The inherent hydrophobicity and large surface area of electrospun synthetic polymeric scaffolds often cause non-specific protein adsorption, thereby influencing macrophage functions and eventually leading to fibrosis at the tissue-scaffold interface. This work reports fabrication of silk fibroin (SF)-functionalized electrospun polycaprolactone (PCL) fibers by single-component layer-by-layer assembly and decorate the SF with heparin disaccharide (HD) by click chemistry, resulting in the non-covalent binding of interleukin-4 (IL-4) with the capacity to modulate macrophage polarization. A modified SF derivative was obtained by diazonium coupling and then covalently bonded with HD via click chemistry to eventually bind IL-4 efficiently and maintain its bioactivity. In vitro studies showed that IL-4 surface-functionalized nanofibrous scaffolds promoted polarization to M2 macrophages in the short term. Importantly, in vivo studies demonstrated that promoting transient shifts in macrophage polarization at early stages can significantly inhibit the extent of foreign body reactions. Furthermore, the results of a transcriptomic profiling showed that MARK, PI3K, JNK and NF-κB signaling pathways played an important role in regulating the macrophage phenotypes in the SF/HD/IL-4-functionalized fibers. Our results suggest that such a strategy offers a new approach for utilizing biological agent surface functionalization to modulate the foreign body reaction to nanofibrous scaffolds.

电纺合成聚合物支架的固有疏水性和大表面积通常会导致非特异性蛋白质吸附，从而影响巨噬细胞功能并最终导致组织支架界面的纤维化。这项工作报告了通过单组分逐层组装来制备丝素蛋白（SF）功能化的电纺聚己内酯（PCL）纤维并通过点击化学用肝素二糖（HD）修饰SF，导致非共价结合的IL-4（IL-4）具有调节巨噬细胞极化的能力。通过重氮偶合获得修饰的SF衍生物，然后通过点击化学与HD共价键合，最终有效地结合IL-4并保持其生物活性。体外研究表明，IL-4表面功能化的纳米纤维支架可在短期内促进M2巨噬细胞的极化。重要的是，体内研究表明，在早期阶段促进巨噬细胞极化的瞬时转变可显着抑制异物反应的程度。此外，转录组分析结果表明，MARK，PI3K，JNK和NF-κB信号通路在调节SF / HD / IL-4功能化纤维中的巨噬细胞表型中起着重要作用。我们的结果表明，这种策略提供了一种利用生物剂表面功能化来调节异物对纳米纤维支架反应的新方法。