A portion of the material in this patent document is subject to copyright protection under the copyright laws of the United States and of other countries. The owner of the copyright rights has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the United States Patent and Trademark Office publicly available file or records, but otherwise reserves all copyright rights whatsoever. The copyright owner does not hereby waive any of its rights to have this patent document maintained in secrecy, including without limitation its rights pursuant to 37 C.F.R. §1.14.
1. Technical Field
This description pertains generally to a chemistry system for three-dimensional (3D) imaging, and more particularly to a bench-top radiochemistry system for 3D imaging.
2. Background Discussion
Positron Emission Tomography (PET) is a dynamic 3D imaging modality that can be used for microorganisms, cells, animals, plants, and humans to quantitatively measure biochemical processes in vivo. It uses “probes” (e.g. small molecules, peptides, proteins, nanoparticles, etc.) that are labeled with positron-emitting radioisotopes such as fluorine-18, carbon-11, nitrogen-13, oxygen-15, iodine-124, and copper-64, which interact on a molecular level with the biological system under study. Thus, PET can provide insight into various functional questions about biology, such as the distribution of metabolic activity (rate) in an organism, the spatial distribution of a target (e.g. cell surface marker or receptor); the movement of cells or microorganisms, the quantification of gene expression levels, the pharmacodynamics and pharmacokinetics of drug perturbation, and many other processes. Due to the high sensitivity of radiation detectors, PET is extremely sensitive compared to other imaging modalities, and can be accomplished with trace amounts of the probe, thereby not further perturbing the biological system under study. Additionally, due to the ability of energetic gamma rays (emitted after annihilation of positrons) to penetrate thick objects, PET can quantitatively image deep inside animal and plant tissues, enabling visualization of processes that cannot be easily seen with optical methods involving fluorescence or bioluminescence. Thus, PET provides a powerful way to safely study biology that can be translated across cells, plants, animals, and humans.
While PET would offer many advantages to the research community if a diversity of probes were routinely available, accessibility to the ˜3,000 known probes is very limited. In fact, the majority of PET studies (˜90%) employ only one probe, the glucose analog, 2-fluoro-2-deoxy-D-glucose (FDG). Due to their short half-life, as determined by the radioactive isotope they are tagged with (i.e. fluorine-18, ˜110 min), probes must be chemically synthesized immediately before use in a manner that provides safety and reliability to the user. Currently, PET probe production is expensive and requires a large capital investment in infrastructure (e.g. cyclotrons, cumbersome lead-shielded chemistry “hot cells”, purification systems, etc.) and specially trained personnel (for radiochemistry and cyclotron operation). Thus, the bulk of PET probes are produced in a centralized manner by commercial PET radiopharmacies established for clinical use of PET, with limited capacity and expertise, and high operating costs that restrict them from including production of new imaging probes. A number of universities have the same infrastructures as the commercial radiopharmacies. In these academic programs, production of probes is also complex, costly, and maintains a limited capacity to provide the diversity in molecular probes that matches the diversity of disciplines and biological problems to be studied.
The present description details a new hybrid approach in contrast to the established, centralized approach, by providing both the traditional radiopharmacies and researchers/clinicians (decentralized model) with the technology to produce on-demand batches of their PET probe of interest in an automated, user-friendly, device with low overall cost.
The systems and methods of the present disclosure use microfluidics for the integration of unit operations of chemical synthesis, purification, and quality control (QC) into a compact, inexpensive, self-shielded device. With the technology of the present disclosure, one would simply need a supply of the radioisotope from commercial radiopharmacies and a kit comprising one-use reagents and a chip. Such systems provide vast improvements to the research and clinical production field by providing the freedom for scientists in diverse disciplines to use molecular imaging probes of their choice without the normal infrastructure, expense, and complexity that is normally associated in existing systems.
In a preferred embodiment of the present disclosure, the system is configured to be operated without a hot cell, allows multiple radiosynthesis runs from a single batch of radioisotope, and ensures that the user is not exposed to radiation when changing a disposable cassette between one radiosynthesis and the next. In another embodiment, the batch of radioisotope can be safely changed without waiting for radioactive decay.
Further aspects of the technology will be brought out in the following portions of the specification, wherein the detailed description is for the purpose of fully disclosing preferred embodiments of the technology without placing limitations thereon.
