System for positioning a subject for improving particle navigation in the subject, and method of use thereof

Abstract

A method of preparing a subject for steering particles to a target site in the subject using a physical field; it includes receiving image information of a body of the subject to obtain an image of at least a part of a vascular system of the subject; and determining a pathway through the vascular system of the subject from a release site to the target site and identifying a target body position of the subject by factoring a force of gravity on a direction of the particles relative to the pathway of the vascular system to improve steering of the particles through the pathway of the vascular system of the subject to the target site when the subject is placed in the target body position.

Description

SYSTEM FOR POSITIONING A SUBJECT FOR IMPROVING PARTICLE NAVIGATION IN THE SUBJECT, AND METHOD OF USE THEREOF

[0001] The present application claims priority from U.S. provisional patent application No. 63 / 620,011 filed on January 11, 2024, incorporated herein by reference.Technical Field

[0002] The present disclosure relates to medical interventions using a physical field, and more particularly to medical interventions employing magnetic particles such as microrobots.Background

[0003] Techniques enabling targeted navigation of micro- or nanorobots in arteries through external actuation sources processes are being implemented for diagnosis, targeted therapy, and intervention. Current approaches for delivering local therapy in interventional radiology are often invasive and require highly skilled operators. For example, to treat advanced hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide (700,000 deaths / year), transarterial chemoembolization (TACE) is the preferred approach. TACE using drug-eluting beads (DEBs) can simultaneously embolize arteries and deliver chemotherapy drugs. Biodegradable DEBs allow sustained release of antineoplastic agents while maintaining local drug concentrations and staying within the therapeutic range with reduced potential for hepatotoxicity. However, DEBs need to be injected supra-selectively into tumor-feeding arteries under fluoroscopy, which remains a technical challenge on a human scale. Besides the possibility of technical failure to reach the arterial feeder of the tumor, visualization of the tumor and assessment of complete tumor coverage under fluoroscopy after embolization are challenging.

[0004] The use of field forces generated by external actuators to navigate biocompatible microrobots in the deeper arteries (>70 cm diameter range) of large animals is an interesting alternative but challenging because of the weak field force, gravity, and high blood flow velocity increasing its thrust force. Two main approaches are commonly used today to increase the steering success rate: using larger robots and reducing the distance between the robot and the actuator. Larger robots have the advantage of providing greater physical -field forces but are not suitable for targeting complex vascular structures as they are unable to penetrate small vessels; for example, in fluoroscopy-guided DEB-TACE, DEBs between 100 and 300 pm have ideal penetration into HCC while smaller ones can cause liver complications. Reducing the distance between the robot and the actuator could provide sufficient force to navigate untethered micro- or nanorobots in thefast bloodstream but cannot be applied in deep arteries (>70 cm diameter range). Optical methods, for example, are generally limited to superficial layers due to their poor ability to penetrate biological tissues (<7 cm depth), and acoustic actuators are only effective for controlling foreign particles inside small-organism vasculatures or superficial layers. Current magnetic navigation techniques using electromagnets and permanent magnets as actuators are only used in in vitro experiments, limbs, heads, superficial organs or small animals such as mice and rabbits because the magnetic field strength of the dipole field is proportional to the dipole moment and inversely proportional to the cube of the distance. For biocompatible superparamagnetic materials like iron oxide nanoparticles, achieving a saturation magnetization level that induces the maximum force due to the magnetic gradients typically requires a minimum magnetic field strength of approximately 1.5 Tesla (T). However, it is difficult to achieve this for other magnetic platforms (beyond MRI platforms) where the gradients decrease rapidly with increasing distance. In such cases, it becomes challenging to attain desired saturation levels in deeper localized body regions, specifically within a 70-centimeter diameter range. In addition to magnetic field intensity, the rapid decrease in magnetic field gradients with distance further weakens the magnetic field force acting on the navigate magnetic microrobots (MMRs).

[0005] Methods for permitting improved steering of microrobots or nanorobots in a localized deep regions of a subject using a physical field would be advantageous.Summary

[0006] The present disclosure relates to methods and systems for determining a position for a subject to improve steering of particles in the body of the subject using a physical field.

[0007] More particularly, the present disclosure pertains to take advantage of the force of gravity to improve the steering of the particles in the body of the subject. The subject is positioned with one or more body rotation angles selected such that the particles can more easily be steered or navigated, the position permitting a force of gravity to assist, and not deter, the steering of the particles through the vascular system of the subject from a release site to a target site.

[0008] The one or more body rotation angles may be selected in accordance with vascular bifurcations identified on the pathway from the release point to the target site, where the blood vessel at the vascular bifurcation leading from the release site to the target site is identified for each bifurcation, the one or more body rotation angles improving steering through these identified blood vessels of the bifurcations by accounting for the force of gravity.

[0009] Imaging is performed on the subject to visualize at least a part of the vascular system of the subject, the visualization for determining a pathway from the release site to the target site through the vascular system of the subject, where the pathway may be plotted through the vascular system of the subject. It will be understood that in some instances, the pathway may be a direction and distance determined from the release site to the target site, instead of a plotted path through the vascular system. The imagery may also provide visual information to determine an appropriate release site for the particles in the vascular system of the subject. The release site may be determined from the imagery information, the target site in the subject, the force of gravity and the vascular system of the subject as detailed from the imagery.

[0010] The present disclosure also relates to methods and systems for treating the subject using a magnetic field and magnetic particles, such as nano-robots or micro-robots, while taking into account the force of gravity to determine a position of the subject with one or more body rotation angles of the subject to be treated as described herein.

[0011] A broad aspect is a method of preparing a subject for steering particles to a target site in the subject using a physical field. The method includes receiving image information of a body of the subject to obtain an image of at least a part of a vascular system of the subject; and determining a pathway through the vascular system of the subject from a release site to the target site and identifying a target body position of the subject by factoring a force of gravity on a direction of the particles relative to the pathway of the vascular system to improve steering of the particles through the pathway of the vascular system of the subject to the target site when the subject is placed in the target body position.

[0012] In some embodiments, the determining a pathway may include identifying vascular bifurcations from the release point to the target site, and wherein the identifying of the target body position includes identifying consecutive vascular bifurcations of the vascular bifurcations that facilitate the navigation of the particles from the release point to the target site while being favoured by the force of gravity in the target body position.

[0013] In some embodiments, the identifying the target range may include defining a range of optimal body rotation angles (9) when angles of the range of optimal body rotation angles meet the following conditions:wherein arargeted\0 is the angle between a horizontal plane and a body rotation angle of a targeted blood vessel at the vessel bifurcation of the selected pathway, and <ZN<mTargeted\0 is the angle between the horizontal plane and an body rotation angle of a non-targeted vessel branch at the vessel bifurcation.

[0014] In some embodiments, the identifying of the target body rotation angle may include selecting the target body position amongst a target range of body rotation angles (9) wherein rotation angles within the target range of body rotation angles satisfy the following conditions:

[0015] In some embodiments, the identifying the target body rotation angle of the subj ect may include performing imagery on the subject in one or more of the following positions of the subject: a right side; a left side; a prone position; and a supine position.

[0016] In some embodiments, the particles may include microrobots.

[0017] In some embodiments, the imagery may be performed using cone-beam computer tomography.

[0018] In some embodiments, the performing of the imagery may be carried out for different positions of the subject.

[0019] In some embodiments, the performing of the imagery may be carried out for each of the following different positions of the subject a supine position; a prone position; a lateral right position; and a lateral left position.

[0020] In some embodiments, the physical field may be a magnetic field and the particles are magnetic particles.

[0021] In some embodiments, the physical field may be one of an electric field, a gravitational field, a temperature field, a velocity field, a pressure field, an acoustic field and a quantum field.

[0022] In some embodiments, the method may include positioning the subject in the target body position.

[0023] In some embodiments, the method may include performing imagery to confirm that a position of the positioned subject is in the target body position.

[0024] Another broad aspect is a method of causing a navigation of the particles to the target site in the subject using the physical field, the method including performing the method of preparing a subject for steering particles to a target site in the subject using a physical field asdefined herein, introducing the particles into the subject at the release site; and applying the physical field to the particles to cause a navigation of the particles to the target site.

[0025] In some embodiments, the method may include partially inflating an occlusion balloon catheter located in a blood vessel of the subject to reduce blood flow rate in the blood vessel.

[0026] In some embodiments, the method may include obtaining phase contrast magnetic resonance imaging sequences to plan and monitor blood flow rate in downstream vessels which comprise the targeted blood vessel.

[0027] In some embodiments, the introducing may be performed via injection of the particles, prepared with an automated injector, to enhance a dipole-dipole interaction and steering force between the particles forming an aggregate.

[0028] In some embodiments, the causing a navigation of the particles to the target site may be for treating the subject.

[0029] In some embodiments, the target site may correspond to a location of one or more of a tumor and a vascular network of the tumor.

[0030] In some embodiments, the physical field may be a magnetic field, and the applying the physical field may include generating a main magnetic field (B0) using a magnetic resonance imaging (MRI) machine, a radiofrequency field (Bl) applied perpendicular to the main magnetic field (Bo), and calibrating distortions of the main magnetic field in x-, y- or z- directions using gradient coils.

[0031] In some embodiments, the method may include locating the particles on magnetic resonance images through distortion caused by the particles on the magnetic resonance magnetic field.

[0032] In some embodiments, the method may include monitoring a number of particles reaching the target site with the located the particles on the magnetic resonance images.

[0033] Another broad aspect is a system for preparing a subject for steering particles to a target site in the subject using a physical field. The system includes a processor; and memory comprising program code that, when executed by the processor, cause the processor to: receive image information of a body of the subject to obtain an image of at least a part of a vascular system of the subject; determine a pathway through the vascular system of the subject from a release site to the target site and identify a target body position of the subject by factoring a force of gravity on a direction of the particles relative to the pathway of the vascular system to improve steering of theparticles through the pathway of the vascular system of the subject to the target site when the subject is placed in the target body position.

[0034] In some embodiments, the determining a pathway may include identifying vascular bifurcations from the release point to the target site, and wherein the identifying of the target body position includes identifying consecutive vascular bifurcations of the vascular bifurcations that facilitate the navigation of the particles from the release point to the target site while being favoured by the force of gravity in the target body position.

[0035] In some embodiments, the identifying the target range may include defining a range of optimal body rotation angles (9) when angles of the range of optimal body rotation angles meet the following conditions:wherein cTargeted\0 is the angle between a horizontal plane and a body rotation angle of a targeted blood vessel at the vessel bifurcation of the selected pathway, and <^NonTargeted\0 is the angle between the horizontal plane and an body rotation angle of a non-targeted vessel branch at the vessel bifurcation.

[0036] In some embodiments, the identifying of the target body position may include selecting the target body rotation angle amongst a target range of body rotation angles (9) wherein body rotation angles within the target range of body rotation angles satisfy the following conditions:

[0037] In some embodiments, identifying the target body position of the subject may include performing imagery on the subject in one or more of the following positions of the subject: a right side; a left side; a prone position; and a supine position.

[0038] In some embodiments, the particles may be microrobots.

[0039] In some embodiments, the imagery may be performed using cone-beam computer tomography.

[0040] In some embodiments, the performing of the imagery may be carried out for different positions of the subject.

[0041] In some embodiments, the performing of the imagery may be carried out for each of the following different positions of the subject a supine position; a prone position; a lateral right position; and a lateral left position.

[0042] In some embodiments, the physical field may be a magnetic field and the particles are magnetic particles.

