School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing, 100083, China.
Beijing Key Lab of Regenerative Medicine in Orthopaedics, Key Laboratory of Musculoskeletal Trauma &War Injuries, PLA Institute of Orthopedics, Chinese PLA General Hospital, Beijing, 100853, China.
Biomaterials. 2025 Mar;314:122875. doi: 10.1016/j.biomaterials.2024.122875. Epub 2024 Oct 18.
The inflammatory microenvironment and inferior chondrogenesis are major symptoms after cartilage defect. Although various modifications strategies associated with hydrogels exhibit remarkable capacity of pro-cartilage regeneration, the adverse effect by prolonging inflammation is still formidable to hamper potential biomedical applications of different hydrogel implants. Herein, inspired by the repair microenvironment of articular cartilage defects, an injectable, immunomodulatory, and chondrogenic L-MNS-CMDA hydrogel is prepared through grafting vinyl and catechol groups to chitosan macromolecules using amide reaction, then further loading MnO nanosheets (MNS). The double crosslinking of photopolymerization and catechol oxidative polymerization endows L-MNS-CMDA hydrogel with preferable mechanical property, affording a suitable mechanical support for cartilage defect repair. Additionally, the robust tissue adhesion capability stemming from catechol groups guarantees the long-term retention of the hydrogel in the defect site. Meanwhile, L-MNS-CMDA hydrogel decomposes exogenous and intracellular HO into O and HO, to effectively alleviate cellular oxidative stress caused by long-term hypoxia. Under the synergies of catechol groups and MNS, L-MNS-CMDA hydrogel not only inhibits macrophages polarizing into M1 phenotype, but encourages them turn into M2 phenotype, thereby, reconstructing an immunization friendly microenvironment to ultimately enhance cartilage regeneration. Predictably, the hydrogel markedly induces rat bone marrow mesenchymal stem cells differentiating into chondrocytes by expressing abundant glycosaminoglycan and type II collagen. A cartilage defect model of rat knee joint indicates that L-MNS-CMDA hydrogel visually regulate the early inflammatory response of post-implantation, and facilitate cartilage regeneration and recovery of joint function after 12 weeks of post-implantation. All in all, this multifunctional L-MNS-CMDA hydrogel exhibits superior immunomodulatory and chondrogenic properties, holding immense clinical potential in the treatment of cartilage defects.
炎症微环境和软骨内形成能力低下是软骨损伤后的主要症状。尽管各种与水凝胶相关的改性策略表现出显著的软骨再生能力，但通过延长炎症来产生不利影响仍然是阻碍不同水凝胶植入物潜在生物医学应用的巨大障碍。受关节软骨缺损修复微环境的启发，本文通过酰胺反应将乙烯基和儿茶酚基团接枝到壳聚糖大分子上，制备了一种可注射的、免疫调节的和软骨形成的 L-MNS-CMDA 水凝胶，然后进一步负载 MnO 纳米片（MNS）。光聚合和儿茶酚氧化聚合的双重交联赋予 L-MNS-CMDA 水凝胶更好的机械性能，为软骨缺损修复提供了合适的机械支撑。此外，源于儿茶酚基团的强大组织黏附能力保证了水凝胶在缺损部位的长期保留。同时，L-MNS-CMDA 水凝胶将外源性和细胞内的 HO 分解为 O 和 HO，有效缓解长期缺氧引起的细胞氧化应激。在儿茶酚基团和 MNS 的协同作用下，L-MNS-CMDA 水凝胶不仅抑制巨噬细胞向 M1 表型极化，还促使其向 M2 表型转化，从而重建免疫友好的微环境，最终增强软骨再生。可以预见，该水凝胶通过表达丰富的糖胺聚糖和 II 型胶原，显著诱导大鼠骨髓间充质干细胞向软骨细胞分化。大鼠膝关节软骨缺损模型表明，L-MNS-CMDA 水凝胶可在植入后早期调节炎症反应，并促进软骨再生和关节功能恢复 12 周后。总之，这种多功能 L-MNS-CMDA 水凝胶表现出优越的免疫调节和软骨生成特性，在治疗软骨缺损方面具有巨大的临床潜力。
