CoChat
Sign Up
Cited by 593D Printing in Biomedical ResearchTissue Engineering and Regenerative MedicineDrug-Induced Hepatotoxicity and Protection

3D Cultivation Techniques for Primary Human Hepatocytes

Open access
Bachmann, Anastasia, Moll, Matthias, Gottwald, Eric, Nies, Cordula, Zantl, Roman, Wagner, Helga, Burkhardt, Britta, Sánchez, Juan +4 more·2015·Microarrays
DOI 10.3390/microarrays4010064PMC PMC4996383
Open this paper in CoChat — free accountOpen PDF

Abstract

One of the main challenges in drug development is the prediction of in vivo toxicity based on in vitro data. The standard cultivation system for primary human hepatocytes is based on monolayer cultures, even if it is known that these conditions result in a loss of hepatocyte morphology and of liver-specific functions, such as drug-metabolizing enzymes and transporters. As it has been demonstrated that hepatocytes embedded between two sheets of collagen maintain their function, various hydrogels and scaffolds for the 3D cultivation of hepatocytes have been developed. To further improve or maintain hepatic functions, 3D cultivation has been combined with perfusion. In this manuscript, we discuss the benefits and drawbacks of different 3D microfluidic devices. For most systems that are currently available, the main issues are the requirement of large cell numbers, the low throughput, and expensive equipment, which render these devices unattractive for research and the drug-developing industry. A higher acceptance of these devices could be achieved by their simplification and their compatibility with high-throughput, as both aspects are of major importance for a user-friendly device.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/microarrays4010064

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Cell-cell and cell-matrix interactions are important for improving hepatic functions in liver models.

    “The development of hepatocyte sandwich cultures (SCs), co-cultures with non-parenchymal cells and even more advanced 3-dimensional culturing techniques has revealed the importance of cell-cell and cell-matrix interactions for improving hepatic functions in liver models (Bachmann et al., 2015[2]; Duval et al., 2017[9]; Wei et al., 2018[45]).”

    From Optimization of extracellular matrix for primary human hepatocyte cultures using mixed collagen-matrigel matrices (2023) · cites this paper as Bachmann et al., 2015[2]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 66

