WO2002039898A2

WO2002039898A2 - Radiation detection catheter

Info

Publication number: WO2002039898A2
Application number: PCT/CA2001/001647
Authority: WO
Inventors: Philippe Leblanc; Guy Leclerc; Guillaume Sulpice; Raymond Carrier
Original assignee: Angiogene Inc.
Priority date: 2000-11-20
Filing date: 2001-11-20
Publication date: 2002-05-23
Also published as: WO2002039898A3; AU2002220403A1

Abstract

A radiation detection catheter is particularly suitable for accurately detecting beta emitters in an in vivo environment to detect the presence of a radioactive therapeutic agent emitting beta radiation delivered locally to a portion of the coronary artery by inserting the catheter into the body through a blood vessel and maneuvered in to the coronary artery. The catheter has an elongated detector sensitive to beta radiation coupled to an optical fiber, and an in situ calibration system which improves the signal-to-noise performance of the catheter for detecting beta radiation.

Description

RADIATION DETECTION CATHETER

TECHNICAL FIELD

The present invention relates to a radiation detection catheter. More particularly the invention relates to a radiation detection catheter that is particularly suitable for accurately detecting beta emitters in an in vivo environment, for example, to detect the presence of a radioactive therapeutic agent emitting beta radiation delivered locally to a portion of the coronary artery by inserting the catheter into the body through a blood vessel and maneuvered in to the coronary artery.

BACKGROUND OF THE INVENTION

Local agent delivery is a strategy where the diagnostic or therapeutic agent is delivered exactly and only at the desired site of therapy. This approach is usually employed in contrast to systemic therapy either to reduce the adverse effects of an agent delivered systemically or to increase locally, at the target site, the amount of agent at a concentration level that systemic delivery could not tolerate.

Many strategies of local agent delivery have been devised to deliver locally an agent to an organ or a tubular structure of a living animal or human. Local delivery can be performed with a catheter inserted into the body with the tip (distal part) of the catheter advanced to the target site. The agent is then infused through the catheter and is deposited on the surface of the target site or into the tissue itself by use of small needles. Several catheter designs exist such as (but not limited to) those products sold under the following trade names: Infiltrator, Transport, Infusasleeve, Dispatch. Other strategies are designed to have the agent coupled or included in a prosthesis, such as a stent, which is installed or deployed at the appropriate site of the body. Conversely, the prosthesis may have a property that preferentially attracts the agent which will localize on the prosthesis following systemic administration of the agent. The agents may be coupled to a polymer or to a biocompatible agent (herein termed carrier), such as collagen, which may be biodegradable or not. The complex agent-carrier can be delivered and implanted at the target site for diagnostic or therapeutic purposes. Finally, the agent may be coupled to an antibody that specifically recognizes a target site in the body through an antigen-antibody reaction.

When developing new therapeutic agents, it is known to attach a radioisotope to the molecules allowing detection and localization of the agents in the body with a radiation detection apparatus. The choice of radioisotope is dictated first by its availability and the configuration and chemistry of the molecule that needs to be tagged with a radioactive atom. Nonetheless this new atom that is attached to the molecule under study should not modify the toxicology of the original molecule. Radioisotopes that are commonly used in the medical field as imaging agents are, ⁹⁹Tc99m, ²⁰⁸TI, ⁶⁷Ga, ¹³³Xe and ¹⁸F. Most of these radioisotopes are used in combination with specific molecules for diagnostic purposes to study the function of organs. To quantify the amount of these molecules which are injected systemically, the radiation detection apparatus used are SPECT gamma cameras and Positron Emission Tomography scanners. These imaging modalities are possible due to the fact that the radiation emitted by the radioisotopes selected can escape the subject body without a high level of attenuation. These radioisotopes are either positron or gamma emitters.

Another family of radioisotopes like ³²P, ¹⁸⁸Re, ⁹⁰Sr/Y are beta ray emitters. Their beta radiation is much more attenuated by matter due to their fundamental physical characteristics and cannot be used as imaging agent with both conventional gamma cameras and PET scanners. There would be an insufficient amount of by product emitted by the radioisotopes escaping the body of the patient to produce a clinically valuable image, and even if there exists a situation where there was enough signal going out, the position information provided by the beta ray escaping the patient would be deteriorated due to the nature of the multiple interactions of the beta ray with the patient before escaping the body. This is known in the field of nuclear medicine as primary and secondary diffusion. For beta rays this effect is much more pronounced and prevents making precise imaging with a beta emitting isotope if the object to image is a volume (self attenuation) and also if it is surrounded by other tissue or material. However, routine microscope slides of cut tissues containing beta-emitters are conventionally imaged by molecular biologists using film or phosphor imager. Therefore to allow imaging with beta emitters particularly with the radioisotope ³²P, the detection apparatus has to be as close as possible of the region of interest to minimize attenuation and diffusion, and the object or region of interest has to be thin compared to the range of the beta ray used. During the course of the drug development, researchers have to determine the pharmacokinetics of the local delivered drug, i.e. the fraction of the drug that remains at the site of interest and also its variation with time during periods of minutes, hours, weeks, days and months.

