Chen Yuhang, Yang Zhuo-Ran, Cheng Zhangrong, Shi Pengzhi, Zhang Anran, Fan Jing-Wen, Zhao Zhiguo, Jiang Hao, Zhu Jintao, Zhang Yukun
Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China.
Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, School of Chemistry and Chemical Engineering, HUST, Wuhan 430074, China.
J Control Release. 2025 Apr 10;380:599-614. doi: 10.1016/j.jconrel.2025.02.016. Epub 2025 Feb 15.
Local inflammation modulation and stem cell therapy have attracted much attention in the treatment of intervertebral disc degeneration (IDD). However, severe oxidative stress and limited nucleus pulposus (NP)-like differentiation of stem cells largely impair biomaterial implantation's therapeutic efficacy. Due to their excellent performance in injectability and flowability, and minor compression to NP tissue, hydrogel microspheres have become an attractive carrier for IDD treatment. Herein, an injectable hydrogel microsphere consisting of Wnt5a-mimetic peptide Foxy5- and the antioxidative peptide-grafted gelatin methacryloyl matrix (GFA), was developed as a stem cell delivery system for IDD therapy. Being fabricated and encapsulating bone marrow-derived mesenchymal stem cells (BMSCs) using the microfluidic technology, GFA hydrogel microspheres ameliorate IDD by promoting inflammation inhibition, NP-like differentiation and extracellular matrix regeneration. They efficiently eliminated reactive oxygen species, and downregulated the inflammation level through the inhibition of interleukin-17B/nuclear factor-κB signaling pathway. Moreover, the NP-like differentiation of BMSCs was effectively stimulated by Foxy5 via the calcium/calmodulin dependent protein kinase kinase 2/protein kinase A/sex determining region Y box protein 9 signaling pathway, thereby leading to a rebalance between the generation and degradation of NP matrix. In vivo rat IDD model demonstrated that BMSC-loaded GFA hydrogel microspheres mitigated local inflammation, preserved disc height, and promoted intervertebral disc regeneration. In conclusion, this study introduces an BMSC-loaded injectable hydrogel microspheres as a promising therapy for regulating the microenvironment and alleviating the progression of IDD.
局部炎症调节和干细胞疗法在椎间盘退变（IDD）的治疗中备受关注。然而，严重的氧化应激和干细胞向髓核（NP）样细胞分化能力的限制，在很大程度上削弱了生物材料植入的治疗效果。由于水凝胶微球在可注射性和流动性方面表现出色，且对NP组织的压迫较小，已成为IDD治疗中颇具吸引力的载体。在此，一种由模拟Wnt5a的肽Foxy5和抗氧化肽接枝的甲基丙烯酰化明胶基质（GFA）组成的可注射水凝胶微球被开发为用于IDD治疗的干细胞递送系统。利用微流控技术制备并封装骨髓间充质干细胞（BMSCs）后，GFA水凝胶微球通过促进炎症抑制、NP样分化和细胞外基质再生来改善IDD。它们有效清除活性氧，并通过抑制白细胞介素-17B/核因子-κB信号通路下调炎症水平。此外，Foxy5通过钙/钙调蛋白依赖性蛋白激酶激酶2/蛋白激酶A/性别决定区Y框蛋白9信号通路有效刺激BMSCs向NP样细胞分化，从而导致NP基质的生成与降解之间重新平衡。体内大鼠IDD模型表明，负载BMSCs的GFA水凝胶微球可减轻局部炎症、维持椎间盘高度并促进椎间盘再生。总之，本研究引入了一种负载BMSCs的可注射水凝胶微球，作为一种有前景的疗法来调节微环境并缓解IDD的进展。
