Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Microengineered Organ-on-a-chip Platforms towards Personalized Medicine

Author(s): Ranjith Kumar Kankala*, Shi-Bin Wang and Ai-Zheng Chen*

Volume 24, Issue 45, 2018

Page: [5354 - 5366] Pages: 13

DOI: 10.2174/1381612825666190222143542

Price: $65

conference banner
Abstract

Current preclinical drug evaluation strategies that are explored to predict the pharmacological parameters, as well as toxicological issues, utilize traditional oversimplified cell cultures and animal models. However, these traditional approaches are time-consuming, and cannot reproduce the functions of the complex biological tissue architectures. On the other hand, the obtained data from animal models cannot be precisely extrapolated to humans because it sometimes results in the distinct safe starting doses for clinical trials due to vast differences in their genomes. To address these limitations, the microengineered, biomimetic organ-on-a-chip platforms fabricated using advanced materials that are interconnected using the microfluidic circuits, can stanchly reiterate or mimic the complex tissue-organ level structures including the cellular architecture and physiology, compartmentalization and interconnectivity of human organ platforms. These innovative and cost-effective systems potentially enable the prediction of the responses toward pharmaceutical compounds and remarkable advances in materials and microfluidics technology, which can rapidly progress the drug development process. In this review, we emphasize the integration of microfluidic models with the 3D simulations from tissue engineering to fabricate organ-on-a-chip platforms, which explicitly fulfill the demand of creating the robust models for preclinical testing of drugs. At first, we give a brief overview of the limitations associated with the current drug development pipeline that includes drug screening methods, in vitro molecular assays, cell culture platforms and in vivo models. Further, we discuss various organ-on-a-chip platforms, highlighting their benefits and performance in the preclinical stages. Next, we aim to emphasize their current applications toward pharmaceutical benefits including the drug screening as well as toxicity testing, and advances in personalized precision medicine as well as potential challenges for their commercialization. We finally recapitulate with the lessons learned and the outlook highlighting the future directions for accelerating the clinical translation of delivery systems.

Keywords: Organ-on-a-chip, tissue engineering, microfluidic platforms, drug delivery systems, personalized precision medicine, microfluidic circuits.

