CAREER: Spatiotemporally addressable hydrogel biomaterials as tools for investigating fibroblast mechanobiology

职业：时空可寻址水凝胶生物材料作为研究成纤维细胞力学生物学的工具

• 批准号: 1941401
• 负责人: Chelsea Magin
• 金额: $ 50.18万
• 依托单位: University of Colorado at Denver
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1941401&HistoricalAwards=false
• 关键词: CAREER; Spatiotemporally; addressable; hydrogel; biomaterials

PART 1: NON-TECHNICAL SUMMARYUsing principles of materials science, materials that closely match the properties of living tissue will be developed. The materials will enable studies of fibrosis, a condition resulting in scarring of the lung, heart, and other tissues, accounting for over one third of global deaths per year. Despite great efforts to study the cellular processes that cause fibrosis, the conditions which lead to fibrosis are still poorly understood. While most studies are typically performed in a Petri dish, recent discoveries show that these flat, stiff dishes cause unintended reactions that produce misleading results. To overcome this limitation, the project aims to create three-dimensional (3D) models of both healthy and scarred lung tissue, using new materials with mechanical properties that can be dynamically changed to match real pulmonary tissues. The materials will combine a synthetic soft plastic with proteins derived from lung tissue. The materials developed will be sensitive to light, changing their stiffness upon illumination, allowing spatial patterning of material stiffness. These improved 3D models will be used to study cell responses in a more natural environment. These models will be used to test how cells respond to changes in their environment, like stiffening from scarring in fibrotic lung disease, to better understand the cellular origins of these conditions. An educational curriculum to engage a range of students from middle to graduate school in the translational aspects of biotechnology and biomedical engineering is proposed to further complement these fundamental biomaterial-based studies.PART 2: TECHNICAL SUMMARYThe overarching goal of this proposal is to design and synthesize hydrolytically stable, dynamically tunable hybrid hydrogel biomaterials. Using fundamental principles of materials science and engineering, photo-addressable hybrid biomaterial platforms that will mimic critical aspects of fibrotic disease progression in vitro will be developed. A new class of photo-addressable poly(ethylene glycol) (PEG)-based hybrid hydrogels will be synthesized. These innovative biomaterials will combine a phototunable PEG backbone with decellularized ECM (dECM) from healthy or diseased lung tissue, to decouple fibrotic tissue composition from subsequent changes in mechanical properties. The chemistries and multi-stage reaction schemes introduced will provide unprecedented reversible spatiotemporal control over microenvironmental mechanical properties with submicron resolution independent of composition. The materials developed will allow studying the influence of cell-matrix interactions on fibroblast mechanobiology in vitro. These materials will improve our understanding of the fundamental cellular and molecular processes underlying chronic diseases such as pulmonary fibrosis. Improved in vitro models that reproduce key aspects of human physiology, including the dimensionality, dynamic heterogeneity, and mechanical properties of the extracellular matrix (ECM) composition, will facilitate studies of critical cell-matrix interactions underlying fibrotic disease. These biomaterial systems will allow answers to fundamental questions related to fibroblast mechanobiology to be answered: 1) How do pathological changes in matrix composition and modulus influence the phenotype of encapsulated fibroblasts? 