Biomaterial-Based Lymphangiogenesis-Enhanced Therapeutic Strategy for Robustly-Integrated Medication-Related Osteonecrosis of Jaw Prevention

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse effect associated with antiresorptive drugs, including bisphosphonates (BPs), and its pathogenesis remains unclear. The incidence of MRONJ is increasing; however, effective preventive strategies remain limited, and few studies have investigated the application of biomaterials for its prevention. In this study, we first demonstrated that zoledronic acid (ZA) suppresses the PI3K/AKT signaling pathway in endothelial cells, a key regulator of angiogenesis and lymphangiogenesis, while simultaneously inducing apoptosis. Building on this finding, we established a rat model of MRONJ-like lesions to examine vascular and lymphatic alterations during disease progression. This model exhibited a marked impairment of angiogenesis and lymphangiogenesis in both the extraction sockets and the surrounding soft tissues. Insulin-like growth factor (IGF-1), a known pathway PI3K/AKT agonist, was subsequently introduced and shown to restore the pathway activity and enhance endothelial cell function in vitro. To further explore its therapeutic potential, we developed an IGF-1-loaded hydrogel for localized administration in an MRONJ prevention model. This hydrogel significantly promoted angiogenesis and lymphangiogenesis and successfully prevented the onset of MRONJ-like lesions in rats. These findings suggest that PI3K/AKT pathway suppression underlies BP-induced vascular and lymphatic dysfunction and that IGF-1 delivered via a straightforward hydrogel system offers a promising strategy for MRONJ prevention.