[0043] In some embodiments, the physical field may be one of an electric field, a gravitational field, a temperature field, a velocity field, a pressure field, an acoustic field and a quantum field.

[0044] In some embodiments, the system may include a source for generating the physical field.

[0045] Another broad aspect is an MRI machine comprising the system as defined herein.

[0046] Another broad aspect is non-transitory computer-readable medium having stored thereon program instructions for preparing a subject for steering particles to a target site in the subject using a physical field, the program instructions executable by a processing unit for receiving image information of a body of the subject to obtain an image of at least a part of a vascular system of the subject; determining a pathway through the vascular system of the subject from a release site to the target site and identifying a target body position of the subject by factoring a force of gravity on a direction of the particles relative to the pathway of the vascular system to improve steering of the particles through the pathway of the vascular system of the subject to the target site when the subject is placed in the target body position.

[0047] In some embodiments, the determining a pathway may include identifying vascular bifurcations from the release point to the target site, and wherein the identifying of the target body position includes identifying consecutive vascular bifurcations of the vascular bifurcations that facilitate the navigation of the particles from the release point to the target site while being favoured by the force of gravity in the target body rotation angle.

[0048] In some embodiments, the identifying the target range may include defining a range of optimal body rotation angles (9) when angles of the range of optimal body rotation angles meet the following conditions:wherein cTargeted\0 is the angle between a horizontal plane and a body rotation angle of a targeted blood vessel at the vessel bifurcation of the selected pathway, and <%NonTargeted\0 is the anglebetween the horizontal plane and an body rotation angle of a non-targeted vessel branch at the vessel bifurcation.

[0049] In some embodiments, the identifying of the target body position may include selecting the target body rotation angle amongst a target range of body rotation angles (9) wherein body rotation angles within the target range of body rotation angles satisfy the following conditions:

[0050] In some embodiments, the identifying the target body position of the subject may include performing imagery on the subject in one or more of the following positions of the subject a right side; a left side; a prone position; and a supine position.

[0051] In some embodiments, the particles may be microrobots.

[0052] In some embodiments, the imagery may be performed using cone-beam computer tomography.

[0053] In some embodiments, the performing of the imagery may be carried out for different positions of the subject.

[0054] In some embodiments, the performing of the imagery may be carried out for each of the following different positions of the subject: a supine position; a prone position; a lateral right position; and a lateral left position.

[0055] In some embodiments, the physical field may be a magnetic field and the particles are magnetic particles.

[0056] In some embodiments, the physical field may be one of an electric field, a gravitational field, a temperature field, a velocity field, a pressure field, an acoustic field and a quantum field.

[0057] Another broad aspect is a MRI machine comprising the non-transitory computer- readable medium as defined herein.Brief Description of the Drawings

[0058] The invention will be better understood by way of the following detailed description of embodiments of the invention with reference to the appended drawings, in which:

[0059] Figure 1 is a block diagram of an exemplary system for preparing a subject for treatment using a physical field, in communication with one or more exemplary imaging devices and one or more physical field sources;

[0060] Figure 2 is a block diagram of an exemplary software architecture for determining a position of a subject for treatment using a physical field;

[0061] Figure 3 is a flowchart diagram of an exemplary method for determining a position of a subject for treatment using a physical field;

[0062] Figure 4 is a flowchart diagram of an exemplary method for treating a subject using a physical field and particles responsive thereto;

[0063] Figure 5A is a drawing of an exemplary 3D model vascular system of a subject obtained through CBCT acquisition (a C arm);

[0064] Figure 5B is a drawing of an exemplary 3D model vascular system of a subject obtained through CBCT acquisition (a C arm) of the subject of Figure 5 A that is rotated after processing the pathways relative to the horizontal plane (HP) to assess the effect of gravity on the target operation;

[0065] Figure 5C is a drawing of an exemplary system for treating the subject of Figures 5 A and 5B using a magnetic field, where the magnetic field is generated by an MRI machine, once the subject is placed in an MRN-compatible position, the hepatic flow is reduced by partially inflating a balloon catheter using a high-precision MRI-compatible balloon inflation system; the MMR injector, connected to the catheter, creates and releases a single particle aggregate with the desired number of particle; after release, the imaging gradients of the MRI are activated to steer the aggregate into the target vessels to reach the target site;

[0066] Figure 6A is a transmission electron microscope micrograph of exemplary iron oxide magnetic nanoparticles;

[0067] Figure 6B is an electron microscope image of the MMRs;

[0068] Figure 6C is a graph illustrating the magnetization curve of the MMRs;

[0069] Figure 7A is an image of angiography showing the anatomy of the liver before embolization; the left gastric and gastroduodenal arteries were embolized with coils before the MMR injection to prevent embolization in the stomach or duodenum;

[0070] Figure 7B is an image of digital subtraction angiography (DSA) acquisition after MMR injection showing no evidence of flow occlusion and no visibility of MMRs;

[0071] Figure 7C is an image of a CBCT showing no visibility of MMRs; only the coils positioned in right gastric and gastroepiploic arteries are visible (arrows);

[0072] Figure 7D is an image of gross pathology with the caudal view of liver lobes annotated in white;

[0073] Figure 7E is an image of particle distributions in a slice of the Tl-VIBE of Figure 7D;

[0074] Figure 7F is an image of particle distributions in a slice of the Tl-VIBE of Figure 7D;

[0075] Figure 8A is an image of a pig, where its vascular trees are imaged at different posture positions in the angiography room, here in the lateral left position;

[0076] Figure 8B is an image of digital subtraction angiography (DSA) of the hepatic vascular artery is obtained when the pig is in the supine position;

[0077] Figure 8C is an image of a 3D model of a segmented vascular tree of the pig of Figure 8A that is registered at four different positions when the proper hepatic artery is aligned;

[0078] Figure 8D is a diagram of a first compatible angular range that can reach the targeted lobes (the right lateral and caudate lobes (RLL+CL)) depending on the pig's posture (individual color); values in the box indicate the postural rotation angles when imaging the vascular tree;

[0079] Figure 8E is a diagram of a second compatible angular range that can reach the targeted lobe (the right medial lobe (RML)) depending on the pig's posture (individual color); values in the box indicate the postural rotation angles when imaging the vascular tree;

[0080] Figure 8F is a diagram of a third compatible angular range that can reach the targeted lobe (the left lateral lobe (LLL)) depending on the pig's posture (individual color); values in the box indicate the postural rotation angles when imaging the vascular tree;

[0081] Figure 8G is a diagram of a fourth compatible angular range that can reach the targeted lobe (the left medial lobe (LML)) depending on the pig's posture (individual color); values in the box indicate the postural rotation angles when imaging the vascular tree;

[0082] Figure 9A are images of a localization procedure for cross-sectional flow measurements in the proper hepatic artery;

[0083] Figure 9B is an image of a 3D reconstruction of the blood vessel structure for vessel diameter measurements, and flow measurements by the 2D cine phase-contrast sequence before the blood flow control;

[0084] Figure 9C is an image of a blood vessel before blood flow control;

[0085] Figure 9D is an image of the blood vessel of Figure 9C after blood flow control;

[0086] Figure 10A is an image of a 3D representation of identification of artifacts in the Tl- VIBE sequence, and segmentation of the hepatic arterial tree from MRA data in a pig;

[0087] Figure 10B in an image of a 3D representation of coordinate alignment of the MRA and CBCT images and segmentation of artifacts;

[0088] Figure 10C is an image of a 3D representation of an identification of the artifacts in pig #3 after inserting the 3D hepatic vascular tree extracted from the CBCT;

[0089] Figure 10D is an image of a 3D representation of an identification of the artifacts in pig #8 after inserting the 3D hepatic vascular tree extracted from the CBCT;

[0090] Figure 10E is an image of 3D representation of an identification of the artifacts in pig #6 after inserting the 3D hepatic vascular tree extracted from the CBCT;

[0091] Figure 11 is a table showing an optimal body rotation angle for each pig and the MMR distributions after the target operation;

[0092] Figure 12 is a table showing locations of HCCs in 19 subjects and the number of bifurcations that need to be crossed to reach them; individual HCCs (green boxes) with the number of bifurcations that can be crossed with the elevation angle below the horizontal plane after optimal positioning (numerator), out of all bifurcations that need to be crossed (denominator); the percentage of all tumors in the same segment that can be targeted successfully by crossing all bifurcations is presented in the last row; note, ID = identification, F = female, and M = male;

[0093] Figure 13 is an image of a simulation of MRN (magnetic resonance navigation) in an atlas of human liver anatomy with the proposed algorithm; for a subject with a nodule in segment VIII, three vascular bifurcations can be crossed, and the subject is to be positioned on the right side;

[0094] Figure 14 is a flowchart diagram of an exemplary method for selecting a single optimal body rotation angle;

[0095] Figure 15A is an image of a 3D model of a vascular bifurcation where combining three-dimensional and two-dimensional space reveals several forces acting on the microrobot, including gravity, buoyancy, and MRN force;

[0096] Figure 15B is an image of vascular bifurcation where the forces acting on the microrobot in the axial direction of the blood vessel, when the microrobot is navigated and the targeted vessel is in the sagittal plane and facing downward;

[0097] Figure 16 is a flowchart diagram of an exemplary method for performing MRN;

[0098] Figure 17 is a graph illustrating an exemplary magnetization curve of the iron oxide superparamagnetic nanoparticles used in MMRs;

[0099] Figure 18 illustrates optimal rotation angles to target different liver lobes of pig#5 and the distribution of the MMR-induced artifacts, with (A) showing vessel identifications feeding different liver lobes and in (B)-(E) the optimal body rotation angles to target 4 liver lobes are calculated by the proposed algorithm, where (F) is the distribution of the MMR-induced artifacts after registration of the segmented hepatic arteries;

[0100] Figure 19 illustrates optimal rotation angles to target different liver lobes of pig#6 and the distribution of the MMR-induced artifacts, with (A) showing vessel identifications feeding different liver lobes and in (B)-(E) the optimal body rotation angles to target 4 liver lobes are calculated by the proposed algorithm, where (F) is the distribution of the MMR-induced artifacts after registration of the segmented hepatic arteries;

[0101] Figure 20 illustrates optimal rotation angles to target different liver lobes of pig#7 and the distribution of the MMR-induced artifacts, with (A) showing vessel identifications feeding different liver lobes and in (B)-(E) the optimal body rotation angles to target 4 liver lobes are calculated by the proposed algorithm, where (F) is the distribution of the MMR-induced artifacts after registration of the segmented hepatic arteries;

[0102] Figure 21 illustrates optimal rotation angles to target different liver lobes of pig#9 and the distribution of the MMR-induced artifacts, with (A) showing vessel identifications feeding different liver lobes and in (B)-(E) the optimal body rotation angles to target 4 liver lobes are calculated by the proposed algorithm, where (F) is the distribution of the MMR-induced artifacts after registration of the segmented hepatic arteries;

[0103] Figure 22 illustrates optimal rotation angles to target different liver lobes of pig#10 and the distribution of the MMR-induced artifacts, with (A) showing vessel identifications feeding different liver lobes and in (B)-(E) the optimal body rotation angles to target 4 liver lobes are calculated by the proposed algorithm, where (F) is the distribution of the MMR-induced artifacts after registration of the segmented hepatic arteries;

[0104] Figure 23 illustrates optimal rotation angles to target different liver lobes of pig#l l and the distribution of the MMR-induced artifacts, with (A) showing vessel identifications feeding different liver lobes and in (B)-(E) the optimal body rotation angles to target 4 liver lobes are calculated by the proposed algorithm, where (F) is the distribution of the MMR-induced artifacts after registration of the segmented hepatic arteries;

[0105] Figure 24 illustrates optimal rotation angles to target different liver lobes of pig#12 and the distribution of the MMR-induced artifacts, with (A) showing vessel identifications feeding different liver lobes and in (B)-(E) the optimal body rotation angles to target 4 liver lobes are calculated by the proposed algorithm, where (F) is the distribution of the MMR-induced artifacts after registration of the segmented hepatic arteries; and

[0106] Figure 25 shows images of the slices of the liver for purposes of comparison with regard to MMR artifacts; the left image is acquired before microrobot injection; the middle image shows imaging immediately after the completion of MRN, while the right image displays the pig being taken out of the magnetic field area for 30 seconds and then brought back to the MRI for reimaging; the areas marked with red lines indicate the clustering of small MMRs or the formation of individual MMRs in the peripheral areas of the liver.Detailed Description

[0107] The present disclosure relates to methods and systems for improving navigation of particles in a body of a subject using a physical field. In one embodiment, the physical field is a magnetic field.

