Abstract
Radiation therapy for head and neck cancers causes salivary gland dysfunction leading to permanent xerostomia. Limited progress in the discovery of new therapeutic strategies is attributed to the lack of in vitro models that mimic salivary gland function and allow high-throughput drug screening. We address this limitation by combining engineered extracellular matrices with microbubble (MB) array technology to develop functional tissue mimetics for mouse and human salivary glands. We demonstrate that mouse and human salivary tissues encapsulated within matrix metalloproteinase-degradable poly(ethylene glycol) hydrogels formed in MB arrays are viable, express key salivary gland markers, and exhibit polarized localization of functional proteins. The salivary gland mimetics (SGm) respond to calcium signaling agonists and secrete salivary proteins. SGm were then used to evaluate radiosensitivity and mitigation of radiation damage using a radioprotective compound. Altogether, SGm exhibit phenotypic and functional parameters of salivary glands, and provide an enabling technology for high-content/throughput drug testing.
Highlights
Radiation therapy for head and neck cancers causes salivary gland dysfunction leading to permanent xerostomia
While druginduced dry mouth is reversible if the medication(s) is stopped or an alternative pharmacologic exists, a permanent loss of saliva is caused by radiation therapy, which is commonly used to treat nearly 600,000 head and neck cancer patients worldwide annually[3]
We demonstrated that encapsulation within matrix metalloproteinase (MMP)degradable PEG hydrogels, which are degradable via cell-dictated processes, compared to hydrolytically degradable counterparts, promoted polarized lumen formation and the expression of acinar cell-specific markers, such as aquaporin 5 (Aqp5) and the sodium–potassium-chloride cotransporter (Nkcc1)[27]
Summary
Radiation therapy for head and neck cancers causes salivary gland dysfunction leading to permanent xerostomia. Limited progress in the discovery of new therapeutic strategies is attributed to the lack of in vitro models that mimic salivary gland function and allow highthroughput drug screening We address this limitation by combining engineered extracellular matrices with microbubble (MB) array technology to develop functional tissue mimetics for mouse and human salivary glands. Interrogation of the fate of acinar cells post-encapsulation revealed a transition to a keratin-expressing duct-like phenotype[26] These studies confirm that further optimization of culture conditions is needed to support acinar cells and maintain functional tissues. Conditions for isolation and in vitro culture of adult mouse and human salivary gland mimetics (SGm) were optimized and high-throughput functional assays were developed to assess calcium signaling and secretory cell function relative to native tissue. The culmination of this work is a tissue chip platform for both mechanistic studies and radioprotective drug screening to mitigate xerostomia
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