A new microfluidic model and metabolomic perspective to unlock the mystery of lingering diabetic CVDs

Nearly 37 million Americans have diabetes with a mortality rate of 82.4/100,000. This project will address a major health challenge: why do diabetic patients have an increased risk of cardiovascular diseases (CVDs) even when their blood glucose levels are well controlled. The answer may lie in long-lasting changes to the blood vessels, especially in the supportive structure called the extracellular matrix (ECM). Current research models do not accurately mimic these changes. This project will develop a laboratory model that uses real human artery tissues and advanced microfluidics technology. The model will closely replicate both healthy and diabetic blood vessels, which will help identify how changes in the ECM affect the cells that line blood vessels. The project will also use metabolomics (the study of small molecules in cells) to determine how these structural changes disrupt cell function and contribute to disease. The results from the research may reveal new ways to treat or prevent lingering heart disease in people with diabetes. The project will also provide hands-on training for graduate, undergraduate, and high school students, and engage the local community through educational outreach. The new model and insights could also help studies of other diseases that involve ECM changes. This project will address the persistent risk of CVDs in diabetic patients, even after glycemic control, by investigating the role of vascular basement membrane ECM remodeling. The hypothesis is that diabetes-induced structural changes in the ECM, beyond chemical glycation, reprogram endothelial cell metabolome networks, leading to long-term endothelial dysfunction. Modular, high-throughput microfluidic endothelium models using decellularized human artery tissues (both healthy and diabetic) will be developed as physiologically relevant ECM scaffolds. Human artery endothelial cells will be cultured on these tissues within 3D-printed microfluidic devices, enabling precise control of flow and shear stress. The model will be validated by assessing endothelial viability, proliferation, nitric oxide production, and expression of key biomarkers. The project will systematically compare how healthy versus diabetic ECM microstructures affect core endothelial metabolomic pathways using mass spectrometry. Mechanistic studies will focus on integrin β1 as a transducer of ECM physical cues to intracellular metabolic rewiring. The outcomes will reveal new metabolomic targets and mechanistic insights for persistent diabetic CVDs, and the platform will be broadly applicable to other ECM-related diseases. The project will leverage biomanufacturing techniques to create innovative platforms for biomedical research with potential translational applications in disease modeling and therapy development. These include biofabrication of ECM scaffolds, modular microfluidic device production, and protocols for decellularized tissue preparation. 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.