[0108] A position of the subject, including one or more body rotation angles, is determined for the subject in order to utilize the force of gravity to assist steering of the particles from a release site of the particles to a target site in the body of the subject using a physical field, defining a pathway in the subject (e.g. a pathway in the vascular system of the subject).

[0109] The present disclosure also relates to systems and methods for treating a subject using a magnetic field and magnetic particles, the treatment taking into account the force of gravity to determine the position of the subject, including one or more body rotation angles, the one or more body rotation angles of the subject for facilitating the steering of the particles from the release site to the target site by accounting for the application of the force of gravity onto the particles.

[0110] Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is as “including, but not limited to.”

[0111] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are notnecessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0112] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0113] From the foregoing it will be appreciated that, although specific embodiments have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the teachings. Accordingly, the claims are not limited by the disclosed embodiments.

[0114] DEFINITIONS:

[0115] In the present disclosure, by “diagnosing” or “diagnosis”, it is meant determining (i) the presence of a condition, disease or disorder, (ii) a risk of developing a condition, disease or disorder, or (iii) a state (aggravation, absence of change or improvement) of a condition, disease or disorder.

[0116] In the present disclosure, by “imaging”, it is meant a medical technique that allows for obtaining information on a subject. In some examples, the imaging allows for viewing of the anatomy of the subject. Such techniques include, but are not limited to, magnetic resonance imaging (MRI), computed tomography (e.g. CT scans, CAT scans), Cone Beam CT (CBCT), digital Subtraction Angiography (DSA), positron emission tomography, single photon-emission computed tomography, electron paramagnetic resonance, ultrasound, X-Rays, etc.

[0117] In the present disclosure, by “magnetic particles”, it is meant particles that can be steered or controlled using a magnetic field (e.g. by modulating the force and direction of the magnetic field). A magnetic particle may be a microrobot, a nanorobot, an organism, such as a bacterium that is a drawn to, or that can navigate with the assistance of, a magnetic field, etc.

[0118] In the present disclosure, by “particles”, it includes micro-scale or nano-scale entities for introduction into the body of a subject, such as microrobots or nanorobots and that respond to a physical field. For instance, when the physical field is a magnetic field, the particles are magnetic. The particles are steerable in the body of the subject using the physical field. If the physical field is gravity, the buoyancy of the particle in the blood will be affected by gravity. In some examples, the particles may be cells, or unicellular organisms, such as bacteria that are responsive to amagnetic field (e.g. navigated toward a magnetic-north or toward a magnetic-south).

[0119] In the present disclosure, by “pathway”, it is meant information on a direction to be taken by the particles from the release site of the particles to the target site by the particles in the body of the subject. The pathway may be a defined as a direction determined from a position of the release site in the subject and a position of the target site in the subject. In some instances, the pathway may include a distance value (e.g. from the release site to the target site in the body of the subject). In some instances, the pathway may a defined as a route through the vascular system of the subject (obtained through imagery performed on the subject) starting from the release site of the particles in the body of the subject to the target site in the body of the subject.

[0120] In the present disclosure, by “physical field”, it is meant a field generated by external actuators that exerts a force on the particles to cause a steering of the particles in the body of the subject, thereby permitting a navigation of the particles in the body of the subject. A physical field may be the sum of a plurality of physical fields generating by a respective plurality of actuators. Exemplary physical fields include a magnetic field (generated by a magnetic source, such as the magnetic field generated by an MRI machine), an electric field, a gravitational field, a temperature field, a velocity field, a pressure field, an acoustic field, a quantum field, etc.

[0121] In the present disclosure, by “position of the subject”, it is meant an overall configuration of the subject represented by the body rotation angles for different portions of the body of the subject (such as the head, the core, the legs, the arms). For instance, the position of the subject may be a supine position, a prone position, the subject lying on a right side, the subject lying on a left side, or a position in-between each of these. Each portion of the body of the subject may have a specific configuration for purposes of improving the travel of the particles in the body of the subject using the force of gravity. Each portion of the body of the subject may be set with a given orientation and tilt, the result of the set position for each portion of the body of the subject being the position for the subject.

[0122] In the present disclosure, by “release site”, it is meant a location at which the particles are introduced into the subject (from a housing or a chamber that contained the particles into the body of the subject). For instance, the release site may be the site at which a syringe or an injector unloads a volume of particles into the vascular system of the subject. The release site may be the injection site (location where the particles are injected into the subject). The release site may be where a catheter or a needle, inserted into the subject, releases the particles into the subject (e.g.the vascular system of the subject), etc.

[0123] In the present disclosure, by “subject”, it is meant mammal and non-mammals. Mammals mean any member of the mammalia class including, but not limited to, humans. Nonmammals include birds, reptiles, etc. The term “subject” should not bring on any limitations as to the sex or age.

[0124] In the present disclosure, by “target body rotation angle”, it is meant the body rotation angle for a portion of the body of the subject (e.g. a head, a core, an arm, a leg) that is desired in order to improve the steering of the particles from a release site to the target site in the subject. A target body rotation angle may include an orientation and a tilt of the body portion of the subject. When all of the body rotation angles for the portions of the body of the subject are set, this results in a target position for the subject. In some instances, the target position may include a single target body rotation angle, where only one portion of the body of the subject may have an adjusted position. In other instances, the body rotation angle may be a general configuration for the entire body of the subject, where the body rotation angle would result in determining a target position of the body (e.g. a prone position, a supine position, the subject resting on a right side, the subject resting on a left side, a position found in-between one of these positions, etc.).

[0125] In the present disclosure, by “target site”, it is meant a location within a body of the subject that is destination for the particles following the steering of the particles within the body of the subject. The target site may be defined as a point in space or a zone. The target site may be a tumor, an organ, etc.

[0126] In the present disclosure, by “treating” or “treatment”, it is meant one or more of (i) preventing part or all of a condition, disease or disorder (temporarily or permanently), (ii) inhibiting or arresting part or all of a condition, disease or disorder (temporarily or permanently), and (iii) relieving part or all of a condition, disease or disorder (temporarily or permanently).

[0127] EXEMPLARY SYSTEM FOR PREPARING A SUBJECT FOR STEERING PARTICLES WITHIN THE BODY OF A SUBJECT:

[0128] Reference is now made to Figure 1, illustrating an exemplary system 100 for preparing a subject for steering particles within the body of the subject using a physical field, such as a magnetic field.

[0129] The system 100 has at least one processor 102, memory 101 and at least one input / output interface 103 for communication with one or more physical field sources 150 and / orone or more imaging device(s) 160.

[0130] The system 100 may have an input / output interface 103 for each of the one or more physical field sources 150. The system 100 may have one or more separate input / output interfaces 103 for each of the one or more imaging devices 160. A separate I / O interface 103 may also be provided in system 100 for communicating with the I / O interface of a remote computer.

[0131] The processor 102 may be a general-purpose programmable processor. In this example, the processor 102 is shown as being unitary, but the processor 102 may also be multicore, or distributed (e.g. a multi-processor).

[0132] The computer readable memory 101 stores program instructions and data used by the processor 102. The computer readable memory 101 may also store 3D models of the vascular system of the subject, images of the vascular system of the subject, properties of particles, location information of the release site, location information of the target site, etc. The memory 101 may also store information regarding the physical field source(s) 150 and / or the imaging device(s) 160 that are accessible by the system 100, such as the identity of the physical field source(s) 150 and / or the imaging device(s) 160, properties of the physical field source(s) 150 and / or the imaging device(s) 160, etc. The memory 101 may be non-transitory. The computer readable memory 101, though shown as unitary for simplicity in the present example, may comprise multiple memory modules and / or caching. In particular, it may comprise several layers of memory such as a hard drive, external drive (e.g. SD card storage) or the like and a faster and smaller RAM module. The RAM module may store data and / or program code currently being, recently being or soon to be processed by the processor 102 as well as cache data and / or program code from a hard drive. A hard drive may store program code and be accessed to retrieve such code for execution by the processor 102 and may be accessed by the processor 102 to store and access data. The memory 101 may have a recycling architecture for storing, for instance, images of at least part of the vascular system of a subject, where older data files are deleted when the memory 101 is full or near being full, or after the older data files have been stored in memory 101 for a certain time.

[0133] The I / O interface 103 is in communication with the processor 102. The I / O interface 103 may include a network interface and may be a wired or wireless interface for establishing a remote connection with, for example, the physical field source(s) 150 and / or the imaging device(s) 160, a remote computer, etc. For instance, the I / O interface 103 may be an Ethernet port, a WAN port, a TCP port, etc.

[0134] The processor 102, the memory 101 and the I / O interfaces 103 may be linked via bus connections.

[0135] The remote computer may be in communication with the I / O interface 103 of the system 100. The remote computer has a processor, a memory, an I / O interface that may be linked via bus connections. The remote computer may have (or be connect to) any suitable I / O device(s), for example, such as a keyboard, a mouse, a touchscreen etc. The remote computer may be a desktop computer, a laptop, a smartphone, a tablet, etc. There may be more than one remote computer in communication with the system 100.

[0136] The physical field source 150 is a device suitable for generating a physical field. For instance, when the physical field is a magnetic field, the physical field source may be a magnetic coil that generates a magnetic field when current passes through the coil. There may be a plurality of physical field sources 150 that each generates a physical field (concurrently, in sequence, etc.)

[0137] The imaging device 160 is a device suitable for performing imagery on the subject. For instance, the imaging device 160 may be a C-arm, or the imaging component of a magnetic resonance imaging (MRI) machine.

[0138] In some embodiments, the system 100 includes the physical field source(s) 150 and / or the imaging device(s) 160.

[0139] In some instances, the system 100 may be part of, or connected to, an MRI machine, where the physical field source(s) 150 and / or the imaging device(s) 160 are those offered by the MRI machine.

[0140] EXEMPLARY SOFTWARE ARCHITECTURE FOR DETERMINING A POSITION OF A SUBJECT FOR TREATMENT USING A PHYSICAL FIELD:

[0141] Reference is now made to Figure 2, illustrating an exemplary software architecture for determining a position of a subject for treatment using a physical field 200.

[0142] The system 100 has program code, stored in memory 101, that includes an image analysis module 210. The system 100 has program code, stored in memory 101, that includes a pathway definition module 220. The system 100 has program code, stored in memory 101, that includes a body rotation module 230. Each of the image analysis module 210, the pathway definition module 220 and body rotation module 230 includes program code configured to implement the functionality of the modules as is described herein.

