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Abstract-Ultrasound super-localization microscopy techniques presented in the last few years enable non-invasive imaging of vascular structures at the capillary level by tracking the flow of ultrasound contrast agents (gas microbubbles). However, these techniques are currently limited by low temporal resolution and long acquisition times. Super-resolution optical fluctuation imaging (SOFI) is a fluorescence microscopy technique enabling sub-diffraction limit imaging with high temporal resolution by calculating high order statistics of the fluctuating optical signal. The aim of this work is to achieve fast acoustic imaging with enhanced resolution by applying the tools used in SOFI to contrast-enhance ultrasound (CEUS) plane-wave scans. The proposed method was tested using numerical simulations and evaluated using two in-vivo rabbit models: scans of healthy kidneys and VX-2 tumor xenografts. Improved spatial resolution was observed with a reduction of up to 50% in the full width half max of the point spread function. In addition, substantial reduction in the background level was achieved compared to standard mean amplitude persistence images, revealing small vascular structures within tumors. The scan duration of the proposed method is less than a second while current superlocalization techniques require acquisition duration of several minutes. As a result, the proposed technique may be used to obtain scans with enhanced spatial resolution and high temporal resolution, facilitating flow-dynamics monitoring. Our method can also be applied during a breath-hold, reducing the sensitivity to motion artifacts.

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The newly developed method allowed quantification of the intraplaque neovascularization as a feature of vulnerability in the carotid plaque and proved to be highly correlated with histopathologic results.

The finite frequency bandwidth of ultrasound transducers and the nonnegligible width of transmitted acoustic beams are the most significant factors that limit the resolution of medical ultrasound imaging. Consequently, in order to recover diagnostically important image details, obscured due to the resolution limitations, an image restoration procedure should be applied. The present study addresses the problem of ultrasound image restoration by means of the blind-deconvolution techniques. Given an acquired ultrasound image, algorithms of this kind perform either concurrent or successive estimation of the point-spread function (PSF) of the imaging system and the original image. In this paper, a blind-deconvolution algorithm is proposed, in which the PSF is recovered as a preliminary stage of the restoration problem. As the accuracy of this estimation affects all the following stages of the image restoration, it is considered as the most fundamental and important problem. The contribution of the present study is twofold. First, it introduces a novel approach to the problem of estimating the PSF, which is based on a generalization of several fundamental concepts of the homomorphic deconvolution. It is shown that a useful estimate of the spectrum of the PSF can be obtained by applying a proper smoothing operator to both log-magnitude and phase of the spectra of acquired radio-frequency (RF) images. It is demonstrated that the proposed approach performs considerably better than the existing homomorphic (cepstrum-based) deconvolution methods. Second, the study shows that given a reliable estimate of the PSF, it is possible to deconvolve it out of the RF-image and obtain an estimate of the true tissue reflectivity function, which is relatively independent of the properties of the imaging system. The deconvolution was performed using the maximum a-posteriori (MAP) estimation framework for a number of statistical priors assumed for the reflectivity function. It is shown in a series of in vivo experiments that reconstructions based on the priors, which tend to emphasize the "sparseness" of the tissue structure, result in solutions of higher resolution and contrast.

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Lysyl oxidase-like 2 (LOXL2), a secreted enzyme that catalyzes the cross-linking of collagen, plays an essential role in developmental angiogenesis. We found that administration of the LOXL2-neutralizing antibody AB0023 inhibited bFGF-induced angiogenesis in Matrigel plug assays and suppressed recruitment of angiogenesis promoting bone marrow cells. Small hairpin RNA-mediated inhibition of LOXL2 expression or inhibition of LOXL2 using AB0023 reduced the migration and network-forming ability of endothelial cells, suggesting that the inhibition of angiogenesis results from a direct effect on endothelial cells. To examine the effects of AB0023 on tumour angiogenesis, AB0023 was administered to mice bearing tumours derived from SKOV-3 ovarian carcinoma or Lewis lung carcinoma (LLC) cells. AB0023 treatment significantly reduced the microvascular density in these tumours but did not inhibit tumour growth. However, treatment of mice bearing SKOV-3-derived tumours with AB0023 also promoted increased coverage of tumour vessels with pericytes and reduced tumour hypoxia, providing evidence that anti-LOXL2 therapy results in the normalization of tumour blood vessels. In agreement with these data, treatment of mice bearing LLC-derived tumours with AB0023 improved the perfusion of the tumour-associated vessels as determined by ultrasonography. Improved perfusion and normalization of tumour vessels after treatment with anti-angiogenic agents were previously found to improve the delivery of chemotherapeutic agents into tumours and to result in an enhancement of chemotherapeutic efficiency. Indeed, treatment with AB0023 significantly enhanced the anti-tumourigenic effects of taxol. Our results suggest that inhibition of LOXL2 may prove beneficial for the treatment of angiogenic tumours.

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