Marginal sealing around integral bilayer scaffolds for repairing osteochondral defects based on photocurable silk hydrogels

Osteochondral repair remains a major challenge in current clinical practice despite significant advances in tissue engineering.In particular,the lateral integration of neocartilage into surrounding native cartilage is a difficult and inadequately addressed problem that determines the success of tissue repair.Here,a novel design of an integral bilayer scaffold combined with a photocurable silk sealant for osteochondral repair is reported.First,we fabricated a bilayer silk scaffold with a cartilage layer resembling native cartilage in surface morphology and mechanical strength and a BMP-2-loaded porous subchondral bone layer that facilitated the osteogenic differentiation of BMSCs.Second,a TGF-β3-loaded methacrylated silk fibroin sealant(Sil-MA)exhibiting biocompatibility and good adhesive properties was developed and confirmed to promote chondrocyte migration and differentiation.Importantly,this TGF-β3-loaded Sil-MA hydrogel provided a bridge between the cartilage layer of the scaffold and the surrounding cartilage and then guided new cartilage to grow towards and replace the degraded cartilage layer from the surrounding native cartilage in the early stage of knee repair.Thus,osteochondral regeneration and superior lateral integration were achieved in vivo by using this composite.These results demonstrate that the new approach of marginal sealing around the cartilage layer of bilayer scaffolds with Sil-MA hydrogel has tremendous potential for clinical use in osteochondral regeneration.

Regulating macrophage-MSC interaction to optimize BMP-2-induced osteogenesis in the local microenvironment

Bone morphogenetic protein(BMP-2)has been approved by the FDA to promote bone regeneration,but uncertain osteogenic effect and dose-dependent side effects may occur.Osteoimmunomodulation plays an important role in growth factor-based osteogenesis.Here,we explored how proinflammatory signals affect the dose-dependent osteogenic potential of BMP-2.We observed that the expression level of local IL-1βdid not increase with the dose of BMP-2 in the mouse osteogenesis model.A low dose of BMP-2 could not promote new bone formation,but trigger the release of IL-1βfrom M1 macrophages.As the dose of BMP-2 increased,the IL-1βexpression and M1 infiltration in local microenvironment were inhibited by IL-1Ra from MSCs under osteogenic differentiation induced by BMP-2,and new bone tissues formed,even excessively.Anti-inflammatory drugs(Dexamethasone,Dex)promoted osteogenesis via inhibiting M1 polarization and enhancing BMP-2-induced MSC osteo-differentiation.Thus,we suggest that the osteogenic effect of BMP-2 involves macrophage-MSC interaction that is dependent on BMP-2 dose and based on IL-1R1 ligands,including IL-1βand IL-1Ra.The dose of BMP-2 could be reduced by introducing immunoregulatory strategies.

Control of lupus activity during pregnancy via the engagement of IgG sialylation:novel crosstalk between IgG sialylation and pDC functions

Immunoglobulin(IgG)glycosylation affects the effector functions of IgG in a myriad of biological processes and has been closely associated with numerous autoimmune diseases,including systemic lupus erythematosus(SLE),thus underlining the pathogenic role of glycosylation aberration in autoimmunity.This study aims to explore the relationship between IgG sialylation patterns and lupus pregnancy.Relative to that in serum samples from the control cohort,IgG sialylation level was aberrantly downregulated in serum samples from the SLE cohort at four stages(from preconception to the third trimester of pregnancy)and was significantly associated with lupus activity and fetal loss during lupus pregnancy.The type I interferon signature of pregnant patients with SLE was negatively correlated with the level of IgG sialylation.The lack of sialylation dampened the ability of IgG to suppress the functions of plasmacytoid dendritic cells(pDCs).RNA-seq analysis further revealed that the expression of genes associated with the spleen tyrosine kinase(SYK)signaling pathway significantly differed between IgG-and deSia-IgG-treated pDCs.This finding was confirmed by the attenuation of the ability to phosphorylate SYK and BLNK in deSia-IgG.Finally,the coculture of pDCs isolated from pregnant patients with SLE with IgG/deSia-IgG demonstrated the sialylation-dependent anti-inflammatory function of IgG.Our findings suggested that IgG influences lupus activity through regulating pDCs function via the modulation of the SYK pathway in a sialic acid-dependent manner.

Preservation of alveolar ridge height through mechanical memory: A novel dental implant design

Irreversible marginal bone loss can hinder recovery around dental implants.Insufficient alveolar osteogenesis and stress concentration during chewing contribute to marginal bone resorption and can result in implant failure.A biomaterial with a micropore-channel structure was developed using 3D printing technology.This design facilitated bony ingrowth and provided similar mechanical stimulation at the implant neck during mastication to a natural tooth.The micropore channels provided a guiding structure for bone mesenchymal stem cell proliferation and differentiation without the need for growth factors.Specifically,this was achieved through mechanical transduction by F-actin remodeling and the activation of Yes-associated protein(YAP).The implants were verified in a canine dental implant surgery model,which demonstrated the promising use of biomaterialbased dental implants in future clinical applications.

Orchestration of energy metabolism and osteogenesis by Mg^(2+)facilitates low-dose BMP-2-driven regeneration

The clinical application of bone morphogenetic protein-2(BMP-2)is limited by several factors,including ineffectiveness at low doses and severe adverse effects at high doses.To address these efficacy and safety limitations,we explored whether orchestration of energy metabolism and osteogenesis by magnesium ion(Mg^(2+))could reduce the dose and thereby improve the safety of BMP-2.Our results demonstrated that rapid metabolic activation triggered by BMP-2 was indispensable for subsequent osteogenesis.Moreover,inadequate metabolic stimulation was shown to be responsible for the ineffectiveness of low-dose BMP-2.Next,we identified that Mg^(2+),as an"energy propellant",substantially increased cellular bioenergetic levels to support the osteogenesis via the Akt-glycolysis-Mrs2-mitochondrial axis,and consequently enhanced the osteoinductivity of BMP-2.Based on the mechanistic discovery,microgel composite hydrogels were fabricated as low-dose BMP-2/Mg^(2+)codelivery system through microfluidic and 3D printing technologies.An in vivo study further confirmed that rapid and robust bone regeneration was induced by the codelivery system.Collectively,these results suggest that this bioenergetic-driven,cost-effective,low-dose BMP-2-based strategy has substantial potential for bone repair.