WO1997016746A1 - Detecteur multiphotonique a bruit de fond ultra-bas - Google Patents

Detecteur multiphotonique a bruit de fond ultra-bas Download PDF

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Publication number
WO1997016746A1
WO1997016746A1 PCT/US1996/016968 US9616968W WO9716746A1 WO 1997016746 A1 WO1997016746 A1 WO 1997016746A1 US 9616968 W US9616968 W US 9616968W WO 9716746 A1 WO9716746 A1 WO 9716746A1
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WIPO (PCT)
Prior art keywords
detector
pulse
pulses
detectors
pmt
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PCT/US1996/016968
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English (en)
Inventor
Andrzej K. Drukier
Igor R. Sagdejev
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Biotraces, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from US08/669,970 external-priority patent/US5866907A/en
Application filed by Biotraces, Inc. filed Critical Biotraces, Inc.
Priority to EP96941945A priority Critical patent/EP0866986A1/fr
Priority to JP9517408A priority patent/JPH11514742A/ja
Priority to KR1019980703222A priority patent/KR19990067259A/ko
Priority to AU11154/97A priority patent/AU700518B2/en
Priority to BR9611171-2A priority patent/BR9611171A/pt
Publication of WO1997016746A1 publication Critical patent/WO1997016746A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01T—MEASUREMENT OF NUCLEAR OR X-RADIATION
    • G01T7/00—Details of radiation-measuring instruments
    • G01T7/08—Means for conveying samples received
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01T—MEASUREMENT OF NUCLEAR OR X-RADIATION
    • G01T1/00—Measuring X-radiation, gamma radiation, corpuscular radiation, or cosmic radiation
    • G01T1/16—Measuring radiation intensity
    • G01T1/20—Measuring radiation intensity with scintillation detectors
    • G01T1/204—Measuring radiation intensity with scintillation detectors the detector being a liquid
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01T—MEASUREMENT OF NUCLEAR OR X-RADIATION
    • G01T1/00—Measuring X-radiation, gamma radiation, corpuscular radiation, or cosmic radiation
    • G01T1/16—Measuring radiation intensity
    • G01T1/20—Measuring radiation intensity with scintillation detectors
    • G01T1/208—Circuits specially adapted for scintillation detectors, e.g. for the photo-multiplier section

Definitions

  • This invention relates to multiphoton radioisotope detectors with ultralow background. These detectors can quantify coincident gamma and X-ray emissions from electron capture (EC) isotopes, combining coincident counting and other background rejection measures to achieve extraordinary sensitivity.
  • EC electron capture
  • Hardware implemented coincidence counting is used in a detector for positron-gamma (pg) emitters disclosed in United States Patent No. 5,083,026.
  • positron-gamma pg
  • the positron annihilates the electron producing two back-to-back gamma photons with energies of 511 keV.
  • Multiple scintillation detectors are used to register the three coincident high energy (E > 250 keV) gammas, and events lacking this triple gamma signature are rejected.
  • E > 250 keV coincident high energy
  • a further object of the invention is to reduce background to less than one count per hour by eliminating all significant sources of background. It is a further objective of the invention to overcome the inherently lower detection efficiency of the selective CGX counting mode as compared to single gamma counters, to provide a sensitivity to sub-pico Curie samples, and an ability to detect less than 5 x IO *21 mole of labeled molecules, a zeptomole/ml, or even a single large labelled biomolecule, with detection efficiency greater than 10% and reproducibility of about 1 %.
  • Detectors according to the invention satisfy these objects. They have multicolor ability in that several isotopes can be measured and distinguished in the same sample. They can measure many separate samples and yield very reproducible results. They inco ⁇ orate sellf- calibration and self -diagnostics. They can provide spatial resolution of 100 micrometers or lower. All these advantages are accomplished in transportable, inexpensive devices much smaller than conventional devices. Because of the increased sensitivity of instruments according to the invention, isotope concentrations may be reduced, thus lowering isotope acquisition costs, exposure of personnel, and radioactive waste disposal problems.
  • coincident e.g. , gamma and X-ray
  • Figure 1 shows a block diagram of multiphoton detector.
  • Figure 2 shows a detector subassembly.
  • Figure 3 is a block diagram of an integrated photomultiplier base including amplifier and high voltage power supply.
  • Figures 3 A to 3C show exemplary embodiments of the component parts in more detail.
  • Figure 3 A shows a PMT base;
  • Figure 3B shows a negative high voltage power supply;
  • Figure 3C shows an amplifier and shaper.
  • Figure 4 graphs the dynamic range of an MPD according to the invention.
  • Figure 5 shows the dynamic range of an MPD device compared to a color spectrometer.
  • Figure 6 shows the layout for a sequential sample MPD with a sample changer.
  • Figure 7 is a block diagram of an MPD embodiment accordinging to the invention.
  • Figures 8a, 8b and 8c are a flow chart of a method according to an embodiment of the invention. DETAILED DESCRIPTION OF THE INVENTION
  • FIG. 1 A typical embodiment of an MPD device system according to the invention is shown in Figure 1.
  • This exemplary system as illustrated has five major components, including: 1. two photon detectors, e.g., scintillator/photosensor modules;
  • shielding components including a separator
  • detection electronics including voltage supplies
  • the dimensions of hole 34 are chosen so that the solid angle of the opening just encompasses the faces of crystals 22.
  • Separator 32 optimally limits cross-talk between crystals 22 and the thickness is selected to limit certain background events.
  • the detectors are placed in composite shield 55 to diminish background due to ambient radioactivity. This shield, depending on applications, can be from 0.5 to 20 kg in weight.
  • Each photosensor 26 is also provided with shielding 27.
  • the software supporting the DSO card-based pulse-shape analysis on the PC is preferably coded in Borland Turbo Pascal and C+ + , which helps make the code highly modular, transparent, and easy to customize. Through changes in the software, the same device can be adapted for a variety of applications without hardware changes.
  • the most time- critical procedures are preferably coded in IBM PC assembly language to maximize efficiency of acquiring and analyzing signals.
  • DSO card 58 has two inputs with at least 8-bit analog-to-digital convertors (ADC's) and an additional input, which is used as an acquisition trigger. It is able to monitor the two input channels simultaneously at a sampling rate of at least 10 MHz. The signals are acquired at a sampling rate of up to 100 megasamples/sec and are continuously stored in on-board memory until a trigger is detected, whereupon a pre-defined number of post-trigger data points are acquired. Once the acquisition is stopped, the contents of the on-board memory become available for the host computer CPU 59. Any of the DSO channels can be used as the trigger, or triggering can be done through software and/or trigger electronics 56.
  • ADC's analog-to-digital convertors
  • the sampling rate, the number of post-trigger points, the gains on the channels, and the triggering conditions can be set through a PC 1/0 port, while the on-board memory can be accessed directly through a 4 Kbyte window, which allows fast retrieval using the CPU's string instructions or DMA transfer to other peripheral devices, for example.
  • the pulse shape analysis functions as a way to discriminate pulses due to radioactive decay from spurious pulses based on the following characteristics.
  • a photon When a photon is absorbed by a scintillator/PMT or scintillator/photodiode combination, it produces a pulse with a characteristic shape and a predictable amplitude proportional to the energy deposited by the photon in the scintillator.
  • the shapes of spurious pulses electromagnetically induced in the readout electronics are not so well defined.
  • Spurious pulses include single narrow spikes, rapid successions of such spikes, random electronic noise and PMT dark pulses. In a pulse-height analyzing system spurious pulses may considerably contaminate the acquired spectra and diminish the system's overall signal-to-background ratio. Also, many others are spurious pulses.
  • the first group of background sources (A1-A4) produces background levels on the order of a few counts per second (cps).
  • Conventional methods of diminishing this class of background involve use of ultrapure materials, often purified to over 99.999%.
  • purification methods are too expensive to be used in low cost instruments for biomedical applications.
  • Statistical methods of background subtraction are limited by statistical artifacts and can be used only if the signal to background ratio (S/B) is large, say > 10.
  • the second group of background sources (B1-B3) is responsible for backgrounds at the 0.1 - 1 counts per minute (cpm) level. Active shielding and sophisticated pulse shape analysis can be used to reject this background, but the use of active shields tends to be very expensive.
  • C1-C2 The third group of background sources (C1-C2) produces a few counts per hour (eph).
  • the fourth group of background sources (D1-D2), electronic and vibrational pick-up noise, is very much system and site dependent.
  • Conventional NIM based electronics show typical noise of 0.1 cpm per unit, depending on the total number of modules used. Even when using well grounded coaxial cables, with 10 to 20 cables used to connect a typical NIM system, the observed electromagnetic noise is about 1 cpm. Also, the use of external high voltage sources negatively influences the level of pick-up noise.
  • EC emitters typically have two coincident photons, of which one is always a rather low energy X-ray emitted due to atomic shell rearrangement. Also, some Auger electrons can be present which can be used advantageously to obtain very high spatial resolution.
  • the second photon also has a low energy; the spectrum has three peaks at 27, 31 and 35 keV, respectively. Designing a MPD detector involves trade-offs between detection efficiency (DE), energy resolution (dE) and temporal response. Photon energies considerably influence the choice of detector elements.
  • the CGX emitter is an isotope of an element that forms covalent bonds, or one that can be chelated to an organic compound. More preferably the isotope is I 123 , 1 125 , 1 126 , Br 76 , or Br 77 , and most preferably is I 125 .
  • the EC isotope I 125 with a half life of 60 days, is particularly preferred. According to results obtained with older instrumentation and recorded in nuclear data tables, coincident emission of a 35 keV nuclear gamma and one of several possible X-rays in the 27-31 keV range occurs in 7% of the I 125 decays. However, with the improved system of the invention, experiments revealed in actuality a coincidence in 25-35% of the decays.
  • the CGX emitter is preferably an isotope of the family of CGX lanthanide isotopes. This family includes 54 isotopes with identical chemical properties which are distinguishable based on their different decay photon energies. CGX lanthanide isotopes can be introduced as labels to biomolecules through the use of chelating groups which capture metallic ions. The chemistry for adducting chelating groups to DNA subunits and their polymers is well known. Material selection for an ultralow background CGX system for I 125 will now be discussed. The detection of gamma rays from I 125 requires scintillator detectors with good energy resolution. Generally, the best energy resolution is achieved with a Na ⁇ (Tl) crystal/PMT combination. However, use of Na ⁇ (Tl) leads to an additional hard X-ray background due to the characteristic iodine abso ⁇ tion edge. This is beneficially eliminated by implementing the preferred CaF 2 /PMT combination according to the invention.
