Cell–Material Interactions in Vascular Tissue Engineering

The vascular system, encompassing blood and lymphatic vessels, is essential for nutrient transport, waste elimination, and homeostasis regulation. Composed of endothelial cells and mural cells, such as smooth muscle cells and pericytes, the vasculature is critical for various physiological processes, including development, organogenesis, wound healing, and tumor metastasis. The interplay between the biophysical properties of the extracellular matrix and its biochemical composition significantly influences vascular function and integrity. However, studying these complex interactions in vivo presents considerable challenges, underscoring the need for innovative research methodologies. For example, traditional 2D cell culture fails to account for the complex, multifaceted environment that cells are exposed to in vivo. Vascular tissue engineering has emerged as a promising approach, aiming to replicate the architecture and functionality of blood vessels to enhance understanding of vascular development and pathology. A central facet of vascular tissue engineering is biomaterial design, in which natural or synthetic polymers are assembled into water-swollen networks, or hydrogels, for 3D cell cultures that can last days or weeks. By utilizing hydrogel biomaterials, researchers can create tunable model systems that closely mimic the natural vascular environment, such as by modifying polymer backbone functionalization and the local biochemical environment or altering the resultant physical properties of the hydrogel. These customizable microenvironments facilitate critical cell–matrix interactions, enabling investigations into key vascular mechanisms such as adhesion, migration, proliferation, and differentiation. This Account explores key aspects of cell–matrix interactions in vascular tissue engineering and the biomaterials designed to study them. We begin with advancements in material design that replicate the spatial and mechanical properties of vascular tissues: matrix stiffness can be tuned to mimic the stiffness of in vivo tissues, viscoelasticity is introduced to replicate the time-dependent strain associated with biologic fluids and tissues, spatial orientation is designed to mimic the architecture common to naturally occurring extracellular matrix, and degradation is an inherent feature of these materials to facilitate cell-caused microenvironment remodeling. We then examine how the biochemical properties of materials influence vascular function: matrix composition can replicate the factors expected in the vascular extracellular matrix, bioactive cues are presented to match the complex gradients formed by paracrine signaling, and hypoxia can be introduced via material design to understand how angiogenesis occurs at the edges of existing vascular networks. Finally, we identify major challenges in the field, highlighting current obstacles and proposing future strategies to enhance the characterization of vascular tissue constructs. These insights aim to advance effective methods in vascular tissue engineering and characterize the biological mechanisms responsible for endothelial cell vascularization.