Effective treatment of intervertebral disc degeneration with biomaterials remains a challenge,owing to the difficulty in simultaneously overcoming oxidative stress and its associated cascades in the nucleus pulposus m...Effective treatment of intervertebral disc degeneration with biomaterials remains a challenge,owing to the difficulty in simultaneously overcoming oxidative stress and its associated cascades in the nucleus pulposus microenvironment,which includes cellular senescence,apoptosis,inflammation,and extracellular matrix(ECM)degradation.To address these issues,a multifunctional hydrogel(HG-QNT)loaded with transforming growth factorβ1(TGFβ1)and quercetin-based nanoparticles(QUNPs)is developed through borate ester bonding and Schiffbase reaction-induced crosslinking.Specifically,QUNPs fabricated via coordination and hydrophobic interactions endow the hydrogel with extraordinary antioxidative properties.Benefiting from the multi-dynamic crosslinking,the hydrogel achieves self-healing,mechanical stability,and pH-responsive release of QUNPs and TGFβ1.The HG-QNT hydrogel is demonstrated to enhance the proliferation of encapsulated nucleus pulposus cells,thereby providing an ideal platform for cell transplantation.The cooperative antioxidation of QUNPs and the hydrogel carrier renders HG-QNT effective in mitigating oxidative stress,resulting in the suppression of cellular senescence,mitochondrial dysfunction,apoptosis,excessive inflammation,and abnormal catabolism.Afterwards,TGFβ1 and QUNPs act in synergy with the hydrogel to restore the anabolic/catabolic balance by enhancing ECM synthesis.Overall,the strategy orchestrating multiple modulation by HG-QNT hydrogel shows great potential for application in intervertebral disc regeneration.展开更多
The poor mechanical properties of pure zinc(Zn)restrain its applications in orthopedics,which requires high loading capacity.Alloying with lithium(Li)element can enhance strength,however,the work-hardening rate is imp...The poor mechanical properties of pure zinc(Zn)restrain its applications in orthopedics,which requires high loading capacity.Alloying with lithium(Li)element can enhance strength,however,the work-hardening rate is impaired with increased Li content.Here,introducing scandium(Sc)into a low Li-containing Zn-0.1Li alloy could effectively refine its microstructure,reducing the average grain size from 10 to 4μm.The refinement in microstructure led to a significant improvement in tensile strength,im-proving from 257 MPa of Zn-0.1Li to 341 MPa of Zn-0.1Li-0.1Sc,meanwhile,the work-hardening rate remained positive during the whole plastic deformation stage.The addition of Sc-impaired elongation is due to numerous microcracks formed at the Zn/ScZn_(12)interfaces,as well as in the large-sized ScZn_(12)particles.Corrosion tests revealed an accelerated corrosion rate due to the galvanic effect between the Zn matrix and ScZn_(12)phase.Even so,the Zn-0.1Li-1.0Sc alloy still exhibited superior biocompatibility with rat/mouse mesenchymal stem cells and close osteogenesis capacity to the original Zn-0.1Li alloy.These findings demonstrated that the addition of Sc in low Li-containing alloys could improve mechanical strength without sacrificing the work-hardening rate and biocompatibility.展开更多
A novel double-layer collagen membrane with unequal pore sizes in each layer was designed and tested in this study. The inner, loose layer has about 100-μm-diameter pores, while the outer, compact layer has about 10-...A novel double-layer collagen membrane with unequal pore sizes in each layer was designed and tested in this study. The inner, loose layer has about 100-μm-diameter pores, while the outer, compact layer has about 10-μm-diameter pores. In a rat model of incomplete spinal cord injury, a large number of neural stem cells were seeded into the loose layer, which was then adhered to the injured side, and the compact layer was placed against the lateral side. The results showed that the transplantation of neural stem cells in a double-layer collagen membrane with unequal pore sizes promoted the differentiation of neural stem cells, attenuated the pathological lesion, and signiifcantly improved the motor function of the rats with incomplete spinal cord injuries. These experimental ifndings suggest that the transplantation of neural stem cells in a double-lay-er collagen membrane with unequal pore sizes is an effective therapeutic strategy to repair an injured spinal cord.展开更多
Antibacterial Ti-5Cu alloy is a promising substitute material for Ti-made cardiovascular implants,so its surface engineering is crucial to expediting clinical implementation.Given the antibacterial and cardiovas-cular...Antibacterial Ti-5Cu alloy is a promising substitute material for Ti-made cardiovascular implants,so its surface engineering is crucial to expediting clinical implementation.Given the antibacterial and cardiovas-cular biological benefits of Cu^(2+)and titanium-nitride-oxide(TiN x O y)coatings,a Cu_(2)O/CuO-TiN x O y coating with upregulated Cu^(2+)release was successfully deposited on Ti-5Cu alloy for the first time using oxygen and nitrogen plasma-based surface modification.The superhydrophilic and nanostructured Cu_(2)O/CuO-TiN x O y coating had a dense structure and was well bonded to the substrate,resulting in enhanced cor-rosion resistance,while CuO/Cu_(2)O in the coating released Cu^(2+)faster than Ti_(2)Cu phase in the matrix.More gratifying,the coating demonstrated perfect antibacterial properties(R>99.9%against S.aureus),owing primarily to direct contact sterilization of Cu_(2)O/CuO.The most encouraging phenomenon was that the coating dramatically accelerated HUVEC adhesion(1.4 times),proliferation(RGR:106%-116%),and particularly migration(RMR:158%-247%)compared with the control Ti.The coating extract also signifi-cantly stimulated in vitro angiogenesis capacity.The rapid endothelialization for Cu_(2)O/CuO-TiN x O y coating was attributed to the surface nanostructure and Cu^(2+)/NO_(2)−release,which upregulated the angiogenesis-related gene expression of HIF-1α,VEGF,and eNOS to increase VEGF secretion and NO production.All of the findings indicated that the Cu_(2)O/CuO-TiN x O y coating could enhance the corrosion resistance,an-tibacterial properties,and endothelialization potential of Ti-Cu alloy,displaying great clinical potential in cardiovascular applications.展开更多
