Skip to main content
SpringerLink
Log in

In vitro microscale systems for systematic drug toxicity study

  • Mini Review
  • Published:
Bioprocess and Biosystems Engineering Aims and scope Submit manuscript

Abstract

After administration, drugs go through a complex, dynamic process of absorption, distribution, metabolism and excretion. The resulting time-dependent concentration, termed pharmacokinetics (PK), is critical to the pharmacological response from patients. An in vitro system that can test the dynamics of drug effects in a more systematic way would save time and costs in drug development. Integration of microfabrication and cell culture techniques has resulted in ‘cells-on-a-chip’ technology, which is showing promise for high-throughput drug screening in physiologically relevant manner. In this review, we summarize current research efforts which ultimately lead to in vitro systems for testing drug’s effect in PK-based manner. In particular, we highlight the contribution of microscale systems towards this goal. We envision that the ‘cells-on-a-chip’ technology will serve as a valuable link between in vitro and in vivo studies, reducing the demand for animal studies, and making clinical trials more effective.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3:711–715

    CAS  Google Scholar 

  2. Dingemanse J, Appel-Dingemanse S (2007) Integrated pharmacokinetics and pharmacodynamics in drug development. Clin Pharmacokinet 46:713–737

    CAS  Google Scholar 

  3. Hughes B (2009) 2008 FDA drug approvals. Nat Rev Drug Discov 8:93–96

    Google Scholar 

  4. Dickson M, Gagnon JP (2004) Key factors in the rising cost of new drug discovery and development. Nat Rev Drug Discov 3:417–429

    CAS  Google Scholar 

  5. Andersen ME, Krewski D (2009) Toxicity testing in the 21st century: bringing the vision to life. Toxicol Sci 107:324–330

    CAS  Google Scholar 

  6. Schoonen WG, Westerink WM, Horbach GJ (2009) High-throughput screening for analysis of in vitro toxicity. EXS 99:401–452

    CAS  Google Scholar 

  7. Davila JC, Rodriguez RJ, Melchert RB, Acosta D Jr (1998) Predictive value of in vitro model systems in toxicology. Annu Rev Pharmacol Toxicol 38:63–96

    CAS  Google Scholar 

  8. Theil FP, Guentert TW, Haddad S, Poulin P (2003) Utility of physiologically based pharmacokinetic models to drug development and rational drug discovery candidate selection. Toxicol Lett 138:29–49

    CAS  Google Scholar 

  9. van Kuilenburg AB (2004) Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer 40:939–950

    Google Scholar 

  10. El-Ali J, Sorger PK, Jensen KF (2006) Cells on chips. Nature 442:403–411

    CAS  Google Scholar 

  11. Park TH, Shuler ML (2003) Integration of cell culture and microfabrication technology. Biotechnol Prog 19:243–253

    CAS  Google Scholar 

  12. Khamsi R (2005) Labs on a chip: meet the stripped down rat. Nature 435:12–13

    CAS  Google Scholar 

  13. Yang ST, Zhang X, Wen Y (2008) Microbioreactors for high-throughput cytotoxicity assays. Curr Opin Drug Discov Devel 11:111–127

    CAS  Google Scholar 

  14. Kim BS, Lee SC, Lee SY, Chang YK, Chang HN (2004) High cell density fed-batch cultivation of Escherichia coli using exponential feeding combined with pH-stat. Bioprocess Biosyst Eng 26:147–150

    CAS  Google Scholar 

  15. Lee PC, Lee SY, Chang HN (2008) Cell recycled culture of succinic acid-producing Anaerobiospirillum succiniciproducens using an internal membrane filtration system. J Microbiol Biotechnol 18:1252–1256

    CAS  Google Scholar 

  16. Walker GM, Zeringue HC, Beebe DJ (2004) Microenvironment design considerations for cellular scale studies. Lab Chip 4:91–97

    CAS  Google Scholar 

  17. Wang Z, Kim MC, Marquez M, Thorsen T (2007) High-density microfluidic arrays for cell cytotoxicity analysis. Lab Chip 7:740–745

    CAS  Google Scholar 

  18. Wu MH, Huang SB, Cui Z, Lee GB (2008) A high throughput perfusion-based microbioreactor platform integrated with pneumatic micropumps for three-dimensional cell culture. Biomed Microdev 10:309–319

