Mr signal-emitting coatings

ES 2 169 708 B2

DESCRIPTION

Coatings that emit magnetic resonance signals.

Cross reference to related requests

This application claims priority date benefit under 35 USC § 119 of US Provisional Application No. 60/086817, filed May 26, 1998.

Statement Concerning Federal Grant Research or Development

This invention was made with support from the US Government under NIH Grant Numbers 1 ROI HL57983; NIH 1 R29 HL57501 from the National Institutes of Health, and NSF-DMR 9711226 and NSF-EEC 8721845 (ERC) from the National Science Foundation. The US Government has certain rights in this invention.

Background of the invention

This invention relates in general terms to coatings that emit magnetic resonance signals and, in particular, to coatings of the type that contain paramagnetic metal ions, and to a method of coating medical devices with such coatings such that the devices are easily visualized on magnetic resonance images during diagnostic or therapeutic procedures performed in conjunction with Magnetic Resonance Imaging (MRI).

Since its introduction, Magnetic Resonance (MR) has been used to a great extent for diagnostic applications only. With the advancement of magnetic resonance imaging, however, it is becoming possible to replace many diagnostic X-ray imaging applications with MR techniques. For example, the accepted standard for visually representing vascular disease was, at one time, X-ray contrast angiography. Today MR angiographic techniques are increasingly being used to detect vascular abnormalities and, in some cases, In specific clinical cases, contrast-enhanced MR angiograms are rapidly focusing on the classic X-ray angiography diagnostic set.

More recently, advances in MR hardware and imaging sequences have begun to allow the use of MR in certain therapeutic processes. That is, certain therapeutic processes or certain therapies are performed on a patient while the patient and the instruments, devices or agents used and / or implanted are being imaged. The use of MR in this modality of image-guided therapy is often referred to as interventional magnetic resonance imaging (interventional MR). These early applications have included: monitoring ultrasound and laser excisions, guiding needle placement for biopsies, and visualizing disease, such as one caused by tumors, between surgeries.

Endovascular therapy is of particular interest in interventional MR. The term "endovascular therapy" refers to a general class of minimally invasive interventional (or surgical) techniques used to treat vascular abnormalities. Unlike conventional surgical techniques, endovascular therapies gain access to and treat disease from within the vascular system (vasculature). The vascular system is usually accessed through the femoral artery. A small incision is made in the groin and the femoral artery is punctured. A cuff is then inserted to gain access to the vascular system. A catheter with the addition of a guidewire can then be manipulated by fluoroscopic guidance to the area of ​​interest. The guidewire is then removed from the catheter lumen, either a therapeutic device (e.g. balloon, stent device, or coil) is inserted with the appropriate delivery device, or an agent is injected (e.g. ., embolizing agent, anti-vasospasm agent) through the catheter. In either case, the catheter functions as a conduit and ensures accurate and localized delivery of the device or therapeutic agent. Once the device or agent is in place, its delivery system is removed, that is, the catheter is removed, the cuff is removed, and the incision is closed. The duration of a median endovascular process is approximately 3 hours, although difficult cases may require more than 8 hours. Traditionally, such procedures have been performed using X-ray fluoroscopic guidance.

Executing these processes under MR guidance provides a number of advantages. Safety issues are associated with the relatively large dosages of ionizing radiation that are required in X-ray fluoroscopy. Although the radiation risk to the patient is of somewhat less concern (as it is more than outweighed by the potential benefit of the process), exposure to the personnel performing the intervention may be a major problem. Furthermore, the degree of complication from MR contrast agents is much less than that of commonly used iodinated X-ray contrast agents.

Other advantages of MR-guided processes include the ability of MR to acquire three-dimensional images. In contrast, most X-ray angiography systems can acquire only one series of images per projection. MR has obvious advantages when multiple views or volume reformatting is required in order to understand the treatment of common three-dimensional vascular abnormalities2

ES 2 169 708 B2 pleas, such as arterial-venous malformations (AVM's) and aneurysms. Furthermore, MR is sensitive to a variety of "functional" parameters including temperature, blood circulation, tissue perfusion, diffusion, and brain activation. This additional diagnostic information, which can in principle be obtained before, during and immediately after a therapy, cannot be acquired by X-ray fluoroscopy alone. It is likely that once appropriate MR-based endovascular processes have been developed, the next challenge will be to integrate this functional information with conventional anatomical imaging and device tracking.