  • Diagnostic applications of the invention include DNA sequencing, DNA finge ⁇ rinting and diverse forms of competitive and/or binding assays, e.g. , radioimmunoassay (RIA).
  • RIA radioimmunoassay
  • This system can be used to quantitate sub-attomole ( ⁇ 10 18 M) amounts of biomolecules in diagnostic tests such as I As, immuno-PCR and DNA probes, and IRMAs.
  • diagnostic tests such as I As, immuno-PCR and DNA probes, and IRMAs.
  • S/B signal to background ratio
  • previous IRMAs have required the use of hazardous quantities of radioisotope. Due to the absence of approved disposal sites, radioactive waste must be stored at the sites that generate the waste (i.e., hospitals, universities and industries), creating potential radiation and bio- hazards. According to the invention, solid assay residuals can be discarded subject only to biohazard regulations, as they are less radioactive than the environmental background.
  • Liquid residuals will contain most of the radioactivity, but at lower activity than those from current biomedical procedures, e.g., radioimmunoassay s (RIA) and typically much below the radioactive level of ground water. Thus, immediate disposal will probably be allowed in many cases.
  • RIA radioimmunoassay s
  • a major source of background counts in scintillator-based gamma counters is radioactive contamination of the components of the detector itself.
  • the volume ofthe scintillator may be optimized.
  • the low energy gamma and X-rays associated with I 125 decays are effectively stopped in less than 1 mm of Na ⁇ (Tl) or 1.5 mm of CaF 2 (Eu) scintillator.
  • producing a well detector with such thin walls is impractical, especially given the need to couple a PMT to the scintillator. Instead, a flat scintillator geometry is preferred even though it has somewhat lower detection efficiency.
  • the detection efficiency of 2" diameter flat detectors is about 40% for a small (few mm diameter) source placed in the middle of the detector.
  • the overall detection efficiency of the system is improved and made less dependent on geometry by using two identical flat round detectors with the source placed between them.
  • Segmentation of the detector has other benefits as well. It provides the ability in half the cases to distinguish 2-photon events from single photon events with double the photon energy. It also provides the ability to discriminate background by using anti-coincidence rejection techniques. However, each detector module has a separate PMT, which increases the non-radioactive background component due to PMT dark pulses and various electronic artifacts. Therefore, effective discrimination of such non-radioactive events by pulse shape analysis in accordance with the invention is preferred.
  • the sandwich detector geometry permits better performance than either well detector or flat detector geometries. The qualitative properties of scintillator detectors built with these three different geometries are shown in Table 1.
  • Detectors with flat geometry are advantageous when samples with a large surface/volume ratio are used, especially when biological samples are distributed inhomogeneously inside of, or attached upon, the surface of a solid state filter, support, or membrane with a non-negligible thickness.
  • Quantitation artifacts can be considerably diminished when using two essentially identical flat detectors, each with independent read-out electronics in accordance with the invention.
  • both detectors give essentially the same count rate.
  • the sandwich geometry permits the use of highly efficient differentiation compensation schemes .
  • a preferred implementation of the invention uses two essentially identical detectors for the detection of the isotope I 125 .
  • two identical thin scintillators can be used.
  • many other important sources emit multiple photons of quite different energies; often one photon is a soft X-ray (E ⁇ 50 keV) while the second photon is a nuclear gamma- ray, e.g., E > 100 keV.
  • Na ⁇ (Tl) or CsI(Tl) based detectors show considerable sensitivity to the geometry and diameter of opening in the separator. Comparisons of a device according to the invention with the detectors at Memorial Sloan Kettering Cancer Center (MSKCC) and elsewhere were performed using binary dilutions of commercially available radio- iodinated TSH antibodies. The molecular weight of this antibody is about 40,000 daltons. Most of the tests were performed using a calibration sample set. Additional calibration runs used water dilutions of Nal 125 and I 125 -dCTP. For radioactive standards, ethidium bromide was iodinated with I 125 to a specific activity of about 0.1 mCi/mL.
  • the calibration set includes ten samples, covering the range from a few thousand dpm to about 0.1 dpm. Hundred microliter volumes of each dilution were placed in 200 microliter Eppendorf vials made of a thin plastic.
  • Table 2 shows some of the most important parameters, namely detection efficiency and background, for a plurality of commercial gamma counters and two MPD detectors according to the invention based on Na ⁇ (Tl) and CaF 2 (Eu), respectively. Table 2 also shows that for an MPD device in an AND mode, when coincidence between two photons emitted by an EC source is used, the background is further diminished as compared to an OR (non-coincident) mode, which leads to considerable increased sensitivity. However, some reduction of detection efficiency is observed in the coincident mode.
  • Sandwich detectors allow a coincident (AND) mode of operation, thus dramatically reducing the background by orders of magnitude.
  • the detection efficiency for this acquisition mode is relatively low (5 to 15% for I 125 sources and 2" to 3" diameter detectors in a sandwich geometry) which considerably extends counting times for low-activity sources.
  • sandwich detectors according to the invention can also operate in a non-coincident mode, which is referred to as an OR mode. In this OR mode, an event registered in either of the detectors is counted.
  • the whole system works as one detector, similar in this respect to a well detector or any non-segmented detector.
  • the detection efficiency is higher (typically, 50% for I 125 sources and 2" diameter detectors in a sandwich geometry), but the additional benefits of better background rejection through coincidence are lost.
  • An MPD in accordance with the invention operated in the OR mode achieves considerable background reduction through the use of: optimal scintillator thickness; correct inte ⁇ retation of a fraction of two-photon events (50% for a two-detector system) which allows reducing the counting region of interest to the single-photon peak; anticoincidence; and pulse shape analysis.
  • the background in the OR mode is 1.5 to 2 cpm and the detection efficiency is 50%.
  • the MPD outputs both OR and AND counting data.
  • the OR data should be used if the activity of the source is above the OR background equivalent activity (about 5 picoCurie, or 2 attomole of I 125 label). These data have a lower statistical uncertainty due to the higher detection efficiency of OR counting. If the OR counts are close to the OR mode background, the AND mode counting data is used, due to its much lower background.
  • the OR mode of operation is better for sources larger than 10 dpm, i.e., about 5 picoCurie.
  • both OR and AND counting modes are beneficially used.
  • software is used combines the OR and AND data to obtain the best estimators of the true count rate. This permits minimizing the artifacts due to statistical uncertainty (AND data) and high background (OR data). Below 1 dpm, the AND mode gives a reasonably better signal to background ratio.
  • One of the important software functions according to the invention is to properly estimate the dead-time and pile-up corrections to the counting rate.
  • the DSO-based acquisition of pulses involves a relatively large amount of dead time, which has to be compensated for, in particular, for high count rates. In MPD devices according to the present invention, this is done using an additional counter/timer card.
  • the counter/timer card preferably has at least two pulse counters and a timer.
  • One counter should count all hardware triggers formed by the signal conditioning/triggering card, and the other should count coincident triggers only.
  • the timer should keep track of the exposed time with good precision.
  • model PCL-720 distributed by JDR Microdevices, is used.
  • This card has 3 counters, one of which can be converted into a timer by internal wiring.
  • the counters are 16-bit, so they should be read out at least once a second to prevent loss of data.
  • the third counter is wired to count time in intervals of 1/2,500 of a second in this embodiment.
  • the MPD software arms the DSO card for acquisition of the first pulse and simultaneously initiates the counters and timer.
  • the count rate in the appropriate counter (total counts divided by the time read from the timer; the coincident trigger counter is used if the DSO is triggered by coincident triggers, the total counts counter otherwise) is used to adjust the count rates of all events, non-rejected events and events in all regions of interest (ROI's) using the formula:
  • Cpm, Adj Cpm, *(Cpm Tou ⁇ Counters /Cpm Tolal DSO ), where Cpm l Adj is the count rate (per minute) for the ith ROI, adjusted for dead time losses, Cpmj is the raw DSO cpm for the ith ROI, Cpm Tota] Coumers is the total cpm in the counter, and Cpm TouU DSO is the total count rate before rejection in the DSO.
  • This adjustment allows full compensation for dead time losses, and effectively makes the linearity of count to be limited only by the pulse pile-up at high count rates.
  • the self- calibration program permits concordance of the OR and AND counting rate data to, for example, within less than three percent.
  • Detectors according to the invention have radically improved performance when compared to conventional devices.
  • the improvements include sensitivity, reproduceability, and dynamic range.
  • Sensitivity A direct indicator of the sensitivity (or limit of detection) of a radiation counter is its background equivalent activity (BEA), i.e., the activity of a source which would produce a count rate equal to the background in the detector. This figure of merit accounts for both the background and the detection efficiency of a counter.
  • BEA background equivalent activity
  • the typical BEA for MPD detectors in accordance with the presen invention in an OR mode is in the range of 3 to 4 decays per minute, which is equivalent to less than 2 picoCurie of I 125 .
  • This is based on a detection efficiency (DE) in the OR mode of approximately 50% and a background count rate in the I 125 energy region of interest of 1.5 to 2 cpm.
  • DE detection efficiency
  • a 5 picoCurie sample will have a S/B of about 3.
  • the typical BEA for MPD detectors according to the present invention in an AND mode is in the range of 1 decay per day, which is equivalent to a few femtoCurie. This is based on a DE in the AND mode of about 7% and a background count rate in the I 125 region of interest of 1 count per two weeks.
  • a small activity source (10 picoCurie)
  • commercially available detectors are either unable to quantitate the sample or provide marginal measurement with S/B close to one.
  • a 10 picoCurie I 125 sample was repeatedly measured with a CGX detector according to the invention, 400 times over a few weeks period. The measured activities are compatible with the known half-life of I 125 . These measurements were obtained using the OR mode of operation, in which coincidence is not employed.
  • the DE In an enhanced performance mode, which is based on coincidence, and more stringent pulse shape analysis, the DE is somewhat lower (5-10% vs. 50%), while the background is lower by a few orders of magnitude.