Conventionally these pharmacokinetic studies of the injection and retention of the new potential drug candidate take place using a series of different animals for each point in time that the drug needs to be tested. At the point in time considered, the animal is sacrificed and the portion of the site of interest is then harvested and counted with an appropriate radiation detector for the remaining activity in the entire region of interest. This technique, if the pharmacokinetics of the drug requires a study over a long time period requires the sacrifice of a large number of animals.

It would thus be desirable to use a radiation detection apparatus and method, measuring at each point in real time and in-situ the amount of remaining drug by means of the remaining radioactivity. This would greatly reduce the number of animals needed in the study and also reduce the component of subject variability in the drug study. Therefore a more rapid, precise and less costly determination of the pharmacokinetics parameters is rendered possible by this new apparatus and method.

Application in Human Therapeutic Local Drug delivery.

The current local drug delivery strategies (in angiogenesis where VEGF, anti-restenosis (taxol)) involve controlled delivery using special tools for controlling dosage, however, no monitoring of agent delivery efficiency is presently carried out. Currently, once the delivery is performed, there are no means taken to verify the efficiency with which the agent is delivered. It is customary to take for granted that the delivery procedure was performed well enough to bring sufficient amounts of the agent to the target site. Unfortunately, most local drug delivery strategies are disappointing in terms of delivery efficiency and should mandate repetitive administration of the agent in the same procedure or during a follow-up procedure.

There is no commercial system currently available to detect precisely in vivo the amount of a beta emitting radioactive drug and its variation with time delivered locally to a coronary artery during an angioplasty procedure.

In US patent 5,811 ,814 granted to Leone et al., there is disclosed a radiation measuring catheter apparatus and method for measuring radiation at a region of interest inside a body. The region of interest being a blood vessel or an organ. The apparatus uses a sodium iodide Nal(TI) scintillator as a detection media, and is inappropriate for detecting beta rays inside a body into a coronary artery.

The use of beta emitters in the application of pharmacokinetic studies has the advantage over the use of gamma emitters that the energy and penetration of the beta radiation are less disruptive to the organism. A higher activity and count rate can be provided without endangering the organism, and thus can lead to more accurate measurement of drug delivery. To benefit from this advantage, however, one needs to overcome the problems of beta radiation detection, namely one must be close to the radiation source to measure the radiation directly without adverse influence of secondary diffusion, and one must discriminate between the beta radiation and background radiation.

In the in vivo environment, as disclosed by Leone et al. in the above- mentioned US patent, this involves placing a detector material at the tip of a catheter so as to be positioned immediately next to the region of interest in the body. However, the catheter disclosed by Leone et al. would be unsuitable for effective detection of beta radiation. For example, Leone et al. proposes that a short length of scintillator can be used to detect radiation and to obtain information about a distribution of radiation activity as a function of position. This is true for gamma radiation, but very difficult, if not impossible, for beta radiation due to secondary diffusion. Furthermore, beta emitters, such as the mentioned family of radioisotopes like ³²P, ¹⁸⁸Re, ⁹⁰Sr/Y, emit beta rays within a range of energy, and do not emit radiation at discrete energies like gamma emitters. Therefore, event discrimination requires calibration of the detector in the case of beta emitters. Calibration of a catheter radiation detector, of the type disclosed by Leone et al., is difficult. The scintillator is connected to the light detector (photomultiplier tube or PMT) via an optical fiber. The optical fiber has a transmission which is variable as a function of the curvature and stresses to which it is subjected. In use, the catheter, and thus the optical fiber, will be subjected to variable curvatures and stresses which cannot be precalibrated.

Summary of the Invention

According to the invention, there is provided a radiation detection catheter comprising a section of scintillation fiber for generating optical wavelength photons in response to nuclear radiation, the section having a length sufficient to provide a sensitive count rate with limited positional sensitivity, at least one optical fiber for conducting light from the section of scintillation fiber, the optical fiber having a proximal end adapted to be coupled outside of a patient to an optical light detector; and a radiopaque connector collar fitting over a proximal end of the section of scintillation fiber and a distal end of the optical fiber, the collar providing mechanical support for an optical coupling between the section of scintillation fiber and the optical fiber.

