Method and apparatus for use with MR imaging

The invention is an apparatus and method for targeted drug delivery into a living patient using magnetic resonance (MR) imaging. The apparatus and method are useful in delivery to all types of living tissue and uses MR Imaging to track the location of drug delivery and estimating the rate of drug delivery. An MR-visible drug delivery device positioned at an target site (e.g., intracranial delivery) delivers a diagnostic or therapeutic drug solution into the tissue (e.g., the brain). The spatial distribution kinetics of the injected or infused drug agent are monitored quantitatively and non-invasively using water proton directional diffusion MR imaging to establish the efficacy of drug delivery at a targeted location.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
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. 
2. Background of the Art 
Although endoscopic, arthroscopic, and endovascular therapies have produced 
significant advances in healthcare, the diagnostic accuracy and clinical 
utility of these procedures is ultimately "surface limited" by what the 
surgeon can see through the device itself or otherwise visualize during 
the course of the procedure. Magnetic Resonance (MR) imaging, by 
comparison, overcomes this limitation by enabling the surgeon to 
non-invasively visualize tissue planes beyond the surface of the tissue 
under direct evaluation. Moreover, MR imaging enables differentiation of 
normal from abnormal tissues, and can display critical structures such as 
blood vessels in three dimensions. Thus, 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 
(&lt;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. Delivery of 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. However, following 
intracerebroventricular injection, 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, which may be up to 18 mm from a 
cerebrospinal fluid surface. 
To optimize a drug's therapeutic efficacy, it should be delivered to its 
target tissue at the appropriate concentration. A number of studies 
reported in the medical literature, for example, Schmitt, Neuroscience, 
13, 1984, pp. 991-1001, have shown that numerous classes of biologically 
active drugs, such as peptides, biogenic amines, and enkephalins have 
specific receptor complexes localized at particular cell regions of the 
brain. Placing a drug delivery device directly into brain tissue thus has 
the notable advantage of initially localizing the injected drug within a 
specific brain region containing receptors for that drug agent. Targeted 
drug delivery directly into tissues also reduces drug dilution, metabolism 
and excretion, thereby significantly improving drug efficacy, while at the 
same time it minimizes systemic side-effects. 
An important issue in targeted drug delivery is the accuracy of the 
navigational process used to direct the movement of the drug delivery 
device. 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. This real-time 
imaging capability makes it possible to use high-speed MR imaging to 
direct the movement of catheters and other drug delivery vehicles to 
specific tissue locations, and thereby observe the effects of specific 
interventional procedures. 
A prerequisite for MRI-guided drug delivery into the brain parenchyma, 
cerebral fluid compartments, or cerebral vasculature is the availability 
of suitable access devices. U.S. Pat. No. 5,571,089 to Crocker et al. and 
U.S. Pat. No. 5,514,092 to Forman et al. disclose endovascular drug 
delivery and dilatation drug delivery catheters which can simultaneously 
dilate and deliver medication to a vascular site of stenosis. U.S. Pat. 
No. 5,171,217 to March describes the delivery of several specific 
compounds through direct injection of microcapsules or microparticles 
using multiple-lumen catheters, such as disclosed by Wolinsky in U.S. Pat. 
No. 4,824,436. U.S. Pat. No. 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. No. 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. U.S. Pat. No. 5,226,902 
to Bae et al. and U.S. Pat. No. 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. No. 5,167,625 to 
Jacobsen et al. discloses an implantable drug delivery system utilizing 
multiple drug compartments which are activated by an electrical circuit. 
U.S. Pat. No. 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. U.S. Pat. Nos. 4,892,538, 4,892,538, 5,106,627, 
5,487,739 and 5,607,418 to Aebischer et al. disclose implantable drug 
therapy systems for local delivery of drugs, cells and neurotransmitters 
into the brain, spinal cord, and other tissues using delivery devices with 
a semipermeable membrane disposed at the distal end. U.S. Pat. No. 