Currently, both “active” and “passive” approaches are being used to monitor interventional device placement under MR guidance. With active tracking, visualization is achieved by incorporating one or more small radio frequency (radio-frequency RF) coils into the device, eg, a catheter. The position of the device is calculated from MR signals detected by the coil. This information is then superimposed on a previously acquired anatomical "road map" type image. Advantages of active tracking include excellent temporal resolution and spatial accuracy, and the ease with which the tip position, e.g., of a catheter, can be fine-tuned at 20 Hz, i.e. 20 times. per second.

However, active methods allow the display of only one or more discrete site (s) on the device. Typically, only the tip of the device is "active", that is, displayed. Although it is possible to incorporate multiple RF coils (4-6 in typical clinical MR systems) into one device, it is still impossible to determine position at more than a few discrete sites along the device. Although this may be acceptable for tracking rigid biopsy needles, this is a major limitation for tracking flexible devices such as endovascular therapy. Additionally, intravascular heating due to RF-induced currents is a concern with active methods.

As noted above, securing the coils on flexible catheters poses numerous challenges. Also, the effect on the mechanical properties of catheters is a concern. Ladd et al. (See Ladd et al., Proc. ISMRM (1997) 1937) have overcome some of the shortcomings of an active catheter by designing an RF coil that is wrapped around the catheter. This allows a considerable length of a catheter to be viewed, but still does not solve the problems caused by RF heating and the mechanical behavior of the catheter.

Passive tracking technologies make use of the fact that endovascular devices generally do not emit a detectable MR signal and therefore result in signal loss or signal gaps in MR imaging. Such loss of signals, for example, occurs with a polyethylene catheter. By tracking the gap, the movement of the catheter can be inferred. An advantage of passive tracking methods over active methods is that the former allow a "visualization" of the entire length of a device. Signal gaps, however, are certainly not optimal for tracking a device, as they can be confused with other sources of signal loss.

An additional source of passive contrast is produced if the device has a very different magnetic susceptibility than tissue (eg, metallic guide wires and stent devices). Differences in susceptibility cause local distortions in the magnetic field and result in regions of signal enhancement and signal loss surrounding the device. A number of published reports describe passive catheter visualization schemes based on signal gaps or susceptibility-induced aberrations. A major disadvantage of currently available passive techniques is that display is dependent on the orientation of the device with respect to the main magnetic field.

As documents of the state of the art to which the invention belongs, the following may be mentioned:

International application WO 9408629, issued in favor of Snow, which describes a liquid contrast composition consisting of polymer units comprising the residue of a chelating agent linked to a polyalkylene oxide moiety, the polymer having a paramagnetic ion associated with it .

European patent application EP 331616, issued to Deutsch, which describes a liquid contrast composition consisting of polymer-bound complex formers.

International application WO 9524225, issued in favor of Margerum, which describes a liquid contrast composition consisting of polychelating compounds useful as intravascular contrast agents and as agents for blood banks.

International application WO 96005888, issued in favor of Ladd, which describes a liquid contrast composition consisting of cross-linked polymers comprising the residue of a polyamine residue linked to a residue of chelating agent and with one or more polyalkylene oxides.

US Patent 4986980, issued to Jacobson, which describes a liquid contrast composition comprising a non-radioactive paramagnetic metal species bound to at least one water-soluble polymerized or polymerized carbohydrate or a water-soluble polymerized sugar-alcohol .

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Fried MP & col. Laryingoscope, 1996, which describes endoscopic sinus surgery guided by magnetic resonance imaging, using a plastic tube filled with the liquid contrast solution consisting of diglumine gadopentatate.

Despite the recognition and study of various aspects of the problems for visualization of medical devices in therapeutic processes, especially endovascular ones, the prior art has not yet produced satisfactory and reliable techniques for visualization and monitoring of the entire device in a process guided by MR. .

Brief summary of the invention

The present invention provides a method of coating medical devices in such a way that the devices are easily visualized, particularly in T1-weighted magnetic resonance imaging. Due to the high signal caused by the coating, all of the coated devices can be easily visualized. during, eg, an endovascular process.

The foregoing and other advantages of the present invention are achieved with it in a magnetic resonance (MR) signal-emitting coating, which includes a complex with a polymer containing a paramagnetic metal ion, and a method of visualizing medical devices by reproduction. magnetic resonance imaging, which includes the operation of coating the devices with a polymer containing a paramagnetic ion. Specifically, the present invention provides a coating for visualizing medical devices in magnetic resonance imaging, comprising a complex of formula (I):

P - X - L - Mⁿ+ (I) where P is a polymer, X is a surface functional group, L is a chelate, M is a paramagnetic ion, and n is an integer that is 2 or greater.

In another aspect, the invention consists of a coating for visualizing medical devices in magnetic resonance imaging, comprising a complex of formula (II):

P - X - J - L - Mⁿ+ (II) where P is a polymer, X is a surface functional group, L is a chelate, M is a paramagnetic ion, n is an integer that is 2 or greater, and J is a linker molecule or spacer.

