Microrobot motion control using a commercial grade MRI scanner

Abstract

The present disclosure provides a method for controlling the movement of a microrobot within a subject's (patient's) body using a commercial grade magnetic resonance imaging (MRI) scanner. The disclosed method further includes an imaging method for determining the location of the microrobot in real time.

Description

[Technical field]

[0001] The present disclosure relates generally to the field of magnetic guidance and imaging of microrobots. In one embodiment, the present disclosure provides a method of using a commercial grade magnetic resonance imaging (MRI) scanner for magnetic guidance and imaging of microrobots.

[0002] Although great progress has been made in the development of cellular medicines and therapeutics, their targeted delivery remains a challenge. Although some therapeutics can be administered locally, systemic administration remains the best option for targets deep within a patient's body or for multiple targets distributed throughout the body. However, systemic administration has problems including the difficulty of delivering therapeutics to the desired location, limited circulation time due to blood filtration by the lungs, spleen, liver, and kidneys, and potential side effects if therapeutics concentrate in non-target tissues.

[0003] To address these issues, researchers are investigating how to navigate millimeter-scale robots through passageways inside a patient's body for highly localized drug delivery or minimally invasive surgery. Remote navigation can be achieved by placing ferromagnetic material inside the robot and generating a controlled magnetic field around the patient's body. Propulsion and manipulation of the robot can be achieved by moving a permanent magnet assembly around the patient's body or by controlling the current in an electromagnet. The most recent solution is often achieved by a magnetic resonance imaging (MRI) scanner, which contains multiple electromagnets. In an MRI scanner, a background magnetic field magnetizes the ferrous parts of the robot, and magnetic field gradient coils generate the magnetic field gradients required to generate the magnetic force. The simultaneous use of an MRI scanner can provide real-time images of the surgical area as well as positioning of the robot.

[0004] The size of magnetic microrobots used in biological tissues (e.g., liver, brain, eyeball, cerebrospinal fluid, blood) ranges from a few hundred micrometers (μm) to 1 cm. It is known that millimeter (mm) scale microrobots can be efficiently moved in biological tissues (e.g., brain tissue) by applying an external magnetic force of a few mN. To generate a magnetic force of a few mN applied to a microrobot with a size of a few hundred micrometers to 1 cm, an external magnetic field gradient of a few hundred mT / m is required. In addition, to control the movement of the microrobot in a safe manner, it is necessary to control the magnetic force in three dimensions at a frequency of up to 20 Hz to respond to the change over time of the position of the microrobot imaged by the tracking modality. Tracking modalities that can be used to control the movement of the microrobot in vivo include X-ray (fluoroscopy) and ultrasound.

[0005] However, the nominal range of magnetic field gradients generated by commercial grade MRI scanners is up to 50 mT / m (up to 200 mT / m in the latest clinical trial MRI scanners). That is, conventional MRI scanners cannot generate the magnetic field gradients (several hundred mT / m) required to move the microrobots efficiently in biological tissue. Furthermore, most commercial MRI scanners are not compatible with real-time X-ray or ultrasound imaging, making real-time tracking of the microrobots problematic. Other highly sensitive magnetic measurement methods generate very strong and time-varying magnetic fields, which are not compatible with MRI scanners. Finally, introducing magnetic microrobots with sizes ranging from several hundred micrometers to 1 cm into an MRI scanner is considered to be a safety issue. In particular, the magnetic field gradient of the MRI scanner (the B0 gradient around the MRI scanner, or the magnetic field gradient generated by the gradient coils) poses a risk because it can pull the microrobots in dangerous ways and damage biological tissue.

