{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T05:47:04Z","timestamp":1791870424026,"version":"4.3.4"},"reference-count":94,"publisher":"SAGE Publications","issue":"5","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"National Cancer Institute","award":["R01 CA256481"],"award-info":[{"award-number":["R01 CA256481"]}]},{"name":"National Cancer Institute","award":["R01 CA279195"],"award-info":[{"award-number":["R01 CA279195"]}]},{"name":"National Cancer Institute","award":["T32 CA009686"],"award-info":[{"award-number":["T32 CA009686"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Tissue Engineering Part C: Methods"],"published-print":{"date-parts":[[2026,5,1]]},"abstract":"<jats:p>Glioblastoma (GBM) is one of the most common malignant brain tumors, with patient mortality driven by invasion into the surrounding brain microenvironment and drug resistance. Multicellular spheroids are an increasingly common model to study GBM invasion and drug response in engineered biomaterials. However, a key design feature of tumor spheroid studies is the size of each spheroid (number of cells, diameter). Given the heterogeneous growth of GBM cells at the surgical margin, spheroids of different sizes may also have clinical relevance. Here, we define shifts in behavior and drug response of wild-type (WT) and temozolomide (TMZ)-resistant GBM spheroids as a function of initial spheroid size. GBM spheroids ranging from 1,000 to 10,000 cells in size were embedded into a methacrylamide-functionalized gelatin hydrogel. GBM spheroid size had an inverse relationship with the number of apoptotic cells. We observed significant spheroid-size-dependent effects on TMZ efficacy for both TMZ-resistant and WT cells. Interestingly, high single doses of TMZ were more effective in reducing three-dimensional migration from smaller spheroids than metronomic dosing, while high single dose and metronomic dosing were equally effective in reducing invasion for large TMZ-resistant spheroids. Our study highlights the importance of considering and reporting spheroid size for cancer tissue engineering studies considering invasion and drug resistance. It also informs future studies of residual GBM at the tumor margins most responsible for patient relapse and mortality.<\/jats:p>","DOI":"10.1177\/19373384261432672","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T11:18:48Z","timestamp":1773659928000},"page":"179-194","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["The Size of Glioblastoma Spheroids Influences Patterns of Invasion and Temozolomide Efficacy"],"prefix":"10.1177","volume":"32","author":[{"given":"Sheridan","family":"Fok","sequence":"first","affiliation":[{"name":"Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anagha","family":"Shreesha","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Appiah-Kubi","sequence":"additional","affiliation":[{"name":"Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca B.","family":"Riggins","sequence":"additional","affiliation":[{"name":"Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5458-154X","authenticated-orcid":false,"given":"Brendan A.C.","family":"Harley","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA."},{"name":"Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA."},{"name":"Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA."},{"name":"Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"e_1_3_5_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00605"},{"key":"e_1_3_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105780"},{"key":"e_1_3_5_4_1","doi-asserted-by":"publisher","DOI":"10.5603\/RPOR.a2022.0113"},{"key":"e_1_3_5_5_1","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.29856"},{"key":"e_1_3_5_6_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1596707"},{"key":"e_1_3_5_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-011-0749-4"},{"key":"e_1_3_5_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.21136"},{"key":"e_1_3_5_9_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/732413"},{"key":"e_1_3_5_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa043330"},{"key":"e_1_3_5_11_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo_00000292"},{"key":"e_1_3_5_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2015.03.015"},{"key":"e_1_3_5_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5196"},{"key":"e_1_3_5_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2012.07.002"},{"key":"e_1_3_5_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2011.07.005"},{"key":"e_1_3_5_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-21-2750"},{"key":"e_1_3_5_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4332"},{"key":"e_1_3_5_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14020443"},{"key":"e_1_3_5_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471141755.ph1416s52"},{"key":"e_1_3_5_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-008-9737-8"},{"key":"e_1_3_5_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-05-2510"},{"key":"e_1_3_5_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2005.06.009"},{"key":"e_1_3_5_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-05-2593"},{"key":"e_1_3_5_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14050993"},{"key":"e_1_3_5_25_1","doi-asserted-by":"publisher","DOI":"10.3791\/58176"},{"key":"e_1_3_5_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s42242-020-00084-6"},{"key":"e_1_3_5_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41578-019-0135-y"},{"key":"e_1_3_5_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2014.08.012"},{"key":"e_1_3_5_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-13-0629"},{"key":"e_1_3_5_30_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-bioeng-082420-124920"},{"key":"e_1_3_5_31_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-2838"},{"key":"e_1_3_5_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noaa215.904"},{"key":"e_1_3_5_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/adtp.202400041"},{"key":"e_1_3_5_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.201404896"},{"key":"e_1_3_5_35_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tea.2021.0117"},{"key":"e_1_3_5_36_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.21353"},{"key":"e_1_3_5_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