[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-444775-105":59,"doc-detail-444775-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","bioprinted-ventilated-3d-alveoliform-epithelial-sacculoids-foundation-for-physiologically-ventilated-human-alveolar-niche-models","Bioprinted Ventilated 3D Alveoliform Epithelial Sacculoids - foundation for physiologically ventilated human alveolar niche models","","Understanding the human distal lung requires ex-vivo models that preserve alveolar structural hierarchy and a physiologic mechanical environment. Current organoid and 2D culture systems lack appropriate 3D architecture, apical access, and ventilation-like actuation, limiting studies of infection and mechanotransduction. Three-dimensional alveolar epithelial sacculoids (AES) were bioprinted from pluripotent stem cell-derived alveolar epithelial type II cells into defined geometries and self-organized into lumenized, polarized, surfactant-secreting units. A custom air-driven platform delivered fluid-mediated 3D ventilation, engaging Hippo signaling and enabling ATII-to-ATII remodeling and junctional stabilization, with influenza infection inducing antiviral responses and injury-repair-like epithelial plasticity.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/bioprinted-ventilated-3d-alveoliform-epithelial-sacculoids-foundation-for-physiologically-ventilated-human-alveolar-niche-models/444775/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/bioprinted-ventilated-3d-alveoliform-epithelial-sacculoids-foundation-for-physiologically-ventilated-human-alveolar-niche-models/444775.png","ImageObject",300,407,{"name":92,"@type":93},"Fans","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem does the AES model address in distal lung research?","Question",{"text":112,"@type":113},"It aims to create an ex-vivo system that captures both the alveolar structural hierarchy and a physiologic mechanical environment, which current organoid and 2D cultures do not adequately provide.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How are alveolar epithelial sacculoids constructed and organized?",{"text":117,"@type":113},"They are bioprinted from pluripotent stem cell-derived alveolar epithelial type II cells into defined 3D geometries, where the tissues reproducibly self-organize into multi-unit lumenized sacs with polarized epithelia and functional heterogeneity.",{"name":119,"@type":110,"acceptedAnswer":120},"What does apical influenza infection reveal using AES?",{"text":121,"@type":113},"It triggers canonical antiviral responses and epithelial plasticity resembling injury-induced alveolar repair, including depletion of functional ATIIs and emergence of proliferative ATIIs and transitional states.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},444775,1790766114,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},5909892330395,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","The Pennsylvania State University  \nThe Pennsylvania State University  \nThe Pennsylvania State University  \n[https://orcid.org/0000-0001-8328-4528](https://orcid.org/0000-0001-8328-4528)  \n[https://orcid.org/0000-0002-4417-5414](https://orcid.org/0000-0002-4417-5414)  \n[https://orcid.org/0000-0001-9794-8196](https://orcid.org/0000-0001-9794-8196)  \nPenn State University College of Medicine  \nPenn State University College of Medicine  \nUniversity of Connecticut Health  \nPenn State University College of Medicine  \nDuke University School of Medicine  \nBioprinting, Organoids, Lungs, Alveolar Sac, Alveolar Epithelial Cells, Development, Disease Model, Ventilation, Mechanotransduction  \n December 30th, 2025  \n [https://doi.org/10.21203/rs.3.rs-8177180/v1](https://doi.org/10.21203/rs.3.rs-8177180/v1)  \n 􀁱 􀅏 This work is licensed under a Creative Commons Attribution 4.0 International License.  \nRead Full License  \n there is potential Competing Interest. Ibrahim Tarik Ozbolat has an equity stake in Biolife4D and is a member of the scienti«c advisory board for Biolife4D and Healshape. The remaining authors declare no competing interests.  \nUnderstanding the human distal lung requires ex-vivo models that capture both the structural hierarchy and mechanical environment of alveolar sacs, yet current ex-vivo systems fall short. Manually cultured organoids and two-dimensional cell cultures lack structural hierarchy, apical access, and physiologic actuation via ventilation, limiting their use in modeling infection and mechano-transduction. Here, we established three-dimensional (3D) alveolar epithelial sacculoids (AES) by bioprinting pluripotent stem cell-derived alveolar epithelial type II cells (ATIIs) into de«ned 3D geometries in high density. AES reproducibly self-organized into multi-unit, lumenized sacs with polarized epithelia, surfactant secretion, and functional heterogeneity including proliferative ATIIs, surfactant-producing ATIIs, and transitional pre-alveolar type I transitional cell state (PATS)-like cells. A custom air-driven platform enabled ¬uidmediated 3D ventilation, producing volumetric oscillations across closed sacs. This actuation engaged canonical (Ser127) and non-canonical (Tyr357, integrin–FAK–dependent) Hippo signaling, driving ATII-toATI remodeling and junctional stabilization. Upon apical infection with in¬ uenza virus, AES recapitulated canonical antiviral responses and epithelial plasticity resembling injury-induced alveolar repair, including depletion of functional ATIIs and emergence of proliferative ATIIs and transitional states. AES represent a physiologically ventilated model of the human alveolar niche, enabling mechanistic studies of epithelial plasticity, viral pathogenesis, and biomechanical signaling under physiologically-relevant conditions. Overall, our model provides a foundation for future integration of stromal, vascular, and immune components toward full alveolar mimicry to facilitate ex-vivo translational respiratory research.  \nAlveolar sacs consist of several intricately organized three-dimensional (3D) alveoli clusters that are interconnected to facilitate gas exchange through cyclical expansion and contraction during respiration. In addition to its gas exchange role, alveolar sacs also provide an important role of maintaining barrier integrity and mediating innate immune responses against pathogenic entry of foreign particles through their epithelium lining 1-3. Two specialized epithelial cell types dominate this niche: ¬at alveolar type I cells (ATIs), which constitute the majority of the alveolar lining and form the thin air–blood barrier, and cuboidal alveolar type II cells (ATIIs), which serve as facultative progenitors of the alveoli3,4 . ATIIs secrete surfactant proteins and lipids to reduce surface tension and prevent alveolar collapse, while also acting as immune sentinels that express pattern-recognition receptors, orchestrating host defense and coordinating repair following injury ","cbCaiikoVetGqdS2","https://ap.wps.com/l/cbCaiikoVetGqdS2","pdf",9014153,46,"English","# Bioprinted alveolar epithelial sacculoids (AES)\n## Rationale and limitations of current ex-vivo lung models\n## Bioprinting strategy and structural organization of AES\n## Ventilation platform and Hippo pathway mechanotransduction\n## Influenza infection and injury-repair-like plasticity\n## Applications toward physiologically relevant respiratory research","[{\"question\":\"What problem does the AES model address in distal lung research?\",\"answer\":\"It aims to create an ex-vivo system that captures both the alveolar structural hierarchy and a physiologic mechanical environment, which current organoid and 2D cultures do not adequately provide.\"},{\"question\":\"How are alveolar epithelial sacculoids constructed and organized?\",\"answer\":\"They are bioprinted from pluripotent stem cell-derived alveolar epithelial type II cells into defined 3D geometries, where the tissues reproducibly self-organize into multi-unit lumenized sacs with polarized epithelia and functional heterogeneity.\"},{\"question\":\"What does apical influenza infection reveal using AES?\",\"answer\":\"It triggers canonical antiviral responses and epithelial plasticity resembling injury-induced alveolar repair, including depletion of functional ATIIs and emergence of proliferative ATIIs and transitional states.\"}]","Bioprinted Ventilated 3D Alveoliform Epithelial Sacculoids - foundation for physiologically ventilated human alveolar niche models | PDF",1790709237,116]