Macrophage-mediated inflammation compromises bone repair in diabetic patients.Electrical signaling cues are known to regulate macrophage functions.However,the biological effects of electrical microenvironment from cha...Macrophage-mediated inflammation compromises bone repair in diabetic patients.Electrical signaling cues are known to regulate macrophage functions.However,the biological effects of electrical microenvironment from charged biomaterials on the immune response for regulating osteogenesis under diabetic conditions remain to be elucidated.Herein the endogeneous electrical microenvironment of native bone tissue was recapitulated by fabricating a ferroelectric BaTiO_(3)/poly(vinylidene fluoridetrifluoroethylene)(BTO/P(VDF-TrFE))nanocomposite membrane.In vitro,the polarized BaTiO_(3)/poly(vinylidene fluoridetrifluoroethylene)(BTO/P(VDF-TrFE))nanocomposite membranes inhibited high glucose-induced M1-type inflammation,by effecting changes in cell morphology,M1 marker expression and pro-inflammatory cytokine secretion in macrophages.This led to enhanced osteogenic differentiation of human bone marrow mesenchymal stem cells(BM-MSCs).In vivo,the biomimetic electrical microenvironment recapitulated by the polarized nanocomposite membranes switched macrophage phenotype from the pro-inflammatory(M1)into the pro-healing(M2)phenotype,which in turn enhanced bone regeneration in rats with type 2 diabetes mellitus.Mechanistic studies revealed that the biomimetic electrical microenvironment attenuated pro-inflammatory M1 macrophage polarization under hyperglycemic conditions by suppressing expression of AKT2 and IRF5 within the PI3K-AKT signaling pathway,thereby inducing favorable osteo-immunomodulatory effects.Our study thus provides fundamental insights into the biological effects of restoring the electrical microenvironment conducive for osteogenesis under DM conditions,and offers an effective strategy to design functionalized biomaterials for bone regeneration therapy in diabetic patients.展开更多
The electrical microenvironment plays an important role in bone repair.However,the underlying mechanism by which electrical stimulation(ES)promotes bone regeneration remains unclear,limiting the design of bone microen...The electrical microenvironment plays an important role in bone repair.However,the underlying mechanism by which electrical stimulation(ES)promotes bone regeneration remains unclear,limiting the design of bone microenvironment-specific electroactive materials.Herein,by simple co-incubation in aqueous suspensions at physiological temperatures,biocompatible regenerated silk fibroin(RSF)is found to assemble into nanofibrils with aβ-sheet structure on MXene nanosheets,which has been reported to inhibit the restacking and oxidation of MXene.An electroactive hydrogel based on RSF and bioencapsulated MXene is thus prepared to promote efficient bone regeneration.This MXene/RSF hydrogel also acts as a piezoresistive pressure transducer,which can potentially be utilized to monitor the electrophysiological microenvironment.RNA sequencing is performed to explore the underlying mechanisms,which can activate Ca^(2+)/CALM signaling in favor of the direct osteogenesis process.ES is found to facilitate indirect osteogenesis by promoting the polarization of M2 macrophages,as well as stimulating the neogenesis and migration of endotheliocytes.Consistent improvements in bone regeneration and angiogenesis are observed with MXene/RSF hydrogels under ES in vivo.Collectively,the MXene/RSF hydrogel provides a distinctive and promising strategy for promoting direct osteogenesis,regulating immune microenvironment and neovascularization under ES,leading to re-establish electrical microenvironment for bone regeneration.展开更多
Piezoelectricity in native bones has been well recognized as the key factor in bone regeneration.Thus,bio-piezoelectric materials have gained substantial attention in repairing damaged bone by mimicking the tissue’s ...Piezoelectricity in native bones has been well recognized as the key factor in bone regeneration.Thus,bio-piezoelectric materials have gained substantial attention in repairing damaged bone by mimicking the tissue’s electrical microenvironment(EM).However,traditional manufacturing strategies still encounter limitations in creating personalized bio-piezoelectric scaffolds,hindering their clinical applications.Three-dimensional(3D)/four-dimensional(4D)printing technology based on the principle of layer-by-layer forming and stacking of discrete materials has demonstrated outstanding advantages in fabricating bio-piezoelectric scaffolds in a more complex-shaped structure.Notably,4D printing functionality-shifting bio-piezoelectric scaffolds can provide a time-dependent programmable tissue EM in response to external stimuli for bone regeneration.In this review,we first summarize the physicochemical properties of commonly used bio-piezoelectric materials(including polymers,ceramics,and their composites)and representative biological findings for bone regeneration.Then,we discuss the latest research advances in the 3D printing of bio-piezoelectric scaffolds in terms of feedstock selection,printing process,induction strategies,and potential applications.Besides,some related challenges such as feedstock scalability,printing resolution,stress-to-polarization conversion efficiency,and non-invasive induction ability after implantation have been put forward.Finally,we highlight the potential of shape/property/functionality-shifting smart 4D bio-piezoelectric scaffolds in bone tissue engineering(BTE).Taken together,this review emphasizes the appealing utility of 3D/4D printed biological piezoelectric scaffolds as next-generation BTE implants.展开更多