  • the performance depends on the sample size.
  • the DE For standard 12 mm diameter sample tubes, the DE is 6.5% and the background is 0.25 eph, yielding a BEA of 4 dph.
  • the DE For small samples (4 mm in diameter or less), the DE is 5-7% and the background is 0.5-1 count per week which is equivalent to a BEA of 3 dpd (decays per day).
  • the measurement reproducibility of MPD devices according to the invention is determined primarily by counting statistics, clock accuracy, and the reproducibility of placing the sample within the instrument.
  • MPD devices according to the invention are reasonably stable over the long term. No variations in background have been observed, and the detection efficiency is stable.
  • the same sample 50 nanoCurie was counted about 1,200 times, removing and replacing it in the holder before each measurement. For each measurement the sample was counted until 10,000 counts were accumulated (equivalent to a statistical uncertainty of ⁇ 1 %).
  • Another advantage of the MPD according to the present invention is the possibility of reliable calibration.
  • Photographic emulsions permit quantitative measurements only over 1.5 logs range.
  • the response of the detectors is limited both at low levels and at high counting rates.
  • the characteristic detector's response is an S- shaped curve.
  • well detectors are seriously limited by the intrinsic background.
  • optical detectors e.g., color spectrometers, are severely limited by photonic background.
  • pile-up or optical interference distorts the linearity of conventional detectors.
  • gamma detectors are close to ideal for high count rates, up to about 1,000,000 cps.
  • typical well counters show a linear response over about 4 logs dynamic range, from about 100 cps to 1,000,000 cps.
  • the background rejection techniques used in MPD devices according to the pressent invention permit reliable quantitation from 1 cpm to 1,000,000. cpm, i.e., over 6 logs dynamic range in the OR mode.
  • the MPD detectors according to the present invention are linear over 9 logs dynamic range.
  • saturation may be caused by pulse pile-up in the scintillator.
  • the dead time ofthe MPD is non-extendable, so that counting can be performed and the results corrected for pile-up.
  • the linearity of response is limited by the background.
  • the results of measurement using MPD are shown in Figure 4. Dilutions of I I2S -labeled reagents show perfect linearity of measured activity over 5 orders of magnitude down to the 0.1 zeptomole/ sample level.
  • the linearity of response of the MPD according to the present invention was compared with commercially available colorimetric detectors and the advantage of the MPD is evident.
  • the dynamic range of the MPD detector is considerably better than for color spectrometers.
  • streptavidin-HRP was iodinated and the same sample was measured using MPD and a commercial color spectrometer used for ELISA tests.
  • the results are presented in Figure 5.
  • the sensitivity of the MPD is at least two orders of magnitude better than that of the color spectrometer, and its dynamic range is about five orders of magnitude better. In the range where the color spectrometers work reliably, identical results were obtained using the MPD according to the present inventon and the color spectrometers.
  • Na ⁇ (Tl) scintillator crystals seem a natural choice for MPD instruments.
  • background rejection is inversely proportional to the square of the energy resolution, which for Na ⁇ (Tl) is about 50% better than for other scintillators.
  • sodium iodide scintillators are fastest. According to standard practice, background rejection is proportional to the square of the timing resolution.
  • the main source of background in the AND mode is the detection of a soft X-ray emitted and absorbed in one crystal coincident with some source of energy detected in the second crystal.
  • any absorbtion of an external photon with E> 35 keV in the crystal leads to remission of 26 keV or 32 keV photons from rearrangement of atomic shells.
  • characteristic iodine X-rays are emitted when the Na ⁇ (Tl) crystal is used. These cannot be distinguished from the 25 and 31 keV Te X-rays emitted by either I 123 or I 125 daughter nucleii.
  • CaF 2 (Eu) is a very slow scintillator with characteristic light decay of about 5 microseconds, i.e., about a factor of 25 slower than Na ⁇ (Tl).
  • Conventional detectors used the fastest possible detectors, with backgrounds of about 1 cps. When background is pushed to a few cpm, the dominating sources of background are due to cosmic rays and dark current pulses from the PMT's. Spurious signals due to energy deposited by cosmic rays in the crystal itself can be partially accounted for by analyzing the amount of energy deposited. Particularly for low energy X- rays, e.g., for I 125 , this method permits rejection of over 95% of cosmic rays crossing scintillators . This includes efficient rejection of secondary particles in the cosmic ray showers .
  • the crystals themselves are very thin and the surface of the PMT cathodes is about fifty times larger than the surface of the crystals.
  • a high energy cosmic ray striking one of the PMT anodes gives rise to an avalanche of electrons which are subsequently amplified.
  • Such pulses lead to an apparent energy deposition much lower than the energy of the cosmic ray, i.e., there is a considerable overlap between the energy spectrum of cosmic ray induced dark current pulses in the PMT's and the energy from radioiodine.
  • this source of background accounts for a few counts per minute in each PMT, or a few counts per hour in the coincidence mode.
  • the energy deposited in the scintillator typically leads to pulses longer than the cosmic induced pulses in the PMT, which have a characteristic time constant of about 0.2 nsec.
  • the rejection capability is limited by several detector characteristics. These include the characteristic response time of the scintillators, the parameters of the shaping amplifier, and the performance of the on-line pulse shape analysis system.
  • DSO digital storage oscilloscope
  • the difference in pulse rise times between cosmic ray induced PMT pulses and those created in CaF 2 (Eu) is large, i.e. , 0.1 nsec and a few microseconds respectively.
  • CaF 2 (Eu) based MPD system over 95% of cosmic ray induced PMT artifacts are rejected on-line.
  • CaF 2 (Eu) scintillators in sandwich geometry permit achievement of excellent background rejection, especially when large diameter samples of radioiodine are measured.
  • the excellent mechanical properties of CaF 2 (Eu) provide another advantage over Na ⁇ (Tl).
  • the typical thickness selected is about twice the stopping power at the energy of interest.
  • the diameter of the selected crystal is 3 or even 4 inches.
  • background is roughly proportional to crystal volume in a complicated nonlinear function of scintillator dimensions. For example, for 3" crystals conventional designs couple them to 3" PMT's. However, 3" inch PMT's are considerably more radioactive than 2" PMT's. This radioactivity originates from naturally occurring isotopes in the PMT glass. The larger surface area and greater thickness of the glass walls in larger PMT's thus leads to significantly higher radioactive background.
  • MPD detectors according to the invention have the advantage that they can be self- calibrated for I 125 using two photon coincident detection.
  • the pair of detectors should be well matched, i.e., should have similar properties.
  • all crystals within a given MPD system are preferably cut from the same large diameter crystal.
  • the crystals are mounted in low radioactive background copper tubes.
  • the X-ray window/reflector is made of MgO and 50 micron thick Al film.
  • thin teflon film is used.
  • the optical window is made of at least 2 mm thick quartz.
  • the optimum scintillator size was found to be 2" diameter.
  • the S/B is highest for the standard sandwich geometry, i.e., when a sample is placed between detectors spaced about 1/2" apart.
  • the optimization curves as a function of crystal size are rather flat. For example, (S/B) [3"] « 1.2.
  • the optimum thickness of the scintillator is 1.5 mm for CaF 2 (Eu); a change of crystal thickness from 1.0 to 3.0 mm changes the (S/B) by only about 50%.
  • each crystal is optically inspected; crystals which are cracked or not perfectly transparent are rejected.
  • the crystals are then mounted on selected low radioactive background PMT's and are submitted to a series of acceptance tests.
  • the first test checks for the energy resolution and the detection efficiency of the whole crystal.
  • PMT's are far from being uniform, and the performance of different zones of the PMT should be measured.
  • the surface of the scintillator/PMT assembly is shielded by rings of lead of increasing diameter with a radioactive source placed in the center.
  • the first lead mask has a 0.5 cm hole.
  • the energy resolution in the center of the scintillator/PMT is then checked.
  • Two other lead masks are also used to check the energy resolution, a one inch and a two inch lead ring. Only CaF 2 (Eu) crystals with dE/E(FWHM)
  • MPD devices according to the invention require considerable care in the selection of PMT's. Custom made quartz PMT's are preferred if the additional cost is tolerable. Off-the-shelf integral scintillator/PMT assemblies and commercially available PMT bases may be used instead, with appropriate modifications in accordance with the invention. A large part of the radioactive background is due to the use of stainless steel in these integral assemblies, and commercially available PMT bases are quite radioactive. PMT bases according to the invention have a composite shield between the base and the PMT to diminish the radioactive background. Also, the PMT's are optically coupled to the scintillators via an appropriate low radioactive background optical coupler (quartz).
  • PMT's are selected which are optimal for both 2" and 3" scintillation crystals.
  • the following PMT parameters are of importance: radioactive background, detection efficiency, energy resolution, homogeneity over the photocathode surface, dark current, long term stability, and dependence of signal on temperature and magnetic field.
  • the PMT's are subjected to a series of tests to determine whether they meet the selection criteria.
  • the first test checks for energy resolution and detection efficiency on an open faced crystal.
  • the energy resolution for the different parts of the PMT is checked. This is done by using three different lead apertures, in which a radioactive sample is placed.
  • the first mask has a 0.5 cm hole and the second mask is a one inch outer lead ring.
  • Electronic parameters are strongly dependent on the energy of the isotope used. For example, there is no correlation found between the energy resolution at about 30 keV (I 125 source) and at about 88 keV (Ga 67 source).
  • the relative radioactive background in the PMT's is measured by placing a PMT next to a 2" diameter, 2 mm thick CaF 2 (Eu) detector coupled to a selected low-background 2" PMT.
  • the whole test system is well shielded with lead, tin and copper.
  • the background in the CaF 2 (Eu) detector is measured in the energy range of 20 to 40 keV (the energy region of interest for I 125 ) and compared with the background without the smdied PMT. Pulse shape analysis is used to discriminate between events and electronic artifacts. Dining testing the background in the CaF 2 (Eu) detector in the absence of the test PMT was found to be 0.7 cpm.
  • ETI PMT's normally increased the count rate only insignificantly, while the Hamamatsu PMT's generally created a large additional background.
  • the radioactive background found in the Hamamatsu PMT's is su ⁇ risingly large; the average background is 3.5 cpm but values as high as 4.2 cpm were observed.