[0143] The image analysis module 210 includes program code stored in memory 101 that,when executed by the processor 102, causes the processor 102 to receive one or more images from the one or more imaging devices 160 of at least a part of the body of the subject. The processor 102 may then be caused to receive user input identifying a vascular system appearing in the images. In some instances, the processor 102 may be caused to perform object recognition on the one or more images to identify at least portions of the vascular system appearing in the image. In some instances, the image analysis module 210 may then cause the processor to alter the image to identify the vascular system appearing in the image (e.g. by highlighting with a colour or a contour on one or more portions of the one or more images associated with the vascular system).

[0144] The pathway definition model 220 includes program code stored in memory 101 that, when executed by the processor 102, causes the processor 102 to receive information regarding a target site for the particles. The information regarding the target site may be user input (e.g. a selection of an area, or a selection of a point, on one or more of the images received of the subject). The information regarding the target site may be generated by analyzing one or more images of the body of the subject to determine (e.g. through object recognition) a specific region in the body of the subject (such as a tumor site, e.g. determined by identifying features within the one or more images indicative of the location of a tumor). The target site is determined from the information on the target site.

[0145] The pathway definition model 220 includes program code stored in memory 101 that, when executed by the processor 102, causes the processor 102 to receive information regarding a release site of the particles into the body of the subject, indicative of the location of the release site. For instance, the information regarding the release site may be an image object of a tip of a syringe used to inject the particles into the body of the subject, appearing on one or more images of the subject (e.g. taken using a C-arm), a feature appearing on one or more images corresponding to a contrast or imaging agent dispersed with the particles when introduced into the body of the subject, etc.

[0146] The pathway definition model 220 includes program code stored in memory 101 that, when executed by the processor 102, causes the processor 102 to determine a pathway in the body of the subject from the release site to the target site. In some instances, the pathway may be defined as a direction in the body of the subject from the release site to the target site, and a distance value from the release site to the target site. In some instances, the pathway is plotted by the processor 102 through the vascular system of the subject identified in the one or more images. The pathwaymay also identify vascular bifurcations present on the pathway. In some instances, the plotting of the pathway through the vascular system may be determined once the target position of the subject has been determined.

[0147] The body rotation module 230 includes program code stored in memory 101 that, when executed by the processor 102, causes the processor 102 to determine a target body rotation angle for the body of the subject, or one or more parts of the body of the subject, resulting in a target position of the subject. The processor 102 is caused to determine the one or more target body rotation angles from the force of gravity, the pathway (in some instances, the vascular bifurcations identified along the pathway), the release site and / or the target site. When a target body rotation angle is determined for the entire body of the subject, the adjusting of the position of the body of the subject in accordance with the body rotation angle may result in the positioning of the body of the subject in one of the following positions: on a left side of the subject, on the right side of the subject, in a supine position, in a prone position (or in a position in between each of these positions). When different parts or portions of the body of the subject have their own target body rotation angle, the processor 102 may be caused to generate an orientation and tilt for each of the body rotation angles. The processor 102 may also be caused to calculate a displacement or translation of one of the body parts of the subject vis-a-vis another body part. For instance, the calculated displacement or translation may be to approach a knee or leg of the subject to the abdomen of the subject, the chin of the subject to the torso of the subject, etc.

[0148] EXEMPLARY METHOD OF PREPARING A SUBJECT FOR STEERING PARTICLES IN THE SUBJECT USING A PHYSICAL FIELD:

[0149] Reference is now made to Figure 3, illustrating an exemplary method 300 of preparing a subject for steering particles in the subject using a physical field. The method 300 may be performed by system 100, or any other system in accordance with the present teachings.

[0150] Imaging information on the body of the subject is received at step 310. The imaging information enables the generation and visualizing of one or more images taken of the body of the subject, such as following one or more of an X-ray (e.g. a computer tomography (CT) scan, using e.g., a C-arm), magnetic resonance imaging, ultrasound, etc. The imaging information includes image(s) of at least part of the vascular system of the subject, information on a release site in the body of the subject, and information on a target site in the body of the subject.

[0151] The vascular system, or part thereof, may be identified in the image(s) of the body ofthe subject at step 320. Object recognition may be performed on the one or more images to define in the one or more images objects corresponding to the parts of the vascular system of the subject (e.g. by using patterns and / or identifiers for locating the vascular system or parts of the vascular system appearing in the image(s)). It will be understood that in some instances, an artificial intelligence model may be trained to perform object recognition of the vascular system or parts of the vascular system appearing in the image(s) (e.g. a convolutional neural network for deep learning).

[0152] The release site may be identified in the image(s). For instance, the release site may correspond to a location of a tip of syringe appearing in the image(s) (when the particles are released into the body of the subject via a syringe). In some examples, the release site may correspond to the tip of a catheter appearing in the image(s) (when the particles are released in the body of the subject via a catheter). In some instances, the release site may be identified by a contrast agent or image agent introduced into the body of the subject at a location where the particles are released into the body of the subject, visible in the one or more image(s). In some instances, the release site may be identified following the receipt of user input identifying on the one or more images a point or an area (or through the receipt of coordinates corresponding to a location in the one or more images). It will be understood that other solutions to identify the release site of the particles in the image(s) may be contemplated.

[0153] The target site is also identified in the one or more images of the body of the subject. For instance, object recognition may be performed on the one or more images to identify one or more objects corresponding to the release site (such as a tumor). It will be understood that in some instances, an artificial intelligence model may be trained to perform object recognition of the one or more objects of interest corresponding to the release site in the image(s) (e.g. a convolutional neural network for deep learning).

[0154] In some instances, the target site may be identified following the receipt of user input identifying on the one or more images a point or an area (or through the receipt of coordinates corresponding to a location in the one or more images). It will be understood that other solutions to identify the target site of the particles in the image(s) may be contemplated.

[0155] A pathway from the release site to the target site is determined at step 330. The pathway may correspond to a vector indicative of a direction from the release site to the target site. The pathway may include a distance from the release site to the target site. In some embodiments, thepathway may be determined from at least the part of the vascular system that has been identified in the one or more images. The pathway may be calculated by plotting a route through the vasculature from the release site to the target site. The plotting may take into account evaluating a shortest distance through the vasculature from the release site to the target site, a number of vascular bifurcations in the vasculature from the release site to the target site, a width of the blood vessels between the release site and the target site, a relative height between the release site and the target site, etc.

[0156] The determined pathway may be further identified on the one or more images of the body of the subject (e.g. by highlighting portions of the vasculature corresponding to the pathway, by delineating portions of the vasculature corresponding to the pathway, by adding a colour to the portions of the vasculature corresponding to the pathway, etc.)

[0157] One or more target body rotation angles of the subj ect are determined at step 340. Each of the one or more target body rotation angles may be for different body parts of the subject (e.g. the core, the head, the legs, etc.). In some instances, there may a single body rotation angle determined for the entire body (e.g. placing the body in a supine position, a prone position, the body lying on a right side, the body lying on a left side). Each target body rotation angle may be represented by an angle value. Each target body rotation angle may include an orientation value and a tilt value. A 3D dimensional representation of the target body of the subject, taking into account the determined target body rotation angle(s), may be displayed on a graphical user interface generated on a screen, thereby providing the medical practitioner with a visual representation of the target position for the subject.

[0158] The one or more target body rotation angles are determined from information on the vascular system of the subject, the release site, the target site and the force of gravity. The body of the subject is positioned in a manner to cause a steering of the particles from the release site, through the pathway, to the target site. In some instances, the pathway within the vascular system of the subject once the one or more target body rotation angles have been determined, as those body rotation angle(s) enable the passing of the particles from the release site to the target site, aided by the force of gravity, the pathway dependent on how the force of gravity will influence the movement of the particles through the vascular system to the target site. In other instances, the pathway may be determined prior to the determining of the target body rotation angles of the subject (e.g. when a specific set of blood vessels of the vascular system are to be favoured for theparticles to navigate therethrough when subject to the physical field).

[0159] Properties of the physical field (such as limitations of the physical field in terms of strength, restrictions in direction of the force applied, etc.) may also be taken into account when determining the position of the body of the subject (one or more target body rotation angles of the subject).

[0160] Certain characteristics of the subject, such as their gender, their age, their weight, their body proportions, etc. may be taken into account when determining the target one or more body rotation angles. In some instances, the determining of the target one or more body rotation angles may take into account disabilities and conditions of the subject (e.g. such as a broken bone, movement restrictions, etc.)

[0161] The one or more body rotation angles may further be determined following an identification of one of the vascular bifurcations along the pathway taken in the vascular system from the release site to the target site. The target body rotation angles would promote steering of the particles, subject to the force of gravity, through one of the two blood vessels of the vascular bifurcation that leads to the release site, the force of gravity promoting steering towards that one of the two blood vessels of the vascular bifurcation.

[0162] In some instances, the determining of the one or more target body rotation angles includes defining a range of optimal body rotation angles (9) when angles of the range of optimal body rotation angles meet the following conditions:^Targeted\6 — 0 > and Targeted\6 — NonTargeted\9^Targeted\e is the angle between a horizontal plane and a body rotation angle of a targeted blood vessel at the vessel bifurcation of the selected pathway, and aNonTargeted gis the angle between the horizontal plane and a body rotation angle of a non-targeted vessel branch at the vessel bifurcation.

[0163] In some instances, the determining the target body rotation angle includes selecting the target body rotation angle amongst a target range of body rotation angles (9) where rotation angles within the target range of body rotation angles satisfy the following conditions: Targeted\6 — 0 ■> and^Targeted ft — NonTargeted\d

[0164] EXEMPLARY METHOD OF TREATING A SUBJECT USING A PHYSICALFIELD:

[0165] Reference is now made to Figure 4, illustrating an exemplary method 400 of treating a subject using a physical field. The method 400 may be performed by system 100, and / or imaging device(s) 160 and / or physical field source(s) 150, or any other system and / or imaging device(s) and / or physical field source(s) in accordance with the present teachings.

[0166] In some instances, when the physical field is a magnetic field and the particles are magnetic particles, the system 100, the imaging device and the physical field source may be part of an MRI machine.

[0167] Method 400 may follow the method 300, from which the target body rotation angles have been determined.

[0168] The body of the subject is positioned or adjusted in accordance with the determined position of the body (defined by the determined target body rotation angle(s)) at step 410. In some instances, one or more cameras may be used to capture an image of the subject. Object recognition may be performed to identify the real-time body of the subject in the image capturing the subject. The real-time position of the body of the subject may be compared to a virtual model of a target position for the body of the subject, facilitating the adjustment of the real-life position of the body of the subject by a medical practitioner.

[0169] In some instances, a balloon catheter is inflated (partially, entirely) at step 420 in a blood vessel of the subject. The balloon catheter reduces the blood flow rate in the blood vessel to adjust the flow of blood in the blood vessel, to facilitate movement of the particles in the blood vessel.

[0170] In some instances, the method may include obtaining phase contrast magnetic resonance imaging sequences to plan and monitor blood flow rate in downstream vessels located along the pathway.

[0171] The particles are released into the body of the subject at step 430. In some instances, the particles may be injected into the body of the subject (e.g. using a syringe, a needle, a catheter, etc.) In some instances, the particles may be introduced inside the arterial, venous and / or lymphatic system. In some instances, the release is performed via injection using a dedicated injector, to enhance a dipole-dipole interaction and steering force between the particles forming an aggregate. It will be understood that other methods for introducing the particles into the subject, depending on the quantity needed, the location of the target site, the nature of the physical field, etc., may be used without departing from the present teachings.

