[1] Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev
Immunol 2005;5:953e64. https://doi.org/10.1038/nri1733.
[2] Yoshimoto Y, Jo JI, Tabata Y. Preparation of antibody-immobilized gelatin
nanospheres incorporating a molecular beacon to visualize the biological
function of macrophages. Regen Ther 2020;14:11e8. https://doi.org/10.1016/
j.reth.2019.12.009.
[3] da Silva MD, Bobinski F, Sato KL, Kolker SJ, Sluka KA, Santos ARS. IL-10
cytokine released from M2 macrophages is crucial for analgesic and antiinflammatory effects of acupuncture in a model of inflammatory muscle
pain. Mol Neurobiol 2015;51:19e31. https://doi.org/10.1007/s12035-0148790-x.
[4] Momotori N, Jo JI, Tabata Y. Preparation of polymer microspheres capable for
pioglitazone release to modify macrophages function. Regen Ther 2019;11:
131e8. https://doi.org/10.1016/j.reth.2019.06.008.
[5] Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages
are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 2006;42:717e27. https://
doi.org/10.1016/j.ejca.2006.01.003.
[6] Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D, et al.
Adenoma-linked barrier defects and microbial products drive IL-23/IL-17mediated tumour growth. Nature 2012;491:254e8. https://doi.org/10.1038/
nature11465.
[7] Tomita T, Sakurai Y, Ishibashi S, Maru Y. Imbalance of Clara cell-mediated
homeostatic inflammation is involved in lung metastasis. Oncogene
2011;30:3429e39. https://doi.org/10.1038/onc.2011.53.
520
A Self-archived copy in
Kyoto University Research Information Repository
https://repository.kulib.kyoto-u.ac.jp
T. Nii and Y. Tabata
Regenerative Therapy 18 (2021) 516e522
€ litz A, Von Jonquie
res G, Wolf[32] Eckstein N, Servan K, Hildebrandt B, Po
Kümmeth S, et al. Hyperactivation of the insulin-like growth factor receptor I
signaling pathway Is an essential event for cisplatin resistance of ovarian
cancer cells. Cancer Res 2009;69:2996e3003. https://doi.org/10.1158/00085472.CAN-08-3153.
[33] Neil JR, Johnson KM, Nemenoff RA, Schiemann WP. Cox-2 inactivates Smad
signaling and enhances EMT stimulated by TGF-b through a PGE2-dependent
mechanisms. Carcinogenesis 2008;29:2227e35. https://doi.org/10.1093/carcin/bgn202.
[34] Nii T, Kuwahara T, Makino K, Tabata Y. A co-culture system of threedimensional tumor-associated macrophages and three-dimensional cancerassociated fibroblasts combined with biomolecule release for cancer cell
migration. Tissue Eng - Part A 2020;26:1272e82. https://doi.org/10.1089/
ten.tea.2020.0095.
[35] Miyazaki K, Oyanagi J, Hoshino D, Togo S, Kumagai H, Miyagi Y. Cancer cell
migration on elongate protrusions of fibroblasts in collagen matrix. Sci Rep
2019;9:1e15. https://doi.org/10.1038/s41598-018-36646-z.
[36] Liu W, Song J, Du X, Zhou Y, Li Y, Li R, et al. AKR1B10 (Aldo-keto reductase
family 1 B10) promotes brain metastasis of lung cancer cells in a multi-organ
microfluidic chip model. Acta Biomater 2019;91:195e208. https://doi.org/
10.1016/j.actbio.2019.04.053.
[37] Mazio C, Casale C, Imparato G, Urciuolo F, Netti PA. Recapitulating spatiotemporal tumor heterogeneity in vitro through engineered breast cancer
microtissues. Acta Biomater 2018;73:236e49. https://doi.org/10.1016/
j.actbio.2018.04.028.
[38] Anada T, Fukuda J, Sai Y, Suzuki O. An oxygen-permeable spheroid culture
system for the prevention of central hypoxia and necrosis of spheroids. Biomaterials 2012;33:8430e41. https://doi.org/10.1016/j.biomaterials.2012.
08.040.
[39] Pedraza E, Coronel MM, Fraker CA, Ricordi C, Stabler CL. Preventing hypoxiainduced cell death in beta cells and islets via hydrolytically activated, oxygengenerating biomaterials. Proc Natl Acad Sci U S A 2012;109:4245e50. https://
doi.org/10.1073/pnas.1113560109.
[40] Patil PS, Mansouri M, Leipzig ND. Fluorinated chitosan microgels to overcome
internal oxygen transport deficiencies in microtissue culture systems. Adv
Biosyst 2020;1900250:1e10. https://doi.org/10.1002/adbi.201900250.