Intervertebral disc herniation(IVDH)is a common manifestation of intervertebral disc degeneration(IVDD)characterized by inflammation that results in the rupture of the annulus fibrosus(AF)and her-niation of the nucleu...Intervertebral disc herniation(IVDH)is a common manifestation of intervertebral disc degeneration(IVDD)characterized by inflammation that results in the rupture of the annulus fibrosus(AF)and her-niation of the nucleus pulposus(NP).While current clinical research primarily focuses on regulating the degenerative NP,the crucial role of the AF in maintaining the mechanical stability and metabolic balance of the intervertebral disc(IVD)has been overlooked.Resolving immunoregulation and AF repair is im-perative to effectively prevent recurrent herniation.Therefore,this study introduces a bioactive sealant(OD/GM/QCS-sEVs),which combines gelatin methacryloyl(GM)and oxidized dextran(OD)with quater-nized chitosan(QCS)and incorporates small extracellular vesicles(sEVs).The developed sealant possesses injectability,self-healing capabilities,tissue adhesiveness,and mechanical stability,with an average ad-hesive strength of 109.63 kPa.In vitro experiments demonstrate that OD/GM/QCS-sEVs effectively seal AF defects while preserving mechanical properties comparable to those of a normal IVD.Additionally,the sealant releases sEVs through a pH-responsive mechanism,thereby modulating macrophage polarization to the M2 phenotype via the NF-κB signaling pathway.This mechanism facilitates immunoregulation and anti-inflammatory effects,and promotes stem cell differentiation into fibrocartilage.Animal experiments confirm the ability of OD/GM/QCS-sEVs to seal defects,prevent proteoglycan loss,inhibit IVDD develop-ment,and promote AF regeneration.Overall,OD/GM/QCS-sEVs hold promise as an innovative bioactive sealant for recurrent herniation by resolving immunoregulation and AF regeneration.展开更多
Tissue engineering aims to offer large-scale replacement of damaged organs using implants with the com-bination of cells,growth factors and scaffolds.However,the intra/peri-implant region is exposed to se-vere hypoxic...Tissue engineering aims to offer large-scale replacement of damaged organs using implants with the com-bination of cells,growth factors and scaffolds.However,the intra/peri-implant region is exposed to se-vere hypoxic stress and oxidative stress during the early stage of implantation with bone graft materials,which endangers the survival,proliferation and differentiation of seed cells within the implants as well as the host cells surrounding the implants.If the bone graft material could spontaneously and intelligently regulate the hypoxic stress and oxidative stress to a moderate level,it will facilitate the vascularization of the implants and the rapid regeneration of the bone tissue.In this review,we will first introduce the signaling pathways of cellular response under hypoxic stress and oxidative stress,then present the clas-sical material designs and examples in response to hypoxic stress and oxidative stress.And finally,we will address the important role of epigenetic mechanisms in the regulation of hypoxic stress and oxida-tive stress and describe the potential applications and prospective smart bone graft materials based on novel epigenetic factors against hypoxic stress and oxidative stress in bone repair.The main content of this review is summarized in the following graphical abstract.展开更多
It has always been a dream to construct tissues and even organs for transplantation to replace those with defects caused by diseases or injuries.Tissue engineering is another milestone in the developmental history of ...It has always been a dream to construct tissues and even organs for transplantation to replace those with defects caused by diseases or injuries.Tissue engineering is another milestone in the developmental history of life science after cellular and molecular bioscience.Nevertheless,despite decades of rapid de-velopment,tissue-engineered biomaterials have not been widely used clinically.Biomaterials constructed by physical and chemical methods have lots of difficulty in precisely mimicking the macroscopic and mi-croscopic structures of human tissues.The ultimate way to build organoid tissue for regeneration is to enable the cells to take the initiative and build suitable functions.Based on the thoughts of tissue engi-neering,organoid technology holds great potential as a research tool for a wide range of fields,including developmental biology,disease pathology,cell biology,precision medicine,and drug toxicity and efficacy testing.This technology also holds tremendous potential for regenerative medicine,as organoids present the possibility for autologous and allogeneic cell therapy through the replacement of damaged or dis-eased tissues with organoid-propagated tissue or stem cell populations.In this review work,we briefly outlook the development history of organoid technology,summarize the current bottlenecks and the un-derlying reasons,and propose the unified term“function-oriented design in tissue engineering”,a new topic that may provide a solution to overcome these bottlenecks.展开更多
