Injectable bone cement is especially useful in minimally invasive surgeries to repair small and irregular bone defects.Amongst different kinds of injectable bone cements,bioactive calcium phosphate bone cement(CPC)has...Injectable bone cement is especially useful in minimally invasive surgeries to repair small and irregular bone defects.Amongst different kinds of injectable bone cements,bioactive calcium phosphate bone cement(CPC)has been widely studied due to its biological activity.However,its dense structure and poor biodegradability prevent the ingrowth of living tissue,which leads to undesirable bone regeneration and clinical translation.To address this issue,we prepared bone cement based on Magnesium-containing microspheres(MMSs)that can not only be cured into a 3D porous scaffold but also have controllable biodegradability that continuously provides space for desired tissue ingrowth.Interestingly,magnesium ions released from MMSs cement(MMSC)trigger positive immunomodulation via upregulation of the anti-inflammatory genes IL-10 and M2 macrophage polarization with increased expression of CD206,which is beneficial to osteogenesis.Moreover,the physicochemical properties of MMSC,including heat release,rheology and setting time,can be tuned to meet the requirements of injectable bone cement for clinical application.Using a rat model,we have demonstrated that MMSC promoted osteogenesis via mediation of tissue ingrowth and anti-inflammatory immunomodulation.The study provides a paradigm for the design and preparation of injectable bone cements with 3D porous structures,biodegradability and anti-inflammatory immunoregulation to efficiently promote osteogenesis.展开更多
Out of the wide range of calcium phosphate(CaP)biomaterials,calcium phosphate bone cements(CPCs)have attracted increased attention since their discovery in the 1980s due to their valuable properties such as bioactivit...Out of the wide range of calcium phosphate(CaP)biomaterials,calcium phosphate bone cements(CPCs)have attracted increased attention since their discovery in the 1980s due to their valuable properties such as bioactivity,osteoconductivity,injectability,hardening ability through a low-temperature setting reaction and moldability.Thereafter numerous researches have been performed to enhance the properties of CPCs.Nonetheless,low mechanical performance of CPCs limits their clinical application in load bearing regions of bone.Also,the in vivo resorption and replacement of CPC with new bone tissue is still controversial,thus further improvements of high clinical importance are required.Bioactive glasses(BGs)are biocompatible and able to bond to bone,stimulating new bone growth while dissolving over time.In the last decades extensive research has been performed analyzing the role of BGs in combination with different CaPs.Thus,the focal point of this review paper is to summarize the available research data on how injectable CPC properties could be improved or affected by the addition of BG as a secondary powder phase.It was found that despite the variances of setting time and compressive strength results,desirable injectable properties of bone cements can be achieved by the inclusion of BGs into CPCs.The published data also revealed that the degradation rate of CPCs is significantly improved by BG addition.Moreover,the presence of BG in CPCs improves the in vitro osteogenic differentiation and cell response as well as the tissue-material interaction in vivo.展开更多
The osteoporotic bone defect caused by excessive activity of osteoclasts has posed a challenge for public healthcare.However,most existing bioinert bone cement fails to effectively regulate the pathological bone micro...The osteoporotic bone defect caused by excessive activity of osteoclasts has posed a challenge for public healthcare.However,most existing bioinert bone cement fails to effectively regulate the pathological bone microenvironment and reconstruct bone homeostasis in the presence of osteoclast overactivity and osteoblast suppression.Herein,inspired by natural bone tissue,an in-situ modulation system for osteoporotic bone regeneration is developed by fabricating an injectable double-crosslinked PEGylated poly(glycerol sebacate)(PEGS)/calcium phosphate cement(CPC)loaded with sodium alendronate(ALN)(PEGS/CPC@ALN)adhesive bone cement.By incorporating ALN,the organic-inorganic interconnection within PEGS/CPC@ALN results in a 100%increase in compression modulus and energy dissipation efficiency.Additionally,PEGS/CPC@ALN effectively adheres to the bone by bonding with amine and calcium ions present on the bone surface.Moreover,this in-situ regulation system comprehensively mitigates excessive bone resorption through the buffering effect of CPC to improve the acidic microenvironment of osteoporotic bone and the release of ALN to inhibit hyperactive osteoclasts,and facilitates stem cell proliferation and differentiation into osteoblasts through calcium ion release.Overall,the PEGS/CPC@ALN effectively regulates the pathological microenvironment of osteoporosis while promoting bone regeneration through synergistic effects of drugs and materials,thereby improving bone ho-meostasis and enabling minimally invasive treatment for osteoporotic defects.展开更多
