Therapeutic delivery using an untethered miniature device

Abstract

Provided are systems and untethered miniature devices configured to be navigated within a patient to perform a therapeutic activity at a predetermined treatment site in the brain and other areas of anatomy, and in particular to such systems which use magnetic fields to direct operation of miniature devices within the patient.

Description

THERAPEUTIC DELIVERY USING AN UNTETHERED MINIATURE DEVICETECHNOLOGICAL FIELD

[0001] The presently disclosed subject matter relates to systems and an untethered miniature device configured to be navigated within a patient to perform a therapeutic activity at a predetermined treatment site in the brain and other areas of anatomy, and in particular to such systems which use magnetic fields to direct operation of miniature devices within the patient.BACKGROUND

[0002] Drug delivery can be done locally at the target tissue, sub-systemic or systemically. Sub- systemic and systemic (ex., IT, ICV) delivery are known to have several significant drawbacks, most notably poor control of:• Reach anatomic locus / loci that needs treatment.• Therapeutic ratio (specific efficacy vs safety, systemic / non-specific toxicity).• Desired longitudinal pharmacokinetics (tissue / lumen vs dose vs exposure vs regimen), especially if the locus is protected by multiple biological barriers exemplified by complex blood-brain, blood-tumor, CSF-blood interfaces.

[0003] Local drug delivery avoids previously mentioned drawbacks but has proven challenging for target locations that are surrounded by sensitive tissue that may cause unacceptable side effects when damaged, e.g., brain tissue. Use of typical local drug delivery methods for these target locations, such as a cannula or catheter, often carry significant and unacceptable clinical risks.SUMMARY

[0004] The inventors have developed an untethered bot (miniature device) along with an external control system to address the shortcomings of systemic and / or sub-systemic drug delivery techniques. The external control system described herein manipulates magnetic fields to propel a millimeter or sub-millimeter sized untethered bot through anatomic fluids, lumens, and tissue to a target location. The bot described herein can deliver a payload including a therapeutic typically in the range of 1-20 micro-grams (1-10 micro-liter in terms of volume). The bot includes three basic components, a propulsion segment, a payload or cargo segment and a release scheme coupling the cargo to the propulsion segment. The techniques developed by the inventors includea pre-operative planning environment to plan treatment location, introduction / retrieval location, and delivery path through tissue.

[0005] Moreover, the disclosed devices, platforms, and techniques enable controlled / remote release of payload in a single dose (bolus), stepwise (multiple discrete drops) or continuous release fashion. This addresses issue(s) associated with passive tissue / lumen diffusion, normal / pathological gradients (ex., pressure, lymph / blood / CSF flows) and allows to create the desired (individual) pattern(s) of payload distribution important in multiple acute and chronic diseases exemplified by solid and diffuse tumors, inflammation, metabolism, neurology / neurodegeneration .

[0006] According to an aspect of the presently disclosed subject matter a method for providing localized treatment via drug delivery at a target site in the brain and other anatomical regions of a patient using an untethered delivery bot, the technique can include:• providing a system comprising a miniature device (e.g., bot) configured to carry one or more therapeutic components for performing the treatment, and an external system configured to direct the miniature device;• inserting the miniature device to a starting location within the patient;• operating the external system to direct the miniature device to travel along an access path from the starting location to the target site; and• administering the therapeutic component at the target site.

[0007] The systems and devices discussed herein build upon delivery technique discussed in a recently filed U.S. Provisional Patent Application Serial Number 63 / 404024, titled “SYSTEM AND METHOD FOR ADMINISTERING A TREATMENT AT A TREATMENT SITE IN THE BRAIN”, which is hereby incorporated by reference in its entirety.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] In the drawings, which are not necessarily drawn to scale, like numerals may describe similar’ components in different views. Like numerals having different letter suffixes may represent different instances of similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document.

[0009] FIGS. 1A-1B are block diagram illustrations of a technique for delivering a localized treatment in accordance with an example of the present disclosure.

[0010] FIG. 2 schematically illustrates a system for delivering a treatment to a target location in accordance with at least one example of the present disclosure.

[0011] FIG. 3A schematically illustrates an external system for delivering a treatment to a target location in accordance with at least one example of the present disclosure.

[0012] FIG. 3B schematically illustrates an external system for delivering a treatment to a target location from a lower lumbar injection point in accordance with at least one example of the present disclosure.

[0013] FIG. 4 is a flowchart illustrating a control technique used to deliver a treatment to a target location from a lower lumbar injection point in accordance with at least one example of the present disclosure.

[0014] FIG. 5 is a flowchart illustrating a control technique used to transition a miniature device between anatomical fluid and anatomical tissue in accordance with at least one example of the present disclosure.

[0015] FIG. 6 is a block diagram illustrating an external system for delivering a treatment to a target location in accordance with at least one example of the present disclosure.

[0016] FIG. 7 is a block diagram illustration of a miniature device for delivering a cargo to a target location in accordance with at least one example of the present disclosure.

[0017] FIG. 8 is a flowchart illustrating a payload delivery technique accordance with multiple examples of the present disclosure.

[0018] FIGS. 9A-9C are block diagram illustrations of a miniature device with a needle-anchor cargo delivery mechanism in accordance with at least one example of the present disclosure.

[0019] FIGS. 10A-10F are block diagram illustrations of a miniature device with a direct liquid ejection cargo delivery mechanism in accordance with at least one example of the present disclosure.

[0020] FIGS. 11 A- 1 ID are block diagram illustrations of a miniature device with a solid pay load delivery mechanism in accordance with at least one example of the present disclosure.

[0021] FIGS. 12A-12C are block diagram illustrations of a cargo portion of a miniature device with a secondary unpacking mechanism in accordance with at least one example of the present disclosure.

[0022] FIG. 13 is a flowchart illustrating treatment technique using a dual miniature device treatment delivery system in accordance with at least one example of the present disclosure.

[0023] FIG. 14A is a perspective view illustrating an introduction / retrieval instrument in accordance with at least one example of the disclosure.

[0024] FIG. 14B is an inset cross-sectional view of a tip of an introduction / retrieval instrument in accordance with at least one example of the disclosure.

[0025] FIG. 15 illustrates a block diagram of an example machine upon which any one or more of the techniques discussed herein may perform in accordance with at least one example of this disclosure.DETAILED DESCRIPTION

[0026] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the presently disclosed subject matter. However, it will be understood by those skilled in the art that the presently disclosed subject matter may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the presently disclosed subject matter.

[0027] In one aspect, provided herein are devices and systems that comprise a millimeter-scale or sub-millimeter- scale tetherless object controlled or manipulated remotely by an external magnetic field, referred to herein as the “miniature device” or the “hot,” and separate from the miniature device an interactive hardware-software platform, referred to herein as the “external system,” that generates, modulates and controls magnetic fields in a defined three-dimensional operational volume to propel and navigate the miniature device to a specific anatomical target to complete a mission.

[0028] In particular, a system may be provided according to the presently disclosed subject matter, comprising a suitable external system and one or more suitable miniature devices. An example of such a system is described in PCT application PCT / US2022 / 40303, the full contents of which are incorporated herein by reference in its entirety.

[0029] The miniature device is propelled and navigated remotely by the external system through specific anatomical milieu, exemplified by the lumen, cavity, vessel, tissue(s), and circuitry (e.g., a network of neurons within brain tissue of a patient). The milieu can include homogeneous or heterogeneous components, such as lumens, respective luminal lining, and adjacent tissue(s). One such heterogeneous compartment is the central nervous system (CNS).

[0030] The miniature device may be navigated through healthy and / or pathological milieu to a target site to administer a treatment to treat diseased tissue at or near the target site. According to some examples, the pathological or diseased tissue is a brainstem glioma (BSG), for example comprising a malignancy. The BSG may be a diffuse intrinsic pontine glioma or a focal glioma, for example located in the pons part of the brainstem. Administering the treatment may comprise delivery of a therapeutic component, for example comprising one or more chemical compounds, one or more small molecules, biologies, cells, one or more radioisotopes, etc., for treating the diseased tissue.

[0031] A microsurgical, diagnostic, or therapeutic mission comprises one or more actions, to be accomplished in the relevant anatomical milieu.

[0032] The devices, systems, and techniques described herein enable minimally invasive procedures, the bot can be introduced in an anatomical fluid (CSF / Blood), propelled through this liquid, and directed to penetrate tissue close a target location. The systems and device discussed herein utilize specialized techniques to address the transition from fluid / liquid milieu into tissue, the techniques involve, among other things, a miniature device designed for both axial (linear) and rotation movement as well as external control systems to activate the different modes of movement to penetrate tissue.

[0033] The devices, systems and techniques of the present invention include a drug delivery system, comprising of an EM-based Magnetic Propulsion System (MPS) placed in proximity of a patient and an untethered drug delivery bot. The disclosed bot is capable of being navigated through both liquid and tissue in a controlled fashion with a significant size reduction in comparison to prior techniques and devices. The MPS includes an array of EM coils that can be activated at a high frequency with low-power magnetic field gradients (e.g., >lHz control resulting in <1 T / m) to move the bot through fluids and a separate power architecture to enable high-power magnetic pulses (e.g., higher magnetic gradients) at lower control frequency (2-20 T / m, developed at 0.1 - 1Hz control) to penetrate tissue and / or activate payload delivery (e.g., drug / therapeutic delivery). The higher gradient magnetic pulses can be generated by the same coils as the lower-power high frequency or through additional custom coils designed for maximum magnetic field gradients directed at a location of the bot penetrating tissue.THE MISSION

[0034] The mission for administering a localized treatment may comprise:(a) travel of the miniature device to the target site inside the patient as described herein;(b) administering the treatment to the pathological or diseased tissue at the target site; and(c) optionally travel of the miniature device to exit the patient.

[0035] The mission may comprise each of several different miniature devices traveling to the target site to administer a treatment, the same miniature device traveling to several target sites, the miniature device administering several treatments at the target site, the miniature device repeatedly administering a single therapeutic component or administering different therapeutic components at one or more target sites at different times, etc.

[0036] Travel of the miniature device within the patient requires control and a set of specific actions mediated by an external system described herein. In some embodiments, travel is performed in a first volume filled with media or liquid such as, but not limited to, cerebrospinal fluid (CSF). Treatment techniques also include transitioning from CSF into brain tissue (e.g., from an anatomical fluid into a tissue).

[0037] In any of the examples, the path traveled by the miniature device can be linear or the three-dimensional path traveled by the miniature device can be curvilinear (or a combination of linear and curvilinear segments).

[0038] The primary mission in the drug / therapeutic compound delivery is to deliver a cargo to a target location. The act of delivery is referred to herein as the cargo release. In some examples, the cargo contains a payload. In an example, the cargo comprises a capsule that houses a payload. The capsule can be made of bioresorbable materials such as polyglycolic acid (PGA) and polylactic-co-glycolic (PLGA). In certain examples, the payload is a liquid that comprises chemical compounds, including but not limited to doxorubissin. In other examples, the cargo can comprise only the payload in a liquid or solid form.

[0039] The cargo release can be performed in a variety of fashions, including but not limited to the following:• In one example, the cargo is jettisoned from bot.• In one example, the cargo is expelled from a cavity inside the bot.• In one example, the cargo is forcefully expelled using a variety of actuation mechanisms set in motion by the release of a finite amount of energy stored inside the bot.• In one example, the finite amount of energy is potential energy stored in a spring compressed inside the hot and released thanks to a triggering event.• In one example, the finite amount of energy is stored as Electric charges in a Capacitor or a Battery.• In one example, the triggering event is an RF signal that is used by a specific electric or electronic circuit inside the bot to release the stored energy• In one example, a certain amount of energy can be harvested by an electric or electronic circuit inside the bot.• In one case, the cargo release is the result of the actuation of an internal piston, the unlatching of an internal or external latch, the swelling or contraction of substance, a chemical reaction, an electro-chemical reaction.• In one case, the cargo is mechanically decoupled from the bot after a dissolvable link has dissolved.• In one case, a mechanical vibration induced by the interaction between the bot and an alternating magnetic field results in a cargo release.

