毕业生知识库

胶质瘤恶性程度高，严重危害人类生命健康。其中最为严重的胶质母细胞瘤，患者的中位总生存期仅有14.6个月。胶质瘤诊疗指南中推荐的首选治疗手段是手术切除，其总体要求是保护神经功能的前提下最大限度切除肿瘤。然而由于胶质瘤呈浸润性生长的特性，外科医生借助现有影像方法及视诊、触诊在术中难以精准识别肿瘤边界，难以实现胶质瘤精准切除。光学分子影像为胶质瘤的精准检测与切除带来了新机遇。

光学分子影像利用光学成像手段可以无创、动态地可视化生物活体内细胞分子水平的生物化学信息，目前已经用于肿瘤检测、肿瘤机理和药物评价等基础研究和手术导航等临床应用，受到国际学者的广泛关注。光学分子影像常需要外源激发，然而外源激发方式导致肿瘤周围的生物组织背景噪声大，成像信背比低，难以实现肿瘤的精准检测；此外，现有的光学分子影像常利用900 nm以下谱段的光进行成像，这一谱段的光，生物组织的吸收散射效应强，光源三维重建病态性较高，断层成像的重建精度受到制约。本论文针对上述挑战性问题，提出了核素多内源激发荧光分子成像方法，提高成像信背比；并提出了基于头部组织特异性近红外二区光传输模型与斜投影匹配追踪算法的光学断层成像方法，提高病灶的定位精度；在此基础上，构建了小动物及临床高灵敏荧光分子成像系统；通过多种动物模型进行实验验证，最终实现了临床转化，开展了胶质瘤患者的术中近红外二区荧光分子成像，实现了胶质瘤边界的术中精准识别，显著提高了肿瘤完整切除率，延长了患者的生存时间，改善了患者的生存质量。论文的主要研究内容如下：

1. 针对胶质瘤高灵敏检测的问题，提出了核素多内源激发荧光分子成像新方法。创新性地利用临床放射药物¹⁸F-FDG衰变产生的低能契伦科夫光子及同步产生的高能β粒子和γ光子，从生物体内部激发铕离子掺杂的氧化钆纳米颗粒，实现能量转移，产生峰值为620 nm的荧光，显著提高了荧光信号强度和成像信背比。与现有的契伦科夫光学成像相比，荧光信号强度提升了369倍，信背比提高了4倍。在此基础上，通过胶质瘤小鼠模型验证了该方法的有效性，实现了胶质瘤的高精准检测，并进一步将该方法拓展到乳腺癌小鼠模型，检出了PET影像遗漏的微小病灶，并成功引导了肿瘤切除。

2. 针对胶质瘤高精准定位的问题，提出了基于头部组织特异性近红外二区光传输模型与斜投影匹配追踪算法的光学断层成像方法。首先通过研究小鼠头部多种组织对近红外二区荧光的吸收特性和散射特性，构建头部组织特异性近红外二区光传输模型，精确描述了近红外二区光子在复杂头部组织中的传输过程。此外，提出了斜投影匹配追踪算法，用于重建过程的逆问题求解。与传统的正交匹配追踪算法相比，在迭代过程中根据荧光信号的强度引入预选数据支撑，并在相关性计算过程中保留非正交分量，以提高病灶的定位精度和形状恢复能力。在此基础上，通过胶质瘤仿真实验与活体动物实验对方法进行验证。与现有的近红外二区荧光断层成像方法相比，胶质瘤的定位误差降低了36%，形状恢复系数提升了55%。

3. 针对临床胶质瘤高灵敏检测与精准切除的问题，在上述成像方法的基础上，构建了临床胶质瘤近红外二区荧光手术导航系统，开展了胶质瘤近红外二区术中荧光成像与精准切除研究。与首都医科大学北京天坛医院神经外科合作，入组33名胶质瘤患者，利用临床获批的荧光染料吲哚菁绿在近红外二区的荧光拖尾，开展随机对照实验。研究表明近红外二区荧光成像能够在术中精准识别胶质瘤的边界，并检测到现有方法难以发现的微小残余病灶，显著提升肿瘤的完整切除率，延长患者生存期。与现有方法相比，肿瘤完整切除率提升50%，患者中位无进展生存期和中位总生存期分别延长2个月和3.5个月，同时可以最大限度减少功能区的损伤，避免患者术后瘫痪。

总体而言，本文针对胶质瘤高灵敏检测与精准定位的问题，提出了核素多内源激发荧光分子成像方法，和基于头部组织特异性近红外二区光传输模型与斜投影匹配追踪算法的光学断层成像方法，并构建了小动物和临床胶质瘤近红外二区荧光分子成像系统，通过动物实验验证，最终实现了临床转化，显著提高了胶质瘤患者的完整切除率，显著延长了患者的生存时间。

Glioma is of severe malignancy and poses a serious threat to human life and health. Patients with glioblastomas, the most malignant gliomas, had a median overall survival of only 14.6 months. The most recommended treatment by the guidelines on the diagnosis and treatment of glioma is surgical resection, in which maximal safe resection is required. However, maximal safe resection of the gliomas is seldom achieved with the existing imaging methods because of the infiltration into the eloquent areas and the difficulty in distinguishing the tumor tissue from the normal tissue in the resection margin even in the non-eloquent area. Optical molecular imaging is expected to provide the accurate detection and resection of gliomas with novel technological support.

