Patent Application
20070144523
The present invention relates to the delivery of polarized noble gases to subjects for evaluations using NMR spectroscopy and/or magnetic resonance imaging (“MRI”).
Polarized inert noble gases can produce improved MRI images of certain areas and regions of the body that have heretofore produced less than satisfactory images in this modality. Polarized helium-3 (“3He”) and xenon-129 (“129Xe”) have been found to be particularly suited for this purpose. Unfortunately, the polarized state of the gases is sensitive to handling and environmental conditions and can, undesirably, decay from the polarized state relatively quickly.
Hyperpolarizers are used to produce and accumulate polarized noble gases. Hyperpolarizers artificially enhance the polarization of certain noble gas nuclei (such as 129Xe or 3He) over the natural or equilibrium levels, i.e., the Boltzmann polarization. Such an increase is desirable because it enhances and increases the MRI signal intensity, allowing physicians to obtain better images of the substance in the body. See U.S. Pat. Nos. 5,545,396; 5,642,625; 5,809,801; 6,079,213, and 6,295,834; the disclosures of these patents are hereby incorporated by reference herein as if recited in full herein.
In order to produce the hyperpolarized gas, the noble gas is typically blended with optically pumped alkali metal vapors such as rubidium (“Rb”). These optically pumped metal vapors collide with the nuclei of the noble gas and hyperpolarize the noble gas through a phenomenon known as “spin-exchange.” The “optical pumping” of the alkali metal vapor is produced by irradiating the alkali-metal vapor with circularly polarized light at the wavelength of the first principal resonance for the alkali metal (e.g., 795 nm for Rb). Generally stated, the ground state atoms become excited, then subsequently decay back to the ground state. Under a modest magnetic field (10 Gauss), the cycling of atoms between the ground and excited states can yield nearly 100% polarization of the atoms in a few microseconds. This polarization is generally carried by the lone valence electron characteristics of the alkali metal. In the presence of non-zero nuclear spin noble gases, the alkali-metal vapor atoms can collide with the noble gas atoms in a manner in which the polarization of the valence electrons is transferred to the noble-gas nuclei through a mutual spin flip “spin-exchange.” After the spin-exchange has been completed, the hyperpolarized gas is typically separated from the alkali metal prior to administration to a patient (to form a non-toxic pharmaceutically acceptable product). Unfortunately, during production and/or during and after collection, the hyperpolarized gas can deteriorate or decay relatively quickly (lose its hyperpolarized state) and therefore must be handled, collected, transported, and stored carefully.
In the past, several researchers have used hyperpolarized gas compatible ventilators for delivering polarized gas to subjects to image hyperpolarized noble gases such as helium and xenon. For example, Hedlund et al., in MR-compatible ventilator for small animals; computer controlled ventilation for proton and noble gas imaging, 18 Magnetic Resonance Imaging, pp. 753-759 (2000), state that ventilators have been in routine use in their laboratory for a number of years. See also, Hedlund et al., Three-dimensional MR microscopy of pulmonary dynamics, Society of Magnetic Resonance (New York, N.Y., 1996); and a poster presented by Hedlund et al. at the Amer. Thoracic Society 1998 International Meeting (Chicago, 1998), entitled MRI of pulmonary airways with hyperpolarized helium; a computer-controlled ventilator for imaging synchronous gas delivery in animal studies (describing ventilator technology). In addition, Black and co-workers have used a hyperpolarized gas-compatible ventilator to generate what is believed to be the first ever in vivo images of hyperpolarized 3He in guinea pig lungs. See Black et al., In vivo He-3MR images of guinea pig lungs, Radiology, 199(3), pp. 867-870 (1996). Unfortunately, the valves used to control the delivery of the polarized gases have, in the past, been limited by one or more of slow response times, relatively limited flow rates, and/or limited respiration rates (about 120 breaths per minute (BPM)).
Despite the foregoing, there remains a need to provide improved valve configurations for ventilation delivery of hyperpolarized gas.
Embodiments of the present invention can provide improved MRI compatible hyperpolarized gas delivery valves that employ spool configurations.
