Many types of cancer therapies target the tumor microenvironment, causing biochemical and morphological changes in tissues. In therapies using ultrasound activated microbubbles, vascular collapse is typically reported. Red blood cells (RBCs) that leak out of the vasculature become exposed to the ceramide that is released from damaged endothelial cells. Ceramide can induce programmed cell death in RBCs (eryptosis), and is characterized by cell shrinkage, membrane blebbing and scrambling. Since the effect of eryptotic cells on generated photoacoustics (PA) signals has not been reported, we investigated the potential PA may have for cancer treatment monitoring by using PA spectral analysis to sense eryptosis. To induce eryptosis, C2-ceramide was added to RBC suspensions and that were incubated for 24 hours at 37°C. A control and ceramide-induced sample was imaged in a vessel phantom using a high frequency PA system (VevoLAZR, 10 – 45 MHz bandwidth) irradiated with multiple wavelengths ranging from 680 to 900 nm. PA spectral parameters were measured and linked to changes in RBCs as it underwent eryptosis. These samples were examined using optical microscopy, a blood gas analyzer and an integrating sphere setup to measure optical properties (wavelengths 600 – 900 nm). The results of the experiment demonstrate how PA spectral analysis can be used to identify eryptosis at a depth of more than 1 cm into the phantom using ultrasound derived the y-intercept and mid bandfit (MBF) parameters at optical wavelengths of 800 – 900 nm. These parameters were correlated to the morphological and biochemical changes that eryptotic RBCs display. The results establish the potential of PA in cancer treatment monitoring through sensing treatment induced eryptosis.
Red blood cell (RBC) rouleaux formation is a reversible phenomenon that occurs during low blood flow and small shearing forces in circulation. Certain pathological conditions can alter the molecular constituents of blood and properties of the RBCs leading to enhanced rouleaux formation, which results in impaired perfusion and tissue oxygenation. In this study rouleaux were artificially generated using Dextran-70 and examined using a photoacoustic (PA) microscope. Individual rouleau were irradiated with a 532 nm pulsed laser focused to a 10 μm spot size, and the resulting PA signals recorded with a 200 MHz transducer. The laser and transducer were co-aligned, with the sample positioned between them. The frequency-domain PA ultrasound spectra were calculated for rouleaux with lengths ranging from 10 to 20 μm. For the rouleaux, a single spectral minimum at 269±4 MHz was observed. The spectral minima were in good agreement with a theoretical thermoelastic expansion model using an infinite length cylindrical absorber, bearing a diameter equivalent to an average human RBC (7.8 μm). These results suggest that PA ultrasound spectroscopy can be potentially used as a tool for monitoring blood samples for the presence of rouleaux.
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