  • selected 2" ETI Model 9266KB PMT's coupled to a Na ⁇ (Tl) or CaF (Eu) scintillator are preferred.
  • the average dE/E(FWHM) 17.4% and the minimum and maximum energy resolution is 16.2% and 20.7%, respectively.
  • the average detection efficiency is 37.4% with minimum and maximum values of 31.1 % and 40.3%, respectively.
  • the radioactive background due to the EMI PMT's is rather low; the average background is 0.2 cpm with minimum and maximum values of 0.1 cpm and 0.55 cpm, respectively. About 20% of PMT's were observed to have backgrounds higher than 0.3 cpm. After these were rejected, the average background is 0.13 cpm with minimum and maximum values of 0.11 cpm and 0.28 cpm, respectively.
  • Another preferred model is ETI model R-2486 PMT.
  • PMT's are typically packaged in prefabricated aluminum or stainless steel tubings. These commercially mounted PMT's have increased radioactive background and so a modified mounting is preferred. PMT's shall be checked for cracks or flaws. The PMT is washed with isopropyl alcohol to remove any particles or contaminants. Next, the glass surface with the exception of the window area is covered with four layers of black electrical tape. After this is complete, one spiral of black electrical tape covers all the bands except for the first (next to the window). Subsequently, two layers of copper foil tape with conductive adhesive cover the whole PMT, including the plastic base. Another spiral layer of black electrical tape covers the copper. Next, a single layer of copper foil tape followed by a single spiral layer of black tape completes the wrapping process.
  • the crystal is coupled to the PMT with silicon optical grease. Care is taken not to introduce air bubbles between the crystal and PMT.
  • white Teflon tape is wrapped around the PMT where the crystal and the PMT meet.
  • the crystal is held in place with four to eight strips of very thin adhesive aluminum foil.
  • a layer of adhesive copper tape is placed around the crystal and PMT to secure the PMT and crystal together, while providing protection against external X-rays.
  • the three inch PMT's have adhesive lead tape securing the two together.
  • a spiral layer of black electrical tape covers the copper.
  • the scintillators should be shielded from radioactivity in the photomultipliers to which they are coupled. It is impossible to shield the detectors from high-energy gamma rays from the PMT's without degrading the optical properties of the scintillator/PMT system. It is possible, however, to shield the scintillators from beta particles and low energy photons by using a transparent window such as quartz between the PMT and the scintillator.
  • This window 24 is shown in the exemplary embodiment of Figure 1, with optical grease layer 23. Quartz was selected both for its excellent optical properties and its high purity. Quartz matches the optical density of CaF 2 (Eu) very well and is acceptable for Na ⁇ (Tl). 5 mm thick quartz windows are preferred. There is no observable radioactive contamination in quartz.
  • High-purity GeO 2 and germanium-based glasses are preferred for this pu ⁇ ose, for they have very low intrinsic radioactive background. Their higher atomic number and density is an advantage over quartz windows. Such windows with a few millimeters thickness efficiently stop low energy photons, as well as beta particles, without degrading the optical qualities of the scintillator/PMT systems.
  • the optical properties of gelica and germanium glass match Na ⁇ (Tl) better than does quartz.
  • Another alternative is to use high density glasses based on lead, particularly high density transparent crystals such as PbF 2 and bismuth germanite (BGO).
  • undoped crystals should be used so as not to generate artifacts due to scintillation within the BGO.
  • the optical density of these materials is higher than for CaF 2 (Eu) or Na ⁇ (Tl).
  • a window consisting of a triple sandwich consisting of gelica/high density window/gelica can be used. The thickness of the gelica may be much smaller than the high density optical window.
  • Shield/Separator External shielding of an MPD according to the invention is required to stop ambient radiation, as shown in the exemplary embodiment of Figure 1 as shield 55.
  • a 2" thick Pb shield is adequate for MPD detectors built around 1-1.5 mm thick scintillator crystals.
  • Increasing the shield thickness further does not significantly reduce the background on the Earth's surface, most probably because the remaining background is predominantly due to cosmic rays.
  • the shielding is made of lead only, secondary lead X-rays are present in the background spectra due to excitations in the shield itself by radioactive particles.
  • Composite shielding is thus preferred, with a 1-5 mm thick layer of tin inside the Pb shield to absorb the lead X-rays and a 1-5 mm thick copper layer inside the tin layer to absorb the tin X-rays.
  • the X-rays of the copper itself are of a sufficiently low energy (8 to 9 keV) to be outside the I 125 region of interest. Both Na ⁇ (Tl) and CaF 2 (Eu) scintillators have sufficient energy resolution to reject these pulses with better than 90% probability.
  • Commercially available Cu foils are sufficiently pure and do not introduce additional radioactive background.
  • the external shield should enclose the detector assemblies, including the PMT's and bases, on all sides. Sample holder/crosstalk eliminators are also made of copper, lead, or composite copper/lead plates 1-5 mm thick. This thickness is sufficient to stop iodine X-rays.
  • the materials for the shield should be tested for the absence of radioactivity, by measuring the background in a CaF 2 (Eu) detector selected for low radioactive background and placed in a selected, low background shield. A test performed for 2 hours yields a statistical uncertainty for each point of about ⁇ 10%.
  • Each shield which has a radioactive background larger than 0.9 cpm may be remeasured for 4 hours. If the new value is still above 0.9 cpm the shield is rejected. Typically, 20% of shields have to be rejected.
  • Integral PMT base assembly for high stability MPD devices is now described. Accurate counting of low activity sources requires a high stability detector system. The observed drifts are predominantly due to changes in ambient temperature, which cause drifts in the yield of the scintillators as well as the gains of the PMT's and the electronic readout.
  • the high voltage power supplies (HVPS) for the PMT's should be stabilized by introducing a high gain negative feedback, using as a reference chips (e.g. , Max 580) with low temperamre coefficient (1-2 ppm/degree Celsius), and using 1 % metal film resistors with a low temperamre coefficient.
  • the voltage divider for the PMT is based on the same type of resistors.
  • the temperamre dependence of the preamplifiers is minimized by using highly stable op-amps and distributing the gain so that each amplifier cascade has a gain lower than 5.
  • PMT Bases Commercially available HVPS and PMT bases are not adequate for low background detectors for biomedical applications due to dependence of HVPS and voltage divider (VD), performance/risk of high voltage cable, radioactive background of elements and electromagnetic pick-up noise between the PMT and preamplifier. Thus, an integral PMT base is preferred, containing a HVPS/VD/preamp/shaping amplifier assembly. Conventional PMT bases use much less integrated designs. Classically, only a voltage divider is placed in the PMT base. This leads to considerable electronic pick-up noise that is undesirable in the MPD. Several commercial devices feamre PMT bases with integral voltage divider and preamplifier.
  • the PMT base For maximal integration of the PMT base, it is preferred to include the HVPS, voltage divider and preamplifier because the use of high voltage cables leads to problems with ground loops and electromagnetic pick-up and may pose the risk of electrocution, especially with portable devices when used in high humidity environments.
  • the radioactive background of PMT bases was measured by placing the PMT next to a 2" diameter, 2 mm thick CaF 2 (Eu) detector coupled to a selected low-background 2" PMT. The whole system was well shielded with lead, tin and copper. Then the background in the CaF 2 (Eu) detector was measured in the energy range of 20 to 40 keV (the region of interest for I 125 ), and compared with the background without the smdied PMT base. Pulse-shape analysis was performed to discriminate between events and electronic artifacts. The background due to PMT bases was measured with bases 2 mm and 5 cm from the surface of the CaF 2 (Eu) crystal.
  • the first positioning permits measurement of the background while the measurement at the second position indicates how much this influences the MPD performance (length of used PMT's is about 5 cm).
  • the background in the CaF 2 (Eu) detector in the absence of test PMT bases was found to be 0.7 cpm.
  • the largest radioactive background is from the plastic high voltage connector, mostly due to beta particles. This background can be very efficiently attenuated by a thin plastic guard ring. After this modification, the PMT base radioactive background accounts for less than 10% of radioactive background of PMT's.
  • Quantitative measurement of low activity sources may require measurement times of up to several hours. Any slow drift of electronics can therefore influence these long term (1 hour) measurements.
  • the main source of this drift is the PMT's.
  • the strong dependence of the amplitude gain on the high voltage from the HVPS leads to temperature-dependent signal drifts.
  • High voltage power supply The voltage divider supplies the negative voltage from the HVPS to the PMT dynods (pins 1-11) and to the cathode C via an RC circuit. This is shown in Figures 3A, 3B, and 3C in PMT base assembly 30.
  • the voltage divider resistors represented as R7 and R8 have a low temperamre coefficient ( ⁇ 100 ppm/°C) and thus stabilize the PMT output signal.
  • Negative HVPS 50 preferably includes a regulated DC to DC convertor 64 from Matsusada Co., voltage regulator 66 and a feedback circuit with precision reference 68 (temperature coefficient about 3 ppm/°C) and comparator amplifier 70. Elements with low temperamre coefficient are preferred because of the importance of diminished temperamre dependence of HVPS output.
  • preamplifier/ shaper 52 Another important element of the PMT base is optimized preamplifier/ shaper 52 shown in Figures 3 and 3C.
  • a triangular pulse shape is optimal when using pulse shape analysis to reject background, e.g., due to dark current pulses in PMT's.
  • the majority of commercial devices use Gaussian pulse shaping, which optimizes the energy resolution for low energy X-rays and is preferred when pulse height analysis is performed, e.g., using multichannel analyzers.
  • the amplifier/shaper preferably includes a pre-amplifier 52 based on an EL 2030 low-noise current feedback amplifier and an output amplifier 54 based on a model OP64 amplifier with high gain and dynamic range. Output amplifier 54 does not need correction and tuning during performance.
  • the first numbers correspond to the use of Na ⁇ (Tl) scintillators while the numbers in parentheses correspond to CaF 2 (Eu) scintillators.
  • the resistor chain R4, R5 defines amplifier 54 gain. The gain was chosen in the interval 20-50 and is adjusted by potentiometers. This value depends on the properties of the given PMT and scintillator crystal and provides an output amplitude of about 2 V for 30 keV photons.
