PDF(Pubmed)
Abstract：
Chondrocyte senescence and reduced lubrication play pivotal roles in the pathogenesis of age-related osteoarthritis (OA). In the present study, highly lubricated and drug-loaded hydrogel microspheres are designed and fabricated through the radical polymerization of sulfobetaine (SB)-modified hyaluronic acid methacrylate using microfluidic technology. The copolymer contains a large number of SB and carboxyl groups that can provide a high degree of lubrication through hydration and form electrostatic loading interactions with metformin (Met@SBHA), producing a high drug load for anti-chondrocyte senescence. Mechanical, tribological, and drug release analyses demonstrated enhanced lubricative properties and prolonged drug dissemination of the Met@SBHA microspheres. RNA sequencing (RNA-seq) analysis, network pharmacology, and in vitro assays revealed the extraordinary capacity of Met@SBHA to combat chondrocyte senescence. Additionally, inducible nitric oxide synthase (iNOS) has been identified as a promising protein modulated by Met in senescent chondrocytes, thereby exerting a significant influence on the iNOS/ONOO-/P53 pathway. Notably, the intra-articular administration of Met@SBHA in aged mice ameliorated cartilage senescence and OA pathogenesis. Based on the findings of this study, Met@SBHA emerges as an innovative and promising strategy in tackling age-related OA serving the dual function of enhancing joint lubrication and mitigating cartilage senescence.
摘要：
软骨细胞衰老和润滑减少在年龄相关性骨关节炎（OA）的发病机制中起关键作用。在本研究中,使用微流控技术，通过磺基甜菜碱（SB）修饰的透明质酸甲基丙烯酸酯的自由基聚合来设计和制造高度润滑和载药的水凝胶微球。该共聚物含有大量的SB和羧基，可以通过水合提供高度的润滑，并与二甲双胍（Met@SBHA）形成静电负载相互作用，产生抗软骨细胞衰老的高载药量。机械,摩擦学,和药物释放分析表明Met@SBHA微球具有增强的润滑特性和延长的药物传播。RNA测序（RNA-seq）分析，网络药理学，体外实验显示，Met@SBHA对抗软骨细胞衰老的非凡能力。此外,诱导型一氧化氮合酶（iNOS）已被确定为Met在衰老软骨细胞中调节的有前途的蛋白质，从而对iNOS/ONOO-/P53通路产生显著影响。值得注意的是,Met@SBHA在老年小鼠中的关节内给药改善了软骨衰老和OA的发病机制。根据这项研究的结果，Met@SBHA成为解决与年龄相关的OA的创新和有前途的策略，具有增强关节润滑和减轻软骨衰老的双重功能。