[1]
Bhatia SN, Ingber DE. Microfluidic organs-on-chips. Nat Biotechnol 2014; 32(8): 760-72.
[2]
Ware BR, Khetani SR. Engineered liver platforms for different phases of drug development. Trends Biotechnol 2017; 35(2): 172-83.
[3]
Balijepalli A, Sivaramakrishan V. Organs-on-chips: Research and commercial perspectives. Drug Discov Today 2017; 22(2): 397-403.
[4]
Kim S, Takayama S. Organ-on-a-chip and the kidney. Kidney Res Clin Pract 2015; 34(3): 165-9.
[5]
Zhang YS, Aleman J, Shin SR, et al. Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors. Proc Natl Acad Sci USA 2017; 114(12): E2293-302.
[6]
Tejavibulya N, Sia SK. Personalized Disease Models on a Chip. Cell Syst 2016; 3(5): 416-8.
[7]
Kidambi S, Yarmush RS, Novik E, Chao P, Yarmush ML, Nahmias Y. Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance. Proc Natl Acad Sci USA 2009; 106(37): 15714-9.
[8]
Grosberg A, Alford PW, McCain ML, Parker KK. Ensembles of engineered cardiac tissues for physiological and pharmacological study: heart on a chip. Lab Chip 2011; 11(24): 4165-73.
[9]
Massa S, Sakr MA, Seo J, et al. Bioprinted 3D vascularized tissue model for drug toxicity analysis. Biomicrofluidics 2017; 11(4): 044109.
[10]
Geraili A, Jafari P, Hassani MS, et al. Controlling Differentiation of Stem Cells for Developing Personalized Organ-on-Chip Platforms. Adv Healthc Mater 2018; 7(2): 7.
[11]
Oleaga C, Bernabini C, Smith AST, et al. Multi-Organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci Rep 2016; 6: 20030.
[12]
Huh D, Hamilton GA, Ingber DE. From 3D cell culture to organs-on-chips. Trends Cell Biol 2011; 21(12): 745-54.
[13]
Shintu L, Baudoin R, Navratil V, et al. Metabolomics-on-a-chip and predictive systems toxicology in microfluidic bioartificial organs. Anal Chem 2012; 84(4): 1840-8.
[14]
Cheng W, Klauke N, Sedgwick H, Smith GL, Cooper JM. Metabolic monitoring of the electrically stimulated single heart cell within a microfluidic platform. Lab Chip 2006; 6(11): 1424-31.
[15]
Sivaraman A, Leach JK, Townsend S, et al. A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction. Curr Drug Metab 2005; 6(6): 569-91.
[16]
Gebhardt R, Hengstler JG, Müller D, et al. New hepatocyte in vitro systems for drug metabolism: metabolic capacity and recommendations for application in basic research and drug development, standard operation procedures. Drug Metab Rev 2003; 35(2-3): 145-213.
[17]
Prot J-M, Videau O, Brochot C, Legallais C, Bénech H, Leclerc E. A cocktail of metabolic probes demonstrates the relevance of primary human hepatocyte cultures in a microfluidic biochip for pharmaceutical drug screening. Int J Pharm 2011; 408(1-2): 67-75.
[18]
Legendre A, Baudoin R, Alberto G, et al. Metabolic characterization of primary rat hepatocytes cultivated in parallel microfluidic biochips. J Pharm Sci 2013; 102(9): 3264-76.
[19]
Kwon SJ, Lee DW, Shah DA, et al. High-throughput and combinatorial gene expression on a chip for metabolism-induced toxicology screening. Nat Commun 2014; 5: 3739.
[20]
Sung JH, Shuler ML. A micro cell culture analog (microCCA) with 3-D hydrogel culture of multiple cell lines to assess metabolism-dependent cytotoxicity of anti-cancer drugs. Lab Chip 2009; 9(10): 1385-94.
[21]
Khetani SR, Bhatia SN. Microscale culture of human liver cells for drug development. Nat Biotechnol 2008; 26(1): 120-6.
[22]
Xu Z, Gao Y, Hao Y, et al. Application of a microfluidic chip-based 3D co-culture to test drug sensitivity for individualized treatment of lung cancer. Biomaterials 2013; 34(16): 4109-17.
[23]
Zhang YS, Aleman J, Arneri A, et al. From cardiac tissue engineering to heart-on-a-chip: beating challenges. Biomed Mater 2015; 10(3): 034006.
[24]
Kankala RK, Zhang YS, Wang SB, Lee CH, Chen AZ. Supercritical Fluid Technology: An Emphasis on Drug Delivery and Related Biomedical Applications. Adv Healthc Mater 2017; 6(16): 6.
[25]
Wagner I, Materne E-M, Brincker S, et al. A dynamic multi-organ-chip for long-term cultivation and substance testing proven by 3D human liver and skin tissue co-culture. Lab Chip 2013; 13(18): 3538-47.
[26]
Puleo CM, McIntosh Ambrose W, Takezawa T, Elisseeff J, Wang T-H. Integration and application of vitrified collagen in multilayered microfluidic devices for corneal microtissue culture. Lab Chip 2009; 9(22): 3221-7.