Hydrogel scaffolds are attractive for tissue defect repair and reorganization because of their human tissue-like characteristics.However,most hydrogels offer limited cell growth and tissue formation ability due to the...Hydrogel scaffolds are attractive for tissue defect repair and reorganization because of their human tissue-like characteristics.However,most hydrogels offer limited cell growth and tissue formation ability due to their submicron-or nano-sized gel networks,which restrict the supply of oxygen,nutrients and inhibit the proliferation and differentiation of encapsulated cells.In recent years,3D printed hydrogels have shown great potential to overcome this problem by introducing macro-pores within scaffolds.In this study,we fabricated a macroporous hydrogel scaffold through horseradish peroxidase(HRP)-mediated crosslinking of silk fibroin(SF)and tyramine-substituted gelatin(GT)by extrusion-based low-temperature 3D printing.Through physicochemical characterization,we found that this hydrogel has excellent structural stability,suitable mechanical properties,and an adjustable degradation rate,thus satisfying the requirements for cartilage reconstruction.Cell suspension and aggregate seeding methods were developed to assess the inoculation efficiency of the hydrogel.Moreover,the chondrogenic differentiation of stem cells was explored.Stem cells in the hydrogel differentiated into hyaline cartilage when the cell aggregate seeding method was used and into fibrocartilage when the cell suspension was used.Finally,the effect of the hydrogel and stem cells were investigated in a rabbit cartilage defect model.After implantation for 12 and 16 weeks,histological evaluation of the sections was performed.We found that the enzymatic cross-linked and methanol treatment SF5GT15 hydrogel combined with cell aggregates promoted articular cartilage regeneration.In summary,this 3D printed macroporous SF-GT hydrogel combined with stem cell aggregates possesses excellent potential for application in cartilage tissue repair and regeneration.展开更多
The osteogenic microenvironment of bone-repairing materials plays a key role in accelerating bone regeneration but remains incompletely defined,which significantly limits the application of such bioactive materials.He...The osteogenic microenvironment of bone-repairing materials plays a key role in accelerating bone regeneration but remains incompletely defined,which significantly limits the application of such bioactive materials.Here,the transcriptional landscapes of different osteogenic microenvironments,including three-dimensional(3D)hydroxyapatite(HA)scaffolds and osteogenic medium(OM),for mesenchymal stromal cells(MSCs)in vitro were mapped at single-cell resolution.Our findings suggested that an osteogenic process reminiscent of endochondral ossification occurred in HA scaffolds through sequential activation of osteogenic-related signaling pathways,along with inflammation and angiogenesis,but inhibition of adipogenesis and fibrosis.Moreover,we revealed the mechanism during OM-mediated osteogenesis involves the ZBTB16 and WNT signaling pathways.Heterogeneity of MSCs was also demonstrated.In vitro ossification of LRRC75A+MSCs was shown to have better utilization of WNT-related ossification process,and PCDH10+MSCs with superiority in hydroxyapatite-related osteogenic process.These findings provided further understanding of the cellular activity modulated by OM conditions and HA scaffolds,providing new insights for the improvement of osteogenic biomaterials.This atlas provides a blueprint for research on MSC heterogeneity and the osteogenic microenvironment of HA scaffolds and a database reference for the application of bioactive materials for bone regeneration.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
Calcium phosphate cements(CPC)are widely anticipated to be an optimum bone repair substitute due to its satisfied biocompatibility and degradability,suitable to be used in minimally invasive treatment of bone defects....Calcium phosphate cements(CPC)are widely anticipated to be an optimum bone repair substitute due to its satisfied biocompatibility and degradability,suitable to be used in minimally invasive treatment of bone defects.However the clinical application of CPC is still not satisfied by its poor cohesiveness and mechanical properties,in particular its osteoinductivity.Hyaluronic acid reinforced calcium phosphate cements(HA/CPC)showed extroadinary potential not only enhancing the compressive strength of the cements but also significantly increasing its osteoinductivity.In our study,the compressive strength of HA/CPC increased significantly when the cement was added 1%hyaluronic acid(denoted as 1-HA/CPC).In the meantime,hyaluronic acid obviously promoted ALP activity,osteogenic related protein and mRNA expression of hBMSCs(human bone marrow mesenchymal stem cells)in vitro,cement group of HA/CPC with 4%hyaluronic acid adding(denoted as 4-HA/CPC)showed optimal enhancement in hBMSCs differentiation.After being implanted in rat tibial defects,4-HA/CPC group exhibited better bone repair ability and bone growth promoting factors,comparing to pure CPC and 1-HA/CPC groups.The underlying biological mechanism of this stimulation for HA/CPC may be on account of higher osteogenic promoting factors secretion and osteogenic genes expression with hyaluronic acid incorporation.These results indicate that hyaluronic acid is a highly anticipated additive to improve physicochemical properties and osteoinductivity performance of CPCs for minimally invasive healing of bone defects.展开更多
