Sustained delivery of growth factors and alendronate using partially demineralized dentin matrix for endogenous periodontal regeneration

Abstract The decreasing number and reduced osteogenic differentiation capacity of mesenchymal stem cells (MSCs) and the excessive proliferation of osteoclasts in periodontal defects lead to difficulty in periodontal regeneration. Growth factors have powerful impacts on stem cell recruitment and differentiation, and alendronate (ALN) is a potent inhibitor of osteoclasts, which exert precise roles in periodontal regeneration. However, they are all hydrophilic molecules, typically delivered in a soluble format and rapidly released at supraphysiologic doses, which have side effects. In this study, we developed a simple and robust approach to the sustained release of bioactive molecules for endogenous periodontal regeneration. The release system was based on partially demineralized dentin matrix (PDD) in which growth factors were entrapped and hydroxyapatite was only distributed in the interior of the dentin tubules. ALN was then anchored inside PDD, after which PDD-ALN was obtained. PDD-ALN could stably release physiological concentrations of BMP-2, VEGFA, and ALN in a sustained manner. This delivery system exhibits three synergistic effects on bone microenvironment: i) PDD-ALN enhanced MSC migration and their osteogenic differentiation related to the BMP/Smad signaling pathway; ii) PDD-ALN inhibited the formation and function of osteoclasts related to the NF-κB, p38, and ERK1/2 signaling pathways; iii) PDD-ALN enhanced angiogenesis in umbilical vein endothelial cells related to the VEGFA/VEGFR2 signaling networks. PDD-ALN ultimately promoted periodontal regeneration in a rat model. This simple and low-cost technology provides a new idea for constructing an efficient delivery system and has promising prospects for the repair of defects in bone metabolic diseases.