  1. [1]Dambach D.M. Andrews B.A. Moulin F. New Technologies and Screening Strategies for Hepatotoxicity: Use of in Vitro Models Toxicol. Pathol. 2004 33 17 26 10.1080/01926230590522284 15805052 · DOI
  2. [2]De Bruyn T. Chatterjee S. Fattah S. Keemink J. Nicolaï J. Augustijns P. Annaert P. Sandwich-cultured hepatocytes: Utility for in vitro exploration of hepatobiliary drug disposition and drug-induced hepatotoxicity Expert Opin. Drug Metab. Toxicol. 2013 9 589 616 23452081
  3. [3]Schyschka L. Sánchez J.J.M. Wang Z. Burkhardt B. Müller-Vieira U. Zeilinger K. Bachmann A. Nadalin S. Damm G. Nussler A.K. Hepatic 3D cultures but not 2D cultures preserve specific transporter activity for acetaminophen-induced hepatotoxicity Arch. Toxicol. 2013 87 1581 1593 10.1007/s00204-013-1080-y 23728527 · DOI
  4. [4]Decaens C. Cassio D. Spatiotemporal expression of catenins, ZO-1, and occludin during early polarization of hepatic WIF-B9 cells Am. J. Physiol. Cell Physiol. 2001 280 C527 C539 11171572
  5. [5]Godoy P. Hengstler J.G. Ilkavets I. Meyer C. Bachmann A. Mueller A. Tuschl G. Mueller S.O. Dooley S. Doole Extracellular matrix modulates sensitivity of hepatocytes to fibroblastoid dedifferentiation and transforming growth factor induced apoptosis Hepatology 2009 49 2031 2043 10.1002/hep.22880 19274752 · DOI
  6. [6]Acosta D. Anuforo D. McMillin R. Soine W.H. Smith R.V. Comparison of cytochrome P-450 levels in adult rat liver, postnatal rat liver, and primary cultures of postnatal rat hepatocytes Life Sci. 1979 1413 1418 10.1016/0024-3205(79)90419-3 522609 · DOI
  7. [7]Enat R. Jefferson D.M. Ruiz-Opazo N. Gatmaitan Z. Leinwand L.A. Reid L.M. Hepatocyte proliferation in vitro: Its dependence on the use of serum-free hormonally defined medium and substrata of extracellular matrix Proc. Natl. Acad. Sci. USA 1984 81 1411 1415 10.1073/pnas.81.5.1411 6584889 PMC344845 · DOI
  8. [10]Chen M. Bisgin H. Tong L. Hong H. Fang H. Borlak J. Tong W. Toward predictive models for drug-induced liver injury in humans: Are we there yet? Biomark. Med. 2014 8 201 213 10.2217/bmm.13.146 24521015 · DOI
  9. [11]Gomez-Lechon M.J. Lahoz A. Gombau L. Castell J.V. Donato M.T. Evaluation of Potential Hepatotoxicity Induced by Drugs Curr. Pharm. Des. 2010 16 1 15 10.2174/1381210202360646128 20236064 · DOI
  10. [13]Lewis D.F. Ioannides C. Parke D.V. Cytochromes P450 and species differences in xenobiotic metabolism and activation of carcinogen Environ. Health Perspect. 1998 106 633 641 10.1289/ehp.98106633 9755138 PMC1533178 · DOI
  11. [14]O’Brien P.J. Chan K. Silber P.M. Human and animal hepatocytes in vitro with extrapolation in vivo Chem. Biol. Interact. 2004 150 97 114 10.1016/j.cbi.2004.09.003 15522264 · DOI
  12. [15]Soldatow V.Y. Griffith L.G. Rusyn I. LeCluyse E.L. In vitro models for liver toxicity testing Toxicol. Res. 2013 2 23 39 10.1039/c2tx20051a PMC3593300 23495363 · DOI
  13. [16]Pfeiffer E. Kegel V. Zeilinger K. Hengstler J.G. Nussler A.K. Seehofer D. Damm G. Isolation, characterization, and cultivation of human hepatocytes and non-parenchymal liver cells Exp. Biol. Med. 2014 10.1177/1535370214558025 PMC4935273 25394621 · DOI
  14. [17]Guguen-Guillouzo C. Guillouzo A. General Review on In Vitro Hepatocyte Models and Their Applications Hepatocytes Methods in Molecular Biology Humana Press Totowa, NJ, USA 2010 Volume 640 1 40 20645044
  15. [18]Guzzardi M.A. Vozzi F. Ahluwalia A.D. Study of the Crosstalk between Hepatocytes and Endothelial Cells Using a Novel Multicompartmental Bioreactor: A Comparison between Connected Cultures and Cocultures Tissue Eng. Part A 2009 15 3635 3645 10.1089/ten.tea.2008.0695 19496676 · DOI
  16. [19]Khetani S.R. Bhatia S.N. Microscale culture of human liver cells for drug development Nat. Biotechnol. 2008 26 120 126 10.1038/nbt1361 18026090 · DOI · Paper page
  17. [20]Lau T.T. Priscilyn Lee L.Q. Leong W. Wang D.A. Formation of model hepatocellular aggregates in a hydrogel scaffold using degradable genipin crosslinked gelatin microspheres as cell carriers Biomed. Mater. 2012 7 1 8 10.1088/1748-6041/7/6/065003 23117748 · DOI
  18. [21]Dash A. Inman W. Hoffmaster K. Sevidal S. Kelly J. Obach R.S. Tannenbaum S.R. Liver tissue engineering in the evaluation of drug safety Expert Opin. Drug Metab. Toxicol. 2009 5 1159 1174 10.1517/17425250903160664 19637986 PMC4110978 · DOI