The technology described herein will be more fully understood by reference to the following drawings which are for illustrative purposes only:
For purposes of the following description, the following terms are defined as follows:
A “radiopharmaceutical” (e.g. “PET probe”, “PET tracer”) is a radioactive pharmaceutical. Radiopharmaceuticals are used in the field of nuclear medicine as tracers in the diagnosis and treatment of many diseases. Radiopharmaceuticals are more commonly known and detailed in the context of this disclosure as a “PET probe” or “PET tracer.”
“Positron Emission Tomography (PET) Imaging” is a nuclear medical imaging technique that produces a three-dimensional image or picture of functional processes in the body. A radioactive PET probe is injected into the patient before they are placed into the PET scanner; the PET scanner is a camera that detects the location of the PET probe in the patient's body.
As the radioactive isotope on the PET probe undergoes positron emission decay (also known as positive beta decay), it emits a positron, an antiparticle of the electron with opposite charge. The emitted positron travels in tissue for a short distance (typically less than 1 mm, but this depends on the isotope), during which time it loses kinetic energy, until it decelerates to a point where it can interact with an electron. The encounter annihilates both electron and positron, producing a pair of annihilation (gamma) photons moving in approximately opposite directions (two 511 keV gamma photons being emitted at almost 180 degrees to each other). These are detected when they reach a scintillator in the scanning device, creating a burst of light, which is detected by photomultiplier tubes or silicon avalanche photodiodes (Si APD). The technique depends on simultaneous or coincident detection of the pair of photons moving in approximately opposite direction (it would be exactly opposite in their center of mass frame, but the scanner has no way to know this, and so has a built-in slight direction-error tolerance). Photons that do not arrive in temporal “pairs” (i.e.
within a timing-window of a few nanoseconds) are ignored.
“Reagents” are any biological or chemical entity that participates in synthesis.
“Synthesis” is the action of chemically adding the radioactive isotope to another entity, e.g. a small molecule, a protein, a peptide, an antibody, etc.
“Positron emitters” are any radioactive isotope that can be used in PET imaging (e.g. C11, F18, O16, Ga68, etc.).
A “radiosynthesizer” is a radiochemistry synthesizer, e.g. device used in the synthesis of PET probes. F-18 is a fluorine radioisotope, which is an important source of positrons. It has a half-life of 109.771 minutes. It decays by positron emission 97% of the time and electron capture 3% of the time. Both modes of decay yield stable oxygen-18 (see O-18).
“O-18”, or “Oxygen-18,” is a natural, stable isotope of oxygen. Enriched water (H2Ô18) is bombarded with hydrogen ions in either a cyclotron or linear accelerator creating fluorine-18 (see F-18).
“Specific activity” is generally defined as the amount of radioactivity per unit mass of the labeled compound. The mass of the labeled compound includes the mass of the radioactive product as well as the mass of the nonradioactive counterpart. Generally given in Ci/mmol. When dealing with the production of PET probes, it's important to minimize the isotopic dilution (contamination from stable isotopes of the same element). For example, in the production of F18, it is desirable to minimize the amount of F19 in the sample). The extent of isotopic dilution is determined by the measurement of the specific activity of the probe.
A “cyclotron” is a type of particle accelerator in which charged particles accelerate outwards from the center along a spiral path, and is typically used in the production of PET isotopes, specifically F-18.
“Pig” refers to the lead or tungsten holder that allows safe and shielded transport of radioactive compounds.
A “cartridge” is a container that holds a filter, absorbent material, chemical substance, or combination of these items that alternately binds and releases substances passing through it. Depending on what it is packed with, a cartridge may also be referred to as “QMA” or “SPE.”
“Eluent” is a liquid used to remove substances trapped on a cartridge
“Shine” is direct radiation emitted from the radioactive source.
“Radioactivity” is referred to as the emission of ionizing radiation or particles caused by the spontaneous disintegration of atomic nuclei.
“Hot” refers to parts of the system that are radioactive and must be shielded. “Cold” refers to nonradioactive, non-shielded areas.
“Half-life” refers to the amount of time required for a quantity to fall to half its value as measured at the beginning of the time period. While the term “half-life” can be used to describe any quantity which follows an exponential decay, for purposes of the present disclosure the term “half-life” is used to define the time required, probabilistically, for half of the unstable, radioactive atoms in a sample to undergo radioactive decay.
“Radiopharmacy”/“Radiochemistry core” refers to any facility that has a cyclotron and produces radioactive isotopes for PET probe synthesis on demand. This can be both commercial (e.g. PETNET, Cardinal Health, etc.) or academic (e.g. UCLA's Crump Center, UCLA's Ahamanson center).
“Preclinical” refers to experiments conducted on any system (cells, animals), not including humans. “Clinical” refers to studies conducted on humans.
