EP1280456A2 - Procede et appareil destines a etre utilises avec une electrode active et un catheter d'administration de medicaments - Google Patents

Procede et appareil destines a etre utilises avec une electrode active et un catheter d'administration de medicaments

Info

Publication number
EP1280456A2
EP1280456A2 EP01931071A EP01931071A EP1280456A2 EP 1280456 A2 EP1280456 A2 EP 1280456A2 EP 01931071 A EP01931071 A EP 01931071A EP 01931071 A EP01931071 A EP 01931071A EP 1280456 A2 EP1280456 A2 EP 1280456A2
Authority
EP
European Patent Office
Prior art keywords
tissue
delivery
volume
magnetic resonance
area
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01931071A
Other languages
German (de)
English (en)
Inventor
John Kucharczyk
Michael E. Moseley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medtronic Inc
Original Assignee
Image Guided Neurologics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/566,798 external-priority patent/US7505807B1/en
Application filed by Image Guided Neurologics Inc filed Critical Image Guided Neurologics Inc
Publication of EP1280456A2 publication Critical patent/EP1280456A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/28—Details of apparatus provided for in groups G01R33/44 - G01R33/64
    • G01R33/285—Invasive instruments, e.g. catheters or biopsy needles, specially adapted for tracking, guiding or visualization by NMR
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/01—Introducing, guiding, advancing, emplacing or holding catheters
    • A61M25/0105—Steering means as part of the catheter or advancing means; Markers for positioning
    • A61M2025/0166—Sensors, electrodes or the like for guiding the catheter to a target zone, e.g. image guided or magnetically guided
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/06—Head
    • A61M2210/0693—Brain, cerebrum

Definitions

  • This invention relates to the design, construction, and use of a catheter with multiple functionality including at least an active electrode and a drug delivery system, with the electrode of the catheter providing at least one functionality different from stimulating or effecting drug delivery or release.
  • the catheter is particularly useful in conjunction with magnetic resonance (MR) imaging to identify areas within a patient where changes in a molecular environment are occurring, as from chemical concentration changes effected by medical procedures.
  • MR magnetic resonance
  • the invention also describes a drug delivery device for targeted drug delivery into a patient using magnetic resonance (MR) imaging combined with conventional catheter placement techniques, particularly including neurosurgical or neuroradiologic techniques used in intracranial drug delivery.
  • MR Magnetic Resonance
  • MR imaging enables differentiation of normal from abnormal tissues, and can display critical structures such as blood vessels in three dimensions.
  • high-speed MR-guided therapy offers an improved opportunity to maximize the benefits of minimally invasive procedures.
  • Prototype high-speed MR imagers which permit continuous real-time visualization of tissues during surgical and endovascular procedures have already been developed.
  • Recent publications in the medical literature have described a number of MR-guided interventions including needle biopsies, interstitial laser therapy, interstitial cryotherapy and interstitial focused ultrasound surgery.
  • the standard current procedure for drug treatment of various focal neurological disorders, neurovascular diseases, and neurodegenerative processes requires neurosurgeons or interventional neuroradiologists to deliver drug agents by catheters or other tubular devices directed into the cerebrovascular or cerebroventricular circulation, or by direct injection of the drug agent, or cells which biosynthesize the drug agent, into targeted intracranial tissue locations.
  • the blood-brain barrier and blood-cerebrospinal fluid barrier almost entirely exclude large molecules like proteins, and control entry of smaller molecules. Small molecules ( ⁇ 200 daltons) that are lipid- soluble, not bound to plasma proteins, and minimally ionized, such as nicotine, ethanol, and some chemotherapeutic agents, readily enter the brain. Water-soluble molecules cross the barriers poorly or not at all.
  • a drug into a ventricle bypasses the blood-brain barrier, and allows for a wide distribution of the drug in the brain ventricles, cisterns, and spaces due to the normal flow pathways of cerebrospinal fluid in the brain.
  • many therapeutic drug agents particularly large-molecular weight hydrophobic drugs, fail to reach their target receptors in brain parenchyma because of metabolic inactivation and inability to diffuse into brain tissues, that may be up to 18 mm from a cerebrospinal fluid surface.
  • it should be delivered to its target tissue at the appropriate concentration.
  • Magnetic resonance imaging will likely play an increasingly important role in optimizing drug treatment of neurological disorders.
  • One type of MR unit designed for image-guided therapy is arranged in a "double-donut" configuration, in which the imaging coil is split axially into two components. Imaging studies are performed with this system with the surgeon standing in the axial gap of the magnet and carrying out procedures on the patient.
  • a second type of high-speed MR imaging system combines high-resolution MR imaging with conventional X-ray fluoroscopy and digital subtraction angiography (DSA) capability in a single hybrid unit. Both of these new generations of MR scanners provide frequently updated images of the anatomical structures of interest.
  • U.S. Pat. 5,171,217 to March describes the delivery of several specific compounds through direct injection of microcapsules or micropar-ticles using multiple-lumen catheters, such as disclosed by Wolinsky in U.S. Pat. 4,824,436.
  • U.S. Pat. 5,580,575 to Unger et al. Discloses a method of administering drugs using gas-filled liposomes comprising a therapeutic compound, and inducing the rupture of the liposomes with ultrasound energy.
  • U.S. Pat. 5,017,566 to Bodor discloses redox chemical systems for brain- targeted drug delivery of various hormones, neurotransmitters, and drugs through the intact blood-brain barrier.
  • Graham et al. disclose drug delivery devices, in which biologically active materials present within a reversibly permeable hydrogel compartment can be delivered into tissues by various endogenous and exogenous stimuli.
  • U.S. Pat.5,167,625 to Jacobsen et al. discloses implantable drug delivery system utilizing multiple drug compartments which are activated by an electrical circuit.
  • U.S. Pat. 4,941,874 to Sandow et al. discloses a device for the injection of implants, including drug implants that may used in the treatment of diseases.
  • STS Biopolymers allows for the drugs to diffuse out of the coating at a controlled rate, thereby maintaining therapeutic drug levels at the coating surface while minimizing systemic concentrations.
  • the coating can incorporate natural or synthetic materials that act as antibiotics, anticancer agents, and antithrombotics, according to the issued patent.
  • U.S. Pat. 5,573,668 to Grosh et al. discloses a microporous drug delivery membrane based on an extremely thin hydrophilic shell.
  • U. S. Pat. 5,569,197 to Helmus et al. discloses a drug device guidewire formed as a hollow tube suitable for drug infusion in thrombolytic and other intraluminal procedures.
  • U.S. Patent No. 5,125,888, 5,707,335, 5,779,694, and 5,843,093 disclose intracranial probes that can be positioned within the brain by magnetic stereotaxis, which are also visible under magnetic resonance (MR) imaging.
  • MR magnetic resonance
  • U.S. Patent No. 5,711,316, 5,713,923, 5,735,814, 5,832,932, and 5,978,702 disclose an implantable pump and catheter for infusing drugs into the brain to treat movement disorders, wherein a sensor detects the symptoms resulting from the movement disorder and a microprocessor algorithm analyzes the output from the sensor in order to regulate the amount of drug delivered to the brain.
  • U.S. Pat. No. 5,607,418 to Arzbaecher discloses an implantable drug delivery apparatus comprising a housing with a plurality of drug compartments which can be opened in a timed manner by a gas generating element to release the drugs into the tissue.
  • Each of the above-cited patents offers advantages for monitoring physiologic parameters related to drug therapy.
  • none of the available patents disclose a method means for image-guided targeted delivery of cells, with and without supportive intracranial drug therapy, as well as a means for non- invasively monitoring the physiologic and metabolic status of the cell implant.
  • U.S. Patent No. 6,026,316 (Kucharczyk and Moseley) describes process and apparatus for the real-time detection of molecular level movement or change in concentration of chemistry within the fluid of tissues, particularly within the tissue of the cranium.
