Dynamic hybrid-hydrogel lung models decouple matrix composition, stiffness, and fibroblast conditioning to define distinct drivers of fibrotic progression
Year: 2026
Type: preprint
Abstract: Idiopathic pulmonary fibrosis is a devastating chronic lung disease characterized by progressive scarring of the lung, which leads to impaired gas exchange and ultimately death. While research has provided us with extensive understanding on end-stage disease, the factors that lead to forward-feedback loops of fibrotic progression are still not fully known. Cell intrinsic phenotype, pathological extracellular matrix (ECM) composition, and increased tissue stiffness are all hallmarks of advanced fibrosis, but the relative contribution of these factors to disease has been difficult to disentangle using classic in vivo models. In this study we created biomaterials-based 3D lung models that incorporate geometrically relevant co-culture of lung epithelial cells and fibroblasts with tunable stiffness, ECM-containing hybrid-hydrogels. Using this model system, we demonstrated that environmental stiffness has the strongest effect on overall fibroblast phenotype. RNAseq analysis revealed unique gene-level changes in both fibroblasts and epithelial cells due to both composition and stiffness, highlighting the importance of incorporating both factors into any in vivo disease models. Overall, these results reinforce the value of biomaterials-based models in understanding and disentangling contributors to disease pathogenesis.
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: National Science Foundation, U.S. Department of Veterans Affairs, National Institutes of Health, Anschutz Medical Campus, University of Colorado, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: G1416828315, G1466128636, G1556872922, G5519776647, Hybrid Hydrogel Biomaterials Comprising Clickable Decellularized Extracellular Matrix for Engineering Dynamic 3D Models of Fibrosis, CAREER: Spatiotemporally addressable hydrogel biomaterials as tools for investigating fibroblast mechanobiology, Fibroblast Resistance to Apoptosis in Pulmonary Fibrosis, Mechanisms Regulating Lung Injury and Early Lung Fibrosis, University of Colorado Anschutz Medical Campus DRC, Colorado Clinical and Translational Sciences Institute (CCTSI)
OpenAlex ID: W7170093288