Structured light enables biomimetic swimming and versatile locomotion of photoresponsive soft microrobots.

Microorganisms move in challenging environments by periodic changes in body shape. In contrast, current artificial microrobots cannot actively deform, exhibiting at best passive bending under external fields. Here, by taking advantage of the wireless, scalable and spatiotemporally selective capabilities that light allows, we show that soft microrobots consisting of photoactive liquid-crystal elastomers can be driven by structured monochromatic light to perform sophisticated biomimetic motions. We realize continuum yet selectively addressable artificial microswimmers that generate travelling-wave motions to self-propel without external forces or torques, as well as microrobots capable of versatile locomotion behaviours on demand. Both theoretical predictions and experimental results confirm that multiple gaits, mimicking either symplectic or antiplectic metachrony of ciliate protozoa, can be achieved with single microswimmers. The principle of using structured light can be extended to other applications that require microscale actuation with sophisticated spatiotemporal coordination for advanced microrobotic technologies.This work was in part supported by the European Research Council under the ERC Grant agreements 278213 and 291349, and the DFG as part of the project SPP 1726 (microswimmers, FI 1966/1-1). SP acknowledges support by the Max Planck ETH Center for Learning Systems.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nmat456

Magnetic Gel Composites for Hyperthermia Cancer Therapy

Hyperthermia therapy is a medical treatment based on the exposition of body tissue to slightly higher temperatures than physiological (i.e., between 41 and 46 °C) to damage and kill cancer cells or to make them more susceptible to the effects of radiation and anti-cancer drugs. Among several methods suitable for heating tumor areas, magnetic hyperthermia involves the introduction of magnetic micro/nanoparticles into the tumor tissue, followed by the application of an external magnetic field at fixed frequency and amplitude. A very interesting approach for magnetic hyperthermia is the use of biocompatible thermo-responsive magnetic gels made by the incorporation of the magnetic particles into cross-linked polymer gels. Mainly because of the hysteresis loss from the magnetic particles subjected to a magnetic field, the temperature of the system goes up and, once the temperature crosses the lower critical solution temperature, thermo-responsive gels undergo large volume changes and may deliver anti-cancer drug molecules that have been previously entrapped in their networks. This tutorial review describes the main properties and formulations of magnetic gel composites conceived for magnetic hyperthermia therapy.Financial from DFG (PRJ 9209720) and University of Regensburg are gratefully acknowledged. D.D.D. thanks DFG for the Heisenberg Professorship Award.We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI)Peer reviewe

Magnetic Gel Composites for Hyperthermia Cancer Therapy

Hyperthermia therapy is a medical treatment based on the exposition of body tissue to slightly higher temperatures than physiological (i.e., between 41 and 46 °C) to damage and kill cancer cells or to make them more susceptible to the effects of radiation and anti-cancer drugs. Among several methods suitable for heating tumor areas, magnetic hyperthermia involves the introduction of magnetic micro/nanoparticles into the tumor tissue, followed by the application of an external magnetic field at fixed frequency and amplitude. A very interesting approach for magnetic hyperthermia is the use of biocompatible thermo-responsive magnetic gels made by the incorporation of the magnetic particles into cross-linked polymer gels. Mainly because of the hysteresis loss from the magnetic particles subjected to a magnetic field, the temperature of the system goes up and, once the temperature crosses the lower critical solution temperature, thermo-responsive gels undergo large volume changes and may deliver anti-cancer drug molecules that have been previously entrapped in their networks. This tutorial review describes the main properties and formulations of magnetic gel composites conceived for magnetic hyperthermia therapy

