3D organ models—Revolution in pharmacological research?

Abstract 3D organ models have gained increasing attention as novel preclinical test systems and alternatives to animal testing. Over the years, many excellent in vitro tissue models have been developed. In parallel, microfluidic organ-on-a-chip tissue cultures have gained increasing interest for their ability to house several organ models on a single device and interlink these within a human-like environment. In contrast to these advancements, the development of human disease models is still in its infancy. Although major advances have recently been made, efforts still need to be intensified. Human disease models have proven valuable for their ability to closely mimic disease patterns in vitro, permitting the study of pathophysiological features and new treatment options. Although animal studies remain the gold standard for preclinical testing, they have major drawbacks such as high cost and ongoing controversy over their predictive value for several human conditions. Moreover, there is growing political and social pressure to develop alternatives to animal models, clearly promoting the search for valid, cost-efficient and easy-to-handle systems lacking interspecies-related differences. In this review, we discuss the current state of the art regarding 3D organ as well as the opportunities, limitations and future implications of their use.

[1]  Antonio Spanevello,et al.  Models of Respiratory Infections: Virus-Induced Asthma Exacerbations and Beyond , 2015, Allergy, asthma & immunology research.

[2]  Gordana Vunjak-Novakovic,et al.  Organs-on-a-Chip: A Fast Track for Engineered Human Tissues in Drug Development. , 2018, Cell stem cell.

[3]  Stewart Robinson,et al.  Model Validation and Testing in Simulation: a Literature Review , 2016, SCOR.

[4]  Horst Wenck,et al.  Role of fibroblasts in the pathogenesis of atopic dermatitis. , 2013, The Journal of allergy and clinical immunology.

[5]  Monica Boffito,et al.  Tissue Engineering Approaches in the Design of Healthy and Pathological In Vitro Tissue Models , 2017, Front. Bioeng. Biotechnol..

[6]  Florian Groeber,et al.  Human barrier models for the in vitro assessment of drug delivery , 2017, Drug Delivery and Translational Research.

[7]  Koert P de Jong,et al.  Human precision-cut liver slices as a model to test antifibrotic drugs in the early onset of liver fibrosis. , 2016, Toxicology in vitro : an international journal published in association with BIBRA.

[8]  Florian Paulus,et al.  Tailored dendritic core-multishell nanocarriers for efficient dermal drug delivery: A systematic top-down approach from synthesis to preclinical testing. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[9]  Kimberly A. Homan,et al.  Bioprinting of 3D Convoluted Renal Proximal Tubules on Perfusable Chips , 2016, Scientific Reports.

[10]  David K. Meyerholz,et al.  Severe Acute Respiratory Syndrome Coronavirus Infection Causes Neuronal Death in the Absence of Encephalitis in Mice Transgenic for Human ACE2 , 2008, Journal of Virology.

[11]  Sangeeta Khare,et al.  Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology. , 2015, ALTEX.

[12]  M. Matthay,et al.  Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. , 2013, American journal of respiratory and critical care medicine.

[13]  Keizo Takao,et al.  Genomic responses in mouse models greatly mimic human inflammatory diseases , 2014, Proceedings of the National Academy of Sciences.

[14]  J. Laffey,et al.  Translational Research in Acute Lung Injury and Pulmonary Fibrosis Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation , 2014 .

[15]  David L. Kaplan,et al.  Bioengineered 3D Human Kidney Tissue, a Platform for the Determination of Nephrotoxicity , 2013, PloS one.

[16]  Marco Schiavon,et al.  Normothermic ex-vivo preservation with the portable Organ Care System Lung device for bilateral lung transplantation (INSPIRE): a randomised, open-label, non-inferiority, phase 3 study. , 2018, The Lancet. Respiratory medicine.

[17]  Jean A. Niles,et al.  Modeling the lung: Design and development of tissue engineered macro- and micro-physiologic lung models for research use , 2014, Experimental biology and medicine.

[18]  Carien M. Niessen,et al.  E-cadherin integrates mechanotransduction and EGFR signaling to control junctional tissue polarization and tight junction positioning , 2017, Nature Communications.

[19]  Guillermo J Tearney,et al.  Development of a Primary Human Co-Culture Model of Inflamed Airway Mucosa , 2017, Scientific Reports.

[20]  Wei Huang,et al.  Vital ex vivo tissue labeling and pathology-guided micropunching to characterize cellular heterogeneity in the tissue microenvironment. , 2018, BioTechniques.

[21]  Thomas Hartung,et al.  Inflammatory findings on species extrapolations: humans are definitely no 70-kg mice , 2013, Archives of Toxicology.

[22]  Yves Poumay,et al.  Modeling dermatophytosis in reconstructed human epidermis: A new tool to study infection mechanisms and to test antifungal agents , 2016, Medical mycology.

