Stroboscopic opto-acoustic scattering (SOAS) flow cytometer for pre-cancerous detection

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ProblemIt is now well described that most malignancies develop along a time-continuum that takes decades, acquiring the malignant phenotype and clonal dominance in a stepwise-manner due to the accumulation of multiple mutations. Early diagnosis and treatment of cancer invariably leads to better outcomes. Identification of these premalignant phases offers improved risk stratification, better deployment of early detection techniques, and possibly even prevention. However, early cellular changes are subtle, and occur in only a small subpopulation of cells, making detection of these targets challenging. We hypothesise that alterations in the physical characteristics of these pre- malignant cells will allow their detection through the use of advanced sensing techniques, and propose to develop this for blood cancers as an exemplar. "Liquid tumours" have the benefits of simple sample acquisition and a predefined premalignant state, so-called clonal haematopoiesis of indeterminate potential (CHIP). Currently, symptomatic patients are "screened" for cellular and biochemical abnormalities in the blood. Automated cell counters assess physical size through light scatter in addition to protein content properties across large numbers of cells. This allows quantitation of cell types/frequencies in comparison to population normal ranges. However, they derive no qualitative measures and are therefore unlikely to find our target premalignant cells. At the other end of the diagnostic scale, overt haematological malignancies are diagnosed using a complicated combination of techniques (Histology, FACS, NGS) that are costly (in time and equipment) and are not feasible for wider screening. Moreover, regarding FACS analysis, prior knowledge of differential protein expression between normal and premalignant cells would be required that is currently lacking. Due to the predicted infrequency of premalignant cells, analysis of sufficient sized cellular populations using these techniques would encounter issues of throughput that our proposed techniques will overcome. SolutionWe propose an innovative approach using fast and efficient quantitative identification and real-time multi-parametric characterisation of biophysical properties of suspended cell components: shape, density, elasticity and compressibility. The scalability of this approach allows the existing throughput limitation to be cost-effectively overcome for the first time. We propose combining acoustic standing gradient forces with novel stroboscopic opto-acoustic scattering tomography integrated onto a Lab-on-chip device. The new multi-parametric stroboscopic opto-acoustic sensors will be used to compare biophysical properties of different cell populations or sub-populations within heterogeneous samples. We have high confidence that we can achieve analysis rates of up to 60,000 cells/second. Such a rate would allow analysis of a 500 ul sample in under 2 minutes (2.25-5.5M cells). The unique ability that our proposed optical technique with acoustic fields offers to measure multiple cells in parallel over several length scales is the route to ultra-fast throughput. Providing information on the mechanical properties of the cellular population at single-cell levels lays the foundation of a new generation of opto-acoustic sensing. More importantly it immediately opens up new clinical opportunities for reducing cancer rates and could have impacts in other areas such as airborne particle analysis, water/soil microbial sensing and production-line industrial particle sensing.