  19. [22]Schmelzer E. Triolo F. Turner M. Thompson R.L. Zeillinger K. Reid L.M. Gridelli B. Gerlach J.G. Three-Dimensional Perfusion Bioreactor Culture Supports Differentiation of Human Fetal Liver Cells Tissue Eng. Part A 2010 16 2007 2016 10.1089/ten.tea.2009.0569 20088704 · DOI
  20. [23]Mueller D. Tascher G. Mueller-Viera U. Nuessler A.K. Zeillinger K. Heinzle E. Noor F. In-depth physiological characterization of primary human hepatocytes in a 3D hollow- fiber bioreactor J. Tissue Eng. Regen. Med. 2011 5 e207 e218 10.1002/term.418 21442764 · DOI
  21. [24]Legendre A. Baudoin R. Alberto G. Paullier P. Naudot M. Bricks T. Brocheton J. Jaques S. Cotton J. Leclerc E. Metabolic Characterization of Primary Rat Hepatocytes Cultivated in Parallel Microfluidic Biochips Eur. J. Pharm. Sci. 2013 102 3264 3276 10.1002/jps.23466 23423727 · DOI
  22. [25]Hegde M. Jindal R. Bhushan A. Bale S.S. McCarty W.J. Golberg I. Usta O.B. Yarmush M.L. Dynamic interplay of flow and collagen stabilizes primary hepatocytes culture in a microfluidic platform Lab Chip 2014 14 2033 2039 10.1039/C4LC00071D 24770663 PMC4036071 · DOI
  23. [26]Inamori M. Eng M. Mizumoto H. Kajiwara T. An Approach for Formation of Vascularized Liver Tissue by Endothelial Cell–Covered Hepatocyte Spheroid Integration Tissue Eng. Part A 2009 15 2029 2037 10.1089/ten.tea.2008.0403 19320555 · DOI
  24. [27]No D.Y. Lee S.A. Choi Y.Y. Park D.Y. Jang J.Y. Kim D.S. Lee H.L. Functional 3D Human Primary Hepatocyte Spheroids Made by Co-Culturing Hepatocytes from Partial Hepatectomy Specimens and Human Adipose-Derived Stem Cells PLoS One 2012 7 1 8 10.1371/journal.pone.0050723 PMC3517565 23236387 · DOI
  25. [28]Knobeloch D. Ehnert S. Schyschka L. Büchler P. Schoenberg M. Kleeff J. Thasler W.E. Nussler N.C. Godoy P. Hengstler J. Human Hepatocytes: Isolation, Culture, and Quality Procedures Hepatocytes Methods in Molecular Biology Humana Press Totowa, NJ, USA 2011 Volume 806 99 120 22057448
  26. [30]Ehnert S. Lukoschek T. Bachmann A. Martínez Sánchez J.J. Damm G. Nussler N.C. Pscherer S. Stöckle U. Dooley S. Mueller S. The right choice of antihypertensives protects primary human hepatocytes from ethanol- and recombinant human TGF-β1-induced cellular damage Hepat. Med. 2013 5 31 41 24695967 PMC3953738
  27. [31]Buxboim A. Ivanovska I.L. Discher D.E. Matrix elasticity, cytoskeletal forces and physics of the nucleus: How deeply do cells “feel” outside and in? J. Cell. Sci. 2010 123 297 308 10.1242/jcs.041186 20130138 PMC2816180 · DOI
  28. [32]Asthana A. Kisaalita W.S. Biophysical microenvironment and 3D culture physiological relevance Drug Discov. Today 2013 18 533 540 10.1016/j.drudis.2012.12.005 23270783 · DOI
  29. [33]Lee W. Cho N.C. Xiong A. Glenn J.S. Frank C.W. Hydrophobic nanoparticles improve permeability of cell-encapsulating poly(ethylene glycol) hydrogelswhile maintaining patternability Proc. Natl. Acad. Sci. USA 2010 107 120709 120714 PMC2996449 21071674
  30. [34]Burkhardt B. Martinez-Sanchez J.J. Bachmann A. Ladurner R. Nussler A.K. Long-term culture of primary hepatocytes: New matrices and microfluidic devices Hepatol. Int. 2013 8 14 22 10.1007/s12072-013-9487-3 26202403 · DOI
  31. [35]Berthiaume F. Moghe P.V. Toner M. Yarmush M.L. Effect of extracellular matrix topology on cell structure, function, and physiological responsiveness: Hepatocytes cultured in a sandwich configuration FASEB 2004 10 1471 1484 8940293
  32. [37]Burkard A. Dähn C. Heinz S. Zutavern A. Sonntag-Buck V. Maltman D. Generation of proliferating human hepatocytes using upcyte® technology: Characterisation and applications in induction and cytotoxicity assays Xenobiotica 2012 42 939 956 10.3109/00498254.2012.675093 22524704 · DOI
  33. [38]Hamilton G.A. Jolley S.L. Gilbert D. Coon J.D. Barros S. LeCluyse E.L. Regulation of cell morphology and cytochrome P450 expressionin human hepatocytes by extracellular matrix and cell-cell interactions Cell Tissue Res. 2012 306 85 99 11683185
  34. [39]Gottwald E. Giselbrecht S. Augspurger C. Lahni B. Dambrowski N. Truckenmueller R. Poitter V. Giezelt T. Wendt O. Pfleging W. A chip-based platform for the in vitro generation of tissues in three-dimensional organization Lab Chip 2007 7 777 785 10.1039/b618488j 17538721 · DOI