[41] Lv D, Yu SC, Ping YF, Wu H, Zhao X, Zhang H, et al. A three-dimensional
collagen scaffold cell culture system for screening anti-glioma therapeutics.
Oncotarget 2016;7:56904e14. https://doi.org/10.18632/oncotarget.10885.
[42] Reynolds DS, Tevis KM, Blessing WA, Colson YL, Zaman MH, Grinstaff MW.
Breast cancer spheroids reveal a differential cancer stem cell response to
chemotherapeutic treatment. Sci Rep 2017;7:1e12. https://doi.org/10.1038/
s41598-017-10863-4.
[43] DelNero P, Lane M, Verbridge SS, Kwee B, Kermani P, Hempstead B, et al. 3D
culture broadly regulates tumor cell hypoxia response and angiogenesis via
pro-inflammatory pathways. Biomaterials 2015;55:110e8. https://doi.org/
10.1016/j.biomaterials.2015.03.035.
[44] Baker AEG, Tam RY, Shoichet MS. Independently tuning the biochemical and
mechanical properties of 3D hyaluronan-based hydrogels with oxime and
diels-alder chemistry to culture breast cancer spheroids. Biomacromolecules
2017;18:4373e84. https://doi.org/10.1021/acs.biomac.7b01422.
[45] Huang YJ, Hsu SH. Acquisition of epithelial-mesenchymal transition and
cancer stem-like phenotypes within chitosan-hyaluronan membrane-derived
3D tumor spheroids. Biomaterials 2014;35:10070e9. https://doi.org/10.1016/
j.biomaterials.2014.09.010.
[46] Moriyama K, Naito S, Wakabayashi R, Goto M, Kamiya N. Enzymatically prepared redox-responsive hydrogels as potent matrices for hepatocellular carcinoma cell spheroid formation. Biotechnol J 2016;11:1452e60. https://
doi.org/10.1002/biot.201600087.
[47] Yang X, Sarvestani SK, Moeinzadeh S, He X, Jabbari E. Three-dimensionalengineered matrix to study cancer stem cells and tumorsphere formation:
effect of matrix modulus. Tissue Eng - Part A 2013;19:669e84. https://doi.org/
10.1089/ten.tea.2012.0333.
[48] Pradhan S, Clary JM, Seliktar D, Lipke EA. A three-dimensional spheroidal
cancer model based on PEG-fibrinogen hydrogel microspheres. Biomaterials
2017;115:141e54. https://doi.org/10.1016/j.biomaterials.2016.10.052.
[49] Nii T, Takeuchi I, Kimura Y, Makino K. Effects of the conformation of PLGA
molecules in the organic solvent on the aerodynamic diameter of spray dried
microparticles. Colloids Surfaces A Physicochem Eng Asp 2018;539:347e53.
https://doi.org/10.1016/j.colsurfa.2017.12.042.
[50] Hinderer S, Layland SL, Schenke-Layland K. ECM and ECM-like materials biomaterials for applications in regenerative medicine and cancer therapy.
Adv Drug Deliv Rev 2016;97:260e9. https://doi.org/10.1016/j.addr.2015.
11.019.
[51] Nii T, Katayama Y. Biomaterial-assisted regenerative medicine. Int J Mol Sci
2021;22:1e18. https://doi.org/10.3390/ijms22168657.
[52] Matsuo T, Masumoto H, Tajima S, Ikuno T, Katayama S, Minakata K, et al.
Efficient long-term survival of cell grafts after myocardial infarction with thick
viable cardiac tissue entirely from pluripotent stem cells. Sci Rep 2015;5:
1e14. https://doi.org/10.1038/srep16842.
[53] Bello AB, Kim D, Kim D, Park H, Lee SH. Engineering and functionalization of
gelatin biomaterials: from cell culture to medical applications. Tissue Eng Part B Rev 2020;26:164e80. https://doi.org/10.1089/ten.teb.2019.0256.
[54] Nakamura K, Saotome T, Shimada N, Matsuno K, Tabata Y. A gelatin hydrogel
nonwoven fabric facilitates metabolic activity of multilayered cell sheets.
[8] Barcellos-de-Souza P, Gori V, Bambi F, Chiarugi P. Tumor microenvironment:
bone marrow-mesenchymal stem cells as key players. Biochim Biophys Acta
Rev Cancer 2013;1836:321e35. https://doi.org/10.1016/j.bbcan.2013.10.004.
[9] Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal
stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an
immunosuppressive MSC2 phenotype. PLoS One 2010;5. https://doi.org/
10.1371/journal.pone.0010088.
