This project is based on our previous development of fundamental techniques and methods for the propulsion and navigation of ferromagnetic cores in the cardiovascular system through the induction of force from magnetic gradients generated by a clinical Magnetic Resonance Imaging (MRI) system.
The treatment of cancer is one of the most challenging tasks of modern medicine and secondary toxicity remains a critical issue. Although intra-arterial chemotherapy or chemo-embolization provides interesting success, the rapid distribution of the drug in the whole body prevents high intra-tumoral drug concentrations to be sustained. Hence, targeting specifically the tumor cells becomes a major goal of modern oncology. As such, providing means of carrying nanoparticles for specific endovascular drug or radioisotopes delivery at the site of the tumor mass would be extremely attractive. The aim of this project is to develop a new method to enhance the treatment efficacy for future potential uses in human through the development of new magnetic carriers with improved targeting using three-dimensional induced controlled forces from magnetic gradients generated by an upgraded clinical Magnetic Resonance Imaging (MRI) system. Unlike presently known magnetic targeting techniques, the imaging feedbacks and computerized control of 3D magnetic gradients generations provided by a clinical MRI system coupled with a carrier based on an agglomeration of nanoparticles made of materials with high saturation magnetization, potentially allow for precise delivery and targeting of a tumor located deeply in the body.
More specifically, this project aims at investigating the possibility of improving the targeting of tumor cells for future targeted chemotherapy, chemo-embolization and/or local hyperthermia through the induction of propulsion forces generated by magnetic gradients from an upgraded clinical MRI system on magnetic carriers for future use in human.
The experimental focus is on the direct delivery and sustainability of magnetic particles acting as potential carriers for researchers to test and to deliver a variety of therapeutic agents directly into the tumor mass through the use of a clinical MRI system upgraded through additional dedicated software and hardware modules. The specific aims are: 1. Assess the delivery of ferromagnetic cores in the arterioles; 2. Assess the arteriolocapillar network entry of ferromagnetic particles; and 3. Assess navigation of ferromagnetic particles in vivo through tumor-induced capillary networks with sustainability in the tumor mass. This proposed platform will be a valuable tool to help enhance the efficiency of cancer threatments while improving patients recovery time.
MRI-based tumor targeting enhancement with magnetotactic bacterial carriers
The delivery of a therapeutic agent through controlled carriers directly to the tumoral lesion can enhance treatment efficacy by reducing dosage while minimizing systemic circulation of toxic compounds through healthy tissues.
As such, the induction of a feedback controlled steering force on ferromagnetic carriers from magnetic gradients generated by an upgraded clinical MRI system has been demonstrated by our group. But the gradient strengths required in some sections of the capillary network surrounding a tumor may be technologically very difficult to achieve for human due mainly to the size and cooling issues of additional gradient coils embedded in the MRI bore. As such, the use of MC-1 Magnetotactic Bacteria (MTB) pushing microbeads with therapeutic agent and nanoparticles to allow real-time tracking with the MRI system of the bacteria may provide complementary means of propulsion in smaller capillaries. More specifically, the aim of this project is to exploit the property of the chain of magnetic single domain nanoparticles (50-100 nm in size) called magnetosomes embedded in each MTB and acting as a navigational compass inside each bacterium combined with the very effective thrust provided by the molecular motor of the bacteria to enhance targeting. Navigation control of such bacterial carriers will be performed by changing the direction of the magnetic field under computer control to “migrate” such bacteria towards the tumoral region.
Development of MRI navigable biocarriers and biosensors in blood vessels
New biocarriers and biosensors made of ferromagnetic particles and special polymeric materials reacting to environmental changes such as pH or oxygen level are being investigated. The integration of ferromagnetic particles allows potential MR-tracking and automatic delivery of these biosensors through induced forces generated by magnetic gradients from an upgraded MRI system to locations inaccessible with any existing technologies. Automatic delivery of these biosensors to specific regions of the brain through the blood-brain barrier is of special interest. This technology may provide an instrument to image and to study brain functions at a higher spatial resolution and non-invasively, with potential use in future brain-machine interfaces. Agglomerations of several of these biosensors can take place when the pH or the oxygen level related to brain activities occurs, shifting the resonant frequency to a lower value when modulated. The corresponding information could theoretically be used to image such functions. Proving the feasibility of this approach is the main objective of this project.
