Surface Modification Of Nanofibers Based On Layer By Layer And Click Chemistry And Their Effect On Inflammatory Reactions

Modern implant design including tissue engineering and drug delivery scaffolds,are typically characterized by their mechanical strength,functional components,topology structure,biodegradable and so on.However,the impact of foreign body response(FBR)is particularly significant for transplantation ultimate functional success or failure in clinical application.Especially the large surface area and inherent small pores of nanofibers will cause high non-specific protein adsorption.Following an initial implant,the fibrosis develop on the protein adsorbed surfaces,not only affecting the integration in the surrounding tissues,but also posing the patient at serious risk of systemic infections.As previously studies,macrophages play a crucial role in determining the outcome of the foreign body response to biomaterials or implanted medical devices.These studies indicate that macrophages possess remarkable functional plasticity and,therefore,can play both positive and negative roles in the pathogenesis of disease and tissue remodeling.The aim of this study was to develop a silk fibroin(SF)functionalized electrospun polycaporlactone(PCL)fibers by single component layer-by-layer(Lb L)assembly and decorate SF with heparin disaccharide(HD)by diazonium coupling and click chemistry leads to a non-covalent binding of IL-4 with capacity to modulate the polarity of macrophages and reduce the thickness of fibrosis tissue.Deposition of fluorescently labeled SF onto PCL fibers resulted in increasing fluorescence intensity and tensile strength in correlation to SF layer number.Using a diazonium coupling reaction,modified SF derivative containing 280 azide groups per SF molecule were obtained and then covalent bonded with HD by CuAAC click chemistry.Interestingly,such SF/HD surface functionalized PCL scaffolds has a low non-specific protein adsorption but can enhance specific protein IL-4 adsorption.Both in vitro and in vivo studies have demonstrated that SF/HD/IL-4 surface functionalized PCL fibers were able to increase the percentage of M2 macrophages and reduce the thickness of fibrous tissue,while promoting the host cell infiltration into scaffolds,and finally improved the integration of tissue and scaffold.Furthermore,the results of whole-genome microarray analysis showed that the signal pathways including TNF,PI3 K,JNK and NF-?B feedback mechanism played an important role in IL-4 functionalized electrospun fibers regulating macrophage phenotype.Our results suggest that such strategy offers new approaches to utilizing biological agent surface functionalization for modulating foreign body reaction of nanofibrous scaffold.