Motorized and manually operated medical devices for radiation-oncology brachytherapy and other applications

Abstract

A medical device with a tracked injection needle or elongated probe is disclosed. The medical device includes a tracking element operably connected to the tip of the elongated probe. The tracking element is operably connected, or connectable, to a tracking apparatus that is configured to actively track positioning of the tip of the elongated probe in substantially real¬ time when the elongated probe is inserted into a tissue. The medical device can be manually driven to the target using information from the tip tracking or coupled with a motor that assists in directing the navigation to the target.

Description

Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 MOTORIZED AND MANUALLY OPERATED MEDICAL DEVICES FOR RADIATION-ONCOLOGY BRACHYTHERAPY AND OTHER APPLICATIONS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U. S. Provisional Patent Application Ser. No.63 / 735,111, filed December 17, 2024, the disclosure of which is incorporated herein by reference.GOVERNMENT RIGHTS

[0002] This disclosure was made with Government support under Contracts No. R01 CA237005 and R01 EB034359-01 awarded by the National Institutes of Health. The Government has certain rights in the invention.FIELD

[0003] The present teachings generally relate to medical devices for performing various medical applications, including radiation-oncology brachytherapy.BACKGROUND

[0004] Interstitial Brachytherapy is a radiation oncology method that involves the insertion of focal radiation sources directly into a tumor and its surroundings. The goal of effective radiation treatment of tumors is to provide maximal radiation dose to all parts of the tumor, while sparing radiation from surrounding normal tissues. In some cases, there are surrounding tissues which are especially sensitive to radiation, or the tissues are very close to the treated region so that it is difficult to reduce the dose they receive. To resolve the above issues, it is now also possible to insert materials in order to increase the space between the tumor and the tissues that should be spared. A common way to do that is to inject polymer hydrogels or liquids into specific interfaces between tissues, so as to create anatomic “pockets” that are filled with this material, which then serves to distance the sensitive tissue and reduce the received radiationAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 dose. These biocompatible polymer hydrogels are intended to be absorbed by the body once the radiation delivery procedure is complete.

[0005] The goal of successful pre-procedural injection is to insert the hydrogel into the correct location and establish that the dimensions of the pocket meet the radiation dose reduction by spacing requirements. This task is commonly accomplished by using an imaging modality that detects the position of the injection needle relative to its desired final location, and can show the topology of the injected pocket. The desire is that this needle deployment procedure: (I) uses a minimal amount of time, (II) provides optimal visualization of the needle position during its navigation to the target region, and (III) shows the hydrogel pocket’s topology (volume, shape) during the filling of the pocket. Hydrogels are used in brachytherapy, in which spatially-localized radiation sources are inserted into the tumor and its surroundings, in order to further distance sensitive non-cancerous normal tissues from the radiation dose. Hydrogels are also used in external beam radiation therapy (EBRT) with the same rationale, to distance non-cancerous normal tissue structures, called organs at risk (OARs).

[0006] Additional applications relevant to Radiation Oncology brachytherapy are the insertion of metallic stylets that are surrounded by plastic cylindrical covers with a sharp tip that are referred to as “catheters”. The stylet, covered by the catheter, is inserted from the skin to regions within or surrounding the tumor(s), which requires use of a strong material that can penetrate the skin and all the tissues between the surface and the tumor(s). The stylet is then withdrawn, while the catheter is left inside the tumor(s). This procedure is repeated, so that multiple stylets remain inside the tumor(s). At the next step, radiation sources are inserted into the catheters, which irradiate the tumor(s), each leading to the death of a region of the tumor that is adjacent to them. There is a need to insert the catheters accurately into all visible and / or suspected regions of the tumor(s).Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02

[0007] Similar situations exist for thermal ablations performed by interventional radiologists. In these cases, special invasive probes are used to deliver thermal or cooling (cryogenic) energy to specific tumor regions, but this energy tends to diffuse or flow away from the delivery location, and can therefore damage surrounding tissues. Here again, it is possible to place pockets of hydrogel that have a low thermal conduction, so that the propagation of the thermal (or cooling) front be steered away from sensitive tissues. Another analogous situation is performing image-guided biopsy of pathologies (tumors), where there is a need to accurately bring the biopsy needle from the skin incision point to the imaging modality visualized regions of the pathology, in order to sample as much of the pathology, which may have heterogenous regions such as necrotic regions, so as to best diagnose the pathology, while not puncturing un-necessary tissues. Additional analogous situations occur during the injection of chemotherapy agents into tumors through their feeding blood vessels, and / or to the blocking of specific blood vessels with embolizing particles.

[0008] In most situations, the interventional devices employed have a very small (<2mm) diameter, in order to minimize tissue puncture injury, and typically have a length / diameter ratio»l, which is needed in order to manipulate them from outside the body (i.e. from their proximal end). The best materials from which these devices are constructed are metals with large (Young’s and Torsional) elastic moduli such as stainless steel or titanium.

[0009] Most of these injection procedures are today performed under X-ray or Ultrasound (ULS) guidance. Magnetic Resonance Imaging (MRI) sequences can be used to visualize the above procedures, but this is not commonly performed. This is because: (A) MRI applications require the use of MRI-conditional interventional devices that can be safely used inside the MRI scanner, which restricts the material choices (ferromagnetic and high paramagnetic materials cannot be used), which may require the use of materials with suboptimal mechanical properties, and may restrict the geometry of the devices, since lengths larger than an MRIAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 Radio-frequency quarter- wavelength typically are not used to reduce the risk of radiofrequency heating; (B) Passive spatial localization (“tracking”) of devices, which entails seeing the needles without adding special sensors onto the device shaft, is easy to perform with X-ray or ULS monitoring, but it is quite time inefficient when used with MRI, since it is difficult to accurately locate metallic devices in the MRI scanner without employing high resolution sequences, which require long imaging times. The image processing to obtain the needle location also requires a significant amount of time, which adversely affects the overall clinical workflow.

[0010] Accordingly, there is a need for additional medical devices, and related aspects, for performing various medical applications, such as radiation-oncology brachytherapy. The medical devices discussed can be manually navigated (i.e. pushed, deflected) by a human operator based on information from sensors on the devices to bring them to the desired target, which is referred to herein as a steerable needle. Alternatively, the devices can be navigated using on-board motors which autonomously steer, or assist in the human operator’s steering, the device to the target, which is referred to herein as a motorized steerable needle.SUMMARY

[0011] In accordance with examples of the present disclosure, a medical device is disclosed. The medical device comprises at least one elongated probe insertable into at least one tissue; at least one tracking element operably connected to the elongated probe, which tracking element is operably connected, or connectable, to at least one tracking apparatus that is configured to actively track positioning of at least portions of the elongated probe in substantially real-time at least when the elongated probe is inserted into the tissue; and, at least one handle operably connected at least to the elongated probe, wherein the elongated probe comprises at least one outer tube structure having an outer tube cavity disposed longitudinallyAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 along at least a portion of a length of the outer tube structure and at least one inner tube structure having an inner tube cavity disposed longitudinally along at least a portion of a length of the inner tube structure, wherein the length of the outer tube structure is less than the length of the inner tube structure, wherein the outer tube structure comprises at least first and second outer tube structure openings disposed proximal to a distal end of, and along at least a segment of the length of, the outer tube structure, which outer tube structure openings are in communication with the outer tube cavity, wherein the inner tube structure comprises at least first and second inner tube structure openings along at least a segment of the length of the inner tube structure, which inner tube structure openings are in communication with the inner tube cavity, wherein the inner tube structure is disposed substantially within the outer tube cavity proximal to the distal end of the outer tube structure such that the outer tube structure openings substantially align with the inner tube structure openings to produce aligned openings, and wherein the tracking element is disposed in at least one of the aligned openings. In some embodiments, the present disclosure provides a catheter that comprises a bevel-tip, wherein an elongated probe of a device described herein is insertable into a channel disposed through the catheter.

[0012] Various additional features of the medical device can be included such as one or more of the following. The elongated probe comprises sufficient flexibility and sufficient strength to bend by about 90° without having a structural failure when inserted in the tissue. The elongated probe is fabricated from nitinol. The elongated probe is at least about 10 cm, about 20 cm, about 30 cm, about 40 cm, about 50 cm, or more in length. The elongated probe comprises a stylet. The medical device further comprises a catheter through which the elongated probe is at least partially disposed, wherein the catheter comprises a bevel-tip. The elongated probe is configured to be manually inserted into the tissue. The elongated probe is configured to be directionally deflected while being manually inserted into the tissue using aAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 motor, or both directionally deflected and inserted into the tissues using multiple motors that are housed within the handle and operably connected to the elongated probe. The tracking element is configured to track positions of at least portions of the elongated probe at one or more time points when the elongated probe is inserted into the tissue. The tracking element comprises one or more of an electromagnetic (EM) tracking element, a light-wave interference tracking element (FBG), a magnetic resonance (MR)-tracking element, and / or an electrical impedance tracking element. The tracking element is operably connected to the inner tube structure. Tracking methods with sensors placed close to the tip which provide only the spatial location of the sensor (3 degrees of freedom), and not the orientation of the sensor (which is an additional 3 degrees of freedom), require use of at least 2 sensors for guidance, since guidance requires knowing the instantaneous location and orientation of the device tip, while tracking methods that provide 5-6 degrees of freedom in a single sensor generally require only one sensor for guidance, but cannot be used in the MRI. A kit comprises the medical device. A system comprises the medical device.

[0013] Various additional features of the medical device can also be included such as one or more of the following. The tracking element comprises at least one magnetic resonance (MR)-tracking coil. The medical device includes a proximal MR-tracking coil and a distal MR-tracking coil, wherein the proximal MR-tracking coil is disposed in a proximal aligned opening, wherein the distal MR-tracking coil is disposed in a distal aligned opening, and wherein the proximal aligned opening is located closer to the handle than the distal aligned opening. Cables operably connect the proximal MR-tracking coil and the distal MR-tracking coil tracking apparatus. At least portions of the cables are disposed through at least a segment of the inner tube cavity. The handle comprises tuning and matching electronic components that are operably connected to the cables, which tuning and matching electronic components areAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 configured to tune an MR-tracking circuit that comprises the proximal MR-tracking coil and the distal MR-tracking coil to a selected frequency and to a selected impedance.

[0014] Various additional features of the medical device can also be included such as one or more of the following. The elongated probe is insertable into the tissue via an ancillary medical apparatus. The elongated probe is sufficiently flexible to bend within a curved pathway fabricated at least partially within the ancillary medical apparatus. The ancillary medical apparatus comprises a gynecological applicator device. The ancillary medical apparatus is configured to deliver one or more doses of a therapeutic agent to the tissue when the ancillary medical apparatus is disposed within sufficient proximity to the tissue. The therapeutic agent comprises a radiopharmaceutical agent.

[0015] Various additional features of the medical device can also be included such as one or more of the following. The medical device further comprises at least one imaging element operably connected to the elongated probe, which imaging element is operably connected, or connectable, to at least one imaging apparatus that is further configured to capture one or more images of the elongated probe and / or the tissue in substantially real-time at least when the elongated probe is inserted into the tissue. The imaging element is disposed in at least one of the aligned openings. The imaging element comprises one or more of an X-ray imaging element, a computed tomography (CT) imaging element, an ultrasound (ULS) imaging element, a magnetic resonance (MR) imaging element, and / or a positron emission tomography (PET) imaging element.

[0016] In accordance with examples of the present disclosure, a system is disclosed. The system a medical device, comprising: at least one elongated probe insertable into at least one tissue; at least one tracking element operably connected to the elongated probe, which tracking element is operably connected, or connectable, to at least one tracking apparatus; and, at least one handle operably connected at least to the elongated probe, wherein the elongated probeAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 comprises at least one outer tube structure having an outer tube cavity disposed longitudinally along at least a portion of a length of the outer tube structure and at least one inner tube structure having an inner tube cavity disposed longitudinally along at least a portion of a length of the inner tube structure, wherein the length of the outer tube structure is less than the length of the inner tube structure, wherein the outer tube structure comprises at least first and second outer tube structure openings disposed proximal to a distal end of, and along at least a segment of the length of, the outer tube structure, which outer tube structure openings are in communication with the outer tube cavity, herein the inner tube structure comprises at least first and second inner tube structure openings along at least a segment of the length of the inner tube structure, which inner tube structure openings are in communication with the inner tube cavity, wherein the inner tube structure is disposed substantially within the outer tube cavity proximal to the distal end of the outer tube structure such that the outer tube structure openings substantially align with the inner tube structure openings to produce aligned openings, and wherein the tracking element is disposed in at least one of the aligned openings; at least one tracking apparatus operably connected, or connectable, to the tracking element, which tracking apparatus comprises at least one controller that comprises, or is capable of access, computer readable media comprising computer-executable instructions which, when executed by at least one electronic processor, perform at least: actively tracking one or more positions of at least portions of the elongated probe in substantially real-time at least when the elongated probe is inserted into the tissue.

[0017] In accordance with examples of the present disclosure, a method of tracking a medical device in a subject is disclosed. The method comprises inserting at least a portion of at least one elongated probe of a medical device into at least one tissue of the subject, wherein the medical device further comprises: at least one tracking element operably connected to the elongated probe, which tracking element is operably connected, or connectable, to at least oneAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 tracking apparatus that is configured to actively track positioning of the elongated probe in substantially real-time at least when the elongated probe is inserted into the tissue; and, at least one handle operably connected at least to the elongated probe, wherein the elongated probe comprises at least one outer tube structure having an outer tube cavity disposed longitudinally along at least a portion of a length of the outer tube structure and at least one inner tube structure having an inner tube cavity disposed longitudinally along at least a portion of a length of the inner tube structure, wherein the length of the outer tube structure is less than the length of the inner tube structure, wherein the outer tube structure comprises at least first and second outer tube structure openings disposed proximal to a distal end of, and along at least a segment of the length of, the outer tube structure, which outer tube structure openings are in communication with the outer tube cavity, wherein the inner tube structure comprises at least first and second inner tube structure openings along at least a segment of the length of the inner tube structure, which inner tube structure openings are in communication with the inner tube cavity, wherein the inner tube structure is disposed substantially within the outer tube cavity proximal to the distal end of the outer tube structure such that the outer tube structure openings substantially align with the inner tube structure openings to produce aligned openings, and wherein the tracking element is disposed in at least one of the aligned openings; and actively tracking one or more positions of at least portions of the elongated probe in substantially real-time when the elongated probe is inserted into the tissue using the tracking element, thereby tracking the medical device in the subject. In some embodiments, the method further comprises delivering one or more hydrogels at least proximal to the tissue and / or one or more doses of a therapeutic agent to the tissue.