[0040] The secondary mission accomplished by releasing the cargo. The secondary mission is determined by the nature of the cargo’s construction and the pay load carried by the cargo. In one example, the cargo is a solid object that comprises a bioresorbable polymer mixed with a drug and the secondary mission is to controllably release the drug from the bio-resorbable polymer matrix. In an example, the cargo is a capsule made of bio-resorbable material. In another example, the capsule comprises multiple sub-compartments housing individual amounts of pay load. In certain examples, the secondary mission is to release individual amounts of liquid in a timely manner dictated by the dissolution of the capsule. This disclosure is focused on delivery of the cargo to a target location or locations, so the details of particular therapeutics as outside the scope of this disclosure.

[0041] FIGS. 1A-1B are block diagram illustrations of a technique 100 for delivering a localized treatment in accordance with an example of the present disclosure. In this example, the technique 100 can include operations such as defining a target location and an introduction / retrieval location at 110, inserting the introduction / retrieval device into the introduction location at 1 12, introducing a miniature device at 114, propelling the miniature device and 116, embedding cargoat the target location at 118, releasing the cargo at 120, propelling the miniature device away from the target location at 122, and retrieving the miniature device at 124.

[0042] In this example, the technique 100 can being at 110 with identification of a target treatment location and an introduction location. In an example, the target treatment location is identified during a pre-operatively planning phase using two-dimensional or three-dimensional medical imaging techniques, such as X-ray or magnetic resonance imaging (MRI). The preoperative planning can also identify an introduction location and plan a route within the milieu (e.g., anatomical fluids and / or tissues) between the introduction location and the target treatment location.

[0043] At 112, the technique 100 can continue with insertion of an introduction / retrieval instrument into the patient’s body. An example introduction / retrieval instrument is discussed below. In an example, an introduction / retrieval instrument can include a movable magnet to secure the miniature device within a lumen of the introduction / retrieval instrument prior to insertion into the patient. The movable magnet can create a hard hold on the miniature device when it is in close proximity to the miniature device (which is typically held near a distal end of the lumen of the introduction / retrieval instrument). Once the introduction / retrieval instrument has pierced the skin at the introduction location (such as shown at operation 112), the internal magnet can be shifted proximally within the introduction / retrieval instrument to transition to a soft hold on the miniature device. The soft hold reduces the magnetic gradient needed to be generated by the control system to transition the miniature device out of the introduction / retrieval instrument. At 114, the technique 100 can continue with the surgeon manipulating the introduction / retrieval instrument to inject the miniature device into the milieu. In an example, injecting the miniature device can include manipulation of an internal magnet generating a hard hold on the miniature device to transition to a soft hold (as discussed above). In some examples, the miniature device is first introduced into an anatomical fluid and transitions into anatomical tissue enroute to the target location. The technique 100 can continue at 116 with an external control system engaging to navigate the miniature device through the milieu to the target location. As described in detail below, the external control system (external system) manipulates magnetic fields to cause the miniature device to migrate in a controlled fashion through various different anatomic fluids, lumens, and tissues as needed to reach the target location.

[0044] At 118, the technique 100 continues with the external system continuing to propel the miniature device through the milieu through application of a variety of different magnetic field strengths and frequencies. In an example, to propel the miniature device through an anatomic fluid, the external device can apply a relatively low-power magnetic field gradient at high frequency. To propel the miniature device through denser tissue, the external system may apply a high-power magnetic pulse at lower frequencies (see discuss below for specific ranges of magnetic field strengths and frequencies). In certain examples, the external system can also move a miniature device through tissue along a biological wall by providing a continuous force that keeps the miniature device intermittently connected to the biological wall surface.

[0045] At 120, the technique 100 continues with the external system manipulating the miniature device into the target location. In this example, the external system propels the miniature device to embed the pay load (cargo) into tissue at the target location. At 120, the technique 100 continues with the miniature device releasing the payload at the target location. Payload release techniques and mechanisms are discussed below in greater detail. At 124, the technique 100 can conclude with the external system propelling the miniature device back to the introduction location and the surgeon utilizing the introduction / retrieval instrument to remove the miniature device from the patient’s body.THE EXTERNAL SYSTEM

[0046] The external system is provided to control the miniature device within anatomical fluid and / or tissue to deliver the cargo / payload to a targeted location within the patient. According to some examples, it may comprise a software module and a hardware system. The external system uses magnetic fields to exert mechanical forces on the miniature device and to control it to perform specific actions. The forces, controllably and predictably exerted on the miniature device, are expected to have various consequences on the milieu and on the path thereto. In some embodiments, the external system mediates propulsion and navigation of the miniature device from one predetermined position to another. For example, the external system controls specific miniature device motion(s) including, but not limited to, standalone axial or diametral spinning, rotation, vibration, tumbling, crawling, rocking, lateral motion, etc. In addition, according to some examples the external system is configured to direct the miniature device to release a therapeutic component.

[0047] FIG. 2 schematically illustrates a system 200 for delivering a treatment to a target location in accordance with at least one example of the present disclosure. The system 200, also referenced as external system 200 or simply external system (ES), includes both hardware and software to achieve control of a miniature device within various milieu within the patient.

[0048] The ES uses magnetic fields to exert mechanical forces on the miniature device and to control it to perform specific actions. The forces, controllably and predictably exerted on the miniature device, are expected to have various consequences on the milieu. In some embodiments, the ES mediates propulsion and navigation of the miniature device from one predetermined position to another. For example, the ES controls specific miniature device motion(s) including, but not limited to, standalone axial or diametral spinning, rotation, vibration, tumbling, crawling, rocking or combined with lateral motion to drill or fenestrate through an obstacle exemplified by a biological wall / membrane. The foregoing action could be performed once or multiple times. The foregoing action could be performed in a single or multiple loci to achieve the desired effect. For example, specific motion around a certain point accomplishes a desired primary effect. In another example, the forces coax the miniature device to remain immobile near a predetermined position.

[0049] In some embodiments, the External System generates magnetic fields using Permanent Magnets (PM). In some embodiments, the permanent magnets can be mounted on a mechanical setup that holds the magnet and can move in three dimensions. In some embodiments, the permanent magnets can rotate. In some embodiments, there is only one permanent magnet. In other embodiments, there are several magnets that are actuated independently.

[0050] In some embodiments, the external system 200 can generate magnetic fields using electromagnets (EM). An electromagnet comprises one, two, three or multiple coils. An electromagnet can, in addition, comprise a bobbin to support the coil and a yoke that modifies the electromagnetic properties of the coil. In some embodiments, the electromagnets are mounted on a mechanical setup that holds them at a fixed location with respect to the milieu where the miniature device resides. In some embodiments, the electromagnets are mounted on a mechanical setup that controllably and predictably determines the position of the electromagnets with respect to the milieu where the miniature device resides. In some embodiments, there is only one electromagnet. In some embodiments, there arc electromagnets that arc actuated according to predetermined control algorithms that take into the account the position, velocity,acceleration and pose of the miniature device extracted using separate algorithms that use X-ray images of the miniature device in real time. In some embodiments, the fields arc generated in such a fashion that the forces applied to the miniature device cause it to rotate about its axis.

[0051] In some embodiments, the external system generates magnetic fields using a combination of electromagnets (EM) and permanent magnets (PM). In some embodiments, both EM and PM are used in concert to generate the fields and applies forces to the miniature device.

[0052] In some embodiments, the external system generates the magnetic fields using six to twelve electromagnetic coils. For example, eight electromagnetic coils are used to generate the magnetic fields. Each coil is between 4 inches x 4 inches x 4 inches and 12 inches x 12 inches x 24 inches in size, for example, each electromagnetic coil is 8 inches x 8 inches x 15 inches in size. Each coil can carry up to 550 Amps, and for example runs at 30 Amps. In some embodiments, the electromagnetic coils have a ferromagnetic yoke. In other embodiments, the electromagnetic coils have no yoke. In some embodiments, the electromagnetic coils are arranged around the head of the subject in use. In some embodiments, the electromagnetic coils are between 5 to 25 cm, e.g., 15 cm, from the milieu.

[0053] The external system may use a variety of visualization or imaging systems to assist with the application of the forces and result in adequate control of the miniature device. In some embodiments, the external system uses X-rays to image the miniature device inside the targeted milieu. In some embodiments, the external system uses two X-rays applied in a stereovision system (e.g., biplane x-ray detectors) to image the miniature device inside the targeted milieu to determine its three-dimensional position with respect to landmarks or fiducial markers used as a reference. In some embodiments, the external system uses optical stereovision to determine the position of the EM or PM with respect to fiducial markers or landmarks used as a reference. In some embodiments, the external system uses a combination of X-ray stereovision and optical stereovision to monitor the position of the miniature device, only visible under X-ray vision, with respect to the external EM or PM, only visible under optical vision. In another embodiment, the external system includes radiopaque markers on the EM or PM coils and includes these markers within the field-of-view of the X-ray system to allow the control system to determine the relative position of the coils in reference to the miniature device. The control system can utilize the relative position between the coils and the miniature device in controlling the magnetic gradients generated to propel the miniature device.

[0054] The external system can include one or more software modules including a planning software submodule and a hardware -control software submodule. In some embodiments, the external system software modules can use pre-recorded digital data, such as magnetic resonance imaging (MRI) scans, computed tomography (CT) scans, etc... to assist with the activities performed by both submodules. In some embodiments, MRI scans are analyzed by the software module and digital three-dimensional objects representing various tissue masses present in the host environment are generated automatically. In some embodiments, the hardware-control software module uses digital information from the optical or X-ray stereovision system and computes automatically the mathematical transformation to allow display, in a single referential, three-dimensional data generated from MRI, vision and X-ray system.

[0055] In this example, the external control system 200 can include components such as computing system 210, driver control board 215, magnetic coil drivers 220A-220N (collectively referenced as coil drivers 220), magnetic coils 230A-230N (collectively referenced as coils 230), x-ray sources 240A, 240B, and x-ray detectors 242A, 242B. In an example, the driver control board 215 can be integrated into the computing system 210. Power is provided to the external system 200 by the power supply 225 that can also include an optional battery bank 226 and an optional capacitor bank 227. The power supply 225 converts standard 110 / 220 volt electrical sources into high and low voltage direct current (DC) as needed within the external system 200. The battery bank 226 and / or capacitor bank 227 can be utilized to assist in supplying power during short duration peak power demands.

[0056] The computing system 210 can perform the various control techniques discussed below in reference to FIGS. 4, 5, 8, and 13. In general, pre-operative treatment plans can be accessed by the computing system 210 through a network or other storage device. The computing system 210 can utilize the pre-operative plans to control (e.g., navigation and propel) a miniature device 250 from an introduction site to a target location within the patient 260 through selective activation of the coils 230 via the driver control board 215 sending command signals to the coil drivers 220. The coils 230 can be configured to generate different levels of magnetic gradients at various frequencies as needed to produce the desired propulsion of the miniature device 250 (discussed in greater detail below).

[0057] FIG. 3A schematically illustrates an external system 300A for delivering a treatment to a target location in accordance with at least one example of the present disclosure. In this example,the external system 300A (magnetic propulsion system (MPS) 300A) is illustrated as including components such as: a biplane X-ray system 340 with table and head-holder 305; an electromagnetic array 310 capable of generating design magnetic field gradients; a control system 330; a miniature device (e.g., drug delivery bot); and a set of tools to introduce and retrieve our bot. In this example, the MPS 300A is designed for treatment of a localized area of anatomy, such as the brain. The electromagnetic array 310 includes a plurality of coils, such as coil 312 A, coil 312B, coil 312C, and coil 312D (collectively referenced as coils 312). The coils 312 are designed to generate magnetic fields to propel and control a miniature device within the target area of anatomy. In this example, the electromagnetic array 310 is affixed to a rail system 314 that allows for precise movement of the electromagnet array 310 along a linear path. The rail system 314 can dock to the table and head-holder 305 via docking mechanism 318. In order to navigate a miniature device within the target anatomy, the MPS 300A system includes a stereo X-ray system, biplane X-ray system 340. The biplane X-ray system 340 includes two pairs of emitters and receivers offset from each other at a known angle. The biplane system 340 includes emitter 342A paired with receiver 344A as well as emitter 342B paired with receiver 344B . The biplane X-ray system 340 is also affixed to a rail system, rail system 346. The biplane X-ray system 340 also optionally includes docking mechanism 348 to dock to the electromagnet array 310. An additional part of a navigation system can optionally include a navigation array 306 that is affixed directly to the head holder 305. The MPS 300A includes a control system 330 that communicates with both the electromagnetic array 310 and the biplane X-ray system 340 to control operation of the MPS 300A.

