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Biomimetic Scaffolds Targeting Remediation of Fibrosis and Regeneration of the Salivary Gland
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Xie, Yubing, Cady, Nathaniel, Larsen, Melinda, Mills, Kristen, Sharfstein, Susan, Chair
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Spring 2022
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2022-05
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Abstract
Fibrosis, characterized by aberrant deposition of extracellular matrix (ECM) is a contributor to about 45% of deaths worldwide. Fibrosis in the salivary gland, caused by Sjogren’s syndrome, diabetes mellitus, or radiation therapy for head and neck cancers, results in salivary hypofunction characterized by reduced saliva output or changes in its composition, leading to poor oral and digestive health. Current therapies for salivary hypofunction are palliative and inefficient, and regenerative strategies are an appealing therapeutic alternative. Mesenchymal stem/stromal cell (MSC) therapy can limit fibrosis but faces translational challenges due to transient therapeutic effects. Scaffold-based approaches can improve the efficacy of MSC delivery by localizing MSCs near the tissue, improving MSC engraftment and persistence, potentially modulating the in vivo tissue-resident cells, and promoting tissue regeneration. Ideally, scaffolds should emulate native soft tissue ECM to provide key physical, biochemical and mechanical cues that maintain the regenerative potential of MSCs. In this work, we address the limitations of current scaffolding technologies, by developing a novel cryoelectrospinning process, and exploring scaffold chemistry to fabricate scaffolds that mimic the minimal fibrous backbone, porous morphology, and viscoelasticity of decellularized salivary glands (DSG). We used elastin and alginate as natural, compliant biomaterials and water as the solvent for cryoelectrospinning biocompatible scaffolds. We optimized process parameters to produce a unique honeycomb topography, similar to DSG, and optimized collector plate geometries to produce a high throughput yield of >100 scaffolds/run. We demonstrated 3D stromal and epithelial growth on our cryoelectrospun scaffolds (CES) and showed that their coculture facilitated cell-cell interactions resembling normal tissue structure. We demonstrated the feasibility of maintaining MSC-like primary embryonic day 16 (E16) mesenchyme on CES and the ability of CES to repress fibrotic activity, similar to DSG. We also determined that FGF2 supplementation improved stromal health of primary embryonic mesenchyme on CES. Finally, we demonstrated the antifibrotic properties of CES, primary E16 mesenchyme, and FGF2 by the repression of fibrotic activity of myofibroblasts. Overall, in this work, we have developed novel scaffolds that mimic soft tissue ECM and show great potential for use in in vitro organ models and stromal cell delivery for in vivo regenerative therapy.