  • Devices for the delivery of chemistry, the stimulation of natural release of chemistry, and associated process for the detection of those activities is taught, particularly in combination with MR imaging to visualize the immediate concentration altering effect of the attendant procedure are also described.
  • copending U.S. patent Application Serial No. 09/ — , — bearing attorney's docket no. 600.471US1 (and 723.037US1) titled "MULTI-PROBE SYSTEM" filed in the name of Dr. John Kucharczyk et al. on April 12, 2000 describes specific multi-probe catheter apparatus that is particularly useful in combination with MR imaging procedures. Both of these references are incorporated herein by reference for their respective disclosures.
  • the present invention is particularly well suited for evaluating the efficacy of cell therapy of Parkinson's disease and other neurodegenerative diseases and disorders.
  • Parkinson's disease is characterized by a deficiency of the neurotransmitter dopamine within the striatum of the brain, secondary to damage or destruction of the dopamine secreting cells of the substantia nigra in the midbrain.
  • direct intraparenchymal delivery of purified or synthetic dopamine, or its precursors, analogs or inhibitors has not demonstrated clear therapeutic benefit because of various problems associated with drug delivery, stability, dosage and cytotoxicity.
  • biologically active macromolecules appear to provide benefits by ameliorating the disease process or stimulating responses that result in therapeutic improvement.
  • models of Alzheimer's disease have been shown to benefit from the introduction of protein growth factors in vivo.
  • Models of primary brain tumors have demonstrated therapeutic responses by introducing cytokines designed to stimulate the immune response against the tumor cells.
  • Implantable miniature osmotic pumps have been used to provide a continuous supply of drugs or other active biologic factors to the brain and other tissues at a controlled rate. Reservoir limitations as well as drug solubility and stability have, however, restricted the usefulness of this technology. Controlled sustained release of dopamine for the treatment of Parkinson's disease has been attempted from within bioabsorbable microcapsules, such as disclosed by U.S. Pat. No.
  • patented inventions referenced above provide useful methods for introducing, delivering, or applying a drug agent to a specific target tissue, but each invention also has inherent problems.
  • some catheter systems that provide endovascular drug delivery require temporary blocking of a segment of the vessel, thereby transiently disrupting brain perfusion.
  • Microencapsulated coatings on catheters permit longer exposure of the tissue to the drug agent, but the physical limitations imposed by microcapsules restrict the volume and concentration of drug that can be effectively applied to any tissue area.
  • Exposed coatings on catheters that contain drug agents usually require some type of sheath that must be removed from the catheter before the drug can be released from the coating.
  • the sheath and any catheter components required to physically manipulate the sheath greatly increase the profile of the catheter, and thereby limit the variety of applications for which the drug delivery system can be employed.
  • the binders or adhesives used in catheter coatings may themselves significantly dilute the concentration of the therapeutic agent.
  • thermal and light energy required to melt and bond coatings such as macroaggregated albumin, to reduce tissue mass by ablation, and to inhibit restenosis by cytotoxic irradiation may also cause damage to blood vessels.
  • Biocompatible and MR-compatible materials which could be used to practice the invention include elastomeric hydrogel, nylon, teflon, polyamide, polyethylene, polypropylene, polysulfone, ceramics, cermets steatite, carbon fiber composites, silicon nitride, and zirconia, plexiglass, and poly-ether-ether-ketone. It is also important that drug delivery devices used under MR guidance are MRcompatible in both static and time-varying magnetic fields. Although the mechanical effects of the magnetic field on ferromagnetic devices present the greatest danger to patients through possible unintended movement of the devices, tissue and device heating may also result from radio-frequency power deposition in electrically conductive material located within the imaging volume.
  • Guidewires for the catheter or drug delivery system are usually made of radiopaque material so that their precise location can be identified during a surgical procedure through fluoroscopic viewing.
  • Exemplary of guidewires used under X-ray viewing is the guidewire disclosed by LeVeen, U.S. Pat. No. 4,448,195, in which a radiopaque wire can be identified on fluoroscopic images by metered bands placed at predetermined locations.
  • the U.S. Patent No. 4,922,924, awarded to Gambale et al. discloses a bifilar arrangement whereby radiopaque and radiotransparent filaments are wrapped on a mandril to form a bifilar coil which provides radiopaque and radiotransparent areas on the guide wire.
  • MRI enables image-guided placement of a catheter or other drug delivery device at targeted intracranial loci.
  • High-resolution visual images denoting the actual position of the drug delivery device within the brain would be extremely useful to the clinician in maximizing the safety and efficacy of the procedure.
  • Drug delivery devices, such as catheters, that are both MR-visible and radio-opaque could be monitored by both X-ray fluoroscopy and MR imaging, thus making intra-operative verification of catheter location possible.
  • the magnetic susceptibility artifact produced by the device should be small enough not to obscure surrounding anatomy, or mask low-threshold physiological events that have an MR signature, and thereby compromise the physician's ability to perform the intervention. These relationships will be in part dependent upon the combined or comparative properties of the device, the particular drug, and the surrounding environment (e.g., tissue).
  • targeted drug delivery can significantly improve therapeutic efficacy, while minimizing systemic side-effects of the drug therapy.
  • Image-guided placement of the tip of a drug delivery catheter directly into specific regions of the brain can initially produce maximal drug concentration close to the loci of tissue receptors following injection of the drug.
  • the limited distribution of drug injected from a single catheter tip presents other problems.
  • the volume flow rate of drug delivery must be very low in order to avoid indiscriminate damage to brain cells and nerve fibers.
  • Another aspect of this invention is therefore to overcome these inherent limitations of single point source drug delivery by devising a multi- lumen catheter with multiple drug release sources which effectively disperse therapeutic drug agents over a brain region containing receptors for the drug, or over an anatomically extensive area of brain pathology.
  • Magnetic Resonance Imaging is used in combination with 1) an MR observable delivery device or 2) an MR observable medical device which can alter a water based molecular environment by performed medical operations, the delivery device or medical device being used in the presence of MR observable (in water, body fluid or tissue) compound(s) or composition(s).
  • MRI images are viewed with respect to a molecular environment to determine the position of the delivery or medical device
  • the delivery device (hereinafter collectively referred to as the "delivery device” unless otherwise specifically identified) and changes in the environment where the delivery device is present as an indication of changes in the molecular environment.
  • the delivery of material from the delivery device is the most significant event within the molecular envirom-nent in the vicinity of the delivery area
  • the changes in the molecular environment are attributable to the delivery of the MR observable compounds or compositions.
  • Changes in signal intensity within the MR images reflect the changes in the molecular environment and therefore track the location of delivered materials, and are indicative of delivery rates and delivery volumes in viewable locations.
  • chemical composition within the molecular environment may also be altered as by the removal of deposits of certain materials into the liquid (water) environment, where those materials can alter the MR response.
  • Some materials which may be removed by medical procedures will not affect the MR response, such as calcium, but fatty materials may.
  • medical treatments which stimulate natural activities of chemical producing systems e.g., the glands, organs and cells of the body which generate chemicals such as enzymes and other chemicals with specific biological activity [e.g., dopamine, insulin, etc.]
  • chemical producing systems e.g., the glands, organs and cells of the body which generate chemicals such as enzymes and other chemicals with specific biological activity [e.g., dopamine, insulin, etc.]
  • any changes in chemical synthetic activity and/or delivery can be seen because of molecular environment changes which occur upon increased synthetic activity.
  • ADC Coefficients
  • ADC is the preferred means within the present invention of mapping the delivery of drug in tissue
  • other embodiments of the invention allow for additional tissue contrast parameters to track the delivery of a drug into tissue.
  • the delivery of a drug into tissue will cause other MRI-observable changes which can be mapped (as is done for ADC) and which can be used to spatially track the delivery and extent of a drug into a tissue. While some of these observations may be larger in magnitude than others, any of the effects can be used as a tracking mechanism.
