Organs-on-a-chip: a new tool for drug discovery

Introduction: The development of emerging in vitro tissue culture platforms can be useful for predicting human response to new compounds, which has been traditionally challenging in the field of drug discovery. Recently, several in vitro tissue-like microsystems, also known as ‘organs-on-a-chip’, have emerged to provide new tools for better evaluating the effects of various chemicals on human tissue. Areas covered: The aim of this article is to provide an overview of the organs-on-a-chip systems that have been recently developed. First, the authors introduce single-organ platforms, focusing on the most studied organs such as liver, heart, blood vessels and lung. Later, the authors briefly describe tumor-on-a-chip platforms and highlight their application for testing anti-cancer drugs. Finally, the article reports a few examples of other organs integrated in microfluidic chips along with preliminary multiple-organs-on-a-chip examples. The article also highlights key fabrication points as well as the main application areas of these devices. Expert opinion: This field is still at an early stage and major challenges need to be addressed prior to the embracement of these technologies by the pharmaceutical industry. To produce predictive drug screening platforms, several organs have to be integrated into a single microfluidic system representative of a humanoid. The routine production of metabolic biomarkers of the organ constructs, as well as their physical environment, have to be monitored prior to and during the delivery of compounds of interest to be able to translate the findings into useful discoveries.

[1]  Mandy B. Esch,et al.  The role of body-on-a-chip devices in drug and toxicity studies. , 2011, Annual review of biomedical engineering.

[2]  J. Castell,et al.  An update on metabolism studies using human hepatocytes in primary culture. , 2008, Expert opinion on drug metabolism & toxicology.

[3]  R. Kamm,et al.  Cell migration into scaffolds under co-culture conditions in a microfluidic platform. , 2009, Lab on a chip.

[4]  Godfrey L. Smith,et al.  Microfluidic systems to examine intercellular coupling of pairs of cardiac myocytes. , 2007, Lab on a chip.

[5]  E. Young Cells, tissues, and organs on chips: challenges and opportunities for the cancer tumor microenvironment. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[6]  Anja van de Stolpe,et al.  Workshop meeting report Organs-on-Chips : human disease models , 2013 .

[7]  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.

[8]  R. Gebhardt,et al.  Perifused monolayer cultures of rat hepatocytes as an improved in vitro system for studies on ureogenesis. , 1979, Experimental cell research.

[9]  Arti Ahluwalia,et al.  Glucose and Fatty Acid Metabolism in a 3 Tissue In-Vitro Model Challenged with Normo- and Hyperglycaemia , 2012, PloS one.

[10]  Hanry Yu,et al.  Towards a human-on-chip: culturing multiple cell types on a chip with compartmentalized microenvironments. , 2009, Lab on a chip.

[11]  B. Helmke Molecular control of cytoskeletal mechanics by hemodynamic forces. , 2005, Physiology.

[12]  Milica Radisic,et al.  Engineered cardiac tissues. , 2011, Current opinion in biotechnology.

[13]  Cheng-Hsien Liu,et al.  Rapid heterogeneous liver-cell on-chip patterning via the enhanced field-induced dielectrophoresis trap. , 2006, Lab on a chip.

[14]  Jong Hwan Sung,et al.  A micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugs. , 2009, Lab on a chip.

[15]  Sharangdhar S. Phatak,et al.  From laptop to benchtop to bedside: structure-based drug design on protein targets. , 2012, Current pharmaceutical design.

[16]  Philip Hewitt,et al.  Performance of novel kidney biomarkers in preclinical toxicity studies. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[17]  Xin Zhang,et al.  Topographically-patterned porous membranes in a microfluidic device as an in vitro model of renal reabsorptive barriers. , 2013, Lab on a chip.

[18]  Yuki Imura,et al.  Micro Total Bioassay System for Oral Drugs: Evaluation of Gastrointestinal Degradation, Intestinal Absorption, Hepatic Metabolism, and Bioactivity , 2012, Analytical sciences : the international journal of the Japan Society for Analytical Chemistry.

