Sculpting microvascular networks in 4D: Dynamic growth factor presentation for engineered tissues

The ability of living tissues to form intricate vascular networks is not a matter of chance, but the result of a finely tuned dialogue between cells and their microenvironment. At the heart of this process lies the extracellular matrix (ECM), a dynamic scaffold that does far more than provide structural support. The ECM stores, releases, and re-presents biochemical signals in a temporally and spatially controlled manner, orchestrating the growth and remodeling of blood vessels as tissues develop and repair themselves. In contrast, most tissue engineering strategies simplify this complexity by relying on static systems that release one or two growth factors in a slow and sustained manner. Such approaches may initiate early vascular sprouting, but they lack the temporal flexibility required to guide vessels through the successive stages of maturation and remodeling. The outcome is often unstable networks that fail to persist, especially when translated from controlled laboratory settings to the unpredictable environment of living systems.

This thesis sets out to bridge that gap by reimagining how engineered tissues can interact with biochemical signals. Drawing inspiration from the ECM, this thesis presents a biomaterial design strategy for dynamically presenting multiple growth factors, allowing their availability to evolve over time. By recreating the shifting gradients that naturally guide vascular morphogenesis, these materials provide cells with a sequence of cues that steer the formation, maturation, and stabilization of blood vessel networks. Through this work, I demonstrate that vascular development can be more effectively controlled when tissues are provided with not just the right signals, but also at the right time and place. In doing so, this research opens the door to more physiologically relevant engineered tissues, bringing us closer to building functional constructs that integrate seamlessly with the body’s own systems.