CAREER: Rational Design of Immune Cell-Homing Biomaterials for Immune Regulation

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This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2)Non-Technical Summary:Biomaterials introduced into the human body often cause immune responses that may result in the dysfunction or rejection of materials. Past research effort has been largely focused on reducing or eliminating the immune responses, i.e., making the biomaterials invisible to the immune system. However, this passive approach fails to capture and leverage the positive side of immune responses, which can instead improve the performance of biomaterials in many disease contexts. This project aims to understand how macroporous biomaterials can be utilized to recruit specific types of immune cells (e.g., dendritic cells and T cells; two prominent types of immune cells in the body), which can be further trained at the material site to better combat cancer cells and pathogens. By hypothesizing that immune cell recruitment is affected by the physical properties of materials, including pore size and mechanics, this project will develop a macroporous biomaterial that enables independent tuning of pore size, stiffness, and viscosity, elucidate the impact of each parameter on the immune cell recruitment, and further rationally design materials that can primarily enrich dendritic cells or T cells. Potential outcomes from this research will be new technologies to precisely control the body’s immune responses, effective cancer immunotherapies for treating cancers that are difficult to tame with existing therapies, and a biomaterial platform for developing future immunotherapies for autoimmune disorders, infectious diseases, and injured tissues. These research efforts will be integrated with education and outreach activities, including the development of biomaterial lectures and demos for middle-school students, high-school students, and freshmen. It aims to raise the awareness of the importance of biomaterials education to match the increasing impact of material science in biomedicine. In view of the lack of general knowledge about immunology and vaccine, as reflected during the covid-19 pandemic, immunology modules will be developed from an engineering perspective and introduced to classes and summer camps to educate the next generation with basic concepts of immunology and vaccination.Technical Summary:The emerging concept of utilizing chemokine-loaded macroporous biomaterials to actively recruit and program desired immune cells in situ and thus regulate systemic immune responses has shown great promise for developing effective immunotherapies against diseases. However, the immune cell recruitment profile, i.e., numbers and fractions of different immune cells, of materials has been unpredictable. This project will elucidate the mechanism for immune cell recruitment and enrichment within macroporous materials and the impact of material properties on immune cell behaviors. Pore size, mechanics, and chemokine release kinetics of materials likely dictate the immune cell recruitment profile, but independent and flexible control of these parameters remains a challenge. This project will develop a macroporous hydrogel system that enables independent tuning of pore size, stiffness, viscosity, and chemokine release kinetics (Aim 1), elucidate the impact of each parameter on the immune cell recruitment, migration, and proliferation in vitro and further rationally design materials that can primarily enrich dendritic cells or T cells (Aim 2), and validate their promise for developing potent cancer immunotherapy (Aim 3). Successful completion of this project will enable rational design of macroporous materials that can preferentially enrich specific types of immune cells, for precise orchestration of immune responses in different disease contexts. Additionally, the research efforts will be integrated with the educational training of students at all levels, especially by promoting biomaterials education to match the rising impact of materials science in biomedicine and educating the next generation with basic concepts of immunology and vaccination from an engineering perspective.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.