In particular embodiments, the valve configuration uses multiple spools to controllably sequentially deliver for inhalation, a plurality of gases, such as a hyperpolarized gas and a non-polarized gas to a subject. The multiple-spool valve can be configured to controllably select between three or more different flow paths that allow for inhale, exhale, and breath-hold flow paths as well as delivery of different gas formulations.
In operation, the spool valve configuration can employ a command pilot gas signal with a pressure of between about 30-60 psi. In addition, the spool valves can be configured to react to the pilot pressure in a relatively short response time, such as in under about 50 ms, and typically in about 40 ms (which is less than about half the response time of diaphragm type valves) to alter the valve flow path to transmit the desired gas to the subject. In certain embodiments, the valve is configured to operate with a respiration or breath rate (breaths per minute or “BPM”) of at least 150 BPM, typically up to at least 180 BPM, and in certain embodiments about 200 BPM or more. Thus, in certain embodiments, the gas delivery valve can provide a fast response time for a high BPM with a low inhale/exhale ratio.
The gas delivery valves using at least one spool to actuate at least one gas flow path in a valve body may be particularly suitable for small animal ventilators used during NMR spectroscopy and/or MRI imaging sessions. The gas delivery valves can provide fast response times, which may be particularly suitable for use in situations where the subject is ventilated at a high BPM breathing rate with a low inhale/exhale ratio (I/E). The I/E ratio is the inspiration time over the expiration time, inspiration is the time during which the gas is provided to the animal (or other subject) while expiration is the time during which the animal (or other subject) is exhaling. Therefore, a high BPM, such as about 180 BPM, means that each breath lasts 333 ms. An I/E of 20/80 means that the device has 67 ms to deliver the desired tidal volume to the animal (or other subject). The speed at which the valve opens can be important, the faster the BPM, the shorter the I%, and the less time the valve has to open and supply the desired amount of gas to the animal (or other subject).
The I/E ratio is typically within about 30/70 to 60/40, but can vary outside of this range, depending on the desired result. The I/E ratio and BPM can be substantially fixed during “normal” (non-imaging) breathing. The BPM and I/E ratio can be adjusted to be different for imaging (hyperpolarized gas) breath runs, but once the image run is over, these operating parameters can return to “normal” breathing parameters.
Also, it is noted that 180 BPM may be an upper range for many small animal species and, in certain embodiments, the ventilator may operate at a lower rate. The operating parameters are animal species/weight driven. For example, mice use a faster BPM than a rabbit. The I/E ratio can change between animals but will typically stay within the range mentioned above.
The gas delivery valve for a ventilator is configured to supply hyperpolarized gas to a subject and includes: (a) a valve body having at least one gas flow path extending between at least one gas inlet port and at least one gas exit port and at least one spool receptacle (or bore), one of the at least one gas inlet ports being in fluid communication with a hyperpolarized gas source; (b) at least one spool member disposed in a respective one of said at least one spool receptacles of said valve body, said spool member configured and sized to cooperate with said valve body to selectively open and close the at least one gas flow path; and (c) at least one pilot fluid port in fluid communication with said spool receptacle. In operation, a pilot fluid command pulse signal having an associated pressure and duration is transmitted into said pilot fluid port forcing said spool to translate an actuation distance in a predetermined direction in said valve body receptacle to thereby open and/or close the at least one gas flow path.
Other embodiments of the present invention are directed to methods for delivering hyperpolarized gas for inhalation by a subject. The methods include: (a) providing a gas delivery valve with at least one gas flow path therein, the valve comprising a valve body and at least one spool held in the valve body; (b) transmitting a pilot command fluid pulse signal to the at least one spool to introduce pressure onto the spool to force the spool to translate an actuation distance in the valve body; and (c) opening and/or closing the at least one gas flow path in response to the transmitted signal to deliver hyperpolarized gas to a subject.
