Progress in recapitulating morphogenesis of blood microvascular structures for microphysiological systems development

Microphysiological systems (MPSs) are complex cell culture platforms, designed to closely replicate the cellular microenvironment of tissues under physiopathological conditions. A critical aspect of these systems is the integration of a vascular network, which facilitates nutrient exchange, supports heterotypic cell interactions, and increases culture viability. A top-down engineering approach, where a prefabricated scaffold is used to introduce endothelial cells, has been widely employed. However, promoting self-organization through a bottom-up paradigm has proven more effective in recapitulating the geometric features of microvasculature, particularly the network nature of it as the capillary diameters. In vivo vasculature formation occurs primarily through two self-organization processes: vasculogenesis and angiogenesis. These processes follow a series of co-ordinated and regulated steps, driven by microenvironmental cues such as cell identity and heterogeneity, soluble factor distribution, extracellular matrix composition and mechanics, and flow-induced mechanical strains. By incorporating these parameters into in vitro platforms, researchers can develop physiologically relevant vascularized MPS for applications in drug development and disease modeling. This review explores the key mechanisms underlying vascular self-organization and highlights how they are being integrated into tissue-specific MPS platforms to achieve vascularization, which enhances the potential of MPS for studying various physiological and pathological processes.