Skeletal diseases, such as nonunion and osteonecrosis, are now treatable with tissue engineering techniques. Single cell sheets called osteogenic matrix cell sheets (OMCSs) grown from cultured bone marrow-derived mese...Skeletal diseases, such as nonunion and osteonecrosis, are now treatable with tissue engineering techniques. Single cell sheets called osteogenic matrix cell sheets (OMCSs) grown from cultured bone marrow-derived mesenchymal stem cells show high osteogenic potential;however, long preparation times currently limit their clinical application. Here, we report a cryopreservation OMCS transplantation method that shortens OMCS preparation time. Cryopreserved rat OMCSs were prepared using slow- and rapid-freezing methods, thawed, and subsequently injected scaffold-free into subcutaneous sites. Rapid- and slow-frozen OMCSs were also transplanted directly to the femur bone at sites of injury. Slow-freezing resulted in higher cell viability than rapid freezing, yet all two cryopreservation methods yielded OMCSs that survived and formed bone tissue. In the rapid- and slow-freezing groups, cortical gaps were repaired and bone continuity was observed within 6 weeks of OMCS transplantation. Moreover, while no significant difference was found in osteocalcin expression between the three experimental groups, the biomechanical strength of femurs treated with slow-frozen OMCSs was significantly greater than those of non-transplant at 6 weeks post-injury. Collectively, these data suggest that slow-frozen OMCSs have superior osteogenic potential and are better suited to produce a mineralized matrix and repair sites of bone injury.展开更多
In this study,injectable bone graft putty samples were developed using fine and coarse melt-quenched 45S5 bioactive glass(BG)incorporated into a carrier system composed of glycerol and polyethylene glycol(PEG)with dif...In this study,injectable bone graft putty samples were developed using fine and coarse melt-quenched 45S5 bioactive glass(BG)incorporated into a carrier system composed of glycerol and polyethylene glycol(PEG)with different average molecular weights.Selected putty samples were further incorporated with varying amounts of Denosumab(5wt%-10wt%)to investigate its influence on rhe-ological behavior and flow properties using mathematical modeling.All PEG/glycerol/45S5-based putty samples exhibited viscoelastic behavior(storage modulus>loss modulus)and pseudoplastic behavior(n<1),with viscosity values required for optimal flow remaining below 1000 Pa∙s.Both viscosity and thixotropic area increased proportionally with higher BG content and smaller-sized BG particles.All putty samples showed more than 98%injectability through a 12G cannula,suggesting potential clinical suitability.However,injectability decreased with smaller cannulas,dropping to 34.7%-58.3%with a 19G cannula and further decreasing with a 23G cannula at higher BG contents.Incorporation of Denosumab preserved viscoelasticity and injectability but modified the flow behavior,shifting it from pseudo-plastic to more Newtonian with higher Denosumab content,while also reducing viscosity and thixotropic area values.Among all tested samples,putty containing a lower amount of Denosumab and smaller-sized BG exhibited the most suitable combination of injectability and rheological features.All putty samples were well described by both the Power law and Herschel-Bulkley rheological models(coeffi-cient of determination>0.95).This study highlights the influence of Denosumab on flowability and rheological relationships and sug-gests potential improvements in bioactivity through a dual synergistic effect of BG and Denosumab in minimally invasive bone graft sys-tems.展开更多