  35. [40]Altmann B. Giselbrecht S. Weibezahn K.F. Welle A. Gottwald E. The three-dimensional cultivation of the carcinoma cell line HepG2 in a perfused chip system leads to a more differentiated phenotype of the cells compared to monolayer culture Biomed. Mater. 2008 3 034120 034110 10.1088/1748-6041/3/3/034120 18765895 · DOI
  36. [41]Zhu J. Marchan R.E. Design properties of hydrogel tissue-engineering scaffolds Expert Rev. Med. Devices 2011 8 607 626 10.1586/erd.11.27 22026626 PMC3206299 · DOI
  37. [42]Kim M. Lee J.Y. Johnes C.N. Revzinc A. Tae G. Heparin-Based Hydrogel as a Matrix for Encapsulation and Cultivation of Primary Hepatocytes Biomaterials 2010 31 3596 3603 10.1016/j.biomaterials.2010.01.068 20153045 PMC2837121 · DOI
  38. [43]Lin C.C. Anseth K.S. PEG Hydrogels for the Controlled Release of Biomolecules in Regenerative Medicine Pharm. Res. 2009 26 631 643 10.1007/s11095-008-9801-2 19089601 PMC5892412 · DOI
  39. [44]Wang S. Nagrath D. Chen P.C. Berthiaume F. Yarmush M.L. Three-Dimensional Primary Hepatocyte Culture in Synthetic Self-Assembling Peptide Hydrogel Tissue Eng. Part A 2008 14 227 236 10.1089/tea.2007.0143 18333775 · DOI
  40. [45]Genove E. Schmitmeier S. Sala A. Borros S. Bader A. Griffith L.G. Semino C.E. Functionalized self-assembling peptide hydrogel enhancemaintenance of hepatocyte activity in vitro J. Cell Mol. Med. 2009 13 3387 3397 10.1111/j.1582-4934.2009.00970.x 19912437 PMC4516494 · DOI
  41. [46]Li J. Pan J. Zhang L. Guo X. Yu Y. Culture of primary rat hepatocytes within porous chitosan scaffolds J. Biomed. Mater. Res. 2003 67 938 943 10.1002/jbm.a.10076 14613242 · DOI
  42. [47]Seo S.J. Choi Y.J. Akaike T. Higuchi A. Cho C.S. Alginate/Galactosylated Chitosan/Heparin Scaffold As a New Synthetic Extracellular Matrix for Hepatocytes Tissue Eng. 2006 12 33 44 10.1089/ten.2006.12.33 16499440 · DOI
  43. [48]Fan J. Shang Y. Yuan Y. Preparation and characterization of chitosan/galactosylated hyaluronic acid scaffolds for primary hepatocytes culture J. Mater. Sci. 2009 21 319 327 19641850
  44. [49]Dvir-Ginzberg M. Gamlieli-Bonshtein I. Agbaria R. Cohen S. Liver Tissue Engineering within Alginate Scaffolds: Effects of Cell-Seeding Density on Hepatocyte Viability, Morphology, and Function Tissue Eng. 2004 9 757 766 10.1089/107632703768247430 13678452 · DOI
  45. [50]Saavedra Y.G.L. Mateescu M.A. Averill-Bates D.A. Denizeau F. Polyvinylalcohol three-dimensional matrices for improved long-term dynamic culture of hepatocytes J. Biomed. Mater. Res. A 2003 66 562 570 10.1002/jbm.a.10583 12918039 · DOI
  46. [51]Wang T. Feng Z.Q. Leach M.K. Wu J. Jiang Q. Nanoporous fibers of type-I collagen coated poly(L-lactic acid) for enhancing primary hepatocyte growth and function J. Mater.Chem. B 2012 1 339 346 10.1039/c2tb00195k 32260757 · DOI
  47. [52]Schutte M. Fox B. Baradez M.O. Devonshire A. Minguez J. Bokhari M. Przyborski S. Marshall D. Rat primary hepatocytes show enhanced performance and sensitivity to acetaminophen during three-dimensional culture on a polystyrene scaffold designed for routine use Assay Drug Dev. Technol. 2011 9 475 486 10.1089/adt.2011.0371 21675871 · DOI
  48. [53]Ohkura T. Ohta K. Nagao T. Kusumoto K. Koeda A. Ueda T. Jomura T. Ikeya T. Ozeki E. Kazuki W. Evaluation of Human Hepatocytes Cultured by Three-dimensional Spheroid Systems for Drug Metabolism Drug Metab. Pharmacokinet. 2014 29 373 378 10.2133/dmpk.DMPK-13-RG-105 24695277 · DOI
  49. [54]Nakamura K. Kato N. Aizawa K. Mizutani R. Yamauchi J. Tanoue A. Expression of albumin and cytochrome P450 enzymes in HepG2 cells cultured with a nanotechnology-based culture plate with microfabricated scaffold J. Toxicol. Sci. 2011 36 625 633 10.2131/jts.36.625 22008537 · DOI
  50. [55]Moghe P.V. Ciger R.N. Toner M. Yarmush M.L. Cell–Cell Interactions Are Essential for Maintenance of Hepatocyte Function in Collagen Gel But Not on Matrigel Biotechnol. Bioeng. 1997 56 706 711 10.1002/(SICI)1097-0290(19971220)56:6<706::AID-BIT14>3.0.CO;2-5 18642343 · DOI
  51. [56]Li K. WAng Y. Xu D. Tang Y. Feng M. Chitosan/gelatin composite microcarrier for hepatocyte culture Biotechnol. Lett. 2004 26 879 883 10.1023/B:bile.0000025896.61490.6d 15269534 · DOI
