{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:20:31Z","timestamp":1790533231693,"version":"4.1.0"},"reference-count":35,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T00:00:00Z","timestamp":1600041600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK084053"],"award-info":[{"award-number":["R01DK084053"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011781","name":"Shriners Hospitals for Children","doi-asserted-by":"publisher","award":["84311"],"award-info":[{"award-number":["84311"]}],"id":[{"id":"10.13039\/100011781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotech &amp; Bioengineering"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Liver tissue engineering aims to create transplantable liver grafts that can serve as substitutes for donor's livers. One major challenge in creating a fully functional liver tissue has been to recreate the biliary drainage in an engineered liver construct through integration of bile canaliculi (BC) with the biliary ductular network that would enable the clearance of bile from the hepatocytes to the host duodenum. In this study, we show the formation of such a hepatic microtissue by coculturing rat primary hepatocytes with cholangiocytes and stromal cells. Our results indicate that within the spheroids, hepatocytes maintained viability and function for up to 7 days. Viable hepatocytes became polarized by forming BC with the presence of tight junctions. Morphologically, hepatocytes formed the core of the spheroids, while cholangiocytes resided at the periphery forming a monolayer microcysts and tubular structures extending outward. The spheroids were subsequently cultured in clusters to create a higher order ductular network resembling hepatic lobule. The cholangiocytes formed functional biliary ductular channels in between hepatic spheroids that were able to collect, transport, and secrete bile. Our results constitute the first step to recreate hepatic building blocks with biliary drainage for repopulating the whole liver scaffolds to be used as transplantable liver grafts.<\/jats:p>","DOI":"10.1002\/bit.27546","type":"journal-article","created":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T15:50:30Z","timestamp":1598629830000},"page":"17-29","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Development of liver microtissues with functional biliary ductular network"],"prefix":"10.1002","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1551-4309","authenticated-orcid":false,"given":"Ehab O. A.","family":"Hafiz","sequence":"first","affiliation":[{"name":"Center for Engineering in Medicine and Surgery, Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"Shriners Hospitals for Children in Boston  Boston Massachusetts USA"},{"name":"Electron Microscopy Research Department Theodor Bilharz Research Institute (TBRI)  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4435-413X","authenticated-orcid":false,"given":"Beyza","family":"Bulutoglu","sequence":"additional","affiliation":[{"name":"Center for Engineering in Medicine and Surgery, Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"Shriners Hospitals for Children in Boston  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9201-7253","authenticated-orcid":false,"given":"Soheir S.","family":"Mansy","sequence":"additional","affiliation":[{"name":"Electron Microscopy Research Department Theodor Bilharz Research Institute (TBRI)  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibin","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Engineering in Medicine and Surgery, Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"Shriners Hospitals for Children in Boston  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoda","family":"Abu\u2010Taleb","sequence":"additional","affiliation":[{"name":"Immunology and Therapeutic Evaluation Department TBRI  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somia A. M.","family":"Soliman","sequence":"additional","affiliation":[{"name":"Pathology Department, Kasr Al Ainy, Faculty of Medicine Cairo University  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali A. F.","family":"El\u2010Hindawi","sequence":"additional","affiliation":[{"name":"Pathology Department, Kasr Al Ainy, Faculty of Medicine Cairo University  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin L.","family":"Yarmush","sequence":"additional","affiliation":[{"name":"Center for Engineering in Medicine and Surgery, Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"Shriners Hospitals for Children in Boston  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2600-7900","authenticated-orcid":false,"given":"Basak E.","family":"Uygun","sequence":"additional","affiliation":[{"name":"Center for Engineering in Medicine and Surgery, Massachusetts General Hospital Harvard Medical School  Boston Massachusetts USA"},{"name":"Shriners Hospitals for Children in Boston  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,9,14]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40472-019-00236-3"},{"key":"e_1_2_9_3_1","volume-title":"Molecular biology of the cell","author":"Alberts B.","year":"2002"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2001.22703"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep25187"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1142\/S2339547819500043"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-230X-6-13"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/bit.21911"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.2144\/000113317"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30918"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.3.2.2914628"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.02.038"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2017.04.026"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-013-1078-5"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.071024"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.159.22.2647"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v22.i2.874"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jamcollsurg.2008.09.024"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tea.2013.0021"},{"issue":"4","key":"e_1_2_9_20_1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1051\/ject\/201143195","article-title":"Extracorporeal bioartificial liver for treating acute liver diseases","volume":"43","author":"Kumar A.","year":"2011","journal-title":"The Journal of Extra\u2010Corporeal Technology"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-30433-6"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/usp.28.1.15.21"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/9547613"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep4.1136"},{"issue":"145","key":"e_1_2_9_25_1","first-page":"1","article-title":"Liver cirrhosis mortality in 187 countries between 1980 and 2010: A systematic analysis","volume":"12","author":"Mohdad A. A.","year":"2014","journal-title":"BMC Medicine"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-804274-8.00001-1"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.033530"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2009.07.020"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-29464-w"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13036-020-0230-z"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-102715-092331"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9BM01143A"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2170"},{"issue":"1","key":"e_1_2_9_34_1","first-page":"303","article-title":"Development and characterization of polarized primary cultures of rat intrahepatic bile duct epithelial cells","volume":"74","author":"Vroman B.","year":"1996","journal-title":"Laboratory Investigation"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1159\/000452761"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1006\/rwei.1999.0237"}],"container-title":["Biotechnology and Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bit.27546","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/bit.27546","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/bit.27546","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T20:13:17Z","timestamp":1760040797000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/bit.27546"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,14]]},"references-count":35,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,1]]}},"alternative-id":["10.1002\/bit.27546"],"URL":"https:\/\/doi.org\/10.1002\/bit.27546","archive":["Portico"],"relation":{},"ISSN":["0006-3592","1097-0290"],"issn-type":[{"value":"0006-3592","type":"print"},{"value":"1097-0290","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,14]]},"assertion":[{"value":"2020-02-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-08-21","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-09-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}