The application of 3D cell models to support drug safety assessment: Opportunities & challenges

Advanced Drug Delivery Reviews

Volumn 69-70, Issue , 2014, Pages 179-189

  Roth, Adrian ^a   Singer, Thomas ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

3R; Drug safety assessment; In vitro toxicology; Mechanistic toxicology; Predictive toxicology

Indexed keywords

CELL CULTURE; CELLS; TOXICITY;

DRUG SAFETY; IN-VITRO; MECHANISTIC TOXICOLOGY; MONOLAYER CULTURE; PHARMACEUTICAL INDUSTRY; PREDICTIVE TOXICOLOGY; SAFETY ASSESSMENTS; TECHNICAL CHALLENGES;

THREE DIMENSIONAL COMPUTER GRAPHICS;

NEW DRUG;

CELL CULTURE; DRUG DEVELOPMENT; DRUG INDUSTRY; DRUG RESEARCH; DRUG SAFETY; DRUG TOXICITY; HUMAN; IN VITRO STUDY; MODEL; NONHUMAN; PREDICTION; PRIORITY JOURNAL; REVIEW; THREE DIMENSIONAL CELL MODEL; ANIMAL; COCULTURE; CULTURE TECHNIQUE; DRUG EFFECTS; DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS; GENE EXPRESSION PROFILING; LIVER CELL; PHYSIOLOGY; PROCEDURES; TRENDS;

ANIMALS; CELL CULTURE TECHNIQUES; COCULTURE TECHNIQUES; DRUG DISCOVERY; DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS; GENE EXPRESSION PROFILING; HEPATOCYTES; HUMANS;

EID: 84899916765     PISSN: 0169409X     EISSN: 18728294     Source Type: Journal    
DOI: 10.1016/j.addr.2013.12.005     Document Type: Review

References (118)

