Preparation And Properties Of Multifunctional Chitosan-Based Drug Controlled-Release Hydrogel Dressing

Hydrogel dressings have become one of the most competitive dressings due to their good liquid absorption and moisture retention,biocompatibility,self-adhesion,structural flexibility,and effective absorption and release of therapeutic agents.However,the problem of explosive drug release is common in hydrogel dressings,which leads to short drug release cycle,low bioavailability,and frequent replacement.Moreover,the explosive drug release is usually accompanied by increased cytotoxicity of the dressing.For highly active drugs,it is difficult for hydrogel carriers to maintain their stability in the wound environment,and which are prone to premature metabolism.In view of the above problems,a variety of multifunctional chitosan-based drug controlled-release hydrogel dressings were designed and prepared by virtue of nano-encapsulation strategy,of which the physical and chemical properties,biological activity,drug controlled-release behavior and wound healing effect were studied.Further,the mechanism of promoting wound healing was discussed.The main research contents are as follows:1.Chitosan based nanogel(CNG)was prepared by W/O microemulsion reaction method with sucrose oxide(OSU)as crosslinking agent.The structure,morphology and particle size distribution of CNG were characterized by FTIR,SEM and nano-laser particle detector.The effects of W/O ratio,Span 80 content,CS/OSU mass ratio,emulsion shear rate and shear rate at emulsion stabilization stage on the morphology and particle size distribution of CNG were investigated.Also,the drug loading and release properties as well as p H-responsive degradation behavior of CNG were characterized.The results showed that when the W/O ratio was 1/8,the content of Span 80 was 1.5%(V/V),the CS/OSU mass ratio was 1/2,the emulsion shear rate was 6000 rpm,and the shear rate at emulsion stabilization stage was 800 rpm,the morphology and particle size distribution of CNG were optimal.Moreover,CNG exhibited good drug loading performance and p H-responsive drug release behavior,meanwhile it could effectively delay the drug release.2.The carboxylation of magnolol(MAG)was carried out by the thiol-ene click chemical reaction of 3-mercaptopropionic acid(3-MA)and MAG,and then MAG-grafted-chitosan hydrochloride(CSCl-MAG)was synthesized by EDC/NHS coupling.The effects of different reaction parameters on the carboxylation and coupling reaction of MAG were investigated.MAG was encapsulated into CNG to prepare MCNG,and their structure,morphology,particle size distribution and drug loading performance were characterized.Further,CSCl-MAG was crosslinked by genipin,and MCNG was introduced in this process to prepare composite hydrogel(MCNG-H).The effects of genipin concentration and MCNG addition on the swelling performance and morphology were studied,and the release behavior of MAG in MCNG-H at different p H was compared.Also,the cytotoxicity,oxidation resistance and in vitro antibacterial activity of MCNG-H were evaluated.Finally,a rat model of wound repair was established to test the curative effect of MCNG-H and explore the mechanism of wound healing.The results suggested that when the molar ratio of MAG/3-MA was 1.2/1,the content of DMPA was 2.5wt%,and the UV irradiation time was 45 min,the carboxylation reaction conditions were optimal with the yield was 75.4%.The water solubility and stability of MAG were improved through chemical grafting,and the biological activity of CSCl-MAG was enhanced.The crosslinking density of the system increased while the swelling property decreased with increased genipin concentration or MCNG addition.MCNG-H revealed p H-responsive release behavior of MAG,in which MCNG and hydrogel matrix had a synergistic effect on the sustained release of MAG.In addition,MCNG-H had good biocompatibility and antioxidant activity,and its antibacterial rates against E.coli and S.aureus were more than 98%.Finally,it significantly accelerated wound healing in the rat wound model.3.Polydatin-loaded CNG(PCNG)was prepared,and copper metal-organic framework nanoparticles(HKUST NPs)were synthesized by solution method.FTIR,SEM,XRD and nano-laser particle detector were used to characterize their structures,morphologies and particle size distributions.Oxidized sodium alginate(OAlg)was prepared by sodium periodate oxidation method,and the degree of oxidation(OD)was determined.Further,the injectable composite hydrogel(PCAC-H)was prepared by using OAlg,CMCs,HKUST NPs and PCNG.FTIR and SEM were carried out to characterize its structure and morphology.The effects of the mass ratio of CMCs/OAlg,the addition of HKUST NPs and PCNG on the morphology,swelling performance and gel time were also investigated.The injectability,self-healing capability,rheology and degradability of PCAC-H as well as the release behavior of copper ions and PD at different p H were studied,and its biocompatibility,oxidation resistance and in vitro antibacterial activity were evaluated.In addition,the healing effect of PCAC-H was studied through a rat model of wound repair,and the healing mechanism was discussed.The experimental results showed that when the OD value was 39.5%,OAlg had high reactivity with CMCs and good chelating effect on copper ions.PCAC-H showed the degradation and drug release behavior related to p H-responsiveness,and it effectively delayed the release of PD and copper ions,thereby reducing cytotoxicity.In addition,PCAC-H had good injectability,self-healing capability,swelling performance,oxidation resistance and in vitro antibacterial activity.The rat trauma model suggested that PCAC-H could completely fit the wound,thus effectively exerted anti-oxidation,anti-inflammatory and antibacterial effects,and promoted the formation of blood vessels and collagen fibers as well as re-epithelization.4.P(SBMA-co-AN)with upper critical solution temperature(UCST)was synthesized by radical copolymerization,of which the structural,molecular weight and UCST transition behavior were characterized,and the optimal synthesis formula was selected.Based on this,UCST type nanogel(SANG)was prepared by precipitation polymerization,and then used as a carrier for epigallocatechin gallate(EGCG)to prepare ENG.The structure,morphology,particle size distribution,drug loading and release behavior were characterized by FTIR,SEM,nano-laser particle detector and UV-vis,respectively.The UCST transition behavior of SANG with different crosslinking agent dosage and SBMA/AN molar ratio was investigated.Further,thiolated chitosan(TCS)was synthesized,and ENG composite hydrogel(ENG-H)was prepared by the thiol-ene click reaction of TCS with polyethylene glycol diacrylate(PEGDA).FTIR,~1H NMR and SEM were employed to characterize its structure and morphology,and the effects of TCS,PEGDA and ENG contents on the morphology and swelling properties were investigated.Also,the cytotoxicity,oxidation resistance and in vitro antibacterial activity of ENG-H as well as the EGCG release behavior at different temperatures was studied.A rat wound model was used to evaluate the enhancing effect of staged hot-compress on the curative effect of ENG-H,and the mechanism of ENG-H in accelerating tissue repair was discussed.The results showed that the UCST transition of SANG could be adjusted by changing the SBMA/AN molar ratio and the amount of MBA.The loading and release of EGCG in ENG were temperature dependent.In addition,ENG-H exhibited good swelling property and biocompatibility.The EGCG release in ENG-H could be significantly enhanced by raising the temperature above the UCST transition point of ENG,thereby improving the antioxidation and in vitro antibacterial activity.Finally,ENG-H treated with staged hot-compress revealed the best healing effect on the wound in the rat wound repair model.5.The drug release kinetics of MCNG-H and ENG-H systems in different environmental media were studied by using various mathematical models.The mechanism of controlled drug release of MCNG-H and ENG-H under external stimulation(p H and temperature),and their relationship with wound healing were discussed.Studies have shown that introducing drugs into hydrogel in the form of nanoencapsulation changed the release mechanism of drugs and added an additional diffusion barrier for their release,which was beneficial to the sustained release of drugs.