[0172] The physical field is generated, applying a force onto the particles at step 440. Many different physical field sources may be used to further control or influence the steering of the particles within the vascular system of the subject. For instance, when the physical field is a magnetic field, the physical field may include a main magnetic field (BO) generated by a magnetic resonance imaging (MRI) machine, a radiofrequency field (Bl) applied perpendicular to the main magnetic field (Bo), and calibrating distortions of the main magnetic field in x-,y- or z-directions using gradient coils.

[0173] The particles are steered to the target site from the release site by using the physical field, assisted by the force of gravity as the subject has been positioned in a manner corresponding to the target body rotation angles at step 450.

[0174] In some instances, the movement of the particles through the vascular system of the subject may be monitored by locating, when the imaging device and the magnetic field source are part of an MRI machine, the particles on magnetic resonance images through distortion caused by the particles on the magnetic resonance magnetic field. For instance, this distortion caused by the particles on the magnetic resonance magnetic field may be used to monitor a number or ratio of particles that have reached the target site. In some instances, this distortion caused by the particles on the magnetic resonance magnetic field may be used to monitor a number or ratio of particles that have left a release site.

[0175] The following exemplary studies are provided to enable the skilled person to better understand the present disclosure. As they are but illustrative and representative examples, they should not limit the scope of the present disclosure, only added for illustrative and representative purposes. It will be understood that other exemplary studies may be used to further illustrate and represent the present disclosure without departing from the present teachings.

[0176] EXEMPLARY STUDY 1 :

[0177] Figure 5A-5C describes the experimental design. Before the experiments, iron oxide superparamagnetic nanoparticles, which are visible on T1 -weighted MR images, were encapsulated into a biocompatible polymer that was made from biodegradable and FDA-approved poly(lactic-co-glycolic acid) (PLGA). For this exemplary study, designed to evaluate the feasibility of the proposed targeting technology, the MMRs were not loaded with chemotherapeutic drugs. However, successful loading of MMRs with the anticancer drug doxorubicin has been previously reported.

[0178] A balloon catheter was placed selectively in the main hepatic artery under fluoroscopy from a femoral approach. The distal branches of the hepatic vascular tree can be obtained from the segmentation of contrast images using cone-beam computed tomography (CBCT) and 3D digital subtraction angiography (DSA). Volumetric images were acquired in supine (0°), lateral right (90°), prone (180°), and lateral left (270°) positions (Fig. 5 A, example of supine position). Then, the range of body rotation angles was examined, i.e., pathways that favor gravity toward the targeted liver lobe (the right lateral+caudate lobes (RLL+CL), the right medial lobe (RML), the left medial lobe (LML), or the left lateral lobe (LLL)), while ensuring that a (Fig. 5B) remains less than 0. Here, a is the angle between the horizontal plane and the targeted branch leading to the tumor at the vessel bifurcation.

[0179] Once optimally positioned, the pig was transferred from the angiography room table to the MRI subject table using a docking table to maintain its optimal position. The balloon lumen was connected to a high-precision MR-compatible inflation device to reduce the flow velocity from ~40 cm / s to ~8 cm / s for MRN (34) (Fig. 5C).

[0180] After controlling the flow, the lumen of the catheter was connected to a specifically designed MMR injector capable of forming suitable particle aggregates and injecting them automatically. When an MMR aggregate was released from the injector, MR imaging gradients were activated in the proper direction to direct the aggregate to the target lobe (Fig. 5C). Serial Tl- weighted volumetric interpolated breath-hold examinations (Tl-VIBE) were acquired to assess the distribution of MMR aggregates in the target and non-target lobes every five injections. After all MMR injections were completed (100 injections), the pig was removed from the MRI field. Outside the magnetic field, the aggregates broke up into individual particles and reached the distal arterioles of the target. Then, the animals were moved back into the MRI bore. Tl-VIBE images were acquired, and the corresponding post-processing method was executed to assess the distribution of MMR aggregates in the target and non-target lobes.

[0181] EXEMPLARY STUDY 2:

[0182] The following describes two main steps in the fabrication of MMRs: producing the superparamagnetic nanoparticles (Fig. 6A) and encapsulating them into the PLGA material (Fig. 6B). The iron oxide nanoparticles (12 ± 3.6 nm) were coated with biocompatible C12- bisphosphonate. The nanoparticles had a saturation magnetization of 70 emu / g (weight = 1 mg, number of measurements = 1, room temperature, see fig. S2) (EV9, Microsense) and account for60% of the total weight of MMRs (mass density = 2.95 g / cm3). The MMRs (number of microrobots = 54, weight = 1.01 mg, number of measurements = 1, room temperature) showed no hysteresis at 0 T and were thus truly superparamagnetic, with a magnetization saturation value at 2 T of 36 emu / g (EV9, Microsense) (Fig. 6C). MMRs were not cytotoxic to human embryonic kidney cells and human umbilical vein endothelial cells (Lonza, Walkersville, MD, USA) when examined by direct and indirect cell viability and proliferation assays.

[0183] The number of MMRs per injection was controlled by the particle injector (Fig. 5C), and the number determined the size of MMR aggregates. The internal diameters of the left and right hepatic arteries are 3.0 ± 0.3 and 3.6 ± 0.4 mm, respectively. The criteria for determining the optimum number of MMRs per aggregate were to maximize the number of particles injected in a single injection while keeping the size of the aggregates smaller than the diameters of the left and right hepatic arteries. Therefore, the number of particles per aggregate was limited to 20 to form an aggregate length of 1.3 mm to 2.1 mm, resulting in 20 ± 6 particles injected each time. The distal branches were less than 2 mm.

[0184] EXEMPLARY STUDY 3:

[0185] Two living pigs were enrolled to examine the control distribution of MMRs in the liver when injected under fluoroscopy in an angiography room without MRN and aggregate formation. For each pig, 2,000 MMRs were released directly into the pig's proper hepatic artery via a 4-French catheter, and then the liver was harvested and imaged with Tl-VIBE images. As shown in Fig. 7A-7F, most of these particles were evenly distributed in all four liver lobes (RLL+CL, RML, LML, and LLL). The particles were mainly concentrated in the peripheral areas of the liver, indicating that they embolized small arteries and arterioles.

[0186] EXEMPLARY STUDY 4:

[0187] A total of 12 pigs were randomly divided into 3 groups: the control group (pigs #l-#4) receiving MMR injection without MRN in a supine position, the R-navigation group (pigs #5-#7), and L-navigation group (pigs #8-#12). The R-navigation group targeted RLL+CL (pigs #5-#6) and RML (pig#7). The L-navigation group targeted LML (pigs #8-#9) and LLL (pigs #10-#12).

[0188] An algorithm and a flowchart were developed, as explained herein, to determine the optimal subject position that will favor gravity toward the target vessel branch. In Figs 8A-8G, the calculation results were presented, which showed the range of optimal body rotation angles obtained based on different vascular trees (Figs. 8A-8C) for targeting different liver lobes (Figs.8D-8G) in pig #8. The single optimal body rotation angle for each individual pig, corresponding to the targeted liver lobe mentioned above, has been provided below herein along with the MRN targeting effect.

[0189] After rotating the pigs to their single optimal body rotation angles, they were immobilized on the docking table and transferred to the MRI suite. Once in the MRI, magnetic resonance angiography (MRA) was used to acquire the hepatic vascular tree.

[0190] EXEMPLARY STUDY 5:

[0191] A high flow rate has been shown to reduce the efficiency of MRN because the weak magnetic steering forces do not have enough time to deflect the aggregate toward the target lobe during the short transit time. On the other hand, low flow can cause microrobots to stick to the bottom of the blood vessels due to gravity and friction. It has previously been shown that the blood flow rate in the main hepatic artery may be in the range of 0.5 to 1.0 mL / s to optimize MRN.

[0192] For the L- and R-navigation groups, the hepatic flow rate was controlled by partially inflating a balloon catheter positioned in the proximal proper hepatic arteries. The infusion volume increment to the balloon was set to 0.01 mL. Each time the measured blood pressure value decreased by 2 mm Hg, the blood flow was measured until the desired flow rate of ~0.5 to 1.0 mL / s was obtained.

[0193] Figures 9A-9D illustrate the procedure for measuring the blood flow rate. Flow rates were measured from cine phase-contrast images at the cross-section of the proper hepatic artery. Free flow (no balloon inflation) was determined at 3.3 ± 2.3 mL / s (N = 12, all pigs), and controlled flow was 0.7 ± 0.3 mL / s (N = 8, two navigation groups) after balloon inflation.

[0194] EXEMPLARY STUDY 6:

[0195] After blood flow control (for the MRN groups) and MRA, 100 MMR aggregates with 20 ± 6 particles per aggregate were injected into the liver of each pig through the coaxial lumen of the balloon catheter. When a particle aggregate was released from the injector's actuator (Figs. 5A- 5C), the MRN sequence was turned on for 30 seconds to ensure that the magnetic force was applied to the MMR aggregate during the entire transit time until it reached the targeted lobe.

[0196] After MMR injections were completed, the pigs were removed from the MRI field for 30 s and then moved back. Artifact locations were verified on Tl-VIBE images (Fig. 10A). To better identify the distribution of these artifacts, the 3D hepatic vessel tree segmented on CBCT images was rigidly co-registered on the segmented MR angiography images (Fig. 10B) using 3D-Slicer (Version 4.11.20200930). This allowed particle distribution to be analyzed based on the volume of the artifacts and their relative spatial relationship to the hepatic artery and four hepatic lobes, as shown in Figs. 10C-10E.

[0197] Comparing Fig. 7C (MMR injection under fluoroscopy) with Fig. 10C (MMR aggregate injection in MRI without steering (control group)), MMRs had evenly distributed over 4 liver lobes in the absence of MRN regardless of the presence of the magnetic field.

[0198] The analysis of particle distributions in different groups indicated that the proposed navigation method significantly increased targeting efficiency. The proportion of particles entering the right liver lobes increased from 47.7 ± 8.8% (control group) to 86.4 ± 3.5% (R-navigation group), with a two-tailed P value of 0.0018. Similarly, the proportion of particles entering the left liver lobes increased from 52.2 ± 8.8% (control group) to 84.1 ± 11.7% (L-navigation group), with a two-tailed P value of 0.0054. Further details on the particle distribution can be found in Figure 11. In Figure 11, in the control group, the distribution ratio of particles is given for the right liver lobes

[0199] The proportion of particles in individual lobes was also examined. In the control group, the proportion of particles entering the RLL+CL, RML, LML and LLL was 24.3 ± 5.2%, 23.4 ± 8.0%, 31.9 ± 12.3% and 20.4 ± 9.7%, respectively; the corresponding values increased to 61.5 ± 15.8% (pigs #5 and #6), 40.8% (pig #7), 75.3 ± 24.1% (pigs #8 and #9) and 52.9 ± 12.9% (pigs #10, #11, and #12) when the four lobes were targeted separately. Therefore, the number of MMRs reaching four different target liver lobes had a 1.7- to 2.6-fold increase in the navigation groups, compared with the control group.

[0200] On the basis that the results of the R- and L-navigation are statistically significant compared to the control group (P < 0.05), a targeted lobe (RLL+CL, RML, LML, or LLL) can be specified to further improve the targeting efficiency of MMRs in the tumor areas.

[0201] In addition to the targeting effect, the disintegration of MMR aggregates into smaller aggregates or individual MMRs after leaving the magnetic field region was also examined. Pig#12 was used for verification. There were indeed some MMR aggregates that would break down in the liver after leaving the MRI magnetic field.