1. Olson H., Betton G., Robinson D., Thomas K., Monro A., Kolaja G., Lilly P., Sanders J., Sipes G., Bracken W., Dorato M., Van Deun K., Smith P., Berger B., Heller A. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul. Toxicol. Pharmacol. 2000, 32:56-67.
2. Shanks N., Greek R., Greek J. Are animal models predictive for humans?. Philos. Ethics Humanit. Med. 2009, 4:2.
3. Ettlin R.A., Kuroda J., Plassmann S., Prentice D.E. Successful drug development despite adverse preclinical findings part 1: processes to address issues and most important findings. J. Toxicol. Pathol. 2010, 23:189-211.
4. Hartung T. Look back in anger - what clinical studies tell us about preclinical work. Altex 2013, 30:275-291.
5. Bass A.S., Cartwright M.E., Mahon C., Morrison R., Snyder R., McNamara P., Bradley P., Zhou Y.Y., Hunter J. Exploratory drug safety: a discovery strategy to reduce attrition in development. J. Pharmacol. Toxicol. Methods 2009, 60:69-78.
6. Ames B.N., Durston W.E., Yamasaki E., Lee F.D. Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc. Natl. Acad. Sci. U. S. A. 1973, 70:2281-2285.
7. Ames B.N., McCann J., Yamasaki E. Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test. Mutat. Res. 1975, 31:347-364.
8. Heddle J.A., Cimino M.C., Hayashi M., Romagna F., Shelby M.D., Tucker J.D., Vanparys P., MacGregor J.T. Micronuclei as an index of cytogenetic damage: past, present, and future. Environ. Mol. Mutagen. 1991, 18:277-291.
9. Sanguinetti M.C., Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature 2006, 440:463-469.
10. Kiss L., Bennett P.B., Uebele V.N., Koblan K.S., Kane S.A., Neagle B., Schroeder K. High throughput ion-channel pharmacology: planar-array-based voltage clamp. Assay Drug Dev. Technol. 2003, 1:127-135.
11. Lecluyse E.L., Alexandre E. Isolation and culture of primary hepatocytes from resected human liver tissue. Methods Mol. Biol. 2010, 640:57-82.
12. Lau Y.Y., Sapidou E., Cui X., White R.E., Cheng K.C. Development of a novel in vitro model to predict hepatic clearance using fresh, cryopreserved, and sandwich-cultured hepatocytes. Drug Metab. Dispos. 2002, 30:1446-1454.
13. Chiba M., Ishii Y., Sugiyama Y. Prediction of hepatic clearance in human from in vitro data for successful drug development. AAPS J. 2009, 11:262-276.
14. Schechtman L.M. Implementation of the 3Rs (refinement, reduction, and replacement): validation and regulatory acceptance considerations for alternative toxicological test methods. ILAR J. 2002, 43:S85-S94. (Suppl.).
15. Bowes J., Brown A.J., Hamon J., Jarolimek W., Sridhar A., Waldron G., Whitebread S. Reducing safety-related drug attrition: the use of in vitro pharmacological profiling. Nat. Rev. Drug Discov. 2012, 11:909-922.
16. Lin Z., Will Y. Evaluation of drugs with specific organ toxicities in organ-specific cell lines. Toxicol. Sci. 2012, 126:114-127.
17. Schuster D., Laggner C., Langer T. Why drugs fail - a study on side effects in new chemical entities. Curr. Pharm. Des. 2005, 11:3545-3559.
18. Stevens J.L., Baker T.K. The future of drug safety testing: expanding the view and narrowing the focus. Drug Discov. Today 2009, 14:162-167.
19. Xu J.J., Diaz D., O'Brien P.J. Applications of cytotoxicity assays and pre-lethal mechanistic assays for assessment of human hepatotoxicity potential. Chem. Biol. Interact. 2004, 150:115-128.
20. Gerets H.H., Tilmant K., Gerin B., Chanteux H., Depelchin B.O., Dhalluin S., Atienzar F.A. Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins. Cell Biol. Toxicol. 2012, 28:69-87.
21. Hultin-Rosenberg L., Jagannathan S., Nilsson K.C., Matis S.A., Sjogren N., Huby R.D., Salter A.H., Tugwood J.D. Predictive models of hepatotoxicity using gene expression data from primary rat hepatocytes. Xenobiotica 2006, 36:1122-1139.
22. Sahi J., Grepper S., Smith C. Hepatocytes as a tool in drug metabolism, transport and safety evaluations in drug discovery. Curr. Drug Discov. Technol. 2010, 7:188-198.
23. Guillouzo A., Guguen-Guillouzo C. Evolving concepts in liver tissue modeling and implications for in vitro toxicology. Expert Opin. Drug Metab. Toxicol. 2008, 4:1279-1294.