In a further aspect, the invention consists of a magnetic resonance imaging system, which includes a magnetic resonance device for generating a magnetic resonance image of a target object (as defined below) in a reproduction region of images (as defined below) and an instrument intended for use with the target object in the image reproduction region. The instrument includes a body sized for use on the target object and a complex of a paramagnetic ion and a polymer, in which the complex is represented by formula (I):

P - X - L - Mn + (I) where P is a polymer, X is a surface functional group, L is a chelate, M is a paramagnetic ion, and n is an integer that is 2 or greater.

In still another aspect, the invention relates to a method of visualizing medical devices in magnetic resonance imaging, including the steps of (a) coating the medical device with a complex of a paramagnetic ion and a polymer, wherein the complex is represented by the formula (I):

P - X - L - Mⁿ+ (I) where P is a polymer, X is a surface functional group, L is a chelate, M is a paramagnetic ion, and n is an integer that is 2 or greater; (b) placing the device within a target object; and (c) imaging the target object and the coated device.

Other advantages and a fuller appreciation of the specific attributes of the invention will emerge upon examination of the following drawings, the detailed description of preferred embodiments, and the appended claims. It is expressly understood that the drawings are presented for the purpose of illustration and description only, and are not construed as a definition of the limits of the invention.

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Brief description of the drawings

The preferred illustrative embodiment of the present invention will now be described in conjunction with the accompanying drawing, in which like designations refer to like elements throughout the figures, and in which:

Figure 1 is a schematic representation of the three-stage coating method in accordance with the present invention;

Figure 2 is a schematic representation of the four-step coating method using a linker;

Figures 3 and 3A are a schematic representation of a plasma reactor for use in the method of the present invention, Figure 3A being an enlarged view of the assembly for supplying steam to the plasma reactor of Figure 3;

Figure 4 depicts various MR images of coated devices in accordance with the present invention;

Figure 5 depicts temporary MR snapshots of a Gd-DTPA filled catheter;

Figure 6 depicts temporary MR snapshots of a Gd-DTPA filled catheter moving within the common carotid of a canine animal; and Figure 7 depicts temporary MR snapshots of a Gd-DTPA filled catheter in the aorta of a canine animal.

Detailed description of the invention

The present invention relates broadly to coating substances, which are capable of emitting magnetic resonance signals. The present invention is intended to be used more particularly in coating medical devices such that they are easily visualized on magnetic resonance images. Correspondingly, the present invention will now be described in detail with respect to such endeavors; however, those skilled in the art will appreciate that such description of the invention is meant to be illustrative only and should not be construed as limiting the full scope thereof.

The present invention provides coatings that contain paramagnetic ions. The coatings of the present invention are characterized by an ability to emit magnetic resonance signals and allow visualization of the entirety of a device or instrument thus coated in interventional MR procedures. The coatings are also valuable in providing improved interoperable MR visibility of surgical instruments after they have been coated with the signal enhancing coatings of the present invention. It is also envisioned that the improved visualization of implanted devices thus coated, eg, Stent devices, may find a multitude of applications in diagnostic MR. These attributes of the coating according to the present invention are achieved through a new combination of physical properties and chemical functionalities.

In the following description of the method of the invention, the process operations are carried out at room temperature (RT) and atmospheric pressure, unless otherwise specified.

Throughout the specification, the term "medical device" is used in a broad sense to refer to any tool, instrument, or other object (eg, a catheter, biopsy needle, etc.) that is used used to perform an operation on a target, or that is useful to perform such an operation, or a device that is itself implanted in the body (human or animal) for some therapeutic purpose, e.g., a Stent device, a graft, etc., and a "target" or a "target object" being the whole or part of a human or animal patient placed in the "imaging region" of a magnetic resonance imaging system (the "imaging region being Imaging ”the space within an MRI system in which a target can be imaged).

Endovascular processes performed under MR guidance are of particular interest. Such endovascular processes include the treatment of partial vascular occlusions with balloons, venous-arterial deformities with embolizing agents, aneurysms with Stent devices or coils, as well as vasospasm induced by a sub-arachnoidal hemorrhage (SAH of sub-arachnoid hemorrhage) with applications local papavefina. In these therapeutic processes, the device or agent is delivered through the lumen of a catheter, the placement of which has traditionally resorted, to varying degrees, to X-ray fluoroscopic guidance.

