CAREER: Dynamic biomimetic materials with multiscale structural complexity for understanding tissue fibrosis

ID: MPS/DMR/BMAT(7623) 1253906 PI: Kloxin， April ORG: University of delaware标题：用于理解组织纤维化的具有多尺度结构复杂性的动态仿生材料知识优点：理解细胞及其微环境之间复杂的相互作用，细胞外基质（ECM），对于设计新的治疗方法以减轻疾病进展或直接组织再生至关重要。仿生材料已经成为探索微环境信号在细胞行为中的作用的工具；然而，创造完全重现动态生物过程的材料仍然很困难。该提案解决了设计和应用材料的关键挑战，这些材料充分模拟了天然ECM的时空和多尺度复杂性，以确定调节组织稳态、疾病和修复的关键信号。例如，在对组织损伤或慢性损伤的反应中，成纤维细胞被激活成肌成纤维细胞，这是一种负责组织修复和ECM重塑的伤口愈合表型。肌成纤维细胞的调控不当和持续存在，通过尚未完全了解的机制，导致过量胶原的沉积和积累，组织硬化，最终纤维化。需要创新的工具来重建纤维化过程中发生的微环境变化，以识别肌成纤维细胞激活和持续的关键信号。为了解决这个问题，PI建议建立一种动态的、结构复杂的水凝胶，使用光介导的、多尺度的仿生和可调的反应化学物质的组合来模拟胶原组织修复和疾病进展的时间进化。目标是设计一个独特的三维（3D）水凝胶培养系统，捕获天然ECM的关键成分，包括纳米到亚微米尺度的原纤维，纳米尺度的整合素结合序列，以及时空进化的生物物理和生化特性，以了解肌成纤维细胞的激活和纤维化。为了实现这一目标，她建议：(1)创造具有可控生物物理和生化特性的水凝胶，模拟从纳米、亚微米到宏观尺度的多种尺寸的软组织；(2)以时空方式增加水凝胶模量并加入整合素结合肽以模拟纤维化进展；(3)确定在该模型系统内2D和3D培养中促进成纤维细胞激活的模量增加的幅度和速率。更广泛的影响：生物材料和生物工程有可能通过开发和应用新工具来解决复杂的健康相关问题，彻底改变我们对生物系统的理解和控制。然而，由于在中学和大学期间没有充分接触相关的工程概念以及教育和职业机会，学生对这些领域的知识往往有限。该提案的教育目标是创建一个全面的计划，以增加学生的供应，特别是代表性不足的群体，通过中学、大学和研究生阶段的新教育努力，参与和培训生物材料和生物工程。为了满足这些需求，PI将：(1)开发和实施生物材料和生物工程博物馆亭以及5-7年级学生家庭星期五和迷你营地；(2)通过科研实习指导高中生生物材料和生物工程；(3)在工程课程中开发新的生物材料与综合生物学课程。该信息亭将使我们的团队能够接触到大量不同的受众（5年内有10万名学生），而有针对性的教育项目将为从五年级到研究生院和继续教育的学生提供更深入的培训。将拟议的研究整合到这些针对中学和大学课程的教育计划中，将通过增加该领域工人的参与、培训和多样性，实现材料、工程和生物学界面的创新。

ID: MPS/DMR/BMAT(7623) 1253906 PI: Kloxin, April ORG: University of DelawareTitle: CAREER: Dynamic biomimetic materials with multiscale structural complexity for understanding tissue fibrosis INTELLECTUAL MERIT: Understanding the complex interplay between cells and their microenvironment, the extracellular matrix (ECM), is essential in designing new therapeutic approaches to mitigate disease progression or direct tissue regeneration. Biomimetic materials have emerged as tools to probe the role of microenvironment signals in cell behavior; however, creating materials that fully recapture dynamic biological processes remains difficult. This proposal addresses a critical challenge in designing and applying materials that adequately mimic the spatiotemporal and multisize scale complexity of the native ECM to determine the key signals that regulate tissue homeostasis, disease, and repair. For example, in response to tissue injury or chronic insults, fibroblasts activate into myofibroblasts, a wound healing phenotype responsible for tissue repair and ECM remodeling. Misregulation and persistence of myofibroblasts, through mechanisms that are not fully understood, leads to deposition and accumulation of excess collagen, tissue stiffening, and ultimately fibrosis. Innovative tools are needed to recreate microenvironment changes that occur during fibrosis to identify the pivotal signals in myofibroblast activation and persistence. To address this, the PI proposes to establish a dynamic, structurally complex hydrogel using a combination of light-mediated, multisize-scale biomimetic, and tunable responsive chemistries to mimic temporally evolving collagenous tissue repair and disease progression. The goal is to design a unique three-dimensional (3D) hydrogel culture system that captures critical components of the native ECM, including nano- to submicron-scale fibrils, nano-scale integrin binding sequences, and spatiotemporally evolving biophysical and biochemical properties, to understand myofibroblastic activation and fibrosis. To achieve this, she proposes to: (1) create hydrogels with controlled biophysical and biochemical properties that mimic soft tissues over multiple size-scales, from nano-, submicron-, to macro-scale; (2) demonstrate increasing hydrogel modulus and incorporating integrin-binding peptides in a spatiotemporal fashion to mimic fibrosis progression; and (3) determine magnitudes and rates of increasing modulus that promote fibroblast activation in both 2D and 3D culture within this model system. BROADER IMPACTS: Biomaterials and bioengineering have the potential to revolutionize our understanding and control of biological systems through the development and application of novel tools to complex health-related problems. However, students often have limited knowledge of these fields, owing to insufficient exposure to related engineering concepts and educational and career opportunities throughout secondary schools and college. The educational goal of this proposal is to create a comprehensive program for increasing the supply of students, especially underrepresented groups, participating and trained in biomaterials and bioengineering through new educational efforts at the secondary, college, and graduate levels. To address these needs the PI will: (1) develop and implement a biomaterials and bioengineering museum kiosk and a 5-7th grade student Family Friday and Mini-camp; (2) mentor high school students in biomaterials and bioengineering through research internships; and (3) develop new Biomaterials & Integrative Biology coursework within the engineering curriculum. The kiosk will allow our team to reach a large and diverse audience ( 100,000 students over 5 years), while the targeted educational programs will enable more in-depth training of students from 5th grade to graduate school and continuing education. Integrating the proposed research within these educational programs aimed at secondary and college curricula will enable innovation at the interface of materials, engineering, and biology through the increased participation, training, and diversity of workers in the field.