24. Clement B., Guguen-Guillouzo C., Campion J.P., Glaise D., Bourel M., Guillouzo A. Long-term co-cultures of adult human hepatocytes with rat liver epithelial cells: modulation of albumin secretion and accumulation of extracellular material. Hepatology 1984, 4:373-380.
25. Fraslin J.M., Kneip B., Vaulont S., Glaise D., Munnich A., Guguen-Guillouzo C. Dependence of hepatocyte-specific gene expression on cell-cell interactions in primary culture. EMBO J. 1985, 4:2487-2491.
26. Goulet F., Normand C., Morin O. Cellular interactions promote tissue-specific function, biomatrix deposition and junctional communication of primary cultured hepatocytes. Hepatology 1988, 8:1010-1018.
27. Zucco F., De Angelis I., Testai E., Stammati A. Toxicology investigations with cell culture systems: 20years after. Toxicol. In Vitro 2004, 18:153-163.
28. Seiler A.E., Spielmann H. The validated embryonic stem cell test to predict embryotoxicity in vitro. Nat. Protoc. 2011, 6:961-978.
29. Ceridono M., Tellner P., Bauer D., Barroso J., Alepee N., Corvi R., De Smedt A., Fellows M.D., Gibbs N.K., Heisler E., Jacobs A., Jirova D., Jones D., Kandarova H., Kasper P., Akunda J.K., Krul C., Learn D., Liebsch M., Lynch A.M., Muster W., Nakamura K., Nash J.F., Pfannenbecker U., Phillips G., Robles C., Rogiers V., Van De Water F., Liminga U.W., Vohr H.W., Wattrelos O., Woods J., Zuang V., Kreysa J., Wilcox P. The 3T3 neutral red uptake phototoxicity test: practical experience and implications for phototoxicity testing - the report of an ECVAM-EFPIA workshop. Regul. Toxicol. Pharmacol. 2012, 63:480-488.
30. Chu V., Einolf H.J., Evers R., Kumar G., Moore D., Ripp S., Silva J., Sinha V., Sinz M., Skerjanec A. In vitro and in vivo induction of cytochrome p450: a survey of the current practices and recommendations: a pharmaceutical research and manufacturers of America perspective. Drug Metab. Dispos. 2009, 37:1339-1354.
31. Burlinson B. The in vitro and in vivo comet assays. Methods Mol. Biol. 2012, 817:143-163.
32. Corvi R., Albertini S., Hartung T., Hoffmann S., Maurici D., Pfuhler S., van Benthem J., Vanparys P. ECVAM retrospective validation of in vitro micronucleus test (MNT). Mutagenesis 2008, 23:271-283.
33. McCann J., Choi E., Yamasaki E., Ames B.N. Detection of carcinogens as mutagens in the Salmonella/microsome test: assay of 300 chemicals. Proc. Natl. Acad. Sci. U. S. A. 1975, 72:5135-5139.
34. Bryce S.M., Avlasevich S.L., Bemis J.C., Lukamowicz M., Elhajouji A., Van Goethem F., De Boeck M., Beerens D., Aerts H., Van Gompel J., Collins J.E., Ellis P.C., White A.T., Lynch A.M., Dertinger S.D. Interlaboratory evaluation of a flow cytometric, high content in vitro micronucleus assay. Mutat. Res. 2008, 650:181-195.
35. Tice R.R., Agurell E., Anderson D., Burlinson B., Hartmann A., Kobayashi H., Miyamae Y., Rojas E., Ryu J.C., Sasaki Y.F. Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ. Mol. Mutagen. 2000, 35:206-221.
36. Dubin A.E., Nasser N., Rohrbacher J., Hermans A.N., Marrannes R., Grantham C., Van Rossem K., Cik M., Chaplan S.R., Gallacher D., Xu J., Guia A., Byrne N.G., Mathes C. Identifying modulators of hERG channel activity using the PatchXpress planar patch clamp. J. Biomol. Screen. 2005, 10:168-181.
37. Blaauboer B.J. The contribution of in vitro toxicity data in hazard and risk assessment: current limitations and future perspectives. Toxicol. Lett. 2008, 180:81-84.
38. Frazier J.M. The role of mechanistic toxicology in test method validation. Toxicol. In Vitro 1994, 8:787-791.
39. Kostadinova R., Boess F., Applegate D., Suter L., Weiser T., Singer T., Naughton B., Roth A. A long-term three dimensional liver co-culture system for improved prediction of clinically relevant drug-induced hepatotoxicity. Toxicol. Appl. Pharmacol. 2013, 268:1-16.
40. Astashkina A., Mann B., Grainger D.W. A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity. Pharmacol. Ther. 2012, 134:82-106.
41. Bertino J., Fish D. The safety profile of the fluoroquinolones. Clin. Ther. 2000, 22:798-817. (discussion 797).