In one aspect, the present invention provides a method of coating the surface of medical devices with a coating that is a polymeric material containing a paramagnetic ion, the coating of which is generally represented by formula (I):

ES 2 169 708 B2 (I)

P - X - L - Mⁿ+ where P is a polymer, X is a surface functional group, L is a chelate, M is a paramagnetic ion that binds to L, and n is an integer that is 2 or greater. It is understood that a medical device can be appropriately constructed of a polymer whose surface is then X-functionalized, or a medical device can be appropriately coated with a polymer whose surface is then appropriately functionalized. Such methods for coating are generally known in the art.

To increase the rotational mobility of Mⁿ+, the coating optionally contains a linker or spacer molecule J, and is represented broadly by formula (II):

P - X - J - L - Mⁿ+ (II) in which P, X, L and M are as previously described and J is the linker or spacer molecule that binds the surface functional group X and the chelate L, that is, J is an intermediate between the surface functional group and the chelate.

P is suitably any polymer that includes, but is not limited to, polyethylene, polypropylene, polyesters, polycarbonates, polyamides such as nylon, poly (tetrafluoroethylene) (Teflon®), and polyurethanes that may be surface functionalized with an X group. that some polymer surfaces may need to be further coated with hydrophilic layers. J is suitably a bifunctional molecule, eg, a lactam having one available amino group and one carboxyl group, a T-diamine having two available amino groups, or a fatty acid anhydride having two available carboxyl groups. X is suitably an amino or carboxyl group. L is appropriately any chelate that has a relatively high stability constant, K (e.g.,> 10²⁰) for the complex of a chelate and a paramagnetic ion. Such chelates include, but are not limited to, diethylenetriamine-pentaacetic acid (DTPA), tetraaza-cyclododecane-tetraacetic acid (DOTA), and tetraazacyclo-tetradecanetetraacetic acid (TETA). The paramagnetic ion is suitably a multivalent paramagnetic metal that includes, but is not limited to, the lanthanide and transition metals, such as iron, manganese, chromium, cobalt, and nickel. Preferably Mⁿ+ is a lanthanide that is highly paramagnetic, of which the gadolinium (III) ion which has seven unpaired electrons in the 4f orbital is highly preferred.

It is pointed out that the gadolinium (III) ion (Gd (III)) is frequently used in MR contrast agents, that is, agents that influence, or intensify, the signals, since it is paramagnetic to a high degree by having a large magnetic moment due to the seven unpaired 4f orbital electrons. In such contrast agents, the gadolinium is generally combined with a chelating agent, such as DTPA. The resulting complex (Gd-DTPA or Magnevist; Berlex Imaging, Wayne, NJ) is very stable in vivo, and has a formation constant of> 10²³, which makes it safe for human use. Similar agents have been developed by chelating the gadolinium ion with other complexes, eg, MS-326, Epix Medical, Cambridge, Massachusetts. Gadolinium (In) causes a localized T1 reduction in protons in its environment, providing enhanced visibility on T1-weighted MR images.

MR signal emitting coatings according to the present invention are synthesized according to a three or four stage process. The three-step method includes: (i) plasma treating the surface of a polymeric material (or a material coated with a polymer) to provide surface functional groups, e.g., using a nitrogen-containing gas or vapor, such as hydrazine (NH2NH2) to provide amino groups; (ii) attach a chelating agent, eg, DTPA, to the surface functional group; and (iii) coordinating a functional paramagnetic metal ion such as Gd (III) with the chelating agent. It is noted that the bond between the surface functional groups and the chelates is often an amide-type bond. In addition to hydrazine, other plasma gases that can be used to provide surface functional amino groups include urea, ammonia, a combination of nitrogen and hydrogen, or combinations of these gases. Plasma gases that provide surface functional carboxyl groups include carbon dioxide or oxygen.

A schematic reaction procedure of a preferred embodiment of the present invention is shown in Figure 1. As specifically seen in Figure 1, a polyethylene is treated with a hydrazine plasma to provide surface functionalized amino groups. The amino groups are reacted with DTPA in the presence of a coupling catalyst, eg, 1,1'-carbonyl-diimidazole, in order to produce an amide bond between amino groups and DTPA. The surface amino-DTPA groups are then treated with gadolinium (III) chloride, coordinating the gadolinium (III) ion with DTPA.

In order to enhance the rotational component of the paramagnetic ion interaction with the environmental water, MR signal emitting coatings are appropriately produced by means of a four-stage process which is similar to the three-stage process except that above of step (ii), i.e. prior to reaction with the chelating agent, a linker or a spacer molecule, e.g. a lactam, it binds to the functional groups on the surface, resulting in the coating of formula (II).

