Advanced Bioresponsive Drug Delivery Systems for Promoting Diabetic Vascularized Bone Regeneration

The treatment of bone defects in diabetes mellitus (DM) patients remains a major challenge since the diabetic microenvironments significantly impede bone regeneration. Many abnormal factors including hyperglycemia, elevated oxidative stress, increased inflammation, imbalanced osteoimmune, and impaired vascular system in the diabetic microenvironment will result in a high rate of impaired, delayed, or even nonhealing events of bone tissue. Stimuli-responsive biomaterials that can respond to endogenous biochemical signals have emerged as effective therapeutic systems to treat diabetic bone defects via the combination of microenvironmental regulation and enhanced osteogenic capacity. Following the natural bone healing processes, coupling of angiogenesis and osteogenesis by advanced bioresponsive drug delivery systems has proved to be of significant approach for promoting bone repair in DM. In this Review, we have systematically summarized the mechanisms and therapeutic strategies of DM-induced impaired bone healing, outlined the bioresponsive design for drug delivery systems, and highlighted the vascularization strategies for promoting bone regeneration. Accordingly, we then overview the recent advances in developing bioresponsive drug delivery systems to facilitate diabetic vascularized bone regeneration by remodeling the microenvironment and modulating multiple regenerative cues. Furthermore, we discuss the development of adaptable drug delivery systems with unique features for guiding DM-associated bone regeneration in the future.