  • the resulting PMT base/operational amplifier assembly according to the invention has the following properties:
  • Noise and temperamre stability The high sensitivity and low background requirements of the MPD drive the specifications for the electronics. Conditions which cause a decrease of spectral sensitivity and S/B ratio can be separated into short-term noise (electronic noise, dark pulses) and long-term drift of electronic parameters (gain, high voltage, temperamre drift).
  • the energy resolution dE/E(FWHM) at 30keV for preferred detectors according to the invention is about 16% for Na ⁇ (Tl) and about 35% for CaF 2 (Eu). If electronics are to contribute less than 10% degradation to the energy resolution, this leads to a noise to signal ratio (N/S) of ⁇ 0.016.
  • the amplifier, high voltage power supply (HVPS) and electromagnetic shielding allow obtaining N/S ⁇ 0.005. The majority of electronic noise sources are filtered by the electronics, while the rest of the noise is rejected by on-line software shape analysis.
  • the temperamre dependence leads to easily measurable drifts of pulse amplitude for I 125 .
  • the temperature dependence of the gain upon ambient temperamre is below measurable accuracy.
  • the voltage divider for the PMT's can be implemented using metalloceramic 1 % resistors with a low temperamre coefficient.
  • current feedback and the use of a super stable source of baseline voltage allow for a small size HVPS (see Figure 3) with the following parameters: • DC voltage input: - 12 to -18 V output: -300 to -1,100 V
  • the pulse noise is a factor of 2-3 better than for commercially available HVPS.
  • the temperamre dependence of HVPS output voltage between 25 °C and 70 °C was compared for commercial HVPS and the HVPS according to the present invention.
  • the baseline/noise shows a better than 1 % stability of the baseline during a 24 hour period (measured in winter with heating switched off, i. e. , leading to a day/night variation of about 15°C).
  • the performance of the negative HVPS according to the invention was compared to HVPS PS1800 series (Electron Tubes, Inc.). Both HVPS's were switched on at the same initial temperamre (25 °C) and then were heated simultaneously up to 60°C.
  • the commercial HVPS showed a few percent drift of voltage, but the output of the HVPS according to the invention demonstrated no discemable variation due to heating.
  • photon detectors e.g., scintillators with PMT read-out
  • CaF 2 (Eu) scintillators are preferred for their good stopping power and reasonable energy resolution as previously described. Such systems achieve exceptional background rejection resulting in an improved capacity to quantitate minute traces of target isotope.
  • the device can be operated in two modes as previously described. In the OR mode we achieved high DE ( > 50% for I 125 ) is achieved with a radioactive background of about 1 count per minute (1 cpm). In the coincident (AND) mode, the DE for I 125 is below 20%, but achieves an ultra-low radioactive background of 1 count per day (1 epd). These results were achieved at the earth's surface with a relatively small shield (about 20 kg of lead). The system is designed around low cost commercially obtainable components and well established technologies.
  • FIG. 1 A block diagram of the MPD detector is shown in Figure 1 and an elevation is shown in Figure 2, including "sandwich" geometry, multiphoton coincidence and pulse shape analysis subsystems.
  • Detector 20 includes two modules separated by low radioactive background separator 32 consisting of heavy metals, typically a sandwich consisting of a few millimeters of Cu/Sn/Pb. Inside separator 32, a hole 34 is disposed into which sample 36 is to be placed.
  • the assembly of the two detector modules 20 is enclosed in a heavy metal composite passive shield 55, built of radioactively pure materials, typically lead, tin and copper as previously described.
  • the highest atomic number material e.g., lead
  • tin is most external and at least 1 inch thick.
  • a lower intermediary atomic number material e.g., tin
  • a few millimeters e.g., 1-2 mm
  • a few mm (typically 2 mm) layer of very pure copper is used.
  • Each of the detector modules includes the following elements: * inorganic scintillator crystal 22, with thickness optimized for a given emitter;
  • Optical window 24 is at least 4 mm thick ultrapure quartz, optically polished and provided with optical coupler 23, a low radioactive background silicon grease.
  • Selected PMT's 26 are made of glass with low contamination by K 40 , preferably 2"
  • PMT's preferably selected to present less than 0.1 cps background. It is preferable to decouple the PMT base 30 from the PMT 26 by means of graded shield 46 having three layers of metal with very different atomic numbers. Typically, such a graded shield includes about 0.2" of Pb, 0.15" of Sn and about 0.1 " of Cu.
  • PMT bases 30 are preferably fabricated from selected materials with low radioactive background, e.g., using pure copper or aluminum for the supporting frame.
  • low radioactive background e.g., using pure copper or aluminum for the supporting frame.
  • the use of resistors and capacitors selected for low radioactive background is disclosed, as well as the use of In-free solder, e.g., made of pure Sn or Sn/Pb alloy. All passive and active elements of the PMT base 30 are selected to have a very low temperature drift, and active compensation techniques to eliminate temperamre dependent gain drift are disclosed.
  • Both an OR and an AND mode are used for data acquisition and analysis, with a multichannel DSO 52 for on-line background rejection. Triangular shaping and software rejection of fast pulses due to signals induced by cosmic rays in the PMT's 26 is employed. A pulse rise time of about 0.75 microseconds and a slow fall time of about 5-10 microseconds are preferred.
  • Self-diagnostic and self-calibration is used for reliably matching the count rates in the OR and AND modes, more specifically, on-line baseline restoration and pile-up rejection techniques.
  • the coincident mode it is crucial to use the DSO 58 for matching the shape and temporal coincidence of pulses from the two detector modules.
  • On-line software based pulse fitting procedures however overcome these conflicting requirements.
  • Pulse shape analysis Data acquisition in a twin scintillator system is based on amplifying and shaping the signals from the PMT of each detector and building a combined energy spectrum for subsequent analysis.
  • the counts in an appropriate energy region of interest (ROI) for the desired isotope are then integrated to determine the count rate.
  • ROI energy region of interest
  • the detection efficiency is typically about 50% when only events in the single-photon energy ROI are counted.
  • I 125 counting both 30 and 60 keV events increases the detection efficiency to about 70%, but effectively doubles the integration energy range and therefore the background. Conversion of the count rate (counts per minute, or cpm) into the acmal activity in the sample (decays per minute, or dpm) requires knowledge of the detection efficiency (DE) of the counter.
  • the DE can be determined from the spectrum itself using the known Eldridge formula.
  • the DE is determined for each detector separately, which allows improvements in the calibration and accuracy, and testing the system integrity and correcting for the sample placement by comparing the two estimates of the actual activity of the calibration sample.
  • the spectrum of coincident events can be used to enhance DE evaluation and for diagnostic pmposes.
  • the predominant component of the non-radioactive background in low-energy gamma/X-ray detectors is due to dark pulses in the PMT's. In the I 125 ROI, these typically produce a few cpm for a two-PMT system. However, the shape of these pulses is different than those produced by scintillation in the detectors, making pulse-shape based discrimination possible. Pulse shape(s) for each event are acquired using a PC-based dual input plug-in DSO card 58 and fast pulse shape analysis is performed. This allows rejection of PMT dark pulses as well as other electromagnetic and vibrational artifacts. After pulse-shape based rejection, the background in the system is almost flat for energies in the 15-100 keV range and is remarkably stable, independent of the activities in the vicinity of the detector.
  • Detectors Flat 2" diameter detectors (1 mm thick Na ⁇ (Tl) or 1.5 mm thick CaF 2 (Eu)) are preferred. Smaller scintillators decrease the DE of the system while for larger crystals the signal to background ratio diminishes.
  • the scintillators are coupled through quartz windows 3-5 mm thick to 2" diameter high energy resolution PMT's which are selected for low background.
  • the PMT signals are read out, amplified and shaped using electronics built into the PMT bases 30. To reduce the flux of background photons from the bases to the scintillators the bases are isolated from the PMT's with 5 mm of lead and 1 mm of copper plating with holes for the PMT pins.
  • Shields and holders The detector assemblies are placed in graded lead + tin + copper shields (2" lead, 1 mm tin, 1 mm copper). The detectors are placed face-to-face half an inch from one another and a sample holder/crosstalk eliminator is placed between them. This is a 1 mm thick copper sheet mounted in a lead frame. Openings are left in the copper sheet for the samples. The shape of the opening is determined by the format of the samples to be used. A delrin guide with copper outer jacket ensures that all samples are centered in the detector system. When the sample format and sample holder are changed, the system can be automatically recalibrated using the Eldridge formula.
  • Data acquisition - hardware The data acquisition hardware is preferably mounted inside the dedicated PC controlling the MPD.
  • the data acquisition electronics in an exemplary embodiment include triggering circuit 56, amplification/attenuation modules for each detector, digital timer/counters 57, and a dual channel 20 MHz digital storage oscilloscope (DSO) 58 which is used both as a 2-input multichannel analyzer and a pulse shape analyzer.
  • DSO digital storage oscilloscope
  • the triggering circuit 56 produces a rectangular trigger pulse whenever a pulse exceeding a preset threshold amplitude is registered in either detector 26. If pulses are registered simultaneously in both detectors a higher amplitude trigger pulse is produced. It is thus possible to count separately coincident and non-coincident events.
  • the trigger pulse is sent to the external trigger input of the DSO.
  • the triggering circuit may be an integral card as described below.
  • the amplification/attenuation modules adjust the amplitudes of the pulses so that the energy region of interest is within the 0-1 Volt window of the DSO and particles of the same energy produce pulses of the same amplitude in both channels.
  • the first of the timer/counters 57 is used as a precise acquisition time timer (counting the 2.5 kHz reference pulses).
  • the second timer/counter counts all trigger pulses produced by the triggering circuit, while the third counts only triggers associated with coincident events.
  • the data acquired from these counters are used to directly evaluate losses due to acquisition system dead time and thus enable the system to conectly count high activity sources.
  • the DSO 58 (preferably a commercial CSLite PC add-on card manufactured by Gage
  • the DSO 58 is rearmed and initialized after each acquired and processed event.
