ulTRafast hOlograPHic FTIR microscopY (TROPHY)

许多人类病理学如癌症是由于复杂的生物化学改变，这些改变始于亚细胞水平，并导致渐进性变化，从而导致异质性肿瘤组成。肿瘤细胞的多克隆性阻碍了诊断和治疗，从而产生肿瘤克隆，导致治疗抗性并促进转移。对肿瘤活检进行准确诊断以识别这些特定的细胞克隆对于提供针对肿瘤特征的靶向治疗、改善患者预后和提高生存率至关重要。为了实现这一愿景，我们引入ulTRafast全息FT-IR显微镜（TROPHY）作为振动显微镜的范式转变，混合光热红外（PT-IR），傅里叶变换（FT）-IR和数字全息显微镜（DHM）的元素。TROPHY将这些技术带到了前所未有的超快时间尺度，其中相干红外振动引起的折射率变化在热弛豫之前的峰值处被探测。TROPHY从PT-IR借用IR振动激发与可见光探测的组合以获得高空间分辨率，从FT-IR借用时域干涉测量的使用以从宽带激发获得高光谱分辨率，从DHM借用折射率（相位）变化的高灵敏度和定量检测。结合人工智能算法，该技术将实现分子生物标志物的定量浓度成像，具有高空间分辨率，高化学选择性和高速度，对医学研究和临床产生变革性影响。在肿瘤学方面，将应用于肿瘤活检的术中诊断，提供肿瘤分级、分期和亚型，支持肿瘤完整切除。它还将允许确定为患者量身定制的最佳治疗方法，并在靶向治疗下识别耐药肿瘤克隆，为癌症的精准医学铺平道路。

Many human pathologies such as cancer are due to complex biochemical alterations that start at a sub-cellular level and lead to progressive changes that result in a heterogeneous tumor composition. The polyclonality of tumor cells hampers the diagnosis and the therapy giving rise to tumor clones that lead to therapy resistance and promote metastases. An accurate diagnosis of tumor biopsies to identify these particular cell clones is crucial to provide targeted therapy tailored to the tumor characteristics, to improve the patient outcomes and increase survival rates. For this vision to come true, we introduce ulTRafast hOlograPHic FT-IR microscopY (TROPHY) as a paradigm shift in vibrational microscopy, blending elements of photo-thermal infrared (PT-IR), Fourier transform (FT)-IR, and Digital Holography Microscopy (DHM). TROPHY brings these techniques to the unprecedented ultrafast timescale, where the refractive index change induced by coherent IR vibrations is probed at its peak value before thermal relaxation. TROPHY borrows from PT-IR the combination of IR vibrational excitation with visible probing for high spatial resolution, from FT-IR the use of time-domain interferometry to obtain a high spectral resolution from broadband excitation, from DHM highly sensitive and quantitative detection of the refractive index (phase) change. Combined with artificial intelligence algorithms, this technology will enable quantitative concentration imaging of molecular biomarkers with high spatial resolution, high chemical selectivity and high speed, with a transformative impact on medical research and clinics. In oncology, it will be applied to intraoperative diagnosis of tumor biopsies, providing tumor grading, staging and subtyping, and supporting complete tumor resection. It will also allow to determine the best therapeutic approach tailored to the patient and identify resistant tumor clones under targeted therapy, paving the way for precision medicine in cancer.