CGRP‐Loaded ROS‐Responsive Hydrogel Restores Neuro‐Angiogenic Signaling to Promote Bone Regeneration in Diabetes‐Associated Periodontitis

Diabetes exacerbates the development and progression of periodontitis through the aggravation of persistent inflammation and tissue destruction. While the impact of diabetes on peripheral sensory nerves is well-documented, little is known about the role of diabetic neuropathy in bone destruction in diabetes-associated periodontitis. Herein, a significant loss of periodontal nerves is observed in the diabetic state of db/db mice, with trigeminal ganglion neurons showing decreased autophagy. These mice exhibit decreased density of calcitonin gene-related peptide (CGRP)⁺ nerves, correlating with the progression of diabetes and inflammatory state. Furthermore, diabetic mice with periodontitis show greater alveolar bone loss, which can be phenocopied by periodontal denervation. Importantly, CGRP receptor-related components are found to be expressed in periodontal endothelial cells. In both diabetic and denervated periodontium, the loss of CGRP signaling is associated with the reduction of type H vessel density and coupled osterix⁺ osteoprogenitors. To elaborate further, an injectable reactive oxygen species-responsive poly(vinyl alcohol) (PVA)/tsPBA hydrogel is developed for sustained CGRP delivery. Notably, the CGRP-loaded hydrogels promote alveolar bone regeneration via inducing type H vessel formation in diabetic mice. The findings highlight that diabetes-induced sensory nerve damage may exacerbate periodontitis-induced bone loss, and CGRP@PVA/tsPBA hydrogels offer a promising therapeutic strategy for bone regeneration.