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

[20]  Thomas Singer,et al.  A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity. , 2013, Toxicology and applied pharmacology.

[21]  H. Clevers,et al.  Slide preparation for single-cell–resolution imaging of fluorescent proteins in their three-dimensional near-native environment , 2011, Nature Protocols.

[22]  David J Beebe,et al.  An inertia enhanced passive pumping mechanism for fluid flow in microfluidic devices. , 2012, Lab on a chip.

[23]  Jiajie Yu,et al.  Microscale 3-D hydrogel scaffold for biomimetic gastrointestinal (GI) tract model. , 2011, Lab on a chip.

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

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

[26]  F A Auger,et al.  A completely biological tissue‐engineered human blood vessel , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  Ying Zheng,et al.  In vitro microvessels for the study of angiogenesis and thrombosis , 2012, Proceedings of the National Academy of Sciences.

[28]  Megan L. McCain,et al.  Ensembles of engineered cardiac tissues for physiological and pharmacological study: heart on a chip. , 2011, Lab on a chip.

[29]  Christopher Moraes,et al.  On being the right size: scaling effects in designing a human-on-a-chip. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[30]  A. Menciassi,et al.  Proliferation and skeletal myotube formation capability of C2C12 and H9c2 cells on isotropic and anisotropic electrospun nanofibrous PHB scaffolds , 2012, Biomedical materials.

[31]  S. Vatner,et al.  Cardioprotection in stunned and hibernating myocardium , 2007, Heart Failure Reviews.

[32]  David J. Beebe,et al.  Organs on Chips 2013. , 2013, Lab on a chip.

[33]  L. Germain,et al.  A human tissue‐engineered vascular media: a new model for pharmacological studies of contractile responses , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[34]  Jun Kameoka,et al.  Chip-based P450 drug metabolism coupled to electrospray ionization-mass spectrometry detection. , 2003, Analytical chemistry.

[35]  E. Verpoorte,et al.  An alternative approach based on microfluidics to study drug metabolism and toxicity using liver and intestinal tissue , 2010 .

[36]  Pierre-Alexandre Vidi,et al.  Breast on-a-chip: mimicry of the channeling system of the breast for development of theranostics. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[37]  M L Yarmush,et al.  Effect of cell–cell interactions in preservation of cellular phenotype: cocultivation of hepatocytes and nonparenchymal cells , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[38]  Sean P Sheehy,et al.  Biohybrid thin films for measuring contractility in engineered cardiovascular muscle. , 2010, Biomaterials.

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

[40]  X. Chu,et al.  Species differences in drug transporters and implications for translating preclinical findings to humans , 2013, Expert opinion on drug metabolism & toxicology.

[41]  Rachelle N. Palchesko,et al.  Development of Polydimethylsiloxane Substrates with Tunable Elastic Modulus to Study Cell Mechanobiology in Muscle and Nerve , 2012, PloS one.

[42]  Josue A. Goss,et al.  Microfluidic heart on a chip for higher throughput pharmacological studies. , 2013, Lab on a chip.

[43]  S. Bolz,et al.  A microfluidic platform for probing small artery structure and function. , 2010, Lab on a chip.

[44]  Shuichi Takayama,et al.  Acoustically detectable cellular-level lung injury induced by fluid mechanical stresses in microfluidic airway systems , 2007, Proceedings of the National Academy of Sciences.

[45]  Zongyuan Chen,et al.  Lab‐on‐a‐Chip Technologies for Oral‐Based Cancer Screening and Diagnostics , 2007, Annals of the New York Academy of Sciences.

[46]  Donghyun Kim,et al.  Fluorescence optical detection in situ for real‐time monitoring of cytochrome P450 enzymatic activity of liver cells in multiple microfluidic devices , 2009, Biotechnology and bioengineering.