Other embodiments are directed to computer program products for delivering hyperpolarized gas using a ventilator and an associated gas delivery valve. The gas delivery valve defines a plurality of selectable gas flow paths using a plurality of individually actuatable spools held in the valve, each spool positioned in the valve so that it is in fluid communication with at least one respective pilot gas port. The computer program product includes a computer readable storage medium having computer readable program code embodied in the medium. The computer-readable program code includes: (a) computer readable program code that determines which gas formulation is to be delivered by the gas delivery valve for inhalation by the subject, the gas selection includes at least one hyperpolarized gas, at least one non-polarized gas, and a combined hyperpolarized gas and non-polarized gas mixture; (b) computer readable program code that determines whether to configure the gas delivery valve for inhale, exhale, or breath hold operation; and (c) computer readable program code that transmits a pilot command pulse signal to each spool to actuate the respective spool to a desired operative position in the valve body to thereby open and/or close the desired gas flow paths and deliver the desired gas therethrough.
Other embodiments are directed to an apparatus for delivering hyperpolarized gas to a ventilated subject undergoing NMR spectroscopic and/or MRI evaluation. The apparatus includes: (a) a gas delivery valve with at least one gas flow path therein, the valve comprising a valve body and at least one spool held in the valve body; (b) means for transmitting a pilot command fluid pulse signal to the at least one spool to introduce pressure onto the spool to force the spool to translate an actuation distance in the valve body; and (c) means for opening and/or closing the at least one gas flow path based on the position of the spool in the valve body in response to the transmitted signal to deliver hyperpolarized gas to a subject.
In certain embodiments, the present invention can provide relatively quick actuation of a double acting spool using a single pulse of pilot air to actuate the spool(s) in the valve, allowing the pilot pressure to then be released in between alternating pulses of pilot air to toggle from inhale to exhale. The spool can be actuated during the rising (initial portion) of the pressure response profile or curve. All or selected operations, functions and/or configurations of the embodiments described above with may be carried out as methods, systems, computer program products, assemblies and/or devices as contemplated by the present invention.
The foregoing and other objects and aspects of the present invention are explained in detail herein.
The present invention will now be described more fully hereinafter with reference to the accompanying figures, in which preferred embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Like numbers refer to like elements throughout. In the drawings, layers, regions, or components may be exaggerated for clarity. In the figures, broken lines indicate optional features unless described otherwise.
In the description of the present invention that follows, certain terms may be employed to refer to the positional relationship of certain structures relative to other structures. As used herein the term “forward” and derivatives thereof refer to the general direction the target gas or target gas mixture travels as it moves through the hyperpolarizer system; this term is meant to be synonymous with the term “downstream,” which is often used in manufacturing environments to indicate that certain material being acted upon is farther along in the manufacturing process than other material. Conversely, the terms “rearward” and “upstream” and derivatives thereof refer to the directions opposite, respectively, the forward and downstream directions.
Also, as described herein, polarized gases are produced and collected and may, in particular embodiments be frozen, thawed, used alone and/or combined with other constituents, for MRI and/or NMR spectroscopy applications. For ease of description, the term “frozen polarized gas” means that the polarized gas has been frozen into a solid state. The term “liquid polarized gas” means that the polarized gas has been or is being liquefied into a liquid state. Thus, although each term includes the word “gas,” this word is used to name and descriptively track the gas that is produced via a hyperpolarizer to obtain a polarized “gas” product. Thus, as used herein, the term “gas” or “target gas” has been used in certain places to descriptively indicate a hyperpolarized noble gas product and may be used with modifiers such as “solid”, “frozen”, and “liquid” to describe the state or phase of that product. As also used herein, the term “polarized gas” includes at least one polarized gas of interest (such as, but not limited to, 3He and/or 129Xe) and may include one or more other constituents such as other carrier, blending or buffer gases. Further, the terms “polarize”, “polarizer”, “polarized”, and the like are used interchangeably with the terms “hyperpolarize”, “hyperpolarizer”, “hyperpolarized” and the like.
The gas delivery valves contemplated by the present invention can be used for any ventilator systems for target subjects and are hyperpolarized gas-compatible for NMR and/or MRI procedures. “Subjects”, according to the present invention, can be any animal subject, and are preferably mammalian subjects (e.g., humans, canines, felines, bovines, caprines, ovines, equines, rodents, porcines, and/or lagomorphs). The term “small animals” includes mice, rats, guinea pigs, dogs, cats, monkeys, pigs, and rabbits.
