Magnetic catheter with soft rotatable tip

Abstract

A microcatheter comprises: a) a tip made of a low stiffness material; b) one or more permanent magnets within said tip; c) a working channel; and d) a ball joint for connecting said tip to said working channel; wherein said one or more permanent magnets is adapted to cause rotational movement of said tip when acted upon by an external rotational magnetic field.

Description

Dkt. 008-22-A-PCT MAGNETIC CATHETER WITH SOFT ROTATABLE TIP FIELD OF THE INVENTION

[0001] The present invention relates to submillimeter magnetic catheter with soft rotatable tip for enhanced endovascular access and treatment efficiency.BACKGROUND OF THE INVENTION

[0002] Endovascular interventions require fast access to affected areas, followed by effective treatment. While conventional catheter-based approaches are effective for large vessel occlusions (LVOs), such as pulmonary embolism (PE) and venous thromboembolism (VTE), they face challenges in terms of accessibility, efficiency, and invasiveness when applied to narrow, tortuous vascular systems. This study presents a submillimeter Magnetic Soft Rotatable-Tipped Microcatheter (MSRM) designed to access small blood vessels and provide efficient, minimally invasive therapeutic interventions for blood clot treatment. The high accessibility is attributed to the MSRM’s rotatable tip design, which provides three degrees of rotational freedom under magnetic actuation. A rotation-assisted active steering strategy is developed that can enlarge the reachable workspace and enhance navigation speed. The improved blood clot treatment efficiency is achieved through the multifunctionality of the MSRM: it can accelerate drug-blood clot interactions, mechanically break down blood clots, and retrieve clot debris. The soft material design and low-frequency actuation achieve low invasiveness, which is experimentally evaluated in an ex vivo human placenta model. To verify the capability of the MSRM in a clinically relevant scenario, it was further demonstrate magnetic navigation through narrow blood vessels and drug-assisted in-situ blood clot treatment in a live rabbit model. The proposed microcatheter offers a promising method to address access difficulties and improve treatment efficiency for endovascular interventions.

[0003] Vascular diseases affecting deep-seated organs in the human body are serious medical conditions that require prompt access to appropriate medical devices and effectiveinterventions. Failure to address these issues in a timely manner can lead to severe consequences. For instance, untreated endovascular blockage in cerebral vessels can lead to an irreversible loss of nervous tissue, equivalent to the brain ageing 3.6 years per hour1. Delayed treatment of myocardial infarction can increase the risk of 1-year mortality by 7.5% for every 30 minutes2.

[0004] Mechanical Thrombectomy (MT), which physically removes or retrieves blood clots, provides prompt and effective endovascular treatment for large vessel diseases. Nevertheless, neither suction catheters nor retrieval stents can easily access distal and tortuous blood vessels, specifically those with diameters less than 2 mm, such as the M3 and M4 segments of the Middle Cerebral Artery (MCA) or the distal segments of coronary arteries. Commercially available suction catheters, which generally have a diameter ranging from 2 mm to 2.7 mm to ensure adequate suction power, demonstrate limited efficacy in small-scale scenarios3. The scale discrepancy not only requires the intervention tools to remain small but also places stricter demands on invasiveness. Smaller blood vessels are more vulnerable to perioperative complications than larger vessels4. During surgery, surgeons must take additional time to minimize frictional damage caused by surgical tools, which can prolong the intraoperative period. Studies have indicated that achieving complete revascularization within a longer intraoperative timeframe is associated with worse neurological outcomes and an increased mortality rate3.

[0005] In recent years, magnetic microrobots designed for medical tasks have provided feasible solutions in otherwise challenging clinical scenarios, such as the delivery of therapeutic drugs to cancer cell target lesions, the non-invasive diagnosis through miniaturized sensors and actuators, and the endovascular recanalization of occluded arteries5 l4. Robotic magnetic microcatheters, another type of magnetic microrobots, integrate magnetic actuation with microcatheter technology to facilitate effective and efficient endovascular interventions1518. The magnetic force and torque can be directly applied to the distal end, allowing it tomaintain high maneuverability at small scales19’20. Additionally, magnetically actuated microcatheters, compared to tendon- or hydraulically-driven ones, provide more on board space to enhance functional developments21. Beyond creating a pathway that connects the interior and exterior of the human body, researchers have equipped the magnetic microcatheter with sensing modules that enable the measurement of endovascular biological information, such as vessel occlusion and temperature18’22. Furthermore, the integration of actuation modules has been demonstrated for rotational atherectomy and capsule delivery7, 23.

[0006] Despite substantial progress in recent years, applying microcatheters in small-scale blood vessels still presents significant challenges. The first issue is how to maintain high flexibility in the complex vascular system. Pre-curved guidewires can lose their steerability due to continuous sharp turns and singular configurations such as looping and buckling24. Upon reaching the affected region, how to deliver efficient and effective therapy poses the second challenge. Limiting the tool size to the vascular scale leads to higher fabrication complexities and lower medication-target interaction efficiency21, 25. Thirdly, the potential endothelial damage from the physical interaction between rigid actuation units and fragile blood vessels should be cautiously tabulated, particularly in terminal arteries that are prone to avulsion or rupture26. The delicate nature of the soft biological material encumbers the utilization of aggressive mechanical interactions, which was once useful in large vessel treatments5, 14, 27.

[0007] To address the challenges mentioned above, a submillimeter-scale, soft-tipped magnetic microcatheter designed for navigating complex vascular systems and delivering efficient endovascular interventions is presented. The miniaturized ball joint connects the working channel to the embedded permanent magnet, providing the tip with three degrees of rotational freedom and a fluid pathway between the inside and outside of the body (Figures 1A and IB). The rotational motion enhances the accessibility to hard-to-reach branches by reducing contact friction at the tip, thus avoiding buckling and looping scenarios. Taking advantage of this, a rotation-assisted active steering strategy is proposed (Figure 1C), and amaximum 50% reachable workspace enhancement is experimentally verified in the Results section (Rotation-assisted active steering). Furthermore, the MSRM enables multiple therapeutic functions, including enhanced drug-thrombus interaction, blood clot mechanical breakdown, and clot debris retrieval (Figures ID to 1G). This all-in-one design provides an effective method to reduce operational duration and improve the overall efficiency of blood clot treatments. The rotatable helical tip, made of low-stiffhess elastomer, mitigates the risk of vascular damage during navigation and mechanical blood clot removal. Unlike previously reported rigid spinners that employ aggressive rotating motion14, 27, the proposed microcatheter could realize efficient treatment without using large contact forces and high rotational speed. The MSRM’s high effectiveness and low invasiveness are experimentally verified in human cerebral vascular silicone phantoms, in an in vivo rabbit model, and in an ex vivo human placenta model.SUMMARY OF THE INVENTION

[0008] This invention provides a microcatheter. In one embodiment, said microcatheter comprises: a) A tip made of a low stiffness material; b) One or more permanent magnets within said tip; c) A working channel; and d) A ball joint for connecting said tip to said working channel; wherein said one or more permanent magnets is adapted to cause rotational movement of said tip when acted upon by an external rotational magnetic field.

[0009] This invention also provides a method for navigating said microcatheter of this invention for therapeutic intervention. In one embodiment, said method comprises the steps of: a) Inserting said microcatheter to a vessel comprising two or more branches; b) Applying a directional magnetic field to align said tip with a desired branch among said two or more branches; c) Advancing said microcatheter to reach entrance of said desired branch; and d) Applying a rotational magnetic field while advancing said microcatheter into said desired branch to establish rotational contact with wall of said desired branch.BRIEF DESCRIPTION OF THE FIGURES

[0010] Figures 1A to 1G show the design of the magnetic microcatheter system for endovascular treatments. Figure 1A shows the schematic illustration of the rotation-assisted steering approach and its advantages, (i-iv). Convention method to navigate the microcatheter to the sharp turn branch where the friction on the tip could cause the catheter to buckle, (iii). Rotational motion at the tip releases the contact friction at the tip and smooths the insertion process (iv). Figure IB shows the exploded view of the microcatheter design. The outer diameter is 0.8 mm and the tip’s length is 3 mm. Figure 1C shows the MSRM prototype which is compared to a one-dollar Hong Kong dollar coin. The inset shows in the microscopic view of Figures ID to 1G. Schematic diagram of the magnetic microcatheter system working principle. The submillimeter magnetic microcatheter can efficiently navigate through narrow blood vessels and generate therapeutic interventions from three aspects: drug-clot interaction acceleration (Figure IE), rotational mechanical breakdown (Figure IF), and clot debris retrieval (Figure 1G).