Magnetogels: prospects and main challenges in biomedical applications

Drug delivery nanosystems have been thriving in recent years as a promising application in therapeutics, seeking to solve the lack of specificity of conventional chemotherapy targeting and add further features such as enhanced magnetic resonance imaging, biosensing and hyperthermia. The combination of magnetic nanoparticles and hydrogels introduces a new generation of nanosystems, the magnetogels, which combine the advantages of both nanomaterials, apart from showing interesting properties unobtainable when both systems are separated. The presence of magnetic nanoparticles allows the control and targeting of the nanosystem to a specific location by an externally applied magnetic field gradient. Moreover, the application of an alternating magnetic field (AMF) not only allows therapy through hyperthermia, but also enhances drug delivery and chemotherapeutic desired effects, which combined with the hydrogel specificity, confer a high therapeutic efficiency. Therefore, the present review summarizes the magnetogels properties and critically discusses their current and recent biomedical applications, apart from an outlook on future goals and perspectives.This work was funded by the Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding of CF-UM-UP (UID/FIS/04650/2013) and CQUM (UID/QUI/00686/2016). S.R.S.V. acknowledges FCT for a research grant under UID/FIS/04650/2013 funding.info:eu-repo/semantics/publishedVersio

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

Fabrication et caractérisation d'hydrogels thermosensibles pour des applications de livraison ciblée de médicament et d'embolisation

RÉSUMÉ Le présent mémoire de maîtrise porte sur l’utilisation d’un matériau thermosensible chargé de nanoparticules magnétiques comme vecteur de livraison ciblée de médicament. Ce projet s’inscrit dans le cadre du projet MR-Sub (Magnetic Resonance Submarine) du laboratoire de Nanorobotique qui consiste à guider des instruments médicaux ferromagnétiques à l’intérieur du réseau vasculaire, à l’aide des forces produites par les gradients magnétiques d’un système d’imagerie à résonance magnétique clinique pour le ciblage de tumeurs. Plusieurs matériaux thermosensibles sont envisagés, et les hydrogels de poly(Nisopropylacrylamide) sont retenus en raison du changement de volume discontinu se produisant autour d’une température de transition ainsi que de la possibilité de les charger de nanoparticules ferromagnétiques. La température à laquelle cette transition s’opère est d’environ 34°C, et peut être ajustée par la copolymérisation du N-isopropylacrylamide avec un monomère hydrophile : on obtient une température de transition de 42°C pour une concentration d’acide acrylique de 5%. L’utilisation de ce type d’hydrogel chargé de nanoparticules superparamagnétiques permettra non seulement le guidage et la localisation du dispositif, mais également l’activation de la libération d’un agent thérapeutique préalablement encapsulé dans la structure de l’hydrogel, par l’application d’un champ magnétique alternatif. Les particules sont synthétisées à l’aide d’un réseau interpénétré d’alginate et d’un champ électrostatique, et permet d’obtenir des diamètres de particules reproductibles et modulables dans un intervalle de 90 μm à 2 mm. Les hydrogels synthétisés sous forme de particules mettent environ 15 minutes à se stabiliser, lorsque la température est élevée au dessus de la température de transition, ce qui est acceptable pour une application clinique. Enfin, des nanoparticules de Fe3O4 sont encapsulées dans les hydrogels, et l’application d’un champ magnétique alternatif sur ces particules a permis de mettre en évidence l’augmentation de la température causée par leur présence.----------ABSTRACT This thesis explores the possibility of using ferromagnetic particles embedded in a thermosensitive material as a vector for targeted drug delivery. This project is part of the MR-sub (Magnetic Resonance Submarine) platform developed by the Nanorobotics Lab, aiming to use a modified clinical MRI scanner to steer and propel ferromagnetic medical devices inside the vascular network for the targeting of tumors. Several thermosensitive materials are evaluated, and poly(N-isopropylacrylamide) hydrogels are selected, because of their ability to change volume around a given transition temperature and the possibility to use them as carriers for ferromagnetic particles. This transition temperature is about 34°C, and may be adjusted by copolymerization of N-isopropylacrylamide with an hydrophilic monomer. We are able to reach a transition temperature of 42°C for a 5% acrylic acid concentration. Using this superparamagnetic nan particles-loaded kind of hydrogel allows both propulsion and tracking of the device as well as the remote-controlled liberation of a therapeutic agent, triggered by application of an alternative magnetic field. Hydrogel particles are synthetized using an alginate interpenetrated network and an electrostatic field. This technique allows to reproductibly produce particles with a flexible diameter from 90 μm to 2 mm. Such hydrogel particles take about 15 minutes to stabilize, when their transition temperature is reached, which is acceptable for clinical use

Transient and Local Increase in the Permeability of the Blood-Brain Barrier and the Blood-Retinal Barrier by Hyperthermia of Magnetic Nanoparticles in a Rat Model