[0018] In accordance with examples of the present disclosure, a method of making a medical device is disclosed. The method includes forming at least one elongated probe that is insertable into at least one tissue such that: the elongated probe comprises at least one outerAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 tube structure having an outer tube cavity disposed longitudinally along at least a portion of a length of the outer tube structure and at least one inner tube structure having an inner tube cavity disposed longitudinally along at least a portion of a length of the inner tube structure, the length of the outer tube structure is less than the length of the inner tube structure, the outer tube structure comprises at least first and second outer tube structure openings disposed proximal to a distal end of, and along at least a segment of the length of, the outer tube structure, which outer tube structure openings are in communication with the outer tube cavity, the inner tube structure comprises at least first and second inner tube structure openings along at least a segment of the length of the inner tube structure, which inner tube structure openings are in communication with the inner tube cavity, and the inner tube structure is disposed substantially within the outer tube cavity proximal to the distal end of the outer tube structure such that the outer tube structure openings substantially align with the inner tube structure openings to produce aligned openings, operably connecting at least one tracking element to the elongated probe, which tracking element is operably connected, or connectable, to at least one tracking apparatus that is configured to actively track positioning of at least portions of the elongated probe in substantially real-time at least when the elongated probe is inserted into the tissue, wherein the tracking element is disposed in at least one of the aligned openings; and, operably connecting at least one handle at least to the elongated probe, thereby making the medical device.BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The accompanying drawings, which are incorporated in, and constitute a part of this specification, illustrate implementations of the present teachings and, together with the description, serve to explain the principles of the disclosure. In the figures:

[0020] FIG. 1A schematically shows a medical device referred to as an MR-actively-tracked metallic stylet with a detailed view of the tip of that device from perspective viewsAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 according to examples of the present disclosure. This device is used for manual (nonmotorized) navigation to the target.

[0021] FIG. 1B schematically shows the tip of the device from FIG. 1A from a sectional side view according to examples of the present disclosure.

[0022] FIGS. 2 A and 2B show photographs of a medical device having an MR-actively-tracked flexible stylet at a distal end of the device and a plastic catheter, which is placed around the device during the brachytherapy insertion procedure, according to examples of the present disclosure.

[0023] FIG. 3 shows a flexible stylet after passage through an ancillary medical apparatus (a gynecological applicator device, namely, an Elektra Venezia Ovoid Ring) from a side view in a phantom tissue according to examples of the present disclosure.

[0024] FIGS. 4A and 4B show pictures of the tuning of MR-tracking coils using a Network Analyzer prior to passage through an ancillary medical apparatus (Elektra Venezia Ovoid Ring) ((A) distal coil (-31dB at 63.8MHz) and (B) proximal coil (-23dB at 63.8MHz)) according to examples of the present disclosure.

[0025] FIGS. 5A and 5B show pictures of the tuning of MR-tracking coils using an electronic Network Analyzer after passage through an ancillary medical apparatus (Elektra Venezia Ovoid Ring) ((A) distal coil (-44dB at 63.8MHz) and (B) proximal coil (-23dB at 63.8MHz)) according to examples of the present disclosure.

[0026] FIGS. 6 A and 6B schematically show a medical device with a motorized handle at its proximal end and an MR-actively-tracked stylet at its distal end (“a motorized steerable needle”) from a side view and a side view with half of the handle removed, respectively, according to examples of the present disclosure.

[0027] FIG. 7 schematically shows aspects of a medical device with a motorized handle at its lower end and an MR-actively-tracked stylet at its upper end (“a motorized steerableAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 needle”) from a side sectional view with a detail view according to examples of the present disclosure.

[0028] FIGS. 8 A and 8B schematically show a medical device with a motorized handle at one end and an MR-actively-tracked stylet at the other end (“a motorized steerable needle”) from a side view and a side sectional view, respectively, according to examples of the present disclosure.

[0029] FIG. 9 schematically shows an MR-tracking coil with integrated tuning and matching circuits according to examples of the present disclosure.

[0030] FIG. 10 is a flow chart that schematically shows exemplary method steps of tracking a medical device in a subject according to examples of the present disclosure.

[0031] FIG. 11 is a flow chart that schematically shows exemplary method steps of making a medical device according to examples of the present disclosure.

[0032] FIG. 12 is a photograph showing an example device used for tracking in manually performed MR-guided brachytherapy according to examples of the present disclosure.

[0033] FIGS. 13A-13C are photographs of (A) an example of a needle equipped with MR-Tracking coils, (B) a needle with the EM-tracking coils fixed inside the needle body using heat shrink tubing, and (C) the bevel-tipped catheter surrounding the needle body according to examples of the present disclosure.

[0034] FIGS. 14A and 14B show (A) a schematic representation of the steerable needle and its sequential motion as it moves with respect to the spatial basis toward a target point and (B) a schematic of the needle’ s motion, which is defined by a body twist for a specified duration according to examples of the present disclosure. The body twist is defined by the inputs at the proximal end.

[0035] FIGS. 15A and 15B show: (A) The evolution of the shape of the steerable needle given new inputs. Depicted are the sensor locations, bⱼ, the a posteriori estimate at index i, x̂ᵢ,Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 the a priori estimate at index i + 1, x̂ᵢ₊₁, and the a posteriori estimate at index i + 1, x̂ᵢ₊₁. (B) A close-up of the dashed box in (A). This detailed view provides a representation of the residual input, for the second sensor. Additionally, the relevant transformations of the covariance matrix are depicted.

[0036] FIG. 16 is a photograph showing an experimental setup with an agarose phantom, an EM-tracker, and a needle driver according to examples of the present disclosure.

[0037] FIGS. 17A-17L are plots showing the distribution of the process noise for a gelatin phantom (A)-(F) and an agarose phantom (G)-(L) according to examples of the present disclosure.

[0038] FIGS. 18A-18D are plots showing simulations observing the trajectory tracking capability by plotting the error with respect to the desired trajectory of the extended Kalman filter (EKF) with different time steps (A)-(B) and different sensor measurement noise values (C)-(D) according to examples of the present disclosure. These plots correspond to tissue parameters defined by the gelatin phantom for (A) and (C) and the agarose phantom for (B) and (D).

[0039] FIGS. 19A-19F are plots showing (A) Trajectory 1 for a gelatin phantom, where U = [0, 0, 2, 2 K, 0, 0]T. (B) Trajectory 2 for the gelatin phantom, where U = [0, 0, 2, 2 K, 0, -0.017]T. (C) Trajectory 3 for the gelatin phantom, where U = [0, 0, 2, 2 K, 0, 0.017]T. (D) Trajectory 1 for the agarose phantom, where U = [0, 0, 2, 2 K, 0, 0]T. (E) Trajectory 2 for the agarose phantom, where U = [0, 0, 2, 2 K, 0, -0.017]T. (F) Trajectory 3 for the agarose phantom, where U = [0, 0, 2, 2 K, 0, 0.017]T.

[0040] FIGS. 20A-20H are plots of the trajectories and their corresponding trajectory following errors can be seen for the gelatin phantom. The four targets for each plot are listed by the variable t. (A)-(D) presents each trajectory set with their desired trajectory shown as a black dashed line. (E)-(H) presents their corresponding errors. Note that the trajectories in (A)Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 correspond to the errors in (E), the trajectories in (B) correspond to the errors in (F), and so on. The error between the estimated state and the trajectory is depicted as a solid line, while the error between the measured ground-truth and the trajectory is represented as a dashed line, according to examples of the present disclosure.

[0041] FIGS. 21A-21H are plots of the trajectories and their corresponding trajectory following errors can be seen for the agarose phantom. The four targets for each plot are listed by the variable t. (A)-(D) presents each trajectory set with their desired trajectory shown as a black dashed line. (E)-(H) presents their corresponding errors. Note that the trajectories in (A) correspond to the errors in (E), the trajectories in (B) correspond to the errors in (F), and so on. The error between the estimated state and the trajectory is depicted as a solid line, while the error between the measured position and the trajectory is represented as a dashed line.

[0042] FIGS. 22A-22D are trajectory plots with a perturbation applied to the phantom during the insertion for the (A) gelatin phantom and the (B) agarose phantom. The desired trajectories are represented by the solid black lines. The desired targets are represented by the variable t. The error plots can be seen for the (C) gelatin phantom and the (D) agarose phantom. In (A) and (B), the direction and magnitudes of the perturbation can be seen with corresponding arrows and text values. In (C) and (D), the time of the applied perturbation can be seen with vertical bars.

[0043] FIGS. 23A-23C: Active MRT stylets (A) Flexible and Rigid stylets. (A2) Enlargement of Distal portion of stylet, (A3) 1.5T MRT coil. Left: CAD model, with 4-layer loop antenna and tuning and matching capacitors, Right: Simulated radio-frequency lobe pattern on a metallic surface. (B) Flexible MRT stylets are used for large-angle small-radius deflections, as encountered going through the Elekta Venezia applicator’ s ovoid ring. (C) Rigid MRT stylets are used to traverse elastically harder tissue, as when using Syed-Neblett applicators that do not require large stylet deflections. Images in B and C are from patients,Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 with the CAD models of the applicators imported, registered to the MRI coordinate frame, and shown as applied in practice.

[0044] FIG. 24: Testing the MRT 1.5T SNR in a Humimic-Medical (Greenville, SC) gel phantom while advancing or retracting a new MRT flexible stylet at 0 to 200+mm / s speed. Two tracking spatial-resolutions (1.1x1.1x1.1mm3and 0.8x0.8x0.8mm3) were used, with 20 tracking-point acquisition-trains between imaging portions, a 90flip angle, and either 2 or 1 signal-averages applied. A 0 to 4500μs extension of the base MRT TR (3500μs) was applied (X-axis) to allow T1 relaxation between MRT-readouts. The MRT SNR is defined as the ratio of the mean MRT peaks to the received noise STD. Note that (1) SNR does drop as motional speed increases. (2) Improving SNR by changing from 1 to 2 signal averages is possible at most speeds, while increasing SNR by increasing TR is effective at low speeds, but its utility drops as the speed increases, since the amount of motion between MRT readouts leads to spin dephasing.

[0045] FIGS. 25A-25C: MR-Tracking User Interface (single time-frame obtained during a patient study). Along with the visualization of the Axial (A), Sagittal (B) and Coronal (C) views of the slices that the navigated catheter is currently transversing, there are overlays of boundaries of the tissues targeted (inner grayscale bounded area) and those to be avoided (Bladder (upper grayscale bounded area), Rectum (lower grayscale bounded area)). The anatomy is also overlaid with the currently-deposited dose, where an inner grayscale bounded zone is 200% and an outer grayscale is 50% dose. D shows all the catheters already inserted and a CAD picture of the applicator, showing catheters going through the Venezia or around it. An instantaneous tracking SNR display (E) shows six grayscale peaks highlighting the ratio of signals in 3 spatial directions for each of the two MRT coils versus the noise. A low ratio is used for QA to indicate malfunction of the tracking coils.Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02

[0046] FIG. 26: Multiple catheters are inserted into a tumor in order to provide a homogeneous radiation region. Panels Ai-Bii show axial and sagittal slices of successive catheters brought to differing regions of the tumor, thus enlarging the 100% dose region (an inner grayscale wash) in order to entirely encompass the pre-defined tumor CTV (grayscale boundaries). Each catheter trajectory is shown in 3D in panel C, with thin grayscale circles in A-B showing their intersection with the axial and sagittal slices shown.

[0047] It should be noted that some details of the figures have been simplified and are drawn to facilitate understanding of the present teachings rather than to maintain strict structural accuracy, detail, and scale.DETAILED DESCRIPTION

[0048] I. INTRODUCTION

[0049] Interstitial brachytherapy is a method for focal delivery of ionizing radiation. It is primarily used to delivery high-doses of radiation to several locations within a tumor for curative purposes, which is performed by inserting "needle"-shaped devices through skin, fat and muscle tissue to the tumor, which can sometimes be 20-30 cm from the body-surface-entry point. Each brachytherapy needle typically includes an elongated probe (e.g., an internal metallic object), referred to as a “stylet”, which is surrounded by a plastic hollow tube, referred to as a "catheter", which has a pointed tip. Once the needle is brought to the proper location by pushing the combined needle device, the stylet is withdrawn from within the catheter and a radiation source is inserted into the catheter, which radiates the section(s) of the tumor that are immediately (3-6mm) adjacent to the trajectory (i.e. the three dimensional path) of the stylet from the skin to the target.

[0050] As such, the brachytherapy needle (A) needs to be strong enough to be pushed by hand (or machine) through relatively stiff tissue for extensive distances and (B) it is desirable that in order to bring each needle to a (pre-)defined desired location, it is possible to observeAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 the location of the device during the insertion process, so as to correct the path if / when it deviates.

[0051] With regard to (A), there are some special cases, such as when the device is inserted via a formed applicator (e.g., an ancillary medical apparatus, such as a plastic vaginal applicator that is inserted into the vaginal cavity up to the cervix) instead of by free-hand, that the needle needs to make an acute turn in a relatively small distance (i.e., a small radius turn in a part of the applicator) in order to exit the applicator in a required spatial direction. This requires that the stylet be flexible enough in order to be turned to such a large degree and yet not break, while at the same time being stiff enough in order to then be pushed further along a relatively straight line through tissue.

[0052] With regard to (B), it is desirable that the clinician advancing the needle be able to observe the location of the needle while advancing it to the target. In this context, it is possible to use an imaging modality (X-ray, Computerized Tomography [CT], Ultrasound [ULS], Magnetic Resonance Imaging [MRI], or the like) to view the tip and shaft of the needle, or use a location-tracking method to know the location of points on the surface of the device. Due to technical or clinical issues such as spatial uncertainty of the localization, extent of modality’s delivered radiation dose, speed of the localization process, or the signal to noise ratio (SNR) of the localization / unit-time, it is frequently preferable to use a dedicated location tracking method instead of relying on an imaging modality. This is oftentimes referred to as active tracking. In addition, with active tracking, it is possible to use an imaging modality more efficiently by directing the imaging to a location provided by the tracking method, especially if the tracking method is faster or more accurate than the imaging method. For example, if the tracking methods provides the location and orientation of the tip of the device, if is possible to then define a single, or a limited number of imaging plane(s) that immediately visualize along theAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 along shaft of the device or image just in front of the device, which can prevent in-adavertent entry into sensitive tissues.

[0053] For example, ULS probes can be rotated and deflected so that the ULS lobe is focused on the location of the tip of the needle, which is provided by an electromagnetic (EM) tracking method that has coils on the tip of the needle. This creates a procedure which is far easier than manipulating the ULS probe in various directions until the location of the needle tip can be seen by the narrow lobe of ULS energy that is emitted by the ULS probe.

[0054] There are several tracking methods, such as those based on EM waves transmitted from multiple antennas and received by small coils on the device, those based on light-wave interferences at points along a fiber-optic cable that runs through the device (Fiber Bragg Grating tracking or FBG tracking), those based on Magnetic Resonance (MR) projections that originate in large coils integrated into the scanner that transmit radio-frequency waves which are received by small radiofrequency micro-coils placed on the device (MR-tracking), those based on the electrical impedance between coils placed on the surface of the subject which transmit KHz electric pulses which are received on small metallic rings placed on the surface of the device (Impedance Tracking), and the like.