[47]  L. Bonassar,et al.  Dense type I collagen matrices that support cellular remodeling and microfabrication for studies of tumor angiogenesis and vasculogenesis in vitro. , 2010, Biomaterials.

[48]  Yuki Imura,et al.  Micro total bioassay system for ingested substances: assessment of intestinal absorption, hepatic metabolism, and bioactivity. , 2010, Analytical chemistry.

[49]  H. Daniel Ou-Yang,et al.  The influence of size, shape and vessel geometry on nanoparticle distribution , 2013, Microfluidics and nanofluidics.

[50]  Laura J. Itle,et al.  Microreactor Microfluidic Systems with Human Microsomes and Hepatocytes for use in Metabolite Studies , 2005, Biomedical microdevices.

[51]  Elizabeth E. Hoskins,et al.  Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro , 2010, Nature.

[52]  Mark-Anthony Bray,et al.  Self-Organization of Muscle Cell Structure and Function , 2011, PLoS Comput. Biol..

[53]  Guy Salama,et al.  Mouse models of long QT syndrome , 2007, The Journal of physiology.

[54]  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.

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

[56]  Bingcheng Lin,et al.  Grafting epoxy-modified hydrophilic polymers onto poly(dimethylsiloxane) microfluidic chip to resist nonspecific protein adsorption. , 2006, Lab on a chip.

[57]  Ji Yoon Kang,et al.  On-chip anticancer drug test of regular tumor spheroids formed in microwells by a distributive microchannel network. , 2012, Lab on a chip.

[58]  Qingming Luo,et al.  Microfluidic chip: next-generation platform for systems biology. , 2009, Analytica chimica acta.

[59]  Shuichi Takayama,et al.  Epithelium damage and protection during reopening of occluded airways in a physiologic microfluidic pulmonary airway model , 2011, Biomedical microdevices.

[60]  I. Tadeo,et al.  Extracellular matrix, biotensegrity and tumor microenvironment. An update and overview. , 2012, Histology and histopathology.

[61]  Jian-Hua Wang,et al.  A radial microfluidic concentration gradient generator with high-density channels for cell apoptosis assay. , 2011, Lab on a chip.

[62]  N. Elvassore,et al.  Reversible alteration of calcium dynamics in cardiomyocytes during acute hypoxia transient in a microfluidic platform. , 2012, Integrative biology : quantitative biosciences from nano to macro.

[63]  C. Normand,et al.  Long‐term maintenance of hepatocyte functional activity in co‐culture: Requirements for sinusoidal endothelial cells and dexamethasone , 1986, Journal of cellular physiology.

[64]  N. Voelcker,et al.  Recent developments in PDMS surface modification for microfluidic devices , 2010, Electrophoresis.

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

[66]  Oliver Eickelberg,et al.  High Throughput Determination of TGFβ1/SMAD3 Targets in A549 Lung Epithelial Cells , 2011, PloS one.

[67]  Dmitry A Markov,et al.  Thick-tissue bioreactor as a platform for long-term organotypic culture and drug delivery. , 2012, Lab on a chip.

[68]  E. Topol,et al.  Pharmacogenomics in clinical practice and drug development , 2012, Nature Biotechnology.

[69]  Don D. Sin,et al.  The airway epithelium: more than just a structural barrier , 2011, Therapeutic advances in respiratory disease.

[70]  A. M. Scher,et al.  Effect of Tissue Anisotropy on Extracellular Potential Fields in Canine Myocardium in Situ , 1982, Circulation research.

[71]  Jun-Jie Zhu,et al.  Lab-on-a-Chip for anticancer drug screening using quantum dots probe based apoptosis assay. , 2013, Journal of biomedical nanotechnology.

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

[73]  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.

[74]  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.

[75]  Ali Khademhosseini,et al.  Dielectrophoretically Aligned Carbon Nanotubes to Control Electrical and Mechanical Properties of Hydrogels to Fabricate Contractile Muscle Myofibers , 2013, Advanced materials.

