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

非技术摘要：该职业奖由俄勒冈州州立大学材料研究部的生物材料项目颁发，重点关注纳米材料研究，以促进国民健康。新的纳米材料结合了联合收割机细胞标记和成像能力，通过光学相干断层扫描（OCT）成像实时纵向可视化跟踪基于干细胞的再生医学疗法。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。高反射性纳米材料提高了OCT成像的分辨率，使单细胞可视化。纳米颗粒表面的改性涂层粘附在治疗性干细胞上，保护纳米材料免受生物环境中的降解，并使它们隐形以逃避免疫系统。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，细胞吸收和保留而不损害细胞健康和功能的理解来推进该领域。它还通过为研究治疗性干细胞的安全性和有效性提供新的工具来推进临床前研究的潜力。该项目将通过解决人类健康和纳米医学的趋同挑战，并通过提供广泛适用的新材料（1）诊断成像，（2）药物输送和（3）临床前研究工具来促进视网膜疾病，癌症和神经变性的细胞疗法，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生物纳米材料研究。该教育平台包括STEM研究计划的基础课程;专注于专业技能的强化课程;以及基于课程的研究体验，为来自服务不足社区的K12和本科生提供真实的经验，作为化学家的可转移技能，以及揭示建立强大的科学和专业身份所需的隐藏课程的机会。技术摘要：目前用于评估基于细胞的疗法的方法，即，对移植后细胞迁移、整合和存活的了解依赖于死后组织的组织学分析。这种方法是昂贵的，需要牺牲许多动物。在体内纵向追踪这些细胞的能力受到当前成像方法无法识别移植细胞的阻碍。该NSF CAREER奖的重点是研究如何将混合膜涂层纳米材料（HMNP）优化为光学相干断层扫描（OCT）造影剂和基于细胞的治疗的纳米标记，独特地提高了专注于细胞移植的临床前研究的能力。制造膜来包覆纳米材料，使其具有“隐身”能力以逃避免疫系统，这是成像、诊断和药物输送领域的前沿纳米技术挑战。这些涂层在基于细胞的成像疗法中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递送，但使用HMNP使用OCT标记和可视化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具有高散射效率和反射率的HMNP，用于OCT成像和膜结构，HMNP上的配体附着在细胞外或细胞内。第二个重点是了解HMNP的大小，形状和表面化学如何影响它们参与和促进细胞吸收和保留的能力。第三个重点是了解HMNP的结构特征和共生细胞标记如何影响其反射特性和OCT对比度。这些目标共同推进了HMNP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领域多样化科学家的数量，方法是：（a）创建一个强大的外展计划，让高中STEM学生参与并与纳米材料研究联系起来，（B）在化学专业实施一个程序化的富集弧，以通过可转移的基于资产的技能在化学领域取得成功，以及（c）创建一个以课程为基础的本科生研究体验（CURE），专注于纳米材料与生物系统的接口。该奖项反映了NSF的法定使命，并被认为值得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来支持。

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.