[0006] Currently, control of microrobots within a patient's body relies on custom design of external hardware to generate magnetic fields (applied externally to the microrobot). Therefore, it is desirable to utilize existing clinically approved hardware to reduce the need for research and development, testing, regulatory approval, marketing, distribution, and maintenance of custom hardware. Therefore, in view of the above challenges, there is a need for improved methods using commercial grade MRI scanners to control the movement of microrobots in an efficient and safe manner. Summary of the Invention [Means for solving the problem]

[0007] The present disclosure provides a method of controlling the movement of one or more magnetic microrobots within a subject's body, the method comprising the steps of: (a) providing an MRI (magnetic resonance imaging) scanner, the MRI scanner including a main magnet, one or more shim coils, a gradient system, an RF system, and a controller configured to direct the operation of other components of the MRI scanner, the MRI scanner further including a tube defining a hollow bore for positioning the subject within the scanner during use; (b) introducing a distal end of an MRI-safe lumen into a target anatomical region within the subject's body; (c) introducing one or more microrobots into the MRI-safe lumen from a proximal end of the lumen; and (d) operating the MRI scanner to generate various magnetic field gradients in the MRI-safe lumen, thereby controlling the movement of the microrobots within the lumen.

[0008] The present disclosure also provides a method for imaging microrobots within a subject using an MRI scanner, the method comprising: (i) acquiring a base image of the subject; (ii) using the MRI scanner to determine real-time positions of one or more microrobots; (iii) overlaying the determined real-time positions of the microrobots with images of the corresponding microrobots; and (iv) operating the MRI scanner to generate various magnetic field gradients in an MRI-safe lumen, thereby controlling the movement of the microrobots within the lumen.

[0009] The above and other aspects of the present invention will be understood by reference to the following detailed description and accompanying drawings. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Untethered magnetic navigation of microrobots inside the human body using magnetic resonance imaging (MRI) scanners is a promising technology in minimally invasive surgery and drug delivery. Existing clinical MRI scanners are classified according to their magnetic field strength into conventional (1-1.5T), high-field (3-4T), and ultra-high-field (7-8T) types. Higher magnetic field strength provides a higher signal-to-noise ratio (S / N ratio) and improves imaging quality. However, as mentioned above, there are problems to be solved in controlling and imaging microrobots using conventional MRI scanners.

[0011] The present disclosure provides a method of using a commercial grade MRI scanner to control the movement of a microbot within a subject's (patient's) body.

[0012] As used herein, the term "MRI-safe," such as an "MRI-safe lumen" or "MRI-safe adapter," refers to equipment that can be safely used near or inside an operating MRI in a manner that is physically safe for a patient undergoing a medical procedure using an MRI scanner. For example, an MRI-safe lumen is made of a non-magnetic material (so as not to be affected by MRI) and / or is secured to the body so as not to be displaced in any way by operating an MRI near the lumen.

[0013] In one aspect, the present disclosure provides a method of controlling the movement of one or more magnetic microrobots within a subject's body, the method comprising: (a) providing an MRI (magnetic resonance imaging) scanner, the MRI scanner including a controller configured to direct the operation of a main magnet, one or more shim coils, a gradient system, an RF system, and other components of the MRI scanner, the MRI scanner further including a tube defining a hollow bore for positioning the subject within the scanner during use; (b) introducing a distal end of an MRI-safe lumen into a target anatomical region within the subject's body; (c) introducing one or more microrobots into the MRI-safe lumen from a proximal end of the lumen; and (d) operating the MRI scanner to produce various magnetic field gradients in the MRI-safe lumen, thereby controlling the movement of the microrobots within the lumen. In one embodiment, the subject is a human. In another embodiment, the subject is an animal. In one embodiment, the target anatomical region is the liver, the brain, or the subarachnoid space.

[0014] In one embodiment, the MRI-safe lumen has a structure that prevents distortion of the lumen when exposed to the high gradient transition region of the MRI scanner. For example, the MRI-safe lumen includes a flexible portion that is inserted into the subject's body and a rigid portion that extends from the interior of the MRI scanner to the exterior of the MRI scanner.

