The use of 3-d cultures for high-throughput screening: the multicellular spheroid model.
Open accessAbstract
Over the past few years, establishment and adaptation of cell-based assays for drug development and testing has become an important topic in high-throughput screening (HTS). Most new assays are designed to rapidly detect specific cellular effects reflecting action at various targets. However, although more complex than cell-free biochemical test systems, HTS assays using monolayer or suspension cultures still reflect a highly artificial cellular environment and may thus have limited predictive value for the clinical efficacy of a compound. Today's strategies for drug discovery and development, be they hypothesis free or mechanism based, require facile, HTS-amenable test systems that mimic the human tissue environment with increasing accuracy in order to optimize preclinical and preanimal selection of the most active molecules from a large pool of potential effectors, for example, against solid tumors. Indeed, it is recognized that 3-dimensional cell culture systems better reflect the in vivo behavior of most cell types. However, these 3-D test systems have not yet been incorporated into mainstream drug development operations. This article addresses the relevance and potential of 3-D in vitro systems for drug development, with a focus on screening for novel antitumor drugs. Examples of 3-D cell models used in cancer research are given, and the advantages and limitations of these systems of intermediate complexity are discussed in comparison with both 2-D culture and in vivo models. The most commonly used 3-D cell culture systems, multicellular spheroids, are emphasized due to their advantages and potential for rapid development as HTS systems. Thus, multicellular tumor spheroids are an ideal basis for the next step in creating HTS assays, which are predictive of in vivo antitumor efficacy.
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Using the hanging drop technique for spheroid creation has logistical issues with media replacements, drug addition, evaporation and downstream analysis of individual spheroids per hanging drop.
“While simple in design, using the hanging drop technique for spheroid creation has logistical issues with media replacements, drug addition, evaporation and downstream analysis of individual spheroids per hanging drop (Kunz-Schughart et al., 2004; Mehta et al., 2012).”
From Three-dimensional modelling of ovarian cancer: from cell lines to organoids for discovery and personalized medicine (2022) · cites this paper as Kunz-Schughart et al., 2004
Cites
Cell and environment interactions in tumor microregions: the multicell spheroid model.
Sutherland, R. M. (1988) · Science · doi:10.1126/science.2451290 · Cited by 1,803 · see citing works
Abbott, A. (2003) · Nature · doi:10.1038/424870a · Cited by 1,237 · see citing works
Johnson, J. I., Decker, S., Zaharevitz, D. W., Rubinstein, L., Venditti, J. M., Schepartz, S. A., Kalyandrug, S., Christian, M. C., Arbuck, S. G., Hollingshead, M. G., et al. (2001) · British Journal of Cancer · doi:10.1054/bjoc.2001.1796 · Cited by 856 · see citing works
The organizing principle: microenvironmental influences in the normal and malignant breast
Bissell, M. J., Radisky, D. C., Rizki, A., Weaver, V. M., & PETERSEN, O. W. (2002) · Differentiation · doi:10.1046/j.1432-0436.2002.700907.x · Cited by 602 · see citing works
Growth of Multicell Spheroids in Tissue Culture as a Model of Nodular Carcinomas 2
Sutherland, R. M., McCredie, J. A., & Inch, W. R. (1971) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/46.1.113 · Cited by 585 · see citing works
High-throughput screening: new technology for the 21st century
Hertzberg, R., & Pope, A. J. (2000) · Current Opinion in Chemical Biology · doi:10.1016/s1367-5931(00)00110-1 · Cited by 547 · see citing works
Three-dimensional cell cultures: from molecular mechanisms to clinical applications
Mueller‐Klieser, W. (1997) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1997.273.4.c1109 · Cited by 537 · see citing works
(2003) · PubMed · Cited by 523 · see citing works
High-throughput and ultra-high-throughput screening: solution- and cell-based approaches
Sundberg, S. (2000) · Current Opinion in Biotechnology · doi:10.1016/s0958-1669(99)00051-8 · Cited by 455 · see citing works
Optimized suspension culture: the rotating-wall vessel
Hammond, T. G., & Hammond, J. (2001) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.2001.281.1.f12 · Cited by 441 · see citing works
Mueller‐Klieser, W. (1987) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/bf00391431 · Cited by 438 · see citing works
Multicellular resistance: a paradigm for clinical resistance?
Desoize, B. (2000) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(00)00086-x · Cited by 400 · see citing works
Growing tissues in microgravity
Unsworth, B. R., & Lelkes, P. I. (1998) · Nature Medicine · doi:10.1038/nm0898-901 · Cited by 393 · see citing works
Mathematical modelling of avascular-tumour growth
Ward, J. (1997) · Mathematical Medicine and Biology · doi:10.1093/imammb/14.1.39 · Cited by 375 · see citing works
A Multiscale Model for Avascular Tumor Growth
Jiang, Y., Pješivac–Grbović, J., Cantrell, C., & Freyer, J. P. (2005) · Biophysical Journal · doi:10.1529/biophysj.105.060640 · Cited by 374 · see citing works
Engineering cellular microenvironments to improve cell-based drug testing
Bhadriraju, K., & Chen, C. S. (2002) · Drug Discovery Today · doi:10.1016/s1359-6446(02)02273-0 · Cited by 355 · see citing works
Comparison of three in vitro human ‘angiogenesis’ assays with capillaries formed in vivo
Donovan, D., Brown, N. J., Bishop, E., & Lewis, C. E. (2001) · Angiogenesis · doi:10.1023/a:1012218401036 · Cited by 342 · see citing works
Multicellular spheroids: a three‐dimensionalin vitroculture system to study tumour biology
Kunz‐Schughart, L. A., Kreutz, M. P., & Knuechel, R. (1998) · International Journal of Experimental Pathology · doi:10.1046/j.1365-2613.1998.00051.x · Cited by 326 · see citing works
Self-citationKerbel, R. S. (2003) · Cancer Biology & Therapy · doi:10.4161/cbt.213 · Cited by 324 · see citing works
An in vitro model of angiogenesis: Basic features
Bishop, E., Bell, G. T., Bloor, S., Broom, I. J., Hendry, N. F. K., & Wheatley, D. N. (1999) · Angiogenesis · doi:10.1023/a:1026546219962 · Cited by 312 · see citing works
Solid stress generated by spheroid growth estimated using a linear poroelasticity model☆
Roose, T., Netti, P. A., Munn, L. L., Boucher, Y., & Jain, R. K. (2003) · Microvascular Research · doi:10.1016/s0026-2862(03)00057-8 · Cited by 301 · see citing works
Andreotti, P. E., Cree, I. A., Kurbacher, C. M., Hartmann, D. M., Linder, D., Harel, G., Gleiberman, I., Caruso, P. A., Ricks, S., & Untch, M. (1995) · PubMed · Cited by 278 · see citing works
Drug and radiation resistance in spheroids: cell contact and kinetics
Olive, P. L., & Durand, R. E. (1994) · Cancer and Metastasis Reviews · doi:10.1007/bf00689632 · Cited by 271 · see citing works
Three-Dimensional Spheroid Model in Tumor Biology
Santini, M. T., & Rainaldi, G. (1999) · Pathobiology · doi:10.1159/000028065 · Cited by 266 · see citing works
A new mathematical model for avascular tumour growth
Sherratt, J. A., & Chaplain, M. A. J. (2001) · Journal of Mathematical Biology · doi:10.1007/s002850100088 · Cited by 250 · see citing works
Structural Polarity and Functional Bile Canaliculi in Rat Hepatocyte Spheroids
Abu-Absi, S. F., Friend, J. R., Hansen, L. K., & Hu, W. (2002) · Experimental Cell Research · doi:10.1006/excr.2001.5467 · Cited by 230 · see citing works
Multicellular tumor spheroids: intermediates between monolayer culture and in vivo tumor
Kunz‐Schughart, L. A. (1999) · Cell Biology International · doi:10.1006/cbir.1999.0384 · Cited by 217 · see citing works
Self-citationTumor biology and experimental therapeutics
Mueller‐Klieser, W. (2000) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(00)00082-2 · Cited by 217 · see citing works
Graff, C. P., & Wittrup, K. D. (2003) · PubMed · Cited by 207 · see citing works
Analysis of growth of multicellular tumour spheroids by mathematical models.