“Customer” refers to people/entities generally falling into 3 main categories: 1) preclinical researchers who want to introduce (and control) PET imaging in their own lab, 2) radiopharmacies/radiochemistry cores that have a dedicated infrastructure to supply PET probes, but are looking to branch out in the menu of probes that they supply to customers, and 3) clinicians who have PET scanners in their facility and want a diversity of FDA-approved or clinical research probes (probes in clinical trials) to give to their patients/study subjects.
The radioactive isotope dispensing subsystem 12 draws isotope (e.g. F18) out of shipping vial or vial in pig 28, quantifies radioactivity, and dispenses user-defined aliquots (metered F18 fluid plug 22) to the concentration subsystem 14. In a preferred embodiment, the radioactive isotope (1-30 mL of liquid form) comes in a 30 mL sealed glass vial 28 (13 mm septum topped and crimp capped) held in a tungsten or lead pig 30. Alternatively, the radioactive isotope could come in a different type of vial (5 mL v-vial), Eppendorf tube, syringe, or direct line from a generator or cyclotron (not shown).
In the concentration subsystem 14, the aliquot of isotope is pushed through a concentrator cartridge 60 (see
The synthesizer subsystem 16 brings reagents (including concentrated radioactive isotope 24 from concentration subsystem 14) to the chip, and includes a disposable cassette 80 for all wetted paths and shielding for waste management, and performs synthesis of crude (unpurified) PET probe. It is noted that the concentration subsystem 14 and synthesizer subsystem 16 may occupy the same space, and/or use the same elements, as their consumables are changed at the same frequency.
Purification/Formulation module 18 removes crude (unpurified) PET probe 26 from the chip, passes it through a cartridge or HPLC column (both accounted for in system), collects purified product into a shielded container, and puts the purified product into proper volume and solution. For the purpose of the present description, cartridge purification (for FDG) is considered.
Computer 80 may also be coupled to each of the subsystems to control calibration and operation of various processes via software 84 stored in memory 86 and executable on processor 82.
In a preferred embodiment, the workflow is as follows. First, a user places pig 30 with radioactive isotope vial 28 in synthesizer 12. A drawer (not shown) may be available on the front of the device housing 32 to allow the user to place the pig 30 into a cavity 38 of housing. The user assembles other subsystem cassettes (e.g. cassette 80 (
If it is the first run of the day, the user interacts with the provided software 84 by first inputting some information about the radioactive isotope 28 (e.g. which isotope, amount of radioactivity, time, etc.). This information may be available from a label on the tungsten pig 30.
The user chooses from list of PET probes and indicates how much activity should be delivered to the synthesis subsystem, and the amount of radioactivity to start the synthesis with (or the user may select the final amount of synthesizer/purified/formulated probe desired, and the system calculates the corresponding starting activity based on the synthesis time and expected yield. The system 10 self-calibrates the radioactivity concentration, and then makes calculations to determine the proper volume to be dispensed.
The synthesizer 10 runs through all subsystems without user intervention. The system 10 (e.g. via software) alerts the user that the run is complete and the user removes the shielded pig 30 with the purified and formulated product in the vial for use in PET imaging. The user removes the used and radioactive reagent-chip-concentrator cassette 90 in a removable shielded holder (if HPLC is used, the system cleans the purification system). If the next user needs a different radioactive isotope (e.g. F-18 vs. Ga-68) or different isotopes are used on the same day (i.e. before the radioactivity has decayed to background levels), the radioactive isotope-dispensing cassette 40 is removed. This could be accomplished either by replacing the whole shielded cassette with a new shielded cassette, or by opening the dose dispensing cassette shielding and replacing just the cassette. In a preferred embodiment, all wetted components of the dose dispensing cassette 40 are disposable, and all paths that contain radioactivity are shielded by material capable of attenuating beta and gamma rays. In a preferred embodiment, all materials are solvent-resistant.
First, the dispensing system 12 lifts the ˜10 lb pig 30 up (e.g. via linear actuator 58 and elevator platform 35 shown in
A pliable tube (not shown) made from a silicone material is connected to the needle 36 and runs through a pump 46, which is fixed to housing 48 of dispensing cassette 40 (see
The first time the fluid path is filled, the fluid is stopped and a radiation sensor 44 measures the amount of radioactivity in the tubing. In a preferred embodiment, the sensor 44 comprises a dual pin diode detector for sensing a gamma photon signal that can be used to obtain dose information. Because the geometry of the tubing and sensor are precisely fixed (and consistent from cassette to cassette), the sensor reading provides a measure of the activity concentration of the isotope. Calibration may be performed at the time a dose is requested, though it may be preferable to perform the calibration as soon as the pig is installed (see above). Calibration is only performed once for each batch of radioisotope (thus, for this generation of the system, once per day).
