Micromechanical interlocking structure at the filler/resin interface for dental composites: a review

Dental resin composites(DRCs)are popular materials for repairing caries or dental defect,requiring excellent properties to cope with the complex oral environment.Filler/resin interface interaction has a significant impact on the physicochemical/biological properties and service life of DRCs.

Recent advances in cell sheet technology for bone and cartilage regeneration: from preparation to application

Bone defects caused by trauma,tumour resection,infection and congenital deformities,together with articular cartilage defects and cartilage–subchondral bone complex defects caused by trauma and degenerative diseases,remain great challenges for clinicians.Novel strategies utilising cell sheet technology to enhance bone and cartilage regeneration are being developed.The cell sheet technology has shown great clinical potential in regenerative medicine due to its effective preservation of cell–cell connections and extracellular matrix and its scaffold-free nature.This review will first introduce several widely used cell sheet preparation systems,including traditional approaches and recent improvements,as well as their advantages and shortcomings.Recent advances in utilising cell sheet technology to regenerate bone or cartilage defects and bone–cartilage complex defects will be reviewed.The key challenges and future research directions for the application of cell sheet technology in bone and cartilage regeneration will also be discussed.

The biological function of type I receptors of bone morphogenetic protein in bone

Bone morphogenetic proteins （BMPs） have multiple roles in skeletal development, homeostasis and regeneration. BMPs signal via type I and type II serine/threonine kinase receptors （BMPRI and BMPRII）. In recent decades, genetic studies in humans and mice have demonstrated that perturbations in BMP signaling via BMPRI resulted in various diseases in bone, cartilage, and muscles. In this review, we focus on all three types of BMPRI, which consist of activin-like kinase 2 （ALK2, also called type IA activin receptor）, activin- llke kinase 3 （ALK3, also called BMPRIA）, and activin-like kinase 6 （ALK6, also called BMPRIB）. The research areas covered include the current progress regarding the roles of these receptors during myogenesis, chondrogenesis, and osteogenesis. Understanding the physiological and pathological functions of these receptors at the cellular and molecular levels will advance drug development and tissue regeneration for treating musculoskeletal diseases and bone defects in the future.

Study of Sr–Ca–Si-based scaffolds for bone regeneration in osteoporotic models

Bone tissue engineering has emerged as a promising alternative therapy for patients who suffer bone fractures or defects caused by trauma,congenital diseases or tumours.However,the reconstruction of bone defects combined with osteoporosis remains a great challenge for clinicians and researchers.Based on our previous study,Ca–Si-based bioceramics(MSCs)showed enhanced bone formation capabilities under normal conditions,and strontium was demonstrated to be therapeutic in promoting bone quality in osteoporosis patients.Therefore,in the present study,we attempted to enlarge the application range of MSCs with Sr incorporation in an osteoporotic bone regeneration model to evaluate whether Sr could assist in regeneration outcomes.In vitro readout suggested that Sr-incorporated MSC scaffolds could enhance the expression level of osteogenic and angiogenic markers of osteoporotic bone mesenchymal stem cells(OVX BMSCs).Animal experiments showed a larger new bone area;in particular,there was a tendency for blood vessel formation to be enhanced in the Sr-MSC scaffold group,showing its positive osteogenic capacity in bone regeneration.This study systematically illustrated the effective delivery of a low-cost therapeutic Sr agent in an osteoporotic model and provided new insight into the treatment of bone defects in osteoporosis patients.

Strontium-incorporated bioceramic scaffolds for enhanced osteoporosis bone regeneration

The restoration of bone defects caused by osteoporosis remains a challenge for surgeons.Strontium ranelate has been applied in preventative treatment approaches due to the biological functions of the trace element strontium(Sr).In this study,we aimed to fabricate bioactive scaffolds through Sr incorporation based on our previously developed modified amino-functional mesoporous bioactive glass(MBG)and to systematically investigate the bioactivity of the resulting scaffold in vitro and in vivo in an osteoporotic rat model.The results suggested that Sr-incorporated amino-functional MBG scaffolds possessed favorable biocompatibility.Moreover,with the incorporation of Sr,osteogenic and angiogenic capacities were upregulated in vitro.The in vivo results showed that the Sr-incorporated amino-functional MBG scaffolds achieved better bone regeneration and vessel formation.Furthermore,bioinformatics analysis indicated that the Sr-incorporated amino-functional MBG scaffolds could reduce reactive oxygen species levels in bone marrow mesenchymal stem cells in the osteoporotic model by activating the cAMP/PKA signaling pathway,thus playing an anti-osteoporosis role while promoting osteogenesis.This study demonstrated the feasibility of incorporating trace elements into scaffolds and provided new insights into biomaterial design for facilitating bone regeneration in the treatment of osteoporosis.