The radiopaque collar allows the catheter to be positioned using X-ray imaging techniques. The more sensitive count rate provided by the length of scintillation fiber allows for a lower dosage of radioactive tracer to be used with the drug or radioactive source whose presence is being measured. The length may be chosen to be approximately the size of the expected region of interest. As used herein, "scintillation fiber" means a scintillator so dimensioned as to fit inside the catheter tip and which also acts as a light guide up to the optical fiber. The invention also provides a radiation detection catheter comprising a section of scintillation fiber for generating optical wavelength photons in response to at least beta radiation, an optical light detector generating a light intensity signal, at least one optical fiber for conducting light from said section of scintillation fiber, the optical fiber having a proximal end adapted to be coupled outside of a patient to the optical light detector, a transmissivity of the photons from the scintillation fiber to the optical light detector being variable and dependent on at least one of curvature of the optical fiber, mechanical stress and temperature, a calibration device causing a predefined calibration transmission of photons from a distal end of the optical fiber to a proximal end of the optical fiber, the calibration transmission being distinguishable from the response of the scintillation fiber to beta radiation, and a beta radiation event discrimination processor analyzing the light intensity signal resulting from the predefined calibration transmission of photons and individual beta radiation scintillation events to output a signal indicative of valid discriminated beta radiation events.

The invention also provides a method for calibrating a radiation detection catheter for detecting beta radiation.

The calibration transmission can be done using a number of different mechanisms. Preferably, a monoenergetic radioactive source is provided at the scintillation fiber. An alpha ray emitter ²⁴¹Am provided on or in the scintillator is preferred for its high energy, suitable half-life and the fact that the alpha rays will not even exit a thin protective sheath, and thus will not interact with the surrounding body tissue when in use. The use of a light-protective jacket or sheath covering at least the optical fiber is strongly preferred according to the invention. It will be appreciated by those skilled in the art that the catheter may be adapted for insertion into the body using a guide wire.

Brief Description of the Drawings

The invention will be better understood by way of the following detailed description of a preferred embodiment with reference to the appended drawings, in which:

Fig. 1 is an illustration of the catheter according to the preferred embodiment in use in a patient;

Fig. 2 is sectional side view of the catheter and guide wire;

Fig. 3 is schematic graph of count rate as a function of energy for a beta emitter and a ²⁴¹Am calibration source;

Fig. 4a is a partly exploded side view of the optical fiber to PMT coupling according to the preferred embodiment;

Fig. 4b is an end view of the coupling of Fig. 4a; Fig. 5 is a cross sectional view of a multi-detector catheter tip according to an alternative embodiment having five radiation detection fibers arranged to be shielded from one another and detect radiation from five azimuthal sectors;

Fig. 6 is an illustration of an alternative embodiment similar to Fig. 5 with only three detection fibers;

Fig. 7a is a sectional view about plan A-A of Fig. 4a showing the arrangement of five optical fibers coupled with five multi-cathode inputs of a multi- cathode PMT according to the embodiment of Fig. 5;

Fig. 7b is an end view of the coupling of Fig. 7a; and Fig. 8 is a flow chart of the calibration and threshold level adjustment process according to the preferred embodiment.

Detailed Description of the Preferred Embodiment

As shown in Figs. 1 and 2, the first fiber [15], which is the active sensor of the catheter, is a plastic scintillator. It emits light when it absorbs and/or interacts with radiation. The quantity of photons emitted is proportional to the energy absorbed from the interacting radiation. Consequently, one can choose various sizes, depending of the intensity of the signal and the resolution needed.

The piece of scintillating fiber [15] is preferably 0.5 mm in diameter by 20 mm long. In the preferred embodiment, a plastic scintillating fiber is chosen for which the radiation absorption coefficient is very close to coefficient of organic tissues and is well adapted to the detection of beta radiation. This fiber consists of a polystyrene core with fluorescent dopants and a polymethylmethacrylate cladding. These fibers are commercially available from Bicron (model BCF-12). This scintillating fiber [15] after being appropriately treated (cut and polished) is glued with an optical glue (Bicron product BC-600 which has an index of refraction similar to the fiber) to a clear optical fiber light pipe [16] (Bicron model BCF-98). The optical fiber [16], also being appropriately treated for maximizing light transmission at the interface scintillating fiber [15], is 0.5 mm in diameter by approximately 2 meters in length. At each end of the scintillating fiber are slid and glued two pieces [14-18] of hypodermic tubing (Small Parts Inc. Miami Lakes FL - Product HTX-21-1/2) with inner diameter approximately 0.023 inch and outer diameter 0.030 inch, 5 mm long necessary to insure appropriate mechanical robustness and optical light transmission of the glued junction- interface on the one hand and also x-ray visibility under x-ray system on the other hand. Both extremities of the scintillating fiber can be imaged under the angiography system assuring proper positioning of the detector at the region of interest. The distal face end of the scintillating fiber can be painted with a white reflective coating [19].