Injectable biomaterial-based treatment is a promising strategy to enhance tissue repair after traumatic spinal cord injury(SCI)by bridging cavity spaces.However,there are limited reports of injectable,electroconductiv...Injectable biomaterial-based treatment is a promising strategy to enhance tissue repair after traumatic spinal cord injury(SCI)by bridging cavity spaces.However,there are limited reports of injectable,electroconductive hydrogels with self-healing properties being employed for the treatment of traumatic SCI.Hence,a natural extracellular matrix(ECM)biopolymer(chondroitin sulphate and gelatin)-based hydrogel containing polypyrrole,which imparted electroconductive properties,is developed for traumatic SCI repair.The resulting hydrogels showed mechanical(~928 Pa)and conductive properties(4.49 mS/cm)similar to natural spinal cord tissues.Moreover,the hydrogels exhibited shear-thinning and self-healing abilities,which allows it to be effectively injected into the injury site and to fill the lesion cavity to accelerate the tissue repair of traumatic SCI.In vitro,electroconductive ECM hydrogels promoted neuronal differentiation,enhanced axon outgrowth,and inhibited astrocyte differentiation.The electroconductive ECM hydrogel activated endogenous neural stem cell neurogenesis in vivo(n=6),and induced myelinated axon regeneration into the lesion site via activation of the PI3K/AKT and MEK/ERK pathways,thereby achieving significant locomotor function restoration in rats with spinal cord injury(p<0.001,compared to SCI group).Overall,the injectable self-healing electroconductive ECM-based hydrogels developed in this study are ideal biomaterials for treatment of traumatic SCI.展开更多
Biomedical implants and devices for tissue engineering in clinics,mainly made of polymers and stiff metallic materials,require possibly secondary surgery or life-long medicine.Biodegradable metals for biomedical impla...Biomedical implants and devices for tissue engineering in clinics,mainly made of polymers and stiff metallic materials,require possibly secondary surgery or life-long medicine.Biodegradable metals for biomedical implants and devices exhibit huge potential to improve the prognosis of patients.In this work,we developed a new type of biodegradable binary zinc(Zn)alloys with 16 rare earth elements(REEs)including Sc,Y,La to Nd,and Sm to Lu,respectively.The effects of REEs on the alloy microstructure,mechanical properties,corrosion behavior and in vitro and in vivo biocompatibility of Zn were systematically investigated using pure Zn as control.All Zn-RE alloys generally exhibited improved mechanical properties,and biocompatibilities compared to pure Zn,especially the tensile strength and ductility of Zn-RE alloys were dramatically enhanced.Among the Zn-RE alloys,different REEs presented enhancement effects at varied extent.Y,Ho and Lu were the three elements displaying greatest improvements in majority of alloys properties,while Eu,Gd and Dy exhibited least improvement.Furthermore,the Zn-RE alloys were comparable with other Zn alloys and also exhibited superior properties to Mg-RE alloys.The in vivo experiment using Zn-La,Zn-Ce,and Zn-Nd alloys as tibia bone implants in rabbit demonstrated the excellent tissue biocompatibility and much more obvious osseointegration than the pure Zn control group.This work presented the significant potential of the developed Zn-RE binary alloys as novel degradable metal for biomedical implants and devices.展开更多
基金supported by the National Natural Science Foun-dation of China(Grant No.52073103,52272276,51873069,and 52373128)Beijing Municipal Health Commission(BMHC-2021-6,BJRITO-RDP-2024)Beijing Municipal Public Welfare Devel-opment and Reform Pilot Project for Medical Research Institutes(JYY2023-11,JYY2023-8).
文摘Effective treatment of intervertebral disc degeneration with biomaterials remains a challenge,owing to the difficulty in simultaneously overcoming oxidative stress and its associated cascades in the nucleus pulposus microenvironment,which includes cellular senescence,apoptosis,inflammation,and extracellular matrix(ECM)degradation.To address these issues,a multifunctional hydrogel(HG-QNT)loaded with transforming growth factorβ1(TGFβ1)and quercetin-based nanoparticles(QUNPs)is developed through borate ester bonding and Schiffbase reaction-induced crosslinking.Specifically,QUNPs fabricated via coordination and hydrophobic interactions endow the hydrogel with extraordinary antioxidative properties.Benefiting from the multi-dynamic crosslinking,the hydrogel achieves self-healing,mechanical stability,and pH-responsive release of QUNPs and TGFβ1.The HG-QNT hydrogel is demonstrated to enhance the proliferation of encapsulated nucleus pulposus cells,thereby providing an ideal platform for cell transplantation.The cooperative antioxidation of QUNPs and the hydrogel carrier renders HG-QNT effective in mitigating oxidative stress,resulting in the suppression of cellular senescence,mitochondrial dysfunction,apoptosis,excessive inflammation,and abnormal catabolism.Afterwards,TGFβ1 and QUNPs act in synergy with the hydrogel to restore the anabolic/catabolic balance by enhancing ECM synthesis.Overall,the strategy orchestrating multiple modulation by HG-QNT hydrogel shows great potential for application in intervertebral disc regeneration.
