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Engineering the design of self-assembling, shear-thinning pentapeptide hydrogels to promote neural cell growth and differentiation

自组装、剪切稀化五肽水凝胶的工程设计可促进神经细胞生长和分化

基本信息

批准号：
2104723
负责人：
Kyle Lampe
金额：
$ 54.87万
依托单位：
University of Virginia Main Campus
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2104723&HistoricalAwards=false
关键词：
Engineering design self assembling shear

项目摘要

PART 1: NON-TECHNICAL SUMMARYThe brain is central to the human experience, but society poorly understands many of the factors that impact brain cell survival and growth. Hydrogel biomaterials can help address this problem because they behave like human tissues, allowing researchers to model healthy and diseased or injured tissue in a simplified lab setting and better understand human health. While hydrogels can emulate a wide variety of tissues, hydrogels that emulate brain tissue are useful to grow cells derived from the brain. This proposal aims to make new hydrogels similar to human tissue because they are composed of the same raw materials, built from natural amino acids strung together in blocks that are simple and cheap to make. Hydrogels prepared from these amino acid building blocks look and act like brain tissue with behavior controlled by the choice of block and block pattern. The right amino acid sequence may result in blocks that find each other and automatically assemble into a 3-dimensional structure, like a designer microscopic city which builds itself. These interchangeable blocks can come together in different shapes, determining whether the hydrogel behaves more like a liquid or a solid, as well as its suitability for growing cells. Hydrogel properties will be studied in the lab as well as in computer simulations to create and test the best possible block combinations. Given the versatility of blocks and ways in which they assemble, this strategy is expected to result in a new family of hydrogel materials that can automatically rebuild themselves after damage. The hydrogels that best mimic brain tissue will be used to guide the behavior of brain-derived cells and control cell growth. This research will impact education by training students in biology, materials science, computer science, engineering, and neuroscience through laboratory and curricular activities. An outreach program centered on paid high school and college internships for underprivileged youth will nurture interests in engineering, provide research skills, and build experience in diverse student groups through research and science communication.PART 2: TECHNICAL SUMMARYIntegral to realizing functional peptide biomaterials is an understanding of the molecular and macroscopic features that govern assembly, morphology, and biological interactions. This research centers on the rational design and investigation of a new family of peptides that assemble under cytocompatible conditions into a robust extracellular matrix (ECM) hydrogel with structure and bioactivity that drive cell fate. This project seeks to develop a new family of short, rapidly gelling, self-healing peptides that emulate a wide variety of tissues. Using short, 5-amino-acid sequences as gelators simplifies synthesis and maximizes adaptability. These new peptides will address existing peptide hydrogel deficiencies, namely 1) gelation mechanisms that lead to poor survival of sensitive cells, like neurons and neural stem cells, and 2) low mechanical stiffnesses. The proposed approach will involve cytocompatible encapsulation of neural cells as a test bed. To improve the design and discovery process, a computational framework will be integrated with the experimental approach. This design strategy could transform biomaterials development and address the challenges of characterizing the dynamic processes that occur in biological matrices. Computational simulations will provide understanding of peptide assembly and more efficiently identify and predict peptide candidates that will cytocompatably assemble into 3D physical hydrogels. The primary goal is to create, model, and characterize peptides that gel under physiological conditions and drive neural stem cell differentiation. Outcomes of this research project will include amino acid sequences conducive to physiological gelation, an atomistic molecular dynamic model of peptide assembly, and a compliant, dynamic matrix appropriate for neural cell culture. Physiologically relevant hydrogels that gel on-demand will dramatically improve the ease and efficacy of cell culture and study. This project will create a comprehensive high school research internship program for socioeconomically challenged students, and broaden their career and college opportunities. As part of this project the PI will cross train PhD students, work-study college students, and high school interns in biomaterials synthesis, molecular simulations, stem cell biology, and neural tissue engineering.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

第一部分：非技术总结大脑是人类体验的中心，但社会对影响脑细胞生存和生长的许多因素知之甚少。水凝胶生物材料可以帮助解决这个问题，因为它们的行为类似于人体组织，使研究人员能够在简化的实验室环境中对健康和患病或受伤的组织进行建模，并更好地了解人类健康。虽然水凝胶可以模拟各种各样的组织，但模拟脑组织的水凝胶对于培养来自大脑的细胞是有用的。这项提议旨在制造类似于人体组织的新型水凝胶，因为它们是由相同的原材料组成的，这些原料是由天然氨基酸串在一起制成的，制造起来既简单又便宜。由这些氨基酸构建块制备的水凝胶看起来和行为都像脑组织，其行为受块和块模式的选择控制。正确的氨基酸序列可能会产生找到彼此的区块，并自动组装成一个三维结构，就像一个设计的微型城市建造自己一样。这些可互换的块可以不同的形状结合在一起，决定水凝胶的行为更像液体还是固体，以及它是否适合生长细胞。将在实验室和计算机模拟中研究水凝胶的特性，以创造和测试可能的最佳区块组合。考虑到积木及其组装方式的多功能性，这一策略有望导致一种新的水凝胶材料家族，这种材料可以在损坏后自动重建。最能模拟脑组织的水凝胶将被用来指导脑源性细胞的行为并控制细胞生长。这项研究将通过实验室和课程活动培训学生在生物、材料科学、计算机科学、工程和神经科学方面的知识，从而影响教育。一个以贫困青年的高中和大学带薪实习为中心的外展计划，将通过研究和科学交流培养对工程的兴趣，提供研究技能，并在不同的学生群体中建立经验。第2部分：技术总结实现功能性多肽生物材料的关键是了解支配组装、形态和生物相互作用的分子和宏观特征。这项研究的核心是合理设计和研究一种新的多肽家族，这些多肽在细胞相容的条件下组装成具有决定细胞命运的结构和生物活性的强大的细胞外基质(ECM)水凝胶。该项目旨在开发一种新的短的、快速凝胶的、自我修复的多肽家族，模拟各种组织。使用短的5-氨基酸序列作为胶凝剂简化了合成并最大限度地提高了适应性。这些新的多肽将解决现有的多肽水凝胶缺陷，即1)导致敏感细胞(如神经元和神经干细胞)存活不良的凝胶机制，以及2)低机械硬度。建议的方法将包括对神经细胞进行细胞兼容的封装作为试验床。为了改进设计和发现过程，将把计算框架与实验方法结合起来。这一设计策略可以改变生物材料的发展，解决描述生物基质中发生的动态过程的挑战。计算模拟将提供对多肽组装的理解，并更有效地识别和预测将以细胞相容性组装成3D物理水凝胶的多肽候选。主要目标是创建、建模和表征在生理条件下凝胶并驱动神经干细胞分化的多肽。这一研究项目的成果将包括有利于生理胶凝的氨基酸序列，多肽组装的原子分子动力学模型，以及适合神经细胞培养的顺应性、动态基质。按需凝胶的生理相关水凝胶将极大地提高细胞培养和研究的简便性和有效性。该项目将为社会经济困难的学生创建一个全面的高中研究型实习计划，并拓宽他们的职业和大学机会。作为该项目的一部分，PI将对博士生、勤工俭学大学生和高中实习生进行生物材料合成、分子模拟、干细胞生物学和神经组织工程方面的交叉培训。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。