[0015] In one embodiment, the MRI-safe lumen comprises an MRI-safe adapter for mechanically introducing the microrobot through the high magnetic field gradient transition region to the target anatomical region. In one embodiment, the MRI-safe adapter includes a non-magnetic flexible grabber. In one embodiment, the disclosed method further comprises guiding the microrobot back into the MRI-safe lumen and retrieving the microrobot using the MRI-safe adapter. In one embodiment, the disclosed method further comprises withdrawing the microrobot from the subject's body in a controllable manner with the MRI-safe adapter.

[0016] In one embodiment, the MRI gradient coil operates with a gradient of 500 mT / m to 1000 mT / m, a maximum frequency of 10 Hz or less, a maximum duration of 5 minutes or less, and is configured to provide a gradient of 1 mm at a distance of 15 cm from the surface of the MRI inner tube. 3 A magnetic force of 1 mN is applied to a microbot with a volume of .

[0017] In one embodiment, the present disclosure provides a method for imaging a microbot, the method comprising the steps of: (i) pre-scanning a subject with an MRI scanner to generate a pre-scan image; (ii) determining a position of the microbot in real time; (iii) overlaying the pre-scan image with the real-time position of the microbot; and (iv) estimating the position of the microbot relative to one or more MRI-visible fiducial markers within the subject's body, thereby determining the position of the microbot in real time.

[0018] In another aspect, the present disclosure provides a method of imaging a microrobot in a subject's body using an MRI scanner, comprising: (i) pre-scanning the subject with the MRI scanner to generate a pre-scan image; (ii) determining the location of the microrobot in real time; (iii) superimposing the pre-scan image with the real-time location of the microrobot; and (iv) estimating the location of the microrobot with respect to one or more MRI-visible fiducial markers in the subject's body, thereby determining the location of the microrobot in real time. In one embodiment, step (iv) above comprises triangulating the location of the microrobot in real time with respect to the fiducials. In one embodiment, step (ii) above comprises detecting distortions in the MRI image due to magnetic material embedded in the microrobot. For example, the location of the microrobot is determined by calculating the geometric center of distortion in the MRI image.

[0019] As used herein, the terms "comprises, comprising, includes, including" or "having" and their conjugations mean "including, but not limited to."

[0020] As used herein, the singular forms "a," "an," and "the" are intended to include the plural of their referents unless the context clearly indicates otherwise. For example, the term "microbot" includes a plurality of molecules.

[0021] Throughout this application, various embodiments of the present invention may be described in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present invention. Thus, a description in range format should be considered to have specifically disclosed not only each numerical value contained within the range, but also all possible subranges contained within the range. For example, a description of a range of 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, . . ., as well as each numerical value (e.g., 1, 2, 3, 4, 5, and 6) contained within the range. This applies regardless of the breadth of the range.

[0022] Whenever a numerical range is specified herein, it is meant to include all numerical values ​​(fractional or integer) contained within the specified numerical range. The phrases "range between" a first specified number and a second specified number, and "range from" a first specified number to a second specified number, are used interchangeably herein and are meant to include the first specified number and the second specified number, and all fractional and integer numbers therebetween.

[0023] As used herein, the term "about" refers to an acceptable error range for a particular value as determined by one of ordinary skill in the art, which error range depends in part on the limitations of how the value is measured or determined, i.e., the measurement system. For example, "about" means within 1 or more standard deviations, as is customary in the art. Alternatively, when referring to a measurable value, such as an amount, it can encompass a variation of ±20% or ±10%, more preferably ±5%, even more preferably ±1%, even more preferably ±0.1% from the specified value, as appropriate for the disclosed value.

[0024] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials that can be used to practice or test embodiments of the present invention are described below, although methods and materials similar or equivalent to those described herein can also be used. All publications, patent applications, patents, and other references cited herein are incorporated by reference in their entirety. In the event of any conflict, the present specification, including definitions, shall control. In addition, the materials, methods, and examples are merely illustrative and not intended to be limiting. Each of the literature or other publications mentioned herein is incorporated by reference in its entirety.

