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

癌症是仅次于心脏病的主要死因之一。传统的肿瘤治疗(放疗和化疗、免疫治疗和靶向治疗)需要新的、协同的方式来提高生存率，而肿瘤治疗领域(TTF)已被誉为癌症治疗的第四种方式。到目前为止，肿瘤治疗领域主要应用于胶质母细胞瘤(FDA批准)，正如正在进行的多项临床试验所证明的那样，将这种疗法应用于其他癌症令人兴奋。这项研究将有助于提高对这种治疗有效的物理机制的理解，发现与关键的化疗和靶向分子治疗的协同作用，并针对每种癌细胞类型--以及潜在地针对每个患者自己的组织--进行优化。使用定制集成电路，我们将开发可以使用甚高频电磁场(100-300 GHz)检测细胞和成像组织的传感器，这种电磁场已被证明在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方面是有效的。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，又能帮助优化肿瘤治疗场的电压和频率。这项研究为未来的植入式设备打开了大门，使用开发的传感器可以实时帮助发现有效的治疗方法-将瞬时细胞反应传送到治疗中，以便实时优化每个患者的治疗-这是个性化药物的最终目标。建议的传感器平台将用于组织规模亚细胞成像的太赫兹传感器阵列集成到传统的互补金属氧化物半导体(CMOS)技术中，允许微型化并与其他功能集成，包括芯片上的信号处理和通信。以前的研究已经证明，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记的情况下识别肿瘤细胞。到目前为止，大多数测量平台要么批量测量细胞，要么一次只能测量一个像素，并且缺乏空间分辨率来测量亚细胞结构。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基于阵列的CMOS技术对更大的组织区域进行成像来实现-从而允许人们动态映射单元内的内容物，同时使用低频电磁场来驱动单元。使用100 GHz以上的频率可以实现单个像素元素的小型化，但这需要创新来提高传感器的灵敏度。通过同时感知高频细胞和激活低频细胞(即所谓的肿瘤治疗场)，人们将有能力主动操纵和监测细胞分裂--癌症治疗的关键。肿瘤治疗场(TTF)被证明通过与强极化分子相互作用来破坏正常的细胞有丝分裂。最近，TTF被证明对某些类型的癌症有效，最著名的是胶质母细胞瘤(GBM)，一种高度侵袭性的脑瘤。这是几十年来这种疾病的第一次这样的进展，并与选定的化疗药物协同作用。这项拟议的研究调查了在更复杂的组织微环境的背景下控制、研究和优化单个细胞上的电磁场的能力，这是优化TTF和选择药物组合所必需的，但到目前为止还无法获得。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.