Marušić, M., Bajzer, Ž., Freyer, J. P., & Vuk‐Pavlović, S. (1994) · Cell Proliferation · doi:10.1111/j.1365-2184.1994.tb01407.x · Cited by 203 · see citing works
Self-citationFrankel, A., Man, S., Elliott, P. J., Adams, J., & Kerbel, R. S. (2000) · PubMed · Cited by 201 · see citing works
Denker, A. E., Nicoll, S. B., & Tuan, R. S. (1995) · Differentiation · doi:10.1046/j.1432-0436.1995.5910025.x · Cited by 201 · see citing works
Freyer, J. P., & Sutherland, R. M. (1980) · PubMed · Cited by 201 · see citing works
Modeling of self-organized avascular tumor growth with a hybrid cellular automaton.
Dormann, S., & Deutsch, A. (2002) · PubMed · Cited by 182 · see citing works
Acker, H., Carlsson, J., Durand, R. E., & Sutherland, R. M. (1984) · Recent results in cancer research/Recent Results in Cancer Research · doi:10.1007/978-3-642-82340-4 · Cited by 176 · see citing works
Wartenberg, M., Dönmez, F., Ling, F. C., Acker, H., Hescheler, J., & Sauer, H. (2001) · The FASEB Journal · doi:10.1096/fj.00-0350com · Cited by 173 · see citing works
Freshney, R. I. (1986) · Cited by 165 · see citing works
In Vitro Engineering of Human Autogenous Cartilage
Anderer, U., & Libera, J. (2002) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.2002.17.8.1420 · Cited by 154 · see citing works
Developmental Therapeutics Program at the NCI: molecular target and drug discovery process
Monga, M., & Sausville, E. (2002) · Leukemia · doi:10.1038/sj.leu.2402464 · Cited by 150 · see citing works
Glucose diffusivity in multicellular tumor spheroids.
Casciari, J. J., Sotirchos, S. V., & Sutherland, R. M. (1988) · PubMed · Cited by 144 · see citing works
Tumor‐associated fibroblasts recruit blood monocytes into tumor tissue
Silzle, T., Kreutz, M. P., Dobler, M. A., Brockhoff, G., Knuechel, R., & Kunz‐Schughart, L. A. (2003) · European Journal of Immunology · doi:10.1002/eji.200323057 · Cited by 142 · see citing works
Self-citationKunz‐Schughart, L. A., Heyder, P., Schroeder, J. A., & Knuechel, R. (2001) · Experimental Cell Research · doi:10.1006/excr.2001.5210 · Cited by 138 · see citing works
Self-citationGrowth of nodular carcinomas in rodents compared with multi-cell spheroids in tissue culture.
Inch, W. R., Ja, M., & Rm, S. (1970) · PubMed · Cited by 135 · see citing works
Use of an ex vivo ATP luminescence assay to direct chemotherapy for recurrent ovarian cancer
Kurbacher, C. M., Cree, I. A., Bruckner, H. W., Brenne, U., Kurbacher, J. A., ller, K. M., Ackermann, T., Gilster, T., Wilhelm, L. M., Engel, H., et al. (1998) · Anti-Cancer Drugs · doi:10.1097/00001813-199801000-00006 · Cited by 121 · see citing works
Spheroids in radiobiology and photodynamic therapy
Dubessy, C. (2000) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(00)00085-8 · Cited by 120 · see citing works
Mathematical modelling of drug transport in tumour multicell spheroids and monolayer cultures
Ward, J., & King, J. R. (2003) · Mathematical Biosciences · doi:10.1016/s0025-5564(02)00148-7 · Cited by 120 · see citing works
Breast cancer risk, meat consumption and N-acetyltransferase (NAT2) genetic polymorphisms
Ambrosone, C. B., Freudenheim, J. L., Sinha, R. R., Graham, S., Marshall, J. R., Vena, J. E., Laughlin, R., Nemoto, T., & Shields, P. G. (1998) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19980316)75:6 · Cited by 112 · see citing works
Hicks, K. O., Pruijn, F. B., Sturman, J. R., Denny, W. A., & Wilson, W. R. (2003) · PubMed · Cited by 108 · see citing works
Metabolic Imaging in Multicellular Spheroids of Oncogene-transfected Fibroblasts
Walenta, S., Doetsch, J., Mueller‐Klieser, W., & Kunz‐Schughart, L. A. (2000) · Journal of Histochemistry & Cytochemistry · doi:10.1177/002215540004800409 · Cited by 108 · see citing works
Self-citationDurand, R. E., & Olive, P. L. (2001) · Methods in cell biology · doi:10.1016/s0091-679x(01)64015-9 · Cited by 107 · see citing works
Spheroid Culture in Cancer Research (1991)
(2017) · CRC Press eBooks · doi:10.1201/9780203710241 · Cited by 106 · see citing works
Multicellular tumour spheroids in radiation biology
Santini, M. T., Rainaldi, G., & Indovina, P. (1999) · International Journal of Radiation Biology · doi:10.1080/095530099139845 · Cited by 101 · see citing works
Ballangrud, Å., Yang, W., Charlton, D. E., McDevitt, M. R., Hamacher, K. A., Panageas, K. S., Ma, D., Bander, N. H., Scheinberg, D. A., & Sgouros, G. (2001) · PubMed · Cited by 98 · see citing works
Hicks, K., Ohms, S., van Zijl, P. L., Denny, W. A., Hunter, P. J., & Wilson, W. (1997) · British Journal of Cancer · doi:10.1038/bjc.1997.481 · Cited by 92 · see citing works
The multilayered postconfluent cell culture as a model for drug screening
Padrón, J. M. (2000) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(00)00083-4 · Cited by 91 · see citing works
Chignola, R., Schenetti, A., Andrighetto, G., Chiesa, E., Foroni, R. I., Sartoris, S., Tridente, G., & Liberati, D. (2000) · Cell Proliferation · doi:10.1046/j.1365-2184.2000.00174.x · Cited by 89 · see citing works
Guðjónsson, Þ., Rønnov‐Jessen, L., Villadsen, R., Bissell, M. J., & PETERSEN, O. W. (2003) · Methods · doi:10.1016/s1046-2023(03)00031-8 · Cited by 88 · see citing works
Vascular endothelial growth factor expression, angiogenesis, and necrosis in renal cell carcinomas
Hemmerlein, B., Kugler, A., Özisik, R., Ringert, R.-H., Radzun, H., & Thelen, P. (2001) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s004280100464 · Cited by 86 · see citing works
A flow injection flow cytometry system for on-line monitoring of bioreactors
Zhao, R., Natarajan, A., & Srienc, F. (1999) · Biotechnology and Bioengineering · doi:10.1002/(sici)1097-0290(19990305)62:5 · Cited by 85 · see citing works
Evolution of Anticancer Drug Discovery and the Role of Cell-Based Screening
Balis, F. M. (2002) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/94.2.78 · Cited by 84 · see citing works
Growth and Chemotherapeutic Response of Cells in a Hollow-Fiber In Vitro Solid Tumor Model
Casciari, J. J., Hollingshead, M. G., Alley, M. C., Mayo, J. G., Malspeis, L., Miyauchi, S., Grever, M. R., & Weinstein, J. N. (1994) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/86.24.1846 · Cited by 83 · see citing works
Lappa, M. (2003) · Biotechnology and Bioengineering · doi:10.1002/bit.10821 · Cited by 81 · see citing works
Human Malignant Glioma Therapy Using Anti-αVβ3 Integrin Agents
Chatterjee, S., Matsumura, A., Schradermeier, J., & Gillespie, G. Y. (2000) · Journal of Neuro-Oncology · doi:10.1023/a:1006444300504 · Cited by 81 · see citing works
Correlation of the clinical response to chemotherapy in breast cancer with ex vivo chemosensitivity
Cree, I. A., Kurbacher, C. M., Untch, M., Sutherland, L., Hunter, E. M., Subedi, A. M. C., James, E. A., Dewar, J. A., PREECE, P. E., Andreotti, P. E., et al. (1996) · Anti-Cancer Drugs · doi:10.1097/00001813-199608000-00002 · Cited by 78 · see citing works
Wilson, W. R., Pullen, S. M., Hogg, A. E., Helsby, N. A., Hicks, K. O., & Denny, W. A. (2002) · PubMed · Cited by 78 · see citing works
Erlanson, M., Daniel-Szolgay, E., & Carlsson, J. (1992) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf00686002 · Cited by 77 · see citing works
Slow penetration of anthracyclines into spheroids and tumors: a therapeutic advantage?
