A dynamic biomaterial-ligand tethering strategy for tissue engineering

使用生物材料来驱动受损生物组织的修复、再生或再生，有可能彻底改变疾病的治疗。那些能够通过附着的肽、蛋白质和碳水化合物向细胞和组织提供强大的生化信号的材料，在控制再生方面特别有效。然而，由于控制这些信号事件的困难，目前我们很难培养出成熟的、功能齐全的组织用于临床。虽然大自然依赖于严密控制的复杂网络，动态信号来驱动修复，但这与合成材料提供的静态信号形成鲜明对比。因此，在这个博士项目中，我们的目标是开发新的化学方法，使肽和蛋白质可逆地附着在生物材料支架上。我们将特别关注新的缀合化学方法的开发，使蛋白质通过稳定的亚胺共价附着在材料表面。我们将确定允许随后的蛋白质在生物相容性条件下裂解的条件，同时再生材料表面上的原始反应基团。通过这样做，我们将能够连接第二个信号蛋白，它本身可以被切割，允许蛋白质呈递的迭代循环。这将代表生物材料架构的一个重大进步，使我们朝着模拟自然组织的复杂性迈出了重要一步。实现这一目标的关键是优化潜在的共轭化学，需要精确理解反应平衡和动力学，我们将使用光物理和材料化学技术的结合进行研究。然后，我们将继续应用我们的新化学方法设计新的软骨再生生物材料，通过顺序呈现生长因子信号蛋白，驱动组织发育，从细胞生长到组织成熟。

The use of biomaterials to drive the repair, regrowth, or regeneration of damaged biologicaltissue has the potential to revolutionise the treatment of disease. Materials that can presentcells and tissues with powerful biochemical signals, through attached peptides, proteins, andcarbohydrates, are particularly effective at controlling regeneration. However, at present westruggle to grow mature, fully-functioning tissues that can be used in the clinic due to thedifficulty of controlling these signalling events. While nature relies on intricate networks oftightly controlled, dynamic signalling to drive repair, this is in stark contrast to the staticsignals provided by synthetic materials. In this PhD project, we therefore aim to develop newchemistries that allow the reversible attachment of peptide and proteins to biomaterialscaffolds.We will particularly focus on the development of novel conjugation chemistries that allowproteins to be covalently attached to material surfaces via stabilised imines. We will identifyconditions that allow subsequent cleavage of the protein under biocompatible conditions,while regenerating the original reactive groups on the material surface. By doing so, we willenable the attachment of a second signalling protein that can itself be cleaved, allowingiterative cycles of protein presentation. This would represent a major advance in biomaterialschemistry, allowing us to take a major step towards mimicking the complexity of naturaltissues. Key to this goal is the optimisation of the underlying conjugation chemistry, requiringprecise understanding of the reaction equilibria and kinetics which we will study using acombination of photo-physical and materials chemistry techniques. We will then go on toapply our novel chemistries in the design of new biomaterials for cartilage regeneration, bysequentially presenting growth factor signalling proteins that drive tissue development fromcell growth through to tissue maturation.