[0055] We previously disclosed an MR-Tracked injection needle (see, Pub. No. US2024 / 0058580 Al) which shares some common attributes with the present disclosure. In that publication, we disclosed an MR-tracked injection needle that was built from two circumferential (e.g., concentric) flexible metallic tubes. The inner tube was used to conduct a liquid (e.g., used for gel that fills regions between the irradiated region and the sensitive tissues, thus displacing these tissues from the damaging radiation), the space between the inner and outer tubes was used to pass the coaxial electrical cables that conduct signals from two MR-tracking micro-coils, located at the tip of the device, to the proximal handle of the device, andAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 the outer tube was used to protect the device from fluid influx. At the proximal end of the injection needle, there were electrical connections as well as a connection from a syringe.

[0056] In some aspects of the present disclosure, we provide an actively tracked flexible brachytherapy needle, among other features. It is also built of two centric hollow nitinol tubes. The inner tube, however, is only located at the very distal end of the device. It serves to stiffen the elasticity of the tip of the device (e.g., so that it can penetrate into tissue) and also serves as a resting place for the two MR-tracking coils. The outer tube runs the full length of the device. Within the outer tube run the coaxial cables that conduct signals from the MR-tracking microcoils. At the very distal end of the device, the outer and inner tube are cut in a fashion that enables (A) insertion of the MR-Tracking coils into two longitudinal slots on the device and (B) creating a dedicated channel to conduct the coaxial coil for the distal MR-tracking coil beneath the most proximal MR-tracking coil, so that its cabling does not need to be passed above the proximal MR-tracking coil, which simplifies the construction of the device and its maintenance. At the proximal end of the device there is a handle, used by the clinician to hold and manipulate the device. The handle includes tuning and matching electronics, used to tune the MR-tracking circuit to the frequency of the MRI (Larmor) resonant frequency and to 50 Ohms impedance at that frequency. The handle also includes a quick disconnect electrical connector.

[0057] Some exemplary attributes of the present disclosure include that the flexibility of the concentric tube design allows for performing the large deflection within a small distance that is generally needed for safe use of the device within an applicator, as referenced above. In some embodiments, this is particularly so because the needle is made of super-elastic nitinol tubes and because the coaxial cables are conducted through the center of the outer tube, so they are less strained by the large deflections. In addition, the devices or constructions of the present disclosure can be used for applications where a variety of location tracking sensors (e.g., forAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 use with different tracking methods) can be inserted into the slots at the distal end of the device (e.g., replacing the MR-tracking micro-coils), and their cables conducted down the shaft of the device. Such an example includes EM tracking, which can be used in conjunction with ULS, X-ray, CT, or PET imaging. When tracking methods other than MR-tracking are used, small changes typically need to be performed to the distal end and the proximal handle. Further, the flexible actively tracked stylets disclosed herein have numerous applications, including radiation oncology, interventional radiology, and interventional cardiology, among other uses. These and other attributes will be apparent upon a complete review of the present disclosure, including the accompanying figures.

[0058] In some aspects, for example, the present disclosure provides a medical device that includes an elongated probe (e.g., a stylet or the like) that is insertable into a tissue. The device also includes at least one tracking element (e.g., two, three, four, five, or more tracking elements) operably connected to the elongated probe. The tracking element is operably connected, or connectable, to a tracking apparatus that is configured to actively track positioning of at least portions of the elongated probe in substantially real-time when the elongated probe is inserted into the tissue. In addition, the device also includes a handle operably connected at least to the elongated probe. The elongated probe comprises an outer tube structure having an outer tube cavity disposed longitudinally along a portion of a length of the outer tube structure and an inner tube structure having an inner tube cavity disposed longitudinally along at least a portion of a length of the inner tube structure. The length of the outer tube structure is less than the length of the inner tube structure. The outer tube structure comprises at least first and second outer tube structure openings disposed proximal to a distal end of, and along at least a segment of the length of, the outer tube structure. The outer tube structure openings are in communication with the outer tube cavity. The inner tube structure comprises at least first and second inner tube structure openings along at least a segment of theAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 length of the inner tube structure. The inner tube structure openings are in communication with the inner tube cavity. The inner tube structure is disposed substantially within the outer tube cavity proximal to the distal end of the outer tube structure such that the outer tube structure openings substantially align with the inner tube structure openings to produce aligned openings. In addition, the tracking element is disposed in at least one of the aligned openings. The medical devices of the present disclosure are typically included as components of kits and / or systems.

[0059] In some embodiments, the elongated probe comprises sufficient flexibility and sufficient strength to bend by about 90° without having a structural failure when inserted in the tissue. In some embodiments, the elongated probe is fabricated from super elastic nitinol or cobalt chromium. In some embodiments, the elongated probe is at least about 10 cm, about 20 cm, about 30 cm, about 40 cm, about 50 cm, or more in length. In some embodiments, the medical device further includes a catheter through which the elongated probe is at least partially disposed. In some embodiments, the elongated probe is configured to be manually inserted into the tissue, whereas in other embodiments, the elongated probe is configured to be inserted into the tissue using a motorized apparatus with or without autonomous robotic direction (e.g., a robotic gripping armature or the like).

[0060] In some embodiments, the tracking element is configured to track positions of at least portions of the elongated probe at one or more time points when the elongated probe is inserted into the tissue. In some embodiments, the tracking element comprises one or more of an electromagnetic (EM) tracking element, a light-wave interference (FBG) tracking element, a magnetic resonance (MR)-tracking element, and / or an electrical impedance tracking element. In some embodiments, the tracking element is operably connected to the inner tube structure. In some embodiments, the tracking element comprises at least one magnetic resonance (MR)-tracking coil. In some embodiments, for example, the medical device includes a proximal MR-tracking coil and a distal MR-tracking coil. The proximal MR-tracking coil is disposed in aAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 proximal aligned opening, the distal MR-tracking coil is disposed in a distal aligned opening, and the proximal aligned opening is located closer to the handle than the distal aligned opening. In some embodiments, cables operably connect (e.g., electrically connect) the proximal MR-tracking coil and the distal MR-tracking coil tracking apparatus. In some embodiments, at least portions of the cables are disposed through at least a segment of the inner tube cavity. In some embodiments, the handle comprises tuning and matching electronic components that are operably connected to the cables. The tuning and matching electronic components are configured to tune an MR-tracking circuit that comprises the proximal MR-tracking coil and the distal MR-tracking coil to a selected frequency and to a selected impedance.

[0061] In some embodiments, the elongated probe is insertable into the tissue via an ancillary medical apparatus (e.g., a gynecological applicator device or the like). In some embodiments, the elongated probe is sufficiently flexible to bend within a curved pathway fabricated at least partially within the ancillary medical apparatus. In some embodiments, the ancillary medical apparatus is configured to deliver one or more doses of a therapeutic agent (e.g., a radiopharmaceutical agent or the like) to the tissue when the ancillary medical apparatus is disposed within sufficient proximity to the tissue.

[0062] In some embodiments, the medical device further includes an imaging element operably connected to the elongated probe. The imaging element is operably connected, or connectable, to an imaging apparatus that is further configured to capture images of the elongated probe and / or the tissue in substantially real-time at least when the elongated probe is inserted into the tissue. In some embodiments, the imaging element is disposed in at least one of the aligned openings. In some embodiments, the imaging element comprises an X-ray imaging element, a computed tomography (CT) imaging element, an ultrasound (ULS) imaging element, a magnetic resonance (MR) imaging element, and / or a positron emission tomography (PET) imaging element.Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02

[0063] To illustrate, FIGS. 1-11 show various aspects of the foregoing features of the medical devices provided by the present disclosure. For example, FIG. 1A schematically shows medical device 100 having an MR-actively-tracked stylet with a detailed view of the tip of that device from perspective views, while FIG. 1B schematically shows tip 102 of medical device 100 from FIG. 1 A from a sectional side view. As shown, medical device 100 includes elongated probe 106 having tip 102 with aligned openings. Elongated probe 106 is operably connected to handle 104. More specifically, tip 102 includes two aligned openings formed in an inner tube coil support and an outer tube. Each aligned opening includes a tracking coil operably connected to the inner tube coil support. As also shown, coaxial cables are electrically connected to the tracking coils and extend into the inner tube cavity, which also includes a coaxial cable insulation.

[0064] In addition, FIGS. 2A and 2B show photographs of a medical device having an MR-actively-tracked flexible stylet at a distal end of the device and a plastic external catheter placed next to a ruler in centimeters as an indication of scale according to examples of the present disclosure. FIG. 3 shows a flexible stylet after passage through an ancillary medical apparatus (a gynecological applicator device, namely, an Elektra Venezia Ovoid Ring) from a side view in a phantom tissue. FIGS. 4A and 4B show pictures of the tuning of MR-tracking coils prior to passage through an ancillary medical apparatus (Elektra Venezia Ovoid Ring) ((A) distal coil (-3 IdB at 63.8MHz) and (B) proximal coil (-23 dB at 63.8MHz)) according to examples of the present disclosure. FIGS. 5A and 5B show pictures of the tuning of MR-tracking coils after passage through an ancillary medical apparatus (Elektra Venezia Ovoid Ring) ((A) distal coil (-44dB at 63.8MHz) and (B) proximal coil (-23 dB at 63.8MHz)) according to examples of the present disclosure.

[0065] To further illustrate, FIGS. 6A and 6B schematically show a motorized medical device 600 having an MR-actively-tracked stylet from a side view and a side view with half ofAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 the handle removed, respectively, according to examples of the present disclosure. As shown, medical device 600 includes (i) a needle with MR-tracking sensors, (ii) a bevel-tipped catheter to facilitate trajectory corrections, (iii) a pneumatic motor for rotating the needle (of which the pneumatic motor can be a piezoelectric motor or hydraulic motor, (iv) a capacitive slip-ring for transmission of the electrical signal originating in the two rotating tracking coils on the needle tip to non-rotating coaxial electrical cables in the device handle, and (v) a Lemo quick-disconnect electrical connector for connection between the coaxial cables in the handle and the MRI receivers in the scanner. FIG. 7 schematically shows a section view of a capacitive slip ring. As shown, the slip ring has 4 channels, 2 channels for each tracking coil. The Lemo connector connects to a tuning and matching circuit (e.g., a PCB) which tunes and matches the circuit to the desired frequency. The capacitive slip ring gap is defined based on the tuning and matching requirements. This gap is guaranteed by the low friction spacer. The micro-coaxial cables from the coils attach to the inner rotary capacitive plate and the coaxial cables from the tuning and matching circuit connect to the outer stationary capacitive plate. As a further illustration, FIGS. 8 A and 8B schematically show medical device 800 having an MR-actively-tracked stylet from a side view and a side sectional view, respectively, according to examples of the present disclosure. In some embodiments, the devices of the present disclosure use a standard optical encoder, whereas in other embodiments, they implement a custom optical fiber encoder.

[0066] In some embodiments, the devices of present disclosure incorporate an automated approach to utilizing MR-tracking for targeting an in-vivo target for cancer treatment. This is a system level implementation that typically includes a pneumatic or piezoelectric motor for use with the MR-tracking technique. To enable the MR-tracking capability, a capacitive slip ring is typically used to facilitate signal transmission. This system also provides an algorithm for state estimation of the needle tip with our sensor setup.Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02

[0067] The devices of the present disclosure can be used in a variety of MR-guided minimally invasive percutaneous interventions to augment surgical capabilities by enabling closed-loop targeting of in-vivo targets. It is not limited to brachytherapy for gynecologic or prostate or neck cancers. Rather, the devices of the present disclosure can be readily adapted for use in neurosurgical interventions (e.g., deep brain stimulation, hematoma evacuation, and the like) and abdominal interventions (e.g., radiofrequency ablation of liver cancers), among other applications.

[0068] Prior approaches generally rely on the surgeon to perform the actual manipulation of the device, requiring visual feedback of the sensor location and making a judgement call accordingly. In contrast, the devices disclosed herein enable complete closed-loop, surgeon-out-of-loop control, if desired in some embodiments. For example, these devices can easily be mounted to a robotic chassis for control of the needle. Importantly, the devices of the present disclosure utilize MR-tracked feedback with tracking coils that close the loop for device control in some implementations.

[0069] As a further illustration, FIG. 9 schematically shows an MR-tracking coil with integrated tuning and matching circuits according to examples of the present disclosure. In some embodiments, the antenna is designed for placement on metallic surfaces. For example, the coil can be built on a flexible printed circuit board (e.g., having about 200 μm of total thickness) in some embodiments. As shown, the MR-tracking coil (having a length of 11.86 mm) includes a radio-frequency antenna with three layers of printed loops and tuning and matching circuitry for a resonating circuit at MRI Larmor frequency (i.e., 63.8 or 123.2 / 127.0 MHz). The tuning and matching circuitry includes a parallel capacitor and a series capacitor. In addition, the tuning and matching circuitry is joined to the antenna by a flexible joint that allows the coil to bend without breaking. Placement of the tuning and matching circuits on the tip MR-tracking coils reduces the losses in the transmission of the radio-frequency signal alongAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 the shaft of the device, since without such tuning and matching there would be significant signal reflection due to the impedance mismatch. Such losses are in addition to signal losses that result from the need to use very thin micro-coaxial cables, which are lossy in signal transmission.

[0070] The present disclosure also provides various methods. For example, FIG. 10 is a flow chart that schematically shows exemplary method steps of tracking a medical device in a subject according to examples of the present disclosure. As shown, method 1000 includes inserting at least a portion of at least one elongated probe of a medical device of the present disclosure into at least one tissue of the subject (step 1002). Method 1000 also includes actively tracking one or more positions of at least portions of the elongated probe in substantially real-time when the elongated probe is inserted into the tissue using the tracking element (step 1004). As a further illustration, FIG. 11 is a flow chart that schematically shows exemplary method steps of making a medical device according to examples of the present disclosure. As shown, method 1100 includes forming at least one elongated probe that is insertable into at least one tissue (step 1102). Method 1100 also includes operably connecting at least one tracking element to the elongated probe, which tracking element is operably connected, or connectable, to at least one tracking apparatus that is configured to actively track positioning at least portions of the elongated probe in substantially real-time at least when the elongated probe is inserted into the tissue, wherein the tracking element is disposed in at least one of the aligned openings (step 1104). In addition, method 1100 also includes operably connecting at least one handle at least to the elongated probe (step 1106).

[0071] II. DESCRIPTION OF EXAMPLE EMBODIMENTS

[0072] EXAMPLE 1: ESTIMATION OF STEERABLE NEEDLES USING LIE THEORY AND ELECTROMAGNETIC NAVIGATION (ENLITEN)Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02

[0073] Medical needles are among the most commonly used interventional medical tools. While their uses in intramuscular and intravenous injection are well-known, they are also commonly used for minimally invasive therapeutic interventions. These include damaging pathological tissue (ablation), tissue sampling and biopsy, localized drug delivery, and brachytherapy. Of these, MR-guided brachytherapy is of significant interest. Accordingly, for this example, the narrative is directed towards brachytherapy as the clinical procedure of interest. However, it should be noted that concentric tube robots like A Surgical Platform for Intracerebral Hemorrhage Robotic Evacuation (ASPIHRE) are also considered as steerable needles, a type of device that can exhibit follow-the-leader behavior. Thus, this example lays the foundation for other embodiments.