Durand, R. E. (1990) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf02897199 · Cited by 76 · see citing works
Mayer, B., Klement, G. L., Kaneko, M., Man, S., Jothy, S., Rak, J. W., & Kerbel, R. S. (2001) · Gastroenterology · doi:10.1053/gast.2001.27989 · Cited by 76 · see citing works
Gillies, R. J., Galons, J., McGovern, K. A., Scherer, P., Lien, Y.-H. H., Job, C., Ratcliff, R., Chapa, F., Cerdán, S., & Dale, B. E. (1993) · NMR in Biomedicine · doi:10.1002/nbm.1940060115 · Cited by 73 · see citing works
3D-biohybrid systems: applications in drug screening
Reininger-Mack, A., Thielecke, H., & Robitzki, A. A. (2002) · Trends in biotechnology · doi:10.1016/s0167-7799(01)01880-7 · Cited by 71 · see citing works
Wartenberg, M., Dönmez, F., Ling, F. C., et al. (2001) · The FASEB Journal · doi:10.1096/fsb2fj000350com · Cited by 69 · see citing works
Application of spheroid culture to human hepatocytes and maintenance of their differentiation
Tong, J. Z., Sarrazin, S., Cassio, D., Gauthier, F., & Álvarez, F. (1994) · Biology of the Cell · doi:10.1016/0248-4900(94)90058-2 · Cited by 67 · see citing works
A multicellular spheroid-based sensor for anti-cancer therapeutics
Thielecke, H., Mack, A., & Robitzki, A. A. (2001) · Biosensors and Bioelectronics · doi:10.1016/s0956-5663(01)00140-3 · Cited by 63 · see citing works
In vitro prediction of gastrointestinal absorption and bioavailability: an experts' meeting report
Pelkonen, O., Boobis, A. R., & Gundert‐Remy, U. (2001) · European Journal of Clinical Pharmacology · doi:10.1007/s002280100369 · Cited by 63 · see citing works
Bioartificial livers (BAL): current technological aspects and future developments
Legallais, C., David, B., & Doré, E. (2001) · Journal of Membrane Science · doi:10.1016/s0376-7388(00)00539-1 · Cited by 61 · see citing works
Olumi, A. F., Dazin, P. F., & Tlsty, T. D. (1998) · PubMed · Cited by 60 · see citing works
Oloumi, A., MacPhail, S. H., Johnston, P. J., Banáth, J. P., & Olive, P. L. (2000) · PubMed · Cited by 59 · see citing works
Yamazaki, T., YOKOYAMA, T., Akatsu, H., Tukiyama, T., & Tokiwa, T. (2003) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1290/1543-706x(2003)039 · Cited by 59 · see citing works
Carlin, S., Cunningham, S. H., Boyd, M., McCluskey, A. G., & Mairs, R. J. (2000) · Cancer Gene Therapy · doi:10.1038/sj.cgt.7700264 · Cited by 57 · see citing works
Optimised helper virus-free production of high-quality adeno-associated virus vectors
Drittanti, L., Jenny, C., Poulard, K., Samba, A., Manceau, P., Soria, N., Vincent, N., Danos, O., & Vega, M. T. (2001) · The Journal of Gene Medicine · doi:10.1002/1521-2254(2000)9999:9999 · Cited by 56 · see citing works
Repetitive 5-aminolevulinic acid-mediated photodynamic therapy on human glioma spheroids
Madsen, S. J., Sun, C.-H., Tromberg, B. J., & Hirschberg, H. (2003) · Journal of Neuro-Oncology · doi:10.1023/a:1023362011705 · Cited by 56 · see citing works
Differentiation and Proliferation of Primary Rat Hepatocytes Cultured as Spheroids
Hamamoto, R., Yamada, K., Kamihira, M., & Iijima, S. (1998) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a022215 · Cited by 55 · see citing works
Minuth, W. W., Schumacher, K., Strehl, R., & Kloth, S. (2000) · Journal of Biomaterials Science Polymer Edition · doi:10.1163/156856200743832 · Cited by 52 · see citing works
O’Connor, K. C. (1999) · Pharmaceutical Research · doi:10.1023/a:1011906709680 · Cited by 52 · see citing works
Martin, C., Walker, J., Rothnie, A. J., & Callaghan, R. (2003) · British Journal of Cancer · doi:10.1038/sj.bjc.6601300 · Cited by 51 · see citing works
Tissue culture in microgravity.
Duray, P. H., Hatfill, S. J., & Pellis, N. R. (1998) · PubMed · Cited by 47 · see citing works
Effect of therapeutic macromolecules in spheroids.
Fracasso, G. (2000) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(00)00084-6 · Cited by 46 · see citing works
Autologous spheroid culture: a screening tool for human brain tumour invasion
DERIDDER, L. (2000) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(00)00081-0 · Cited by 45 · see citing works
Lehnert, L., Lerch, M. M., Hirai, Y., Kruse, M., Schmiegel, W., & Kalthoff, H. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.152.5.911 · Cited by 45 · see citing works
Determination of Diffusion Constants for Metabolites in Multicell Tumor Spheroids
Freyer, J. P., & Sutherland, R. M. (1983) · Advances in experimental medicine and biology · doi:10.1007/978-1-4684-7790-0_39 · Cited by 42 · see citing works
Boyd, M., Mairs, S. C., Stevenson, K. S., Livingstone, A., Clark, A. M., Ross, S. C., & Mairs, R. (2002) · The Journal of Gene Medicine · doi:10.1002/jgm.293 · Cited by 41 · see citing works
Bigelow, C. E., Mitra, S., Knuechel, R., & Foster, T. H. (2001) · British Journal of Cancer · doi:10.1054/bjoc.2001.1977 · Cited by 41 · see citing works
Jääskeläinen, J. E., Kalliomäki, P., Paetau, A. E., & Timonen, T. T. (1989) · The Journal of Immunology · doi:10.4049/jimmunol.142.3.1036 · Cited by 39 · see citing works
Clejan, S., O’Connor, K. C., & Rosensweig, N. (2001) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2001.tb00138.x · Cited by 39 · see citing works
Roberts, R. A. (1993) · Fundamental and Applied Toxicology · doi:10.1006/faat.1993.1084 · Cited by 39 · see citing works
ATP Chemosensitivity Testing in Ovarian and Breast Cancer: Early Clinical Trials
Kurbacher, C. M., Grecu, O., Stier, U., Gilster, T., Janát, M.-M., Untch, M., Konecny, G. E., Bruckner, H. W., & Cree, I. A. (2003) · Recent results in cancer research/Recent Results in Cancer Research · doi:10.1007/978-3-642-19022-3_17 · Cited by 36 · see citing works
Groebe, K., Erz, S., & Mueller‐Klieser, W. (1994) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-1875-4_114 · Cited by 36 · see citing works
Kwok, T., & Twentyman, P. R. (1985) · International Journal of Cancer · doi:10.1002/ijc.2910350517 · Cited by 36 · see citing works
Modulation of Cell Differentiation in Perfusion Culture
Minuth, W. W., Steiner, P., Strehl, R., Schumacher, K., de Vries, U., & Kloth, S. (1999) · Nephron Experimental Nephrology · doi:10.1159/000020637 · Cited by 35 · see citing works
Knedlitschek, G., Schneider, F., Gottwald, E., Schaller, T., Eschbach, E., & Weibezahn, K. F. (1999) · Journal of Biomechanical Engineering · doi:10.1115/1.2798040 · Cited by 35 · see citing works
McFadden, R., & Kwok, C. S. (1988) · PubMed · Cited by 35 · see citing works
Regrowth kinetics of cells from different regions of multicellular spheroids of four cell lines
Freyer, J. P., & Schor, P. L. (1989) · Journal of Cellular Physiology · doi:10.1002/jcp.1041380222 · Cited by 35 · see citing works
Tonn, J., Ott, M. M., Bouterfa, H., Kerkau, S., Kapp, M., Müller‐Hermelink, H. K., & Roosen, K. (1997) · Neurosurgery · doi:10.1097/00006123-199711000-00027 · Cited by 34 · see citing works
Spheroids: relation between tumour and endothelial cells
Oudar, O. (2000) · Critical Reviews in Oncology/Hematology · doi:10.1016/s1040-8428(00)00080-9 · Cited by 33 · see citing works
Flasks, fibres and flanks – pre-clinical tumour models for predicting clinical antitumour activity
Newell, D. R. (2001) · British Journal of Cancer · doi:10.1054/bjoc.2001.1797 · Cited by 33 · see citing works
Willbold, E., Reinicke, M., Lance-Jones, C. C., Lagenaur, C. F., Lemmon, V., & Layer, P. G. (1995) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.1995.tb00648.x · Cited by 33 · see citing works
Nakamura, K., Hanibuchi, M., Yano, S., Tanaka, Y., Fujino, I., Inoue, M., Takezawa, T., Shitara, K., Sone, S., & Hanai, N. (1999) · PubMed · Cited by 33 · see citing works
Essand, M., Grönvik, C., Hartman, T., & Carlsson, J. (1995) · International Journal of Cancer · doi:10.1002/ijc.2910630315 · Cited by 33 · see citing works
Dulong, J., Legallais, C., Darquy, S., & Reach, G. (2002) · Biotechnology and Bioengineering · doi:10.1002/bit.10230 · Cited by 31 · see citing works
Pervez, S., Kirkland, S. C., Epenetos, A. A., Mooi, W. J., Evans, D. J., & Krausz, T. N. (1989) · International Journal of Cancer · doi:10.1002/ijc.2910440532 · Cited by 30 · see citing works
Unravelling novel intracellular pathways in cell-based assays
Giese, K., Kaufmann, J., Pronk, G. J., & Klippel, A. (2002) · Drug Discovery Today · doi:10.1016/s1359-6446(01)02126-2 · Cited by 30 · see citing works
Hepatocyte Polarity and the Peroxisomal Compartment: A Comparative Study
Depreter, M., Walker, T. M., Smet, K. D., Beken, S., Kerckaert, I., Rogiers, V., & Roels, F. (2002) · The Histochemical Journal · doi:10.1023/a:1020990414190 · Cited by 28 · see citing works
Automated selective dissociation of cells from different regions of multicellular spheroids
Freyer, J. P., & Schor, P. L. (1989) · In Vitro Cellular & Developmental Biology - Plant · doi:10.1007/bf02624405 · Cited by 28 · see citing works
chting, W. D. U., Ginsberg, T., & Ulmer, W. (1995) · Stem Cells · doi:10.1002/stem.5530130737 · Cited by 27 · see citing works
Civiale, C., Paladino, G. M., Marino, C., Trombetta, F., Pulvirenti, T., & Enea, V. (2003) · Ophthalmic Research · doi:10.1159/000070047 · Cited by 27 · see citing works
Offner, F. A., Ensinger, C., Schiefer, J., Wirtz, H.-C., Bigalke, I., Hollweg, G., Klosterhalfen, B., Mittermayer, C., Pavelka, M., & Kirkpatrick, C. J. (1996) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/bf00193937 · Cited by 26 · see citing works
Diffusion and Binding of Monoclonal Antibody TNT-1 in Multicellular Tumor Spheroids
Chen, F.-M., Hansen, E. B., Taylor, C. R., & Epstein, A. L. (1991) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/83.3.200 · Cited by 26 · see citing works
Layer, P. G., Rothermel, A., & Willbold, E. (1998) · Seminars in Cell and Developmental Biology · doi:10.1006/scdb.1998.0234 · Cited by 25 · see citing works
Layer, P. G., Rothermel, A., Hering, H., Wolf, B., DeGrip, W. J., Hicks, D., & Willbold, E. (1997) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.1997.tb00746.x · Cited by 25 · see citing works
Thielecke, H., Mack, A., & Robitzki, A. A. (2001) · Fresenius Journal of Analytical Chemistry · doi:10.1007/s002160000606 · Cited by 24 · see citing works
Yoshida, D., Watanabe, K., Noha, M., Takahashi, H., Teramoto, A., & Sugisaki, Y. (2003) · Neurosurgery · doi:10.1097/00006123-200301000-00024 · Cited by 24 · see citing works
Assay and screening methods for bioactive substances based on cellular signaling pathways
Umezawa, Y. (2002) · Reviews in Molecular Biotechnology · doi:10.1016/s1389-0352(01)00051-4 · Cited by 24 · see citing works
Advanced technique for long term culture of epithelia in a continuous luminal–basal medium gradient
Schumacher, K., Strehl, R., de Vries, U., & Minuth, W. W. (2002) · Biomaterials · doi:10.1016/s0142-9612(01)00186-7 · Cited by 24 · see citing works
Yoshida, D., Watanabe, K., Noha, M., Takahashi, H., Teramoto, A., & Sugisaki, Y. (2002) · Brain Tumor Pathology · doi:10.1007/bf02478930 · Cited by 22 · see citing works
Identification of genes expressed in tumor-associated macrophages
Gottfried, E., Faust, S., Fritsche, J., Kunz‐Schughart, L. A., Andreesen, R., Miyake, K., & Kreutz, M. P. (2003) · Immunobiology · doi:10.1078/0171-2985-00246 · Cited by 22 · see citing works
Self-citationTumour fragment spheroids from human non-small-cell lung cancer maintained in organ culture
Fjellbirkeland, L., Laerum, O.-D., & Bjerkvig, R. (1995) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/bf00192639 · Cited by 22 · see citing works
Mitochondrial function in oncogene-transfected rat fibroblasts isolated from multicellular spheroids
Kunz‐Schughart, L. A., Habbersett, R. C., & Freyer, J. P. (1997) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1997.273.5.c1487 · Cited by 22 · see citing works
Self-citationViable sorting of intact multicellular spheroids by flow cytometry
Freyer, J. P., Wilder, M. E., & Jett, J. H. (1987) · Cytometry · doi:10.1002/cyto.990080413 · Cited by 21 · see citing works
Hyytinen, E., Frierson, H. F., Sipe, T. W., Li, C., Degeorges, A., Sikes, R. A., Chung, L. W. K., & Dong, J. (1999) · The Prostate · doi:10.1002/(sici)1097-0045(19991101)41:3 · Cited by 20 · see citing works
Hollow‐Spheres: A New Model for Analyses of Differentiation of Pancreatic Duct Epithelial Cells
Lehnert, L., TROST, H., Schmiegel, W., Röder, C., & Kalthoff, H. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb09512.x · Cited by 20 · see citing works
Thomsen, L. L., Baguley, B. C., & Wilson, W. R. (1992) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf00685103 · Cited by 19 · see citing works
Activated eosinophils infiltrate MCF-7 breast multicellular tumor spheroids.
Furbert-Harris, P. M., Laniyan, I., Harris, D., Dunston, G. M., Vaughn, T. R., Abdelnaby, A. A., Parish‐Gause, D., & Oredipe, O. A. (2003) · PubMed · Cited by 17 · see citing works
Time‐resolved confocal analysis of antibody penetration into living, solid tumor spheroids
Myrdal, S. E., & Foster, M. (1994) · Scanning · doi:10.1002/sca.4950160316 · Cited by 17 · see citing works
Global high-throughput screens for cellular function
Hauptschein, R. S., Eustace, B. K., & Jay, D. G. (2002) · Experimental Hematology · doi:10.1016/s0301-472x(02)00783-x · Cited by 17 · see citing works
Photodynamic therapy of transitional cell carcinoma multicellular tumor spheroids with hypericin
Kamuhabwa, A. A. R., Huygens, A., & de Witte, P. A. M. (2003) · International Journal of Oncology · doi:10.3892/ijo.23.5.1445 · Cited by 15 · see citing works
Stelck, S., Robitzki, A. A., Willbold, E., & Layer, P. G. (1999) · Glycobiology · doi:10.1093/glycob/9.11.1171 · Cited by 15 · see citing works
Ja, A. (1996) · PubMed · Cited by 15 · see citing works
Kunz‐Schughart, L. A., & Mueller-Kliesert, W. (2000) · doi:10.1093/oso/9780199637973.003.0005 · Cited by 15 · see citing works
Self-citationKosaka, T., Tsuboi, S., Fukaya, K., Pu, H., Ohno, T., Tsuji, T., Miyazaki, M., & Namba, M. (1996) · PubMed · doi:10.18926/amo/30490 · Cited by 14 · see citing works
Heimdal, J. H., Aarstad, H. J., Olsnes, C., & Olofsson, J. S. (2001) · Scandinavian Journal of Immunology · doi:10.1046/j.1365-3083.2001.00853.x · Cited by 14 · see citing works
Lichtenbeld, H., Muller, A. D., van Dam-Mieras, M. C. E., & Blijham, G. H. (1993) · Journal of Cell Science · doi:10.1242/jcs.106.2.657 · Cited by 14 · see citing works
Berglund, Å., Glimelius, B. L. G., Bergh, J. C. S., Brodin, O., Fjällskog, M.-L., Hagberg, H., von Heideman, A., Larsson, R. L., Tholander, B., de la Torre, M., et al. (2002) · Medical Oncology · doi:10.1385/mo:19:3:151 · Cited by 13 · see citing works
Response to BCNU of spheroids grown from mixtures of drug-sensitive and drug-resistant cells
Tofilon, P., Arundel, C. M., & Deen, D. F. (1987) · Cancer Chemotherapy and Pharmacology · doi:10.1007/bf00253960 · Cited by 12 · see citing works
Mechanisms for monocyte activation in co-culture with autologous tumor spheroids
Olsnes, C., Heimdal, J. H., Kross, K. W., Olofsson, J. S., & Aarstad, H. J. (2002) · Cellular Immunology · doi:10.1016/s0008-8749(02)00615-9 · Cited by 12 · see citing works
Mairs, R., Angerson, W. J., Babich, J. W., & Murray, T. J. (1991) · PubMed · Cited by 11 · see citing works
Frenzel, K. R., Saller, R., Kummermehr, J. C., & Schultz-Hector, S. (1995) · PubMed · Cited by 11 · see citing works
Kosaka, T., Fukaya, K., Tsuboi, S., Pu, H., Ohno, T., Tsuji, T., & Namba, M. (1996) · PubMed · doi:10.18926/amo/30502 · Cited by 10 · see citing works
Ginsberg, T., Ulmer, W., & Düchting, W. (1993) · PubMed · Cited by 10 · see citing works
Kloth, S., Kobuch, K., Domokos, J., Wanke, C., & Monzer, J. (2000) · Toxicology in Vitro · doi:10.1016/s0887-2333(00)00010-2 · Cited by 8 · see citing works
Mutations of the human MUT S homologue 6 gene in ampullary carcinoma and gastric cancer
Imai, Y., Inoue, T., & Ishikawa, T. (1998) · International Journal of Cancer · doi:10.1002/(sici)1097-0215(19981123)78:5 · Cited by 7 · see citing works
Cell death induced by a 131I-labeled monoclonal antibody in ovarian cancer multicell spheroids
Filippovich, I. V., Sorokina, N., Robillard, N., Faivre-Chauvet, A., Bardiès, M., & Chatal, J. (1996) · Nuclear Medicine and Biology · doi:10.1016/0969-8051(96)00059-5 · Cited by 6 · see citing works
FURTHER DEVELOPMENT OF MICROSTRUCTURED CULTURE SYSTEMS AND THEIR USE IN TISSUE ENGINEERING
Giselbrecht, S., Gottwald, E., Knedlitschek, G., Weibezahn, K. F., Welle, A., Guber, A. E., Herrmann, D., Muslija, A., & Schomburg, W. K. (2002) · Biomedizinische Technik/Biomedical Engineering · doi:10.1515/bmte.2002.47.s1a.373 · Cited by 6 · see citing works
Reconstruction of trabecular tissue from human trabecular cells as a multicellular spheroid.
Matsuo, T., & Matsuo, N. (1997) · PubMed · doi:10.18926/amo/30767 · Cited by 4 · see citing works
Yoshida, D., Watanabe, K., Noha, M., Takahashi, H., Teramoto, A., & Sugisaki, Y. (2003) · Neurosurgery · doi:10.1227/00006123-200301000-00024 · Cited by 4 · see citing works
Overview. Cancer drug discovery: pathway promise or covalent certainty for drug effect--quo vadis?
Ea, S. (2000) · PubMed · Cited by 3 · see citing works
[Comparative studies on collagen expression of chondrocytes in monolayer and spheroid culture].
Rixen, H., Dyckhoff, G., Kauhl, W., Kirkpatrick, C. J., & Mittermayer, C. (1990) · PubMed · Cited by 1 · see citing works
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The third dimension bridges the gap between cell culture and live tissue
Pampaloni, F., Reynaud, E. G., & Stelzer, E. H. K. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2236 · Cited by 2,817 · see citing works
Spheroid-based drug screen: Considerations and practical approach
Friedrich, J., Seidel, C., Ebner, R., & Kunz-Schughart, L. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.226 · Cited by 1,742 · see citing works
Self-citationModeling Tissue Morphogenesis and Cancer in 3D
Yamada, K. M., & Cukierman, E. (2007) · Cell · doi:10.1016/j.cell.2007.08.006 · Cited by 1,751 · see citing works
Multicellular tumor spheroids: An underestimated tool is catching up again
Hirschhaeuser, F., Menne, H., Dittfeld, C., West, J., Mueller-Klieser, W., & Kunz-Schughart, L. A. (2010) · Journal of Biotechnology · doi:10.1016/j.jbiotec.2010.01.012 · Cited by 1,674 · see citing works
Self-citationThree-dimensional cell culture: the missing link in drug discovery
Breslin, S., & O’Driscoll, L. (2013) · Drug Discovery Today · doi:10.1016/j.drudis.2012.10.003 · Cited by 1,332 · see citing works
Recent advances in three‐dimensional multicellular spheroid culture for biomedical research
Lin, R., & Chang, H. (2008) · Biotechnology Journal · doi:10.1002/biot.200700228 · Cited by 1,264 · see citing works
Organ printing: Tissue spheroids as building blocks
Mironov, V., Visconti, R. P., Kasyanov, V., Forgacs, G., Drake, C. J., & Markwald, R. R. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2008.12.084 · Cited by 1,238 · see citing works
Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy
Mehta, G., Hsiao, A. Y., Ingram, M., Luker, G. D., & Takayama, S. (2012) · Journal of Controlled Release · doi:10.1016/j.jconrel.2012.04.045 · Cited by 1,172 · see citing works
Vinci, M., Gowan, S., Boxall, F., Patterson, L., Zimmermann, M., Court, W., Lomas, C., Mendiola, M., Hardisson, D., & Eccles, S. A. (2012) · BMC Biology · doi:10.1186/1741-7007-10-29 · Cited by 1,024 · see citing works
High-throughput 3D spheroid culture and drug testing using a 384 hanging drop array
Tung, Y.-C., Hsiao, A. Y., Allen, S. G., Torisawa, Y.-S., Ho, M., & Takayama, S. (2011) · The Analyst · doi:10.1039/c0an00609b · Cited by 969 · see citing works
Three-dimensional culture systems in cancer research: Focus on tumor spheroid model
Nath, S., & Devi, G. R. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.03.013 · Cited by 919 · see citing works
Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform
Skardal, A., Murphy, S. V., Devarasetty, M., Mead, I., Kang, H.-W., Seol, Y.-J., Shrike Zhang, Y., Shin, S.-R., Zhao, L., Aleman, J., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-08879-x · Cited by 623 · see citing works
Rapid Generation of Single-Tumor Spheroids for High-Throughput Cell Function and Toxicity Analysis
Ivascu, A., & Kubbies, M. (2006) · SLAS DISCOVERY · doi:10.1177/1087057106292763 · Cited by 598 · see citing works
Cell line-based platforms to evaluate the therapeutic efficacy of candidate anticancer agents
Sharma, S. V., Haber, D. A., & Settleman, J. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2820 · Cited by 585 · see citing works
Nonlinear modelling of cancer: bridging the gap between cells and tumours
Lowengrub, J. S., Frieboes, H. B., Jin, F., Chuang, Y.-L., Li, X., Macklin, P., Wise, S. M., & Vittorio Cristini, C. (2009) · Nonlinearity · doi:10.1088/0951-7715/23/1/r01 · Cited by 549 · see citing works
Organoid-on-a-chip and body-on-a-chip systems for drug screening and disease modeling
Skardal, A., Shupe, T., & Atala, A. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2016.07.003 · Cited by 512 · see citing works
Strained Ruthenium Complexes Are Potent Light-Activated Anticancer Agents
Howerton, B. S., Heidary, D. K., & Glazer, E. C. (2012) · Journal of the American Chemical Society · doi:10.1021/ja3009677 · Cited by 499 · see citing works
Revisiting lab-on-a-chip technology for drug discovery
Neužil, P., Giselbrecht, S., Länge, K., Huang, T. J., & Manz, A. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3799 · Cited by 490 · see citing works
Organoid and Spheroid Tumor Models: Techniques and Applications
Gunti, S., Hoke, A. T. K., Vu, K., & London, N. R. (2021) · Cancers · doi:10.3390/cancers13040874 · Cited by 492 · see citing works
Matrigel: From discovery and ECM mimicry to assays and models for cancer research
Benton, G., Arnaoutova, I., George, J., Kleinman, H. K., & Koblinski, J. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.06.005 · Cited by 477 · see citing works
Frith, J. E., Thomson, B. M., & Genever, P. G. (2009) · Tissue Engineering Part C Methods · doi:10.1089/ten.tec.2009.0432 · Cited by 478 · see citing works
Experimental anti-tumor therapy in 3-D: Spheroids – old hat or new challenge?
Friedrich, J., Ebner, R., & Kunz‐Schughart, L. A. (2007) · International Journal of Radiation Biology · doi:10.1080/09553000701727531 · Cited by 445 · see citing works
Self-citationA novel 3D mammalian cell perfusion-culture system in microfluidic channels
Toh, Y.-C., Zhang, C., Zhang, J., Khong, Y. M., Chang, S., Samper, V. D., van Noort, D., Hutmacher, D. W., & Yu, H. (2007) · Lab on a Chip · doi:10.1039/b614872g · Cited by 414 · see citing works
Longati, P., Jia, X., Eimer, J., Wagman, A., Witt, M.-R., Rehnmark, S., Verbeke, C., Toftgård, R., Löhr, M., & Heuchel, R. L. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-95 · Cited by 394 · see citing works
High content screening: seeing is believing
Zanella, F., Lorens, J. B., & Link, W. (2010) · Trends in biotechnology · doi:10.1016/j.tibtech.2010.02.005 · Cited by 391 · see citing works
In vitro Toxicity Testing of Nanoparticles in 3D Cell Culture
Lee, J., Lilly, G. D., Doty, C., Podsiadlo, P., & Kotov, N. A. (2009) · Small · doi:10.1002/smll.200801788 · Cited by 375 · see citing works
Multiscale modelling and nonlinear simulation of vascular tumour growth
Macklin, P., McDougall, S. R., Anderson, A. R. A., Chaplain, M. A. J., Vittorio Cristini, C., & Lowengrub, J. S. (2008) · Journal of Mathematical Biology · doi:10.1007/s00285-008-0216-9 · Cited by 364 · see citing works
High-resolution three-dimensional imaging of large specimens with light sheet–based microscopy
Verveer, P. J., Swoger, J., Pampaloni, F., Greger, K., Marcello, M., & Stelzer, E. H. K. (2007) · Nature Methods · doi:10.1038/nmeth1017 · Cited by 362 · see citing works
In vitro three‐dimensional (3D) models in cancer research: An update
Kimlin, L., Casagrande, G. M. S., & Virador, V. M. (2011) · Molecular Carcinogenesis · doi:10.1002/mc.21844 · Cited by 340 · see citing works
3D cell culture opens new dimensions in cell-based assays
Justice, B. A., Badr, N. A., & Felder, R. A. (2008) · Drug Discovery Today · doi:10.1016/j.drudis.2008.11.006 · Cited by 340 · see citing works
Microfluidic system for formation of PC-3 prostate cancer co-culture spheroids
Hsiao, A. Y., Torisawa, Y.-S., Tung, Y.-C., Sud, S., Taichman, R. S., Pienta, K. J., & Takayama, S. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.02.047 · Cited by 323 · see citing works
Biomaterials offer cancer research the third dimension
Hutmacher, D. W. (2010) · Nature Materials · doi:10.1038/nmat2619 · Cited by 324 · see citing works
Engineering cancer microenvironments for in vitro 3-D tumor models
Asghar, W., El Assal, R., Shafiee, H., Pitteri, S., Paulmurugan, R., & Demirci, U. (2015) · Materials Today · doi:10.1016/j.mattod.2015.05.002 · Cited by 316 · see citing works
Barrila, J., Radtke, A. L., Crabbé, A., Sarker, S. F., Herbst-Kralovetz, M. M., Ott, C. M., & Nickerson, C. A. (2010) · Nature Reviews Microbiology · doi:10.1038/nrmicro2423 · Cited by 302 · see citing works
Drug compound screening in single and integrated multi-organoid body-on-a-chip systems
Skardal, A., Aleman, J., Forsythe, S. D., Rajan, S. A. P., Murphy, S. V., Devarasetty, M., Zarandi, N. P., Nzou, G., Wicks, R. T., Sadri‐Ardekani, H., et al. (2020) · Biofabrication · doi:10.1088/1758-5090/ab6d36 · Cited by 277 · see citing works
Modeling neoplastic disease with spheroids and organoids
Zanoni, M., Cortesi, M., Zamagni, A., Arienti, C., Pignatta, S., & Tesei, A. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00931-0 · Cited by 265 · see citing works
The multicellular tumor spheroid model for high-throughput cancer drug discovery
LaBarbera, D. V., Reid, B. G., & Yoo, B. H. (2012) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2012.708334 · Cited by 254 · see citing works
Modelling tissues in 3D: the next future of pharmaco-toxicology and food research?
Mazzoleni, G., Lorenzo, D. D., & Steimberg, N. (2008) · Genes & Nutrition · doi:10.1007/s12263-008-0107-0 · Cited by 252 · see citing works
Yu, L., Chen, M. C. W., & Cheung, K. C. (2010) · Lab on a Chip · doi:10.1039/c004590j · Cited by 247 · see citing works
Artificial Virus Delivers CRISPR-Cas9 System for Genome Editing of Cells in Mice
Li, L., Song, L., Liu, X., Yang, X., Li, X., He, T., Wang, N., Yang, S., Yu, C., Yin, T., et al. (2017) · ACS Nano · doi:10.1021/acsnano.6b04261 · Cited by 244 · see citing works
Gao, W., Xiang, B., Meng, T., Liu, F., & Qi, X. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.02.014 · Cited by 238 · see citing works
Can tissue engineering concepts advance tumor biology research?
Hutmacher, D. W., Loessner, D., Rizzi, S. C., Kaplan, D. L., Mooney, D. J., & Clements, J. A. (2010) · Trends in biotechnology · doi:10.1016/j.tibtech.2009.12.001 · Cited by 237 · see citing works
Ivanov, D. P., Parker, T. L., Walker, D. A., Alexander, C., Ashford, M. B., Gellert, P. R., & Garnett, M. C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0103817 · Cited by 235 · see citing works
Multicellular Tumor Spheroids (MCTS) as a 3D In Vitro Evaluation Tool of Nanoparticles
Lu, H., & Stenzel, M. H. (2018) · Small · doi:10.1002/smll.201702858 · Cited by 229 · see citing works
A reliable tool to determine cell viability in complex 3-d culture: the acid phosphatase assay
Friedrich, J., Eder, W., Castaneda, J., Doss, M., Huber, E., Ebner, R., & Kunz-Schughart, L. A. (2007) · SLAS DISCOVERY · doi:10.1177/1087057107306839 · Cited by 227 · see citing works
Skardal, A., Devarasetty, M., Forsythe, S., Atala, A., & Soker, S. (2016) · Biotechnology and Bioengineering · doi:10.1002/bit.25950 · Cited by 230 · see citing works
Diversity of cell-mediated adhesions in breast cancer spheroids
Ivascu, A., & Kubbies, M. (2007) · International Journal of Oncology · doi:10.3892/ijo.31.6.1403 · Cited by 229 · see citing works
Life in 3D is never flat: 3D models to optimise drug delivery
Fitzgerald, K. A., Malhotra, M., Curtin, C. M., O’Brien, F. J., & O’Driscoll, C. M. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.07.020 · Cited by 226 · see citing works
Costa, E. C., de Melo‐Diogo, D., Moreira, A. F., Carvalho, M. P., & Correia, I. J. (2018) · Biotechnology Journal · doi:10.1002/biot.201700417 · Cited by 224 · see citing works
Regulation of Tumor Progression by Programmed Necrosis
Lee, S. Y., Ju, M. K., Jeon, H. M., Jeong, E. K., Lee, Y. J., Kim, C. H., Park, H. G., Han, S. I., & Kang, H. S. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/3537471 · Cited by 225 · see citing works
Patra, B., Peng, C.-C., Liao, W.-H., Lee, C.-H., & Tung, Y.-C. (2016) · Scientific Reports · doi:10.1038/srep21061 · Cited by 215 · see citing works
Molecular description of a 3D in vitro model for the study of epithelial ovarian cancer (EOC)
Zietarska, M., Maugard, C. M., Filali‐Mouhim, A., Alam‐Fahmy, M., Tonin, P. N., Provencher, D. M., & Mes‐Masson, A. (2007) · Molecular Carcinogenesis · doi:10.1002/mc.20315 · Cited by 209 · see citing works
Multizone Paper Platform for 3D Cell Cultures
Derda, R., Tang, S. K. Y., Laromaine, A., Mosadegh, B., Hong, E., Mwangi, M., Mammoto, A., Ingber, D. E., & Whitesides, G. M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018940 · Cited by 213 · see citing works
3D tumor models: History, advances and future perspectives
Benien, P., & Swami, A. (2014) · Future Oncology · doi:10.2217/fon.13.274 · Cited by 208 · see citing works
High-Content Assays for Characterizing the Viability and Morphology of 3D Cancer Spheroid Cultures
Sirenko, O., Mitlo, T., Hesley, J., Luke, S., Owens, W., & Cromwell, E. F. (2015) · Assay and Drug Development Technologies · doi:10.1089/adt.2015.655 · Cited by 208 · see citing works
Drug discovery through stem cell-based organoid models
Ranga, A., Gjorevski, N., & Lutolf, M. P. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.02.006 · Cited by 195 · see citing works
Microfluidic 3D models of cancer
Sung, K. E., & Beebe, D. J. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.07.002 · Cited by 190 · see citing works
Generation of Multicellular Breast Cancer Tumor Spheroids: Comparison of Different Protocols
Fröhlich, K., Häeger, J.-D., Héger, J., Pastuschek, J., Photini, S. M., Yan, Y., Lupp, A., Pfarrer, C. D., Mrowka, R., Schleußner, E., et al. (2016) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1007/s10911-016-9359-2 · Cited by 189 · see citing works
Automated 3D bioassembly of micro-tissues for biofabrication of hybrid tissue engineered constructs
Mekhileri, N. V., Lim, K. S., Lindberg, G. C. J., Mutreja, I., Schon, B. S., Hooper, G. J., & Woodfield, T. B. F. (2017) · Biofabrication · doi:10.1088/1758-5090/aa9ef1 · Cited by 189 · see citing works
Three-dimensional tissue cultures: current trends and beyond
Page, H., Flood, P. F., & Reynaud, E. G. (2012) · Cell and Tissue Research · doi:10.1007/s00441-012-1441-5 · Cited by 186 · see citing works
Moreno‐Sánchez, R., Marín‐Hernández, Á., Saavedra, E., Pardo, J. P., Ralph, S. J., & Rodríguez‐Enríquez, S. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.01.025 · Cited by 185 · see citing works
Kunz‐Schughart, L. A., Schroeder, J. A., Wondrak, M., van Rey, F., Lehle, K., Hofstaedter, F., & Wheatley, D. N. (2006) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00248.2005 · Cited by 184 · see citing works
Self-citationComparative analysis of tumor spheroid generation techniques for differentialin vitrodrug toxicity
Raghavan, S. A., Mehta, P., Horst, E. N., Ward, M. R., Rowley, K. R., & Mehta, G. (2016) · Oncotarget · doi:10.18632/oncotarget.7659 · Cited by 184 · see citing works
Karlsson, H., Fryknäs, M., Larsson, R., & Nygren, P. (2012) · Experimental Cell Research · doi:10.1016/j.yexcr.2012.03.026 · Cited by 180 · see citing works
A multicellular spheroid array to realize spheroid formation, culture, and viability assay on a chip
Torisawa, Y.-S., Takagi, A., Nashimoto, Y., Yasukawa, T., Shiku, H., & Matsue, T. (2007) · Biomaterials · doi:10.1016/j.biomaterials.2006.08.054 · Cited by 176 · see citing works
Pampaloni, F., Ansari, N., & Stelzer, E. H. K. (2013) · Cell and Tissue Research · doi:10.1007/s00441-013-1589-7 · Cited by 177 · see citing works
Booij, T. H., Price, L., & Danen, E. H. J. (2019) · SLAS DISCOVERY · doi:10.1177/2472555219830087 · Cited by 176 · see citing works
Basuki, J. S., Duong, H. T. T., Macmillan, A., Erlich, R. B., Esser, L., Åkerfeldt, M. C., Whan, R. M., Kavallaris, M., Boyer, C. A., & Davis, T. P. (2013) · ACS Nano · doi:10.1021/nn404407g · Cited by 172 · see citing works
Coaxial 3D bioprinting of self-assembled multicellular heterogeneous tumor fibers
Dai, X., Liu, L., Ouyang, J., Li, X., Zhang, X., Lan, Q., & Xu, T. (2017) · Scientific Reports · doi:10.1038/s41598-017-01581-y · Cited by 175 · see citing works
A gel-free 3D microfluidic cell culture system
Ong, S.-M., Zhang, C., Toh, Y.-C., Kim, S. H., Foo, H. L., Tan, C. H., van Noort, D., Park, S., & Yu, H. (2008) · Biomaterials · doi:10.1016/j.biomaterials.2008.04.022 · Cited by 172 · see citing works
Ho, W. Y., Yeap, S. K., Ho, C. L., Rahim, R. A., & Alitheen, N. B. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044640 · Cited by 173 · see citing works
Ware, M. J., Colbert, K. L., Keshishian, V., Ho, J., Corr, S. J., Curley, S. A., & Godin, B. (2016) · Tissue Engineering Part C Methods · doi:10.1089/ten.tec.2015.0280 · Cited by 171 · see citing works
Engineered 3D vascular and neuronal networks in a microfluidic platform
Osaki, T., Sivathanu, V., & Kamm, R. D. (2018) · Scientific Reports · doi:10.1038/s41598-018-23512-1 · Cited by 168 · see citing works
Liu, T., Lin, B., & Qin, J. (2010) · Lab on a Chip · doi:10.1039/c000022a · Cited by 163 · see citing works
Maloney, E., Clark, C., Sivakumar, H., Yoo, K. M., Aleman, J., Rajan, S. A. P., Forsythe, S. D., Mazzocchi, A. R., Laxton, A. W., Tatter, S. B., et al. (2020) · Micromachines · doi:10.3390/mi11020208 · Cited by 163 · see citing works
Sung, S., Hsieh, C., Law, A., Zhau, H. E., Pathak, S., Multani, A. S., Lim, S., Coleman, I. M., Wu, L.-C., Figg, W. D., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-2492 · Cited by 161 · see citing works
Aleman, J., & Skardal, A. (2019) · Biotechnology and Bioengineering · doi:10.1002/bit.26871 · Cited by 160 · see citing works
Nonadhesive Culture System as a Model of Rapid Sphere Formation with Cancer Stem Cell Properties
Chen, S.-F., Chang, Y., Nieh, S., Liu, C., Yang, C., & Lin, Y. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031864 · Cited by 158 · see citing works
Design of Custom-Shaped Vascularized Tissues Using Microtissue Spheroids as Minimal Building Units
Kelm, J. M., Djonov, V., Ittner, L. M., Fluri, D. A., Born, W., Hoerstrup, S. P., & Fussenegger, M. (2006) · Tissue Engineering · doi:10.1089/ten.2006.12.2151 · Cited by 157 · see citing works
Mazzocchi, A. R., Rajan, S. A. P., Votanopoulos, K. I., Hall, A. R., & Skardal, A. (2018) · Scientific Reports · doi:10.1038/s41598-018-21200-8 · Cited by 151 · see citing works
Watson, J. L., Greenshields, A. L., Hill, R., Hilchie, A. L., Lee, P. W. K., Giacomantonio, C. A., & Hoskin, D. W. (2009) · Molecular Carcinogenesis · doi:10.1002/mc.20571 · Cited by 147 · see citing works
Engineering liver tissue spheroids with inverted colloidal crystal scaffolds
Lee, J., Cuddihy, M. J., Cater, G. M., & Kotov, N. A. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.05.024 · Cited by 145 · see citing works
Gordon, S. (2015) · ALTEX · doi:10.14573/altex.1510051 · Cited by 142 · see citing works
Generation of an in vitro 3D PDAC stroma rich spheroid model
Ware, M. J., Keshishian, V., Law, J. J., Ho, J. C., Favela, C. A., Rees, P. C. T., Smith, B., Sayeeduddin, M., Hwang, R. F., Rajapakshe, K., et al. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2016.08.041 · Cited by 146 · see citing works
New dimensions in tumor immunology: what does 3D culture reveal?
Feder-Mengus, C., Ghosh, S., Reschner, A., Martin, I., & Spagnoli, G. C. (2008) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2008.06.001 · Cited by 139 · see citing works
Senkowski, W., Zhang, X., Olofsson, M. H., Isacson, R., Höglund, U., Gustafsson, M. G., Nygren, P., Linder, S. T., Larsson, R. L., & Fryknäs, M. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0792 · Cited by 142 · see citing works
Dufau, I., Frongia, C., Sicard, F., Dedieu, L., Cordelier, P., Ausseil, F., Ducommun, B., & Valette, A. (2012) · BMC Cancer · doi:10.1186/1471-2407-12-15 · Cited by 141 · see citing works
Hsiao, A. Y., Tung, Y., Qu, X., Patel, L. R., Pienta, K. J., & Takayama, S. (2011) · Biotechnology and Bioengineering · doi:10.1002/bit.24399 · Cited by 137 · see citing works
Raghavan, S. A., Ward, M. R., Rowley, K. R., Wold, R. M., Takayama, S., Buckanovich, R. J., & Mehta, G. (2015) · Gynecologic Oncology · doi:10.1016/j.ygyno.2015.04.014 · Cited by 136 · see citing works
Integration column: microwell arrays for mammalian cell culture
Charnley, M., Textor, M., Khademhosseini, A., & Lütolf, M. P. (2009) · Integrative Biology · doi:10.1039/b918172p · Cited by 136 · see citing works
Energy metabolism transition in multi‐cellular human tumor spheroids
Rodríguez‐Enríquez, S., Gallardo‐Pérez, J. C., Avilés‐Salas, A., Marín‐Hernández, Á., Carreño‐Fuentes, L., Lagunas, V. M., & Moreno‐Sánchez, R. (2008) · Journal of Cellular Physiology · doi:10.1002/jcp.21392 · Cited by 136 · see citing works
Translating tissue engineering technology platforms into cancer research
Hutmacher, D. W., Horch, R. E., Loessner, D., Rizzi, S. C., Sieh, S., Reichert, J. C., Clements, J. A., Beier, J. P., Arkudas, A., Bleiziffer, O., et al. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00853.x · Cited by 136 · see citing works
Engineering a scaffold-free 3D tumor model for in vitro drug penetration studies
Ong, S., Zhao, Z., Arooz, T., Zhao, D., Zhang, S., Du, T., Wasser, M., van Noort, D., & Yu, H. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.10.049 · Cited by 135 · see citing works
Multi-Organs-on-Chips: Towards Long-Term Biomedical Investigations
Zhao, Y., Kankala, R. K., Wang, S., & Chen, A. (2019) · Molecules · doi:10.3390/molecules24040675 · Cited by 136 · see citing works
Multicellular tumor spheroid models to explore cell cycle checkpoints in 3D
Laurent, J., Frongia, C., Cazalès, M., Mondésert, O., Ducommun, B., & Lobjois, V. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-73 · Cited by 131 · see citing works
Hsiao, A. Y., Tung, Y.-C., Kuo, C.-H., Mosadegh, B., Bedenis, R., Pienta, K. J., & Takayama, S. (2012) · Biomedical Microdevices · doi:10.1007/s10544-011-9608-5 · Cited by 129 · see citing works
Dutta, D., Pulsipher, A., Luo, W. F., & Yousaf, M. N. (2011) · Journal of the American Chemical Society · doi:10.1021/ja2022569 · Cited by 130 · see citing works
3D tumour spheroids for the prediction of the effects of radiation and hyperthermia treatments
Brüningk, S. C., Rivens, I., Box, C., Oelfke, U., & ter Haar, G. (2020) · Scientific Reports · doi:10.1038/s41598-020-58569-4 · Cited by 125 · see citing works
Krause, S., Maffini, M. V., Soto, A. M., & Sonnenschein, C. (2010) · BMC Cancer · doi:10.1186/1471-2407-10-263 · Cited by 124 · see citing works
Chia, S. L., Tay, C. Y., Setyawati, M. I., & Leong, D. T. (2014) · Small · doi:10.1002/smll.201401915 · Cited by 121 · see citing works
- Authors
- Kunz-Schughart, L. A., Freyer, J. P., Hofstaedter, F., & Ebner, R.
- Affiliations
- Los Alamos National Laboratory (US)
- University of Regensburg (DE)
- Avalon Pharma (United States) (US)
- Venue
- SLAS DISCOVERY
- Publisher
- Elsevier BV
- Published
- 2004-06
- Volume
- 9
- Issue
- 4
- Pages
- 273-285
- ISSN
- 2472-5552 (ISSN-L)
- OpenAlex
- W2140723257
- Cited by
- 797
- References
- 163
- Citations by year
- 2026: 21 · 2025: 26 · 2024: 24 · 2023: 29 · 2022: 38 · 2021: 38 · 2020: 45 · 2019: 39 · 2018: 51 · 2017: 61 · 2016: 63 · 2015: 50 · 2014: 46 · 2013: 58 · 2012: 29
- FWCI
- 11.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- SLAS DISCOVERY (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
- Keywords
- tumor spheroids, 3D cell culture, high-throughput screening, anticancer drug screening, drug development, solid tumors, cell-based assays
- MeSH terms
- Animals, Antineoplastic Agents, Drug Evaluation, Preclinical, Drug Screening Assays, Antitumor, Humans, Models, Biological, Tumor Cells, Cultured, Spheroids, Cellular, In Vitro Techniques
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