Ionic Liquid Functionalized Hydrogels Coupled With Electrical Stimulation For Efficient Repair Of Diabetic Skin Wound

Chronic wound is a wound that can not reach the complete state of anatomy and function chamber through normal and orderly repair process.Diabetic wounds are representative of chronic wounds with high recurrence,high amputation,and high mortality.According to the statistics,there are over 6.5 million patients suffering from chronic wounds worldwide and the annual health care costs are over 25 billion US dollars.The main clinical treatments for diabetic wounds include growth factors,skin substitutes,negative pressure wound therapy,hyperbaric oxygen and so on.These routine therapeutic strategies are charactered by a long course of treatment,high costs,and fail to produce satisfactory results.Therefore,accelerated and thorough healing of diabetic wounds remains a great challenge.Electrical stimulation（ES）which involves putting separated electrodes near the wound or placing one electrode in the wound bed for delivery of a low-intensity electric current,has attracted increasing attention of more and more researchers due to its safety,effectiveness and low cost.The in vitro investigation has shown that exogenous ES can enhance the migration and proliferation of fibroblasts and keratinocytes and stimulated fibroblasts to secrete more extracellular matrix for wound closure.Some in vivo and clinical investigations have also proven the positive effect of ES therapy on treating chronic wounds.Electrically conductive polymers have been proved that they can regulate cellular activities including promoting cell adhesion,proliferation,migration,and differentiation of electrically excitable cells.Furthermore,skin is a kind of electrical signal sensitive tissues and owns conductivity values from 2.6 m S/cm to1?×?10^-4?m S/cm.Thus,designing novel functional wound dressing with conductivity would be more helpful on promoting the wound healing process.Hydrogel,with a 3D network structure and excellent biocompatibility,can provides a moist environment around the wounded area and thus it has been widely used in wound therapy.Ionic liquid is a sort of liquid organic molten salt under 100℃ with excellent conductivity and biocompatibility.According to the requirements of the reaction,the researchers can prepare ionic liquids with different properties and functions through different combinations of anions and cations,made them have specific functions.Therefore,ionic liquid functionalized hydrogels are expected to be combined with ES to accelerate the treatment of chronic wounds.The main contents of this dissertation are detailed as following:（1）1-vinyl-3-aminopropyl-imidazolium tetrafluoroborate ionic liquid（VAPim BF₄）were copolymerized with acrylamide to form stable poly（ionic liquid）.The amino group of the poly（ionic liquid）is reacted with the carboxyl group of acrylic acid grafted on konjac glucomannan（KGM）by amide bond to prepare a novel conductive hydrogel PIL-KGM.The mechanical properties and stability of poly（ionic liquid）are improved.The prepared hydrogels possess high water content,swelling rate and excellent biocompatibility.In addition,functional monomer,VAPim BF₄（containing positive charges）,can be polymerized into hydrogel to provide the hydrogel antibacterial properties with no substance release.In a full-thickness diabetic mouse skin defect test,these novel hydrogels coupled with ES can promote the healing process of diabetic wound.The healing rate and the healing effect are superior than that based on electrode-ES strategies.Therefore,this therapeutic strategy based on ionic liquid functionalized hydrogels coupled with ES provides new idea for the treatment of chronic wounds.（2）A diamino imidazole tetrafluoroborate ionic liquid,1,1’-（ethyl-1,2）-bis-(3-（3-aminopropyl）-1H imidazole tetrafluoroborate ionic liquid（PBAim BF₄）,with a positive charge active group was prepared.After being polymerized,the obtained poly（ionic liquid）was reacted with oxidized hyaluronic acid（OHA）through Schiff reaction,thus to produce a novel injectable antibacterial hydrogel PIL-OHA.The results indicate that the obtained injectable hydrogel possesses excellent electrical conductivity and mechanical property.The antibacterial rate of E.coli and S.aureus up to 99%,and without antibiotics.In addition,the wound healing rate of ES+PIL-OHA hydrogels（97.66%）was much greater than that of commercial Tegaderm^TM film（84.52%）and ES（62.31%）in the treatment of skin defect in diabetic model mice.