    Google Scholar 

  19. Sugiura S, Edahiro J, Kikuchi K, Sumaru K, Kanamori T (2008) Pressure-driven perfusion culture microchamber array for a parallel drug cytotoxicity assay. Biotechnol Bioeng 100:1156–1165

    CAS  Google Scholar 

  20. King KR, Wang S, Irimia D, Jayaraman A, Toner M, Yarmush ML (2007) A high-throughput microfluidic real-time gene expression living cell array. Lab Chip 7:77–85

    CAS  Google Scholar 

  21. Meyvantsson I, Warrick JW, Hayes S, Skoien A, Beebe DJ (2008) Automated cell culture in high density tubeless microfluidic device arrays. Lab Chip 8:717–724

    CAS  Google Scholar 

  22. Warrick J, Meyvantsson I, Ju J, Beebe DJ (2007) High-throughput microfluidics: improved sample treatment and washing over standard wells. Lab Chip 7:316–321

    CAS  Google Scholar 

  23. Lee PJ, Ghorashian N, Gaige TA, Hung PJ (2007) Microfluidic system for automated cell-based assays. JALA Charlottesv Va 12:363–367

    Google Scholar 

  24. Lee PJ, Gaige TA, Hung PJ (2009) Dynamic cell culture: a microfluidic function generator for live cell microscopy. Lab Chip 9:164–166

    CAS  Google Scholar 

  25. Keenan TM, Folch A (2008) Biomolecular gradients in cell culture systems. Lab Chip 8:34–57

    CAS  Google Scholar 

  26. Tirella A, Marano M, Vozzi F, Ahluwalia A (2008) A microfluidic gradient maker for toxicity testing of bupivacaine and lidocaine. Toxicol In Vitro 22:1957–1964

    CAS  Google Scholar 

  27. Hung PJ, Lee PJ, Sabounchi P, Lin R, Lee LP (2005) Continuous perfusion microfluidic cell culture array for high-throughput cell-based assays. Biotechnol Bioeng 89:1–8

    CAS  Google Scholar 

  28. Lee PJ, Hung PJ, Rao VM, Lee LP (2006) Nanoliter scale microbioreactor array for quantitative cell biology. Biotechnol Bioeng 94:5–14

    CAS  Google Scholar 

  29. Walker GM, Monteiro-Riviere N, Rouse J, O’Neill AT (2007) A linear dilution microfluidic device for cytotoxicity assays. Lab Chip 7:226–232

    CAS  Google Scholar 

  30. Weuster-Botz D, Puskeiler R, Kusterer A, Kaufmann K, John GT, Arnold M (2005) Methods and milliliter scale devices for high-throughput bioprocess design. Bioprocess Biosyst Eng 28:109–119

    CAS  Google Scholar 

  31. Prokop A, Prokop Z, Schaffer D, Kozlov E, Wikswo J, Cliffel D, Baudenbacher F (2004) NanoLiterBioReactor: long-term mammalian cell culture at nanofabricated scale. Biomed Microdev 6:325–339

    CAS  Google Scholar 

  32. Maharbiz MM, Holtz WJ, Howe RT, Keasling JD (2004) Microbioreactor arrays with parametric control for high-throughput experimentation. Biotechnol Bioeng 86:485–490

    Google Scholar 

  33. Korin N, Bransky A, Dinnar U, Levenberg S (2007) A parametric study of human fibroblasts culture in a microchannel bioreactor. Lab Chip 7:611–617

    CAS  Google Scholar 

  34. Kim L, Vahey MD, Lee HY, Voldman J (2006) Microfluidic arrays for logarithmically perfused embryonic stem cell culture. Lab Chip 6:394–406

    CAS  Google Scholar 

  35. Abbott A (2003) Cell culture: biology’s new dimension. Nature 424:870–872

    CAS  Google Scholar 

  36. Cushing MC, Anseth KS (2007) Materials science. Hydrogel cell cultures. Science 316:1133–1134

    CAS  Google Scholar 

  37. Park JK, Chang HN (2000) Microencapsulation of microbial cells. Biotechnol Adv 18:303–319

    CAS  Google Scholar 

  38. Petersen OW, Ronnov-Jessen L, Howlett AR, Bissell MJ (1992) Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proc Natl Acad Sci USA 89:9064–9068

    CAS  Google Scholar 

  39. Liu H, Roy K (2005) Biomimetic three-dimensional cultures significantly increase hematopoietic differentiation efficacy of embryonic stem cells. Tissue Eng 11:319–330

