Pearson Joseph J, Mao Jiahui, Temenoff Johnna S
Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech, Emory University, Atlanta, Georgia, USA.
Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA.
Tissue Eng Part A. 2025 Feb;31(3-4):195-207. doi: 10.1089/ten.tea.2024.0241. Epub 2024 Nov 18.
Muscle degeneration after rotator cuff tendon tear is a significant clinical problem. In these experiments, we developed a poly(ethylene glycol)-based injectable granular hydrogel containing two heparin derivatives (fully sulfated [Hep] and fully desulfated [Hep-]) as well as a matrix metalloproteinase-sensitive peptide to promote sustained release of tumor necrosis factor-stimulated gene 6 (TSG-6) over 14+ days in a rat model of rotator cuff muscle injury. The hydrogel formulations demonstrated similar release profiles , thus facilitating comparisons between delivery from heparin derivatives on the level of tissue repair in two different areas of muscle (near the myotendious junction [MTJ] and in the muscle belly [MB]) that have been shown previously to have differing responses to rotator cuff tendon injury. We hypothesized that sustained delivery of TSG-6 would enhance the anti-inflammatory response following rotator cuff injury through macrophage polarization and that release from Hep would potentiate this effect throughout the muscle. Inflammatory/immune cells, satellite cells, and fibroadipogenic progenitor cells were analyzed by flow cytometry 3 and 7 days after injury and hydrogel injection, while metrics of muscle healing were examined via immunohistochemistry up to day 14. Results showed controlled delivery of TSG-6 from Hep caused heightened macrophage response (day 7 macrophages, 4.00 ± 1.85% single cells, M2a, 3.27 ± 1.95% single cells) and increased markers of early muscle regeneration (embryonic heavy chain staining) by day 7, particularly in the MTJ region of the muscle. This work provides a novel strategy for localized, controlled delivery of TSG-6 to enhance muscle healing after rotator cuff tear.
肩袖肌腱撕裂后的肌肉退化是一个重大的临床问题。在这些实验中，我们开发了一种基于聚乙二醇的可注射颗粒水凝胶，其中含有两种肝素衍生物（全硫酸化[Hep]和全脱硫酸化[Hep-]）以及一种基质金属蛋白酶敏感肽，以促进肿瘤坏死因子刺激基因6（TSG-6）在肩袖肌肉损伤大鼠模型中持续释放超过14天。水凝胶制剂表现出相似的释放曲线，从而便于比较两种肝素衍生物在肌肉两个不同区域（肌腱结合处[MTJ]附近和肌腹[MB]）的组织修复水平上的递送情况，先前已表明这两个区域对肩袖肌腱损伤有不同的反应。我们假设TSG-6的持续递送将通过巨噬细胞极化增强肩袖损伤后的抗炎反应，并且从Hep释放将在整个肌肉中增强这种作用。在损伤和水凝胶注射后3天和7天通过流式细胞术分析炎症/免疫细胞、卫星细胞和成纤维脂肪生成祖细胞，同时通过免疫组织化学检查直至第14天的肌肉愈合指标。结果显示，从Hep中可控递送TSG-6导致巨噬细胞反应增强（第7天巨噬细胞，单细胞为4.00±１.85%，M2a，单细胞为3.27±1.95%），并在第7天时增加了早期肌肉再生的标志物（胚胎重链染色），特别是在肌肉的MTJ区域。这项工作为局部、可控递送TSG-6以增强肩袖撕裂后的肌肉愈合提供了一种新策略。