[27]
Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006; 7(1): 41-53.
[28]
Knowlton S, Tasoglu S. A Bioprinted Liver-on-a-Chip for Drug Screening Applications. Trends Biotechnol 2016; 34(9): 681-2.
[29]
Lang JD, Berry SM, Powers GL, Beebe DJ, Alarid ET. Hormonally responsive breast cancer cells in a microfluidic co-culture model as a sensor of microenvironmental activity. Integr Biol 2013; 5(5): 807-16.
[30]
Jeon JS, Zervantonakis IK, Chung S, Kamm RD, Charest JL. In vitro model of tumor cell extravasation. PLoS One 2013; 8(2): e56910.
[31]
Lewis DM, Gerecht S. Microfluidics and biomaterials to study angiogenesis. Curr Opin Chem Eng 2016; 11: 114-22.
[32]
Griep LM, Wolbers F, de Wagenaar B, et al. BBB on chip: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function. Biomed Microdevices 2013; 15(1): 145-50.
[33]
Achyuta AKH, Conway AJ, Crouse RB, et al. A modular approach to create a neurovascular unit-on-a-chip. Lab Chip 2013; 13(4): 542-53.
[34]
Yang K, Han S, Shin Y, et al. A microfluidic array for quantitative analysis of human neural stem cell self-renewal and differentiation in three-dimensional hypoxic microenvironment. Biomaterials 2013; 34(28): 6607-14.
[35]
Tsantoulas C, Farmer C, Machado P, Baba K, McMahon SB, Raouf R. Probing functional properties of nociceptive axons using a microfluidic culture system. PLoS One 2013; 8(11): e80722.
[36]
Ziegler L, Grigoryan S, Yang IH, Thakor NV, Goldstein RS. Efficient generation of schwann cells from human embryonic stem cell-derived neurospheres. Stem Cell Rev 2011; 7(2): 394-403.
[37]
Yang K, Park H-J, Han S, et al. Recapitulation of in vivo-like paracrine signals of human mesenchymal stem cells for functional neuronal differentiation of human neural stem cells in a 3D microfluidic system. Biomaterials 2015; 63: 177-88.
[38]
Shi M, Majumdar D, Gao Y, et al. Glia co-culture with neurons in microfluidic platforms promotes the formation and stabilization of synaptic contacts. Lab Chip 2013; 13(15): 3008-21.
[39]
Shayan G, Shuler ML, Lee KH. The effect of astrocytes on the induction of barrier properties in aortic endothelial cells. Biotechnol Prog 2011; 27(4): 1137-45.
[40]
Ma SH, Lepak LA, Hussain RJ, Shain W, Shuler ML. An endothelial and astrocyte co-culture model of the blood-brain barrier utilizing an ultra-thin, nanofabricated silicon nitride membrane. Lab Chip 2005; 5(1): 74-85.
[41]
Seidi A, Kaji H, Annabi N, Ostrovidov S, Ramalingam M, Khademhosseini A. A microfluidic-based neurotoxin concentration gradient for the generation of an in vitro model of Parkinson’s disease. Biomicrofluidics 2011; 5(2): 22214.
[42]
Booth R, Kim H. Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB). Lab Chip 2012; 12(10): 1784-92.
[43]
Piccini JP, Whellan DJ, Berridge BR, et al. Current challenges in the evaluation of cardiac safety during drug development: translational medicine meets the Critical Path Initiative. Am Heart J 2009; 158(3): 317-26.
[44]
Kankala RK, Zhu K, Sun X-N, Liu C-G, Wang S-B, Chen A-Z. Cardiac Tissue Engineering on the Nanoscale. ACS Biomater Sci Eng 2018; 4: 800-18.
[45]
Kankala RK, Zhu K, Li J, Wang C-S, Wang S-B, Chen A-Z. Fabrication of arbitrary 3D components in cardiac surgery: from macro-, micro- to nanoscale. Biofabrication 2017; 9(3): 032002.
[46]
McCain ML, Sheehy SP, Grosberg A, Goss JA, Parker KK. Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip. Proc Natl Acad Sci USA 2013; 110(24): 9770-5.
[47]
Kim SB, Bae H, Cha JM, et al. A cell-based biosensor for real-time detection of cardiotoxicity using lensfree imaging. Lab Chip 2011; 11(10): 1801-7.
[48]
Chen MB, Srigunapalan S, Wheeler AR, Simmons CA. A 3D microfluidic platform incorporating methacrylated gelatin hydrogels to study physiological cardiovascular cell-cell interactions. Lab Chip 2013; 13(13): 2591-8.
[49]
Annabi N, Selimović Š, Acevedo Cox JP, et al. Hydrogel-coated microfluidic channels for cardiomyocyte culture. Lab Chip 2013; 13(18): 3569-77.
[50]
Gopalan SM, Flaim C, Bhatia SN, et al. Anisotropic stretch-induced hypertrophy in neonatal ventricular myocytes micropatterned on deformable elastomers. Biotechnol Bioeng 2003; 81(5): 578-87.
[51]