[0025] The description provided herein describes the steps of the invention and variations thereof, and it is to be understood that this description is not intended to be limiting, and that modifications of components, order of steps, and other variations are within the scope of the invention.

[0026] It will be appreciated that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination with each other in a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or in any other embodiment of the invention, as appropriate. Certain features described in the context of various embodiments are not to be regarded as essential features of those embodiments, unless the embodiment is inoperative without those features.

[0027] Various embodiments and aspects of the present invention as described herein and as claimed in the claims section below find experimental support in the following examples.

[0028] Working Example

[0029] Microbot Motion Control Using a Commercial-Grade MRI Scanner

[0030] To generate the signals required for accurate MRI soft tissue imaging, magnetic field gradients must be rapidly switched at very high slew rates (50-200 T / m / s), which constrains the nominal range of magnetic field gradients generated by commercial grade MRI scanners. To achieve this very high slew rate and high frequency, high voltages and currents are supplied to the gradient coils by the gradient amplifiers (up to 2500 V and up to 1000 A). Typically, an MRI scan takes 15-45 minutes. Such high currents at high frequencies for long periods of time will significantly heat the gradient coils (including eddy current effects). Gradient coils are typically water-cooled, so the maximum gradients are limited to avoid overheating, but are still sufficient to generate an MRI image.

[0031] In contrast, the microrobot control disclosed herein does not require an identical set of parameters. Indeed, available data describes control of the microrobot in the frequency range below 10 Hz (corresponding to the frame rates of available in vivo imaging modalities) where eddy current effects are minimal, and operation at maximum current for up to 2 minutes at a time. It is assumed that a low slew rate of up to 20 T / m / s (lower than the slew rate of the MRI scanner) will be required. By lowering the frequency by a factor of 500-1000 and shortening the operation time by a factor of 7-20, for a given current, the effective coil resistance during the MRI procedure can be reduced by a factor of 2-5 and the thermal energy by a factor of 25-100. This allows the maximum voltage to be maintained for a longer period per duty cycle, and by using the same hardware or by slightly modifying the hardware (e.g., to support a current 5-10 times higher), effective currents 5-10 times higher than the maximum operating current of current MRI scanners can be achieved. Considering that the current is a linear gradient, this translates to a gradient more than 5 times the maximum gradient of a given MRI scanner, i.e., a gradient of several 100s of mT / m. A 2-5 times reduction in resistance would allow 2-5 times higher currents at the same supply voltage from the gradient amplifier, thereby maximizing system efficiency. With the slew rate of existing MRI scanners, a 10 times increase in the time of maximum voltage would allow a maximum representative gradient of 1 T / m to be reached in less than 20 ms, a short time window associated with a frequency of 10 Hz (matching a 100 ms cycle), making the design practical for gradient-based control of microbots.

[0032] It has also been reported that metal components embedded in biological tissues are visible in MRI images as image distortions (e.g., large black spots). Image distortions are usually considered an obstacle to using microrobots in MRI scanners. However, real-time soft tissue imaging is not necessary for the purpose of controlling the microrobot. The position of the microrobot can be estimated in real time by calculating the geometric center of distortion in MRI imaging (or other image processing techniques) in real time. In one embodiment, the patient can be pre-scanned with MRI, and then MRI visible fiducial markers on the patient's body can be utilized to triangulate the position of the microrobot in real time with reference to the fiducial markers by overlaying the pre-scanned image on the real-time position of the microrobot. This method is practical because microrobots embedded with magnetic materials of a few hundred micrometers in size will generate clearly visible distortions on the images.