The optical fiber [16] is then coupled to the window of a photo-detector [3] preferably a photomultiplier suitable for plastic scintillators (Electron Tubes Model 9902 KB) using an optical grease (Bicron model BC-630) with the appropriate index of refraction. As best shown in Figs. 4a and 4b, the proximal portion of the optical fiber [36] is maintained in place by using an appropriate retention mechanism [35], either a standard connector or a system carefully designed to maintain the end of the fiber [36] in close contact with the photomultiplier tube window [4]. The tube and its window are maintained in the dark by using a light tight enclosure and cover parts [38].

The photomultiplier tube [3] is shielded against the effects of the earth's magnetic field by using a sheet of mu-metal that is rolled around the tube. The tube is inserted in the appropriate socket (Electron Tube model C674A socket- divider) for voltage divider and for supplying the high voltage to the tube providing the signal out of the tube to the signal processor analyzer [2]. The photomultiplier [3] transforms light pulses emitted by the scintillating fiber [15] which are traveling along the optical fiber [16] into electrical signals. The photo-multiplier tube (PMT) is powered by a high voltage source and the electrical signal going out of the tube is a signal related to the amount of radioactivity detected by the scintillating fiber. The signal is either sent directly or amplified to a discriminator, incorporated within the analyzer [2], which produces an electrical signal if and only if the electrical signal is above a certain threshold.

The discriminated signal is either multi-channel analyzed or directly counted. In the case of multi-channel analysis, the analyzer [2] may include a multi-channel analyzer system such as a Canberra (model 1510). In the case of direct counting, the analyzer [2] may comprise a counter, such as a LUDLUM model Sealer Ratemeter 2200. The activity measured with time can be displayed on a monitor [1]. For a significant reduction in size and weight of the photomultiplier [3], a

Hamamatsu miniature metal package photomultiplier tube model R7400U can also be used with the scintillation detection assembly mentioned above. This photomultiplier features a major reduction in size over conventional photomultiplier tube, and has volume of only 2 cubic centimeters.

In the preferred embodiment, the plastic scintillating material is doped with a small amount of ²⁴¹Am atoms, an element being radioactive with a half-life of 433 days. These atoms are alpha emitters and the energy that is released is 5.5 MeV which allows real time calibration of the detector apparatus. Alpha particles are composed of two protons and two neutrons, have a very short path length and would interact with the plastic scintillator leaving about 5 MeV. The signal produced by these ²⁴¹Am atoms disintegrating would be distinct from the signal produced by ³²P atoms (in the preferred embodiment, the beta emitter drug tracer is ³²P. Thus, the ²⁴¹Am signal is used as a calibration signal and results in a system for defining the integrity of the detector apparatus especially the scintillating fiber, the optical light pipe and the fiber-light pipe interface.

The jacket assembly [6-17-37] is then slid over the scintillating material [15] and the optical light pipe [16] up to the connector [35] where it is attached there either by gluing it to the connector or by retaining it on the connector by an appropriate mechanism. The specially designed jacket consists of three individual plastic (black nylon) tubing extrusions, one for the proximal section [6], one for the distal section [17], which will enter into the coronary and the last distal section which comprises the tip of the jacket [11] and the saddle [20] for the guide wire [7]. The proximal section [6] has to be designed carefully to allow for light tightness and also for correct pushability, the distal section [17] has to provide enough support to allow for guiding and maneuvering into the coronary and also for light tightness using a cap [19] to close the lumen. The jacket has to be adapted with the fiber flexibility and support. The size of the jacket is designed such as, the fiber assembly and the x-ray markers has to slide easily in the jacket, meaning that the inner diameter of the jacket could be around 0.033 inch. The outside diameter of the jacket in the proximal section [6] has to be selected considering two criteria, the outside diameter (0.055") has to be selected to keep enough wall thickness to insure the jacket to be light tight and also the outside diameter has to be appropriate to allow an insertion in an aorta catheter with a 0.014 inch guide wire and providing enough support to be able to maneuver into the body.

