CAREER: Training Diverse Scientists to Design Bionanomaterials for Imaging and Labeling of Therapeutic Stem cells

非技术摘要：这个职业奖项由俄勒冈州立大学材料研究部生物材料计划颁发，重点是纳米材料研究，以促进国民健康。新的纳米材料结合了细胞标记和成像能力，通过光学相干断层扫描(OCT)成像，纵向实时跟踪基于干细胞的再生医学治疗。该项目的材料将使研究人员能够研究体内移植后的迁移和存活，这是目前尚不存在的能力。高反射纳米材料提高了OCT成像的分辨率，以可视化单个细胞。纳米颗粒表面的改性涂层附着在治疗性干细胞上，保护纳米材料在生物环境中不被降解，并使它们隐形以躲避免疫系统。该项目开发安全稳定的纳米材料，并通过提高对涂层纳米材料的性质如何影响其稳定性、细胞摄取和保留而不损害细胞健康和功能的理解，推动该领域的发展。它还为研究治疗性干细胞的安全性和有效性提供了新的工具，从而提高了临床前研究的潜力。该项目将通过解决人类健康和纳米医学方面的共同挑战，并为(1)诊断成像、(2)药物输送和(3)临床前研究工具提供广泛适用的新材料，以推进视网膜疾病、癌症和神经退化的基于细胞的治疗，从而造福社会。研究人员将这项研究与一个全面的教育计划相结合，以激励和培训下一代不同的科学家在纳米医学的生物材料研究方面。教育平台包括Ignite in STEM研究计划；专注于专业技能的丰富课程；以及基于课程的研究经验，为来自缺乏服务的社区的K12和本科生提供真实的经验、可移植的化学家技能，以及揭示建立强大的科学和专业身份以保留STEM所需的隐藏课程的机会。技术摘要：目前评估基于细胞的疗法的方法，即了解细胞移植后的迁移、整合和存活依赖于死后组织的组织分析。这种方法代价高昂，需要牺牲许多动物。由于无法用目前的成像方法识别移植细胞，在体内纵向追踪这些细胞的能力受到了阻碍。这一NSF职业奖致力于研究杂化薄膜涂层纳米材料(HMNPs)如何作为光学相干断层扫描(OCT)造影剂和纳米标记用于基于细胞的治疗，从而独特地提高专注于细胞移植的临床前研究的能力。创造薄膜来覆盖纳米材料，使其具有“隐形”能力来逃避免疫系统，这是成像、诊断和药物输送方面的前沿纳米技术挑战。在基于细胞的成像疗法中，这些涂层的设计规则仍然未知。虽然先前的工作表明，基于膜的纳米颗粒改善了生物相容性和药物传递，但本项目目标是使用HMNPs标记和可视化OCT移植细胞的能力尚未实现。该项目的第一个目标是合成和表征用于OCT成像的具有高散射效率和高反射率的HMNPs，以及在HMNPs上的配体与细胞外或细胞内附着的膜结构。第二个重点是了解HMNPs的大小、形状和表面化学如何影响它们的参与能力，并促进它们的细胞摄取和保留。第三个重点是了解HMNPs的结构特征和共生细胞标记对其反射特性和OCT对比度的影响。这些目标共同促进了HMNPs作为临床前工具的基础知识，以改善基于细胞的疗法的研究。该项目整合了研究和专业发展技能，以增加STEM中不同科学家的数量，方法是：(A)创建一个强大的外展计划，以吸引和联系高中STEM学生进行纳米材料研究；(B)在化学专业实施一个程序性的富集弧，以通过可转让的基于资产的技能实现化学方面的成功；以及(C)创建一个以课程为基础的本科生研究体验(CURE)，专注于将纳米材料与生物系统相结合。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。

Non-technical abstract: This CAREER award made by the Biomaterials Program in the Division of Materials Research to Oregon State University focuses on nanomaterials research to advance national health. New nanomaterials combine cell-labeling and imaging capabilities to visually track stem-cell-based regenerative medicine therapies longitudinally in real-time via optical coherence tomography (OCT) imaging. The materials from this project will allow researchers to study the migration and survival after transplantation in vivo, capabilities that currently do not exist. Highly reflective nanomaterials improve the resolution of OCT imaging to visualize single cells. The modified coatings on nanoparticle surfaces adhere to therapeutic stem cells, protect nanomaterials from degradation in biological environments, and make them stealthy to evade the immune system. The project develops safe and stable nanomaterials and advances the field by improving understanding of how the properties of the coated nanomaterials influence their stability, cellular uptake, and retention without compromising cell health and function. It also advances the potential of preclinical research by providing new tools for studying the safety and efficacy of therapeutic stem cells. The project will benefit society by addressing convergent challenges in human health and nanomedicine and by providing broadly applicable new materials for (1) diagnostic imaging, (2) drug delivery, and (3) preclinical research tools to advance cell-based therapies for retinal diseases, cancer, and neurodegeneration. The investigator integrates this research with a comprehensive education program to inspire and train the next generation of diverse scientists in bionanomaterials research for nanomedicine. The educational platform comprises an Ignite in STEM research program; enrichment curriculum focused on professional skills; and a course-based research experience that provides K12 and undergraduate students from underserved communities with authentic experiences, transferable skills as chemists, and opportunities to reveal the hidden curriculum needed to build strong scientific and professional identities for retention in STEM.Technical abstract:Current methods for evaluating cell-based therapies, i.e., gaining insights into cell migration, integration, and survival after transplantation rely on histological analysis of tissues post-mortem. This approach is costly and requires that many animals be sacrificed. The ability to track these cells longitudinally in vivo is hampered by the inability to identify transplanted cells with current imaging methods. This NSF CAREER award is focused on studying how hybrid membrane-coated nanomaterials (HMNPs) may be optimized as optical coherence tomography (OCT) contrast agents and nanolabels for cell-based therapies, uniquely advancing the capabilities of preclinical studies focused on cell transplantation. Creating membranes to coat nanomaterials that give them “stealth” abilities to evade the immune system represents a frontline nanotechnology challenge in imaging, diagnostic, and drug delivery. The design rules for these coatings in imaging cell-based therapies remain unknown. While prior work shows that membrane-based nanoparticles improve biocompatibility and drug delivery, the ability to use HMNPs to label and visualize transplanted cells using OCT, as this project aims to do, has not yet been realized. The first aim of the project focuses on the synthesis and characterization of HMNPs with high scattering efficiency and reflectance for OCT imaging and membrane architectures with ligands on the HMNPs that attach extracellularly or intracellularly to cells. The second focuses on understanding how the size, shape, and surface chemistry of HMNPs influence their ability to engage and facilitate their cellular uptake and retention. The third focuses on understanding how the structural features of HMNPs and symbiotic cell-labeling influence their reflectance properties and OCT contrast. Together these aims advance fundamental knowledge of HMNPs as preclinical tools to improve the study of cell-based therapies. This project integrates research and professional development skills to increase the number of diverse scientists in STEM by (a) creating a strong outreach program to engage and connect high school STEM students with nanomaterials research, (b) implementing a programmatic enrichment arc in the chemistry majors to hardwire success in chemistry with transferable asset-based skills, and (c) creating a Course-based Undergraduate Research Experience (CURE) focused on interfacing nanomaterials with biological systems.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.