5,120,322 to Davis et al. describes the process of coating the surface 
layer of a stent or shunt with lathyrogenic agent to inhibit scar 
formation during reparative tissue formation, thereby extending exposure 
to the drug agent. U.S. Pat. Nos. 4,807,620 to Strul and 5,087,256 to 
Taylor are examples of catheter-based devices which convert 
electromagnetic Rf energy to thermal energy. Technology practiced by STS 
Biopolymers (Henrietta, N.Y.) allows incorporation of pharmaceutical 
agents into thin surface coatings during or after product manufacture. 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. No. 5,573,668 to Grosh et al. discloses a 
microporous drug delivery membrane based on an extremely thin hydrophilic 
shell. U.S. Pat. No. 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. 
A number of articles published in the medical literature, for example, 
Chandler et al., Ann. N.Y. Acad. Sci., 531, 1988, pp. 206-212, Bouvier et 
al., Neurosurgery 20(2), 1987, pp. 286-291, Johnston et al., Ann. N.Y. 
Acad. Sci., 531, 1988, pp. 57-67, and Sendelbeck et al., Brain Res., 328, 
1985, pp. 251-258 describe implantable pump systems designed for 
continuous or episodic delivery of therapeutic drugs into the central 
nervous system via systemic, intrathecal, intracerebroventricular, and 
intraparenchymal injection or infusion. 
The 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. For example, 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. Furthermore, the binders or adhesives 
used in catheter coatings may themselves significantly dilute the 
concentration of the therapeutic agent Finally, 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. No. 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 remote tissue site by activation of a 
photosensitive chemical linker. In the invention disclosed by Lindall, 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. 
Although U.S. Pat. No. 5,470,307 to Lindall describes significant 
improvements over previous catheter-based drug delivery systems, there are 
nonetheless some problems. First, in common with other currently used 
endovascular access devices, such as catheters, microcatheters, and 
guidewires, the catheter tip is difficult to see on MRI because of 
inadequate contrast with respect to surrounding tissues and structures. 
This makes accurate localization difficult and degrades the quality of the 
diagnostic information obtained from the image. Also, the mere observation 
of the location of the catheter in the drug delivery system does not 
reliably or consistently identify the position, movement and/or efficient 
delivery of drugs provided through the system. Thus, 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 MR visible must not contribute significantly to the overall 
magnetic susceptibility of the catheter, or imaging artifacts could be 
introduced during the MR process. Moreover, 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. Also, 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. 
Examples of such 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. Consequently, 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. Pat. 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. 5,375,596 to Twiss 
et al. discloses a method for locating catheters and other tubular medical 
devices implanted in the human body using an integrated system of wire 
transmitters and receivers. 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. 
However, 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. Thus, 
in all of these examples of implantable medical probes, the presence of 
MR-incompatible wire materials causes large imaging artifacts. The lack of 
clinically adequate MR visibility and/or imaging artifact contamination 
caused by the device is also a problem for most commercially available 
catheters, microcatheters and shunts. 
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. 
Initial attempts to position and visualize endovascular devices in MR 
imaging were based on passive susceptibility artifacts produced by the 
device when exposed to the MR field. Magnetic susceptibility is a 
quantitative measure of a material's tendency to interact with and distort 
an applied magnetic field. U.S. Pat. No. 4,827,931, to Longmore and U.S. 
