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Clinically Ready Magnetic Microrobots for Targeted Therapies
Fabian C. Landers, Lukas Hertle, Vitaly Pustovalov, Derick Sivakumaran, Oliver Brinkmann, Kirstin Meiners, Pascal Theiler, Valentin Gantenbein, Andrea Veciana, Michael Mattmann, Silas Riss, Simone Gervasoni, Christophe Chautems, Hao Ye, Semih Sevim, Andreas D. Flouris, Josep Puigmartí-Luis, Tiago Sotto Mayor, Pedro Alves, Tessa Lühmann, Xiangzhong Chen, Nicole Ochsenbein, Ueli Moehrlen, Philipp Gruber, Miriam Weisskopf, Quentin Boehler, Salvador Pané, Bradley J. Nelson
TL;DR
Clinical translation of microrobotic drug delivery is limited by the lack of an integrated system combining navigation, therapeutic loading, and imaging. This paper presents a clinically oriented magnetic microrobot platform and demonstrates precise navigation in physiological conditions, including large-animal models.
Problem
Clinical translation is limited by fragmented development of microrobot locomotion, therapeutic loading, imaging, and human-scale navigation.
Method
The platform integrates a clinical electromagnetic navigation system, release catheter, and biodegradable capsule containing magnetic, radiopaque, and therapeutic materials.
Results
The system enabled precise navigation and in vivo visualization and manipulation in large-animal models under clinically relevant conditions.
Takeaways & Limitations
The findings establish a foundation for translating integrated microrobotic platforms toward precise, minimally invasive therapeutic interventions.
Takeaways & Limitations
Clinical application still requires long-term safety studies, scalability, and automated navigation to reduce operator dependence.
Abstract
from arXiv · showhide
Systemic drug administration often causes off-target effects limiting the efficacy of advanced therapies. Targeted drug delivery approaches increase local drug concentrations at the diseased site while minimizing systemic drug exposure. We present a magnetically guided microrobotic drug delivery system capable of precise navigation under physiological conditions. This platform integrates a clinical electromagnetic navigation system, a custom-designed release catheter, and a dissolvable capsule for accurate therapeutic delivery. In vitro tests showed precise navigation in human vasculature models, and in vivo experiments confirmed tracking under fluoroscopy and successful navigation in large animal models. The microrobot balances magnetic material concentration, contrast agent loading, and therapeutic drug capacity, enabling effective hosting of therapeutics despite the integration complexity of its components, offering a promising solution for precise targeted drug delivery.
1 Multi-scale Robotics Laboratory, ETH. Zurich, Tannenstrasse 3, 8092 Zurich, Switzerland … 11 Department of Obstetrics, University Hospital of Zurich, Rämistrasse 100, Zürich, 8092 Switzerland
The paper involves affiliated researchers from institutions in Barcelona, Shanghai, and Zurich, spanning materials chemistry, optoelectronics, and fetal diagnosis and therapy.
- 4 FAME Laboratory, University of Thessaly, Trikala, 42100, Greece: Researchers are affiliated with the University of Barcelona in Barcelona, Spain, through its Department of Materials Science and Physical Chemistry.
- 8 Associate Laboratory in Chemical Engineering (ALICE), Engineering Faculty, Porto University, Portugal: The author affiliations include the Institute of Optoelectronics at Fudan University in Shanghai, People’s Republic of China.
- 11 Department of Obstetrics, University Hospital of Zurich, Rämistrasse 100, Zürich, 8092 Switzerland: The Zurich Center for Fetal Diagnosis and Therapy is affiliated with the University of Zurich in Zürich, Switzerland.
13 Department of Pediatric Surgery, University Children's Hospital Zurich, Steinwiesstrasse 75, Zürich, 8092 Switzerland · 15 Center for Preclinical Development, University Hospital Zurich, University of Zurich, Zurich, Switzerland · Introduction
The paper introduces an integrated clinically oriented magnetic microrobot platform combining navigation, imaging, release, and therapeutic delivery components. It addresses constraints in magnetic actuation, physiological-flow navigation, drug loading, tracking, and controlled dissolution.
- 13 Department of Pediatric Surgery, University Children's Hospital Zurich, Steinwiesstrasse 75, Zürich, 8092 Switzerland: The author affiliations include the Department of Pediatric Surgery at University Children's Hospital Zurich and the Center for Preclinical Development at University Hospital Zurich.The introduction also identifies Kantonsspital Aarau AG’s diagnostic and interventional radiology department.
- Introduction: Severe side effects accompany systemic drug administration, causing 30% of drug failures during clinical trials and motivating targeted magnetic micro- and nanorobot delivery.These devices aim to transport higher therapeutic concentrations directly to disease sites while reducing systemic exposure.