[0202] EXEMPLARY STUDY 7:

[0203] An atlas of 19 subjects who had undergone a TACE in 2018 / 2019, some with multifocal HCCs representing a total of 32 nodules, was used to determine whether the tumor distributionwas compatible with the proposed MRN approach to reach the tumor. According to the Michels classification of hepatic artery anatomy, these subjects have type 1 anatomy in 79% of cases (N = 15) with 26% of them having multiple HCCs (N = 5), as shown in Figure 12. Two subjects are type 2, one subject is type 3, and one subject is type 5. The location of HCC nodules regardless of the liver classification predominates in the medial lobes.

[0204] From this atlas, the number of bifurcations that can be crossed over the total number of bifurcations to reach the tumor was determined.

[0205] Figure 13 shows an example of a HCC subject from the atlas. If the subject is lying on the right side (optical subject position between 22° and 110°), the first three bifurcations towards the target branch can be crossed. The last bifurcation (4th) cannot be reached regardless of the subject’s position.

[0206] Two bifurcations are generally sufficient to reach the left lobe nodules (segment II, III and IV). To reach the right lobe nodules, three bifurcations are usually sufficient. Basically, if there is a nodule in the left lobe, the subject may be in a prone position or on the left side. For right-sided nodules, a supine position was generally more appropriate, except for segment VIII, which required a right-sided position. At the optimal body position obtained by our proposed algorithm, 78% (25 / 32) of HCC nodules (see Figure 12) can be targeted, provided that all vessel bifurcations leading to the targeted lobe favor gravity during MRN. There are only 2 cases where the bifurcation elevation angle (a, see Fig. 5B) was above 20° (i.e., 23° and 36.5°). Therefore, only 2 out of 32 HCC nodules (6.2%) were unreachable by this method. Only with such a small proportion of nodules, the proposed MRN procedure would have no additional therapeutic effect.

[0207] EXEMPLARY STUDY 8:

[0208] The feasibility of navigating MMRs to target a specific lobe of the liver in clinical MRI was demonstrated using 1) a balloon catheter placed in the proper hepatic artery for flow control, 2) a custom-purpose MMR injector to generate MMR aggregates, 3) magnetic steering forces generated by the imaging gradient of a clinical MRI, and 4) a new algorithm that can predict the optimal body position to favor the effect of gravity during MRN.

[0209] Although several systems have been proposed for propelling microrobots in vivo, these systems are generally limited to small animals or specific regions of the body due to weak actuator-based field forces. Clinical translation of these technologies to humans requires the ability to navigate microrobots at the human scale, which is possible by using clinical MRI with itshuman-sized imaging gradient coils to steer MMRs within the human vascular network. The 1.5 or 3T main magnetic field of the MRI fully magnetizes superparamagnetic nanoparticles within the magnetic microrobots. MRI is the most sensitive imaging modality to detect HCC or liver metastasis. Additionally, the Tl-VIBE sequence allows for the imaging and 3D localization of magnetic microrobots due to the magnetic artifacts they produce on MRI acquisitions, enabling quantification of their distribution. This is a significant advantage compared to current fluoroscopy-guided DEB-TACE where DSA in combination with or without CBCT cannot confirm complete tumor coverage following embolization.

[0210] Previous studies on the steering of MMRs identified fast blood flow as a major limitation of MRN. The blood flow in the liver arteries ranges between 3 to 4 mL / s. To be compatible with MRN, the flow rate was reduced to approximately 0.7 mL / s by precisely inflating an occlusion balloon catheter in the proximal proper hepatic artery with a dedicated inflation device. Using phase-contrast sequences was very convenient to monitor the flow during MRN experiments.

[0211] In a clinical setting, an implantable port can be easily inserted percutaneously into the proper hepatic artery with a dual-lumen catheter for balloon inflation, allowing DEB-TACE to be performed in the MR unit without hospitalization and subsequent catheterizations. This approach also allows the staging of DEB-TACE procedures with minimal morbidity.

[0212] Performing simulations of the present methods to a database of 19 TACE subjects showed that the proposed approach was viable in over 94% of HCC nodules. Regardless of the nodule's location, one-third of them could be reached within two bifurcations (Figure 12). Other locations requiring three to four bifurcations could be reached after the initial MRN followed by disaggregating the MMRs by removing the subject from the MRI. In humans, there are up to ten types of vascular anatomies in the liver. The wide range of optimal rotation angles confirmed that several angular positions could access the targeted liver lobe, which means that the body could be positioned with slight angular variations while maintaining the reproducibility of the pathways that reached the desired lobe. Knowing the angular range with the proposed framework informs MRN planning and its potential success. A narrow angle with a limited range would leave very little room for positional error. The selection of the target lobe was random and not based on the principle of easiness. The experimental results revealed a clear statistical significance between the control group and the two experimental groups.

[0213] In a clinical workflow, CT angiography or 3D DSA acquisitions in four positions (0°, 90°, 180°, and 270°) are required to minimize errors associated with elastic deformation of the hepatic arteries induced by subject rotation in the MRN position. This can be done during the installation of the implantable arterial port. Additionally, it may be helpful to consider using computational flow modelling techniques in combination with particle transport algorithms to simulate the effects of the flow thrust force, and the magnetic and gravitational forces on MRN performance. These simulations are useful to optimize blood flow and subject positioning during MRN. They can also be used to estimate the transit time of the aggregates between each bifurcation and to synchronize directional sequences with different angles.

[0214] The targeting approach described is applicable to humans. Firstly, both pigs and humans exhibit a similar alignment of the common hepatic artery, which primarily follows the length of the body or the B0 direction when inside an MRI bore. Secondly, the structure of the hepatic artery (vascular system) in pigs bears a high degree of resemblance to that in humans. Many similarities including the vascular structure have led to ongoing scientific exploration regarding the feasibility of liver xenotransplantation from pigs to humans.

[0215] The navigation method proposed here has several advantages in clinical applications. In cases of liver embolization, MRN eliminates the need for repeated invasive catheterizations. Since MMR-TACE with MRN requires a hepatic arterial port, it is compatible with multimodal therapy. MMR-TACE can be combined with an intra-arterial infusion of chemotherapeutic drugs to facilitate the treatment of advanced-stage disease. It can also be combined with novel therapeutic agents injected intra arterially, for example, oncolytic viruses and immune checkpoint inhibitors; MMR-TACE with MRN is a localized treatment that improves efficacy while reducing morbidity and healthy tissue at risk. Finally, MMRs can also be loaded with a new generation of drugs (tyrokinase inhibitors).

[0216] Moreover, a piezoelectrically actuated, MRI-compatible balloon inflation system was used. The system is mainly divided into two parts, an MRI-compatible actuator near the scanner, and a controller in the control room. A piezoelectric rotatory motor (diameter: 45 mm, thickness: 25 mm, made at Nanjing University of Aeronautics and Astronautics, China) was fitted to the actuator to accurately control the plunger flange of a syringe (3 mL syringe, inner diameter = 8.66 mL with Becton, Dickinson and Company) forward and backwards, controlling the inflation and deflation of the balloon catheter with an injection accuracy of 0.00067 ml. A piezoresistivedifferential pressure transducer (MPX 5050DP, NXP USA Inc.) was placed in the actuator, and it could monitor the blood pressure changes in front of the catheter tip during balloon inflation.

[0217] EXEMPLARY STUDY 9:

[0218] At vessel bifurcations, if one artery leads to the tumor and the other does not, it is helpful to facilitate particle migration through the first artery. Particles are subject to gravity because of their weight. Therefore, at the bifurcation, the MMRs naturally migrate towards the lowest artery, in other words, towards the artery with the most negative bifurcation angle (a, see Fig. 5B) with respect to the horizontal plane, a is always in the range of -90° to 90°. After obtaining the vascular tree from digital subtraction angiography (DSA), Cone Beam CT (CBCT), CT or MR angiography, the 3D geometry of the segmented hepatic artery centerlines is extracted in the VMTK library (movie SI); the algorithm stores the vascular tree as a binary tree. The root corresponds to the first division of the hepatic artery. Branches divisions are defined by their 3D bifurcation vector. The pathway to the targeted liver lobe and the number of bifurcations to cross are determined by optimizing angle below the horizontal plane for each bifurcation.

[0219] The main hepatic artery is mostly aligned in the cranio-caudal direction close to the B0 (z-axis) in the headfirst supine position. While the first and second bifurcations are more in the transverse direction and affected by the individual's rotation angle (9) along the main hepatic artery, i.e. z-axis or slice axis. Hence, the 3D rotation matrix is:

[0220] The individual’s rotation angle (9) can range between 0° and 359°, with 0° a supine position of the subject and with positive 9 for a right-side rotation (see Fig. 8 A).

[0221] An optimal rotation range of the subject (9) is obtained if all bifurcations leading to the targeted lobe meet the following conditions:where ccTargeted\0 is the angle between the horizontal plane and the targeted vessel branch at the vessel bifurcation (Fig. 5B), which was obtained by analyzing the 3D geometry of centerlines of the segmented hepatic arteries in MATLAB. Correspondingly, ccNonTargeted\0 is the angle corresponding to the non-targeted vessel branch.

[0222] For each rotation angle range (9), a decision tree is applied to determine if the 9 is optimal. If the 9 is optimal, all x-Targeted\e values along the pathway to the tumor meet the conditions above. If the 9 is not optimal, the number of consecutive bifurcations that facilitate particle navigation to the tumor is maximized. This step provides information on the number of consecutive bifurcations that can be favored by gravity.

[9223] After obtaining the range of optimal body rotation angles, the single optimal body rotation angle is determined based on the method outlined in the flowchart in Fig. 14. The existence of Vmin here is to ensure that there is minimal rotation from the body's postural angle to the single body rotation angle, thereby reducing vascular deformation.

[9224] EXEMPLARY STUDY 10:

[0225] The present study pertained to evaluating the MMR distribution when injected in an angiography suite without magnetic fields and aggregate formation. Two pigs had MMR injections. A 5-French introducer was placed via the femoral approach. The main hepatic artery was catheterized with a 4-French glidecath cobra catheter (Terumo, Tokyo, Japan). Following a selective angiography (DSA) of the hepatic artery, selective catheterization of the gastroduodenal and left gastric arteries was performed with a 2.5-French microcatheter (Cantata, Cook Medical, Bloomington). To prevent non-target embolization outside the liver, embolization of both arteries was performed using an experimental gel made of chitosan-sodium tetradecyl sulfate and / or microcoils (Nester® Embolization Microcoil, Cook Medical) (Fig. 8B). Then, 2,999 MMRs were injected in free flow in the angiography suite. An MRI of the explanted liver was performed after the sacrifice of the 2 animals (Tl-VIBE acquisitions, out-of-phase: TR = 5.2 ms, TE = 1.4 ms; in- phase: TR = 5.2 ms, TE = 2.6 ms, flip angle (FA) = 9°, matrix size = 195 x 329, slice thickness = 3 mm, field-of-view (FOV) = 282 mm x 347 mm, BW = 1949 Hz, slice = 72). In all in vivo experiments, the imaging parameters of the Tl-VIBE sequence were kept constant.

[9226] EXEMPLARY STUDY 11:

[9227] The present study pertains to performing a 3D assessment of the anatomy of the hepatic artery and its branch divisions to each liver segment and to determine the best pig position to favor gravity for MRN. The 3D DSA acquisitions of the hepatic artery were performed by manual injection to localize the branch divisions of the hepatic artery. An embolization of the gastroduodenal and left gastric branches was also performed to prevent non-target embolization in the upper gastrointestinal system.

