| Titanium(Ti)and titanium alloy have been widely used as clinical orthopedic implants because of their good mechanical properties,chemical stability and biocompatibility.However,the surface biological inertia of Ti-based implants caused poor integration between them and the surrounding bone tissue(osseointegration),leading to aseptic loosening.In addition,the Ti-based implant itself lacked antibacterial properties,and the surface was easy to cause bacterial adhesion and even biofilm formation,which finally led to the implant-related infection,resulting in serious consequences of implant failure.Generally,bacterial adhesion-biofilm formation and cell adhesion-osseointegration occurred at the surface or interface of Ti implants.Therefore,through surface modification,endowing Ti-based implants with excellent antibacterial ability and great osseointegration was essential for their long-term service.Considering that,this study constructed several Ti-based implants with osteogenic or/and antibacterial properties through micro-nanotopological structure,layer-by-layer self-assembly,nanoparticle functionalization,light-controlled interfaces,and other strategies.Furthermore,in vitro cell experiments and in vivo animal models were used to evaluate their effectiveness.The main contents and conclusions of these researches were listed as follows:(1)Investigation of osteogenic responses of Fe-incorporated micro/nano-hierarchical structures on titanium surfacesThe combination of physical factors(topological structure)and biochemical factors(active elements)is an effective surface modification strategy to endow Ti-based implants with great osteogenic responses.In this study,after simple double acid treatment and hydrothermal treatment in a salt solution containing iron ions,obtained Ti had a micro/nanotopology doped with iron ions.The results of scanning electron microscope(SEM),X-ray photoelectron spectroscopy(XPS)and water contact angle assay showed that the Fe-doped micro/nano-hierarchical structures had been successfully constructed.Iron mainly existed in the form of iron titanate(Fe Ti O3).In vitro cell tests showed that the micro/nano-hierarchical structure had good cytocompatibility and could promote early protein adsorption,further improving the early adhesion of osteoblasts and promoting cell proliferation,osteogenic differentiation.Moreover,the modified titanium implants could accelerate bone formation around them under the synergistic effect of micro-nanotopological structure and Fe ion.(2)Fabrication and evaluation of titanium implant surface with enzyme-triggered antibacterial propertiesIn this study,an“adaptive”antibacterial surface triggered by bacterial infection microenvironment(highly expressed enzyme)was constructed on titanium implant surface,and it was endowed with great osteogenic ability.First,two biomolecules functionalized with catechol groups,dopamine-modified hyaluronic acid(HA-c)and dihydrocaffeic acid-modified chitosan(Chi-c)were synthesized,respectively.Then,titanium dioxide nanotube(TNT)arrays were prepared on Ti substrate and used to load vancomycin(Van).In addition,biocompatible polyelectrolyte multilayer films were prepared by layer-by-layer self-assembly(LBL)on the Van-loaded TNT surface using Chi-c and HA-c.Due to the coating had strong hydrophilicity,it could inhibit the initial adhesion of bacteria.Moreover,the coating could realize the on-demand release of Van triggered by hyaluronidase(HAase)in the microenvironment of bacterial infection.Importantly,even if the multilayers had strong hydrophilicity,the TNT@Van-LBLc surface had abundant catechol groups,which could up-regulate the expression of adhesion-related genes(integrin?v and integrin?3),thus effectively promoting the early adhesion of osteoblasts.Furthermore,animal studies of implant infections have shown that TNT@Van-LBLc implants could effectively inhibit the adhesion and proliferation of bacteria,but also accelerated the bone formation after bacteria clearance.