BIOENGINEERING AND BACTERIA-BASED MICROSYSTEMS
Controlled displacement of a swarm of bacteria. (Video 1)
Controlled displacement of one bacterium. (Video 2)
Magnetotactic Bacteria (MTB) based microsystems and methods for the implementation of computer controlled biocarriers and biosensors
The use and integration of bacteria and in particular Magnetotactic Bacteria (MTB) as a mean of controlled directional propulsion for micro-objects and microrobots (also referred to as bacterial carriers, Autonomous Bacterial Systems (ABS), etc.) has been proposed and described publicly for the first time by our group.
Unlike several other research groups that were studying bacteria with the vision of mimicking its flagellar motor through micro-technologies, our proposed strategy being influenced by known technological constraints aimed at not only integrating and exploiting the flagellar motor of the bacteria as a mean of propulsion for micro-entities but more importantly, to propose and validate a method to control their swimming paths or in other words, to be able to navigate them in a controlled manner from computer software. Our recent progress is described in several papers with experimental results showing the feasibility of such method and describing its potential in many applications including but not limited to the fast detection of pathogenic bacteria, as biosensors, bio-carriers particularly in micro-fluidic systems, in the concept of bacterial micro-factories and high density screening in pharmacology and genetics, for the implementation of fully autonomous aqueous biosensing microrobots, and even for operations in the complex arteriolocapillar networks of the human cardiovascular system.
Development of microsystems and phage-based biosensors propelled by MC-1 Magnetotactic Bacteria (MTB) operating under computer navigation control for the fast detection of pathogenic bacteria
The goal of this multidisciplinary project is the development of novel biosensing systems for the detection of bacteria and bacterial growth with shorter detection periods and higher sensitivities. The proposed biosensing microsystems use magnetotactic bacteria being controlled by a miniature computer integrated onto each detection microsystem.
In this particular project, magnetotactic bacteria of type MC-1 are mixed with 2-3 micrometer beads being previously coated with phages (approx. size: 100 nanometers) chosen specifically for a targeted type of pathogenic bacteria. With another coating of antibodies specifically developed in our Laboratory, the MC-1 bacteria attach to the microbeads forming biosensors that can be propelled by the action of the flagella of the MC-1 bacteria. Then these bacterial sensors are mixed with the samples containing a variety of bacteria and potentially some targeted pathogenic bacteria. Through the generation of a directional local magnetic field inducing a torque on the chain of magnetosomes (membrane-based nanoparticles) embedded in the magnetotactic bacteria, fast controlled directional sweep of the medium is achieved. When a phage-based microbead being pushed by a single MC-1 bacterium comes in contact with a target bacterium, the latter sticks to it otherwise it is being pushed away providing specificity. In turn, the biosensors are forced to navigate between pairs of microelectrodes for detection by measuring electrical impedances by an embedded microelectronic circuit.
Development of microfluidic-based microsystems and techniques based on magnetotactic bacteria being controlled through software algorithms for Lab-on-a-Chip and micro-Total-Analysis Systems (µTAS)
The integration of magnetotactic bacteria for the implementation of computer controlled biosensors and biocarriers for operations in microfluidic systems is investigated. Such controlled bacterial micro-actuation has many advantages compared to known existing method used in microfluidic systems such as dielectrophoresis to name but only one method. For instance, unlike other methods, controlled bacterial actuation allows specificity in transport or manipulation of micro-objects among other micro-objects having similar dielectric properties. Other significant advantages include but are not limited to very low electrical power requirements, DC instead of relatively high frequency electrical signals being modulated and possibly inducing errors on sensitive measurement electronics in close proximity, while not requirement relatively high voltage levels as other methods do, allowing further miniaturization of the microsystems. Other parameters are also investigated such as the effects of temperature, viscosity of the medium, effects of contaminants on the swimming behavior of the bacteria to be used as potential environmental biosensors, retarding effects or increase in drag forces caused by microfuidic channel walls and possible compensation by the bacteria, the development of new navigational control algorithms in different conditions, etc.
Platform for computer controlled automatic coordinated manipulations and operations by bacteria at the sub-micrometer scale
The orientation of magnetotactic bacteria (MTB) are controlled by inducing a torque on a chain of small particles named magnetosomes, acting as a compass embedded in each bacterium. Such torque is achieved by circulating a small electrical current through selected conductors in a microcircuit in order to use the motility of the bacteria to push micro-objects towards desired locations. The microcircuit containing both the bacteria and the micro-objects being manipulated are placed under an optical microscope to provide information that are processed and fed back to the microcircuit to activate specific conductors in order to achieve optimal coordination and control of the MTB. The integrated electronic circuit contains an embedded matrix that is made of two layers of vertical and horizontal conductor lines spaced 330 nanometers apart.
