CAREER: Biomaterial-mediated control over macrophage activation

职业：生物材料介导的巨噬细胞激活控制

• 批准号: 1750788
• 负责人: Kara Spiller
• 金额: $ 50万
• 依托单位: Drexel University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1750788&HistoricalAwards=false
• 关键词: CAREER; Biomaterial; mediated; control; over

Non-technical Inflammation, and our ability to control it, is a central theme in modern medicine. The success of implanted biomaterials in particular hinges on the behavior of macrophages, the primary cells of the innate immune system that dictate whether a biomaterial will be successfully integrated with the body or will be rejected. Thus, there is a need for a versatile biomaterial modification strategy to precisely control the behavior of infiltrating macrophages for different applications. The protein-ligand binding pair biotin and avidin is known for its exceptional strength. However, it was recently discovered that this binding strength decreases when biotin is attached to larger molecules like proteins and drugs, causing the bond to break and the protein to be released, with resultant effects on the behavior of infiltrating immune cells. The rate of protein release can be tuned over a wide range by modifying preparation parameters, and the selected protein can be chosen to precisely manipulate macrophage behavior, allowing the biomaterials designer to tune the immune system for each intended application. When this system is incorporated into the three-dimensional environment of a biomaterial, the rate that the bond breaks and the protein diffuses from the biomaterial likely depends on the biomaterial environment, including the biomaterial itself and its surrounding milieu, but these phenomena have never been explored. Thus, in this project the effects of biomaterial properties like microstructure and density, and how these properties are changed by the inclusion of the dynamic biotin-avidin-binding system, will be thoroughly characterized, in order to advance fundamental knowledge of the interactions between the binding system and biomaterials. In addition, the effects of the external biomaterial microenvironment will be assessed, including the infiltration of immune cells and blood vessels, an inevitable outcome for all implanted biomaterials. The results of this project will pave the way for the design of biomaterials that can modulate the immune system for biomedical applications, while contributing fundamental understanding of binding interactions in three dimensions with applications in basic biology, biosensors, and nanotechnology. In addition, this project integrates an educational program with Drexel engineering students in collaboration with early childhood educators to repeatedly introduce Philadelphia school students to biomaterials engineering principles as they progress from kindergarten to grade 3. The major goals of this program are to: 1) pilot educational activities for development as curriculum units to share with other teachers, and 2) improve mentorship skills of Drexel students. A secondary goal of this program is to collect preliminary data on the effectiveness of the program to improve students' STEM performance.Technical The success of implanted biomaterials hinges on the behavior of macrophages, the primary cells of the innate immune system that dictate whether a biomaterial will be encapsulated in a fibrous capsule or vascularized and integrated with the surrounding tissue. Thus, there is a need for a versatile biomaterial modification strategy to precisely control the phenotype of infiltrating macrophages for different applications. The goal of this project is to determine how changes in affinity binding interactions and the biomaterial microenvironment affect the release of cytokines from biomaterials to modulate macrophage behavior. The affinity binding pair biotin and avidin will be utilized to identify how dissociation kinetics are altered upon conjugation of biotin to larger molecules like proteins to result in controlled release from biomaterials, a new application of biotin-avidin technology that has never been explored. The effects of bioconjugation parameters like biotin valency and the length of the spacer arm as well as biomaterial properties like crosslinking density and spatial distribution on release of macrophage-modulating cytokines will be determined in vitro. Combination with biomaterials design strategies for spatiotemporal control will be explored, including 3D bioprinting and the sequential release of multiple proteins. Finally, the effects of interactions with the in vivo microenvironment, such as the presence of endogenous biotin, number of infiltrating macrophages, and biomaterial vascularization, on cytokine release will be investigated using a combination of in vitro and in vivo experiments. These results will also contribute preliminary data on how biomaterial-mediated control over macrophage behavior affects biomaterial vascularization. In addition, this project integrates an educational program with Drexel engineering students in collaboration with early childhood educators to repeatedly introduce Philadelphia school students to biomaterials engineering principles as they progress from kindergarten to grade 3. The major goals of this program are to: 1) pilot educational activities for development as curriculum units to share with other teachers, and 2) improve mentorship skills of Drexel students. A secondary goal of this program is to collect preliminary data on the effectiveness of the program to improve students' STEM performance.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.

