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太赫兹波(terahertz, THz)是位于微波和红外之间介观尺度波长的电磁波, 因其低电离性和指纹性的特点, 在生物医学领域有着巨大的应用潜力, 尤其是在肿瘤的术中定位定性诊断方面. 而对于定位定性诊断需求最迫切的肿瘤为胶质瘤, 因其侵袭性和异质性, 切除后极易复发且对临近脑区神经功能有显著影响, 快速确定瘤体边界以及肿瘤病理学特征, 是开展胶质瘤精准诊疗和临床研究的重要前提. 本文总结了胶质瘤诊断的生物物理技术, 梳理了太赫兹波这一新兴技术在胶质瘤诊断方面所取得的研究成果. 进一步, 基于胶质瘤组织病理和分子病理整合诊断研究进展, 提出不同分子分型肿瘤组织在太赫兹波段可能具有不同 “特异性蛋白组成”的太赫兹肿瘤亚型识别机制假说, 结合脑组织生物学特点与体液中胶质瘤标志物检测潜力, 全面设想了未来太赫兹波在胶质瘤临床诊疗中的应用模式和发展前景.Terahertz wave is an electromagnetic wave, whose wavelength is located between microwave wavelength and infrared wavelength. Based on low ionization and fingerprint characteristics, it has great potential applications in biomedical field, especially in the intraoperative localization and qualitative diagnosis of tumors. Glioma is the most urgent tumor for positioning qualitative diagnosis. Owing to its invasiveness and heterogeneity, it is easy to relapse after resection and has a significant influence on the nerve function of adjacent brain regions. Therefore, rapid determination of tumor boundary and pathological characteristics is an important prerequisite for accurate diagnosis, treatment and clinical research of glioma. Here, we summarize the biophysical technology of glioma diagnosis, and expound the new technique of terahertz wave and its research results in diagnosis of glioma. Furthermore, based on the research progress of integrated diagnosis of glioma histopathology and molecular pathology, we propose a hypothesis that different molecular subtypes of tumor tissue may have a consistent 'differential terahertz wave protein composition' of terahertz tumor subtype recognition mechanism. Finally, combining the biological characteristics of brain tissue and the potential of glioma marker detection in body fluids, we discuss the clinical application model and prospects of terahertz technologies in glioma detection.
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Keywords:
- terahertz technology /
- glioma /
- molecular markers /
- diagnosis
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表 1 当前胶质瘤临床诊断方法
Table 1. Current clinical diagnosis of glioma.
诊断方式 标记物 对健康组织损伤 局限性 应用效果对比 检测信息 影像学
诊断CT 18F; 11C; 64Cu 微量辐射暴露 对软组织的分辨率和敏感性相对较低, 成像参数少 适用于术后早期病人的检查及因手术银夹不能行MRI检查者 实现定位, 部分定性 PET-CT 碘剂; 钡剂; 金 辐射引起微量
组织损伤辐射大、价格昂贵,
缺乏解剖相关性特异性高, 具有较高阳性预测值与准确性, 阴性预测值较CT和MRI低 SPECT 放射药物 辐射剂量小,
价格低廉空间分辨率、特异性低 可应用于判断胶质瘤恶性程度 MRI 顺磁性或超顺磁性粒子钆 无创、需造影剂 检查时间长、费用高, 对患者自身因素有限制 敏感性高, 具有较高的诊断准确性 病理学
诊断术中冰冻病理 HE试剂 有创、局部组织 取材局限、容易漏诊,
图像解释具有主观性可用于术中胶质瘤形态观察, 确定手术范围 实现定性 术后免疫组化 标记物抗体 有创、病灶组织 周期长、滞后 为后期胶质瘤治疗提供指导建议 分子生物学技术 生物芯片、基因检测和测序 依赖检测平台 有创、局部病灶组织、血液 准入门槛高、滞后性、
价格昂贵提供药物筛查、靶向精准治疗 其他新型技术 拉曼光谱 — 抗干扰强, 结果
重复性好散射效率低, 单次检测面积小 介观尺度胶质瘤病灶精准检测及分级识别 可同时获取“定位定性”信息 太赫兹波 — 无创、非电离 穿透深度低, 水敏感 宏观到介观尺度病灶分布与肿瘤边界, 肿瘤组织与正常组织, 肿瘤分子分型特异性识别 表 2 近10年太赫兹技术在肿瘤诊断中的工作模式
Table 2. Patterns of THz technique in tumor diagnosis over the last 10 years.
