Expanding the Functionality of Engineered Extracellular Matrices

项目摘要 尽管基于水凝胶的材料构成了数十亿美元的市场，但药物的商业应用仍然是一个挑战。 交付和再生医学是非常有限的。水凝胶已经引起了强烈的兴趣， 细胞外基质（ECM）模拟物由于其可定制的渗透性、力学和降解性，但其 该领域的临床应用很大程度上依赖于生物材料如蛋白质。虽然取得了一些成功， 由于这些天然来源的材料与天然来源的ECM接触，因此这些天然来源的材料通常受到长期监管的限制。 由于可能与其他生物制剂发生反应，批准时间表。合成材料因此具有吸引力 由于其已知的化学成分，但其使用的挑战在于缺乏复杂性， 与生物系统相比，这意味着在临床上缺乏疗效。因此，这一目标 我们的研究实验室的建议是将工具箱扩展到构建复杂性和功能， 通过使用动态化学和基于单体序列的合成水凝胶生物材料 战略布局这种策略从自然界中获得了很多灵感，如生物聚合物的结构和功能 它们的氨基酸或核苷酸的精确位置。此外，细胞能够重塑， 随着时间的推移重新配置自然ECM。这两个特性都被证明是很难工程化的 合成网络因此，我们未来五年的目标是：1）开发具有可逆性的水凝胶， 交联来定量设计可重构矩阵，2）开发合成的序列控制的接头， 控制水凝胶性质（例如，力学、降解、活性）使用类多肽，以及3）联合收割机 开发用于组织工程的自组装结构的方法。我们相信我们的目标将有助于 在再生医学、治疗输送和药物组织临床前模型中的广泛应用 发展此外，我们预计，改变目前水凝胶思维模式的潜力， 生物材料的设计是高，我们的工作将揭示生物过程的细胞基质 交互.由于这些原因，这项工作非常适合R35最大化研究者研究奖 早期调查员。

PROJECT ABSTRACT Although hydrogel-based materials constitute a multibillion-dollar market, commercial applications for drug delivery and regenerative medicine are extremely limited. Hydrogels have garnered intense interest as extracellular matrix (ECM) mimics due to their tailorable permeability, mechanics, and degradability, yet their clinical use in this area largely depends on biological materials such as proteins. Although some success has been met with naturally-derived ECM, these naturally derived materials are often limited by long regulatory approval timelines due to the potential to react with other biologics. Synthetic materials are therefore attractive due to their known chemical compositions, but the challenge with their use lies in the lack of complexity as compared to biological systems, which translates to a lack of efficacy in the clinic. Hence, the goal of this proposal, and of our research lab, is to expand the toolbox for building complexity and functionality into synthetic hydrogel biomaterials by using dynamic chemistries and monomer sequence-based strategies. This strategy takes much inspiration from nature, as the structure and function of biological polymers arise from the precise placement of their amino acids or nucleotides. In addition, cells are able to remodel and reconfigure the natural ECM over time. Both of these characteristics have proven difficult to engineer into synthetic networks. Hence, our goals over the next five years are to 1) develop hydrogels with reversible crosslinks to quantitatively design reconfigurable matrices, 2) develop synthetic sequence-controlled linkers to control hydrogel properties (e.g., mechanics, degradation, activity) using polypeptoids, and 3) combine these approaches to develop self-assembled constructs for tissue engineering. We believe our goals will be useful for broad applications in regenerative medicine, therapeutic delivery, and preclinical models of tissue for drug development. In addition, we anticipate that the potential to alter current modes of thinking in hydrogel and biomaterial design is high, and that our work will shed insight to the biological processes underlying cell-matrix interactions. For these reasons, this work is well suited for the R35 Maximizing Investigators' Research Award for Early Stage Investigators.