{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:56:25Z","timestamp":1791197785051,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK117425"],"award-info":[{"award-number":["DK117425"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK132211"],"award-info":[{"award-number":["DK132211"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK131209"],"award-info":[{"award-number":["DK131209"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK106667"],"award-info":[{"award-number":["DK106667"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["EEC\u20101941543"],"award-info":[{"award-number":["EEC\u20101941543"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["aiche.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Bioengineering &amp;amp; Transla Med"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Hepatic spheroids are widely used in bioartificial liver (BAL) systems, hepatotoxicology, and pharmacology due to improved functional stability compared with monolayer cultures. However, many existing methods rely on specialized equipment or static platforms that limit scalability and dynamic culture applications. Primary rat hepatocytes were cultured as three\u2010dimensional spheroids using a rocker\u2010based suspension system. Spheroid formation was evaluated across a range of rocking speeds (7\u201318\u2009cycles per minute [cpm]) and inoculation densities. Spheroid morphology was quantified over time using two\u2010dimensional imaging. Functional performance was assessed by urea and albumin production on days 1, 4, 7, and 10. Spheroid formation efficiency was evaluated using volumetric modeling. Mean spheroid diameter decreased from 199\u2009\u00b1\u200941\u2009\u03bcm at 7\u2009cpm to 80.2\u2009\u00b1\u200917.6\u2009\u03bcm at 18\u2009cpm. The spheroid area was significantly influenced by both culture day (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) and rocker speed, with significant differences observed across speeds at all time points (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001, days 1\u20137). Mean spheroid area at 10\u2009cpm was 13,750\u2009\u00b1\u20099051\u2009\u03bcm\n                    <jats:sup>2<\/jats:sup>\n                    (day 1), 26,730\u2009\u00b1\u20098658\u2009\u03bcm\n                    <jats:sup>2<\/jats:sup>\n                    (day 4), and decreased to 22,526\u2009\u00b1\u20098705\u2009\u03bcm\n                    <jats:sup>2<\/jats:sup>\n                    (day 7). Urea production differed across speeds (ANOVA,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.043), with peak performance at 12\u2009cpm (median 3.47\u2009\u03bcg\/\u03bcg DNA) compared to 7\u2009cpm (median 0.11\u2009\u03bcg\/\u03bcg DNA). Albumin production was 1086.8\u2009ng\/\u03bcg DNA on day 1 and 1534.4\u2009ng\/\u03bcg DNA on day 10. Urea production was 0.62\u2009\u03bcg\/\u03bcg DNA on day 1 and 1.25\u2009\u03bcg\/\u03bcg DNA on day 10. Median hepatocyte incorporation was 86% (range 73%\u2013116%) by day 4. This rocker\u2010based method provides a simple, low\u2010cost, and scalable approach for generating hepatic spheroids with tunable size distributions under dynamic conditions. The system supports progressive functional maturation and is compatible with established scale\u2010up strategies, supporting its potential for translational applications.\n                  <\/jats:p>","DOI":"10.1002\/btm2.70154","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T11:40:46Z","timestamp":1780659646000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The effect of rocking speed and cell inoculation density on hepatic spheroid size: A simple method for size modulation"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1198-6610","authenticated-orcid":false,"given":"Michael G.","family":"Megaly","sequence":"first","affiliation":[{"name":"Division of Transplantation, Department of Surgery University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"Tobolt","sequence":"additional","affiliation":[{"name":"Division of Transplantation, Department of Surgery University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony An\u2010Fa Dahm","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Transplantation, Department of Surgery University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bat\u2010Erdene","family":"Namsrai","sequence":"additional","affiliation":[{"name":"Division of Transplantation, Department of Surgery University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Fisher","sequence":"additional","affiliation":[{"name":"Division of Transplantation, Department of Surgery University of Minnesota  Minneapolis Minnesota USA"},{"name":"Department of Mechanical Engineering University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph Sushil","family":"Rao","sequence":"additional","affiliation":[{"name":"Division of Transplantation, Department of Surgery University of Minnesota  Minneapolis Minnesota USA"},{"name":"Schulze Diabetes Institute University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srivasupradha","family":"Ramesh","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anudari","family":"Chimedtseren","sequence":"additional","affiliation":[{"name":"Division of Transplantation, Department of Surgery University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott L.","family":"Nyberg","sequence":"additional","affiliation":[{"name":"William J von Liebig Transplant Center Mayo Clinic College of Medicine  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Clemens","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences University of North Carolina  Charlotte North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles Y.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering and Engineering Science University of North Carolina  Charlotte North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6726-7111","authenticated-orcid":false,"given":"John C.","family":"Bischof","sequence":"additional","affiliation":[{"name":"Schulze Diabetes Institute University of Minnesota  Minneapolis Minnesota USA"},{"name":"Institute for Engineering in Medicine University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3899-6985","authenticated-orcid":false,"given":"Erik B.","family":"Finger","sequence":"additional","affiliation":[{"name":"Division of Transplantation, Department of Surgery University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.2008.175380"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcyt.2016.03.295"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.12804"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfx289"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep25187"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms221910214"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2012.11.029"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1858"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2007.08.033"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2012.03.004"},{"issue":"10","key":"e_1_2_14_12_1","first-page":"3639","article-title":"A simplified method for production and growth of multicellular tumor spheroids","volume":"37","author":"Yuhas JM","year":"1977","journal-title":"Cancer Res"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.15283\/ijsc.2010.3.2.69"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.3727\/215517915X689056"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.3727\/096368909X474258"},{"key":"e_1_2_14_16_1","unstructured":"NybergSL.Bioartificial liver system. Mayo Foundation for Medical Education and Research; 7 160 719 B2.2007."},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22674"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.4254\/wjh.v2.i1.1"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/xen.12512"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.28299"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1095\u20106433(02)00374\u20104"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2008.01.016"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204\u2010017\u20102002\u20101"},{"key":"e_1_2_14_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441\u2010005\u20100148\u20102"},{"key":"e_1_2_14_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.reth.2019.04.011"},{"key":"e_1_2_14_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2018.12.014"},{"key":"e_1_2_14_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22651"},{"key":"e_1_2_14_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.03.021"},{"key":"e_1_2_14_29_1","doi-asserted-by":"publisher","DOI":"10.1039\/c5lc00237k"},{"key":"e_1_2_14_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)30334-4"},{"key":"e_1_2_14_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432\u20101033.1988.tb13911.x"},{"key":"e_1_2_14_32_1","doi-asserted-by":"publisher","DOI":"10.1039\/c8nr00226f"},{"key":"e_1_2_14_33_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M071183"},{"key":"e_1_2_14_34_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.26540"}],"container-title":["Bioengineering &amp; Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/aiche.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/btm2.70154","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/aiche.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/btm2.70154","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/aiche.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/btm2.70154","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:54:30Z","timestamp":1791194070000},"score":1,"resource":{"primary":{"URL":"https:\/\/aiche.onlinelibrary.wiley.com\/doi\/10.1002\/btm2.70154"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,5]]},"references-count":33,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/btm2.70154"],"URL":"https:\/\/doi.org\/10.1002\/btm2.70154","archive":["Portico"],"relation":{},"ISSN":["2380-6761","2380-6761"],"issn-type":[{"value":"2380-6761","type":"print"},{"value":"2380-6761","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,5]]},"assertion":[{"value":"2026-01-30","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70154"}}