[10] Waterman RS, Henkle SL, Betancourt AM. Mesenchymal stem cell 1 (MSC1)Based therapy attenuates tumor growth whereas MSC2-treatment promotes
tumor growth and metastasis. PLoS One 2012;7. https://doi.org/10.1371/
journal.pone.0045590.
[11] Nii T, Makino K, Tabata Y. Three-dimensional culture system of cancer cells
combined with biomaterials for drug screening. Cancers (Basel) 2020;12:
1e24. https://doi.org/10.3390/cancers12102754.
Costa R, Gomes-Alves P, Aspegren A, et al.
[12] Abecasis B, Aguiar T, Arnault E,
Expansion of 3D human induced pluripotent stem cell aggregates in bioreactors: bioprocess intensification and scaling-up approaches. J Biotechnol
2017;246:81e93. https://doi.org/10.1016/j.jbiotec.2017.01.004.
[13] Nii T, Makino K, Tabata Y. Influence of shaking culture on the biological
functions of cell aggregates incorporating gelatin hydrogel microspheres.
J Biosci Bioeng 2019;128:606e12. https://doi.org/10.1016/j.jbiosc.2019.
04.013.
[14] Nunes AS, Barros AS, Costa EC, Moreira AF, Correia IJ. 3D tumor spheroids as
in vitro models to mimic in vivo human solid tumors resistance to therapeutic
drugs. Biotechnol Bioeng 2019;116:206e26. https://doi.org/10.1002/
bit.26845.
[15] Brüningk SC, Rivens I, Box C, Oelfke U, Ter Haar G. 3D tumour spheroids for
the prediction of the effects of radiation and hyperthermia treatments. Sci Rep
2020;10:1e13. https://doi.org/10.1038/s41598-020-58569-4.
[16] Kim J, Koo BK, Knoblich JA. Human organoids: model systems for human
biology and medicine. Nat Rev Mol Cell Biol 2020;21:571e84. https://doi.org/
10.1038/s41580-020-0259-3.
[17] Lancaster MA, Huch M. Disease modelling in human organoids. DMM Dis
Model Mech 2019;12. https://doi.org/10.1242/dmm.039347.
[18] Driehuis E, Kretzschmar K, Clevers H. Establishment of patient-derived cancer
organoids for drug-screening applications. Nat Protoc 2020;15:3380e409.
https://doi.org/10.1038/s41596-020-0379-4.
[19] Fukuda J, Sakai Y, Nakazawa K. Novel hepatocyte culture system developed
using microfabrication and collagen/polyethylene glycol microcontact printing. Biomaterials 2006;27:1061e70. https://doi.org/10.1016/j.biomaterials.
2005.07.031.
rez JC, Avile
s-Salas A, Marín-Hern
[20] Rodríguez-Enríquez S, Gallardo-Pe
andez A,
~ o-Fuentes L, Maldonado-Lagunas V, et al. Energy metabolism transition
Carren
in multi-cellular human tumor spheroids. J Cell Physiol 2008;216:189e97.
https://doi.org/10.1002/jcp.21392.
[21] Lin RZ, Chang HY. Recent advances in three-dimensional multicellular
spheroid culture for biomedical research. Biotechnol J 2008;3:1172e84.
https://doi.org/10.1002/biot.200700228.
[22] Nii T, Makino K, Tabata Y. A cancer invasion model of cancer-associated fibroblasts aggregates combined with TGF-b1 release system. Regen Ther
2020;14:196e204. https://doi.org/10.1016/j.reth.2020.02.003.
[23] Kellner K, Liebsch G, Klimant I, Wolfbeis OS, Blunk T, Schulz MB, et al.
Determination of oxygen gradients in engineered tissue using a fluorescent
sensor. Biotechnol Bioeng 2002;80:73e83. https://doi.org/10.1002/bit.10352.
~ V, Guzma
n J, Riande E. A potentiostatic study of oxygen trans[24] Compan
missibility and permeability through hydrogel membranes. Biomaterials
1998;19:2139e45. https://doi.org/10.1016/S0142-9612(98)00113-6.
[25] Hayashi K, Tabata Y. Preparation of stem cell aggregates with gelatin microspheres to enhance biological functions. Acta Biomater 2011;7:2797e803.
https://doi.org/10.1016/j.actbio.2011.04.013.
[26] Tajima S, Tabata Y. Preparation of epithelial cell aggregates incorporating
matrigel microspheres to enhance proliferation and differentiation of
epithelial cells. Regen Ther 2017;7:34e44. https://doi.org/10.1016/
j.reth.2017.07.001.
[27] Desai SD, Reed RE, Burks J, Wood LM, Pullikuth AK, Haas AL, et al. ISG15
disrupts cytoskeletal architecture and promotes motility in human breast
cancer cells. Exp Biol Med 2012;237:38e49. https://doi.org/10.1258/
ebm.2011.011236.
