Nasiri Rohollah, Kurosu Jalil Myra, Ibanez Gaspar Veronica, Flores Perez Andrea Sofia, Nguyen Hieu Thi Minh, Khan Syamantak, Tang Sindy K Y, Yang Yunzhi Peter, Pratx Guillem
Department of Radiation Oncology, Stanford University, Stanford, CA, USA.
Department of Mechanical Engineering, Stanford University, Stanford, CA, USA.
Lab Chip. 2025 Aug 5. doi: 10.1039/d5lc00373c.
Most solid tumors contain regions of hypoxia that pose a significant challenge to the efficacy of radiation therapy. This study introduces a novel 3D lung tumor-on-a-chip (ToC) model designed to replicate the hypoxic tumor microenvironment while also providing a platform for clinically relevant interventions such as radiotherapy and positron emission tomography (PET) imaging. To simulate the heterogeneous oxygen distribution found in tumors, the ToC model incorporates an oxygen gradient achieved through a straightforward chemical oxygen scavenging system. A unique innovation of this device is the integration of a thin scintillator plate, which enables high-resolution radioluminescence microscopy imaging of tumor metabolism under hypoxia and normoxia conditions using clinically approved PET tracers such as fluorodeoxyglucose (FDG). The response of this hypoxic model to radiation therapy (10 Gy X-ray) demonstrated ∼4-fold higher radioresistance compared to the normoxic ToC model, as assessed by colony formation potential. Additionally, DNA damage observed in the normoxic ToC model was ∼5-fold higher than that in the hypoxic model. Furthermore, the metabolic consumption of glucose was found to mirror the localization of hypoxia, validating the use of this biomarker for planning radiation therapy. The integration of high-resolution radionuclide imaging within ToC models enables on-chip PET imaging and facilitates oncology research and discovery, offering innovative capabilities for the preclinical testing of novel cancer therapies in a clinically relevant environment.
大多数实体瘤都含有缺氧区域，这对放射治疗的疗效构成了重大挑战。本研究引入了一种新型的三维肺肿瘤芯片（ToC）模型，该模型旨在复制缺氧肿瘤微环境，同时还提供一个用于放疗和正电子发射断层扫描（PET）成像等临床相关干预的平台。为了模拟肿瘤中发现的异质氧分布，ToC模型采用了通过简单的化学氧清除系统实现的氧梯度。该装置的一个独特创新是集成了一个薄闪烁体板，它能够使用临床批准的PET示踪剂，如氟脱氧葡萄糖（FDG），在缺氧和常氧条件下对肿瘤代谢进行高分辨率放射发光显微镜成像。通过集落形成潜力评估，该缺氧模型对放射治疗（10 Gy X射线）的反应显示出比常氧ToC模型高约4倍的放射抗性。此外，在常氧ToC模型中观察到的DNA损伤比缺氧模型高约5倍。此外，发现葡萄糖的代谢消耗反映了缺氧的定位，验证了这种生物标志物在放射治疗计划中的应用。在ToC模型中集成高分辨率放射性核素成像能够实现芯片上的PET成像，并促进肿瘤学研究和发现，为在临床相关环境中对新型癌症治疗进行临床前测试提供了创新能力。
