Implant-associated Staphylococcus aureus(S.aureus)osteomyelitis is a severe challenge in orthopedics.While antibiotic-loaded bone cement is a standardized therapeutic approach for S.aureus osteomyelitis,it falls short...Implant-associated Staphylococcus aureus(S.aureus)osteomyelitis is a severe challenge in orthopedics.While antibiotic-loaded bone cement is a standardized therapeutic approach for S.aureus osteomyelitis,it falls short in eradicating Staphylococcus abscess communities(SACs)and bacteria within osteocyte-lacuna canalicular network(OLCN)and repairing bone defects.To address limitations,we developed a borosilicate bioactive glass(BSG)combined with ferroferric oxide(Fe_(3)O_(4))magnetic scaffold to enhance antibacterial efficacy and bone repair capabilities.We conducted comprehensive assessments of the osteoinductive,immunomodulatory,antibacterial properties,and thermal response of this scaffold,with or without an alternating magnetic field(AMF).Utilizing a well-established implant-related S.aureus tibial infection rabbit model,we evaluated its antibacterial performance in vivo.RNA transcriptome sequencing demonstrated that BSG+5%Fe_(3)O_(4)enhanced the immune response to bacteria and promoted osteogenic differentiation and mineralization of MSCs.Notably,BSG+5%Fe_(3)O_(4)upregulated gene expression of NOD-like receptor and TNF pathway in MSCs,alongside increased the expression of osteogenic factors(RUNX2,ALP and OCN)in vitro.Flow cytometry on macrophage exhibited a polarization effect towards M2,accompanied by upregulation of anti-inflammatory genes(TGF-β1 and IL-1Ra)and downregulation of pro-inflammatory genes(IL-6 and IL-1β)among macrophages.In vivo CT imaging revealed the absence of osteolysis and periosteal response in rabbits treated with BSG+5%Fe_(3)O_(4)+AMF at 42 days.Histological analysis indicated complete controls of SACs and bacteria within OLCN by day 42,along with new bone formation,signifying effective control of S.aureus osteomyelitis.Further investigations will focus on the in vivo biosafety and biological mechanism of this scaffold within infectious microenvironment.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support from National Key R&D Program of China(2023YFC2416900and 2021YFC2400500)The International Postdoctoral Exchange Fellowship Program of Chongqing(2021JLPY004)+4 种基金The Fellowship of China Postdoctoral Science Foundation(2021M693758)National Natural Science Foundation of China(U22A20357,52072398and 32161160327)Natural Science Foundation Postdoctoral Science Foundation Project of Chongqing(cstc2021jcyj-bsh0019)Natural Science Foundation of Chongqing(cstc2021jcyj-msxmX0134)Shenzhen Science and Technology Program(JCYJ20230807140714030)。
文摘Implant-associated Staphylococcus aureus(S.aureus)osteomyelitis is a severe challenge in orthopedics.While antibiotic-loaded bone cement is a standardized therapeutic approach for S.aureus osteomyelitis,it falls short in eradicating Staphylococcus abscess communities(SACs)and bacteria within osteocyte-lacuna canalicular network(OLCN)and repairing bone defects.To address limitations,we developed a borosilicate bioactive glass(BSG)combined with ferroferric oxide(Fe_(3)O_(4))magnetic scaffold to enhance antibacterial efficacy and bone repair capabilities.We conducted comprehensive assessments of the osteoinductive,immunomodulatory,antibacterial properties,and thermal response of this scaffold,with or without an alternating magnetic field(AMF).Utilizing a well-established implant-related S.aureus tibial infection rabbit model,we evaluated its antibacterial performance in vivo.RNA transcriptome sequencing demonstrated that BSG+5%Fe_(3)O_(4)enhanced the immune response to bacteria and promoted osteogenic differentiation and mineralization of MSCs.Notably,BSG+5%Fe_(3)O_(4)upregulated gene expression of NOD-like receptor and TNF pathway in MSCs,alongside increased the expression of osteogenic factors(RUNX2,ALP and OCN)in vitro.Flow cytometry on macrophage exhibited a polarization effect towards M2,accompanied by upregulation of anti-inflammatory genes(TGF-β1 and IL-1Ra)and downregulation of pro-inflammatory genes(IL-6 and IL-1β)among macrophages.In vivo CT imaging revealed the absence of osteolysis and periosteal response in rabbits treated with BSG+5%Fe_(3)O_(4)+AMF at 42 days.Histological analysis indicated complete controls of SACs and bacteria within OLCN by day 42,along with new bone formation,signifying effective control of S.aureus osteomyelitis.Further investigations will focus on the in vivo biosafety and biological mechanism of this scaffold within infectious microenvironment.
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.