The distal section [17] which will reach the coronary has to be profiled enough, meaning with an outer diameter of 0.045" providing also enough flexibility and support for access. In the last 0.5" distal section there is also provided a saddle [20] for the insertion of the guide wire [7] 0.014" in diameter and haying a soft tip [11] for preventing damage to the artery. A radio-opaque marker (visible under cine-fluoroscopy) [12] is also provided for the visibility of the tip of the jacket. The end of the lumen of the jacket has also to be sealed by a seal [19] to prevent any body fluid from coming into contact with the fibers.

The jacket material is sterilizable using ethylene oxide. The jacket serves the following purposes. It allows the catheter to be inserted and maneuvered up to the region of interest (e.g. coronary artery). The jacket prevents visible light from reaching the scintillating and optical fibers, and thus from simulating radioactivity. It protects the fibers from contamination by body fluids. The fibers are sensitive to water, etc. The jacket also assures trackability, flexibility and support of the catheter. The jacket can be coated by a hydrophilic substance to allow better sliding in the artery. The detection catheter may also be adapted to be harnessed to a pullback system such as the one used in intra-vascular ultrasound (Endosonics: Pullback system Trak Back Pullback)

The present invention permits the precise detection at the site of delivery of the presence of a drug or agent and the quantification of the amount of agent present at this site. The detection system may be linked through the catheter to a system able to transmit the information gathered by the detection system to an apparatus able to quantify the signal thus received from the catheter. The catheter will thus be able to detect any diagnostic or therapeutic agent, delivered locally to a site in an organ of the body or a tubular structure of the body of an animal or a human. The agent is preferably a beta radiation emitter, although a gamma radiation emitter may also be used, Thus, the present invention may be used in conjunction with a local agent delivery strategy where the following steps are followed: 1 - Local delivery of agent to organ or tubular structure of body.

2- Removal of the local drug delivery system.

3- Insertion and removal of a detection catheter system.

4- Evaluation of local agent delivery efficiency. 5- Termination of procedure or repetition of local drug delivery, according to efficiency evaluation.

In the case of a lost prosthesis, the device will be inserted in vivo, using fluoroscopic guidance, to detect and locate the lost prosthesis. This localization will then enable treating physicians to make the proper therapeutic decisions The purpose of the detection catheter (or probe) is to determine, both in real time and in-situ, the presence of the therapeutic agent, quantify the amount of the agent present and, consequently, permit the operator to modify accordingly the local agent delivery strategy. Its primary use is intended in interventiona! cardiology in anti-restenosis treatment. It may be used also to guide the therapy of other proliferative disorders occurring in any tubular structure or any organ. A radiolabelled agent would be locally delivered with the use of a specifically designed device, such as a catheter or a stent /or through an antibody-antigen reaction, then the radiation detection device would be inserted to measure the overall amount of radiation at the delivery site of interest. This disorder may be benign or malignant. Hence, the device may be used to guide the local therapy of a neoplastic disease by a radio-oncology team. Its secondary use would also be in the research and development of new locally delivered therapeutic agents by virtue of determining the pharmacokinetics of the agent, .i.e. its biological interactions both spatially and with time. The detection apparatus and method of the present invention has been designed to allow detection of radioactivity of a beta emitter such as ³²P at a region of interest inside a human body or animal preferably inside a coronary artery during an interventional cardiology procedure. This apparatus comprises a detection catheter adapted to be inserted in a blood vessel and maneuvered to the region of interest of the coronary artery. The detection catheter preferably comprises a visible light tight jacket which has a special shape and features; the distal end of the jacket being profiled in a way to allow access to the coronary artery and the proximal end of the jacket being rigid enough to allow pushability and also long enough to remain outside the body while maneuvering to reach the coronary artery, a section of a scintillation material long enough to insure to cover all the region of interest, preferably cylindrical in shape. This piece of scintillating material is attached to a fiber optic light pipe long enough to allow the pipe to reach the outside of the body either by gluing with a special optical glue or by fusing with heat the two sections. This scintillating material of tubular shape when hit by ionizing particles emits light (light at 350-600 nm) isotropically over a 4π solid angle. Some of the light is then trapped in the scintillating material and will exit the material at the proximal face entering the light pipe to be guided up to the photosensitive device. A reflector can be painted at the distal end of the tubular scintillating material to maximize light collection efficiency by reflecting the light emitted in distal direction that would be lost.

To maintain mechanical integrity and maximal light transmission efficiency of the junction, a piece of hypodermic tubing is slid and glued over the junction and also permits visibility of the proximal end of the scintillating material under X- ray imaging. At the distal end of the scintillating material a piece of hypodermic tubing is also glued to allow visibility of the distal end of the scintillating material under X-rays.