[0033] The B0 gradient in the working region of the MRI ranges from 1 μT / m, making the magnetic field very stable and reducing the risk of uncontrolled microbot movement. However, there is still a risk of transition from outside the MRI to the working region inside the MRI. In this transition region, B0 has a gradient as high as 5 T / m. In one embodiment, this problem can be solved by a method comprising the following steps (a) to (f): (a) Prior to placing the patient in the MRI scanner, as a pre-treatment step, standard interventional techniques are used to introduce an MRI-safe lumen (e.g., sheath or catheter) into the patient's target anatomical region (e.g., subarachnoid space, liver, brain). (b) The MRI-safe lumen has a structure that is safely accessible from outside the MRI and can prevent deformation of the lumen when subjected to an internal force of up to 1 N in the high gradient transition region. For example, the MRI-safe lumen has a flexible portion that is inserted into the patient and a rigid portion that extends from inside the MRI to a safe distance away from the MRI outside the MRI and is fixed to fixtures inside and outside the MRI. (c) The MRI-safe lumen comprises an MRI-safe adapter configured to controllably mechanically introduce the microbot through a high gradient transition region to a target anatomical region within a patient's body. (d) Once the microbot reaches the appropriate location or region inside the patient, it is released. Note that there is no risk of uncontrolled movement in that region due to the low B0 gradient. (e) Once the MRI procedure is complete, the microrobot is guided back to the insertion site and grasped with a mechanical adapter (an MRI-safe adapter). (f) The MRI-safe adapter is withdrawn from the patient and the MRI in a controllable manner, mirroring the insertion method.

[0034] In one embodiment, the MRI-safe adapter can be a non-magnetic, flexible grabber. In one embodiment, the grabber, preloaded with the microbot, is introduced into the MRI-safe lumen and advanced through the MRI through the high-gradient transition region. The MRI-safe lumen prevents the microbot from moving laterally and the grabber prevents the microbot from moving towards the MRI.

[0035] While certain features of the invention have been illustrated and described herein, various modifications, substitutions, changes, and equivalents will occur to those skilled in the art, and it is therefore to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit and scope of the invention.

Claims

1. 1. A method for controlling the movement of one or more magnetic microrobots within a subject, comprising: (a) providing an MRI (magnetic resonance imaging) scanner, the MRI scanner including a main magnet, one or more shim coils, a gradient system, an RF system, and a controller configured to direct operation of other components of the MRI scanner, the MRI scanner further including a tube defining a hollow bore for positioning the subject within the scanner during use; (b) introducing a distal end of an MRI-safe lumen into a target anatomical region within the subject; (c) introducing one or more microbots into the MRI-safe lumen from the proximal end of the lumen; (d) operating the MRI scanner to produce various magnetic field gradients in the MRI-safe lumen, thereby controlling movement of the microrobot within the lumen.

2. 10. The method of claim 1, The MRI scanner operates at a frequency of 20 Hz or less.

3. 10. The method of claim 1, The MRI scanner operates at a slew rate of about 40 T / m / s or less.

4. 10. The method of claim 1, The method includes operating the MRI scanner for up to five minutes to control the microrobot to traverse between the distal end and the proximal end of the MRI-safe lumen.

5. 10. The method of claim 1, The MRI scanner applies a magnetic force of about 200 mN to about 1 N to the microbot at a distance of less than about 20 cm from a surface of the MRI scanner facing the subject.

6. 10. The method of claim 1, The microbots are approximately 1 mm ３ having a volume of less than

7. 10. The method of claim 1, said step (d) of operating said MRI scanner further comprising an imaging step; The imaging step includes: (i) acquiring a base image of the subject; (ii) determining the real-time position of the microbot using the MRI scanner; (iii) overlaying an image of the microbot corresponding to the determined real-time location of the microbot.

8. 8. The method of claim 7, The method, wherein the step (i) of obtaining a base image of the subject comprises pre-scanning the subject using the MRI scanner.

9. 8. The method of claim 7, the base image includes a plurality of reference positions; the imaging step further comprises providing an MRI-visible fiducial marker at a location corresponding to the fiducial location in the base image; wherein the step (ii) of determining the real-time position of the microbot comprises determining the position of the fiducial marker and associating the determined position of the fiducial marker with the reference position in the base image.

