Construction And Application Of Antibacterial Hydrogel With Functional Small Molecule

Hydrogel is a kind of soft and porous materials with good histocompatibility,which is one of the most promising biomedical materials.Because they can realize local long-acting drug delivery,antibacterial hydrogels effectively avoid the problems existing in traditional systematic drug delivery,such as frequent drug administration and serious side effects.In recent years,antibacterial hydrogel materials have been vigorously developed,there are still some problems in traditional antibacterial hydrogels.For example,antibacterial hydrogels encapsulating antibacterial agents have weaknesses such as low drug loading,poor stability,and unable to be released on demand.Hydrogels with covalent modification of antibacterial components always require complex synthesis,which limit the large scale and repeatable preparation of corresponding gels.In addition,most of the polymer frameworks of these traditional antibacterial hydrogels are difficult to degrade.How to overcome these problems and develop novel antibacterial hydrogels according to the clinical requirement have become the major challenge for these materials.In this thesis,we proposed to use naturally available functional small molecules as gelators to build kinds of hydrogels by dynamic covalent chemical bond or noncovalent bonds and explore their therapeutic effects in various anti-infection applications.The theis is divided into six chapters.In chapter one,the definition and classification of hydrogels are introduced,Subsequently,the recent applications of hydrogels in tissue regeneration,intelligent devices,drug delivery and antibacterial materials were described.Then the historical background of bacterial infection and antibacterial agents,the application and development of antibacterial hydrogels in recent years are expounded.Finally,the research concept and contents of this thesis are provided.The second chapter mainly introduces a class of all-small-molecule dynamic covalent gels constructed by tannic acid and boric acid derivatives.The transparent hydrogels can be formed by the borate ester bond between boric acid derivatives and tannic acid which contains high density of pyrogallol groups on the surface.Depending on the different boric acid building blocks selected,the gel exhibits a variety of stimulus responsiveness,such as responsive to acid,base,reduction,and oxidation.Gel formation and stimulation responsiveness were characterized by ¹¹B nuclear magnetic resonance.In addition,the hydrogel also has good antibacterial properties.Facile modular design,multi-stimulus responsiveness,simple green synthesis and good antibacterial properties make tannin-borate gels ideal candidates for developing smart soft materials.In chapter three,a hydrogel constructed by tannic acid,tobramycin and a bifunctional anchor is illustrated.The bifunctional anchor bearing both aldehyde and boronic acid groups was introduced and gelated with naturally occurring building blocks(tobramycin and tannic acid)to build a novel all-small-molecule dynamic covalent smart hydrogel.Besides showing the inherited advantages(multistimuli-responsiveness,high drug loading and adjustable mechanical properties)of this kind of hydrogels,the hydrogel also exhibits some promising features such as adjustable mechanical properties and excellent antibacterial activities both in vitro and in vivo.This work provided a new strategy to efficiently expand the scope of the all-small-molecule smart hydrogels via the integration of the naturally occurring building blocks and the molecular bifunctional adapters.In chapter four,we propose a type of all-small-molecule supramolecular hydrogel assembled from guanosine-5'-monophosphate disodium salt and tobramycin for the treatment of bacterial keratitis.Guanosine-5'-monophosphate disodium salt assemble into guanosine-quartet nanofibers via hydrogen bonding and?-?stacking,and tobramycin with five primary amine groups further crosslinks the nanofibers bearing multiple phosphate moieties into gel networks via ionic interactions.The supramolecular gel shows shear thinning and thixotropic properties,good biocompatibility,and antibacterial activity.The gel treatment significantly ameliorates P.aeruginosa induced bacterial keratitis,and shows higher therapeutic efficacy compared to tobramycin eye drop.This study provides a facile and efficient antibiotic gel formulation for clinical treatment of bacterial keratitis.In chapter five,we propose a kind of antibacterial hydrogel by simply mixing of aminoglycosides with cellulose nanocrystal(CNC).The rigid and crystalline structure of CNC enhance the gel stability and significantly improve the sustained release profile of aminoglycosides.The gel shows excellent rheological behaviors,which allows it to be easily injected subcutaneously or sprayed on the skin wound,and high potential for clinical translation to treat various infections.The sixth chapter summarizes and looks forward to the whole thesis.In this paper,bacterial hydrogels were proposed by naturally occurring functional small molecules via dynamic covalent chemical bonds or noncovalent bonds.The building strategies are facile for constructing stable,biocompatible,long-term and on-demand drug release antibacterial hydrogels,which also provide new ideas for the design of antibacterial materials for clinical translation.Besides,the design and performance optimization of all-small-molecule dynamic covalent gels bring more possibilities for the preparation and application of this kind of novel hydrogels.