  • the pulse traces are transferred from the DSO 58 to the host PC 59 memory and are analyzed for amplitude and shape by software. Initially the DSO 58 is set up to continuously chart the input voltages in the two channels and wait for a triggering pulse in the trigger input. When a trigger pulse is registered, the DSO 58 is allowed to capture a predetermined number of post-trigger points and is then stopped. The relevant portion of the traces (typically 20 pre-trigger and 108 post- trigger points at 20 Mhz sampling) is transferred to the host PC 59 memory for analysis. The transfer procedure takes less than 200 microseconds per trace for a 486 DX66 computer for example.
  • the trigger circuitry is used to: 1) generate a trigger signal whenever a pulse is produced by either PMT;
  • This hardware is preferably implemented as a signal conditioning/processing card (SCPC) 56 placed inside the computer.
  • SCPC signal conditioning/processing card
  • the SCPC card 56 feamres adjustable gain and trigger levels for each channel and produces a TTL trigger pulse.
  • the SCPC card receives as inputs the signals directly from the PMT bases 30.
  • the conditioned signals and the trigger pulse are passed directly to the inputs of the DSO card 58.
  • the two-channel SCPC 56 is designed for:
  • the SCPC 56 has the following parameters:
  • Output signal (positive pulses) analog signal 0.1 - 1 V amplitude; 0.1 - 10 ms pulse duration TTL level: amplitude ⁇ 4.5 V; duration 4 - 5 ms.
  • analog trigger amplitude 0.5 V for "OR” mode, 1 V for "AND” mode duration 4 -5 ms.
  • the on-line pulse rejection software rejects pulses whose shape is not compatible with pulses produced by particles stopped in the scintillation detector. Most of the rejected background is due to noise in the PMT, electromagnetic interference and vibrational noise.
  • the shape of the pulses caused by radioactive events does not change with time and does not depend on the amplitude of the pulse within the linear range of amplification.
  • one approach to pulse shape rejection is to normalize the registered pulses to a common amplitude and to compare the shape of the normalized pulse to a "standard" shape using, e.g., a chi-square test. This however, involves massive floating-point computations which are much too time consuming for effective implementation on currently available low-cost microprocessors.
  • the pulse shape rejection can be performed by determining a number of parameters related to the pulse shape which can be computed using predominantly or solely interger arithmetic.
  • Step S3 to SI 4 After initial steps of setting the DSO for aquisition and waiting for a trigger, analysis begins with computation of the baseline and the pulse amplitudes in each detector (Steps S3 to SI 4). From this it is known whether the event occurred in detector A, detector B or both. The pulse amplitudes are adjusted for the current baselines, and if the latter are unacceptably distorted the event is rejected. Then, a number of pulse shape parameters are evaluated and compared with the ranges of acceptable values established by the software at system set-up. These include, for example, pulse widths at 1/4, 1/2 and 3/4 of peak pulse height ( Figures 8b and 8c).
  • the parameters may include: pulse amplimde; rise time fall time total pulse width; shape of the rising part of the pulse; the shape of the falling part of the pulse; the delay between the pulses from the two detectors; pulse multiplicity; the pre-pulse trace; and comparator of the pulse shape with a standard high energy photon pulse shape using a least squares technique.
  • the DSO 58 acquires 128 points with 8-bit resolution for each input channel for each pulse.
  • the time window spans the whole width of the shaped pulse (5 microseconds) and approximately 1 microsecond before the rise of the pulse.
  • Digital processing of the pulse begins with calculating the average of the first 8 points S4, which gives the current baseline.
  • step S5 to S7 If the computed baseline differs significantly from 0, the event is rejected (steps S5 to S7) as distorted by pile-up. Next 120 points of the trace are scanned (using the fast LODS instruction of the 80X86 processors) for the maximum value. If overflow is detected, the event is rejected (steps S5 to S7). Otherwise, the amplimde is computed as the difference between the peak value and the current baseline (steps S8 to S10). The program also stores the time offset of the peak. A fast (LODS-based) scan is then done forward and backwards from the peak to determine the time offsets of the crossing-points for the levels, for example, of 1/4, '/ 2 and 3/4 of the amplimde (steps S15 to S20, and S26 to S28).
  • the acquisition can be preset to collect data either for a given interval of time or until a certain number of counts within a selected ROI have been acquired.
  • the acquisition can also be terminated by the user at any time.
  • the automatic device calibration ROI setting routine is as follows. The user can request the software to perform this procedure at any time. No calibrated sample is needed, but a reasonably high activity (optimally 50,000 to 200,000 dpm) I 125 sample is required. After placing such a source into the detector the program acquires 100,000 events with all pulse-height and pulse-shape rejections enabled. Once the acquisition is finished the spectrum is analyzed to determine the region of interest (ROI) for a single photon (27-35 keV) peak. The count rate (cpm) within this ROI is determined. If the actual activity (dpm) in the sample is known, the detection efficiency could be established from the ratio of cpm/dpm.
  • ROI region of interest
  • cpm count rate
  • the program now starts a second round of data acquisition with pulse-shape rejection disabled (as the calibration sample activity is high, there is no need to reject the background, and no real events are discarded).
  • Spectra for both detectors (A and B) are built until 200,000 events are acquired.
  • the spectrum of each detector is analyzed to estimate the count rates in the 1 -photon and 2-photon peaks (the coincident spectrum is also used to enhance separation of these peaks).
  • the Eldridge formula is used to estimate the detection efficiencies of the detectors and the decay rate for the calibration sample.
  • the data are checked for consistency by comparing the estimates from detector A and detector B, and the average of the two is accepted as the absolute activity, from which the detection efficiency is estimated.
  • the DE is normally in the range of 50-60% for 2" systems. Only the 1 -photon peak is used for counting, which in the case of a sandwich detector with electronic noise rejection decreases the detection efficiency only by about 15% while diminishing the background about 2 to 3- fold.
  • the system is ready to count samples of the same geometry as the last calibration sample used. Acquisition is performed either for a preset time or until a preset number of counts (determining the statistical uncertainty of counting) have been acquired in the ROI.
  • the program estimates the acmal decay rate in the sample using the previously computed DE.
  • the sample counting data are then typically stored to disk in an ASCII data file which can be transferred to a database or spreadsheet program for analysis.
  • the software sets the acquisition/rejection parameters for each newly assembled detector system. This determines the optimal trigger levels and pulse shape rejection parameters for the system and creates internal data files to store these parameters. These parameters generally do not have to be redetermined during the lifetime of the system unless a major component (e.g. , a PMT/base or DSO card) is replaced.
  • a major component e.g. , a PMT/base or DSO card
  • the system program can be pre-set by the user to count more than one sample or to count the same sample repeatedly a requested number of times. If a batch of samples is counted, the program prompts the user to change the sample after each measurement, and all data are stored in the same ASCII file.
  • the file contains a header with a date/time stamp and system settings, as well as an extended description of the sample(s) entered by the user using a GUI edit window before the counting begins, for example.
  • the program may also be provided with a simple data file browser which allows viewing and analysis of data from single samples and batches of samples.
  • the user can select a data file to be viewed through a system of menus, see the counting uncertainty for each sample, plot the count and decay rates vs. sample number and print out the data with statistical uncertainties.
  • a more extensive analysis and merging of data can be performed using a commercial spreadsheet program, for example.
  • the software is preferably coded in Borland Pascal and Assembly language to speed up the pulse processing and operates under DOS using a Windows-like GUI shell.
  • software under MS-Windows can use the recently released Delphi software development system (Borland International), which uses the extended Borland Pascal language.
  • Borland International Delphi software development system
  • MPD devices include self-diagnostics and self-calibration using the redundancy in spectral information characteristic for EC sources , i. e. , the one- and two-photon peaks in single-detector spectra and the 2D spectrum of coincident events (the scatter plot of energy in detector A vs. energy in detector B). Additional benefits stem from the MPD using two separate pulse counting subsystems, namely the DSO 58 and the pulse counters 57, which allows monitoring of discrepancies in the count rates between the two detector subsystems and to detect possible hardware failures.
  • the MPD software uses data acquired from a source of known isotope to check the operation of the detectors, PMT's, HVPS and the readout electronics. Possible contamination of the MPD is detected by measuring and analyzing background spectra.
  • the software automatically computes the detection efficiency in both the coincident and non-coincident modes for a given EC isotope using a calibration sample of that isotope. Diagnostic routines track any drift in the gains and thresholds in the device and calculate any required adjustments.
  • the MPD After tuning, the MPD has excellent long term stability; short time (less than 1 week) drifts are less than 1 % in the I 125 peak. 1,200 independent measurements performed with
  • MPD show reproducability is much better than the statistical uncertainty of these measurements. MPD devices permit better than 1 % measurement precision for sources in the 0.1-1 ,000 picoCurie range. Over six months of operation the drifts were smaller than 3 % .
  • the two detectors are made from different materials, e.g., two different types of scintillator can be used, or one scintillator and one semiconducting detector may be used;
  • the two detectors are of different size, typically one very small to diminish background and one large to increase the detection efficiency;
  • the two detectors serve different functions, e.g., one is spatially resolving and other is a non spatially resolving detector which serves as a triggering device.
  • the spatially resolved detector is partially obscured by an appropriate pattern of coded apertures while the second detector is fully exposed to the source.
  • Optimal configurations use a combination of elements.
  • one detector includes a Na ⁇ (Tl) crystal coupled to spatially resolving PMT.
  • the triggering detector is a CaF 2 (Eu) scintillator coupled to a different type of PMT from another producer.
  • the system performance depends on optimizing all parts of the system, e.g., the type of scintillator, scintillator diameter, scintillator thickness, thickness of the optical window, and the type and geometry of the coded aperture mask.
  • the single sample MPD permits considerable background reduction when using a single sample labeled with CGX isotopes, especially I 125 .
  • one needs good spatial resolution e.g., when measuring radiolabeled distributions obtained in separation processes (electrophoretic gels, dot blots, thin layer and paper chromatography), and in anatomic studies of tissue preparates.
  • Very popular 2D radiolabeled distributions include products of separation by electrophoresis, thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) which can be subsequently filtered upon an appropriate medium. These may be referred to as chromatograms.
  • electrophoretic separation products trapped inside gels.
  • the gels can be cured or dried to improve their mechanical properties. In this and many other many cases, however, it is more practical to sandwich the biomedical sample between two thin films of material.
  • electrophoretic separation products are often transferred or blotted upon elastic membranes, either nitrocellulose or plastic. These products are called blots.
