Xurui Liu, Liu Wan, Yuanzhuo Xiang,  Fan Liao, Na Li, Jiyu Li, Jiaxin Wang, Qingyang Wu, Cheng Zhou, Youzhou Yang, Yuanshi Kou, Yueying Yang, Hanchuan Tang, Ning Zhou, Chidan Wan, Zhouping Yin, Guang-Zhong Yang, Guangming Tao, Jianfeng Zang

 

Science Robotics 2024, 9,eadh2479.

 

Abstract

Cerebral aneurysms and brain tumors are leading life-threatening diseases worldwide. By deliberately occluding the target lesion to reduce the blood supply, embolization has been widely used clinically to treat cerebral aneurysms and brain tumors. Conventional embolization is usually performed by threading a catheter through blood vessels to the target lesion, which is often limited by the poor steerability of the catheter in complex neurovascular networks, especially in submillimeter regions. Here, we propose magnetic soft microfiberbots with high steerability, reliable maneuverability, and multimodal shape reconfigurability to perform robotic embolization in submillimeter regions via a remote, untethered, and magnetically controllable manner. Magnetic soft microfiberbots were fabricated by thermal drawing magnetic soft composite into microfibers, followed by magnetizing and molding procedures to endow a helical magnetic polarity. By controlling magnetic fields, magnetic soft microfiberbots exhibit reversible elongated/aggregated shape morphing and helical propulsion in flow conditions, allowing for controllable navigation through complex vasculature and robotic embolization in submillimeter regions. We performed in vitro embolization of aneurysm and tumor in neurovascular phantoms and in vivo embolization of a rabbit femoral artery model under real-time fluoroscopy. These studies demonstrate the potential clinical value of our work, paving the way for a robotic embolization scheme in robotic settings.

 

Introduction and Methods

Here, we present magnetic soft microfiber robots (hereafter referred to as microfiberbots) with enhanced steerability, reliable maneuverability, and shape reconfigurability to perform robotic embolization in a remotely controllable manner. Magnetic soft microfiberbots have a helical geometry with a customizable diameter that can be compatible with existing catheters to maximize their clinical effectiveness. A standard catheterization can be first performed by threading a commercial catheter through blood vessels until the intravascular advancement is stopped. Thereafter, the microfiberbots can be deployed into blood vessels through the catheter. Enabled by the contact friction, the microfiberbot can anchor to the blood vessel after deployment without being flushed away by blood flow. By remotely applying magnetic fields, the microfiberbot can be actively steered in the blood flow (both upstream and downstream) via helical propulsion. The microfiberbots can be elongated for passing narrow regions and aggregated at the target lesion. The aggregated microfiberbot can either block the blood flow to the target aneurysm/tumor or protect the normal blood vessel, allowing for three embolization applications: aneurysm coil embolization, tumor coil embolization, and tumor particle embolization. We demonstrate both in vitro embolization of aneurysm and tumor in neurovascular phantoms and in vivo embolization of a rabbit femoral artery model under real-time fluoroscopy. As a supplement to conventional catheter-based embolization, our work presents a substantial advancement for the minimally invasive treatment of cerebral aneurysms and brain tumors in a robotic setting.

 

Key Results and Conclusions

We further demonstrated in vivo robotic embolization of a rabbit blood vessel on the right hind leg (diameter is from 500 to 800 μm) under real-time fluoroscopy. The microfiberbot was first injected into the femoral artery through a Terumo 2.6-French (Fr) catheter. The tortuous vessel was marked with four sites. Guided by fluoroscopic imaging (x-ray), the microfiberbot is helically propelled from site 1 to site 4, returned to site 2, and eventually aggregated at site 2. To validate the completed embolization, we then obtained the angiography of the femoral artery by injecting iodinated contrast medium. Before embolization, we can see iodinated contrast medium throughout the femoral artery, suggesting a normal flow in the artery. After embolization, no contrast medium was observed because of the blockage of the flow by the aggregated microfiberbot. The angiography conducted 3 weeks after embolization indicated that the microfiberbots have successfully facilitated a stable vascular embolism, with no signs of recanalization. The presence of the aggregated microfiberbot blocked the blood flow from the proximal to the distal end of the vessel, which led to the formation of thrombosis inside the artery, as validated by the histological analysis 3 weeks after embolization. It is worth noting that no inflammation or pathological abnormalities were observed from the hematoxylin and eosin (H&E) staining results of the main organs, including the lung, liver, spleen, kidney, and heart, after 3 weeks. Additionally, compared with those of an untreated control group, the numbers of blood cells, such as red blood cells (RBCs), white blood cells, platelets, and lymphocytes, after the robotic embolization procedure remained at normal levels after 3 weeks, suggesting that the proposed robotic embolization by magnetically steering microfiberbots was safe.

