Study Of Hyaluronic Acid-based Medical Adhesion Materials For Wet Tissue Closure And Wound Hraling

Wound repair is a complex and dynamic process involving the coordinated interaction of multiple cells and extracellular matrix in the wound microenvironment,which ultimately results in the reconstruction and repair the morphology and function of the injured tissue.In clinical practice,sutures and tissue fixation staples are commonly used for wound closure and repair,but there are some shortcomings in the clinical use of these techniques that need to be addressed,including:easy wound splitting under tension,tissue exudate or gas leakage that hinders wound healing,and local inflammatory reactions caused by non-degradable temporary implants.At the same time,with the improvement of modern living standards,new requirements for wound healing have been proposed.In addition to effective closure,there is also a strong desire for faster and higher quality wound healing and achieving a perfect repair.Faced with the shortage of existing products,clinical new dressings for wound closure has an urgent need for new materials,new technologies and multi-functional integration and the development and transformation of new products.This thesis addresses the construction mechanism of medical adhesives for wound closure,the adhesion force of adhesives to wounds,the strength of adhesives,the adhesion failure problems caused by residual interface water,and the physiological characteristics of wound healing process susceptible to bacterial invasion and wound microenvironment,a series of new wound closure dressings that can achieve wet wound adhesion,anti-infection and microbial barrier were constructed by selecting polysaccharides with easy functional modification and good biosafety,and through the introduction of functional groups,innovation of dressing application methods,delivery of antimicrobial drugs and compounding with functional polymers,providing a basis and idea for the development and transformation of new medical dressings.First,the key function of wound closure adhesives is to form a strong adhesion under physiological conditions,and unlike adhesion at other interfaces,interfacial water（body fluid）at the wound usually prevents effective contact between the tissue and the adhesive.Therefore,how to achieve interfacial adhesion and maintain good intrinsic strength between wound closure adhesives and tissues while removing interfacial water is the biggest challenge in the design and construction of wound closure medical dressings.Facing these challenges,a novel powder adhesive（HADEX）was designed and developed in Chapter 2 of this thesis,which was composed of a mixture of aldehydized hyaluronic acid（OHA）powder and aminoglycosylated dextran（Dex-NH₂）powder.The aldehyde group and primary amine obtained after modification can undergo Schiff base reaction,which enables HADEX to rapidly cross-link and form adhesive in situ after water absorption.In addition,the aldehyde group can also react with the amino group in the tissue,thus achieving good interfacial adhesion with the tissue.By investigating the physico-chemical properties,water absorption and adhesion mechanism to wet tissues,HADEX showed superior adhesion properties compared to commercially available adhesives.Also,in vivo degradation experiments showed that HADEX was almost completely degraded within 14 days and had good biodegradability.In the animal incision model,HADEX could achieve rapid wound closure with excellent ability to promote wound healing.Histological analysis further revealed that HADEX could reduce immune stress and moderate the inflammatory response,which could help the wound to move smoothly to the next healing stage and finally achieved rapid and high-quality healing.Secondly,there is a significant need for infection control during clinical wound care.Therefore,the third chapter of this thesis further optimizes the construction concept of a powder adhesive with antimicrobial function（ADHT）based on the second chapter.ADHT consists of two parts:the first part is an adhesive powder prepared from dopamine-hydrochloride-modified sodium hyaluronate（HA-Dopa）and poly（acrylic acid）grafted with N-succinimide ester（PAA-NHS ester）,and the second part is tobramycin（TOB）powder that can simultaneously participate in adhesive cross-linking and provide antibacterial function.After mixing the two powders,the resulting ADHT can rapidly absorb interfacial water and form multiple cross-linked network gels,which can form multiple hydrogen bonds and chemical bonds with the tissue interface and provide good wet adhesion;TOB can act as a cross-linking center during the gel formation process with multiple primary amines,which can enhance the mechanical properties of the adhesive and also achieve antimicrobial function at the wound.In vitro and in vivo studies have shown that the constructed ADHT has good biocompatibility,as well as excellent antimicrobial and wound closure abilities,offering great potential for clinical translation.Finally,during wound care,external microorganisms are prone to adhere and invade in the wound and thereby cause infection.Therefore,chapter 4 of this thesis further designed and developed a two-layer structured anti-infection patch（ABA）based on the study of tissue adhesion mechanism in chapters 2 and 3.ABA consists of two layers:the bottom layer is the adhesion layer（ADP）,which consists of HA-Dopa,gelatin and PAA-NHS ester as the backbone materials and exhibits excellent adhesion to tissues through the introduction of adhesive functional groups;the top layer is an amphoteric layer（ATP）consisting of 3-[[2-（methacryloyloxy）ethyl]dimethylammonio]propane-1-sulfonate（SBMA）copolymerized with methacrylate-based gelatin（Gel MA）.In simulated physiological environment conditions,the ABA anti-infection patch exhibited good adhesion properties,closure properties,anti-protein adhesion and anti-bacterial adhesion effects.In animal model,ABA anti-infection patch showed good wound closure ability and barrier effect against bacterial penetration,which can effectively reduce the risk of infection and provide a new idea for the development of multifunctional barrier dressings.In summary,this thesis addressed the shortcomings of current medical adhesives and clinical needs,intensively explored the adhesion mechanism for wet tissue interfaces,designed and developed a series of new powdered medical dressings with good adhesion to wet wounds,and further constructed powdered antibacterial dressings and wound adhesion anti-infection patches by compounding with commonly used clinical antibiotics or amphoteric polymers.These studies provide the basis for the development of medical adhesives and provide ideas for the transformation of new medical dressings.