Clinically Ready Magnetic Microrobots for Targeted Therapies

Introduction

• The integrated platform combines a clinical electromagnetic navigation system, release catheter, and capsule designed to balance magnetic actuation, X-ray visibility, therapeutic capacity, biocompatibility, and biodegradability.Its modular arrangement is designed to adapt to clinical settings using infrastructure such as fluoroscopes; capsule materials have prior FDA approval for intravenous applications.Source: Introduction · pp. 3, 5
• The coupled Navion system provided a 20 cm × 20 cm × 20 cm workspace and gradients up to 1 T/m at 30 mT, while its catheter gripper released capsules and withstood 16.07 N tensile load.The flexible gripper recovered 77% elastically after ten deployments.Source: Introduction · p. 7
• Microfluidic fabrication produced spherical capsules averaging 1.69 mm in diameter; at 30 mT they reached 72 memu magnetization, while zinc-substituted iron oxide nanoparticles had 190 W/g specific loss power.The nanocubes averaged 18.4 nm ± 1.3 nm in edge length and had 96.9 emu/g magnetic saturation.Source: Introduction · p. 7
• Gradient pulling propelled capsules against flows up to 21.2 cm/s, while interface rolling reached 0.37 cm/s and was suited to low-flow regions rather than cardiovascular navigation.Rolling velocity varied with magnetic-field rotation frequency, including an intermediate decrease from capsule bouncing.Source: Figure 3 · p. 8, Introduction · p. 9
• More than 95% of capsules reached the selected branch in tested flows up to 84 cm/s using in-flow navigation, with computational fluid dynamics supporting the approach.The flow carries the capsule while magnetic gradients steer its trajectory at a vascular junction.Source: Figure 3 · p. 8, Introduction · p. 9
• Fluoroscopy with a mobile C-arm tracked capsules ex vivo beneath a porcine head, and contrast levels correlated with X-ray tube power across background contrast levels.The capsule uses radiopaque tantalum nanoparticles for X-ray visibility.Source: Introduction · pp. 5, 9, Figure 3 · p. 8
• The capsule was tested with doxorubicin and ciprofloxacin; rtPA adsorption onto nanoparticles reduced enzymatic activity to 58%, while its single-chain form remained sufficiently stable to meet European Pharmacopoeia requirements.These tests assessed drug loading, release profiles, and compatibility with a biologic.Source: Introduction · p. 9
• Hyperthermic stimulation at 510 kHz and 20 mT triggered gelatin-capsule dissolution and drug release within 40 seconds, enabling controlled delivery or rapid dissolution at an undesirable location.The incorporated nanoparticles heat the thermo-responsive gelatin; diffusion offers slower release when appropriate.Source: Figure 3 · p. 8, Introduction · pp. 9–10

Cytotoxicity evaluation of the microrobot system

• No statistically significant viability decrease occurred in three tested cell lines at capsule concentrations up to 0.25 mg/mL.Pure magnetic nanoparticles reduced viability at lower concentrations, depending on cell line. Endothelial cells showed a significant decrease with DOX at 0.2 µg/mL and reduced viability at ciprofloxacin-loaded capsule concentrations above 0.5 mg/mL; SK-BR-3 and HEK-293 cells responded to higher DOX concentrations, and ciprofloxacin-loaded capsules did not significantly increase their viability versus pure ciprofloxacin.Source: Cytotoxicity evaluation of the… · p. 11

In-flow navigation

• At 37 cm/s flow, microrobots reached three distal vessels in a patient-specific vascular model using a 30 mT field and gradients up to 350 mT/m.Navigation took 53 ms to the ACA, 67 ms to the MCA M2 inferior trunk, and 100 ms to the MCA M2 superior trunk.Source: Figure 4 · p. 12, Cytotoxicity evaluation of the… · p. 13

Targeted delivery

• Clot lysis began within 7.5 minutes of rtPA release, with most thrombus broken down or flushed out within 19 minutes.A thermally dissolved rtPA-loaded microrobot delivered the agent to a human blood-clot occlusion in an MCA model under low-flow conditions.Source: Cytotoxicity evaluation of the… · p. 13

