Multi-Domain Self-Assembled Gels: From Multi-Component Materials to Spatial and Temporal Control of Multi-Component Biology

干细胞是所有其他类型细胞的前体细胞，为医学的未来开辟了全新的可能性，因为它们可以被鼓励转化为不同类型的有用生长组织。特别是，干细胞技术提供了促进关节修复、神经组织再生、骨重建和体内心血管修复的潜力。更复杂的，也是潜在的价值，是使用干细胞体外培养整个器官，适合移植到病人体内。这可能会满足许多等待死亡的患者对器官的未满足需求。此外，这将提供由于使用干细胞而将针对患者的免疫系统定制的器官，从而防止器官排斥，并因此避免与抗排斥药物相关的巨额成本。该项目探索了一类新的软凝胶相材料，它将能够以比目前更精确和复杂的方式指导和控制组织生长。我们将创建多域凝胶，其中材料的不同区域具有不同的化学成分，因此具有不同的特性。因此，生长的生物组织在材料的不同领域会有不同的表现。虽然创造与组织生长相容的简单凝胶相对简单，但为了指导干细胞在材料的不同区域做不同的事情而对多个组件进行图案化要困难得多。已经朝着使用聚合物凝胶来图案化用于组织生长的凝胶的目标取得了进展，但是我们的方法利用了自组装小分子胶凝剂，其具有更可编程和响应更快的潜力。光将用于图案化凝胶组装，将我们的技术与已建立的聚合物凝胶相结合，以创建具有刚性和柔性域的连贯图案化材料。预计这种材料将鼓励干细胞分化成不同类型-例如，在较硬的区域上分化为骨骼，在较软的区域上分化为脂肪。生物活性剂，如组织生长因子，将被纳入我们的新材料的特定领域。这些试剂的受控释放将能够影响生长的组织-原则上，这可以通过空间和时间控制来实现。通过这种方式，生长中的细胞在特定位置的选定时间暴露于特定刺激。导电单元也将嵌入到特定的凝胶结构域中，使得导电通路可以仅在凝胶的特定区域中组装。我们预计，这些传导通路将使生长中的组织培养物能够在选定的时间点以选择性的方式被电刺激--潜在地鼓励细胞以独特和可控的方式发育。多域凝胶的开发具有高度的创新性，在这个项目中需要解决一些重要的挑战。基本的理解将发展和控制在一个单一的材料中的多个组件将实现。将活性剂掺入多结构域凝胶中用于空间和时间控制释放，以及在这种凝胶内开发传导途径以前从未实现过。因此，该项目构成了多域凝胶技术的一个阶段性变化。我们相信这种方法可能会彻底改变组织工程的方法，我们将展示其潜力。采用软材料的超分子理解，以控制它们与活性剂和在其直接环境中生长的生物有机体相互作用的方式，使定向组装的EPSRC化学“大挑战”远远超出其当前的化学状态-通过使用超分子化学的原理与生命系统生物学进行交互。

Stem cells - cells which are precursor cells to all other types of cells - open up radical new possibilities for the future of medicine as they can be encouraged to convert into different types of useful growing tissue. In particular, stem cell technology offers potential to encourage joint restoration, nerve tissue regeneration, bone reconstruction and cardiovascular repair in vivo. More complex, and potentially valuable, is the use of stem cells to grow whole organs ex vivo, suitable for transplantation into patients. This would potentially satisfy the unmet need for organs faced by many patients, who die waiting. Further, this would provide organs which, because of the use of stem cells, will be tailored to the patient's immune system preventing organ rejection, and hence avoiding the massive cost associated with anti-rejection medication. This project explores a new class of soft gel-phase materials which will be able to direct and control tissue growth in more precise and sophisticated ways than can currently be achieved. We will create multi-domain gels in which different regions of the material have different chemical compositions and hence different properties. As a result, growing biological tissue will behave differently in different domains of the material. Although creating simple gels which are compatible with tissue growth is relatively straightforward, patterning multiple components in order to direct stem cells to do different things in different regions of the material is much harder. Progress has been made towards the goal of patterning gels for tissue growth using polymer gels, but our approach makes use of self-assembling small-molecule gelators, which have the potential to be much more programmable and responsive. Light will be used to pattern gel assembly, combining our technology with established polymer gels to create coherent patterned materials which have both rigid and soft domains. It would be expected that such materials would encourage stem cells to differentiate into different types - e.g. bone on the harder domains and fat on the softer domains. Biologically active agents, such as tissue growth factors, will then be incorporated within specific domains of our new materials. The controlled release of these agents will then be able to influence the growing tissue - in principle, this can be achieved with both spatial and temporal control. In this way, the growing cells are exposed to specific stimuli at chosen times in specific locations. Conducting units will also be embedded into specific gel domains, so that conducting pathways can be assembled only in specific regions of the gel. We anticipate that these conducting pathways will enable parts of growing tissue culture to be electrically stimulated in a selective manner at a chosen time point - potentially encouraging cells to develop in unique and controllable ways.The development of multi-domain gels is highly innovative and a number of important challenges will need to be solved in this project. Fundamental understanding will develop and control over multiple components within a single material will be achieved. Incoporating active agents into multi-domain gels for spatially and temporally controlled release, and the development of conducting pathways within such gels have never previously been achieved. As such, this project constitutes a step-change in multi-domain gel technology. We believe this approach may revolutionise approaches to tissue engineering and we will demonstrate its potential. Employing a supramolecular understanding of soft materials in order to control the ways in which they interact both with active agents, and biological organisms growing in their direct environment, moves the EPSRC Chemistry 'Grand Challenge' of Directed Assembly well beyond its current chemical state-of-the art by using the principles of supramolecular chemistry to interface with living systems biology.