Passive Cavitation Monitoring Of Self-made Microbubbles Under Low Frequency Focused Ultrasound Irradiation

Recent studies have found that focused ultrasound(FUS)combined with microbubble(MB)can open blood brain barrier(BBB)transiently,locally and reversibly.This method has now become a focus of target delivery in the treatment of brain diseases.However,the process of FUS combined MB opening BBB are unsafe in some cases.When the ultrasonic energy is too large or the irradiation time is too long,it will cause brain tissue damage.Research shows that the most important mechanism of FUS opening BBB is the cavitation effect of MB,which is related to MB performance,FUS parameters and physiological structure of tissues.Because of the high price of commercial MB,to develop a MB with high cost performance,the research group has developed a kind of MB by mechanical oscillation.But in order to achieve the goal of safe and effective opening of BBB,we need to choose appropriate FUS parameters.In this paper,the passive cavitation monitoring technique was used to monitor the cavitation behavior of the self-made MB under FUS,in order to obtain the best ultrasonic treatment parameters for opening BBB safely.First,one dimensional isolated passive cavitation monitoring platform was put up,which using single-element probe to receive the sound signals produced by MB during FUS irradiation.The cavitation behavior of self-made MB under FUS was studied through setting different the parameters such as center frequency,sound pressure,pulse repetition frequency and pulse length.The peak-peak value,root mean square,frequency spectrum,time frequency diagram and cavitation dose were calculated to measure the degree of MB.And the best ultrasonic treatment parameters were obtained.The experimental results of one dimensional passive cavitation monitoring show that:(1)the MB is dominated by steady cavitation when the sound pressure is low.When the sound pressure rises to a certain extent,the MB is dominated by inertial cavitation,and the critical value of the steady cavitation and inertial cavitation of the self-made MB is about 0.3MPa.(2)Under the same sound pressure,the cavitation degree produced by FUS with a center frequency of 1.1MHz is stronger than that produced by 3.3MHz.(3)The cavitation degree using a pulse length of 5000cycles FUS is stronger than that produced by 100cycles.(4)The cavitation effect of MB using pulse repetition rate of 1kHz FUS is more intense than that of 10Hz.Conclusion:When the average concentration of MB is 7×10~7~9×10~7bubbles/mL,the self-made MB is in the critical state of steady cavitation and inertial cavitation when the parameters of FUS are setted as follow:frequency=1.1MHz,sound pressure=0.3MPa,pulse length=5000cycles,pulse repetition rate=10Hz.A preliminary live experiment with 4 mices(weight:20±2g)was carried out.The passive cavitation monitoring platform can detect the cavitation signal of MB in vivo.The results show that the sound pressure is closely related to the cavitation effect of MB,that is,the greater the sound pressure,the more intense the cavitation effect of MB and there are some bleeding points in the brain tissue when the sound pressure is 0.4MPa.Based on the Time Exposure Acoustics(TEA)algorithm,the two-dimensional passive cavitation imaging is simulated,and a two-dimensional passive cavitation monitoring experimental platform is built by using the Verasonics ultrasound imaging system.The two-dimensional cavitation distribution map of MB is preliminarily obtained.One of the innovations of this paper is that the second generation ultrasound microbubbles coated with inert gas and lipid shell are produced by mechanical oscillation.The cost of ultrasound microbubbles is far lower than that of commercial microbubbles,moreover,the method is simple;The another of the innovations of this paper is one dimensional and two-dimensional passive cavitation platform can be built independently.Through one dimensional passive cavitation platform,we can find the pressure threshold value of stable cavitation and inertial cavitation of self-made microbubbles.The cavitation distribution can be obtained by two dimensional passive cavitation platform.