Fluorescence molecular imaging is a type of optical molecular imaging that has received extensive attention in recent years. It can facilitate the visualization and investigation of complex biochemical phenomena by labeling tumor-specific biomarkers. The conventional FMI uses the emission light of 700-900 nm. It has shown broad application prospects in basic research and clinical applications, including detection of tumors, evaluation of drug efficacy, and fluorescence image-guided surgery. However, the light with a wavelength of 700 – 900 nm was greatly affected by surrounding tissues as it passes through. The obligatory scattering and absorption effects of tissue lead to obvious background noise to the images, resulting in a low signal-to-background ratio. Besides, it even leads to the ill-posedness of fluorescence molecular tomography (FMT), which strictly limited the accuracy of light source reconstruction.

In view of the above challenging problems, a novel triple-excited fluorescence imaging (TEFI) method and a second near-infrared window (NIR-II) fluorescence imaging method was first established, which realized the improvement of signal intensity, signal-to-background ratio, and localization accuracy of lesions. Based on the imaging methods, an optical molecular imaging system was constructed and verified by a variety of animal experiments. With all the efforts made, the clinical application of the imaging method was finally achieved. Patients with gliomas were involved in the clinical trials of NIR-II fluorescence imaging and image-guided surgery. During the surgery, the tumor margins of gliomas were clearly distinguished by the NIR-II fluorescence imaging. The tumor was then resected under the guidance of NIR-II fluorescence images, with a complete resection rate significantly increased to 100% from 50% of the conventional surgical method. Survival of patients was prolonged and the quality of life of patients was improved.

The main research contents of the dissertation are as follows:

To achieve an improved detection sensitivity of gliomas, a novel Triple-excited fluorescence imaging (TEFI) method was developed by combining radio-pharmaceuticals and metal oxide nanoparticles. The ¹⁸F-fludeoxyglucose (¹⁸F-FDG) was applied as the excitation source. Cerenkov light, β particles, and γ ray that were generated along with the decay of ¹⁸F-FDG were used to interact with the Eu³⁺ doped Gadolinium Oxide (Gd₂O₃: Eu) to achieve a red-shifted fluorescence with an emission peak of 620 nm. Compared with Cerenkov luminescence imaging, the fluorescence signal intensity of the novel TEFI method reached 369 times higher than that of CLI. Based on the establishment of the TEFI method, in vivo TEFI imaging of gliomas in a subcutaneous model of small animals verified the effectiveness of the method in detecting gliomas in living animals. The method was further expanded to the guidance of breast tumor resection using small animal models. Using the TEFI method, small tumor lesions of breast tumor that were omitted by pre-operative PET imaging was detected. And the TEFI method was applied successfully in the resection of the tumor.

To achieve the localization of gliomas with high precision, an FMT method of NIR-II fluorescence was then raised based on a tissue-specific transmission model of NIR-II fluorescence and oblique projection matching pursuit algorithm. The absorption and scattering coefficients of NIR-II fluorescence in various tissues of the head were analyzed, based on which a tissue-specific transmission model of NIR-II light in the head was constructed. Therefore, the transmission process of NIR-II photons in complex head tissues was accurately described. Besides, the matching pursuit method was further modified by intraducing the oblique projection operator. Compared with the traditional orthogonal matching pursuit method, a pre-selected data support set was introduced according to the intensity of the fluorescence signal, and the non-orthogonal components were retained in the correlation calculation during the iterative process. Both operations aimed to improve the localization accuracy and shape recovery ability. In simulation experiments, the localization error of the tumor was reduced by 36% and the shape recovery coefficient was improved by 55%.

Based on the development of the imaging methods, a randomized controlled clinical trial on NIR-II fluorescence image-guided surgery of gliomas was carried out to further verify the clinical use. A NIR-II fluorescence imaging system was specially designed for gliomas to facilitate the clinical trial. Clinically approved indocyanine green (ICG) was injected as an imaging probe. With the approval of the ethics committee of Beijing Tiantan Hospital, Capital Medical University, 33 patients were involved in the trial.The NIR-II fluorescence can assist in the accurate identification of tumor resection margin and the detection of small residual tumor lesions that were omitted by the existing methods. The use of the NIR-II fluorescence imaging significantly improved the complete resection rate of the tumor and prolonged the survival time of patients. Compared with patients assigned to surgery under white light, the complete resection rate of the tumor was significantly increased by 50%, and the median progression-free survival and median overall survival were significantly prolonged by 2 months and 3.5 months, respectively. At the same time, the damage to the eloquent areas was minimized and paralysis after surgery can be avoided.

In summary, this dissertation raised the triple-excitation fluorescence imaging method and an FMT method of NIR-II fluorescence based on a tissue-specific transmission model of NIR-II fluorescence and oblique projection matching pursuit algorithm. Based on that, a clinical imaging system used for NIR-II fluorescence image-guided surgery of gliomas was constructed. With all the efforts made, a clinical trial of NIR-II fluorescence imaging and image-guided precise surgery of gliomas was then performed, which brought patients clinical benefits.