EP0981761A1 - Procede et appareil d'administration ciblee de medicament a un patient, mettant en oeuvre une imagerie par resonance magnetique - Google Patents

Procede et appareil d'administration ciblee de medicament a un patient, mettant en oeuvre une imagerie par resonance magnetique

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Publication number
EP0981761A1
EP0981761A1 EP98921222A EP98921222A EP0981761A1 EP 0981761 A1 EP0981761 A1 EP 0981761A1 EP 98921222 A EP98921222 A EP 98921222A EP 98921222 A EP98921222 A EP 98921222A EP 0981761 A1 EP0981761 A1 EP 0981761A1
Authority
EP
European Patent Office
Prior art keywords
tissue
delivery device
volume
area
magnetic resonance
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Withdrawn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
EP98921222A
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.)
University of Minnesota
Original Assignee
University of Minnesota
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 US08/857,043 external-priority patent/US6026316A/en
Priority claimed from US08/856,894 external-priority patent/US6061587A/en
Application filed by University of Minnesota filed Critical University of Minnesota
Publication of EP0981761A1 publication Critical patent/EP0981761A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
    • 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
    • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
    • A61M31/005—Devices for introducing or retaining media, e.g. remedies, in cavities of the body for contrast media
    • 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
    • A61M25/0021—Catheters; Hollow probes characterised by the form of the tubing
    • A61M25/0023—Catheters; Hollow probes characterised by the form of the tubing by the form of the lumen, e.g. cross-section, variable diameter
    • A61M25/0026—Multi-lumen catheters with stationary elements
    • A61M2025/0034—Multi-lumen catheters with stationary elements characterized by elements which are assembled, connected or fused, e.g. splittable tubes, outer sheaths creating lumina or separate cores
    • 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
    • A61M25/0021—Catheters; Hollow probes characterised by the form of the tubing
    • A61M25/0023—Catheters; Hollow probes characterised by the form of the tubing by the form of the lumen, e.g. cross-section, variable diameter
    • A61M25/0026—Multi-lumen catheters with stationary elements
    • A61M2025/0036—Multi-lumen catheters with stationary elements with more than four lumina
    • 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
    • A61M25/0021—Catheters; Hollow probes characterised by the form of the tubing
    • A61M25/0023—Catheters; Hollow probes characterised by the form of the tubing by the form of the lumen, e.g. cross-section, variable diameter
    • A61M25/0026—Multi-lumen catheters with stationary elements
    • A61M2025/004—Multi-lumen catheters with stationary elements characterized by lumina being arranged circumferentially
    • 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
    • A61M25/0043—Catheters; Hollow probes characterised by structural features
    • A61M2025/0057—Catheters delivering medicament other than through a conventional lumen, e.g. porous walls or hydrogel coatings
    • 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
    • A61M25/0067—Catheters; Hollow probes characterised by the distal end, e.g. tips
    • A61M25/0068—Static characteristics of the catheter tip, e.g. shape, atraumatic tip, curved tip or tip structure
    • A61M2025/0073—Tip designed for influencing the flow or the flow velocity of the fluid, e.g. inserts for twisted or vortex flow
    • 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
    • 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
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/563—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution of moving material, e.g. flow contrast angiography

