Bioinspired, Single-molecule Based Shear Switchable Nanomaterials

非技术总结：剪切流广泛存在于生理环境中，在各种正常和病理过程中起着重要作用，特别是在循环系统中。因此，具有可剪切结构和功能的生物材料是检测和纠正由体内异常血流引起的病理过程的有力工具。在过去的几十年里，剪切反应水凝胶和分子组装得到了广泛的研究。然而，基于单生物分子的剪切响应剂仍然是一个很少开发的主题，尽管这种材料可以更好地模拟循环中的自然功能，提供更准确的时空响应和功能可逆性。该项目将设计和表征具有可切换结构和响应剪切流（SMORES）功能的新型单分子材料。由于模块化设计，材料概念可以推广到其他结构，能够响应循环系统中的异常流动，从而长期用于心血管疾病的新型诊断和治疗。该项目将为聚合物器件在配体和流动环境影响下的生物力学提供基础见解，这是以前尚未深入研究的观点。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、生物偶联、分子工程和生物运输等领域的发展。从这项工作中获得的知识将为止血应用提供新的诊断和治疗方法，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外展计划将研究成果广泛传播给公众。技术概述：该设计的灵感来自循环中的凝血分子，von Willebrand Factor (vWF)，它以每秒5000的剪切速率将血小板与受损血管壁交联。该功能通过高剪切下的构象变化开启，并通过极其复杂的分子结构实现：vWF由数十到数百个单体单元组成，每个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相似的功能，即在高剪切下结合细胞，我们提出构建SMORES来抑制或促进剪切控制下vWF血小板结合结构域的细胞结合活性。通过单分子力谱、微流体成像实验和计算机建模研究，剪切依赖细胞与所提出材料的结合将被表征并与分子构象相关联。除了展示材料设计概念外，本研究还将着重于不同生化环境下单分子生物力学行为的基础研究，特别是配体的存在和缺失。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。

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.