Design considerations for engineering 3D models to study vascular pathologies in vitro

Many cardiovascular diseases (CVD) are driven by pathological remodelling of blood vessels, which can lead to aneurysms, myocardial infarction, ischaemia and strokes. Aberrant remodelling is driven by changes in vascular cell behaviours combined with degradation, modification, or abnormal deposition of extracellular matrix (ECM) proteins. The underlying mechanisms that drive the pathological remodelling of blood vessels are multifaceted and disease specific; however, unravelling them may be key to developing therapies. Reductionist models of blood vessels created in vitro that combine cells with biomaterial scaffolds may serve as useful analogues to study vascular disease progression in a controlled environment. This review presents the main considerations for developing such in vitro models. We discuss how the design of blood vessel models impacts experimental readouts, with a particular focus on the maintenance of normal cellular phenotypes, strategies that mimic normal cell-ECM interactions, and approaches that foster intercellular communication between vascular cell types. We also highlight how choice of biomaterials, cellular arrangements and the inclusion of mechanical stimulation using fluidic devices together impact the ability of blood vessel models to mimic in vivo conditions. In the future, by combining advances in materials science, cell biology, fluidics and modelling, it may be possible to create blood vessel models that are patient-specific and can be used to develop and test therapies. STATEMENT OF SIGNIFICANCE: Simplified models of blood vessels created in vitro are powerful tools for studying cardiovascular diseases and understanding the mechanisms driving their progression. Here, we highlight the key structural and cellular components of effective models and discuss how including mechanical stimuli allows researchers to mimic native vessel behaviour in health and disease. We discuss the primary methods used to form blood vessel models and their limitations and conclude with an outlook on how blood vessel models that incorporate patient-specific cells and flows can be used in the future for personalised disease modelling.