  • the tissue contrast changes apparent on an MR image can arise from ADC, from alterations in the BO magnetic field (often referred to as magnetic susceptibility or ABO produced by the presence of a substance in said tissue), from alterations in local tissue Tl relaxation times, from local T2 relaxation times, from T2* relaxation times (which can be created by susceptibility differences), from the magnetization transfer coefficients
  • MTC is an effect produced by local communication between free water protons and those of nearby macromolecular structures
  • ADC anisotropy observed in oriented matter and also from local differences in temperature which will affect in varying degrees all of the included tissue contrast parameters
  • the delivery of drug can also be tracked from magnetic filed frequency shifts caused by the drug or arising from agents added with unique frequency shifts from those of the local protons
  • MR imaging of the alterations in the BO magnetic field can reveal the spatial distribution of a drug from the interaction of the drug with the otherwise homogeneous magnetic field found in
  • the invention includes a device and a method for MR-guided targeted drug delivery into a patient, such as intracranial drug delivery, intraspinal drug delivery, intrarenal drug delivery, intracardial drug delivery, etc.
  • the MR-visible drug delivery device is guided to target entrance points to the patient such as periventricular, intracerebroventricular, subarachnoid, or intraparenchymal tissues magnetic resonance imaging, or conventional methods of neurosurgical or neuroradiologic catheter manipulation.
  • the drug delivery device has a linearly arranged array of radiopaque and MR-visible markers disposed at its distal end to provide easily identifiable reference points for trackability and localization under susceptibility MR imaging and X-ray fluoroscopy guidance. Additionally, active MR visualization of the drug delivery device is achieved by means of R-F microcoils positioned along the distal axis of the device.
  • MR visibility can be variably adjustable based on requirements related to degree of signal intensity change for device localization and positioning, enhancement along the shaft of the device, enhancement around the body of the device, visibility of the proximal and distal ends of the device, degree of increased background noise associated with device movement, and other factors which either increase or suppress background noise associated with the device. Since the tip of the drug delivery device can be seen on MR and X-ray images and thus localized within the brain, the multiple point source locations of drug delivery are therefore known and can be seen relative to the tip or the shaft of the device.
  • Targeted delivery of drug agents is performed utilizing MR-compatible pumps connected to variable-length concentric MR-visible dialysis probes each with a variable molecular weight cut-off membrane, or by another MR-compatible infusion device which injects or infuses a diagnostic or therapeutic drug solution.
  • Imaging of the injected or infused drug agent is performed by MR diffusion mapping using the R- F microcoils attached to the distal shaft of the injection device, or by imaging an MR- visible contrast agent that is injected or infused through the walls of the dialysis fiber into the brain.
  • One aspect of the present invention is to provide a non-invasive, radiation-free imaging system for tracking a drug delivery device to a target intracranial location.
  • Another aspect of the present invention is to provide an imaging system for visualizing the distal tip of the drug delivery device at the target intracranial location.
  • a third aspect of this invention is to provide for an MR-compatible and visible device that significantly improves the efficacy and safety of intracranial drug delivery using MR guidance.
  • a fourth aspect of the present invention is to provide for interactive MR imaging of injected or infused MR-visible drug agents superimposed upon diagnostic MR images of the local intracranial anatomy.
  • a fifth aspect of the present invention is provide an MR imaging method for quantitative monitoring of the spatial distribution kinetics of a drug agent injected or infused from a drug delivery device into the central nervous system, in order to determine the efficacy of drug delivery at various intracranial target sites.
  • a sixth aspect of the present invention is to provide an MR imaging method to evaluate how the spatial distribution kinetics of a drug agent injected or infused from a drug delivery device into the central nervous system is influenced by infusion pressure, flow rate, tissue swelling and other material properties of the brain, and by the physicochemical nature of the drug agent infused.
  • FIG. 1 is a schematic of the drug delivery device illustrating an exemplary method of practicing the present invention.
  • FIG. 2 is a cross-sectional view of the preferred embodiment of the drug delivery device, shown on a platform located above an anatomically targetted site in the brain.
  • the view shows the disposition of a pump or reservoir containing the injectable material in relation to the other components of the device.
  • FIGS. 3 A and 3B illustrate the preferred arrangement of the individual delivery catheters within the assembly of the multi-lumen delivery device.
  • FIG. 4 is a further cross-sectional view of the preferred embodiment of the device which shows the disposition of R.F microcoil elements along the distal shaft of the delivery device.
  • FIG. 5 is an elevated cross-sectional view of the preferred embodiment of the device showing the disposition of the individual tubular probes at the distal tip of the delivery device.
  • FIG. 6A, 6B and 6C are side elevational views of the preferred embodiment of the device illustrating the relationship between the R-F microcoils and individual tubular components of the distal tip of each drug delivery catheter.
  • FIG. 7 is a flowchart of the MR imaging methods used to establish the position and orientation of the delivery device, and to track the spatial distribution kinetics of a material injected or infused from the delivery device into tissue.
  • FIG. 8 illustrates how the method of the invention is used to track the spatial distribution kinetics of different drug agents based on their signal intensity decay profiles following injection into a homogeneous cavity in the brain extracellular compartment.
  • FIG. 9 illustrates how the method of the invention is used to track the spatial 10 distribution kinetics of different drug agents based on their respective signal intensity decay profiles following injection into the heterogeneous extracellular space of the brain.
  • FIG. 10 illustrates how the method of the invention is used to track the spatial distribution of a drug agent that is injected into heterogeneous brain tissue comprised of 5 nerve cells and nerve fibers.
  • FIG. 11 illustrates how the method of the invention is used to track the spatial distribution of a drug agent injected into the region of a brain tumor.
  • newer medical treatments may include procedures which remove unwanted deposits of materials with an expectation that the removal will be assisted by physical removal (by a withdrawal system) or natural bodily function removal (e.g., the circulatory system), or which may attempt to stimulate the body to produce natural chemicals (of which a patient may be deficient) at an increased rate (e.g., electrical stimulation to increase the production of dopamine). Because these procedures are usually highly invasive, it would be extremely desirable to have a real time indication of immediate, transient and persistent effectiveness of the procedure.
  • the basic operation of the present invention therefor involves the initial MR imaging observation of a molecular environment of a patient (e.g., a particular area or region of a patient, such as tissue, particularly such tissue as that present in organs or systems of animal bodies and especially the human body, including, but not limited to the intracranial compartment and the various anatomic regions of the brain, including the cerebral ventricles, cisterns, epidural and subdural spaces, sinuses, and blood vessels, the spinal cord, including disks, nerves and associated vascular system, the heart and the coronary vascular circulation, liver and the hepatic vascular circulation, kidney and the renal vascular circulation, spleen and the splenic vascular system, gastrointestinal system, special senses, including the visual system, auditory system, and olfactory system endocrine system including the pituitary gland, thyroid gland, adrenal gland, testes, and ovaries, with observation of an MR image signal intensity at a given time and/or state (e.g.,
  • the distribution of the material in the tissue is determined by releasing an amount of the material through a drug delivery device positioned in the tissue, allowing the material to diffuse in the tissue, and analyzing the resulting MR signal intensity.
  • a drug delivery device positioned in the tissue
  • the MR image of the molecular state within the same general area is observed. Changes in the characteristics, properties or quality of the image, such as the image signal intensity within the area are presumptively (and in most cases definitively) the result of the introduction of material into the original molecular environment and alteration of the
  • the change in MR image signal intensity qualities can be related to the change in material concentration between times T, and T2, whether that change is from a starting point of zero concentration or from an existing concentration level.
  • the observations therefore relate to the actual delivery of material into the molecular environment in an observable, and to some lesser degree, quantifiable manner.
  • a device useful in medical procedures comprising an electrode electrically connected to a signal sending system or a signal receiving system, and a drug delivery system comprising material delivery system comprising a source of material that can be delivered from the device to a site within a pateint, the electrode having a signal sending capability and/or signal receiving capability distinct from the material delivery delivery system.
