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Ozdemir T, Fowler EW, Liu S, et al. Tuning Hydrogel Properties to Promote the Assembly of Salivary Gland Spheroids in 3D. ACS Biomater Sci Eng. 2016;2(12):2217-2230doi: 10.1021/acsbiomaterials.6b00419.
Ozdemir, T., Fowler, E. W., Liu, S., Harrington, D. A., Witt, R. L., Farach-Carson, M. C., Pradhan-Bhatt, S., & Jia, X. (2016). Tuning Hydrogel Properties to Promote the Assembly of Salivary Gland Spheroids in 3D. ACS biomaterials science & engineering, 2(12), 2217-2230. https://doi.org/10.1021/acsbiomaterials.6b00419
Ozdemir, Tugba, et al. "Tuning Hydrogel Properties to Promote the Assembly of Salivary Gland Spheroids in 3D." ACS biomaterials science & engineering vol. 2,12 (2016): 2217-2230. doi: https://doi.org/10.1021/acsbiomaterials.6b00419
Ozdemir T, Fowler EW, Liu S, Harrington DA, Witt RL, Farach-Carson MC, Pradhan-Bhatt S, Jia X. Tuning Hydrogel Properties to Promote the Assembly of Salivary Gland Spheroids in 3D. ACS Biomater Sci Eng. 2016 Dec 12;2(12):2217-2230. doi: 10.1021/acsbiomaterials.6b00419. Epub 2016 Oct 18. PMID: 27990487; PMCID: PMC5155608.
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ACS Biomater Sci Eng. 2016 Dec 12;2(12):2217-2230. doi: 10.1021/acsbiomaterials.6b00419. Epub 2016 Oct 18.

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

ACS biomaterials science & engineering

Tugba Ozdemir, Eric W Fowler, Shuang Liu, Daniel A Harrington, Robert L Witt, Mary C Farach-Carson, Swati Pradhan-Bhatt, Xinqiao Jia

Affiliations

  1. Department of Materials Science and Engineering, University of Delaware, 210 South College Ave., Newark, DE 19716, USA.
  2. Department of BioSciences, Rice University, 6100 Main St., Houston, TX 77005, USA.
  3. Department of Biological Sciences, University of Delaware, 210 South College Ave., Newark, DE, 19716, USA; Helen F. Graham Cancer Center and Research Institute, Christiana Care Health Systems, 4701 Ogletown Stanton Rd., Newark, DE, 19713, USA.
  4. Department of BioSciences, Rice University, 6100 Main St., Houston, TX 77005, USA; Department of Biological Sciences, University of Delaware, 210 South College Ave., Newark, DE, 19716, USA; Department of Bioengineering, Rice University, 6100 Main St., Houston, TX 77005, USA.
  5. Department of Biological Sciences, University of Delaware, 210 South College Ave., Newark, DE, 19716, USA; Helen F. Graham Cancer Center and Research Institute, Christiana Care Health Systems, 4701 Ogletown Stanton Rd., Newark, DE, 19713, USA; Department of Biomedical Engineering, University of Delaware, 210 South College Ave., Newark, DE 19716, USA.
  6. Department of Materials Science and Engineering, University of Delaware, 210 South College Ave., Newark, DE 19716, USA; Department of Biological Sciences, University of Delaware, 210 South College Ave., Newark, DE, 19716, USA; Department of Biomedical Engineering, University of Delaware, 210 South College Ave., Newark, DE 19716, USA.

PMID: 27990487 PMCID: PMC5155608 DOI: 10.1021/acsbiomaterials.6b00419

Abstract

Current 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.

Keywords: Elastic Modulus; Hyaluronic Acid-Based Hydrogels; Permissive Network; Salivary Human Stem/Progenitor Cells; Thiol/Acrylate Ratio; Xerostomia

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