Expanding the Functionality of Engineered Extracellular Matrices

扩展工程细胞外基质的功能

• 批准号: 10263226
• 负责人: Adrianne Rosales
• 金额: $ 37.27万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10263226
• 关键词: Amino Acids; Area; Award; Base Sequence; Biocompatible Materials; Biological; Biological Process; Breathing; Cell Culture Techniques; Cells; Characteristics; Chemicals; Chemistry; Clinic; Clinical; Drug Delivery Systems; Engineering; Extracellular Matrix; Goals; Hydrogels; Mechanics; Nature; Nucleotides; Permeability; Polymers; Pre-Clinical Model; Property; Proteins; Regenerative Medicine; Research; Research Personnel; Structure; Therapeutic; Thinking; Time; TimeLine; Tissue Engineering; Tissue Model; Translating; Work; base; biological systems; commercial application; crosslink; design; drug development; insight; interest; monomer; scaffold; success

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.

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 分娩和再生医学极其有限。水凝胶引起了人们的浓厚兴趣 细胞外基质（ECM）由于其可定制的渗透性、力学和可降解性而模仿，但它们的 该领域的临床应用很大程度上取决于蛋白质等生物材料。尽管取得了一些成功 当遇到天然来源的 ECM 时，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，因此需要批准时间表。因此合成材料很有吸引力 由于它们的化学成分已知，但其使用的挑战在于缺乏复杂性，因为 与生物系统相比，这意味着临床上缺乏功效。因此，本次活动的目标 我们研究实验室的建议是将工具箱扩展为将复杂性和功能构建到 使用动态化学和基于单体序列的合成水凝胶生物材料 策略。这种策略从大自然中汲取了很多灵感，因为生物聚合物的结构和功能 源于其氨基酸或核苷酸的精确位置。此外，细胞能够重塑和 随着时间的推移重新配置自然 ECM。事实证明，这两个特性都很难实现 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 交联以定量设计可重构矩阵，2) 开发合成的序列控制连接体 使用多肽控制水凝胶特性（例如力学、降解、活性），并且 3) 将这些特性结合起来 开发组织工程自组装结构的方法。我们相信我们的目标将有助于 在再生医学、治疗递送和药物组织临床前模型中的广泛应用 发展。此外，我们预计水凝胶和水凝胶有可能改变当前的思维模式 生物材料设计水平很高，我们的工作将深入了解细胞基质的生物过程 互动。由于这些原因，这项工作非常适合获得 R35 最大化研究者研究奖 对于早期研究人员。