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 im...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.展开更多
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, g...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), activinlike 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.展开更多
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,...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.展开更多
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 combi...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.展开更多
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 Gins...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.展开更多
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 str...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.展开更多
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 s...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.展开更多
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 ...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.展开更多
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 controlla...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.展开更多
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 ...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.展开更多
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 gro...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.展开更多
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 ...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.展开更多
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...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.展开更多
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 limitat...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.展开更多
With the development of magnetic manipulation technology based on magnetic nanoparticles(MNPs),scaffold-free microtissues can be constructed utilizing the magnetic attraction of MNP-labeled cells.The rapid in vitro co...With the development of magnetic manipulation technology based on magnetic nanoparticles(MNPs),scaffold-free microtissues can be constructed utilizing the magnetic attraction of MNP-labeled cells.The rapid in vitro construction and in vivo vascularization of microtissues with complex hierarchical architectures are of great importance to the viability and function of stem cell microtissues.Endothelial cells are indispensable for the formation of blood vessels and can be used in the prevascularization of engineered tissue constructs.Herein,safe and rapid magnetic labeling of cells was achieved by incubation with MNPs for 1 h,and ultrathick scaffold-free microtissues with different sophisticated architectures were rapidly assembled,layer by layer,in 5 min intervals.The in vivo transplantation results showed that in a stem cell microtissue with trisection architecture,the two separated human umbilical vein endothelial cell(HUVEC)layers would spontaneously extend to the stem cell layers and connect with each other to form a spatial network of functional blood vessels,which anastomosed with the host vasculature.The“hamburger”architecture of stem cell microtissues with separated HUVEC layers could promote vascularization and stem cell survival.This study will contribute to the construction and application of structural and functional tissues or organs in the future.展开更多
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 fa...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.展开更多
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 angiogen...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.展开更多
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 re...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.展开更多
基金the support from the National Natural Science Foundation of China(Grant nos.81921002,82201115)China Postdoctoral Science Foundation(no.2021M702166)the Innovative Research Team of High-level Local Universities in Shanghai,Oral and Maxillofacial Regeneration and Functional Restoration。
文摘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.
基金supported by the National Natural Science Foundation of China (No. 81500814) (SXL)the National Natural Science Foundation of China (No. 81430012 and No. 81170939) (XJ)+2 种基金the National Basic Research Program of China (973 Program, 2012CB933604)the National Science Fund for Distinguished Young Scholars of China (No. 81225006)the National Institutes of Health Grants DE025014 and R56DE022789 (JQF)
文摘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), activinlike 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.
基金supported by the National Key Research and Development Program of China (2016YFC1102900)the National Natural Science Foundation of China (No.81620108006, No.81430012, and No.31700848)
文摘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.
基金This work has been jointly supported by the National Natural Science Foundation of China(No.81900970 and 81921002)Young Elite Scientists Sponsorship Program CAST(2018QNRC001)Shanghai Sailing Program(19YF1426000).
文摘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.
基金supported by National Natural Science Foundation of China (81600828)Shanghai Sailing Program (16YF1406600)
文摘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.
基金supported by the National Natural Science Foundation of China(No.81921002,No.81900970,No.82130027)Young Physician Innovation Team Project(No.QC202003)from Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine+1 种基金Shanghai Sailing Program(19YF1426000)jointlysupport from the Young Elite Scientists Sponsorship Program CAST(2018QNRC001)is also acknowledged.
文摘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.
基金supported by the National Natural Science Foundation of China(No.81921002,No.81900970)Young Physician Innovation Team Project(No.QC202003)from Ninth People’s Hospital,Shanghai Jiao Tong University School of MedicineShanghai Sailing Program(19YF1426000)jointly。
文摘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.
基金funded by the National Natural Science Foundation of China(Nos.81801006,31870953,81901048,81620108006,81991505,81921002,81801023,and 82100963)Shanghai Rising-Star Program(21QA1405400)+1 种基金the National Key Research and Development Program of China(No.2016YFC1102900)Innovative Research Team of High-Level Local Universities in Shanghai(No.SSMU-ZDCX20180900)。
文摘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.