42. Liguori M.J., Blomme E.A., Waring J.F. Trovafloxacin-induced gene expression changes in liver-derived in vitro systems: comparison of primary human hepatocytes to HepG2 cells. Drug Metab. Dispos. 2008, 36:223-233.
43. Shaw P.J., Ganey P.E., Roth R.A. Tumor necrosis factor alpha is a proximal mediator of synergistic hepatotoxicity from trovafloxacin/lipopolysaccharide coexposure. J. Pharmacol. Exp. Ther. 2009, 328:62-68.
44. Zhang L., Mu X., Fu J., Zhou Z. In vitro cytotoxicity assay with selected chemicals using human cells to predict target-organ toxicity of liver and kidney. Toxicol. In Vitro 2007, 21:734-740.
45. Dunn J.C., Tompkins R.G., Yarmush M.L. Long-term in vitro function of adult hepatocytes in a collagen sandwich configuration. Biotechnol. Prog. 1991, 7:237-245.
46. Swift B., Pfeifer N.D., Brouwer K.L. Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity. Drug Metab. Rev. 2010, 42:446-471.
47. Borel J.F. Comparative study of in vitro and in vivo drug effects on cell-mediated cytotoxicity. Immunology 1976, 31:631-641.
48. Tennant R.W., Margolin B.H., Shelby M.D., Zeiger E., Haseman J.K., Spalding J., Caspary W., Resnick M., Stasiewicz S., Anderson B., et al. Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. Science 1987, 236:933-941.
49. Couture L.A., Abbott B.D., Birnbaum L.S. A critical review of the developmental toxicity and teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin: recent advances toward understanding the mechanism. Teratology 1990, 42:619-627.
50. Safe S., Mason G., Sawyer T., Zacharewski T., Harris M., Yao C., Keys B., Farrell K., Holcomb M., Davis D., et al. Development and validation of in vitro induction assays for toxic halogenated aromatic mixtures: a review. Toxicol. Ind. Health 1989, 5:757-775.
51. Suter W. Predictive value of in vitro safety studies. Curr. Opin. Chem. Biol. 2006, 10:362-366.
52. Yang Y., Abel S.J., Ciurlionis R., Waring J.F. Development of a toxicogenomics in vitro assay for the efficient characterization of compounds. Pharmacogenomics 2006, 7:177-186.
53. Wetmore B.A., Merrick B.A. Toxicoproteomics: proteomics applied to toxicology and pathology. Toxicol. Pathol. 2004, 32:619-642.
54. Heijne W.H., Kienhuis A.S., van Ommen B., Stierum R.H., Groten J.P. Systems toxicology: applications of toxicogenomics, transcriptomics, proteomics and metabolomics in toxicology. Expert Rev. Proteomics 2005, 2:767-780.
55. Xu J.J., Henstock P.V., Dunn M.C., Smith A.R., Chabot J.R., de Graaf D. Cellular imaging predictions of clinical drug-induced liver injury. Toxicol. Sci. 2008, 105:97-105.
56. Steiner G., Suter L., Boess F., Gasser R., de Vera M.C., Albertini S., Ruepp S. Discriminating different classes of toxicants by transcript profiling. Environ. Health Perspect. 2004, 112:1236-1248.
57. Abernethy D.R., Woodcock J., Lesko L.J. Pharmacological mechanism-based drug safety assessment and prediction. Clin. Pharmacol. Ther. 2011, 89:793-797.
58. Lee K.S., Oh S.J., Kim H.M., Lee K.H., Kim S.K. Assessment of reactive metabolites in drug-induced liver injury. Arch. Pharm. Res. 2011, 34:1879-1886.
59. Labbe G., Pessayre D., Fromenty B. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam. Clin. Pharmacol. 2008, 22:335-353.
60. Hespeling U., Puschel G.P., Jungermann K., Gotze O., Zwirner J. Stimulation of glycogen phosphorylase in rat hepatocytes via prostanoid release from Kupffer cells by recombinant rat anaphylatoxin C5a but not by native human C5a in hepatocyte/Kupffer cell co-cultures. FEBS Lett. 1995, 372:108-112.
61. Gressner A.M., Lahme B., Brenzel A. Molecular dissection of the mitogenic effect of hepatocytes on cultured hepatic stellate cells. Hepatology 1995, 22:1507-1518.
62. Finkenzeller G., Arabatzis G., Geyer M., Wenger A., Bannasch H., Stark G.B. Gene expression profiling reveals platelet-derived growth factor receptor alpha as a target of cell contact-dependent gene regulation in an endothelial cell-osteoblast co-culture model. Tissue Eng. 2006, 12:2889-2903.