Pat. Nos. 5,154,179 and 4,989,608 to Ratner disclose the incorporation of 
paramagnetic material into endovascular devices to make the devices 
visible under MR imaging. U.S. Pat. No. 5,211,166 to Sepponen similarly 
discloses the use of surface impregnation of various "relaxants", 
including paramagnetic materials and nitrogen radicals, onto surgical 
instruments to enable their MR identification. However, these patents do 
not provide for artifact-free MR visibility in the presence of rapidly 
alternating magnetic fields, such as would be produced during echo-planar 
MR imaging pulse sequences used in real-time MR guidance of intracranial 
drug delivery procedures. Nor do these patents teach a method for 
monitoring with MR-visible catheters the outcomes of therapeutic 
interventions, such as, for example, drug delivery into brain tissues, 
cerebral ventricles, or subarachnoid space. Ultrafast imaging sequences 
generally have significantly lower spatial resolution than conventional 
spin-echo sequences. Image distortion may include general signal loss, 
regional signal loss, general signal enhancement, regional signal 
enhancement, and increased background noise. 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 Werne (Ser. No. 08/554,446) 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. In the method of the invention disclosed by ITI, 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. By using 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. At the same time, 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. ISMRM, 3, 1997, p. 1931. 
Exemplary of methods for active MR visualization of implanted medical 
devices is U.S. Pat. No. 5,211,165 to Dumoulin et al., which discloses an 
MR tracking system for a catheter based on transmit/receive microcoils 
positioned near the end of the catheter by which the position of the 
device can be tracked and localized. Applications of such catheter-based 
devices in endovascular and endoscopic imaging have been described in the 
medical literature, for example, Hurst et al., Mag. Res. Med., 24, 1992, 
pp. 343-357, Kantor et al., Circ. Res., 55, 1984, pp. 55-60; Kandarpa et 
al., Radiology, 181, 1991, pp. 99; Bornert et al., Proc. ISMRM, 3, 1997, 
p. 1925; Coutts et al., Proc. ISMRM, 3, 1997, p. 1924; Wendt et al., Proc, 
ISMRM, 3, 1997, p. 1926; Langsaeter et al., Proc. ISMRM, 3, 1997, p. 1929; 
Zimmerman et al., Proc. ISMRM, 3, 1997, p. 1930; and, Ladd et al., Proc. 
ISMRM, 3, 1997, p. 1937. 
In the treatment of neurological diseases and disorders, 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. At the same time, the 
limited distribution of drug injected from a single catheter tip presents 
other problems. For example, 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. 
SUMMARY OF THE INVENTION 
Magnetic Resonance Imaging (MRI) 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. As the 
delivery of material from the delivery device is the most significant 
event within the molecular environment 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. With the medical device, 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. Additionally, 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.] can be viewed under direct MR observation and any changes in 
chemical synthetic activity and/or delivery can be seen because of 
molecular environment changes which occur upon increased synthetic 
activity. 
One recently established method of reading the data obtained from the MR 
imaging is technically founded upon existing knowledge of Apparent 
Diffusion Coefficients (ADC) in particular regions of the body. There is 
significant published literature with respect to ADC values for specific 
tissues in various parts of animals, including various tissues of humans 
(e.g., Joseph V. Hajnal, Mark Doran, et al., "MR Imaging of 
Anisotropically Restricted Diffusion of Water in the Nervous System: 
Technical, Anatomic, and Pathological Considerations," Journal of Computer 
Assisted Tomography, 15(1): 1-18, January/February, 1991, pp. 1-18). It is 
also well established in the literature that loss of tissue structure 
through disease results in a decrease of the ADC, as the tissue becomes 
more like a homogeneous suspension. Clinical observations of changes in 
diffusion behavior have been made in various tissue cancers, multiple 
sclerosis, in stroke, where the reduction in diffusion precedes the 
increase in T2, and in epilepsy. Thus, 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. 
While the 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. In other words, 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 B0 magnetic field (often referred to as magnetic 
susceptibility or .DELTA.B0 produced by the presence of a substance in 
said tissue), from alterations in local tissue T1 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. In addition, 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 B0 magnetic field (also known as 
imaging of the local magnetic susceptibility) can reveal the spatial 
distribution of a drug from the interaction of the drug with the otherwise 
homogeneous magnetic field found in MRI. To enhance the alterations in the 
magnetic field B0 caused by the drug, small amounts of a B0-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. In addition, vehicles containing differing gases (N2, O2, 
CO2) will also alter the local magnetic field and thus produce a magnetic 
susceptibility effect which can be imaged. 