Stem cells from human exfoliated deciduous teeth(SHED)uniquely exhibit high proliferative and neurogenic potential.Charged biomaterials have been demonstrated to promote neural differentiation of stem cells,but the do...Stem cells from human exfoliated deciduous teeth(SHED)uniquely exhibit high proliferative and neurogenic potential.Charged biomaterials have been demonstrated to promote neural differentiation of stem cells,but the dose-response effect of electrical stimuli from these materials on neural differentiation of SHED remains to be elucidated.Here,by utilizing different annealing temperatures prior to corona poling treatment,BaTiO_(3)/P(VDF-TrFE)ferroelectric nanocomposite membranes with varying charge polarization intensity(d_(33)≈0,4,12 and 19 pC N^(-1))were fabricated.Enhanced expression of neural markers,increased cell elongation and more prominent neurite outgrowths were observed with increasing surface charge of the nanocomposite membrane indicating a dose-response effect of surface electrical charge on SHED neural differentiation.Further investigations of the underlying molecular mechanisms revealed that intracellular calcium influx,focal adhesion formation,FAK-ERK mechanosensing pathway and neurogenic-related ErbB signaling pathway were implicated in the enhancement of SHED neural differentiation by surface electrical charge.Hence,this study confirms the dose-response effect of biomaterial surface charge on SHED neural differentiation and provides preliminary insights into the molecular mechanisms and signaling pathways involved.展开更多
基金This work was supported by the National Key R&D Program of China(2018YFC1105303/04)National Natural Science Foundation of China(Nos.51772006,31670993,51973004,81991505,82022016)+3 种基金Beijing Municipal Science&Technology Commission Projects(Z181100002018001)Peking University Medicine Fund(Nos.PKU2020LCXQ009,BMU2020PYB029)Natural Science Foundation of Hunan Province(2019JJ50779)Health and Family Planning Commission of Hunan Province(20180246).
文摘Macrophage-mediated inflammation compromises bone repair in diabetic patients.Electrical signaling cues are known to regulate macrophage functions.However,the biological effects of electrical microenvironment from charged biomaterials on the immune response for regulating osteogenesis under diabetic conditions remain to be elucidated.Herein the endogeneous electrical microenvironment of native bone tissue was recapitulated by fabricating a ferroelectric BaTiO_(3)/poly(vinylidene fluoridetrifluoroethylene)(BTO/P(VDF-TrFE))nanocomposite membrane.In vitro,the polarized BaTiO_(3)/poly(vinylidene fluoridetrifluoroethylene)(BTO/P(VDF-TrFE))nanocomposite membranes inhibited high glucose-induced M1-type inflammation,by effecting changes in cell morphology,M1 marker expression and pro-inflammatory cytokine secretion in macrophages.This led to enhanced osteogenic differentiation of human bone marrow mesenchymal stem cells(BM-MSCs).In vivo,the biomimetic electrical microenvironment recapitulated by the polarized nanocomposite membranes switched macrophage phenotype from the pro-inflammatory(M1)into the pro-healing(M2)phenotype,which in turn enhanced bone regeneration in rats with type 2 diabetes mellitus.Mechanistic studies revealed that the biomimetic electrical microenvironment attenuated pro-inflammatory M1 macrophage polarization under hyperglycemic conditions by suppressing expression of AKT2 and IRF5 within the PI3K-AKT signaling pathway,thereby inducing favorable osteo-immunomodulatory effects.Our study thus provides fundamental insights into the biological effects of restoring the electrical microenvironment conducive for osteogenesis under DM conditions,and offers an effective strategy to design functionalized biomaterials for bone regeneration therapy in diabetic patients.
基金This work was supported by National Natural Science Foundation of China,China(No.82272457,81972508,82172738)“Technology Innovation Action Plan”of Science and Technology Commission of Shanghai Municipality,China(21S11902700)+3 种基金Natural Science Foundation of Shanghai,China(21ZR1412300)Shanghai Talent Development Fund,China(2020067)Shanghai“Rising Stars of Medical Talent”Youth Development Program,China(Youth Medical Talents-Specialist Program,[2020]087),Shanghai Sailing Program,China(No.19YF1406800)Xiamen Medical and Health Guidance Project,China(3502Z20214ZD1078).
