A Multimodal CMOS Platform for Electromagnetic-Based Tissue Treatment and Dynamic Imaging Using Terahertz Spectroscopy

癌症是导致死亡的主要原因之一，仅次于心脏病。 传统的癌症治疗（放疗和化疗，免疫治疗和靶向治疗）需要新的协同模式来提高生存率，肿瘤治疗领域（TTF）已被誉为癌症治疗的“第四模式”。 迄今为止，肿瘤治疗领域主要应用于胶质母细胞瘤（FDA批准），并且令人兴奋的是将这种疗法应用于其他癌症，如多项正在进行的临床试验所证明的那样。 这项研究将有助于提高对这种治疗工作的物理机制的理解，发现与关键化疗和靶向分子疗法的协同作用，并针对每种癌细胞类型进行优化-并可能针对每个患者自己的组织。 使用定制的集成电路，我们将开发可以使用非常高频的电磁场（100-300 GHz）检测细胞和成像组织的传感器，这些电磁场已被证明可以有效区分肿瘤细胞和健康细胞，以及活跃分裂细胞和非分裂细胞。这将被用作在向细胞施加肿瘤治疗场期间检测细胞状态的工具。 希望既能了解肿瘤治疗场疗效的生物学原因，也能帮助优化肿瘤治疗场的电压和频率。 这项研究打开了一扇大门，未来植入式设备使用开发的传感器，可以在真实的时间在发现有效的治疗-传送即时细胞反应的治疗，以允许实时优化治疗为每个病人-个性化医疗的最终目标。将细胞成像技术与传统的互补金属氧化物半导体（CMOS）技术相结合，实现了微型化，并与包括片上信号处理和通信在内的其他功能集成在一起。先前的研究已经证明，通过测量介电常数的频散，可以在不使用任何特殊标记或标签的情况下识别肿瘤细胞。 迄今为止，大多数测量平台要么大量测量细胞，要么一次只能测量单个像素，并且缺乏测量亚细胞结构的空间分辨率。 可以在非常小的空间分辨率上测量介电常数的真正成像平台将通过利用CMOS技术的基于阵列的性质来实现，用于对较大的组织区域进行成像，从而允许在使用低频电磁（EM）场致动细胞的同时动态地映射细胞内的内容物。 使用超过100 GHz的频率可以实现单个像素元件的小型化，但这需要创新来提高传感器的灵敏度。 通过同时以高频率感测细胞并以低频率激活细胞（所谓的肿瘤治疗场），人们将有能力主动操纵和监测细胞分裂-这是癌症治疗的关键。肿瘤治疗场（TTF）已被证明通过与强极化分子相互作用来破坏正常细胞有丝分裂。 最近，TTF已被证明可有效治疗某些类型的癌症，最值得注意的是胶质母细胞瘤（GBM），一种高度侵袭性的脑肿瘤。这是几十年来这种疾病的第一个进展，并且与选择的化疗有协同作用。该研究旨在探索在更复杂的组织微环境中控制、研究和优化单细胞电磁场的能力，这对于优化TTF和选择药物组合是必要的，但迄今为止还无法实现。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

Cancer is one of the leading causes of death, second only to heart disease. Traditional cancer treatment (radiotherapy and chemotherapy, immunotherapy, and targeted therapy) is in need of new and synergistic modalities to increase survival, and tumor-treating fields (TTF) have been heralded as the "fourth modality" in cancer treatment. To date tumor-treating fields has been applied mostly to glioblastoma (FDA approved) and there is excitement to apply this therapy to other cancers, as evidenced by multiple ongoing clinical trials. This research will help to improve the understanding of the physical mechanisms by which this treatment works, discovering synergies with key chemotherapeutic and targeted molecular therapies, and optimizing it for each cancer cell type - and potentially to each patient's own tissue. Using a custom integrated circuit, we will develop sensors that can detect cells and image tissue using very high frequency electromagnetic fields (100-300 GHz) which have been shown to be effective at differentiating between tumor cells and healthy cells, and also between actively dividing cells and non-dividing cells. This will be used as a tool to detect the cell state during the application of tumor-treating fields to the cell. The hope is to both understand the biological reasons for the efficacy of tumor-treating fields and also to help optimize the voltage and frequency of the tumor-treating fields. This research opens the door to a future implantable device using the developed sensors that could in real time aid in the discovery of efficacious treatments - conveying instantaneous cellular response to therapy to allow real-time optimization of treatment for each patient - the ultimate goal of personalized medicine.The proposed sensor platform integrates arrays of terahertz sensors for tissue-scale sub-cellular imaging into traditional Complementary Metal Oxide Semiconductor (CMOS) technology, allowing miniaturization and integration with other functions including on-chip signal processing and communication. Previous research has demonstrated that tumor cells can be identified without using any special markers or labels by measurement of the frequency dispersion of the dielectric constant. Most measurement platforms to date either measure cells in bulk or can only measure a single pixel at a time, and lack spatial resolution to measure sub-cellular structures. A true imaging platform that can measure the dielectric constant over a very small spatial resolution will be realized by leveraging the array-based nature of CMOS technology for imaging larger tissue areas - thereby permitting one to dynamically map the contents within a cell while using lower frequency electromagnetic (EM) fields to actuate the cell. Using frequencies over 100 GHz allows miniaturization of individual pixel elements, but this requires innovation to improve the sensitivity of the sensors. By simultaneously sensing the cells with high frequencies and activating the cells with low frequencies (so called Tumor Treating Fields), one will have the ability to actively manipulate and monitor cell division - key to cancer treatment. Tumor Treating Fields (TTF) have been shown to disrupt normal cell mitosis by interacting with strongly polarized molecules. Recently, TTF has been shown to be effective in treatment of certain kinds of cancers, most notably glioblastoma (GBM), a highly aggressive brain tumor. This is the first such advance in this disease in decades, and is synergistic with select chemotherapies. The proposed research investigates the ability to control, study and optimize EM fields on single cells within the context of a more complex tissue microenvironment, which is necessary to optimize TTF and select drug combinations but has heretofore been unattainable.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.