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 RF 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 RF 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. The delivery and distribution kinetics of 
injections or infusions of drug agents at rates between 1 ul/min to 1000 
ul/min are monitored quantitatively and non-invasively using real-time 
contrast-enhanced magnetic susceptibility MR imaging combined with water 
proton directional diffusion MR imaging. 
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.

DETAILED DESCRIPTION OF THE INVENTION 
One of the significant difficulties with delivery of materials such as 
drugs, hormones, or neurotransmitters to living tissue is assuring that 
the materials are delivered to the target receptor location in the 
intended amount. Many materials which are delivered to a patient, even 
though beneficial in the treatment of a specific condition, may be 
moderately or even strongly noxious or damaging to healthy tissue. It is 
therefore one object of conventional materials application treatment to 
maximize dosage to a desired location and to minimize dosage to locations 
which do not require the delivery of the material. Additionally, 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. 
Where undesired deposits or collections of materials are being dispersed, 
it would be desirable to visualize the actual movement of materials to 
assist in collecting them (e.g., through catheters) or tracking them to 
assure that they are not again depositing or collecting (as in intravenous 
or cerebrospinal fluid blockage), or moving in segments which are too 
large and could cause blockage in other parts of the body as they are 
carried about. 
Unfortunately, with in vivo delivery of materials, particularly extremely 
small doses in small volumes delivered by small instrumentation into 
tissue regions protected by the blood-brain barrier, or the 
brain-cerebrospinal fluid barrier, or into visually inaccessible areas, it 
has not been possible to observe real time distribution of the material 
delivery, or the dispersion or distribution of the material at the 
injection or infusion site within the tissue. Where even small variations 
or miscalculations about the location of the target sight and the delivery 
device can significantly affect the delivery of material and the 
effectiveness of the delivered material, real time observation of the 
material delivery is even more critical than in topical or gross (e.g., 
massive systemic injection) delivery events. There has been no truly 
effective observation system for such delivery prior to the present 
invention. 
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., prior to material 
introduction or at some defined stage of material diffusion into the 
molecular environment. In an example of the method of the invention, 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. On a continual basis or at some subsequent 
time interval later (e.g., a pulsed interval, preselected interval, random 
interval, frequent or sporadic intervals), 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 MR response for regions of the 
environment where delivered material concentration has changed. By 
repeating observation of the MR image signal intensity within an area at 
least once (e.g., first taking the initial observation at a material 
concentration state at a time T.sub.1, and at least one subsequent 
observation of MRI-observable changes such as in the signal intensity 
qualities at a time T.sub.2), the change in MR image signal intensity 
qualities can be related to the change in material concentration between 
times T.sub.1 and T.sub.2, 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 T1 tissue relaxivity (T1); 
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. 
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 MR 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. Unlike other observational techniques, these 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. 
The availability of an MR-visible drug delivery device combined with 
MR-visible chemical or drug agents would make it possible to obtain near 
real-time 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 & neck surgery and radiology, ENT surgery and radiology, 
and oncology. In addition to direct tissue injection, the method of the 
invention applies to drug delivery via intraluminal, intracavitary, 
laparoscopic, endoscopic, intravenous, intraarterial applications. 
There is currently considerable interest in the therapeutic use of 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. While the importance of large 
molecular weight molecules in direct parenchymal drug therapy is growing, 
little is known about the time course and the spatial range of their 
actions, since dynamic visualization methods for studying macromolecular 
diffusion have not been available. 
Diffusion of drug and/or water protons in a complex medium, such as a brain 
cell microenvironment, 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 microenvironment 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. 
