Salivary Gland Tissue Engineering and Repair

Pradhan-Bhatt, Swati; Cannon, Kevin S.; Zakheim, Daniel Ross; Harrington, Daniel A.; Duncan, Randall L.; Jia, Xinqiao; Farach-Carson, Mary C.; Witt, Robert L.

doi:10.1016/b978-0-12-397157-9.00050-3

Cited by 4 publications

(7 citation statements)

References 63 publications

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“…These spheroids are not loose aggregates of multiple cells; they are organized entities with a compact spherical structure that are reminiscent of the basic acini units in the salivary gland. 21 Well organized spherical structures with cortical F-actin were detected in DRC18/DRC36 gels, and individual spheroids contained multiple, closely packed cells with distinct nuclei and diminished cytoskeletal actin filaments. In sharp contrast, hS/PCs, when encapsulated in a similarly cross-linked HA hydrogel known to support spheroid formation for cancer cells, 9,10 remained as single cells throughout the culture for up to 28 days (Figure S3A) and eventually died, despite the gel's relatively low stiffness.…”

Section: Acs Biomaterials Science and Engineeringmentioning

confidence: 95%

“…In our study, hS/ PC cultures were terminated once organized spheroids reached phsyiologically relevant dimensions of 50 μm, a prerequisite for the proper function of salivary gland epithelial cells. 12,21 Prolonged incubation of spheroid-laden hydrogel will likely lead to merging of neighboring structures without structural reorganization. 13 The utility of the DRC gels is gauged by the ability of the resident hS/PCs to reach this critical dimension within the time frame of the experiments.…”

Section: Acs Biomaterials Science and Engineeringmentioning

confidence: 99%

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

Özdemir

Fowler

Liu

et al. 2016

ACS Biomater. Sci. Eng.

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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.

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Section: Acs Biomaterials Science and Engineeringmentioning

confidence: 95%

Section: Acs Biomaterials Science and Engineeringmentioning

confidence: 99%

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

Özdemir

Fowler

Liu

et al. 2016

ACS Biomater. Sci. Eng.

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“…The organelles and membrane proteins in these cells segregate heterogeneously in various locations of the intracellular space such that apical, lateral and basal surfaces form. 1, 5 …”

Section: Salivary Gland Anatomy and Physiologymentioning

confidence: 99%

“…Ultimately, the engineered construct containing integrated structural components will be implanted to the site of radiation injury for tissue regeneration purposes. 5 Such an autologous cell-based, reverse engineering approach for salivary gland restoration is challenging, as the tissue development and maturation depends on the reciprocal interactions between various types of cells and tissues comprising and surrounding the gland to promote cell survival, proliferation, apoptosis, adhesion, motility and morphological changes. Ex vivo culture of mouse embryonic submandibular gland tissues has revealed key insights in developmental biology, 6–8 that can inform and direct biomaterials-based approaches for reconstitution of salivary gland architecture and function.…”

Section: Introductionmentioning

confidence: 99%

Biomaterials-based strategies for salivary gland tissue regeneration

et al. 2016

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The salivary gland is a complex, secretory tissue that produces saliva and maintains oral homeostasis. Radiation induced salivary gland atrophy, manifested as “dry mouth” or xerostomia, poses a significant clinical challenge. Tissue engineering recently has emerged as an alternative, long-term treatment strategy for xerostomia. In this review, we summarize recent efforts towards the development of functional and implantable salivary glands utilizing designed polymeric substrates or synthetic matrices/scaffolds. Although the in vitro engineering of a complex implantable salivary gland is technically challenging, opportunities exist for multidisciplinary teams to harvest the regenerative potential of stem/progenitor cells found in the adult glands and combine them with biomimetic and cell-instructive materials to assemble implantable tissue modules.

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“…Multiple laboratories, including our own, have contributed discoveries toward the broader goal of bioengineering salivary glands for replacement of irradiated, dysfunctional salivary glands. These contributions include integration of select cell populations and implementation in multiple biomaterial matrices [20][21][22][23][24]. Ultimately, clinical translation of these models will require a biocompatible matrix that will enable incorporation of the implanted neotissue.…”

Section: Introductionmentioning

confidence: 99%

Functionalized Biomimetic Hydrogels Enhance Salivary Stem/Progenitor Cell Organization

Martinez

Witt

Farach‐Carson

et al. 2021

Preprint

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Complex branched salivary structures remain challenging to replicate within implant ready hydrogels. We showed previously that hyaluronic acid (HA)-based hydrogels enable growth and organization of primary salivary-derived human stem/progenitor cells (hS/PCs) into multicellular spheroids. Here, we systematically functionalized three components of migration-permissive hydrogels to foster salivary tissue morphogenesis. We separately analyzed contributions of an enzymatically degradable crosslinker, a pendant integrin-binding site, and hydrogel porosity to best support high viability, integrin-dependent cell adhesion and migration. Structure size, frequency, and morphology were all affected by hydrogel crosslink density and integration of biofunctional peptides. Viability and proliferation data suggested that integration of integrin binding sites had the greatest effect on hS/PCs behavior. A larger internal matrix space, created by increasing both crosslinker length and PEG content, was needed to form large multicellular hS/PC structures. Peptide-modified hydrogels with more internal space shifted hS/PC organization from spheroidal, surrounded by thick basement membrane, to an asymmetric arrangement with punctate matrix proteins defining a “wrinkled” perimeter. Integrin-binding peptides activated integrin β1, with highest activation observed in hydrogels having both cleavable peptide and integrin ligand. The design parameters we prescribe allowed us to encapsulate hS/PCs in a humanized biomimetic hydrogel matrix able to support morphogenesis needed for salivary restoration.

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Salivary Gland Tissue Engineering and Repair

Cited by 4 publications

References 63 publications

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

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

Biomaterials-based strategies for salivary gland tissue regeneration

Functionalized Biomimetic Hydrogels Enhance Salivary Stem/Progenitor Cell Organization

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