[0011] Figures 2A to 2E show the rotation-assisted active steering strategy. Figure 2A shows the key frames of the experiment using rotation-assisted steering strategy to enter the sharp-turn branch, (i-ii). The directional field guides the microcatheter’s tip to the entrance. The stuck at the tip results in tension accumulation on the body of the catheter, (iii). Further advancement caused failure to enter the branch, (iv). Rotation motion decreases the friction force at the tip and directs the microcatheter to the desired branch. The magnetic field directions are marked by the purple arrows. Figure 2B shows the key frames of the experiment using the directional magnetic field to guide the microcatheter to the bifurcation phantom and the reachable workspace comparison between the directional magnetic field steering method (DMF-guided) and rotational magnetic field guided steering method (RMF-guided). A maximum 50% reachable workspace enhancement is observed at a magnetic field of 25 mT.Figure 2C shows the insertion force comparisons between passive insertion and rotation-assisted insertion through navigating a sharp turn. The L-shaped channel is divided into three segments by the point from Ato D. The diameter of the channel is 2 mm. In the rotation-assisted group, the norm direction of the rotation field 3nis determined by the trajectory tangent direction. The branch angle 3t describes the sharpness of the comer. Figure 2D shows the results of insertion force comparison that shows the rotational magnetic field (RMF) guided group uses the lowest insertion force compared with the directional magnetic field (DMF) guided group, the commercial guidewire group, and the non-guided group. The insertion force drop in segment C-D shows contact friction release by the rotational motion. The color belts show the standard deviation, and the lines show the mean value. Each group of tests is repeated 5 times. Figure 2E shows the required rotational magnetic field strength when the microcatheter is in various branch angles.

[0012] Figures 3A to 3G show the In vitro accessibility verification Figure 3A shows the In vitro navigation in full-size human cerebral blood vessel model. Two regions of interest are: (i). The M3 to M4 transition region of the MCA, (ii). The S-shape tortuous blood vessel of the internal carotid artery (ICA). Figure 3B shows the dimension details of the phantom region (i).Figure 3C shows the dimension details of the phantom region (ii). Ri and R2 are the curvature radius of the first and the second turn, respectively. Figure 3D shows the key frames of navigation in the region (i). The microcatheter navigated two bifurcations and arrived at two destinations in the distal branches. The red arrow highlights the position of the microcatheter tip. Figure 3E shows the key frames of navigation in region (ii). The microcatheter passes two continuous 180-degree turns with small radius curvature. The scale bar is 5 mm. Figure 3F shows the navigation efficiency comparison of the region (i). Each group of tests is repeated three times. Figure 3G shows the navigation efficiency comparison of the region (ii). Each group of tests is repeated three times.

[0013] Figures 4A to 4N show the rotational actuation design and endovascular treatment functions validation. Figure 4A shows different tip designs: cylinder, straight fins, helical finswith different rotation directions. Corresponding velocity contours with streamlines on the a-a plane illustrate flow towards the micro-rotor. The rotating frequency f= 5 Hz, and the outer diameter of all the designs is 0.8 mm. Figure 4B shows the side edge pressure distribution with respect to the distance to the catheter’s rear end at 5 Hz. Figure 4C shows the pressure distribution of retrieving mode and pumping mode. Figure 4D shows the simulation results to optimize the structural design of the rotatable tip. The central angle a and the pitch angle 6Pare two design variables of interest. The optimal values are 6P= 60° and a = 45°. Figure 4E shows the simulation settings to investigate the optimal tip profde. Figure 4F shows the simulation result that shows the affected area of different tip profile designs. Figure 4G shows the pumping effect comparing with natural diffusion at rotation velocity of 5 Hz. Each group of tests is repeated 3 times. Figure 4H shows the schematic flow status of the pumping mode and retrieving mode. Figure 41 shows the experiment results to verify the blood clot-drug interaction enhancement. Blood clot in-situ breaking down with the combination of mechanical interaction and the thrombolytic drug (tPa: 0.3 mol / ml, 0.2 m ). The blood clot is extracted from the channel at 5 min, 10 min, and 20 min to evaluate the volume reduced. The control group is injected with the thrombolytic drug (tPa: 0.3 mol / ml, 0.2 m ). Figure 4J shows the treatment efficiency comparison using three methods to treat blood clots 2 mm x 5 mm, 30 minutes). Each group of tests is repeated 3 times. Figure 4K shows the mechanical rubbing blood clot clearing efficiency at 1 Hz, 3 Hz, 5 hz and 7 Hz. The blood clot dimension: 2mmx5 mm. Each group of tests is repeated 3 times. Figure 4L shows the schematic working principle a experimental demonstration of the blood clot retrieval strategy. Figure 4M shows the blood clot retrieval efficiency on blood clots of different lengths: 2.5 mm, 5 mm, 10 mm, 15 mm. Each group of tests is repeated 3 times. Figure 4N shows the blood clot retrieval efficiency and mechanical rubbing efficiency on blood clots of different ages: 30 min, 60 min, 90 min, 120 min. The rotating frequency is 5 Hz. Each group of tests is repeated 3 times.

[0014] Figures 5A to 51 show the In vivo demonstrations in a rabbit model. Figure 5Ashows two key regions: the carotid artery region and the iliac artery to kidney region. Figure 5B shows the system setup for X-ray imaging guided in vivo microcatheter navigation. Figure 5C shows the In vivo navigation to kidney artery. The dotted line highlights the desired trajectory and the bifurcation branches are highlighted in blue. The scale bar is 10 mm. Figure 5D shows navigation with static field actuation. The microcatheter can be steered towards the desired branch, but large friction at the tip may cause buckling on the microcatheter, as the arrow shows. The scale bar is 10 mm. Figure 5E shows navigation with rotational field guidance. The rotation-assisted steering mechanism can facilitate a smoother insertion process with a shorter duration and less tension on the catheter body. The scale bar is 10 mm. Figure 5F shows the system setup for in vivo blood clot clearance. Figure 5G shows the preoperative stage of the in vivo blood clot clearance demonstration. The selected segment of the carotid artery is ligated at one end and connected to a catheter sheath at the other. In the preoperative stage, the blood clot is inserted through the sheath, filling the artery to the ligature site. Figure 5H shows the intraoperative blood clot clearance demonstration. The microcatheter advanced deeper every 5 minutes. After 15 minutes, the blood clot is thoroughly broken down. Figure 51 shows the postoperative stage of the in vivo blood clot clearance demonstration. The blood clot has disappeared from the imaging plane and cannot be observed after inflating the blood vessel.

[0015] Figures 6Ato 6E show the invasiveness evaluation in human placenta blood vessels.Figure 6A shows the setup of the invasiveness evaluation test. Four segments from the superficial blood vessels of the human placenta were chosen. In segment I, the proposed microcatheter contacts the blood vessel’s inner wall and is rotational actuated for 30 minutes. In segment II, the proposed microcatheter contacts the blood vessel’s inner wall and is repeatedly inserted 100 times. In segment III, a commercial guidewire is inserted into the blood vessel with tip contact on the vessel wall 100 times. The segment IV is blank control. Figures 6B to 6E show the example images of the histological analysis that show the physical impacton the endothelial cell layer and the inner vessel wall. The black arrows show the cell layer detachments and the dotted line shows the tom and missing cell layer (Rotational actuation and Contact frictional insertion (commercial)).

[0016] Figure 7 shows the setup and results of applicability tests, (i). The bifurcation phantom for bending and rotating assessment. The scale bar is 5 mm. (ii). Experiment setup of the evaluation test for maximum in-plane bending angle. The scale bar is 5 mm. (iii). Results for the in-plane bending test that show the proposed microcatheter can be bent by the static magnetic field of 20 mT from -90° to 90°. n = 3.

[0017] Figure 8 shows the robotic arm-assisted rotatable magnetic system. The 5-DOF robotic arm carries a stepper motor-assisted permanent magnet to generate both static field and rotational field.

[0018] Figure 9A shows navigation in a silicone phantom with features of narrow diameters and continuous sharp turns. Different magnetic navigation strategies are adopted for different angles to ensure efficiency and steerability after passing through sharp turns. Figure 9B shows the key frames of magnetic navigation in the four regions of interest. The scale bar is 4 mm.Figure 9C shows the quantitative evaluation of the performance of the navigation. With magnetic guidance, the navigation efficiency in terms of duration and repeated times is improved. In region (ii), where the microcatheter took a sharp turn, the magnetically guided group is 30 times faster with only 1 - 2 repeated insertions. Moreover, the magnetically guided microcatheter demonstrated selective steering ability into regions (iv) and (iii), indicating its maintained steerability after navigating acute turns while the non-guided group cannot access region (iv). In the distal branches, successful rotational actuation of the microcatheter was achieved, indicating its maintained functionality after taking sharp turns. Without magnetic guidance, the microcatheter loses steerability after passing through region (ii) and cannot enter region (iv). n = 5 samples, the error bar indicates the standard deviation.

