Medical Imaging of Microrobots: Toward In Vivo Applications

Medical microrobots (MRs) have been demonstrated for a variety of non-invasive biomedical applications, such as tissue engineering, drug delivery, and assisted fertilization, among others. However, most of these demonstrations have been carried out in in vitro settings and under optical microscopy, being significantly different from the clinical practice. Thus, medical imaging techniques are required for localizing and tracking such tiny therapeutic machines when used in medical-relevant applications. This review aims at analyzing the state of the art of microrobots imaging by critically discussing the potentialities and limitations of the techniques employed in this field. Moreover, the physics and the working principle behind each analyzed imaging strategy, the spatiotemporal resolution, and the penetration depth are thoroughly discussed. The paper deals with the suitability of each imaging technique for tracking single or swarms of MRs and discusses the scenarios where contrast or imaging agent's inclusion is required, either to absorb, emit, or reflect a determined physical signal detected by an external system. Finally, the review highlights the existing challenges and perspective solutions which could be promising for future in vivo applications

An Electromagnetic Steering System for Magnetic Nanoparticle Drug Delivery

Targeted delivery of pharmaceutical agents to the brain using magnetic nanoparticles (MNPs) is an efficient technique to transport molecules to disease locations. MNPs can cross the blood–brain barrier (BBB) and can be concentrated at a specific location in the brain using non-invasive electromagnetic forces. The proposed EMA consists of two coil-core system. The cores are added in the center of each coil to concentrate the flux in the region of interest. The EMA can enhance the gradient field 10 times compared to only coil system and generate the maximum magnetic field of 160 mT and 5.6 T/m. A 12-kW direct-current power supply was used to generate sufficient magnetic forces on the MNPs by regulating the input currents of the coils. Effective guidance of MNPs is demonstrated via simulations and experiments using 800-nm-diameter MNPs in a Y-shaped channel. The developed EMA system has high potentials to increase BBB crossing of MNPs for efficient drug targeting to brain region

A Soft Magnetic Core can Enhance Navigation Performance of Magnetic Nanoparticles in Targeted Drug Delivery

Magnetic nanoparticles (MNPs) are a promising candidate for use as carriers in drug delivery systems. A navigation system with real-time actuation and monitoring of MNPs is inevitably required for more precise targeting and diagnosis. In this paper, we propose a novel electromagnetic navigation system with a coil combined with a soft magnetic core. This system can be used for magnetic particle imaging (MPI) and electromagnetic actuator functions with a higher steering force and enhanced monitoring resolution. A soft magnetic core with coils can increase the magnetic gradient field. However, this also generates harmonic noise, which makes it difficult to acquire MNP monitoring signals with MPI. Therefore, the use of amplitude modulation magnetic particle imaging (AM MPI) is suggested. AM MPI uses a low-amplitude excitation field combined with a low-frequency drive field. Using this system, the measured signal becomes less sensitive to the soft magnetic core. Based on the new MPI scheme and the combination of the coil with the magnetic cores, the proposed navigation system can implement one-dimensional (1-D) MNP navigation and 2-D MPI. The proposed navigation system can shorten the 1-D guidance time by about 25% for MNPs in the size range of 45-60 nm and give an improved 2-D imaging resolution of 43%, compared with an air-coil structure

Modeling and design of an electromagnetic actuation system for the manipulation of microrobots in blood vessels