63. LeCluyse E.L., Witek R.P., Andersen M.E., Powers M.J. Organotypic liver culture models: meeting current challenges in toxicity testing. Crit. Rev. Toxicol. 2012, 42:501-548.
64. Khetani S.R., Bhatia S.N. Microscale culture of human liver cells for drug development. Nat. Biotechnol. 2008, 26:120-126.
65. Khetani S.R., Kanchagar C., Ukairo O., Krzyzewski S., Moore A., Shi J., Aoyama S., Aleo M., Will Y. Use of micropatterned cocultures to detect compounds that cause drug-induced liver injury in humans. Toxicol. Sci. 2013, 132:107-117.
66. Hoebe K.H., Witkamp R.F., Fink-Gremmels J., Van Miert A.S., Monshouwer M. Direct cell-to-cell contact between Kupffer cells and hepatocytes augments endotoxin-induced hepatic injury. Am. J. Physiol. Gastrointest. Liver Physiol. 2001, 280:G720-G728.
67. Russmann S., Kullak-Ublick G.A., Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr. Med. Chem. 2009, 16:3041-3053.
68. Adams D.H., Ju C., Ramaiah S.K., Uetrecht J., Jaeschke H. Mechanisms of immune-mediated liver injury. Toxicol. Sci. 2010, 115:307-321.
69. Hasmall S., James N., Hedley K., Olsen K., Roberts R. Mouse hepatocyte response to peroxisome proliferators: dependency on hepatic nonparenchymal cells and peroxisome proliferator activated receptor alpha (PPARalpha). Arch. Toxicol. 2001, 75:357-361.
70. Roberts R.A., Ganey P.E., Ju C., Kamendulis L.M., Rusyn I., Klaunig J.E. Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. Toxicol. Sci. 2007, 96:2-15.
71. Dash A., Inman W., Hoffmaster K., Sevidal S., Kelly J., Obach R.S., Griffith L.G., Tannenbaum S.R. Liver tissue engineering in the evaluation of drug safety. Expert Opin. Drug Metab. Toxicol. 2009, 5:1159-1174.
72. Gerlach J.C., Mutig K., Sauer I.M., Schrade P., Efimova E., Mieder T., Naumann G., Grunwald A., Pless G., Mas A., Bachmann S., Neuhaus P., Zeilinger K. Use of primary human liver cells originating from discarded grafts in a bioreactor for liver support therapy and the prospects of culturing adult liver stem cells in bioreactors: a morphologic study. Transplantation 2003, 76:781-786.
73. Zeilinger K., Schreiter T., Darnell M., Soderdahl T., Lubberstedt M., Dillner B., Knobeloch D., Nussler A.K., Gerlach J.C., Andersson T.B. Scaling down of a clinical three-dimensional perfusion multicompartment hollow fiber liver bioreactor developed for extracorporeal liver support to an analytical scale device useful for hepatic pharmacological in vitro studies. Tissue Eng. Part C Methods 2011, 17:549-556.
74. Messner S., Agarkova I., Moritz W., Kelm J.M. Multi-cell type human liver microtissues for hepatotoxicity testing. Arch. Toxicol. 2013, 87:209-213.
75. Domansky K., Inman W., Serdy J., Dash A., Lim M.H., Griffith L.G. Perfused multiwell plate for 3D liver tissue engineering. Lab Chip 2010, 10:51-58.
76. Chen M., Vijay V., Shi Q., Liu Z., Fang H., Tong W. FDA-approved drug labeling for the study of drug-induced liver injury. Drug Discov. Today 2011, 16:697-703.
77. van Acker F.A., van Acker S.A., Haenen G.R., Bast A., van der Vijgh W.J. In vitro screening of antitumour agents for cardiotoxicity by means of isolated mouse left atria. Anticancer Res 2000, 20:4483-4487.
78. Guo L., Abrams R.M., Babiarz J.E., Cohen J.D., Kameoka S., Sanders M.J., Chiao E., Kolaja K.L. Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol. Sci. 2011, 123:281-289.
79. Braam S.R., Tertoolen L., van de Stolpe A., Meyer T., Passier R., Mummery C.L. Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes. Stem Cell Res. 2010, 4:107-116.
80. Serena E., Cimetta E., Zatti S., Zaglia T., Zagallo M., Keller G., Elvassore N. Micro-arrayed human embryonic stem cells-derived cardiomyocytes for in vitro functional assay. PLoS One 2012, 7:e48483.
81. Hussain A., Collins G., Yip D., Cho C.H. Functional 3-D cardiac co-culture model using bioactive chitosan nanofiber scaffolds. Biotechnol. Bioeng. 2013, 110:637-647.
82. Ward R.K., Hubbard A.W., Sulley H., Garle M.J., Clothier R.H. Human keratinocyte cultures in an in vitro approach for the assessment of surfactant-induced irritation. Toxicol. In Vitro 1998, 12:163-173.