基金National Natural Science Foundation of China(Nos.82130027,82100963,82270953,81991505 and 81921002)Shanghai Rising-Star Program(21QA1405400)+1 种基金Natural Science Foundation of Shanghai(22ZR1436400)Innovative Research Team of High-Level Local Universities in Shanghai.
文摘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.
基金This work was jointly supported by the National Natural Science Foundation of China(Grant Nos.81991505,82130027,81921002,82101071,82270953)the Innovative research team of high-level local universities in Shanghai(SHSMU-ZLCX20212400)+1 种基金the Natural Science Foundation of Jiangsu Province(No.BK20210528)The author would like to show gratitude for the support from Shanghai Post-doctoral Excellence Program(2020328).
文摘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.
基金This study was jointly supported by the National Natural Science Foundation of China(82130027,81921002,81900960,82270955,81991505)the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZLCX20212400)the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD,2018-87).
文摘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.
基金funded by the National Natural Science Foundation of China(No.81921002,No.82100963,No.81873709)the Natural Science Foundation of Shanghai Science and Technology Commission(21ZR1437100)Shanghai Rising-Star Program(21QA1405400).
文摘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.
基金the National Natural Science Foundation of China(No.81921002,81620108006,81991505,31700848)the National Key Research and Development Program of China(2016YFC1102900).
文摘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.
基金the National Natural Science Foundation of China(No.82130027,No.81921002 and No.31900971)Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZLCX20212400)Shanghai Sailing Program(21YF1424400).
文摘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.
基金the National Natural Science Foundation of China(Grant Nos.81921002,81620108006,31700848,82001009)the National Key Research and Development Program of China(2016YFC1102900)。
文摘With the development of magnetic manipulation technology based on magnetic nanoparticles(MNPs),scaffold-free microtissues can be constructed utilizing the magnetic attraction of MNP-labeled cells.The rapid in vitro construction and in vivo vascularization of microtissues with complex hierarchical architectures are of great importance to the viability and function of stem cell microtissues.Endothelial cells are indispensable for the formation of blood vessels and can be used in the prevascularization of engineered tissue constructs.Herein,safe and rapid magnetic labeling of cells was achieved by incubation with MNPs for 1 h,and ultrathick scaffold-free microtissues with different sophisticated architectures were rapidly assembled,layer by layer,in 5 min intervals.The in vivo transplantation results showed that in a stem cell microtissue with trisection architecture,the two separated human umbilical vein endothelial cell(HUVEC)layers would spontaneously extend to the stem cell layers and connect with each other to form a spatial network of functional blood vessels,which anastomosed with the host vasculature.The“hamburger”architecture of stem cell microtissues with separated HUVEC layers could promote vascularization and stem cell survival.This study will contribute to the construction and application of structural and functional tissues or organs in the future.
基金the National Natural Science Foundation of China(No.81921002,81620108006,31700848,31870945)the National Key Research and Development Program of China(2016YFC1102900)the Doctoral Innovation Fund Projects of Shanghai Jiao Tong University,School of Medicine(BXJ201937).
文摘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.
基金funded by China Postdoctoral Science Foundation(2021M692249)National Key R&D Program of China 2017YFC1104304(YB)+1 种基金National Natural Science Foundation of China grant 82071144,Shanghai Rising-Star Program(21QA1405400)Innovative research team of high-level local universities in Shanghai(SSMU-ZDCX20180900).
文摘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.
基金This study was supported by the National Natural Science Foundation of China(51703127,31600777,81620108006,81901048,81801006,81991505)the National Key Research and Development Program of China(2016YFC1102900)+1 种基金Innovative research team of high-level local universities in Shanghai(SSMU-ZDCX20180900)Young Elite Scientist Sponsorship Program by CAST(2017QNRC001).
文摘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.
