Vascularization is one of the great challenges that tissue engineering faces in order to achieve sizeable tissue and organ substitutes that contain living cells. There are instances, such as skin replacement, in which a tissue-engineered substitute does not absolutely need a preexisting vascularization. However, tissue or organ substitutes in which any dimension, such as thickness, exceeds 400 μm need to be vascularized to ensure cellular survival. Consistent with the wide spectrum of approaches to tissue engineering itself, which vary from acellular synthetic biomaterials to purely biological living constructs, approaches to tissue-engineered vascularization cover numerous techniques. Those techniques range from micropatterns engineered in biomaterials to microvascular networks created by endothelial cells. In this review, we strive to provide a critical overview of the elements that must be considered in the pursuit of this goal and the major approaches that are investigated in hopes of achieving it.

Delayed or absence of vascularization is one of the major reasons for skin engraftment failure in patients with extensive burns. For such trauma victims, the best alternative to a split-thickness graft would be wound coverage with an autologous in vitro reconstructed skin (RS) combining dermis and epidermis with an appropriate microvascularization. We have developed an endothelialized RS based on our self-assembly approach, which is generated from autologous cultured cells without any exogenous angiogenic growth factor or scaffold. After transplantation in athymic mice, an early inosculation between the graft and host vasculatures occurred within 4 days. We also concurrently detected an active invasion of the dermis by host capillaries sprouting from the wound bed. Thus, the microvascular network constructed in vitro within our three-dimensional skin substitute did not only develop functional anastomoses with the host's blood vessels but also promoted a rapid, complete, and optimal vascularization of the implanted tissues by exerting an angiogenic effect compared with control RS. Our model may bring about interesting possibilities for regenerative medicine by leading to faster vascularization in clinical applications. In addition, the endothelialized RS can be a useful in vitro angiogenesis model.