10. 10. The method of claim 9, wherein step (ii) of determining a real-time position of the microbot comprises triangulating the position of the microbot in real time relative to the reference position.

11. The method according to any one of claims 7 to 10, wherein said step (ii) of determining the real-time position of said microbot comprises detecting distortions in an MRI image due to magnetic material embedded in said microbot.

12. 12. The method of claim 11, The location of the microbot is determined by calculating the geometric center of the distortion in an MRI image.

13. 10. The method of claim 1, The method, wherein the MRI-safe lumen has a structure that prevents distortion of the lumen when magnetic field gradients occur in a transition region of the MRI scanner.

14. 10. The method of claim 1, The method, wherein the MRI-safe lumen includes a flexible portion that is inserted into the subject's body and a rigid portion that extends from inside the MRI scanner to outside the MRI scanner.

15. 10. The method of claim 1, The method, wherein the MRI-safe lumen comprises an MRI-safe adapter for mechanically introducing the microbot through a high magnetic field gradient transition region into the target anatomical region.

16. 16. The method of claim 15, The MRI-safe adapter includes a non-magnetic flexible grabber.

17. 16. The method of claim 15, guiding the microbot back into the MRI-safe lumen; retrieving the microbot using the MRI-safe adapter.

18. 18. The method according to any one of claims 15 to 17, The method further comprises the step of controllably withdrawing the microbot from within the subject's body with the MRI-safe adapter.

19. 10. The method of claim 1, The method, wherein the subject is a human.

20. 20. The method of claim 19, The method, wherein the target anatomical region is the brain.

21. 21. The method of claim 20, The method, wherein the target anatomical region is the subarachnoid space.

22. 20. The method of claim 19, The method wherein the target anatomical region is selected from the group consisting of the liver, eyes, ears, neck, lungs, pancreas, kidneys, nasal cavity, mouth, digestive tract, bladder, and stomach.

23. 1. A method for imaging microbots within a subject using an MRI scanner, comprising: (i) acquiring a base image of the subject; (ii) using the MRI scanner to determine the real-time location of one or more microbots; (iii) superimposing an image of the microbot on the determined real-time position of the microbot; (iv) operating the MRI scanner to produce various magnetic field gradients in an MRI-safe lumen, thereby controlling the movement of the microbot within the lumen.

24. 24. The method of claim 23, The method, wherein the step (i) of obtaining a base image of the subject comprises pre-scanning the subject using the MRI scanner.

25. 24. The method of claim 23, the base image includes a plurality of reference positions; wherein the step (iv) of operating the MRI scanner further comprises providing MRI-visible fiducial markers at locations corresponding to the reference locations in the base image; wherein the step (ii) of determining the real-time position of the microbot comprises determining the position of the fiducial marker and associating the determined position of the fiducial marker with the reference position in the base image.

26. 26. The method of claim 25, wherein step (ii) of determining a real-time position of the microbot comprises triangulating the position of the microbot in real time relative to the reference position.

27. 24. The method of claim 23, wherein said step (ii) of determining the real-time position of said microbot comprises detecting distortions in an MRI image due to magnetic material embedded in said microbot.

28. 24. The method of claim 23, wherein said step (ii) of determining the real-time position of said microbot comprises detecting distortions in an MRI image due to magnetic material embedded in said microbot.

29. 24. The method of claim 23, The MRI scanner operates at a frequency of 20 Hz or less.

30. 24. The method of claim 23, The MRI scanner operates at a slew rate of about 40 T / m / s or less.

31. 24. The method of claim 23, The method includes operating the MRI scanner for up to five minutes to control the microbot to traverse between the distal and proximal ends of the MRI-safe lumen.

32. A method according to any one of claims 23 to 31, comprising: The MRI scanner applies a magnetic force of about 200 mN to about 1 N to the microbot at a distance of less than about 20 cm from a surface of the MRI scanner facing the subject.

33. A method according to any one of claims 23 to 27, comprising: The microbots are approximately 1 mm ３ having a volume of less than