  • the electrode in addition to the signal sending capability and/or signal receiving capability distinct from the material delivery delivery system, may transmit signals useful in altering a rate of material delivery in the material delivery system.
  • the signal sending capability and/or signal receiving capability may be distinct from the material delivery delivery system and the b) material delivery system may operate in an electrically parallel or serial mode.
  • the signals useful in altering a rate of material delivery in the material delivery system may be electrical signals that modify a rate delivery function of a material dehvery device, as by modifying a) the rate delivery function as a mechanical function of material delivery (e.g., a pump, a variable dimensioned orifice, sliding overlays of pores, etc.), b) an iontopheresis function of material delivery, or a thermally activated function of material dehvery (e.g., the viscosity of a material is altered, changing its flow rate, the temeprature of a carrier is altered (e.g., softened or even melted) to alter a rate of rlease from the carrier, the trnsmission properties of a carrier are thermally altered, the absorption properties of a carrier or absorber are thermally altered, etc.
  • a rate delivery function as a mechanical function of material delivery (e.g., a pump, a variable dimensioned orifice, sliding overlays of pores, etc.),
  • One of the various methods for practice of the present invention could comprise: a) observing by Magnetic Resonance Imaging a visible image within an area or volume comprising tissue of the living patient, the area or volume including the device of the invention, b) delivering at least some material by the device into the area or volume comprising tissue of a living patient, c) observing a change in a property of the visible image of an area or volume comprising tissue of a living patient while the device is still present within the area or volume.
  • This method could have the change in a property of the visible image is a change in signal intensity of the visible image and could have the observing performed in real time or near (within less than 10 seconds) real-time or at intervals or periodically.
  • the process may be used to estimate a rate of material delivery within the area or volume of tissue, as by an apparent image change observed within the area or volume.
  • the process may initiate changes in a procedure, particulalrly by the device being relocated to improve dehvery of material to a desired location.
  • there may be a propagation of material mass flow into the area or volume of tissue from the material dehvery device, and the propagation of material mass flow may be observed in real time or near real-time to observe delivery of the material to tissue within the area or volume of tissue.
  • a system for practicing the invention might comprise: a) a magnetic resonance imaging system comprising a magnetic resonance source, a magnetic resonance signal reader capable of reading magnetic resonance amplitude, and a device according to the invention, said system providing a visible image of a magnetic resonance signal from the magnetic resonance signal reader, b) the device can be placed within tissue of a living patient and observed within the tissue of a living patient by magnetic resonance imaging, and c) a source of material to be delivered by the device attached to the device so that at least some of the material may be delivered by the device, the material comprising material which affects the amplitude of an MR signal in an aqueous solution.
  • the system might have the material delivery device comprise at least one devive selected from the group consisting of A) a catheter assembly comprising at least two lumens;
  • the system might also comprise an element (e.g., an iontophoretic element) capable of providing a charge as part of the device.
  • the charge when provided by the charge providing element, is at a location on the device which assists in orienting of ionic material being delivered by the device within an area electrostatically near a point of release of the material from the device. For example, this could be effected where a charge providing element is present to deliver electrical charge onto the device electrostatically near a point of release of the material from the device and the charge providing element is electrically connected to the electrode.
  • Another method for observing the increase of material within aqueous environments or tissue in a living patient comprises the steps of: a) observing by Magnetic Resonance Imaging a visible image within an area or volume comprising tissue of the living patient, the area or volume including the device of the invention, which device can be observed by Magnetic Resonance
  • Imaging b) causing by the device at least some material which causes an alteration in the magnetic response of water in which the material is dispersed or dissolved to increase its concentration within the area or volume comprising an aqueous environment or tissue of a living patient, c) observing a change in a property of the visible image of an area or volume comprising tissue of a living patient while the device is still present within the volume, d) observing a change in a property of the visible image after the device has been moved from within the area or volume of tissue.
  • the medical device may stimulate a part of the patient to increase or decrease its production of a chemical whose presence in water causes a change in a property of the visible image.
  • Another type of medical device could comprise at least electrode and at least one medical-procedure-functional element in addition to the electrode, the electrode having A) a distal function providing a task selected from the group consisting of sending an electrical signal and receiving an electrical signal, and a proximal function selected from the group consisting of delivering an electrical charge or sensing an electrical singnal, respectively, and B) a second proximal function of delivering material to a site within a patient.
  • Such a device could be constructed of materials that are compatible with use of the device under MR imaging.
  • the device could comprise a catheter having both the electrode and a drug delivery lumen system or a third function within the device could comprises at least one pair of microcoils, as where the at least one pair of microcoils comprises at least two microcoils which are spaced apart from each other to provide a volume of response around the medical device which can assist in providing magnetic resonance imaging signals to analyze for magnetic resonance images within the volume.
  • a hollow lumen may be present within the device and the hollow lumen could comprise a core of the device around which at least two other distinct components are physically attached to the core, the at least two other distinct components selected from the group consisting of radiation transmitting elements, thermal transmission elements, thermal generating elements, and fluid transport elements.
  • a magnetic resonance imaging system comprising a magnetic resonance source, a magnetic resonance signal reader capable of reading magnetic resonance amplitude, and an imaging device capable of providing a visible image of a magnetic resonance signal from the magnetic resonance signal reader
  • a material dehvery device comprising the device of claim 1 which material delivery device can be placed within tissue of a living patient and observed within the tissue of a living patient by magnetic resonance imaging
  • the material dehvery device comprising a catheter system for delivering fluid to a selected site within a tissue comprising:
  • the catheter having a distal and a proximal end, the catheter comprising a first tubular portion and a second tubular portion, the first tubular portion being made from a relatively impen-neable material and having a lumen, the second tubular portion having an open end disposed within the distal end of the lumen and a closed eiria disposed distally of the distal end of the lumen, the second tubular portion being made of a porous material having a semi-permeable membrane with pre-selected molecular weight exclusion that permits fluid to flow through the lumen and out of the catheter through the second tubular portion into the tissue, the semi-permeable membrane being adapted to provide for complete irrigation of any anatomically extensive tissue region.
  • the change in the signal e.g., the change in the amplitude of the MR signal in the visible image may be altered by: a) a change in the apparent diffusion coefficient (ADC) of tissue water protons; b) a change in tissue magnetic susceptibility (BO); c) a change in Tl tissue relaxivity (T 1 ) ; d) a change in T2 tissue relativity (T2); e) a change in tissue magnetization transfer coefficients (MTC); f) a change in tissue chemical shift frequency; g) a change in tissue temperature; or h) a combination of any one or more of a) - g) alone or with other effects.
  • ADC apparent diffusion coefficient
  • BO tissue magnetic susceptibility
  • T 1 Tl tissue relaxivity
  • MTC tissue magnetization transfer coefficients
  • g) a change in tissue temperature or h) a combination of any one or more of a) - g) alone
  • the association of an electrode in combination with the material 9especially dru) dehvery function could be done in numerous ways.
  • the cathode could leak energy (electrical or thermal) into the drug release functionality to promote or alter material delivery.
  • the cathode could serially or in parallel power the drug delivery function.
  • the electrode is carrying signals from the proximal treatment site, the voltages would be generally lower than where delivering electrical stimuli to the treatment site. In the former, leakage stimulation of iontopheresis would seem more appropriate, while in the latter condition, serial or parallel control of a rate dehvery function (alone or in combination with other (e.g., RF) signals would appear more appropriate.
  • the MR signal is dephased by the random motion of diffusing water molecules, and the presence of the delivered material locally affects the degree to which the amplitude of the signal is altered by the dephasing. If the amount of active ingredient to be delivered is quite small, or the effect of that material on the alteration of the amplitude is minimal, the delivered material may be associated with a larger amount of a second material or another more NM signal responsive material, which are preferably selected on a basis of similarity in diffusion rates through like materials or at least comparable (mathematically relatable) diffusion rates. In this manner, using such a taggant material, the diffusion of the delivered material may be assumed to relate to the diffusion/delivery of the taggant material.
