Li Yan, Zhang Yuxiang, Wang Shuqin, Ma Xiaojing, Dai Chengxin, Wang Yifan, Ye Chenyi, Pan Sunwen, Gao Changyou, Li Weixu
Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310020, China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, China.
Department of Plastic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
Acta Biomater. 2025 Jun 6. doi: 10.1016/j.actbio.2025.06.011.
Intervertebral disc degeneration (IDD) is intricately linked to the aging process, wherein reactive oxygen species (ROS) and inflammatory responses markedly contribute to matrix degradation and hyperplasia. Injectable antioxidant hydrogels loaded with pharmacological agents hold immense promise for clinical translation in early intervention of IDD. Our previous study revealed that the tissue inhibitor of metalloproteinase-3 (TIMP3) is a pivotal regulator of matrix remodeling and inflammation.
We developed a biodegradable ROS-responsive hydrogel functionalized with phenylboronic acid (R-gel) as a controlled release carrier of TIMP3 (R-gel-TIMP3). R-gel-TIMP3 effectively scavenged ROS and provided sustained TIMP3 delivery, thereby attenuating inflammation-driven disc degeneration. In vitro, R-gel-TIMP3 exhibited negligible cytotoxicity, reduced ROS levels in the nucleus pulposus cells, and alleviated cellular senescence and apoptosis. In vivo, it decreased ROS accumulation, inflammatory M1 macrophages, matrix degradation, and neovascularization, significantly ameliorating IDD pathology.
The synergistic action of ROS-responsive TIMP3 delivery markedly amplified the therapeutic efficacy against IDD, underscoring the therapeutic potential of R-gel-TIMP3 in IDD management.
1 We synthesized an injectable bioactive ROS-responsive hydrogel as an anti-oxidative vehicle for TIMP3 protein delivery. 2 The hydrogel enabled sustained release of TIMP-3 in situ and acted as an efficient ROS scavenger to protect NPs against oxidative stress. 3 This treatment could effectively intervene in the progression of IDD from early stage, promote extracellular matrix synthesis, and ultimately reduce IDD in a rat model.
椎间盘退变（IDD）与衰老过程密切相关，其中活性氧（ROS）和炎症反应显著促进基质降解和增生。负载药物的可注射抗氧化水凝胶在IDD早期干预的临床转化方面具有巨大潜力。我们之前的研究表明，金属蛋白酶组织抑制剂-3（TIMP3）是基质重塑和炎症的关键调节因子。
我们开发了一种用苯硼酸功能化的可生物降解的ROS响应水凝胶（R-凝胶）作为TIMP3的控释载体（R-凝胶-TIMP3）。R-凝胶-TIMP3有效地清除ROS并提供持续的TIMP3释放，从而减轻炎症驱动的椎间盘退变。在体外，R-凝胶-TIMP3表现出可忽略不计的细胞毒性，降低了髓核细胞中的ROS水平，并减轻了细胞衰老和凋亡。在体内，它减少了ROS积累、炎性M1巨噬细胞、基质降解和新血管形成，显著改善了IDD病理。
ROS响应性TIMP3递送的协同作用显著增强了对IDD的治疗效果，突出了R-凝胶-TIMP3在IDD管理中的治疗潜力。
1.我们合成了一种可注射的生物活性ROS响应水凝胶作为TIMP3蛋白递送的抗氧化载体。2.该水凝胶能够原位持续释放TIMP-3，并作为一种有效的ROS清除剂保护髓核细胞免受氧化应激。3.这种治疗可以有效地从早期干预IDD的进展，促进细胞外基质合成，并最终在大鼠模型中减轻IDD。