Definitions

  • This invention relates to the design, construction, and use of 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.
  • 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 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 cerebro ventricular 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) which 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.
  • 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. 5,580,575 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.
  • Pat. 4,973,304 to 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.
  • the invention disclosed by 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.
  • 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 which 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 which 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.
  • U.S. Pat. 5,470,307 to Lindall discloses a low-profile catheter system with an exposed coating containing a therapeutic drug agent, which can be selectively released at a remote tissue site by activation of a photosensitive chemical linker.
  • the linker is attached to the substrate via a complementary chemical group, which is functionalized to accept a complementary bond to the therapeutic drug agent.
  • the drug agent is in turn bonded to a molecular lattice to accommodate a high molecular concentration per unit area and the inclusion of ancillary compounds such as markers or secondary emitters.
  • one objective of this invention is to provide for an MR- compatible and visible device that significantly improves the efficacy and safety of drug delivery using MR guidance.
  • any material that might be added to the structure of a pliable catheter to make it visible must not contribute significantly to the overall magnetic susceptibility of the catheter, or imaging artifacts could be introduced during the MR process.
  • forces might be applied to such a catheter by the superconducting magnetic manipulation coils of a nonlinear magnetic stereotaxis system which might be used in the practice of the present invention. In either case, the safety and efficacy of the procedure might be jeopardized, with resulting increased risk to the patient.
  • an MR-visible catheter must be made of material that is temporally stable and of low thrombolytic potential if it is to be left indwelling in either the parenchymal tissues or the cerebral vasculature.
  • 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 MR compatible 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.
  • all cables, wires, and devices positioned within the MR imager must be made of materials that have properties that make them compatible with their use in human tissues during MR imaging procedures.
  • Many materials with acceptable MR-compatibility such as ceramics, composites and thermoplastic polymers, are electrical insulators and do not produce artifacts or safety hazards associated with applied electric fields.
  • Some metallic materials, such as copper, brass, magnesium and aluminum are also generally MR-compatible, viz. large masses of these materials can be accommodated within the imaging region without significant image degradation.
  • 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.
  • U.S. Pat. No. 4,572,198 to Codrington also provides for conductive elements, such as electrode wires, for systematically disturbing the magnetic field in a defined portion of a catheter to yield increased MR visibility of that region of the catheter.
  • conductive elements such as electrode wires
  • the presence of conductive elements in the catheter also introduces increased electronic noise and the possibility of Ohmic heating, and these factors have the overall effect of degrading the quality of the MR image and raising concerns about patient safety.
  • the presence of MR-incompatible wire materials causes large imaging artifacts.
  • 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).
  • An improved method for passive MR visualization of implantable medical devices has recently been disclosed by Weme ( Ser. No. 08/554446) ITI Medical Technologies (Application Pending). This invention minimizes MR susceptibility artifacts, and controls eddy currents in the electromagnetic scattering environment, so that a bright "halo" artifact is created to outline the device in its approximately true size, shape, and position.
  • an ultra thin coating of conductive material comprising 1-10% of the theoretical skin depth of the material being imaged - typically about 250,000 angstroms - is applied.
  • a coating of 2,000- 25,000 angstroms thickness ITI has found that the susceptibility artifact due to the metal is negligible due to the low material mass.
  • the eddy currents are limited due to the ultra-thin conductor coating on the device.
  • a similar method employing a nitinol wire with Teflon coat in combination with extremely thin wires of a stainless steel alloy included between the nitinol wire and Teflon coat, has recently been reported in the medical literature by Frahm et al., Proc.
  • 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. Delivery of a drug from a single point source also limits the distribution of the drug by decreasing the effective radius of penetration of the drug agent into the surrounding tissue receptor population.
  • 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 (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 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.
  • ADC Apparent Diffusion Coefficients
  • ADC values are specific for specific types of tissues. Accordingly, as different drugs/chemicals are introduced into a tissue volume under MR observation, the ADC resulting from each drug/chemical interaction can be observed and the change in the ADC can be determined for that drug/chemical interaction with that particular tissue/drug environment.
  • 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), from the 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.
  • ADC alterations in the BO magnetic field
  • ABO magnetic susceptibility or ABO produced by the presence of a substance in said tissue
  • MTC magnetization transfer coefficients
  • 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 (such as that created from F- 19 or fluorine- 19 agents found in or added to the drug).
  • 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 MRI.
  • small amounts of a BO-altering added agents can be added to the drug during delivery. This can include iron oxide particles, or materials comprising lanthanide-, manganese-, and iron-chelates.
  • 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 targeted 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. 6 A, 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 I 0 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 are presumptively (and in most cases definitively) the result of the introduction of material into the original molecular environment and alteration of the MR response for regions of the envirom-nent where delivered material concentration has changed.
  • 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.
  • 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 (Tl); 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
  • Tl tissue relaxivity
  • MTC tissue magnetization transfer coefficients
  • 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.
  • 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 functional 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 realtime information on drug delivery during interventional 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.
  • 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 properties becomes much more complicated when the boundary has a complex geometry, or when macromolecular interactions involve exogenous solutions injected into tissues.
  • 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.
  • Nicholson, Biophysical J., 1993; 65, pp. 2277-2290 yields an apparent diffusion coefficient from digitized images, and enables precise determination of the diffusion characteristics of fluoresently 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.
  • Nicholson and Tao Hindered diffusion of high molecular weight compounds in brain extracellular microenvironment measured with integrative optical imaging. Biophysical J. 1993; 65:2277-2290) does not, however, yield a direct measurement of the molecular distribution in a three- dimensional sample, and furthermore requires use of large fluorescent markers which are not suitable for repeated injections in human patients.
  • 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.
  • 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- ments 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, 3b or other temporary reservoir 1, la, lb, which circulates a therapeutic drug solution or MRsensitive contrast agent through a dialysis fiber into a target tissue or pathological lesion.
  • 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.
  • 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.
  • 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 delivery 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 delivery 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 1 Ob 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. As different medical procedures are performed in different environments, with different shapes and different variations in densities, 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. For example, as illustrated in FIG. 3, 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. For example, in addition to a primary treatment chemistry being delivered, saline solutions or specifically tailored solutions to dilute potential oversized deliveries could be desirable. Some treatments may require sequences of drug delivery 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.
  • 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 performance 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. This is the simplest geometry and provides for smallest diameter sizing of the device. As illustrated in FIG.
  • 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.
  • any other sensing or detection element which would be useful during medical procedures.
  • These individual elements are each extendable to permit optimal positioning within the tissue would be configured as desired or needed for the particular procedure intended for the device.
  • 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 delivery 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.
  • 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).
  • water soluble which would dissolve in a timely manner after insertion
  • solvent soluble with solvent delivered into the distal end during a preliminary procedure
  • 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.
  • the 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 well-known 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.
  • the distal markers when the delivery device is positioned intracranially, the distal markers will be identifiable in an MR image and by X-rays.
  • 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 micro liter/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 air bubbles, such as argon, carbon dioxide, or air, as a contrast agent.
  • R-F microcoils 41a-f are positioned at the distal ends of individual delivery 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 aspartate, in a separate reservoir 3b.
  • energy-related metabolites such as lactate, pyruvate, glucose, adenosine, and inosine
  • excitatory amino acids such as glutamate and aspartate
  • 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, Tl, 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 application of diffusion gradients in three orthogonal directions.
  • Trapezoidal diffusion gradients are applied 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-millisecond 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 slice 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 of the 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 invention.
  • the injected volume can form a fluid filled 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 tortuosity.
  • diffusion as a 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.
  • two continuity conditions involving flux and concentration apply. Since the amount of material leaving the first region, per unit area of the interface, must be equal to the amount arriving at the second, the phase averages of the fluxes in the two regions must be equal.
  • the injected material does not form a cavity but instead infiltrates the extracellular space.
  • the diffusion of 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.
  • FIG. IO 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.
  • 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 applied, and therefore of the orientation of the patient in the magnet.
  • two measurements are of particular interest.
  • the trace of the tensor i.e. the sum of the diagonal elements
  • the diffusion coefficient averaged over all directions 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.