There is a need for synthetic grafts to reconstruct large bone defects using minimal invasive surgery.Our previous study showed that incorporation of Sr into bioactive borate glass cement enhanced the osteogenic capac...There is a need for synthetic grafts to reconstruct large bone defects using minimal invasive surgery.Our previous study showed that incorporation of Sr into bioactive borate glass cement enhanced the osteogenic capacity in vivo.However,the amount of Sr in the cement to provide an optimal combination of physicochemical properties and capacity to stimulate bone regeneration and the underlying molecular mechanism of this stimulation is yet to be determined.In this study,bone cements composed of bioactive borosilicate glass particles substituted with varying amounts of Sr(0 mol%to 12 mol%SrO)were created and evaluated in vitro and in vivo.The setting time of the cement increased with Sr substitution of the glass.Upon immersion in PBS,the cement degraded and converted more slowly to HA(hydroxyapatite)with increasing Sr substitution.The released Sr2+modulated the proliferation,differentiation,and mineralization of hBMSCs(human bone marrow mesenchymal stem cells)in vitro.Osteogenic characteristics were optimally enhanced with cement(designated BG6Sr)composed of particles substituted with 6mol%SrO.When implanted in rabbit femoral condyle defects,BG6Sr cement supported better peri-implant bone formation and bone-implant contact,comparing to cements substituted with 0mol%or 9mol%SrO.The underlying mechanism is involved in the activation of Wnt/β-catenin signaling pathway in osteogenic differentiation of hBMSCs.These results indicate that BG6Sr cement has a promising combination of physicochemical properties and biological performance for minimally invasive healing of bone defects.展开更多
基金This work was supported by the National Key R&D Project(2018YFC1105701)National Natural Science Foundation of China(81801850,81901897,31870960)China Postdoctoral Science Foundation Grant(2018M642851).
文摘Injectable bone cement is especially useful in minimally invasive surgeries to repair small and irregular bone defects.Amongst different kinds of injectable bone cements,bioactive calcium phosphate bone cement(CPC)has been widely studied due to its biological activity.However,its dense structure and poor biodegradability prevent the ingrowth of living tissue,which leads to undesirable bone regeneration and clinical translation.To address this issue,we prepared bone cement based on Magnesium-containing microspheres(MMSs)that can not only be cured into a 3D porous scaffold but also have controllable biodegradability that continuously provides space for desired tissue ingrowth.Interestingly,magnesium ions released from MMSs cement(MMSC)trigger positive immunomodulation via upregulation of the anti-inflammatory genes IL-10 and M2 macrophage polarization with increased expression of CD206,which is beneficial to osteogenesis.Moreover,the physicochemical properties of MMSC,including heat release,rheology and setting time,can be tuned to meet the requirements of injectable bone cement for clinical application.Using a rat model,we have demonstrated that MMSC promoted osteogenesis via mediation of tissue ingrowth and anti-inflammatory immunomodulation.The study provides a paradigm for the design and preparation of injectable bone cements with 3D porous structures,biodegradability and anti-inflammatory immunoregulation to efficiently promote osteogenesis.
基金financial support from the European Union’s Horizon 2020 research and innovation programme under the grant agreement No 857287(BBCE).
文摘Out of the wide range of calcium phosphate(CaP)biomaterials,calcium phosphate bone cements(CPCs)have attracted increased attention since their discovery in the 1980s due to their valuable properties such as bioactivity,osteoconductivity,injectability,hardening ability through a low-temperature setting reaction and moldability.Thereafter numerous researches have been performed to enhance the properties of CPCs.Nonetheless,low mechanical performance of CPCs limits their clinical application in load bearing regions of bone.Also,the in vivo resorption and replacement of CPC with new bone tissue is still controversial,thus further improvements of high clinical importance are required.Bioactive glasses(BGs)are biocompatible and able to bond to bone,stimulating new bone growth while dissolving over time.In the last decades extensive research has been performed analyzing the role of BGs in combination with different CaPs.Thus,the focal point of this review paper is to summarize the available research data on how injectable CPC properties could be improved or affected by the addition of BG as a secondary powder phase.It was found that despite the variances of setting time and compressive strength results,desirable injectable properties of bone cements can be achieved by the inclusion of BGs into CPCs.The published data also revealed that the degradation rate of CPCs is significantly improved by BG addition.Moreover,the presence of BG in CPCs improves the in vitro osteogenic differentiation and cell response as well as the tissue-material interaction in vivo.