[0228] Then, CBCT acquisitions were performed with contrast injection through the 4-French catheter positioned in the proper hepatic artery to obtain a 3D model of the liver arterial system, in four different positions (0°, 90°, 180°, and 270°). In the blood vessel segmentation process from CBCT images, the reconstruction of segmented vessels was verified by referring to angiography images (Fig. 7A). It was ensured that even small vessels were visible, and that vessel information, including those crucial for navigating to different liver lobes, was not lost during the segmentation process.

[0229] EXEMPLARY STUDY 12:

[0230] The present study pertains to MMR injection in the control and navigation groups.

[0231] For the 4 pigs in the control group, the cobra Glidecath catheter was placed 3 cm below the first bifurcation (left and right hepatic arteries) in preparation for aggregate injections. All control pigs were positioned in the supine position.

[0232] For the pigs in the two navigation groups, a 5-French balloon catheter (2-cm long balloon with 6-mm inflated diameter, Powerflex P3, Cordis, USA) was positioned in the proper hepatic artery. The pigs were rotated to the optimal MRN position (Figure 11) obtained by using the algorithm proposed above.

[0233] Animals were transferred to the MRI room. MRA was acquired in the coronal plane according to the arterial phase with a Tl-weighted gradient-recalled sequence (TR = 3.33 ms, TE = 1.23 ms, flip angle = 19°, FOV=300, 0.78 mm in-plane isotropic voxel and 0.8 slice thickness) under breath hold, after intravenous injection of 0.5 mmol / kg of gadolinium (Prohance, Bracco Imaging, Anjou, Quebec). The imaging has a seven-second delay after bolus tracking in the proximal abdominal aorta.

[0234] For each pig in the control group, the cobra catheter was connected to the MRI- compatible injector to allow the injection of microrobots in free flow and without navigation.

[0235] For the pigs in the navigation groups, the blood flow rate in the proper hepatic artery was reduced to an appropriate range compatible with MRN. The high-precision MRI-compatible balloon inflation system was connected to 1) the balloon inflation port of the catheter to inflate the balloon and 2) the guidewire lumen port to monitor the blood pressure. The blood flow rate in the proper hepatic artery was measured using the 2D cine phase-contrast sequence (TR = 50.32 ms, TE = 3.61 ms, FA = 20°, FOV = 200 mm, voxel size = 0.39 mm x 0.39 mm x 3.70 mm) under cardiac gating and breath hold. The measurement was taken on a cross-section perpendicular tothe long axis of the proper hepatic artery. Flow measurements were repeated for different balloon inflation volumes until the blood flow rate was reduced to ~0.5 to 1.0 mL / s. Then, the balloon inflation port was closed, and the guidewire lumen port of the catheter was connected to the MRI- compatible injector to allow the injection of MMRs in the proper hepatic artery.

[0236] EXEMPLARY STUDY 13:

[0237] When magnetic microrobots move within blood vessels, their motion can be simply decomposed into two components: Uf along the direction of blood flow and Ug perpendicular to the direction of blood flow (Figs. 15A-15B). Here, we aim to minimize the value toincrease the targeting efficiency of microrobots. Friction of the microrobots with the vessel wall can be considered negligible when the blood flow rate reaches at least approximately 0.7 ml / s, corresponding in these conditions to the minimum value of Uf required. Therefore, to enhance the targeting effectiveness of the microrobot, it is crucial to maximize the velocity Ug) of the microrobot directed towards the target vessel in the radial direction within the blood vessel. It can be deduced that by aligning the gravitational force and the force from MRN towards the target vessel in the radial direction (indicated by the purple arrow direction in Fig. 15 A) within the blood vessel, will increase targeting effectiveness. When performing single branch navigation, it is preferable for the target vessel to be in the sagittal plane and facing downwards, as shown in Fig. 15B. Under this condition, the mechanical equilibrium equation in the direction of Ug is given by

[0238] where Fmis the magnetic force, Fgis the gravitational force of the microrobot, Fbis the buoyant force acting on the microrobot, and Fdis the drag force exerted by the fluid slowing down the microrobot.

[0239] In the field of magnetic gradients, the magnetic force on a particle is Fm= Vp(MV)B where Vp represents the total effective volume of MMRs [m3], M denotes the magnetization level [A / m], and VB is the spatial variation or gradient of the magnetic field [T / m],

[0240] When the particle is moving in a liquid along Ug, the force (Fm+ Fg— Fb) needs to be balanced with the drag force caused by the induced velocity.where p represents the dynamic viscosity of the liquid and r is the particle radius.

[0241] To increase Ug while keeping Fgand Fbconstant, Fmneeds to be increased . Therefore, during the MRN, Uf along the direction of blood flow is the sum of the drag force and thrust force on the microrobot in the blood flow. Ug perpendicular to the direction of blood flow is of the sum of the gravity, buoyancy, and MRN forces.

[0242] EXEMPLARY STUDY 14:

[0243] The magnetic iron oxide nanoparticles were synthesized using the coprecipitation method. To enhance their functionality, the nanoparticles were coated with C12-bisphosphonate. To incorporate these nanoparticles into micro-robotics, a 3D printed micro coflowing system was utilized. In this system, a disperse phase solution (DP) consisting of a 10% (weight / volume) PLGA / dichloromethane mixture and 60 weight% iron oxide nanoparticles was used to generate small droplets through shear force provided by a continuous phase solution, which was a 2% aqueous solution of polyvinyl alcohol (PVA). The droplets were collected in a 500 mL beaker (containing 200 mL of 2% PVA solution) and then subjected to 24 hours of stirring at 200 rpm (revolutions per minute) to facilitate solvent evaporation and densification. Subsequently, the resulting particles were washed three times with water and stored in a freeze-dried environment.

[0244] EXEMPLARY STUDY 15:

[0245] The present study pertained to the fabrication of an MRI-compatible injector to automatically form and inject microrobot aggregates into a catheter inside the MRI bore. The injector is mainly composed of two functional parts: a controller and an MRI-compatible actuator. The controller sets a threshold of resistance, proportional to the number of particles, to capture magnetic microrobots and release one microrobot aggregate. The actuator, located 185 cm away from the MRI iso-center, measures the resistance signal to monitor the particle counts while acting as a mechanical actuator to trap and release particle aggregates.

[0246] EXEMPLARY STUDY 16:

[0247] The present study pertains to determining an MRN sequence.

[0248] MRN uses gravity and magnetic gradients to steer the magnetic aggregates across the bifurcations of the hepatic arteries. The MRN sequence is based on the Echo Planar Readout code which takes account into gradient cooling, ensuring that the MRI scanner can maintain its nominal value for the steering duration. The gradient durations are 8 ms in the horizontal direction (26.5 mT / m, left or right) and gravity direction (18 mT / m), yielding a 32 mT / m nominal amplitude for 29.5% duty cycle given the TR = 14 ms and the maximum gradient = 43 mT / m. After MRA wascompleted in pigs, the orientation of the first targeted vessel branch (left or right hepatic artery) was examined. A gradient of 18 mT / m was applied in the downward direction (gravity direction), and the gradient magnitude in the horizontal direction (left or right) was adjusted to try to align the vector direction of the total gradients to the targeted vessels in the transverse plane, indicating the orientation of MRN force as shown in Figure 15A on the right side. Therefore, after rotating the subject to the optimized rotation angle, we further maximized the MRN gradient directed towards the target vessel.

[0249] EXEMPLARY STUDY 17:

[0250] The present study pertains to calculating a rang of optimal body positions.

[0251] After obtaining the vascular tree from CBCT, the 3D geometry of the segmented hepatic artery centerlines is extracted in the VMTK library.

[0252] All results from the VMTL library are pasted into a subfolder (‘example subjectl’) under the ‘data’ folder in our developed MATLAB toolbox. Run ‘test_l subjectin’ in MATLAB.

[0253] The blood vessel number that needs to be targeted in the generated image was confirmed, and the blood vessel number was renewed to line 32 (for example, idArtery = 6;) of ‘test lsubject.m’, and run ‘test lsubject.m’ in MATLAB.

[0254] EXEMPLARY STUDY 18:

[0255] The present study pertains to selecting a single body position angle to target each liver lobe.

[0256] Here, Fig. 8 and Fig. 14 are combined to illustrate how to determine the single body position angle to target each liver lobe in pig#8. After the hepatic artery was assessed during CBCT acquisitions in four positions (supine (0°), lateral right (90°), prone (180°), and lateral left (270°), see Figs. 8A-8C)), the ranges of the optimal body positions were calculated (Figs. 8D-8G). The Vmin in Fig. 14 was calculated based on the results Figs. 8D-8G. The selected Vmin (based on the flowchart provided in Fig. 14) has been marked with a yellow background. To target the RLL+CL (j = 1), RML (j = 2), LLL ( j = 3) and LML (j = 4), the optimal pig’s position angle can respectively be -50° (posture position 0° (i = 1), Vmin = 0°, Fig. 8D), -175° (posture position 180° (i = 3), Vmin = 0°, table S2 and Fig. 8E), -210° (posture position 180° (i = 3), Vmin = 10°, Fig. 8F) and -250° (posture position 270° (i = 4), Vmin = 0°, Fig. 8G).

[0257] Table 1 illustrates the proportion of MMRs entering four lobes (control group) and the targeted liver lobe (navigation groups):Table 1: The proportion of MMRs entering four liver lobes (control group) and the targeted liver lobe (navigation groups).Table 2 shows the Vmin values to target each liver lobe in pig#8.Table 2: The Vmin values to target each liver lobe in pig#8.

[0258] EXEMPLARY STUDY 19:

[0259] The present study pertains to post-processing of MMR-induced artifacts on the Tl- VIBE acquisitions.

[0260] After Tl-VIBE imaging, the original MR images were loaded into a post-processing software (3D Slicer) to analyze the susceptibility artifact volume. MMR artifacts were segmented slice by slice; and the number of particles in each artifact was calculated from the relationshipbetween the number of voxels in the artifact and the number of particles. Vascular segmentations of CBCT acquisitions including segmental and subsegmental arteries were manually aligned with segmentations of MRA on proximal arteries to localize MMR aggregates in the proper segment.

[0261] Although the invention has been described with reference to preferred embodiments, it is to be understood that modifications may be resorted to as will be apparent to those skilled in the art. Such modifications and variations are to be considered within the purview and scope of the present invention.

[0262] Representative, non-limiting examples of the present invention were described above in detail with reference to the attached drawing. This detailed description is merely intended to teach a person of skill in the art further details for practicing preferred aspects of the present teachings and is not intended to limit the scope of the invention. Furthermore, each of the additional features and teachings disclosed above and below may be utilized separately or in conjunction with other features and teachings.

[0263] Moreover, combinations of features and steps disclosed in the above detailed description, as well as in the experimental examples, may not be necessary to practice the invention in the broadest sense, and are instead taught merely to particularly describe representative examples of the invention. Furthermore, various features of the above-described representative examples, as well as the various independent and dependent claims below, may be combined in ways that are not specifically and explicitly enumerated in order to provide additional useful embodiments of the present teachings.