Tese de mestrado integrado em Física, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2015A navegação de nano/microdispositivos apresenta um grande potencial para aplicações biomédicas, oferecendo meios de diagnóstico e procedimentos terapêuticos no interior do corpo humano. Dada a sua capacidade de penetrar quase todos os materiais, os campos magnéticos são naturalmente adequados para controlar nano/microdispositivos magnéticos em espaços inacessíveis. Uma abordagem recente é o uso de um aparelho personalizado, capaz de controlar campos magnéticos. Esta é uma área de pesquisa prometedora, mas mais simulações e experiências são necessárias para avaliar a viabilidade destes sistemas em aplicações clínicas. O objectivo deste projecto foi a simulação e desenho de um sistema de atuação eletromagnética para estudar a locomoção bidimensional de microdispositivos. O primeiro passo foi identificar, através da análise de elementos finitos, usando o software COMSOL, diferentes configurações de bobines que permitiriam o controlo de dispositivos magnéticos em diferentes escalas. Baseado nos resultados das simulações, um protótipo de um sistema de atuação magnética para controlar dispositivos com mais de 100 m foi desenhado e construído de raiz, tendo em conta restrições de custos. O sistema consistiu num par de bobines de Helmholtz e rotacionais e um par de bobines de Maxwell dispostas no mesmo eixo. Além disso, componentes adicionais tiveram de ser desenhados ou selecionados para preencher os requisitos do sistema. Para a avaliação do sistema fabricado, testes preliminares foram realizados. A locomoção do microrobot foi testada em diferentes direções no plano x-y. As simulações e experiências confirmaram que é possível controlar a força magnética e o momento da força que atuam num microdispositivo através do campos produzidos pelas bobines de Maxwell e Helmholtz, respectivamente. Assim, este tipo de atuação magnética parece ser uma forma adequada de transferência de energia para futuros microdispositivos biomédicos.Navigation of nano/microdevices has great potential for biomedical applications, offering a means for diagnosis and therapeutic procedures inside the human body. Due to their ability to penetrate most materials, magnetic fields are naturally suited to control magnetic nano/microdevices in inaccessible spaces. One recent approach is the use of custom-built apparatus capable of controlling magnetic devices. This is a promising area of research, but further simulation studies and experiments are needed to estimate the feasibility of these systems in clinical applications. The goal of this project was the simulation and design of an electromagnetic actuation system to study the two dimensional locomotion of microdevices. The first step was to identify, through finite element analysis using software COMSOL, different coil configurations that would allow the control of magnetic devices at different scales. Based on the simulation results, a prototype of a magnetic actuation system to control devices with more than 100 m was designed and built from the ground up, taking into account cost constraints. The system comprised one pair of rotational Helmholtz coils and one pair of rotational Maxwell coils placed along the same axis. Furthermore, additional components had to be designed or selected to fulfil the requirements of the system. For the evaluation of the fabricated system, preliminary tests were carried out. The locomotion of a microdevice was tested along different directions in the x-y plane. The simulations and experiments confirmed that it is possible to control the magnetic force and torque acting on a microdevice through the fields produced by Maxwell and Helmholtz coils, respectively. Thus, this type of magnetic actuation seems to provide a suitable means of energy transfer for future biomedical microdevices

Scalable strategies for tumour targeting of magnetic carriers and seeds

With the evolving landscape of medical oncology, focus has shifted away from nonspecific cytotoxic treatment strategies toward therapeutic paradigms more characteristic of targeted therapies. These therapies rely on delivery vehicles such as nano-carriers or micro robotic devices to boosts the concentration of therapeutics in a specific targeted site inside the body. The use of externally applied magnetic field is suggested to be a predominant approach for remote localisation of magnetically responsive carriers and devices to the target region that could not be otherwise reached. However, the fast decline of the magnetic fields and gradients with increasing distances from the source is posing a major challenge for its clinical application. The aim of this thesis was to investigate potential magnetic delivery strategies which can circumvent some of the typical limitations of this technique. Two different approaches were explored to this end. The first approach was to characterise the ability of a conventional permanent magnet on targeting individual nano-carriers and develop novel magnetic designs which improve the targeting efficiency. The second approach was evaluating the feasibility of a magnetic resonance imaging system to move a millimetre-sized magnetic particle within the body. Phantom and in vivo magnetic targeting experiments illustrated the significant increase in effective targeting depth when our novel magnetic design was used for targeting nano-carriers compared with conventional magnets. In the later part of the thesis, the proof of concept and characterisation experiments showed that a 3 mm magnetic particle can be moved in ex vivo brain tissue using a magnetic resonance imaging system using clinically relevant gradient strengths. The magnetic systems introduced in this thesis provide the potential to target nano-carriers and millimetre-sized thermoseeds to tumours located at deep regions of human body through vasculature and soft tissue respectively

