{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T12:40:05Z","timestamp":1793968805207,"version":"4.8.0"},"reference-count":45,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2015,11,1]],"date-time":"2015-11-01T00:00:00Z","timestamp":1446336000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2015,11,1]],"date-time":"2015-11-01T00:00:00Z","timestamp":1446336000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2015,8,5]],"date-time":"2015-08-05T00:00:00Z","timestamp":1438732800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004191","name":"Novo Nordisk","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004191","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["81371748"],"award-info":[{"award-number":["81371748"]}],"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":["R01 HL107904"],"award-info":[{"award-number":["R01 HL107904"]}],"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":["R01 HL109442"],"award-info":[{"award-number":["R01 HL109442"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.jp","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Biomaterials"],"published-print":{"date-parts":[[2015,11]]},"DOI":"10.1016\/j.biomaterials.2015.08.004","type":"journal-article","created":{"date-parts":[[2015,8,5]],"date-time":"2015-08-05T22:18:49Z","timestamp":1438813129000},"page":"84-93","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":128,"special_numbering":"C","title":["Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B"],"prefix":"10.1016","volume":"70","author":[{"given":"Jin","family":"Su","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liqing","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Sherman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shina","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aditya","family":"Kamesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joey H.","family":"Norikane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Streatfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland W.","family":"Herzog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Daniell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.biomaterials.2015.08.004_bib1","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1038\/nbt.3040","article-title":"Biopharmaceutical benchmarks","volume":"32","author":"Walsh","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib2","doi-asserted-by":"crossref","DOI":"10.1016\/j.tplants.2015.07.004","article-title":"Engineered chloroplast genome just got smarter","author":"Jin","year":"2015","journal-title":"Trends Plant Sci."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib3","doi-asserted-by":"crossref","DOI":"10.1111\/pbi.12471","article-title":"Plant-made vaccines against human diseases\u2013 are we there yet?","author":"Chan","year":"2015","journal-title":"Plant Biotechnol. J."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib4","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.addr.2012.10.005","article-title":"Oral delivery of human biopharmaceuticals, autoantigens and vaccine antigens bioencapsulated in plant cells","volume":"65","author":"Kwon","year":"2013","journal-title":"Adv. Drug Deliv. Rev."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib5","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1111\/pbi.12008","article-title":"Oral delivery of bioencapsulated exendin-4 expressed in chloroplasts lowers blood glucose level in mice and stimulates insulin secretion in beta-TC6 cells","volume":"11","author":"Kwon","year":"2013","journal-title":"Plant Biotechnol. J."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib6","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1111\/j.1467-7652.2007.00258.x","article-title":"Field production and functional evaluation of chloroplast-derived interferon-\u03b12b","volume":"5","author":"Arlen","year":"2007","journal-title":"Plant Biotechnol. J."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib7","doi-asserted-by":"crossref","first-page":"e1001221","DOI":"10.1371\/journal.pbio.1001221","article-title":"Recognition and degradation of plant cell wall polysaccharides by two human gut symbionts","volume":"9","author":"Martens","year":"2011","journal-title":"PLoS Biol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib8","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrmicro1817","article-title":"Polysaccharide utilization by gut bacteria: potential for new insights from genomic analysis","volume":"6","author":"Flint","year":"2008","journal-title":"Nat. Rev. Microbiol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib9","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1096\/fj.05-5134fje","article-title":"Receptor-mediated oral delivery of a bioencapsulated green fluorescent protein expressed in transgenic chloroplasts into the mouse circulatory system","volume":"20","author":"Limaye","year":"2006","journal-title":"FASEB J."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib10","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1111\/j.1467-7652.2007.00259.x","article-title":"Expression of cholera toxin B\u2013proinsulin fusion protein in lettuce and tobacco chloroplasts \u2013 oral administration protects against development of insulitis in non-obese diabetic mice","volume":"5","author":"Ruhlman","year":"2007","journal-title":"Plant Biotechnol. J."