Increasing complexity in vascular microphysiological systems: considerations and advances for disease modeling.

Microphysiological systems (MPS) and organ-on-chip (OoC) platforms are miniaturized in vitro models of human tissues that have transformed approaches to disease modeling and drug screening. Compared to traditional cell culture systems, MPS/OoC enable precise control over parameters such as tissue architecture, cell-cell interactions, and biophysical and biochemical cues, allowing recapitulation of native tissue microenvironments and mechanistic studies of disease progression. In the vascular field, MPS have been developed across multiple levels of the vascular hierarchy, including microvascular capillary networks, arteriole- and venule-scale systems, and larger artery and tissue-engineered blood vessel models. These platforms support the investigation of diverse vascular pathologies, ranging from macrovascular disease, such as atherosclerosis, to microvascular dysfunction and barrier failure. In this review, we summarize key engineering and biological considerations for, and pivotal advancements in, vascular MPS development with added complexities such as informed cell sourcing strategies, incorporation of mural and immune populations, the selection and use of dynamic biomaterials, sustained hemodynamic, pulsatile flow, and architectures tailored to specific vascular scales. We conclude by outlining future considerations, including integrating models across the vascular hierarchy, expanding organ-specific vascular platforms, and leveraging single-cell transcriptomics to improve mechanistic analysis and support rational model design.