Building a single-cell sensor platform for labelless identification of cells and their components (protein, DNA, molecules) with extremely rapidly alternating electric fields.
Significance and Importance: Identification of cells, and by extension their components, is essential for a wide range of healthcare and scientific applications. There is key need for real-time measurements, for example during cancer surgery where leaving unidentified cancer cells behind leads to increased cancer recurrence. Unfortunately, current techniques cannot identify biological molecules without the use of secondary molecules with a signaling tag attached, necessitating multiple steps often in a laboratory setting. Therefore there is a need for rapid identification of cells and molecules to guide real-time clinical decision making.
The Solution: To enable direct, and near instantaneous, identification of molecules and single cells, this proposal measures their innate response to extremely high frequency electrical fields to identify a unique frequency signature. In particular, this project aims to extend the ability to measure these characteristic vibrations into the Terahertz range, with electric fields alternating within a picosecond. At these speeds, the vibrations of molecules are measured, potentially identifying biological molecules without the use of secondary labels.
Advancing the Field: The overarching goal of this research is to establish the frequency characteristics for a wide range of biomolecules and cancer cell lines using a single-cell high frequency measurement platform. If unique spectral signatures of cancer cells are found, the possibility of rapid labelless identification can be realized.
Benefits to Society: Of key importance in cancer therapy is the need to identify and treat all disease. Instantaneous identification of tumor cells, made possible by measuring the innate electrical properties of the molecules themselves, enables instantaneous assessment of tissue to guide resection of all tumor cells. Furthermore, measurements on single cells at this frequency have never been done before. Through publications, this information will be disseminated to the community, potentially enabling new biomedical applications.
Education and Diversity: The educational goals of this research include the training of graduate student researchers in the art and science of terahertz signal generation, detection, and processing, and the development of a new undergraduate curriculum targeting freshman electrical engineering students and outreach to underrepresented groups.
The focus of this research proposal is to enable labelless investigation of biological systems by obtaining wide frequency spectrum information on the molecular and cellular level through development of a sensor platform operating from DC to the THz regime. This capability, coupled with microfluidics that enable single cell interrogation, has an immense advantage in the characterization, identification, and, possibly diagnosis of disease, potentially solving a variety of problems faster, less expensively, or perhaps even in a point of care settings. This research will advance the state-of-the-art by 10X in frequency and allows for inexpensive and rapid Terahertz cell and biomolecule characterization. Combining Giga and Terahertz sensing allows a broad range of information to be gathered on individual cells and biomolecules. Moving to higher frequencies, from 100 GHz to 1 THz, opens up the possibility to sense molecular rotational resonance signatures, identifying key molecular components of cells.
The work is divided into three interrelated thrusts. In the first thrust, the focus is on the development of the DC-THz sensor array. Our group has identified powerful architectures that are amenable to integration in CMOS, built around performing interferometry between on-chip voltage-controlled oscillators (VCOs), which are easily integrated in CMOS technology into a very small area. The architecture has high sensitivity and immunity from phase noise. In the second thrust, we will be co-designing the microfluidic package and sensor interface so that we can reliably and repeatedly flow materials such as biomolecules or cells into the sensor to perform measurements (1 THz for biomolecules, 0.5 THz for cells). In the third thrust, we will begin an extensive study of the spectral signature of biomolecules and cells from microwave bands up to the terahertz regime.