    CAS  Google Scholar 

  40. Elkayam T, Amitay-Shaprut S, Dvir-Ginzberg M, Harel T, Cohen S (2006) Enhancing the drug metabolism activities of C3A—a human hepatocyte cell line–by tissue engineering within alginate scaffolds. Tissue Eng 12:1357–1368

    CAS  Google Scholar 

  41. Themistocleous GS, Katopodis H, Sourla A, Lembessis P, Doillon CJ, Soucacos PN, Koutsilieris M (2004) Three-dimensional type I collagen cell culture systems for the study of bone pathophysiology. In Vivo 18:687–696

    CAS  Google Scholar 

  42. Smitskamp-Wilms E, Pinedo HM, Veerman G, Ruiz van Haperen VW, Peters GJ (1998) Postconfluent multilayered cell line cultures for selective screening of gemcitabine. Eur J Cancer 34:921–926

    CAS  Google Scholar 

  43. McGuigan AP, Bruzewicz DA, Glavan A, Butte MJ, Whitesides GM (2008) Cell encapsulation in sub-mm sized gel modules using replica molding. PLoS ONE 3:e2258

    Google Scholar 

  44. Kim MS, Lee W, Kim YC, Park JK (2008) Microvalve-assisted patterning platform for measuring cellular dynamics based on 3D cell culture. Biotechnol Bioeng 101:1005–1013

    CAS  Google Scholar 

  45. Kim MS, Yeon JH, Park JK (2007) A microfluidic platform for 3-dimensional cell culture and cell-based assays. Biomed Microdev 9:25–34

    CAS  Google Scholar 

  46. Koh WG, Pishko MV (2006) Fabrication of cell-containing hydrogel microstructures inside microfluidic devices that can be used as cell-based biosensors. Anal Bioanal Chem 385:1389–1397

    CAS  Google Scholar 

  47. Torisawa YS, Shiku H, Yasukawa T, Nishizawa M, Matsue T (2005) Multi-channel 3-D cell culture device integrated on a silicon chip for anticancer drug sensitivity test. Biomaterials 26:2165–2172

    CAS  Google Scholar 

  48. Spielberg SP (1980) Acetaminophen toxicity in human lymphocytes in vitro. J Pharmacol Exp Ther 213:395–398

    CAS  Google Scholar 

  49. Tabatabaei AR, Thies RL, Farrell K, Abbott FS (1997) A rapid in vitro assay for evaluation of metabolism-dependent cytotoxicity of antiepileptic drugs on isolated human lymphocytes. Fundam Appl Toxicol 37:181–189

    CAS  Google Scholar 

  50. Vignati L, Turlizzi E, Monaci S, Grossi P, Kanter R, Monshouwer M (2005) An in vitro approach to detect metabolite toxicity due to CYP3A4-dependent bioactivation of xenobiotics. Toxicology 216:154–167

    CAS  Google Scholar 

  51. Guengerich FP (2001) Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 14:611–650

    CAS  Google Scholar 

  52. Gomez-Lechon MJ, Donato MT, Castell JV, Jover R (2003) Human hepatocytes as a tool for studying toxicity and drug metabolism. Curr Drug Metab 4:292–312

    CAS  Google Scholar 

  53. Lee MY, Kumar RA, Sukumaran SM, Hogg MG, Clark DS, Dordick JS (2008) Three-dimensional cellular microarray for high-throughput toxicology assays. Proc Natl Acad Sci USA 105:59–63

    CAS  Google Scholar 

  54. Ma B, Zhang G, Qin J, Lin B (2009) Characterization of drug metabolites and cytotoxicity assay simultaneously using an integrated microfluidic device. Lab Chip 9:232–238

    CAS  Google Scholar 

  55. Kiang TK, Ensom MH, Chang TK (2005) UDP-glucuronosyltransferases and clinical drug–drug interactions. Pharmacol Ther 106:97–132

    CAS  Google Scholar 

  56. Ma B, Zhou X, Wang G, Dai Z, Qin J, Lin B (2007) A hybrid microdevice with a thin PDMS membrane on the detection window for UV absorbance detection. Electrophoresis 28:2474–2477

    CAS  Google Scholar 

  57. Chang R, Nam J, Sun W (2008) Direct cell writing of 3D microorgan for in vitro pharmacokinetic model. Tissue Eng Part C Methods 14:157–166