  52. [57]Mikos A.G. Sarakinos G. Leite S.M. Vacanti J.P. Langer R. Laminated three-dimensional biodegradable foams for use in tissueengineering Biomaterials 2002 14 323 330 10.1016/0142-9612(93)90049-8 8507774 · DOI
  53. [60]Kermanizadeh A. Løhr M. Roursgaard M. Messner S. Gunness P. Kelm J.M. Møller P. Stone V. Loft S. Hepatic toxicology following single and multiple exposure of engineered nanomaterials utilising a novel primary human 3D liver microtissue model Part. Fibre Toxicol. 2014 11 1 15 10.1186/s12989-014-0056-2 25326698 PMC4207326 · DOI
  54. [61]Tilles A.W. Baskaran H. Roy P. Yarmus M.L. Toner M. Effects of oxygenation and flow on the viability and function of rat hepatocytes cocultured in a microchannel flat-plate bioreactor Biotechnol. Bioeng. 2015 73 379 389 10.1002/bit.1071 11320508 · DOI
  55. [63]Tanaka Y. Yamato M. Okano T. Kitamori T. Sato K. Evaluation of effects of shear stress on hepatocytes by a microchip-based system Meas. Sci. Technol. 2006 17 3167 3170 10.1088/0957-0233/17/12/S08 · DOI
  56. [64]Nussler A.K. Wang A. Neuhaus P. Fischer J. Yuan J. Liu L. Zeilinger K. Gerlach J. Arnold P.J. Albrecht W. The suitability of hepatocyte culture models to study various aspects of drug metabolism ALTEX 2001 18 91 101 11378681
  57. [65]Hoffmann S.A. Muller-Viera U. Biemel K. Knobeloch D. Heydel S. Luebberstedt M. Nuessler A.K. Andersson T.B. Gerlach J.C. Katrin Z. Analysis of drug metabolism activities in a miniaturized liver cell bioreactor for use in pharmacological studies Biotechnol. Bioeng. 2012 109 3172 3181 10.1002/bit.24573 22688505 · DOI
  58. [66]Müller-Vieira U. Biemel K.M. Darnell M. Hoffmann S.A. Knöspel F. Wönne E.C. Knobeloch D. Nüssler A.K. Gerlach J.C. Andersson T.B. Serum-free culture of primary human hepatocytes in a miniaturized hollow-fibre membrane bioreactor for pharmacological in vitro studies J. Tissue Eng. Regen. Med. 2012 10.1002/term.1652 23165723 · DOI
  59. [67]Mazzei D. Guazzardi S. A low shear stress modular bioreactor for connected cell culture under high flow rates Bioctechnol. Bioeng. 2010 106 127 137 20091740
  60. [68]Unger K.J. Kuehlein G. Schroers A. Gerlach J.G. Rossaint R. Adsorption of xenobiotics to plastic tubing incorporated into dynamic in vitro systems used in pharmacological research * limits and progress Biomaterials 2001 22 2031 2037 10.1016/S0142-9612(00)00389-6 11426882 · DOI
  61. [69]Miranda J.P. Rodrigues A. Tostoes R.M. Leite S. Zimmerman H. Carrondo M.J.T. Alves P.M. Extending Hepatocyte Functionality for Drug-Testing Applications Using High-Viscosity Alginate–Encapsulated Three-Dimensional Cultures in Bioreactors Tissue Eng. Part C 2010 16 1223 1232 10.1089/ten.tec.2009.0784 20184401 · DOI
  62. [70]Vinci B. Duret C. Klieber S. Gerbal-Chaloin S. Sa-Cunha A. Laporte Z. Suc B. Maurel P. Ahluwalia A. Daujat-Chavanieu M. Modular bioreactor for primary human hepatocyte culture: Medium flow stimulates expression and activity of detoxification genes Biotechnol. J. 2011 6 554 564 10.1002/biot.201000326 21259441 PMC3123466 · DOI
  63. [71]Sbrana T. Ahuluwalia A. Engineering Quasi-Vivo® in Vitro Organ Models Advances in Experimental Medicine and Biology Advances in Experimental Medicine and Biology Springer US New York, NY, USA 2012 Volume 745 138 153 22437817
  64. [72]Sivaraman A. Leach J.K. Townsend S. Iida T. Hogan B.J. Stolz D.B. Fry R. Samson L.D. Tannenbaum S.R. Griffith L.G. A microscale in vitro physiological model of the liver: Predictive screens for drug metabolism and enzyme induction Curr. Drug Metab. 2005 6 569 591 10.2174/138920005774832632 16379670 · DOI
  65. [73]Vivares A. Salle-Lefort S. Arabeyre-Fabre C. Ngo R. Penarier G. Bremond M. Moliner P. Gallas J.F. Fabre G. Klieber S. Morphological behaviour and metabolic capacity of cryopreserved human primary hepatocytes cultivated in a perfused multiwell device Xenobiotica 2015 45 29 44 10.3109/00498254.2014.944612 25068923 · DOI
  66. [74]Schuette J. Hagmeyer B. Holzner F. Kubon M. Werner S. Freudigmann C. Benz K. Boettger J. Gebhardt R. Becker H. “Artificial micro organs”—A microfluidic device for dielectrophoretic assembly of liver sinusoids Biomed. Microdevices 2011 13 493 501 10.1007/s10544-011-9517-7 21347825 · DOI