- Introduction: Clinical translation remains difficult because prior work is fragmented despite drug-loading, small-animal efficacy, and contrast-agent tracking demonstrations.The cited studies established proof of concept but did not resolve the full set of clinical requirements in one platform.
- Introduction: Clinical microrobots must balance biocompatibility, biodegradability, magnetic actuation, navigation scale, imaging visibility, drug loading, and reliable release.Magnetic-field strength decays with the cube of distance, while safe materials constrain achievable magnetization and clinical navigation systems are often impractical.
- Introduction: The proposed platform integrates a clinical eMNS, release catheter, and microrobotic capsule that balances magnetic material, contrast-agent, and therapeutic-drug capacities.The capsule uses a gelatin matrix containing zinc-doped iron oxide nanoparticles, tantalum nanoparticles, and therapeutic agents.
- Introduction: The coupled Navion systems generated fields and gradients across a 20 cm x 20 cm x 20 cm workspace designed to accommodate a patient’s head and C-arm imaging.A custom 7 Fr catheter with a flexible polymer gripper enabled controlled microrobot deployment and avoided navigation through strong counterflow.
- Introduction: Gradient pulling propelled the microrobot against flow velocities up to 21.2 cm/s, while interface rolling reached 0.37 cm/s and in-flow steering enabled branch selection.Rolling was suited to low-flow regions, whereas gradient pulling supported stronger counterflow conditions.
- Introduction: Fluoroscopy confirmed capsule traceability, and the platform supported multiple drugs and biologics while magnetic stimulation enabled dissolution within 40 seconds.The tested agents included doxorubicin, ciprofloxacin, and rtPA; nanoparticle adsorption reduced rtPA enzymatic activity to 58%.
Cytotoxicity evaluation of the microrobot system
In vitro cytotoxicity testing assessed dissolved microrobots and their components across endothelial, breast cancer, and kidney cell lines. DOX-loaded capsules produced viability effects comparable to pure DOX in endothelial cells, with a significant decrease at 0.2 µg/mL versus non-drug-loaded capsules.
- Biocompatibility evaluation: Cell viability was evaluated for dissolved microrobots and their components in EA.hy926, SK-BR-3, and HEK-293 cells across different particle concentrations.The study also examined how particle–hydrogel interactions influenced viability in the microrobot formulation.
- DOX-loaded microrobots: Endothelial cells showed a similar viability decrease after exposure to equivalent amounts of pure DOX or DOX released from loaded capsules.Non-drug-loaded capsules served as the control condition.
- DOX-loaded microrobots: 0.2 µg/mL DOX caused a significant decrease in endothelial-cell viability compared with non-drug-loaded capsules.This effect was observed for both pure DOX and DOX from loaded capsules.
Discussion
The study demonstrates clinically relevant microrobot navigation, imaging, and therapeutic delivery in large-animal models and realistic physiological environments. The platform supports precise, minimally invasive targeted interventions, while long-term safety, scalability, and automated navigation remain necessary for clinical translation.
- Clinical translation: The integrated system combines microrobot navigation, therapeutic delivery, and imaging under clinical conditions, addressing longstanding challenges in microrobotics.The materials include FDA-approved components used in other intravenous applications.
- Therapeutic delivery: The platform demonstrated precise navigation under physiological conditions, effective drug loading and release, and compatibility with standard imaging modalities.These features support localized administration while reducing off-target effects relative to systemic delivery.
- Large-animal validation: In vivo visualization and manipulation succeeded in porcine and ovine models within clinically relevant workspace and flow environments.The study describes this as the first demonstration of effective microrobot operation in such conditions.
- Therapeutic applications: Targeted thrombolytic therapy in an in vitro vascular occlusion model and navigation through anatomically complex regions highlight the platform’s therapeutic potential.The reported complex regions include the central nervous system, where conventional surgery is highly invasive.
- Remaining challenges: Future work should address long-term safety, scalability, and automated navigation to reduce operator dependence and improve clinical applicability.The study presents these needs alongside a framework for addressing challenges in targeted drug delivery.
Conflict of interests
Several authors disclose co-founder roles in NanoFlex Robotics AG, Magnebotix AG, and Swiss Vascular GmbH.
- C.C. and B.J.N. are co-founders of NanoFlex Robotics AG.
- B.J.N. is a co-founder of Magnebotix AG.
- F.C.L., O.B., P.T., S.P., and B.J.N. are co-founders of Swiss Vascular GmbH.