[23]  K M Eckl Update: advanced methods in three‐dimensional organotypic tissue engineering for congenital ichthyosis and other rare keratinization disorders , 2014, The British journal of dermatology.

[24]  Dong-Woo Cho,et al.  3D cell printing of in vitro stabilized skin model and in vivo pre-vascularized skin patch using tissue-specific extracellular matrix bioink: A step towards advanced skin tissue engineering. , 2018, Biomaterials.

[25]  Michael B Bracken,et al.  Is animal research sufficiently evidence based to be a cornerstone of biomedical research? , 2014, BMJ : British Medical Journal.

[26]  Yi Guan,et al.  Tropism and replication of Middle East respiratory syndrome coronavirus from dromedary camels in the human respiratory tract: an in-vitro and ex-vivo study , 2014, The Lancet Respiratory Medicine.

[27]  P ? ? ? ? ? ? ? % ? ? ? ? , 1991 .

[28]  Nick Barker,et al.  Organoids as an in vitro model of human development and disease , 2016, Nature Cell Biology.

[29]  Jennifer Couzin-Frankel,et al.  When mice mislead. , 2013, Science.

[30]  D. Gerber,et al.  Editor's Highlight: Modeling Compound-Induced Fibrogenesis In Vitro Using Three-Dimensional Bioprinted Human Liver Tissues. , 2016, Toxicological sciences : an official journal of the Society of Toxicology.

[31]  Petra J. Kluger,et al.  Integration of Mature Adipocytes to Build-Up a Functional Three-Layered Full-Skin Equivalent , 2016, Tissue engineering. Part C, Methods.

[32]  J. Bouwstra,et al.  TNF-α and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents. , 2014, The Journal of investigative dermatology.

[33]  Eva-Maria Materne,et al.  Use of a three-dimensional humanized liver model for the study of viral gene vectors. , 2015, Journal of biotechnology.

[34]  J. Schalkwijk,et al.  Immortalized N/TERT keratinocytes as an alternative cell source in 3D human epidermal models , 2017, Scientific Reports.

[36]  Stefan Hippenstiel,et al.  Tyk2 as a target for immune regulation in human viral/bacterial pneumonia , 2017, European Respiratory Journal.

[37]  G. Cuniberti,et al.  Developing a Customized Perfusion Bioreactor Prototype with Controlled Positional Variability in Oxygen Partial Pressure for Bone and Cartilage Tissue Engineering. , 2017, Tissue engineering. Part C, Methods.

[38]  T. Singer,et al.  Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro , 2016, PloS one.

[39]  Helen Horton,et al.  Precision-cut human liver slice cultures as an immunological platform. , 2018, Journal of immunological methods.

[40]  Danna Zhou,et al.  d. , 1934, Microbial pathogenesis.

[41]  Paul Walker,et al.  Innovative organotypic in vitro models for safety assessment: aligning with regulatory requirements and understanding models of the heart, skin, and liver as paradigms , 2018, Archives of Toxicology.

[42]  Andrew R. Hall,et al.  Rapid production of human liver scaffolds for functional tissue engineering by high shear stress oscillation-decellularization , 2017, Scientific Reports.

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

[44]  Jo Lambert,et al.  In vitro psoriasis models with focus on reconstructed skin models as promising tools in psoriasis research , 2017, Experimental biology and medicine.

[45]  Heinz Redl,et al.  Abandon the Mouse Research Ship? Not Just Yet! , 2014, Shock.

[46]  Steven J. Jonas,et al.  Development of a Three‐Dimensional Bioengineering Technology to Generate Lung Tissue for Personalized Disease Modeling , 2016, Stem cells translational medicine.

[47]  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.

[48]  R. Gamelli,et al.  Genomic responses in mouse models poorly mimic human inflammatory diseases , 2013, Proceedings of the National Academy of Sciences.

[49]  Dong-Woo Cho,et al.  Muscle-derived extracellular matrix on sinusoidal wavy surfaces synergistically promotes myogenic differentiation and maturation. , 2018, Journal of materials chemistry. B.

[50]  Albert Zlotnik,et al.  The top skin-associated genes: a comparative analysis of human and mouse skin transcriptomes , 2014, Biological chemistry.

[51]  Armin Braun,et al.  Evaluation of inflammatory and immune responses in long-term cultured human precision-cut lung slices , 2017, Human vaccines & immunotherapeutics.

[52]  Byung Jun Kim,et al.  Skin-on-a-chip model simulating inflammation, edema and drug-based treatment , 2016, Scientific Reports.

[53]  Marco Soriani,et al.  3D Reconstruction of the Human Airway Mucosa In Vitro as an Experimental Model to Study NTHi Infections , 2016, PloS one.

