Spatial Control of Cell Behavior via Interfacial Bioorthogonal Chemistry

通过界面生物正交化学空间控制干细胞行为（NSF DMR，生物材料计划# DMR-1506613）非技术：组织工程有望创造现成的可植入组织或器官，以改善人类健康。功能组织的成功工程化需要离体重建细胞最初在体内驻留的环境。在这个项目中，仿生支架将通过将具有所需空间梯度的凝胶状材料与以重复方式显示生化信号的合成纤维相结合来创建。单个组件和集成支架将使用一种新的工艺生产，该工艺利用了超快，高效的偶联反应。这样的过程允许支架特性的空间控制，而不必依赖于外部的、潜在有毒的触发物或模板，从而使得能够在3D中将患者的细胞容易地掺入支架中。细胞填充的支架将被机械刺激以增强组织生长。最终目标是创造具有正确组织和适当功能的组织。这项工作将使生产先进的材料，以改善患有各种疾病的病人的生活质量，从而证明公众的支持是合理的。 PI的推广和教育工作将有助于保持美国的全球竞争力。除了课程开发、学生培训之外，我们还将致力于培养和增强职前幼儿教师的能力，他们将激励下一代科学家。技术：该奖项授予特拉华州大学（UD），旨在开发具有各向异性特征和空间梯度的合成基质，以控制3D封装的间充质干细胞（MSC）的行为。用于机械活性软组织的工程设计。PI将通过将基于透明质酸（HA）的水凝胶与使用设计的单体重新生产的合成纤维整合来实现这一目标。HA水凝胶将表现出基质刚度和配体密度的空间变化，而合成纤维将模拟天然细胞外基质中发现的纤维蛋白的结构和功能。凝胶和纤维组分都将通过一种新型的界面聚合工艺生产，该工艺利用了s-四嗪（Tz）和反式环辛烯（TCO）之间的快速、生物正交和高效的环加成反应。PI将评估合成基质结合动态培养装置在引导MSC空间分化方面的潜力。最终目标是产生具有各向异性特征的多层结构，其反映靶组织的微观结构。拟议的研究计划将为本科生和研究生提供肥沃的培训基地，从而有助于UD生物医学工程项目的持续增长。该研究项目还将为幼儿教师的参与和赋权提供一个平台。

Spatial Control of Stem Cell Behavior via Interfacial Bioorthogonal Chemistry (NSF DMR, Biomaterials Program # DMR-1506613)Non-technical: Tissue engineering holds promise for creating off-the-shelf, implantable tissues or organs for the betterment of human health. Successful engineering of functional tissues requires the environment in which the cells originally reside in vivo be recreated ex vivo. In this project, a biomimetic scaffold will be created by combining a gelatinous material exhibiting desired spatial gradients with synthetic fibers displaying biochemical signals in a repetitive fashion. The individual components and the integrated scaffold will be produced using a novel process that takes advantage of an ultrafast, highly efficient coupling reaction. Such a process permits the spatial control of scaffold properties without having to rely on external, potentially toxic triggers or templates, thereby enabling facile incorporation of the patient's cells in the scaffold in 3D. The cell-populated scaffold will be mechanically stimulated to enhance tissue growth. The ultimate goal is to create tissues with the correct organization and proper functions. This work will enable the production of sophisticated materials to improve the quality of life for patients suffering from various diseases, thus justifying the public support. The PIs outreach and education efforts will help maintain the United States' global competitiveness. In addition to course development, student training, effort will be dedicated to the engaging and empowering of pre-service, early childhood teachers who will inspire the next generation scientists.Technical: This award to the University of Delaware (UD) aims to develop synthetic matrices with anisotropic features and spatial gradients to control the behavior of 3D encapsulated mesenchymal stem cells (MSCs) for the engineering of mechanically active soft tissues. The PIs will accomplish this goal by integrating a hyaluronic acid (HA)-based hydrogel with synthetic fibers produced de novo using designed monomers. The HA hydrogel will exhibit spatial variations of matrix stiffness and ligand density while the synthetic fibers will mimic the structure and the function of fibrous proteins found in the native extracellular matrix. Both the gel and the fiber components will be produced via a novel interfacial polymerization process that takes advantage of the rapid, bioorthogonal and highly efficient cycloaddition reaction between s-tetrazine (Tz) and trans-cyclooctene (TCO). The PIs will evaluate the potential of the synthetic matrix, combined with a dynamic culture device, in guiding the spatial differentiation of MSCs. The ultimate goal is to produce a multilayered construct with anisotropic features that reflect the microstructure of the targeted tissue. The proposed research program will provide a fertile training ground for undergraduate and graduate students, thus contributing to the continued growth of the biomedical engineering program at UD. The research project will also provide a platform for engaging and empowering early childhood teachers.