Ultrasound Combined With Magnetic Microbubbles In The Treatment Of Total Obstructive Thrombus Under The Guidance Of Magnet

BackgroundThrombotic disease is a common disease associated with high morbidity and mortality worldwide.Early recanalization of occluded blood vessels,which is the key of thrombolytic therapy,can save ischemic tissue and improve the prognosis of patients.There are many methods of thrombolytic therapy,including intravenous thrombolytic therapy and catheter intervention.However,these methods have limitations when used clinically,such as strict exclusion criteria,severe complications,and invasiveness.Microbubbles(MB)have been used as contrast agents for ultrasound diagnosis,and later improved for specific molecular imaging of thrombus.In recent years,more and more attention has been paid to the role of MB in the field of treatment,especially in ultrasound thrombolysis,because the ultrasound cavitation effect mediated by MB can not only effectively dissolve thrombus,but also noninvasive,economical,convenient,and without obvious contraindications.Many studies have focused on the tolerance and effectiveness of MB,but complete occlusion of blood flow in the anterior segment is still a major challenge,because MB is difficult to reach the thrombus site through systemic injection,which may hinder the clinical application of ultrasound-mediated microbubble thrombolysis.It has been reported that direct injection of MB into the thrombus of occluded blood vessels can increase the concentration of local MB,thus achieving complete recanalization through microbubble thrombolysis.However,this method is invasive and inconvenient in clinical application,so can the local concentration of microbubbles near the thrombus be increased by a non-invasive and simple method?Magnetic targeted therapy refers to controlling the movement of a magnetically responsive agent under an externally applied magnetic field to drive the relevant drug to the desired location to enhance the therapeutic effect of drug.On one hand,drug therapy mediated by magnetic microbubbles has attracted more and more attention at present.For example,through the application of magnetic field,therapeutic drugs can be increased to reach the tumor site and their therapeutic effect can be enhanced under the effect of ultrasonic cavitation.On the other hand,as for magnetic thrombolytic drugs,related studies have proved that magnetic micron/nano particles combined with thrombolytic drugs can reach the thrombus site under the action of magnetic field,thus enhancing the thrombolytic effect.Currently,there are relatively few studies on magnetic microbubble mediated thrombolysis,which mainly focus on non-clogging thrombolysis.On completely occlusive thrombus,magnetic microbubble-mediated thrombolysis is not currently available.Previous research in our laboratory has determined the feasibility of manipulating magnetic MB,which can overcome high shear stress and stay away from the centerline under the guidance of a magnetic field in aorta.In addition,another study has demonstrated the feasibility of using a magnetic field to guide a magnetic carrier into a specific branch of Y-branch in an completely occluded blood vessel network.Moreover,related studies have also demonstrated that magnetic micro/nanoparticles combined with thrombolytic drugs can reach the completely occluded thrombus site under the action of a magnetic field.It is worth further exploring whether magnetic microvesicles can be induced to completely block thrombus and enhance the thrombolytic effect with microvesicle-mediated ultrasonic cavitation.Research methods and results1.experimental materialMain experimental instruments:German company Siemens diagnostic instrument(Sequoia512).Main experimental reagents:Perfluoropropane lipid microbubble contrast agent(ordinary microbubble),Perfluoropropane lipid magnetic microbubble contrast agent,Urokinase2.Experimental method:(1)To prepare microbubbles and verify the magnetic responsiveness and stability of microbubbles.(2)In vitro study of ultrasound combined with microbubbles to dissolve red and white thrombus for 3 hours under magnet navigation.(3)In vitro study of ultrasound combined with microbubbles to dissolve red and white thrombus for 12 hours under magnet navigation.(4)In vivo study and prognostic evaluation of ultrasound combined with microbubble lysis of red and white thrombus in left iliac artery in rats.(5)Safety evaluation of ultrasound combined with magnetic microbubble therapy.Results:(1)Magnetic responsiveness and stability of microbubblesThe experimental results show that the magnetic response of the prepared magnetic microbubbles is good,and there is no significant difference in the stability between ordinary microbubbles and magnetic microbubbles.(2)Ultrasonic microbubble thrombolysis in vitroThe thrombolytic effect of US+M-MB group and US+M-MB+r-tPA group was significantly better than that of the other two groups.In terms of white thrombus,there was no significant difference in thrombolytic effect between US+M-MB group and US+M-MB+r-tPA group,but in red thrombus,the thrombolytic effect of US+M-MB+r-tPA group was better than that of US+M-MB group.In 12-hour-old thrombus,the thrombolytic effect of microbubbles in each group was worse than that in 3-hour-old thrombus,but the thrombolytic effect in US+M-MB group and US+M-MB+r-tPA group was still better than that in the other two groups.(3)Ultrasonic microbubble thrombolysis in vivoThe thrombolytic effect of US+M-MB group and US+M-MB+r-tPA group was significantly better than that of the other two groups.At the same time,the blood perfusion of affected limb tissue in these two groups was significantly higher than that in the other two groups.In terms of tissue apoptosis and tissue injury index,US+M-MB group and US+M-MB+r-tPA group were also significantly improved than the other two groups.(4)Safety evaluation of magnetic bubbles and ordinary bubbles under ultrasonic treatmentUltrasound-mediated bubble therapy under magnetic navigation has no obvious side effects.Conclusion:(1)under the guidance of magnetic field,compared with ordinary microbubbles,the number of microbubbles in the vascular segment that has reached complete occlusion increases significantly;(2)under the guidance of magnetic field,ultrasound combined with magnetic microbubbles can significantly enhance the thrombolytic effect of complete clotting;(3)under magnetic field navigation,ultrasound combined with magnetic microbubbles can improve the tissue blood perfusion after thrombolysis and reduce the damage of related tissues.