Supplementary Material · 1 Multi-scale Robotics Laboratory, ETH. Zurich, Tannenstrasse 3, 8092 Zurich, Switzerland · 2 Magnebotix AG, Zurich, Switzerland
The supplementary material lists the paper’s authors and institutional affiliations, including the Multi-scale Robotics Laboratory at ETH Zurich and Magnebotix AG in Zurich. It also includes an Institute of Pharmacy and Food Chemistry affiliation at the University of Würzburg.
- Supplementary Material: The supplementary material lists Fabian C. Landers, Lukas Hertle, Vitaly Pustovalov, and Derick Sivakumaran among the contributing authors.
- Supplementary Material: The author list includes Oliver Brinkmann, Kirstin Meiners, Pascal Theiler, Valentin Gantenbein, and Andrea Veciana.
- Supplementary Material: The author list further includes Michael Mattmann, Silas Riss, Simone Gervasoni, Christophe Chautems, Hao Ye, and Semih Sevim.
- Supplementary Material: The supplementary material identifies Andreas D. Flouris, Josep Puigmartí-Luis, Tiago Sotto Mayor, Pedro Alves, Tessa Lühmann, and Xiangzhong Chen as contributors.
- Supplementary Material: The listed contributors also include Nicole Ochsenbein, Ueli Moehrlen, Philipp Gruber, Miriam Weisskopf, Quentin Boehler, Salvador Pané, and Bradley J.
- 2 Magnebotix AG, Zurich, Switzerland: The affiliations include Magnebotix AG in Zurich, Switzerland.
- Supplementary Material: The supplementary affiliations include the Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
4 FAME Laboratory, University of Thessaly, Trikala, 42100, Greece
The supplied passage lists an affiliation with the University of Barcelona in Barcelona, Spain.
- The affiliation is the Departament de Ciència dels Materials i Química Física, Institut de Química Teòrica i Computacional, University of Barcelona, Barcelona, Spain.
6 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain · 7 Transport Phenomena Research Centre (CEFT), Engineering Faculty, Porto University, Portugal
The listed affiliations include research institutions in Barcelona, Porto, and Shanghai. They represent ICREA, CEFT, ALICE, and Fudan University.
- 6 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain: ICREA is based in Barcelona, Spain.
- 7 Transport Phenomena Research Centre (CEFT), Engineering Faculty, Porto University, Portugal: The Transport Phenomena Research Centre is affiliated with Porto University, Portugal.
- 7 Transport Phenomena Research Centre (CEFT), Engineering Faculty, Porto University, Portugal: CEFT is located within Porto University’s Engineering Faculty.
- 7 Transport Phenomena Research Centre (CEFT), Engineering Faculty, Porto University, Portugal: The Associate Laboratory in Chemical Engineering (ALICE) is part of Porto University’s Engineering Faculty.
- 7 Transport Phenomena Research Centre (CEFT), Engineering Faculty, Porto University, Portugal: The Institute of Optoelectronics is affiliated with Fudan University.
- 7 Transport Phenomena Research Centre (CEFT), Engineering Faculty, Porto University, Portugal: Fudan University is located in Shanghai 200438, People’s Republic of China.
10 Yiwu Research Institute of Fudan University, Yiwu 322000, Zhejiang, People’s Republic of China
The supplied section lists affiliations spanning the University Hospital of Zurich, University of Zurich centers, University Children's Hospital Zurich, Kantonsspital Aarau AG, and the Center for Preclinical Development. These institutions are based in Switzerland, with one listed affiliation in Yiwu, Zhejiang, China.
- The Department of Obstetrics is affiliated with University Hospital of Zurich in Zürich, Switzerland.The address is Rämistrasse 100, 8092 Zürich.
- The Zurich Center for Fetal Diagnosis and Therapy is part of the University of Zurich in Zürich, Switzerland.Its address is Rämistrasse 71, 8092 Zürich.
- The Department of Pediatric Surgery is based at University Children's Hospital Zurich in Zürich, Switzerland.The listed address is Steinwiesstrasse 75, 8092 Zürich.
- Kantonsspital Aarau AG includes an Institute for Radiology and a department for diagnostic and interventional radiology in Aarau, Switzerland.The listed address is Tellstrasse 25, CH-5001 Aarau.
- The Center for Preclinical Development is affiliated with University Hospital Zurich and the University of Zurich in Zurich, Switzerland.The passage identifies the center as part of the University Hospital Zurich, University of Zurich.
Materials and Methods
The study used established and modified chemical protocols to synthesize and functionalize magnetic nanoparticles, then incorporated them into hydrogel capsule microrobots. Capsules were loaded with biologics or small-molecule drugs and evaluated through structural, magnetic, release, cellular, and navigation experiments.