[0074] Brachytherapy is a deep percutaneous needle intervention that uses radiation seeds to locally treat cancer. Its use in MR-guided interventions is gaining rapid adoption due to the absence of systemically applied ionizing imaging radiation, which occurs during Computed Tomography (CT)-guided brachytherapy, and the ability to provide effective tumor visualization that enables accurate administration of the radiation dose. An example of a brachytherapy system with one of the stylets of the present disclosure can be seen in Figure 12. During this intervention, a set of semi-flexible metallic stylets sheathed in brachytherapy catheters (constructed from hollow plastic tubing with a pointed, sealed end) are carefully guided into the areas of interest using a custom-designed guide. After achieving placement within the target region, the stylet is removed from the catheter, and a radiation seed is introduced into the catheter for local treatment of the cancerous tissue. While this treatment modality can be an effective form of treatment for both gynecological and prostate cancers, its efficacy is dependent significantly upon targeting accuracy by virtue of radiation dose falling quickly as the distance from the shaft of the catheter increases (the inverse square law). Unfortunately, accurate advancement of the conventional catheter stylet pair is lacking in theAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 clinical setting due to the limited dexterity of existing stylets and catheters. Consequently, procedure duration and tissue disruption is increased due to the multiple in-and-out stylet manipulations necessary to correct deviations in the catheter trajectory.

[0075] In the past, a variety of steerable needle devices have been developed to improve dexterity and targeting accuracy in deep percutaneous needle interventions. These include metallic stylets with kinked or beveled tips, bio-inspired designs that modify the tip geometry using either interlocking tips or sliding internal wires, waterjet needles with steerable nozzles, and concentric tube systems that exhibit follow-the-leader deployment. However, several of these aforementioned designs cannot be used with existing catheters. For example, stylets with kinked and beveled tips would be shielded by the catheter, preventing the needle-tissue interaction needed for steering. Similarly, the designs of interlocking tips and waterjet needles would also be incompatible with existing brachytherapy catheters. Concentric tube robots may be usable with the existing brachytherapy catheters, but the trajectory and tube pre-curvatures must be determined a priori for follow-the-leader deployment. Thus, the focus here is on designs that can both be used directly with brachytherapy catheters and exhibit interventional trajectory adjustments.

[0076] An intuitive approach toward developing a steerable system that is compatible with existing catheters is to emulate the current method of intraprocedural needle manipulation. In these approaches, the proximal end of the needle is manipulated by the surgeon, and, due to the interaction forces of the needle body with the tissue and the guiding template, dexterous motion is permitted at the distal tip. Others developed a model that leverages this manipulation approach using time-delayed tissue fracture mechanics to predict the needle trajectory. Inputs to the model were the force and torques applied to the base of the needle carrier. Notable for this model, maximum trajectory prediction errors remained below 2 mm. However, this model does require a global parameter fit for estimating the tissue parameters. Other approachesAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 leverage the mechanics of the needle body without knowing the tissue properties. In these approaches, iterative adjustments at the proximal end of the needle are performed to enable dexterous movements at the distal end. However, these approaches require systems with a relatively large robotic workspace to adequately manipulate the proximal end of the needle, which may present limited opportunities in the MR-environment due to the tight spatial constraints.

[0077] To enhance dexterity without a large workspace at the proximal end of the stylet, several groups have developed novel dexterous manipulation techniques that can be transferred through the device to the distal tip within brachytherapy catheters. In the past, our group developed handheld tendon-driven stylets that permitted local deflection at the distal tip. In these designs, asymmetric cutouts on the stylet body reduce stylet stiffness and enable bending in the direction of the cutouts when the tendon is retracted. These design concepts are reminiscent of the designs for tendon-driven continuum robots. However, these devices had a large offset between the cutouts and the distal tip to accommodate placement of our MR-tracking (MRT) coils (more details to come below). Consequently, the distal tip displacement was negligible when the stylet was already inside the tissue and trajectories remained straight. However, the phantom had stiffness significantly less than that of tissues other than the prostate, and targeting experiments were not performed to evaluate device efficacy. Others developed a novel two-tendon design that deflects a nitinol stylet with a diamond pattern cut into it. This design was able to successfully provide trajectory deviations and trajectory tracking capability within tissue, which is likely due to the close proximity of the applied tendon moment to the distal tip. Others also generated a design that is capable of deflection within tissue. This design used optical heating of an SMA wire to perform the deflection.

[0078] While the prior designs used tendons, another commonly used approach that has been adopted for needle steering is the use of bevel-tipped needles. Bevel-tipped needles enableAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 curved trajectories during insertion due to the asymmetric forces applied to the bevel -tip. Bevel-tipped needles are normally spun rapidly in the clinical setting to maintain a straight trajectory. However, by varying the spinning speed with insertion, the bevel -tip can be exploited to provide a continuum of needle path curvatures. For example, a bevel -tipped needle was adjusted variably in the MRI to reach targets within phantoms. However, this needle was not usable with brachytherapy catheters, as the bevel-tip was on the metallic stylet itself.

[0079] Although each of the previously detailed frameworks present feasible methods for providing dexterous needle manipulation, to perform accurate targeting, needle state sensing and estimation is needed. Within MRI, there are generally two different methods of needle sensing: (i) proprioception, which provides information regarding the internal state of the needle (e.g., strain, which is similar to our ability as humans to detect our limbs in 3-D space without vision), and (ii) exteroception, which provides information regarding the needle’s state with respect to its environment (e.g., position, which is similar to our ability as humans to see our limbs in 3-D space). Naturally, the most common form of exteroception in the medical environment is to use the imaging feedback of the imaging modality to visualize the location of the device tip in the anatomical images. However, in MR-guided interventions, autonomous needle tracking using the feedback from the anatomical images is challenging and limited by the imaging modality itself. For example, two sets of orthogonal 2D slices were used to detect the tip position of the needle. As the needle moved, the scan geometry of the 2D slices was updated to ensure the needle tip remained in the scanned images for needle tip position estimation. However, while update rates of approximately 1 Hz were achieved, a remarkable feat when using MR-imaging feedback, this is still slower than the update rates that can be achieved with other imaging modalities. Specifically, ultrasound has reported tracking rates using imaging feedback as high as 30 Hz. Additionally, exteroceptive electromagnetic trackers (such as those by Northern Digital), which do not use imaging feedback and are registered toAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 the imaging modality, are compatible with CT and ultrasound and can provide tracking at a rate of 40 Hz. Further, MR-tracking via imaging feedback has generally been limited to either automated position tracking of the needle tip or surgeon-in-loop analysis, whereas commercial electromagnetic trackers provide sensors that are able to measure multiple degrees of freedom (>5), providing nearly full state estimation of steerable needles.

[0080] Unfortunately, no commercial electromagnetic tracker system is compatible with the MRI, as it would interfere with the magnetic field of the MRI. This has motivated groups to develop MR-conditional proprioceptive localization techniques that exhibit faster update rates than MR-imaging based tracking. For example, others developed a shape reconstruction algorithm using fiber Bragg grating sensors to track the steerable needle’s shape. Three fibers were used to enable complete reconstruction of the shape without implicit assumptions. Conversely, another group used a single fiber core and assumed the bending direction is in the direction of the asymmetric cutouts cut into the device. While these proprioceptive techniques are fast and precise (sampling at 100 Hz), the system-level performance is dependent on accurate registration with respect to the imaging modality and the anatomy.

[0081] The concerns regarding tracking in the MRI using exteroceptive imaging with anatomical images or proprioceptive sensing, i.e., the update rate and tracking accuracy relative to the imaging modality, have motivated the development of exteroceptive MRT coils. This tracking modality tracks the interventional device without direct imaging feedback of the anatomical images and can provide update rates as fast as 30 Hz. One of the earliest examples of using MRT coils is reported where researchers developed a tracking method that exhibited tracking accuracy similar to the MRI images in a vascular channel phantom. Since then, there have been several reported instances of tracking of interventional devices. However, MRT coils have been limited to position-only measurements, and, to date, estimation methods of MR-tracked devices with MRT coils have been limited to surgeon-in-loop tracking of continuumAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 devices or insertion vector calculation of straight, rigid devices between two coils with known transformations. There currently does not exist in the literature a state estimation method for steerable needles in the MRI using MRT coils.

[0082] From the prior discussion, it is clear that there are two unmet clinical needs that need to be addressed to facilitate effective MR-guided brachytherapy, (i) a method of dexterous manipulation of a brachytherapy stylet that is compatible with brachytherapy catheters, and (ii) a method of estimating the state of the steerable system (position and orientation) in the MRI using MRT coils that only provide position feedback. Previous work developed an exteroceptive tracking technique with MRT coils that can provide positional feedback with an accuracy of 0.3 × 0.3 × 0.3 mm3at an update rate of 30 Hz. These coils have been implemented on several devices, including catheters, brachytherapy stylets, and injection needles. However, an algorithm for estimating the full-state pose of any of these devices given MRT coil positional feedback can be developed. It should also be noted that a path interpolator can also be developed that can define a trajectory from the estimated state to the target region subject to curvature and length constraints based on the stepwise control law presented in this example, which requires a curve to be parameterized with respect to arc-length. Therefore, there is a third need for a suitable path interpolator that can define a trajectory from the current estimated needle state to the target region that can be parameterized with respect to arc-length. As such, aspects of the present example include as follows:

[0083] 1. A steerable system for MR-guided brachytherapy that can be equipped with MRT coils and provide dexterity during insertion, addressing the limited dexterity observed in prior work for brachytherapy.

[0084] 2. An algorithm that can provide estimation of the state of the needle tip (position and orientation) given only exteroceptive MRT coil position measurements for trajectoryAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 tracking. This algorithm has reconstruction errors below 1 mm given that commercial systems that do not use MRT coils have been observed to achieve errors of 2.5 mm and lower.

[0085] 3. A path interpolator that defines a trajectory from the current estimated needle state to the target and that can be parameterized with respect to arc length.

[0086] Catheter Design and Fabrication

[0087] The steerable needle system presented here consists of a stiff, MR-conditional, nitinol stylet that is equipped with electromagnetic tracking capability at the distal tip. The metallic stylet has a 1.40 mm outer diameter (OD) and a 1.20 mm inner diameter (ID). The stylet has two cutouts for sensor placement. These cutouts are 12.7 mm long and the gap between them is 3 mm. This cutout configuration accommodates the MRT coils that would be used in the MR-environment (see Figure 13 (A)-(B)). The stylet is covered with a standard brachytherapy catheter, which has a 2.00 mm OD and a 1.45 mm ID.

[0088] To provide a method of dexterous manipulation using brachytherapy catheters, a production method is used that produces a bevel-tip on existing brachytherapy catheters. First, a drill is used to drill a hole at an angle into an aluminum block that serves as a manufacturing fixture. This hole is slightly larger than the diameter of the catheter and acts as a guide for the catheter. The angle of the hole is determined by the desired bevel-tip angle. The catheter is then inserted into the hole until the tip reaches the opposite side of the aluminum block. Then, a flat heating iron is used to melt the plastic tip as the catheter is pushed further through the guide. Note that the melted plastic material is not removed, rather, it is allowed to accumulate in the fixture and plug the distal end of the catheter. This results in a catheter with a sealed bevel-tip. An example of the bevel-tip produced on a catheter by the proposed method can be seen in Figure 13 (C). After the bevel is produced on the catheter, a razor knife is used to remove any excess plastic from the tip. The system presented in Figure 13 (B)-(C) was used in the experiments detailed below.Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02

[0089] Lie Group Kinematic Formulation

[0090] A Lie group is a mathematical concept originating from mathematician Sophus Lie, and its underlying theory is prevalent in robotics. In this example, portions of Lie theory are leveraged to facilitate the kinematic modeling and state estimation of electromagnetically guided bevel-tipped steerable needles.

[0091] Review of Kinematic Model

[0092] Throughout the remainder of this example, the steerable catheter and stylet pair will be referred to as a steerable needle or needle. In this example, the nonholonomic unicycle steering model for bevel-tipped needles described previously is adopted to describe the kinematic model of the steerable needle. The model represents the needle tip pose as an elementx g (where * 3) jsthe Lie group) containing the needle tip position Peand orientation R e (which is another Lie group), as shown in Figure 14 (A), ■!.'v a point moving on the Lie group’s manifoldwith respect to time, is written ase SE{3) (9. D01x3

[0093] This point has a corresponding body velocity, Awhich is the needle tip’sbody velocity written as a twist, This twist is isomorphic with ^3 written as- TV' _ v or T € »6(9.2)w V6 se(3)01x3 0’TvcL •? where = orresponds to translational velocities of the needle tip,corresponds to rotational velocities, andis the Lie algebra of -ST a). Note that the vector space v t3associated with the Euclidean space aligns directly with its Lie algebra (i.e.,Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 (i.e. J v ' = V),asEuclidean space is a flat space. The vector space <= is passed to its Lie algebra via(9.3)where A’L is the skew symmetric matrix representation of some vectorNote that due to the nonholonomic constraints of the unicycle model, the movement of the needle tip is generated by two possible inputsand which correspond to the needle insertion velocity and axial rotation velocity, respectively, as shown in Figure 14(B). Their influence oncan be written as followsr -j TV* = o ()UiKMi 0 *9.4)where «is the curvature of the needle as a result of the interaction between the needle’s bevel-tip and the tissue. Thus, a new needle tip pose,as a result of a control input vector,= V 'A; = [pT, «T. where is an input of short duration, applied to pose -f- can be written as= A) @ u1+i(9.5 )Given a sequential set of A’ control inputs, wherefor each input index*c' ' ' - the final needle tip pose can be written sequentially as= A’o Ui S «2 ®. ® iij (P... @ u* (9.6)Additional details are provided herein.

[0094] Needle Pose Estimation

[0095] Although the nonholonomic needle steering model has been applied in numerous research articles, it is susceptible to process noise due to uncertainties during insertion through the guiding medium. Thus, a nominal control input, is subject to additive Gaussian noise w ~ A t,0TW ■,writtenasAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 ui+1= ūi+1+ w ∈ ℝ6(9.7)W = diag(σ²_ξ₁, σ²_ξ₂, ..., σ²_ξ₆)Δt ∈ ℝ6×6where σ²_ξi is the variance of the ithbasis of the process noise during insertion due to uncertainties in the medium andis the input duration. Thus, given an a priori state estimate of the needle tip, an errorwith covariance, C+i- will exist, written asAxi+i= A'+1© Al+1(9.8)I’,UAE! T: r; 1; U';1oACf]Due to this potential error, an extended Kalman filter is derived to leverage the measurements from electromagnetic sensors to improve needle tip estimation. The sensor measurements are measured in the electromagnetic frame (either the MRI or the electromagnetic field generator). These measurements are susceptible to zero mean Gaussian noise, written as n ~ 풩(0, N) ∈ ℝ³. Thus, thesensor measurement is written asb_j = b̄_j + n ∈ ℝ³(9.9)N = dia Kg-((7p t,. J, - a V22. V;>wherebis the actual sensor location, is the sensor measurement, andis the variant of the - "basis of the measurement in the tracking frame due to the sensor measurement noise. These measurements are converted to the a priori estimate of the needle tip’s body frame to be used as an observation during evaluation of the innovation of the EKF viam?- = bj (9.10)where the numeric 1 appended to each vector is implied.