年份 癌症种类 辐射源 工作模式 参考文献 2011 肝癌(兔) 脉冲式 反射式光谱成像系统 [46] 2011 结肠癌(人) 脉冲式 反射式成像系统 [47] 2011 基底细胞癌(BCC) 连续式 光纤扫描近场显微镜透射成像系统 [61] 2011 乳腺癌 脉冲式 透射式成像系统 [38] 2011 结肠癌 脉冲式 反射式成像系统 [48] 2011 宫颈癌 脉冲式 反射式成像模式 [49] 2011 皮肤癌 连续式 透射式成像模式 [41] 2011 胶质瘤 脉冲式 反射式成像模式 [62] 2013 结肠癌 连续式 反射式成像模式 [63] 2013 肝癌 脉冲式 光纤扫描近场显微镜透射成像系统 [64] 2013 恶性黑色素瘤 脉冲式 反射式成像模式 [65] 2013 乳腺癌 连续式 反射式成像模式 [51] 2013 口腔癌 脉冲式 反射式成像模式 [50] 2014 结肠癌 连续式 反射式成像模式 [66] 2014 皮肤病 脉冲式 反射式成像模式 [52] 2014 皮肤癌 脉冲式 反射式成像模式 [67] 2014 皮肤癌 连续式 反射式成像模式 [68] 2014 胶质瘤 脉冲式 反射式成像模式 [69] 2014 肠癌 脉冲式 反射式成像模式 [70] 2014 胶质瘤 脉冲式 透射式光谱模式 [42] 2015 结肠癌组织 脉冲式 透射式近场成像模式 [71] 2015 结肠癌组织 脉冲式 透射式光谱模式 [39] 2015 胃癌 脉冲式 透射式光谱模式 [72] 2015 乳腺癌 脉冲式 反射式成像模式 [73] 2015 肝癌组织 连续式 透射式同轴全息成像模式 [74] 2016 结肠癌 连续式 反射式光谱及成像模式 [40] 2015 胃癌 脉冲式 反射式光谱及成像模式 [75] 2016 NMSC组织 连续式 反射式成像模式 [76] 2016 胶质瘤 脉冲式 反射式光谱模式 [53] 2016 皮肤癌 连续式 反射式光谱及成像模式 [77] 2016 胶质瘤 脉冲式 反射式光谱及成像模式 [78] 2016 胶质瘤 脉冲式 反射式成像系统 [79] 2017 胃癌 脉冲式 透射式光谱模式 [43] 2017 乳腺癌 脉冲式 反射式成像模式 [80] 2017 乳腺癌 脉冲式 透射式光谱及反射式成像模式 [44] 2018 肝癌 脉冲式 反射式光谱模式 [81] 2018 乳腺癌 脉冲式 透射式成像模式 [82] 2018 乳腺癌 连续式 反射式成像模式 [83] 2018 乳腺癌 脉冲式 反射式光谱及成像模式 [84] 2019 胃癌 脉冲式 反射式光谱模式 [85] 2019 胶质瘤 连续式 反射式成像模式 [58] 2019 乳腺癌 脉冲式 反射式成像模式 [86] 2019 胶质瘤 脉冲式 反射式光谱及成像模式 [87] 2020 乳腺癌 脉冲式 反射式光谱及成像模式 [88] 2020 胶质瘤组织 连续式 反射成像模式 [59] 2020 胶质瘤组织 连续式 反射式成像模式 [89] 2021 皮肤癌 脉冲式 透射式光谱模式 [45] 2021 胶质瘤 脉冲式 — [90] 2021 胶质瘤 脉冲式 反射式光谱及成像系统 [91] 2021 胶质瘤组织 连续式 反射式光谱及成像系统 [60] 表 3 当前基于太赫兹技术研究胶质瘤的结果
Table 3. Current results of glioma studies using the terahertz techniques.
