Adhesive Injectable Nanocomposite Hydrogel And Its Application In Periodontal Therapy

Periodontitis is one of the two major oral diseases with a high prevalence in the world,and its prevalence in China is higher than that of caries.Periodontitis is caused by dental plaque,immune and inflammatory response,genetic and environmental factors.The degeneration of periodontal tissue is mainly caused by inflammation and immune processes.Therefore,the basic principle of periodontitis treatment is to eliminate pathogenic plaque,secondary immune and inflammatory response.Systemic application of antibiotics can cause adverse reactions such as allergic reactions,gastrointestinal intolerance,and antibiotic resistance.To overcome the above shortcomings,hydrogel drug-loaded local drug delivery systems have been applied in the treatment of periodontitis.Hydrogel is a kind of porous material with a threedimensional network structure formed by physical or chemical crosslinking of various water-soluble polymers.Hydrogels have been applied in various fields due to their soft texture,swelling and degradation properties.Hydrogels with good biocompatibility have been widely used in biomedical engineering.Photodynamic therapy inhibits bacterial growth by generating reactive oxygen species through photoactivation,which can effectively avoid adverse reactions caused by the use of antibiotics and reduce infection in periodontal pockets.It has been widely used in the treatment of periodontitis.Due to the presence of activities such as saliva cleaning and tooth chewing in the mouth,it is required that the carrier material selected for oral treatment should be sufficiently sticky to be attached to the surface mucosa of the teeth and periodontium or supported in the tooth gap.To develop a new type of carrier material for periodontitis treatment and achieve effective treatment of periodontitis,two kinds of adhesive injectable hydrogels loaded with nanoparticles and photosensitizer methylene blue(MB)were prepared in this paper.The hydrogel precursor solution was injected into the periodontal area to form a hydrogel in situ.The MB loaded in the hydrogel induced the generation of reactive oxygen species under red light irradiation to achieve local photodynamic bacteriostasis and treatment of periodontal disease.In the first part of this paper,an injectable hydrogel was prepared with dopaminemodified alginate as the skeleton and nano-hydroxyapatite as the sustained-release calcium ion cross-linking agent.The PLGA nanospheres and photosensitizer MB were embedded in situ during the formation of the hydrogel.The properties of the hydrogel were studied and its effect on periodontal photodynamic therapy was evaluated.Firstly,The PLGA nanoparticles embedded with protein drugs were prepared by PLGA.Dopamine-modified sodium alginate(Alg-DA)and hydroxyapatite(HA)were used to prepare drug unloaded hydrogel(Alg-DA)and drug-loaded hydrogel which loaded with MB and protein-loaded PLGA microspheres(Alg-DA(MB@PNPS)).The gelation time was about 10 min,which ensured the injectability of the hydrogel.The three-dimensional network structure of prepared hydrogel makes the hydrogel with good swelling performance,mechanical properties and adhesion.The hydrogel showed the best compression performance at 1.5 wt% HA and 1.5 wt% Alg-DA.The compressive strength of the drug-unloaded and drug-loaded hydrogels was 48 k Pa and55 k Pa,respectively,and the lap shear viscosity with pig skin was 1.31 k Pa and 1.56 k Pa,respectively.The embeddedprotein-loaded microspheres with improve the mechanical properties and adhesion of hydrogels.The hydrogel provides effective sustained release of MB for up to 44 h.The protein-loaded microspheres can also achieve sustained protein release for up to 28 days.The induced ROS release behavior of MB-loaded hydrogel extract under 660 nm red light irradiation was explored.The hydrogel could continuously release ROS under red light irradiation and showed a good photodynamic inhibition effect on both E.coli and S.aureus.The drug unloaded hydrogel and drug-loaded hydrogel exhibits good biocompatibility,low cytotoxicity,and certain osteogenic effects.This modified sodium alginate injectable adhesive composite hydrogel with good mechanical properties,drug-sustained release properties,biocompatibility,photodynamic antibacterial,and osteogenic effects exhibits a good application prospect in photodynamic therapy of periodontitis.In the second part,CMCS/AHA hydrogels and CMCS/AHA@(MB-PLNPs)composite hydrogels loaded with long lingering nanoparticles and MB were prepared by the reaction of hyaluronic acid(AHA)and carboxymethyl chitosan(CMCS)based on Schiff base,and the periodontal antibacterial application was discussed.The gelation time of the hydrogels prepared with different AHA and CMCS contents is between 1～10 min,and the gelation time can be adjusted by adjusting the content of AHA and CMCS.Considering the mechanical properties and operability of hydrogels,0.5 wt% AHA and 5 wt% CMCS were selected to prepare the follow-up hydrogels.The gelation time was about 2 min,which ensured the injectability of hydrogels.The long afterglow nanoparticles(PLNPS)were prepared by hydrothermal method and high temperature solid phase method.The crystal structure of PLNPS is a spinel structure.The red light of 703 nm wavelength can be generated by 254 nm ultraviolet excitation,and it has a long afterglow effect.The prepared hydrogel exhibits a three-dimensional network structure,good swelling properties and mechanical properties.The compressive strength of CMCS/AHA hydrogel prepared by 0.5 wt% AHA and 5 wt%CMCS was 132 k Pa,and the compressive strength of the hydrogel increased to 290 k Pa after loading PLNPS.Rheological tests showed excellent gel strength of the two hydrogels.The storage modulus of CMCS/AHA and CMCS/AHA@(MB-PLNPS)hydrogels were 2670 Pa and 3110 Pa,respectively.CMCS/AHA and CMCS/AHA@(MB-PLNPS)hydrogelsexhibit good adhesion,and the lap shear strength with pig skin is 250 k Pa and 290 k Pa,respectively.The embedding of PLNPS nanoparticles into CMCS/AHA hydrogel improves the density and crosslinking density of the hydrogel matrix,and effectively improve the network structure,mechanical strength,and adhesion of the hydrogel.The hydrogel provides effectively slow-release MB for up to 34 h,and the cumulative release rate reaches 72.34%.The afterglow effect of the prepared PLNPS nanoparticles effectively induces MB to release ROS for a long time.The photodynamic antibacterial ability of CMCS/AHA@(MB-PLNPS)hydrogel effectively inhibits the growth of E.coli and S.aureus through the afterglow effect of PLNPS.The CMCS/AHA@(MB-PLNPS)injectable hydrogel with good mechanical properties,drug controlled release properties,photodynamic antibacterial properties,and biocompatibility shows a good application prospect in the treatment of periodontitis.