基金supported by the National Natural Science Foundation of China(Grant Nos.U22A20121 and 52101283)the Suzhou Science and Technology Project(Grant No SJC2023005)+3 种基金the Science and Technology Planning Project of Guangzhou(Grant No 202102010008)the High-Level Hospital Construction Project(Grant No KJ012019520)the Beijing Mu-nicipal Health Commission(BMHC-2021-6,BJRITO-RDP-2024)the Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes(Nos.JYY2023-11 and JYY2023-8).
文摘The poor mechanical properties of pure zinc(Zn)restrain its applications in orthopedics,which requires high loading capacity.Alloying with lithium(Li)element can enhance strength,however,the work-hardening rate is impaired with increased Li content.Here,introducing scandium(Sc)into a low Li-containing Zn-0.1Li alloy could effectively refine its microstructure,reducing the average grain size from 10 to 4μm.The refinement in microstructure led to a significant improvement in tensile strength,im-proving from 257 MPa of Zn-0.1Li to 341 MPa of Zn-0.1Li-0.1Sc,meanwhile,the work-hardening rate remained positive during the whole plastic deformation stage.The addition of Sc-impaired elongation is due to numerous microcracks formed at the Zn/ScZn_(12)interfaces,as well as in the large-sized ScZn_(12)particles.Corrosion tests revealed an accelerated corrosion rate due to the galvanic effect between the Zn matrix and ScZn_(12)phase.Even so,the Zn-0.1Li-1.0Sc alloy still exhibited superior biocompatibility with rat/mouse mesenchymal stem cells and close osteogenesis capacity to the original Zn-0.1Li alloy.These findings demonstrated that the addition of Sc in low Li-containing alloys could improve mechanical strength without sacrificing the work-hardening rate and biocompatibility.
文摘A novel double-layer collagen membrane with unequal pore sizes in each layer was designed and tested in this study. The inner, loose layer has about 100-μm-diameter pores, while the outer, compact layer has about 10-μm-diameter pores. In a rat model of incomplete spinal cord injury, a large number of neural stem cells were seeded into the loose layer, which was then adhered to the injured side, and the compact layer was placed against the lateral side. The results showed that the transplantation of neural stem cells in a double-layer collagen membrane with unequal pore sizes promoted the differentiation of neural stem cells, attenuated the pathological lesion, and signiifcantly improved the motor function of the rats with incomplete spinal cord injuries. These experimental ifndings suggest that the transplantation of neural stem cells in a double-lay-er collagen membrane with unequal pore sizes is an effective therapeutic strategy to repair an injured spinal cord.
基金supported by the National Key R&D Program of China(No.2022YFB3804400)and(No.2022YFE0122800)Research Program(No.62602010113)+1 种基金Na-tional Natural Science Foundation of China(No.31971253/C1002)Beijing Municipal Health Commission(Nos.BMHC-2021-6,BMHC-2019-9,PXM 2020_026275_000002).
文摘Antibacterial Ti-5Cu alloy is a promising substitute material for Ti-made cardiovascular implants,so its surface engineering is crucial to expediting clinical implementation.Given the antibacterial and cardiovas-cular biological benefits of Cu^(2+)and titanium-nitride-oxide(TiN x O y)coatings,a Cu_(2)O/CuO-TiN x O y coating with upregulated Cu^(2+)release was successfully deposited on Ti-5Cu alloy for the first time using oxygen and nitrogen plasma-based surface modification.The superhydrophilic and nanostructured Cu_(2)O/CuO-TiN x O y coating had a dense structure and was well bonded to the substrate,resulting in enhanced cor-rosion resistance,while CuO/Cu_(2)O in the coating released Cu^(2+)faster than Ti_(2)Cu phase in the matrix.More gratifying,the coating demonstrated perfect antibacterial properties(R>99.9%against S.aureus),owing primarily to direct contact sterilization of Cu_(2)O/CuO.The most encouraging phenomenon was that the coating dramatically accelerated HUVEC adhesion(1.4 times),proliferation(RGR:106%-116%),and particularly migration(RMR:158%-247%)compared with the control Ti.The coating extract also signifi-cantly stimulated in vitro angiogenesis capacity.The rapid endothelialization for Cu_(2)O/CuO-TiN x O y coating was attributed to the surface nanostructure and Cu^(2+)/NO_(2)−release,which upregulated the angiogenesis-related gene expression of HIF-1α,VEGF,and eNOS to increase VEGF secretion and NO production.All of the findings indicated that the Cu_(2)O/CuO-TiN x O y coating could enhance the corrosion resistance,an-tibacterial properties,and endothelialization potential of Ti-Cu alloy,displaying great clinical potential in cardiovascular applications.
