Tuning Hydrogel Properties to Promote the Assembly of Salivary Gland Spheroids in 3D

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dc.citation.firstpage2217en_US
dc.citation.issueNumber12en_US
dc.citation.journalTitleACS Biomaterials Science & Engineeringen_US
dc.citation.lastpage2230en_US
dc.citation.volumeNumber2en_US
dc.contributor.authorOzdemir, Tugbaen_US
dc.contributor.authorFowler, Eric W.en_US
dc.contributor.authorLiu, Shuangen_US
dc.contributor.authorHarrington, Daniel Antonen_US
dc.contributor.authorWitt, Robert L.en_US
dc.contributor.authorFarach-Carson, Mary C.en_US
dc.contributor.authorPradhan-Bhatt, Swatien_US
dc.contributor.authorJia, Xinqiaoen_US
dc.date.accessioned2017-01-27T22:23:42Zen_US
dc.date.available2017-01-27T22:23:42Zen_US
dc.date.issued2016en_US
dc.description.abstractCurrent treatments for chronic xerostomia, or “dry mouth”, do not offer long-term therapeutic benefits for head and neck cancer survivors previously treated with curative radiation. Towards the goal of creating tissue-engineered constructs for the restoration of salivary gland functions, we developed new hyaluronic acid (HA)-based hydrogels using thiolated HA (HA-SH) and acrylated HA (HA-AES) with a significant molecular weight mismatch. Four hydrogel formulations with varying HA concentration, (1–2.4 wt%) and thiol/acrylate ratios (2/1 to 36/1) and elastic moduli (G’: 35 to 1897 Pa, 2 h post-mixing) were investigated. In our system, thiol/acrylate reaction was initiated rapidly upon mixing of HA-SH/HA-AES to establish thioether crosslinks with neighboring ester groups, and spontaneous sulfhydryl oxidation occurred slowly over several days to install a secondary network. The concurrent reactions cooperatively create a cell-permissive network to allow for cell expansion and aggregation. Multicellular spheroids formed readily from a robust ductal epithelial cell line (Madin-Darby Canine Kidney, MDCK cells) in all hydrogel formulations investigated. Primary salivary human stem/progenitor cells (hS/PCs), on the other hand, are sensitive to the synthetic extracellular environment, and organized acini-like structures with an average diameter of 50 µm were obtained only in gels with G’ ≤ 216 Pa and a thiol/acrylate ratio ≥18. The spheroid size and size distribution were dependent on the HA content in the hydrogel. Cells in hS/PC spheroids formed tight junctions (occludin), remained viable and proliferative, secreted structural proteins (collagen IV and laminin) found in the basement membrane and maintained key stem/progenitor markers. We conclude that incorporation of time-dependent, dynamic features into a covalently crosslinked HA network produces an adaptable hydrogel framework that promotes hS/PC assembly and supports early aspects of salivary morphogenesis, key to reconstitution of a fully functional implantable salivary gland.en_US
dc.identifier.citationOzdemir, Tugba, Fowler, Eric W., Liu, Shuang, et al.. "Tuning Hydrogel Properties to Promote the Assembly of Salivary Gland Spheroids in 3D." <i>ACS Biomaterials Science & Engineering,</i> 2, no. 12 (2016) American Chemical Society: 2217-2230. http://dx.doi.org/10.1021/acsbiomaterials.6b00419.en_US
dc.identifier.doihttp://dx.doi.org/10.1021/acsbiomaterials.6b00419en_US
dc.identifier.urihttps://hdl.handle.net/1911/93793en_US
dc.language.isoengen_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the American Chemical Society.en_US
dc.subject.keywordXerostomiaen_US
dc.subject.keywordSalivary Human Stem/Progenitor Cellsen_US
dc.subject.keywordHyaluronic Acid-Based Hydrogelsen_US
dc.subject.keywordThiol/Acrylate Ratioen_US
dc.subject.keywordElastic Modulusen_US
dc.subject.keywordPermissive Networken_US
dc.titleTuning Hydrogel Properties to Promote the Assembly of Salivary Gland Spheroids in 3Den_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpost-printen_US
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