    CAS  Google Scholar 

  58. Li AP (2008) In vitro evaluation of human xenobiotic toxicity: scientific concepts and the novel integrated discrete multiple cell co-culture (IdMOC) technology. ALTEX 25:43–49

    CAS  Google Scholar 

  59. Li AP, Bode C, Sakai Y (2004) A novel in vitro system, the integrated discrete multiple organ cell culture (IdMOC) system, for the evaluation of human drug toxicity: comparative cytotoxicity of tamoxifen towards normal human cells from five major organs and MCF-7 adenocarcinoma breast cancer cells. Chem Biol Interact 150:129–136

    CAS  Google Scholar 

  60. Koebe HG, Deglmann CJ, Metzger R, Hoerrlein S, Schildberg FW (2000) In vitro toxicology in hepatocyte bioreactors-extracellular acidification rate (EAR) in a target cell line indicates hepato-activated transformation of substrates. Toxicology 154:31–44

    CAS  Google Scholar 

  61. Gerlowski LE, Jain RK (1983) Physiologically based pharmacokinetic modeling: principles and applications. J Pharm Sci 72:1103–1127

    CAS  Google Scholar 

  62. Aarons L (2005) Physiologically based pharmacokinetic modelling: a sound mechanistic basis is needed. Br J Clin Pharmacol 60:581–583

    Article  CAS  Google Scholar 

  63. Materi W, Wishart DS (2007) Computational systems biology in drug discovery and development: methods and applications. Drug Discov Today 12:295–303

    CAS  Google Scholar 

  64. Sweeney LM, Shuler ML, Babish JG, Ghanem A (1995) A cell culture analogue of rodent physiology: application to naphthalene toxicology. Toxicol In vitro 9:307–316

    CAS  Google Scholar 

  65. Ghanem A, Shuler ML (2000) Characterization of a perfusion reactor utilizing mammalian cells on microcarrier beads. Biotechnol Prog 16:471–479

    CAS  Google Scholar 

  66. Ghanem A, Shuler ML (2000) Combining cell culture analogue reactor designs and PBPK models to probe mechanisms of naphthalene toxicity. Biotechnol Prog 16:334–345

    CAS  Google Scholar 

  67. Quick DJ, Shuler ML (1999) Use of in vitro data for construction of a physiologically based pharmacokinetic model for naphthalene in rats and mice to probe species differences. Biotechnol Prog 15:540–555

    CAS  Google Scholar 

  68. Shuler ML, Ghanem A, Quick D, Wong MC, Miller P (1996) A self-regulating cell culture analog device to mimic animal and human toxicological responses. Biotechnol Bioeng 52:45–60

    CAS  Google Scholar 

  69. Sin A, Chin KC, Jamil MF, Kostov Y, Rao G, Shuler ML (2004) The design and fabrication of three-chamber microscale cell culture analog devices with integrated dissolved oxygen sensors. Biotechnol Prog 20:338–345

    CAS  Google Scholar 

  70. Viravaidya K, Sin A, Shuler ML (2004) Development of a microscale cell culture analog to probe naphthalene toxicity. Biotechnol Prog 20:316–323

    CAS  Google Scholar 

  71. Tatosian DA, Shuler ML (2009) A novel system for evaluation of drug mixtures for potential efficacy in treating multidrug resistant cancers. Biotechnol Bioeng 103:187–198

    CAS  Google Scholar 

  72. Sung JH, Shuler ML (2009) 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 9:1385–1394

    CAS  Google Scholar 

  73. Bissett D, Ahmed F, McLeod H, Cassidy J (2000) Oral fluoropyrimidines in the treatment of colorectal cancer. Clin Oncol (R Coll Radiol) 12:240–245

    CAS  Google Scholar 

  74. Leucuta SE, Vlase L (2006) Pharmacokinetics and metabolic drug interactions. Curr Clin Pharmacol 1:5–20

    CAS  Google Scholar 

  75. Brandon EF, Raap CD, Meijerman I, Beijnen JH, Schellens JH (2003) An update on in vitro test methods in human hepatic drug biotransformation research: pros and cons. Toxicol Appl Pharmacol 189:233–246

    CAS  Google Scholar 

  76. Gebhardt R, Hengstler JG, Muller D, Glockner R, Buenning P, Laube B, Schmelzer E, Ullrich M, Utesch D, Hewitt N, Ringel M, Hilz BR, Bader A, Langsch A, Koose T, Burger HJ, Maas J, Oesch F (2003) 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 35:145–213