The dispensing subsystem 12a dispenses fluid until the requested volume (computed from the requested activity) is in the fluid line. Then the valve 42 on the output changes state. This allows the output metered volume fluid plug 22 to be driven by gas pressure to the concentration subsystem. The dispensing subsystem 12a then may retract the remaining fluid in the lines back into the radioactive isotope source vial 28, minimizing the activity outside of the pig 30. This reduces the radiation exposure to users from activity that remains in the tubing when this subsystem is not being utilized. During the retraction phase a valve (or alternate mechanism) may be used to disconnect this subsystem from the next subsystem and the peristaltic pump 46 may run in reverse. This is because the next two subsystems 14 and 16 have disposable components that are ideally replaced after every synthesis, while the isotope dispensing subsystem's disposable parts only need to be replaced once per day.
However, it is also appreciated that an alternative embodiment may have the needle and dispensing fluid path may be integrated into a disposable cassette that also houses the concentrator module 14 and the synthesis module 16, if so desired. This configuration would still interface with the shielded vial 30, elevator 35, and radiation sensor 44 as provided in
The radioactive isotope dispensing subsystem 10 outputs metered “activity” fluid plugs 22 to the concentration subsystem 14. The activity is defined by the user and may be requested via a USB or Ethernet connection (not shown). The output fluid plug 22 is ideally followed by air/inert gas 52 to ensure it can be pushed all the way through the concentration subsystem 14 and to avoid retaining activity in the output line. The vial 28 may also be vented with filter 56.
At this point, the isotope dispensing subsystem 12a has completed its operation and can await a new request for additional radioactivity. One 100 mCi vial 28 can support many syntheses.
Every time the radioactive isotope vial is changed, the wetted path 54 that interacts with this subsystem should be changed. This includes needles, valves (if disposable), tubing, vials, etc. In a preferred embodiment, this is achieved via disposable cassette 40 that is safe and easy to insert and remove (e.g. to avoid “spaghetti” tubing and unprotected needles). Additionally, the entire radioactive isotope dispensing subsystem 12 is designed as compact as possible to reduce fluid path lengths.
An alternative embodiment dispensing subsystem 12b is shown schematically in
In one embodiment, an H-bridge driver or stepper driver is used as the actuator 58 for driving up the elevator platform 35 (see
As detailed above, one embodiment of this design incorporates a valve 42 to disconnect the radioactive isotope vial from the peristaltic pump. The dispensing unit 12 could then drive air into the concentration subsystem 14. This may include 1 or 2 more DC drivers for valve actuation.
Additional sensors, along with associated circuitry, may also be incorporated to sense one or more of: the presence of a particular (e.g. BIODEX) pig 30, drawer/door state (e.g. open/closed), elevator platform 35 up or down, proper cassette engagement, shielding, etc. Many of these sensors may comprise interlock type sensors that simply use a contact switch or similar mechanism.
As shown in
An amount of radioactivity (metered dose 22) from the dose dispensing subsystem 12 is directed through a cartridge 60 capable of trapping the radioactivity and sending the eluent to waste or collection vial 66. In particular, for F18 fluoride, the source of activity may be in several m Ls of O18-enriched water, and thus it is necessary to reduce both the volume of the delivered droplet as well as the water content, which inhibits the reactivity of the F18 fluoride, while still maintaining the same amount of radioactivity. To do this, a “trap and release” mechanism is used. The benefit of this trap-and-release mechanism is to decrease downstream evaporation time, due to lower water content and smaller final volume. The concentration also acts as a purification step, eliminating metallic impurities that might adversely affect the synthesis.
The concentration is achieved by trapping the radioactivity onto a solid-phase extraction cartridge 60 typically filled with an ion exchange material such as quaternary methylammonium (QMA). The QMA material is positively charged and will trap the anions (e.g. F18 fluoride) from the solution, exchanging them with the anions previously bound to the QMA 60 (e.g. the anions used in preconditioning the cartridge). The user will often want to recycle the O18-enriched water after stripping it of F18 fluoride, since the water could be returned to the supplier for re-purification and reuse. Therefore, the O18 water is captured in a vial 62. The trapped F18 is then eluted off the QMA cartridge 60 by passing an eluent (liquid) 66 through the QMA 60 in the desired final volume. This concentrated F18 24 is then pushed into the synthesizer subsystem 16 to act as a reagent in the synthesizer subsystem.