基金supported by the National Natural Science Foundation of China(Grant Nos.51873069,52272276,52073103,52203164)the Zhongshan Innovation Project of high-end Scientific Research Institutions(Grant No.2020AG020)+2 种基金the Key-Area Research and Development Program of Guangdong Province(No.2020B090924004)Beijing Municipal Health Commission(Grant Nos.BMHC-2018-4,BMHC-2019-9,PXM2020026275000002)the Postdoctoral Research Foundation of China(No.2022M711183).
文摘Intervertebral disc herniation(IVDH)is a common manifestation of intervertebral disc degeneration(IVDD)characterized by inflammation that results in the rupture of the annulus fibrosus(AF)and her-niation of the nucleus pulposus(NP).While current clinical research primarily focuses on regulating the degenerative NP,the crucial role of the AF in maintaining the mechanical stability and metabolic balance of the intervertebral disc(IVD)has been overlooked.Resolving immunoregulation and AF repair is im-perative to effectively prevent recurrent herniation.Therefore,this study introduces a bioactive sealant(OD/GM/QCS-sEVs),which combines gelatin methacryloyl(GM)and oxidized dextran(OD)with quater-nized chitosan(QCS)and incorporates small extracellular vesicles(sEVs).The developed sealant possesses injectability,self-healing capabilities,tissue adhesiveness,and mechanical stability,with an average ad-hesive strength of 109.63 kPa.In vitro experiments demonstrate that OD/GM/QCS-sEVs effectively seal AF defects while preserving mechanical properties comparable to those of a normal IVD.Additionally,the sealant releases sEVs through a pH-responsive mechanism,thereby modulating macrophage polarization to the M2 phenotype via the NF-κB signaling pathway.This mechanism facilitates immunoregulation and anti-inflammatory effects,and promotes stem cell differentiation into fibrocartilage.Animal experiments confirm the ability of OD/GM/QCS-sEVs to seal defects,prevent proteoglycan loss,inhibit IVDD develop-ment,and promote AF regeneration.Overall,OD/GM/QCS-sEVs hold promise as an innovative bioactive sealant for recurrent herniation by resolving immunoregulation and AF regeneration.
基金financially supported by the National Nat-ural Science Foundation of China(Nos.32071341,82202741,52003302,31430030,51973021,32201111,and 52202358)the Chinese Postdoctoral Science Foundation(Nos.2021M703710 and 2021M691464)+1 种基金the Guangdong Basic and Applied Basic Re-search Foundation(Nos.2021A1515111040,2019A1515110841 and 2019A1515011935)the Beijing Municipal Health Commis-sion(Nos.BMHC-20216 and PXM 2020_026275_000002)。
文摘Tissue engineering aims to offer large-scale replacement of damaged organs using implants with the com-bination of cells,growth factors and scaffolds.However,the intra/peri-implant region is exposed to se-vere hypoxic stress and oxidative stress during the early stage of implantation with bone graft materials,which endangers the survival,proliferation and differentiation of seed cells within the implants as well as the host cells surrounding the implants.If the bone graft material could spontaneously and intelligently regulate the hypoxic stress and oxidative stress to a moderate level,it will facilitate the vascularization of the implants and the rapid regeneration of the bone tissue.In this review,we will first introduce the signaling pathways of cellular response under hypoxic stress and oxidative stress,then present the clas-sical material designs and examples in response to hypoxic stress and oxidative stress.And finally,we will address the important role of epigenetic mechanisms in the regulation of hypoxic stress and oxida-tive stress and describe the potential applications and prospective smart bone graft materials based on novel epigenetic factors against hypoxic stress and oxidative stress in bone repair.The main content of this review is summarized in the following graphical abstract.
基金This work was financially supported by the National Natural Science Foundation of China(Nos.U22A20162,31900583,32071351,81772400,82102604,and 81960395)the Natural Science Foundation of Guangzhou City(No.201807010031)+5 种基金the Foundation of Shenzhen Committee for Science and Technology Innovation(Nos.JCYJ20190809142211354,and GJHZ20180929160004704)the Sanming Project of Medicine in Shenzhen(No.SZSM201911002)the Beijing Municipal Health Commission(Nos.BMHC-2021-6,BMHC-2019-9,BMHC-2018-4,and PXM2020_026275_000002)the AOCMF Translational approaches for bone constructs(No.AOCMF-21-04S)the Sun Yatsen University Clinical Research 5010 Program(No.2019009)the Academic Affairs Office of Sun Yat-sen University(Nos.202211583,and 202211589).
文摘It has always been a dream to construct tissues and even organs for transplantation to replace those with defects caused by diseases or injuries.Tissue engineering is another milestone in the developmental history of life science after cellular and molecular bioscience.Nevertheless,despite decades of rapid de-velopment,tissue-engineered biomaterials have not been widely used clinically.Biomaterials constructed by physical and chemical methods have lots of difficulty in precisely mimicking the macroscopic and mi-croscopic structures of human tissues.The ultimate way to build organoid tissue for regeneration is to enable the cells to take the initiative and build suitable functions.Based on the thoughts of tissue engi-neering,organoid technology holds great potential as a research tool for a wide range of fields,including developmental biology,disease pathology,cell biology,precision medicine,and drug toxicity and efficacy testing.This technology also holds tremendous potential for regenerative medicine,as organoids present the possibility for autologous and allogeneic cell therapy through the replacement of damaged or dis-eased tissues with organoid-propagated tissue or stem cell populations.In this review work,we briefly outlook the development history of organoid technology,summarize the current bottlenecks and the un-derlying reasons,and propose the unified term“function-oriented design in tissue engineering”,a new topic that may provide a solution to overcome these bottlenecks.