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib11","doi-asserted-by":"crossref","first-page":"7101","DOI":"10.1073\/pnas.0912181107","article-title":"Oral delivery of bioencapsulated coagulation factor IX prevents inhibitor formation and fatal anaphylaxis in hemophilia B mice","volume":"107","author":"Verma","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib12","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1182\/blood-2013-10-528737","article-title":"Suppression of inhibitor formation against FVIII in a murine model of hemophilia A by oral delivery of antigens bioencapsulated in plant cells","volume":"124","author":"Sherman","year":"2014","journal-title":"Blood"},{"key":"10.1016\/j.biomaterials.2015.08.004_bib13","doi-asserted-by":"crossref","first-page":"2418","DOI":"10.1182\/blood-2014-08-597070","article-title":"Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells","volume":"125","author":"Wang","year":"2015","journal-title":"Blood"},{"key":"10.1016\/j.biomaterials.2015.08.004_bib14","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1161\/HYPERTENSIONAHA.114.03871","article-title":"Oral delivery of angiotensin-converting enzyme2 and angiotensin-(1-7) bioencapsulated in plant cells attenuates pulmonary hypertension","volume":"64","author":"Shenoy","year":"2014","journal-title":"Hypertension"},{"key":"10.1016\/j.biomaterials.2015.08.004_bib15","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1038\/mt.2014.179","article-title":"Oral delivery of ACE2\/Ang-(1\u20137) bioencapsulated in plant cells protects against experimental uveitis and autoimmune uveoretinitis","volume":"22","author":"Shil","year":"2014","journal-title":"Mol. Ther."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib16","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/mt.2013.273","article-title":"Oral delivery of bioencapsulated proteins across blood\u2013brain and blood\u2013retinal barriers","volume":"22","author":"Kohli","year":"2014","journal-title":"Mol. Ther."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib17","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1016\/S0140-6736(11)61139-2","article-title":"Modern haemophilia care","volume":"379","author":"Berntorp","year":"2012","journal-title":"Lancet"},{"key":"10.1016\/j.biomaterials.2015.08.004_bib18","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/bjh.12028","article-title":"Immune tolerance in haemophilia: the long journey to the fork in the road","volume":"159","author":"DiMichele","year":"2012","journal-title":"Br. J. Haematol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib19","doi-asserted-by":"crossref","first-page":"4449","DOI":"10.1182\/blood-2013-01-478669","article-title":"Progress toward inducing immunologic tolerance to factor VIII","volume":"121","author":"Scott","year":"2013","journal-title":"Blood"},{"key":"10.1016\/j.biomaterials.2015.08.004_bib20","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1111\/j.1365-2141.2007.06657.x","article-title":"Inhibitor development in haemophilia B: an orphan disease in need of attention","volume":"138","author":"DiMichele","year":"2007","journal-title":"Br. J. Haematol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib21","doi-asserted-by":"crossref","first-page":"S166","DOI":"10.1038\/515S166a","article-title":"Immunology: oral solutions","volume":"515","author":"Dolgin","year":"2014","journal-title":"Nature"},{"key":"10.1016\/j.biomaterials.2015.08.004_bib22","doi-asserted-by":"crossref","first-page":"2088","DOI":"10.1104\/pp.109.152017","article-title":"The role of heterologous chloroplast sequence elements in transgene integration and expression","volume":"152","author":"Ruhlman","year":"2010","journal-title":"Plant Physiol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib23","doi-asserted-by":"crossref","first-page":"6879","DOI":"10.1073\/pnas.0702219104","article-title":"Transgene containment by maternal inheritance: effective or elusive?","volume":"104","author":"Daniell","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib24","first-page":"365","article-title":"Engineering the chloroplast genome for hyperexpression of human therapeutic proteins and vaccine antigens","volume":"267","author":"Kumar","year":"2004","journal-title":"Methods Mol. Biol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib25","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/nprot.2007.522","article-title":"A\u00a0protocol for expression of foreign genes in chloroplasts","volume":"3","author":"Verma","year":"2008","journal-title":"Nat. Protoc."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib26","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1002\/emmm.201302859","article-title":"Effective gene therapy for haemophilic mice with pathogenic factor IX antibodies","volume":"5","author":"Markusic","year":"2013","journal-title":"EMBO Mol. Med."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib27","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1038\/mt.2014.43","article-title":"Immune tolerance induction to factor IX through B cell gene transfer: TLR9 signaling delineates between tolerogenic and immunogenic B cells","volume":"22","author":"Wang","year":"2014","journal-title":"Mol. Ther."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib28","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1177\/2211068212460037","article-title":"Automated production of plant-based vaccines and pharmaceuticals","volume":"17","author":"Wirz","year":"2012","journal-title":"J.\u00a0Lab. Autom."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib29","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1006\/jmbi.2001.4921","article-title":"Expression of the native cholera toxin B subunit gene and assembly as functional oligomers in transgenic tobacco chloroplasts","volume":"311","author":"Daniell","year":"2001","journal-title":"J.\u00a0Mol. Biol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib30","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1111\/j.1348-0421.1995.tb03262.x","article-title":"Monomer of the B subunit of heat-labile enterotoxin from enterotoxigenic Escherichia coli has little ability to bind to GM1 ganglioside compared to its coligenoid","volume":"39","author":"Tsuji","year":"1995","journal-title":"Microbiol. Immunol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib31","first-page":"24","article-title":"Antigen sampling by epithelial tissues: implication for vaccine design","volume":"98","author":"Kraehenbuhl","year":"1997","journal-title":"Behring Inst. Mitt."