[0019] Figure 10 shows the soft fin deformation under rotating field. The fins were exposedto continuous blood flow with a maximum flow rate of 1.1 cm / s, which was the flow rate under the desired rotation frequency of 8 Hz. The viscosity of the fluid was set to 20 cP to represent the blood viscosity at stagnant condition. a= 45° was selected to have a deformation less than 10%. The deformation is calculated by the area difference divided by the original area.

[0020] Figure HA shows the system design for the pumping effect demonstration, which was comprised of a plastic lumen that was tilted at 15° on a slope and filled with a 75% glycerin solution. To initiate the demonstration, 15 pL of red dye was injected from the working channel and released at the opening located on the distal end of the MSDM. The external magnetic field actuates the helical tip to rotate and propel the dye uphill. The red dye boundary’s position indicates the fluid mixing speed and is extracted from the CCD camera images. Figure 11B shows the system setup for blood clot mechanical rubbing test. The system consists of a silicone lumen, which is immersed in a 37° water bath, and a microcatheter that is magnetically actuated by a rotating magnetic field. The microcatheter mechanically rubs against an artificial blood clot, which is fabricated inside the silicone lumen that is filled with PBS. From the images captured by the CCD camera, the area of the red clot was derived, which serves as an indicator of the clear rate.

[0021] Figure 12 shows the experiment results that show a clear rate comparison between hard design and soft design. The average clearance rate of mechanical rubbing for the soft design is 28.4% of that of the hard helical tip design. However, under the assistance of the thrombolytic drug, the clearance rate of the soft design escalates to 96.13% of the hard helical tip design. The data are presented as mean values, and standard deviation for the number of trials n = 5.

[0022] Figure 13 shows the demonstration of the fibrin-rich blood clot retrieval.

[0023] Figure 14 shows the demonstration of the fibrin-rich blood clot retrieval. Retrieval artificial blood clot under the US imaging. The strong Doppler signals in the test group indicatethe effective retrieval flow.

[0024] Figure 15 shows the performance comparison of the previous magnetic catheter with the current work (Dreyfus, R. et. al., 2024. Dexterous helical magnetic robot for improved endovascular access. Science Robotics, 9(87), p.eadh0298. Mao, L. et al., 2024. Magnetic steering continuum robot for transluminal procedures with programmable shape and functionalities. Nature Communications, 15(1), p.3759. Nguyen, K.T. et al., 2020. Guide-wired helical micro robot for percutaneous revascularization in chronic total occlusion in-vivo validation. IEEE Transactions on Biomedical Engineering, 68(8), pp.2490-2498. Pittiglio, G. et al., (2022). Patient-specific magnetic catheters for atraumatic autonomous endoscopy. Soft robotics, 9(6), 1120-1133.) The proposed MSRM is evaluated compared to other magnetic microcatheters for medical applications. Device diameter refers to the microcatheter’s maximum diameter, which suggests its accessibility. Reachable workspace describes the range of bending angles the microcatheter can achieve in its application scenarios. Tip Rotational DOF suggests the microcatheter tip’s ability to rotate along the x, y, and z axes. Tip softness is determined by the Young’s modulus of the microcatheter’s tip. Multi-functionality refers to the number of integrated functions in the microcatheter. The MSRM’s functions include static field active steering, rotation-assisted navigation, clot-drug interaction acceleration, mechanical thrombectomy, and clot debris retrieval.

[0025] Figure 16 shows the structural design and bending mechanism.

[0026] Figure 17 shows the fabrication process of the MSRM. The fabrication process includes three parts: the ball joint is made from a dip and cure process; the soft helical sheath is made by negative molding technique, and the ball joint chamber is 3-D printed. Different stiffness support tubes are used for the creation of a stiffness gradient design.

[0027] Figure 18 shows the fabrication process of the MSRM. The fabrication process includes three parts: the ball joint is made from a dip and cure process; the soft helical sheath is made by negative molding technique, and the ball joint chamber is 3-D printed. Differentstiffness support tubes are used for the creation of a stiffness gradient design.

[0028] Figures 19A to 19C show the system setup of the insertion performance evaluation.Figure 19A shows the experiment setup of the MSRM navigation and actuation under X-ray imaging. The robotic arm carries the rotatable permanent magnetic source and shares the same workspace as the X-ray imaging system. The bifurcation phantom simulates the human brain vessel’s tortuosity and dimension. Figure 19B shows the safe distance demonstration and insertion machine setup. Figure 19C shows the integrated navigation results. Guiding by the permanent magnetic system, the MSRM can be navigated to the desired branch. The embedded permanent magnet can be regarded as a contrast marker.DETAILED DESCRIPTION OF THE INVENTION

[0029] This invention provides a microcatheter. In one embodiment, said microcatheter comprises: a) A tip made of a low stiffness material; b) One or more permanent magnets within said tip; c) A working channel; and d) A ball joint for connecting said tip to said working channel; wherein said one or more permanent magnets is adapted to cause rotational movement of said tip when acted upon by an external rotational magnetic field.

[0030] In one embodiment, said low stiffness material is an elastomer.

[0031] In one embodiment, said elastomer is one or more selected from the group consisting of PDMS, rubber, polyurethane, polybutadiene, neoprene and silicone.

[0032] In one embodiment, said low stiffness material is one or more selected from the group consisting of silicone, nylon, rubber, resin, thermoplastic polyurethane (TPU), and polyvinyl chloride (PVC).

[0033] In one embodiment, said tip comprises a shape selected from the group consisting of helical, cylindrical, cylindrical with straight fins, spindle.

[0034] In one embodiment, said tip has an outer diameter of less than 1 mm.

[0035] In one embodiment, said ball joint comprises: a) a ball joint chamber comprising a through hole; and b) a hollow ball joint comprising a connection hole; wherein said tip is inserted into said through hole and connected to said connection hole.

[0036] In one embodiment, said rotational movement comprises three degrees of rotational freedom.

[0037] In one embodiment, said permanent magnet is cylindrical, donut-shaped, sphere, cubic or hexagonal pyramid.

[0038] In one embodiment, said working channel has stepped stiffness. To ensure both pushability and steerability, the working channel is designed with materials of varying stiffness. The proximal end is made from a stiffer material, allowing the insertion force to be effectively transmitted to the distal end. At the distal end, a relatively softer material is used, enabling the tip to achieve a larger steering angle when a magnetic field is applied. In one design, this gradient in stiffness is achieved by connecting tubes made from different materials: a nitinol tube serves as the base, a Polytetrafluoroethylene (PTFE) tube forms the middle section, and a soft polyethylene (PE) tube is used for the tip.

[0039] In one embodiment, said microcatheter further comprises a fluid pathway running through said working channel, said ball joint and said tip.

[0040] In one embodiment, said microcatheter further comprises a syringe pump and / or a vacuum pump connected to said working channel.

[0041] This invention also provides a method for navigating said microcatheter of this invention for therapeutic intervention. In one embodiment, said method comprises the steps of: a) Inserting said microcatheter to a vessel comprising two or more branches; b) Applying a directional magnetic field to align said tip with a desired branch among said two or more branches; c) Advancing said microcatheter to reach entrance of said desired branch; and d) Applying a rotational magnetic field while advancing said microcatheter into said desired branch to establish rotational contact with wall of said desired branch.

[0042] In one embodiment, said therapeutic intervention comprises drug-clot interaction acceleration, biofilm eradication, endovascular embolization, stent delivery, rotational mechanical breakdown or clot debris retrieval.

[0043] Results

[0044] Magnetic microcatheter system design. The proposed magnetic microcatheter is designed for navigating vascular systems with a diameter of 1 mm or larger, such as cortical branch arteries in the M2 and M3 segments or transition bifurcations from the M3 to M4 segments of the Middle Cerebral Artery (MCA)28. As shown in Figure la, the magnetically steerable tip includes a helical-shaped elastomer sheath, a cylindrical permanent magnet, and a miniaturized ball j oint that provides three degrees of rotational freedom . The bearing chamber is installed on a flexible hollow working channel, which provides pushability and fluid delivery. With its largest outer diameter designed to be 800 pm, the device is comparable in scale to a neurovascular guidewire (Nitrex® Nitinol Guidewire, Medtronic). The prototype is illustrated in Figure IB, and the detailed dimensions are presented in Table 1. The proposed microcatheter can be regarded as a steerable magnetic guidewire that can navigate sharp comers in the blood vessels (Figure 1C) and can also be regarded as a micropump for drugclot interaction acceleration, a spinning tool to conduct mechanical breakdown and a retrieval tool for capturing blood clot debris to the support catheter (Figure 1G). At the proximal end, a syringe pump and a vacuum pump are connected to the working channel and the support sleeve, respectively, to enable fluid delivery and suction.Table 1: Detailed dimensions of helical tip design.