Various techniques have been employed to accumulate and capture polarized gases. For example, U.S. Pat. No. 5,642,625 to Cates et al. describes a high volume hyperpolarizer for spin-exchange polarized noble gas and U.S. Pat. No. 5,809,801 to Cates et al. describes a cryogenic accumulator for spin-polarized 129Xe. As used herein, the terms “hyperpolarize,” “polarize,” and the like, are used interchangeably and mean to artificially enhance the polarization of certain noble gas nuclei over the natural or equilibrium levels. Such an increase is desirable because it allows stronger imaging signals corresponding to better NMR spectroscopy and/or MRI images of the substance and a targeted area of the body. As is known by those of skill in the art, hyperpolarization can be induced by spin-exchange with an optically pumped alkali-metal vapor or alternatively by metastability exchange. See Albert et al., U.S. Pat. No. 5,545,396.
Turning now to
In certain embodiments, the pilot gas signal can have a pulse length between about 10-40 ms, and typically between about 20-30 ms (block 105). The pilot gas signal can be provided as a gas stream having a pressure between about 30-60 psi. The gas delivery valve can be configured to operate with predetermined inhale, exhale, and breath-hold sequences (block 112). The gas delivery valve can be configured to ventilate hyperpolarized gas alone, hyperpolarized gas combined in situ with a selected non-polarized gas, and a non-polarized gas alone. The in situ combination can be caused by the positions of the spools in the valve body. The spools can be actuated by the steep rising edge of the pilot pressure curve associated with the pulsed pilot gas signal (block 108). The gas delivery valve may be adapted to accommodate or deliver at a breath rate of at least 150 BPM, typically up to at least up to about 180 BPM (block 122). In certain embodiments, the gas delivery valve may accommodate a breath rate of at least about 200 BPM (peak inspiration).
Referring again to
In operation, pilot air is directed to enter either port 43 or 41 and, apply pressure to the respective face of the spool head 20h. Increasing and decreasing the pilot air pressure will adjust the speed (faster and slower, respectively). The pressure from the pilot air against the spool head 20h forces the spool 20 to translate away from the pilot air input port. The translation positions the spool stem 20s in different operative and/or inoperative locations in the valve body 10b. In operation, the spool 20 translates (back and forth) to open and close selected gas flow paths in response to pilot gas transmitted into the valve body cavity of the spool head. The receptacle 10r for the spool head 20h is sized and configured so that the head of the spool 20h can translate a desired stroke distance “S” to open and close one or more gas flow paths.
It is noted that, although shown in
In certain embodiments, the spools are double acting spools that allow a single pulse of pilot air to actuate the valve to cause the spool 20 to move to the desired position and open or close the selected gas flow path. The pilot pressure can be released to atmosphere in between alternating pulses of pilot air to “toggle” the spool 20 from “inhale” to “exhale.” The spool actuation (back and forth) either opens and/or closes one or more gas paths. The actuation can occur during the steep rising edge of the pilot pressure curve as shown, for example, in
The volume of the pilot air circuit can be sized for quick response by optimizing the volume, port diameters and the like to provide a reduced spool stroke cycle. In certain embodiments, the spool stroke can be about 0.125 inches, the pilot circuit volume can be about 0.00306 in3 per inch of tubing. For example for 180 inches of tubing line, the pilot circuit volume may be about 0.5508 in3. The pilot port diameters may be about 0.0625 inches. The spool head size may be about 0.625 inches (diameter). In certain embodiments, the spool head is sized to have an area of between about 0.05-0.45 in2. The spool can be configured to weigh less than about 1 gram.