  • taggant materials may be readily provided as non-toxic, inexpensive taggant materials since there is such a wide variety of materials which could be so used, and their only ftmctional requirements would be diffusion rate and non-toxicity. Many dyes commonly used in medical procedures could be used for this purpose.
  • MR-visible drug delivery device combined with NM- visible chemical or drug agents would make it possible to obtain near real-time information on drug delivery during inter-ventional procedures in an intra-operative MR system, as well as for pre-operative and post-operative confirmation of the location of the drug delivery device.
  • Medical and surgical applications would include vascular surgery and interventional radiology, cardiac surgery and cardiology, thoracic surgery and radiology, gastrointestinal surgery and radiology, obstetrics, gynecology, urology, orthopedics, neurosurgery and neurointerventional radiology, head and neck surgery and radiology, ENT surgery and radiology, and oncology.
  • the method of the invention applies to drug delivery via intraluminal, intracavitary, laparoscopic, endoscopic, intravenous, intraarterial applications.
  • small ions as well as macromolecules in the treatment of various neurologic diseases.
  • To be effective, such molecules must be able to reach target tissue receptors.
  • Many molecules that are used in therapeutic drugs are large in size, for example, neuroleukin, a neuromodulator drug tested for treatment of amyotrophic lateral sclerosis is about 56 kDa, bethanechol chloride used in treatment of Alzheimer's Disease is about 196 kDa and nerve growth factor is about 13 kDa.
  • Diffusion of drug and/or water protons in a complex medium is influenced by numerous factors. Materials injected into the brain or spinal cord do not move unimpeded through the aggregations of neurons, glia, capillaries, and nerve fibers.
  • the distribution of a drug volume in the brain cell microenvirom-nent following injection directly into brain tissue is governed by a number of factors including the physicochemical characteristics of the drug, capillary uptake, metabolism, excretion, size of the extracellular space (the volume fraction), and geometry of the brain cell microenvironment (tortuosity).
  • the degree to which each of these factors influences the distribution of a particular drug agent within the brain or spinal cord is an important determinant of the effectiveness of drug treatment of diseases of the central nervous system.
  • the mean free path of an ion at the typical ionic strength of the mammalian nervous system is only about 0.01 nm.
  • Tl, T2, MTC magnetic susceptibility
  • water proton diffusion anisotropy water proton diffusion anisotropy
  • chemical shift frequency chemical shift frequency
  • temperature temperature of the protons within each imaged voxel. This represents the distance traveled between collisions with other molecules. Almost all these collisions actually take place with water molecules since the concentration of water is 55 M.
  • ions intrinsic to the brain rarely encounter cell membranes and generally behave as though they were in a free medium.
  • the diffusivity proper-ties becomes much more complicated when the boundary has a complex geometry, or when macromolecular interactions involve exogenous solutions injected into tissues.
  • D the diffusion coefficient
  • ADC* D / tortuosity factor 2
  • the source strength is divide by the volume fraction of the extracellular space so that a given quantity of released material becomes more concentrated than it would have been in a free medium.
  • tortuosity and volume fraction are essentially dimensionless factors that depend only on the geometrical constraints imposed by local structures.
  • k' a third factor, non-specific uptake, is present in the diffusion equation as a term, k', for loss of material across the cell membranes.
  • k' can be expressed as P (S) / volume fraction, where P is the membrane permeability and (S) is the volume average of the membrane surface area.
  • Complex local boundary conditions imposed by cell membranes can thus be removed by averaging the local diffusion equations and boundary conditions over some characteristic volume of tissue a few micrometers in extent.
  • the source term becomes q/tortuosity in a complex medium while the diffusion coefficient ADC is modified to be ADC/volume fraction 2 in the new equation, which is the apparent diffusion coefficient.
  • Diffusion has been determined employing radioactive or fluorescent tracers, in which the concentration profiles of the tracer are monitored over time, and its diffusivity is inferred from the data. Microscopic displacements can be seen with tracers on the scale of millimeters. Spatially resolved methods, such as infrared spectroscopy or Rayleigh scattering, have been used allowing resolution in the micrometer range. Such tracer techniques have been successfully applied in biological systems, such as the brain. However, because of the inherent invasiveness of using exogenous tracers, such techniques cannot be used in vivo with humans.
  • Biophysical J., 1993; 65, pp. 2277-2290 yields an apparent diffusion coefficient from digitized images, and enables precise determination of the diffusion characteristics of fluoreseently labeled compounds of high molecular weight.
  • the generalized equations disclosed by Nicholson and Tao have two nondimensional factors that incorporate the structure of the tissue into the imaging solution. The first factor, the tortuosity, accounts for the hindrance to extracellular diffusion that arises from the obstructions presented by cell membranes.
  • the second structural factor is the volume fraction, which is defined as the ratio of the volume of the brain extracellular microenvironment to the total volume of tissue averaged over some small reference domain.
  • Molecular water-proton diffusion is caused by thermally induced random Brownian motion.
  • D diffusion coefficient
  • the diffusion process is continuous, so that the average displacement of any population of water protons increases with MR imaging time.
  • the diffusion behavior of protons can be hindered by impermeable or semi-permeable barriers, such as cell membranes, and macromolecules, which may themselves contain populations of diffusing protons.
  • Molecular size, shape, microenvironment, and temperature all influence the diffusion rate of molecules. Generally, larger molecules will translate (diffuse) more slowly than smaller molecules, such as water protons, and the differences in diffusion rates between different populations of molecules can be distinguished by signal intensity differences on diffusion-weighted MR images, particularly MR images which employ large diffusion gradients (b values). Thus, the measurable diffusion of smaller versus large molecules with MR imaging can be used as an in vivo tracer to probe the structural orientation of the tissues into which the drug agent has been injected. Advances in diffusion-weighted MR imaging have been made possible by major technical improvements in MR scanner hardware and software. High-speed MR echo- planar imaging now enables subsecond diffusion-sensitive imaging of water proton behavior in brain and spinal cord.
  • MR-visible molecules may exist in a variety of environments in brain tissue, which modify the way in which the molecules can move.
  • the space in which the molecules can move may be small (e.g., intracellular) or large (e.g., an enlarged extracellular space).
  • the amount of dissolved compounds and proteins may alter the viscosity of the substance injected into the tissue.
  • the random movement of the molecules is characterized by its diffusion coefficient ADC as the mean square distance moved for unrestricted isotropic (i.e. same in all directions) diffusion (for example a large sample of pure water).
  • ADC is high in pure water, and lower by about a factor of 10 in tissue. As tissue becomes destroyed by disease processes, ADC is expected to rise toward its free water value.
  • Diffusion-weighted imaging in which field gradients are applied to attenuate the signal from rapidly diffusing water, shows increased image intensity in areas of low ADC.
  • the presence of a drug in tissue, or its transport through tissue extracellular, intercellular or intracellular microenvirom-nents will also alter the magnetic susceptibility, Tl, T2, MTC, water proton diffusion anisotropy, chemical shift frequency, and temperature of protons within each imaged voxel.
  • the medical treatment and the medical device used in the practice of the present invention may also be a diagnostic device rather than only a treatment device.
  • a diagnostic device for example, there are numerous diseases which alter the thickness of specific layers or coverings within the body, such as the myelin around nerves.
  • the present invention provides a diagnostic tool to the degree that alterations in the thickness or existence of coatings such as myelin will alter the transport of chemical from one part of the body to another.
  • the administration of chemicals into an area under MR imaging guidance according to the present invention can enable viewing of the variations in the rate of migration or transport of these observable chemicals to different areas of the myclinated nerve.