[0058] A potential clinical implementation of the mission described herein could involve development of a treatment plan, potentially using MRI scans made prior to the procedure. The MRI scan with treatment plan information is subsequently merged with a live X-ray view. The system detects the bot and provides a magnetic field that propels the bot to its desired target defined in the treatment plan.

[0059] As a safety feature, fluoroscopy frequency is potentially adjusted based on the speed of the bot. For example: a control algorithm will not require the same control frequency if the bot is supported by tissue, and hence a lower imaging frequency compared to control while the bot is in fluids can still provide sufficient feedback to the system.

[0060] A key to this invention is combining the highly accurate current control for fluid motion, while utilizing a different power circuit for high power tissue penetration.

[0061] FIG. 3B schematically illustrates an external system for delivering a treatment to a target location from a lower lumbar injection point in accordance with at least one example of the present disclosure. Most Magnetic Propulsion Systems (MPS) are designed for very small treatment areas or involve large and heavy equipment as magnet field strength rapidly declines as a function of distance from the coil system. However, there are benefits to providing a large treatment area, such as greatly flexibility in injection points for a miniature device, among others.

[0062] The MPS illustrated in FIG. 3B, MPS 300B, is designed to enable procedures that involve a large treatment volume to allow for traversing a miniature device from a lower lumbar punction (injection site) in the spine to a treatment location within the brain. The MPS 300B can enable treatment techniques that involve traversing a miniature device 360 from a lumbar punction in the spine, along the spine towards the brain, and subsequently control the miniature device 360 within the brain to a final target location 365. To enhance clinical adoption, the MPS 300B is modular, and optionally portable, due to the combination of rail-mounted (robotic arm mounted) magnet propulsion system and stationary array of coils for specialized control within the brain (or other targeted portion of anatomy). While not illustrated in the schematic for clarity purpose, the MPS 300B can include all of the components discussed above in reference to MPS 300A with the addition of the mobile magnetic component 320.

[0063] The MPS 300B is designed around the required degrees of freedom (DOF) of miniature device movement within the different parts of anatomy that must be traversed. For example, movement of the miniature device within the spine is significantly less demanding as the miniature device travels primarily unidirectionally along the spine. Additionally, movement within the spinal fluid milieu requires smaller magnet gradients as compared to movement though other anatomical tissues, such as portions of the brain. In contrast, movement within the brain requires precise 5 DOF movement of the miniature device.

[0064] The MPS 300B includes 2 primary components, as mobile magnetic component 320 and an array of magnets 310 that surround a target portion of anatomy, such as the brain. The MPS 300B also includes a control system 330 that controls the magnetic fields generated by the twodifferent magnetic components and receives outside inputs, such as real-time medical imaging to assist in controlling the position of the miniature device within the body.

[0065] In an example, the mobile magnetic component 320 includes rail(s) 322 or an extending arm(s) containing one or more electromagnets to enable movement of the miniature device 360 along primarily fluidic anatomical paths, such as through CSF along the spine. The array of magnets 310 are positioned within a frame in an orientation suitable to surround a target portion of anatomy, such as the brain.

[0066] The control system 330 operates the mobile magnetic component 320 and array of magnets 310 cooperatively to enable treatment techniques involving traversing a miniature device through the spine and into a target location within the brain. One of the key aspects of the control system 330 is controlling the handoff of control of the miniature device between the mobile magnetic component 320 and the array of magnets 310. An example handoff control technique, technique 400, is detailed below in reference to FIG. 4.

[0067] FIG. 4 is a flowchart illustrating a control technique 400 used to deliver a treatment to a target location from a lower lumbar injection point. In this example, the control system 330 can execute the control technique 400 to operate the mobile magnet component 320 and the array of magnets 310 to traverse a miniature device from a location in the spine into the brain. The control technique 400 can include operations such as insertion of the miniature device (bot) at 410, actuation of the miniature device (e.g., bot) through anatomical fluids at 420, parking the miniature device at a safe location near the target tissue at 430, control handover to the array of magnets at 440, optionally verifying control by array of magnets at 450, and delivery of miniature device within anatomic tissue by the array of magnets at 460. In certain examples, the actuation of the miniature device through anatomical fluids at 420 can include looping through operations such as detecting a location of the miniature device at 422, determining propulsion parameters at 424, and controlling the magnetic components at 426. In an example, the technique 400 is performed under live fluoroscopy to enable the control system 330 to detect a real-time location of the miniature device and track the miniature device within the patient until it reaches a predetermined target location.

[0068] In this example, the control technique 400 can begin at 410 with the miniature device 360 being inserted (or injected) into the patient. In an example, the injection point can be in the lumbar spine into spinal fluid. At 420, the control technique 400 can continue with the controlsystem 330 operating the mobile magnetic component 320 to propel the miniature device 360 from an injection point in the spine towards the brain (c.g., target location 365). The control system 330 at 420 can utilize navigation components (e.g., x-ray and optionally an optical navigation system) to detect a location of the miniature device 360 within the patient 370. Based on the detected location, the control system 330 can determine the appropriate propulsion parameters to control the mobile magnetic component 320 to implement the pre-operative treatment plan. For example, based on the detect location and pre-operative plan the control system 330 can determine appropriate magnetic gradients needs to continue moving the miniature device 360 within the patient 370. At 426, the control system 330 can operate / control the mobile magnetic component 320 to propel the miniature device 360 as needed. At 430, the control technique 400 can continue with the control system 330 detecting that the miniature device 360 has arrived at a pre-defined safe parking location in or near the brain (e.g., target tissue). At 440, the control technique 400 can continue with the control system 330 initiating the handoff of position control and propulsion of the miniature device 360 between the mobile magnetic component 320 and the array of magnets 310. The handoff process can include gradually increasing the magnetic field produced by the array of magnets 310 while the miniature device 360 is held in the safe parking location. While the control system 330 ramps up the array of magnets 310, the mobile magnetic system 320 is disengaged to release control of the miniature device 360 over to the array of magnets 310. At 450, the control technique 400 continues with the control system 330 determining that the array of magnet 310 is ready to propel and control the miniature device 360 within the brain tissue while the miniature device 360 remains at the pre-defined safe parking location (or optionally, has been shifted to a second safe parking location in or near the brain). At 460, the control technique 400 can conclude with the control system 330 using the array of magnets 310 to propel the miniature device to a target location within the brain or similar target tissue. During operation 460, the control system 330 can utilize operations similar to operations 422-426 to operate the array of magnets 310 to guide the miniature device 360 to the target location 365 within the patient 370.

[0069] FIG. 5 is a flowchart illustrating a control technique 500 used to transition a miniature device between anatomical fluid and anatomical tissue. One significant challenge in using a miniature device to deliver a pay load to a target location within an anatomical tissue such as within the brain is transitioning between a fluid and a tissue. In an example, using a miniaturedevice to deliver a therapeutic substance (e.g., a payload) to a location within the brain involves injecting the miniature device into cerebrospinal fluid (CSF) surrounding the spinal cord and navigating the miniature device along the spinal cord to the brain. Once the miniature device reaches a location adjacent the brain, the system needs to transition the miniature device into brain tissue. Propulsion of a miniature device within the CSF (or any anatomical fluid) is considered easier than propulsion within tissue, such as the brain. Tissue is denser and also less tolerance of disruption, so navigation needs to be more precise. The design of the MPS 300B discussed above is a direct result of the realities of propulsion and control of a miniature device within different milieu, such as CSF versus brain tissue. As indicated, a key challenge in using a spinal entry point for brain tissue treatment is the transition between CSF and brain tissue. The control technique 500 is an example technique for handling the transition. The technique 500 is described below in reference to MPS 300B with the handoff being coordinated by the control system 330 between the mobile magnetic component 320 and the array of magnets 310.

[0070] In this example, the control technique 500 can include operations such as propelling the miniature device (e.g., BOT) in fluid at 502, positioning the miniature device adjacent a transition zone at 504, propelling the miniature device into the transition zone at 506, detecting rotational orientation of the miniature device at 508, activating rotational and linear propulsion at 510, monitoring rotational and linear translation at 512, determining whether the miniature device has traction at 514, optionally adjusting propulsion parameters at 516, continuing rotational propulsion only at 518, and determining if the target has been reached at 520.

[0071] In this example, the technique 500 can begin at 502 with the MPS 300B using the mobile magnetic component 320 to propel the miniature device in a fluid. In an example, the miniature device is injected into CSF in the lumbar spine and the mobile magnetic component 320 is used to propel the miniature device through the CSF to a position adjacent the brain. At 504, the technique 500 continue with the mobile magnetic component 320 positioning the miniature device adjacent a transition zone (e.g., an area where the miniature device is positioned to transition between the CSF and brain tissue). At 506, the technique 500 continues with the MPS 300B using the mobile magnetic component 320 and in some examples the array of magnets 310 to propel the miniature device into the transition zone. In certain examples, operation 506 can optionally include the technique 400 discussed above to coordinate a handoff between the mobile magnetic component 320 and the array of magnets 310.

[0072] Once in the transition zone, the technique 500 continues at 508 with the control system 330 determining the rotational orientation of the miniature device. In some examples, the miniature device can include a radiographic indicator to assist in determining rotational orientation as well as whether the miniature device is rotating in response to magnetic fields generated by the MPS 300B. At 510, the technique 500 continues with the control system 330 activating circuits to generate both rotational and linear translational propulsion. The combination of rotational and linear propulsion is used to embed the miniature device into the tissue and then rotationally bore through the tissue.

[0073] At 514, the technique 500 continues with the control system 330 determining whether the miniature device has traction within the tissue. The control system 330 can utilize the biplane X- ray system 340 to detect whether the miniature device is progressing into the tissue with the rotational propulsion. If the miniature device does not appear to have traction at 514, the technique 500 loops back to operation 512 (optionally through operation 516) and the linear and rotational propulsion is continued. At 516, the control system 330 can adjust propulsion parameters used to deliver linear and / or rotational translation. For example, the control system 330 can increase the magnetic gradients generated to increase axial forces driving the linear translation of the miniature device to enhance penetration into the tissue. If the miniature device is progressing into the tissue (e.g., has traction), then the technique 500 continues at 518 with the MPS 300B transitioning to rotational propulsion only. Once the miniature device has traction within the tissue, the miniature device of this example is designed to use rotational propulsion within the denser tissue. At 520, the technique 500 continues with the control system 330 determining whether the miniature device has reached the target location (e.g., target location 365). If the miniature device has reached the target location the technique 500 can conclude and a payload ejection or jettison technique can begin. If the miniature device has not reached the target location, the technique 500 loops back to operation 514 to continue to monitor traction and continue propulsion of the miniature device.

[0074] FIG. 6 is a block diagram illustrating an external system 600 for delivering a treatment to a target location. More specifically, the external system 600 is a magnetic propulsion and control system that uses two power circuits to run a single array of magnetic coils 620 including a plurality of coils 622A-622N (collectively referenced as magnetic coils 620). In this example, one power circuit is designed to have high accuracy and low power, enabling movement of aminiature device in anatomical fluids by current drivers. The second power circuit in this example is a low accuracy high-powcr circuit that enables movement through tissue by controlled discharge of a large capacitor bank, such as pulsed capacitor bank 616.

[0075] The system 600 outlined in the block diagram can utilize a method involving connecting a plurality of electromagnets to a plurality of solid-state relays to produce a configurable arrangement of circuits that can be energized by an energy storage system. In this example, the electromagnets are placed in symmetric positions around an isocenter and receive a sequence of electrical pulses from the energy storage system to produce a magnet field with arbitrary polarization at the isocenter. The magnetic field is received by the miniature device that translates the magnetic energy into a force in a single direction with each electrical pulse. In this example, the position of the miniature device can be measured by an external position measurement unit (such as through real-time medical imaging and analysis of the images). The amplitude of the electrical pulse is controllable, which translates into a controllable pulsating force on the miniature device. In an example, the amplitude of the pulse is controlled by the solid-state relays. In another example, the amplitude of the pulse is controlled by the charge state of the energy storage system. The solid-state relays can be operatively connected to a controller (such as control system 630) such that the controller can alter the configuration of the circuits connected to the electromagnets. Control of the solid-state relays can be done in response to position of the miniature device, with an algorithm updating commands delivered to the solid- state relays in response to position of the miniature device.