A schematic and illustrative reaction procedure, using a lactam, is shown in Figure 2. As

ES 2 169 708 B2 is seen in Figure 2, a polyethylene with an amino functionalized surface is reacted with a lactam. Amino groups and lactam molecules are coupled through an amide bond. It is noted that "m" in the designation of the amino-lactam bond is suitably an integer greater than 1. The polyethylene-amino-lactam complex is then reacted with DTPA, which forms a second amide bond at the distal end of the lactam molecule. The last step in the procedure, that of coordinating the gadolinium ion (III) with DTPA (not shown in Figure 2), is the same as that shown in Figure 1.

Specific reaction conditions for forming a coating according to the present invention, utilizing surface functionalized amino groups, include plasma treatment of a polymeric surface, e.g., a polyethylene surface, with an input power of 50 W in a hydrazine atmosphere within a plasma chamber, schematically represented in Figure 3, for 5-6 min., At a pressure of 13 Pa to 106 Pa (100 mT800 mT).

As seen in Figure 3, an exemplary plasma chamber, generally designated by reference numeral 20, includes a cylindrical reaction chamber 22 of stainless steel suitably having a diameter of 20 cm, a lower electrode 24, which it is grounded, and an upper electrode 26, both suitably made of stainless steel. Electrodes 24 and 26 are suitably 0.8 cm thick. The upper electrode 26 is connected to a source of RF energy (not shown). Both electrodes are removable, which facilitates cleaning operations after plasma treatment. The lower electrode 24 is also part of a vacuum line 28 through a circularly perforated conical support pipe 30 made of stainless steel, having a check valve 31. Vacuuming of chamber 22 is done uniformly through a narrow gap (3 mm) that exists between lower electrode 24 and the bottom of chamber 22. Upper electrode 26 is directly connected to a threaded end of a metallic / ceramic feeding duct 32, vacuum-tight, which ensures both the isolation of the conduction of RF energy from the reactor and the dissipation of the RF energy towards the electrodes. A space 34 located between the upper electrode 26 and the upper wall of the chamber 22 is occupied by three removable discs 36 with a thickness of 1 cm and a diameter of 20 cm, made of Pyrex® glass. Disks 36 isolate the top electrode from the top, stainless steel portion of reactor 20 and allow for adjustment of the gap between electrodes. The volume of the reactor located outside the perimeter of the electrodes is occupied by two Pyrex glass cylinders 38^®, provided with four symmetrically positioned through holes 40 for diagnostic purposes.

This reactor configuration substantially eliminates plasma-free zones from the gaseous environment and considerably reduces radial diffusion of the plasma species, thereby leading to more uniform plasma exposure of the substrates (electrodes). As a result, uniform surface treatment and deposition processes can be achieved (with a film thickness variation of 6-10%).

The removable upper part of the reactor 20 seals the chamber 22 from vacuum with the help of a copper sealing gasket and fixing bolts 42. This part of the reactor also houses a narrow circular chamber 44 for gas mixing, provided with a system of holes with a diameter of 0.5 mm of the type of a shower, and a connection 46 for supplying gases and monomers. This gas supply configuration ensures uniform penetration and circulation of gases and vapors through the reaction zone. The entire reactor 20 is thermostatically regulated by electric heaters attached to the external surface of the chamber 22 and embedded in an aluminum sheet 48 that protects a glass wool blanket 50 to avoid extensive loss of thermal energy.

For diagnostic purposes, four symmetrically placed stainless steel port 51 pipes are connected and welded through insulation blanket 50 to the reactor wall. These ports are provided with optically smooth and interchangeable quartz windows 52. A steam supply assembly 54, as seen in Figure 3A, includes a plasma reservoir 56, valves 58, VCR connectors 60, and a stainless steel connection pipe 62. The assembly 54 is embedded in two copper jackets 64 1 cm thick, fitted with controlled electric heaters for the treatment of low volatility chemicals. Assembly 54 is insulated using a glass wool blanket liner. The thermostatic regulation capacities of reactor 20 are in the range of 25-250 ° C.

Once the device to be coated has been surface functionalized, it is then immersed in a solution of the chelating agent, eg DTPA in, eg, anhydrous pyridine, typically with a coupling catalyst, eg. eg, 1,1'-carbonyl-diimidazole, for a period of time sufficient for the chelate to react with the amino groups, eg, 20 hours. The surface is washed consecutively with solvents, eg, pyridine, chloroform, methanol, and water. The chelated surface is then soaked in a solution of a salt of the paramagnetic ion, eg, GdCl₃A6H₂Or in water, for a period of time sufficient for the paramagnetic ion to react with the chelate, eg, 12 hours. Then the surface is washed with water.