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib32","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/86373","article-title":"Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria","volume":"2","author":"Rescigno","year":"2001","journal-title":"Nat. Immunol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib33","doi-asserted-by":"crossref","DOI":"10.1155\/2013\/578786","article-title":"Persistent suppression of type 1 diabetes by a multicomponent vaccine containing a cholera toxin B subunit-autoantigen fusion protein and complete Freund's adjuvant","author":"D\u00e9nes","year":"2013","journal-title":"Clin. Dev. Immunol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib34","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/nbt1098-934","article-title":"A\u00a0plant-based cholera toxin B subunit-insulin fusion protein protects against the development of autoimmune diabetes","volume":"16","author":"Arakawa","year":"1998","journal-title":"Nat. Biotechnol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib35","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1111\/j.1365-2036.2009.04185.x","article-title":"Clinical trial: the safety and short-term efficacy of recombinant cholera toxin B subunit in the treatment of active Crohn's disease","volume":"31","author":"St\u00e5l","year":"2010","journal-title":"Aliment. Pharmacol. Ther."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib36","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/S1473-3099(06)70494-7","article-title":"Oral cholera vaccines: use in clinical practice","volume":"6","author":"Hill","year":"2006","journal-title":"Lancet Infect. Dis."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib37","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/j.1365-2249.2004.02520.x","article-title":"Oral tolerization with peptide 336-351 linked to cholera toxin B subunit in preventing relapses of uveitis in Behcet's disease","volume":"137","author":"Stanford","year":"2004","journal-title":"Clin. Exp. Immunol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib38","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1016\/S0264-410X(99)00337-0","article-title":"Safety evaluation of recombinant cholera toxin B subunit produced by Bacillus brevis as a mucosal adjuvant","volume":"18","author":"Goto","year":"2000","journal-title":"Vaccine"},{"key":"10.1016\/j.biomaterials.2015.08.004_bib39","doi-asserted-by":"crossref","first-page":"e0118562","DOI":"10.1371\/journal.pone.0118562","article-title":"Induction of indoleamine 2, 3-dioxygenase in human dendritic cells by a cholera toxin B subunit\u2013proinsulin vaccine","volume":"10","author":"Mbongue","year":"2015","journal-title":"PLoS One"},{"key":"10.1016\/j.biomaterials.2015.08.004_bib40","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nm1408","article-title":"Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25\u2013LAP+ T cells","volume":"12","author":"Ochi","year":"2006","journal-title":"Nat. Med."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib41","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/mi.2013.62","article-title":"Highly prevalent colorectal cancer-infiltrating LAP \u00fe Foxp3 T cells exhibit more potent immunosuppressive activity than Foxp3 \u00fe regulatory T cells","volume":"7","author":"Scurr","year":"2014","journal-title":"Mucosal Immunol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib42","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1038\/81161","article-title":"Removal of antibiotic resistance genes from transgenic tobacco plastids","volume":"18","author":"Iamtham","year":"2000","journal-title":"Nat. Biotechnol."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib43","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1111\/j.1467-7652.2011.00604.x","article-title":"The chloroplast transformation toolbox: selectable markers and marker removal","volume":"9","author":"Day","year":"2011","journal-title":"Plant Biotechnol. J."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib44","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1111\/pbi.12139","article-title":"Precise excision of plastid DNA by large serine recombinase Bxb1","volume":"12","author":"Shao","year":"2014","journal-title":"Plant Biotechnol. J."},{"key":"10.1016\/j.biomaterials.2015.08.004_bib45","doi-asserted-by":"crossref","first-page":"3869","DOI":"10.1074\/jbc.271.7.3869","article-title":"Structural integrity of the \u03b3-carboxyglutamic acid domain of human blood coagulation factor IXa is required for its binding to cofactor VIIIa","volume":"271","author":"Larson","year":"1996","journal-title":"J.\u00a0Biol. Chem."}],"container-title":["Biomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0142961215006560?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0142961215006560?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T16:10:57Z","timestamp":1758903057000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0142961215006560"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11]]},"references-count":45,"alternative-id":["S0142961215006560"],"URL":"https:\/\/doi.org\/10.1016\/j.biomaterials.2015.08.004","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.726318730.793517597","asserted-by":"object"}]},"ISSN":["0142-9612"],"issn-type":[{"value":"0142-9612","type":"print"}],"subject":[],"published":{"date-parts":[[2015,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Low cost industrial production of coagulation factor IX bioencapsulated in lettuce cells for oral tolerance induction in hemophilia B","name":"articletitle","label":"Article Title"},{"value":"Biomaterials","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.biomaterials.2015.08.004","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Copyright \u00a9 2015 The Authors. Published by Elsevier Ltd.","name":"copyright","label":"Copyright"}]}}