Cited by

Sorted by citations

Authors
Bachmann, A., Moll, M., Gottwald, E., Nies, C., Zantl, R., Wagner, H., Burkhardt, B., Sánchez, J., Ladurner, R., Thasler, W., Damm, G., & Nussler, A.
Affiliations
  • University of Tübingen (DE)
  • Karlsruhe Institute of Technology (DE)
  • GmbH, Am Klopferspitz 19, 82152 Martinsried, Germany
  • Ludwig-Maximilians-Universität München (DE)
  • Stiftung Charité (DE)
Corresponding author
Nussler, Andreas
ORCID
Venue
Microarrays
Publisher
MDPI AG
Published
2015-02-16
Volume
4
Issue
1
Pages
64-83
ISSN
2076-3905 (ISSN-L)
DOI
10.3390/microarrays4010064
PMC
PMC4996383
OpenAlex
W1976530797
Cited by
59
References
6
Citations by year
2026: 1 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 8 · 2020: 11 · 2019: 6 · 2018: 11 · 2017: 4 · 2016: 3 · 2015: 1
FWCI
0.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Microarrays (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Repository KITopen (Karlsruhe Institute of Technology) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
  • KITopen (cc-by)
Funders
  • Bundesministerium für Bildung und Forschung (0316058E, 0315741)
  • University of Tuebingen (PK 2014-2-16)
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
primary human hepatocytes, 3D cell culture, microfluidics, perfusion bioreactor, collagen gel, scaffolds, hepatocyte function, drug metabolism, drug transporters, in vitro toxicity prediction, high-throughput screening

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review