(3)Construction of Mo S2/PDA-RGD coating with both osteogenesis and remote light-controlled bactericidal action on titanium implant surfaceIn this study,a molybdenum disulfide(Mo S2)/polydopamine(PDA)-arginine-glycine-aspartic acid(RGD)coating with both osteogenesis and remote light-controlled bactericidal action was constructed on the titanium implant surface.Mo S2nanosheets were prepared on titanium dioxide nanotubes(TNT)arrays by hydrothermal treatment.Then,the biocompatible RGD polypeptide was covalently immobilized on Mo S2nanosheets with the assistance of polydopamine(PDA)coating.The Mo S2/PDA-RGD coating showed effective bactericidal action under near-infrared(NIR)light irradiation.The antibacterial mechanism was that,after NIR irradiation,the Mo S2/PDA-RGD produced local hyperthermia to accelerate the oxidation of GSH inside the bacteria,which made the bacteria more sensitive to oxidative stress.Whereas Mo S2 nanosheets exhibited ROS-independent oxidative stress that physically destroyed the permeability and integrity of the membrane and effectively killed bacteria.In addition,the cytocompatibility of Mo S2 samples was improved after RGD polypeptide modification.Co-culture of bacteria and MSCs experiments showed that,after NIR irradiation,bacteria could be effectively eliminated from Mo S2/PDA-RGD surface.Meanwhile,after bacteria elimination,it could still accelerate MSCs adhesion,proliferation and differentiation on Mo S2/PDA-RGD surface.Eventually,in an animal model of implant-related infection,Mo S2/PDA-RGD implants could effectively accelerate new bone formation after NIR irradiation in vivo.(4)Study of NIR-regulated biofilm elimination and osteogenesis on titanium surfaceIn this study,a novel surface construction strategy of both non-invasive photo-triggered biofilm elimination and osteogenesis was proposed for the surface modification of titanium implants.First,Mesoporous polydopamine(MPDA)nanoparticles with near-infrared photothermal properties were synthesized and anchored onto Ti surface.Due to abundant aromatic ring and mesoporous structure,MPDA could load photosensitizer(ICG)through the?-?stacking.Then,on the MPDA surface,the dihydroxyindole/indolequinone group benefited to covalently immobilize RGD polypeptide.We named the constructed surface as Ti-M/I/RGD.The surface of Ti-M/I/RGD showed effective biofilm elimination ability under near infrared(NIR)irradiation in vitro and in vivo through the synergistic photothermal and photodynamic effect.The antibacterial mechanism is that,NIR-stimulated ICG produced a large amount of ROS,which exerting the PDT effect to destroy the membrane structure of bacteria.Consequently,S.aureus in the biofilm became very sensitive to hyperthermia.The results of in vitro and animal experiments showed that the efficient removal of biofilm on the implant surface could be achieved under relatively bio-safe photothermal temperature under NIR irradiation,and the efficiency reached 95.4%in vivo.At the same time,due to the presence of RGD polypeptide,Ti-M/I/RGD substrates displayed good cell/tissue compatibility,and the Ti-M/I/RGD implants could significantly promote new bone formation and osseointegration.(5)CO gas pro-drug and DNase I functionalization of titanium surface and its evaluation of light-controlled anti-biofilm abilityIn order to inhibit biofilm formation on the surface of titanium in the microenvironment of infection and reduce the local temperature required for photothermal therapy(PTT),the carbonyl iron(CO gas pro-drug)and deoxyribonuclease I(DNase I)functionalized polydopamine nanoparticles(DNase-CO@MPDA)were anchored to the surface of titanium.In vitro antibacterial experiments showed that the DNase I of nanoparticle-functionalized surfaces effectively inhibited biofilm formation by degrading the e DNA in extracellular polymers(EPS)to collapse the biofilm framework.Meanwhile,under near infrared light(NIR)irradiation,the functionalized titanium interface can not only locally produce moderate hyperthermia,but also realize the on-demand release of CO gas.By the synergistic effect of CO gas therapy and moderate-PTT,the surrounding non-adherent planktonic bacteria and the adhered bacteria on the Ti surface were effectively killed.By live dead staining,TEM observation and ONPG hydrolysis experiments,we found that the membrane structure of naked bacteria was destroyed under the synergistic effect.Under NIR irradiation,DNase-CO@MPDA nanoparticle-functionalized titanium substrates not only displayed effective bactericidal performance but also have good cytocompatibility. |
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