Despite the fact that the average spacing between brain cells may be no 
more than 20 nm, the mean free path of an ion at the typical ionic 
strength of the mammalian nervous system (about 0.15) is only about 0.01 
nm. In ways similar to altering the local ADC of the water protons, 
presence and transport of a drug through a tissue will also alter the 
magnetic susceptibility, T1, T2, MTC, water proton diffusion anisotropy, 
chemical shift frequency, and 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. Thus ions 
intrinsic to the brain rarely encounter cell membranes and generally 
behave as though they were in a free medium. However, the diffusivity 
properties becomes much more complicated when the boundary has a complex 
geometry, or when macromolecular interactions involve exogenous solutions 
injected into tissues. 
In complex media such as brain tissue, diffusion obeys Ficks Law, subject 
to two important modifications. First, the diffusion coefficient, D, is 
reduced by the square of the tortuosity factor to an apparent diffusion 
coefficient ADC*=D/tortuosity factor 2 because a diffusing material 
encounters membranous obstructions as it executes random movements between 
cells. Second, 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. 
In most media, tortuosity and volume fraction are essentially dimensionless 
factors which depend only on the geometrical constraints imposed by local 
structures. In brain tissue, however, a third factor, non-specific uptake, 
is present in the diffusion equation as a term, k', for loss of material 
across the cell membranes. In fact 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. Thus in the case where a 
substance is injected from a point source at a rate of q moles/sec in a 
free medium, 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. 
Knowledge of the properties of the brain extracellular microenvironment is 
thus essential to understanding the role of diffusion in delivering 
metabolic or therapeutic agents to brain or spinal cord cells. 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. 
Techniques have also been developed for determining the diffusion 
characteristics of small molecules in local regions of the brain using 
radiotracers, microiontophoresis, or pressure microinjection combined with 
ion-selective microelectrodes. The applications of these methods to 
intracranial drug delivery have been described in the medical literature, 
for example, Lux et al., Exp. Brain Res., 17, 1973, pp. 190-205, 
Gardner-Medwin, Neurosci. Res. Progr. Bull., 1980, 18, pp. 208-226, 
Nicholson et al., J. Physiol., 1981, 321, pp. 225-257, Nicholson et al., 
Brain Res., 1979, 169, pp. 580-584. However, these techniques have several 
key limitations. First, these techniques provide a measurement at only a 
single point in the tissue so that spatial patterns of diffusion cannot be 
determined. Second, ion-selective microelectrodes can only be used with a 
few small ions. Third, since radiotracer techniques rely on postmortem 
counting of particles in fixed and sectioned tissues, they provide limited 
spatial resolution and no dynamic information. 
Several previous studies have obtained estimates of the ADC of large 
fluorescent molecules from digitized images of fluorescent molecules as 
they diffused away from blood vessels. However, the complicated geometry 
of the source and inability to precisely characterize the emitted flux, 
substantially limit the clinical utility of the information. Similarly, 
new optical imaging methods, in which a uniform distribution of 
fluorescent tracer is first established in the sample and then a region is 
photobleached with a strong laser, has serious limitations because the 
laser beam can also damage the tissue area being imaged. Studies with 
optical fluorescence methods suggest that molecules as large as 70 kDa can 
pass through the brain extracellular microenvironment Below some limit 
between 10 and 40 kDa, molecular diffusion is not restricted any more than 
with much smaller molecules. Similar constraints have been found for 
diffusion in the brain intracellular microenvironment, whereby all 
molecules diffuse at least three times slower than in aqueous solution, 
suggesting a similar tortuosity in the intracellular environment. 
An integrative optical imaging technique disclosed by Tao and 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 fluorescently 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. The method disclosed by 
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. 
An alternative approach to measuring diffusivity of therapeutic drug 
injections is to monitor the diffusion process itself, i.e. the random 
motions of an ensemble of particles. Einstein showed that the diffusion 
coefficient measured in nonequilibrium concentration cell experiments is 
the same quantity that appears in the variance of the conditional 
probability distribution, P(r/ro, t), the probability of finding a 
molecule at a position r at a time t, which was initially at a position 
ro. For free diffusion, this conditional probability distribution obeys 
the same diffusion relation. Thus, MR imaging parameters which reflect the 
differences in relative water proton-diffusion path lengths may serve to 
enable imaging differentiation between tissue water protons and protons in 
macromolecular solutions that are injected into brain tissues. 