Microvasculature targeting

• Thermal dissolution and low-frequency rotating magnetic fields enabled microvasculature targeting, with embolization reducing flow and magnetic chains propelling drug-loaded nanoparticles in- and against-flow.Source: Cytotoxicity evaluation of the… · p. 13

Clinical-condition tracking

• In a porcine model, microrobots released in the common carotid artery were tracked through cranial arteries by C-arm fluoroscopy at 30 fps and DSA at 15 fps.An ex vivo human-placenta vasculature model was also used to assess capsule visibility and magnetic responsiveness.Source: Cytotoxicity evaluation of the… · p. 15

Ovine navigation

• In an ovine model, microrobots released into the cisterna magna were magnetically guided into the fourth ventricle using rotating magnetic and gradient fields.The experiments tested navigation through an anatomically complex region under clinical conditions.Source: Cytotoxicity evaluation of the… · p. 15

Discussion

• The platform integrates navigation, therapeutic delivery, and imaging, demonstrating precise navigation under physiological conditions, effective drug loading and release, and compatibility with standard imaging modalities.Its modular design and materials FDA-approved for other intravenous applications are intended to support adaptability to clinical workflows.Source: Discussion · p. 15
• Microrobots were visualized and manipulated in porcine and ovine models, operating in a clinically relevant workspace and flow environment and navigating anatomically complex regions such as the central nervous system.The authors describe this as the first demonstration of microrobots operating effectively within such a workspace and flow environment.Source: Discussion · pp. 15–16
• Targeted thrombolytic therapy in an in vitro vascular occlusion model highlights potential for acute interventions such as ischemic stroke treatment, while proposed applications include localized infections and tumors.The discussion also identifies vascular occlusions as a potential therapeutic context.Source: Discussion · p. 15
• Long-term safety studies, scalability, and automated navigation algorithms remain priorities to reduce operator dependency and advance clinical applicability.The authors note that significant work remains for clinical translation, while describing the results as a framework for addressing targeted drug-delivery challenges.Source: Discussion · p. 16

• C.C. and B.J.N. are co-founders of NanoFlex Robotics AG; B.J.N. co-founded Magnebotix AG; and F.C.L., O.B., P.T., S.P., and B.J.N. co-founded Swiss Vascular GmbH.Source: Conflict of interests · p. 20

Materials and Methods

• Zinc-substituted iron oxide nanoparticles were synthesized by thermal decomposition, while nitrodopamine was used to functionalize them and commercial tantalum particles.Nitrodopamine hydrogensulfate was synthesized from dopamine hydrochloride; nanoparticle ligand exchange and tantalum functionalization were performed under the described procedures.Source: Materials and Methods · p. 22

Structural analysis

• Nanoparticle and capsule characterization used microscopy, spectroscopy, diffraction, scattering, thermal analysis, magnetic hysteresis, and specific-loss-power measurements.Specific loss power was assessed under a 510 kHz, 20 mT AC magnetic field; magnetic hysteresis loops were measured at 300 K over fields up to 2 T.Source: Materials and Methods · p. 22, Structural analysis · p. 23
• Capsules combined gelatin with nitrodopamine-functionalized magnetic and tantalum nanoparticles, with protocols for rtPA incorporation, small-molecule loading, and release testing.Capsules were formed by hydrogel/oil co-flow and cooled; doxorubicin or ciprofloxacin was loaded by 96-hour incubation, and release was assessed at pH 7.4 and 6 at 37°C.Source: Structural analysis · pp. 23–24
• rtPA stability and compatibility protocols measured enzyme activity, single-chain content, storage effects, and interactions with iron oxide nanoparticles.Activity and storage stability were assessed across three months at 5°C or 25°C; nanoparticle mixtures and supernatants were also tested for residual activity.Source: Structural analysis · p. 24

