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

该奖项的全部或部分资金来自《2021年美国救援计划法案》(公法117-2)非技术概述：引入人体的生物材料通常会引起免疫反应，从而可能导致材料功能障碍或排斥反应。过去的研究主要集中在减少或消除免疫反应，即使生物材料对免疫系统不可见。然而，这种被动的方法无法捕捉和利用免疫反应的积极一面，相反，这可以改善生物材料在许多疾病背景下的性能。该项目旨在了解如何利用大孔生物材料招募特定类型的免疫细胞(例如，树突状细胞和T细胞；体内两种主要类型的免疫细胞)，这些细胞可以在材料现场进行进一步培训，以更好地对抗癌细胞和病原体。通过假设免疫细胞募集受到材料物理性质的影响，包括孔径大小和力学性能，本项目将开发一种大孔生物材料，能够独立调节孔径、硬度和粘度，阐明每个参数对免疫细胞募集的影响，并进一步合理设计主要能够富集树突状细胞或T细胞的材料。这项研究的潜在成果将是精确控制人体免疫反应的新技术，用于治疗用现有疗法难以驯服的癌症的有效癌症免疫疗法，以及为开发未来针对自身免疫性疾病、传染病和受损组织的免疫疗法的生物材料平台。这些研究工作将与教育和推广活动相结合，包括为中学生、高中生和新生开发生物材料讲座和演示。它的目的是提高人们对生物材料教育重要性的认识，以适应材料科学在生物医学中日益增长的影响。鉴于缺乏免疫学和疫苗的一般知识，正如新冠肺炎大流行所反映的那样，免疫学模块将从工程的角度开发，并引入课堂和夏令营，用免疫学和疫苗的基本概念教育下一代。技术综述：利用加载趋化因子的大孔生物材料在原位积极招募和编程所需的免疫细胞，从而调节系统免疫反应的新兴概念，在开发有效的针对疾病的免疫疗法方面显示出巨大的前景。然而，材料的免疫细胞招募情况，即不同免疫细胞的数量和比例，一直是不可预测的。该项目将阐明免疫细胞在大孔材料中募集和浓缩的机制，以及材料性质对免疫细胞行为的影响。材料的孔大小、力学和趋化因子释放动力学可能决定免疫细胞的募集情况，但独立和灵活地控制这些参数仍然是一个挑战。该项目将开发一种大孔水凝胶系统，能够独立调节孔径、硬度、粘度和趋化因子释放动力学(目标1)，阐明每个参数对免疫细胞在体外招募、迁移和增殖的影响，并进一步合理设计能够主要浓缩树突状细胞或T细胞的材料(目标2)，并验证它们在开发有效的癌症免疫治疗方面的前景(目标3)。该项目的成功完成将使大孔材料的合理设计成为可能，这种材料可以优先浓缩特定类型的免疫细胞，以便在不同的疾病背景下精确协调免疫反应。此外，研究工作将与各级学生的教育培训相结合，特别是通过促进生物材料教育，以匹配材料科学在生物医学中日益增长的影响，并从工程角度教育下一代免疫学和疫苗的基本概念。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.