Despite innovations in surgical interventions, treatment of cartilage injury in osteoarthritic joints remains a challenge due to concomitant inflammation. Obstructing a single dominant inflammatory cytokine has shown remarkable clinical benefits in rheumatoid arthritis, and similar strategies are being suggested to target inflammatory pathways in osteoarthritis (OA). Here, we describe the utility of gelatin microspheres that are responsive to proteolytic enzymes typically expressed in arthritic flares, resulting in on‐demand and spatiotemporally controlled release of anti‐inflammatory cytokines for cartilage preservation and repair. These microspheres were designed with a net negative charge to sequester cationic anti‐inflammatory cytokines, and the magnitude of the negative charge potential increased with an increase in crosslinking density. Collagenase‐mediated degradation of the microspheres was dependent on the concentration of the enzyme. Release of anti‐inflammatory cytokines from the loaded microspheres directly correlated with the degradation of the gelatin matrix. Exposure of the IL‐4 and IL‐13 loaded microspheres reduced the inflammation of chondrocytes up to 80%. Hence, the delivery of these microspheres in an OA joint can attenuate the stimulation of chondrocytes and the resulting secretion of catabolic factors such as proteinases and nitric oxide. The microsphere format also allows for minimally invasive delivery and is less susceptible to mechanically induced drug release. Consequently, bioresponsive microspheres can be an effective tool for cartilage preservation and arthritis treatment.

中文翻译：

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用于按需递送用于关节软骨修复的抗炎细胞因子的生物响应性微球。

尽管在手术干预方面有所创新，但由于伴随的炎症，骨关节炎关节软骨损伤的治疗仍然是一个挑战。阻断单一的主要炎性细胞因子在类风湿性关节炎中显示出显着的临床益处，并且有人提出了类似的策略来靶向骨关节炎 (OA) 中的炎症通路。在这里，我们描述了对通常在关节炎发作中表达的蛋白水解酶有反应的明胶微球的效用，从而导致抗炎细胞因子的按需和时空控制释放，用于软骨保存和修复。这些微球被设计为带有净负电荷以隔离阳离子抗炎细胞因子，并且负电荷电位的大小随着交联密度的增加而增加。胶原酶介导的微球降解取决于酶的浓度。从负载的微球中释放抗炎细胞因子与明胶基质的降解直接相关。负载 IL-4 和 IL-13 的微球的暴露可将软骨细胞的炎症降低 80%。因此，这些微球在 OA 关节中的递送可以减弱对软骨细胞的刺激以及由此产生的分解代谢因子（如蛋白酶和一氧化氮）的分泌。微球形式还允许微创递送并且不太容易受到机械诱导的药物释放。因此，生物响应微球可以成为软骨保存和关节炎治疗的有效工具。