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

职业：用于免疫调节的免疫细胞归巢生物材料的合理设计

• 批准号: 2143673
• 负责人: Hua Wang
• 金额: $ 69.69万
• 依托单位: University of Illinois at Urbana-Champaign
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2143673&HistoricalAwards=false
• 关键词: CAREER; Rational; Design; Immune; Cell

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.

该奖项全部或部分由2021年美国救援计划法案（公法117-2）资助。非技术摘要：引入人体的生物材料通常会引起免疫反应，可能导致材料功能障碍或排斥。过去的研究工作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方面，而免疫反应可以在许多疾病环境中改善生物材料的性能。本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（如树突状细胞和T细胞，这是体内两种主要的免疫细胞），这些免疫细胞可以在材料部位进一步训练，以更好地对抗癌细胞和病原体。本项目通过假设免疫细胞募集受材料的物理性质（包括孔径和力学）的影响，开发一种能够独立调节孔径、刚度和粘度的大孔生物材料，阐明各参数对免疫细胞募集的影响，进一步合理设计主要富集树突状细胞或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，有效的癌症免疫疗法，用于治疗现有疗法难以治愈的癌症，以及开发未来免疫疗法的生物材料平台，用于自身免疫性疾病，感染性疾病和损伤组织。这些研究工作将与针对初中生、高中生和新生的生物材料讲座和演示等教育和推广活动相结合。它旨在提高人们对生物材料教育重要性的认识，以配合材料科学在生物医学领域日益增长的影响。鉴于在2019冠状病毒病大流行期间，人们对免疫学和疫苗缺乏普遍的了解，我们将从工程的角度开发免疫学模块，并将其引入课堂和夏令营，向下一代传授免疫学和疫苗接种的基本概念。技术概述：利用装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，从而调节全身免疫反应的新兴概念，为开发有效的疾病免疫疗法显示了巨大的希望。然而，免疫细胞募集概况，即不同免疫细胞的数量和分数，材料是不可预测的。本项目将阐明免疫细胞在大孔材料内募集和富集的机制以及材料性质对免疫细胞行为的影响。材料的孔径、力学和趋化因子释放动力学可能决定了免疫细胞的募集情况，但对这些参数的独立和灵活控制仍然是一个挑战。该项目将开发一种大孔水凝胶系统，该系统能够独立调节孔径、刚度、粘度和趋化因子释放动力学（Aim 1），阐明每个参数对体外免疫细胞募集、迁移和增殖的影响，并进一步合理设计主要富集树突状细胞或T细胞的材料（Aim 2），并验证其开发强效癌症免疫治疗的前景（Aim 3）。该项目的成功完成将使大孔材料的合理设计成为可能，这些大孔材料可以优先丰富特定类型的免疫细胞，从而精确地协调不同疾病背景下的免疫反应。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，以适应材料科学在生物医学领域日益增长的影响，并从工程角度向下一代教育免疫学和疫苗接种的基本概念。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Bio-adhesive Macroporous Hydrogels for In Situ Recruitment and Modulation of Dendritic Cells

• DOI: 10.1007/s12195-023-00770-2
• 发表时间: 2023-07-03
• 期刊: CELLULAR AND MOLECULAR BIOENGINEERING
• 影响因子: 2.8
• 作者: Han，Joonsu;Bhatta，Rimsha;Wang，Hua
• 通讯作者: Wang，Hua

A double crosslinking adhesion mechanism for developing tough hydrogel adhesives

• DOI: 10.1016/j.actbio.2022.07.028
• 发表时间: 2022-08-31
• 期刊: ACTA BIOMATERIALIA
• 影响因子: 9.7
• 作者: Han, Joonsu;Park, Jihoon;Wang, Hua
• 通讯作者: Wang, Hua

Recyclable cell-surface chemical tags for repetitive cancer targeting

• DOI: 10.1016/j.jconrel.2022.05.007
• 发表时间: 2022-05-11
• 期刊: JOURNAL OF CONTROLLED RELEASE
• 影响因子: 10.8
• 作者: Bhatta，Rimsha;Han，Joonsu;Wang，Hua
• 通讯作者: Wang，Hua

Spotlight—author’s view for “Metabolic glycan labeling immobilizes dendritic cell membrane and enhances antitumorefficacy of dendritic cell vaccine”

Spotlight——作者对“代谢聚糖标记固定树突状细胞膜并增强树突状细胞疫苗的抗肿瘤功效”的观点

• DOI: 10.1038/s41435-023-00245-4
• 发表时间: 2023
• 期刊: Genes & Immunity
• 影响因子: 5
• 作者: Zhou, Jiadiao;Wang, Hua
• 通讯作者: Wang, Hua