Regeneration of pathological wounds,such as diabetic ulcers,poses a significant challenge in clinical settings,despite the widespread use of drugs.To overcome clinical side effects and complications,drug-free therapeu...Regeneration of pathological wounds,such as diabetic ulcers,poses a significant challenge in clinical settings,despite the widespread use of drugs.To overcome clinical side effects and complications,drug-free therapeutics need to be developed to promote angiogenesis while overcoming inflammation to restore regenerative events.This study presents a novel bioactive nanozyme based on cobalt-doped nanoglass(namely,CoNZ),which exhibits high enzymatic/catalytic activity while releasing therapeutic ions.Cobalt oxide“Co3O4”tiny crystallites produced in situ through a chemical reaction with H2O2 within CoNZ nanoparticles play a crucial role in scavenging ROS.Results showed that CoNZ-treatment to full-thickness skin wounds in mice significantly accelerated the healing process,promoting neovascularization,matrix deposition,and epithelial lining while reducing pro-inflammatory signs.Notably,CoNZ was highly effective in treating pathological wounds(streptozotocin-induced diabetic wounds).Rapid scavenging of ROS by CoNZ and down-regulation of pro-inflammatory markers while up-regulating tissue healing signs with proliferative cells and activated angiogenic factors contributed to the observed healing events.In vitro experiments involving CoNZ-cultures with macrophages and endothelial cells exposed to high glucose and ROS-generating conditions further confirmed the effectiveness of CoNZ.CoNZ-promoted angiogenesis was attributed to the release of cobalt ions,as evidenced by the comparable effects of CoNZ-extracted ionic medium in enhancing endothelial migration and tubule formation via activated HIF-1α.Finally,we compared the in vivo efficacy of CoNZ with the clinically-available drug deferoxamine.Results demonstrated that CoNZ was as effective as the drug in closing the diabetic wound,indicating the potential of CoNZ as a novel drug-free therapeutic approach.展开更多
Therapeutic options are quite limited in clinics for the successful repair of infected/degenerated tissues.Although the prevalent treatment is the complete removal of the whole infected tissue,this leads to a loss of ...Therapeutic options are quite limited in clinics for the successful repair of infected/degenerated tissues.Although the prevalent treatment is the complete removal of the whole infected tissue,this leads to a loss of tissue function and serious complications.Herein the dental pulp infection,as one of the most common dental problems,was selected as a clinically relevant case to regenerate using a multifunctional nanotherapeutic approach.For this,a mesoporous bioactive glass nano-delivery system incorporating silicate,calcium,and copper as well as loading epidermal growth factor(EGF)was designed to provide antibacterial/pro-angiogenic and osteo/odontogenic multiple therapeutic effects.Amine-functionalized Cu-doped bioactive glass nanospheres(Cu-BGn)were prepared to be 50–60 nm in size,mesoporous,positive-charged and bone-bioactive.The Cu-BGn could release bioactive ions(copper,calcium and silicate ions)with therapeutically-effective doses.The Cu-BGn treatment to human umbilical vein endothelial cells(HUVEC)led to significant enhancement of the migration,tubule formation and expression of angiogenic gene(e.g.vascular endothelial growth factor,VEGF).Furthermore,the EGF-loaded Cu-BGn(EGF@Cu-BGn)showed pro-angiogenic effects with antibacterial activity against E.faecalis,a pathogen commonly involved in the pulp infection.Of note,under the co-culture condition of HUVEC with E.faecalis,the secretion of VEGF was up-regulated.In addition,the osteo/odontogenic stimulation of the EGF@Cu-BGn was evidenced with human dental pulp stem cells.The local administration of the EGF@Cu-BGn in a rat molar tooth defect infected with E.faecalis revealed significant in vivo regenerative capacity,highlighting the nanotherapeutic uses of the multifunctional nanoparticles for regenerating infected/damaged hard tissues.展开更多
基金supported by the National Research Foundation of Korea(2021R1A5A2022318,2018K1A4A3A01064257,2019R1A6A1 A11034536,RS-2023-00220408,2022K1A3A1A08085419,2021R1I1 A1A01049104).