Last, a faster thrombus formation is always desired for occluding the blood flow, leading to a successful embolization. In this regard, we present two potential solutions that have been reported in the literature for enhancing embolization efficiency. The first solution is to coat the microfiberbot with thrombin such that blood cells can be absorbed into the microfiberbot, as validated by the reduced blood clotting index and scanning electron microscope images in fig. S19. The formed thrombus can resist a pressure of up to 22 kPa, which is large enough to block the blood flow in vivo. The second solution is to further coat the microfiberbot with a thin functional layer (20 μm) of iron oxide (Fe3O4) nanoparticles that can generate heat upon radio frequency (RF) stimulation. By remotely heating the aggregated microfiberbot at the target lesion via an RF coil (200 kHz), we can generate local hyperthermia that promotes thrombus formation. In vitro demonstration in the blood vessel phantom shows that a thrombus can be formed within 5 min. The mechanism of local hyperthermia–induced thrombus formation lies in the activation and aggregation of platelets. When the temperature increases to about 41°C, platelets are activated in vivo and aggregate to form a thrombus. This mechanism has been reported in the literature and is also validated by our experiments in which the activated coagulation time of the porcine blood decreases as the temperature rises from 37° to 50°C. In summary, we envisage that our magnetic soft microfiberbots will pave the way for the untethered robotic embolization of cerebral aneurysms and brain tumors in the future.

 

Fig. 1：Magnetic soft microfiberbots for robotic embolization.

(A) Schematic illustration of functionalities and potential applications of magnetic soft microfiberbots. The microfiberbot can anchor to a blood vessel after being released, navigate in the blood vessels via helical propulsion, pass through narrow regions by elongation, and block the blood flow by aggregation. The aggregated microfiberbots can be used as embolic agents for coil embolization of aneurysms and tumors and as protection devices for selective particle embolization of tumors. (B) Fabrication process of magnetic soft microfiberbots: thermal drawing of magnetic soft microfiber, magnetizing by a strong impulse magnetic field (2.5 T), and molding/demolding into a helix shape. (C) Optical imaging of magnetic soft microfibers with different fiber diameters denoted as d. (D) Optical images of magnetic soft microfiberbots with different helical diameters denoted as D. (E) An image of magnetic soft microfiberbots deployed via a Terumo 2.6-Fr catheter to the surface of the brain phantom. Scale bar, 5 mm.

 

Fig. 2：Shape-morphing capability and magnetic maneuverability in flow conditions.

(A) The microfiberbot can anchor to the vessel in the absence of magnetic fields. By further applying static magnetic field B parallel to its net magnetization (denoted as Mnet), the magnetic soft microfiberbot can have reversible elongated and aggregated states. Scale bar, 1 mm. The finite element analysis (FEA) reveals that the maximum contact pressure occurring between the microfiberbots and the vessel wall is 4.3 kPa. (B) Schematic illustration of manipulating the microfiberbot by controlling a cubic magnet with a 6-DOF robotic arm. The helical propulsion is enabled by axially rotating the magnet (rotating axis is parallel with the x axis), whereas magnetic pulling is enabled by rotating the magnet in the xy plane. (C) The magnetic soft microfiberbots can perform aggregation and elongation shape morphing by changing the external magnetic field. The elongated state of the microfiberbot is achieved by controlling the magnet to generate the magnetic field along with Mnet, and the aggregated state is achieved by controlling the magnet to generate the magnetic field opposite Mnet. The upstream helical propulsion is achieved by rotating the magnet in a clockwise manner, and magnetic pulling is achieved by moving the magnet. (D) Experimental pictures show that the microfiberbot (d = 60 μm, p = 800 μm, and D = 800 μm) can steadily anchor to a vessel phantom (inner diameter H = 800 μm) in the absence of magnetic fields, achieve upstream/downstream helical propulsion under rotating magnetic fields (B = 40 mT, frequency of 5 Hz), undergo magnetic pulling under a magnetic field gradient, and recover to the helical shape. Scale bars, 2 mm.