    CAS  Google Scholar 

  77. Nahmias Y, Berthiaume F, Yarmush ML (2007) Integration of technologies for hepatic tissue engineering. Adv Biochem Eng Biotechnol 103:309–329

    Google Scholar 

  78. Mehta K, Linderman JJ (2006) Model-based analysis and design of a microchannel reactor for tissue engineering. Biotechnol Bioeng 94:596–609

    CAS  Google Scholar 

  79. Roy P, Baskaran H, Tilles AW, Yarmush ML, Toner M (2001) Analysis of oxygen transport to hepatocytes in a flat-plate microchannel bioreactor. Ann Biomed Eng 29:947–955

    CAS  Google Scholar 

  80. Allen JW, Khetani SR, Bhatia SN (2005) In vitro zonation and toxicity in a hepatocyte bioreactor. Toxicol Sci 84:110–119

    CAS  Google Scholar 

  81. Camp JP, Capitano AT (2007) Induction of zone-like liver function gradients in HepG2 cells by varying culture medium height. Biotechnol Prog 23:1485–1491

    CAS  Google Scholar 

  82. Leclerc E, Sakai Y, Fujii T (2003) Cell culture in 3-dimensional microfluidic structure of PDMS (polydimethylsiloxane). Biomed Microdevices 5:109–114

    CAS  Google Scholar 

  83. Leclerc E, Sakai Y, Fujii T (2004) Microfluidic PDMS (polydimethylsiloxane) bioreactor for large-scale culture of hepatocytes. Biotechnol Prog 20:750–755

    CAS  Google Scholar 

  84. Leclerc E, Sakai Y, Fujii T (2004) Perfusion culture of fetal human hepatocytes in microfluidic environments. Biochem Eng J 20:143–148

    CAS  Google Scholar 

  85. Bhatia SN, Balis UJ, Yarmush ML, Toner M (1999) Effect of cell–cell interactions in preservation of cellular phenotype: cocultivation of hepatocytes and nonparenchymal cells. FASEB J 13:1883–1900

    CAS  Google Scholar 

  86. Nakanishi J, Takarada T, Yamaguchi K, Maeda M (2008) Recent advances in cell micropatterning techniques for bioanalytical and biomedical sciences. Anal Sci 24:67–72

    CAS  Google Scholar 

  87. Khetani SR, Bhatia SN (2008) Microscale culture of human liver cells for drug development. Nat Biotechnol 26:120–126

    CAS  Google Scholar 

  88. Mufti NA, Shuler ML (1995) Induction of cytochrome P-450IA1 activity in response to sublethal stresses in microcarrier-attached Hep G2 cells. Biotechnol Prog 11:659–663

    CAS  Google Scholar 

  89. White CR, Frangos JA (2007) The shear stress of it all: the cell membrane and mechanochemical transduction. Philos Trans R Soc Lond B Biol Sci 362:1459–1467

    CAS  Google Scholar 

  90. Powers MJ, Domansky K, Kaazempur-Mofrad MR, Kalezi A, Capitano A, Upadhyaya A, Kurzawski P, Wack KE, Stolz DB, Kamm R, Griffith LG (2002) A microfabricated array bioreactor for perfused 3D liver culture. Biotechnol Bioeng 78:257–269

    CAS  Google Scholar 

  91. Powers MJ, Janigian DM, Wack KE, Baker CS, Beer Stolz D, Griffith LG (2002) Functional behavior of primary rat liver cells in a three-dimensional perfused microarray bioreactor. Tissue Eng 8:499–513

    Google Scholar 

  92. Sivaraman A, Leach JK, Townsend S, Iida T, Hogan BJ, Stolz DB, Fry R, Samson LD, Tannenbaum SR, Griffith LG (2005) A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction. Curr Drug Metab 6:569–591

    CAS  Google Scholar 

  93. Vozzi F, Heinrich JM, Bader A, Ahluwalia AD (2009) Connected culture of murine hepatocytes and HUVEC in a multicompartmental bioreactor. Tissue Eng Part A 15:1291–1299

    CAS  Google Scholar 

  94. Sung JH, Dhiman A, Shuler ML (2009) A combined pharmacokinetic-pharmacodynamic (PK-PD) model for tumor growth in the rat with UFT administration. J Pharm Sci 98:1885–1904

