Development of an in vitro Sjögren’s disease tissue chip for mechanistic studies and drug screening 2300053

Abstract

Abstract Introduction This project aims to develop a Sjögren’s disease (SjD) tissue chip for disease modeling and drug discovery. SjD is a chronic autoimmune disorder affecting up to 1% of the global population, characterized by lymphocytic infiltration and destruction of salivary glands, leading to hyposalivation in over 90% of patients. Current treatments are palliative and do not halt disease progression. Although genetic, epigenetic, hormonal, and environmental factors are implicated in SjD development, its etiology remains unclear. While animal models are commonly used, they are costly, low-throughput, and raise ethical concerns. Methods To address these limitations, we are developing an in vitro SjD tissue chip (SDTC) using microbubble (MB) array technology and diseased salivary gland mimetics (SGm) derived from 12-13-week-old MRL/lpr mice, a validated SjD model. The MB array enables generation of > 20 chips per mouse, each containing ∼40 uniform SGm, thereby reducing animal use and increasing assay throughput. Flow cytometry characterized epithelial and immune cells in glands from MRL/lpr mice and C57BL/6 controls. SDTC validation included viability staining and calcium signaling assay as functional readouts in SGm from young (6-7 weeks) and aged (12-13 weeks) MRL/lpr mice, and aged-matched controls. Results The SDTC maintained >90% viability and promoted SGm spheroid growth by day 7. Aged MRL-SGm showed reduced carbachol-induced calcium flux, consistent with SjD secretory dysfunction. Flow cytometry showed acinar-to-ductal cell ratios in C57BL/6 glands matching previous studies, supporting methodological accuracy. Notably, aged MRL glands exhibited increased CD45+ leukocyte infiltration, predominantly T cells. Ongoing studies will assess SDTC cellular composition, gene expression, and tissue architecture. Conclusion This work establishes the first in vitro SjD tissue chip with increased assay throughput and reduced animal use for mechanistic studies and drug screening. Funding Source University of Rochester Environmental Health Sciences Center (EHSC) and NIH Office of Autoimmune Disease Research Topic Categories Technological Innovations in Immunology (TECH)