[0264] References:1. Dupont PE, Nelson BJ, Goldfarb M, et al. A decade retrospective of medical robotics research from 2010 to 2020. Sci Robot 2021;6:eabi8017.2. Nelson BJ, Kaliakatsos IK, Abbott JJ. Microrobots for minimally invasive medicine. Annu Rev Biomed Eng 2010;12:55-85.3. Li J, Li X, Luo T, et al. Development of a magnetic microrobot for carrying and delivering targeted cells. Sci Robot 2018;3:eaat8829.4. Li J, Esteban-Fernandez de Avila B, Gao W, Zhang L, Wang J. Micro / nanorobots for biomedicine: Delivery, surgery, sensing, and detoxification. Sci Robot 2017;2:eaam6431.5. Law J, Wang X, Luo M, et al. Microrobotic swarms for selective embolization. Sci Adv 2022;8:eabm5752.6. Sitti M. Mobile microrobotics: MIT Press; 2017.7. Lee C-Y, Chau G-Y, Wei C-Y, et al. Surgical resection could provide better outcomes for subjects with hepatocellular carcinoma and tumor rupture. Sci Rep 2022;12: 1-9.8. Odisio BC, Ashton A, Yan Y, et al. Transarterial hepatic chemoembolization with 70-150 microm drug-eluting beads: assessment of clinical safety and liver toxicity profile. J Vase Interv Radiol 2015;26:965-71.9. He M, Jiang N, Yin X, Xu A, Mu K. Conventional and drug-eluting beads transarterial chemoembolization in subjects with unresectable intrahepatic cholangiocarcinoma: a systematic review and pooled analysis. J Cancer Res Clin Oncol 2023;149:531-40.10. Gaba RC, Lokken RP, Hickey RM, et al. Quality Improvement Guidelines for Transarterial Chemoembolization and Embolization of Hepatic Malignancy. J Vase Interv Radiol 2017;28: 1210-23 e3.11. Popovic P, Stabuc B, Jansa R, Garbajs M. Survival of subjects with intermediate stage hepatocellular carcinoma treated with superselective transarterial chemoembolization using doxorubicin-loaded DC Bead under cone-beam computed tomography control. Radiat Oncol 2016;50:418-26.12. Tous C, Li N, Dimov IP, et al. Navigation of microrobots by MRI: Impact of gravitational, friction and thrust forces on steering success. Ann Biomed Eng 2021;49:3724-36.13. Fonseca ADC, Kohler T, Ahmed D. Ultrasound-Controlled Swarmbots Under Physiological Flow Conditions. Adv Mater Interfaces 2022;9:2200877.14. Chen R, Folio D, Ferreira A. Analysis and comparison of electromagnetic microrobotic platforms for biomedical applications. Appl Sci 2022; 12:456.15. Salehizadeh M, Diller E. Three-dimensional independent control of multiple magnetic microrobots via inter-agent forces. Int J Robot Res 2020;39: 1377-96.16. Pane S, lacovacci V, Ansari MHD, Menciassi A. Ultrasound-guided navigation of a magnetic microrobot using acoustic phase analysis. Sci Rep 2021;l l :23239.17. Bigot A, Tremblay C, Soulez G, Martel S. Magnetic resonance navigation of a bead inside a three-bifurcation pmma phantom using an imaging gradient coil insert. IEEE Trans Robot 2014;30:719-27.18. Martel S, Mathieu J-B, Felfoul O, et al. Automatic navigation of an untethered device in the artery of a living animal using a conventional clinical magnetic resonance imaging system. Appl Phys Lett 2007;90: 114105.19. Lee KH, Liapi E, Vossen JA, et al. Distribution of iron oxide-containing Embosphere particles after transcatheter arterial embolization in an animal model of liver cancer: evaluation with MR imaging and implication for therapy. J Vase Interv Radiol 2008; 19: 1490-6.20. Jeon S, Kim S, Ha S, et al. Magnetically actuated microrobots as a platform for stem cell transplantation. Sci Robot 2019;4:eaav4317.21. Go G, Yoo A, Nguyen KT, et al. Multifunctional microrobot with real-time visualization and magnetic resonance imaging for chemoembolization therapy of liver cancer. Sci Adv 2022;8:eabq8545.22. Wu Z, Li L, Yang Y, et al. A microrobotic system guided by photoacoustic computed tomography for targeted navigation in intestines in vivo. Sci Robot 2019;4:eaax0613.23. Li D, Liu C, Yang Y, Wang L, Shen Y. Micro-rocket robot with all-optic actuating and tracking in blood. Light Sci Appl 2020;9:84.24. Jooss VM, Bolten JS, Huwyler J, Ahmed D. In vivo acoustic manipulation of microparticles in zebrafish embryos. Sci Adv 2022;8:eabm2785.25. Yu J, Jin D, Chan K-F, Wang Q, Yuan K, Zhang L. Active generation and magnetic actuation of microrobotic swarms in bio-fluids. Nat Commun 2019;10: 1-12.26. Kim E, Jeon S, An H-K, et al. A magnetically actuated microrobot for targeted neural cell delivery and selective connection of neural networks. Sci Adv 2020;6:eabb5696.27. Ramos-Sebastian A, Gwak SJ, Kim SH. Multimodal Locomotion and Active Targeted Thermal Control of Magnetic Agents for Biomedical Applications. Adv Sci 2022;9:2103863.28. Son D, Ugurlu MC, Sitti M. Permanent magnet array-driven navigation of wireless millirobots inside soft tissues. Sci Adv 2021;7:eabi8932.29. Wang Q, Chan KF, Schweizer K, et al. Ultrasound Doppler-guided real-time navigation of a magnetic microswarm for active endovascular delivery. Sci Adv 2021;7:eabe5914.30. Graser M, Thieben F, Szwargulski P, et al. Human-sized magnetic particle imaging for brain applications. Nat Commun 2019; 10: 1936.31. Li N, Michaud F, Nosrati Z, et al. MRI-compatible injection system for magnetic microparticle embolization. IEEE Trans Biomed Eng 2018;66:2331-40.32. Pouponneau P, Leroux J-C, Soulez G, Gaboury L, Martel S. Co-encapsulation of magnetic nanoparticles and doxorubicin into biodegradable microcarriers for deep tissue targeting by vascular MRI navigation. Biomaterials 2011 ;32: 3481 -6.33. Li N. Flow control and MRI-compatible particle injector: application to magnetic resonance navigation. Canada: thesis, Ecole Polytechnique, Montreal; 2019.34. Michaud F, Li N, Plantefeve R, et al. Selective embolization with magnetized microbeads using magnetic resonance navigation in a controlled-flow liver model. Med Phys 2019;46:789-99.35. Ramos-Sebastian A, Gwak SJ, Kim SH. Multimodal Locomotion and Active Targeted Thermal Control of Magnetic Agents for Biomedical Applications. Adv Sci 2022;9:2103863. 36. Fan Q, Eichner C, Afzali M, et al. Mapping the human connectome using diffusion MRI at 300 mT / m gradient strength: Methodological advances and scientific impact. Neuroimage 2022;254: 118958.

Claims

What is claimed is:

1. A method of preparing a subject for steering particles to a target site in the subject using a physical field, comprising: receiving image information of a body of the subject to obtain an image of at least a part of a vascular system of the subject; and determining a pathway through the vascular system of the subject from a release site to the target site and identifying a target body position of the subject by factoring a force of gravity on a direction of the particles relative to the pathway of the vascular system to improve steering of the particles through the pathway of the vascular system of the subject to the target site when the subject is placed in the target body position.

2. The method as defined in claim 1, wherein the determining a pathway includes identifying vascular bifurcations from the release point to the target site, and wherein the identifying of the target body position includes identifying consecutive vascular bifurcations of the vascular bifurcations that facilitate the navigation of the particles from the release point to the target site while being favoured by the force of gravity in the target body position.

3. The method as defined in claim 2, wherein identifying the target range includes defining a range of optimal body rotation angles (ri) when angles of the range of optimal body rotation angles meet the following conditions: Targeted\6 — 0 ■> <1114^■Targeted\6 — NonTargeted\9 wherein aTargetedigis the angle between a horizontal plane and a body rotation angle of a targeted blood vessel at the vessel bifurcation of the selected pathway, and aNonTargeted gis the angle between the horizontal plane and an body rotation angle of a non-targeted vessel branch at the vessel bifurcation.

4. The method as defined in any one of claims 1 to 3, wherein the identifying of the target body rotation angle comprises selecting the target body position amongst a target range of body rotation angles (0) wherein rotation angles within the target range of body rotation angles satisfy the following conditions: Targeted\6 — 0 ■> <1114^Targeted\ 6 — ^NonTargeted\6 •5. The method as defined in any one of claims 1 to 4, wherein identifying the target body rotation angle of the subject comprises performing imagery on the subject in one or more of the following positions of the subject:- a right side;- a left side;- a prone position; and- a supine position.

6. The method as defined in any one of claims 1 to 5, wherein the particles are microrobots.

7. The method as defined in any one of claims 1 to 6, where the imagery is performed using cone-beam computer tomography.

8. The method as defined in any one of claims 1 to 7, wherein the performing of the imagery is carried out for different positions of the subject.

9. The method as defined in claim 8, wherein the performing of the imagery is carried out for each of the following different positions of the subject:- a supine position;- a prone position;- a lateral right position; and- a lateral left position.

10. The method as defined in any one of claims 1 to 9, wherein the physical field is a magnetic field and the particles are magnetic particles.

11. The method as defined in any one of claims 1 to 9, wherein the physical field is one of an electric field, a gravitational field, a temperature field, a velocity field, a pressure field, an acoustic field and a quantum field.

12. The method as defined in any one of claims 1 to 10, further comprising positioning the subject in the target body position.

13. A method of causing a navigation of the particles to the target site in the subject using the physical field comprising: performing the method as defined in claim 12; introducing the particles into the subject at the release site; and applying the physical field to the particles to cause a navigation of the particles to the target site.

14. The method as defined in claim 13, further comprising partially inflating an occlusion balloon catheter located in a blood vessel of the subject to reduce blood flow rate in the blood vessel.

15. The method as defined in claim 13 or claim 14, further comprising obtaining phase contrast magnetic resonance imaging sequences to plan and monitor blood flow rate in downstream vessels which comprise the targeted blood vessel.

16. The method as defined any one of claims 13 to 15, wherein the introducing is performed via injection of the particles, prepared with an automated injector, to enhance a dipole-dipole interaction and steering force between the particles forming an aggregate.

17. The method as defined in any one of claims 13 to 16, wherein physical field is a magnetic field, and the applying the physical field comprises generating a main magnetic field (BO) using a magnetic resonance imaging (MRI) machine, a radiofrequency field (B ) applied perpendicular to the main magnetic field (Bo), and calibrating distortions of the main magnetic field in x-,y- or z- directions using gradient coils.

18. The method as defined in any one of claims 13 to 17, further comprising locating the particles on magnetic resonance images through distortion caused by the particles on the magnetic resonance magnetic field.

19. A system for preparing a subject for steering particles to a target site in the subject using a physical field, the system comprising: a processor; and memory comprising program code that, when executed by the processor, cause the processor to: receive image information of a body of the subject to obtain an image of at least a part of a vascular system of the subject; determine a pathway through the vascular system of the subject from a release site to the target site and identify a target body position of the subject by factoring a force of gravity on a direction of the particles relative to the pathway of the vascular system to improve steering of the particles through the pathway of the vascular system of the subject to the target site when the subject is placed in the target body position.

20. A non-transitory computer-readable medium having stored thereon program instructions for preparing a subject for steering particles to a target site in the subject using a physical field, the program instructions executable by a processing unit for: receiving image information of a body of the subject to obtain an image of at least a part of a vascular system of the subject; determining a pathway through the vascular system of the subject from a release site to the target site and identifying a target body position of the subject by factoring a force of gravity on a direction of the particles relative to the pathway of the vascular system to improve steering of the particles through the pathway of the vascular system of the subject to the target site when the subject is placed in the target body position.

Images