In test procedures, each operation has been verified to confirm that bonding actually occurs. To verify functionalization with amino groups, X-ray photoelectron spectroscopy (XPS) was used. An XPS spectrum was taken from the surface of the polyethylene before and after plasma treatment. The XPS spectrum of polyethylene before treatment did not show any peak for nitrogen. After treatment, the nitrogen peak was 5.2% relative to the peaks for carbon and oxygen, 63.2% and 31.6% respectively.

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To determine whether amino groups were accessible to chemical reactions, after step (i) the surface was reacted with p-fluorophenone-propionic acid and rinsed with a solvent (tetrahydrofuran). This reactant, chosen because of the good sensitivity of fluorine atoms to XPS, produces photoelectron spots when excited by X-rays. The result of the XPS experiment showed a significant fluorine signal. The peaks for fluorine, nitrogen, carbon and oxygen were: 3.2%, 1.5%, 75.7% and 19.6% respectively. This showed that the amino groups were accessible and able to react chemically.

Since the coatings according to the present invention are advantageously applied to catheters and since a catheter surface is cylindrical, it is pointed out that in order to coat commercial catheters, the plasma reaction must be carried out by rotating the shaft. of the catheter perpendicular to the direction of propagation of the plasma envelope. Such rotary devices are known and can be easily used in the plasma reactor depicted in Figure 3. In order to verify that a surface amination occurs for such surfaces, atomic force spectroscopy (AFM) is used to study surface morphology, since XPS requires a well-defined flat surface relative to the incident X-ray beam. Once coated, the coating densities are measured (e.g., in nanomoles of Gd³+ / m²) using nuclear magnetic resonance imaging (NMR) and optimal coating densities can be determined.

It is also understood that metal surfaces can be treated with the coatings according to the present invention. Metal surfaces, eg, guide wires, can be coated with a polymer, eg, polyethylene, by various known surface coating techniques, eg, melt coating, which is a process well known for superior coating of polymers on metal surfaces. Once the metal surfaces have been topcoated with a polymer, all the other chemical operations described here apply.

The present invention is further explained by way of the following examples which should not be construed as limiting the scope of the present invention.

Example 1

Preparation of coated polyethylene sheets

Polyethylene sheets were coated by the three-step procedure described herein.

Superficial amination. A polyethylene sheet (with a diameter of 4.5 and a thickness of 25.4 microns) was placed inside a 50 kHz, capacitively coupled, stainless steel plasma reactor (as shown schematically in Figures 3 and 3A). and the hydrazine plasma treatment of the polyethylene film was performed. The substrate film was placed on the lower electrode. First, the base pressure was established in the reactor. Then, the hydrazine pressure was slowly increased by opening the valve that connects to the liquid hydrazine reservoir. The following plasma conditions were used: base pressure = 60 mT; hydrazine treatment pressure = 350 mT; RF power = 25W; treatment time = 5 min; source temperature (hydrazine reservoir) = 60 ° C; substrate temperature = 40 ° C. The surface atomic compositions of untreated and plasma-treated surfaces were evaluated using an XPS (Perkin-Elmer Phi-5400; power 300 W; Mg source; 15 kV; 45 ° angle).

Coating with DTPA. In a 25 ml dry flask, 21.5 mg of DTPA was added to 8 ml of anhydrous pyridine. In a small container, 8.9 mg of carbonyl diimidazole (CDI), as a coupling catalyst, was dissolved in 2 ml of anhydrous pyridine. The CDI solution was slowly added to the reaction flask while stirring, and the mixture was stirred at room temperature for 2 hours. Then the solution was poured into a dry Petri dish, and the hydrazine plasma treated polyethylene film was dipped into the solution. The Petri dish was sealed inside a desiccator after being purged with argon and dried for 10 min. After a reaction for 20 hours, the polyethylene film was carefully washed consecutively with pyridine, chloroform, methanol and water. The surface was checked with an XPS and the results revealed the presence of carboxyl groups, which demonstrate the presence of DTPA.

Coordination with gadolinium (III). 0.70 g of GdCl₃A6H₂Or they were dissolved in 100 ml of water. The DTPA-treated polyethylene film was soaked in the solution for 12 h. The film was washed with water. The surface was checked with an XPS and revealed two peaks with binding energies (BE of binding energy) = 153.4 eV and BE = 148.0 eV, corresponding respectively to Gd³+ chelated and Gd³+ free. The film was repeatedly washed with water until the peak for Gd³+ free at 148.0 eV disappeared from the XPS spectrum.

The treatment results, in terms of relative surface atomic concentrations, are given below in Table 1.