  • MPD detectors can be implemented to replace classical autoradiography and phosphor imagers.
  • the biomedical sample is essentially a 2D object, thickness being much smaller than the two other dimensions. Often, it is supported on one side by an appropriate thin membrane.
  • the thin support may be produced from a material with low atomic number, e.g. , plastic. Such a thin mechanical support can be implemented so that it has relatively small absorbtion of X- rays, say less than 5%.
  • Three competing requirements on the physical presentation of radiolabeled 2D distributions are:
  • samples should be hermetically sealed to eliminate detector contamination by direct contact or by degassing of aerosols
  • the sample should be as flat as possible, because a change of distance from the sample to the detector surface leads to artifacts in the measured activity.
  • Conventional detectors are typically calibrated to within ⁇ 5% whereas the MPD achieves ⁇ 1 % calibration and reproducibility.
  • the unprecedented sensitivity of the MPD means that even the smallest contamination is fatal for measurement integrity. Often, not only the biomaterial but also the supporting material is contaminated. This is the case for blots because the blotting is performed using a special buffer liquid, and a small fraction of radiolabeled electrophoretic product is transported by diffusion to the reverse side of the membrane.
  • Another practical method is to use thin adhesive tape made of either plastic or very thin ( ⁇ 0.1 mm) aluminum tape.
  • Thin pouches may be used, preferably pouches made of thin films of beryllium.
  • pouches or bags made of plastic or very thin aluminum are adequate.
  • lamination is a very practical method of providing them mechanical properties and radiochemical purity required by the SR-MPD instrumentation. As lamination is typically achieved by rolling the foil- sample-foil-sandwich between two hot surfaces, care should be taken that the lamination machine itself is not contaminated. Also, care should be taken that the lamination foils are not contaminated.
  • a scanning MPD device is now described. In most symmetric MPD systems, spatial resolution is comparable to the crystal diameter.
  • the spatial resolution can be drastically improved by inclusion of a "pin hole” or “slit” aperture. Then, 2D isotopic distributions can be mechanically displaced between two detectors, one of which has the above said aperture.
  • This implementation is referred to as the MPD-Scanner.
  • the MPD-Scanner permits dynamic data acquisition with excellent S/B. It allows the system resolution to be directly proportional to the precision of the aperture movement upon the surface of the blot or other 2D sample format.
  • the collimator (slit) width is of the same order of magnimde as the characteristic physical band width of the sample.
  • a stationary collimator measures the total signal coming into the entire slit area, e.g., the signal from 4 mm 2 of the sample for a 1 mm x 4 mm slit. The situation is different when time resolving detectors are used.
  • A min ⁇ S/B ; sqrt(N) ⁇ , where S/B is the signal to background ratio and Sqrt(N) is the statistical uncertainty of the measurement when N photons are detected for a given slit position.
  • the "edge effect" will limit resolution to about 100 micrometers. This limit can be as low as 20 micrometers for lower energy EC isotopes.
  • the count-rate is drastically reduced.
  • the optimum dimensions and material of the aperture are dependent on the application and the activity of the 2D distribution. Preferred are lead films with thickness from 0.2 to 1 mm.
  • lead films with thickness from 0.2 to 1 mm.
  • an aperture in the form of a slit with an opening width of 2 mm and length of 2 cm is preferred.
  • slits with 1 mm width and a few mm length.
  • the spatial resolution is much better than the aperture dimensions; typically 0.2 mm resolution.
  • this case involves reconstruction software in which for each step of the mechanical mover, the optimal count-rate is calculated. This optimal count rate depends on the signal-background ratio at the given place of the 2D distribution.
  • the preferred scan routine is iterative. First, a low precision, constant step statistically limited map of the 2D isotopic distribution is obtained. Afterwards, an optimized scan is performed in which the acquisition time at each spot is calculated to optimize the total scan time under the constraint of minimal spatial resolution and statistical uncertainty. The operator may choose some part of the 2D sample to be scanned with higher precision.
  • the counting rate in the MPD-Scanner depends on the dimensions of the crystal.
  • An optimal configuration is one in which two crystals have different diameter.
  • the detector on which the aperture is placed is smaller, typically 0.75 or 1 inch in diameter.
  • the second crystal is much larger, typically 3 or 4 inches in diameter.
  • the MPD-Scanner should be asymmetric not only in dimensions but in the use of different scintillators. For example, signal/background can be improved by about a factor of two when the smaller crystal is Na ⁇ (Tl) and larger is CaF 2 (Eu).
  • the two detectors used in the MPD-Scanner according to the invention are the small diameter (0.5-1 inch) primary detector which determines the spatial resolution, and the secondary detector used for coincidence/anticoincidence analysis.
  • the surface of the primary detector is covered with an absorbing mask (of Pb or Cu) with an aperture (usually in the shape of a rectangular slit).
  • the computer-controlled mover moves the sample in front of the slit with a step which can be equal to or smaller than the slit width.
  • the acquisition logic is as follows. The triggering is performed from the signal in the primary detector.
  • Each pulse from the primary detector is analyzed for the shape (for background rejection) and amplitude.
  • the trace recorded simulteneously from the secondary detector is also analyzed, and coincidence/anticoincidence analysis is performed.
  • the energy spectra of all non-rejected events in the primary detector and of coincident events are built during the measurement. Before the sample is moved to the next position, the counts in ROIs set for different isotopes are integrated and the data appended to the scan data disk file.
  • the user interface for the MPD-Scanner includes the scan definition and the data analysis modules.
  • the scan definition module permits the user to preset the geometrical parameters for multiple scans: the starting points, the scan lengths and steps, as well as the measurement times per step (which can be different for different scans), and the user descriptions for each scan.
  • the data analysis module permits viewing the scan profiles in different modes (a profile graph or a simulated autoradiogram). This module also permits analysis of profiles, as well as sending the data to a spreadsheet for customized analysis.
  • MPD-Scanners Very high spatial resolution scanning MPD is now discussed. In many applications, a few microns spatial resolution is required. An MPD with such spatial resolution permits considerable improvement in a plurality of biomedical studies, e.g., anatomical and cellular studies.
  • the spatial resolution of MPD-Scanners is generally about 100 microns.
  • the spatial resolution of all detectors is limited by the following effects: 1) thickness of the 2D distribution of the radioisotope. 2) the limited stopping power of the detectors, leading to parallax errors in the crystal;
  • the first error source can be eliminated using devices analogous to those used in conventional optical and electron microscopy.
  • the second source of error is a fundamental limitation leading to positioning uncertainty in all detectors using proximity imaging. This is the main limitation upon the spatial resolution of autoradiography or phosphor imagers. As mentioned above, in the case of beta sources, the range of the particle limits the resolution of classical detectors for all sources but tritium. Obviously, there is a trivial solution, which is to make the scintillator as thin as the required spatial resolution, but this leads to very low detection efficiency.
  • scintillators are not the best detectors.
  • the second detector detects only higher energy photons, e.g., 27 and 31 keV photons in the case of I 125 .
  • it can be a relatively large, say 2-3 inch diameter, scintillator, e.g., CaF 2 (Eu).
  • a gas detector can be used for detection of very low energy X-rays.
  • a windowless gas detector can be used using pressurized gas flowing through the film aperture. This film itself is used as an electrode of the gas detector amplifying system.
  • a fourth source of errors in the MPD-Scanner is the precision of the mechanical displacement system. Piezoelectric mechanical displacement generators exist with sub-micron resolution. Additionally, the problem of the precision of mechanical parts of the MPD- Scanner is facilitated in those applications where only relative, rather than absolute indexing, is required.
  • An exemplary Spatially Resolving MPD (SR-MPD) is now described. The Scintillator- based Spatially Resolving SR-MPD detectors feamre low cost, excellent sensitivity and good spatial resolution.
  • the SR-MPD concurrently quantitates up to 50 samples of biological material labeled with CGX isotopes, e.g., I 125 , with reasonable detection efficiency and minimal cross-talk (below 1 %).
  • the background is about 0.3 count per sample per day.
  • the spatial resolution of the SR-MPD is about 2-3 mm.
  • the SR-MPD can be successfully applied to analysis of biologicals presented in the form of dot blots or contained in standard 8x12 well microtiter plates.
  • a prefe ⁇ ed SR-MPD according to the invention includes three parts: an auxiliary detector, a spatially resolving detector and data acquisition electronics.
  • the auxiliary detector uses a 3" CaF 2 (Eu) scintillator coupled to a low background non spatially resolving PMT.
  • the performance of the auxiliary detector is optimized by selection of a crystal diameter and thickness which provides the best trade-off between detection efficiency and low background.
  • the methods disclosed for the single sample MPD selection of low background PMT's, use of thin quartz window, special packaging, temperature stabilization of read-out electronics, special design of PMT high Voltage base) are used here. They permit a factor of five decreased background as compared with the commercially available assemblies.
  • the spatially resolving detector includes a thin 2-3 " diameter Na ⁇ (Tl) crystal coupled to a spatially resolving PMT (SR-PMT).
  • Preferred SR-MPD devices are implemented using a 3" diameter SR-PMT manufactured by Hamamatsu.
  • a lead mask about 1 mm thick is placed on the surface of the SR detector.
  • Coded aperture masks made of tungsten, gold or platinides permit further improvement of spatial resolution. For example, samples a ⁇ anged as a dot blot are placed next to the apertures in the mask. This configuration allows up to half of the single-sample MPD detection efficiency for each of about 50 samples.
  • One of the problems is non-linear SR-PMT response. To maximize the number of samples measured concu ⁇ ently the samples can be a ⁇ anged so that the sample spacing increases towards the outer edge of the SR-PMT.
  • the SR-MPD permits up to 20 times higher throughput than the SS-MPD at about three times the cost.
  • the X-rays are very soft. This permits imaging when using a parallel hole collimator.
  • the use of SR-PMT 's in conjunction with scanning devices permits excellent spatial resolution, down to 0.2 mm. This is adequate for nearly all molecular biology applications.
  • SR-PMT techniques can be adapted to the exacting standards of ultralow- radioactive background applications.
  • SR-PMT's have previously been developed for high counting rate applications, typically 100 cpm, whereas according to the invention they are used at count rates lower than 0.1 cpm. Thus, the radioactive background of the PMT's, vibrational and electromagnetic noise must be rejected and spatial resolution inhomogeneities and artifacts accounted for.
