Ultrasound Doppler-guided real-time navigation of a magnetic microswarm for active endovascular delivery

Abstract

Swarming micro/nanorobots offer great promise in performing targeted delivery inside diverse hard-to-reach environments. However, swarm navigation in dynamic environments challenges delivery capability and real-time swarm localization. Here, we report a strategy to navigate a nanoparticle microswarm in real time under ultrasound Doppler imaging guidance for active endovascular delivery. A magnetic microswarm was formed and navigated near the boundary of vessels, where the reduced drag of blood flow and strong interactions between nanoparticles enable upstream and downstream navigation in flowing blood (mean velocity up to 40.8 mm/s). The microswarm-induced three-dimensional blood flow enables Doppler imaging from multiple viewing configurations and real-time tracking in different environments (i.e., stagnant, flowing blood, and pulsatile flow). We also demonstrate the ultrasound Doppler-guided swarm formation and navigation in the porcine coronary artery ex vivo. Our strategy presents a promising connection between swarm control and real-time imaging of microrobotic swarms for localized delivery in dynamic environments.

Fig. 1. Schematic illustration of ultrasound Doppler imaging–guided swarm formation and navigation in blood vessels.

(A to C) Schematic of the swarm navigation in blood vessels. The microswarm is formed, navigated, and tracked in blood vessels with different viewing configurations. (D) The formation process of a microswarm. Rotating nanoparticle chains are formed, and the hydrodynamic and magnetic interactions among them yield the gathering of nanoparticles to a rotating microswarm. The left (light microscope image) and right panels (B-mode ultrasound image) show a microswarm in glycerol-water solution (viscosity, 4 centipoise) and porcine whole blood, respectively. (E) The ultrasound Doppler signal around a rotating microswarm in blood. The Doppler signals near the microswarm in stagnant and flowing blood environments were observed, and the microswarm was tracked and navigated in real time using Doppler feedback. Blue dashed lines denote the theoretical position of the microswarm in the B-mode ultrasound images (right column).

Fig. 2. Swarm formation in blood.

(A) Magnetic field distribution of a 25-mm-diameter permanent magnet. The swarm plane represents the formation position of a microswarm. d_ms denotes the distance between the top surface of the magnet and the swarm plane. (B) A horizontal slice (z = 32.5 mm) of field strength distribution at d_ms = 20 mm. (C) Field strength along the X axis at d_ms of 5 to 20 mm. Dots and lines denote simulated data and fitted curves, respectively. (D) Simulation of the merging process of two rotational flows. The grayscale and white lines denote the flow velocity and streamlines, respectively. (E) The phase diagram shows the gathering of nanoparticles under different field strengths and frequencies. The right figures correspondingly show the representative experimental results in the three regions. (F) Experimental results of the reversible spreading-regathering of nanoparticles. The applied fields are schematically illustrated.

Fig. 3. Swarm formation and navigation in stagnant blood under ultrasound Doppler imaging.

Simulation results of induced flow (A) on the swarm plane and (B) 1 mm above the microswarm. The input frequency is 8 Hz. (C) Distribution of induced flow velocity above the swarm plane. (D) Ultrasound Doppler signals on and above the swarm plane. The ultrasound propagation direction is marked on the top right corner. (E) The mean area ratio between the color region and swarm in 3 s (14 frames per second) with different input frequencies and doses of nanoparticles. Each error bar denotes the SD from three experiments. (F) Simulation results of the motion trajectories of simulated RBCs (6-μm-diameter microparticles) near a rotating microswarm. The arrows represent the locomotion direction of the microswarm. (G) Doppler signal under (g1) different input frequencies and (g2) PRF values. In (g1), PRF = 1.25 kHz; in (g2), f = 6 Hz. (H) Navigation of the microswarm under ultrasound Doppler guidance. Parameters: PRF = 1.25 kHz and f = 6 Hz.

Fig. 4. Simulation and experimental results of swarm navigation in flowing environments.

(A) Simulated blood flow in a branching pipe (diameter, 2.6 mm). The input velocity is 10 ml/min. (B) Simulated flow distribution along the Z axis [enlarged region marked by the rectangle in (A)]. (C) Range of field parameters (d_ms and f) during swarm navigation in flowing conditions. (D) Simulation of RBCs flowing through a rotating microswarm. (d2 to d4) Cross sections that have distances of 6 mm (left), 1 mm (left), and 1 mm (right) to the swarm center, corresponding to ①, ②, and ③ in (d1). The input rotating frequency is 6 Hz with a flow rate of 10 ml/min. (E) Navigation of a swarm in flowing blood at a mean flow velocity of 31.4 mm/s. White and yellow arrows show the flow and swarm navigation directions, respectively. (F) Minimal frequency requirements for tracking a microswarm under different flow velocities. PRF: 1.0 kHz (12.6 mm/s), 1.25 kHz (22.0 to 31.4 mm/s), 1.5 kHz (40.8 mm/s), and 1.75 kHz (50.2 mm/s). Each error bar denotes the SD from three experiments. (G) Recycled residual nanoparticles after navigation under different flow velocities. The zero case represents the control group. Each error bar denotes the SD from five experiments. (H) Navigation of a microswarm in a pulsatile flow condition. The blue and yellow arrows represent the flow direction and the swarm navigation direction, respectively. (I) Comparison between the real-time tracked position and the position of the magnet. The blue dashed line represents the flow profile.

Fig. 5. Real-time navigation in porcine coronary artery ex vivo.

(A) Schematic illustration of the nanoparticle release, followed by swarm formation and navigation. The viewing configuration was switched between configurations II and III. (B) The artery is marked by the dashed yellow curves in (b1) and (b2). Blue circles refer to the target region (b1) before and (b2) after releasing nanoparticles into the artery, respectively. (b3 and b4) Ultrasound images before and after applying the rotating magnet. (b1 and b2) and (b3 and b4) are observed with configurations II and III, respectively. (C) Navigation of the microswarm in stagnant blood. The insets show the enlarged images of the region marked by the dashed rectangles. The ultrasound probe was moved along the X axis. (D) Real-time tracked position of the microswarm. Dots and the red line represent the tracked position and the fitted curve, respectively. (E) Real-time navigation in flowing blood. PRFs were 1.5 kHz in (C and D) and 1.75 kHz in (E).