At the proximal end of the optical fiber light pipe, a specially designed connector is slid and glued over the light pipe. This connector with the fiber inserted and glued in it will be inserted in a socket that is disposed in intimate contact with the window of the photosensitive device on top of the window of the photo- sensitive device. To allow intimate contact of the optical light pipe with the window of the photosensitive device and also to maximize light transmission, optical grease is used between the window and the optical light pipe.

The light tight jacket is then slid over the scintillating material and the optical light pipe up to the connector where it is attached there either by gluing it to the connector or by retaining it on the connector by an appropriate mechanism. The specially designed jacket consists of three individual plastic tubing extrusions, one for the proximal section, one for the initial part of the distal section which will enter into the coronary, and the last distal section which comprises the tip of the jacket and the saddle for the guiding wire. The proximal section has to be designed carefully to allow for light tightness and also for correct pushability, the distal section has to provide enough support to allow for guiding and maneuvering into the coronary. The jacket has to be adapted with the fiber flexibility and support. The jacket material is sterilizable using ethylene oxide. This assembly comprising the scintillating material, the optical light pipe with the connector at the proximal end and the jacket is plugged into an appropriate socket facing the photosensitive device. The jacket is inserted and slid up to its proximal end in a tubular shape cover that is disposed over the photosensitive window to prevent ambient light to reach the photosensitive device.

The photosensitive device is preferably a photo-multiplier tube. The photomultiplier tube is mounted into a socket for appropriate connections to the high voltage power supply and for the output signal. The photo-multiplier tube (PMT) converts into electric charges the light signal resulting from the interactions of the ionizing radiation with the scintillating material that is guided along the optical light pipe. One ionizing particle interacting with the scintillation material, such as a beta-ray or alpha-ray, results in the emission by the scintillating material of many individual photons during a time interval (burst) and their number is proportional to the energy deposited in the scintillation material. The time interval called scintillation time is dependent upon the type of scintillation material. This time can range from ns for plastic scintillators to hundreds of ns for inorganic scintillators like Nal(TI) These individual photons in a burst will reach the photomultiplier and will be converted into electric charges proportionally with the number of photons in the burst. So the number of bursts in a time interval will be related to the activity present in the surrounding of the scintillation material and the amplitude of the bursts will be related to the energy deposited by the ionizing particle.

As illustrated schematically in the graph of Fig. 3, the ²⁴¹Am peak is a single monoenergetic peak, while the ³²P beta radiation is spread over a wide range, namely they have a maximal energy of 1.7 MeV with an average of 0.69 MeV. The calibration of the PMT and the discriminator is carried out as follow with reference to the steps illustrated in Fig. 8. For calibration purposes allowing to monitor in real time the integrity of the scintillating material, the junction between scintillating material and the optical light pipe, a small amount of ²⁴¹Am atoms is either embedded, deposited or painted onto the scintillating material. It would also be preferable to doped the scintillating material with the ²⁴¹Am atoms. The preferred choice of ²⁴¹Am atoms as a calibration source is governed by the three facts that 241 Am: 1) is an alpha emitter (i.e. low penetration into tissue of the radiation); 2) its half-life is 433 days (i.e. it is stable for the duration of the calibration period and remains active for the service life of the catheter); and 3) its high energy 5.5 MeV which is clear not to be confused with the maximum beta ray energy of 1.7 MeV from the ³²P beta radiation.

More specifically, because of its double charge +2e, alpha particles emitted by ²⁴¹Am have a very high rate of energy loss in matter and the range of these particles in scintillating material or other material is very small. Consequently, no alpha particles will escape the jacket and prevent any irradiation from reaching the patient body, thus making this calibration source particularly safe. Its half-life is also sufficiently long to allow a stable and reliable calibration for the lifetime of the invention. Lastly, alpha particles from disintegrations of ²⁴¹Am have an energy of approximately 5.5 MeV and will be discriminated against the energy deposited by beta particles from the ³²P which have a maximal energy of 1.7 MeV with an average of 0.69 MeV. These two types of disintegration can de disentangled using the energy spectrum produced by a spectroscopic multi-channel analyzer system. Two distinct energy discrimination windows can be set on this system for counting the calibration source and the locally delivered radioactive agent.

As illustrated in Fig. 8, in steps 100 to 104, the high voltage power supply of the PM tube is adjusted for optimum signal-to-noise ratio (SNR). For calibration, the catheter is placed in a stable environment, typically under no physical stress. The voltage is swept through an operational range of the PMT with no ³²P beta radiation source present, and the activity as a function of voltage is recorded (step 100). The activity measured increases with voltage. The step is repeated with the ³²P beta radiation source positioned near the scintillating fiber 15 (step 102). The recorded values are compared and a suitable voltage for the PMT is determined at which the SNR is optimized in step 104.