Khanal G, Chung K, Solis-Wever X, Johnson B, Pappas D. Ischemia/reperfusion injury of primary porcine cardiomyocytes in a low-shear microfluidic culture and analysis device. Analyst (Lond) 2011; 136(17): 3519-26.
[52]
Zhang YS, Arneri A, Bersini S, et al. Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. Biomaterials 2016; 110: 45-59.
[53]
Hsu Y-H, Moya ML, Hughes CCW, George SC, Lee AP. A microfluidic platform for generating large-scale nearly identical human microphysiological vascularized tissue arrays. Lab Chip 2013; 13(15): 2990-8.
[54]
Hasan A, Paul A, Vrana NE, et al. Microfluidic techniques for development of 3D vascularized tissue. Biomaterials 2014; 35(26): 7308-25.
[55]
Chung S, Sudo R, Zervantonakis IK, Rimchala T, Kamm RD. Surface-treatment-induced three-dimensional capillary morphogenesis in a microfluidic platform. Adv Mater 2009; 21(47): 4863-7.
[56]
Wood DK, Soriano A, Mahadevan L, Higgins JM, Bhatia SN. Biophysical Indicator of Vaso-occlusive Risk in Sickle Cell Disease. Sci Transl Med 2012; 4: 123-6.
[57]
Nguyen D-HT, Stapleton SC, Yang MT, et al. Biomimetic model to reconstitute angiogenic sprouting morphogenesis in vitro. Proc Natl Acad Sci USA 2013; 110(17): 6712-7.
[58]
Moya ML, Hsu YH, Lee AP, Hughes CC, George SC. In vitro perfused human capillary networks. Tissue Eng Part C Methods 2013; 19(9): 730-7.
[59]
Baker BM, Trappmann B, Stapleton SC, Toro E, Chen CS. Microfluidics embedded within extracellular matrix to define vascular architectures and pattern diffusive gradients. Lab Chip 2013; 13(16): 3246-52.
[60]
Bischel LL, Young EWK, Mader BR, Beebe DJ. Tubeless microfluidic angiogenesis assay with three-dimensional endothelial-lined microvessels. Biomaterials 2013; 34(5): 1471-7.
[61]
Fritsche CS, Simsch O, Weinberg EJ, et al. Pulmonary tissue engineering using dual-compartment polymer scaffolds with integrated vascular tree. Int J Artif Organs 2009; 32(10): 701-10.
[62]
Chen MB, Whisler JA, Jeon JS, Kamm RD. Mechanisms of tumor cell extravasation in an in vitro microvascular network platform. Integr Biol 2013; 5(10): 1262-71.
[63]
Doryab A, Amoabediny G, Salehi-Najafabadi A. Advances in pulmonary therapy and drug development: Lung tissue engineering to lung-on-a-chip. Biotechnol Adv 2016; 34(5): 588-96.
[64]
Tavana H, Zamankhan P, Christensen PJ, Grotberg JB, Takayama S. Epithelium damage and protection during reopening of occluded airways in a physiologic microfluidic pulmonary airway model. Biomed Microdevices 2011; 13(4): 731-42.
[65]
Huh D, Fujioka H, Tung Y-C, et al. Acoustically detectable cellular-level lung injury induced by fluid mechanical stresses in microfluidic airway systems. Proc Natl Acad Sci USA 2007; 104(48): 18886-91.
[66]
Lococo F, Cesario A, Del Bufalo A, et al. Novel therapeutic strategy in the management of COPD: A systems medicine approach. Curr Med Chem 2015; 22(32): 3655-75.
[67]
Chao P, Maguire T, Novik E, Cheng KC, Yarmush ML. Evaluation of a microfluidic based cell culture platform with primary human hepatocytes for the prediction of hepatic clearance in human. Biochem Pharmacol 2009; 78(6): 625-32.
[68]
Allen JW, Khetani SR, Bhatia SN. In vitro zonation and toxicity in a hepatocyte bioreactor. Toxicol Sci 2005; 84(1): 110-9.
[69]
Kane BJ, Zinner MJ, Yarmush ML, Toner M. Liver-specific functional studies in a microfluidic array of primary mammalian hepatocytes. Anal Chem 2006; 78(13): 4291-8.
[70]
Lee PJ, Hung PJ, Lee LP. An artificial liver sinusoid with a microfluidic endothelial-like barrier for primary hepatocyte culture. Biotechnol Bioeng 2007; 97(5): 1340-6.
[71]
Allen JW, Bhatia SN. Formation of steady-state oxygen gradients in vitro: Application to liver zonation. Biotechnol Bioeng 2003; 82(3): 253-62.
[72]
Esch MB, Mahler GJ, Stokol T, Shuler ML. Body-on-a-chip simulation with gastrointestinal tract and liver tissues suggests that ingested nanoparticles have the potential to cause liver injury. Lab Chip 2014; 14(16): 3081-92.
[73]
Nguyen TA, Yin TI, Reyes D, Urban GA. Microfluidic chip with integrated electrical cell-impedance sensing for monitoring single cancer cell migration in three-dimensional matrixes. Anal Chem 2013; 85(22): 11068-76.
[74]
Song JW, Cavnar SP, Walker AC, et al. Microfluidic endothelium for studying the intravascular adhesion of metastatic breast cancer cells. PLoS One 2009; 4(6): e5756.
