Novel Photocrosslinkable Hyperbranched Polymers for Injectable Scaffolds: Design, synthesis, characterisations and in vitro evaluation

可注射支架可以提供在整个支架中均匀分布细胞和分子信号的可能性，并且可以直接注射到具有不规则形状和尺寸的腔中。大多数研究都是关于骨和软骨组织修复的可注射支架的开发，还有一些用于角膜伤口愈合。最具挑战性的问题是找到合适的材料，可以在原位固化形成三维支架。经由光聚合的交联提供了许多益处，包括在生理条件下的快速聚合时间。目前，用于组织工程的合成聚合物多为线型结构，但其存在溶液性质差、交联不均匀、聚合物改性可控性差等问题。树枝状聚合物由于其三维结构而具有独特的性质，例如良好的溶解性、低粘度和高官能度。Grinstaff合成了一种用于角膜伤口愈合密封剂和软骨修复的可光交联树枝状聚合物。然而，树枝状大分子必须通过溶剂密集型和多步合成路线来制备，最重要的是，很难针对广泛的特殊应用定制树枝状大分子的组成和结构。相比之下，超支化聚合物，较少控制的树枝状聚合物结构，可以通过一系列合成策略通过单步反应更容易地合成。这种超支化聚合物的使用能克服树枝状聚合物的合成障碍吗？目前超支化聚合物的合成策略的局限性是需要特殊的单体（ABn或AB* inimer），和/或只能获得差的控制结构和低支化度的聚合物。因此，到目前为止，这种材料在医学应用中很难被考虑。我认识到，使用更容易获得的单体合成具有受控链结构和高度支化的超支化材料的突破可以促进其生物和生物医学应用的全新方法。最近，诺丁汉团队开发了一种去活化增强ATRP方法，其显著地开拓了该领域，并允许简单地使用容易获得且便宜的多官能乙烯基单体来合成具有高的支化度、受控的分子量和链结构。这种超支化聚合物材料对于生物和生物医学应用可能是极其重要的。此外，产品带有大量反应性官能团（例如双键和卤素官能团），可以通过短链封端、有机分子和末端接枝进行后官能化和改性以用于特定应用。通过这些改性，超支化聚合物的材料性能，如官能度、极性、溶解性和柔性，可以方便地定制以满足应用要求。聚乙烯基官能团可以作为光刺激的交联位点，形成三维结构。我的目标是设计和合成一个广泛的定制，新型超支化聚合物的生物和生物医学应用，使用最近开发的简易合成策略，失活增强ATRP。该提案的目标是开发新型可光交联超支化聚合物作为软骨组织修复的可注射支架材料。来自靶向超支化聚合物的水凝胶将实现更好的生物响应，具有定制的机械性能、整合素介导的细胞粘附和生长因子释放的控制。研究将包括三个任务和一些子任务，详见支持案例。

Injectable scaffolds can offer the possibility of homogeneously distributing cells and molecular signals throughout the scaffold, and can be injected directly into cavities with irregular shape and size. Most studies have been on the development of injectable scaffolds for bone and cartilage tissue repair, some others for corneal wound healing. The most challenging issue is to find suitable materials which can solidify in situ to form 3-D scaffolds. Crosslinking via photopolymerisation provides many benefits, including rapid polymerisation times under physiological conditions. At present, most synthetic polymers used in tissue engineering are linear structure, however, they suffer from poor solution properties, non-homogenous crosslinking properties and limited control of polymer modification. Dendritic polymers have unique properties, such as good solubility, low viscosity and high functionality, due to their 3-D architecture. Grinstaff synthesised a photocrosslinkable dendrimer for corneal wound healing sealant and cartilage repair. However, dendrimers have to be prepared by solvent-intensive and multi-step synthetic routes, most importantly, it is difficult to tailor the composition and structure of dendrimers for a wide range of special applications. By contrast, hyperbranched polymers, less controlled dendritic polymer architectures, can be synthesised more easily by a single-step reaction via a range of synthetic strategies. Could the use of such hyperbranched polymers overcome the synthetic barrier of dendrimers? The limitation of current synthetic strategies for hyperbranched polymers are either the need of special monomers (ABn or AB* inimer), and/or, only poor controlled structure and low degree of branching polymers can be obtained. Therefore, up till now, such materials are difficult to be considered in medical applications. I have recognised that a breakthrough in synthesis of hyperbranched materials with controlled chain structure and high degree of branching using more accessible monomers could facilitate a completely new approach to their biological and biomedical applications.Recently, the Nottingham team has developed a deactivation enhanced ATRP method, which opens up the field significantly and allows simple use of readily available and inexpensive multifunctional vinyl monomers to synthesise hyperbranched polymers with high degree of branching, controlled molecular weight and chain structure. Such hyperbranched polymer materials could be extremely important for biological and biomedical applications. Furthermore, the products carry a multitude of reactive functionalities (e.g. double bonds and halogen functional groups) that can be post-functionalised and modified for specific applications by end capping with short chains, organic molecules and terminal grafting. By these modifications, the material properties, such as functionality, polarity, solubility and flexibility of the hyperbranched polymers, can be conveniently tailored to meet the application requirements. The polyvinyl functional groups can be used as corsslinking sites by photo stimuli to form 3-D structure. My aim is to design and synthesise a broad spectrum of tailored, novel hyperbranched polymers for biological and biomedical applications using the recently developed facile synthetic strategy, deactivation enhanced ATRP. This proposal targets the development of novel photocrosslinkable hyperbranched polymers as injectable scaffold materials for cartilage tissue repair. The hydrogels from the targeted hyperbranched polymers will achieve better biological response with tailored mechanical properties, integrin-mediated cell adhesion and control of growth factor release. The research will include three tasks with some subtasks as detailed in the Case of Support.