Song Wei, Guo Ying, Liu Wencai, Yao Yijing, Zhang Xuancheng, Cai Zhuochang, Yuan Chenrui, Wang Xin, Wang Yifei, Jiang Xiping, Wang Haoyuan, Yu Weilin, Li Haiyan, Zhu Yanlun, Kong Lingzhi, He Yaohua
Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, P. R. China.
Department of Cardiology, Heart Center, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China.
Adv Mater. 2024 Sep;36(39):e2408255. doi: 10.1002/adma.202408255. Epub 2024 Aug 9.
Modulating the inflammatory microenvironment to reconstruct the fibrocartilaginous layer while promoting tendon repair is crucial for enhancing tendon-to-bone healing in rotator cuff repair (RCR), a persistent challenge in orthopedics. Small extracellular vesicles (sEVs) hold significant potential to modulate inflammation, yet the efficient production of highly bioactive sEVs remains a substantial barrier to their clinical application. Moreover, achieving minimally invasive local delivery of sEVs to the tendon-to-bone interface presents significant technical difficulties. Herein, the circadian rhythm of adipose-derived stem cells is modulated to increase the yield and enhance the inflammatory regulatory capacity of sEVs. Circadian rhythm-regulated sEVs (CR-sEVs) enhance the cyclic adenosine monophosphate signaling pathway in macrophage (Mφ) via platelet factor 4 delivery, thereby inhibiting Mφ M1 polarization. Subsequently, a triphasic microneedle (MN) scaffold with a tip, stem, and base is designed for the local delivery of CR-sEVs (CR-sEVs/MN) at the tendon-to-bone junction, incorporating tendon-derived decellularized extracellular matrix in the base to facilitate tendon repair. CR-sEVs/MN mitigates inflammation, promotes fibrocartilage regeneration, and enhances tendon healing, thereby improving biomechanical strength and shoulder joint function in a rat RCR model. Combining CR-sEVs with this triphasic microneedle delivery system presents a promising strategy for enhancing tendon-to-bone healing in clinical settings.
调节炎症微环境以重建纤维软骨层，同时促进肌腱修复，对于增强肩袖修复（RCR）中的肌腱-骨愈合至关重要，这是骨科领域一直面临的挑战。小细胞外囊泡（sEVs）在调节炎症方面具有巨大潜力，然而高效生产高生物活性的sEVs仍然是其临床应用的重大障碍。此外，将sEVs微创局部递送至肌腱-骨界面存在重大技术困难。在此，通过调节脂肪干细胞的昼夜节律来提高sEVs的产量并增强其炎症调节能力。昼夜节律调节的sEVs（CR-sEVs）通过血小板因子4传递增强巨噬细胞（Mφ）中的环磷酸腺苷信号通路，从而抑制Mφ M1极化。随后，设计了一种具有尖端、杆部和基部的三相微针（MN）支架，用于在肌腱-骨交界处局部递送CR-sEVs（CR-sEVs/MN），在基部掺入肌腱衍生的脱细胞细胞外基质以促进肌腱修复。CR-sEVs/MN减轻炎症，促进纤维软骨再生，并增强肌腱愈合，从而改善大鼠RCR模型中的生物力学强度和肩关节功能。将CR-sEVs与这种三相微针递送系统相结合，为临床环境中增强肌腱-骨愈合提供了一种有前景的策略。
