Zhang Peng, Yang Jianhai, Wang Zhuoya, Wang Hongying, An Mingyang, Yakufu Maihemuti, Wang Wenliang, Liu Yujie, Liu Wenguang, Li Chunbao
Department of Orthopedics, The Fourth Medical Center of Chinese PLA General Hospital, Beijing 100048, China; Department of Sports Medicine, Characteristic Medical Center of Chinese People's Armed Police Forces, Tianjin 300162, China.
School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin 300350, China.
J Control Release. 2024 Dec;376:20-36. doi: 10.1016/j.jconrel.2024.09.052. Epub 2024 Oct 8.
Globally, osteoarthritis (OA) is the most prevalent joint disease and is characterized by infiltration of M1 macrophages in the synovium, anabolic-catabolic imbalance of the extracellular matrix (ECM), increased articular shear force and overproduction of reactive oxygen species (ROS). Disease-modifying OA drugs are not yet available, and treatments for OA focus solely on reducing pain and inflammation and have limited therapeutic effect. Herein, we developed an injectable self-lubricating poly(N-acryloyl alaninamide) (PNAAA) hydrogel loaded with platelet lysate (PL) (termed "PNAAA@PL") for treating OA. Tribological and drug release tests revealed suitable lubrication properties and sustained release of bioactive factors in PNAAA@PL. In vitro experiments showed that PNAAA@PL alleviated interleukin-1β (IL-1β)-induced anabolic-catabolic imbalance of chondrocytes and repolarized pro-inflammatory M1 macrophages to the anti-inflammatory M2 phenotype via intracellular ROS scavenging. Additionally, the PNAAA@PL hydrogel enhanced the migratory capacity and chemotaxis ability of stem cells, which are essential for chondrogenesis. In vivo, the functionalized PNAAA@PL hydrogel acted like synovial fluid following intra-articular injection into a rat OA model with anterior cruciate ligament transection, ultimately attenuating cartilage degeneration and synovitis. According to molecular mechanism studies, PNAAA@PL repairs cartilage in the OA model by inhibiting the NF-ĸB pathway. Overall, this self-lubricating PNAAA@PL hydrogel offers a comprehensive strategy for preventing OA progression by engineering a biophysiochemical microenvironment to generate high-quality hyaline cartilage.
在全球范围内，骨关节炎（OA）是最普遍的关节疾病，其特征是滑膜中M1巨噬细胞浸润、细胞外基质（ECM）的合成代谢 - 分解代谢失衡、关节剪切力增加以及活性氧（ROS）过度产生。目前尚无改善病情的OA药物，OA的治疗仅侧重于减轻疼痛和炎症，治疗效果有限。在此，我们开发了一种负载血小板裂解物（PL）的可注射自润滑聚（N - 丙烯酰丙氨酸酰胺）（PNAAA）水凝胶（称为“PNAAA@PL”）用于治疗OA。摩擦学和药物释放测试表明PNAAA@PL具有合适的润滑性能和生物活性因子的持续释放。体外实验表明，PNAAA@PL通过细胞内ROS清除减轻白细胞介素 - 1β（IL - 1β）诱导的软骨细胞合成代谢 - 分解代谢失衡，并将促炎M1巨噬细胞重新极化至抗炎M2表型。此外，PNAAA@PL水凝胶增强了干细胞的迁移能力和趋化能力，这对软骨形成至关重要。在体内，功能化的PNAAA@PL水凝胶在关节内注射到前交叉韧带横断的大鼠OA模型后，表现得像滑液一样，最终减轻软骨退变和滑膜炎。根据分子机制研究，PNAAA@PL通过抑制NF - κB途径修复OA模型中的软骨。总体而言，这种自润滑的PNAAA@PL水凝胶通过构建生物物理化学微环境以生成高质量透明软骨，为预防OA进展提供了一种综合策略。