[0045] Rotation-assisted active steering. When navigating microcatheters from the trunk vascular system to narrow collateral branches, the pre-curved or magnetically guided tip often encounters frictional resistance at the entrance. This resistance may lead to buckling or misdirection upon further advancement of the microcatheter, as shown in Figure 1C. This issue was addressed by releasing the accumulated contact force through rotational actuation. The proposed steering strategy includes three steps: Firstly, a directional magnetic field was used to align the microcatheter tip with the desired branch. Subsequently, the microcatheter advances, allowing the tip to reach the branch entrance. Finally, a rotating magnetic field is applied to guide the microcatheter to the desired branch and avoid buckling or looping due to rotational contact with the blood vessel wall. Figure 2A shows the failure case using the directional field to guide the microcatheter and the successful case using the proposed steering strategy. Figure 2B shows the keyframes of the experimental demonstration using the proposed navigation strategy in a bifurcation phantom, and the effect of magnetic field strength on steerability enhancement was further characterized. The experimental results show that the rotation-assisted method was able to enlarge the reachable workspace under varying magnetic fields and can realize a maximum 50% increment under a magnetic field strength of 25 mT. The detailed navigation demonstration is provided in Supplementary Movie 1 (All supplementary movies are available for download at https : / / www. science .org / doi / 10.1126 / sciadv.adv 1682#supplementary-materials) .

[0046] In addition to improving steerability, the rotational motion can enhance navigation efficiency when passing through sharp turns. Conventional catheters typically rely on the contact force between the tip and the blood vessel wall to passively change the catheter’s body shape and tip orientation, conforming to the shape of the blood vessel. The friction and contact forces increase throughout this process, posing a potential risk of tissue puncture. The rotation-assisted steering method can mitigate this adverse effect by actively orienting the tip to the desired direction and reducing the friction. This advantage was validated by experimentally comparing the insertion forces required for navigating through an L-shaped channel under four different cases: with directional magnetic field guidance (DMF-guided), with rotational magnetic field navigation (RMF-guided), without magnetic field guidance (Non-guided), and with commercially available guidewire (Boston Scientific, TRANSEND EX Guidewire, 0.41 mm diameter). Figure 2C shows the schematic experiment setup. The microcatheter was fixed to the tensile measurement system (MACH-1) and inserted along the positive z-axis direction into the curved PDMS model at a speed of 0.1 mm / s. The model was filled with glycerol fluid to simulate the viscosity of blood. The insertion force was recorded to characterize the degree of navigation difficulty between different navigation strategies, and the results are presented in Figure 2D.

[0047] Compared with the other cases, the RMF-guided strategy decreased the insertion force in different sections with adaptable mechanisms. During navigation in the straight channel, e.g., from point A to B, keeping the catheter tip centered within the lumen to avoid contact with the wall is difficult. This contact can lead to excess friction, increasing the necessary insertion force and potentially causing damage to the vessel wall. The RMF-guided microcatheter contacted the blood vessel wall with its soft rotating tip, which converts slide friction to rotation friction, reducing the navigation resistance. From point A to B, the Fzof the RMF-guided case is the lowest and the most stable one. Navigation from point B to C is to simulate the condition of the catheter passing through a sharp turn. The non-guided case showsa substantial increase in insertion force due to the accumulated friction. For the RMF-guided case, the Fzfirst fluctuated due to the rotation constantly releasing the accumulated friction. When the contact and friction are large enough to stop the rotation, the magnetic torque continues to provide both bending and propulsive force. Navigation from point C to D is to simulate the condition of the catheter after it passes through the curved lumen. With the rotation resumed, the decrease in the insertion force is observed due to friction force release at the tip, as highlighted by the black arrow in Figure 2D. It is worth noting that the tip rotation also detached the catheter body from the blood vessel wall, thus alleviating the friction of the entire distal end. Experiment results suggest that the proposed method reduces maximum insertion force by 69%, 18%, and 25% compared to the non-guided group, DMF -guided group, and commercial group, respectively. A detailed navigation test is presented in Supplementary Movie 2.

[0048] Maintaining rotational actuation can be challenging when the microcatheter works at a vessel branch with a large bending angle. Bending and rotating assessments were conducted to verify the applicability of the rotation-assisted steering method when the microcatheter enters the branch with sharp turns. The setup for these assessments is presented in Figure 7.Initially, the microcatheter is positioned in a bending channel and actuated with a rotational magnetic field. The minimum actuation field is recorded and presented in Figure 2E. The rotatable tip can be successfully actuated by a rotational magnetic field with strengths ranging from 2 mT to 8 mT, even in large bending angles (135°). This magnetic field requirement can be met by several clinically feasible magnetic actuation systems5’29’30, which suggests its clinical application potentials.

[0049] In vitro navigation demonstration. Manually rotating the proximal end allows for the steering of a pre-curved guidewire or microcatheter during branch selection. However, after navigating through multiple turns, the torque at the proximal end becomes limited, which restricts control efficiency. Additionally, maneuvering the catheter tip through sharp turns —such as entering a recurrent branch vessel that originates at an angle greater than 90° to the parent vessel or navigating multiple consecutive sharp turns with a limited curvature radius — presents significant challenges24. Experiments were conducted in a full-size human brain vessel phantom to validate the proposed microcatheter’s advantage in addressing these navigation difficulties.

[0050] As illustrated in Figure 3A, two vascular segments have been selected for an accessibility demonstration, with detailed dimensions provided in Figures 3B and 3C.Navigating the blood vessel bifurcations of the M3 and M4 segments (region (i)) requires first traversing a 3D tortuous bifurcated lumen, followed by accessing distal narrow branches with diameters of 1 mm and 0.8 mm. The experimental demonstration is depicted in Figure 3D and Supplementary Movie 3. By applying the rotation-assisted steering strategy, navigation proves to be more efficient than using a static magnetic field across all bifurcations. A quantitative efficiency comparison for the region (i) between the RMF-guided and DMF-guided strategies (with proximal end rotation assistance) is shown in Figure 3F. The results indicate that the RMF-guided approach is approximately three times faster in navigating the first bifurcation and about 1.9 and 1.7 times faster in reaching the first and second destinations, respectively. As the microcatheter advances, a robotic arm positions a rotatable magnet based on the microrobot’s location to provide the necessary magnetic guidance. The robotic arm-assisted permanent magnetic system is illustrated in Figure 8.

[0051] The second demonstration was conducted in the 3D tortuous S-shaped segment of the internal carotid artery (ICA) within the silicone vascular model (region (ii)). This segment features two continuous 180° turns with diameters ranging from 3 mm to 2 mm. When using conventional guidewires, careful navigation through this region is crucial to prevent damage to the blood vessel wall, which can occur due to increased friction from tight contact. In contrast, the rotation-assisted navigation strategy enhances navigation efficiency by reducing frictional forces. The experimental demonstration is illustrated in Figure 3E and Supplementary Movie4. The microcatheter was guided by a rotating magnetic field as it navigated through the S-shaped lumen. The direction of the rotational magnetic field was adjusted to align with the shape of the phantom. This rotation-assisted strategy resulted in approximately twice the operational speed compared to the control group, where the microcatheter was passively inserted while its proximal end was manually rotated to facilitate navigation (Figure 3G).

[0052] The maintained steerability and rotational capability after long-distance vascular travel were further demonstrated, as shown in Figure 9A. The phantom features three consecutive turns with varying degrees of curvature and diameters ranging from 3 mm to 0.5 mm. The total navigation distance covered was nearly 300 mm, with the most distal branch positioned at 165° relative to the entrance direction. A robotic arm-controlled permanent magnet is positioned beneath the phantom, and the desired magnetic field is calculated based on a preregistered trajectory. Depending on the degree of bending curvature, it was alternated between directional magnetic actuation and rotation-assisted active bending. A detailed demonstration is presented in Supplementary Movie 5. A quantitative evaluation of the steerability after long-distance travel is provided in Figures 9B and 9C, showing that the proposed microcatheter offers advantages in navigation speed and the reachable workspace compared to the non-guided baseline.

[0053] Structural optimization for enhanced blood clot treatment. The MSRM’s pumping effect and blood clot debris-retrieving ability are attributed to the directional flow induced by rotational motion and the pressure drop between the rear and front ends. Computational Fluid Dynamics (CFD) is employed to investigate the hydrodynamics of various rotatable tip designs to achieve optimal performance. Starting with a rotating micro cylinder, the most intuitive design for generating flow, the flow velocity field and pressure distribution were analyzed. As shown in Figure 4A, a rotating cylinder (5 Hz) inside a tube generates localized negative pressure that attracts surrounding fluids, as indicated by the flow velocity direction (black arrows) on the a-a plane towards the micro-rotor. In the second design, straight fins wereincorporated to increase the pressure drop by facilitating greater flow. The two evenly spaced straight fins can achieve nearly ten times the flow velocity. The fluid flow rate can be further enhanced and made reversible by adding helical fins, as illustrated in the third design in Figure 4A. This is evidenced by both high flow velocity and a larger pressure drop between the rear and front of the micro-rotor, as shown in Figure 4B. Unlike the cylinder and straight fins designs, which tend to retain clot debris on the rotor, the helical fins design creates a pressure difference between the rear and front of the micro-rotor. The resulting backward flow carries the debris to the supporting suction catheter.