  • the degree of advance of the disease can thus be observed, and it is possible to diagnose or even quantify the stage of the disease more acutely and comparatively within a given patient.
  • a chemical material would be introduced into the patient, and the relative movement of that chemical through supposedly similar structures in the area could be observed.
  • FIGS. 1 and 2 illustrate an MR-compatible drug delivery device made in accordance with the most preferred embodiment of the present invention.
  • a variable- length concentric MR-visible multi-lumen catheter 4 is formed by extruding a tubular assembly with both porous 4b and non-porous 4a tubular components,
  • the non-porous tubular component 4a is made of MR-visible elastomeric hydrogel, various polymeric compositions including polyvinylchloride, polyacrylonitrile, polyvinylidene fluoride, polystyrene, polyurethane, and polyamides, or other similar low friction material intended to minimize abrasive damage to the brain during insertion.
  • One or more of the tubing conduits 2, 2a, 2b in the multi-lumen catheter are connected to a pump 3, 3a,
  • each porous tubular component 4b has a dialysis probe 17 with a variable molecular weight cut-off membrane 18 which permits unimpeded movement of cerebrospinal fluid, small ions, and small molecular weight drugs, but is substantially impermeable to blockage by cellular material, said semipermeable membrane having a molecular weight exclusion of approximately 100-200 kD.
  • the dialysis membranes can be made of regenerated cellulose hollow fiber tubing, as well as various polymeric compositions including polyvinylehloride, polyacrylonitrile, polyvinylidene fluoride, polystyrene, polyurethane, polyamides, cellulose acetates and nitrates, polymethylmethacrylate, polysulfones, polyacrylates, and derivatives, copolymers and mixtures thereof.
  • the inlet tubing of the dialysis probe is connected to a microinjection pump 3 or reservoir 1 providing a flow of 0.1-10 ml/minute of drug solution or sterile Ringer's solution perfuming the inside of the probe.
  • the outlet tubing 2a is connected to a section of plastic tubing leading to a collection vial 3 a.
  • Regenerated cellulose hollow fiber dialysis tubing is cemented into the distal end of the plastic tubing with clear epoxy or other MR-compatible bonding material.
  • the dialysis fiber (Spectra/Or; Spectrum Medical) or other similar commercially available semi-permeable membrane has a nominal molecular weight cut-off of 100-200 kD, an I.D. (interior diameter) of 5- 50 micrometers and a membrane length of 1-10 mm.
  • the outlet tubing 2a is incorporated into the probe into the dialysis chamber 1 via a small perforation in the inlet tubing.
  • the outer tubing consists of 5-10 cm length of flexible fused silica tubing (Polymicro Technologies). These probes are inexpensive and easy to construct, and the small o.d. (Outside diameter) minimizes the tissue damage.
  • the concentric design makes it simple to implant the probe into different intracranial locations.
  • active MR visualization of drug delivery is achieved by means of one or more RF microcoils 9, 9a, 10, 10a positioned along the longitudinal axis of the device 4.
  • an RF coil consisting of a circular loop of gold or other conductive material 9 positioned around the widest part of the drug delivery device, which would project the field-of vision (FOV) furthermost into the tissue.
  • FOV field-of vision
  • single microcoils may be used separately or may be constructed in an array that may be used together to optimally image the surrounding tissue structure and contrast.
  • the coil material is sputter-coated onto the surface of the drug dehvery device.
  • Preferred also for very small (nanoliter or microliter) injections is a solenoid volume R-F microcoil 9a, which by design is sensitive only to the volume inside the coil, said imaging volume being directly related to the diameter of the R-F coil.
  • Another preferred MR imaging method which can be used to practice the invention is a combination of R-F microcoil and surface coil positioned on the surface of the patient's head.
  • telescoping coil 10 inside of the catheter, expanding it when one wants to image and then withdraw the coil and move on. One may see several cm with this idea.
  • Another preferred method of MR imaging involves the use of an oblong surface loop of wire at the end of a slanted drug dehvery device or along the shank of the device, thereby yielding a long FOV.
  • the transmitting coil would be the head or body volume RF coil inside of the MR imager.
  • the R-F surface coil is used only for detection purposes.
  • a preamplifier 10b positioned near the distal end of the delivery device 4 serves to amplify signals from the R-F microcoils 9, 9a, 10, 10a.
  • the medical device used in the preferred practice of the present invention for delivery of materials may vary widely with respect to its structure, being highly dependent upon the particular procedural use to which it is being intended. However, there are many features which can be common to all of the devices or which should at least be considered in the various constructions.
  • the simplest device could be a single delivery tube (catheter) which has MR responsive material in or on the composition of the tubing 19, preferably near the distal end or outlet of the delivery tube for assisting in detection by the MR imaging system.
  • the next level of simplified construction would be the presence of MR coils or microcoils 9, 9a, 10, 10a at or near the distal end of the catheter.
  • each coil acts as a detector of local MR intensity, and each coil supports a volume around the coil which is observable by MRI systems.
  • the coils may add or integrate their detectable volumes, defining a combined volume which can be efficiently observed by the MR system.
  • the coils may be located, sized, angled, or otherwise designed to provide specific MR signals and/or responses tailored to the anticipated needs of a particular procedure.
  • the invention is best practiced by employing an array of R-F microcoils, such that an image is obtained for any orientation of the drug delivery device.
  • the device may also include numerous catheter elements and/or ports and/or supplemental or independent functional elements.
  • at least two ports 21, 22 may be needed, one to carry in on chemical material and another to deliver a second distinct chemical material which is or may become desirable during a medical procedure.
  • saline solutions or specifically tailored solutions to dilute potential oversized deliveries could be desirable.
  • Some treatments may require sequences of drug dehvery or delivery of various drugs which may not be storage stable prior to delivery to a patient.
  • Separate ports 23, 24 would be desirable in those events. Additionally, ports may be used to evacuate undesirable materials which are directly or indirectly introduced by the medical procedure.
  • the withdrawal port 25 may comprise a tube with a port which can be attached to negative pressure with respect to the an opening in such a withdrawal port, thus being able to reduce liquid or small particle solids volumes within the area of the procedure.
  • the MR viewable device may be directed towards specific locations or areas and the ports targeted towards those specific areas.
  • the various ports may be marked or designed to provide distinct signals when viewed by MR systems so that they may be distinguished during perfon-nance of the procedures.
  • MR insensitive materials may be used to line a port 26 or materials with different distributions or intensities of MR response may be used in the various ports to differentiate the elements while being observed during performance of procedures.
  • a withdrawal tube 27 has openings through which materials may be withdrawn
  • the orientation of that opening within the device becomes important.
  • the position and orientation of the opening can be readily determined.
  • Particularly preferred is a 2,000-5,000 angstrom thick coating of MR-visible material along the distal shaft of the device.
  • the configuration of the different components should be tailored for a particular procedure.
  • the different components may be associated by various orientations. As illustrated in FIG. 3B, the most preferred is generally a central tube or tubes with other tubes forming a circular distribution around the central tube or tubes.
  • An MR-visible guidewire may be inserted within the device 4 to assist in positioning the device at a target anatomical location.
  • a guidewire or other structural support made of NitinolTM or other MR-compatible shape memory metal.
  • thermal elements 30 for providing heat
  • radiation carrying elements 31 e.g., ultraviolet radiation, visible radiation, infrared radiation, and even hard radiation carrying elements, such as optical fibers or other internal reflection radiation carrying systems
  • detection elements 32 e.g., pH indicators, electronic activity indicators, pressure detectors, ion detectors, thermal detectors, etc.
  • sensing or detection element which would be useful during medical procedures.
  • Procedurally inert elements such as structural supports, reinforcing elements or coatings, back-up elements, and the like, may also be present within the device.
  • Particularly preferred as structural supports or reinforcing elements are circumferential bands of Nitinol or other MR-compatible shape memory metals 35 which, when activated, can facilitate accurate directed placement of the functional tip of the device.