[0076] Essentially, the control system 630 is connected to a multi-leg bidirectional converter with independent high and low-side FETs / IGBTs, which can be used to pulse all of the MPS coils with any polarity, and optionally using PWM. This allows the system to command synchronized pulses in arbitrary directions at a high rate.

[0077] In the example illustrated in FIG. 6, the external control system 600 (also referred to as magnetic propulsion system (MBS) 600) can include three primary components a power system 610, an array of magnetic coils 620, and a control system 630. The power system 610 can include an alternating current (AC) power supply 611 coupled to an AC / DC converter 612. The AC / DC converter 612 converts the incoming AC power into direct current (DC) power used to energize the magnetic coils 620. In this example, the AC / DC converter 612 feeds a low voltage DC supply 613 (LVDC supply 613) and a high voltage DC (HVDC supply 614) supply 614. TheLVDC supply 613 charges an inverter capacitor bank 615 which is connected to the DC input of the Inverters 617. The inverters 617 arc electrically connected to the Coils 622A-622N through an HV Blocking device 618, which isolates the inverters 617 output from the pulsed capacitor bank 616, which is charged by the HVDC supply 614. The solid state relays 624A-624N are connected to the pulse controller 634, which switches the state of the relays in order to deliver power with the correct polarity and to the correct coils. The pulse controller 634 and the inverters 617 are connected to the system controller 632, which ensures that each power system is operating appropriately per the commands of the system controller 632.THE MINIATURE DEVICE

[0078] The miniature device may be provided as described in PCT application PCT / US2022 / 40303. The miniature device’s dimensions, geometry, etc., are selected to facilitate performance of its mission within the milieu. Modifications to the miniature device discussed in the PCT application are outlined below in reference to at least FIGS. 7-12C. The referenced PCT application provides insights into the basic design of certain miniature devices, in particular dimensions and magnetic characteristics remain relevant to the present disclosure. However, modifications discussed herein include payload release mechanisms among other things.

[0079] In some embodiments, the miniature device is elongated in one dimension. In some embodiments, the miniature device has a total length between about 1 mm and about 20 mm, for example about 7 mm. In some embodiments, the miniature device has an outer diameter between about 1 mm and about 5 mm, for example about 2.5 mm. In some embodiments, the miniature device has a total length between about 50 pm and about 10,000 pm. In some embodiments, the miniature device has an outer diameter between about 50 pm and about 50,000 pm.

[0080] The miniature device comprises a body having any suitable shape, including, but not limited to, a cylinder, a cone, a trapezoid, a sphere, or a spheroid. In some embodiments, the body is made of or comprises a permanent magnet magnetized along a longitudinal axis of the miniature device. In some embodiments, the permanent magnet is magnetized along a direction that is substantially perpendicular to a longitudinal axis of the miniature device. In some embodiments, the body is made of a radiopaque material. In some embodiments, the body is made of a rare earth magnet, coated with electroplated nickel and gold, ceramic, plastic, or other substantially non-magnetic biocompatible material.

[0081] In some embodiments, the body of the miniature device is made from a neodymium magnet. In some embodiments, the grade of the neodymium magnet is from N40 to N55, e.g., N50. In some embodiments, the magnet’s residual induction (Br) is between about 12 kG and about 15 kG, e.g., about 14 kG. In some embodiments, (BH)max is between about 38 MGOe and about 56 MGOe, e.g., about 47 MGOe. In some embodiments, the magnet’s intrinsic coercivity, (Hci) is greater than about 11 kOe. In some embodiments, the magnet’s intrinsic normal coercivity, (HcB) is greater than about 10 kOe. In some embodiments, the magnet’s maximum operating temperature is about 60°C to about 80°C, preferably about 80°C.

[0082] In some embodiments, the miniature device is configured to be driven by a static unidirectional force, for example arising from the interaction between the magnetic field generated by the external system and a permanent magnet of the miniature device.

[0083] FIG. 7 is a block diagram illustration of a miniature device 700 for delivering a cargo to a target location. In this example, the miniature device 700 includes three basic components, a magnetic propulsion section 710, a cargo section 720, and a release scheme 730. The components are illustrated in block diagram fashion and are not intended to depict actual dimensions or configurations, but rather simply illustrate the basic components of a drug deliver miniature device. The magnetic propulsion section 710 is the portion of the miniature device that interacts with the MPS (external control system) discussed above. The magnetic propulsion section 710 is configured to allow for the necessarily manipulations of the miniature device within anatomical fluids and / or tissues. The magnetic propulsion section 710 can be designed to enable both linear and curvilinear motion profiles as needed to reach the target anatomical location for delivery of the cargo.

[0084] The cargo section 720 is designed to deliver a solid or liquid payload to a target location. The cargo section 720 can be designed to be ejected from the miniature device or to deposit (or eject) payload held within the cargo section 720. The release scheme 730 is illustrated as a separate section within miniature device 700. In examples using a separate release section, the cargo section 720 can be ejected or deposited at the target location though separation of the release section, such as through melting, dissolving, or otherwise releasing (jettisoning) the cargo section 720. In other examples, the release scheme 730 can be integrated into the cargo section 720, such as when the cargo section 720 is a solid or liquid reservoir that releases the payload but otherwise remains part of the miniature device 700. Various specific examples of miniaturedevices with various different payload delivery mechanisms are discussed below in reference to FIGS. 9A-12.

[0085] FIG. 8 is a flowchart illustrating a payload delivery technique 800. In this example, the payload delivery technique 800 covers a wide variety of triggering mechanisms and ejection or jettisoning arrangements that can be used to deliver a liquid or solid payload with a miniature device as discussed herein. The technique 800 can include operations such as release trigger 810, eject / jettison pay load 820, and optionally eject pay load 840 or jettison pay load 850. The payload 802 represents the portion of the miniature device that will be delivered to one or more target locations within the patient’s body. In this example, technique 800 begins at 810 with the release mechanism within the miniature device receiving or sensing a release trigger, such as an RF signal 812, passage of time 814, or change in temperature 816. At 820, the technique 800 continues with the release mechanism within the miniature device responding to the release trigger 810. The release mechanism can respond to the release trigger 810 by ejecting or jettisoning the payload at 820. The release mechanism can perform the eject / jettison payload operation 820 via a chemical reaction 822, an electro-chemical reaction 824, heating 826, through release of storage energy 830, or a combination of these mechanisms. The release of storage energy 830 can include releasing a mechanical spring 832, discharging a battery or capacitor 834, a magnetic interaction 836 or a shape memory material change 838.

[0086] In this example, the release trigger 810 operation can involve a radio frequency (RF) signal 812, time 814, or temperature 816. In an example using RF signal 812, the release trigger 810 can involve transmitting a particular RF signal towards the miniature device. The miniature device in this example, includes a release mechanism that is sensitive to a certain RF signal signature, and outputting the RF signal 812 activates the release mechanism. For example, the miniature device can include a release mechanism that heats up in response to the RF signal 812. Alternatively, the miniature device can include a release mechanism where the RF signal 812 triggers an electro-chemical reaction.

[0087] In another example, the release trigger 810 operation can involve the passage of time 814. In this example, the miniature device includes a release mechanism that activates after a certain time period as elapsed. The time-based trigger 814 can be coupled with the RF signal 812, where the time delay is initiated by a certain RF signal. In some examples, the time-based trigger 814 isdesigned into a portion of the miniature device, such as a dissolvable element associated with the release mechanism.

[0088] The last example release trigger 810 involves a change in temperature (AT). In some examples, the AT is created by an external introduction of energy, such as through RF signal 812 and effects the miniature device directly. In other examples, the AT occurs within the surrounding of the miniature device. In these examples, the AT is a condition created within the target anatomy, such as through introduction of cold / warm saline or some similar benign operation conducted by the surgeon as part of the treatment procedure performed on the patient. The miniature device can include a release mechanism that is sensitive to the change in temperature as discussed further below.

[0089] Once the release trigger 810 has occurred, the technique 800 continues with the release mechanism on the miniature device activating to either eject the payload or jettison (detach) the payload at 820. The release mechanism of the miniature device can include a chemical-based activation 822, an electro-chemical activation 824, a heat-based activation 826 or a stored energy activation 830. In some examples, the stored energy activation 830 can include a beamed energy mechanism where the release mechanism within the miniature device receives energy beamed from an external source and converts it into heat or mechanical energy within the device. For example, the RF signal 812 can be received by the miniature device and converted into energy used by the release mechanism to eject or jettison the payload.

[0090] In an example, the release mechanism within the miniature device can involve a chemical reaction 822 that can be triggered by an externa RF signal (RF signal 812), time (time delay 814), or a temperature change (AT 816). In another example, the release mechanism within the miniature device can involve an electro-chemical reaction 824, which can be triggered by similar inciting events as the chemical reaction 822. In still other examples, the eject / jettison operation 820 can include a heat-based release mechanism (heat 826) that can cause melting or a similar change in the release mechanism within the miniature device. Finally, certain examples can involve a stored energy 830 mechanism within the release mechanism in the miniature device. Examples of stored energy mechanism can include a mechanical spring 832, a battery 834, magnets 836, or a shape memory alloy 838.

[0091] The technique 800 can conclude with the miniature device either ejecting the payload at 840 or jettisoning the payload at 850 based on some combination of release trigger 810 andeject / jettison payload operation 820. As noted above, the release trigger 810 and eject / jettison payload 820 operations can involve a combination of internal and external events to result in ejecting or jettisoning the payload at a target location.

[0092] The following discusses a variety of example miniature devices and release mechanisms that follow the technique 800 discussed above.

[0093] FIGS. 9A-9C are block diagram illustrations of a miniature device 900 with a needleanchor cargo delivery mechanism 910. In this example, the miniature device 900 releases pay load 910 at a target location using a needle- anchored patch with or without external reservoir technology (NAP, NAP-ER).

[0094] The first application is targeting an area that is close to the Pia (ex: a tumor in the brain stem) and that can be readily accessed without the need for long trip inside the parenchyma.

[0095] This method is applicable to the (yet untreatable) BSG. In this method, a bot travels in the cerebrospinal fluid (CSF) and carries a detachable “patch” that be anchored to the PIA. The patch comprises one or more sub-millimeter to millimeter size needle and, when applicable, a reservoir that links the needles and that remains outside the PIA. This avoids the need to travel through parenchyma and limit tissue disruption. For large tumors that abuts the PIA, more than one patch of needle can be anchored, using several bots to, one after the other, drive to the area of concern, and deliver a patch. When applicable, the microneedle patch is made of bioresorbable material that is loaded within its mass with the molecule or therapeutic agent of choice (ex DOXORUBISSIN). If the treatment of the ailment calls for a liquid agent, the patch may comprise hollow-out needles connected to an auxiliary reservoir and an auxiliary pressure mechanism that can push out the liquid, from the reservoir, into the tissue, through the needles.

[0096] FIG. 9A is a block diagram illustrating miniature device 900. In this example, the miniature device 900 can include a propulsion section 905, a pay load 910, a temporary link 915, and a temporary coating 920. The propulsion section 905 includes a magnetic body that can be directed through anatomical fluids and / or tissue to a target location by an external control system. The payload 910 is coupled to the propulsion section 910 by a temporary link 915. The pay load 910 is in the form of a needle-anchored patch that is jettisoned from the propulsion section 905 by dissolution of the temporary link 915. Dissolution of the temporary link 915 can be triggered by a time-based delay built into the material of the temporary link 915 or by some external trigger, such as an RF signal or change in environmental temperature. In an example, theminiature device 900 can be heated by an external RF signal to cause the dissolution of the temporary link 915.

[0097] In this example, the miniature device 900 also includes a temporary coating 920 that covers barbs on the payload 910 and streamlines the miniature device while the device traverses anatomical fluids and / or tissues to reach the delivery location. The temporary coating 920 can be formed from a material that dissolves over time or can involve an external dissolution trigger similar to the temporary link 915. Note, the temporary link 915 and the temporary coating 920 are preferably designed to dissolve at different times, as it is desirable for the temporary coating 920 to be removed prior to delivery of the payload 910.

[0098] FIG. 9B is a series of block diagrams illustrating the based operations to be performed by the miniature device 900 in delivering the payload 910 to a target location. The miniature device 900 is shown initially reaching the target location. The next frame illustrates the temporary coating 920 removed to expose the barbs of the needle-anchored patch payload 910 and the barbs being embedded into tissue at the target location. Next, is illustrated the removal (dissolution) of the temporary link 915 that separates the propulsion section 905 from the payload 910. Finally, the pay load 910 is illustrated embedded in tissue at the target location and the propulsion section 905 removed from the patient.

