Wang Hui, Yu Ruyue, Wang Meng, Wang Shikun, Ouyang Xingyu, Yan Zhiwen, Chen Shuai, Wang Wei, Wu Fei, Fan Cunyi
Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, PR China; Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai 200233, PR China.
School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China.
J Control Release. 2023 Apr;356:162-174. doi: 10.1016/j.jconrel.2023.02.039. Epub 2023 Mar 3.
Tendon injury is one of the most common musculoskeletal disorders that impair joint mobility and lower quality of life. The limited regenerative capacity of tendon remains a clinical challenge. Local delivery of bioactive protein is a viable therapeutic approach for tendon healing. Insulin-like growth factor binding protein 4 (IGFBP-4) is a secreted protein capable of binding and stabilizing insulin-like growth factor 1 (IGF-1). Here, we applied an aqueous-aqueous freezing-induced phase separation technology to obtain the IGFBP4-encapsulated dextran particles. Then, we added the particles into poly (L-lactic acid) (PLLA) solution to fabricate IGFBP4-PLLA electrospun membrane for efficient IGFBP-4 delivery. The scaffold showed excellent cytocompatibility and a sustained release of IGFBP-4 for nearly 30 days. In cellular experiments, IGFBP-4 promoted tendon-related and proliferative markers expression. In a rat Achilles tendon injury model, immunohistochemistry and quantitative real-time polymerase chain reaction confirmed better outcomes by using the IGFBP4-PLLA electrospun membrane at the molecular level. Furthermore, the scaffold effectively promoted tendon healing in functional performance, ultrastructure and biomechanical properties. We found addition of IGFBP-4 promoted IGF-1 retention in tendon postoperatively and then facilitated protein synthesis via IGF-1/AKT signaling pathway. Overall, our IGFBP4-PLLA electrospun membrane provides a promising therapeutic strategy for tendon injury.
肌腱损伤是最常见的肌肉骨骼疾病之一，会损害关节活动能力并降低生活质量。肌腱有限的再生能力仍然是一个临床挑战。生物活性蛋白的局部递送是一种可行的肌腱愈合治疗方法。胰岛素样生长因子结合蛋白4（IGFBP - 4）是一种能够结合并稳定胰岛素样生长因子1（IGF - 1）的分泌蛋白。在此，我们应用水 - 水冷冻诱导相分离技术来获得包封有IGFBP4的葡聚糖颗粒。然后，我们将这些颗粒添加到聚（L - 乳酸）（PLLA）溶液中，以制备用于高效递送IGFBP - 4的IGFBP4 - PLLA电纺膜。该支架表现出优异的细胞相容性，并且IGFBP - 4能持续释放近30天。在细胞实验中，IGFBP - 4促进了肌腱相关和增殖标志物的表达。在大鼠跟腱损伤模型中，免疫组织化学和定量实时聚合酶链反应在分子水平上证实使用IGFBP4 - PLLA电纺膜有更好的效果。此外，该支架在功能性能、超微结构和生物力学性能方面有效地促进了肌腱愈合。我们发现添加IGFBP - 4可促进术后IGF - 1在肌腱中的保留，然后通过IGF - 1/AKT信号通路促进蛋白质合成。总体而言，我们的IGFBP4 - PLLA电纺膜为肌腱损伤提供了一种有前景的治疗策略。