[0096] The extended Kalman filter (EKF) is employed on the manifold. This derivation starts by considering the a priori state estimate,, that is a result of a nominal control input vector, applied to a previous a posteriori state estimate, A;, written as= A) ® Uj-s-i (9.11)Attorney Docket No. 0184.0326-PCT Client Ref No. Pl 8398-02 Based on the nominal input, the a priori estimate covariance matrix of the a priori estimated state resulting from the steerable needle model dynamics can be written asP:. = I i’ lT4- WGT(.12;where E is the a posteriori covariance matrix, F is the state transition Jacobian that maps the uncertainty att0and G is the control-input model that maps the process noise W into the uncertainty atThese Jacobians are defined as followsF ≜ J^{P_{i+1}}_{X_i} = J^{X̃_i⊕ū_{i+1}}_{X̃_i} = Ad⁻¹_{Exp(ū_{i+1})} (9.13)GA= J^+l= Jr(ui+1) (9.14)Additional details are provided herein. At each observed sample, EKF estimation is applied. This estimation starts with evaluating the measurement residual, written asz = m - ȳ (9.15)where z is the innovation,mnii’ 'd!,'A*!*2’ is the a priori estimated sensor position in the body-frame of the needle tip. It is argued here thatis a function of the a priori needle tip shape, which is defined by both T‘;+;and the previous nominal control inputs. A justification for this derivation is found herein. The a priori sensor position is derived by considering an element attached to the sensor position, ). This element evolves with the needle state and can be written with respect tousingy= -(■T+i © X) ® e e -C«) * -6, (9.16) This expression can be rewritten in terms of the current and previous nominal control inputs as= I® — u;-i ® -H,.. ® (9.17;Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 where is the input index that is just distal to the ■|li' sensor position along the arc length of the needle body andis the residual input to the sensor location, which is a fraction oflh«- t (these can be seen depicted in Figure 15). Given N- can be extracted.

[0097] The innovation covariance is then evaluated viaZ = HPi+1HT+ N (9.18) whereH= H•H= JA which is the Jacobian that defines how the sensor position changes given a change in the estimated state. Due to the close proximity of the sensors to the needle tip (<35 mm), it is assumed that a change in the sensor position corresponds to a direct change in the needle tip. Thus, a local perturbation due to tissue deformation would treat the distal segment of the needle like a rigid body. Herein, is written as— [I 03x3] (9.19) Note that a discussion will be provided below regarding this choice. Given the structure of fl, is ablock diagonal matrix written in the form ofN=liia£(N-. NJ.

[0098] Given the innovation covariance, the Kalman gain,Kcan now be written as K= Pi+1HTZ1(9,20) and the observed error can be written asAx = Kz (9.21) Knowing the observed error, the a posteriori estimated state and covariance matrix can be updated viaA i = i @ Ax (9.22)P,;+1= P,;+1- KZKT(9.23)

[0099] Controller Design

[0100] For control of a needle along a desired trajectory, an approach similar to a previous controller design is adopted. However, this approach is designed directly on '’■NT and it isAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 discretized to accommodate the EKF derivation disclosed herein. The goal of the control law is to sequentially define a nominal control input that drives the steerable needle along a pathr: IKon Openinterval=parameterized to arc lengthtor s eas the a posteriori estimated steerable needle state evolves. To write the control law, the path, r.is first discretized into k increments for ■' *= *:such that G =To define adesired state, from an a posteriori estimated state, the path at point j and the a posterioriR.,v =01.-: 3estimate,.. L, are used. This derivation starts by considering a target point in the body-frame of the needle defined byu ' T.;Mr?= — pz; e 1K" (9.24)wherebC representsrin the body-frame at A It is desired to keep in the plane of the cutting edge of the needle with the cutting edge cutting toward ' '*9. Thus, a rotation of theneedle body by an angle °—rjei'— r?e2 > js neec[ec[ (where the size ofand ea are implied). Given this angle and the target position, the desired state can now be written as(9.25)

[0101] Given the above, the nominal control input is defined as=.-tj © <•£* (9.26)where11• ■ is the input applied at A- Note that this control input does not satisfy the nonholonomic constraints, which are described by the following equationAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 Aūi+1= 0where0 I- fl0 0 0(9.28)-1 0,!0 I 0Consequently,must be projected onto the controls. A suitable projection is written as iūi+1= (I6×6- AT(AAT)-1A)ū*i+1(9.29) which is the first application of A in a closed-loop control law.

[0102] Pythagorean Hodograph Path Identification

[0103] The step-wise control law detailed herein has an intuitive interpretation when the curve is parameterized with respect to arc length. However, it has been shown to be impossible to parameterize any curve, other than a straight line, by rational functions of its arc length. Notably, this limitation can be rectified for polynomial curves through the use of Pythagorean hodograph curves [Farouki, R. T. " Pythagorean hodograph curves in practical use." Geometry processing for design and manufacturing SI AM (\991)\. In this example, quintic spatial Pythagorean hodograph curve (PHC) interpolants with first-order Hermite data are proposed for identifying a curve,r!A, fromto a desired target, t. This method has been proposed previously for the modeling of continuum robots due to the ability to construct smooth curve segments that match given end points and derivatives, as well as for use in unmanned aerial vehicles (UAV) for simultaneous arrival. Here, this methodology is proposed because it can provide a curve that is easily reparametrized to arc length for use in the control law through an iterative minimization.

[0104] Review of Quintic PHC Interpolation

[0105] A PHC is a curve with a hodograph, >'( ‘ that abides by the following Pythagorean constraintAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02jr'fe)] = 4“ (9,30)whereds / deis the parametric speed and **r**' is the derivative of the curve, **r**, both with respect to ε. The hodograph can be expressed as a quaternion product of the form= Ac iqAp) (9.31 )where 9 “His any fixed unit quaternion,-4€ 1S a’r / i" degree quaternion polynomial for a degree-n PHC, such that » ■ => + 1. and 4* is the conjugate of. Writing A in Bernstein form facilitates the development of an expression that ensures that the hodograph abides by the Pythagorean constraint, written as= v A; (7) 0 - f (9.32:i=0 Evaluating the Bernstein form for a quintic PHC («• = =:9,.4 is written asX(d = A(1 “ f)2+ 2e^4i(l “ e) + (9.33)It is clear from Equation 9.31 and Equation 9.33 that the following relationships exist for the end-derivatives of the curve / (0) = do = (9.34)I) = da = q (9.35)where ^0 is the derivative of the curve at the first control point, Co, written in quaternion form (co = O-rp Jts-.8 / (U)j+ (0)k)or0=and dsjsderivative of the curve at the fifthcontrol point,c5’ written in quaternion form tc?‘=0 +:K!l)i + •ril ij +.21)k or c5=,,r(0).:y(0),,?(<))]), where i = ]0, 1.0. ( j = i(), 0, 1,0]. and I- _ ffi jJ PK— », <>, ip general solution to Equation 9.34 and Equation 9.35 that abides by the Pythagorean constraint can be written asAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 An= V!d„J ExpfiAq )(9.36)q +f+ MJwhere * ■ is a unit vector in the direction of < U-rlis obtained via Equation 9.34 and Equation9.35, «... is the unit bisector ofand q, and represents free angular variables. Thehodograph of Equation 9.31 only depends on the difference of ‘A A- ^.nd A- Thus, by settingand writing! —~ ‘Aand p = <-:>2 ~asolution for n °r m= d, 1. 2 jswritten as.4o = JAI no Exp((7 - A = VkM »2 Exp((7 + ^. Aq) (9.37) A = — \ / jdi j nr — j ( A? +, A$ Jwhere is found using di = 120(cs- c0) — 15(do + d5) + 5(At4-24- AL4(i) (9.38J

[0106] Using Ah A,and.42:the control points of the PHC can be found by integrating Equation 9.31, written asci = c0+ | Aq.431 Ci = ci 4- — (AqAi + AqAl’ C3 = C9 3p^u4<;qfc4.?! •i».4iq»4j -b. AqAi / )9..?9) c.i = eg + -^7 (AiqAa + AqAi) c5= c.i + - 04- -h? / •' 1 )| -j-;(T;k0andrV!can be evaluated usingr(e) = c.;(', j (1 — (9.40)4— C"with arc lengthAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02(9.41)Note that with a curve identified, the curvature along that curve can be evaluated using(9.42)where 1’ is obtained via differentiation of Equation 9.31, written as4-.4(e)q.4**(f.’) (9.43)

[0107] Path Identification

[0108] Given the representation detailed above, a suitable curve in Euclidean space can be identified. To solve the Hermite interpolation problem, the first-order Hermite data is first expressed as pure vector quaternions. Specifically, the initial point of the PHC isc,;i =E and the end point of the PHC is G = t both written as pure vector quaternions. Additionally, note that the end-derivative of the PHC at the initial point can be written asdo = a ■; O. (Keg / : = u ■ f«, where fo = )), (R>e3)Tj provides the direction of the end-derivativeand d is a constant that scales its magnitude (similar to before, the size of es is implied). In the context of this path identification procedure, the aim is to identify a path that meets the endconditions of the PHC and minimizes the arc length of the PHC. This formulation can be written as followsargmin / (9.44) d, d; J{i

[0109] The free variables that are manipulated to define the PHC are the scalar d and the derivative of the PHC at C5, notated as d2. This minimization is subject to the constraint that the direction of the derivative at the start of the PHC must be the same as the current a posteriori= f„estimated direction the needle is pointing towards, written as and the curvature of theAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 PHC cannot be greater than the curvature defined by that of the interaction between the needle tip and the tissue, written as CGV k

[0110] Note that oncer! <:!is determined, it must be reparametrized with respect to arc length to obtain equally spaced waypoints along the curve. In this example, onceis identified, k nodes of C are identified that map to equally spaced arc length values notated as In other words,<, = ar ami ii ^4(,r; (9.45)

[0111] Experimental Validation

[0112] As mentioned previously, the EKF evaluated herein uses a steerable needle only in a bench-top setting. However, efforts are made to emulate the MR-environment in terms of sensor noise, as detailed below. A depiction of the overall system can be seen in Figure 16. Electromagnetic measurements were obtained using an Aurora EM-tracker (NDI Medical, Canada), emulating the MR-environment. The sensors used were selected from the smallest available sensor model provided by Aurora, which is a 5-DoF sensor (610099, NDI Medical, Canada). Note that only two sensors could fit inside the steerable needle and the offset from the sensor tip to the sensor measurement is approximately 4 mm. This is similar to the designs that use MRT coils, which only accommodate two sensors and have a sensor measurement offset. To provide a ground-truth for comparison in the experimental evaluations, the EM sensor location without added noise was used. Since there is an offset from the estimated state to the sensor location, comparison between the ground-truth and the estimated needle state was performed by leveraging the follow-the-leader deployment exhibited by the steerable needlesystem. Specifically, the a posteriori state estimate by the EKF at the ithtime index,was compared with the ground-truth sensor measurement of the most distal sensor at time index? a. Time index i 4- « represents the time index where the measured sensor position reachesAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 the EKF estimation that occurred at time index i. Thus, in general, = Pand bj at < + u is equal to b( t •; when referred to in the error metrics below. Note that the ground-truth sensor provides only 5 Degrees of Freedom (since roll cannot be measured). Thus, the EKF tip position and tip direction are compared to the sensor’s measured tip position and tip direction across the trajectory. To produce noisy measurements for evaluation of the EKF, noise was added using Equation 9.9 to the ground-truth sensor measurements, and the noisy sensor measurements were used for EKF state estimation to emulate the MR-environment. Throughout these experiments, σε= 0.6 mm,asthis was the accuracy identified, and it has been suggested that the standard deviation can be defined by the resolution of the sensor in the imaging modality.

[0113] A short justification is provided here for using the EM-tracker sensors as the ground-truth. First and foremost, during these needle insertion procedures, the needle tip cannot be observed in 3-D visually across the trajectory. Thus, an internal sensor must be used. While the manufacturer reports that these EM-sensors have a root-mean-square error of 0.7 mm in position and 0.2° in orientation over the entire workspace (for which the orientation deviation is satisfactory for our purposes), these sensors exhibited a standard deviation in measurement of position of A..= 1 ‘ R*1 intiwithin the relevant workspace of the experiments detailed here. Thus, it can be concluded that the EM-sensors are suitable for serving as a ground-truth. Additionally, EM-trackers have been used as a ground-truth in prior work as well.

[0114] The experiments performed are implemented using an Arduino® Mega and MATLAB® simulation software. MATLAB® was used to perform the high-level estimation computations and send speed axis commands while the Arduino® Mega was used to perform the low-level driving of the steerable needle at a prescribed control input velocity using the AccelStepper() library. The needle was inserted using a NEMA 23 stepper motor that wasAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 attached to a linear rail with a ball-screw that had a 5 mm pitch. The needle was rotated using a NEMA 17 stepper motor.

[0115] Phantom Process Noise Characterization

[0116] To evaluate the efficacy of the EKF, two different phantoms were created. One phantom was created using 5% by weight Knox™ (Kraft Foods Global, Inc., USA) gelatin, while the other phantom was created using 10% by weight agarose. These two phantoms were used to provide two significantly different mediums for insertion, the densities of which were shown to be drastically different. To use the EKF, quantification of both the process noise and the curvature during insertion is needed. To characterize both the process noise and the curvature of each phantom, five insertions to a depth of 90 mm were performed into each phantom using a constant insertion speed of "! =1and a constant; = 1 s. This resulted in a total of 450 samples for each phantom. To quantify the process noise across the samples for each phantom, the electromagnetic sensor system was used to measure the sensor’s state before and after each constant control input. The process noise, normalized with respect to time, was then evaluated by comparing the covariance between all samples. The resulting histograms and the evaluated Gaussian distribution with the same covariance can be seen in Figure 17(A)-(F) for the gelatin phantom and Figure 17(G)-(L) for the agarose phantom. In the experimental evaluations below, the process noise W was defined as zero mean with the diagonal elements of defined in Figure 17. To quantify the curvature value used in Equation 9.4 during insertion, the fourth element of each actual control vector input sample was divided by the third element of each actual control vector input sample and the mean was used as the corresponding K. Specifically, these K values result in a radius of curvature of 1092 mm for the gelatin phantom and 214 mm for the agarose phantom, further demonstrating the significant difference in phantom density.

[0117] Simulated ObservationsAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02

[0118] Before experimental evaluation of the EKF, simulations were performed to evaluate the trajectory following capability of the system with varying time steps and measurement noises using the characterized parameters from each phantom. The target point for each trajectory was=and the trajectories were identified using the approach detailed above. The algorithm was initialized with three control input vectors. Note that these are not 'F; rather, they are input vectors that map back to the known sensor locations and represent the initial shape of the needle inside of the tissue. The last control input vector was all zeros to represent that the needle was not initially moving, and the other two are defined by straight line insertions back to the sensor locations01= A A AT,A lot), 0. o, U]T, u, = [U. A 0, 0. u, (J] ) Forclarity, the first sensor was measured to be 10.00 mm from the distal tip and the second sensor was measured to be 25.00 mm from the distal tip in the constructed device. The corresponding first estimated state and covariance matrix was thus ^3and A. All target points were selected with a z-component depth of 150 mm and an x- and y-component of 0 mm. For comparison, an error metricis defined that is the minimum distance between the trajectory and state position.

