| With the increasingly aging society,hernia,a common disease in general surgery,is sweeping the world at a rate of 20 million new patients every year,and the prevalence is higher than that of any kind of malignant tumor.An adult hernia has no possibility of self-healing.If it is not treated in time,it will cause incarceration or even life-threatening.At present,the only effective way to treat hernias clinically is to implant a mesh through tension-free hernia repair to achieve the reinforcement of the defect tissue.The warp-knitted mesh has become the most indispensable mainstream product in hernia repair due to its unique textile structure advantages（light weight,porous,mechanical anisotropy,flexibility,and free cutability）,and has a huge clinical demand.Especially the polypropylene（PP）-based warp-knitted mesh has been widely used in clinical surgery.Nevertheless,the PP warp-knitted mesh could trigger a strong and long-lasting host immune response after implantation into the body,and due to the negative inflammation,postoperative complications caused by excessive fibrosis afflict nearly one-third of patients.Therefore,constructing an anti-inflammatory warp-knitted mesh to suppress the inflammation and to repair the defective tissue has become the focus and difficulty in the current medical textile field.This dissertation takes the construction of an anti-fouling layer to passively avoid immune recognition and the introduction of a biomimetic layer to achieve benign communication as the antiinflammation strategy,and designs efficient modification methods suitable for the PP warp-knitted mesh,and explores the effect of the modified mesh on the immune behaviors of macrophages,and realizes the local inflammation-relieved effects and tissue remodeling.The specific research contents are as follows:（1）Starting from the source of the host immune response（non-specific protein adsorption）,with the help of the adhesive polydopamine（PDA）,through co-deposition or sequential deposition,the sulfobetaine-type zwitterionic polymer（poly（sulfobetaine methacrylate）,PSBMA）was fixed on the PP monofilament to form an anti-fouling barrier that hindered protein adsorption and reduced the macrophage activation.Meanwhile,it combined the antioxidant property of polyphenol groups in the PDA segment to achieve the synergistic anti-inflammation.By exploring the influence of PSBMA on the cohesive assembly and adhesion behaviors of PDA,the sequential deposition method was selected as the final strategy for constructing the anti-inflammatory coating.The twolayer structure（PSBMA-PDA）constructed by this method had no effects on the mechanical properties of the warp-knitted mesh,and meanwhile,it gave the mesh better hydration capacity（water contact angle of 30.7o）and lower protein adsorption（82 % less BSA adsorption）and stronger oxidative activity（2.25 m M Fe SO4/cm2）.In vitro inflammatory response results showed that the modified mesh had no cytotoxicity and played a role in the acute inflammatory period.The adhesion,proliferation,and polarization of macrophages were significantly suppressed compared with other coated meshes,which confirmed its synergistic anti-inflammatory effects.（2）Based on the verification of the feasibility of constructing an anti-fouling layer for passive evasion of immune recognition,the two-layer structure of the anti-fouling synergistic antiinflammatory coating was preserved.The metal phenolic network composed of tannic acid（TA）and Fe3+ acted as the intermediate adhesive layer（I）to mediate poly（（2-methacryloyloxyethyl phosphorylcholine）-co-（acrylic acid））-g-dopamine（PMAD）as the anti-fouling layer（II）to be constructed on the PP warp-knitted mesh.By investigating the dynamic assembly process of TAFe3+ ligands on the mesh surface,layer I with controllable thickness and oxidative activity was obtained;then,driven by multiple forces between phenol groups,PMAD（layer II）was adsorbed on layer I and charged side chains;finally,“zipping up” effects induced by the aryloxy coupling reaction realized the I-II interface grafting and I internal crosslinking,which anchored the PMADTA/Fe coating on the PP mesh.The charged brush of PMAD-TA/Fe resisted 91.3 % of protein adsorption;in addition,the introduction of catechol and the protection for the phenolic hydroxyl groups from the anti-fouling outer layer improved the oxidative activity of PMAD-TA/Fe（4.64 m M Fe SO4/cm2）;by testing the structure and bending stiffness of the PP warp-knitted mesh before and after coating,PMAD-TA/Fe retained the original substrate properties and had high stability in cyclic stretching under the constant load of 16 N/cm and had antioxidation durability under the static degradation in vitro for 7 days.Excellent functionality endowed PMAD-TA/Fe-PP with significant synergistic anti-inflammatory effects in vitro,and ultimately reduced in vivo inflammation and 39.0 % of collagen deposition.