83. Gibbs S., van de Sandt J.J., Merk H.F., Lockley D.J., Pendlington R.U., Pease C.K. Xenobiotic metabolism in human skin and 3D human skin reconstructs: a review. Curr. Drug Metab. 2007, 8:758-772.
84. Roguet R., Regnier M., Cohen C., Dossou K.G., Rougier A. The use of in vitro reconstituted human skin in dermotoxicity testing. Toxicol. In Vitro 1994, 8:635-639.
85. Kirsch-Volders M., Decordier I., Elhajouji A., Plas G., Aardema M.J., Fenech M. In vitro genotoxicity testing using the micronucleus assay in cell lines, human lymphocytes and 3D human skin models. Mutagenesis 2011, 26:177-184.
86. Lelievre D., Justine P., Christiaens F., Bonaventure N., Coutet J., Marrot L., Cotovio J. The EpiSkin phototoxicity assay (EPA): development of an in vitro tiered strategy using 17 reference chemicals to predict phototoxic potency. Toxicol. In Vitro 2007, 21:977-995.
87. Wagner I., Materne E.M., Brincker S., Sussbier U., Fradrich C., Busek M., Sonntag F., Sakharov D.A., Trushkin E.V., Tonevitsky A.G., Lauster R., Marx U. 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, 13:3538-3547.
88. Vorsmann H., Groeber F., Walles H., Busch S., Beissert S., Walczak H., Kulms D. Development of a human three-dimensional organotypic skin-melanoma spheroid model for in vitro drug testing. Cell Death Dis. 2013, 4:e719.
89. Genschow E., Spielmann H., Scholz G., Seiler A., Brown N., Piersma A., Brady M., Clemann N., Huuskonen H., Paillard F., Bremer S., Becker K. The ECVAM international validation study on in vitro embryotoxicity tests: results of the definitive phase and evaluation of prediction models. European Centre for the Validation of Alternative Methods. Altern. Lab. Anim. 2002, 30:151-176.
90. Whitlow S., Burgin H., Clemann N. The embryonic stem cell test for the early selection of pharmaceutical compounds. Altex 2007, 24:3-7.
91. Festag M., Viertel B., Steinberg P., Sehner C. An in vitro embryotoxicity assay based on the disturbance of the differentiation of murine embryonic stem cells into endothelial cells. II. Testing of compounds. Toxicol. In Vitro 2007, 21:1631-1640.
92. Ge F., He Q.Y. Genomic and proteomic approaches for predicting toxicity and adverse drug reactions. Expert Opin. Drug Metab. Toxicol. 2009, 5:29-37.
93. Li W., Lam M., Choy D., Birkeland A., Sullivan M.E., Post J.M. Human primary renal cells as a model for toxicity assessment of chemo-therapeutic drugs. Toxicol. In Vitro 2006, 20:669-676.
94. Wu Y., Connors D., Barber L., Jayachandra S., Hanumegowda U.M., Adams S.P. Multiplexed assay panel of cytotoxicity in HK-2 cells for detection of renal proximal tubule injury potential of compounds. Toxicol. In Vitro 2009, 23:1170-1178.
95. Astashkina A.I., Mann B.K., Prestwich G.D., Grainger D.W. Comparing predictive drug nephrotoxicity biomarkers in kidney 3-D primary organoid culture and immortalized cell lines. Biomaterials 2012, 33:4712-4721.
96. DesRochers T.M., Suter L., Roth A., Kaplan D.L. Bioengineered 3D human kidney tissue, a platform for the determination of nephrotoxicity. PLoS One 2013, 8:e59219.
97. Huh D., Hamilton G.A., Ingber D.E. From 3D cell culture to organs-on-chips. Trends Cell Biol. 2011, 21:745-754.
98. Huh D., Torisawa Y.S., Hamilton G.A., Kim H.J., Ingber D.E. Microengineered physiological biomimicry: organs-on-chips. Lab Chip 2012, 12:2156-2164.
99. Huh D., Matthews B.D., Mammoto A., Montoya-Zavala M., Hsin H.Y., Ingber D.E. Reconstituting organ-level lung functions on a chip. Science 2010, 328:1662-1668.
100. Huh D., Leslie D.C., Matthews B.D., Fraser J.P., Jurek S., Hamilton G.A., Thorneloe K.S., McAlexander M.A., Ingber D.E. A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice. Sci. Transl. Med. 2012, 4:159ra147.
101. Chang R.C., Emami K., Jeevarajan A., Wu H., Sun W. Microprinting of liver micro-organ for drug metabolism study. Methods Mol. Biol. 2011, 671:219-238.
102. Schimek K., Busek M., Brincker S., Groth B., Hoffmann S., Lauster R., Lindner G., Lorenz A., Menzel U., Sonntag F., Walles H., Marx U., Horland R. Integrating biological vasculature into a multi-organ-chip microsystem. Lab Chip 2013, 13:3588-3598.