基金financial support from National Key Research and Development Program of China(No.2022YFB3804300)and(No.2022YFC2405702)Program of Shanghai Academic/Technology Research Leader(22XD1433900)+2 种基金Frontiers Science Center for Materiobiology and Dynamic Chemistry(No.JKVD1211002)Chinese Academy of Sciences-WEGO Research and Development Program([2023]005)the National Natural Sci-ence Foundation of China(No.32271401)。
文摘The osteoporotic bone defect caused by excessive activity of osteoclasts has posed a challenge for public healthcare.However,most existing bioinert bone cement fails to effectively regulate the pathological bone microenvironment and reconstruct bone homeostasis in the presence of osteoclast overactivity and osteoblast suppression.Herein,inspired by natural bone tissue,an in-situ modulation system for osteoporotic bone regeneration is developed by fabricating an injectable double-crosslinked PEGylated poly(glycerol sebacate)(PEGS)/calcium phosphate cement(CPC)loaded with sodium alendronate(ALN)(PEGS/CPC@ALN)adhesive bone cement.By incorporating ALN,the organic-inorganic interconnection within PEGS/CPC@ALN results in a 100%increase in compression modulus and energy dissipation efficiency.Additionally,PEGS/CPC@ALN effectively adheres to the bone by bonding with amine and calcium ions present on the bone surface.Moreover,this in-situ regulation system comprehensively mitigates excessive bone resorption through the buffering effect of CPC to improve the acidic microenvironment of osteoporotic bone and the release of ALN to inhibit hyperactive osteoclasts,and facilitates stem cell proliferation and differentiation into osteoblasts through calcium ion release.Overall,the PEGS/CPC@ALN effectively regulates the pathological microenvironment of osteoporosis while promoting bone regeneration through synergistic effects of drugs and materials,thereby improving bone ho-meostasis and enabling minimally invasive treatment for osteoporotic defects.
文摘Skeletal diseases, such as nonunion and osteonecrosis, are now treatable with tissue engineering techniques. Single cell sheets called osteogenic matrix cell sheets (OMCSs) grown from cultured bone marrow-derived mesenchymal stem cells show high osteogenic potential;however, long preparation times currently limit their clinical application. Here, we report a cryopreservation OMCS transplantation method that shortens OMCS preparation time. Cryopreserved rat OMCSs were prepared using slow- and rapid-freezing methods, thawed, and subsequently injected scaffold-free into subcutaneous sites. Rapid- and slow-frozen OMCSs were also transplanted directly to the femur bone at sites of injury. Slow-freezing resulted in higher cell viability than rapid freezing, yet all two cryopreservation methods yielded OMCSs that survived and formed bone tissue. In the rapid- and slow-freezing groups, cortical gaps were repaired and bone continuity was observed within 6 weeks of OMCS transplantation. Moreover, while no significant difference was found in osteocalcin expression between the three experimental groups, the biomechanical strength of femurs treated with slow-frozen OMCSs was significantly greater than those of non-transplant at 6 weeks post-injury. Collectively, these data suggest that slow-frozen OMCSs have superior osteogenic potential and are better suited to produce a mineralized matrix and repair sites of bone injury.
基金supported by Yildiz Technical University Scientific Research Projects Coordination Unit under project number FBA-2023-5377support from the Scientific and Technological Research Council of Turkey(TUBITAK)under the BIDEB/2211-A National PhD Scholarship Program and 2250-Performance-Based Scholarships Program for PhD.