基金This work was financially supported by the National Natural Science Foundation of China(Grant nos.52073103,51873069 and 51873071)the National Key R&D Program of China(Grant No.2018YFC1106300)+1 种基金Beijing Municipal Health Commission(Grant nos.BMHC-2019-9,BMHC-2018-4 and PXM2020_026275_000002)the funds for Zhongshan Innovation Project of high-end Scientific Research Institutions(Grant No.2020AG020).
文摘Hydrogel scaffolds are attractive for tissue defect repair and reorganization because of their human tissue-like characteristics.However,most hydrogels offer limited cell growth and tissue formation ability due to their submicron-or nano-sized gel networks,which restrict the supply of oxygen,nutrients and inhibit the proliferation and differentiation of encapsulated cells.In recent years,3D printed hydrogels have shown great potential to overcome this problem by introducing macro-pores within scaffolds.In this study,we fabricated a macroporous hydrogel scaffold through horseradish peroxidase(HRP)-mediated crosslinking of silk fibroin(SF)and tyramine-substituted gelatin(GT)by extrusion-based low-temperature 3D printing.Through physicochemical characterization,we found that this hydrogel has excellent structural stability,suitable mechanical properties,and an adjustable degradation rate,thus satisfying the requirements for cartilage reconstruction.Cell suspension and aggregate seeding methods were developed to assess the inoculation efficiency of the hydrogel.Moreover,the chondrogenic differentiation of stem cells was explored.Stem cells in the hydrogel differentiated into hyaline cartilage when the cell aggregate seeding method was used and into fibrocartilage when the cell suspension was used.Finally,the effect of the hydrogel and stem cells were investigated in a rabbit cartilage defect model.After implantation for 12 and 16 weeks,histological evaluation of the sections was performed.We found that the enzymatic cross-linked and methanol treatment SF5GT15 hydrogel combined with cell aggregates promoted articular cartilage regeneration.In summary,this 3D printed macroporous SF-GT hydrogel combined with stem cell aggregates possesses excellent potential for application in cartilage tissue repair and regeneration.
基金This study was supported by the National Key R&D Program of China(Grant no.2017YFC1105000)the National Natural Science Foundation of China(Grant no.81772400,31900583,31430030)+4 种基金the Fundamental Research Funds for the Central Universities(Grant no.19ykzd05)the Natural Science Foundation of Guangzhou City(Grant no.201704030082,201807010031)the Foundation of Shenzhen Committee for Science and Technology Innovation(Grant no.JCYJ20190809142211354,GJHZ20180929160004704)the Sanming Project of Medicine in Shenzhen(Grant no.SZSM201911002)and the Beijing Municipal Health Commission(Grant no.BMHC-2021-X,BMHC-2019-9,BMHC-2018-4,PXM2020_026275_000002).Special thanks are extended to Dr.Cheng Ruijuan for technical support.
文摘The osteogenic microenvironment of bone-repairing materials plays a key role in accelerating bone regeneration but remains incompletely defined,which significantly limits the application of such bioactive materials.Here,the transcriptional landscapes of different osteogenic microenvironments,including three-dimensional(3D)hydroxyapatite(HA)scaffolds and osteogenic medium(OM),for mesenchymal stromal cells(MSCs)in vitro were mapped at single-cell resolution.Our findings suggested that an osteogenic process reminiscent of endochondral ossification occurred in HA scaffolds through sequential activation of osteogenic-related signaling pathways,along with inflammation and angiogenesis,but inhibition of adipogenesis and fibrosis.Moreover,we revealed the mechanism during OM-mediated osteogenesis involves the ZBTB16 and WNT signaling pathways.Heterogeneity of MSCs was also demonstrated.In vitro ossification of LRRC75A+MSCs was shown to have better utilization of WNT-related ossification process,and PCDH10+MSCs with superiority in hydroxyapatite-related osteogenic process.These findings provided further understanding of the cellular activity modulated by OM conditions and HA scaffolds,providing new insights for the improvement of osteogenic biomaterials.This atlas provides a blueprint for research on MSC heterogeneity and the osteogenic microenvironment of HA scaffolds and a database reference for the application of bioactive materials for bone regeneration.
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.
基金the National Key R&D Program of China(Grant No.2018YFC1106300 and 2017YFC1105000)the National Natural Science Foundation of China(Grant No.52072398,51802340,31870956,81860385,81672227,U2001221,51772210)+2 种基金the Frontier Science Key Research Programs of CAS(Grant No.QYZDB-SSW-JSC030)the Shenzhen Significant Strategy Layout Project(Grant No.JCYJ20170413162104773 and JCYJ20200109114620793)Beijing Municipal Health Commission(Grant No.BMHC-2018-4,BMHC-2019-9,PXM2020_026275_000002).