The osteogenesis of Ginsenoside Rb1 incorporated silk/micro-nano hydroxyapatite/sodium alginate composite scaffolds for calvarial defect

Ginsenoside Rb1, the effective constituent of ginseng, has been demonstrated to play favorable roles in improving the immunity system. However, there is little study on the osteogenesis and angiogenesis effect of Ginsenoside Rb1. Moreover, how to establish a delivery system of Ginsenoside Rb1 and its repairment ability in bone defect remains elusive. In this study, the role of Ginsenoside Rb1 in cell viability, proliferation, apoptosis, osteogenic genes expression, ALP activity of rat BMSCs were evaluated firstly. Then,micro-nano HAp granules combined with silk were prepared to establish a delivery system of Ginsenoside Rb1, and the osteogenic and angiogenic effect of Ginsenoside Rb1 loaded on micro-nano HAp/silk in rat calvarial defect models were assessed by sequential fluorescence labeling, and histology analysis, respectively. It revealed that Ginsenoside Rb1 could maintain cell viability, significantly increased ALP activity, osteogenic and angiogenic genes expression. Meanwhile, micro-nano HAp granules combined with silk were fabricated smoothly and were a delivery carrier for Ginsenoside Rb1. Significantly, Ginsenoside Rb1 loaded on micro-nano HAp/silk could facilitate osteogenesis and angiogenesis. All the outcomes hint that Ginsenoside Rb1 could reinforce the osteogenesis differentiation and angiogenesis factor’s expression of BMSCs. Moreover, micro-nano HAp combined with silk could act as a carrier for Ginsenoside Rb1 to repair bone defect.

Establishment and assessment of rodent models of medication-related osteonecrosis of the jaw(MRONJ)

Medication-related osteonecrosis of the jaw(MRONJ)is primarily associated with administering antiresorptive or antiangiogenic drugs.Despite significant research on MRONJ,its pathogenesis and effective treatments are still not fully understood.Animal models can be used to simulate the pathophysiological features of MRONJ,serving as standardized in vivo experimental platforms to explore the pathogenesis and therapies of MRONJ.Rodent models exhibit excellent effectiveness and high reproducibility in mimicking human MRONJ,but classical methods cannot achieve a complete replica of the pathogenesis of MRONJ.Modified rodent models have been reported with improvements for better mimicking of MRONJ onset in clinic.This review summarizes representative classical and modified rodent models of MRONJ created through various combinations of systemic drug induction and local stimulation and discusses their effectiveness and efficiency.Currently,there is a lack of a unified assessment system for MRONJ models,which hinders a standard definition of MRONJ-like lesions in rodents.Therefore,this review comprehensively summarizes assessment systems based on published peer-review articles,including new approaches in gross observation,histological assessments,radiographic assessments,and serological assessments.This review can serve as a reference for model establishment and evaluation in future preclinical studies on MRONJ.

Adhesion-enhancing coating embedded with osteogenesis-promoting PDA/HA nanoparticles for peri-implant soft tissue sealing and osseointegration

Following dental implantation,the characteristic bacterial milieu of the oral cavity may lead to peri-implant inflammation,which can negatively impact osseointegration and cause implant failure.To improve soft tissue sealing around the implant,enhance osseointegration,and improve implant success rates,this paper proposes a composite multifunctional coating(PHG)prepared using gelatin and polydopamine/hydroxyapatite nanoparticles,investigates the effects of this novel coating on cell adhesion,proliferation,antibacterial activity,osteogenic differentiation,and evaluates its immune-related properties.The PHG coating was proved to have satisfactory hydrophilicity and wettability for cell attachment.Furthermore,it improved the expression of adhesion-related genes and proteins in human gingival fibroblasts,indicating its adhesion-promoting effect.Additionally,bone marrow mesenchymal stem cells exhibited strong osteogenic differentiation potential and mineralization on PHG-coated surfaces.Notably,the PHG coating exhibited antibacterial activity against Streptococcus mutans,as well as anti-inflammatory effects,potentially via the regulation of macrophages.Therefore,the proposed PHG coating may promote soft tissue sealing and bone bonding,providing a potential strategy for the surface modification of dental implants.