[0119] For each set of characterized parameters, the time step was varied from 1.00 s, 0.1 s, and 0.01 s while= 0.6 mm, as shown in Figure 18(A) for the gelatin phantom parameters and Figure 18(B) for the agarose phantom parameters. Note that performance is similar across each time step, though the time step of 0.01 s approaches an error of 0 mm tracking error more frequently. In addition to the time step variation, the measurement noises were also varied while the time step was held constant at 1.00 s. The standard deviation of the measurement noise was varied from= 0.3 mm,£'s= 0.6 mm, ‘l<;= 0.9 mm,and = 1.2 mm, as shown in Figure 18(C) for the gelatin phantom parameters and Figure 18(D) for the agarose phantom parameters. Although trajectory tracking performance seems to improve with reduced measurement noise for the agarose phantom, the same trend is not observed for the gelatinAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 phantom. The simulations demonstrate that, if the process and measurement noise are both well-understood, the EKF performance can be maintained. Additionally, it should be noted that the trajectory tracking and end-point targeting performance in the simulation is similar to the experimental performance below.

[0120] Open-Loop Validation

[0121] The EKF was first evaluated experimentally by performing open-loop insertions with three different constant control input vectors, each to an insertion depth of 150 mm and with a At = 1 s. These are « = [0, 0, 2, 2, 0, 0]T, u = [0, 0, 2, 2 K, 0, 0.017]T, and u = [0, 0, 2, 2 K, 0, - 0.017]T, where the first three elements are in mm and the last three elements are in radians. Each open-loop insertion was performed for both the gelatin (Figure 19(A)-(C)) and agarose (Figure 19(D)-(F)) phantoms.

[0122] The results of these experiments are detailed in Table 1. The error results detailed in Table 1 are defined as the ‘-'2norm between the estimated position and the ground-truth position for positional error and the angular difference defined by the dot product between the estimated tangent vector direction and the actual tangent vector direction. For clarity, note again that = 0.6 mm. In addition to the EKF, the non-filtered (NF) estimated trajectory was also compared. As shown in Table 1 and Figure 19, the EKF significantly improves the prediction, both in terms of position and orientation. Notably, mean reconstruction errors of commercial systems that do not use MRT have previously been observed to be 2.5 mm and lower, and this example demonstrates similar to significantly improved results.Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 Table 1: Open-Loop EKF Validation ResultsGeiaJis. Phantom Agarose Phantom Filter Error Fi_ i < B) < C) (D> {El {F) Position [nun] I. G3+O.36 1.06+0.61 0.68+0.23 j.9i±0.92 1.53±l.i)3 1.33+9.43 Max imal] 2.63 4.20 1.24 3.64 3.32 2.24 Taageritn 2.98+1.11 2.54+1.58 1.31+123 6.68+1.90 4.62+2.45 4.26+0.73 Max }'3! 5.90 4.78 3.80? 1.42 50.41 5.63 Position [ram] 5.15+2.68 1.77+073 3.47+1.71 15.69+8.86 14.31+7.67 8.87+5.26 Max 9.96 5.66 6.04 35.42 27.24 18.18 Tawni P! 4.17+0.57 2.96+1.53 i.83+084 11.64+2.27 1029+1.93 699+2.26Max }'3} 5.36 5.92 3.43 15.66 14.67 10.82

[0123] Trajectory Following Validation

[0124] After the open-loop validation confirmed the utility of the EKF for estimation, a set of trajectory following experiments was performed. The initialization procedure of the algorithm was the same as the procedure detailed above. For clarity, note again that= 0.6 mm. Sixteen target points were identified in each phantom. Eight target points were selected with a z-component depth of 150 mm and eight target points were selected with a z-component depth of 175 mm. For the gelatin phantom, the target points at 150 mm were selected so that they circumscribed a circle in the x-y plane with a radius of 8 mm, and the target points at 175 mm were selected so that they circumscribed a circle in the x-y plane of 12 mm. For the agarose phantom, the target points at 150 mm were selected so that they circumscribed a circle in the x-y plane with a radius of 20 mm, and the target points at 175 mm were selected so that they circumscribed a circle in the x-y plane of 24 mm. The trajectories were identified by using thederivation detailed above. The initial conditions of the trajectory were defined by -A and the boundary condition was defined by the target point. The specific target points can be seen in Figure 20(A)-(D) and Figure 21 (A)-(D) for the gelatin and agarose phantoms, respectively. For comparison, the error metric A detailed above is used based on the estimated state instead of the actual state, as the actual state could only be measured in simulation. However, given the validation for estimation in the prior section, this method is suitable for comparison. Nonetheless, to ensure these results are representative of the ground-truth, this metric is also used to compare the distance between the trajectory and the measured ground-truth sensorAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 position, &1W, as it crosses the location where the state was estimated, providing a secondary validation method.

[0125] The plots of thenorm of these errors can be seen in Figure 20(E)-(H) and Figure 21(E)-(H) for the gelatin and agarose phantoms, respectively. For comparison of the mean targeting error at the end of the trajectory, the steerable needle was inserted an additional 10.00 mm after the target point was reached so that the ground-truth sensor could measure the location of the state of the needle at the end of the trajectory. The mean targeting error at the end of the trajectory was 1.93±1.26 mm for the gelatin phantom and 1.53±1.05 mm for the agarose phantom. These targeting errors are comparable to other MR-guided steerable needle studies. While these errors are higher than other EM-tracked steerable needle experiments (where the full 5-DoF of the EM-sensors can be exploited), the results presented herein are better than manual positioning techniques, which can exhibit errors as high as 11 mm and are typically in the range of 3-6 mm. The max targeting error for the endpoint was 3.79 mm for the gelatin phantom and 3.95 mm for the agarose phantom. Note that in one trajectory the maximum error exhibited was 6.56 mm. However, the remaining trajectories exhibited errors below 4.00 mm.

[0126] Trajectory Following with Disturbance

[0127] After the closed-loop validation confirmed the trajectory following capability of the EKF and the control law, trajectory following experiments were performed with a disturbance applied to the phantom. Each perturbation was applied to the entire phantom in the x-direction with a random magnitude, as shown in Figure 22(A) and Figure 22(B). The time at which the perturbation was applied was also random; however, it was within the first 20 seconds of the start of the trajectory, as shown in Figure 22(C) and Figure 22(D). For clarity, note again that "7"C;= 0.6 mm. Three target points were identified in each phantom. The initialization procedure of the algorithm was the same as the procedure detailed above. All the target points wereAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 selected with a z-component depth of 150 mm. For both phantoms, one target point had an x-and y-component of zero while the other two target points in each phantom were arbitrarily selected. The trajectories were identified by using the derivation detailed above. The initial conditions of the trajectory were defined by ‘^3 and the boundary condition was defined by the target point. The specific target points can be seen in Figure 22(A) and Figure 22(B) for the gelatin and agarose phantoms, respectively. Additionally, the same error metric as detailed in the closed-loop validation was used.

[0128] The plots of thenorm of these errors can be seen in Figure 22(C) and Figure 22(D) for the gelatin and agarose phantoms, respectively. Similar to the closed-loop trajectory following without a perturbation, for comparison of the mean targeting error at the end of the trajectory, the steerable needle was inserted an additional 10.00 mm after the target point was reached so that the ground-truth sensor could measure the location of the state of the needle at the end of the trajectory. The mean targeting error at the end of the trajectory was 1.37±0.45 mm for the gelatin phantom and 3.39±1.11 mm for the agarose phantom. The max targeting errors for the endpoints were 1.85 mm for the gelatin phantom and 4.48 mm for the agarose phantom.

[0129] Discussion

[0130] In this example, bench-top implementation was performed of an extended Kalman filter on - L(4>for pose estimation of a steerable needle with only exteroception feedback in the form of positional measurements provided by electromagnetic sensors at the distal end of the steerable needle. The intent of this study is to develop an algorithm that can be used in the MR-environment with MRT sensors from prior work for deep percutaneous brachytherapy. It should be noted that insertion depths of 175 mm are higher than those used in prior studies, which range between 40 mm and 140 mm, further demonstrating the efficacy of the algorithm. This depth consideration is relevant, as insertion depths in clinical brachytherapy are as highAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 as 160 mm, and accuracy in the range of 4 mm with fine-repositioning techniques is preferred. The system presented here demonstrates the ability to achieve these desired outcomes. Additionally, the estimation error of the needle tip remained below 2 mm, non-straight paths were achieved in both the agarose and gelatin phantoms, and the path interpolator worked well for the target positions defined in this chapter. Nonetheless, during the evaluation, there were several observations that should be discussed.

[0131] First, regarding the derivation ofand H other derivations were initiallyattempted that resulted in instability, as detailed below. Regarding the calculation of5-?, derivation on the sequential difference between the a posteriori estimates,instead of the nominal control inputs was first implemented, written asi. V.;. G A) ® @ & Xj ® ti(9.46) J = I G — Uj+1® — U,... G -utl, ® —11,However, as the state evolved, a diverging helix was consistently observed in simulation. This would occur even if the nominal inputs were a vector of zeros, which makes sense considering each correction applied to a non-moving needle would imply the needle is continuing to move in an infeasible way (effectively tying knots around itself). This motivated the use of the nominal control inputs for the derivation with robust performance and consistency. Notably, the proposed derivation is applicable due to the follow-the-leader motion and the close H • = J 'proximity of the sensors to the distal tip. Regarding the derivation of ' •*' a derivation of the formAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 H,sA1MJXIwas first implemented, which can be thought of as mapping the change atto the change at HAs- However, this also diverged. Given the ineffectiveness of this approach,?was then projected onto the nullspace of the controls. Unfortunately, this also presented poor performance, as this projection limited Ax to only changes that abide by the non-holonomic constraints, which may not occur if, for example, the whole guiding medium is displaced, as done in the disturbance experiments. Thus, given that the sensor positions were localized to the distal tip=I was adopted. Notably, this enables a straightforward formulation that can be easily implemented. However, it should be noted that in future work, it may be constructive to explore different derivations ofH?based on the distance of the sensor from the distal tip and the tissue stiffness. This will be particularly relevant as algorithms are developed for estimating the pose of intracardiac catheters given sensor measurements along the catheter body. For example, in a straight intracardiac catheter, a change alonge:;in the body-frame at the distal tip may map directly to a change alonge3 at a proximal sensor, but a change ine2 at the distal tip clearly may not map directly to a change alongat a proximal sensor due to the elastic nature of the intracardiac catheter.

[0132] In addition to the experiments above, the system was also evaluated in ex vivo bovine and porcine muscle tissue. However, it was interesting to note that the tested steerable needle, made of nitinol, was ineffective at steering through the medium. Instead, the steerable needle followed the path defined by the muscular fiber striations, rendering the bevel-tipAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 ineffective. Notably, this is likely the reason bevel-tipped steering is typically evaluated in phantoms and organ tissue. This suggests that when traversing smooth muscles, such as vaginal tissue, or when traversing organ tissue, the needle proposed in this work would be suitable. However, when traversing skeletal muscle, adopting a stiffer stylet would likely be preferred. Notably, this suggestion is also compatible with existing interstitial grids used in gynecological brachytherapy. When guiding a needle through the inner obturator (a picture of which can be seen in Figure 12), the steerable needle proposed in this example is suitable, as it traverses smooth muscle tissue and the flexibility of the needle is needed due to the sharp angles of the guiding obturator (tungsten will plastically deform in the obturator depicted in Figure 12). However, when guiding the needle through some other guiding grids, a stiffer (non superelastic) tungsten stylet or (superelastic) cobalt-chromium stylet is more suitable, as the stylet will traverse skeletal muscle and does not need to bend through these other guiding grids.

[0133] Finally, a closing note on the use of Pythagorean hodograph curves is provided. This derivation was adopted for defining a path due to the ability to generate a smooth curve that considers the relevant initial and boundary conditions of the curve. Further, it can be easily reparametrized to arc length. However, another unique feature of this interpolator is its ability to generate piecewise splines based on the data available from the SE(3) representation (position and orientation). This utility is leveraged in 3-D modeling of computer aided designs in software packages such as SolidWorks®. While obstacles were not considered in this example, future work will consider anatomical structures that should be avoided; piecewise PHC splines will be used to drive the steerable system from the entry location to the target in a safe manner. This interpolator will likely be extended to approaches where, for example, an optimal path was identified to avoid white matter tracts and intracerebral vessels during ICH evacuation. However, the computation time was prohibitive in those approaches. However, thisAttorney Docket No. 0184.0326-PCT Client Ref No. Pl 8398-02 interpolator can be used to improve the computational efficiency and streamline the path identification workflow, which will in turn improve patient outcomes.

