Dexamethasone Long-Term Controlled Release from Injectable Dual-Network Hydrogels with Porous Microspheres Immunomodulation Promotes Bone Regeneration

Long-lasting, controlled-release, and minimally invasive injectable platforms that provide a stable blood concentration to promote bone regeneration are less well developed. Using hexagonal mesoporous silica (HMS) loaded with dexamethasone (DEX) and poly(lactic-co-glycolic acid) (PLGA), we prepared porous DEX/HMS/PLGA microspheres (PDHP). In contrast to HMS/PLGA microspheres (HP), porous HMS/PLGA microspheres (PHP), DEX/PLGA microspheres (DP), and DEX/HMS/PLGA microspheres (DHP), PDHP showed notable immuno-coordinated osteogenic capabilities and were best at promoting bone mesenchymal stem cell proliferation and osteogenic differentiation. PDHP were combined with methacrylated silk (SilMA) and sodium alginate (SA) to form an injectable photocurable dual-network hydrogel platform that could continuously release the drug for more than 4 months. By adjusting the content of the microspheres in the hydrogel, a zero-order release hydrogel platform was obtained in vitro for 48 days. When the microsphere content was 1%, the hydrogel platform exhibited the best biocompatibility and osteogenic effects. The expression levels of the osteogenic gene alkaline phosphatases, BMP-2 and OPN were 10 to 15 times higher in the 1% group than in the 0% group, respectively. In addition, the 1% microsphere hydrogel strongly stimulated macrophage polarization to the M2 phenotype, establishing an immunological milieu that supports bone regrowth. The aforementioned outcomes were also observed in vivo. The most successful method for correcting cranial bone abnormalities in SD rats was to use a hydrogel called SilMA/SA containing 1% drug-loaded porous microspheres (PDHP/SS). The angiogenic and osteogenic effects of this treatment were also noticeably greater in the PDHP/SS group than in the control and blank groups. In addition, PDHP/SS polarized M2 macrophages and suppressed M1 macrophages in vivo, which reduced the local immune-inflammatory response, promoted angiogenesis, and cooperatively aided in situ bone healing. This work highlights the potential application of an advanced hydrogel platform for long-term, on-demand, controlled release for bone tissue engineering.