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TABLE 1

Relative surface atomic concentration of untreated and treated PE surfaces

<td></td><td>% of Gd</td><td>% ofN</td><td>% of O</td><td>% of C</td>

<td>Untreated PE</td><td> 0,0</td><td> 0,0</td><td> 2,6</td><td> 97,4</td>

<td>PE treated with hydrazine plasma</td><td> 0,0</td><td> 15,3</td><td> 14,5</td><td> 70,2</td>

<td>DTPA coated PE</td><td> 0,0</td><td> 5,0</td><td> 37,8</td><td> 57,2</td>

<td>PE coated with Gd</td><td> 0,1</td><td> 3,7</td><td> 35,0</td><td> 60,3</td>

Example 2

Preparation of Polyethylene Coated Sheets, Including a Bonding Agent

Coated polyethylene sheets are prepared according to the method of Example 1, except that after surface amination, the polyethylene sheet is reacted with a lactam and the sheet is washed before proceeding to the chelation operation. The surface of the film is checked for the existence of amino groups using an XPS.

Example 3

Imaging of Polyethylene and Polypropylene Coated Sheets

MR signal enhancement was verified by imaging polyethylene and polypropylene coated sheets, which had been prepared as described in Example 1, with gradient-recalled echo (GRE) and gradient-recalled echo techniques. spin (SE of spin-echo) in a 1.5 T clinical scanner (explorer). The sheets were held stationary within a beaker filled with a tissue mimetic, yogurt, and the enhancement of the coating contrast was calculated by normalizing the signal near the sheet by the signal from the yogurt. T1-weighted MR images of GRE and SE revealed signal enhancement near the coated polymer sheet. Estimates of T1 near the coated surface and in the yogurt were 0.4 s and 1.1 s, respectively. No enhancement was observed near control slides. The acquired MR images are shown in Figure 4.

Example 4

In vitro assay of the visualization of a Gd-DTPA filled catheter

The following examples demonstrate the utility of Gd-DTPA to visualize a catheter through MR guidance.

A 3-6 French (1-2 mm) catheter with a single lumen and filled with Gd-DTPA was imaged on an acrylic phantom using a conventional MR Scanner (1.5 T Signa, from General Electric Medical Systems) while which was manually moved at discrete intervals over a predetermined distance either in the reading direction or in the phase encoding direction. The mannequin consisted of a block of acrylic material in which a series of channels had been perforated. The arrangement allowed the determination of the position of the catheter tip with an accuracy of V 1 mm (square root of the mean of the squares of the instantaneous values). Snapshots of the catheter are shown in Figure 5.

Example 5

In Vivo Assay of Visualization of a Gd-DTPA Filled Catheter

For in vivo evaluation, commercially available single lumen catheters filled with Gd-DTPA (in 4-6% solution) ranging in size from 3 to 6 French (1-2 mm), and combinations of a catheter and a guidewire were imaged in either the aorta or the carotid artery of four canine animals. All animal experiments were performed in conjunction with institutionally approved protocols and were carried out on animals under general anesthesia. The catheter lumen is open at one end and closed at the other by a spigot. This keeps the Gd-DTPA solution inside the catheter. The possibility of the Gd-DTPA spilling out of the catheter lumen through the open end was small and is considered safe since the Gd-DTPA used in these experiments is commercially available and approved for use in MR. The reconstructed images produced during catheter tracking were overlaid on previously acquired angiographic "road map" images, which had typically been acquired using a TRICKS 3D imaging sequence (FR Korosec, R. Frayne, TM Grist, CA Mistretta , 36 Magn. Reson. Medicine. (1996) 345-351, incorporated herein by reference) in conjunction with either an intravenous or intra-arterial injection of Gd-DTPA (0.1 mmol / kg). On some occasions, subtractive techniques were used to eliminate the

ES 2 169 708 B2 background signal from the catheter images before superimposing them on a road map image. The snapshots of the carotids and aortas of the canine animals are shown in Figures 6 and 7, respectively. Example 6

MR visualization of an in vivo catheter

Using canine animals, a catheter coated with a combination of the coating according to the present invention and a guide wire is initially placed in the femoral artery. Using MR guidance, the catheter is moved first to the aorta, then to the carotid artery, then to the circle of Willis, and over the central cerebral artery. The movement of the catheter is clearly observed in the vessels. The length of time to perform this process and the smallest glass that has been successfully traded are recorded.

Example 7

Paramagnetic ion safety test

A gadolinium leaching test is performed to find out the stability of the Gd-DTPA complex. Polyethylene sheets coated with a coating according to the present invention are subjected to simulated buffers of blood plasma and the blood plasma itself. NMR scans are performed and these distinguish between Gd³⁺ chelated and Gd³⁺ free. The results indicate that the complex with Gd³⁺ it is stable under simulated blood conditions.