11538-012-9786-1"},{"key":"e_1_3_5_38_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-200606000-00001"},{"key":"e_1_3_5_39_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.can-03-2073"},{"key":"e_1_3_5_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.201700687"},{"key":"e_1_3_5_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2018.06.013"},{"key":"e_1_3_5_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/intbio\/zyaa010"},{"key":"e_1_3_5_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202201888"},{"key":"e_1_3_5_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.202400779"},{"key":"e_1_3_5_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nop030"},{"key":"e_1_3_5_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clon.2023.01.012"},{"key":"e_1_3_5_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-25588-1"},{"issue":"1","key":"e_1_3_5_48_1","first-page":"33","article-title":"Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas","volume":"16","author":"Kim JT","year":"2006","unstructured":"47.Kim JT, , Kim JS, , Ko KW, et al. Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas. Oncol Rep 2006;16(1):33\u201339.","journal-title":"Oncol Rep"},{"key":"e_1_3_5_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/mabi.201700018"},{"key":"e_1_3_5_50_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7BM01195D"},{"key":"e_1_3_5_51_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmats.2018.00039"},{"key":"e_1_3_5_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-020-02026-6"},{"key":"e_1_3_5_53_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.38536"},{"key":"e_1_3_5_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2017.11.012"},{"key":"e_1_3_5_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep23490"},{"key":"e_1_3_5_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmat4610"},{"key":"e_1_3_5_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2022.05.048"},{"key":"e_1_3_5_58_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7659"},{"key":"e_1_3_5_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2015.07.042"},{"key":"e_1_3_5_60_1","doi-asserted-by":"publisher","DOI":"10.1101\/2025.07.08.663674"},{"key":"e_1_3_5_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.201700529"},{"key":"e_1_3_5_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2013.06.024"},{"key":"e_1_3_5_63_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10439-014-1223-1"},{"key":"e_1_3_5_64_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.can-13-3426"},{"key":"e_1_3_5_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2014.07.003"},{"key":"e_1_3_5_66_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0101771"},{"key":"e_1_3_5_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2021.06.012"},{"key":"e_1_3_5_68_1","doi-asserted-by":"publisher","DOI":"10.1063\/5.0043338"},{"key":"e_1_3_5_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2019.119371"},{"key":"e_1_3_5_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtbio.2025.101475"},{"key":"e_1_3_5_71_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0044640"},{"key":"e_1_3_5_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep41160"},{"key":"e_1_3_5_73_1","doi-asserted-by":"publisher","DOI":"10.2144\/btn-2020-0081"},{"key":"e_1_3_5_74_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-06-4353"},{"key":"e_1_3_5_75_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0004632"},{"key":"e_1_3_5_76_1","doi-asserted-by":"publisher","DOI":"10.1093\/noajnl\/vdaf174"},{"key":"e_1_3_5_77_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.3.239"},{"key":"e_1_3_5_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0733-8651(05)70195-8"},{"key":"e_1_3_5_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-020-00150-z"},{"key":"e_1_3_5_80_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1349"},{"issue":"1","key":"e_1_3_5_81_1","first-page":"17","article-title":"Mechanisms of temozolomide resistance in glioblastoma - A comprehensive review","volume":"4","author":"Neha S","year":"2021","unstructured":"80.Neha S, , Alexandra M, , Lauren H, et al. Mechanisms of temozolomide resistance in glioblastoma - A comprehensive review. Cancer Drug Resistance 2021;4(1):17\u201343.","journal-title":"Cancer Drug Resistance"},{"key":"e_1_3_5_82_1","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol31070296"},{"key":"e_1_3_5_83_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-5-67"},{"key":"e_1_3_5_84_1","doi-asserted-by":"publisher","DOI":"10.3892\/etm.2014.2144"},{"key":"e_1_3_5_85_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-025-07617-w"},{"key":"e_1_3_5_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2020.09.002"},{"key":"e_1_3_5_87_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1115083109"},{"key":"e_1_3_5_88_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15567"},{"key":"e_1_3_5_89_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.10.5724"},{"key":"e_1_3_5_90_1","doi-asserted-by":"publisher","DOI":"10.1080\/0284186x.2020.1744719"},{"key":"e_1_3_5_91_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/5483791"},{"key":"e_1_3_5_92_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-17-2429"},{"key":"e_1_3_5_93_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adj5962"},{"key":"e_1_3_5_94_1","doi-asserted-by":"publisher","DOI":"10.1087\/20150211"},{"key":"e_1_3_5_95_1","doi-asserted-by":"publisher","DOI":"10.1038\/508312a"}],"container-title":["Tissue Engineering Part C: Methods"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/19373384261432672","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/19373384261432672","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/19373384261432672","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T05:18:21Z","timestamp":1791868701000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/19373384261432672"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,16]]},"references-count":94,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5,1]]}},"alternative-id":["10.1177\/19373384261432672"],"URL":"https:\/\/doi.org\/10.1177\/19373384261432672","relation":{},"ISSN":["1937-3384","1937-3392"],"issn-type":[{"value":"1937-3384","type":"print"},{"value":"1937-3392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,16]]}}}