[76]  André Guillouzo,et al.  Evolving Concepts in Liver Tissue Modeling and Implications for in Vitro Toxicology 1. Introduction , 2022 .

[77]  Tal Nawy Receptive cells feel the squeeze. , 2013, Nature methods.

[78]  Long Zhao,et al.  Analysis of chemoresistance in lung cancer with a simple microfluidic device , 2010, Electrophoresis.

[79]  Pengcheng Zhou,et al.  Co‐culture with mesenchymal stem cells enhances metabolic functions of liver cells in bioartificial liver system , 2013, Biotechnology and bioengineering.

[80]  Glaucius Oliva,et al.  Modern drug discovery technologies: opportunities and challenges in lead discovery. , 2011, Combinatorial chemistry & high throughput screening.

[81]  Roger D Kamm,et al.  Microfluidic devices for studying heterotypic cell-cell interactions and tissue specimen cultures under controlled microenvironments. , 2011, Biomicrofluidics.

[82]  G. Jobst,et al.  Cell culture monitoring for drug screening and cancer research: a transparent, microfluidic, multi-sensor microsystem. , 2014, Lab on a chip.

[83]  L. Samson,et al.  A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction. , 2005, Current drug metabolism.

[84]  Fred H. Gage,et al.  Induced pluripotent stem cells: the new patient? , 2012, Nature Reviews Molecular Cell Biology.

[85]  Akon Higuchi,et al.  Physical cues of biomaterials guide stem cell differentiation fate. , 2013, Chemical reviews.

[86]  F. Yuan,et al.  A microfluidic system for investigation of extravascular transport and cellular uptake of drugs in tumors , 2012, Biotechnology and bioengineering.

[87]  Kapil Pant,et al.  SyM-BBB: a microfluidic Blood Brain Barrier model. , 2013, Lab on a chip.

[88]  Ali Khademhosseini,et al.  Hydrogel-coated microfluidic channels for cardiomyocyte culture. , 2013, Lab on a chip.

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

[90]  Theo Arts,et al.  Optimizing ventricular fibers: uniform strain or stress, but not ATP consumption, leads to high efficiency. , 2002, American journal of physiology. Heart and circulatory physiology.

[91]  D. Beebe,et al.  PDMS absorption of small molecules and consequences in microfluidic applications. , 2006, Lab on a chip.

[92]  Irene Kwan,et al.  Does animal experimentation inform human healthcare? Observations from a systematic review of international animal experiments on fluid resuscitation , 2002, BMJ : British Medical Journal.

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

[94]  Shuichi Takayama,et al.  Combination of fluid and solid mechanical stresses contribute to cell death and detachment in a microfluidic alveolar model. , 2011, Lab on a chip.

[95]  E. Verpoorte,et al.  Microfluidic devices for in vitro studies on liver drug metabolism and toxicity. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[96]  Claudio Domenici,et al.  Metabolic control through hepatocyte and adipose tissue cross-talk in a multicompartmental modular bioreactor. , 2011, Tissue engineering. Part A.

[97]  Takanori Takebe,et al.  Vascularized and functional human liver from an iPSC-derived organ bud transplant , 2013, Nature.

[98]  R. MacLaren,et al.  Translating induced pluripotent stem cells from bench to bedside: application to retinal diseases. , 2013, Current gene therapy.

[99]  Teruo Fujii,et al.  Bile canaliculi formation by aligning rat primary hepatocytes in a microfluidic device. , 2011, Biomicrofluidics.

[100]  S. Haswell,et al.  Evaluation of heart tissue viability under redox‐magnetohydrodynamics conditions: Toward fine‐tuning flow in biological microfluidics applications , 2012, Biotechnology and bioengineering.

[101]  D. Saint The cardiac persistent sodium current: an appealing therapeutic target? , 2008, British journal of pharmacology.

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

[103]  Paraskevi Giannakakou,et al.  Functional Characterization of Circulating Tumor Cells with a Prostate-Cancer-Specific Microfluidic Device , 2012, PloS one.