[0099] FIG. 9C illustrates the needle-anchored patch payload 910 in either solid or liquid form. In a solid form, the pay load 910 can include a treatment within a carrier that is designed to slowly dissolve to release the embedded therapeutic agent. In contrast, with a liquid therapeutic, the payload 910 includes a liquid reservoir with an opening to release the therapeutic contained held within the reservoir.

[0100] FIGS. 10A-10F are block diagram illustrations of a miniature device 1000 with a direct liquid ejection cargo delivery mechanism 1020. In this example, the miniature device 1000 can use GBM and intra-parenchymal direct liquid ejection (DLE) technology.

[0101] For a target area that is deep inside the parenchyma, the bot must physically travel through parenchyma before it can complete its mission (i.e., release its payload). In this example, the auxiliary reservoir and an auxiliary pressure mechanism that can push out the liquid, from the reservoir, into the tissue remains with the bot.

[0102] In this example, the miniature device 1000 can include a propulsion section 1010 and a DLE delivery (release) mechanism 1020. The DLE delivery mechanism 1020 can include a firstmagnet 1022, a second magnet 1024, and a fluid reservoir 1030 positioned between the magnets (c.g., first magnet 1022 and second magnet 1024). The fluid reservoir 1030 can include an outlet 1032. The fluid reservoir 1030 can be configured to receive fluid via a needle 1050, allowing the fluid reservoir 1030 to be filled immediately prior to treatment with a desired therapeutic.

[0103] In this example, the DLE delivery mechanism 1020 can also include a retention material 1026 that holds the first magnet 1022 in position until the miniature device reaches the target treatment location. As illustrated in FIGS. 10C-10F, the retention material 1026 dissipates over time due to interaction with anatomical fluids via inlet 1040 in the propulsion section 1010. The retention material 1026 and inlet 1040 can be designed to provide a known time delay while exposed to various anatomical fluids during delivery. Once the retention material 1026 is sufficiently dissolved, the first magnet 1022 compresses the fluid reservoir 1030 to eject the therapeutic 1035 as shown in FIG. 10F.

[0104] FIGS. 11A-1 ID are block diagram illustrations of a miniature device 1100 with a solid payload delivery mechanism. In this example, the miniature device 1100 can utilize intra- parenchymal jettisoning of a solid payload technology (JSP). A dry or solid payload can offer notable advantages over liquid from the handling or manufacturing point of view, including (a) potential ease to handle, assemble or mount onto the miniature device, (b) arbitrary shape and size, using compressing or molding for example, to best fit the miniature device size and shape, or (c) latch-on to, stick or grip to and subsequently drop off or release. Among many methods of release, the jettisoning of a solid payload (JSP) is very attractive from a variety of reasons: can require minimal energetic expenditure (ex: "un-latching" is easier than "pushing-out"), it can be timed in a variety of fashions, it can be mounted anywhere long the hull of the miniature device; and the means of JETTISONING can be simply a degradable linker that melts or erodes within an adequate time frame.

[0105] In all three cases, the act of release can be triggered by an event. The event is controlled by the timing of dissolution or swelling of a polymer. Glucose or polyvinyl alcohol (PVA)can be used as a melting of a linker that keeps the payload secured to the miniature device. Glucose of polyvinyl alcohol (PVA) that hold a magnet away from another magnet and "let's" go of the magnet once dissolved. Hydrogel can we used to swell and expulse from its socket a frictionbased fit between the miniature device and the cargo.

[0106] Enhancing the effects of the trigger can include storing energy internally. Energy can be stored in the miniature device in forms of a compressed spring or two magnets that arc separated by a distance. FIGS. 11A-1 ID illustrate a spring-based energy storage mechanism that can be used to jettison a payload.

[0107] In this example, the miniature device 1100 can include a propulsion section 1110 and a JSP mechanism 1120. The propulsion section 1110 can include a first magnet 1122 and a second magnet 1124 that interact with externally generated magnetic fields to generate rotation and / or linear pulsating propulsion to propel the miniature device 1100 to a target location. The JSP mechanism 1120 can include a spring mechanism 1126 and a payload component 1130. The spring mechanism 1126 can be triggered by a time-based dissolution of a glucose or polyvinyl alcohol (PVA) material retaining the spring. A polyvinyl alcohol, is a soft and biodegradable polymer that is highly sensitive to moisture. When exposed to water, PVA will dissolve. The propulsion section 1110 optionally includes an inlet 1140 that allows anatomical fluids to interact with the retention material within the spring mechanism 1126. Other mechanisms for releasing the spring can include an RF signal that would heat and melt the retention material. In this example, the propulsion section 1110 can also include a forward bearing 1128 that can assist in jettisoning of the pay load component 1130.

[0108] In this example, the pay load component 1130 can include a release mechanism to eject a therapeutic 1135 stored within a reservoir in the body of the pay load component 1130. The release mechanism can include a hydrogel 1132 and a piston 1134. After the payload component 1130 is jettisoned from the propulsion section 1110 see FIGS. 11C-1 ID), the hydrogel 1132 can be triggered to expand and push the piston 1134 towards the pointed end of the pay load component 1130 expelling the therapeutic 1135.

[0109] FIGS. 12A-12C are block diagram illustrations of a cargo portion 1200 of a miniature device with a secondary unpacking mechanism 1220. In this example, the cargo (payload) portion 1200 is illustrated after it was jettisoned from a miniature device that delivered to a target location. The cargo portion 1200 can include a cylindrical body 1210 that forms a fluid reservoir to hold a therapeutic 1235. The cylindrical body 1210 can also include a filling hole 1240 and a blow hole 1242. A distal end of the cylindrical body 1210 can include a fixed magnet 1226 held in place by a seal component 1242. The proximal end of the cylindrical body 1210 can include that unpacking mechanism 1220 that includes a mobile magnet 1222 held in position by a- T1 -retention material 1228. In an example, the mobile magnet 1222 can include a coating 1224. In an example, the coating 1224 is a parylene coating.

[0110] In an example, the unpacking mechanism 1220 functions to eject the therapeutic 1135 upon dissolution of the retention material 1228. When the retention material 1228 dissolves or melts, the mobile magnet 1222 is free to move in response to the attraction field of the fixed magnet 1226, which results in ejecting the therapeutic 1135 from the proximal end of the cylindrical body 1210 as well as the filling hole 1240 and the blow hole 1242.

[0111] FIG. 13 is a flowchart illustrating treatment technique 1300 using a dual miniature device treatment delivery system. In this example, the technique 1300 can utilize two specialized miniature devices, a first miniature device designed to create a path to the treatment location (e.g., a boring miniature device or boring bot) and a second miniature device designed for payload delivery. In this example treatment technique, the boring miniature device is used to create a path to the target tissue location within the patient, and then the payload deliver miniature device is navigated through the same path to deliver a therapeutic payload to the target location. The benefits gained with this approach include utilizing specialized miniature devices purpose built for a particular mission. The boring miniature device can be specialized for propulsion through fluids and particularly tissue without the added bulk or reduction in propulsion capabilities that often accompanies a miniature device designed to carry a payload. Conversely, as the payload miniature device will be navigated through disrupted tissue, it can be designed with greater payload carrying capabilities as the need for high-powered propulsion is reduced.

[0112] In this example, the technique 1300 can include operations such as inserting a boring miniature device at 1302, navigating the boring miniature device through fluids at 1304, transitioning the boring miniature device into tissue at 1306, navigating the boring miniature device to a target location in tissue at 1308, retrieving the boring miniature device at 1310, inserting the delivery miniature device at 1312, navigating the delivery miniature device along the path created by the boring miniature device at 1314, delivering a pay load at the target location at 1316, and retrieving the delivery miniature device at 1318. The technique 1300 can be performed by any of the MPS (external control systems) discussed within this disclosure. Further, the technique 1300 can be combined with other techniques discussed herein, such as the technique 500 for transitioning a miniature device between fluids and tissue (such as betweenCSF and brain tissue). The technique 1300 is discussed as including navigating (propelling) a miniature device through both fluids and tissue, the technique can be modified to introduce one or both miniature devices directly into a tissue or to deliver a payload within a fluid milieu (which would eliminate certain operations discussed below, without changing the overall concept of using a boring miniature device to create a pathway to a target location to ease delivery of a pay load with a delivery miniature device).

[0113] The technique 1300 can begin at 1302 with a boring miniature device being introduced into a patient using an introduction instrument. In an example, the boring miniature device is introduced into the CSF in the spine of the patient. At 1304, the technique 1300 continues with the MPS propelling and controlling (e.g., navigating) the boring miniature device within the fluid milieu. The boring miniature device can include additional propulsion features and a greater percentage of magnetic material allowing for easier propulsion and control of the device. At 1306, the technique 1300 can continue with the MPS transitioning the boring miniature device into tissue. For example, the MPS can transition the boring miniature device from CSF into brain tissue using the technique 500. The transition to tissue may also include implementation of the technique 400 that involves hand off of control and propulsion of the boring miniature device from a mobile magnetic component to an array of electromagnets for use in navigation through the tissue.

[0114] At 1308, the technique 1300 continues with the MPS navigating the boring miniature device to a target location within the tissue. Navigation through the tissue can be done using an array of electromagnets such as the array of magnets 310 discussed above. Once boring miniature device reaches the target location the MPS saves the navigation path for future reference in navigating the delivery miniature device. At 1310, the technique 1300 continues with the MPS navigating the boring miniature device back to the insertion point or to a different extraction location to retrieve the boring miniature device. At 1312, the delivery miniature device is inserted in the same insertion point as in operation 1302. The technique 1300 continues at 1314 with the MPS using the saved navigation path from the boring miniature device to navigate the delivery miniature device to the target tissue location. Once at the delivery location, the technique 1300 continues at 1316 with the delivery miniature device delivering a pay load. The payload delivery can be performed in any of the method discussed within this disclosure or by other means known in the art. At 1318, the technique 1300 can conclude with the MPSretrieving the delivery miniature device. The retrieval can include use of insertion / retrieval instruments and can occur at the insertion point or at another suitable extraction location.THE INTRODUCTION / RETRIEVAL KITFIG. 14A is a perspective view illustrating an introduction / retrieval instrument 1400 in accordance with at least one example of the disclosure. FIG. 14B is an inset cross-sectional view of a tip 1410 of an introduction / retrieval instrument 1400 in accordance with at least one example of the disclosure. In an example, the introduction / retrieval instrument 1400 (hereinafter “instrument 1400”) includes a hold adjustment knob 1405 on a proximal end and an insertion tip 1410 on a distal end. The insertion tip 1410 terminates a cannula 1408 that extends from the body of the instrument 1400. The cannula 1408 is a rigid structure made from titanium or other non-magnetic metal or a plastic material. The cross-section illustration of tip 1410 in FIG. 14B details additional components of the instrument 1400 including a curved distal end 1412 and a magnetic retention mechanism 1420 that can provide adjustable magnetic retention for a miniature device 1450 during introduction or retrieval. The magnetic retention mechanism 1420 is adjusted using the hold adjustment knob 1405. Within the distal end of the cannula 1408, the magnetic retention mechanism includes a retention magnet 1422 and an adjustment shaft 1424. FIG. 14B illustrates the magnetic retention mechanism 1420 in a hard hold position 1426A and a soft hold position 1426B. In the hard hold position 1426A, the retention magnet 1422 is extended to a distal end of the cannula adjacent the miniature device 1450. In the hard hold position 1426A, the miniature device 1450 is firmly retained within the instrument 1400 to avoid accidental release while the instrument 1400 is manipulated into an introduction site. In the soft hold position 1426B, the retention magnet 1422 is retracted proximally into the cannula to reduce the magnetic hold on the miniature device 1450. Rotation of the hold adjustment knob 1405 can transition the magnetic retention mechanism 1420 between the hard hold position 1426A and the soft hold position 1426B through manipulation of an effective length of the adjustment shaft 1424 that the retention magnet is attached to.