文摘In this study,injectable bone graft putty samples were developed using fine and coarse melt-quenched 45S5 bioactive glass(BG)incorporated into a carrier system composed of glycerol and polyethylene glycol(PEG)with different average molecular weights.Selected putty samples were further incorporated with varying amounts of Denosumab(5wt%-10wt%)to investigate its influence on rhe-ological behavior and flow properties using mathematical modeling.All PEG/glycerol/45S5-based putty samples exhibited viscoelastic behavior(storage modulus>loss modulus)and pseudoplastic behavior(n<1),with viscosity values required for optimal flow remaining below 1000 Pa∙s.Both viscosity and thixotropic area increased proportionally with higher BG content and smaller-sized BG particles.All putty samples showed more than 98%injectability through a 12G cannula,suggesting potential clinical suitability.However,injectability decreased with smaller cannulas,dropping to 34.7%-58.3%with a 19G cannula and further decreasing with a 23G cannula at higher BG contents.Incorporation of Denosumab preserved viscoelasticity and injectability but modified the flow behavior,shifting it from pseudo-plastic to more Newtonian with higher Denosumab content,while also reducing viscosity and thixotropic area values.Among all tested samples,putty containing a lower amount of Denosumab and smaller-sized BG exhibited the most suitable combination of injectability and rheological features.All putty samples were well described by both the Power law and Herschel-Bulkley rheological models(coeffi-cient of determination>0.95).This study highlights the influence of Denosumab on flowability and rheological relationships and sug-gests potential improvements in bioactivity through a dual synergistic effect of BG and Denosumab in minimally invasive bone graft sys-tems.
基金supported by the National Key R&D Program of China(Grant No.2018YFC1106300 , 2017YFC1105000)the National Natural Science Foundation of China(Grant No.51802340,31870956,31771041 , 81672227)+6 种基金the Science and Technology Project of Guangdong Province-Doctoral startup fund of 2017(Grant No.2017A030310318)the Frontier Science Key Research Programs of CAS(Grant No.QYZDB-SSW-JSC030)the Strategic Priority Research Program of CAS(Grant No.XDA16021000)the Shenzhen significant strategy layout project(Grant No.JCYJ20170413162104773)the Economic,Trade and information Commission of Shenzhen Municipality“Innovation and Industry Chain”(Grant No.20170502171625936)the Beijing Municipal Natural Science Foundation(Grant No.7161001)Beijing Municipal Commission of Health and Family Planning(Grant No.PXM2018_026275_000001).
文摘There is a need for synthetic grafts to reconstruct large bone defects using minimal invasive surgery.Our previous study showed that incorporation of Sr into bioactive borate glass cement enhanced the osteogenic capacity in vivo.However,the amount of Sr in the cement to provide an optimal combination of physicochemical properties and capacity to stimulate bone regeneration and the underlying molecular mechanism of this stimulation is yet to be determined.In this study,bone cements composed of bioactive borosilicate glass particles substituted with varying amounts of Sr(0 mol%to 12 mol%SrO)were created and evaluated in vitro and in vivo.The setting time of the cement increased with Sr substitution of the glass.Upon immersion in PBS,the cement degraded and converted more slowly to HA(hydroxyapatite)with increasing Sr substitution.The released Sr2+modulated the proliferation,differentiation,and mineralization of hBMSCs(human bone marrow mesenchymal stem cells)in vitro.Osteogenic characteristics were optimally enhanced with cement(designated BG6Sr)composed of particles substituted with 6mol%SrO.When implanted in rabbit femoral condyle defects,BG6Sr cement supported better peri-implant bone formation and bone-implant contact,comparing to cements substituted with 0mol%or 9mol%SrO.The underlying mechanism is involved in the activation of Wnt/β-catenin signaling pathway in osteogenic differentiation of hBMSCs.These results indicate that BG6Sr cement has a promising combination of physicochemical properties and biological performance for minimally invasive healing of bone defects.