Swarm of Magnetic Nanoparticles Steering in Multi-Bifurcation Vessels under Fluid Flow

Magnetic drug targeting has emerged as a promising approach for enhancing the efficiency of drug delivery. Recent developments in real-time monitoring techniques have enabled the guidance of magnetic nanoparticles (MNPs) in the vascular network. Despite recent developments in magnetic navigation, no comprehensive strategy for swarm of nanoparticles steering under fluid flow exists. This paper introduces a strategy for MNPs steering in a vascular network under fluid flow. In the proposed scheme, the swarm of nanoparticles are initially guided to an area that guarantees their successful guidance towards a desired direction (called safe zone) using an asymmetrical field function to handle swarm of nanoparticles. Then, a transporter field function is used to transfer the particles between the safe zones, and finally a sustainer field function is used to keep the particles within the safe zone. A steering algorithm is proposed to enhance the targeting performance in the multi-bifurcation vessel. Utilizing the proposed concept, a high success rate for targeting is achieved in simulations, which demonstrates the potential and limitations of swarm of nanoparticles steering under fluid flow

Guidage magnétique par champs de dipôles pour l’administration ciblée d’agents thérapeutiques

Les chimiothérapies modernes utilisées pour le traitement des cancers consistent souvent à l’injection systémique de molécules toxiques dont généralement une infime partie atteint la tumeur. Pour augmenter l’efficacité de ces traitements et réduire leurs effets secondaires, une solution consiste à guider magnétiquement des agents thérapeutiques afin de les diriger dans le réseau vasculaire, à partir du point d’injection directement vers la zone à traiter. Ceci peut être accompli en appliquant des champs et des gradients magnétiques de manière contrôlée sur les agents, qui sont alors soumis à des forces de propulsion permettant de les attirer à travers les bifurcations artérielles désirées. Pour le guidage de micro-agents, cette approche requiert des champs et des gradients magnétiques forts. Le champ permet de magnétiser les agents et doit idéalement être suffisamment fort pour les amener à saturation magnétique. Les gradients (variations spatiales du champ) peuvent alors induire des forces magnétiques de propulsion, mais doivent atteindre une certaine amplitude pour que ces forces soient suffisantes. Avec les limites technologiques actuelles, il est difficile de rencontrer ces deux critères pour le guidage de micro-agents à l’échelle humaine. Dans les tissus profonds, les méthodes existantes sont généralement limitées à des champs de <0.1T et des gradients de <400 mT/m, ou peuvent générer un champ assez fort pour obtenir une magnétisation à saturation mais au détriment de gradients faibles (e.g. <100mT/m ou typiquement <40 mT/m). Dans le cadre de ce projet de recherche, une nouvelle méthode de guidage magnétique, baptisée guidage par champs de dipôles, ou Dipole Field Navigation (DFN), est proposée et étudiée pour surmonter les limitations des méthodes précédentes pour le guidage de micro-agents. Contrairement aux autres méthodes de guidage magnétique, DFN bénéficie à la fois d’un champ magnétique fort et de gradients d’amplitudes élevées dans les tissus profonds chez l’humain. Ceci est accompli à l’aide de corps ferromagnétiques précisément positionnés autour du patient à l’intérieur d’un appareil clinique d’imagerie par résonance magnétique. Ces appareils génèrent un puissant champ magnétique, typiquement de 1.5-3 T, qui est suffisant pour atteindre la saturation magnétique des agents. Les corps ferromagnétiques ont pour effet de distordre le champ de l’appareil de sorte que des gradients excédant 400mT/m peuvent être générés à une profondeur de 10 cm dans le patient. Grâce aux distorsions complexes du champ autour de ceux-ci, il est théoriquement possible d’induire, dans une certaine mesure, les forces magnétiques nécessaires au guidage des agents le long de trajectoires prédéfinies dans le réseau vasculaire. Le paramétrage adéquat d’une disposition de corps ferromagnétiques, dont le nombre requis est a priori inconnu, est toutefois complexe et doit être effectué en fonction de la trajectoire vasculaire désirée, spécifique à chaque patient. Différentes contraintes reliées à l’environnement d’IRM, dont l’espace restreint à l’intérieur de l’appareil, doivent également être prises en compte. Ainsi, des