In the embodiment shown in
The functionality of the concentration subsystem 14 is largely dependent on changes in valve state. For the embodiment shown in
To trigger valve state changes, liquid sensors may also be placed at different locations, e.g. the inlet to the waste vial 64 and the inlet to the loop 74. These sensors inform the system when the loop has be filled and is ready for injection. Each liquid sensor may also be coupled with an ADC for sampling the phototransistor. An alternative would be to use a comparator, and instead detect the presence of liquid with a single digital input. The advantage to using an ADC is the added algorithmic flexibility, to both debounce and filter the response and avoid miss-triggers. Note that this subsystem ideally will communicate with the isotope delivery subsystem 12 (e.g. via computer 80 and software 84). For example, after the liquid is detected at a certain point, then the delivery is complete and the delivery subsystem 12 can stop delivering gas.
Additionally, a preferred embodiment includes a radiation sensor (not shown) that is placed on the QMA cartridge 60 and is used to ensure proper trapping of the F-18 as well as proper release. Trap and release efficiency can thus be approximated in real time. Similar to the radiation sensor 44 used in the dispensing subsystem 12, a solid-state PIN diode can be used with the appropriate analog processing circuitry. Another ADC would be used for sampling the output from this sensor.
In the embodiment shown in
In a preferred embodiment, all wetted paths in the concentration subsystem 14 are disposable, compact, and in cassette form. Furthermore, all wetted paths and vials (except the initial eluent vial 66) are hot and should be shielded. Preferably, disposable valves 70 are used to actuate these steps. In an alternative embodiment (not shown) the concentration subsystem 14 may be integrated with the synthesizer subsystem 16 to reduce shielding, and the wetting paths of both subsystems could be combined to reduce costs. In a preferred embodiment, disposable valves are used to actuate the above-detailed steps. Alternatively, non-disposable valves could be used. In a preferred embodiment, all materials are solvent-resistant.
Referring now to
As illustrated in
In a preferred embodiment, all wetted paths are disposable and any wetted paths that are radioactive are contained within shielding that can attenuate beta and gamma rays. Any wetted paths that are not radioactive are contained outside shielding. Furthermore, the shielding that holds the reagent-chip cassette (e.g. cassette 90) and concentrator subsystem 14 can be removed from the main system 10 and placed away from the main system 10 to allow the radioactivity to safely decay.
The reagent-chip-concentrator cassette/cassettes is/are preferably made from solvent-resistant materials. The reagents (100-106) may be held in sealed vials (see reservoirs 152 in
On-demand delivery of μL volumes from 100 s of μL are accomplished as follows: reservoirs 120 in the form of reagent vials having caps 122 with septums 124 are placed vertically below the EWOD chip 92. A vertical needle 128 (“liquid needle”) is dipped into the reservoir 120 and leads up through gasket 134 to the corresponding inlet hole 136 on the bottom substrate 135 of the EWOD chip 92. A separate shorter needle 142 (“gas needle”) allows introduction of compressed gas 140 into the vial. On demand, the vial 120 is gently pressurized (controlled through a gas valve 138 and pressure regulator (not shown)) in order to send the liquid 126 up towards the EWOD chip 92 against gravity. Short pulses (e.g. 100 ms) of low pressure (˜0.5-10 kPa) are used to pump liquid from vials 120 into the chip 92.
At the loading site 132 on the chip 92, the activated EWOD electrode 130 provides a retention force to hold the liquid 126 in the chip 92, as well as detects impedance change as the liquid enters the gap. Once sufficient liquid has been detected at the loading site 132, the pressure is turned off (e.g. by switching from the pressure source to vent using a pneumatic valve), so that gravity pulls back the liquid column 126 back into the reservoir 120. The liquid retained using EWOD at the loading site 132 stays on the chip 92, while the rest of the liquid is pulled back into the reservoir 120.
