State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Preventive Dentistry, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China.
State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China.
Adv Sci (Weinh). 2022 Jul;9(21):e2105650. doi: 10.1002/advs.202105650. Epub 2022 May 23.
Inflammation plays a crucial role in triggering regeneration, while inadequate or chronic inflammation hinders the regenerative process, resulting in refractory wounds. Inspired by the ideal regeneration mode in lower vertebrates and the human oral mucosa, realigning dysregulated inflammation to a heightened and acute response provides a promising option for refractory wound therapy. Neutrophils play important roles in inflammation initiation and resolution. Here, a hybrid biomaterial is used to stimulate transiently heightened inflammatory responses by precise tempospatial regulation of neutrophil recruitment and apoptosis. The hybrid biomaterial (Gel@fMLP/SiO -FasL) is constructed by loading of formyl-met-leu-phe (fMLP) and FasL-conjugated silica nanoparticles (SiO -FasL) into a pH-responsive hydrogel matrix. This composition enables burst release of fMLP to rapidly recruit neutrophils for heightened inflammation initiation. After neutrophils act to produce acids, the pH-responsive hydrogel degrades to expose SiO -FasL, which induces activated neutrophils apoptosis via FasL-Fas signaling triggering timely inflammation resolution. Apoptotic neutrophils are subsequently cleared by macrophages, and this efferocytosis activates key signalings to promote macrophage anti-inflammatory phenotypic transformation to drive regeneration. Ultimately, Gel@fMLP/SiO -FasL successfully promotes tissue regeneration by manipulating inflammation in critical-sized calvarial bone defects and diabetic cutaneous wound models. This work provides a new strategy for refractory wound therapy via inducing transiently heightened inflammatory responses.
炎症在触发再生中起着至关重要的作用，而不足或慢性炎症会阻碍再生过程，导致难治性伤口。受低等脊椎动物和人类口腔黏膜理想再生模式的启发，将失调的炎症重新调整为高度急性反应为难治性伤口治疗提供了一个有前途的选择。中性粒细胞在炎症的启动和解决中起着重要作用。在这里，通过精确的时空调节中性粒细胞募集和凋亡，使用混合生物材料来刺激短暂的高度炎症反应。混合生物材料（Gel@fMLP/SiO-FasL）是通过将甲酰基-甲硫氨酸-亮氨酸-苯丙氨酸（fMLP）和 FasL 缀合的二氧化硅纳米颗粒（SiO-FasL）加载到 pH 响应水凝胶基质中构建的。这种组成允许 fMLP 的爆发释放，以快速募集中性粒细胞以启动高度炎症。中性粒细胞产生酸后，pH 响应水凝胶降解以暴露 SiO-FasL，通过 FasL-Fas 信号触发激活的中性粒细胞凋亡，从而及时解决炎症。随后，巨噬细胞清除凋亡的中性粒细胞，这种吞噬作用激活关键信号通路，促进巨噬细胞抗炎表型转化，从而促进再生。最终，Gel@fMLP/SiO-FasL 通过在临界尺寸颅骨骨缺损和糖尿病皮肤伤口模型中操纵炎症成功促进组织再生。这项工作通过诱导短暂的高度炎症反应为难治性伤口治疗提供了一种新策略。