[28] Nii T, Makino K, Tabata Y. A cancer invasion model combined with cancerassociated fibroblasts aggregates incorporating gelatin hydrogel microspheres containing a p53 inhibitor. Tissue Eng - Part C Methods 2019;25:
711e20. https://doi.org/10.1089/ten.tec.2019.0189.
[29] Leung WH, Vong QP, Lin W, Janke L, Chen T, Leung W. Modulation of NKG2D
ligand expression and metastasis in tumors by spironolactone via RXRg
activation. J Exp Med 2013;210:2675e92. https://doi.org/10.1084/jem.
20122292.
[30] Chen Z, Zhang D, Yue F, Zheng M, Kovacevic Z, Richardson DR. The iron
chelators Dp44mT and DFO inhibit TGF-b-induced epithelial-mesenchymal
transition via up-regulation of N-Myc downstream-regulated gene 1
(NDRG1). J Biol Chem 2012;287:17016e28. https://doi.org/10.1074/
jbc.M112.350470.
[31] Nakayama K. CAMP-response element-binding protein (CREB) and NF-kB
transcription factors are activated during prolonged hypoxia and cooperatively regulate the induction of matrix metalloproteinase MMP1. J Biol Chem
2013;288:22584e95. https://doi.org/10.1074/jbc.M112.421636.
521
A Self-archived copy in
Kyoto University Research Information Repository
https://repository.kulib.kyoto-u.ac.jp
T. Nii and Y. Tabata
[55]
[56]
[57]
[58]
[59]
Regenerative Therapy 18 (2021) 516e522
[60] Chaicharoenaudomrung N, Kunhorm P, Noisa P. Three-dimensional cell culture systems as an in vitro platform for cancer and stem cell modeling. World
J Stem Cells 2019;11:1065e83. https://doi.org/10.4252/wjsc.v11.i12.1065.
[61] Desai PK, Tseng H, Souza GR. Assembly of hepatocyte spheroids using magnetic 3D cell culture for CYP450 inhibition/induction. Int J Mol Sci 2017;18.
https://doi.org/10.3390/ijms18051085.
[62] Nii T. Strategies using gelatin microparticles for regenerative therapy and
drug screening applications. Molecules 2021;26:1e10. https://doi.org/
10.3390/molecules26226795.
[63] Kawai K, Suzuki S, Tabata Y, Ikada Y, Nishimura Y. Accelerated tissue regeneration through incorporation of basic fibroblast growth factor-impregnated
gelatin microspheres into artificial dermis. Biomaterials 2000;21:489e99.
https://doi.org/10.1016/S0142-9612(99)00207-0.
[64] Mitsui R, Matsukawa M, Nakagawa K, Isomura E, Kuwahara T, Nii T, et al.
Efficient cell transplantation combining injectable hydrogels with control
release of growth factors. Regen Ther 2021;18:372e83. https://doi.org/
10.1016/j.reth.2021.09.003.
[65] Inoo K, Bando H, Tabata Y. Enhanced survival and insulin secretion of insulinoma cell aggregates by incorporating gelatin hydrogel microspheres. Regen
Ther 2018;8:29e37. https://doi.org/10.1016/j.reth.2017.12.002.
Tissue Eng - Part C Methods 2019;25:344e52. https://doi.org/10.1089/
ten.tec.2019.0061.
Tabata Y, Ikada Y. Protein release from gelatin matrices. Adv Drug Deliv Rev
1998;31:287e301. https://doi.org/10.1016/S0169-409X(97)00125-7.
Tabata Y, Ikada Y. Vascularization effect of basic fibroblast growth factor
released from gelatin hydrogels with different biodegradabilities. Biomaterials
1999;20:2169e75.
https://doi.org/10.1016/S0142-9612(99)
00121-0.
Tajima S, Tabata Y. Preparation and functional evaluation of cell aggregates
incorporating gelatin microspheres with different degradabilities. J Tissue Eng
Regen Med 2013;7:801e11. https://doi.org/10.1002/term.
Cave DD, Rizzo R, Sainz B, Gigli G, Del Mercato LL, Lonardo E. The revolutionary roads to study cellecell interactions in 3d in vitro pancreatic cancer
models. Cancers (Basel) 2021;13:1e19. https://doi.org/10.3390/cancers
13040930.
Peng WC, Logan CY, Fish M, Anbarchian T, Aguisanda F, Alvarez-Varela
A, et al.
Inflammatory cytokine TNFa promotes the long-term expansion of primary
hepatocytes in 3D culture. Cell 2018;175:1607e1619.e15. https://doi.org/
10.1016/j.cell.2018.11.012.
522
...