(Iminium)thiolactone-Functional Hyaluronic Acid Hydrogels as Tissue Engineering Scaffolds

建立了一种针对慢性创面治疗的新型材料平台。慢性伤口是数百万人遭受痛苦的主要原因，很大一部分费用来自国家医疗保险制度的负担。他们大多停留在愈合过程的炎症阶段。这种炎症状态阻碍支持细胞隔离新鲜和健康的人类细胞外基质(ECM)成分。其主要成分是透明质酸，它已成为化妆品或抗衰老产品的重要成分，在人体细胞外基质中也发现了这种成分。因此，透明质酸被修饰了一种化学官能团(硫代内酯)。完成了这些硫代内酯的合成，并阐述了与透明质酸结合的策略。与透明质酸骨架结合的刺内酯提供了将结合/生长因子等多肽和蛋白质直接结合到透明质酸上的可能性，用于细胞信号传递和刺激生长。硫代内酯通常用于大分子蛋白质或酶的修饰，因为它们对相应蛋白质的氨基表现出良好的反应性。在第二反应步骤中，用于葫芦脲化学的客体或主体分子与硫醇(在第一反应步骤开环后从硫代内酯释放)反应。南瓜脲是一种大环分子，可以承载某些带正电荷的客体分子形成稳定的包合物。主人和客人的互动以一种非共价的方式进行。这一反应策略将允许(I)生长/结合因子、药物和多肽/蛋白质与透明质酸共价结合，以及(Ii)非共价交联。后者提供了一种极具延展性的材料，通过形状重塑，与感兴趣的表面保持高表面积接触。因此，在空间上适应伤口的个体形态是可能的。在这一最终应用之前，健康细胞在这种凝胶中的嵌入和增殖作为3D支架进行了研究和调整，以利于使用过的细胞的茁壮成长。在我们的方法中，这种材料可以替代有缺陷的细胞外基质，并促进嵌入的细胞重塑和再生自然产生的细胞外基质成分。随着愈合过程的重新推进，人工ECM将被慢慢降解，并被身体自己的ECM取代。

A novel materials platform is established which is aimed for the treatment of chronic wounds. Chronic wounds play a major part for which millions of people suffer from and a substantial share of costs comes to burden of the national health insurance systems. They are mostly stuck in an inflammatory stage of the healing process. This inflammatory state hinders the supporting cells to sequester fresh and healthy components of the human extracellular matrix (ECM). The main component is hyaluronic acid, which has become a prominent ingredient for cosmetics or anti-aging products and is also found in the human ECM. Therefore, hyaluronic acid is modified with a chemical functionality (thiolactones). The synthesis of these thiolactones is accomplished, and strategies for the attachment to hyaluronic acid are elaborated. The tholactones bound the the hyaluronic acid backbone offer the possibity to bind peptides and proteins such as binding/growth factors directly to the hyaluronic acid for cell signaling and stimulation of growth. The thiolactones have often been used for the modification of large proteins or enzymes, because they show good reactivity towards the amino groups of respective proteins. In a second reaction step, either guest or host molecules for cucubituril chemistry are reacted with the thiols (released from the thiolactone after ring-opening at the first reaction step). Cucuriturils are macrocyclic molecules, which can host certain positively charged guest molecules to form stable inclusion complexes. The interaction of host and guest proceeds in a non-covalent manner. This reaction strategy will allow (i) the covalent incorporation of growth/binding factors, drug agents and peptides/proteins to the hyaluronic acid and (ii) the non-covalent cross-linking. The latter delivers a material which is extremely malleable and, through shape remodeling, maintains high surface area contact with a surface of interest. Thus, spacial adaption to the individual morphology of the wound is possible. Prior to this final application, the embedding and proliferation of healthy cells in this gel as 3D scaffold is investigated and tuned to favour the thriving and growth of the used cells. In our approach, this material can substitute the defective ECM and promote the embedded cells to remodel and regenerate naturally occuring ECM components. As the healing process is re-boosted, the artificial ECM will be slowly degraded and replaced by the body's own.