Rapid Thrombolysis Technology Based On Controlled Fe₃O₄ Nanoparticles By Composite Magnetic Field

The thrombotic diseases seriously threaten human life and health.In particular,the effective treatment time for cerebral infarction caused by thrombosis is usually limited to a few hours after the onset.The current clinical treatment for the cerebral thrombosis infarction mainly rely on surgical operations and thrombolytic therapy.The former will cause huge pain and postoperative complications to patients,while the latter will induce bleeding complications when large dosage is used for rapid thrombolysis.It is of great practical significance to carry out research on rapid thrombolysis technology under low dose of thrombolytics.The study aimed at the theories and technologies of achieving rapid dissolution of thrombus under low-dose of thrombolytic drug urokinase driven by Fe₃O₄nanoparticles（NPs）controlled by the composite magnetic field.The main research contents and results include:Throw light upon the mechanism of accelerating thrombolysis with the motion of magnetic nanoparticles（MNPs）at the boundary of thrombus and thrombolytic drugs.Analyze the influence of the MNPs’translation and rotation on the fluid flow from the micro perspective.The principle of fluid motion caused by particle motion is analyzed from the perspective of energy conversion.Based on the fluid dynamics and fluid convective diffusion theory,the mechanisms of deep focusing,rapid thrombolysis through improving drug concentration,impact destruction and acceleration of drug diffusion driven by the translation and rotation of MNPs were elucidated.A theoretical model of rapid thrombolysis in microchannels based on convection diffusion theory was established.Establish the deep focusing,rotation and translation model of MNPs under the coupling effect of magnetic field and flow field and the current control strategy.The magnetic properties of MNPs were modeled according to the magnetization theory.The deep focusing,translation and rotation equations of MNPs under magnetic and fluid coupling field were deduced.The agglomeration,rotation and translation of MNPs in the flow field were analyzed and verified by MATLAB and COMSOL software.The magnetic parameters of magnetic strength,magnetic gradient,magnetic frequency and the magnetic point with local high intensity for motion control applied for the clinic use were determined.Analyze the magnetic field distribution of one-dimensional and multi-dimensional hollow axis electromagnetic coils.Based on Particle Swarm Optimization（PSO）algorithm,a hollow axis composite magnetic field coil group which could control the deep focusing and rotation and translation of MNPs in the flow field was designed.The particles motion control strategy was established by applying pulse current,alternating current and adjusting current amplitude,frequency and phase for different magnetic control levels.Then the results were verified and analyzed by the simulation software COMSOL.A method for preparing MNPs loaded with thrombolytic drug urokinase was proposed.Polymaleic anhydride-1-octadecene was attached to the surface of MNPs to achieve carboxylation of NPs.Furthermore,the immobilization of urokinase on the surface of MNPs was realized by covalent bonding.On the basis of the above,an in-vitro rapid thrombolysis experimental system motivated by MNPs was set up.The feasibility of assisting rapid thrombolysis using composite magnetic field was verified by the in-vitro thrombolysis.The results show that the translation and rotation of MNPs driven by composite magnetic field can effectively improve the rate of thrombolysis with low dose of urokinase to about two times.When the urokinase was conjugated to the surface of the MNPs,the thrombolysis rate was improved to three times or more.It provides a scheme for rapid thrombolysis while avoiding the risk of bleeding.This research has laid a theoretical and technological foundation of achieving rapid dissolution of thrombus in clinic research and application under low-dose of thrombolytic drug urokinase utilizing Fe₃O₄MNPs controlled by the composite magnetic field.