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1部分：非技术总结大脑对人类的经验至关重要，但是社会不了解影响脑细胞存活和生长的许多因素。水凝胶生物材料可以帮助解决这个问题，因为它们的行为像人体组织一样，使研究人员可以在简化的实验室环境中对健康，患病或受伤的组织进行建模，并更好地了解人类健康。虽然水凝胶可以模仿多种组织，但模仿脑组织的水凝胶可用于生长源自大脑的细胞。该建议旨在使新水凝胶与人体组织相似，因为它们由相同的原材料组成，这些原材料由天然氨基酸制成，将它们串在一起的块中简单而便宜。由这些氨基酸构建块制备的水凝胶看起来和作用像脑组织，其行为由块和块模式的选择控制。右氨基酸序列可能会导致彼此找到并自动组装成三维结构的块，例如设计师的微观城市，该城市的建立自身。这些可互换的块可以以不同的形状融合在一起，确定水凝胶的表现更像液体还是固体，以及其适合生长细胞的适合性。水凝胶属性将在实验室以及计算机模拟中进行研究，以创建和测试最佳的块组合。鉴于块的多功能性及其组装方式，预计该策略会导致新的水凝胶材料系列，可以在伤害后自动重建自己。最佳模拟脑组织的水凝胶将用于指导脑衍生细胞的行为并控制细胞生长。这项研究将通过培训生物学，材料科学，计算机科学，工程和神经科学的学生通过实验室和课程活动来影响教育。一项集中在付费高中和大学实习的外展计划将培养工程学的利益，提供研究技能并通过研究和科学传播在不同的学生群体中建立经验。第2部分：技术摘要以实现功能性肽生物材料的技术概述是对分子和循环特征的理解，这些特征是对组成和构建互动的理解。这项研究集中于在细胞兼容条件下组装的新肽家族的合理设计和研究，这些肽属于稳健的细胞外基质（ECM）水凝胶，具有驱动细胞命运的结构和生物活性。该项目旨在开发一个新的短，快速胶粘，自我修复的肽，这些肽模仿各种组织。使用简短的5-氨基酸序列作为凝胶剂，可以简化合成并最大化适应性。这些新肽将解决现有的肽水凝胶缺陷，即1）胶凝机制，导致敏感细胞的存活不良，如神经元和神经干细胞，以及2）低机械刚度。所提出的方法将涉及将神经细胞作为测试床的细胞兼容封装。为了改善设计和发现过程，将与实验方法集成一个计算框架。这种设计策略可以改变生物材料的发展，并应对表征生物矩阵中发生的动态过程的挑战。计算模拟将提供对肽组装的理解，并更有效地识别和预测候选肽的候选物，这些肽可以综合地组装成3D物理水凝胶。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肽。该研究项目的结果将包括有利于生理凝胶化的氨基酸序列，肽组装的原子分子动态模型以及适合神经细胞培养的合规性动态基质。凝胶在生理上相关的水凝胶将显着提高细胞培养和研究的易感性和功效。该项目将为社会经济挑战的学生创建全面的高中研究实习计划，并扩大他们的职业和大学机会。作为该项目的一部分，PI将跨培训博士生，工作学生的大学生以及生物材料合成，分子模拟，干细胞生物学和神经组织工程的高中实习生。该奖项反映了NSF的法定任务，并被认为是通过基金会的知识分子优点和广泛的影响来通过评估来进行评估的法定任务。