modèles et algorithmes d’optimisation permettant de résoudre ce problème sont développés et présentés. Le fonctionnement de la méthode est validé in vitro par le guidage de particules à travers des réseaux ayant jusqu’à trois bifurcations consécutives avec un taux de ciblage supérieur à 90%. Il est démontré que la taille et la forme des corps ferromagnétiques peuvent être variées afin d’augmenter les capacités de génération de gradients. En particulier, les formes de disque et de demie-sphère sont identifiées comme étant les plus efficaces. Par ailleurs, l’environnement d’IRM n’étant typiquement pas compatible avec la présence de matériaux magnétiques, les effets des corps ferromagnétiques sur l’imagerie sont étudiés. Il est démontré que l’imagerie demeure possible, dans une certaine mesure malgré les distorsions, dans des régions spécifiques autour d’une sphère magnétisée à l’intérieur de l’appareil. La qualité des images obtenues dans ces conditions est suffisante pour permettre de valider le succès du ciblage. Ainsi, des vérifications périodiques du déroulement de l’intervention seraient possibles en éloignant momentanément le ou les corps ferromagnétiques du patient. D’autre part, à cause des forces magnétiques exercées sur ceux-ci, le nombre et la taille des corps ferromagnétiques doivent être limités afin de faciliter leur insertion et leur positionnement sécuritaire dans l’appareil. Bien que certaines trajectoires puissent nécessiter plusieurs corps ferromagnétiques de grande taille, un certain compromis doit donc être recherché par rapport à la qualité des gradients générés. Enfin, le potentiel de la méthode pour le guidage de microagents dans les tissus profonds chez l’humain est évalué en utilisant un modèle du réseau vasculaire du foie d’un patient. Les résultats indiquent que, pour des trajectoires vasculaires multi-bifurcations relativement complexes, un compromis est inévitable entre les amplitudes et la précision angulaire des gradients générés. Par exemple, des gradients d’environ 150mT/m ont été obtenus pour le guidage à travers trois bifurcations consécutives dans ce modèle, mais avec une erreur angulaire moyenne d’environ 20_. Finalement, les capacités de DFN à générer des gradients forts dépendent de nombreux paramètres, comme la complexité et la profondeur de la trajectoire vasculaire visée, mais peuvent, selon les conditions, surpasser grandement celles des méthodes existantes pour le guidage de micro-agents dans les tissus profonds. À la lumière des résultats présentés dans cette thèse, le potentiel de la méthode est prometteur et justifie la poursuite du projet, notamment vers la réalisation des premiers essais in vivo. À ce titre, différentes pistes de recherches et de travaux futurs sont discutées.----------ABSTRACT Modern chemotherapies used in cancer treatment often involve the systemic administration of toxic molecules, of which usually a tiny fraction reaches the tumor. To increase the efficacy of these treatments while significantly reducing their secondary effects, a solution consists in magnetically guiding therapeutic agents in the vascular network, from an injection point directly towards the diseased site. This can be accomplished by applying controlled combinations of magnetic fields and gradients on the agents, which are then subjected to propulsive directional forces that can be used to steer them through the desired arterial bifurcations. For the navigation of micro-agents, this approach requires both a strong magnetic field and high gradients. The field strength is required to magnetize the agents and is ideally high enough to bring them at saturation magnetization. The gradients (spatial variations of the field) can then induce magnetic propulsion forces, but must reach a certain magnitude so that these forces are sufficient. Because of current technological limitations, it is challenging to meet both criteria for the navigation of micro-agents at the human scale. In deep tissues, current methods are in fact usually limited to <0.1T fields and <400mT/m gradients, or can provide the field to reach saturation magnetization but at the expense of weak gradients (e.g. <100mT/m or typically <40 mT/m). In this research project, a new method dubbed Dipole Field Navigation (DFN) is proposed and studied to overcome the limitations of existing magnetic navigation methods for guiding micro-agents. Unlike other methods, DFN can provide both a strong magnetic field and high gradients in deep tissues for whole-body interventions. This