Effect Evaluation And Mechanisms Of Diabetic Microenvironment Responsive "Dual-Logical" Hydrogel To Promote Bone Defect Repair In Glucose Fluctuation

Background:Diabetic mellitus is a global metabolism-compromised disease that negatively influenced osteogenesis because of its complicated microenvironment including glucose fluctuation（GF）,high oxidative responsive species（ROS）and high level of MMPs.Besides,immune regulation represented by macrophage polarization play an important role in downstream pre-osteoblast differentiation.Therefore,to design a“smart”hydrogel with a“diagnostic”logic to interpret pathological cues（GF,ROS,MMPs）and determine when to release drug in a diabetic microenvironment and a therapeutic logic to program different cargo release to match immune-osteo cascade for better tissue regeneration become a potential strategy for diabetic bone regeneration.Method:Here in this study,we have designed a double network hydrogel containing the 1^st network of TSPBA crosslinked PVA and the 2^nd network of GNPs.IL-10 and BMP-2 were loaded in the composite hydrogel（denoted as HIB）.SD rats,macrophages,pre-osteoblasts were used to evaluate the in vivo and in vitro HIB potential to orchestrate osteoimmunomodulation followed by mitochondrial function measurement to reveal the underlying mechanism.Results:In DM rat model with glucose fluctuation,HIB ideally promoted bone defect regeneration.Meanwhile,HIB excellently boosted M2macrophage polarization and then increased the downstream osteogenic differentiation of pre-osteoblasts.Furthermore,mitochondrial dysfunctional was proved to aggravate the inflammatory microenvironment and to repair mitochondrial function could reduce ROS and recover the endogens redox homeostasis.Conclusion:To sum up,the hydrogel with“diagnostic”and therapeutic logic was proved effective for diabetic osteogenesis and has paved the way to diabetic tissue regeneration treatment for future clinic.