Celoptics, Inc., Rockville, Maryland; Section on Quantitative Imaging and Tissue Sciences Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Section on Quantitative Imaging and Tissue Sciences Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Biophys J. 2020 Dec 15;119(12):2378-2390. doi: 10.1016/j.bpj.2020.11.002. Epub 2020 Nov 13.
We have developed a novel, to our knowledge, in vitro instrument that can deliver intermediate-frequency (100-400 kHz), moderate-intensity (up to and exceeding 6.5 V/cm pk-pk) electric fields (EFs) to cell and tissue cultures generated using induced electromagnetic fields (EMFs) in an air-core solenoid coil. A major application of these EFs is as an emerging cancer treatment modality. In vitro studies by Novocure reported that intermediate-frequency (100-300 kHz), low-amplitude (1-3 V/cm) EFs, which they called "tumor-treating fields (TTFields)," had an antimitotic effect on glioblastoma multiforme (GBM) cells. The effect was found to increase with increasing EF amplitude. Despite continued theoretical, preclinical, and clinical study, the mechanism of action remains incompletely understood. All previous in vitro studies of "TTFields" have used attached, capacitively coupled electrodes to deliver alternating EFs to cell and tissue cultures. This contacting delivery method suffers from a poorly characterized EF profile and conductive heating that limits the duration and amplitude of the applied EFs. In contrast, our device delivers EFs with a well-characterized radial profile in a noncontacting manner, eliminating conductive heating and enabling thermally regulated EF delivery. To test and demonstrate our system, we generated continuous, 200-kHz EMF with an EF amplitude profile spanning 0-6.5 V/cm pk-pk and applied them to exemplar human thyroid cell cultures for 72 h. We observed moderate reduction in cell density (<10%) at low EF amplitudes (<4 V/cm) and a greater reduction in cell density of up to 25% at higher amplitudes (4-6.5 V/cm). Our device can be readily extended to other EF frequency and amplitude regimes. Future studies with this device should contribute to the ongoing debate about the efficacy and mechanism(s) of action of "TTFields" by better isolating the effects of EFs and providing access to previously inaccessible EF regimes.
我们开发了一种新颖的、据我们所知的、在体外仪器,可以将中频(100-400 kHz)、中强度(高达 6.5 V/cm pk-pk 并超过该值)的电场(EFs)传递到使用空心螺线管线圈中感应电磁场(EMFs)产生的细胞和组织培养物中。这些 EFs 的主要应用之一是作为一种新兴的癌症治疗方式。Novocure 的体外研究报告称,中频(100-300 kHz)、低幅度(1-3 V/cm)的 EFs,他们称之为“肿瘤治疗电场(TTFields)”,对多形性胶质母细胞瘤(GBM)细胞具有抗有丝分裂作用。发现该作用随着 EF 幅度的增加而增加。尽管持续进行理论、临床前和临床研究,但作用机制仍不完全清楚。以前所有关于“TTFields”的体外研究都使用附加的、电容耦合电极将交变 EFs 传递到细胞和组织培养物。这种接触式传递方法存在 EF 轮廓特征差和导电加热的问题,限制了所施加的 EFs 的持续时间和幅度。相比之下,我们的设备以非接触的方式以特征良好的径向轮廓传递 EFs,消除了导电加热并实现了热调节的 EF 传递。为了测试和演示我们的系统,我们生成了具有 0-6.5 V/cm pk-pk 幅度轮廓的连续 200 kHz EMF,并将其应用于代表性的人类甲状腺细胞培养物中 72 小时。我们观察到在低 EF 幅度(<4 V/cm)下细胞密度适度降低(<10%),而在较高幅度(4-6.5 V/cm)下细胞密度降低更大,可达 25%。我们的设备可以很容易地扩展到其他 EF 频率和幅度范围。使用该设备的未来研究应该通过更好地隔离 EFs 的影响并提供以前无法访问的 EF 范围,为关于“TTFields”的功效和作用机制的持续争论做出贡献。
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