 

Fig. 3：Catheter-assisted deployment of the microfiberbot.

(A) The microfiberbot can be injected into a commercial catheter with a microneedle syringe. The microfiberbot quickly recovers its helical shape after injection. (B) The microfiberbot travels inside the catheter by perfusing saline under x-ray imaging guidance. Catheter-assisted deployment of the microfiberbot for embolization at (C) target 1 and (D) target 2 in a blood vessel phantom with bifurcation branches. All scale bars, 1 mm.

 

Fig. 4：Steerability of the microfiberbot in submillimeter regions.

(A) Schematic illustration and experimental demonstration of the microfiberbot navigating in a blood vessel phantom with bifurcation branches of 30° and 60°. (B) Schematic illustration and experimental pictures of the microfiberbot navigating in a blood vessel phantom with bifurcation branches of 90° and 120°. Scale bars in (A) and (B), 2 mm. (C) Experimental demonstrations of the microfiberbot navigating in a vessel phantom with a narrowing diameter (1 mm to 100 μm). (D) Demonstration of the microfiberbot navigating an S-shaped vessel phantom. (E) Demonstrations of the microfiberbot navigating a 3D vessel phantom. Scale bars in (C) to (E), 1 mm.

 

Fig. 5： In vitro robotic embolization in neurovascular vessel phantoms.

(A) Demonstration of aneurysm coil embolization by magnetic soft microfiberbot. Scale bar, 1 mm. (B) Validation of the embolization results under x-ray fluoroscopy. The flow into the aneurysm is reduced after coil embolization. Scale bar, 1 mm. (C) Demonstration of tumor coil embolization in which branch 2 is assumed to be a tumor vessel. Two microfiberbots are steered subsequently to completely occlude branch 2. (D) The contrast agent is released to validate the occluded branch 2. (E) Demonstration of tumor particle embolization protection in which branch 1 is assumed to be a healthy vessel. (F) After the microfiberbot blocks the healthy branch 1, the embolic particles are released to occlude tumor vessels (branches 2 and 3). (G) The microfiberbot can be safely retrieved after particle embolization is completed. (H) The contrast agent is released to validate the occluded vessel branches 2 and 3. Scale bars in (C) to (H), 2 mm.

 

Fig. 6：Robotic embolization with multiple microfiberbots.

(A) The blocking ratio is defined as the ratio of the cross-sectional area between the aggregated microfiberbots and the blood vessels. The average blocking ratios (± SD) are 14.92 ± 2.2%, 51.35 ± 13.4%, and 88.65 ± 8.6% for the respective measurements (N = 3). (B) Demonstration showing that particles are fully blocked with dual aggregated microfiberbots. (C) Demonstration of aggregated microfiberbot in different vessel branches. (D) Demonstration of quadruple aggregation at the same target in a vessel phantom. All scale bars, 1 mm.

 

Fig. 7：Robotic embolization in a rabbit blood vessel in vivo.

(A) Schematic illustration of robotic embolization in rabbit blood vessel on the leg under real-time fluoroscopy. (B) The magnetic soft microfiberbot is released into the blood vessel by a catheter. Scale bar, 5 mm. (C) The angiology of targeted blood vessel before embolization by infusing iodinated contrast media. (D) Fluoroscopy images of microfiberbot navigating from site 1 to site 4. (E) Fluoroscopy images of microfiberbot returning from site 4 to site 2 and aggregated. (F) The angiology of blood vessel after embolization by infusing iodinated contrast medium. (G) The blood vessel is separated for histological analysis 3 weeks after embolization. Scale bar in (D) to (G), 1 mm. (H) The H&E staining cross-sectional images of the blood vessel. Cross sections 1 and 2 show the formation of thrombus after embolization. Scale bar, 250 μm.

 

https://www.science.org/doi/10.1126/scirobotics.adh2479