文摘The electrical microenvironment plays an important role in bone repair.However,the underlying mechanism by which electrical stimulation(ES)promotes bone regeneration remains unclear,limiting the design of bone microenvironment-specific electroactive materials.Herein,by simple co-incubation in aqueous suspensions at physiological temperatures,biocompatible regenerated silk fibroin(RSF)is found to assemble into nanofibrils with aβ-sheet structure on MXene nanosheets,which has been reported to inhibit the restacking and oxidation of MXene.An electroactive hydrogel based on RSF and bioencapsulated MXene is thus prepared to promote efficient bone regeneration.This MXene/RSF hydrogel also acts as a piezoresistive pressure transducer,which can potentially be utilized to monitor the electrophysiological microenvironment.RNA sequencing is performed to explore the underlying mechanisms,which can activate Ca^(2+)/CALM signaling in favor of the direct osteogenesis process.ES is found to facilitate indirect osteogenesis by promoting the polarization of M2 macrophages,as well as stimulating the neogenesis and migration of endotheliocytes.Consistent improvements in bone regeneration and angiogenesis are observed with MXene/RSF hydrogels under ES in vivo.Collectively,the MXene/RSF hydrogel provides a distinctive and promising strategy for promoting direct osteogenesis,regulating immune microenvironment and neovascularization under ES,leading to re-establish electrical microenvironment for bone regeneration.
基金supported by grants from the National Natural Science Foundation of China(52205363)Fundamental Research Funds for the Central Universities(2019kfyRCPY044 and 2021GCRC002)+3 种基金Program for HUST Academic Frontier Youth Team(2018QYTD04)Program for Innovative Research Team of the Ministry of Education(IRT1244)Shenzhen-Hong Kong Science and Technology Innovation Cooperation Zone Shenzhen Park Project:HZQB-KCZYB-2020030the Guangdong Provincial Department of Science and Technology(Key-Area Research and Development Program of Guangdong Province)under the Grant 2020B090923002。
文摘Piezoelectricity in native bones has been well recognized as the key factor in bone regeneration.Thus,bio-piezoelectric materials have gained substantial attention in repairing damaged bone by mimicking the tissue’s electrical microenvironment(EM).However,traditional manufacturing strategies still encounter limitations in creating personalized bio-piezoelectric scaffolds,hindering their clinical applications.Three-dimensional(3D)/four-dimensional(4D)printing technology based on the principle of layer-by-layer forming and stacking of discrete materials has demonstrated outstanding advantages in fabricating bio-piezoelectric scaffolds in a more complex-shaped structure.Notably,4D printing functionality-shifting bio-piezoelectric scaffolds can provide a time-dependent programmable tissue EM in response to external stimuli for bone regeneration.In this review,we first summarize the physicochemical properties of commonly used bio-piezoelectric materials(including polymers,ceramics,and their composites)and representative biological findings for bone regeneration.Then,we discuss the latest research advances in the 3D printing of bio-piezoelectric scaffolds in terms of feedstock selection,printing process,induction strategies,and potential applications.Besides,some related challenges such as feedstock scalability,printing resolution,stress-to-polarization conversion efficiency,and non-invasive induction ability after implantation have been put forward.Finally,we highlight the potential of shape/property/functionality-shifting smart 4D bio-piezoelectric scaffolds in bone tissue engineering(BTE).Taken together,this review emphasizes the appealing utility of 3D/4D printed biological piezoelectric scaffolds as next-generation BTE implants.
基金supported by the National Key Research and Development Program of China(2021YFB3800800,2021YFC2400400)the National Natural Science Foundation of China(Nos.82022016,81991505,51973004,52103312)+1 种基金the Beijing Municipal Natural Science Foundation(7222226)Peking University Medicine Fund(PKU2020LCXQ009).
文摘Stem cells from human exfoliated deciduous teeth(SHED)uniquely exhibit high proliferative and neurogenic potential.Charged biomaterials have been demonstrated to promote neural differentiation of stem cells,but the dose-response effect of electrical stimuli from these materials on neural differentiation of SHED remains to be elucidated.Here,by utilizing different annealing temperatures prior to corona poling treatment,BaTiO_(3)/P(VDF-TrFE)ferroelectric nanocomposite membranes with varying charge polarization intensity(d_(33)≈0,4,12 and 19 pC N^(-1))were fabricated.Enhanced expression of neural markers,increased cell elongation and more prominent neurite outgrowths were observed with increasing surface charge of the nanocomposite membrane indicating a dose-response effect of surface electrical charge on SHED neural differentiation.Further investigations of the underlying molecular mechanisms revealed that intracellular calcium influx,focal adhesion formation,FAK-ERK mechanosensing pathway and neurogenic-related ErbB signaling pathway were implicated in the enhancement of SHED neural differentiation by surface electrical charge.Hence,this study confirms the dose-response effect of biomaterial surface charge on SHED neural differentiation and provides preliminary insights into the molecular mechanisms and signaling pathways involved.
