Application Of Bioinspired Multifunctional Hybrid Hydrogel For Promoting Wound Healing

Background and objectiveWound healing and tissue repair are a fundamental healthcare concern,and have been researched for over 2000 years.To date,many kinds of biomaterials have been developed for realizing rapid wound healing,including electrospun nanofiber,biocompatible membranes,porous foams,and functional hydrogels.Among these biomaterials,hydrogels,especially chitosan,polyethylene glycol,and their derivatives,cause the most concerns due to their functions of maintaining a moist wound environment,cooling the wound surface,promoting cell proliferation and migration,as well as allowing oxygen to permeate.In particular,with the application of injectable hydrogels,hydrogels could directly form in situ in the wound bed,fill and stick various wound shapes,especially deep tissue defects.Wound healing methods could include the additional functions of wound site filling and in situ drug encapsulation,antioxidative and anti-infection.Although the application of hydrogel materials can promote wound healing in a certain degree,biological wound healing process includes four unique yet overlapping stages of hemostasis,inflammation,proliferation,and remodeling,the recently developed hydrogels could only act on one or two stages.This will greatly affect the final healing effect of the wound and limite their wide application in the clinic.Hence,the creation of novel hydrogel that can contribute their functions on the whole healing processes of different wounds is still anticipated.MethodologyDodecyl-modifed chitosan(DCS)and benzaldehyde-terminated polyethylene glycol(BAPEG)were synthesized by graft polymerization of the compounds,and structure of the monomer was determined by NMR.The VEGF-loaded DCS/BAPEG hybrid hydrogel was prepared by mixing specific proportion of DCS solution,BAPEG solution and vascular endothelial growth factor(VEGF).Rheological analysis was tested to detect the basic physical and chemical parameters of the hybrid hydrogel,such as gel forming time,mechanical properties,elasticity and self-healing.The capabilities of biocompatibility,swelling,self-healing,injectable,antibacterial,hemostasis,tissue adhesion and controlled release of drugs were evaluated through in vitro experiments.In vivo degradation animal model was established to evaluate in vivo degradation and cell recruitment ability of the hybrid hydrogel.Needle/hybrid hydrogel patches were developeded and the effects on hemostasis of veins were evaluated.The acute liver injury model was established to evaluate its effect on visceral hemostasis.an infectious full-thickness skin defect model was established,and granulation tissues on the wound bed was taken for histological analysis,immunohistochemistry and immunofluorescence staining to evaluate its ability to promote the repair of chronic wounds.ResultsThe hybrid hydrogel was developed through the reversible Schiff base between the benzaldehyde and amino groups in the compounds,and endowed self-healing capability when the compounds were injected together.As the dodecyl tails could insert into and be anchored onto the the cell membrane's lipid bilayer,the hybrid hydrogel had outstanding tissue adhesion,blood cell coagulation,hemostasis and cell recruitment capabilities.Furthermore,the hybrid hydrogel could also exhibit superior anti-infection property with the coordinate effects of the dodecyl's bacterial anchoring ability and inherent bacterial destruction abilities of the chitosan and aromatic Schiff base.Moreover,by loading and controllably releasing VEGF,the processes of cell proliferation and tissue remodeling in the wound bed could be significantly promoted by the hybrid hydrogel.It was demonstrated from the in vivo study that acute tissue injuries such as vessel or liver bleeding could be repaired immediately due to the outstanding adhesion and hemostasis features of the hybrid hydrogel.In addition,by promoting angiogenesis,collagen deposition,macrophage polarization,and granulation tissue formation,the chronic wound-healing process of an infectious full-thickness skin defect model could be significantly enhanced too.ConclusionThe DCS/BAPEG hybrid hydrogel has the properties of injectable,self-healing,strong adhesion,hemostasis,antibacterial,cell recruitment,drug release and so on,and can be applied to versatile wound healing and other biomedical applications.