Efficacy Of Methotrexate-loaded Hyaluronic Acid-based Hydrogel In The Treatment Of Knee Osteoarthritis In Mice

BackgroundOsteoarthritis(OA)is the commonest joint disease among older adults over 60 years old,causing pain,stiffness,disability,and a heavy cost burden.Since current research reveal that inflammation,especially synovial macrophages-mediated inflammation,plays crucial role in the progression of OA,there is a growing interest in taking synovitis and macrophages as targets for OA treatment.Methotrexate(MTX)has been well known for its anti-inflammatory ability,and it has been revealed by previous studies that MTX can regulate the polarization of macrophages toward an anti-inflammatory M2 phenotype and eventually improve the quality of life for OA patients.However,the application of MTX in OA is limited by its rapid clearance in joint and potential organ toxicity,raising the urgent need for developing new strategies to overcome it.Hydrogel,composed of a hydrophilic polymer network,offers a satisfactory solution for sustained drug release and improved biocompatibility.Hyaluronic acid(HA)and dopamine(DP)are two commonly used substances,which demonstrate independent ability of anti-inflammation and alleviate OA,for the construction of hydrogel.Thus,constructing an HA-DP hydrogel to encapsulate MTX is anticipated in OA therapy research.MethodsHA-DP-MTX hydrogels were synthesized by the quinone oxide crosslinking method.The morphology,photothermal properties and biocompatibility of the HA-DP-MTX hydrogel were first evaluated.Then,we examined the drug release properties and the in vitro antiinflammatory ability of the HA-DP-MTX hydrogel.Finally,we explored the therapeutic effect of the HA-DP-MTX hydrogel on the collagenase-induced OA mouse model(CIOA).ResultsWe successfully synthesized MTX-loaded HA-based hydrogels(HA-DP-MTX).The HADP-MTX hydrogel had good biocompatibility and could continually release MTX in vitro for 5 days.The HA-DP-MTX also demonstrated satisfactory photothermal properties,which could be used for the control of the release rate of MTX.In vitro and in vivo experiments found that the HA-DP-MTX hydrogel effectively alleviate OA pain and progression,by ROS scavenging and repolarization of macrophages for anti-inflammatory phenotype.ConclusionWe successfully constructed the HA-DP-MTX hydrogels.The sustained release of MTX,ROS scavenging,and repolarization of macrophages for anti-inflammatory phenotype may provide a potentially effective and safe therapeutic strategy for OA treatment,significantly decreasing cartilage degradation,OA-related pain and synovitis.