Molecular water-proton diffusion is caused by thermally induced random 
Brownian motion. As the protons continually collide with their 
microenvironments, their average random traveled pathlength &lt;L&gt;, along one 
direction (e.g. along the magnet-bore direction) is described according to 
Einstein as: &lt;L2&gt;=2 TD where over an observation time of T (seconds) the 
displacement is expressed by a "diffusion coefficient, D" in mm.sup.2 /s 
or cm.sup.2 /s. The diffusion process is continuous, so that the average 
displacement of any population of water protons increases with MR imaging 
time. However, 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. For tissue water protons diffusing within a tissue matrix, the 
observed diffusion rate and direction will reflect the molecular and 
macromolecular barriers or hindrances that the diffusing protons encounter 
during their translational processes. One example of the application of 
this concept in human neurobiology is that myelinated nerve fibers in the 
brain and spinal cord preferentially dispose the diffusion of water 
protons along, rather than across, myelin tracts thereby giving rise to 
diffusional anisotropy MR imaging properties (Moseley et al., Mag. Res. 
Med., 19, 1991, pp. 321-326, Moseley et al., Topics Mag. Res. Med., 3, 
1991, pp. 50-68). 
Although noted for its effects on high-resolution, high-field MR spectra 
more than 25 years ago, molecular (water proton) diffusion has just 
recently been shown to have an important impact in clinical MR 
neuroimaging applications. While T1 and T2 relaxation times reflect 
frequency-dependent rotational and proton exchange processes, diffusion is 
caused solely by molecular or proton displacements or translations. 
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. 
Thus, MR-visible molecules may exist in a variety of environments in brain 
tissue, which modify the way in which the molecules can move. First, the 
space in which the molecules can move may be small (e.g., intracellular) 
or large (e.g., an enlarged extracellular space). Second, 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. Similarly, the presence of a drug in 
tissue, or its transport through tissue extracellular, intercellular or 
intracellular microenvironments, will also alter the magnetic 
susceptibility, T1, 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, even when a delivery device, may also be a diagnostic 
device rather than only a treatment 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. Where, as in certain 
myelin deficiency diseases such as Multiple Sclerosis, the effect on the 
myelin is progressive and not uniform, 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 myelinated 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 According to that method, 
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. Significant differences in penetration rates 
and/or concentrations of these chemicals through similar tissue material 
(e.g., the myelin) would be indicative of different properties (e.g., 
thickness, hydrophilicity, porosity, etc.) which would be symptomatic of a 
disease. The observation would therefore provide data that could support 
or prove a clinical diagnosis of a disease which is known to affect the 
specific properties 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, 
1a, 1b, which circulates a therapeutic drug solution or MR-sensitive 
contrast agent through a dialysis fiber into a target tissue or 
pathological lesion. The distal terminus of 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 polyvinylchloride, 
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 .mu.l/minute of drug 
solution or sterile Ringer's solution perfusing the inside of the probe. 
The outlet tubing 2a is connected to a section of plastic tubing leading 
to a collection vial 3a. 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 .mu.m, and a membrane length of 
1-10 mm. 
With further reference to FIGS. 1-3 of the drawings, the outlet tubing 2a 
is incorporated into the probe into the dialysis chamber 1 via a small 
perforation in the inlet tubing. The entire upper portion of the assembly, 
including the junction between the inlet tubing and plastic cannula, is 
sealed with epoxy. 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. minimizes the tissue damage. The 
concentric design makes it simple to implant the probe into different 
intracranial locations. 
With reference to FIG. 4, 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. Particularly preferred is 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. 
