Smart Antibacterial Hydrogel Based On Chitosan Derivatives

Wound infections can have serious consequences,such as lengthy healing periods,complications,and even life-threatening situations for patients.To combat this problem,an ideal antibacterial material should mimic the dynamic characteristics of skin under biophysical/biochemical stimuli,release antibacterial drugs in situ,and destroy invading pathogens promptly.Chitosan,a natural polysaccharide possessing excellent biocompatibility,antibacterial properties,biodegradability,and tissue adhesive ability,has been pursued in various biomedical applications.Chitosan-based wound dressings have been successfully used in the clinic to effectively inhibit bacterial growth and proliferation.Thus,the development of chitosan-based smart hydrogels can further enhance the capabilities of chitosan wound dressings,making them a valuable tool in clinical practice.To prevent the emergence of "superbugs" resulting from the overuse of antibiotics,we have turned our attention to the development of antibacterial nanoparticles in recent years.Specifically,we have focused on developing a hydrogel complex containing nanoparticles with stimuli-responsive properties.While using nanoparticle-hydrogel complexes for on-demand drug delivery,challenges arise such as aggregation,uneven distribution,and incomplete release of nanoparticles.These issues limit the ability to adjust mechanical and stimuli-responsive properties.It appears that there is a gap in research regarding the potential effects of interactions between nanoparticles and hydrogel.Herein,we selected three types of antibacterial nanoparticles that form a hydrogel complex through different interactions: physical encapsulation,secondary interactions,and dynamic covalent bonding.Additionally,we systematically modified chitosan to study the "structure-and-performance" relationship.We then employed the hydrogel complexes as wound dressing,antibacterial coating,and hemostatic agent,respectively,depending on their own unique stimuli-responsive properties.This dissertation is divided into three bellowing parts based on the types of stimuli present and the interactions between the nanoparticles and hydrogel:(1)The antibacterial nanoparticles-encapsulated hydrogel that is responsive to lysozyme:The activity of lysozyme is up-regulated in the microenvironment of bacterial infection.We chemically modified the hydroxyethyl chitosan with the crosslinking sites and lysozymeresponsive degradable sites.We then mixed chitosan and nanoparticles to create a photocrosslinked hydrogel with controllable mechanical properties(storage modulus G’ up to11 k Pa)that can effectively cover wounds.In vitro testing confirmed the lysozyme-responsive degradation of the hydrogel,with degradation rates influenced by the degree of N-acetylation.We demonstrated the responsive antibacterial behavior of the nanoparticle-hydrogel complex under different lysozyme activity.We applied the hydrogel as a wound dressing for treating epidermal wound infections in mice,achieving positive therapeutic results in reducing bacterial infections and promoting wound healing.(2)The polyoxometalate nanoparticles(POM)-crosslinked hydrogel that is thermoresponsive: The physical crosslinking between the POM and chitosan derivatives results in the formation of the hydrogel.The POM contains a silver ion in its cavity,that is protected from precipitation in physiological environments.We investigated how the chemical structure of the chitosan derivatives affects the hydrogel’s mechanical properties and found that electrostatic interactions and hydrogen bonds contribute significantly to gel formation.The mechanical properties of the hydrogel are adjustable(G’ up to 1 k Pa).The gel-sol-transition occurs when the temperature is increased,and the critical transition temperature varies depending on the solution concentration.This hydrogel is self-healing and thermo-responsive,making it ideal for coating various materials.It can be used as an antibacterial coating for implantable medical devices,eliminating bacterial colonization during long-term storage.(3)The polyhedral oligomeric silsesquioxanes(POSS)-linked hydrogel through a dynamic covalent bond that is p H-responsive: The guanidine-bearing POSS exhibites antibacterial properties and is connected to hydroxyethyl chitosan via an imine bond,which is a p H-labile dynamic covalent bond.The aqueous solution of guanidine-bearing POSS results in POSS aggregation and the formation of the hydrogel.The mechanical properties of this hydrogel are adjustable(G’ up to 2 k Pa),and the guanidine-bearing POSS is released in acidic p H of the infection sites to enhance the antibacterial efficacy.The hydrogel has low cytotoxicity and hemolysis rates,and its excellent swelling properties make it an ideal hemostatic agent for acute wounds.In the mouse tail amputation model,the hydrogel powders effectively reduce bleeding amount and shorten the time required to stop bleeding.The hydrogel’s p H sensitivity makes it easy to remove and coupled with its impressive antibacterial properties,it is an ideal option for managing and healing wounds in the advanced stages.In summary,this dissertation investigate the strategy to construct smart stimuli-responsive antibacterial hydrogel based on chitosan and its derivatives.Three new types of broad-spectrum antibacterial nanoparticles are incorporated into chitosan-based hydrogel,respectively.These hydrogels were designed to be responsive to lysozyme,temperature,and p H value.The study explores the use of the hydrogels as external coatings for hemostatic agents and wound dressings.This work reveals the important contribution of the interactions between hydrogel and nanoparticles in constructing stimuli-responsive materials,providing innovative strategies for the design and development of smart antibacterial chitosan-based hydrogel.