- Chemical synthesis: Nitrodopamine hydrogensulfate was synthesized from 21 mmol dopamine hydrochloride using 72.4 mmol sodium nitrite and 40 ml of 20 vol/vol% sulfuric acid.The reaction mixture was cooled to 0°C during acid addition and then allowed to proceed for 16 hours at room temperature.
- Nanoparticle synthesis and functionalization: Cubic zinc-substituted iron oxide nanoparticles were synthesized by a modified thermal-decomposition protocol using iron(III) acetylacetonate, zinc(II) acetylacetonate, sodium oleate, and benzyl ether.The nanoparticles were subsequently ligand-exchanged with nitrodopamine to improve colloidal stability in aqueous media.
- Characterization: Microscopy, FTIR, NMR, TGA, XRD, and vibrating-sample magnetometry were used to characterize capsule and nanoparticle morphology, composition, crystal structure, and magnetic behavior.Magnetic hysteresis loops were measured at 300 K over fields of 0.1, 0.2, 0.3, 0.4, and 2 T.
- Capsule fabrication: Magnetic hydrogel capsules comprised 5 wt% gelatin, 37 wt% nitrodopamine-functionalized magnetic nanoparticles, and 16 wt% nitrodopamine-functionalized Ta nanoparticles dispersed in 1 ml water at 55 °C.The formulation was prepared using mechanical stirring and ultrasound before capsule fabrication with olive oil containing 2% Span-80.
- Therapeutic loading and release: rtPA was incorporated at 9 mg/ml, while doxorubicin and ciprofloxacin were loaded by incubation in 18.4 mM and 30.2 mM stock solutions, respectively, for 96 hours.Drug-loaded capsules were dried and washed three times with deionized water; release was assessed in phosphate-buffered saline at pH 7.4 and 6 at 37°C.
- Navigation and catheter fabrication: Navigation experiments were conducted in water at room temperature using a Navion system, including rolling tests in 6.3 mm-inner-diameter tubes under a 10 mT rotating magnetic field.A release catheter was fabricated from high-density polyethylene medical tubes with a 0.0287 in inner diameter and 0.0335 in outer diameter.
Supplementary Text 1
Numerical simulations modeled turbulent or transitional flow and magnetically guided capsule motion through a bifurcation under experimental conditions. Predicted navigation success followed experimental trends across varied flow velocities and magnetic gradients, while friction-factor agreement supported the flow model.
- Flow and turbulence modeling: The finite-volume simulations modeled bifurcation flow at 0.65 < ū < 0.85 m s–1 and 3200 < Re < 4250, spanning transitional to turbulent regimes.Velocity and pressure were coupled with the γ−Reθ transition model.
- Capsule motion model: The capsule was represented as a 1.4 mm sphere with density 3187.74 kg m–3, and its trajectory was computed using one-way Lagrangian coupling with drag, gravity, buoyancy, and magnetic forces.Magnetization depended on the applied magnetic field of approximately 30 mT, using experimentally obtained magnetization curves.
- Model validation: The model reproduced the bifurcation friction factor as f ≈ 0.0403, closely matching the smooth-pipe Moody-chart value f ≈ 0.04.This agreement supported accurate prediction of turbulent flow in the bifurcation.
- Experimental design: Five flow velocities from 0.65 - 0.85 m·s–1 and ten magnetic gradients from 0 - 450 mT·m-1 were combined in a full factorial set of independent experimental and simulation cases.The design varied both parameters systematically to compare observed and predicted navigation success.
- Navigation results: Navigation success generally increased with magnetic gradient and decreased with flow velocity in both experiments and simulations.The simulations followed experimental navigation values across a wide range of flow velocities and magnetic gradients, supporting the modeled force balance.
Supplementary Text 2
The microrobot was evaluated for small-molecule loading, long-term release, and compatibility with the large therapeutic protein rtPA. rtPA activity decreased to 58% after nanoparticle adsorption, while hyperthermic capsule dissolution did not significantly affect activity.
- Pharmacological Evaluation: DOX and CIPRO were incorporated into capsules by diffusion from highly concentrated aqueous solutions to assess drug loading and long-term release.The selected drugs represent chemotherapeutic and antibiotic applications, respectively.
- Pharmacological Evaluation: 58% overall rtPA enzymatic activity remained after the protein adsorbed onto nanoparticles embedded in the microrobot.This adsorption reduced rtPA activity during evaluation of compatibility with large molecules.
- Pharmacological Evaluation: No significant difference in rtPA activity was detected between 38 °C water dissolution and hyperthermic dissolution.Each dissolution method was evaluated using 5 capsules, and rtPA stability was also assessed after incubation from 37 to 70 °C for 90 minutes.