A multi-functionalized calcitriol sustainable delivery system for promoting osteoporotic bone regeneration both in vitro and in vivo

lMicelle and HA combined into hydrogel for long-term small molecule drug delivery.lCal and HA synergetic enhanced OVX-rBMSCs viability and osteogenic differentiation.lGel+HA-D+M+Cal biocompatibility, degradation, bone regeneration investigated in vivo.lPolydopamine coating increased HA dispersity, provided anchoring sites for micelles. Among metabolic and systemic bone diseases, osteoporosis is known as one of the most progressive disease characterized by bone microstructural deterioration and bone mass reduction. Calcitriol (Cal) is widely accepted as a fat-soluble small molecule drug with reported anti-osteoporotic activity. However, delivery systems capable of local sustained release of small molecule drugs remain a significant challenge. Herein, based on poly(D, L-lactide)-poly(ethylene glycol)-poly(D, L-lactide) (PDLLA-PEG-PDLLA) hydrogels, we developed a thermosensitive and multifunctional sustainable delivery system by doubly integrating with polydopamine modified nano-hydroxyapatite (HA-D) and calcitriol-loaded amino-terminated poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PCL-PEG-NH2) micelles to realize the long-term delivery of small molecule drugs. The sustained release of Cal from the system was associate with triple controlled release effects including the protective screen of the hydrogels over micelles, the reservoir effect of the HA nanoparticles for Cal, and the encapsulation of Cal in micelles. In vitro, results from the present study demonstrated that sustainable delivery system effectively activated osteogenesis, proliferation and migration in these bone mesenchymal stromal cells of ovariectomized rats (OVX-rBMSCs). In vivo, the composite Cal-loaded system was verified to promote bone regeneration in the critical-size femoral epicondyle bone defect model. Meanwhile, little cytotoxicity and appropriate degradation rate of the composite Cal delivery system were revealed. Thus, incorporating Cal into a multifunctional delivery system to perform a long-acting drug delivery in an injectable hydrogel form is a promising therapeutic to improve anti-osteoporotic ability and promote bone regeneration of osteoporosis. We report here the construction of multi-functionalized drug delivery system via integrating thermal-sensitive triblock copolymers with polydopamine coated hydroxyapatite (HA-D) and calcitriol-loaded amino-terminated PCL-PEG-NH2 micelles to realize long-term calcitriol delivery for critical-size bone defect repair in oste