Urchin-like multiscale structured fluorinated hydroxyapatite as versatile filler for caries restoration dental resin composites

Caries is one of the most prevalent human diseases,resulting from demineralization of tooth hard tissue caused by acids produced from bacteria,and can progress to pulpal inflammation.Filling restoration with dental resin composites(DRCs)is currently the most common treatment for caries.However,existing DRCs suffer from low fracture strength and lack comprehensive anti-caries bioactivity including remineralization,pulp protection,and anti-cariogenic bacteria effects.In this study,inspired by plant roots’ability to stabilize and improve soil,fluorinated urchin-like hydroxyapatite(FUHA)with a three-dimensional whisker structure and bioactive components of calcium,phosphorus,and fluorine was designed and synthesized by a dynamic self-assembly method.Furthermore,versatile FUHA particles with different loading fractions were used as functional fillers to fabricate methacrylate-based DRCs,where the urchin-like hydroxyapatite(UHA)filled DRCs and commercial DRCs(Z350XT and BEAUTIFIL II)served as the control groups.The results demonstrated that FUHA with 50 wt%loading in resin matrix endowed DRC(F5)with excellent physicochemical properties,dentin remineralization property,cell viability,promotion of dental pulp stem cells mineralization,and antibacterial properties.Meanwhile,F5 also presented good clinical handling and aesthetic characteristics.Therefore,structure/functional-integrated FUHA filled DRCs have potential as a promising strategy for tooth restoration and anti-caries bioactivity.

Micromechanical interlocking-inspired dendritic porous silicabased multimodal resin composites for the tooth restoration

Porous silica particles have shown great potential application as reinforcing fillers in the field of dentistry due to their ability to construct the micromechanical interlocking effect at filler-matrix interface.However,how to accurately regulate the pore structure,especially the pore size,to increase the degree of the micromechanical interlocking and the performance of materials remains a challenge.Herein,we have proposed a facile self-assembly process to synthesize dendritic porous silica with tunable pore sizes(DPS-x)by adjusting the chain-length of the alcohols in the microemulsion.The mechanism of nucleation-growth is further put forward.The results indicate that the pore size of DPS-x indeed affects the mechanical property of composites,where the DPSpen particles with intermediate pore size are chosen as the optimal reinforcing fillers.The bimodal and multimodal filler formulations are further established to address the loading limitation of unimodal DPS-pen(46 wt.%).In virtue of the closepacked structure of identical spheres,the particle sizes of secondary silica embedded into the maximally loaded bimodal D3S7 composite(DPS-pen:Si430=30:70,w/w)are theoretically calculated without trials.Among all formulations,the developed multimodal D3S7+Si178+Si90 filler exhibits superior mechanical properties,the lowest shrinkage,and high polymerization conversion for dental composites,along with satisfied waster sorption and solubility,and good biocompatibility in vitro and in vivo,which are comparable to commercial composite Z350 XT(3M,USA).These DPS-x particles and their multimodal fillers can also be applied to other polymer-based biomaterials.

An Injectable silk-based hydrogel as a novel biomineralization seedbed for critical-sized bone defect regeneration

The healing process of critical-sized bone defects urges for a suitable biomineralization environment. However, the unsatisfying repair outcome usually results from a disturbed intricate milieu and the lack of in situ mineralization resources. In this work, we have developed a composite hydrogel that mimics the natural bone healing processes and serves as a seedbed for bone regeneration. The oxidized silk fibroin and fibrin are incorporated as rigid geogrids, and amorphous calcium phosphate (ACP) and platelet-rich plasma serve as the fertilizers and loam, respectively. Encouragingly, the seedbed hydrogel demonstrates excellent mechanical and biomineralization properties as a stable scaffold and promotes vascularized bone regeneration in vivo. Additionally, the seedbed serves a succinate-like function via the PI3K-Akt signaling pathway and subsequently orchestrates the mitochondrial calcium uptake, further converting the exogenous ACP into endogenous ACP. Additionally, the seedbed hydrogel realizes the succession of calcium resources and promotes the evolution of the biotemplate from fibrin to collagen. Therefore, our work has established a novel silk-based hydrogel that functions as an in-situ biomineralization seedbed, providing a new insight for critical-sized bone defect regeneration.