[0134] Review of Lie Theory

[0135] A Lie groupA is a set, M that is both a group and a smooth manifold. The composition operation, o, defines how elements of the manifold can be used to form new elements on the manifold. This operation also satisfies the following group axioms for three arbitrary elements,Z & M (of which to be clear, there are infinitely more; choosing three simply allows the articulation of the group axioms): (i) the composition of elements on the manifold remain on the manifold* fA (ii) one of these elements, £, is the identity(iii) eache|ementjn the group has an inverse also on the manifold t<¥-1o A - A o A-i- f);anc] (iv) the composition operation, o, is associative ((A <>y) o2 = Ao (y

[0136] Consider an element that evolves over time on the manifold In the case ofthe manifold the body velocity of this element, written as twist is given through left translation by=This expression represents the body velocity as a twist at the tangent space ofss$) at the identity element,The tangent space at the identity, ^£5(3}, is known as the Lie algebra of the manifold and is denotedSf,A' -T<-SE(3y The Lie algebra is a vector space, and its elements forcan be represented as infinitesimal tangent increments of the body velocity over timet, written as(f 'e). The Lie algebra can be mapped onto elements of the group through the exponential map. A local inverse of the exponential map, defined in a neighborhood around the identity element, £, is the logarithmic map. These maps can be written asexp: <se(3) S®(8) (r*)AM- A = exp((r'!')A)(B.l)log: jee(3) A' H- (rA" — tog(A’)Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 Notably, the elements of can be passed fromt0 an(jvjce versa,viatwo isomorphisms, written asA: R6: r H rA= 7‘<=1where is the basis ofand is a set of matrices that represent the basis of the Lie algebra. Since the Cartesian vector spaceisoften preferred for its readability, the capitalized exponential and logarithmic maps are now presented as shorthand to avoid the repeated inclusion of the A andvoperators in the derivation, written asExp: R6— > S'EfB): r1’ A' — Exp(r*)(B 3)Log: SE(%) R6: A M T* = Lc-g(A')which by definition is= Expt ') L expO T V' ’ ' (B.4)A’ — Log. T) logt'A'AThese maps are used locally at element A’ with the right-plus and right-minus operators ( ® and &), written asright-®: y — A ® 4 A o Exp(V| e > SS(3)(B.5)right"©: r‘ “ y © A == LogfA"1o € R8

[0137] Finally, a relation between velocity twist coordinates (such as the body frame and special frame) is needed for this work. This can be related by an action performed in the vector space using the adjoint matrix, written asA< U: Rb■■■>; r;‘ H T5— Ad^r*(B.6)=(A(ri‘)AA“i)vwhere, in the case of the manifoldis an infinitesimal tangent increment over time i of the special velocity, given as a twist through right translation by -■''1= CZ, written as (TS)A= (V'!)Ae ®t(3)Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02

[0138] Derivation for Adjoint of •-’’CC

[0139] The state transition matrix, F, of the EKF requires the calculation of. Consider thatcan be written as some arbitrary inputL J, where P and & are the first three elements and last three elements of r, respectfully. First, noting the property fB-71R;R’p |Exp(r)'along withx J, the inverse of the adjoint can be written as

[0140] Derivation of Jacobians for the Estimator

[0141] The control-input model G is written asG— Consider that “s+i can bewritten as some arbitrary inputU‘+iJ, where and & are the first three elements and last three elements of r, respectfully. The right Jacobian,can be written as a function of the left Jacobian, T, as= F.(-p, where U'!?is written in closed form aswhere isthe left Jacobian of80'^ identified as1 — cos Sr, S — sin &.= U. S + 7U +,, -[< (B.10)and is identified as+ Hxf»]x + MxHxBx)->~V-M»(M»w> + Wi< [s]s _ 3(0], M4e],) _ 1 / j _ 1 ~ ~ i — cos (J?) — Q _ — sin ( _C _ — _ 2_ |2 c c yAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02

[0142] EXAMPLE 2: MR-GUIDED HDR BRACHYTHERAPY IN CERVICAL CANCER PATIENTS: ACCURATE AND FAST CATHETER POSITIONING WITH REAL-TIME RADIATION DOSIMETRY

[0143] Introduction: High-Dose-Rate Brachytherapy (HDR-brachy) involves insertion of 2-20 catheters from the surface, traversing muscle tissues, ending in pre-designated locations in the tumor, which requires use of mechanically stiff, metallic inserts (“stylets”) to advance the catheters. Later, “seed” radiation sources placed in the catheters irradiate the tumor. However, catheter paths deflect during insertion, requiring multiple insertions for proper placement, increasing procedure time and bleeding risk. We previously developed MR-Tracked (MRT) navigation of HDR-brachy catheters using microcoil-antennas placed in groves on metallic-stylets, coupled with MRT sequences accounting for B0 and Bl complexities encountered with metallic devices and thereafter placed catheters into ~70 patients more accurately and faster than passive tracking. We recently (a) improved MRT SNR by -25% (1.5T) and -30% (3T), by replacing the microcoil flexible printed circuits (Fig. 23) with ones carrying, besides antennas, on-board tuning and matching capacitors.(b) We developed flexible (concentric-tube-Nitinol) stylets, for use with Elekta’s Venezia applicator, that require sharp >20degree deflections in a <25mm diameter, complementing rigid (tungsten-rod) stylets used before, which cannot substantially deform (Fig. 23C). (c) We developed optimized MRT SNR protocols for Siemens’ VX platform for differing MRT spatial-resolutions, frames-per-second (fps) and stylet-advancement-speeds (up to 250mm / s) in a human-emulating phantom, based on Humimic-Medical gels. We optimized T1 -relaxation within and between successive tracking-point acquisitions by placing delays between MRT readouts (Figure 24). (d) Via a high-speed link with Elekta’s Oncentra-research workstation, we provided dosimetry during catheter insertion, guiding catheter placement to improve theAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 radiation-dose spatial-distribution, possibly reducing uncovered tumor regions as well as neighboring-tissue inadvertent dose.

[0144] We explored: (1) whether the new hardware and software improved tracking performance and (2) whether new on-line dosimetry provided user advantages.

[0145] Methods: Patients: we intervened in 7 patients with the new hardware and software platform, with patients receiving 1 to 5 MR-Tracked HDR-Brachy fractions (totaling 15 interventions). As before, the navigational-roadmap was composed of a 48-slice 2D T2-weighted-FSE image-set with 0.8x0.8x3.0mm3resolution, requiring ~1.5 minutes, acquired prior to navigation, and covering the entire imaging volume. This image-set was then segmented using Al means to detail the High-risk Critical Target Volume (HR-CTV) planned to be radiated, as well as surrounding Bladder, Rectum and GI regions to be avoided.

[0146] The User-Interface displayed in the MRI room during navigation (Figure 25) showed Axial, Sagittal and Coronal slices, resliced from the navigational-roadmap and displayed at the instantaneous tip location and orientation of the actively-manipulated catheter. The slices included a color overlay of the currently achieved radiation dose, showing the 200% (11 Gy) and 50% (2.75Gy) isodose lines, as well as circles denoting locations of previously inserted catheters. The real-time MRT catheter dosimetry was performed by collecting the catheter trajectories, using a custom time- and location-clustering method, providing dose-maps at 5 fps. The real-time dosimetry was later compared to the final CT-determined dosimetry to determine its success in providing improved coverage and lower surrounding tissue radiation, The Tracking SNR was displayed in the form of a real-time SNR meter (Figure 25D). The normalized vertical axis compares the 3-directional instantaneous MRT peaks and the tracking noise standard deviation whereas the horizontal axis are the tracking frequencies, binned at 268 Hz (0.8 mm) increments in the 3 spatial directions. 1.5T MRT was performed using the Hadamard method with 2 Averages and 3 Phase-dithering-angles per location. To maintain aAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 high tracking SNR, we tried different delays between tracking-points (0-5000μs) as well as varying-length (10-50) tracking-point acquisition-trains, prior to a ~5s GRE-imaging interlude, with 0.1s delay between imaging and tracking.

[0147] The clinician observed the catheter trajectories by looking at the MRI in-room display (Figure 25) and brought catheters to their designated locations.

[0148] Results: In phantoms at 1.5T, the improved MRT sequence and stylet hardware, provided an SNR of ~12 with 20 tracking-point acquisition-trains and 6500μs (3500 μs +3000 μs) between tracking points at insertion-speeds of 40-80mm / s (Fig. 24D), permitted increasing the MRT (fps) from 8 to 12 fps at a 0.8x0.8x0.8mm3spatial resolution. In patients, using the above MRT parameters, insertion-time / catheter for a 12cm depth placement dropped to ~1 min / catheter. All patient procedures were successful at bringing all catheters to the desired locations in 10-20min navigations. Additionally, with the increased fps, the catheter-trajectory spatial-resolution was improved during insertion, which thereby enhanced the real-time dosimetry quality (Figure 26). Real-time dosimetry provides real-time quantitative feedback, otherwise not available, about the convergence of the already-achieved to the targeted dose, reducing procedure time and possibly reducing dose inhomogeneity.

[0149] Conclusions: The benefits of MR-Tracked navigation were substantially improved, primarily due to higher-speed tracking and on-line dosimetry.

[0150] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the present teachings are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all sub-ranges subsumed therein. For example, a range of "less than 10" can include any and all sub-ranges between (and including) the minimum value of zero and theAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 maximum value of 10, that is, any and all sub-ranges having a minimum value of equal to or greater than zero and a maximum value of equal to or less than 10, e.g., 1 to 5. In certain cases, the numerical values as stated for the parameter can take on negative values. In this case, the example value of range stated as “less than 10” can assume negative values, e.g. -1, -2, -3, -10, -20, -30, etc.

[0151] Some further aspects are defined in the following clauses:

[0152] Clause 1: A medical device, comprising: at least one elongated probe insertable into at least one tissue; at least one tracking element operably connected to the elongated probe, which tracking element is operably connected, or connectable, to at least one tracking apparatus that is configured to actively track positioning of at least portions of the elongated probe in substantially real-time at least when the elongated probe is inserted into the tissue; and, at least one handle operably connected at least to the elongated probe, wherein the elongated probe comprises at least one outer tube structure having an outer tube cavity disposed longitudinally along at least a portion of a length of the outer tube structure and at least one inner tube structure having an inner tube cavity disposed longitudinally along at least a portion of a length of the inner tube structure, wherein the length of the outer tube structure is less than the length of the inner tube structure, wherein the outer tube structure comprises at least first and second outer tube structure openings disposed proximal to a distal end of, and along at least a segment of the length of, the outer tube structure, which outer tube structure openings are in communication with the outer tube cavity, wherein the inner tube structure comprises at least first and second inner tube structure openings along at least a segment of the length of the inner tube structure, which inner tube structure openings are in communication with the inner tube cavity, wherein the inner tube structure is disposed substantially within the outer tube cavity proximal to the distal end of the outer tube structure such that the outer tube structure openingsAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 substantially align with the inner tube structure openings to produce aligned openings, and wherein the tracking element is disposed in at least one of the aligned openings.

[0153] Clause 2: The medical device of Clause 1, wherein the elongated probe comprises sufficient flexibility and sufficient strength to bend by about 90° without having a structural failure when inserted into the tissue.

[0154] Clause 3: The medical device of Clause 1 or Clause 2, wherein the elongated probe is fabricated from nitinol.

[0155] Clause 4: The medical device of any one of the preceding Clauses, wherein the elongated probe is at least about 10 cm, about 20 cm, about 30 cm, about 40 cm, about 50 cm, or more in length.

[0156] Clause 5: The medical device of any one of the preceding Clauses, wherein the elongated probe comprises a stylet.

[0157] Clause 6: The medical device of any one of the preceding Clauses, further comprising a catheter through which the elongated probe is at least partially disposed, wherein the catheter comprises a bevel-tip.

[0158] Clause 7: The medical device of any one of the preceding Clauses, wherein the elongated probe is configured to be manually inserted into the tissue.

[0159] Clause 8: The medical device of any one of the preceding Clauses, wherein the elongated probe is configured to be directionally deflected while being manually inserted into the tissue using a motor, or both directionally deflected and inserted into the tissues using multiple motors that are housed within the handle and operably connected to the elongated probe.

[0160] Clause 9: The medical device of any one of the preceding Clauses, wherein the tracking element is configured to track positions of at least portions of the elongated probe at one or more time points when the elongated probe is inserted into the tissue.Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02

[0161] Clause 10: The medical device of any one of the preceding Clauses, wherein the tracking element comprises one or more of an electromagnetic (EM) tracking element, a lightwave interference tracking element, a magnetic resonance (MR)-tracking element, and / or an electrical impedance tracking element.

[0162] Clause 11: The medical device of any one of the preceding Clauses, wherein the tracking element is operably connected to the inner tube structure.

[0163] Clause 12: The medical device of any one of the preceding Clauses, wherein the tracking element comprises at least one magnetic resonance (MR)-tracking coil that is integrally tuned and matched to 50 Ohms at the desired MRI operational frequency to reduce reflections at the tracking coil coaxial cable interface and thus increase the transmitted tracking signal.

[0164] Clause 13: The medical device of any one of the preceding Clauses, comprising a proximal MR-tracking coil and a distal MR-tracking coil, wherein the proximal MR-tracking coil is disposed in a proximal aligned opening, wherein the distal MR-tracking coil is disposed in a distal aligned opening, and wherein the proximal aligned opening is located closer to the handle than the distal aligned opening.

[0165] Clause 14: The medical device of any one of the preceding Clauses, wherein cables operably connect the proximal MR-tracking coil and the distal MR-tracking coil tracking apparatus.

[0166] Clause 15: The medical device of any one of the preceding Clauses, wherein at least portions of the cables are disposed through at least a segment of the inner tube cavity.

[0167] Clause 16: The medical device of any one of the preceding Clauses, wherein the handle comprises tuning and matching electronic components that are operably connected to the cables, which tuning and matching electronic components are configured to tune an MR-Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 tracking circuit that comprises the proximal MR-tracking coil and the distal MR-tracking coil to a selected frequency and to a selected electrical impedance at the selected frequency.

[0168] Clause 17: The medical device of any one of the preceding Clauses, wherein the elongated probe is insertable into the tissue via an ancillary medical apparatus.

[0169] Clause 18: The medical device of any one of the preceding Clauses, wherein the elongated probe is sufficiently flexible to bend within a curved pathway fabricated at least partially within the ancillary medical apparatus.

[0170] Clause 19: The medical device of any one of the preceding Clauses, wherein the ancillary medical apparatus comprises a gynecological applicator device.

[0171] Clause 20: The medical device of any one of the preceding Clauses, wherein the ancillary medical apparatus is configured to deliver one or more doses of a therapeutic agent to the tissue when the ancillary medical apparatus is disposed within sufficient proximity to the tissue.

[0172] Clause 21: The medical device of any one of the preceding Clauses, wherein the therapeutic agent comprises a radiopharmaceutical agent.

[0173] Clause 22: The medical device of any one of the preceding Clauses, further comprising at least one imaging element operably connected to the elongated probe, which imaging element is operably connected, or connectable, to at least one imaging apparatus that is further configured to capture one or more images of the elongated probe and / or the tissue in substantially real-time at least when the elongated probe is inserted into the tissue.

[0174] Clause 23: The medical device of any one of the preceding Clauses, wherein the imaging element is disposed in at least one of the aligned openings.

[0175] Clause 24: The medical device of any one of the preceding Clauses, wherein the imaging element comprises one or more of an X-ray imaging element, a computed tomographyAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 (CT) imaging element, an ultrasound (ULS) imaging element, a magnetic resonance (MR) imaging element, and / or a positron emission tomography (PET) imaging element.

[0176] Clause 25: A kit comprising the medical device of any one of the preceding Clauses.

[0177] Clause 26: A system comprising the medical device of any one of the preceding Clauses.

[0178] Clause 27: A system, comprising: a medical device, comprising: at least one elongated probe insertable into at least one tissue; at least one tracking element operably connected to the elongated probe, which tracking element is operably connected, or connectable, to at least one tracking apparatus; and, at least one handle operably connected at least to the elongated probe, wherein the elongated probe comprises at least one outer tube structure having an outer tube cavity disposed longitudinally along at least a portion of a length of the outer tube structure and at least one inner tube structure having an inner tube cavity disposed longitudinally along at least a portion of a length of the inner tube structure, wherein the length of the outer tube structure is less than the length of the inner tube structure, wherein the outer tube structure comprises at least first and second outer tube structure openings disposed proximal to a distal end of, and along at least a segment of the length of, the outer tube structure, which outer tube structure openings are in communication with the outer tube cavity, wherein the inner tube structure comprises at least first and second inner tube structure openings along at least a segment of the length of the inner tube structure, which inner tube structure openings are in communication with the inner tube cavity, wherein the inner tube structure is disposed substantially within the outer tube cavity proximal to the distal end of the outer tube structure such that the outer tube structure openings substantially align with the inner tube structure openings to produce aligned openings, and wherein the tracking element is disposed in at least one of the aligned openings; at least one tracking apparatus operably connected, or connectable, to the tracking element, which tracking apparatus comprises at leastAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 one controller that comprises, or is capable of access, computer readable media comprising computer-executable instructions which, when executed by at least one electronic processor, perform at least: actively tracking one or more positions of at least portions of the elongated probe in substantially real-time at least when the elongated probe is inserted into the tissue.