[54]  W. Yeong,et al.  Proof-of-concept: 3D bioprinting of pigmented human skin constructs , 2018, Biofabrication.

[55]  HuberBirgit,et al.  Integration of Mature Adipocytes to Build-Up a Functional Three-Layered Full-Skin Equivalent , 2016 .

[56]  A. Vickers,et al.  Liver Effects of Clinical Drugs Differentiated in Human Liver Slices , 2017, International journal of molecular sciences.

[57]  Marc-Olivier Boldi,et al.  Propagation of respiratory viruses in human airway epithelia reveals persistent virus-specific signatures , 2017, Journal of Allergy and Clinical Immunology.

[58]  Christian Drosten,et al.  Emerging human middle East respiratory syndrome coronavirus causes widespread infection and alveolar damage in human lungs. , 2013, American journal of respiratory and critical care medicine.

[59]  P. Högger,et al.  Comparison of the bronchodilating effects of inhaled β₂-agonists after methacholine challenge in a human lung reperfusion model. , 2012, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[60]  Monika Schäfer-Korting,et al.  Influence of Th2 Cytokines on the Cornified Envelope, Tight Junction Proteins, and ß-Defensins in Filaggrin-Deficient Skin Equivalents. , 2016, The Journal of investigative dermatology.

[61]  Jack P. C. Kleijnen,et al.  EUROPEAN JOURNAL OF OPERATIONAL , 1992 .

[62]  David J Mooney,et al.  Mechanical confinement regulates cartilage matrix formation by chondrocytes , 2017, Nature materials.

[63]  May Win Naing,et al.  Skin Bioprinting: Impending Reality or Fantasy? , 2016, Trends in biotechnology.

[64]  Pierre Bourdoncle,et al.  Efficient replication of primary or culture hepatitis C virus isolates in human liver slices: A relevant ex vivo model of liver infection , 2012, Hepatology.

[65]  Alke Petri-Fink,et al.  Aerosol Delivery of Functionalized Gold Nanoparticles Target and Activate Dendritic Cells in a 3D Lung Cellular Model. , 2017, ACS nano.

[66]  Heike Walles,et al.  Evaluation of a Miniaturized Biologically Vascularized Scaffold in vitro and in vivo , 2018, Scientific Reports.

[67]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[68]  Michael W. Davidson,et al.  Applying systems-level spectral imaging and analysis to reveal the organelle interactome , 2017, Nature.

[69]  John W. Haycock,et al.  Immunocompetent 3D Model of Human Upper Airway for Disease Modeling and In Vitro Drug Evaluation , 2014, Molecular pharmaceutics.

[70]  Michael J Sanderson,et al.  Cryopreserved Human Precision-Cut Lung Slices as a Bioassay for Live Tissue Banking. A Viability Study of Bronchodilation with Bitter-Taste Receptor Agonists. , 2016, American journal of respiratory cell and molecular biology.

[71]  Joo-Yeon Yoo,et al.  Freeform micropatterning of living cells into cell culture medium using direct inkjet printing , 2017, Scientific Reports.

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

[73]  Gunilla Westergren-Thorsson,et al.  Bronchial extracellular matrix from COPD patients induces altered gene expression in repopulated primary human bronchial epithelial cells , 2018, Scientific Reports.

[74]  Jason P. Gleghorn,et al.  Microfluidic chest cavities reveal that transmural pressure controls the rate of lung development , 2017, Development.

[75]  Tara Srinivasan,et al.  Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing , 2017, Nature Medicine.

[76]  Ralph Rühl,et al.  Alterations in Epidermal Eicosanoid Metabolism Contribute to Inflammation and Impaired Late Differentiation in FLG-Mutated Atopic Dermatitis. , 2017, The Journal of investigative dermatology.

[77]  D. Kaplan,et al.  3D in vitro modeling of the central nervous system , 2015, Progress in Neurobiology.

[78]  S. Perrin Preclinical research: Make mouse studies work , 2014, Nature.

[79]  Gianaurelio Cuniberti,et al.  Developing a Customized Perfusion Bioreactor Prototype with Controlled Positional Variability in Oxygen Partial Pressure for Bone and Cartilage Tissue Engineering. , 2017, Tissue engineering. Part C, Methods.

[80]  Tsuyoshi Murata,et al.  {m , 1934, ACML.

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

[82]  M. Auger,et al.  A 3D-psoriatic skin model for dermatological testing: The impact of culture conditions , 2016, Biochemistry and biophysics reports.

[83]  Christian Zoschke,et al.  The barrier function of organotypic non-melanoma skin cancer models. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[84]  Mayte Suárez-Fariñas,et al.  Major differences between human atopic dermatitis and murine models, as determined by using global transcriptomic profiling , 2016, The Journal of allergy and clinical immunology.