Ouajdi Felfoul

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.

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.

In Vivo MR-Tracking Based on Magnetic Signature Selective Excitation

A novel magnetic resonance (MR)-tracking method specifically developed to locate the ferromagnetic core of an untethered microdevice, microrobot, or nanorobot for navigation or closed-loop control purpose is described. The tracking method relies on the application of radio-frequency (RF) excitation signals tuned to the equipotential magnetic curves generated by the magnetic signature of the object being tracked. Positive contrast projections are obtained with reference to the position of the magnetic source. A correlation function performed on only one k-space line for each of the three axes and corresponding to three projections, is necessary to obtain a 3-D location of the device. In this study, the effects of the sphere size and the RF frequency offset were investigated in order to find the best contrast noise ratio (CNR) for tracking. Resolution and precision were also investigated by proper measurement of the position of a ferromagnetic sphere by magnetic resonance imaging (MRI) acquisition and by comparing them with the real position. This method is also tested for a moving marker where the positions found by MRI projections were compared with the ones taken with a camera. In vitro and in vivo experiments show the operation of the technique in tortuous phantom and in animal models. Although the method was developed in the prospect of new interventional MR-guided endovascular operations based on miniature untethered devices, it could also be used as a passive tracking method using tools such as catheters or guide wires.

Three-dimensional remote aggregation and steering of magnetotactic bacteria microrobots for drug delivery applications

Magnetotactic bacteria (MTB) can be viewed as self-propelled natural microrobots. These bacterial microrobots can be remotely controlled using magnetic fields due to their internal chain of iron-oxide nanoparticles acting like a compass needle. This internal chain enables them to adopt a magnetotactic behavior that can be exploited to perform a variety of microscale tasks from microassembly and micro-manufacturing to the delivery through microvascular networks of therapeutic agents to tumors. To effectively support these applications, three-dimensional (3D) aggregations of MTB become essential in order to manipulate and guide the bacteria effectively in the human microvasculature to deliver a predefined dose of therapeutics. To achieve such aggregations in a 3D volume, time-varying magnetic field sequences were developed enabling us to simulate in time the existence of a magnetic monopole. This article presents and compares three different time-varying magnetic field sequences generated by three orthogonal pairs of electromagnets able to generate such 3D aggregations of MTB.

Adapting the clinical MRI software environment for real-time navigation of an endovascular untethered ferromagnetic bead for future endovascular interventions

A dedicated software architecture for a novel interventional method allowing the navigation of ferromagnetic endovascular devices using a standard real‐time clinical MRI system is shown. Through a specially developed software environment integrating a tracking method and a real‐time controller algorithm, a clinical 1.5T Siemens Avanto MRI system is adapted to provide new functionality for potential automated interventional applications. The proposed software architecture was successfully validated through in vivo controlled navigation inside the carotid artery of a swine. Here we present how this MRI‐upgraded software environment could also be used in more complex vasculature models through the real‐time navigation of a 1.5 mm diameter chrome steel bead in two different MR‐compatible phantoms with flowless and quiescent flow conditions. The developed platform and software modules needed for such navigation are also presented. Real‐time tracking achieved through a dedicated positioning method based on an off‐resonance excitation technique has also been successfully integrated in the software platform while maintaining adequate real‐time performance. These preliminary feasibility experiments suggest that navigation of such devices can be achieved using a similar software architecture on other conventional clinical MRI systems at an operational closed‐loop control frequency of 32 Hz. Magn Reson Med 59:1287–1297, 2008.

A computer-assisted protocol for endovascular target interventions using a clinical MRI system for controlling untethered microdevices and future nanorobots.

The possibility of automatically navigating untethered microdevices or future nanorobots to conduct target endovascular interventions has been demonstrated by our group with the computer-controlled displacement of a magnetic sphere along a pre-planned path inside the carotid artery of a living swine. However, although the feasibility of propelling, tracking and performing real-time closed-loop control of an untethered ferromagnetic object inside a living animal model with a relatively close similarity to human anatomical conditions has been validated using a standard clinical Magnetic Resonance Imaging (MRI) system, little information has been published so far concerning the medical and technical protocol used. In fact, such a protocol developed within technological and physiological constraints was a key element in the success of the experiment. More precisely, special software modules were developed within the MRI software environment to offer an effective tool for experimenters interested in conducting such novel interventions. These additional software modules were also designed to assist an interventional radiologist in all critical real-time aspects that are executed at a speed beyond human capability, and include tracking, propulsion, event timing and closed-loop position control. These real-time tasks were necessary to avoid a loss of navigation control that could result in serious injury to the patient. Here, additional simulation and experimental results for microdevices designed to be targeted more towards the microvasculature have also been considered in the identification, validation and description of a specific sequence of events defining a new computer-assisted interventional protocol that provides the framework for future target interventions conducted in humans.

Flagellated bacterial nanorobots for medical interventions in the human body

We show that a combination of various types of nanorobots will prove to be more important as we attend to enhance targeting in the smallest blood vessels found in the human microvasculature. As such, various interdependent concepts for the implementation of these different types of medical bio-nanorobots including nanorobots propelled in the microvasculature by flagellated bacteria to target deep regions in the human body are presented. Through experimental results and theoretical formulations, we also showed the advantages of integrating biological components and more specifically Magnetotactic Bacteria (MTB) for the development of hybrid (made of synthetic and biological components) nanorobots adapted to operate in the human microvasculature. We also show a method capable to track using MRI as imaging modality, steerable microbeads and MTB that could be integrated in the implementation of future sophisticated bio-nanorobots operating inside the complex vascular network. As such, we show that these nanorobots including the ones propelled by a single flagellated bacterium could be guided or controlled directly towards specific locations deep inside the human body. We also show experimentally that flagellated bacterial nanorobots could be propelled and steered in vivo through the interstitial region of a tumor for enhanced therapeutic results.

Magnetic Resonance Imaging of Fe 3 O 4 Nanoparticles Embedded in Living Magnetotactic Bacteria for Potential Use as Carriers for In Vivo Applications

MC-1 Magnetotactic Bacteria (MTB) are studied for their potential use as bio-carriers for drug delivery. The exploitation of the flagella combined with nanoparticles magnetite or magnetosomes chain embedded in each bacterium and used to change the swimming direction of each MTB through magnetotaxis provide both propulsion and steering in small diameters blood vessels. But for guiding these MTB towards a target, being capable to image these living bacteria in vivo using an existing medical imaging modality is essential. Here, it is shown that the magnetosomes embedded in each MTB can be used to track the displacement of these bacteria using an MRI system. In fact, these magnetosomes disturb the local magnetic field affecting T1 and T2-relaxation times during MRI. MR T1- weighted and T2-weighted images as well as T2-relaxivity of MTB are studied in order to validate the possibility of monitoring MTB drug delivery operations using a clinical MR scanner. This study proves that MTB affect much more the T2-relaxation than T1-relaxation rate and can be though as a negative contrast agent. The signal decay in the T2-weighted images is found to change proportionally to the bacterial concentration. These results show that a bacterial concentration of 2.2times107 cells/mL can be detected using a T2-weighted image, which is very encouraging to further investigate the application of MTB for in vivo applications.