Cytotoxicity/Cell viability

• Capsule and ingredient cytotoxicity was assessed in HEK293, SK-BR-3, and EA.hy926 cells using 24-hour treatments and WST-1 absorbance measurements.Test materials included empty capsules and capsules loaded with doxorubicin or ciprofloxacin; statistical comparisons used ANOVA with p-value <0.05 considered significant.Source: Cytotoxicity/Cell viability · p. 25
• In vitro navigation protocols tested capsule rolling, motion against and with flow, three-dimensional vascular navigation, and microvasculature targeting and embolization.Tests used magnetic fields and gradients in tubes, a Y-junction, a patient-based vascular model, and a Rete Mirabile model.Source: Cytotoxicity/Cell viability · p. 25
• Ex vivo protocols assessed fluoroscopic capsule locomotion in a perfused human placenta and rtPA-capsule dissolution of a clot in a flowing artery model.The clot model used 35 cm/s flow at 37°C, followed by capsule dissolution at 41°C for 2 minutes while the capsule was magnetically held at the clot.Source: Cytotoxicity/Cell viability · p. 26
• Animal protocols evaluated fluoroscopic capsule visibility after carotid release in pigs and electromagnetic capsule navigation through the ovine subarachnoid space.In sheep, capsules were released into the cisterna magna and guided toward the fourth ventricle and back using rotating magnetic fields or magnetic gradients.Source: Cytotoxicity/Cell viability · pp. 26–27

Supplementary Text 1

• Bifurcation flow was modeled with RANS and γ-Re transition equations; mesh-independence tests supported selecting a mesh of about 1.4 million elements.The model used experimental flow velocities as inlet conditions, with no-slip walls and zero-gauge-pressure outlets.Source: Supplementary Text 1 · p. 28
• Capsule trajectories were simulated with a one-way-coupled Lagrangian sphere model accounting for drag, gravity, buoyancy, magnetic force, and elastic wall collisions.Measured magnetic-field and field-gradient values were interpolated along each trajectory to calculate magnetization and magnetic force.Source: Supplementary Text 1 · pp. 28–29

Validation of the modelling approach

• The predicted friction factor, f ≈ 0.0403, closely matched the smooth-pipe Moody-chart value, f ≈ 0.04, supporting the model’s turbulent-flow predictions.The comparison was made for the bifurcation at Re ≈ 4250; a separate T3A flat-plate comparison also showed a good match with experimental skin-friction data.Source: Validation of the modelling approach · p. 29

Cases considered in the experiments and simulations

• The study combined five flow velocities and ten magnetic-gradient magnitudes in a full factorial design, with 18–19 experiments and 20 simulated capsule entry positions per condition.This yielded 1,000 simulations; navigation success was measured as the fraction of capsules reaching the desired outlet.Source: Cases considered in the experiments… · p. 30
• Predictions tracked experiments across tested flows and gradients, differing by only 1–4 of 20 capsules per case; both showed successful magnetic navigation was possible at every tested flow.Navigation success generally increased with stronger magnetic gradients and lower flow velocities.Source: Cases considered in the experiments… · p. 30

Pharmacological Evaluation

• Capsules released doxorubicin and ciprofloxacin in a pH-dependent manner, enabling release tailored to the surrounding tissue environment.Both drugs were loaded by diffusion from highly concentrated aqueous solutions.Source: Supplementary Text 2 · p. 31, Figure S10 · p. 42
• rtPA adsorption onto embedded nanoparticles reduced overall enzymatic activity to 58%, while storage at 5°C maintained the sc-rtPA quality requirement for three months.The European Pharmacopoeia requirement is at least 60% sc-rtPA among rtPA-related substances.Source: Supplementary Text 2 · p. 31, Figure S10 · p. 42
• At 25°C, rtPA activity increased 1.7-fold in 5% gelatin versus 3.1-fold in water; at 5°C, gelatin samples showed no increased activity.The gelatin stability study lasted three months.Source: Supplementary Text 2 · pp. 31, 43, Figure S10 · p. 42
• No significant difference in rtPA activity was detected between 38°C and hyperthermic capsule dissolution methods.Each dissolution method was tested with five capsules.Source: Supplementary Text 2 · pp. 31, 43, Figure S10 · p. 42