Subharmonic contrast imaging promises to improve ultrasound-imaging quality by taking advantage of an increased contrast to tissue signal. However, acoustic pressures beyond the subharmonic generation threshold using common ultrasound pulses may induce significant contrast microbubble destruction. In this work, a chirp excitation technique is presented to enhance the subharmonic emission from encapsulated microbubbles. Chirp signals with a center frequency of 5 MHz, variable frequency range and duration time are employed to drive microbubbles in numerical simulation and experimental studies. We provide a theoretical evaluation of the chirp excitation pressure threshold and the acoustic pressure dependence of subharmonic based on Church's model and demonstrate that the amplitude and axial resolution of the subharmonic can be optimized by proper selection of the frequency range and time duration of the chirp signal. Measurements are qualitatively in agreement with the simulation. Moreover, we demonstrate that chirp excitation may be able to improve the amplitude of the subharmonic component up to 22 dB over the pulse excitation. The chirp excitation technique could potentially be used for improving the subharmonic contrast imaging quality.

Mesenchymal stem cell (MSC) therapy shows considerable promise for the treatment of myocardial infarction (MI). However, the inefficient migration and homing of MSCs after systemic infusion have limited their therapeutic applications. Ultrasound-targeted microbubble destruction (UTMD) has proven to be promising to improve the homing of MSCs to the ischemic myocardium, but the concrete mechanism remains unclear. We hypothesize that UTMD promotes MSC homing by upregulating SDF-1/CXCR4, and this study was aimed at exploring this potential mechanism. We analyzed SDF-1/CXCR4 expression after UTMD treatment in vitro and in vivo and counted the number of homing MSCs in MI areas. The in vitro results demonstrated that UTMD not only led to elevated secretion of SDF-1 but also resulted in an increased proportion of MSCs that expressed surface CXCR4. The in vivo findings show an increase in the number of homing MSCs and higher expression of SDF-1/CXCR4 in the UTMD combined with MSCs infusion group compared to other groups. In conclusion, UTMD can increase SDF-1 expression in the ischemic myocardium and upregulate the expression of surface CXCR4 on MSCs, which provides a molecular mechanism for the homing of MSCs assisted by UTMD via SDF-1/CXCR4 axis.

We test the hypothesis that ultrasound-targeted microbubble destruction (UTMD) technique increases the renoprotective effect of kidney-targeted transplantation of bone-marrow-derived mesenchymal stem cells (BM-MSCs) in diabetic nephropathy (DN) rats. Diabetes was induced by streptozotocin injection (60 mg/Kg, intraperitoneally) in Sprague-Dawley rats. MSCs were administered alone or in combination with UTMD to DN rats at 4 weeks after diabetes onset. Random blood glucose concentrations were measured at 1, 2, 4, and 8 weeks, and plasma insulin levels, urinary albumin excretion rate (UAER) values, the structures of pancreas and kidney, the expressions of TGF-β1, synaptopodin, and IL-10 were assessed at 8 weeks after MSCs transplantation. MSCs transplantation decreased blood glucose concentrations and attenuated pancreatic islets/β cells damage. The permeability of renal interstitial capillaries and VCAM-1 expression increased after UTMD, which enhanced homing and retention of MSCs to kidneys. MSCs transplantation together with UTMD prevented renal damage and decreased UAER values by inhibiting TGF-β1 expression and upregulating synaptopodin and IL-10 expression. We conclude that MSCs transplantation reverts hyperglycemia; UTMD technique noninvasively increases the homing of MSCs to kidneys and promotes renal repair in DN rats. This noninvasive cell delivery method may be feasible and efficient as a novel approach for personal MSCs therapy to diabetic nephropathy.

Thrombosis is the common mechanism of various diseases of heart and vasculature and their major morbility and mortality. An efficient, safe and easy thrombolysis method is needed. We tried to develop a new type of ultrasound microbubbles carrying thrombolytics and simultaneously targeting to thrombus, which could bind with thrombus specifically and release the encapsulated drug locally under the ultrasound exposure. Microbubbles carrying tissue plasminogen activator (tPA) and Arg-Gly-Asp-Ser tetrapeptide (RGDS) were prepared by lyopyilization. Their properties were detected, including morphology, particle size, surface potential and pH. The results showed that the microbubbles were suitable for intravenous injection. The envelope rate of tPA, detected by ELISA, was (81.12 +/- 2.44%), and the conjugate rate of RGDS, detected by flow cytometer, was (94.49 +/- 6.19%). The tPA encapsulated in microbubbles kept fibrinolysis activity under the conditions of both natural releasing and ultrasound exposure, checked by agarose fibrin plate process. The contrast-enhanced ultrasonography (CEU) in rabbit liver showed that they were good for enhanced ultrasound imaging. The in vitro thrombolysis of the microbubbles to the blood clots from healthy human was detected with a mimical flowing model propelled by peristaltic pump. The drug-loaded microbubbles plus ultrasound irradiation got higher thrombolysis with the lowest dosage. The tPA-loaded microbubbles targeting to thrombus can be prepared by lyopyilization, which will bring out a novel way for the targeting drug-released thrombolysis therapy.

Early-stage diabetic patients showed an impaired left ventricular strain that was worsened by coexistent hypertension, although blood glucose and blood pressure were well controlled. Three-dimensional speckle-tracking echocardiography was able to detect these subclinical changes.

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ObjectiveThe objective of this study was to investigate nanobubbles carrying androgen receptor (AR) siRNA and their in vitro and in vivo anti-tumor effects, when combined with ultrasonic irradiation, on androgen-independent prostate cancer (AIPC).Materials and MethodsNanobubbles carrying AR siRNA were prepared using poly-L-lysine and electrostatic adsorption methods. Using C4-2 cell activity as a testing index, the optimal irradiation parameters (including the nanobubble number/cell number ratio, mechanical index [MI], and irradiation time) were determined and used for transfection of three human prostate cancer cell lines (C4-2, LNCaP, and PC-3 cells). The AR expression levels were investigated with RT-PCR and Western blot analysis. Additionally, the effects of the nanobubbles and control microbubbles named SonoVue were assessed via imaging in a C4-2 xenograft model. Finally, the growth and AR expression of seven groups of tumor tissues were assessed using the C4-2 xenograft mouse model.ResultsThe nanobubbles had an average diameter of 609.5±15.6 nm and could effectively bind to AR siRNA. Under the optimized conditions of a nanobubble number/cell number ratio of 100∶1, an MI of 1.2, and an irradiation time of 2 min, the highest transfection rates in C4-2, LNCaP, and PC-3 cells were 67.4%, 74.0%, and 63.96%, respectively. In the C4-2 and LNCaP cells, treatment with these binding nanobubbles plus ultrasonic irradiation significantly inhibited cell growth and resulted in the suppression of AR mRNA and protein expression. Additionally, contrast-enhanced ultrasound showed that the nanobubbles achieved stronger signals than the SonoVue control in the central hypovascular area of the tumors. Finally, the anti-tumor effect of these nanobubbles plus ultrasonic irradiation was most significant in the xenograft tumor model compared with the other groups.ConclusionNanobubbles carrying AR siRNA could be potentially used as gene vectors in combination with ultrasonic irradiation for the treatment of AIPC.