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In this study, novel tri\u2010layered and gel\u2010like nanofibrous scaffolds, consisting of poly(lactic\u2010<jats:italic>co<\/jats:italic>\u2010glycolic) acid (PLGA) and poly(aspartic acid) (PASP), are fabricated by a combination of positive\/negative conjugate electrospinning and bioactive hydrogel post\u2010processing. The nanofibrous PLGA\u2010PASP scaffolds present tri\u2010layered structures, resulting in anisotropic mechanical properties that are comparable with native heart valve leaflets. Biological tests show that nanofibrous PLGA\u2010PASP scaffolds with high PASP ratios significantly promote the proliferation and collagen and glycosaminoglycans (GAGs) secretions of human aortic valvular interstitial cells (HAVICs), compared to PLGA scaffolds. Importantly, the nanofibrous PLGA\u2010PASP scaffolds are found to effectively inhibit the osteogenic differentiation of HAVICs. Two types of porcine VICs, from young and adult age groups, are further seeded onto the PLGA\u2010PASP scaffolds. The adult VICs secrete higher amounts of collagens and GAGs and undergo a significantly higher level of osteogenic differentiation than young VICs. RNA sequencing analysis indicates that age has a pivotal effect on the VIC behaviors. This study provides important guidance and a reference for the design and development of 3D tri\u2010layered, gel\u2010like nanofibrous PLGA\u2010PASP scaffolds for TEHV applications.<\/jats:p>","DOI":"10.1002\/adhm.202200053","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T10:21:52Z","timestamp":1647339712000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Tri\u2010Layered and Gel\u2010Like Nanofibrous Scaffolds with Anisotropic Features for Engineering Heart Valve Leaflets"],"prefix":"10.1002","volume":"11","author":[{"given":"Shaohua","family":"Wu","sequence":"first","affiliation":[{"name":"College of Textiles and Clothing Qingdao University  Qingdao 266071 China"},{"name":"Mary &amp; Dick Holland Regenerative Medicine Program and Division of Cardiology Department of Internal Medicine University of Nebraska Medical Center  Omaha NE 68198 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Li","sequence":"additional","affiliation":[{"name":"College of Textiles and Clothing Qingdao University  Qingdao 266071 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caidan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Yarn Materials Forming and Composite Processing Technology of Zhejiang Province Jiaxing University  Jiaxing 314001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Litao","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science Creighton University  Omaha NE 68178 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell","family":"Kuss","sequence":"additional","affiliation":[{"name":"Mary &amp; Dick Holland Regenerative Medicine Program and Division of Cardiology Department of Internal Medicine University of Nebraska Medical Center  Omaha NE 68198 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Yul","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Materials Engineering University of Nebraska\u2010Lincoln  Lincoln NE 68588 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Butcher","sequence":"additional","affiliation":[{"name":"Meinig School of Biomedical Engineering Cornell University  Ithaca NY 14850 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5647-3793","authenticated-orcid":false,"given":"Bin","family":"Duan","sequence":"additional","affiliation":[{"name":"Mary &amp; Dick Holland Regenerative Medicine Program and Division of Cardiology Department of Internal Medicine University of Nebraska Medical Center  Omaha NE 68198 USA"},{"name":"Department of Mechanical and Materials Engineering University of Nebraska\u2010Lincoln  Lincoln NE 68588 USA"},{"name":"Department of Surgery College of Medicine University of Nebraska Medical Center  Omaha NE 68198 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,21]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcdd7040057"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.183020"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/smll.201900873"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtbio.2019.100038"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2021.03.022"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/sji.13018"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/jfb12010020"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-020-0422-8"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2018.12.005"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.2217\/rme-2019-0078"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/17434440.2018.1419865"},{"key":"e_1_2_9_12_1","first-page":"2025","volume":"10","author":"Liu Y.","year":"2020","journal-title":"Mater. 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