  • a central core element my comprise a single tube for dehvery of a material, a pair of tubes for delivery of two chemicals, a delivery and withdrawal tube, or a procedurally inert structural support element 11.
  • a central core element may be disposed multiple additional elements 21-27, usually seeking as near to a circular distribution about the central core as geometries allow. The attempt at the circular distribution is primarily for purposes of optimizing a small size for the diameter of the article, and is not necessarily a functional aspect to the performance of the device.
  • the MR responsive materials may be located within the central core 33, around the central core 34 (beneath any next layering of elements), or over the elements surrounding the central core 34a. Where one or more of the elements receive, transmit or are powered by electrical signals, it is desirable that these elements be electrically separated by either or both of physical separation or additional insulation to prevent mixing or cross-transmission of signals between the distinct elements.
  • Carrying and withdrawing tubes may also secondary functions. For example, a carrying tube may be conductive (by being naturally conductive or by having a conductive coating in or outside of the tube) and the electrical connection may be associated with an electronic element or component at the distal end of the device.
  • the tube may thereby act as a carrying tube and electrical connection to the electronic component or element.
  • Structural or adhesive support materials between different elements may also provide such functions.
  • the various individual elements within the device must be structurally associated, especially away from the distal end, and during insertion, may need structural association at the distal end 11.
  • the structural support or structural integrity may be provided by some physical means of attaching the various elements. This may be done by adhesive materials between the individual elements (which adhesive should be MR compatible), fusion of the various elements, or by coextrusion of the tubes into a single unit (or single component of a multiple element device).
  • the adhesive may be an organic or inorganic adhesive.
  • the distal end of the device may have the ends of the elements temporarily or controllably bonded during insertion.
  • the adhesive could be water soluble (which would dissolve in a timely manner after insertion), solvent soluble (with solvent delivered into the distal end during a preliminary procedure, or radiation disruptable (e.g., a positive-acting resist adhesive composition which is sensitive to UV, visible or IR radiation which may be delivered through a radiation carrying port).
  • the dialysis probe is replaced by an MR-visible microcatheter 38, which is a single extrusion catheter made from one of several possible sizes of a polyethylene terephthalate proximal shaft, e.g. 30 ga.
  • 12 mm distal segment of the microcatheter drug delivery device is made of elastomeric hydrogel or similar soft material which minimizes tissue damage during insertion.
  • a plurality of semipermeable membranes 38b are placed circumferentially at regular intervals along the distal segment of the microcatheter, thus enabling wide dispersion of an injected agent, semipermeable membrane consisting of a 0. 1 8-0.22 ml millipore filter.
  • the companion microguidewire in this example is made of nitinol or similar memory metal which enables directed placement of the tip of the catheter.
  • the microguidewire 37 is threaded into a clear hub luek-lock cap 39 made of poly-methel- pentene or similar MR-compatible plastic.
  • Both the catheter and guidewire have a linearly arranged array of radiopaque and MR-visible markers 40 disposed at the distal end to provide easily identifiable reference points for trackability and localization under MR imaging and Xray fluoroscopy guidance.
  • the microcatheter can also be made from any of the wellknown soft, biocompatible plastics used in the catheter art such as Percuflex, a trademarked plastic manufactured by Boston Scientific Corporation of Watertown, Massachusetts. With further reference to FIG. 6a of the drawings, when the delivery device is positioned intracranially, the distal markers will be identifiable in an MR image and by X-rays. In another preferred embodiment, two or more R-F microcoils are placed along the distal shaft of the microcatheter.
  • the delivery device can be employed to deliver pharmacologic therapies in order to reduce morbidity and mortality associated with cerebral ischemia, intracranial vasospasm, subarachnoid hemorrhage, and brain tumors.
  • the distal tip of the multi-lumen catheter assembly is typically positioned a few millimeters above the intracranial target structure using MR imaging.
  • surface modifications of the material components of the dialysis probe 18 enable timed-release kinetics of MR-visible biologic response modifiers, including peptide macromolecules.
  • a pump or other infusion or injection device circulates a solution containing a therapeutic drug or an MRvisible contrast agent through the walls of the dialysis fiber into the brain at rates between 0.01 microliter/min to 10 microliter/min.
  • pressure ejection techniques well described in the medical literature are used to deliver a predetermined amount of a therapeutic drug agent or MR-visible contrast through one or more of the tubular components of the multi-lumen device.
  • the catheter is backfilled with the drug or contrast agent, which is functionally connected to a PicospritzerTM (General Valve Corp, Fairfield, NJ) or a similar instrument that is able to deliver pulses of nitrogen or compressed air with a duration ranging from a few milliseconds to several seconds at a pressure of 10-50 psi.
  • a pressure ejection mode of drug delivery the concentration of the released substance in the vicinity of the tip is accurately defined by the concentration of the material in the delivery device.
  • a binary solution can also be released, in that two therapeutic or diagnostic compounds can be delivered at the same time by pressure ejection of two materials from two or more separate microcatheters.
  • the MR-visible solution contains stoically stabilized liposomes, with lipophilic or hydrophilic chelators, such as polyaminocarboxylic acids and their salts, such as DTPA on phosphatidyl ethanolamine for steric acid embedded within the external bilayer, or double-label liposomes that chelate a T2-sensitive metal ion within the internal aqueous space and another Tl -sensitive metal ion on the outside membrane surface, or liposomes which contain 100-1000 airbubbles, such as argon, carbon dioxide, or air, as a contrast agent.
  • R-F microcoils 41a-f are positioned at the distal ends of individual dehvery tubes, said microcoils acting as local MR detectors.
  • the implantable MR-visible multilumen catheter includes in another tubing conduit a hydrocephalus pressure valve IC and self-sealing port ID preferably made of Nitino, Tm or other similar MR-compatible material for regulating the flow of cerebrospinal fluid through the catheter after placement of the catheter tip into cerebral ventricle or other intracranial fluid compartment under MR imaging guidance.
  • a hydrocephalus pressure valve IC and self-sealing port ID preferably made of Nitino, Tm or other similar MR-compatible material for regulating the flow of cerebrospinal fluid through the catheter after placement of the catheter tip into cerebral ventricle or other intracranial fluid compartment under MR imaging guidance.
  • the implantable MR-visible multilumen catheter also includes in another tubing conduit a metabolic biopsy microcatheter which is used to collect and measure the number of small molecules present in the extracellular fluid, including energy-related metabolites, such as lactate, pyruvate, glucose, adenosine, and inosine, and excitatory amino acids, such as glutamate and aspar-tate, in a separate reservoir 3b.
  • energy-related metabolites such as lactate, pyruvate, glucose, adenosine, and inosine
  • excitatory amino acids such as glutamate and aspar-tate
  • MR imaging is used to differentiate normal brain tissues from various pathologic conditions, including solid brain tumor, abscess cavity, edema, necrotic infarcts, reversibly ischemic infarcts, demyelination, and hemorrhage, based on the characteristic ADC of these tissue pathologies already well established in the medical literature.
  • a sequence of MR images are collected over a period of time t, which is preferably ⁇ 100 min and > 10 sec.
  • the MR intensity distribution and spatial variation of the calculated ADC of the tissue volume undergoing MR imaging prior to drug delivery is compared with the ADC in the same region following drug delivery in order to determine the efficacy of drug delivery to the targeted intracranial loci.
  • an express objective of the present invention is to evaluate the efficacy of MR image-guided drug delivery by measuring restricted diffusion with localized MR pulse sequences.
  • modeling of restricted diffusion is used to estimate the size of the diffusion spaces and the permeability of the barriers to drug agents injected into the brain microenvironment.
  • a conventional imaging sequence is repeated with field gradients of increasing strength or duration. The signal decays away exponentially as e -bD , where b depends on the strength, duration and timing of the diffusion-sensitizing gradients.
  • the diffusion gradients make the sequence extremely sensitive to motion.
