the small airways: Can we treat it more effectively? , 2010, Pediatric pulmonology.

[63]  S. Fare',et al.  Design, synthesis and properties of polyurethane hydrogels for tissue engineering , 2003, Journal of materials science. Materials in medicine.

[64]  Lei Wang,et al.  Simultaneous generation of gradients with gradually changed slope in a microfluidic device for quantifying axon response. , 2013, Analytical chemistry.

[65]  S. Hofmann,et al.  Controlled Positioning of Cells in Biomaterials—Approaches Towards 3D Tissue Printing , 2011, Journal of functional biomaterials.

[66]  Hanseup Kim,et al.  Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB). , 2012, Lab on a chip.

[67]  Ying Huang,et al.  Organ Bioprinting: Are We There Yet? , 2018, Advanced healthcare materials.

[68]  S. Rees,et al.  Principles of early drug discovery , 2011, British journal of pharmacology.

[69]  Ali Khademhosseini,et al.  Chip-Based Comparison of the Osteogenesis of Human Bone Marrow- and Adipose Tissue-Derived Mesenchymal Stem Cells under Mechanical Stimulation , 2012, PloS one.

[70]  Anthony Atala,et al.  3D bioprinting of tissues and organs , 2014, Nature Biotechnology.

[71]  Luke P. Lee,et al.  An artificial liver sinusoid with a microfluidic endothelial-like barrier for primary hepatocyte culture. , 2007, Biotechnology and bioengineering.

[72]  B. Hogan,et al.  Lung organoids: current uses and future promise , 2017, Development.

[73]  D. Jonigk,et al.  Assessment of long-term cultivated human precision-cut lung slices as an ex vivo system for evaluation of chronic cytotoxicity and functionality , 2017, Journal of Occupational Medicine and Toxicology.

[74]  Animal models of asthma and chronic obstructive pulmonary disease. , 2008, Pulmonary pharmacology & therapeutics.

[75]  H. Alsaid,et al.  An Orally Active TRPV4 Channel Blocker Prevents and Resolves Pulmonary Edema Induced by Heart Failure , 2012, Science Translational Medicine.

[76]  F. Bois,et al.  Zonation related function and ubiquitination regulation in human hepatocellular carcinoma cells in dynamic vs. static culture conditions , 2012, BMC Genomics.

[77]  Z. Memish,et al.  Surveillance for emerging respiratory viruses , 2014, The Lancet Infectious Diseases.

[78]  Josue A. Goss,et al.  Muscle on a chip: in vitro contractility assays for smooth and striated muscle. , 2012, Journal of pharmacological and toxicological methods.

[79]  Yi-Chung Tung,et al.  Electrofluidic pressure sensor embedded microfluidic device: a study of endothelial cells under hydrostatic pressure and shear stress combinations. , 2013, Lab on a chip.

[80]  Yordan Kostov,et al.  The Design and Fabrication of Three‐Chamber Microscale Cell Culture Analog Devices with Integrated Dissolved Oxygen Sensors , 2008, Biotechnology progress.

[81]  Barbara Rothen-Rutishauser,et al.  Engineering an in vitro air-blood barrier by 3D bioprinting , 2015, Scientific Reports.

[82]  A. Berg,et al.  BBB ON CHIP: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function , 2013, Biomedical microdevices.

[83]  S. Hecht,et al.  Carcinogenicity studies of inhaled cigarette smoke in laboratory animals: old and new. , 2005, Carcinogenesis.

[84]  Nitish V. Thakor,et al.  Efficient Generation of Schwann Cells from Human Embryonic Stem Cell-Derived Neurospheres , 2011, Stem Cell Reviews and Reports.

[85]  Jean-Marc Baste,et al.  Precision cut lung slices as an efficient tool for in vitro lung physio-pharmacotoxicology studies , 2013, Xenobiotica; the fate of foreign compounds in biological systems.

[86]  Thomas Ferkol,et al.  The global burden of respiratory disease. , 2014, Annals of the American Thoracic Society.

[87]  Donald E Ingber,et al.  Commendation for Exposing Key Advantage of Organ Chip Approach. , 2016, Cell systems.

[88]  M. Sanderson Exploring lung physiology in health and disease with lung slices. , 2011, Pulmonary pharmacology & therapeutics.

[89]  E. Messina,et al.  Human Lung Spheroids as In Vitro Niches of Lung Progenitor Cells with Distinctive Paracrine and Plasticity Properties , 2016, Stem cells translational medicine.

[90]  Mark A. Skylar-Scott,et al.  Three-dimensional bioprinting of thick vascularized tissues , 2016, Proceedings of the National Academy of Sciences.

[91]  E. Yoshimura,et al.  Microcirculation system with a dialysis part for bioassays evaluating anticancer activity and retention. , 2013, Analytical chemistry.

[92]  Simon Festing,et al.  The ethics of animal research , 2007, EMBO reports.

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

[94]  Christopher E Brightling,et al.  Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. , 2011, American journal of respiratory and critical care medicine.

[95]  J. Wedzicha Role of viruses in exacerbations of chronic obstructive pulmonary disease. , 2004, Proceedings of the American Thoracic Society.

[96]  R. Murray,et al.  Smoking cessation in chronic obstructive pulmonary disease. , 2009, Respiratory medicine.

[97]  Michael L Shuler,et al.  Incorporation of 3T3‐L1 Cells To Mimic Bioaccumulation in a Microscale Cell Culture Analog Device for Toxicity Studies , 2008, Biotechnology progress.