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: 9531474
• 负责人: Fake Lu
• 金额: $ 24.88万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9531474
• 关键词: Agar; Algorithms; Applications Grants; Area; Artificial Intelligence; Atypia; Award; Axon; Basic Science; Biological; Biological Markers; Biological Preservation; Biophotonics; Biophysics; Bone marrow biopsy; Brain; Brain Neoplasms; Brain imaging; Cancerous; Cell Density; Cellular Morphology; Chromatin Structure; Clinical; Clinical Pathology; Clinical Research; Collagen; Computational algorithm; Computer Vision Systems; Computer software; Computers; Data; Decision Making; Devices; Diagnosis; Diagnostic; Dimensions; Documentation; Effectiveness; Excision; Fine-needle biopsy; Frequencies; Fresh Tissue; Frozen Sections; Funding; Glioma; Goals; Gold; Healthcare; Hematoxylin and Eosin Staining Method; Histologic; Histology; Histopathology; Home environment; Hospitals; Image; Image Analysis; Image-Guided Surgery; Imagery; Imaging Techniques; Injury; International; K-Series Research Career Programs; Knowledge; Label; Laboratories; Lead; Learning Skill; Linear Algebra; Lipids; Machine Learning; Magnetic Resonance Imaging; Malignant Neoplasms; Medicine; Mentors; Methodology; Methods; Microscopy; Mitotic; Molecular; Morphologic artifacts; Morphology; Multimodal Imaging; 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 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; fluorescence-guided surgery; 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; public health relevance; research clinical testing; screening; skills; standard care; symposium; tool; tumor; vibration; 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在不引起永久性神经功能缺损的情况下最大限度地切除肿瘤。研究表明，患者的结果很大程度上取决于这两个变量，然而，这很困难，因为肿瘤组织通常难以区分。通过神经导航从手术室的健康组织中获取术前和术中MRI可用于指导脑肿瘤手术，但由于手术过程中脑变形和脑移位，它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，但由于组织伪影、劳动强度大和开始使用荧光引导手术的时间延迟等限制，它不用于指导常规切除范围。刺激拉曼成像（SRI）可用于引导脑肿瘤手术，但通常对低级别胶质瘤没有用处，这些肿瘤对延长生存期和提高生活质量构成最大的挑战和机会，已被用于快速无标记。最近，我们开发了一种利用 SRI 成像核酸以及蛋白质和脂质的新方法，可以定义核形态和染色质结构，从而实现临床相关细胞形态的病理评估。这项转化研究的目标是建立使用 SRI 进行脑肿瘤诊断的无标记组织病理学的方法和实践，并最终将其开发成用于新鲜血液的环境 SR 成像的临床设备。如果目标实现，该项目将通过提供实时组织诊断来更精确地控制切除范围和保留神经功能，从而极大地改善当前脑肿瘤手术的临床实践。更多,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）有价值。该奖项的候选人 Fake Lu 博士是布莱根妇女医院的博士后研究员，拥有丰富的经验。和专业知识BWH 致力于生物光子学和生物医学光学领域，专门从事受激拉曼显微镜和多光子显微镜在生物医学应用方面的系统创新，是人类疾病基础、临床和转化研究领域的国际领先者，并建立了多个研究项目来促进工作和专业职业发展。 BWH 也是国家图像引导治疗中心 (P41) 和先进多模态图像引导操作套件 (AMIGO) 基础设施的所在地，这将为拟议的研究提供大力支持。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，以提高对癌症等疾病的理解、诊断、治疗和预防，以实现更好的医疗保健。一位从事转化研究前沿的独立研究者，五年奖励期的直接目标是 1) 建立和评估用于脑肿瘤诊断的无标记组织病理学 SRI，2) 证明手术切除的新鲜组织诊断的环境成像。脑肿瘤的实时指导神经外科切除，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质生物标志物筛选，4) 开发用于 SR 图像分析的计算机算法，以实现自动化脑肿瘤诊断，5) 最后通过集成仪器和软件来构建和演示用于指导脑肿瘤神经外科切除的临床设备原型。该设备也可用于其他肿瘤手术和手术。为了开展这项研究，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，卢博士还计划接受更多的教育和培训，以丰富和扩展他的知识和能力。具备以下四个领域的专业知识：1）接受进行转化研究的关键培训，2）丰富知识并加深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）独立准备撰写资助申请和寻求资助。陆博士将参加Harvard Catalyst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，生物医学系列研讨会。麻省理工学院计算机科学与人工智能实验室组织的图像分析每年还会参加一到两次年会，展示他的工作以供同行讨论，为卢博士的研究和职业发展提供坚实的支持。 ,包括 BWH 神经外科领域的 Alexandra Golby 博士、哈佛大学相干拉曼显微镜领域的 X. Sunney Xie 教授、BWH 分子癌症诊断领域的 Nathalie Agar 教授、麻省理工学院计算机图像分析领域的 Polina Golland 教授以及BWH 神经病理学领域的 Sandro Santagata 该职业发展奖将为 Lu 博士提供转型研究独立研究者所需的培训和技能。