（3）To establish a benign communication between the PP warp-knitted mesh and the immune system,a natural glycosaminoglycan—chondroitin sulfate（CS）was used as the main component to build a biomimetic surface on the mesh.CS with high immunomodulatory activity was mediated by multiple hydrogen bonds of TA to complex to form colloidal particles and was immobilized on the PP mesh by oxidative co-deposition of TA.Through the systematic characterization of the size,zeta potential and micro-morphology of colloidal particles,it was found that the mass ratio（MR）of TA and CS affected the assembly behavior of TA and CS,which in turn influenced the particle structure,and ultimately changed the morphology of oxidized co-deposits.When MR=5:1,the intermolecular forces of TA/CS colloidal particles could be balanced,and colloidal particles with a regular shape were obtained,and then the oxidation co-deposition coating（TC）of "chrysanthemum-shaped" particles was obtained.In addition,the multiple hydrogen bonds between TA and CS promoted TA deposition,and also protected partial phenolic hydroxyl groups of TA from excessive oxidation,endowing TC with higher oxidative activity（3.68 m M Fe SO4/cm2）than the pure TA oxidation deposition coating（OT）.TC did not damage the PP warp-knitted mesh properties and showed synergistic anti-inflammatory activity in vitro by its biomimetic and antioxidation properties,which was specifically manifested in the significantly reduced macrophage adhesion,proliferation,and polarization.（4）To further promote the benign communication between the PP warp-knitted mesh and the immune system,the natural structure and composition of the extracellular matrix were simulated.CS was still used as the biomimetic component,and gelatin（Gel）was used as the biomimetic framework,and then cross-linked by TA,a hydrogel-type biomimetic coating on the mesh was constructed.Firstly,based on the difficulty of compatibility between the hydrogel and the PP warpknitted mesh,it was proposed to construct a pre-gel layer（CG）on the PP monofilament without bonding monofilaments and blocking pores;then CG was cross-linked in situ to obtain a filamentanchored hydrogel layer（FAHL）.The FAHL cross-linked by TA（CG/TA）not only had good oxidative activity（1.53 m M Fe SO4/cm2）,and the oxidized TA also could undergo the Michael addition reaction with CG molecules to reinforce FAHL.The results showed that FAHL preserved the structural advantages of the warp-knitted mesh and maintained its integrity in a simulated human physiological environment and resisted static degradation in vitro for at least 15 days,thus the coating and the mesh could exert their individual functions.In the end,CG/TA-PP showed superior synergistic anti-inflammatory properties both in vivo and in vitro by its biomimetic and antioxidant properties,which ultimately reduced 63.2 % of collagen deposition and promoted the normal regeneration of blood vessels.In summary,this dissertation aims at the multiple complications induced by the PP warpknitted mesh implantation.The antioxidant and highly adhesive polyphenols were used as mediation to construct anti-fouling or biomimetic coatings on the mesh with synergistic anti-inflammatory effects,and the two anti-inflammatory meshes with preserved structural characteristics and mechanical compliance were obtained.The anti-inflammatory mesh with the biomimetic coating had advantages in modulating FBR,meaning it is expected to achieve defective tissue repair and long-term implants retention as well as provides a reference for anti-inflammatory surface modification on other medical devices such as implanted biomaterials,drug delivery vehicles,and biosensors. |
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