[0054] Another function of the helical design is to generate thrust flow and pressurize the surrounding fluid. As shown in the fourth design in Figure 4A, by switching the rotation direction, the micro-rotor can transition from retrieval mode to pumping mode. This pumping effect is critical for mixing the thrombolytic drug with the blood clot. The fluid environment in small-scale vessels is characterized by low Reynolds numbers (< 0.1), which leads to slow fluid diffusion and inefficient suction force31. Actively generating directional flow to pump the fluid to the desired region and increase the blood clot-drug mixing rate can overcome the challenges of diffusion. The pumping effect is optimized by achieving the best combination of critical parameters through the CFD simulation. Similar to an axial flow pump, the helical pitch angle (3P) and the fin’s central angle (a) are two key variables influencing the pumping efficiency, as shown in Figure 4D. The simulation results showed that the optimal performance is achieved at =60°, with fluid pumping performance increasing with the central angle a. To ensure good structural integrity for effective pumping, a = 45° is adopted for the subsequent studies. Simulation tests are conducted to verify the structural integrity of the fins during rotation, as shown in Figure 10.

[0055] The MSRM’s clot-breaking mechanism is attributed to the shear force applied to the clot. The rotating micro-rotor contacts the blood clot and generates a continuous shear force to break down the coagulation of red blood cells. The contact region where the shear stressexceeds the shear stress of the blood clot fraction is deemed as the affected area32. Computer-aided engineering (CAE) is employed to investigate the optimal tip profde for maximizing the affected area when the tip of the MSRM is rotated and inserted into the blood clot, as illustrated in Figure 4E. Three tip profile designs — round, tapered, and flat — are tested, with each design resulting in different shear stress distributions, as shown on the right side. More details regarding the simulations can be found in the Methods section (MSRM and blood clot contact simulation). Figure 4F presents simulation results indicating that when the tip is inserted into the blood clot, the affected area of the round tip design is nearly 130% of that of the tapered design and 300% of that of the flat design. Therefore, the round tip design was selected in this embodiment.

[0056] Guided by the simulation results, the prototype of the microcatheter (Figure IB) was fabricated and experimentally verified its thrust flow generation capacity. The system setup is detailed in Figure 11A. The microcatheter generated thrust flow to propel the red dye uphill in a silicone tubular model, overcoming the gravitational pressure barrier. The movement of the red dye boundary served as a measure of performance. The results in Figure 4G verify the pumping mode’s performance. Upon reaching the midpoint, the MSRM could increase the red dye boundary moving speed by nearly ten times compared to the control group. A detailed demonstration can be found in Supplementary Movie 6.

[0057] Treatment function demonstration of the rotational microcatheter. Previous studies have reported the use of rotational motion to mechanically break blood clots14’23, but the aggressive mechanical motion of rigid rotors has raised safety concerns regarding blood vessel wall injury33. Alternatively, researchers have demonstrated the use of thrombolytic drugs to accelerate blood clot clearance. However, systematic drug administration can lead to internal bleeding. The presented MSRM offers a hybrid solution by combining rotational physical interaction with local thrombolytic drug administration. As shown in Figure 4H, the thrombolytic drug can be injected through the working channel and released at the openings onthe rear end of the micro-rotor. The thrust flow carries the drug forward to the blood clot while switching the rotation direction induces backward flow to transport the clot debris to the supporting suction catheter. Herein, an in vitro thrombosis treatment was used as a case study to demonstrate the effectiveness of this hybrid strategy.

[0058] As shown in Figure 11B, an artificial blood clot was fabricated in the phantom using a 37°C water bath. The microcatheter was navigated to the blood clot and rotational actuated to pump the thrombolytic drug, Tissue Plasminogen Activator (tPA, 3mg / ml, 0.2 ml), forward to the clot. A rotating permanent magnet below the phantom generated the required rotational magnetic actuation. Then, the microcatheter advanced and made contact with the blood clot. As clot removal progressed, the microcatheter was advanced to maintain contact for mechanical interaction. After 25 minutes, the clot was entirely cleared with no residual debris, which was approximately 10 times faster than in the control group. In the control group, the same amount of tPA was injected, and the phantom was kept in the water bath for the same time period as the experiment group. The detailed demonstration is presented in Supplementary Movie 7. To highlight the blood clot clearance performance, another experiment was performed and the residual clots from both experimental and control groups were extracted at 0 minutes, 5 minutes, 10 minutes, and 20 minutes to visualize the volume reduction. The results are presented in Figure 41.

[0059] Further experiments were conducted to investigate the efficiency improvements of the proposed hybrid treatment (thrombolytic drug mixing and mechanical blood clot breakdown), as shown in Figure 4J. A batch of blood clots2 mm x 5 mm, cured for 30 minutes) was treated using three methods: thrombolytic drug treatment (tPA 3 mg / ml, 0.2 ml), mechanical breakdown by the MSRM (rotating frequency: 5 Hz), and the proposed hybrid method. Notably, the proposed hybrid method demonstrated treatment speeds that were nearly 300% and 500% faster than the thrombolytic drug treatment and mechanical breakdown methods, respectively. Additionally, the influence of rotating frequency on the clearanceefficiency was investigated, as shown in Figure 4K. Blood clots measuring 5 mm in length and 30 minutes in age were cleared by the proposed hybrid method under rotating frequencies of 1 Hz, 3 Hz, 5 Hz and 7 Hz. For higher frequencies (5 Hz and 7 Hz), the clot volume reduction rate was similar; they can achieve over 80% volume reduction in 15 minutes. The effects of tip stiffness and thrombolytic drug efficacy were further investigated, as shown in Figure 12. Both the soft (PDMS-based) and rigid (Resin-based) tips were tested with and without the assistance of the thrombolytic drug. The comparison results suggested that the treatment performance was not compromised by the soft material design (97.36%).

[0060] The complexity of thrombus compositions makes in-situ blood clot breakdown difficult34. Fibrin-rich components are more resistant to shear forces and thrombolytic drugs. Red blood cell-rich clots are prone to fragmentation and can travel to distal branches, causing serious distal blockages. To address this, a retrieval strategy was proposed to collect unbreakable blood clot debris. By employing both mechanical interaction and fluid manipulation, the clot debris from small vascular structures could be attracted to the aspiration catheter and capture it via suction. The detailed working principle is shown in Figure 4L.Initially, the microcatheter rotates in a direction that generates a backward flow that attracts and captures the blood clot debris in the tip’s helical grooves. Then, the retraction of the microcatheter, combined with the flow, pushes the debris toward the rear end. Finally, the debris is collected through negative pressure. The effectiveness of this strategy is experimentally verified, as shown in Figure 4M and Figure 13. This method was utilized to capture two types of blood clots: red blood cell -rich and fibrin-rich clots. A detailed demonstration is presented in Supplementary Movie 8. To identify the flow status of the retrieval mode, ultrasound (US) imaging was utilized to monitor the clot retrieval process. As shown in Figure 14, artificial clot debris was placed in a silicone vascular phantom, and the MSRM was positioned close to the clot. Under a rotating magnetic field, the MSRM was actuated into retrieval mode, transporting the clot debris to the aspiration catheter (Figure 14(i-ii)). The clot was then retrieved by the aspiration catheter through the combined forces of the rotating motion of the MSRM and negative pressure (104 Pa), as shown in Figure 14 (iii).Furthermore, the Doppler signals (Figure 14 (iv-vi)) indicated that the fluid in the lumen flowed toward the aspiration catheter, which is highlighted by green arrows. In contrast, the negative pressure generated by the AC alone was insufficient to attract the blood clot, resulting in Doppler signals appearing only near the entrance of the aspiration catheter in the control group. Detailed demonstrations are provided in Supplementary Movie 9. The effects of rotating frequency and clot volume (length) on retrieval efficiency were then characterized. A batch of blood clots of varying lengths (2.5 mm, 5 mm, 10 mm, and 15 mm) was retrieved while rotating at frequencies of 1, 3, 5, and 7 Hz. The results shown in Figure 4M indicate that retrieval efficiency increases with rotating frequency and decreases with blood clot length. However, at higher frequencies, the efficiency levels off, and increased frequency may lead to greater invasiveness.

