Arlov Ø, Öztürk E, Steinwachs M, Skjåk-Bræk G, Zenobi-Wong M
Cartilage Engineering & Regeneration, ETH Zürich, Otto-Stern-Weg 7, 8093 Zürich,
Eur Cell Mater. 2017 Feb 7;33:76-89. doi: 10.22203/eCM.v033a06.
Loss of articular cartilage from ageing, injury or degenerative disease is commonly associated with inflammation, causing pain and accelerating degradation of the cartilage matrix. Sulphated glycosaminoglycans (GAGs) are involved in the regulation of immune responses in vivo, and analogous polysaccharides are currently being evaluated for tissue engineering matrices to form a biomimetic environment promoting tissue growth while suppressing inflammatory and catabolic activities. Here, we characterise physical properties of sulphated alginate (S-Alg) gels for use in cartilage engineering scaffolds, and study their anti-inflammatory effects on encapsulated chondrocytes stimulated with IL-1β. Sulphation resulted in decreased storage modulus and increased swelling of alginate gels, whereas mixing highly sulphated alginate with unmodified alginate resulted in improved mechanical properties compared to gels from pure S-Alg. S-Alg gels showed extensive anti-inflammatory and anti-catabolic effects on encapsulated chondrocytes induced by IL-1β. Cytokine-stimulated gene expression of pro-inflammatory markers IL-6, IL-8, COX-2 and aggrecanase ADAMTS-5 were significantly lower in the sulphated gels compared to unmodified alginate gels. Moreover, sulphation of the microenvironment suppressed the protein expression of COX-2 and NF-κB as well as the activation of NF-κB and p38-MAPK. The sulphated alginate matrices were found to interact with IL-1β, and proposed to inhibit inflammatory induction by sequestering cytokines from their receptors. This study shows promising potential for sulphated alginates in biomimetic tissue engineering scaffolds, by reducing cytokine-mediated inflammation and providing a protective microenvironment for encapsulated cells.
因衰老、损伤或退行性疾病导致的关节软骨缺失通常与炎症相关，会引发疼痛并加速软骨基质的降解。硫酸化糖胺聚糖（GAGs）参与体内免疫反应的调节，目前正在评估类似的多糖用于组织工程基质，以形成促进组织生长同时抑制炎症和分解代谢活动的仿生环境。在此，我们表征了用于软骨工程支架的硫酸化藻酸盐（S-Alg）凝胶的物理性质，并研究了它们对经白细胞介素-1β刺激的包封软骨细胞的抗炎作用。硫酸化导致藻酸盐凝胶的储能模量降低和肿胀增加，而将高度硫酸化的藻酸盐与未改性的藻酸盐混合，与纯S-Alg凝胶相比，其机械性能得到改善。S-Alg凝胶对白细胞介素-1β诱导的包封软骨细胞显示出广泛的抗炎和抗分解代谢作用。与未改性的藻酸盐凝胶相比，细胞因子刺激的促炎标志物白细胞介素-6、白细胞介素-8、环氧化酶-2和聚集蛋白聚糖酶ADAMTS-5的基因表达在硫酸化凝胶中显著降低。此外，微环境的硫酸化抑制了环氧化酶-2和核因子-κB的蛋白表达以及核因子-κB和p38丝裂原活化蛋白激酶的激活。发现硫酸化藻酸盐基质与白细胞介素-1β相互作用，并提出通过从其受体中隔离细胞因子来抑制炎症诱导。这项研究表明，硫酸化藻酸盐在仿生组织工程支架中具有广阔的应用前景，可减少细胞因子介导的炎症并为包封细胞提供保护性微环境。
