Stimulated Raman imaging for label-free histology to guide brain tumor surgery

用于无标记组织学的受激拉曼成像指导脑肿瘤手术

• 批准号: 9140064
• 负责人: Fake Lu
• 金额: $ 9.45万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-08 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9140064
• 关键词: Agar; Algorithms; Applications Grants; Area; Artificial Intelligence; Atypia; Award; Axon; Basic Science; Biological; Biological Markers; Biological Preservation; Biophotonics; Bone marrow biopsy; Brain; Brain Neoplasms; Cancerous; Cell Density; Cellular Morphology; Chromatin Structure; Clinical; Clinical Pathology; Clinical Research; Collagen; Computational algorithm; Computer Vision Systems; Computer software; Computers; Cryoultramicrotomy; Data; Decision Making; Devices; Diagnosis; Diagnostic; Documentation; Effectiveness; Evaluation; Excision; Fine-needle biopsy; Fluorescence; Frequencies; Fresh Tissue; Frozen Sections; Funding; Glioma; Goals; Gold; Health; Healthcare; Hematoxylin and Eosin Staining Method; Histology; Histopathology; Home environment; Hospitals; Image; Image Analysis; Imagery; Imaging Techniques; Injury; International; K-Series Research Career Programs; Knowledge; Label; Laboratories; Lead; Learning Skill; Life; Linear Algebra; Lipids; Machine Learning; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Medicine; Mentors; Methodology; Methods; Microscopy; Mitotic; Modality; Molecular; Morphologic artifacts; Morphology; Myelin Sheath; Necrosis; Neoplasm Metastasis; Nervous System Physiology; Neurologic Deficit; Neuronavigation; Neurosurgeon; Normal tissue morphology; Nuclear; Nucleic Acids; Online Systems; Operating Rooms; Operative Surgical Procedures; Optics; Outcome; Pathologic; Patient-Focused Outcomes; Patients; Pituitary Gland Adenoma; Postoperative Period; Preparation; Procedures; Process; Proteins; Quality of life; Raman Spectrum Analysis; Research; Research Infrastructure; Research Personnel; Residual Tumors; Resolution; Sampling; Series; Shapes; Signal Transduction; Solid; Specimen; Speed; Staining method; Stains; Structure; Surgical Injuries; Surgical Oncology; System; Technology; Time; Tissue Banking; Tissue Banks; Tissue Stains; Tissues; Training; Training and Education; Translational Research; Treatment Step; Tumor Biology; Tumor Tissue; Universities; Validation; Woman; Work; World Health Organization; Writing; Xenograft procedure; angiogenesis; base; bioimaging; brain tissue; brain tumor resection; cancer cell; cancer diagnosis; career; career development; catalyst; chemical bond; chemical group; clinical practice; clinically relevant; commercialization; computer science; disorder prevention; experience; frontier; gray matter; human disease; image guided; image guided therapy; imaging system; improved; innovation; instrument; meningioma; microscopic imaging; mouse model; neuropathology; neurosurgery; novel; novel strategies; operation; outcome forecast; peer; programs; prototype; screening; skills training; standard care; symposium; tool; tumor; white matter

 DESCRIPTION (provided by applicant): The goal of brain tumor surgery is to maximize removal of tumor without causing permanent neurologic deficits. Studies have shown that outcomes for patients depend strongly on these two variables. However, this is difficult because tumor tissue is often indistinguishable from healthy tissue in the operating room. Preoperative and intraoperative MRI through neuronavigation can be used to guide brain tumor surgery, but it is not able to accurately delineate the tumor margin due to the brain deformation and brain shift during surgery. H&E staining as the current gold standard is often performed intraoperatively for preliminary diagnosis, but it is not used to guide extent of resection routinely due to the limitations including tissue artifacts, labor-intensiveness, and time delay. Fluorescence guided surgery is beginning to be used to guided brain tumor surgery, but is generally not useful for low grade gliomas, the tumors which pose the greatest challenge and opportunity to extend survival and improve quality of life. Stimulated Raman imaging (SRI) has been used for rapid label-free biomolecular mapping in live tissue. Recently we have developed a novel approach with SRI to image nucleic acids, together with protein and lipids. Visualization of nucleic acids allows definition of nuclear morphology