Referring back to
The valve body and its internal components can be formed from and/or coated with a material or materials selected for the ability to inhibit depolarization of hyperpolarized gas (such as due to relaxation attributed to gas interaction therewith). Coatings such as sol-gel coatings, deuterated polymer coatings, metal film coatings and other coatings and non-magnetic materials that inhibit depolarization have also been proposed. See, e.g., U.S. patent application Ser. No. 09/485,476 and U.S. Pat. Nos. 5,612,103 and 6,423,387, the contents of which are hereby incorporated by reference as if recited in full herein. For example, the valve body and/or components may be formed of materials such as, but not limited to, aluminum, TEDLAR, TEFLON, PTFE, DELRIN (acetal), and the like. Care should be taken to reduce the sources of friction by providing a smooth surface finish, and reducing the number of O-rings or selecting the O-ring material to reduce friction. In addition, the valve body can be fabricated to tolerances to provide sufficient seals and yet provide reduced friction between the spool and valve body receptacle. Thus, the valve body bore finishes, O-ring compression, and lubricants may all be considered to reduce the sources of friction.
Similarly, the flow of Gas B from an external source and through the Gas B input port 31 to exit port 235 is controlled by the positioning of second spool 20B. The second spool 20B also has two operative positions, B1 and B2. Valve body 10b defines a second elongate flowpath 35 extending in fluid communication between the spool receptacle for spool 20B and an aperture 37 opening into the spool receptacle for spool 20C. Aperture 37 desirably is located opposite the open end of flowpath 135 from the spool receptacle for spool 20A, although they may be arranged differently, or even co-extensively. The positioning of the spool segments 20s1, 2s2 of spools 20A and 20B can be adjusted to allow Gas B to be output alone or combined with Gas A, as will be further described for
The third spool 20C is configured to control the inhale and exhale configuration of the valve 10. As such, the third spool 20C has an IN position and an EX position. The valve body 10b defines an exit ports 235 and 236 in fluid communication with the spool receptacle 10r for spool 20C. The position of the third spool 20C cooperates with the associated valve receptacle 10r to either direct flow from about spool segment 20s2 and out exit port 235 when spool 20C is in the IN (or inhale) position, or from exit port 235, about spool segment 20s1 and out exit port 236 when spool 20C is in the EX (or exhale) position, as desired. The gas flow path depicted in
Whereas flowpaths 35 and 135, which are considered to extend outside the plane of the view depicted in
As shown and further described below, the valve 10 can be actuated to accommodate or provide (a) Gas “A” inhale; (b) Gas “B” inhale; (c) Gas “A”+Gas “B” inhale; (d) exhale; (e) partial exhale and breath hold; (f) Gas “A” inhale and breath hold; (g) Gas “B” inhale and hold; and (h) Gas “A”+Gas “B” inhale and breath hold. The valve spool configuration can be adjusted to provide all or selected ones of these ventilation breath inputs/outputs and may use lesser or greater numbers of spools and/or respective spool segments as well as different porting configurations to provide the desired breath outputs/inputs.
The valve spool positions and sequencing of operation can be automated and controlled by a computer control program. The actuation or piloting of the valve spools 20A, 20B, 20C, can be driven through the computer control program by six (6) electric three-way normally closed solenoid valves. Examples of suitable solenoid valves include, Clippard EC-#M-12V, Cincinnati, Ohio., and MAC 42A-AMP-000-GDDB-1BE, Wixom, Mich. In certain embodiments, a command is given to actuate an individual spool to a desired position. The command triggers the transmission of a 20-30 ms pilot command pulse signal to the individual spool. The single command pulse toggles the spool to the desired position. After the pulse, the normally closed solenoid valve vents to atmosphere so that the pilot pressure for that spool does not generate undue resistance to the opposing pilot gas (air) when it is actuated to drive the spool back to its previous position.
The hyperpolarized gas may be a hyperpolarized noble gas such as 3He and/or 129Xe. The non-polarized gas may be a mixture of non-polarized gases. The non-polarized gas can be selected to inhibit depolarization of the hyperpolarized gas, and may be also selected for biocompatibility. Examples of suitable non-polarized gases include, but are not limited to, nitrogen, xenon, and helium.
The valve body 10b (
As will be appreciated by one of skill in the art, the present invention may be embodied as a method, data or signal processing system, or computer program product. Accordingly, the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment or an embodiment combining software and hardware aspects. Furthermore, the present invention may take the form of a computer program product on a computer-usable storage medium having computer-usable program code means embodied in the medium. Any suitable computer readable medium may be utilized including hard disks, CD-ROMs, optical storage devices, or magnetic storage devices.