RÉSUMÉ Après avoir réussi à propulser des agents thérapeutiques encapsulés dans des micro-transporteurs magnétiques à un endroit précis à l'intérieur d'un modèle animal en utilisant le gradient de champ magnétique dans un appareil de résonance magnétique (RM) modifié, nous visons maintenant à livrer une drogue localement dans le système nerveux central (SNC). Afin de réussir la livraison de la drogue de façon localisée et augmenter l'efficacité du traitement, ce projet met de l’avant que les agents thérapeutiques doivent être administrés par des moyens pas plus envahissants qu’une injection intraveineuse, suivis par la propulsion à distance, contrôlée, et actionnée sur commande dans le SNC. La fonction exigeante du tissu neuronal dans le SNC (haute sensibilité/complexité du système) nécessite un environnement extrêmement stable. Un changement minime dans la composition du liquide interstitiel dans le SNC peut jouer un rôle prépondérant dans la régulation de son microenvironnement et de l'activité neuronale. Par conséquent, le SNC est conçu pour se protéger des fluctuations fréquentes de la concentration extracellulaire d’hormones, d’acides aminés, et des niveaux d'ions produits après les repas, l'exercice ou le stress (ainsi que d'agents pathogènes toxiques qui peuvent être en circulation dans le sang). Cette protection du SNC est permise grâce à la présence d’une barrière, nommée barrière hémato-encéphalique (BHE). Cette barrière préventive se compose essentiellement de cellules endothéliales étroitement reliées entre elles qui tapissent la surface intérieure de la plupart des vaisseaux sanguins dans le SNC. Bien que ceci offre un environnement neuronal stable, plus de 98% des molécules que constituent les drogues ne sont pas en mesure de franchir la BHE et leur pénétration est uniquement déterminée par les caractéristiques de perméabilité de la barrière. Ceci est alors un frein pour les traitements ciblant le SNC. Par conséquent, la recherche pharmaceutique fait un réel effort pour maximiser la livraison des médicaments vers le SNC. Pour autant, la présence des barrières physiologiques, bien qu’essentielles à la survie en conditions physiologiques, limitent les traitements qu’on a à notre disposition en conditions pathologiques.----------ABSTRACT After successfully propelling therapeutic agents encapsulated in magnetic micro-carriers to a specific location inside an animal model by the gradient magnetic field of a modified clinical Magnetic Resonance (MR) scanner, we are now aiming to perform local drug delivery in the region of the central nervous system (CNS). To achieve localized drug delivery and increase efficacy, this project advances the theme that the therapeutic agents must be administered by means no more invasive than an intravenous injection followed by remote propulsion, controlled tracking, and on-command actuation in the CNS. The demanding function of the CNS requires an extremely stable environment. In fact, any small change in the composition of the interstitial fluid in the CNS plays a predominant role in regulating its microenvironment and neuronal activity. Therefore, the CNS is conceived to protect itself from frequent fluctuations of extracellular concentration of hormones, amino acids, and ion levels that occur after meals, exercise, or stress - as well as from toxic pathogens that may be circulating in the blood stream. This preventive barrier consists mainly of tightly interconnected endothelial cells that carpet the inner surface of most blood vessels in the CNS. While it provides a stable neuronal environment, more than 98% of all drug molecules are not able to cross this barrier and the extent to which a molecule enters is determined only by the permeability characteristics of the barrier. Therefore, while pharmaceutical research progresses for drug delivery to the CNS, it is limited by its pharmacokinetics through physiological barriers. Successful transient and local opening of the barrier for diffusion of therapeutics could strongly support the feasibility of treating a variety of neurological disorders. A recent effort presented in this dissertation provides evidence for the emergence of a novel approach to overcome this problem. This technique uses magnetic nanoparticles (MNPs) in conjunction with an alternating magnetic field to transiently increase barrier permeability for drug delivery. MNPs can act as miniaturized heat sources that, when under the influence of the alternating magnetic field, dissipate thermal energy directly and exclusively to the barrier (hyperthermia). In addition to its novelty, the findings confirm that the technique does not damage the neurovascular unit, i.e. neurons, astrocytes, etc