Bioinspired Andrias Davidianus-derived Hydrogel For Localized Drug-elution

Objective: In recent years,local delivery of therapeutics has received increasing attention because of the serious side effects caused by systemic usage of high doses of some medicine.Local drug application could not only reduce drug-induced systemic toxicity,but improve drug bioavailability locally.However,this approach is still limited by some shortcomings,such as the complex wound sites in the oral cavity.Many stimulus,such as saliva scour,chewing food,may greatly affect the therapeutic effect due to their rapid clearance of medicine.As such,we are going to use a biological-derived hydrogel(skin secretion of Andrias davidianus,SSAD)as local wound dressings,to investigate its performance in promoting wound healing after loading drugs.Methods: In this study,SSAD powder were prepared from the skin secretion of Andrias davidianus after a series of process.After collection of SSAD with different particle sizes(20,60,and 200 meshes).The SSAD powder or the mixed powder(SSAD mixed with aminoguanidine(AG))was mixed with PBS to form SSAD or SSAD+AG hydrogels,and then characterize the materials structure and explore the mechanism of drug loading.Besides,drug release properties of SSAD in vitro was also conducted.At the same time,SSAD hydrogel extracts with different concentrations were prepared to detect its biocompatibility and verify the effects of SSAD on the proliferation and migration of L929 fibroblasts(L929)and human umbilical vein endothelial cells(HUVECs)in vitro.Then,animal experiments with a palatal mucosal defect model were conducted to fully verify the bifunctions of SSAD for simultaneous local delivery of drugs and promotion of wound healing in vivo.Besides,transcriptome sequencing of the regenerated tissue after treated with SSAD or not in a full-thickness palatal mucosa defect model of normal rats was performed to explore the mechanism of SSAD hydrogel in promoting wound healing.Results: SSAD powders with different mesh sizes were well-fabricated,and these powders resulted in hydrogels with different porous properties.With the increase of the mesh of SSAD powders,the pore sizes decrease accordingly and resulting hydrogels composites with a more compact and uniform form.The results of drug sustained release in vitro showed that the sustained release rate of SSAD hydrogel varies with the mesh size.With the increasing of particle size of the SSAD powder,the drug release rate of the corresponding SSAD hydrogel increased.Cytological studies in vitro indicated that SSAD exhibited a good biocompatibility and could promote cell migration and proliferation.The Hard palate mucosal injury model in this study showed that SSAD hydrogel loaded with AG could significantly promote tissue regeneration under hyperglycemia with a higher quality of regenerated tissue by accelerating collagen synthesis and maturation.Sequencing results also indicated that after SSAD treatment,the pathways and biological processes related to tissue regeneration were significantly activated,as well as the recruitment of endogenous stem cells.Conclusion: The role of SSAD in sustained releasing drugs,promoting cell migration and proliferation,accelerating ECM deposition,and recruiting endogenous stem cells were studied in this study.In summary,the SSAD hydrogels based on different particle sizes were proven to be an effective local drug sustained-release system.Our unique SSAD wound dressing system shows considerable potential as a local drug delivery system for sustained drug release and wound healing-promotion.