文摘Regeneration of pathological wounds,such as diabetic ulcers,poses a significant challenge in clinical settings,despite the widespread use of drugs.To overcome clinical side effects and complications,drug-free therapeutics need to be developed to promote angiogenesis while overcoming inflammation to restore regenerative events.This study presents a novel bioactive nanozyme based on cobalt-doped nanoglass(namely,CoNZ),which exhibits high enzymatic/catalytic activity while releasing therapeutic ions.Cobalt oxide“Co3O4”tiny crystallites produced in situ through a chemical reaction with H2O2 within CoNZ nanoparticles play a crucial role in scavenging ROS.Results showed that CoNZ-treatment to full-thickness skin wounds in mice significantly accelerated the healing process,promoting neovascularization,matrix deposition,and epithelial lining while reducing pro-inflammatory signs.Notably,CoNZ was highly effective in treating pathological wounds(streptozotocin-induced diabetic wounds).Rapid scavenging of ROS by CoNZ and down-regulation of pro-inflammatory markers while up-regulating tissue healing signs with proliferative cells and activated angiogenic factors contributed to the observed healing events.In vitro experiments involving CoNZ-cultures with macrophages and endothelial cells exposed to high glucose and ROS-generating conditions further confirmed the effectiveness of CoNZ.CoNZ-promoted angiogenesis was attributed to the release of cobalt ions,as evidenced by the comparable effects of CoNZ-extracted ionic medium in enhancing endothelial migration and tubule formation via activated HIF-1α.Finally,we compared the in vivo efficacy of CoNZ with the clinically-available drug deferoxamine.Results demonstrated that CoNZ was as effective as the drug in closing the diabetic wound,indicating the potential of CoNZ as a novel drug-free therapeutic approach.
基金a National Research Foundation of Korea(NRF)grant funded by the Ministry of Science and ICT(2019R1C1C1002490,2018R1A2B3003446)by the Global Research Development Center Program(2018K1A4A3A01064257)by the Priority Research Center Program provided by the Ministry of Education(2019R1A6A1A11034536)。
文摘Therapeutic options are quite limited in clinics for the successful repair of infected/degenerated tissues.Although the prevalent treatment is the complete removal of the whole infected tissue,this leads to a loss of tissue function and serious complications.Herein the dental pulp infection,as one of the most common dental problems,was selected as a clinically relevant case to regenerate using a multifunctional nanotherapeutic approach.For this,a mesoporous bioactive glass nano-delivery system incorporating silicate,calcium,and copper as well as loading epidermal growth factor(EGF)was designed to provide antibacterial/pro-angiogenic and osteo/odontogenic multiple therapeutic effects.Amine-functionalized Cu-doped bioactive glass nanospheres(Cu-BGn)were prepared to be 50–60 nm in size,mesoporous,positive-charged and bone-bioactive.The Cu-BGn could release bioactive ions(copper,calcium and silicate ions)with therapeutically-effective doses.The Cu-BGn treatment to human umbilical vein endothelial cells(HUVEC)led to significant enhancement of the migration,tubule formation and expression of angiogenic gene(e.g.vascular endothelial growth factor,VEGF).Furthermore,the EGF-loaded Cu-BGn(EGF@Cu-BGn)showed pro-angiogenic effects with antibacterial activity against E.faecalis,a pathogen commonly involved in the pulp infection.Of note,under the co-culture condition of HUVEC with E.faecalis,the secretion of VEGF was up-regulated.In addition,the osteo/odontogenic stimulation of the EGF@Cu-BGn was evidenced with human dental pulp stem cells.The local administration of the EGF@Cu-BGn in a rat molar tooth defect infected with E.faecalis revealed significant in vivo regenerative capacity,highlighting the nanotherapeutic uses of the multifunctional nanoparticles for regenerating infected/damaged hard tissues.
