Vascularization remains a major challenge in tissue engineering. In tissue repair with the involvement of biomaterials, both the material properties and material-induced immune response can affect angiogenesis. However, there is a scarcity of research on biomaterials that modulate angiogenesis simultaneously from both perspectives. Meanwhile, the effects and mechanisms of biomaterial-induced macrophages on angiogenesis remain controversial. In this study, a cytokine-controlled release system from our previous work was employed, and the effects thereof on angiogenesis through both direct and indirect means were investigated. Alginate/chitosan multilayer films were fabricated on interleukin (IL)-4-loaded titania nanotubes to achieve a sustained release of IL-4. The released IL-4 and the multilayers synergistically promoted angiogenic behaviors of endothelial cells (ECs), while up-regulating the expression of early vascular markers. Furthermore, polarized macrophages (both M1 and M2) notably elevated the expression of late vascular markers in ECs via the high expression of pro-maturation factor angiogenin-1.

After subcutaneous implantation, the IL-4-loaded implants induced increased neovascularization in a short period, with the surrounding tissue returning to normal at the later stage. Therefore, the proposed IL-4-loaded implants exhibited superior pro-angiogenic capability in vitro and in vivo through both direct stimulation of ECs and the indirect induction of a suitable immune microenvironment.

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Mishita
Jornal co-ordinator
Journal of Heart and Cardiovascular Research