Environmentally Responsive Drug Delivery Materials For Wound Healing

The skin is the first natural barrier of the human body,protecting it from external physical,chemical and biological agents.The occurrence of skin wounds due to cuts,burns,falls,surgeries,etc.are inevitable in daily life.Skin wounds are divided into acute wounds and chronic wounds.Acute wounds do not require external intervention and can heal through an immune response.However,a variety of factors,especially excessive inflammation and bacterial infection,always lead to the conversion of acute wounds to chronic wounds,which can delay healing or even lead to non-healing.As for chronic wounds resulting from excessive inflammation,the inflammatory phase at the wound site is usually prolonged,delaying healing or even leading to non-healing.Currently,oral anti-inflammatory drugs are commonly used for clinical treatment,but they can result in adverse effects such as cardiovascular toxicity and gastrointestinal damage.Therefore,in response to this kind of wounds,there is an urgent need to design and fabricate anti-inflammatory wound dressing that can ondemand release anti-inflammatory drugs to inhibit excessive inflammation effectively while the inflammatory phase occurs at its wound site,thus promoting wound healing.For bacterial-infected wounds,the common clinical treatment is to kill the bacteria at the wound site by using antimicrobial dressings or spraying antimicrobial drugs.However,inappropriate use of antimicrobial drugs induces bacterial resistance occasionally.Thus,to treat the bacterial-infected wounds,there is an urgent need to design an intelligent material system for the purpose of ondemand antimicrobial drug release,avoiding the development of bacterial resistance,and at the same time avoiding local toxicity at the wound site due to excessive release of antimicrobial drugs,thus promoting wound healing.This thesis combines the two types of wounds and their different needs in the healing process,designing environmentally responsive controlled drug delivery materials,integrating the advantages of electrospun nanofibrous scaffolds and hydrogels.Based on the above research themes,we designed wound dressings suitable for different wound types to facilitate wound repair.The main research of this thesis is as follows.In Chapter 2,a prodrug of an inflammation-responsive controlledrelease anti-inflammatory drug was designed and synthesized.Indomethacin,a commonly used anti-inflammatory drug in clinical was selected as a model drug,and an intermediate monomer was synthesized by esterification of the carboxyl group of indomethacin with the hydroxyl group of N-(2-hydroxyethyl)acrylamide.Then,this intermediate monomer was polymerized by a free radical polymerization reaction to obtain the prodrug(PIDCM).Since the level of cholesterol esterase secretion was elevated in the inflammatory environment,the release of the antiinflammatory drug indomethacin from the prodrug was triggered by cholesterol esterase stimulation in an inflammatory-induced environment through ester bond breaking.In contrast,only a small amount of drug was released in the absence of the enzyme.Taken together,the system allowed for drug release triggered by the inflammatory environment.In vitro studies showed that the enzyme-responsive prodrug could effectively alleviate the inflammatory response induced by lipopolysaccharide induced inflammatory response of RAW264.7 cells.For chronic wounds caused by excessive inflammation,the prolonged inflammatory phase leads to delaying wound healing or even non-healing.Thus Chapter 3 investigated the enzyme-responsive triggered drug delivery scaffold materials.Inflammation-responsive electrospun nanofibrous scaffolds were prepared by combining the inflammation-responsive prodrugs with electrospun nanofibers.Nanofibrous scaffolds were loaded with different contents of PIDCM,and the properties of the scaffolds were investigated,such as fiber morphology,surface chemical composition,hydrophilicity,in vitro biocompatibility and anti-inflammatory properties.In vitro studies showed that the electrospun nanofibrous scaffolds loaded with different contents of PIDCM had good biocompatibility and could effectively alleviate the lipopolysaccharide-induced inflammatory response of RAW264.7 cells.For bacterial-infected skin wounds,trigger-responsive antimicrobial drug delivery can improve drug utilization and avoid the development of bacterial resistance.Near-infrared(NIR)light has time-domain controllability and thus has advantages in skin wound repair,which cannot be matched by other stimulation signals.In Chapter 4,NIR light-triggered drug-delivery nanomaterials were prepared by co-blending antibacterial drugs,phase change materials(PCMs)and NIR photothermal converters loaded into HNTs tubes.Under NIR light irradiation,the PCM absorbed heat and undergoes a solid-liquid transition to release drugs from the nanotubes,while there was almost no release of the drug without NIR light irradiation,enabling controlled delivery of the drug triggered by multiple light cycles.This method is universal and can be applied to the delivery of various kinds of drugs.Alginate hydrogels are widely applied to promote skin wound healing.Based on Chapter 4,Chapter 5 introduced a light-triggered responsive skin wound dressing,which was prepared by sodium alginate hydrogel as a matrix for HNTs loading with antimicrobial drugs.The hydrogel material was capable of controlled delivery of antimicrobial drugs triggered by NIR light.Additionally,the number of bacteria decreased with the increase of NIR light irradiation rounds,showing efficient bacterial inhibition with good biocompatibility.Furthermore,a rat full-thickness skin woundinfected model indicated that the light-responsive hydrogel significantly inhibited the proliferation of bacteria and effectively suppressed the inflammatory response due to bacteria,thus accelerating wound closure and promoting angiogenesis and collagen deposition.Taken together,the hydrogel has great potential in the treatment of bacterial-infected wounds.In summary,this thesis designed and prepared environmentally responsive controlled drug delivery systems,including endogenous enzyme-responsive anti-inflammatory drug-triggered delivery nanofibrous scaffolds,and exogenous light-responsive antimicrobial drug-triggered delivery hydrogel scaffolds.By investigating their applications in skin wound repair,we revealed their potential in the field of skin wound repair.