CAREER: Biomaterial-mediated control over macrophage activation

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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.