[0061] The effect of blood clot stiffness on retrieval and breakdown efficiency was also evaluated. Researchers have reported that the modulus of fabricated blood clots can be regulated by different curing times (clot age)35. Blood clots measuring 5 mm in length of varying ages (30 min, 60 min, 90 min, and 120 min) were retrieved and broken down (rotating frequency: 5 Hz) using the proposed strategy. The measurements indicate that the Young’s modulus of these blood clots is 23.7±2.5 KPa, 25.7±2.0 KPa, 31.2±2.9 KPa, and 44.1±3.9 KPa, respectively. The results illustrated in Figure 4N suggest that the age of the blood clot influences the breakdown efficiency but cannot compromise the retrieval efficiency.

[0062] In vivo demonstration. Figures 5A and 5B demonstrate the proposed navigation strategy and therapeutic functions in an in vivo rabbit model. In the navigation test, the microcatheter is inserted from the iliac artery and is aimed at navigating two turns with branch angles of approximately 30° and 90° to reach the renal artery (Figures 5C). This navigation task is designed to simulate the conditions of navigating sharp angles in narrow human distalblood vessels with diameters ranging from 1 to 4 mm36. X-ray imaging provides positional feedback, guiding the permanent magnetic system in generating the desired field for actuation. Both rotation-assisted active bending and static field bending are employed to navigate the microcatheter, and the different bending curvatures are presented in Figures 5D to 5E.Observations indicate that the rotation-assisted method mitigates microcatheter stress and prevents buckling that may occur with static field guidance. Furthermore, rotation-assisted navigation is approximately 50% faster than static field navigation. Supplementary Movie 10 includes a detailed navigation and actuation process. Notably, the fluid delivery function is highlighted by injecting a contrast agent through the working channel, with rotational actuation enhancing the diffusion of the contrast agent.

[0063] To investigate the effectiveness of the MSRM’s drug -assisted mechanical breakdown function in vivo, a blood clot treatment was performed within the rabbit carotid artery using ultrasound imaging to visualize the procedure, as shown in Figure 5F. Initially, the distal end of the carotid artery was ligated and accessed with a catheter sheath. An artificial blood clot, created from the rabbit’s own blood, was inserted through the sheath and positioned inside the artery (Figure 5G). The microcatheter was then inserted and navigated to the target. Similar to the in vitro experiments, tPA was injected at a dose of 3 mg / ml (0.2 ml), and the MSRM was actuated by a rotating magnetic field of 5 Hz. The catheter was advanced deeper every five minutes to ensure closer contact with the blood clot (Figure 5H). After 15 minutes, the blood clot disappeared from the imaging plane. To confirm the thorough clearance of the clot, saline was injected to inflate the artery, providing additional details of the clearance, as shown in Figure 51. After confirming that the blood clot was broken down, the fluid was extracted from the artery, and no visible blood clot debris was found. The rate of blood clot clearance closely aligned with that of the in vitro experiments using the same dosage of the thrombolytic drug and the same magnetic field actuation, verifying the proposed microcatheter’s clinical application potential.

[0064] Invasiveness evaluation in human placenta blood vessels. Previous studies have used micro device ’s rotational motion for mechanical thrombectomy14, 21, 23. Performance-enhancing designs, including sharp rigid profdes, high-friction coatings, and large rotational velocities, have been employed to maximize blood clot clearance efficiency. However, these mechanical interactions raise safety concerns due to the fragile nature of blood vessels, particularly in narrow distal vessels with thinner walls and simpler support structures. In contrast, the proposed microcatheter adopts a soft material design and a tissue-friendly implementation method to balance efficacy and invasiveness. Firstly, the rotatable helical structure is constructed from PDMS. A fabrication process that combines inverted molding and 3D printing was employed to create a soft helical sheath that encases the permanent magnet, thereby avoiding hard contact with the inner vessel wall. This soft design does not compromise accessibility or therapeutic performance, as confirmed in earlier sections. Secondly, the proposed microcatheter’s ability to establish a fluid pathway for localized thrombolytic drug administration reduces the reliance on high rotational velocities. During implementation, the rotation frequency for rotation-assisted navigation is 2 - 5 Hz, and for thrombectomy and drug delivery is 5 - 8 Hz. This frequency range, significantly lower than prior actuation methods14, induces limited fluid stress on the blood vessel wall. A comprehensive comparison with the previously published rotor-tipped micro machine is provided in Table 2. Among the current state-of-the-art technologies, the proposed microcatheter features the smallest outer diameter (OD), the lowest hardness, and the lowest angular velocity.Table 2: Comparison of untethered and tethered rotor-tipped micro machine.

[0065] To evaluate the potential impact of the microcatheter’s rotational actuation and contact frictional insertion on the blood vessel wall, an ex vivo invasiveness evaluation experiment was conducted using human placenta blood vessels, as illustrated in Figure 6A.These arteries have diameters and wall thicknesses comparable to those of human cerebral arteries30. Four segments of the superficial blood vessels, corresponding to four testing groups, were selected. In segment I, the microcatheter was inserted and rotated at 8 Hz in contact with the phantom’s inner surface for 30 minutes. In segment II, the microcatheter was frictionally inserted against the blood vessel’s inner wall 100 times. In segment III, a commercial guidewire (Boston Scientific, TRANSEND EX Guidewire) was repeatedly inserted into the blood vessel 100 times. Segment IV served as the blank control group. After the experiments, these four vessel segments were removed for damage assessment using hematoxylin and eosin (H&E) histological staining. The results, presented in Figure 6C, indicate that the blank control group displayed an intact inner blood vessel wall, while the contact friction insertion (commercial) group exhibited notable damage to the inner cell layers, including detachments and missing layers. In contrast, the rotational actuation and contact frictional insertion (MSRM) groups showed minimal missing cells, with no detachment observed.

[0066] Discussion

[0067] In this study, a submillimeter magnetic catheter designed to access narrow, tortuous vessels and perform endovascular treatments was introduced. The proposed microcatheter offers three significant advantages over previously published magnetic microcatheters. First, its miniaturized design and rotation-assisted navigation strategy ensure superior accessibility in narrow distal blood vessels (< 2 mm). Second, the microcatheter of this invention integrates multiple functionalities, including active steering, rotation-assisted navigation, accelerated drug-thrombus interactions, mechanical breakdown, and debris retrieval. This all-in-one design enhances treatment efficiency and offers a potential method for physically retrieving drugresistant components from blood clots. Finally, the soft tip design and tissue-friendly actuation strategy help mitigate the risk of vascular injury during navigation and actuation, as demonstrated in previous sections. A detailed comparison with the state of the art is provided in Figure 15.

[0068] To fabricate the prototype of MSRM, a fabrication process that combines a submillimeter soft structure and magnetic material was developed. Traditional 3D printing methods make it difficult to integrate materials of varying hardness. In this work, a soft helical sheath was first created using molding techniques and attached to the outer surface of a micro permanent magnet with a waterproof adhesive treatment. Next, the helical sheath was combined with the 3D-printed miniaturized ball joint and the working channel, creating a soft, rotatable magnetic catheter tip. The detailed fabrication process is illustrated in the Method section. The prototype discussed in this embodiment measures 800 pm in diameter, but with the use of the advanced micro-assembly platform37, its size could be further reduced to approximately 100 pm.

[0069] Ex vivo and in vivo tests demonstrated the effectiveness and efficiency of the thrombolytic drug-assisted mechanical thrombectomy. Notably, the proposed method can not only rapidly increase the local drug concentration with a small dosage but also accelerate theclearance process through mechanical interaction. Systematic experiments validate that the dosage and treatment duration are theoretically superior to traditional thrombolytic drug administration and catheter-directed thrombosis treatments. Quantitatively evaluate the optimal drug dosage and magnetic actuation parameters through animal experiments is being planned.

[0070] Methods

[0071] Magnetic field actuation method. The proposed microcatheter incorporates a rotatable, radially magnetized tip. The method for controlling its orientation is as follows: Firstly, the bending plane that encompasses both the existing and desired orientation of the microrobot was established. As depicted in Figure 16, the rotation angle of the bending plane is denoted as (p. Secondly, the desiredin-plane bending field Bpwas computed by the desired in-plane bending angle 9d. The relationship between Bpand 9dare described in a look-up table which is obtained by experiments offline.where M represents the searching in the loop-up table process. To obtain the actuation field B, the in-plane magnetic field was transformed to the global frame:< < < < <Where the Rz(■) is the rotation matrix around the z axis . In the rotational actuation, the desired magnetic field is determined by the microcatheter’s orientation of the tip and can be described< < < <where A is the magnetic field strength and f is the rotating frequency.