[75]
Sung KE, Yang N, Pehlke C, et al. Transition to invasion in breast cancer: A microfluidic in vitro model enables examination of spatial and temporal effects. Integr Biol 2011; 3(4): 439-50.
[76]
Kankala RK, Liu C-G, Chen A-Z, et al. Overcoming Multidrug Resistance through the Synergistic Effects of Hierarchical pH-Sensitive, ROS-Generating Nanoreactors. ACS Biomater Sci Eng 2017; 3: 2431-42.
[77]
Kankala RK, Tsai P-Y, Kuthati Y, Wei P-R, Liu C-L, Lee C-H. Overcoming multidrug resistance through co-delivery of ROS-generating nano-machinery in cancer therapeutics. J Mater Chem B Mater Biol Med 2017; 5: 1507-17.
[78]
Arrigoni C, Gilardi M, Bersini S, Candrian C, Moretti M. Bioprinting and Organ-on-Chip Applications Towards Personalized Medicine for Bone Diseases. Stem Cell Rev 2017; 13(3): 407-17.
[79]
O’Neill AT, Monteiro-Riviere NA, Walker GM. Characterization of microfluidic human epidermal keratinocyte culture. Cytotechnology 2008; 56(3): 197-207.
[80]
Sun YS, Peng SW, Cheng JY. In vitro electrical-stimulated wound-healing chip for studying electric field-assisted wound-healing process. Biomicrofluidics 2012; 6(3): 34117.
[81]
Torisawa YS, Spina CS, Mammoto T, et al. Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro. Nat Methods 2014; 11(6): 663-9.
[82]
Hanke M, Hoffmann I, Christophis C, et al. Differences between healthy hematopoietic progenitors and leukemia cells with respect to CD44 mediated rolling versus adherence behavior on hyaluronic acid coated surfaces. Biomaterials 2014; 35(5): 1411-9.
[83]
Kim HJ, Ingber DE. Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation. Integr Biol 2013; 5(9): 1130-40.
[84]
Kim HJ, Huh D, Hamilton G, Ingber DE. Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. Lab Chip 2012; 12(12): 2165-74.
[85]
Esch MB, Sung JH, Yang J, et al. On chip porous polymer membranes for integration of gastrointestinal tract epithelium with microfluidic ‘body-on-a-chip’ devices. Biomed Microdevices 2012; 14(5): 895-906.
[86]
Skardal A, Shupe T, Atala A. Organoid-on-a-chip and body-on-a-chip systems for drug screening and disease modeling. Drug Discov Today 2016; 21(9): 1399-411.
[87]
Gnecco JS, Anders AP, Cliffel D, et al. Instrumenting a Fetal Membrane on a Chip as Emerging Technology for Preterm Birth Research. Curr Pharm Des 2017; 23(40): 6115-24.
[88]
Sung JH, Kam C, Shuler ML. A microfluidic device for a pharmacokinetic-pharmacodynamic (PK-PD) model on a chip. Lab Chip 2010; 10(4): 446-55.
[89]
Novik E, Maguire TJ, Chao P, Cheng KC, Yarmush ML. A microfluidic hepatic coculture platform for cell-based drug metabolism studies. Biochem Pharmacol 2010; 79(7): 1036-44.
[90]
Viravaidya K, Shuler ML. Incorporation of 3T3-L1 cells to mimic bioaccumulation in a microscale cell culture analog device for toxicity studies. Biotechnol Prog 2004; 20(2): 590-7.
[91]
Chen C-S, Lin JT, Goss KA, He YA, Halpert JR, Waxman DJ. Activation of the anticancer prodrugs cyclophosphamide and ifosfamide: identification of cytochrome P450 2B enzymes and site-specific mutants with improved enzyme kinetics. Mol Pharmacol 2004; 65(5): 1278-85.
[92]
Tirella A, Marano M, Vozzi F, Ahluwalia A. A microfluidic gradient maker for toxicity testing of bupivacaine and lidocaine. Toxicol In Vitro 2008; 22(8): 1957-64.
[93]
Toh Y-C, Lim TC, Tai D, Xiao G, van Noort D, Yu H. A microfluidic 3D hepatocyte chip for drug toxicity testing. Lab Chip 2009; 9(14): 2026-35.
[94]
Choucha-Snouber L, Aninat C, Grsicom L, et al. Investigation of ifosfamide nephrotoxicity induced in a liver-kidney co-culture biochip. Biotechnol Bioeng 2013; 110(2): 597-608.
[95]
Jameson JL, Longo DL. Precision medicine--personalized, problematic, and promising. N Engl J Med 2015; 372(23): 2229-34.
[96]
Benam KH, Novak R, Nawroth J, et al. Matched-Comparative Modeling of Normal and Diseased Human Airway Responses Using a Microengineered Breathing Lung Chip. Cell Syst 2016; 3(5): 456-466.e4.
[97]
Musah S, Mammoto A, Ferrante TC, et al. Mature induced-pluripotent-stem-cell-derived human podocytes reconstitute kidney glomerular-capillary-wall function on a chip Nature Biomedical Engineering 2017; 1: 0069.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy