Roles of Spheroid Formation of Hepatocytes in Liver Tissue Engineering
Open accessAbstract
The liver plays an important role in a broad spectrum of physiological functions and detoxifies endogenous and exogenous substances. The liver failure is associated with a high risk of mortality because it is one of important organs in our body. Various bioartificial liver (BAL) systems have been used for clinical trials as a bridge for liver transplantations in patients with liver failure. Long term and stable liver-specific functions of hepatocytes in the development of BAL support systems should be considered. Spheroid formation of hepatocytes enhances liver-specific functions. In this review, hepatocyte spheroid formation methods such as galactose density, topology of extracellular matrix, micro-molding technique, hanging-drop culture, non-adhesive surface, positive charged surface, spinner culture, rocked technique, medium component, external forces, coculture system and polymeric nanospheres are explained for enhancing liver-specific functions.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Spheroid cell culture has been developed for research on cancer, stem cells, and many organs, including liver, kidney, and heart.
“This approach has been developed in the research of cancer (7, 76, 102), stem cells (17, 120), and many organs (such as liver, kidney, heart, etc.) (3,16,64,75).”
From Modeling physiological events in 2D vs. 3D cell culture (2017) · cites this paper as [64]
Cites
A completely biological tissue-engineered human blood vessel
L’Heureux, N., Pâquet, S., Labbé, R., Germain, L., & Auger, F. A. (1998) · The FASEB Journal · doi:10.1096/fasebj.12.1.47 · Cited by 1,388 · see citing works
Francois Berthiaume, B., Moghe, P. V., Toner, M., & Yarmush, M. L. (1996) · The FASEB Journal · doi:10.1096/fasebj.10.13.8940293 · Cited by 397 · see citing works
Dynamic analysis of hepatoma spheroid formation: roles of E-cadherin and β1-integrin
Lin, R.-Z., Chou, L.-F., Chien, C.-C. M., & Chang, H.-Y. (2006) · Cell and Tissue Research · doi:10.1007/s00441-005-0148-2 · Cited by 305 · see citing works
Stable immobilization of rat hepatocyte spheroids on galactosylated nanofiber scaffold
Chua, K. N., Lim, W. S., Zhang, P., Lu, H., Wen, J., Ramakrishna, S., Leong, K. W., & Mao, H. (2004) · Biomaterials · doi:10.1016/j.biomaterials.2004.07.040 · Cited by 258 · see citing works
Feng, Z.-Q., Chu, X., Huang, N.-P., Wang, T., Wang, Y., Shi, X., Ding, Y., & Gu, Z.-Z. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.01.053 · Cited by 216 · see citing works
Dean, D. M., Napolitano, A. P., Youssef, J., & Morgan, J. R. (2007) · The FASEB Journal · doi:10.1096/fj.07-8710com · Cited by 167 · see citing works
Fukuda, J., Sakai, Y., & Nakazawa, K. (2005) · Biomaterials · doi:10.1016/j.biomaterials.2005.07.031 · Cited by 163 · see citing works
Galactosylated alginate as a scaffold for hepatocytes entrapment
Yang, J., Goto, M., Ise, H., Cho, C.-S., & Akaike, T. (2002) · Biomaterials · doi:10.1016/s0142-9612(01)00129-6 · Cited by 153 · see citing works
Self-citationCell patterning using magnetite nanoparticles and magnetic force
Ino, K., Itô, A., & Honda, H. (2007) · Biotechnology and Bioengineering · doi:10.1002/bit.21322 · Cited by 152 · see citing works
Brophy, C. M., Luebke-Wheeler, J. L., Amiot, B. P., Khan, H., Remmel, R. P., Rinaldo, P., & Nyberg, S. L. (2008) · Hepatology · doi:10.1002/hep.22674 · Cited by 145 · see citing works
Nyberg, S. L., Hardin, J. A., Amiot, B. P., Argikar, U. A., Remmel, R. P., & Rinaldo, P. (2005) · Liver Transplantation · doi:10.1002/lt.20446 · Cited by 142 · see citing works
Toward development of an implantable tissue engineered liver
Davis, M. W., & Vacanti, J. P. (1996) · Biomaterials · doi:10.1016/0142-9612(96)85575-x · Cited by 128 · see citing works
Seo, S.-J., Kim, I.-Y., Choi, Y., Akaike, T., & Cho, C. (2005) · Biomaterials · doi:10.1016/j.biomaterials.2005.09.018 · Cited by 126 · see citing works
Self-citationMicrofluidic hydrodynamic cellular patterning for systematic formation of co-culture spheroids
Torisawa, Y., Mosadegh, B., Luker, G. D., Morell, M. H., O’Shea, K., & Takayama, S. (2009) · Integrative Biology · doi:10.1039/b915965g · Cited by 114 · see citing works
The role of actin filaments and microtubules in hepatocyte spheroid self-assembly
Tzanakakis, E. S., Hansen, L. K., & Hu, W. (2001) · Cell Motility and the Cytoskeleton · doi:10.1002/1097-0169(200103)48:3 · Cited by 112 · see citing works
Takezawa, T., Yamazaki, M., Mori, Y., Yonaha, T., & Yoshizato, K. (1992) · Journal of Cell Science · doi:10.1242/jcs.101.3.495 · Cited by 110 · see citing works
Tobe, S., Takei, Y., Kobayashi, K., & Akaike, T. (1992) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(92)91182-p · Cited by 84 · see citing works
Jian, L., Kuznetsova, L. A., Edwards, G. O., Xu, J., Ma, M., Purcell, W. M., Jackson, S. K., & Coakley, W. T. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21345 · Cited by 83 · see citing works
Sebastian, A., Buckle, A., & Markx, G. H. (2007) · Biotechnology and Bioengineering · doi:10.1002/bit.21416 · Cited by 82 · see citing works
Enhanced Cytochrome P450 IA1 Activity of Self-Assembled Rat Hepatocyte Spheroids
Wu, F. J., Friend, J. R., Remmel, R. P., Cerra, F. B., & Hu, W. (1999) · Cell Transplantation · doi:10.1177/096368979900800304 · Cited by 82 · see citing works
Kikuchi, K., Sumaru, K., Edahiro, J., Ooshima, Y., Sugiura, S., Takagi, T., & Kanamori, T. (2009) · Biotechnology and Bioengineering · doi:10.1002/bit.22253 · Cited by 73 · see citing works
Adhesion contact dynamics of HepG2 cells on galactose-immobilized substrates
Yin, C. (2002) · Biomaterials · doi:10.1016/s0142-9612(02)00416-7 · Cited by 59 · see citing works
Kobayashi, A., Kobayashi, K., & Akaike, T. (1992) · Journal of Biomaterials Science Polymer Edition · doi:10.1163/156856292x00466 · Cited by 59 · see citing works
Hepatocyte spheroid culture on a polydimethylsiloxane chip having microcavities
Nakazawa, K., Izumi, Y., Fukuda, J., & Yasuda, T. (2006) · Journal of Biomaterials Science Polymer Edition · doi:10.1163/156856206777996853 · Cited by 52 · see citing works
Technology Insight: liver support systems
Millis, J. M., & Losanoff, J. E. (2005) · Nature Clinical Practice Gastroenterology & Hepatology · doi:10.1038/ncpgasthep0254 · Cited by 43 · see citing works
Yoshimoto, K., Ichino, M., & Nagasaki, Y. (2009) · Lab on a Chip · doi:10.1039/b818610n · Cited by 41 · see citing works
Huang, H., Hanada, S., Kojima, N., & Sakai, Y. (2006) · Cell Transplantation · doi:10.3727/000000006783981486 · Cited by 39 · see citing works
Verma, P., Verma, V., Ray, P., & Ray, A. R. (2007) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/s11626-007-9045-1 · Cited by 38 · see citing works
Nelson, L. J., Walker, S. W., Hayes, P. C., & Plevris, J. N. (2010) · Cells Tissues Organs · doi:10.1159/000308893 · Cited by 37 · see citing works
Kojima, R., Yoshimoto, K., Takahashi, E., Ichino, M., Miyoshi, H., & Nagasaki, Y. (2009) · Lab on a Chip · doi:10.1039/b903388b · Cited by 36 · see citing works
Progress in bioreactors of bioartificial livers.
Yu, C., Pan, X., & Li, L. (2009) · PubMed · Cited by 35 · see citing works
Spheroid Formation of Hepatocytes Using Synthetic Polymer
Kamihira, M., Yamada, K., Hamamoto, R., & Iijima, S. (1997) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1997.tb52213.x · Cited by 35 · see citing works
Takahashi, R., Sonoda, H., Tabata, Y., & Hisada, A. (2010) · Tissue Engineering Part A · doi:10.1089/ten.tea.2009.0662 · Cited by 30 · see citing works
Bazou, D. (2009) · Cell Biology and Toxicology · doi:10.1007/s10565-009-9123-0 · Cited by 25 · see citing works
ENDOTHELIUM‐SMOOTH MUSCLE INTERACTIONS IN BLOOD VESSELS
van Breemen, C., Skarsgard, P. L., Laher, I., McManus, B. M., & Wang, X. (1997) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.1997.tb02737.x · Cited by 25 · see citing works
Formation of rat hepatocyte spheroids on agarose
HASEBE, Y., Okumura, N., KOH, T., KAZAMA, H., Watanabe, G., SEKI, T., & ARIGA, T. (2005) · Hepatology Research · doi:10.1016/j.hepres.2005.03.012 · Cited by 25 · see citing works
Lee, K.-W., Lee, S. K., Joh, J., Kim, S. J., Lee, B.-B., Kim, K.-W., & Lee, K. U. (2004) · Tissue Engineering · doi:10.1089/ten.2004.10.965 · Cited by 19 · see citing works
Dexamethasone Effects on Rat Hepatocyte Spheroid Formation and Function
Abu-Absi, S. F., Hu, W., & Hansen, L. K. (2005) · Tissue Engineering · doi:10.1089/ten.2005.11.415 · Cited by 17 · see citing works
Preconditioned Cell Array Optimized for a Three-Dimensional Culture of Hepatocytes
Miyamoto, Y., Ikeya, T., & Enosawa, S. (2009) · Cell Transplantation · doi:10.1177/096368970901805-624 · Cited by 15 · see citing works
Gwak, S., Choi, D., Paik, S. S., Cho, S., Kim, S. S., Choi, C. Y., & Kim, B. (2006) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.30687 · Cited by 12 · see citing works
Direct Self-assembly of Hepatocytes Spheroids within Hollow Fibers in Presence of Collagen
Meng, Q., Wu, D., Zhang, G., & Qiu, H. (2006) · Biotechnology Letters · doi:10.1007/s10529-005-5531-2 · Cited by 10 · see citing works
Liver Stem Cells Derived from the Bone Marrow and Umbilical Cord Blood
Ryu, K. (2009) · International Journal of Stem Cells · doi:10.15283/ijsc.2009.2.2.97 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Modeling physiological events in 2D vs. 3D cell culture
Duval, K., Grover, H., Han, L.-H., Mou, Y., Pegoraro, A. F., Fredberg, J., & Chen, Z. (2017) · Physiology · doi:10.1152/physiol.00036.2016 · Cited by 1,849 · see citing works
Engineering 3D Hydrogels for Personalized In Vitro Human Tissue Models
Liaw, C., Ji, S., & Güvendiren, M. (2018) · Advanced Healthcare Materials · doi:10.1002/adhm.201701165 · Cited by 170 · see citing works
Constrained spheroids for prolonged hepatocyte culture
Tong, W. H., Fang, Y., Yan, J., Hong, X., Singh, N. H., Wang, S. R., Nugraha, B., Xia, L., Fong, E. L. S., Iliescu, C., et al. (2015) · Biomaterials · doi:10.1016/j.biomaterials.2015.11.036 · Cited by 36 · see citing works
Janani, G., & Mandal, B. B. (2021) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.1c00719 · Cited by 31 · see citing works
3D Hepatic Organoid-Based Advancements in LIVER Tissue Engineering
Panwar, A., Das, P., & Tan, L. P. (2021) · Bioengineering · doi:10.3390/bioengineering8110185 · Cited by 31 · see citing works
A Model of Hepatic Steatosis with Declined Viability and Function in a Liver-Organ-on-a-Chip
Wiriyakulsit, N., Keawsomnuk, P., Thongin, S., Ketsawatsomkron, P., & Muta, K. (2023) · Scientific Reports · doi:10.1038/s41598-023-44198-0 · Cited by 29 · see citing works
Calitz, C., Hamman, J. H., Fey, S. J., Wrzesinski, K., & Gouws, C. (2018) · Toxicology Mechanisms and Methods · doi:10.1080/15376516.2017.1422580 · Cited by 28 · see citing works
Toivonen, S., Malinen, M. M., Küblbeck, J., Petsalo, A., Urtti, A. O., Honkakoski, P., & Otonkoski, T. (2016) · Tissue Engineering Part A · doi:10.1089/ten.tea.2016.0127 · Cited by 24 · see citing works
From Single Cells to Engineered and Explanted Tissues
Bergmann, S., & Steinert, M. (2015) · International review of cytology · doi:10.1016/bs.ircmb.2015.06.003 · Cited by 17 · see citing works
Zebularine upregulates expression of CYP genes through inhibition of DNMT1 and PKR in HepG2 cells
Nakamura, K., Aizawa, K., Aung, K. H., Yamauchi, J., & Tanoue, A. (2017) · Scientific Reports · doi:10.1038/srep41093 · Cited by 16 · see citing works
Cleavable cellulosic sponge for functional hepatic cell culture and retrieval
Sun, M., Wong, J. Y., Nugraha, B., Ananthanarayanan, A., Liu, Z., Lee, F., Gupta, K., Fong, E. L. S., Huang, X., & Yu, H. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.01.046 · Cited by 15 · see citing works
Khademi, F., Ai, J., Soleimani, M., Verdi, J., Tavangar, S. M., Sadroddiny, E., Massumi, M., & Hashemi, S. M. (2016) · Journal of Biomedical Materials Research Part B Applied Biomaterials · doi:10.1002/jbm.b.33758 · Cited by 14 · see citing works
Stampella, A., Rizzitelli, G., Donati, F., Mazzarino, M., de la Torre, X., Botrè, F., Giardi, M. F., Dentini, M., Barbetta, A., & Massimi, M. (2015) · Toxicology in Vitro · doi:10.1016/j.tiv.2015.10.002 · Cited by 10 · see citing works
Chou, X., Cheng, K., Yin, W., Cheng, T., Chen, R. L. C., Hsu, S., & Hou, Y. (2024) · Macromolecular Bioscience · doi:10.1002/mabi.202300411 · Cited by 9 · see citing works
In Vitro Toxicology: Next Generation Models and Methods to Improve Safety Evaluation
Fortin, M. C., & Szilagyi, J. T. (2024) · Springer eBooks · doi:10.1007/978-3-031-35529-5_120 · Cited by 6 · see citing works
Ha, D.-H., Thi, P. M., Chaudhary, P., & Jeong, J. (2019) · Macromolecular Research · doi:10.1007/s13233-019-7103-7 · Cited by 4 · see citing works
Engineering Protective Polymer Coatings for Liver Microtissues
Chen, X., Jiang, W., Ahmed, A., Mahon, C. S., Müllner, M., Cao, B., & Xia, T. (2018) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.8b00120 · Cited by 3 · see citing works
Biomaterials and Microfluidics for Liver Models
Morais, A. D. S., Oliveira, J. M., & Reis, R. L. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-36588-2_5 · Cited by 3 · see citing works
Functional Liver Cell–Based Platforms in Biomedical Research
Hashemian, Z., Taleahmad, S., Shokouhian, B., Najimi, M., & Vosough, M. (2025) · Pharmacology Research & Perspectives · doi:10.1002/prp2.70128 · Cited by 2 · see citing works
Dash, A., & Proctor, W. R. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-813671-3.00006-2 · Cited by 2 · see citing works
In vitro toxicology: Next generation models and methods to improve safety evaluation
Fortin, M. C., & Szilagyi, J. T. (2023) · Springer eBooks · doi:10.1007/978-3-030-73317-9_120-1 · Cited by 1 · see citing works
Megaly, M. G., Tobolt, D. K., Chen, A. W., Namsrai, B., Fisher, B., Rao, J. S., Ramesh, S., Chimedtseren, A., Nyberg, S. L., Clemens, D. M., et al. (2026) · Bioengineering & Translational Medicine · doi:10.1002/btm2.70154
- Authors
- Jiang, H.-L., Kim, Y.-K., Cho, K.-H., Jang, Y.-C., Choi, Y.-J., Chung, J.-H., & Cho, C.-S.
- Affiliations
- Seoul National University (KR)
- Hallym University (KR)
- Venue
- International Journal of Stem Cells
- Published
- 2010-05-31
- Volume
- 3
- Issue
- 2
- Pages
- 69-73
- ISSN
- 2005-3606 (ISSN-L)
- 2005-5447
- PMC
- PMC4021799
- OpenAlex
- W1970117644
- Cited by
- 22
- References
- 42
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2021: 2 · 2020: 1 · 2019: 2 · 2018: 4 · 2017: 2 · 2016: 2 · 2015: 3
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- International Journal of Stem Cells (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- hepatocyte spheroids, liver tissue engineering, bioartificial liver, liver failure, liver transplantation, liver-specific function, hanging drop culture, spinner culture, micromolding, co-culture, polymeric nanospheres, external forces
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