Sylvain Martel

Flagellated Magnetotactic Bacteria as Controlled MRI-trackable Propulsion and Steering Systems for Medical Nanorobots Operating in the Human Microvasculature

Although nanorobots may play critical roles for many applications in the human body, such as targeting tumoral lesions for therapeutic purposes, miniaturization of the power source with an effective onboard controllable propulsion and steering system have prevented the implementation of such mobile robots. Here, we show that the flagellated nanomotors combined with the nanometer-sized magnetosomes of a single magnetotactic bacterium can be used as an effective integrated propulsion and steering system for devices, such as nanorobots, designed for targeting locations only accessible through the smallest capillaries in humans while being visible for tracking and monitoring purposes using modern medical imaging modalities such as magnetic resonance imaging. Through directional and magnetic field intensities, the displacement speeds, directions, and behaviors of swarms of these bacterial actuators can be controlled from an external computer.

Automatic navigation of an untethered device in the artery of a living animal using a conventional clinical magnetic resonance imaging system

The feasibility for in vivo navigation of untethered devices or robots is demonstrated with the control and tracking of a 1.5mm diameter ferromagnetic bead in the carotid artery of a living swine using a clinical magnetic resonance imaging (MRI) platform. Navigation is achieved by inducing displacement forces from the three orthogonal slice selection and signal encoding gradient coils of a standard MRI system. The proposed method performs automatic tracking, propulsion, and computer control sequences at a sufficient rate to allow navigation along preplanned paths in the blood circulatory system. This technique expands the range of applications in MRI-based interventions.The feasibility for in vivo navigation of untethered devices or robots is demonstrated with the control and tracking of a 1.5mm diameter ferromagnetic bead in the carotid artery of a living swine using a clinical magnetic resonance imaging (MRI) platform. Navigation is achieved by inducing displacement forces from the three orthogonal slice selection and signal encoding gradient coils of a standard MRI system. The proposed method performs automatic tracking, propulsion, and computer control sequences at a sufficient rate to allow navigation along preplanned paths in the blood circulatory system. This technique expands the range of applications in MRI-based interventions.

Controlled manipulation and actuation of micro-objects with magnetotactic bacteria

Bacterial actuation and manipulation are demonstrated where Magnetospirillum gryphiswaldense magnetotactic bacteria (MTB) are used to push 3 μ m beads at an average velocity of 7.5 μ m s − 1 along preplanned paths by modifying the torque on a chain of magnetosomes in the bacterium with a directional magnetic field of at least 0.5 G generated from a small programmed electrical current. But measured average thrusts of 0.5 and 4 pN of the flagellar motor of a single Magnetospirillum gryphiswaldense and MC-1 MTB suggest that average velocities greater than 16 and 128 μ m s − 1 , respectively could be achieved.

Method of propulsion of a ferromagnetic core in the cardiovascular system through magnetic gradients generated by an MRI system

This paper reports the use of a magnetic resonance imaging (MRI) system to propel a ferromagnetic core. The concept was studied for future development of microdevices designed to perform minimally invasive interventions in remote sites accessible through the human cardiovascular system. A mathematical model is described taking into account various parameters such as the size of blood vessels, the velocities and viscous properties of blood, the magnetic properties of the materials, the characteristics of MRI gradient coils, as well as the ratio between the diameter of a spherical core and the diameter of the blood vessels. The concept of magnetic propulsion by MRI is validated experimentally by measuring the flow velocities that magnetized spheres (carbon steel 1010/1020) can withstand inside cylindrical tubes under the different magnetic forces created with a Siemens Magnetom Vision 1.5 T MRI system. The differences between the velocities predicted by the theoretical model and the experiments are approximately 10%. The results indicate that with the technology available today for gradient coils used in clinical MRI systems, it is possible to generate sufficient gradients to propel a ferromagnetic sphere in the larger sections of the arterial system. In other words, the results show that in the larger blood vessels where the diameter of the microdevices could be as large as a couple a millimeters, the few tens of mT/m of gradients required for displacement against the relatively high blood flow rate is well within the limits of clinical MRI systems. On the other hand, although propulsion of a ferromagnetic core with diameter of /spl sim/600 /spl mu/m may be possible with existing clinical MRI systems, gradient amplitudes of several T/m would be required to propel a much smaller ferromagnetic core in small vessels such as capillaries and additional gradient coils would be required to upgrade existing MRI systems for operations at such a scale.

Co-encapsulation of magnetic nanoparticles and doxorubicin into biodegradable microcarriers for deep tissue targeting by vascular MRI navigation

Magnetic tumor targeting with external magnets is a promising method to increase the delivery of cytotoxic agents to tumor cells while reducing side effects. However, this approach suffers from intrinsic limitations, such as the inability to target areas within deep tissues, due mainly to a strong decrease of the magnetic field magnitude away from the magnets. Magnetic resonance navigation (MRN) involving the endovascular steering of therapeutic magnetic microcarriers (TMMC) represents a clinically viable alternative to reach deep tissues. MRN is achieved with an upgraded magnetic resonance imaging (MRI) scanner. In this proof-of-concept preclinical study, the preparation and steering of TMMC which were designed by taking into consideration the constraints of MRN and liver chemoembolization are reported. TMMC were biodegradable microparticles loaded with iron-cobalt nanoparticles and doxorubicin (DOX). These particles displayed high saturation magnetization (Ms = 72 emu g(-1)), MRI tracking compatibility (strong contrast on T2∗-weighted images), appropriate size for the blood vessel embolization (∼50 μm), and sustained release of DOX (over several days). The TMMC were successfully steered in vitro and in vivo in the rabbit model. In vivo targeting of the right or left liver lobes was achieved by MRN through the hepatic artery located 4 cm beneath the skin. Parameters such as flow velocity, TMMC release site in the artery, magnetic gradient and TMMC properties, affected the steering efficiency. These data illustrate the potential of MRN to improve drug targeting in deep tissues.