After the loaded droplet is moved off the loading site (e.g. to the manifold/reactor 98) by EWOD, the same process can be repeated to load multiple droplets from one or more reservoirs. This technique works with most organic and aqueous liquids used in radiochemistry, providing an accuracy of ±10% for ˜2 uL droplet volume delivered to the chip 92. At the end of the synthesis, one of the lines (see
In one exemplary embodiment, actuation of EWOD chip 92 electrodes may be achieved via a 50 conductor ribbon cable (not shown) with standard 50 mil spacing for carrying actuation voltages to the EWOD chip 92. The chip contact pads (e.g. electrode 130 of
Additionally, a feedback-controlled heating system (not shown) may be used with temperature sensing through a thermocouple and configured for heating occurring through a heat transfer rod (not shown). The rod is integrated into the shielding 158 around the chip 92. The rod may be made from tungsten or lead to provide shielding, and may incorporate a thin layer of thermal insulation around the rod. It may be desirable to have a complex shape through the shielding to avoid shine via the insulating material (e.g. a cylinder of two different diameters). Heating (and cooling) will be provided by the fixed platform. The heat transfer rod in the chip shielding will contact this temperature actuator at the time of shielded chip installation. The heating rod may have a circular shape (12 mm diam.) at the end in contact with the chip 92 inside the shielding 158.
With respect to the HPLC and cartridge formulation and purification module/subsystem 18, immediately after on-chip synthesis, the desired PET tracer (raw product 26) resides in a mixture of different unwanted solvents, side products, and unused precursor that must be removed. After the PET tracer is synthesized on chip it will be transferred off of the chip to one of the 2 purification methods: (1) Cartridge Purification and (2) HPLC purification. The pathway may be selected by a valve, or, the chip manifold may be specifically tailored for certain types of probes and only contain the pathway to the corresponding purification method. For both cartridge purification and HPLC purification, the final product is to be formulated into a solvent and volume appropriate to animal or human injection.
After purification, the purified fraction is often not suitable for injection and must therefore be diluted in or replaced by saline buffer of the appropriate salt concentration and pH. This “formulation” requires a separate module. Heating in an evacuated container evaporates the solvent present in the purified fraction.
Once most of the solvent is removed, the purified product is re-dissolved in a saline buffer having the appropriate pH and salt concentration for injection.
Another method of performing the solvent exchange is to use a cartridge. The sample is passed through the cartridge and the species of interest remains trapped on the resin. The species of interest is then released by an eluent. Ideally, this eluent is safe for injection directly. Sometimes, e.g. if the eluent is ethanol, the eluent must be diluted in saline prior to injection.
The entirety of the purified product can be sent to a shielded collection vial or syringe (or other apparatus/location). In another embodiment, a portion of the purified product is sent to an integrated quality control system that analyzes the contents of the product for its purity, composition, and sterility.
In another embodiment, purification can be performed on-chip.
In the preferred embodiments detailed above, the system 10 is described for use with the synthesis of radiochemical PET tracers, but it is appreciated that system 10 can be configured for use with other radioactive material processing such as generation of SPECT tracers, radiotherapeutic or theranostic agents, etc. Furthermore, the system 10 can also be used for other general chemistry and biological manipulations.
Embodiments of the present technology may be described with reference to flowchart illustrations of methods and systems according to embodiments of the technology, and/or algorithms, formulae, or other computational depictions, which may also be implemented as computer program products. In this regard, each block or step of a flowchart, and combinations of blocks (and/or steps) in a flowchart, algorithm, formula, or computational depiction can be implemented by various means, such as hardware, firmware, and/or software including one or more computer program instructions embodied in computer-readable program code logic. As will be appreciated, any such computer program instructions may be loaded onto a computer, including without limitation a general purpose computer or special purpose computer, or other programmable processing apparatus to produce a machine, such that the computer program instructions which execute on the computer or other programmable processing apparatus create means for implementing the functions specified in the block(s) of the flowchart(s).
Accordingly, blocks of the flowcharts, algorithms, formulae, or computational depictions support combinations of means for performing the specified functions, combinations of steps for performing the specified functions, and computer program instructions, such as embodied in computer-readable program code logic means, for performing the specified functions. It will also be understood that each block of the flowchart illustrations, algorithms, formulae, or computational depictions and combinations thereof described herein, can be implemented by special purpose hardware-based computer systems which perform the specified functions or steps, or combinations of special purpose hardware and computer-readable program code logic means.
Furthermore, these computer program instructions, such as embodied in computer-readable program code logic, may also be stored in a computer-readable memory that can direct a computer or other programmable processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable memory produce an article of manufacture including instruction means which implement the function specified in the block(s) of the flowchart(s). The computer program instructions may also be loaded onto a computer or other programmable processing apparatus to cause a series of operational steps to be performed on the computer or other programmable processing apparatus to produce a computer-implemented process such that the instructions which execute on the computer or other programmable processing apparatus provide steps for implementing the functions specified in the block(s) of the flowchart(s), algorithm(s), formula(e), or computational depiction(s).