    CAS  Google Scholar 

  95. Oh TI, Sung JH, Tatosian DA, Shuler ML, Kim D (2007) Real-time fluorescence detection of multiple microscale cell culture analog devices in situ. Cytometry A 71:857–865

    Google Scholar 

  96. Tatosian DA, Shuler ML, Kim D (2005) Portable in situ fluorescence cytometry of microscale cell-based assays. Opt Lett 30:1689–1691

    Google Scholar 

  97. Novak L, Neuzil P, Pipper J, Zhang Y, Lee S (2007) An integrated fluorescence detection system for lab-on-a-chip applications. Lab Chip 7:27–29

    CAS  Google Scholar 

  98. Yu H, Alexander CM, Beebe DJ (2007) A plate reader-compatible microchannel array for cell biology assays. Lab Chip 7:388–391

    CAS  Google Scholar 

  99. Sung JH, Choi JR, Kim DH, Shuler ML (2009) Fluorescence optical detection in situ for real-time monitoring of cytochrome P450 enzymatic activity of liver cells in multiple microfluidic devices. Biotechnol Bioeng. doi:10.1002/bit.22413

  100. Xing JZ, Zhu L, Gabos S, Xie L (2006) Microelectronic cell sensor assay for detection of cytotoxicity and prediction of acute toxicity. Toxicol In Vitro 20:995–1004

    CAS  Google Scholar 

  101. Natarajan A, Molnar P, Sieverdes K, Jamshidi A, Hickman JJ (2006) Microelectrode array recordings of cardiac action potentials as a high throughput method to evaluate pesticide toxicity. Toxicol In Vitro 20:375–381

    CAS  Google Scholar 

  102. Asphahani F, Zhang M (2007) Cellular impedance biosensors for drug screening and toxin detection. Analyst 132:835–841

    CAS  Google Scholar 

  103. Kang L, Chung BG, Langer R, Khademhosseini A (2008) Microfluidics for drug discovery and development: from target selection to product lifecycle management. Drug Discov Today 13:1–13

    CAS  Google Scholar 

  104. Kim L, Toh YC, Voldman J, Yu H (2007) A practical guide to microfluidic perfusion culture of adherent mammalian cells. Lab Chip 7:681–694

    CAS  Google Scholar 

  105. Sung JH, Shuler ML (2009) Prevention of air bubble formation in a microfluidic perfusion cell culture system using a microscale bubble trap. Biomed Microdev. doi:10.1007/s10544-009-9286-8

  106. Kang JH, Kim YC, Park JK (2008) Analysis of pressure-driven air bubble elimination in a microfluidic device. Lab Chip 8:176–178

    CAS  Google Scholar 

  107. Skelley AM, Voldman J (2008) An active bubble trap and debubbler for microfluidic systems. Lab Chip 8:1733–1737

    CAS  Google Scholar 

  108. Melin J, Quake SR (2007) Microfluidic large-scale integration: the evolution of design rules for biological automation. Annu Rev Biophys Biomol Struct 36:213–231

    CAS  Google Scholar 

  109. Horner M, Miller WM, Ottino JM, Papoutsakis ET (1998) Transport in a grooved perfusion flat-bed bioreactor for cell therapy applications. Biotechnol Prog 14:689–698

    CAS  Google Scholar 

  110. Balagadde FK, You L, Hansen CL, Arnold FH, Quake SR (2005) Long-term monitoring of bacteria undergoing programmed population control in a microchemostat. Science 309:137–140

    CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by Nanobiotechnology center (NBTC, project CM-2 (Nanotechnological Assessment of Drug Toxicity)), NSF (National Science Foundation), and CNF (Cornell Nanoscale Science and Technology Facility), and by the Army Corp of Engineers (CERL) W9132T-07.

Author information

Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, USA

    Jong Hwan Sung & Michael L. Shuler

  2. Department of Biomedical Engineering, Cornell University, Ithaca, USA

    Michael L. Shuler

Authors
  1. Jong Hwan Sung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael L. Shuler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael L. Shuler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sung, J.H., Shuler, M.L. In vitro microscale systems for systematic drug toxicity study. Bioprocess Biosyst Eng 33, 5–19 (2010). https://doi.org/10.1007/s00449-009-0369-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00449-009-0369-y

Keywords

Search

Navigation