Acellular implantable and injectable hydrogels for vascular regeneration

In recent years, therapeutic angiogenesis has been sought as a treatment for many vascular disorders, including peripheral artery disease and coronary artery disease. As mechanisms of angiogenesis and vasculogenesis have been elucidated, the functions of important growth factors and cytokines have been identified. Bolus injections of these growth factors have had limited clinical success because of their short half-lives and difficulty controlling their systemic effects. Over the last 15 years, many hydrogel technologies have been developed to help solve these issues. Many of these hydrogel technologies have aimed to conjugate pro-angiogenic growth factors with controlled, local delivery. However, in order to attain maximum therapeutic effects, multiple growth factors are necessary, owing to the complex nature of the angiogenic pathway. While many groups have successfully conjugated growth factors controlling different steps of angiogenesis, clinical success remains elusive and will likely rely on both spatial and temporal control over growth factor release as these systems evolve in the future. A number of physical factors of the microenvironment also play a vital role in regulating angiogenesis, including ultrastructure, degradability, and matrix stiffness. Vascular engineering research has been advanced by design of hydrogels that decouple the effects of physical and biological factors, to enhance the understanding of the myriad factors involved in vascular morphogenesis. Recently, hydrogels have been developed to influence microenvironmental factors, such as hypoxia, upstream of growth factor production. By triggering angiogenesis further upstream, a more robust angiogenic response may be achieved by promoting the entire array of growth factors and cytokines necessary for new vessel formation and stabilization. As the field moves forward, study of other upstream environmental factors will likely provide insights into the formation of neovascularature as well as providing opportunities for design of novel hydrogel systems with vast therapeutic potential.