[0179] Clause 28: A method of tracking a medical device in a subject, the method comprising: inserting at least a portion of at least one elongated probe of a medical device into at least one tissue of the subject, wherein the medical device further comprises: at least one tracking element operably connected to the elongated probe, which tracking element is operably connected, or connectable, to at least one tracking apparatus that is configured to actively track positioning of the elongated probe in substantially real-time at least when the elongated probe is inserted into the tissue; and, at least one handle operably connected at least to the elongated probe, wherein the elongated probe comprises at least one outer tube structure having an outer tube cavity disposed longitudinally along at least a portion of a length of the outer tube structure and at least one inner tube structure having an inner tube cavity disposed longitudinally along at least a portion of a length of the inner tube structure, wherein the length of the outer tube structure is less than the length of the inner tube structure, wherein the outer tube structure comprises at least first and second outer tube structure openings disposed proximal to a distal end of, and along at least a segment of the length of, the outer tube structure, which outer tube structure openings are in communication with the outer tube cavity, wherein the inner tube structure comprises at least first and second inner tube structure openings along at least a segment of the length of the inner tube structure, which inner tube structure openings are in communication with the inner tube cavity, wherein the inner tube structure is disposed substantially within the outer tube cavity proximal to the distal end of the outer tube structure such that the outer tube structure openings substantially align with the inner tube structure openings to produce aligned openings, and wherein the tracking element is disposed in at leastAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 one of the aligned openings; and, actively tracking one or more positions of at least portions of the elongated probe in substantially real-time when the elongated probe is inserted into the tissue using the tracking element, thereby tracking the medical device in the subject.

[0180] Clause 29: The method of Clause 28, further comprising delivering one or more hydrogels at least proximal to the tissue and / or one or more doses of a therapeutic agent to the tissue.

[0181] Clause 30: A method of making a medical device, the method comprising: forming at least one elongated probe that is insertable into at least one tissue such that: the elongated probe comprises at least one outer tube structure having an outer tube cavity disposed longitudinally along at least a portion of a length of the outer tube structure and at least one inner tube structure having an inner tube cavity disposed longitudinally along at least a portion of a length of the inner tube structure, the length of the outer tube structure is less than the length of the inner tube structure, the outer tube structure comprises at least first and second outer tube structure openings disposed proximal to a distal end of, and along at least a segment of the length of, the outer tube structure, which outer tube structure openings are in communication with the outer tube cavity, the inner tube structure comprises at least first and second inner tube structure openings along at least a segment of the length of the inner tube structure, which inner tube structure openings are in communication with the inner tube cavity, and the inner tube structure is disposed substantially within the outer tube cavity proximal to the distal end of the outer tube structure such that the outer tube structure openings substantially align with the inner tube structure openings to produce aligned openings, operably connecting at least one tracking element to the elongated probe, which tracking element is operably connected, or connectable, to at least one tracking apparatus that is configured to actively track positioning of at least portions of the elongated probe in substantially real-time at least when the elongated probe is inserted into the tissue, wherein the tracking element is disposed in atAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 least one of the aligned openings; and, operably connecting at least one handle at least to the elongated probe, thereby making the medical device.

[0182] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the present teachings are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Moreover, all ranges disclosed herein are to be understood to encompass any and all sub-ranges subsumed therein. For example, a range of "less than 10" can include any and all sub-ranges between (and including) the minimum value of zero and the maximum value of 10, that is, any and all sub-ranges having a minimum value of equal to or greater than zero and a maximum value of equal to or less than 10, e.g., 1 to 5. In certain cases, the numerical values as stated for the parameter can take on negative values. In this case, the example value of range stated as “less than 10” can assume negative values, e.g. -1, -2, -3, -10, -20, -30, etc.

[0183] While the present teachings have been illustrated with respect to one or more implementations, alterations and / or modifications can be made to the illustrated examples without departing from the spirit and scope of the appended claims. For example, it will be appreciated that while the process is described as a series of acts or events, the present teachings are not limited by the ordering of such acts or events. Some acts may occur in different orders and / or concurrently with other acts or events apart from those described herein. Also, not all process stages may be required to implement a methodology in accordance with one or more aspects or implementations of the present teachings. It will be appreciated that structural components and / or processing stages can be added or existing structural components and / or processing stages can be removed or modified. Further, one or more of the acts depicted herein may be carried out in one or more separate acts and / or phases. Furthermore, to the extent thatAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 the terms “including,” “includes,” “having,” “has,” “with,” or variants thereof are used in either the detailed description and the claims, such terms are intended to be inclusive in a manner similar to the term “comprising.” The term “at least one of’ is used to mean one or more of the listed items can be selected. As used herein, the term “one or more of’ with respect to a listing of items such as, for example, A and B, means A alone, B alone, or A and B. Further, in the discussion and claims herein, the term “on” used with respect to two materials, one “on” the other, means at least some contact between the materials, while “over” means the materials are in proximity, but possibly with one or more additional intervening materials such that contact is possible but not required. Neither “on” nor “over” implies any directionality as used herein. The term “about” indicates that the value listed may be somewhat altered, as long as the alteration does not result in nonconformance of the process or structure to the illustrated implementation. Finally, “exemplary” indicates the description is used as an example, rather than implying that it is an ideal. Other implementations of the present teachings will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the present teachings being indicated by the following claims.

Claims

Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 WHAT IS CLAIMED IS:

1. A medical device, comprising:at least one elongated probe insertable into at least one tissue;at least one tracking element operably connected to the elongated probe, which tracking element is operably connected, or connectable, to at least one tracking apparatus that is configured to actively track positioning of at least portions of the elongated probe in substantially real-time at least when the elongated probe is inserted into the tissue; and, at least one handle operably connected at least to the elongated probe,wherein the elongated probe comprises at least one outer tube structure having an outer tube cavity disposed longitudinally along at least a portion of a length of the outer tube structure and at least one inner tube structure having an inner tube cavity disposed longitudinally along at least a portion of a length of the inner tube structure,wherein the length of the outer tube structure is less than the length of the inner tube structure,wherein the outer tube structure comprises at least first and second outer tube structure openings disposed proximal to a distal end of, and along at least a segment of the length of, the outer tube structure, which outer tube structure openings are in communication with the outer tube cavity,wherein the inner tube structure comprises at least first and second inner tube structure openings along at least a segment of the length of the inner tube structure, which inner tube structure openings are in communication with the inner tube cavity,wherein the inner tube structure is disposed substantially within the outer tube cavity proximal to the distal end of the outer tube structure such that the outer tube structure openings substantially align with the inner tube structure openings to produce aligned openings, andwherein the tracking element is disposed in at least one of the aligned openings.Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 2. The medical device of claim 1, wherein the elongated probe comprises sufficient flexibility and sufficient strength to bend by about 90° without having a structural failure when inserted into the tissue.

3. The medical device of claim 1, wherein the elongated probe is fabricated from ni tinol.

4. The medical device of claim 1, wherein the elongated probe is at least about 10 cm, about 20 cm, about 30 cm, about 40 cm, about 50 cm, or more in length.

5. The medical device of claim 1, wherein the elongated probe comprises a stylet.

6. The medical device of claim 1, further comprising a catheter through which the elongated probe is at least partially disposed, wherein the catheter comprises a bevel-tip.

7. The medical device of claim 1, wherein the elongated probe is configured to be manually inserted into the tissue.

8. The medical device of claim 1, wherein the elongated probe is configured to be directionally deflected while being manually inserted into the tissue using a motor, or both directionally deflected and inserted into the tissues using multiple motors that are housed within the handle and operably connected to the elongated probe.

9. The medical device of claim 1, wherein the tracking element is configured to track positions of at least portions of the elongated probe at one or more time points when the elongated probe is inserted into the tissue.Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 10. The medical device of claim 1, wherein the tracking element comprises one or more of an electromagnetic (EM) tracking element, a light-wave interference tracking element, a magnetic resonance (MR)-tracking element, and / or an electrical impedance tracking element.

11. The medical device of claim 1, wherein the tracking element is operably connected to the inner tube structure.

12. The medical device of claim 1, wherein the tracking element comprises at least one magnetic resonance (MR)-tracking coil that is integrally tuned and matched to 50 Ohms at the desired MRI operational frequency to reduce reflections at the tracking coil coaxial cable interface and thus increase the transmitted tracking signal.

13. The medical device of claim 12, comprising a proximal MR-tracking coil and a distal MR-tracking coil, wherein the proximal MR-tracking coil is disposed in a proximal aligned opening, wherein the distal MR-tracking coil is disposed in a distal aligned opening, and wherein the proximal aligned opening is located closer to the handle than the distal aligned opening.

14. The medical device of claim 13, wherein cables operably connect the proximal MR-tracking coil and the distal MR-tracking coil tracking apparatus.

15. The medical device of claim 14, wherein at least portions of the cables are disposed through at least a segment of the inner tube cavity.

16. The medical device of claim 14, wherein the handle comprises tuning and matching electronic components that are operably connected to the cables, which tuning and matching electronic components are configured to tune an MR-tracking circuit that comprisesAttorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 the proximal MR-tracking coil and the distal MR-tracking coil to a selected frequency and to a selected electrical impedance at the selected frequency.

17. The medical device of claim 1, wherein the elongated probe is insertable into the tissue via an ancillary medical apparatus.

18. The medical device of claim 17, wherein the elongated probe is sufficiently flexible to bend within a curved pathway fabricated at least partially within the ancillary medical apparatus.

19. The medical device of claim 17, wherein the ancillary medical apparatus comprises a gynecological applicator device.

20. The medical device of claim 17, wherein the ancillary medical apparatus is configured to deliver one or more doses of a therapeutic agent to the tissue when the ancillary medical apparatus is disposed within sufficient proximity to the tissue.

21. The medical device of claim 20, wherein the therapeutic agent comprises a radiopharmaceutical agent.

22. The medical device of claim 1, further comprising at least one imaging element operably connected to the elongated probe, which imaging element is operably connected, or connectable, to at least one imaging apparatus that is further configured to capture one or more images of the elongated probe and / or the tissue in substantially real-time at least when the elongated probe is inserted into the tissue.

23. The medical device of claim 22, wherein the imaging element is disposed in at least one of the aligned openings.Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-0224. The medical device of claim 22, wherein the imaging element comprises one or more of an X-ray imaging element, a computed tomography (CT) imaging element, an ultrasound (ULS) imaging element, a magnetic resonance (MR) imaging element, and / or a positron emission tomography (PET) imaging element.

25. A kit comprising the medical device of claim 1.

26. A system comprising the medical device of claim 1.

27. A system, comprising:a medical device, comprising:at least one elongated probe insertable into at least one tissue;at least one tracking element operably connected to the elongated probe, which tracking element is operably connected, or connectable, to at least one tracking apparatus; and,at least one handle operably connected at least to the elongated probe, wherein the elongated probe comprises at least one outer tube structure having an outer tube cavity disposed longitudinally along at least a portion of a length of the outer tube structure and at least one inner tube structure having an inner tube cavity disposed longitudinally along at least a portion of a length of the inner tube structure, wherein the length of the outer tube structure is less than the length of the inner tube structure,wherein the outer tube structure comprises at least first and second outer tube structure openings disposed proximal to a distal end of, and along at least a segment of the length of, the outer tube structure, which outer tube structure openings are in communication with the outer tube cavity,Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 wherein the inner tube structure comprises at least first and second inner tube structure openings along at least a segment of the length of the inner tube structure, which inner tube structure openings are in communication with the inner tube cavity, wherein the inner tube structure is disposed substantially within the outer tube cavity proximal to the distal end of the outer tube structure such that the outer tube structure openings substantially align with the inner tube structure openings to produce aligned openings, andwherein the tracking element is disposed in at least one of the aligned openings;at least one tracking apparatus operably connected, or connectable, to the tracking element, which tracking apparatus comprises at least one controller that comprises, or is capable of access, computer readable media comprising computer-executable instructions which, when executed by at least one electronic processor, perform at least:actively tracking one or more positions of at least portions of the elongated probe in substantially real-time at least when the elongated probe is inserted into the tissue.

28. A method of tracking a medical device in a subject, the method comprising: inserting at least a portion of at least one elongated probe of a medical device into at least one tissue of the subject, wherein the medical device further comprises:at least one tracking element operably connected to the elongated probe, which tracking element is operably connected, or connectable, to at least one tracking apparatus that is configured to actively track positioning of the elongated probe in substantially real-time at least when the elongated probe is inserted into the tissue; and,at least one handle operably connected at least to the elongated probe, wherein the elongated probe comprises at least one outer tube structure having an outer tube cavity disposed longitudinally along at least a portion of a length of the outer tube structure and at least one inner tube structure having an inner tube cavity disposed longitudinally along at least a portion of a length of the inner tube structure,Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 wherein the length of the outer tube structure is less than the length of the inner tube structure,wherein the outer tube structure comprises at least first and second outer tube structure openings disposed proximal to a distal end of, and along at least a segment of the length of, the outer tube structure, which outer tube structure openings are in communication with the outer tube cavity,wherein the inner tube structure comprises at least first and second inner tube structure openings along at least a segment of the length of the inner tube structure, which inner tube structure openings are in communication with the inner tube cavity, wherein the inner tube structure is disposed substantially within the outer tube cavity proximal to the distal end of the outer tube structure such that the outer tube structure openings substantially align with the inner tube structure openings to produce aligned openings, andwherein the tracking element is disposed in at least one of the aligned openings; and,actively tracking one or more positions of at least portions of the elongated probe in substantially real-time when the elongated probe is inserted into the tissue using the tracking element, thereby tracking the medical device in the subject.

29. The method of claim 28, further comprising delivering one or more hydrogels at least proximal to the tissue and / or one or more doses of a therapeutic agent to the tissue.

30. A method of making a medical device, the method comprising:forming at least one elongated probe that is insertable into at least one tissue such that:the elongated probe comprises at least one outer tube structure having an outer tube cavity disposed longitudinally along at least a portion of a length of the outer tube structure and at least one inner tube structure having an inner tube cavity disposed longitudinally along at least a portion of a length of the inner tube structure,Attorney Docket No. 0184.0326-PCT Client Ref. No. Pl 8398-02 the length of the outer tube structure is less than the length of the inner tube structure,the outer tube structure comprises at least first and second outer tube structure openings disposed proximal to a distal end of, and along at least a segment of the length of, the outer tube structure, which outer tube structure openings are in communication with the outer tube cavity,the inner tube structure comprises at least first and second inner tube structure openings along at least a segment of the length of the inner tube structure, which inner tube structure openings are in communication with the inner tube cavity, andthe inner tube structure is disposed substantially within the outer tube cavity proximal to the distal end of the outer tube structure such that the outer tube structure openings substantially align with the inner tube structure openings to produce aligned openings,operably connecting at least one tracking element to the elongated probe, which tracking element is operably connected, or connectable, to at least one tracking apparatus that is configured to actively track positioning of at least portions of the elongated probe in substantially real-time at least when the elongated probe is inserted into the tissue, wherein the tracking element is disposed in at least one of the aligned openings; and,operably connecting at least one handle at least to the elongated probe, thereby making the medical device.

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