Abstract

Cette invention se rapporte à un appareil et à un procédé d'administration ciblée de médicament à un patient au moyen de l'imagerie par résonance magnétique (IRM). Cet appareil et ce procédé servent à l'administration de médicament à tous types de tissu vivant et font appel à l'imagerie par résonance magnétique pour suivre la trace du médicament administré et estimer la vitesse d'administration du médicament. Un dispositif d'administration de médicament par résonance magnétique visible, positionné au niveau d'un site cible (par exemple, en vue d'une administration intracrânienne) administre au tissu (par exemple, au tissu cérébral) une solution médicamenteuse diagnostique ou thérapeutique. La cinétique de distribution spatiale de l'agent médicamenteux injecté ou infusé fait l'objet d'une surveillance quantitative, non invasive, par IRM à diffusion directionnelle de protons dans l'eau permettant d'évaluer l'efficacité de l'administration du médicament au niveau de l'emplacement cible.
EP98921222A 1997-05-15 1998-05-15 Procede et appareil d'administration ciblee de medicament a un patient, mettant en oeuvre une imagerie par resonance magnetique Withdrawn EP0981761A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US08/857,043 US6026316A (en) 1997-05-15 1997-05-15 Method and apparatus for use with MR imaging
US857043 1997-05-15
US08/856,894 US6061587A (en) 1997-05-15 1997-05-15 Method and apparatus for use with MR imaging
US856894 1997-05-15
PCT/US1998/009942 WO1998052064A1 (fr) 1997-05-15 1998-05-15 Procede et appareil d'administration ciblee de medicament a un patient, mettant en oeuvre une imagerie par resonance magnetique

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