Bioinspired, Single-molecule Based Shear Switchable Nanomaterials

仿生单分子剪切可切换纳米材料

• 批准号: 2004475
• 负责人: Xuanhong Cheng
• 金额: $ 40.36万
• 依托单位: Lehigh University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2004475&HistoricalAwards=false
• 关键词: Bioinspired; Single; molecule; Based; Shear

Nontechnical Summary: Shear flow is widely present in physiological environments and contributes significantly to various normal and pathological processes, especially in the circulatory system. Consequently, biomaterials with structure and function tunable by shear represent powerful tools to detect and rectify pathological processes induced by abnormal flows in the body. For the past few decades, shear-responsive hydrogels and molecular assemblies have been widely explored. However, single-biomolecule based shear responders remains a poorly-tapped subject, despite such materials could better mimic natural functions in circulation, delivering more accurate spatial and temporal responses with function reversibility. This project will design and characterize novel Single-MOlecule based materials with switchable structures and functions REsponsive to Shear flows (SMORES). Owing to the modular design, the material concept can be generalized to other constructs capable of responding to abnormal flows in the circulatory system towards novel diagnostics and therapeutics for cardiovascular diseases in the long term. This project will provide fundamental insights into biomechanics of polymer devices under the influence of ligands and the flow environment, perspectives that have not been studied in depth before. Rational design of biomaterials containing both bio- and nonbio- functionalities to achieve predictable flow responses will advance the fields of materials science, biomechanics, bio-conjugation, molecular engineering and bio-transport. Knowledge from this work will enable new diagnostics and theranostics for hemostatic applications, advancing the national health. The PIs will actively recruit underrepresented students to their research and disseminated discoveries from the research broadly to the general public through various K12 outreach programs.Technical Summary: The design is inspired by a coagulation molecule in circulation, the von Willebrand Factor (vWF), which executes its function of crosslinking platelets to damaged blood vessel wall at shear rates 5,000 per sec. The function is switched on by conformational changes under high shear and is enabled by an extremely complicated molecular structure: vWF is comprised of tens to hundreds of monomer units, each of which contains more than ten domains. To demonstrate that an artificial material of modular design could achieve a similar function to vWF, i.e. binding cells at high shear, we propose the construction SMORES to inhibit or promote the cell binding activity of the vWF’s platelet binding domain under shear control. Shear dependent cell binding to the proposed material will be characterized and correlated with molecular conformations studied by single-molecular force spectroscopy, microfluidic imaging experiments and computer modeling. Besides demonstrating the material design concept, the proposed work will emphasize fundamental studies of single-molecule biomechanical behaviors in different biochemical environment, especially the presence and absence of ligands.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.

非技术性总结：剪切流广泛存在于生理环境中，并对各种正常和病理过程，特别是在循环系统中有重要贡献。因此，具有可通过剪切调节的结构和功能的生物材料代表了检测和纠正体内异常流动引起的病理过程的有力工具。在过去的几十年里，剪切响应水凝胶和分子组装体已经被广泛探索。然而，基于单生物分子的剪切响应器仍然是一个开发不足的主题，尽管这样的材料可以更好地模拟循环中的自然功能，提供更准确的空间和时间响应与功能可逆性。该项目将设计和表征具有可切换结构和功能的新型单分子材料，以响应剪切流（SMORES）。由于模块化设计，材料概念可以推广到其他能够响应循环系统中的异常流动的结构，长期用于心血管疾病的新诊断和治疗。该项目将提供基本的见解聚合物设备的生物力学的配体和流动环境的影响下，以前没有深入研究的观点。合理设计具有生物和非生物功能的生物材料以实现可预测的流动响应将推动材料科学、生物力学、生物缀合、分子工程和生物运输领域的发展。这项工作的知识将使新的诊断和治疗诊断学用于止血应用，促进国民健康。PI将积极招募代表性不足的学生参与他们的研究，并通过各种K12外展计划向公众广泛传播研究发现。技术总结：该设计的灵感来自循环中的凝血分子von Willebrand Factor（vWF），它以每秒5，000的剪切速率执行将血小板交联到受损血管壁的功能。该功能通过高剪切下的构象变化来开启，并且通过极其复杂的分子结构来实现：vWF由数十至数百个单体单元组成，每个单体单元包含十个以上的结构域。为了证明模块化设计的人工材料可以实现与vWF类似的功能，即在高剪切下结合细胞，我们提出了SMORES结构，以抑制或促进剪切控制下vWF的血小板结合结构域的细胞结合活性。剪切依赖细胞结合到拟议的材料将被表征和相关的分子构象研究单分子力光谱，微流控成像实验和计算机建模。除了展示材料设计概念外，拟议的工作将强调在不同生物化学环境中的单分子生物力学行为的基础研究，特别是配体的存在和不存在。该奖项反映了NSF的法定使命，并通过使用基金会的智力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

Loss of pulsatility with continuous-flow left ventricular assist devices and the significance of the arterial endothelium in von-Willebrand factor production and degradation.

• DOI: 10.1111/aor.14456
• 发表时间: 2022-11
• 期刊: Artificial organs
• 影响因子: 2.4
• 作者: G. Giridharan;Ian C. Berg;Esraa Ismail;Khanh T Nguyen;Jana Hecking;J. Kirklin;Xuanhong Cheng;P. Sethu

Effect of pulsatility on shear-induced extensional behavior of Von Willebrand factor.

脉动性对剪切诱导的von Willebrand因子延伸行为的影响。

• DOI: 10.1111/aor.14133
• 发表时间: 2022-05
• 期刊: Artificial organs
• 影响因子: 2.4