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CONVENTIONAL flow cytometry using fluorescent and scattering detection methods has been a fundamental tool of discoveries in cell biology and disease diagnosis for many years. However, invasive sampling of small blood volumes only (typically ≤10 ml) leads to missing rare biomarkers, especially at early disease stage. Assessment of larger blood volumes is possible in in vivo flow cytometry with fluorescent, photoacoustic (PA), and combined PA-fluorescence detection of circulating biomarkers directly in the bloodstream of animals and recently humans (1–5). In particular, in vivo advanced multicolor PA flow cytometry (PAFC) with many innovations (e.g., high pulse rate multispectral lasers, linear beam shape, focused ultrasound transducers, nanobubble-induced sensitivity amplification, skin pigmentation tolerant signal processing, and cell focusing in blood flow) demonstrated label-free detection of circulating tumor cells (CTCs) in melanoma patients, malaria-infected cells, bacteria at bacteremia, and sickled erythrocytes with ~1,000× improved sensitivity and potential to prevent deadly metastasis, sepsis, stroke, and sickle cell crisis by well-timed treatment, (5). Moreover, theranostics by integration of PAFC and pulsed photothermal (PT) therapy showed in preclinical studies photomechanical destruction of CTCs, bacteria (Staphylococcus aureus), and infected cells directly in blood flow (3–6). In these in vivo methods, especially in the case of rare objects, it is important to know which fraction of the entire blood volume in the organism has been assessed in a certain time, how much time is needed to analyze a desired fraction of the fluid volume, and how often the same circulating cells can return to the detection (treatment) points. As yet (see, e.g., (4,5,7,8)) the addressed fraction fA and the measurement time t were related by fA = Qt/Vb, with Q being the local volumetric flow rate in the selected vessels and Vb the total fluid volume in the organism. While being valid for very short times associated with fractions fA << 1, in general this ignores the fact that the selected vessel usually is a peripheral branch of the entire circulatory system. Furthermore, the above estimation ignores that addressing a certain blood volume more than once does not increase the total treated volume fraction. This leads to a gross underestimation of the required time to reach a given fraction, or an overestimation of the addressed fraction for a given time. Here, we present further analysis of this issue with focus on ultimate detection of a few pathologic cells or disease biomarkers in the entire blood volume, and on blood treatment, for which the volume fraction counts which has been targeted at least once. We assume a setting in which blood flowing through a vessel is the diagnostic or therapeutic target, and we regard all

Towards Reaching the Total Blood Volume by in vivo Flow Cytometry and Theranostics