Vascularization is a prerequisite for the in vivo survival of tissue engineering constructs, especially large-scale ones. However, due to inadequate research on the underlying mechanisms of physiological angiogenesis in biomaterials, the ability of emerging biotechnologies to facilitate the clinical translation of regenerative medicine strategies is compromised. In contrast, systematic research on these relevant mechanisms can provide key theoretical insights for the development of novel engineering strategies. Taking subcutaneous implantation of a thin, unloaded porous scaffold as the experimental model, this study investigates the progression of its spontaneous physiological vascularization. The experimental results reveal that vascularization is driven by sprouting angiogenesis and subsequent splitting angiogenesis. Specifically, the scaffold is neovascularized by sprouting which is induced by pro-angiogenic factors in the avascular area. This is a spatial process in which a primary vascular network forms and expands from the superficial to the deep regions of the scaffold, and the neovascularization capacity determines the upper limit of the size of living tissue formed within the scaffold. Subsequently, the primary vascular network undergoes remodeling and hierarchical development through splitting, which depends on the response to hemodynamic stress. This is a progressive temporal process, and the developmental capacity of the primary vascular network determines the survival time of this living tissue. Based on this, we propose that engineering interventions be used to provide artificial microenvironmental support in regions and at stages beyond spontaneous vascularization capacity to induce sprouting or facilitate splitting. This way, physiological vascularization of large-scale scaffolds is expected to be achieved.
Zhan et al. (Wed,) studied this question.