MRI-based Medical Nanorobotic Platform for the Control of Magnetic Nanoparticles and Flagellated Bacteria for Target Interventions in Human Capillaries

Medical nanorobotics exploits nanometer-scale components and phenomena with robotics to provide new medical diagnostic and interventional tools. Here, the architecture and main specifications of a novel medical interventional platform based on nanorobotics and nanomedicine, and suited to target regions inaccessible to catheterization, are described. The robotic platform uses magnetic resonance imaging (MRI) for feeding back information to a controller responsible for the real-time control and navigation along pre-planned paths in the blood vessels of untethered magnetic carriers, nanorobots, and/or magnetotactic bacteria (MTB) loaded with sensory or therapeutic agents acting like a wireless robotic arm, manipulator, or other extensions necessary to perform specific remote tasks. Unlike known magnetic targeting methods, the present platform allows us to reach locations deep in the human body while enhancing targeting efficacy using real-time navigational or trajectory control. We describe several versions of the platform upgraded through additional software and hardware modules allowing enhanced targeting efficacy and operations in very difficult locations such as tumoral lesions only accessible through complex microvasculature networks.

Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions

Oxygen depleted hypoxic regions in the tumour are generally resistant to therapies1. Although nanocarriers have been used to deliver drugs, the targeting ratios have been very low. Here, we show that the magneto-aerotactic migration behaviour2 of magnetotactic bacteria3, Magnetococcus marinus strain MC-14, can be used to transport drug-loaded nanoliposomes into hypoxic regions of the tumour. In their natural environment, MC-1 cells, each containing a chain of magnetic iron-oxide nanocrystals5, tend to swim along local magnetic field lines and towards low oxygen concentrations6 based on a two-state aerotactic sensing system2. We show that when MC-1 cells bearing covalently bound drug-containing nanoliposomes were injected near the tumour in SCID Beige mice and magnetically guided, up to 55% of MC-1 cells penetrated into hypoxic regions of HCT116 colorectal xenografts. Approximately 70 drug-loaded nanoliposomes were attached to each MC-1 cell. Our results suggest that harnessing swarms of microorganisms exhibiting magneto-aerotactic behaviour can significantly improve the therapeutic index of various nanocarriers in tumour hypoxic regions.

Magnetic nanoparticles encapsulated into biodegradable microparticles steered with an upgraded magnetic resonance imaging system for tumor chemoembolization

In this work, therapeutic magnetic micro carriers (TMMC) guided in real time by a magnetic resonance imaging (MRI) system are proposed as a mean to improve drug delivery to tumor sites. MRI steering constraints and physiological parameters for the chemoembolization of liver tumors were taken into account to design magnetic iron-cobalt nanoparticles encapsulated into biodegradable poly(d,l-lactic-co-glycolic acid) (PLGA) microparticles with the appropriate saturation magnetization (M(s)). FeCo nanoparticles displayed a diameter of 182nm and an M(s) of 209 emicrog(-1). They were coated with a multilayered graphite shell to minimize the reduction of M(s) during the encapsulation steps. FeCo-PLGA microparticles, with a mean diameter of 58 microm and an M(s) of 61emicrog(-1), were steered in a phantom mimicking the hepatic artery and its bifurcation, with a flow in the same order of magnitude as that of the hepatic artery flow. The steering efficiency, defined as the amount of FeCo-PLGA microparticles in the targeted bifurcation channel divided by the total amount of FeCo-PLGA microparticles injected, reached 86%. The data presented in this paper confirms the feasibility of the steering of these TMMC.

Real-Time MRI-Based Control of a Ferromagnetic Core for Endovascular Navigation

This paper shows that even a simple proportional-integral-derivative (PID) controller can be used in a clinical MRI system for real-time navigation of a ferromagnetic bead along a predefined trajectory. Although the PID controller has been validated in vivo in the artery of a living animal using a conventional clinical MRI platform, here the rectilinear navigation of a ferromagnetic bead is assessed experimentally along a two-dimensional (2D) path as well as the control of the bead in a pulsatile flow. The experimental results suggest the likelihood of controlling untethered microdevices or robots equipped with a ferromagnetic core inside complex pathways in the human body.

Using a swarm of self-propelled natural microrobots in the form of flagellated bacteria to perform complex micro-assembly tasks

Many science fiction novels have envisioned swarms of artificial microrobots capable of performing complex collective tasks. Unfortunately, todays technological constraints have prevented such powerful concept to be a reality when considering artificial microrobots. In this paper, we show that a swarm of computer-controlled flagellated Magnetotactic Bacteria (MTB) acting as natural microrobots of approximately 1 to 2 micrometers in diameter can perform many of the same complex collective tasks envisioned with these futuristic self-propelled artificial microrobots. To prove the concept, magnetotaxis-based control has been used to coordinate a swarm made of thousands of these self-propelled natural microrobots to build in a collective effort, a miniature version of an ancient Egyptian pyramid.