  • a navigator echo technique, or its variants are used to suppress the contaminating effects of patient motion on the ADC measured with MR imaging.
  • high speed echoplanar imaging is used without movement artifact.
  • localized measurements of the ADC, ABO, TI, T2, MTC, chemical shift frequency, and temperature are acquired from images produced from single-shot or multi-shot stimulated echo (STEAM), gradient echo (GRE or FLASH), or fast spin-echo (FSE) MRI sequences.
  • STEAM single-shot or multi-shot stimulated echo
  • GRE gradient echo
  • FSE fast spin-echo
  • a 1.5 tesla, 80 - cm- bore MR imager with actively shielded gradients of at least 20 mT/m is used to acquire axial diffusion-weighted echoplanar images through a volume of brain tissue one slice at a time, with separate apphcation of diffusion gradients in three orthogonal directions.
  • Trapezoidal diffusion gradients are apphed in the vertical (anterior-posterior) direction, and phase-encoding gradients are applied in the horizontal (left-right) direction.
  • a 5-cm field-of-view and 200-kHz continuous readout sampling is preferred, which requires a plateau readout gradient of 12 mT/m.
  • readout gradient trapezoids with 320-microsecond ramps and 640 microsecond plateaus, resulting in 1.28-miUisecond readout lobes and 82- millisecond total readout time.
  • the spin echo is placed coincident with the zero-phase- encoded gradient echo.
  • Diffusion-weighted images are preferably acquired as 16 contiguous 1.5 mm slices at I slice per second in an interleaved order to minimize magnetization transfer and shce cross-talk effects.
  • At least four diffusion strength, preferably b 10, 207, 414, and 621 S/mm 2 , should be applied separately in each primary orthogonal direction.
  • Reference scans are acquired without phase-encoding gradients to allow correction of echo position and phase before Fourier transformation reconstruction, to minimize image ghosts.
  • a total of 384 diffusion-weighted echo-planar scans are acquired in approximately 6.4 minutes.
  • the resulting 128 x 128 images are reconstructed by two-dimensional Fourier transformation. Nominal image resolution is mm x 2.1 mm x 5 mm, giving a 17- microL nominal voxel.
  • a therapeutic drug agent is injected from an MR visible drug delivery device into the intraparcnchymal extracellular space ofthe brain.
  • the solution containing the macromolecular drug agent may either form a cavity or infiltrate the extracellular space depending on a number of factors.
  • subsequent diffusion is governed by the volume fraction (extracellular or pore fraction), the tortuosity of the brain tissue (apparent increase in path length of the diffusing particle), and the diffusion coefficient of the substance itself.
  • a finite and specified concentration of the substance with a finite and specified volume is deposited in the tissue in a period that is effectively instantaneous (i.e. « time-scale of subsequent diffusion measurements).
  • the injected volume of substance can exhibit at least two distinct behaviors disclosed by MR imaging in the method of the present 5 invention.
  • the injected volume can form a fiuidfilled cavity in the tissue, within which the volume fraction and tortuosity take the value of unity which corresponds to a free aqueous solution.
  • the brain tissue has a volume fraction and tor-tuosity.
  • diffusion as a _10 function of distance from the injected substance can be represented as a series of curves denoting the concentration as a function of distance from the center of the cavity at successive time intervals. Different drug agents will diffuse at different rates thereby yielding characteristic individual signal intensity delay curves on MR imaging.
  • each agent is related to its molecular weight, molecular radius, and the tissue matrix structure into which the material is injected. Throughout the whole brain tissue, the diffusion behavior is governed by the volume fraction and tortuosity and no discontinuity exists.
  • MR visualization of a drug agent injected into a region of nerve fibers in the brain or spinal cord is performed with diffusion-weighted anisotropic MR imaging.
  • anisotropic imaging a 3 x 3 matrix (tensor) is used, and the signal loss is measured for at least six directions of diffusion gradient.
  • the matrix can be transformed to one that is independent of the directions along which the gradients were - -30 applied, and therefore of the orientation of the patient in the magnet.
  • two measurements are of particular interest. First, the trace of the tensor (i.e. the sum of the diagonal elements) is relatively uniform throughout normal brain, despite its anisotropic structure. It can be thought of as the diffusion coefficient averaged over all directions.
  • an anisotropy index such as the ratio of the diffusion coefficient in the most freely diffusible direction to that in the least freely diffusible, is highly sensitive to the directionality of the tissue structure.
  • the voxel size should be small enough so that there is no averaging of directions within the voxel. Loss of tissue structure is likely to decrease the anisotropy, as the tissue becomes more like a homogenous suspension. Clinical observations of changes in diffusion behavior have been made in multiple sclerosis, in stroke, where the reduction in diffusion precedes the increase in T2, and in experimental epilepsy.
  • a catheter system for delivering fluid to a selected site within a tissue comprises a pump for delivering the fluid and a catheter coupled to the pump.
  • the catheter comprises a first tubular portion that has a generally cylindrical lumen of a first internal diameter and is composed of a relatively impermeable material.
  • a second tubular portion that has an open end is disposed within the lumen and a closed distal end is disposed without the lumen.
  • the second tubular portion is composed of a flexible, porous material having a preselected microporosity that is operable to permit fluid to flow from the catheter into the tissue.
  • the second tubular portion is selectively moveable with respect to the first tubular portion.
  • a catheter for delivering fluid to a selected site within a tissue comprises a first tubular portion that has a generally cylindrical lumen of a first internal diameter and is composed of a relatively impermeable material.
  • a second tubular portion that has an open end is disposed within the lumen and a closed distal end is disposed without the lumen.
  • the second tubular portion is composed of a flexible, porous material that has a semipermeable membrane with pre-selected molecular weight exclusion that is operable to permit fluid to flow from the catheter into the organism.
  • the second tubular portion is selectively moveable with respect to the first tubular portion.

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  • Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • General Physics & Mathematics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Pathology (AREA)
  • Radiology & Medical Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Magnetic Resonance Imaging Apparatus (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne un appareil et un procédé de traitement et d'administration ciblée de médicaments sur un patient vivant, notamment mais non exclusivement en utilisant l'imagerie par résonance magnétique. Cet appareil et ce procédé, qui conviennent pour l'administration de tous types de tissus vivants, font appel à l'imagerie par résonance magnétique afin de suivre les médicaments administrés et d'en estimer la vitesse. Un dispositif d'administration de médicaments visible par résonance magnétique positionné sur un site cible (par exemple, administration intracrânienne) administre au tissu (par exemple, le cerveau) une solution médicamenteuse diagnostique ou thérapeutique. La cinétique de distribution spatiale de l'agent médicamenteux injecté ou infusé est surveillée de manière quantitative et non invasive en utilisant l'imagerie par résonance magnétique à diffusion directionnelle protonique par l'eau afin de déterminer l'efficacité de l'administration de médicaments sur un point ciblé.
EP01931071A 2000-05-08 2001-05-04 Procede et appareil destines a etre utilises avec une electrode active et un catheter d'administration de medicaments Withdrawn EP1280456A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US09/566,798 US7505807B1 (en) 1997-05-15 2000-05-08 Magnetic resonance apparatus for use with active electrode and drug deliver catheter
US566798 2000-05-08
PCT/US2001/014524 WO2001085027A2 (fr) 2000-05-08 2001-05-04 Procede et appareil destines a etre utilises avec une electrode active et un catheter d'administration de medicaments

Publications (1)

Publication Number Publication Date
EP1280456A2 true EP1280456A2 (fr) 2003-02-05

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EP01931071A Withdrawn EP1280456A2 (fr) 2000-05-08 2001-05-04 Procede et appareil destines a etre utilises avec une electrode active et un catheter d'administration de medicaments

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EP (1) EP1280456A2 (fr)
WO (1) WO2001085027A2 (fr)

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Publication number Publication date
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WO2001085027A2 (fr) 2001-11-15

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