Development of vessel-on-chip device to study mechanisms of deep vein thrombosis

点击翻译按钮获取中文摘要

Deep vein thrombosis (DVT) is a life-threatening disease with mortality exceeding that from breast cancer, HIV, and traffic accidents, combined. Current methods to study mechanisms of DVT are heavily based on animal models and, therefore, development of in vitro approaches that would include the entire complexity of factors to study the disease is timely and highly desirable. DVT develops in a special location inside the veins: valve pockets, a region with a very specific blood flow geometry, where overall flow rate is strongly reduced. This results in inflammation-like changes in the vessel wall leading to thrombosis. Most of the existing flow chamber/microfluidic devices either don't have valves at all or have valves with fixed immobile leaflets. We have recently developed a unique microfluidic chamber containing flexible valve leaflets, which allows for full recapitulation of venous hemodynamics in humans. Moreover, we were able to develop a method to coat the surface of such chamber with human endothelium. In the proposed project, we plan to continue this research direction and further mimic the complexity of the vessel wall by including smooth muscle cells, mast cells, fibroblasts, and extracellular matrix proteins, into cell culture. In particular, based upon our previous studies (Schofield et al. Commun Mater 2020; Baksamawi et al. Front Cardiovasc Med 2023) and in collaboration with the Healthcare Technologies Institute (Prof. Liam Grover, the second supervisor), we will pursue the following objectives:To develop a multi-cell culture including major components of the venous wall inside the microfluidic chamber, and validate the model comparing it to published data obtained in animal-based research.Determine the role of each vessel wall cell type in DVT.Explore/verify the effects of major antithrombotic drugs.As a result, we will create a complete "vessel-on-chip" model and use it to explore mechanisms of DVT initiation. The model will have the following advantages: 1) represent a model of human vein, which by definition removes issues originating from differences between animals and humans 2) better standardized, more reproducible and cheaper than any animal model 4) technically simple and allows for testing of multiple factors 5) allows for easy and fast genetic manipulations with all cellular components to evaluate the impact of separate genes 6) allows for testing blood of patients, which cannot be implemented in animal models 7) may represent a useful clinical tool for predicting the likelihood of DVT in patients 8) does not require Home Office ethical approval.