Institute of Materials Science, Max Bergmann Center of Biomaterials, TU Dresden, Budapester Str. 27, 01069 Dresden, Germany.
Structural Bioinformatics, BIOTEC TU Dresden, Tatzberg 47-51, Dresden 01307, Germany.
ACS Appl Bio Mater. 2021 Jan 18;4(1):494-506. doi: 10.1021/acsabm.0c01001. Epub 2020 Dec 17.
In order to restore the regeneration capacity of large-size vascularized tissue defects, innovative biomaterial concepts are required. Vascular endothelial growth factor (VEGF) is a key factor of angiogenesis interacting with sulfated glycosaminoglycans (sGAG) within the extracellular matrix. As this interplay mainly controls and directs the biological activity of VEGF, we used chemically modified sGAG derivatives to evaluate the structural requirements of sGAG for controlling and tuning VEGF function and to translate these findings into the design of biomaterials. The in-depth analysis of this interaction by surface plasmon resonance and ELISA studies in combination with molecular modeling stressed the relevance of the substitution position, degree of sulfation, and carbohydrate backbone of GAG. Acrylated hyaluronan (HA-AC)/collagen (coll)-based hydrogels containing cross-linked acrylated, sulfated hyaluronan (sHA-AC) derivatives with different substitution patterns or an acrylated chondroitin sulfate (CS-AC) derivative function as multivalent carbohydrate-based scaffolds for VEGF delivery with multiple tuning capacities. Depending on the substitution pattern of sGAG, the release of biologically active VEGF was retarded in a defined manner compared to pure HA/coll gels, which further controlled the VEGF-induced stimulation of endothelial cell proliferation and extended morphology of cells. This indicates that sGAG can act as modulators of protein interaction profiles of HA/coll hydrogels. In addition, sHA-AC-containing gels with and even without VEGF strongly stimulate endothelial cell proliferation compared to gels containing only CS-AC or HA-AC. Thus, HA/coll-based hydrogels containing cross-linked sHA-AC are biomimetic materials able to directly influence endothelial cells , which might translate into an improved healing of injured vascularized tissues.
为了恢复大尺寸血管化组织缺损的再生能力，需要创新的生物材料概念。血管内皮生长因子（VEGF）是血管生成的关键因子，与细胞外基质中的硫酸化糖胺聚糖（sGAG）相互作用。由于这种相互作用主要控制和指导 VEGF 的生物学活性，我们使用化学修饰的 sGAG 衍生物来评估 sGAG 控制和调整 VEGF 功能的结构要求，并将这些发现转化为生物材料的设计。通过表面等离子体共振和 ELISA 研究与分子建模的深入分析，强调了 GAG 的取代位置、硫酸化程度和糖骨架的相关性。含有交联的丙烯酰化、硫酸化透明质酸（sHA-AC）衍生物的丙烯酰化透明质酸（HA-AC）/胶原（coll）基水凝胶或丙烯酰化硫酸软骨素（CS-AC）衍生物具有不同取代模式，作为多功能基于碳水化合物的 VEGF 递送支架，具有多种调谐能力。根据 sGAG 的取代模式，与纯 HA/coll 凝胶相比，生物活性 VEGF 的释放以特定方式被延迟，这进一步控制了 VEGF 诱导的内皮细胞增殖和细胞扩展形态的刺激。这表明 sGAG 可以作为 HA/coll 水凝胶中蛋白质相互作用谱的调节剂。此外，与仅含有 CS-AC 或 HA-AC 的凝胶相比，含有 sHA-AC 的凝胶甚至不含 VEGF 也能强烈刺激内皮细胞增殖。因此，含有交联 sHA-AC 的 HA/coll 基水凝胶是能够直接影响内皮细胞的仿生材料，这可能转化为受伤的血管化组织的愈合得到改善。