Depending on orientation of the coil with the magnetic B0, 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. In order to reduce the thickness of the RF microcoil, 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 RF 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 RF coil. Another preferred MR imaging method which can 
be used to practice the invention is a combination of RF microcoil and 
surface coil positioned on the surface of the patient's head. Also 
preferred is 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. In each of these preferred embodiments of the invention, the 
transmitting coil would be the head or body volume RF coil inside of the 
MR imager. The RF surface coil is used only for detection purposes. In 
another preferred embodiment, a preamplifier 10b positioned near the 
distal end of the delivery device 4 serves to amplify signals from the RF 
microcoils 9, 91, 10, 10a. 
With further reference to FIGS. 3 and 4, 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. This again, as elsewhere described, improves 
the visibility of the viewable signal observable by the MRI system. More 
than one coil or microcoil may be present, as the distribution of 
microcoils along a length of the catheter helps define the region within 
which local signals are detected at efficient intensities. That is, 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. In 
general, the invention is best practiced by employing an array of RF 
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. 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. Where the 
liquid volume or solids are MR viewable, the MR viewable device may be 
directed towards specific locations or areas and the ports targeted 
towards those specific areas. In addition, 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. For 
example, 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. For example, where a withdrawal 
tube 27 has openings through which materials may be withdrawn, the 
orientation of that opening within the device becomes important. By lining 
the edges of the opening with material having unique MR responsiveness 
within the device 28, 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. 
Where multiple catheters or ports or functional elements are combined into 
a single 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. Particularly preferred is a 
guidewire or other structural support made of Nitinol.TM. 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. 5A, other configurations such as parallel alignment of the elements 
in a strip-like orientation, stacking of elements in rows and columns, or 
mixtures of these and other configurations may also be useful. Other 
elements which may be included within the device, in addition to or 
separate from the use of delivery and/or withdrawal tubes 29, include 
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.), and 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. 
One type of configuration which is presently considered as the preferred 
embodiment of the invention is the use of a core of element(s) surrounded 
by a sheath or distribution of additional elements. For example, with 
further reference to FIGS. 3A and 3B, 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. Around the 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. With 
respect to FIG. 5, the MR responsive materials, including MR microcoils, 
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 (as well as 
other elements) 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 system may have the material delivery device comprise a 
catheter assembly of from 2 to 10 mass transporting elements. 
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. This may be beneficial because it may be 
desirable to have the individual elements fan out or separate during a 
medical procedure, for example, as in the case of a target tissue or area 
of pathology which is anatomically extensive. 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). Many other 
variations and combinations of these considerations and constructions may 
be used within the practice of the present invention. 
With reference to FIG. 6a, in another embodiment 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 1-2.dagger. 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 0.18-0.22 m.mu. 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 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 
X-ray 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, Mass. 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 RF microcoils are placed along 
the distal shaft of the microcatheter. 
With further reference to FIG. 6 of the drawings, 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. In the method of the 
invention the distal tip of the multi-lumen catheter assembly is typically 
positioned a few millimeters above the intracranial target structure using 
MR imaging. In one preferred embodiment of the invention illustrated in 
FIGS. 6B and 6C, surface modifications of the material components of the 
dialysis probe 18 enable timed-release kinetics of MR-visible biologic 
response modifiers, including peptide macromolecules. In another preferred 
embodiment of the invention, a pump or other infusion or injection device 
circulates a solution containing a therapeutic drug or an MR-visible 
contrast agent through the walls of the dialysis fiber into the brain at 
rates between 0.01 ul/min to 10 ul/min. In another preferred embodiment of 
the invention, 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. In one specific preferred embodiment 
of the invention, the catheter is backfilled with the drug or contrast 
agent, which is functionally connected to a Picospritzer.TM. (General 
Valve Corp, Fairfield, N.J.) 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. Using 
such 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. 
