Background: Identifying and studying the rare ovarian cancer cell found within blood or small biopsies equates to retrieving the elusive "needle in a haystack." As such, there is a need for novel technologies that can (1) reliably identify these cells from a sea of other non-cancerous cells and (2) for safety and convenience, interrogate them in a way that does not require ample amounts of samples. We propose to develop and optimize a novel device based on the "Hall effect," which converts magnetic information into electrical signals. This effect drives many widely used sensing devices, including odometers in cars and electronic compasses within GPS systems. We have established proof-of-concept that a miniaturized, micrometer-scale Hall (micro-Hall) element can "sense" circulating tumor cells from the peripheral blood of ovarian cancer patients. These cells are decorated with cancer-related magnetic beads (known as "nanoparticles"). Use of magnetism is favorable because of the inherently negligible magnetic properties of biological samples, meaning any signal generated is likely genuine and not misleading. Measurements can thus be achieved in native samples. This means no additional purification steps are needed unlike flow cytometry, a laboratory standard that relies on light. Less sample manipulation can lead to reduced sample loss -- a key advantage when working with rare cells.

Objective: The overall objective of this proposal is to transform micro-Hall technology into a novel magnetic platform, named iHD (for imaging Hall Detector). This goal would transcend micro-Hall from a grayscale cancer "sensor" to a magnetic color "imager." If our proposed aims are met, we will create the world's first magnetic imager. The engineering challenge is to integrate a vast array of micro-Hall sensors and their associated electronics (which currently adds much bulk) into a single IC (integrate-circuit) chip for portable analyses. Each Hall unit will be interpreted as a pixel in the iHD, producing real-time images to accelerate the pace of analyses. Achieving "magnetic color" would also be very innovative. By exploiting the distinct magnetic properties of various nanoparticles and assigning them a color based on size or magnetism, the iHD platform will revolutionize the existing "gray-scale" modality of magnetic detection. We will link iHD with mobile terminals (e.g., smartphone) for handheld operation and data transmission. If successful, the proposed product would help launch a robust research approach that will -- using a handheld device -- count, track, and profile ovarian cancer cells in blood or potentially any other biological substances such as ascites or urine. The cells would be readily visualized on-screen and various cancer or other biological markers of interest displayed in color, if present.

Relevance: Our iHD system will help address key OCRP priorities including improved imaging modalities and assessment of tumor heterogeneity. Current imaging modalities lack the resolution for early cancer detection, much less single-cell visualization. Regarding tumor heterogeneity, there is increased appreciation that tumors across patients and even within a patient maintain different profiles, which can challenge testing and treatments. Currently, heterogeneity is explored with high-tech and elaborate equipment that precludes widespread adoption.

Impact: The developed iHD platform could expand the reach of both preclinical and clinical ovarian cancer research. By enabling sensitive detection and analyses of rare cells, iHD, in the short-term, would allow for their robust testing using ovarian cancer patient blood and potentially other specimen types. Importantly, this would help the field understand how well such cells align with the primary tumor site and whether they offer additional insight into treatment response. Moreover, by eschewing the need for elaborate equipment to measure heterogeneity, the approach would help decentralize existing approaches to expand the field of committed ovarian cancer researchers. This would render a more accessible investigational tool without reliance on central labs. Appreciating that existing imaging systems (e.g., CT or MRI), whether used for screening new cancers or recurrences, lack the resolution to detect early cancers, a long-term outcome of this work could improve on those limitations. Due to iHD's high portability and user-friendly operations via mobile platforms, adoption of this tactic to achieve such lofty goals would be very feasible.