非技术性炎症以及我们控制它的能力是现代医学的中心主题。植入生物材料的成功尤其取决于巨噬细胞的行为，巨噬细胞是先天免疫系统的主要细胞，决定生物材料是否会成功地与身体整合或会被排斥。因此，需要一种多功能的生物材料修饰策略来精确控制不同应用的浸润巨噬细胞的行为。蛋白质-配体结合对生物素和亲和素以其卓越的强度而闻名。然而，最近发现，当生物素附着在蛋白质和药物等较大分子上时，这种结合强度会降低，导致键断裂并释放蛋白质，从而影响浸润免疫细胞的行为。通过修改制备参数，可以在大范围内调节蛋白质释放速率，并且可以选择选定的蛋白质来精确操纵巨噬细胞的行为，从而使生物材料设计者能够针对每种预期应用调整免疫系统。当该系统融入生物材料的三维环境时，键断裂和蛋白质从生物材料扩散的速率可能取决于生物材料环境，包括生物材料本身及其周围环境，但这些现象从未被研究过。探索过。因此，在这个项目中，将彻底表征生物材料特性（如微观结构和密度）的影响，以及这些特性如何通过包含动态生物素-亲和素结合系统而改变，以推进关于生物材料之间相互作用的基础知识。结合系统和生物材料。此外，还将评估外部生物材料微环境的影响，包括免疫细胞和血管的浸润，这是所有植入生物材料不可避免的结果。该项目的结果将为生物材料的设计铺平道路，该生物材料可以调节生物医学应用的免疫系统，同时有助于对三维结合相互作用与基础生物学、生物传感器和纳米技术应用的基本理解。此外，该项目还与德雷克塞尔工程学院的学生和幼儿教育工作者合作，整合了一项教育计划，在费城学校的学生从幼儿园到三年级的过程中反复向他们介绍生物材料工程原理。该计划的主要目标是：1) 试点发展教育活动作为课程单元与其他教师分享，2) 提高德雷克塞尔学生的指导技能。该计划的第二个目标是收集有关该计划有效性的初步数据，以提高学生的 STEM 表现。技术 植入生物材料的成功取决于巨噬细胞的行为，巨噬细胞是先天免疫系统的主要细胞，决定生物材料是否成功将被包裹在纤维囊中或血管化并与周围组织整合。因此，需要一种多功能的生物材料修饰策略来精确控制不同应用的浸润巨噬细胞的表型。该项目的目标是确定亲和力结合相互作用和生物材料微环境的变化如何影响生物材料释放细胞因子以调节巨噬细胞行为。亲和结合对生物素和抗生物素蛋白将用于确定生物素与蛋白质等较大分子缀合时如何改变解离动力学，从而导致生物材料的受控释放，这是生物素-抗生物素蛋白技术的一种从未被探索过的新应用。生物共轭参数（如生物素价和间隔臂长度）以及生物材料特性（如交联密度和空间分布）对巨噬细胞调节细胞因子释放的影响将在体外确定。将探索与生物材料设计策略相结合的时空控制，包括 3D 生物打印和多种蛋白质的顺序释放。最后，将结合体外和体内实验来研究与体内微环境的相互作用，例如内源性生物素的存在、浸润巨噬细胞的数量和生物材料血管化对细胞因子释放的影响。这些结果还将提供有关生物材料介导的巨噬细胞行为控制如何影响生物材料血管化的初步数据。此外，该项目还与德雷克塞尔工程学院的学生和幼儿教育工作者合作，整合了一项教育计划，在费城学校的学生从幼儿园到三年级的过程中反复向他们介绍生物材料工程原理。该计划的主要目标是：1) 试点发展教育活动作为课程单元与其他教师分享，2) 提高德雷克塞尔学生的指导技能。该计划的第二个目标是收集有关该计划有效性的初步数据，以提高学生的 STEM 表现。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。