CAREER: Investigating Biophysical and Biochemical Drivers of Fibrosis Progression and Regression Across Diverse Engineered In Vitro Platforms

Fibrosis, or excess tissue production, can occur as a result of injury or inflammation in many tissues throughout the body. If unchecked, fibrosis can disrupt organ function. How specific cells within tissues contribute to fibrosis in certain organs is unknown, which makes it difficult to develop targeted treatments. This project will develop in vitro models to study fibrosis in the pancreas, skin, and uterine fibroids. The pancreatic fibrosis model will study how tissue stiffness, which increases during fibrosis, encourages or prevents cells from participating in fibrosis. The skin model will study how tissue stiffness and stretching influence how cells communicate across skin layers during fibrosis. The uterine fibroid model will examine how hormones and hormone disruptors impact fibroid cell growth. The outcomes of this work will expand knowledge of how cells behave in fibrosis in different organs and how certain cells can be targeted to develop therapies in the future. This award will support STEM activities for high school students as well as community engagement activities to improve patient education and healthcare understanding. Fibrosis contributes to 45% of deaths in industrialized nations through chronic pathological conditions, yet knowledge gaps remain about fibrosis initiation, progression, and resolution in different tissues. A critical barrier to fibrosis treatment is limited understanding of how tissue-specific features of the extracellular matrix (ECM) affect how fibrogenic and non-fibrogenic cells participate in fibrosis. This CAREER project aims to engineer many in vitro fibrosis models—pancreas, skin, and uterine fibroids—that designed to enable control over tissue-specific ECM features (stiffness, microstructure), cellular composition, and/or exogenous biochemical interactions for targeted investigation into fibrotic processes. The pancreatic model uses ECM materials with tunable stiffness—methacrylated type I collagen and hyaluronic acid—to study how stiffness and ECM remodeling direct, protect, or hinder cell fate transformations of fibrogenic (pancreatic stellate cells, macrophages) and non-fibrogenic cells (pancreatic epithelial cells, mesenchymal stem cells). The skin fibrosis model recreates skin’s layered structure to independently alter cellular composition and ECM properties (stiffness, alignment, microstructure) and examine cellular crosstalk across skin layers. A novel intramural uterine fibroid model is used to investigate biochemical interactions—sex hormones and endocrine disrupting agents—as drivers of fibrosis that influence fibroid cell growth, ECM deposition, and lymphatic vascular infiltration. Overall, this project uses distinct, yet complementary, approaches to advance in vitro fibrosis models and lower barriers to resolving fibrosis at a cellular level. Integrated education goals focus on expanding STEM participation and increasing STEM and medical literacy. Activities include a re-designed summer biomaterials course for high school students through Worcester Polytechnic Institute’s Frontiers program and a new outreach partnership with the Epworth Free Clinic in Worcester, MA to promote medical literacy and awareness. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.