Example 8

Biocompatibility test

A biocompatibility test is carried out on polymeric surfaces coated in accordance with the present invention using a fluorescent dye-labeled serum albumin adsorption method. If albumin is irreversibly adsorbed, as detected by fluorescence from the coated surfaces of the catheter it is decided that the coating is bioincompatible.

Example 9

Determination of coating signal intensities

A 1.5 T clinical scanner (Signa, General Electric Medical Systems) is used to determine the optimal range of coating densities (in mmol of Gd³+ m ²) to produce appreciable signal enhancement in a series of silicone wafers coated with a coating containing polyethylene and Gd in accordance with the present invention. The wafers are placed in a water bath and scanned in cross-section using a moderately high resolution fast gradient-recalled echo (FGRE) sequence with TR. 7.5 ms / TE. 1.5 ms, 256 X 256 acquisition matrix and a 16 cm X 16 cm field of view (FOV of fieldof-vision). The flap angle is varied from 10 ° to 90 ° in 10 ° increments for each coating density. A region of interest (ROI) is placed in the water adjacent to the wafer and the absolute signal is calculated.

For a calibration of the signal measurements obtained in different imaging experiments, a series of ten calibration vials are also imaged. The vials contain different concentrations of Gd-DTPA, ranging from 0 mmol ml^-1 to 0.5 mmol ml^-1. This concentration range corresponds to a range of T1 relaxation times (from &lt;10 ms to 1000 ms) and a range of T2 relaxation times. The signals in each vial are also measured and used to normalize the signals obtained near the wafers. Normalization corrections for effects due to different pre-scan settings between acquisitions and for variable image grading are applied by the scanner. A range of concentrations in the vials facilitates piecewise standardization. An optimal range of coating densities is determined.

In summary, the present invention provides a method of visualizing medical devices under MR guidance using a coating, which is a complex of a polymer and a paramagnetic ion, on medical devices.

Although the present invention has now been described and illustrated with some specificity, those skilled in the art will appreciate the various modifications, including variations, additions, and omissions, that can be made to what has been described. Correspondingly, it is considered that these modifications are also encompassed by the present invention and that the scope of the present invention is limited only by the broadest interpretation that can be legally assigned to the appended claims.

ES 2 169 708 B2

Reference symbols list

Figure 1:

P = Plasma

CD = 1,1'-Carbonyl-diimidazole

PI = Pyridine

Figure 2:

PO = polyethylene

LA = lactam

Figure 4:

MR Imaging of Gd Coated PE and PP

PR = polyethylene coated with Gd

PP = polypropylene coated with Gd

PS = uncoated polyethylene

PPS = uncoated polypropylene

Figure 5 (a, b) Two time snapshots from a time series of 27 coronal images of a 6 French catheter filled with Gd-DTPA during movement through a static phantom. Scan parameters: TR = 4.6 ms, TE = 1.3 ms, acquisition matrix = 160 X 256, reconstruction matrix = 256 X 256, fOv = 20 cm X 20 cm, slice thickness = 2 cm, angle flutter = 40 ° and temporal cadence of taking images = 3 images / s. Note that the background signal is very high since no projection phase shifter was used. (c, d) Image shooting timing similar to those shown in (a) and (b) except that the projection phase shifter was enabled. Flipping the projection phase shifter upward provides better background suppression.

Figure 6 (a, b). Two time snapshots from a time series of 27 coronal images of a 6 French catheter filled with Gd-DTPA moving in the common carotid of a canine animal. Scan parameters: TR = 4.6 ms, TE = 1.3 ms, acquisition matrix = 160 X 256, 256 X 256 reconstruction matrix, FOV = 20 cm X 20 cm, slice thickness = 2 cm, angle of flutter = 40 ° and temporal cadence of taking images = 3 images / s. Enabling the projection phase shifter (a, b) suppresses the background signal and makes the catheter more visible. (c, d) The same image timing rates as shown in (a) and (b) superimposed on a previously acquired road map image.

Figure 7 (a) A temporary snapshot of a 6 French catheter filled with Gd-DTPA in the aorta of a canine animal with the projection phase shifter enabled. (b) The same image-taking time frame as in (a) after masking by an image with a previous image-taking time frame. Scan parameters: TR = 4.6 ms, TE = 1.3 ms, acquisition matrix = 160 X 256, reconstruction matrix = 256 X 256, FOV = 20 cm X 20 cm, slice thickness = 2 cm, angle flutter = 40 ° and temporal cadence of taking images = 3 images / s. The catheter images in (a) and (b) are shown superimposed on a previously acquired road map image in (c) and (d) respectively, after zeroing the catheter image by a factor of 2 in both both read and encode addresses in phase.