Design,preparation And Application In Diabetic Wounds Management Of Nanocomposite Smart Polymer Antibacterial Materials

Diabetes mellitus(DM)is a metabolic disorder-related chronic disease characterized by hyperglycemia that affects more than 422 million people worldwide.In 2019,DM became the ninth leading cause of death globally and has received widespread attention.The probability of diabetic foot ulcer(DFU)in diabetic patients is 15%-25%.As a typical chronic wound,the impaired healing properties of DFU significantly increase the possibility of drug-resistant bacteria and biofilm infection.Studies have shown that DFU infection significantly increases the lower extremity amputation rate and post-amputation mortality of diabetic patients,which brings huge economic pressure to public health care,patients'families and individuals.Inorganic nano-antibacterial materials have multiple antibacterial mechanisms and can replace traditional antibiotics to solve the infection problem of DFU.However,the poor molecular recognition ability,systemic toxicity caused by the uncontrollable drug activity,and the ease of rapid clearance limit its clinical application.Smart polymers,are a class of polymers that can undergo conformational or aggregation changes in response to external stimuli,can effectively solve the above problems by combining with inorganic nanoparticles to construct smart nanocomposite antibacterial materials.In addition,due to the complex non-healing mechanism of DFU,the development of multifunctional antibacterial nanocomposites has brought breakthrough progress in wound infection,multi-channel combined treatment and monitoring of DFU.Therefore,this dissertation is based on inorganic nano-antibacterial materials with high antibacterial activity,composited with smart polymer materials.Through the co-loading of other types of active drugs,several smart nanocomposite antibacterial systems have been successively designed and constructed to realize the multi-channel treatment of diabetic infected wounds,including phosphate-responsive PAA-Ca Ps@Nps@GOx nanocomposite antibacterial hydrogels,multifunctional Pd-MOF@PAzo@SNP nanocomposite antibacterial microgels with light-controlled"switches",and reactive oxygen species(ROS)-responsive nanocomposite antibacterial/antioxidant and integrated sensing function PDA-PLA@Fe³⁺@MXene/Ag hydrogel dressing.The details are as follows:1.In the first part,to solve the problems of high toxicity,uncontrollable medication,easy removal of inorganic antibacterial nanoparticles,and the easy inactivation of protein drugs in the treatment of DFU,inspired by the mineralization of collagen fibers with biological metal ions in vivo,polyacrylic acid(PAA)and Ca²⁺were self-assembled and then combined with PO₄^3-to form the cross-linking point,while in situ loading Fe₃O₄/Ti O₂/Ag₃PO₄ nanospheres and glucose oxidase(GOx)to construct phosphate-responsive PAA-Ca Ps@Nps@GOx nanocomposite antibacterial hydrogel.It is demonstrated that the constructed PAA-Ca Ps@Nps@GOx nanocomposite hydrogels exhibit Fe₃O₄/Ti O₂/Ag₃PO₄ and GOx release in response to the physiological environment based on the precipitation/dissolution equilibrium of Ca Ps,the catalytic cascade mechanism of Fe₃O₄/Ti O₂/Ag₃PO₄ and GOx can be used to reduce the blood glucose in the wound and slowly generate hydroxyl radicals(·OH),enhance the antibacterial effect of Ag⁺,and promote the healing of diabetic wounds.2.In the second part,while solving the problem of the uncontrollable activity of inorganic antibacterial nanoparticles,the endogenous regulator nitric oxide(NO)-donor sodium nitroprusside(SNP)was introduced to solve the problem of impaired vascular remodeling in DFU.Palladium(Pd)nanozymes were used as antibacterial-active drugs,MOF(Ui O-66)were used as the encapsulant,and photoresponsive polyazobenzene(PAzo)was in situ modified on the surface of the MOF to adsorb SNPs while self-assembling through the host-guest interaction of azophenyl groups and?-cyclodextrin-modified hyaluronic acid(?-CD-HA)to construct Pd-MOF@PAzo@SNP nanocomposite microgel with light-controlled"switching"capability.In response to UV light radiation,the conformation of PAzo changes,dis-assembles with?-CD-HA,releases SNP and provides NO.Then,Pd catalyzes the substrate hydrogen peroxide(H₂O₂)to generate singlet molecular oxygen(¹O₂)and·OH,which are subsequently react with NO to generate reactive nitrogen species(RNS),realizing the synergistic antibacterial/anti-biofilm of ROS and RNS,and utilize the enhanced antibacterial effect and the endogenous regulatory function of NO to promote angiogenesis and collagen deposition,accelerate the healing of biofilm-infected diabetic wounds.3.Nerve damage in diabetic patients leads to the loss of their sense of response to external stimuli,and eventually develops chronic non-healing wound after repeated minor sprains and contusions.In the early stage of wound healing,ROS accumulation caused by hyperglycemia,and external bacterial infection aggravate impaired wound healing.In the third part,a ROS-responsive PDA-PLA@Fe³⁺@MXene/Ag nanocomposite hydrogel dressing with integrated sensing function was constructed to address these issues.By introducing filler MXene/Ag with antibacterial and conductive functions,the dressing was endowed with sensing properties and antibacterial activity.The existence of dynamic disulfide covalent bonds,inter-ionic interactions and hydrogen bonding interactions in the polydopamine-polylipoic acid(PDA-PLA)hydrogel matrix allows the hydrogel to exhibit excellent self-healing properties.The PLA in the matrix can react with ROS to cause defects in the hydrogel skeleton and achieve ROS-responsive release of Ag nanoparticles(Ag NPs).Therefore,the synthesized PDA-PLA@Fe³⁺@MXene/Ag nanocomposite hydrogel can utilize its excellent antibacterial and antioxidant effects to reduce the inflammatory response and promote healing of diabetic infection wound,at the same time,act as a sensor to monitor the external forces(such as pressure and torque)on the skin,and human movement behavior,which realizes the integration of monitoring and treatment of diabetic wounds.In conclusion,this dissertation is based on the interdisciplinary research of inorganic chemistry,polymer physics,polymer chemistry,electrochemistry and life sciences,expounds the design and preparation of smart nanocomposites antibacterial materials based on inorganic nanoparticles,which are used in the multi-channel management of diabetic wounds,has opened up new ideas for the development of new multi-effect integrated nanocomposite antibacterial dressings for the treatment of non-healing chronic wounds.