It will further be appreciated that the terms “programming” or “program executable” as used herein refer to one or more instructions that can be executed by a processor to perform a function as described herein. The instructions can be embodied in software, in firmware, or in a combination of software and firmware. The instructions can be stored local to the device in non-transitory media, or can be stored remotely such as on a server, or all or a portion of the instructions can be stored locally and remotely. Instructions stored remotely can be downloaded (pushed) to the device by user initiation, or automatically based on one or more factors. It will further be appreciated that as used herein, that the terms processor, computer processor, central processing unit (CPU), and computer are used synonymously to denote a device capable of executing the instructions and communicating with input/output interfaces and/or peripheral devices.
From the description herein, it will be appreciated that that the present disclosure encompasses multiple embodiments which include, but are not limited to, the following:
1. A self-shielded, bench-top radio chemistry system, comprising: a radioactive isotope dispensing module configured to draw an isotope out of a reservoir and dispense a metered dose of said isotope; a concentration module configured to receive the metered dose from the dispensing module and concentrate the metered dose into a droplet amount of isotope; and a synthesizer module configured to receive the droplet amount of isotope from the concentration module and deliver the droplet amount of isotope along with one or more reagents to a microfluidic chip to produce a radiolabeled molecule.
2. The system of any preceding embodiment, wherein the dispensing module, concentration module and synthesizer module are integrated and automated so that fluidic, electrical, and mechanical connections run from each module to the next without substantial loss of fluid or radioactivity.
3. A system as recited in claim provided in any of the previous embodiments: wherein each of the dispensing module, concentration module and synthesizer module are connected in fluid communication via one or more wetted paths; wherein the one or more wetted paths are exposed to said isotope; and wherein portions of the one or more of the dispensing module, concentration module and synthesizer module corresponding to said one or more wetted paths are disposed in a shielded, disposable cassette.
4. The system of any preceding embodiment: wherein the dispensing module comprises a sensor for measuring radioactivity at a location within the dispensing module; and wherein the dispensing module is configured to dispense said metered doses as a function of radioactivity measured at the location.
5. The system of any preceding embodiment, wherein the dispensing module comprises a pumping mechanism to draw the isotope from the reservoir and generate the metered dose.
6. The system of any preceding embodiment, the dispensing module further comprising: a needle disposed within the dispensing module; and an actuator coupled to either the needle or the reservoir such that operation of the actuator automatically draws the needle into or out of the reservoir.
7. The system of any preceding embodiment: wherein the concentration module comprises a concentrator cartridge; and wherein the metered dose is delivered through the cartridge along with an eluent to generate said droplet amount of isotope.
8. The system of any preceding embodiment, wherein the synthesizer module comprises a micro-fluidic manifold configured to deliver the droplet amount of isotope and one or more reagents in individual channels to the microfluidic chip.
9. The system of any preceding embodiment, wherein at least portions of two or more of the dispensing module, concentration module and synthesizer module are integrated on to a single disposable cassette.
10. The system of any preceding embodiment, further comprising: a purification and formulation module configured to collect unpurified product from the synthesizer module and generate a purified product.
11. A method for generating a radiolabled molecule, comprising: drawing a radioactive isotope out of a reservoir and dispensing a metered dose of said isotope; receiving the metered dose and concentrating the metered dose into a droplet amount of isotope; and delivering the droplet amount of isotope along with one or more reagents to a microfluidic chip to produce a radiolabled molecule.
12. A method as provided in any of the previous embodiments, wherein the dispensing, concentration and delivery of the isotope to the microfluidic chip are automatically performed within a shielded apparatus without substantial loss of fluid or radioactivity.
13. The method of any preceding embodiment: wherein the isotope is dispensed, concentrated and delivered to the microfluidic chip within the apparatus along one or more wetted paths that expose to said isotope; and
14. The method of any preceding embodiment, further comprising: measuring radioactivity at a location within the apparatus corresponding to the dispensing of the metered dose of said isotope; and dispensing said metered doses as a function of radioactivity measured at the location.
15. The method of any preceding embodiment, wherein peristaltic pump is used to draw the isotope from the reservoir and generate the metered dose.
16. The method of any preceding embodiment, wherein the apparatus comprises a needle disposed within the apparatus, the method further comprising: automatically drawing the needle into or out of the reservoir
17. The method of any preceding embodiment: wherein concentrating the metered dose comprises delivering the metered dose and an eluent through a cartridge to generate said droplet amount of isotope.