[0115] In another example, the system may comprise an introduction / retrieval kit may be provided, for example as described in PCT application PCT / US2022 / 40303, the full contents of which are incorporated herein by reference. The introduction / retrieval kit comprises a sharp rigid pointed surgical instrument fitted with a cannula. In some embodiments, the cannula is rigid and made of titanium or other non-magnetic metal or plastic. In some embodiments, the cannula isflexible. In some embodiments, the cannula outer diameter ranges from about 1 mm to about 10 mm, for example about 3.5 mm. In some embodiments, the cannula is stabilized by a mechanical arm. In some embodiments, the cannula is designed to be stabilized by a user. In some embodiments, the cannula is configured to be guided using X-rays. In some embodiments, the cannula is configured to be guided using a stereotactic technique.

[0116] In some embodiments, the introduction / retrieval kit further comprises an introducer comprising a separate, interchangeable miniature device holder configured to insert the miniature device into the subject and to release it into, e.g., the cisterna magna. In some embodiments, the introducer is disposable and / or configured for a single use. In some embodiments, the introducer is pre-loaded at its distal end with the miniature device. The miniature device may be held in place by a small, e.g., having a diameter of 0.75 mm, magnet at the distal end of the introducer. The small magnet may be disposed at the bottom of the introducer, thereby holding the miniature device in place, and facilitating controlled orientation of it before introduction of the miniature device into the patient.

[0117] In some embodiments, the introduction / retrieval kit further comprises a separate, interchangeable miniature retriever, which may replace the introducer in the cannula and is used to retrieve the miniature device from the patient, for example once the mission is complete. In some embodiments, the retriever is disposable and / or configured for a single use. In some embodiments, the retriever has a tip with a magnet at its distal end that is used to attract and capture the miniature device and remove it from the subject. The tip of the retriever may comprise a cage having a small, e.g., no greater than about 2 mm, spherical magnet that is configured to freely rotate, thereby facilitating controlling the orientation of the miniature device during retrieval 5 from the patient.

[0118] In some embodiments, a single mechanism constitutes the introducer and the retriever. In some embodiments, the retriever is a separate tool that comprises a net to catch the miniature device and a magnet at the end of a wire to attract the miniature device towards the net. In some embodiments, the external system drives the miniature device back to the net and the net is mechanically actuated using tethers to close around the miniature device.

[0119] In some embodiments, a sharp rigid pointed surgical instrument fitted with a cannula enters the body in the neck area and is pushed through the soft tissue. In some embodiments, thetip of the sharp rigid pointed surgical instrument is fitted with a cannula and advanced until it reaches the cistcrna magna.

[0120] In some embodiments, the external system monitors the position of the sharp rigid pointed surgical instrument fitted with a cannula using a stereo vision camera. In some embodiments, the route of the sharp rigid pointed surgical instrument fitted with a cannula is planned in advance by medical personnel using the planning submodule. In some embodiments, the route is charted in the planning submodule using MRI data. In some embodiments, the position of the sharp rigid pointed surgical instrument fitted with a cannula is represented, as perceived by an optical stereovision system, in real time, on an electronic display station.

[0121] In some embodiments, the proximal end of the cannula is equipped with a valve-like system through which the sharp rigid instrument can be removed while preventing fluids from inside the body to drain out. In some embodiments, the sharp instrument is removed to make way for the miniature device to travel up and down the cannula. In some embodiments, the miniature device is placed inside the cannula, through the valve-like system and coaxed to travel all the way to the tip of the cannula by flushing a fluid. In some embodiments, a miniature device holder that fits inside the cannula and that holds the miniature device on its distal end is inserted into the cannula. In some embodiments, the miniature device holder is longer than the cannula. In some embodiments, the miniature device holder distal end is advanced further, until the miniature device is removed fully from the cannula. In some embodiments, the miniature device holder can be coaxed to release its hold on the miniature device on demand using mechanical levers or release wires available on the proximal end.

[0122] In some embodiments, the action of releasing the hold on the miniature device is monitored by the external system. In some embodiments, the action of releasing the hold on the miniature device is synchronized with the external system. In some embodiments, the external system uses stereo X-ray vision system to evaluate the position of the miniature device. In some embodiments, the external system starts generating magnetic fields of adequate intensity and characteristic as the miniature device is being released from the miniature device holder.

[0123] FIG. 15 illustrates a block diagram of an example machine 1500 upon which any one or more of the techniques (processes) discussed herein may perform in accordance with some embodiments. The example machine 1500 can also be used to operate the control system 330 discussed above in reference to FIGS. 3A-3B as well as the control system 630 discussed abovein reference to FIG. 6. In alternative embodiments, the machine 1500 may operate as a standalone device and / or may be connected (c.g., networked) to other machines. In a networked deployment, the machine 1500 may operate in the capacity of a server machine, a client machine, or both in server-client network environments. In an example, the machine 1500 may act as a peer machine in peer-to-peer (P2P) (or other distributed) network environment. The machine 1500 may be a personal computer (PC), a tablet PC, a set-top box (STB), a personal digital assistant (PDA), a mobile telephone, a web appliance, a network router, switch or bridge, or any machine capable of executing instructions (sequential or otherwise) that specify actions to be taken by that machine. Further, while only a single machine is illustrated, the term "machine" shall also be taken to include any collection of machines that individually or jointly execute a set (or multiple sets) of instructions to perform any one or more of the methodologies discussed herein, such as cloud computing, software as a service (SaaS), other computer cluster configurations.

[0124] Machine (e.g., computer system) 1500 may include a hardware processor 1502 (e.g., a central processing unit (CPU), a graphics processing unit (GPU), a hardware processor core, or any combination thereof), a main memory 1504 and a static memory 1506, some or all of which may communicate with each other via an interlink (e.g., bus) 1508. The machine 1500 may further include a display unit 1510, an alphanumeric input device 1512 (e.g., a keyboard), and a user interface (UI) navigation device 1514 (e.g., a mouse). In an example, the display unit 1510, input device 1512 and UI navigation device 1514 may be a touch screen display. The machine 1500 may additionally include a storage device (e.g., drive unit) 1516, a signal generation device 1518 (e.g., a speaker), a network interface device 1520, and one or more sensors 1521, such as a global positioning system (GPS) sensor, compass, accelerometer, or another sensor. The machine 1500 may include an output controller 1528, such as a serial (e.g., Universal Serial Bus (USB), parallel, or other wired or wireless (e.g., infrared (IR), near field communication (NFC), etc.) connection to communicate and / or control one or more peripheral devices (e.g., a printer, card reader, etc.).

[0125] The storage device 1516 may include a machine readable medium 1522 on which is stored one or more sets of data structures or instructions 1524 (e.g., software) embodying or utilized by any one or more of the techniques or functions described herein. The instructions 1524 may also reside, completely or at least partially, within the main memory 1504, withinstatic memory 1506, or within the hardware processor 1502 during execution thereof by the machine 1500. In an example, one or any combination of the hardware processor 1502, the main memory 1504, the static memory 1506, or the storage device 1516 may constitute machine readable media.

[0126] While the machine readable medium 1522 is illustrated as a single medium, the term "machine readable medium" may include a single medium or multiple media (e.g., a centralized or distributed database, and / or associated caches and servers) configured to store the one or more instructions 1524. The term "machine readable medium" may include any medium that is capable of storing, encoding, or carrying instructions for execution by the machine 1500 and that cause the machine 1500 to perform any one or more of the techniques of the present disclosure, or that is capable of storing, encoding, or carrying data structures used by or associated with such instructions. Non-limiting machine-readable medium examples may include solid-state memories, and optical and magnetic media.

[0127] The instructions 1524 may further be transmitted or received over a communications network 1526 using a transmission medium via the network interface device 1520 utilizing any one of a number of transfer protocols (e.g., frame relay, internet protocol (IP), transmission control protocol (TCP), user datagram protocol (UDP), hypertext transfer protocol (HTTP), etc.). Example communication networks may include a local area network (LAN), a wide area network (WAN), a packet data network (e.g., the Internet), mobile telephone networks (e.g., cellular networks), Plain Old Telephone (POTS) networks, and wireless data networks (e.g., Institute of Electrical and Electronics Engineers (IEEE) 802.11 family of standards known as Wi-Fi®, IEEE 802.16 family of standards known as WiMax®), IEEE 802.15.4 family of standards, peer-to-peer (P2P) networks, among others. In an example, the network interface device 1520 may include one or more physical jacks (e.g., Ethernet, coaxial, or phone jacks) or one or more antennas to connect to the communications network 1526. In an example, the network interface device 1520 may include a plurality of antennas to wirelessly communicate using at least one of single-input multiple-output (SIMO), multiple-input multiple-output (MIMO), or multiple-input single-output (MISO) techniques. The term “transmission medium” shall be taken to include any intangible medium that is capable of storing, encoding, or carrying instructions for execution by the machine 1500, and includes digital or analog communications signals or other intangible medium to facilitate communication of such software.

[0128] Method / technique examples described herein may be machine or computer-implemented at least in part. Some examples may include a computer-readable medium or machine-readable medium encoded with instructions operable to configure an electronic device to perform methods as described in the above examples. An implementation of such methods may include code, such as microcode, assembly language code, a higher-level language code, or the like. Such code may include computer readable instructions for performing various methods. The code may form portions of computer program products. Further, in an example, the code may be tangibly stored on one or more volatile, non-transitory, or non-volatile tangible computer-readable media, such as during execution or at other times. Examples of these tangible computer- readable media may include, but are not limited to, hard disks, removable magnetic disks, removable optical disks (e.g., compact disks and digital video disks), magnetic cassettes, memory cards or sticks, random access memories (RAMs), read only memories (ROMs), and the like.

[0129] It will be recognized that examples, embodiments, modifications, options, etc., described herein are to be construed as inclusive and non-limiting, i.e., two or more examples, etc., described separately herein are not to be construed as being mutually exclusive of one another or in any other way limiting, unless such is explicitly stated and / or is otherwise clear. Those skilled in the ail to which this invention pertains will readily appreciate that numerous changes, variations, and modifications can be made without departing from the scope of the presently disclosed subject matter, mutatis mutandis.

[0130] The following, non-limiting examples, detail certain aspects of the present subject matter to solve the challenges and provide the benefits discussed herein, among others.

[0131]

[0132] Example 1 is a method for delivering a payload to a target location. The method can include introducing a miniature device into a first anatomical location within a patient; navigating the miniature device through a first type of anatomical milieu; navigating the miniature device through a second type of anatomical milieu to reach a second anatomical location; and releasing a payload at the second anatomical location.

[0133] In Example 2 the subject matter of Example 1 can include navigating the miniature device back to the first anatomical location.

[0134] In Example 3 the subject matter of any one of Examples 1 and 2 can include the navigating the miniature device back to the first anatomical location by propelling the miniature device through the first type of milieu and the second type of milieu.

[0135] In Example 4 the subject matter of any one of Examples 1 to 3 can include navigating the miniature device through the first type of milieu by propelling the miniature device using a first set of control parameters.

[0136] In Example 5 the subject matter of Example 4 can include propelling the miniature device using the first set of control parameters by operating a set of electromagnet coils with a first magnetic strength and a first frequency.

[0137] In Example 6 the subject matter of any one of Examples 1 to 5 can include navigating the miniature device through the first type of milieu by propelling the miniature device through an anatomical fluid.

[0138] In Example 7 the subject matter of any one of Examples 1 to 6 can include navigating the miniature device through the second type of milieu by propelling the miniature device using a second set of control parameters.

[0139] In Example 8 the subject matter of Example 7 can include propelling the miniature device using the second set of control parameters by operating the set of electromagnet coils with a second magnetic strength and a second frequency.

[0140] In Example 9 the subject matter of any one of Examples 1 to 8 can include navigating the miniature device through the second type of milieu by propelling the miniature device through an anatomical tissue.

[0141] In Example 10 the subject matter of any one of Examples 1 to 9 can include introducing the miniature device by puncturing a patient’s skin adjacent the first anatomical location with a cannula holding the miniature device.

[0142] In Example 11 the subject matter of Example 10 can include introducing the miniature device by releasing the miniature device from within the cannula.

[0143] In Example 12 the subject matter of any one of Examples 10 or 11 can include releasing the miniature device by disconnecting the miniature device from a magnet within the cannula holding it in place during the introducing.

[0144] In Example 13 the subject matter of any one of Examples 10 to 12 can include disconnecting the miniature device from the magnet within the cannula by moving the magnetwithin the cannula away from the miniature device to reduce a holding force on the miniature device.