[104]  Sang-Hoon Lee,et al.  Spheroid-based three-dimensional liver-on-a-chip to investigate hepatocyte-hepatic stellate cell interactions and flow effects. , 2013, Lab on a chip.

[105]  David Beebe,et al.  Engineers are from PDMS-land, Biologists are from Polystyrenia. , 2012, Lab on a chip.

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

[107]  C. Grund,et al.  The area composita of adhering junctions connecting heart muscle cells of vertebrates. I. Molecular definition in intercalated disks of cardiomyocytes by immunoelectron microscopy of desmosomal proteins. , 2006, European journal of cell biology.

[108]  G. Hasenfuss,et al.  Animal models of human cardiovascular disease, heart failure and hypertrophy. , 1998, Cardiovascular research.

[109]  R. Bellomo,et al.  The future of extracorporeal support , 2008, Critical care medicine.

[110]  David J Beebe,et al.  From the cellular perspective: exploring differences in the cellular baseline in macroscale and microfluidic cultures. , 2009, Integrative biology : quantitative biosciences from nano to macro.

[111]  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.

[112]  L. Germain,et al.  In Vitro Evaluation of the Angiostatic Potential of Drugs Using an Endothelialized Tissue-Engineered Connective Tissue , 2005, Journal of Pharmacology and Experimental Therapeutics.

[113]  Louise Hecker,et al.  Engineering the heart piece by piece: state of the art in cardiac tissue engineering. , 2007, Regenerative medicine.

[114]  Kevin Kit Parker,et al.  Myofibrillar Architecture in Engineered Cardiac Myocytes , 2008, Circulation research.

[115]  Monya Baker,et al.  Tissue models: A living system on a chip , 2011, Nature.

[116]  Yu-Hsiang Hsu,et al.  In vitro perfused human capillary networks. , 2013, Tissue engineering. Part C, Methods.

[117]  Anne E Carpenter,et al.  An algorithm-based topographical biomaterials library to instruct cell fate , 2011, Proceedings of the National Academy of Sciences.

[118]  Paul C H Li,et al.  Contraction study of a single cardiac muscle cell in a microfluidic chip. , 2006, Methods in molecular biology.

[119]  T. Hibi,et al.  Development of a novel microRNA promoter microarray for ChIP-on-chip assay to identify epigenetically regulated microRNAs. , 2012, Biochemical and biophysical research communications.

[120]  N. L'Heureux,et al.  Human tissue-engineered blood vessels for adult arterial revascularization , 2007, Nature Medicine.

[121]  Kapil Pant,et al.  Microfluidic devices for modeling cell-cell and particle-cell interactions in the microvasculature. , 2011, Microvascular research.

[122]  Wenxin Wang,et al.  Application of a microfluidic chip-based 3D co-culture to test drug sensitivity for individualized treatment of lung cancer. , 2013, Biomaterials.

[123]  C Ronco,et al.  The future of the artificial kidney: moving towards wearable and miniaturized devices. , 2011, Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia.

[124]  J. Cooper,et al.  Tumors on chips: oncology meets microfluidics. , 2010, Current opinion in chemical biology.

[125]  Mandy B. Esch,et al.  Microfabricated mammalian organ systems and their integration into models of whole animals and humans. , 2013, Lab on a chip.

[126]  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.

[127]  R Langer,et al.  Functional arteries grown in vitro. , 1999, Science.

[128]  J. Kong,et al.  Construction of a biomimetic surface on microfluidic chips for biofouling resistance. , 2006, Analytical chemistry.

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

[130]  John P. Wikswo,et al.  Engineering Challenges for Instrumenting and Controlling Integrated Organ-on-Chip Systems , 2013, IEEE Transactions on Biomedical Engineering.

[131]  Sandro Carrara,et al.  NutriChip: nutrition analysis meets microfluidics. , 2013, Lab on a chip.