Synergizing stem cells with biomaterials for therapeutic angiogenesis in ischemic diseases

Therapeutic angiogenesis (TA) is a promising strategy for treating ischemic diseases, mainly by targeting the angiogenesis pathways and cells, particularly VEGF and endothelial progenitor cells. Although stem cell therapy has been extensively investigated, its clinical translation remains limited by challenges such as poor cell retention, low survival rates, and inefficient integration. In this review, we propose a mechanism-based framework of angiogenesis to discuss how biomaterials act synergistically with stem cells mainly through two distinct pathways: enhancing paracrine capacity and promoting direct differentiation of vascular lineage cells for vascular repair. Firstly, we go through the scientific literature and clinical studies, and summary the researches on biomaterials serve as artificial microenvironments to improve the retention and secretory function of mesenchymal stem cells (MSCs) and adipose-derived stem cells (ADSCs), thereby maximizing the release of angiogenic factors such as VEGF, bFGF, NGF, microRNA and so on. Secondly, we explore how functionalized biomaterials guide the in situ recruitment of endothelial progenitor cells (EPCs) and support the structural maturation of induced pluripotent stem cell (iPSC)-derived endothelial cells. By integrating these mechanism-driven approaches, we offer new perspectives on future directions for preclinical research and clinical translation of biomaterial-based therapies. Overall, this review has examined the role of individual stem cells and biomaterials, especially enhanced angiogenesis by stem cells focusing on their mechanisms of action and preclinical and clinical applications. We further discussed the challenges encountered by stem cell therapy in advancing to the stage of clinical transformation and considered future prospects.