New MEMS-based bacterial microsystems
Magnetotactic bacteria are being used as controlled bio-actuators to create novel bio-MEMS such as bacterial micro-motors, micro-switches, micro-valves, and micro-pistons, to name but a few examples. Thrust forces exceeding 4 pN/bacterium has been achieved.
Autonomous bacterial microsystems and microrobots
The proposed autonomous microrobot is a microsystem built with silicon MEMS using standard CMOS process, with electronics and bacteria. This microrobot consists of a die containing micro-reservoirs that shelter magnetotactic bacteria to form a bacterial propulsion system. Inside each micro-reservoir, there is a coil. With the flow of an electrical current along the conductive coil, a magnetic field likely to influence the bacteria is generated.
Through magnetotaxis, their swimming directions can be changed towards a wall of the micro-reservoir towards which point the lines of the magnetic field emanating from the inside of the solenoid coil is used to create a controlled pushing or propelling force on the microrobot from an agglomeration of Magnetotactic Bacteria (MTB). Presently, the bacterial reservoirs acting as bacterial engines are 90 μm × 54 μm, and 90 μm × 186 μm (length × width). The project would then lead new type of instrumented platforms where miniature autonomous instruments are mixed with the samples and performing coordinated tasks through collective behavior and swarm intelligence.
Bacterial culture, binding techniques, fundamental researches, and genetic modifications
Efforts are underway to improve bacterial culture to obtain bacteria with enhanced characteristics. Binding techniques between bacteria and various micro-structures by the development of antibodies or other techniques are also under investigation. Fundamental researches on magnetotactic bacteria with the goal of exploiting new findings to be exploited for the conception of novel bio-carriers, bio-sensors, and microsystems, are also important for the Laboratory. Other researches efforts aim at genetically modify existing bacteria to create “super bacteria” or “bio-components” better suited for particular tasks and/or environmental conditions.
NEW MICRO- NANOROBOTICS PLATFORMS AND MICRO- NANOFABRICATION TECHNIQUES
Although the NanoRobotics Laboratory makes extensive uses of state-of-the-art micro-, nano-fabrication, and characterization techniques in several clean room facilities, several new techniques need to be developed to address challenges that cannot be met with existing technology. The development of such new techniques and methods is an important part of the research and development that take place in our Laboratory.
Microheatpipe fabrication. (Video 1)
Nanowalker rotation. (Video 2)
Development of a platform based on a fleet of miniature instrumented robots capable of fast operations at the molecular scale – NanoWalker project
Development of a high throughput platform based on a fleet of scientific instruments configured as autonomous miniature robots capable of fast operations at the nanometer scale. These robots equipped with the same or different instruments are coordinated from a central computer based on specific tasks given by the user through a Graphical User Interface (GUI). Accurate and fast displacements of each robot are essential to achieve high throughput operations. Each untethered instrumented robot has three piezoceramic legs formed as a triangular shape with the apex upward for fast and accurate displacements (approx. 4000 steps/second), an onboard computer, various microelectronic systems, wireless communication, and an onboard instrument that generally consists of a Scanning Probe Microscope (SPM) such as Scanning Tunneling Microscope (STM).
Development of new micro- and nano-fabrication techniques, structures, and platforms
Computer controlled platforms for high-speed fabrication of 3D micro and nanostructures are being developed for various applications.
One platform is dedicated to the fabrication of micro-heat pipes (100 to 200 micrometers in diameter) 3D networks providing high-density heat dissipation through higher surface to volume ratios for microsystems or for systems with space constraints. Potential applications under investigations include but are not limited to satellites and high-powered microcircuits and microrobots. Laser scans are used to fit and guide the fabrication of the 3D structures with minimum thermal impedance with the 3D circuits in order to achieve maximum performance. The robotic system operates at 3G acceleration with a resolution of approx. 300 nanometers.
The same technology can be used for the reproduction and fabrication of 3D structures and phantoms such as blood vessels networks previously taken from angiography.
Another platform with new techniques is being developed for the fabrication of 3D structures built from nanofibers. The platform operates in class 10 environment with humidity and temperature controls. The resolution of the platform is 0.1 nanometer (nm). Applications include but are not limited to new 3D interconnections for NEMS/MEMS and microelectronic circuits, biomedical micro-devices and carriers, to name but a few examples.