[0072] Magnetic system design. To fulfill the need for navigation using fluoroscopy in the operation room, the robotic arm-based permanent magnetic system is placed side to the testingmodel and generates a 5 - 10 Hz, 10 mT rotating magnetic field, and a static directional field with a safe distance of 75 mm. This magnetic system provides sufficient support for the navigation and actuation of the proposed microcatheter, which has been proved in the previous sections. The hardware information is detailed in the Table 3.Table 3: Hardware details of the permanent magnetic system.

[0073] Fabrication of the PDMS-based Helical Catheter Tip. The fabrication process begins with the creation of negative molds for the helical tip using 3D printing (NanoArch S130, BMF Precision, China). These molds undergo UV light curing at 100°C for 60 minutes, followed by 15 minutes of plasma treatment and 3 hours of silane steam treatment using pure triethoxy (lH,lH,2H,2Hperfluoro-l -octyl) silane. This process renders the resin mold hydrophobic, aiding later demolding. The molds are held together with non-magnetic clips and submerged in thoroughly mixed PDMS fluid (base and crosslinker mass ratio 10: 1). A permanent magnet (NdFeB, ( / > 0.3 mm x 2 mm) is inserted into the mold before curing at 70°C for 3 hours. After demolding and manual removal of the base material, the PDMS-based helical tip is obtained. The ball joint chamber and hollow ball joint are 3D-printed using the same resin as the negative molds. The microcatheter is then assembled and prepared fortesting. Detailed fabrication steps can be found in Figure 17. MSRM and Blood Clot Contact Simulation. The microcatheter is rotated at 5 Hz and inserted into a blood clot measuring 1.5 mm in diameter and 3 mm in length.The blood clot has a modulus of 957 Pa and a fraction shear force of 499 Pa, based on clots made from human platelet-rich plasma (PRP) blood samples32. The maximum insertion depth is 0.3 mm, corresponding to the length of the tip. Preparation of the Artificial Blood Clot. In the in vitro blood clot clearance test, the artificial blood clot is made by mixing the sterile pig blood anti-coagulated with sodium citrate (Guangzhou Hongquan Biotechnology Co., Ltd.) with calcium chloride (0.5 mol / ml, lOpl) fluid and curing the mixture at 36.5°C. Calcium chloride directly activates platelets, which facilitates clot formation independently and in cooperation with the coagulation pathway35. Researchers have elaborated the relationship between age and the elasticity of the thrombus38. The curing time determines the dissolvability of the blood clot. In the invitro test, the curing time is 30 minutes. In the clot debris retrieval test, the fibrin-rich blood clot is first cured for 1 hour and washed out the extra red blood cells. The RBC-rich blood clot is cured for 30 minutes. In the in vivo thrombectomy test, the blood clot is made of the rabbit’s blood and cured for 30 minutes.

[0074] Remote microcatheter insertion method. The design of the filament extruder in the Material-Extrusion-Based 3D printers was utilized to realize insertion motion control. The working principle is described in Figure 18. The insertion machine uses torque and a pitch system to feed and retract the microcatheter in precise amounts. The microcatheter working channel has stepped stiffness for sufficient pushability at the proximal and flexibility at the distal end. The insertion performance was experimentally verified through magnetic navigation under X-ray imaging. The setup is presented in Figure 19A. The host computer remotely controls the robotic arm, the step motor of the magnet, and the catheter advance machine. The magnetic source is positioned at one side of the phantom, leaving enough imaging space as shown in Figure 19B. The contrast agent (120 mg / mL Sodium diatrizoate hydrate fluid) was first injected into the phantom to outline the vascular model under X-ray. As the embedded permanent magnet is radio-opaque, it acted as an X-ray marker for the localization of the catheter tip. The robotic arm adjusted the position and orientation of the permanent magnet tosteer the microcatheter to the desired branch, where the desired bending angle and external magnetic source pose were precalculated. Some key frames during the navigation into the branches are depicted in Figure 19C.

[0075] Rabbit model preparation. Two adult New Zealand rabbits used in the experiment were food-restricted for 24 hours before the procedures. The ethical approval from the Institutional Animal Care and Use Committee was obtained before the research (AMS D2303010R)

[0076] Human placenta model preparation. The human placenta was collected from the Prince of Wales Hospital, which was approved and overseen by the Joint Chinese University of Hong Kong (CUHK)-New Territories East Cluster Clinical Research Ethics Committee (ref. no. 2020.384). The placenta used in this study was donated by a pregnant woman who underwent a cesarean section at Prince of Wales Hospital in collaboration with the Department of Obstetrics and Gynaecology at CUHK. The patient provided written informed consent to participate in the study. To be eligible for the study, pregnant women had to be healthy, between the ages of 20 and 45, of any ethnic origin, and give birth via cesarean section between 37 and 42 weeks of gestation. They also needed to have a singleton pregnancy, be determined as healthy by their treating physicians based on laboratory results, physical examination, and medical history, and have the ability to provide written informed consent voluntarily. Participants who had abnormal prenatal development, hypercholesterolemia, a family history of stroke or vascular diseases, diabetes, gestational diabetes, or cancer were excluded from the study. Once collected, the placenta was thoroughly washed with saline to remove any impurities, and the blood inside the blood vessels was carefully drained to prevent blockage.

