| BackgroundsMicrobubble-enhanced ultrasound(MEUS) cavitation has been widely applied in the researches of the treatment of many diseases, including gene transfection, drug delivery,thrombolysis, tumor therapy and blood brain barrier(BBB) opening. Ultrasound(US)excited microbubbles destruction can open BBB, enhance drug delivery to brain across BBB, which shows great potentials in both research and clinical.Hynynen et al. tried to open up BBB using pulsed focused US with Optison microbubble in rabbit or rat, and the results showed that focal BBB was successfully opened. Although there were a lot of studies on BBB opening with US and microbubble,few studies were found on the control of BBB permeability by different peak negative pressures(PNP) or the opening of BBB unilaterally or bilaterally. PNP is the most important parameter in ultrasound cavitation, so it is highly related to the opening of BBB.It is of great importance to evaluate the effect of pressure amplitudes on BBB, to avoid the side effect. Acoustic cavitation can usually be divided into stable and inertial cavitation.The former is a symmetry oscillation produced when the frequency of microbubble is close to the acoustic frequency under the alternating pressure sound field. The kinetic process can produce circumferential stress on vascular cavity mechanical pull and stretch, and accompanied by the occurrence of secondary phenomenon, such as microstreaming caused by micro bubble oscillation. When the microstreaming eddying on the micro bubble surface can produce shear force and ultrasonic radiation force, which will promote micro bubble to move to the vessel wall and to communicate with endothelial cells. The latter is a alternating periodic oscillation even split produced when negative pressure phase of micro bubble rapidly expands, positive pressure phase sudden contraction under a higher sound field.Based on those problems, the key factor to control the opening of BBB assisted by USirradiated microbubble destruction is to regulate the cavitation activity and the biological effects of US. In this study, a spectific therapeutic US apparatus and a diagnostic US system were used to induce microbubble cavitation, aiming to explore the control and regulation of BBB opening with therapeutic US and unilateral or bilateral BBB opening with diagnostic US. The feasibility, safety and efficacy results of BBB opening can provide support for future application to BBB opening.Objectives1. To explore the efficient and safe PNP value and its range on BBB permeability control via the regulation of US cavitation with therapeutic US.2. To explore the feasibility, efficacy and safety of unilateral or bilateral BBB opening with diagnostic US.Materials and Methods1. Different PNP levels(43-708 k Pa) were tried to irradiate microbubbles, EB was used to trace the ranges and grades of BBB opening, to find out the safe, efficient value ranges of PNP.2. A fixed mechanical index of diagnostic US equipment was performed, and the unilateral and bilateral BBB opening were examined.3. The safety of MEUS assessed with the neural and behavioral function.4. S-100 B was analyzed with ELISA to evaluate the injury of BBB.5. Histology changes of brain injury were detected with HE dye.6. Ultra-structure changes of BBB permeability was observed under electronic microscopy.Main results and conclusions1. MEUS can regulate and control BBB opening using different PNP levels(43-708 k Pa) from the therapeutic US. EB quantification analysis showed that the EB extravasation changed from 1.83±0.04 μg/g(86 kPa) to 10.56±0.13 μg/g(708 kPa) with significant differences(P<0.01),and there was a positive linear correlation of the BBB opening extent and PNP(R2=0.96). S-100 B was(1.93 ± 0.03 ng/L) at the peak value ofPNP(708 k Pa), which indicated a mild injury. Lanthanum nitrate extravasations demonstrated that the permeability of BBB was increased with PNP.2. Diagnostic US was performed to irradiate the cavitation of microbubbles, and the ranges of unilateral and bilateral BBB permeability were increased via changing the acoustic window, angle of detector. EB quantification analysis indicated a much higher amount of EB extravasation was observed at the irradiated side(9.85±0.75 μg/g) than the control side(2.69±0.72 μg/g) by 75% with significant differences(P<0.05), but there were no significant differences of EB extravasations when irradiated bilaterally. Quantification of S-100 B was(0.36 ± 0.02 ng/L) at unilateral irradiation and(0.68 ± 0.45) bilaterally. A dispersivity distribution of EB was found in the brain.3. Both the therapeutic and diagnostic US irradiated microbubble can produce cavitation and control BBB permeability in rats, The extent and ranges(unilateral and bilateral brain) of BBB opening can be regulated via controlling the PNP and the acoustic window and angle. |
PDF Full Text Request