参考文献 年份 样本类型 THz 技术 研究特点 生物学对照 机理解释 组织 [62] 2011 SD大鼠胶质瘤模型 反射式太赫兹脉冲成像系统 首次开展THz胶质瘤成像 MRI, 可见光 水含量 [69] 2014 SD大鼠胶质瘤及瘤旁
(石蜡3 μm)反射式太赫兹脉冲成像系统 解释THz波生物组织成像机制 MRI, HE 除水含量外, 细胞密度、髓鞘分布 [42] 2014 C57小鼠胶质瘤模型, 大脑组织石蜡1—2.5 mm 透射式太赫兹脉冲光谱系统 测量了石蜡包埋的脑胶质瘤和正常脑组织的折射率、吸收系数和复介电常数, 分析最佳太赫兹频率 — 脑胶质瘤具有更高的折射率、吸收系数和介电常数 [78] 2016 SD大鼠胶质瘤模型(新鲜、石蜡) 反射式太赫兹脉冲光谱系统 定量解释THz光谱检测胶质瘤可行性 HE 细胞密度、含水量增加肿瘤折射率 [76] 2016 SD大鼠胶质瘤模型(新鲜) 反射式太赫兹脉冲光谱成像系统 探究利用复折射率值获得太赫兹图像检测脑肿瘤的可能性 HE 水含量、细胞密度 [79] 2016 Balb裸鼠原位异种移植、临床新鲜标本 反射式太赫兹脉冲成像系统 回答TRI解决临床组织移动性及无标记成像可能性 HE, 核磁 水、脂质 [87] 2019 临床人脑胶质瘤(明胶包埋) 反射式太赫兹脉冲光谱成像系统 应用于临床分级组织 HE 水、细胞密度、血肿成分 [58] 2019 C57胶质瘤组织 反射连续波太赫兹成像系统 反射连续波太赫兹成像系统应用与胶质瘤成像可能性 MRI, HE 血管、坏死碎片、水肿、细胞密度 [59] 2020 大鼠/小鼠胶质瘤组织 衰减全反射连续波太赫兹成像系统 提高成像有效面积 HE 水、细胞密度、血管密度 [89] 2020 大鼠胶质瘤 反射连续波太赫兹成像系统 提高分辨率 HE 水、细胞密度、血管密度 [91] 2021 SD大鼠胶质瘤模型(新鲜) 反射式太赫兹脉冲光谱系统 胶质瘤异质性 HE 微血管生成、组织异质性 [60] 2021 SD小鼠胶质瘤组织 反射式连续性太赫兹光谱成像系统 提高分辨率及扫描面积 HE、MRI 细胞、血管密度、组织坏死 [90] 2021 临床胶质瘤样品(明胶包埋) 脉冲太赫兹光谱系统 验证介电常数的物理模型可靠性 — — 细胞系 [98] 2021 胶质瘤细胞系 透射式太赫兹脉冲光谱系统 首次提出THz检测不同分子分型 — 细胞形态、大小、分子分型 [97] 2019 神经胶质细胞和胶质瘤细胞 衰减全反射太赫兹脉冲式光谱系统 从细胞系角度解释THz可区分肿瘤组织 — 形态、含水量 分子
标记物[99] 2019 GABA/COC 1:15—1:18 透射式太赫兹脉冲光谱系统 率先推进了太赫兹神经递质检测 — — [101] 2016 A-GLU/b-Glu 太赫兹时域光谱系统 区分不同构型谷氨酸 — — [37] 2016 2-HG及其异构体 太赫兹时域光谱系统 区分不同构型代谢物 — 碳链质子转移 [102] 2021 EGFR抗体结合 太赫兹时域光谱系统 提升EGFR检测灵敏性 — — -
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