[0077] References1. Saver, J. L. Time is brain-quantified. Stroke 37 (1), 263-266 (2006).De Luca, G., Suryapranata, H., Ottervanger, J. P. & Antman, E. M. Time delay to treatment and mortality in primary angioplasty for acute myocardial infarction: every minute of delay counts. Circulation 109 (10), 1223-1225 (2004).Schartz, D., Ellens, N., Kohli, G. S., Rahmani, R., Akkipeddi, S. M. K., Colby, G. P, Hui, F., Bhalla, T, Mattingly, T. & Bender, M. T. Impact of aspiration catheter size on clinical outcomes in aspiration thrombectomy. Journal of neurointerventional surgery 15 (el), elll-ell6 (2023).Wardlaw, J. M., Smith, C. & Dichgans, M. Small vessel disease: mechanisms and clinical implications. The Lancet Neurology 18 (7), 684-696 (2019).Kim, Y, Genevriere, E., Harker, P, Choe, J., Balicki, M., Regenhardt, R. W., Vranic, J. E., Dmytriw, A. A., Patel, A. B. & Zhao, X. Telerobotic neurovascular interventions with magnetic manipulation. Science Robotics 7 (65), eabg9907 (2022).Piskarev, Y, Shintake, J., Chautems, C., Lussi, J., Boehler, Q., Nelson, B. J. & Floreano, D. A variable stiffness magnetic catheter made of a conductive phase-change polymer for minimally invasive surgery. Advanced Functional Materials 32 (20), 2107662 (2022).Yang, Z., Yang, L., Zhang, M., Xia, N. & Zhang, L. Ultrasound-guided wired magnetic microrobot with active steering and ejectable tip. IEEE Transactions on Industrial Electronics 70 (1), 614-623 (2023).Yang, Z., Yang, H., Cao, Y, Cui, Y. & Zhang, L. Magnetically actuated continuum medical robots: A review. Advanced Intelligent Systems 5 (6), 2200416 (2023).Hu, J., Huang, S., Zhu, L., Huang, W., Zhao, Y, Jin, K. & ZhuGe, Q. Tissue plasminogen activator-porous magnetic microrods for targeted thrombolytic therapy after ischemic stroke. ACS applied materials & interfaces 10 (39), 32988-32997 (2018).Wang, T., Ugurlu, H., Yan, Y, Li, M., Li, M., Wild, A.-M., Yildiz, E., Schneider, M., Sheehan, D., Hu, W. et al. Adaptive wireless millirobotic locomotion into distal vasculature. Nature Communications 13 (1), 4465 (2022).Tang, X., Manamanchaiyapom, L., Zhou, Q., Huang, C., Li, L., Li, Z., Wang, L., Wang, J., Ren, L., Xu, T, Yan, X. & Zheng, Y. Synergistic integration and pharmacomechanical function of enzyme-magnetite nanoparticle swarms for low-dose fast thrombolysis. Small 18 (34), 2202848 (2022).Xu, H., Medina-Sanchez, M., Maitz, M. F., Werner, C. & Schmidt, O. G. Sperm micromotors for cargo delivery through flowing blood. ACS nano 14 (3), 2982-2993 (2020).Pozhitkova, A. V., Kladko, D. V., Vinnik, D. A., Taskaev, S. V. & Vinogradov, V. V. Reprogrammable soft swimmers for minimally invasive thrombus extraction. ACS Applied Materials & Interfaces 14 (20), 23896-23908 (2022).Leclerc, J., Zhao, H., Bao, D. & Becker, A. T. In vitro design investigation of a rotating helical magnetic swimmer for combined 3-d navigation and blood clot removal. IEEE Transactions on Robotics 36 (3), 975-982 (2020).Nelson, B. J., Gervasoni, S., Chiu, P. W, Zhang, L. & Zemmar, A. Magnetically actuated medical robots: an in vivo perspective. Proceedings of the IEEE 110 (7), 1028- 1037 (2022).Kim, Y, Parada, G. A., Liu, S. & Zhao, X. Ferromagnetic soft continuum robots. Science Robotics 4 (33), eaax7329 (2019).Dong, Y, Wang, L., lacovacci, V, Wang, X., Zhang, L. & Nelson, B. J. Magnetic helical micro-Znanomachines: Recent progress and perspective. Matter 5 (1), 77-109 (2022). Pancaldi, L., Dirix, P, Fanelli, A., Lima, A. M., Stergiopulos, N., Mosimann, P. J., Ghezzi, D. & Sakar, M. S. Flow driven robotic navigation of microengineered endovascular probes. Nature Communications 11 (1), 6356 (2020).Edelmann, J., Petruska, A. J. & Nelson, B. J. Magnetic control of continuum devices. The International Journal of Robotics Research 36 (1), 68-85 (2017).von Arx, D., Fischer, C., Torlakcik, H., Pane, S., Nelson, B. J. & Boehler, Q. Simultaneous localization and actuation using electromagnetic navigation systems. IEEE Transactions on Robotics 40, 1292-1308 (2024). https: / / doi.org / 10.1109 / TRO.2023.3340324.Heunis, C. M., Behrendt, K. J., Hekman, E. E., Moers, C., Vries, J.-P. P. d. & Misra, S. Design and evaluation of a magnetic rotablation catheter for arterial stenosis. IEEE / ASME Transactions on Mechatronics 27 (3), 1761-1772 (2022).Yan, Y, Wang, T, Zhang, R., Liu, Y, Hu, W. & Sitti, M. Magnetically assisted soft millitools for occluded lumen morphology detection. Science Advances 9 (33), eadi3979 (2023). https: / / doi.org / 10.1126 / sciadv.adi3979.Yang, H., Yang, Z., Jin, D., Su, L., Chan, K.-F., Chong, K. K.-L., Pang, C. P. & Zhang, L. Magnetic micro-driller system for nasolacrimal duct recanalization. IEEE Robotics and Automation Letters 7 (3), 7367-7374 (2022).Settecase, F., Sussman, M. S., Wilson, M. W, Hetts, S., Arenson, R. L., Malba, V, Bernhardt, A. F., Kucharczyk, W. & Roberts, T. P. Magnetically-assisted remote control (marc) steering of endovascular catheters for interventional mri: A model for deflection and design implications. Medical physics 34 (8), 3135-3142 (2007).Zhang, B., Wu, H., Kim, H., Welch, P. J., Cornett, A., Stocker, G., Nogueira, R. G., Kim, J., Owens, G., Dayton, P. A. et al. A model of high-speed endovascular sonothrombolysis with vortex ultrasound-induced shear stress to treat cerebral venous sinus thrombosis. Research 6, 0048 (2023).Gupta, R. Risks of microcatheter injections in acute stroke treatment. Nature Reviews Neurology 5 (4), 181-182 (2009).Lee, W, Nam, J., Kim, J., Jung, E., Kim, N. & Jang, G. Steering, tunneling, and stentdelivery of a multifunctional magnetic catheter robot to treat occlusive vascular disease . IEEE Transactions on Industrial Electronics 68 (1), 391-400 (2021).Saver, J. L., Chapot, R., Agid, R., Hassan, A. E., Jadhav, A. P., Liebeskind, D. S., Lobotesis, K., Meila, D., Meyer, L., Raphaeli, G. et al. Thrombectomy for distal, medium vessel occlusions: a consensus statement on present knowledge and promising directions. Stroke 51 (9), 2872-2884 (2020).Boehler, Q., Gervasoni, S., Charreyron, S. L., Chautems, C. & Nelson, B. J. On the workspace of electromagnetic navigation systems. IEEE Transactions on Robotics 39 (1), 791-807 (2022).Dreyfus, R., Boehler, Q., Lyttle, S., Gruber, P, Lussi, J., Chautems, C., Gervasoni, S., Berberat, J., Seibold, D., Ochsenbein-Kolble, N., Reinehr, M., Weisskopf, M., Remonda, L. & Nelson, B. J. Dexterous helical magnetic robot for improved endovascular access. Science Robotics 9 (87), eadh0298 (2024). https: / / doi.org / 10.1126 / scirobotics.adh0298.Wiegand, S. Thermal diffusion in liquid mixtures and polymer solutions. Journal of Physics: Condensed Matter 16 (10), R357 (2004).Riha, P, Wang, X., Liao, R. & Stoltz, J. Elasticity and fracture strain of whole blood clots. Clinical hemorheology and microcirculation 21 (1), 45-49 (1999).Wang, Z., Wang, K. & Xu, Y. Priction injury of the central vein caused by catheter for hemodialysis: an in vitro study. Scientific Reports 14 (1), 5836 (2024).Abbasi, M., Larco, J. A., Mereuta, M. O., Liu, Y, Fitzgerald, S., Dai, D., Kadirvel, R., Savastano, L., Kallmes, D. F. & Brinjikji, W. Diverse thrombus composition in thrombectomy stroke patients with longer time to recanalization. Thrombosis research 209, 99-104 (2022).Mfoumou, E., Tripette, J., Blostein, M. & Cloutier, G. Time-dependent hardening of blood clots quantitatively measured in vivo with shear-wave ultrasound imaging in arabbit model of venous thrombosis. Thrombosis research 133 (2), 265-271 (2014). Chu, Y., Liu, H., Xing, P, Lou, G. & Wu, C. The morphology and haemodynamics of the rabbit renal artery: evaluation by conventional and contrast-enhanced ultrasonography. Laboratory animals 45 (3), 204-208 (2011).Das, A. N., Murthy, R., Popa, D. O. & Stephanou, H. E. A multiscale assembly and packaging system for manufacturing of complex micro-nano devices. IEEE Transactions on Automation Science and Engineering 9 (1), 160-170 (2012). https: / / doi.org / 10.1109 / TASE.2011.2173570.Toyoda, T, Isobe, K., Tsujino, T, Koyata, Y, Ohyagi, F., Watanabe, T, Nakamura, M., Kitamura, Y, Okudera, H., Nakata, K. et al. Direct activation of platelets by addition of cacl 2 leads coagulation of platelet-rich plasma. International journal of implant dentistry 4, 1-11 (2018).

Claims

Dkt. 008-22-A-PCT What is claimed is:

1. A microcatheter, comprising:a. A tip made of a low stiffness material;b. One or more permanent magnets within said tip;c. A working channel; andd. A ball joint for connecting said tip to said working channel;Wherein said one or more permanent magnets is adapted to cause rotational movement of said tip when acted upon by an external rotational magnetic field.

2. The microcatheter of claim 1, wherein said low stiffness material is an elastomer.

3. The microcatheter of claim 2, wherein said elastomer is one or more selected from the group consisting of PDMS, rubber, polyurethane, polybutadiene, neoprene and silicone.

4. The microcatheter of claim 1, wherein said low stiffness material is one or more selected from the group consisting of silicone, nylon, rubber, resin, thermoplastic polyurethane (TPU), and polyvinyl chloride(PVC).

5. The microcatheter of claim 1, wherein said tip comprises a shape selected from the group consisting of helical, cylindrical, cylindrical with straight fins, spindle.

6. The microcatheter of claim 1, wherein said tip has an outer diameter of less than 1 mm.

7. The microcatheter of claim 1, wherein said ball joint comprises:a. a ball joint chamber comprising a through hole; andb. a hollow ball joint comprising a connection hole;wherein said tip is inserted into said through hole and connected to said connection hole.

8. The microcatheter of claim 1, wherein said rotational movement comprises three degrees of rotational freedom.

9. The microcatheter of claim 1, wherein said permanent magnet is cylindrical, donutshaped, sphere, cubic or hexagonal pyramid.

10. The microcatheter of claim 1, wherein said working channel has stepped stiffness.

11. The microcatheter of claim 1, further comprising a fluid pathway running through said working channel, said ball joint and said tip.

12. The microcatheter of claim 10, further comprising a syringe pump and / or a vacuum pump connected to said working channel.

13. A method for navigating said microcatheter of claim 1 for therapeutic intervention, comprising the steps of:a. Inserting said microcatheter to a vessel comprising two or more branches; b. Applying a directional magnetic field to align said tip with a desired branch among said two or more branches;c. Advancing said microcatheter to reach entrance of said desired branch; and d. Applying a rotational magnetic field while advancing said microcatheter into said desired branch to establish rotational contact with wall of said desired branch.

14. The method of claim 12, wherein said therapeutic intervention comprises drug -clot interaction acceleration, biofilm eradication, endovascular embolization, stent delivery, rotational mechanical breakdown or clot debris retrieval.

Images