Multifunctionalized carbon-fiber-reinforced polyetheretherketone implant for rapid osseointegration under infected environment

Carbon fiber reinforced polyetheretherketone(CFRPEEK)possesses a similar elastic modulus to that of human cortical bone and is considered as a promising candidate to replace metallic implants.However,the bioinertness and deficiency of antibacterial activities impede its application in orthopedic and dentistry.In this work,titanium plasma immersion ion implantation(Ti-PⅢ)is applied to modify CFRPEEK,achieving unique multi-hierarchical nanostructures and active sites on the surface.Then,hybrid polydopamine(PDA)@ZnO-EDN1 nanoparticles(NPs)are introduced to construct versatile surfaces with improved osteogenic and angiogenic properties and excellent antibacterial properties.Our study established that the modified CFRPEEK presented favorable stability and cytocompatibility.Compared with bare CFRPEEK,improved osteogenic differentiation of rat mesenchymal stem cells(BMSCs)and vascularization of human umbilical vein endothelial cells(HUVECs)are found on the functionalized surface due to the zinc ions and EDN1 releasing.In vitro bacteriostasis assay confirms that hybrid PDA@ZnO NPs on the functionalized surface provided an effective antibacterial effect.Moreover,the rat infected model corroborates the enhanced antibiosis and osteointegration of the functionalized CFRPEEK.Our findings indicate that the multilevel nanostructured PDA@ZnO-EDN1 coated CFRPEEK with enhanced antibacterial,angiogenic,and osteogenic capacity has great potential as an orthopedic/dental implant material for clinical application.

Promoting lacunar bone regeneration with an injectable hydrogel adaptive to the microenvironment

Injectable hydrogel is suitable for the repair of lacunar bone deficiency.This study fabricated an injectable,self-adaptive silk fibroin/mesoporous bioglass/sodium alginate(SMS)composite hydrogel system.With controllable and adjustable physical and chemical properties,the SMS hydrogel could be easily optimized adaptively to different clinical applications.The SMS hydrogel effectively showed great injectability and shapeability,allowing defect filling with no gap.Moreover,the SMS hydrogel displayed self-adaptability in mechanical reinforcement and degradation,responsive to the concentration of Ca2+and inflammatory-like pH value in the microenvi-ronment of bone deficiency,respectively.In vitro biological studies indicated that SMS hydrogel could promote osteogenic differentiation of bone marrow mesenchymal stem cells by activation of the MAPK signaling pathway.The SMS hydrogel also could improve migration and tube formation of human umbilical vein endothelial cells.Investigations of the crosstalk between osteoblasts and macrophages confirmed that SMS hydrogel could regulate macrophage polarization from M1 to M2,which could create a specific favorable environment to induce new bone formation and angiogenesis.Meanwhile,SMS hydrogel was proved to be antibacterial,especially for gram-negative bacteria.Furthermore,in vivo study indicated that SMS could be easily applied for maxillary sinus elevation,inducing sufficient new bone formation.Thus,it is convincing that SMS hydrogel could be potent in a simple,minimally invasive and efficient treatment for the repair of lacunar bone deficiency.

Biomineralization inspired 3D printed bioactive glass nanocomposite scaffolds orchestrate diabetic bone regeneration by remodeling micromilieu

TypeⅡdiabetes mellitus(TIIDM)remains a challenging clinical issue for both dentists and orthopedists.By virtue of persistent hyperglycemia and altered host metabolism,the pathologic diabetic micromilieu with chronic inflammation,advanced glycation end products accumulation,and attenuated biomineralization severely impairs bone regeneration efficiency.Aiming to“remodel”the pathologic diabetic micromilieu,we 3D-printed bioscaffolds composed of Sr-containing mesoporous bioactive glass nanoparticles(Sr-MBGNs)and gelatin methacrylate(GelMA).Sr-MBGNs act as a biomineralization precursor embedded in the GelMA-simulated extracellular matrix and release Sr,Ca,and Si ions enhancing osteogenic,angiogenic,and immunomodulatory properties.In addition to angiogenic and anti-inflammatory outcomes,this innovative design reveals that the nanocomposites can modulate extracellular matrix reconstruction and simulate biomineralization by activating lysyl oxidase to form healthy enzymatic crosslinked collagen,promoting cell focal adhesion,modulating osteoblast differentiation,and boosting the release of OCN,the noncollagenous proteins(intrafibrillar mineralization dependent),and thus orchestrating osteogenesis through the Kindlin-2/PTH1R/OCN axis.This 3D-printed bioscaffold provides a multifunctional biomineralization-inspired system that remodels the“barren”diabetic microenvironment and sheds light on the new bone regeneration approaches for TIIDM.

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.

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.