With the PMT voltage set, the calibration continues. The spectrum is recorded over a period of time for both background activity and ³²P beta radiation source activity. By comparing the spectra, a minimum PMT signal threshold and a maximum PMT signal threshold for ³²P beta radiation events is determined in step 106. The PMT signal value from the ²⁴¹Am peak is also recorded in step 108.

The calibration phase is then complete, and the catheter is ready to be used under in vivo conditions with real-time continuous recalibration. Since the ²⁴ⁱAm peak is monoenergetic, the PMT signal value for this peak is easily detected in step 110. This PMT signal value is then compared with the calibration value. An offset ratio is then calculated in step 112, and this offset ratio is applied to the minimum and maximum PMT signal thresholds for the ³²P beta radiation events. The adjusted threshold values in step 112 are then used to discriminate energies of PMT signals to determine valid ³²P beta radiation events. The recalculation of the offset ratio may be done every second or even more frequently, as desired. The steps 100 to 114 are carried out using the signal processor analyzer [2], with the steps 100 to 108 being implemented with suitable user instructions and user prompts displayed on the device [1].

There is provided with this calibration a means to monitor in real time the integrity of the detection assembly and also to provide some feedback for the calibration. The number of ²⁴¹ Am disintegrations is then measured and the shape of the spectrum analyzed over time during the lifetime of the invention. Differences in the number of disintegration per time unit or differences in the shape of the energy spectrum provide both a means to evaluate in real time the state of the invention and to react to any drift of the calibration either by providing a new calibration constant (a gain factor) or by replacing the fiber that has been damaged during the course of the intervention. For providing precise position information on the activity measurement and on the positioning of the special detection catheter, the catheter can be harnessed to a system that could automatically retract (pullback) by successive steps of typically 0.5-1 mm along the region of interest, the detection catheter. For each position, a measurement of the activity can take place allowing for an assessment of the distribution of the activity along the region of interest. This data can be analyzed and processed to determine the profile of the activity distribution at the region of interest. A modification of the present invention can be made possible to allow for the measurement of the azimuthal distribution of the activity in the cylindrical region of interest by using a set of individual fiber assemblies (scintillating material + optical light pipe and connector) tightly packed with individual photosensitive devices, one for each assembly. In the first alternative embodiment, the bundle of tightly packed optical fibers entering the PMT as shown in cross-section in Fig. 7b. Five scintillator members [15] as shown in Fig. 5 are arranged in parallel to one another. Each scintillator member will detect radiation within a solid angle sector to which it is exposed. A shielding separator 21 is provided to at least partly block radiation from other sectors. The light detector preferably comprises multiple photosensitive devices all provided in one package, namely a multi-cathodes photomultiplier tube, the input face of which is shown in Fig. 7a. This modification of the present invention could be used as the one described above with the feature that the individual counts provided by each of the individual fiber would be related to the azimuthal distribution of the radioactivity of the beta emitter and the sum of all fibers would be an indication of the radioactivity in the region of interest. In the further alternative embodiment of Fig. 6, only three scintillator members 15 are arranged, thus giving better sensitivity with less azimuthal resolution. While the scintillation members 15 in Figs. 5 and 6 are shown as cylindrical fibers, they may also be shaped to fill the pie-shaped prismatic cavities of the shielding 21.

Another way of monitoring the optical state of the fibers assembly would be to use a stable light source that would be injected at the distal end of the fiber assembly and would reach the photo-multiplier tube. This system would be composed of a stable calibrated light source, preferably an LED source, whose light would be sent through a standard optical fiber usually 50 μm in diameter. The light produced by the LED and which is guided through the optical fiber would be reinjected in the scintillating fiber at the distal end and finally detected by the PM tube. Any fluctuation in the light detection level would be interpreted as a damage produced to the fiber and adjustment to the gain of the system would be done to compensate for this damage. This calibration system would be totally automatic for the user. Two ways of monitoring could be used in this device, either the LED is consistently pulsing light at a specific intensity and with a certain repetition rate with a light intensity corresponding to a particle energy higher than the energy of the studied radiation particle and the calibration is in quasi real time and the LED js shining even during counting activity, or the LED is on for a calibration period and subsequently off for the counting. The latter way requires no light shielding of the detecting fiber assembly against the calibration optical fiber at the expense of having calibration and counting periods during different time intervals. The first regime provides real time calibration but requires that the calibration fiber and the detecting fiber assembly should be light shielded against each other so as not to contaminate each other.

