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

可注射支架可以在支架中均匀分布细胞和分子信号，并可以直接注射到形状和大小不规则的空洞中。大多数研究都是关于可注射支架的开发，用于骨和软骨组织的修复，也有一些用于角膜伤口的愈合。最具挑战性的问题是寻找合适的材料，使其能够原位固化形成三维支架。通过光聚合进行的交联有许多优点，包括生理条件下的快速聚合。目前，用于组织工程的合成聚合物大多为线型结构，但存在溶液性能差、交联性不均一、聚合物改性控制有限等问题。树枝状聚合物由于其三维结构而具有独特的性质，如良好的溶解性、低粘度和高官能度。格林斯塔夫合成了一种可光交联的树枝状大分子，用于角膜伤口愈合、密封剂和软骨修复。然而，树枝状大分子的制备必须通过溶剂密集型和多步骤合成路线，最重要的是，很难定制树枝状大分子的组成和结构以适应广泛的特殊应用。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一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大分子的合成障碍吗？目前超支化聚合物的合成策略要么需要特殊的单体(ABN或AB*亚聚体)，要么只能得到结构可控、支化程度较低的聚合物。因此，到目前为止，这类材料在医学上的应用还很难考虑。我已经意识到，使用更易获得的单体合成具有可控链结构和高度支化程度的超支化材料方面的突破，可以促进一种全新的方法应用于生物和生物医学应用。最近，诺丁汉团队开发了一种失活增强型ATRP方法，该方法显著开拓了这一领域，允许简单使用容易获得和廉价的多功能乙烯基单体来合成支化度高、相对分子质量和链结构可控的超支化聚合物。这种超支化聚合物材料在生物和生物医学应用中可能是极其重要的。此外，产品还带有多种反应性官能团(如双键和卤素官能团)，可通过短链封端、有机分子和末端接枝进行后官能化和修饰以用于特定应用。通过这些改性，可以方便地定制超支化聚合物的功能、极性、溶解性和柔韧性等材料性质，以满足应用要求。通过光刺激，聚乙烯基官能团可作为交联点形成三维结构。我的目标是利用最近开发的简易合成策略-失活增强ATRP-设计和合成一系列用于生物和生物医学应用的量身定制的新型超支化聚合物。这项建议的目标是开发新型光交联型超支化聚合物作为软骨组织修复的可注射支架材料。来自目标超支化聚合物的水凝胶将获得更好的生物响应，具有定制的机械性能、整合素介导的细胞黏附和控制生长因子的释放。这项研究将包括三项任务和一些子任务，详见支助案例。

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.