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

可注射支架可以提供细胞和分子信号在整个支架内均匀分布的可能性，并且可以直接注射到不规则形状和大小的空腔中。大多数研究都是用于骨和软骨组织修复的可注射支架，还有一些是用于角膜伤口愈合的。最具挑战性的问题是找到合适的材料，可以在原地固化，形成三维支架。通过光聚合交联提供了许多好处，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大多为线性结构，但存在溶液性能差、交联不均匀、聚合物改性控制有限等问题。树突状聚合物由于其三维结构，具有良好的溶解度、低粘度和高功能等独特性能。Grinstaff合成了一种光交联树突状分子，用于角膜伤口愈合密封剂和软骨修复。然而，树状大分子的制备必须通过溶剂密集和多步骤的合成路线，最重要的是，很难定制树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，较少控制的枝状聚合物结构，可以通过一系列合成策略更容易地通过一步反应合成。这种超支化聚合物能否克服树状大分子的合成屏障？目前超支化聚合物的合成策略的局限性在于要么需要特殊的单体（ABn或AB*对映体），要么只能得到结构控制差、支化程度低的聚合物。因此，到目前为止，这种材料在医学上的应用还很难被考虑。我已经认识到，使用更容易获得的单体合成具有可控链结构和高度分支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，诺丁汉大学的研究小组开发了一种失活增强的ATRP方法，这一方法大大开辟了这一领域，并允许简单地使用现成的廉价多功能乙烯基单体来合成具有高度分支，分子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非常重要。此外，该产品具有多种活性官能团（例如双键和卤素官能团），可以通过短链、有机分子和末端接枝进行后官能团化和修饰，用于特定应用。通过这些修饰，可以方便地定制超支化聚合物的功能，极性，溶解度和柔韧性等材料性能，以满足应用要求。聚乙烯烃官能团在光刺激下可作为交联位点形成三维结构。我的目标是设计和合成广泛的定制，新型超支化聚合物，用于生物和生物医学应用，使用最近开发的简易合成策略，失活增强的ATRP。该建议的目标是开发新型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。由靶向超支化聚合物制成的水凝胶将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，从而实现更好的生物反应。研究将包括三个任务和一些子任务，如支持案例中详细介绍的。

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.