In another embodiment of the invention, the MR-visible solution contains 
sterically stabilized liposomes, with lipophilic or hydrophilic chelators, 
such as polyaminocarboxylic acids and their salts, such as DTPA on 
phosphatidyl ethanolamine or 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 T1-sensitive metal ion on 
the outside membrane surface, or liposomes which contain 100-1000 nm 
air-bubbles, such as argon, carbon dioxide, or air, as a contrast agent In 
another preferred embodiment, RF microcoils 41a-f are positioned at the 
distal ends of individual delivery tubes, said microcoils acting as local 
MR detectors. 
With further reference to FIGS. 1 and 2, in a method of the invention, the 
implantable MR-visible multilumen catheter includes in another tubing 
conduit a hydrocephalus pressure valve 1C and self-sealing port 1D 
preferably made of Nitinol.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. 
With further reference to FIGS. 1 and 2, in the method of the invention, 
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. 
With reference to FIG. 7 to FIG. 11 of the drawings, in the method of the 
invention, 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. In 
order to determine the delivery and distribution kinetics of 
intracerebrovascular, intrathecal, and intra-parenchymal injections or 
infusions of drug or contrast agents within the brain for purposes of 
creating a means of acquiring a "metabolic" biopsy, a sequence of MR 
images are collected over a period of time t, which is preferably &lt;100 min 
and &gt;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. 
Methods to obtain absolute measurements of ADC using MR imaging have been 
described in the medical literature, for example, Moseley et al., Mag. 
Res. Med., 19, 1991, pp. 321-326, and Moseley et al., Topics Mag. Res. 
Med., 3, 1991, pp. 50-68). It is well established that if there is 
restriction to diffusion (e.g. from cell walls), then the measured ADC 
will decrease with increasing diffusion time. Thus, 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. In the method of the present invention, 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. However, the diffusion 
gradients make the sequence extremely sensitive to motion. Thus, in a 
preferred embodiment of the invention, a navigator echo technique, or its 
variants, are used to suppress the contaminating effects of patient motion 
on the ADC measured with MR imaging. In another preferred embodiment, high 
speed echoplanar imaging is used without movement artifact. In a further 
preferred embodiment of the present invention, localized measurements of 
the ADC, .DELTA.B0, T1, 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. 
In one preferred embodiment of the imaging method of the invention, 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, equal in magnitude and duration, 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. Also preferred are 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. To attain the preferred diffusion 
gradient of b=600 s/mm2, a spin-echo time of 90 milliseconds was used, and 
the center of k-space is placed symmetrically. Diffusion-weighted images 
are preferably acquired as 16 contiguous 1.5 mm slices at 1 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/mm2, 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. 
Thus, in the preferred method of the invention, a total of 384 
diffusion-weighted echo-planar scans are acquired in approximately 6.4 
minutes. The resulting 128.times.128 images are reconstructed by 
two-dimensional Fourier transformation. Nominal image resolution is 1.6 
mm.times.2.1 mm.times.5 mm, giving a 17-uL nominal voxel. 
With reference to FIGS. 8-11 of the drawings, in the most preferred 
embodiment of the MR imaging method of the invention, a therapeutic drug 
agent is injected from an MR visible drug delivery device into the 
intraparenchymal 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. In either case, 
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. &lt;&lt;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. 
In the first example, summarized in FIG. 8, 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. Outside this region, the brain tissue has a volume fraction and 
tortuosity. In this example, 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. At the interface between the fluid-filled cavity and 
surrounding brain tissue 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. 
In the second example, summarized in FIG. 9, 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. 
In the third example of the MR imaging method of the invention summarized 
in FIG. 10, 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. In the preferred method of 
anisotropic imaging, a 3.times.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. In the preferred method, 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. Second, 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. To measure high 
values in a directional 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. 
In the fourth example of the MR imaging method of the invention (FIG. 11) 
macromolecular transport of drugs in tumor tissue is hindered to a lesser 
extent than in normal tissue, resulting in an altered ADC which enables 
the visualization of injected drug in neoplastic versus normal tissues. 
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. 
Alternatively, 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 semi-permeable 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.