There is also another method for providing some azimuthal information about the radiation distribution in the region of interest. The scintillating fiber could be shielded asymmetrically using a piece of dense material like tungsten of tantalum that is slid over the scintillating section for a certain azimuthal section. The metallic piece would be a cylinder where an azimuthal section has been removed. To obtain azimuthal information, the complete detecting fiber assembly has to be turned on itself inside the jacket. For each azimuthal position the number of counts is recorded and azimuthal distribution of radioactive agent can be measured.

Claims

We claim:

1. A radiation detection catheter comprising: a section of scintillation fiber for generating optical wavelength photons in response to nuclear radiation, said section having a length sufficient to provide a sensitive count rate with limited positional sensitivity; at least one optical fiber for conducting light from said section of scintillation fiber, said at least one optical fiber having a proximal end adapted to be coupled outside of a patient to an optical light detector; and a radiopaque connector collar fitting over a proximal end of said section of scintillation fiber and a distal end of said at least one optical fiber, said collar providing mechanical support for an optical coupling between said section of scintillation fiber and said at least one optical fiber.

2. The catheter as claimed in claim 1 , further comprising an optically opaque jacket covering said section of scintillation fiber and said at least one optical fiber.

3. The catheter as claimed in claim 1 , further comprising a further radiopaque collar fitting over a distal end of said section of scintillation fiber.

4. The catheter as claimed in claim 1 , further comprising: an optical light detector generating a light intensity signal; a calibration device causing a predefined calibration transmission of photons from a distal end of said optical fiber to a proximal end of said optical fiber, said calibration transmission being distinguishable from said response to beta radiation; and a beta radiation event discrimination processor analyzing said light intensity signal resulting from said predefined calibration transmission of photons and individual beta radiation scintillation events to output a signal indicative of valid discriminated beta radiation events; wherein a transmissivity of said photons from said scintillation fiber to said optical light detector is variable and dependent on at least one of curvature of said optical fiber, mechanical stress and temperature.

5. The catheter as claimed in claim 4, wherein said calibration device comprises a source of monoenergetic radiation positioned at a distal end of said scintillation fiber.

6. The catheter as claimed in claim 4, wherein said calibration device comprises a source of monoenergetic alpha radiation to which said scintillation fiber is responsive.

7. The catheter as claimed in claim 6, wherein said source is a small amount of ²⁴¹Am atoms embedded or doped in the scintillating fiber.

8. The catheter as claimed in claim 6, wherein said source is a small amount of ²⁴¹Am atoms deposited or painted onto the scintillating fiber.

9. The catheter as claimed in claim 1 , wherein said scintillation fiber comprises a plastic scintillator material.

10. The catheter as claimed in claim 1 , wherein: said section of scintillation fiber comprises a plurality of elongated members extending parallel to one another and shielding positioned between said members for at least partly shielding radiation incident on each of said members from others of said members; and said optical fiber comprises a plurality of optical fibers connected to each of said members and communicating light from each of said members to a separate light detector.

11. The catheter as claimed in claim 10, wherein said separate light detector comprises a multi-cathode PMT.

12. A radiation detection catheter comprising: a section of scintillation fiber for generating optical wavelength photons in response to at least beta radiation; an optical light detector generating a light intensity signal; at least one optical fiber for conducting light from said section of scintillation fiber, said at least one optical fiber having a proximal end adapted to be coupled outside of a patient to said optical light detector, a transmissivity of said photons from said scintillation fiber to said optical light detector being variable and dependent on at least one of curvature of said optical fiber, mechanical stress and temperature; a calibration device causing a predefined calibration transmission of photons from a distal end of said optical fiber to a proximal end of said optical fiber, said calibration transmission being distinguishable from said response to beta radiation; and a beta radiation event discrimination processor analyzing said light intensity signal resulting from said predefined calibration transmission of photons and individual beta radiation scintillation events to output a signal indicative of valid discriminated beta radiation events.

13. The catheter as claimed in claim 12, wherein said calibration device comprises a source of monoenergetic radiation positioned at a distal end of said scintillation fiber.

14. The catheter as claimed in claim 12, wherein said calibration device comprises a source of monoenergetic alpha radiation to which said scintillation fiber is responsive.

15. The catheter as claimed in claim 14, wherein said source is a small amount of ²⁴¹Am atoms embedded or doped in the scintillating fiber.

16. The catheter as claimed in claim 14, wherein said source is a small amount of ²⁴¹Am atoms deposited or painted onto the scintillating fiber.

17. The catheter as claimed in claim 12, wherein said section of scintillating fiber has a length sufficient to provide a sensitive count rate with limited positional sensitivity.