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Purpose Microvascular processes play key roles in many diseases including diabetes. Improved understanding of the microvascular changes involved in disease development could offer crucial insight into the relationship of these changes to disease pathogenesis. Super-resolution ultrasound (SR-US) imaging has showed the potential to visualize microvascular detail down to the capillary level (i.e., subwavelength resolution) but optimization is still necessary. The purpose of this study was to investigate in vivo SR-US imaging of skeletal muscle microvascularity using microbubble (MB) contrast agents of various size and concentration while evaluating different ultrasound (US) system level parameters such as imaging frame rate and image acquisition length. Methods An US system equipped with a linear array transducer was used in a harmonic imaging mode at low transmit power. C57BL/6J mice fed a normal diet were used in this study. An assortment of size-selected MB contrast agents (1–2 μm, 3–4 μm, and 5–8 μm in diameter) were slowly infused in the tail vein at various doses (1.25 × 107, 2.5 × 107 or 5 × 107 MBs). US image data was collected before MB injection and thereafter for 10 min at 30 frames per sec (fps). The US transducer was fixed throughout and between each imaging period to help capture microvascular patterns along the same image plane. An adaptive SR-US image processing technique was implemented using custom Matlab software. Results Experimental findings illustrate the use of larger MB results in better SR-US images in terms of skeletal muscle microvascular detail. A dose of 2.5 × 107 MBs resulted in SR-US images with optimal spatial resolution. An US imaging rate of at least 20 fps and image acquisition length of at least 8 min also resulted in SR-US images with pronounced microvascular detail. Conclusions This study indicates that MB size and dose and US system imaging rate and data acquisition length have significant impact on the quality of in vivo SR-US images of skeletal muscle microvascularity.

Objectives— To evaluate the use of super-resolution ultrasound (SR-US) imaging for quantifying microvascular changes in skeletal muscle using a mouse model of type 2 diabetes. Methods— Study groups were young, standard chow–fed male C57BL/6J mice (lean group) and high fat diet–fed older mice (obese group). After an overnight fast, dynamic contrast-enhanced US imaging was performed on the proximal hind limb adductor muscle group for 10 minutes at baseline and again at 1 and 2 hours during administration of a hyperinsulinemic-euglycemic clamp. Dynamic contrast-enhanced US images were collected on a clinical US scanner (Acuson Sequoia 512; Siemens Healthcare, Mountain View, CA) equipped with a 15L8 linear array transducer. Dynamic contrast-enhanced US images were processed with a spatiotemporal filter to remove tissue clutter. Individual microbubbles were localized and counted to create an SR-US image. A frame-by-frame analysis of the microbubble count was generated (ie, time-microbubble count curve [TMC]) to estimate tissue perfusion and microvascular blood flow. The conventional time-intensity curve (TIC) was also generated for comparison. Results— In vivo SR-US imaging could delineate microvascular structures in the mouse hind limb. Compared with lean animals, insulin-induced microvascular recruitment was attenuated in the obese group. The SR-US-based TMC analysis revealed differences between lean and obese animal data for select microvascular parameters (P < .04), which was not true for TIC-based measurements. Whereas the TMC and TIC microvascular parameters yielded similar temporal trends, there was less variance associated with the TMC-derived values. Conclusions— Super-resolution US imaging is a new modality for measuring the microvascular properties of skeletal muscle and dysfunction from type 2 diabetes.