[0145] In Example 14 the subject matter of any one of Examples 1 to 13 can include retrieving the miniature device from the first anatomical location.

[0146] In Example 15 the subject matter of Example 14 can include retrieving the miniature device by propelling the miniature device into a retrieval instrument.

[0147] In Example 16 the subject matter of any one of Examples 1 to 15 can include releasing the payload by activation of a release trigger.

[0148] In Example 17 the subject matter of Example 16 can include activation of the release trigger by sending an RF signal towards the miniature device.

[0149] In Example 18 the subject matter of Example 16 can include activation of the release trigger by passage of a pre-defined time period.

[0150] In Example 19 the subject matter of Example 18 can include the passage of the predefined time period being triggered by receiving a pre-defined RF signal.

[0151] In Example 20 the subject matter of Example 16 can include activation of the release trigger by sensing a change in temperature in an environment surrounding the miniature device.

[0152] In Example 21 the subject matter of Example 20 can include sensing the change in temperature in the environment by detecting introduction of a chilled saline solution into the second anatomical location.

[0153] In Example 22 the subject matter of Example 20 can include sensing the change in temperature in the environment causing dissolution of a material within the miniature device that allows for release of the payload.

[0154] In Example 23 the subject matter of Example 20 can include sensing the change in temperature in the environment causing a change in a shape memory material within the miniature device to trigger release of the payload.

[0155] In Example 24 the subject matter of any one of Examples 1 to 23 can include releasing the payload by jettisoning a portion of the miniature device at the second anatomical location.

[0156] In Example 25 the subject matter of any one of Examples 1 to 23 can include releasing the payload by ejecting a therapeutic substance from within the miniature device at the second anatomical location.

[0157] In Example 26 the subject matter of any one of Examples 24 or 25 can include jettisoning of the portion or ejecting of the therapeutic substance being triggered by a trigger selected from the following group of triggers: a chemical reaction, a time delay, an electro-chemical reaction, a heat-based release mechanism, a stored energy release, and a received energy conversion.

[0158] In Example 27 the subject matter of any one of claims 24 or 25 can include jettisoning of the portion or the ejecting of the therapeutic substance being triggered by the stored energy release.

[0159] In Example 28 the subject matter of Example 27 can include the stored energy release including releasing energy stored in one of the following mechanisms: a spring, a battery, a capacitor, one or more magnets, and a shape memory alloy.

[0160] In Example 29 the subject matter of Example 24 can include jettisoning the portion of the miniature device through dissolution of a temporary link between the payload and a propulsion section of the miniature device.

[0161] In Example 30 the subject matter of Example 24 can include jettisoning the portion of the miniature device by activating a stored energy mechanism to release the payload from a propulsion section of the miniature device.

[0162] In Example 31 the subject matter of Example 30 can include activating the stored energy mechanism by releasing a spring to jettison the portion of the miniature device.

[0163] In Example 32 the subject matter of Example 31 can include releasing the spring by melting or dissolving a material within the miniature device restraining the spring.

[0164] In Example 33 the subject matter of Example 32 can include melting or dissolving the material by melting or dissolving a glucose or polyvinyl alcohol (PVA) material.

[0165] In Example 34 the subject matter of Example 25 can include ejecting the therapeutic substance from within the miniature device by jettisoning a portion of the miniature device containing the therapeutic substance.

[0166] In Example 35 the subject matter of Example 34 can include jettisoning the portion by exposing an opening to a fluid reservoir to tissue at the second anatomical location.

[0167] In Example 36 the subject matter of Example 34 can include jettisoning the portion by triggering a stored energy release mechanism within the portion to release the therapeutic substance.

[0168] In Example 37 the subject matter of Example 36 can include triggering the stored energy release mechanism by melting or dissolving a retention material to release one or more magnets that translate to eject the therapeutic substance.

[0169] In Example 38 the subject matter of Example 26 can include triggering the stored energy release mechanism by triggering a hydrogel to expand within the portion and eject the therapeutic substance.

[0170] In Example 39 the subject matter of Example 25 can include ejecting the therapeutic substance from within the miniature device by exposing a retention material to anatomic fluids.

[0171] In Example 40 the subject matter of Example 39 can include exposing the retention material by dissolving the retention material to trigger the ejecting of the therapeutic substance.

[0172] In Example 1 the subject matter of Example 40 can include dissolving of the retention material causes release of one or more magnets that operate to eject the therapeutic substance.

[0173] Example 42 is a system for propelling a miniature device through anatomical fluids and tissues to a target location. The system can include a first magnetic propulsion system, a second magnetic propulsion system, and a control system. The first magnetic propulsion system can include a mobile magnetic component coupled to a translation mechanism. The second magnetic propulsion system can include an array of electromagnets arranged to surround a target anatomic area. The control system can include a processor and memory device containing instructions that, when executed by the processor, cause the system to perform operations including: propel a miniature device from an insertion point through an anatomical fluid using the first magnetic propulsion system; transition control of the miniature device from the first magnetic propulsion system to the second magnetic propulsion system; and propel the miniature device to a target location within the target anatomic area at least partially through anatomical tissue using the second magnetic propulsion system. The system of Example 42 can perform any of the subject matter discussed in any one of Examples 1 to 41.

[0174] In Example 43 the subject matter of Example 42 can include instructions that further cause the system to park the miniature device in a safe location using the first magnetic propulsion system prior to transitioning control of the miniature device to the second magnetic propulsion system.

[0175] In Example 44 the subject matter of Example 43 can include transition control of the miniature device by gradually increasing the magnetic field produced by the array of electromagnets while the miniature device is in the safe location.

[0176] In Example 45 the subject matter of any one of Examples 42 to 44 can include the transition control of the miniature device including verifying control of the miniature device by the second magnetic propulsion system.

[0177] In Example 46 the subject matter of Example 45 can include verifying control of the miniature device by navigating the miniature device to a second safe location using the second magnetic propulsion system.

[0178] In Example 47 the subject matter of any one of Examples 42 to 46 can include instructions that further cause the system to transition the miniature device between the anatomical fluid and the anatomical tissue to propel the miniature device to the target location within the anatomical tissue.

[0179] In Example 48 the subject matter of Example 47 can include transitioning the miniature device between the anatomical fluid and the anatomical tissue including detecting rotational orientation of the miniature device.

[0180] In Example 49 the subject matter of any one of examples 47 or 48 can include transitioning the miniature device between the anatomical fluid and the anatomical tissue including activating rotational and linear propulsion of the miniature device into the anatomical tissue.

[0181] In Example 50 the subject matter of any one of examples 47 to 49 can include transitioning the miniature device between the anatomical fluid and the anatomical tissue including monitoring rotational and linear translation of the miniature device into the anatomical tissue.

[0182] In Example 51 the subject matter of Example 50 can include monitoring rotational and linear translation of the miniature device into the anatomical tissue including determining whether the miniature device is gaining traction within the anatomical tissue.

[0183] In Example 52 the subject matter of Example 51 can include in response to determining that the miniature device is gaining traction transitioning to rotational propulsion only to propel the miniature device to the target location within the anatomical tissue.

[0184] In Example 53 the subject matter of Example 51 can include in response to determining that the miniature device is not gaining traction continuing with both rotational and linear propulsion and continuing to monitor rotational and linear translation within the anatomical tissue.

[0185] In Example 54 the subject matter of any one of Examples 42 to 53 can include the miniature device being a delivery miniature device including a payload adapted to be ejected or jettisoned at the target location. As well as including a boring miniature device configured to create a path to the target location for the delivery miniature device to follow.

[0186] In Example 55 the subject matter of Example 54 can include instructions that further cause the system to navigate the boring miniature device to the target location in advance of propelling the delivery miniature device from the insertion point to the target location.

[0187] In Example 56 the subject matter of Example 55 can include navigating the boring miniature device to the target location by propelling the boring miniature device from an insertion point through an anatomical fluid using the first magnetic propulsion system; transitioning control of the boring miniature device from the first magnetic propulsion system to the second magnetic propulsion system; and propelling the boring miniature device to a target location within the target anatomic area at least partially through anatomical tissue using the second magnetic propulsion system.

[0188] In Example 57 the subject matter of any one of Examples 55 or 56 can include instructions that further cause the system to retrieve the boring miniature device.

[0189] In Example 58 the subject matter of any one of Examples 55 to 57 can include instructions that further cause the system to insert, after the boring miniature device has been propelled to the target location, the delivery miniature device.

[0190] In Example 59 the subject matter of any one of Examples 42 to 57 can include instructions that further cause the system to deliver a payload from the delivery miniature device at the target location, wherein the delivery mechanism within the delivery miniature device can release the payload using any of the techniques of any one of Examples 16 to 41.

[0191] Example 60 is a system for delivering a payload to a target location within a patient. The system can include a delivery miniature device, a boring miniature device, a magnetic propulsion system, and a control system. The delivery miniature device including a payload release mechanism to release a therapeutic at the target location. The boring miniature device configuredto create a path to the target location for the delivery miniature device. The magnetic propulsion system configured to generate magnetic fields adapted to propel the boring miniature device and subsequently the delivery miniature device to the target location. The control system can include a processor and memory device containing instructions that, when executed by the processor, cause the system to perform operations including: propel the boring miniature device from an insertion point to the target location through anatomical fluids and tissue; retrieve the boring miniature device; and propel the delivery miniature device from the insertion point to the target location along a path created by the boring miniature device. The system of Example 60 can perform any of the subject matter discussed in any one of Examples 1 to 41. The system of Example 60 is also combinable with the subject matter discussed in any one of Examples 42-59.

[0192] In Example 61 the subject matter of Example 60 can include instructions that further cause the system to deliver a payload from the delivery miniature device at the target location through activation of the payload release mechanism.

[0193] In Example 62 the subject matter of Example 61 can include activation of the pay load release mechanism within the delivery miniature device which releases the payload using any of the methods of any one of claims 16 to 41.

[0194] Example 63 is a system for propelling a miniature device through anatomical fluids and tissues. The system can include a magnetic propulsion system and a control system. The magnetic propulsion system including an array of electromagnetic coils. The control system can include a processor and memory device containing instructions that, when executed by the processor, cause the system to perform operations including: operating the magnetic propulsion system at a first magnetic strength and a first frequency to manipulate the miniature device according to a first characteristic; and operating the magnetic propulsion system at a second magnetic strength and a second frequency to manipulate the miniature device according to a second characteristic. The system of Example 63 can perform any of the subject matter discussed in any one of Examples 1 to 41. The system of Example 63 is also combinable with the subject matter discussed in any one of Examples 42-62.

[0195] In Example 64 the subject matter of Example 63 can include manipulating the miniature device according to the first characteristic enables propulsion through an anatomical fluid.

[0196] In Example 65 the subject matter of any one of Examples 63 or 64 can include manipulating the miniature device according to the first characteristic to cause a linear propulsion of the miniature device.

[0197] In Example 66 the subject matter of any one of Examples 63 to 65 can include manipulating the miniature device according to the second characteristic to cause propulsion through an anatomical tissue.

[0198] In Example 67 the subject matter of any one of Examples 63 to 66 can include manipulating the miniature device according to the second characteristic to cause rotational propulsion of the miniature device.

[0199] In Example 68 the subject matter of any one of Examples 63-67 can include a biplane x- ray system communicatively coupled to the control system, wherein the manipulating the miniature device according to either the first characteristic or the second characteristic includes analyzing output from the biplane x-ray system to determine a location of the miniature device within the anatomical fluid or the anatomical tissue.

[0200] In Example 69 the subject matter of Example 68 can include the array of electromagnetic coils including a radiopaque marker adapted to enable the control system to determine location of the array of electromagnetic coils in reference to the miniature device within output from the biplane x-ray system.

[0201] In Example 70 the subject matter of any one of Examples 1 to 42 can include receiving output from a biplane x-ray system communicatively coupled to a control system of a magnetic propulsion system that propels and / or navigates the miniature device, and determining, within the control system from the output, a position and orientation of the miniature device within the patient.

[0202] In Example 71 the subject matter of Example 70 can include determining a relative location of an array of magnetic coils in reference to the miniature device from the output from the biplane x-ray system, and adjusting propulsion parameters based on the relative location.

[0203] In Example 72 the subject matter of Example 72 can include adjusting the propulsion parameters by adjusting magnetic gradient or frequency of magnetic pulses generated by the array of magnetic coils.