and chromatin structures, thereby enabling pathologic evaluation of clinically relevant cellular morphology, providing almost equivalent information to H&E staining. The goal of this translational research is to establish the methodology and practice for label-free histopathology with SRI for brain tumor diagnosis, and eventually develop it into a clinical device for ambient SR imaging of fresh tissue in the operating room in real time If the aims are achieved, this project will greatly improve the current clinical practice of brain tumor surgery by providing real time tissue diagnosis for more precise control of the extent of resection and preservation of neurologic function. Furthermore, this approach may be of value for all oncologic surgeries and other clinical pathology such as fine needle biopsies and bone marrow biopsy. The candidate for this award Dr. Fake Lu is a postdoctoral research fellow at Brigham and Women's Hospital. Dr. Lu has extensive experience and expertise in biophotonics and biomedical optics, specialized in system innovations of stimulated Raman microscopy and multiphoton microscopy for biomedical applications. BWH is an international leader in basic, clinical and translational research on human diseases, and has established multiple research programs to promote the work and professional career development of young investigators. BWH is also home to the National Center for Image Guided Therapy (P41) and the Advanced Multi-modality Image Guided operating suite (AMIGO) infrastructure which will greatly support to proposed research. Dr. Lu's long term research goal is to develop and apply advanced biophysical and optical technologies and devices to improve understanding, diagnosis, treatment, and prevention of diseases, such as cancers, for better health care. His long-term career goal is to become an independent investigator working at the frontier of translational research. The immediate objectives for the five-year award period is to 1) establish and evaluate label-free histopathology SRI for brain tumor diagnosis, 2) to demonstrate ambient imaging of surgically removed fresh tissue for diagnosis of brain tumors for real time guidance of neurosurgical resection, 3) to develop a novel stimulated Raman microscopy to collect full spectral data in parallel for label-free histopathology, as well as lipid biomarker screening, 4) t develop a computer algorithm for SR image analysis to realize automatic brain tumor diagnosis, and 5) finally by integrating the instrument and software to build and demonstrate a prototype of a clinical device for guiding neurosurgical resection of brain tumors. This device could also be used for other oncologic surgeries and will have great potential for commercialization. To conduct the proposed research, in addition to further develop his current strengths in biophotonics, stimulated Raman microscopy, and nonlinear optical microscopy, Dr. Lu plans to receive more education and training to enrich and expand his knowledge and expertise in the following four areas: 1) to receive critical training in conducting translational research, 2) to enrich his knowledge and deepen his understanding in brain tumor biology and medicine, 3) to learn skills in developing computer algorithms for SR image analysis, and 4) to prepare for writing grant applications and seeking funding independently. Dr. Lu will participate in 12 formal courses selected from those offered by Harvard Catalyst and Cold Spring Harbor Laboratory. He will attend weekly seminars at BWH and Harvard University, seminar series on biomedical image analysis organized by MIT Computer Science and Artificial Intelligence Laboratory. He will also attend one or two annual conferences per year to present his work for peer discussion. A strong mentoring team was organized to provide solid support to the proposed research and Dr. Lu's career development, including Dr. Alexandra Golby in neurosurgery at BWH, Prof. X. Sunney Xie in coherent Raman microscopy at Harvard, Prof. Nathalie Agar in molecular cancer diagnosis at BWH, Prof. Polina Golland in computer-based image analysis at MIT, and Dr. Sandro Santagata in neuropathology at BWH. This career development award will provide Dr. Lu with the training and skills needed to transition into an independent investigator in translational research.

