Fabrication And Immunomodulatory Osteogenesis Of Quercetin Solid Lipid Nanoparticle Composite Temperature-Sensitive Hydrogel Scaffolds

【Background】Bone defects represent an ongoing challenge in clinical practice.Although repair therapies based on tissue-engineered materials have attracted increasing attention,the treatment of large-scale bone defects still has a lot of drawbacks.In contrast,bone immunomodulation is emerging with great interest recently,as an approach to modulate the immune microenvironment around the wound by implanting scaffolds with bone immunomodulatory properties around the bone defect site.Macrophages play an influential role in mediating bone immunomodulation by serving as an essential entry point for bone immunomodulation.Primitive M0-type macrophages regulate bone reconstruction by polarizing into different types.Quercetin has been reported to possess the capacity to attenuate M1-type polarization,which drives osteoclastic and inflammatory processes,while driving macrophages to M2-type polarization,which favors osteogenesis,thereby inhibiting osteoclastic processes and promoting osteogenesis,thus facilitating bone reconstruction.In this study,we aim to develop a scaffold based on the immunomodulatory properties of quercetin to promote bone defect reconstruction and validate it in rat models with critical size cranial defects.【Methods】Based on the immunomodulatory inflammatory microenvironmental properties of quercetin,we encapsulated quercetin solid lipid nanoparticles(SLNs)in hydrogels.Temperature-responsive poly(ε-caprolactone-co-polymer)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-polymer)(PCLA)modifications were coupled to the backbone of hyaluronic acid(HA)hydrogels to construct a novel,injectable QueSLN@HA-PCLA bone immunomodulatory hydrogel scaffold.The scaffold characterization was used to reveal the basic properties of the scaffold construction and scaffold,and the affinity of the material for cells and the effect of promoting osteogenesis were investigated from cellular experiments,as well as the intrinsic mechanism of immunomodulatory macrophage polarization affecting its osteogenic effect was confirmed and explored.Furthermore,we established rat cranial defect models to further reveal the ability of the composite hydrogel scaffold to promote bone repair from the perspective of animal experiments,followed by an in-depth investigation of the mechanism of immune regulation of macrophage polarization by histological methods of section staining.【Results】Characterization of the scaffold exposed the excellent stability and drug release capacity of the scaffold.Extensive in vitro and in vivo data in this study indicated that this bone immunomodulatory scaffold possesses promising cellular affinity and forms an anti-inflammatory microenvironment by reducing M1 polarization while increasing M2 polarization.A synergistic effect on angiogenesis and anti-osteoclast differentiation has been observed as well.【Conclusion】The Que-SLN@HA-PCLA bone immunomodulatory scaffold which was developed in this study can effectively assist bone defect reconstruction in rats through the immunomodulatory ability of macrophage polarization,providing new insights for large-scale bone defect repair.