103. Marx-Stoelting P., Adriaens E., Ahr H.J., Bremer S., Garthoff B., Gelbke H.P., Piersma A., Pellizzer C., Reuter U., Rogiers V., Schenk B., Schwengberg S., Seiler A., Spielmann H., Steemans M., Stedman D.B., Vanparys P., Vericat J.A., Verwei M., van der Water F., Weimer M., Schwarz M. A review of the implementation of the embryonic stem cell test (EST). The report and recommendations of an ECVAM/ReProTect Workshop. Altern. Lab. Anim. 2009, 37:313-328.
104. Genschow E., Spielmann H., Scholz G., Pohl I., Seiler A., Clemann N., Bremer S., Becker K. Validation of the embryonic stem cell test in the international ECVAM validation study on three in vitro embryotoxicity tests. Altern. Lab. Anim. 2004, 32:209-244.
105. Leist M., Lidbury B.A., Yang C., Hayden P.J., Kelm J.M., Ringeissen S., Detroyer A., Meunier J.R., Rathman J.F., Jackson G.R., Stolper G., Hasiwa N. Novel technologies and an overall strategy to allow hazard assessment and risk prediction of chemicals, cosmetics, and drugs with animal-free methods. Altex 2012, 29:373-388.
106. Kandarova H., Liebsch M., Spielmann H., Genschow E., Schmidt E., Traue D., Guest R., Whittingham A., Warren N., Gamer A.O., Remmele M., Kaufmann T., Wittmer E., De Wever B., Rosdy M. Assessment of the human epidermis model SkinEthic RHE for in vitro skin corrosion testing of chemicals according to new OECD TG 431. Toxicol. In Vitro 2006, 20:547-559.
107. Eskes C., Cole T., Hoffmann S., Worth A., Cockshott A., Gerner I., Zuang V. The ECVAM international validation study on in vitro tests for acute skin irritation: selection of test chemicals. Altern. Lab. Anim. 2007, 35:603-619.
108. Barratt M.D., Brantom P.G., Fentem J.H., Gerner I., Walker A.P., Worth A.P. The ECVAM international validation study on in vitro tests for skin corrosivity. 1. Selection and distribution of the test chemicals. Toxicol. In Vitro 1998, 12:471-482.
109. Groeber F., Holeiter M., Hampel M., Hinderer S., Schenke-Layland K. Skin tissue engineering - in vivo and in vitro applications. Adv. Drug Deliv. Rev. 2011, 63:352-366.
110. Martin-Murphy B.V., Holt M.P., Ju C. The role of damage associated molecular pattern molecules in acetaminophen-induced liver injury in mice. Toxicol. Lett. 2010, 192:387-394.
111. Riccalton-Banks L., Liew C., Bhandari R., Fry J., Shakesheff K. Long-term culture of functional liver tissue: three-dimensional coculture of primary hepatocytes and stellate cells. Tissue Eng. 2003, 9:401-410.
112. Ferri N., Siegl P., Corsini A., Herrmann J., Lerman A., Benghozi R. Drug attrition during pre-clinical and clinical development: understanding and managing drug-induced cardiotoxicity. Pharmacol. Ther. 2013, 138:470-484.
113. Maguire T.J., Novik E., Chao P., Barminko J., Nahmias Y., Yarmush M.L., Cheng K.C. Design and application of microfluidic systems for in vitro pharmacokinetic evaluation of drug candidates. Curr. Drug Metab. 2009, 10:1192-1199.
114. Jakab K., Norotte C., Marga F., Murphy K., Vunjak-Novakovic G., Forgacs G. Tissue engineering by self-assembly and bio-printing of living cells. Biofabrication 2010, 2:022001.
115. Marga F., Jakab K., Khatiwala C., Shepherd B., Dorfman S., Hubbard B., Colbert S., Gabor F. Toward engineering functional organ modules by additive manufacturing. Biofabrication 2012, 4:022001.
116. Novik E., Maguire T.J., Chao P., Cheng K.C., Yarmush M.L. A microfluidic hepatic coculture platform for cell-based drug metabolism studies. Biochem. Pharmacol. 2010, 79:1036-1044.
117. Huh D., Kim H.J., Fraser J.P., Shea D.E., Khan M., Bahinski A., Hamilton G.A., Ingber D.E. Microfabrication of human organs-on-chips. Nat. Protoc. 2013, 8:2135-2157.
118. Marx U., Walles H., Hoffmann S., Lindner G., Horland R., Sonntag F., Klotzbach U., Sakharov D., Tonevitsky A., Lauster R. 'Human-on-a-chip' developments: a translational cutting-edge alternative to systemic safety assessment and efficiency evaluation of substances in laboratory animals and man?. Altern. Lab. Anim. 2012, 40:235-257.