CAREER: Harnessing Dynamic Cell-Scaffold Interactions to Develop Adaptive Biohybrid Systems

职业：利用动态细胞支架相互作用开发自适应生物混合系统

• 批准号: 2239647
• 负责人: Herdeline Ann Ardona
• 金额: $ 65万
• 依托单位: University of California-Irvine
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2239647&HistoricalAwards=false
• 关键词: CAREER; Harnessing; Dynamic; Cell; Scaffold

Non-Technical SummaryIn the human body, we have cells in our muscle tissues that perpetually contract to allow us to move, breathe, and have a functional heart. For cardiac tissues, the contractile behavior of cardiomyocytes as their main cellular component serves as an important indicator whether these tissues are healthy or diseased. Here, the PI proposes to develop a class of materials that can be interfaced with cardiomyocytes and also have a capability to report real-time changes in cardiac contractility through read-outs based on changes in their optical properties. Specifically, these materials will be made possible by using polymeric components that are force-sensitive or “mechanoresponsive” due to molecular-level rearrangements that they can afford in response to external mechanical stimuli such as cardiac contractions. These force-induced molecular bond transformations are proposed to lead to changes in the way that these soft materials absorb or emit light, therefore, serving as optical read-outs for biological force sensing. These materials will also be designed to bear cell-adhering peptides that improve the sensing of contractile stress at the interface of cells and the proposed biomaterial. In addition to understanding how cellular contractions can cause molecular transformations that may lead to instantaneous changes in their optical properties, this project aims to use the proposed materials for assessing the long-term effects of contractile cells on the bulk properties of materials that serve as their scaffolds in vitro. By developing a contractile cell-interfaceable biomaterial with force-sensing capability, the PI sets the stage for quantitatively visualizing biological forces in real-time and being able to directly assess how environmental parameters affect cardiac function through contractility. In the future, this class of adaptive materials could be adopted for model platforms used in screening drug cardiotoxicity and investigating mechanisms of debilitating cardiac diseases. The proposed research will be integrated with educational objectives that aims to help with the recruitment, retention, and promotion of biomaterials researchers at multiple career stages, particularly those from historically underrepresented backgrounds. Technical SummaryCell-generated forces play a crucial role in regulating several biological processes—from tissue morphogenesis to disease pathophysiology. Currently available measurement techniques enable multi-scale force quantification, but these often involve approaches that are destructive, focuses on 2D traction forces, and do not offer real-time measurements. In this CAREER proposal, the PI proposes to develop a class of adaptive peptide biomaterials that exhibit reversible, quantifiable changes in optical properties in response to mechanobiological forces. This class of mechanochromic material will be engineered as hydrogel networks bearing force-responsive, π-conjugated chromophores and have covalent linkages that can autonomously rearrange in response to cardiac contractions. The proposed adaptive biohybrid system can thus allow for in situ visualization of contractile forces that are directly correlated with cell/tissue health and function, and a platform to evaluate the dynamic mechanical interaction at biotic-abiotic interfaces. This sensory capability adds more functionality to conventional peptide bioscaffolds, and therefore, offers a transformative advance to bioscaffolds for tissue engineering applications that are only traditionally designed to recapitulate the composition, mechanical properties, and topography of native extracellular matrix (ECM) environments. These efforts serve as a foundational pillar towards the PI’s long-term career goal, which is to leverage designer biomaterials that uniquely transduce optical or electronic phenomena at the cellular interface to control or probe biological processes at multiple spatiotemporal scales. Together with our proposed research activities on developing an adaptive biomaterial technology, we will implement educational activities such as summer workshops, mentorship activities, and public seminars that aims to strengthen the interdisciplinary training pipeline for the current and next generation of diverse biomaterials researchers.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.

在人体中，我们的肌肉组织中有细胞，它们不断收缩，使我们能够移动、呼吸，并有一个功能齐全的心脏。对于心脏组织来说，心肌细胞作为其主要的细胞成分，其收缩行为是心脏组织健康与否的重要标志。在这里，PI建议开发一类可以与心肌细胞连接的材料，并且还具有通过基于其光学特性变化的读出来报告心脏收缩力实时变化的能力。具体来说，这些材料将通过使用具有力敏感或“机械反应性”的聚合物组分而成为可能，这是由于分子水平的重排，它们可以对外部机械刺激（如心脏收缩）做出反应。这些力诱导的分子键转换被提出导致这些软材料吸收或发射光的方式发生变化，因此，作为生物力传感的光学读出。这些材料还将被设计为承载细胞粘附肽，以改善细胞和拟议生物材料界面上的收缩应力的感知。除了了解细胞收缩如何引起可能导致其光学特性瞬时变化的分子转化外，该项目还旨在使用所提出的材料来评估可收缩细胞对体外支架材料体积特性的长期影响。通过开发具有力传感能力的可收缩细胞界面生物材料，PI为实时定量可视化生物力奠定了基础，并能够直接评估环境参数如何通过收缩性影响心脏功能。在未来，这类自适应材料可用于筛选药物心脏毒性和研究衰弱性心脏病机制的模型平台。拟议的研究将与教育目标相结合，旨在帮助在多个职业阶段招募、保留和提升生物材料研究人员，特别是那些历史上代表性不足的背景的研究人员。技术总结细胞产生的力量在调节从组织形态发生到疾病病理生理的几个生物过程中起着至关重要的作用。目前可用的测量技术可以实现多尺度力量化，但这些方法通常是破坏性的，专注于二维牵引力，并且不能提供实时测量。在这个CAREER提案中，PI建议开发一类适应性肽生物材料，这些材料在机械生物学力的作用下，在光学特性上表现出可逆的、可量化的变化。这类机械致色材料将被设计成水凝胶网络，承载力响应，π共轭发色团，并具有共价键，可以响应心脏收缩自主重排。因此，提出的自适应生物杂交系统可以实现与细胞/组织健康和功能直接相关的收缩力的原位可视化，以及评估生物-非生物界面动态机械相互作用的平台。这种感知能力为传统的肽生物支架增加了更多的功能，因此，为组织工程应用的生物支架提供了一种变革性的进步，这些生物支架传统上只能重现天然细胞外基质（ECM）环境的组成、机械性能和地形。这些努力是PI长期职业目标的基础支柱，该目标是利用设计生物材料，在细胞界面上独特地传递光学或电子现象，以控制或探测多个时空尺度的生物过程。与我们提出的开发适应性生物材料技术的研究活动一起，我们将实施教育活动，如夏季研讨会，指导活动和公开研讨会，旨在加强当前和下一代不同生物材料研究人员的跨学科培训管道。该奖项反映了美国国家科学基金会的法定使命，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。