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.

非技术性炎症和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特别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被排斥。因此，需要一种通用的生物材料改性策略，以精确控制浸润巨噬细胞的行为，用于不同的应用。蛋白质-配体结合对生物素和抗生物素蛋白以其特殊的强度而闻名。然而，最近发现，当生物素与蛋白质和药物等较大分子连接时，这种结合强度会降低，导致键断裂并释放蛋白质，从而对浸润免疫细胞的行为产生影响。蛋白质释放的速率可以通过修改制备参数在很宽的范围内进行调整，并且可以选择所选择的蛋白质来精确地操纵巨噬细胞行为，从而允许生物材料设计者针对每个预期应用调整免疫系统。当该系统被纳入生物材料的三维环境中时，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，但这些现象从未被探索过。因此，在这个项目中，生物材料的性能，如微观结构和密度的影响，以及这些性能是如何改变的动态生物素-亲和素结合系统的列入，将彻底的特点，以推进结合系统和生物材料之间的相互作用的基础知识。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的必然结果。该项目的结果将为生物材料的设计铺平道路，这些生物材料可以调节免疫系统用于生物医学应用，同时有助于对基础生物学，生物传感器和纳米技术中应用的三维结合相互作用的基本理解。此外，该项目整合了教育计划与德雷克塞尔工程的学生与幼儿教育工作者合作，反复介绍费城学校的学生从幼儿园到3年级的进展，生物材料工程的原则。该计划的主要目标是：1）试点教育活动的发展，作为课程单元与其他教师分享，和2）提高辅导技能的德雷克塞尔学生。该项目的第二个目标是收集项目有效性的初步数据，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，需要一种通用的生物材料修饰策略，以精确控制浸润巨噬细胞的表型，用于不同的应用。该项目的目标是确定亲和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中细胞因子的释放，以调节巨噬细胞的行为。亲和结合对生物素和抗生物素蛋白将被用来确定解离动力学如何改变后，生物素的共轭大分子，如蛋白质，导致控制释放的生物材料，生物素-抗生物素蛋白技术的一个新的应用，从来没有探索。将在体外确定生物缀合参数如生物素价和间隔臂长度以及生物材料性质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。结合生物材料的时空控制设计策略将被探索，包括3D生物打印和多种蛋白质的顺序释放。最后，与体内微环境的相互作用，如内源性生物素的存在下，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将使用在体外和体内实验的组合进行研究。这些结果也将有助于初步的数据如何生物材料介导的控制巨噬细胞的行为影响生物材料血管化。此外，该项目整合了教育计划与德雷克塞尔工程的学生与幼儿教育工作者合作，反复介绍费城学校的学生从幼儿园到3年级的进展，生物材料工程的原则。该计划的主要目标是：1）试点教育活动的发展，作为课程单元与其他教师分享，和2）提高辅导技能的德雷克塞尔学生。该项目的第二个目标是收集项目有效性的初步数据，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。