Facile Nanocomposite Hydrogel Scaffold with Sustained Drug Release and Osteo-Immunomodulatory Effects to Enhance Bone Regeneration

High-quality repair of critical bone defects without exogenous cells remains a major clinical challenge worldwide. Herein, we fabricated a nanocomposite hydrogel scaffold (ASA/MSNs/CSH) by incorporating aspirin (ASA)-loaded mesoporous silica nanoparticles (MSNs) into genipin-cross-linked chitosan hydrochloride (CSH). The resulting scaffold was designed to provide immunomodulatory support during the process of bone regeneration. ASA-loaded MSNs were encapsulated in CSH, forming a composite hydrogel capable of sustained drug release for over 35 days. This composite hydrogel was able to meet key criteria for physicochemical properties, mechanical strength, biocompatibility, and cell affinity. The study showed that the scaffolds could create a beneficial immune microenvironment through reducing inflammation and inducing macrophages toward M2-polarized phenotype in vitro. The scaffold also enhanced the osteogenesis of bone marrow mesenchymal stromal cells, as demonstrated by enhancing the alkaline phosphatase activity and the formation of calcium nodules. Meanwhile, the TGF-β/Smad pathway was identified as an important regulatory mechanism via Western blot analysis. Moreover, the critical size defect models were established in rat skulls, and the results demonstrated that the ASA/MSNs/CSH nanocomposite scaffolds exhibited adequate biocompatibility, superior anti-inflammatory effect, and an admirable capacity for bone regeneration in vivo.