New approaches to sense intra-cellular properties such as nuclear characteristics in a compact and non-invasive fashion are needed to increase the speed and accuracy of cancer diagnosis. Such approaches will also enable real-time dynamic monitoring of a cell nucleus, which can contribute to fundamental understanding of cell development and malignancy progression. Currently, nuclear morphology and DNA content are inspected through optical microscopy and flow cytometry, both are bulky, delicate and require cell labeling. To satisfy the need of portable and inexpensive technologies for cancer screening, broadband electrical sensing is proposed here to extract information about nuclear morphology and DNA content from a single cell. The proposed work is built on the research team's work in broadband electrical sensing of single-cell intra-cellular resistance and capacitance. The proposed electrical sensor can be readily integrated with a lab-on-chip system to enable its wide-spread use at the point of care, which will have broader impacts on healthcare. The capability to monitor intra-cellular organelles without physically penetrating a cell membrane not only will contribute to cancer cytology, but also will permit real-time monitoring of nuclear dynamics, which can transform the research on cell development, cancer therapeutics, and many other aspects of cell biology. Through classroom teaching, conferences, publications, and other outreach efforts, knowledge from this research will be disseminated to students, professionals, and general public. The research will allow multi-disciplinary training to participating K-12, undergraduate and graduate students, especially female and minority students. The PI and co-PI have strong track records in recruiting underrepresented students to research and graduate education.
The proposed research intends to build a microwave equivalent of confocal microscopy for single cell depth profiling, revealing intracellular details such as alterations in nuclear morphology and DNA content. This work is based on the hypothesis that broadband electrical sensing can reveal dielectric properties of different intra-cellular compartments that have distinct complex permittivities and relaxation frequencies. The following aims will be achieved: 1) Design and fabricate multi-port coplanar waveguides with sensitivity and spatial resolution meeting the needs for intra-cellular broadband electrical sensing from 9 kHz to 9 GHz. 2) Develop a multi-scale model to understand the interaction of electric fields with cell membrane, cytoplasm and nucleus, including variation of the size, shape and location of the nucleus as well as its DNA content. 3) Perform broadband electrical sensing and signal analysis of single live human cells to validate the multi-scale model and to extract nuclear morphology and DNA content. Knowledge from this research will provide fundamental understanding of how electric fields interact with a cell and its organelles in a broad range of frequencies. Broadband electrical biosensors and multi-scale models will be developed to allow dielectric characterization of intra-cellular compartments with high spatial resolution, signal-to-noise ratio, throughput and reproducibility, which will broadly impact both bioengineering and electrical engineering, especially bioelectronics, biophysics, cancer biology and cell biology.
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.