Claims

WHAT IS CLAIMED IS:

1. A method comprising: introducing a miniature device into a first anatomical location within a patient; navigating the miniature device through a first type of anatomical milieu; navigating the miniature device through a second type of anatomical milieu to reach a second anatomical location; and releasing a payload at the second anatomical location.

2. The method of claim 1, further comprising: navigating the miniature device back to the first anatomical location.

3. The method of claim 2, wherein the navigating the miniature device back to the first anatomical location includes propelling the miniature device through the first type of milieu and the second type of milieu.

4. The method of any one of claims 1 to 3, wherein navigating the miniature device through the first type of milieu includes propelling the miniature device using a first set of control parameters.

5. The method of claim 4, wherein the propelling the miniature device using the first set of control parameters includes operating a set of electromagnet coils with a first magnetic strength and a first frequency.

6. The method of any one of claims 1 to 5, wherein navigating the miniature device through the first type of milieu includes propelling the miniature device through an anatomical fluid.

7. The method of any one of claims 1 to 6, wherein navigating the miniature device through the second type of milieu includes propelling the miniature device using a second set of control parameters.

8. The method of claim 7, wherein the propelling the miniature device using the second set of control parameters includes operating the set of electromagnet coils with a second magnetic strength and a second frequency.

9. The method of any one of claims 1 to 8, wherein navigating the miniature device through the second type of milieu includes propelling the miniature device through an anatomical tissue.

10. The method of any one of claims 1 to 9, wherein the introducing the miniature device includes puncturing a patient’s skin adjacent the first anatomical location with a cannula holding the miniature device.

11. The method of claim 10, wherein the introducing the miniature device includes releasing the miniature device from within the cannula.

12. The method of claim 11, wherein releasing the miniature device includes disconnecting the miniature device from a magnet within the cannula holding it in place during the introducing.

13. The method of claim 12, wherein disconnecting the miniature device from the magnet within the cannula includes moving the magnet within the cannula away from the miniature device to reduce a holding force on the miniature device.

14. The method of any one of claims 1 to 13, further comprising retrieving the miniature device from the first anatomical location.

15. The method of claim 13, wherein retrieving the miniature device includes propelling the miniature device into a retrieval instrument.

16. The method of any one of claims 1 to 15, wherein the releasing the payload includes activation of a release trigger.

17. The method of claim 16, wherein the activation of the release trigger includes sending an RF signal towards the miniature device.

18. The method of claim 16, wherein the activation of the release trigger includes passage of a pre-defined time period.

19. The method of claim 18, wherein the passage of the pre-defined time period is triggered by receiving a pre-defined RF signal.

20. The method of claim 16, wherein the activation of the release trigger includes sensing a change in temperature in an environment surrounding the miniature device.

21. The method of claim 20, wherein the sensing the change in temperature in the environment includes detecting introduction of a chilled saline solution into the second anatomical location.

22. The method of claim 20, wherein the sensing the change in temperature in the environment causes dissolution of a material within the miniature device that allows for release of the payload.

23. The method of claim 20, wherein the sensing the change in temperature in the environment causes a change in a shape memory material within the miniature device to trigger release of the payload.

24. The method of any one of claims 1 to 23, wherein the releasing the payload includes jettisoning a portion of the miniature device at the second anatomical location.

25. The method of any one of claims 1 to 23, wherein the releasing the payload includes ejecting a therapeutic substance from within the miniature device at the second anatomical location.

26. The method of any one of claims 24 or 25, wherein the jettisoning of the portion or ejecting of the therapeutic substance is triggered by a trigger selected from the following group of triggers: a chemical reaction; a time delay; an electro-chemical reaction; a heat-based release mechanism; a stored energy release; and a received energy conversion.

27. The method of any one of claims 24 and 25, wherein the jettisoning of the portion or the ejecting of the therapeutic substance is triggered by the stored energy release.

28. The method of claim 27, wherein the stored energy release includes releasing energy stored in one of the following mechanisms: a spring; a battery; a capacitor; one or more magnets; and a shape memory alloy.

29. The method of claim 24, wherein the jettisoning the portion of the miniature device includes dissolution of a temporary link between the payload and a propulsion section of the miniature device.

30. The method of claim 24, wherein jettisoning the portion of the miniature device includes activating a stored energy mechanism to release the payload from a propulsion section of the miniature device.

31. The method of claim 30, wherein activating the stored energy mechanism includes releasing a spring to jettison the portion of the miniature device.- M -32. The method of claim 31, wherein releasing the spring includes melting or dissolving a material within the miniature device restraining the spring.

33. The method of claim 32, wherein the melting or dissolving the material includes melting or dissolving a glucose or polyvinyl alcohol (PVA) material.

34. The method of claim 25, wherein the ejecting the therapeutic substance from within the miniature device includes jettisoning a portion of the miniature device containing the therapeutic substance.

35. The method of claim 34, wherein the jettisoning the portion includes exposing an opening to a fluid reservoir to tissue at the second anatomical location.

36. The method of claim 34, wherein the jettisoning the portion includes triggering a stored energy release mechanism within the portion to release the therapeutic substance.

37. The method of claim 36, wherein the triggering the stored energy release mechanism includes melting or dissolving a retention material to release one or more magnets that translate to eject the therapeutic substance.

38. The method of claim 26, wherein the triggering the stored energy release mechanism includes triggering a hydrogel to expand within the portion and eject the therapeutic substance.

39. The method of claim 25, wherein the ejecting the therapeutic substance from within the miniature device includes exposing a retention material to anatomic fluids.

40. The method of claim 39, wherein the exposing the retention material includes dissolving the retention material to trigger the ejecting of the therapeutic substance.41 . The method of claim 40, wherein the dissolving of the retention material releases one or more magnets that operate to eject the therapeutic substance.

42. A system for propelling a miniature device through anatomical fluids and tissues, the system comprising: a first magnetic propulsion system including a mobile magnetic component coupled to a translation mechanism; a second magnetic propulsion system including an array of electromagnets arranged to surround a target anatomic area; and a control system including a processor and memory device containing instructions that, when executed by the processor, cause the system to perform operations including: propel a miniature device from an insertion point through an anatomical fluid using the first magnetic propulsion system; transition control of the miniature device from the first magnetic propulsion system to the second magnetic propulsion system; and propel the miniature device to a target location within the target anatomic area at least partially through anatomical tissue using the second magnetic propulsion system.

43. The system of claim 42, wherein the instructions further cause the system to park the miniature device in a safe location using the first magnetic propulsion system prior to transitioning control of the miniature device to the second magnetic propulsion system.

44. The system of claim 43, wherein the transition control of the miniature device includes gradually increasing the magnetic field produced by the array of electromagnets while the miniature device is in the safe location.

45. The system of claim 42, wherein the transition control of the miniature device includes verifying control of the miniature device by the second magnetic propulsion system.

46. The system of claim 45, wherein verifying control of the miniature device includes navigating the miniature device to a second safe location using the second magnetic propulsion system.

47. The system of any one of claims 42 to 46, wherein the instructions further cause the system to transition the miniature device between the anatomical fluid and the anatomical tissue to propel the miniature device to the target location within the anatomical tissue.

48. The system of claim 47, wherein the transitioning the miniature device between the anatomical fluid and the anatomical tissue includes detecting rotational orientation of the miniature device.

49. The system of any one of claims 47 or 48, wherein the transitioning the miniature device between the anatomical fluid and the anatomical tissue includes activating rotational and linear propulsion of the miniature device into the anatomical tissue.

50. The system of any one of claims 47 to 49, wherein the transitioning the miniature device between the anatomical fluid and the anatomical tissue includes monitoring rotational and linear translation of the miniature device into the anatomical tissue.

51. The system of claim 50, wherein the monitoring rotational and linear translation of the miniature device into the anatomical tissue includes determining whether the miniature device is gaining traction within the anatomical tissue.

52. The system of claim 51, wherein in response to determining that the miniature device is gaining traction transitioning to rotational propulsion only to propel the miniature device to the target location within the anatomical tissue.

53. The system of claim 51, wherein in response to determining that the miniature device is not gaining traction continuing with both rotational and linear propulsion and continuing to monitor rotational and linear translation within the anatomical tissue.

54. The system of any one of claims 42 to 53, wherein the miniature device is a delivery miniature device including a payload adapted to be ejected or jettisoned at the target location; and further comprising a boring miniature device configured to create a path to the target location for the delivery miniature device to follow.

55. The system of claim 54, wherein the instructions further cause the system to navigate the boring miniature device to the target location in advance of propelling the delivery miniature device from the insertion point to the target location.

56. The system of claim 55, wherein the navigating the boring miniature device to the target location includes: propelling the boring miniature device from an insertion point through an anatomical fluid using the first magnetic propulsion system; transitioning control of the boring miniature device from the first magnetic propulsion system to the second magnetic propulsion system; and propelling the boring miniature device to a target location within the target anatomic area at least partially through anatomical tissue using the second magnetic propulsion system.

57. The system of any one of claims 55 and 56, wherein the instructions further cause the system to retrieve the boring miniature device.

58. The system of any one of claims 55 to 57, wherein the instructions further cause the system to insert, after the boring miniature device has been propelled to the target location, the delivery miniature device.

59. The system of any one of claims 42 to 57, wherein the instructions further cause the system to deliver a payload from the delivery miniature device at the target location, wherein thedelivery mechanism within the delivery miniature device can release the payload using any of the methods of any one of claims 16 to 41.

60. A system for delivering a payload to a target location within a patient, the system comprising: a delivery miniature device including a payload release mechanism to release a therapeutic at the target location; a boring miniature device configured to create a path to the target location for the delivery miniature device; a magnetic propulsion system configured to generate magnetic fields adapted to propel the boring miniature device and subsequently the delivery miniature device to the target location; and a control system including a processor and memory device containing instructions that, when executed by the processor, cause the system to perform operations including: propel the boring miniature device from an insertion point to the target location through anatomical fluids and tissue; retrieve the boring miniature device; and propel the delivery miniature device from the insertion point to the target location along a path created by the boring miniature device.

61. The system of claim 60, wherein the instructions further cause the system to deliver a payload from the delivery miniature device at the target location through activation of the payload release mechanism.

62. The system of claim 61, wherein the activation of the payload release mechanism within the delivery miniature device can release the payload using any of the methods of any one of claims 16 to 41.

63. A system for propelling a miniature device through anatomical fluids and tissues, the system comprising: a magnetic propulsion system including an array of electromagnetic coils; anda control system including a processor and memory device containing instructions that, when executed by the processor, cause the system to perform operations including: operating the magnetic propulsion system at a first magnetic strength and a first frequency to manipulate the miniature device according to a first characteristic; and operating the magnetic propulsion system at a second magnetic strength and a second frequency to manipulate the miniature device according to a second characteristic.

64. The system of claim 63, wherein the manipulating the miniature device according to the first characteristic enables propulsion through an anatomical fluid.

65. The system of any one of claims 63 or 64, wherein the manipulating the miniature device according to the first characteristic enables a linear propulsion of the miniature device.

66. The system of any one of claims 63 to 65, wherein the manipulating the miniature device according to the second characteristic enables propulsion through an anatomical tissue.

67. The system of any one of claims 63 to 66, wherein the manipulating the miniature device according to the second characteristic enables rotational propulsion of the miniature device.

68. The system of any one of claims 63-67, further comprising: a biplane x-ray system communicatively coupled to the control system; and wherein the manipulating the miniature device according to either the first characteristic or the second characteristic includes analyzing output from the biplane x-ray system to determine a location of the miniature device within the anatomical fluid or the anatomical tissue.

69. The system of claim 68, wherein the array of electromagnetic coils includes a radiopaque marker adapted to enable the control system to determine location of the array of electromagnetic coils in reference to the miniature device within output from the biplane x-ray system.

70. The method of any one of claims 1 to 42, further comprising:receiving output from a biplane x-ray system communicatively coupled to a control system of a magnetic propulsion system that propels the miniature device; and determining, within the control system from the output, a position and orientation of the miniature device within the patient.

71. The method of claim 70, wherein the determining includes determining a relative location of an array of magnetic coils in reference to the miniature device from the output from the biplane x-ray system; And adjusting propulsion parameters based on the relative location.

72. The method of claim 71, wherein the adjusting the propulsion parameters includes adjusting magnetic gradient or frequency of magnetic pulses generated by the array of magnetic coils.

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