Co‐Delivery of Ca‐MOF and Mg‐MOF Using Nanoengineered Hydrogels to Promote In Situ Mineralization and Bone Defect Repair: In Vitro and In Vivo Analysis

Abstract Severe bone defects resulting from traumatic injuries or infections are severe skeletal deficiencies that are unable to regenerate on their own. Despite their effectiveness, current treatments including allografts and artificial bone substitutes, have several drawbacks. This includes poor osseointegration, low biocompatibility and biodegradability, limited cell infiltration, and adverse side effects arising from drug‐loaded substitutes. To overcome these challenges, mineral‐based metal–organic frameworks (MOFs) nanoparticles are successfully synthesized and incorporated into polymeric hydrogels to promote bone healing. The study demonstrates that the combination of Ca‐MOF and Mg‐MOF (Ca/Mg‐MOF) nanoparticles, when incorporated into a hydrogel scaffold, can take various forms: sprayable, injectable, and coating material for orthopedic implants. Furthermore, nanoengineered hydrogels significantly enhance osteogenic differentiation and mineral deposition of preosteoblast cells compared to control groups and individual MOFs. This osteogenic property can be attributed to the cumulative release of Ca ²⁺ and Mg ²⁺ that reached 62.89% ± 3.05 and 18.60% ± 0.65 by day 8, respectively. Micro‐computed tomography and histological analysis of rat model with critical‐size bone defects demonstrate that the bioactive hydrogel can significantly improve new bone formation without using any supplemental drug molecules. These findings underscore the clinical significance of nanoengineered mineral‐based hydrogels to promote osteogenesis and accelerate bone healing.