文摘Calcium phosphate cements(CPC)are widely anticipated to be an optimum bone repair substitute due to its satisfied biocompatibility and degradability,suitable to be used in minimally invasive treatment of bone defects.However the clinical application of CPC is still not satisfied by its poor cohesiveness and mechanical properties,in particular its osteoinductivity.Hyaluronic acid reinforced calcium phosphate cements(HA/CPC)showed extroadinary potential not only enhancing the compressive strength of the cements but also significantly increasing its osteoinductivity.In our study,the compressive strength of HA/CPC increased significantly when the cement was added 1%hyaluronic acid(denoted as 1-HA/CPC).In the meantime,hyaluronic acid obviously promoted ALP activity,osteogenic related protein and mRNA expression of hBMSCs(human bone marrow mesenchymal stem cells)in vitro,cement group of HA/CPC with 4%hyaluronic acid adding(denoted as 4-HA/CPC)showed optimal enhancement in hBMSCs differentiation.After being implanted in rat tibial defects,4-HA/CPC group exhibited better bone repair ability and bone growth promoting factors,comparing to pure CPC and 1-HA/CPC groups.The underlying biological mechanism of this stimulation for HA/CPC may be on account of higher osteogenic promoting factors secretion and osteogenic genes expression with hyaluronic acid incorporation.These results indicate that hyaluronic acid is a highly anticipated additive to improve physicochemical properties and osteoinductivity performance of CPCs for minimally invasive healing of bone defects.
基金We thank L.Fan for his help in drawing the schematic diagram and typesetting figures.This work was supported by the National Natural Science Foundation of China(Nos.51932002,51903087,and 31771080)the Science and Technology Innovation Team Project of Foshan(No.2018IT100101)+1 种基金Sino-Singapore International Joint Research Institute(No.203-A018004)and the Joint Fund of Ministry of Education for Equipment Preresearch(No.6141A02022632).
文摘Injectable biomaterial-based treatment is a promising strategy to enhance tissue repair after traumatic spinal cord injury(SCI)by bridging cavity spaces.However,there are limited reports of injectable,electroconductive hydrogels with self-healing properties being employed for the treatment of traumatic SCI.Hence,a natural extracellular matrix(ECM)biopolymer(chondroitin sulphate and gelatin)-based hydrogel containing polypyrrole,which imparted electroconductive properties,is developed for traumatic SCI repair.The resulting hydrogels showed mechanical(~928 Pa)and conductive properties(4.49 mS/cm)similar to natural spinal cord tissues.Moreover,the hydrogels exhibited shear-thinning and self-healing abilities,which allows it to be effectively injected into the injury site and to fill the lesion cavity to accelerate the tissue repair of traumatic SCI.In vitro,electroconductive ECM hydrogels promoted neuronal differentiation,enhanced axon outgrowth,and inhibited astrocyte differentiation.The electroconductive ECM hydrogel activated endogenous neural stem cell neurogenesis in vivo(n=6),and induced myelinated axon regeneration into the lesion site via activation of the PI3K/AKT and MEK/ERK pathways,thereby achieving significant locomotor function restoration in rats with spinal cord injury(p<0.001,compared to SCI group).Overall,the injectable self-healing electroconductive ECM-based hydrogels developed in this study are ideal biomaterials for treatment of traumatic SCI.
基金supported by the National Key R&D Program of China[2018YFE0104200]the National Natural Science Foundation of China[51931001,52171233,52271243,U22A20121]+2 种基金the INTERNATIONAL COOPERATION and Exchange project of NSFC-RFBR[52111530042]the Beijing Natural Science Foundation[L212014]the Beijing Nova Program.
文摘Biomedical implants and devices for tissue engineering in clinics,mainly made of polymers and stiff metallic materials,require possibly secondary surgery or life-long medicine.Biodegradable metals for biomedical implants and devices exhibit huge potential to improve the prognosis of patients.In this work,we developed a new type of biodegradable binary zinc(Zn)alloys with 16 rare earth elements(REEs)including Sc,Y,La to Nd,and Sm to Lu,respectively.The effects of REEs on the alloy microstructure,mechanical properties,corrosion behavior and in vitro and in vivo biocompatibility of Zn were systematically investigated using pure Zn as control.All Zn-RE alloys generally exhibited improved mechanical properties,and biocompatibilities compared to pure Zn,especially the tensile strength and ductility of Zn-RE alloys were dramatically enhanced.Among the Zn-RE alloys,different REEs presented enhancement effects at varied extent.Y,Ho and Lu were the three elements displaying greatest improvements in majority of alloys properties,while Eu,Gd and Dy exhibited least improvement.Furthermore,the Zn-RE alloys were comparable with other Zn alloys and also exhibited superior properties to Mg-RE alloys.The in vivo experiment using Zn-La,Zn-Ce,and Zn-Nd alloys as tibia bone implants in rabbit demonstrated the excellent tissue biocompatibility and much more obvious osseointegration than the pure Zn control group.This work presented the significant potential of the developed Zn-RE binary alloys as novel degradable metal for biomedical implants and devices.