 描述（由申请人提供）：脑肿瘤手术的目标是最大限度地切除肿瘤，而不会造成永久性神经功能缺损。研究表明，患者的结局在很大程度上取决于这两个变量。然而，这是困难的，因为在手术室中肿瘤组织通常与健康组织难以区分。神经导航下的术前和术中MRI可用于指导脑肿瘤手术，但由于术中脑变形和脑移位，无法准确勾画肿瘤边缘。H&E染色作为目前的金标准，通常在术中进行初步诊断，但由于其局限性，包括组织伪影，劳动强度和时间延迟，它并不用于指导切除范围。荧光引导手术开始用于引导脑肿瘤手术，但通常不适用于低级别胶质瘤，这些肿瘤对延长生存期和改善生活质量提出了最大的挑战和机会。受激拉曼成像（SRI）已被用于快速无标记的生物分子在活组织中的映射。最近，我们开发了一种利用SRI对核酸以及蛋白质和脂质进行成像的新方法。核酸的可视化允许定义核形态和染色质结构，从而能够对临床相关的细胞形态进行病理学评价，提供与H&E染色几乎等同的信息。这项转化研究的目标是建立用于脑肿瘤诊断的SRI无标记组织病理学的方法学和实践，并最终将其开发成用于手术室新鲜组织真实的实时环境SR成像的临床设备。该项目将通过提供真实的时间组织诊断以进行更精确的控制，切除的范围和神经功能的保留。此外，这种方法可能对所有肿瘤手术和其他临床病理学（如细针活检和骨髓活检）具有价值。该奖项的候选人Fake Lu博士是布里格姆妇女医院的博士后研究员。卢博士在生物光子学和生物医学光学领域拥有丰富的经验和专业知识，专注于生物医学应用中的受激拉曼显微镜和多光子显微镜的系统创新。BWH是人类疾病基础、临床和转化研究的国际领导者，并建立了多个研究项目，以促进年轻研究人员的工作和职业发展。BWH也是国家图像引导治疗中心（P41）和高级多模态图像引导手术套件（AMIGO）基础设施的所在地，这将极大地支持拟议的研究。卢博士的长期研究目标是开发和应用先进的生物物理和光学技术和设备，以提高对疾病（如癌症）的理解、诊断、治疗和预防，从而实现更好的医疗保健。他的长期职业目标是成为一名在转化研究前沿工作的独立调查员。五年奖励期的近期目标是1）建立和评估用于脑肿瘤诊断的无标记组织病理学SRI，2）展示用于脑肿瘤诊断的手术切除新鲜组织的环境成像，用于神经外科切除的真实的时间指导，3）开发一种新型受激拉曼显微镜，并行收集全光谱数据，用于无标记组织病理学，以及脂类生物标志物筛选; 4）开发SR图像分析的计算机算法，实现脑肿瘤的自动诊断; 5）最终通过仪器与软件的集成，构建并演示了一台指导脑肿瘤神经外科切除的临床设备样机。该设备也可用于其他肿瘤手术，具有巨大的商业化潜力。为了进行拟议的研究，除了进一步发展他目前在生物光子学，受激拉曼显微镜和非线性光学显微镜方面的优势外，卢博士计划接受更多的教育和培训，以丰富和扩大他在以下四个领域的知识和专业知识：1）接受进行翻译研究的关键培训，2）丰富他的知识，加深他对脑肿瘤生物学和医学的理解，3）学习开发用于SR图像分析的计算机算法的技能，以及4）准备撰写拨款申请和独立寻求资金。卢博士将参加从哈佛催化剂和冷泉港实验室提供的12门正式课程。他将参加BWH和哈佛大学的每周研讨会，麻省理工学院计算机科学和人工智能实验室组织的生物医学图像分析系列研讨会。他还将每年参加一次或两次年度会议，介绍他的工作，供同行讨论。我们组织了一个强大的指导团队，为拟议的研究和卢博士的职业发展提供坚实的支持，包括BWH神经外科的Alexandra Golby博士，X教授。Sunney Xie在哈佛的相干拉曼显微镜中，Nathalie Agar教授在BWH的分子癌症诊断中，Polina Golland教授在麻省理工学院的计算机图像分析中，Sandro Scarlata博士在BWH的神经病理学中。该职业发展奖将为陆博士提供转变为转化研究独立研究者所需的培训和技能。