Bidirectional differentiation of BMSCs induced by a biomimetic procallus based on a gelatin-reduced graphene oxide reinforced hydrogel for rapid bone regeneration

Developmental engineering strategy needs the biomimetic composites that can integrate the progenitor cells,biomaterial matrices and bioactive signals to mimic the natural bone healing process for faster healing and reconstruction of segmental bone defects.We prepared the gelatin-reduced graphene oxide(GOG)and constructed the composites that mimicked the procallus by combining the GOG with the photo-crosslinked gelatin hydrogel.The biological effects of the GOG-reinforced composites could induce the bi-differentiation of bone marrow stromal cells(BMSCs)for rapid bone repair.The proper ratio of GOG in the composites regulated the composites’mechanical properties to a suitable range for the adhesion and proliferation of BMSCs.Besides,the GOG-mediated bidirectional differentiation of BMSCs,including osteogenesis and angiogenesis,could be activated through Erk1/2 and AKT pathway.The methyl vanillate(MV)delivered by GOG also contributed to the bioactive signals of the biomimetic procallus through priming the osteogenesis of BMSCs.During the repair of the calvarial defect in vivo,the initial hypoxic condition due to GOG in the composites gradually transformed into a well-vasculature robust situation with the bi-differentiation of BMSCs,which mimicked the process of bone healing resulting in the rapid bone regeneration.As an inorganic constituent,GOG reinforced the organic photo-crosslinked gelatin hydrogel to form a double-phase biomimetic procallus,which provided the porous extracellular matrix microenvironment and bioactive signals for the bi-directional differentiation of BMSCs.These show a promised application of the bio-reduced graphene oxide in biomedicine with a developmental engineering strategy.

Biocompatible reduced graphene oxide stimulated BMSCs induce acceleration of bone remodeling and orthodontic tooth movement through promotion on osteoclastogenesis and angiogenesis

We has synthesized the biocompatible gelatin reduced graphene oxide(GOG)in previous research,and in this study we would further evaluate its effects on bone remodeling in the aspects of osteoclastogenesis and angiogenesis so as to verify its impact on accelerating orthodontic tooth movement.The mouse orthodontic tooth movement(OTM)model tests in vivo showed that the tooth movement was accelerated in the GOG local injection group with more osteoclastic bone resorption and neovascularization compared with the PBS injection group.The analysis on the degradation of GOG in bone marrow stromal stem cells(BMSCs)illustrated its good biocompatibility in vitro and the accumulation of GOG in spleen after local injection of GOG around the teeth in OTM model in vivo also didn’t influence the survival and life of animals.The co-culture of BMSCs with hematopoietic stem cells(HSCs)or human umbilical vein endothelial cells(HUVECs)in transwell chamber systems were constructed to test the effects of GOG stimulated BMSCs on osteoclastogenesis and angiogenesis in vitro.With the GOG stimulated BMSCs co-culture in upper chamber of transwell,the HSCs in lower chamber manifested the enhanced osteoclastogenesis.Meanwhile,the co-culture of GOG stimulated BMSCs with HUVECs showed a promotive effect on the angiogenic ability of HUVECs.The mechanism analysis on the biofunctions of the GOG stimulated BMSCs illustrated the important regulatory effects of PERK pathway on osteoclastogenesis and angiogenesis.All the results showed the biosecurity of GOG and the biological functions of GOG stimulated BMSCs in accelerating bone remodeling and tooth movement.

Biocompatibility and bone regeneration of PEO/Mg-Al LDH-coated pure Mg:an in vitro and in vivo study

Forming a stable anti-corrosion surface layer on magnesium(Mg)and its alloys has become a major challenge in developing a desirable degradable medical implant in bone.In this study,a porous MgO layer was first formed on Mg by plasma electrolytic oxidation(PEO),and then a Mg-Al layered double hydroxide(LDH)layer was prepared to seal the porous structure of the PEO layer(LDH-2h and LDH-12h)via hydrothermal treatment.The bilayer structure composite coating,which can effectively resist the penetration of surrounding media,is similar to plain Chinese tiles.The in vitro results revealed that compared with other coatings,the LDH-12h composite coating can reduce the release of Mg ions and induce a milder change in pH when immersed in phosphate-buffered saline(PBS).In vitro rat bone marrow stem cell(rBMSC)culture suggested that the LDH-12h composite coating is favorable for cell activity,proliferation and could improve the osteogenic activity of rBMSCs.A subcutaneous implantation test revealed that the as-prepared sample showed enhanced corrosion resistance and histocompatibility in vivo,especially in the LDH-12h group.Moreover,LDH-12h had the lowest rate of degradation and the closest combination with the new bone after being inserted into a rat femur for 12 weeks with no major organ dysfunction.In summary,the asprepared PEO/Mg-Al LDH composite coating is able to improve the corrosion resistance and biocompatibility of Mg and to enhance osteogenic activity in vivo,suggesting its promising prospects for orthopedic 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.