Complications of diabetic wounds are a serious cause of disability worldwide,whose disabling rate and fatality rate are increasing year by year.It imposes a huge burden on patients and society.Persistent hyperglycemia at the wound site in diabetic patients causes aggravated bacterial infection,impaired oxygen supply,and poor immune function that severely hinders wound healing,resulting in a prolonged inflammatory response and chronic diabetic wounds.Therefore,there is an urgent need to develop diabetic wound intervention treatment techniques.Currently,wound dressings are commonly used in clinical practice to treat diabetic wounds,but these dressings have a single function and are difficult to achieve precise regulation of the microenvironment of chronic diabetic wounds,which cannot meet the treatment needs of chronic diabetic wounds.The main manifestations are:(1)most dressings do not regulate the problem of hyperglycemia at the wound site;(2)dressings with antibiotics or common antimicrobial agents are difficult to kill bacteria and are highly susceptible to drug resistance;(3)they cannot effectively replenish oxygen,resulting in a hypoxic microenvironment that is difficult to repair.Also,these dressings cannot completely fit diabetic wounds of varying depths,especially bleeding wounds,and offer limited protection to the wounds.Thus,the development of multifunctional hydrogel dressings that can actively regulate hyperglycemia in diabetic wound sites,stop bleeding,effectively resist infection,replenish oxygen in the late stage of wound healing,moisturize and adaptively adhere to wounds is of great significance to promote the repair and reconstruction of diabetic wound tissues.Based on this,in this project,glucose oxidase GOx and ultra-small Fe2O3 nanoparticles were incorporated into ZIF-8 to form a degradable nanoparticle with cascade catalytic activity.Then,these nanoparticles were copolymerized with aldehyde groups-contained oxidized hyaluronic acid,and water-soluble carboxyethyl chitosan to form a multifunctional hydrogel.This hydrogel can catalyze glucose at the diabetic wound sites to produce gluconic acid and H2O2,through the loaded GOx,which thus can reduce the blood glucose concentration at the wound site.Meanwhile,the hydrogel associated with the nanoparticles could be degraded in the acidic wound microenvironment to release zinc ions and expose the Fe2O3 nanoparticles.Consequently,the Fe2O3nanoparticles could catalyze the Fenton reaction of excess H2O2 to produce hydroxyl radicals(ROS)at the acidic wound sites,which together with the zinc ions achieve effective synergistic antibacterial.Furtherly,with the increased pH at the later stage of wound healing,the exposed Fe2O3 particles can catalyze the decomposition of excess H2O2 in the wound site to produce oxygen,which thus could relieve hypoxia to facilitate the wound healing.This synergistic cascade catalytic activities of the biodegradable nanoparticles,combined with the moisturizing,hemostatic,and tissue exudate absorption properties of the oxidized hyaluronic acid-chitosan-based composite biocompatible hydrogel,make this multifunctional hydrogel prepared in this work an advanced new biomaterial for diabetic wound repairing.The specific research is divided into two aspects as follows.(1)synthesis and characterizations of multifunctional hydrogels:including the synthesis of ultra-small Fe2O3 nanoparticles,the encapsulation of GOx and Fe2O3 into ZIF-8 by co-assembly of Zn2+and 2-methylimidazole(abbreviated as F-GZ),preparation of composite hydrogels via co-polymerization of oxidized hyaluronic acid and carboxyethyl chitosan with F-GZ(abbreviated as F-GZ@G).Relevant tests were performed to characterize F-GZ and F-GZ@G,optimize the encapsulation amounts of GOx and Fe2O3,and explore the optimal loading of F-GZ in the gel.(2)In vitro and in vivo evaluation of multifunctional hydrogels:In vitro investigations of the enzyme activity including the GOx activity,peroxidase activity,and catalase activity of F-GZ;Evaluation of the antibacterial efficacy(Escherichia coli,Staphylococcus aureus),the degradability and also the biocompatibility of F-GZ as well as F-GZ@G;Evaluation of the effects of different materials and hydrogel dressings for diabetic mice wound healing.In summary,this multifunctional hydrogel with cascade enzyme catalytic activity was designed and prepared in this work,which can consume glucose from diabetic wound sites and realize the synergistical antibacterial activity through catalytically generated hydroxyl radicals and Zn2+.Meanwhile,it can release oxygen and maintain oxygen balance and thus effectively promote the healing of diabetic wounds.This work provided an alternative multifunctional dressing for potential diabetic wound healing. |