The computer-usable or computer-readable medium may be, for example but not limited to, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, device, or propagation medium. More specific examples (a nonexhaustive list) of the computer-readable medium would include the following: an electrical connection having one or more wires, a portable computer diskette, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), an optical fiber, and a portable compact disc read-only memory (CD-ROM). Note that the computer-usable or computer-readable medium could even be paper or another suitable medium upon which the program is printed, as the program can be electronically captured, via, for instance, optical scanning of the paper or other medium, then compiled, interpreted or otherwise processed in a suitable manner if necessary, and then stored in a computer memory.
Computer program code for carrying out operations of the present invention may be written in an object oriented programming language such as Java7, Smalltalk, Python, or C++. However, the computer program code for carrying out operations of the present invention may also be written in conventional procedural programming languages, such as the “C” programming language or even assembly language. The program code may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user=s computer and partly on a remote computer or entirely on the remote computer. In the latter scenario, the remote computer may be connected to the user=s computer through a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).
As shown in
The I/O device drivers 358 typically include software routines accessed through the operating system 352 by the application programs 354 to communicate with devices such as I/O data port(s), data storage 356 and certain memory 314 components and/or the image acquisition system 320. The application programs 354 are illustrative of the programs that implement the various features of the data processing system 305 and preferably include at least one application that supports operations according to embodiments of the present invention. Finally, the data 356 represents the static and dynamic data used by the application programs 354, the operating system 352, the I/O device drivers 358, and other software programs that may reside in the memory 314.
While the present invention is illustrated, for example, with reference to the Sequence Module 350 for selective actuation of spools in a gas delivery valve being an application program in
In certain embodiments, the Sequence Module 350 includes computer program code for timing the delivery of the desired inhalation gas(es) and may include code for tracking polarization level data of the dispensed hyperpolarized gas. The Module 350 can direct initiation of operations that will automatically sequence the spools to output at a desired breath per minute rate and may automatically adjust the rate based on sensed activity of the ventilated subject or upon clinician input by increasing or decreasing the pressure of the pilot command pulse signal.
The I/O data port can be used to transfer information between the data processing system 305 and the NMR data acquisition system 320 or another computer system, a network (e.g., the Internet) or other device controlled by the processor. These components may be conventional components such as those used in many conventional data processing systems, which may be configured in accordance with the present invention to operate as described herein.
While the present invention is illustrated, for example, with reference to particular divisions of programs, functions and memories, the present invention should not be construed as limited to such logical divisions. Thus, the present invention should not be construed as limited to the configuration of
The flowcharts and block diagrams of certain of the figures herein illustrate the architecture, functionality, and operation of possible implementations of probe cell estimation means according to the present invention. In this regard, each block in the flow charts or block diagrams represents a module, segment, or portion of code, which comprises one or more executable instructions for implementing the specified logical function(s). Certain of the flowcharts and block diagrams illustrate methods to operate hyperpolarizers or components thereof to yield polarized gas according to embodiments of the present invention. In this regard, each block in the flow charts or block diagrams represents a module, segment, or portion of code, which comprises one or more executable instructions for implementing the specified logical function(s). It should also be noted that in some alternative implementations, the functions noted in the blocks may occur out of the order noted in the figures. For example, two blocks shown in succession may in fact be executed substantially concurrently or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved.
The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. Although a few exemplary embodiments of this invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the claims. In the claims, means-plus-function clauses, where used, are intended to cover the structures described herein as performing the recited function and not only structural equivalents but also equivalent structures. Therefore, it is to be understood that the foregoing is illustrative of the present invention and is not to be construed as limited to the specific embodiments disclosed, and that modifications to the disclosed embodiments, as well as other embodiments, are intended to be included within the scope of the appended claims. The invention is defined by the following claims, with equivalents of the claims to be included therein.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US04/05567 | 2/25/2004 | WO | 8/18/2006 |
| Number | Date | Country | |
|---|---|---|---|
| 60450209 | Feb 2003 | US |
