Fibrin-based factor delivery for therapeutic angiogenesis: friend or foe?

Therapeutic angiogenesis aims at promoting the growth of blood vessels to restore perfusion in ischemic tissues or aid tissue regeneration. Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis in development, repair, and disease. However, exploiting VEGF for therapeutic purposes has been challenging and needs to take into account some key aspects of VEGF biology. In particular, the spatial localization of angiogenic signals within the extracellular matrix is crucial for physiological assembly and function of new blood vessels. Fibrin is the provisional matrix that is universally deposited immediately after injury and supports the initial steps of tissue regeneration. It provides therefore several ideal features as a substrate to promote therapeutic vascularization, especially through its ability to present growth factors in their physiological matrix-bound state and to modulate their availability for signaling. Here, we provide an overview of fibrin uses as a tissue-engineering scaffold material and as a tunable platform to finely control dose and duration of delivery of recombinant factors in therapeutic angiogenesis. However, in some cases, fibrin has also been associated with undesirable outcomes, namely the promotion of fibrosis and scar formation that actually prevent physiological tissue regeneration. Understanding the mechanisms that tip the balance between the pro- and anti-regenerative functions of fibrin will be the key to fully exploit its therapeutic potential.