is achieved by precisely positioning ferromagnetic cores around the patient inside a clinical magnetic resonance imaging scanner. Conventional scanners generate a strong magnetic field, typically of 1.5-3 T, which is sufficient to bring the agents at saturation magnetization. The ferromagnetic cores distort the scanner’s field such that gradients exceeding 400mT/m can be generated at a 10 cm depth inside the patient. Due to the complex distortion patterns around the cores, it is theoretically possible to induce, to a certain extent, the magnetic forces required for navigating agents along predefined vascular routes. The parameterization of core configurations, in which the required number of cores is a priori unknown, is however complex and must be performed according to the specific vasculature of a given patient. Several constraints related to the MRI environment must also be considered, such as the limited space inside the scanner. Therefore, models and optimization algorithms are developed and presented for solving this problem. The feasibility of the method is validated in vitro by guiding particles through up to three consecutive bifurcations, achieving a targeting efficiency of over 90%. It is shown that the size and shape of the cores can be varied to increase the capabilities of the method for generating gradients. In particular, discs and hemispheres are shown to be the most effective shapes. Moreover, the MRI environment typically no being compatible with the presence of magnetic materials, the effects of the cores on imaging are studied. It is shown that, despite distortions, imaging is still possible, to a certain extent, in specific regions around a magnetized sphere placed in the scanner. The images obtained in these conditions are of sufficient quality for targeting assessment. Thus, periodic validations of the procedure could be achieved by momentarily moving the cores away from the patient. On another hand, due to the potentially strong magnetic forces exerted on the cores, their number and sizes must be limited to ensure their safe insertion and positioning in the scanner. Consequently, although the navigation in some vascular routes may require several large ferromagnetic cores, a certain compromise must be made with respect to the quality of the gradients generated. Finally, the potential of the method for guiding micro-agents in a human vasculature in deep tissues is evaluated using the vascular model of a patient liver. The results indicate that, for relatively complex vascular routes having multiple bifurcations, a compromise is also required between the amplitudes and the angular precision of the gradients. For example, gradient strengths around 150mT/m were obtained for routes having three consecutive bifurcations in this model, but with an average angular error of about 20_. Overall, the capabilities of DFN for generating strong gradients depend on several parameters, such as the complexity and depth of the desired vascular route, but can in a range of cases greatly exceed those achievable by previous methods for the navigation of micro-agents in deep tissues. In view of the results presented in this thesis, the promising potential of DFN motivates the continuation of this project, in particular towards the first in vivo experiments. As such, different avenues of research and future works are discussed

Micro/nanoscale magnetic robots for biomedical applications

Magnetic small-scale robots are devices of great potential for the biomedical field because of the several benefits of this method of actuation. Recent work on the development of these devices has seen tremendous innovation and refinement toward ​improved performance for potential clinical applications. This review briefly details recent advancements in small-scale robots used for biomedical applications, covering their design, fabrication, applications, and demonstration of ability, and identifies the gap in studies and the difficulties that have persisted in the optimization of the use of these devices. In addition, alternative biomedical applications are also suggested for some of the technologies that show potential for other functions. This study concludes that although the field of small-scale robot research is highly innovative ​there is need for more concerted efforts to improve functionality and reliability of these devices particularly in clinical applications. Finally, further suggestions are made toward ​the achievement of commercialization for these devices