18. The method of any preceding embodiment, wherein the droplet amount of isotope and one or more reagents are delivered in individual channels of a micro-fluidic manifold to the microfluidic chip.
19. The method of any preceding embodiment the method further comprising: removing the cassette containing the wetted paths while the reservoir remains disposed within the apparatus; installing a second, unused cassette; drawing radioactive isotope out of the reservoir and dispensing a second metered dose of said isotope; receiving the second metered dose and concentrating the second metered dose into a second droplet amount of isotope; and delivering the second droplet amount of isotope along with one or more reagents to a microfluidic chip to produce a second radiolabled molecule.
20. The method of any preceding embodiment, wherein the microfluidic chip comprises an EWOD chip.
21. A fully-integrated chip-based chemical synthesizer, comprising: a dispensing module configured to draw an agent out of a reservoir and dispense a metered dose of said agent; and a synthesizer module configured to receive the metered dose of agent from the concentration module and deliver the droplet amount of agent along with one or more reagents to a microfluidic chip to produce a labeled molecule.
22. The synthesizer of any preceding embodiment, further comprising: a concentration module configured to receive the metered dose from the dispensing module and concentrate the metered dose into a droplet amount of agent for deliver to the synthesizer module.
23. The synthesizer of any preceding embodiment: wherein the agent comprises an isotope; and wherein the dispensing module, concentration module and synthesizer module are integrated and automated so that fluidic, electrical, and mechanical connections run from each module to the next without substantial loss of fluid or radioactivity.
24. The synthesizer of any preceding embodiment: wherein each of the dispensing module, concentration module and synthesizer module are connected in fluid communication via one or more wetted paths; wherein the one or more wetted paths are exposed to said isotope; and wherein portions of the one or more of the dispensing module, concentration module and synthesizer module corresponding to said one or more wetted paths are disposed in a shielded, disposable cassette.
25. The synthesizer of any preceding embodiment, wherein the dispensing module comprises a sensor for measuring radioactivity at a location within the wherein the dispensing module; and wherein the dispensing module is configured to dispense said metered doses as a function of radioactivity measured at the location.
26. The synthesizer of any preceding embodiment, wherein the dispensing module comprises a pump to draw the isotope from the reservoir and generate the metered dose.
27. The synthesizer of any preceding embodiment, the dispensing module further comprising: a needle disposed within the dispensing module; and an actuator coupled to either the needle or the reservoir such that operation of the actuator automatically draws the needle into or out of the reservoir.
28. The synthesizer of any preceding embodiment: wherein the concentration module comprises a concentrator cartridge; and wherein the metered dose is delivered through the cartridge along with an eluent to generate said droplet amount of isotope.
29. The synthesizer of any preceding embodiment, wherein the synthesizer module comprises a micro-fluidic manifold configured to deliver the droplet amount of isotope and one or more reagents in individual channels to the microfluidic chip.
30. The synthesizer of any preceding embodiment, wherein at least portions of two or more of the dispensing module, concentration module and synthesizer module are integrated on to a single disposable cassette.
31. The synthesizer of any preceding embodiment, further comprising: a purification and formulation module configured to collect unpurified product from the synthesizer module and generate a purified product.
32. The synthesizer of any preceding embodiment, wherein the microfluidic chip comprises an EWOD chip.
Although the description herein contains many details, these should not be construed as limiting the scope of the disclosure but as merely providing illustrations of some of the presently preferred embodiments. Therefore, it will be appreciated that the scope of the disclosure fully encompasses other embodiments which may become obvious to those skilled in the art.
In the claims, reference to an element in the singular is not intended to mean “one and only one” unless explicitly so stated, but rather “one or more.” All structural, chemical, and functional equivalents to the elements of the disclosed embodiments that are known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be encompassed by the present claims. Furthermore, no element, component, or method step in the present disclosure is intended to be dedicated to the public regardless of whether the element, component, or method step is explicitly recited in the claims. No claim element herein is to be construed as a “means plus function” element unless the element is expressly recited using the phrase “means for”. No claim element herein is to be construed as a “step plus function” element unless the element is expressly recited using the phrase “step for”.
This application claims priority to, and the benefit of, U.S. provisional patent application Ser. No. 62/008,997 filed on Jun. 6, 2014, incorporated herein by reference in its entirety.
This invention was made with Government support under MH097271 awarded by the National Institutes of Health and under DE-SC0006238 awarded by the U.S. Department of Energy. The Government has certain rights in the invention.
|Filing Document||Filing Date||Country||Kind|