2) Which of these inputs is the more potent driver of fibrosis, i.e., the best target for therapeutics? and 3) Are these phenotypic changes reversible? An educational curriculum to engage a range of students from middle to graduate school in the translational aspects of biotechnology and biomedical engineering is proposed to further complement these fundamental biomaterial-based studies. These research and educational objectives will advance knowledge and train the next generation of engineers and scientists. Sharing the results of this project across multiple platforms within local public schools and bioengineering courses will inspire teachers and students to use STEM-principles to solve problems in life sciences and healthcare.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： 非技术性总结利用材料科学的原理，将开发出与活组织特性紧密匹配的材料。这些材料将使纤维化的研究成为可能，纤维化是一种导致肺、心脏和其他组织瘢痕形成的疾病，占每年全球死亡人数的三分之一以上。尽管对导致纤维化的细胞过程进行了大量研究，但导致纤维化的条件仍然知之甚少。虽然大多数研究通常是在皮氏培养皿中进行的，但最近的发现表明，这些扁平、僵硬的培养皿会引起意想不到的反应，从而产生误导性的结果。为了克服这一限制，该项目旨在使用具有机械特性的新材料创建健康和疤痕肺组织的三维（3D）模型，这些材料可以动态改变以匹配真实的肺组织。这些材料将把一种合成的软塑料与来自肺组织的蛋白质结合起来。开发的材料将对光敏感，在光照下改变它们的硬度，允许材料硬度的空间图案。这些改进的3D模型将用于研究更自然环境中的细胞反应。这些模型将用于测试细胞如何应对其环境的变化，例如纤维化肺病中疤痕的硬化，以更好地了解这些疾病的细胞起源。提出了一个教育课程，使从中学到研究生院的一系列学生参与生物技术和生物医学工程的转化方面，以进一步补充这些基本的生物材料为基础的研究。 技术概述本提案的首要目标是设计和合成水解稳定的、动态可调的杂化水凝胶生物材料。利用材料科学和工程的基本原理，将开发出模拟体外纤维化疾病进展关键方面的光寻址混合生物材料平台。将合成一类新的光寻址聚（乙二醇）（PEG）为基础的杂化水凝胶。这些创新的生物材料将结合联合收割机的光可调PEG骨干与脱细胞ECM（dECM）从健康或患病的肺组织，解耦纤维化组织组成的后续变化的机械性能。引入的化学和多阶段反应方案将提供前所未有的可逆时空控制微环境的机械性能与亚微米分辨率独立的组合物。开发的材料将允许研究细胞-基质相互作用对体外成纤维细胞机械生物学的影响。这些材料将提高我们对慢性疾病（如肺纤维化）的基本细胞和分子过程的理解。改进的体外模型，再现人体生理学的关键方面，包括细胞外基质（ECM）组成的维度，动态异质性和机械性能，将促进关键的细胞-基质相互作用的纤维化疾病的研究。这些生物材料系统将允许回答与成纤维细胞机械生物学相关的基本问题：1）基质组成和模量的病理变化如何影响包封的成纤维细胞的表型？2)这些输入中的哪一个是纤维化的更有力的驱动因素，即，治疗的最佳靶点这些表型变化是可逆的吗？一个教育课程，从事从中学到研究生院的学生在生物技术和生物医学工程的翻译方面提出了进一步补充这些基本的生物材料为基础的研究。这些研究和教育目标将促进知识和培养下一代工程师和科学家。通过在当地公立学校和生物工程课程的多个平台上分享该项目的成果，将激励教师和学生使用STEM原则解决生命科学和医疗保健领域的问题。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Evaluating How Exposure to Scientific Role Models and Work-Based Microbadging Influences STEM Career Mindsets in Underrepresented Groups

评估接触科学榜样和基于工作的微徽章如何影响代表性不足群体的 STEM 职业心态

• DOI: 10.1007/s43683-022-00096-x
• 发表时间: 2023
• 期刊: Biomedical Engineering Education
• 作者: Davis-Hall, Duncan;Farrelly, Laura;Risteff, Melissa;Magin, Chelsea M.
• 通讯作者: Magin, Chelsea M.

Clickable decellularized extracellular matrix as a new tool for building hybrid-hydrogels to model chronic fibrotic diseases in vitro.

• DOI: 10.1039/d0tb00613k
• 发表时间: 2020-08-21
• 期刊: Journal of materials chemistry. B

Alveolar epithelial cells and microenvironmental stiffness synergistically drive fibroblast activation in three-dimensional hydrogel lung models.

• DOI: 10.1039/d2bm00827k
• 发表时间: 2022-12-06
• 期刊: BIOMATERIALS SCIENCE
• 影响因子: 6.6
• 作者: Caracena, Thomas;Blomberg, Rachel;Hewawasam, Rukshika S.;Fry, Zoe E.;Riches, David W. H.;Magin, Chelsea M.
• 通讯作者: Magin, Chelsea M.