  • the Hamamatsu 3" SR-PMT, model R2486 is prefe ⁇ ed.
  • the electronic readout system of the Hamamatsu SR-PMT provides the user with four inputs, from which the coordinates of the detected events can be calculated.
  • the SR-PMT is physically a 3" device which has however, only an approximately 2.5" diameter active area, i.e., an area in which good spatial resolution can be achieved.
  • the signal drops drastically at about 1.1" from the PMT center which for X-rays leads to drastic artifacts in the measured position of the optical photon cascade in the scintillator.
  • 2"- 2.5" diameter scintillators are optimal for the SR-MPD, and good spatial resolution can be obtained by appropriate hardware and by using iterative position calculation software, described below. For I 125 this means that 49 samples can be well resolved, as compared with the 32 samples which can be resolved using the manufacmrer's electronics and the manufacturer's suggested position calculation software.
  • the crystal is significantly smaller than the SR-PMT diameter; use of a 2" diameter scintillator leads to three-fold lower background than when using a 3" crystal. Furthermore, the use of a very thin, say 0.5-2 mm thick quartz coupler between the SR-PMT and the scintillator crystal helps diminish background due to beta particles emanating from the PMT glass about five-fold.
  • An alternative SR-MPD instrument is based on the 5" diameter Hamamatsu SR-PMT' s. Spatial resolution is only slightly worse than with the Hamamatsu 3" SR-PMT. It permits considerably more resolved pixels per detector surface than the 3" SR-PMT.
  • the 5" SR- PMT' s are not prefe ⁇ ed for a low background device.
  • the 5" SR-PMT utilizes an approximately 6 mm thick front glass window that is highly contaminated with K 40 , leading to about a factor of four higher radioactive background than with non-spatially resolving 3" PMT's.
  • a larger SR-MPD is preferably based on a 5" SR-PMT made of quartz.
  • the SR-MPD data acquisition software has to process more than two traces for each event.
  • the signal acquisition and processing software analyzes six signals, SL, SR, ST, SB, TS and the signal from the non-spatially resolving trigger electronics (TR).
  • the signals from the spatially resolved detector can have very different shape than the signals from the auxiliary detector.
  • the signals from Na ⁇ (Tl) are much faster than from CaF 2 (Eu).
  • the software uses this dichotomy to better reject the background.
  • Sum pulse TS and pulse TR from the secondary detector are analyzed for amplimde and shape to reject electronic and other artifacts, while the four original signals from the SR- PMT are analyzed for amplimde only .
  • the amplimde of the sum pulse is roughly proportional to the particle energy and is analyzed in dedicated hardware for compatibility with the source used. However, there is a dependence of the signal on the photon impact position on the crystal. Thus, after the position of the event is established, the amplitude of the total signal is software analyzed and all events with energies outside of the pre-set energy ROI are rejected.
  • the different modes of hardware and software event analysis permit rejection of over 95% of the background events.
  • the main source of background are upsets due to cosmic rays
  • the main source of background is a combination of electromagnetic interferance and dark cunents in the PMT.
  • the location of the event on the surface of the detector is calculated from the four outputs of the SR-PMT.
  • the calibration functions a(x), b(x), c(y) and d(y) have to be established empirically for each SR-PMT. Unfortunately, this function depends also on the source energy.
  • a 2D image co ⁇ esponding to the surface of the detector is built. Following the acquisition, the counts in the areas associated with apertures in the mask are integrated to obtain the count rate for each sample, which is then converted to dpm using the calibration data.
  • the parts of the image co ⁇ esponding to the apertures and the detection efficiency and background values for each aperture are determined during the calibration of the device by placing samples of known activity into the apertures, acquiring the image, and analyzing it.
  • the software mask construction is performed automatically by the software using a straightforward peak detection routine.
  • the MPD Imager is now described. Scintillator-based MPD-Imagers feamre low cost, excellent sensitivity, high throughput and sub-millimetric spatial resolution.
  • the MPD- Imagers can be used for quantitation of fractionated biological materials , e. g. , chromatographic outputs and DNA sequencing gels and blots.
  • the spatial resolution of the MPD-Imager can reach or exceed 0.2 mm.
  • the MPD-Imager permits sub-millimeter resolution and is appropriate for quantitation of fractionation outputs, e.g., sequencing gels or chromatographic plates.
  • the SR-MPD is coupled to a high precision 2D mover. High resolution is obtained by using a multi-aperture pattern; each event is assigned to a spatial ROI and reconstructed from the knowledge of the position of the mover.
  • the MPD-Imager is much more sensitive and faster than phosphor imagers, which are increasingly used in molecular biology. DNA sequencing blots were quantified using the MPD-Imager and dot/bar patterns were spatially resolved at few zeptomole level.
  • a prefe ⁇ ed MPD-Imager includes the following sub-systems:
  • the MPD-Imager permits dynamic acquisition of information with excellent S/B. It allows system resolution to be directly proportional to the precision of the aperture movement upon the surface of the blot.
  • the collimator (slit) width is of the same order of magnimde as the physical width of the DNA band.
  • a stationary collimator measures the total signal coming into the entire slit area, e.g., the signal from 4 mm 2 of the blot for a 1 mm x 4 mm slit. The situation is different when time resolving detectors are used. As the collimator moves to a new position across the blot, one measures a relative increase or decrease of activity in the area of the blot that is opened to the detector by the movement of the leading edge of the slit.
  • the test pattern consisted of equally spaced horizontal bars of 3 mm, 2 mm and 1 mm, with the bar spacing equal to the bar width.
  • the pattern and its image were obtained with the MPD Imager and a Molecular Dynamics brand phosphor imager. After a 48 hour exposure, the phosphor imager detected the 3 mm pattern well, although the background is quite high. It only partially resolves the 2 mm pattern, and the 1 mm pattern is unmeasurable. In contrast, the MPD-Imager clearly resolved even the 1 mm pattern with S/B of about 10. The 0.5 mm pattern is also resolved, but requires a longer scanning time.
  • the MPD-Imager combines the functionality of the SR- MPD and that of the MPD scanner.
  • the mask on the primary (SR) detector has an a ⁇ ay of apertures, defining the spatial resolution of the imager.
  • the 2D sample is placed on a computer-controlled mover which sequentially places the sample in the measurement positions. In each position, the counting is performed for a pre-set time (using the same acquisition logic as that for the SR-MPD). The count rates for all apertures are obtained and stored in a disk file.
  • the resolution- defining aperture pattern is such that, to obtain a continuous image, the pixels have to be interleaved in both X and Y dimensions.
  • the pattern should allow such interleaving, although it does not necessarily have to be rectangular.
  • the system has a separate calibration file containing the software mask defining the mapping of the apertures to the image surface. The mask is constructed automatically by the software during calibration.
  • the user interface allows selecting a rectangular area to be scanned and pre-setting the counting time for each pixel.
  • the data analysis module reconstructs the image from the counting data, permits visualization of the image in false colors, shades of grey, a contour map, or as a 3D surface, as well as storing the image in a number of standard formats for analysis by other image processing programs.
  • a Large MPD-Imager is now discussed. For a large MPD-Imager, the spatially resolving part of the system is engineered to enable higher throughput for large 2D fractionation outputs. Commercial value of MPD-Imagers depends on providing throughput sufficient to perform overnight analyses of 2D gels and blots at the IO "19 mole level. To achieve this, one may use a large area, say 12 inch x 8 inch, MPD-Imager.
  • Three types of large spatially resolving gamma detectors which can be used in a large MPD-Imager are: detectors using one or several SR-PMT's; detectors using a few tens of small diameter PMT's in an Auger camera configuration; and detectors using microchannel plates and CCD imagers.
  • a prefe ⁇ ed new scintillator Yttrium Aluminum Perovskite doped with Cerium (YAP(Ce)
  • YAP(Ce) YAP(Ce)
  • the beneficial characteristics of a large MPD-Imager are: 1) lowest possible radioactive background, permitting zeptomole sensitivity in a plurality of biological tasks; 2) instrumentation permitting high throughput even for the samples with very low levels of radioactivity; 4) low cost, user friendly devices with software facilitating biological tasks.
  • a single computer controls the concu ⁇ ent and coordinated operation of four spatially resolving sub- units. This is made possible by the relatively low count rates in targeted applications at count rates of between a few tens per second to a few counts per minute per pixel. Pulse shape analysis takes only about 100 microseconds and can be diminished to about 10 microseconds. Losses due to pile-up of events in different detectors can be fully accounted for.
  • the number of detectors in the multi-detector instrument is limited by the DSO 58 bus throughput, pulse shape analysis time including speed of the controlling microprocessor, the number of available bus slots, and cost considerations.
  • a four detector MPD may be interfaced on a Pentium 120 MHz in full-tower configuration and motherboard with 12 bus slots, for example.
  • Four SR-PMT's can be multiplexed on a single computer.
  • This exemplary embodiment has four modules:
  • the auxiliary detector is based on CaF 2 (Eu) scintillators coupled to a plurality of selected, low background PMT's.
  • Prefe ⁇ ed auxiliary detector modules are as follows. First, a large, say 8" x 8" crystal is coupled by means of appropriate light guide to a 6" PMT. This is the simplest and lowest cost implementation, but it leads to a rather large device. Second, a single CaF 2 (Eu) scintillator is coupled to an a ⁇ ay of PMT's. For example, a 9"x9" scintillator can be coupled to an array of nine matched 3" PMT's.
  • a 8" x 8" crystal is coupled to the a ⁇ ay of 16 matched 2" PMT's.
  • the outputs of all PMT's are summed and pulse height and pulse shape are analyzed by low noise electronics, including DSO 58.
  • Pulses of appropriate amplimde can be used as the trigger for acquisition and analysis of data from the spatially resolved detector.
  • the trigger detector can consist of four sub-assemblies, each consisting of 4"x4" CaF 2 (Eu) crystals coupled to a single, 4" PMT.
  • the PMT is square or hexagonal, but cylindrical PMT's can be used with optical coupling using an appropriate acrylic waveguide.
  • PMT's can be used with optical coupling using an appropriate acrylic waveguide.
  • much simpler computer calibration can be used.
  • inhomogeneities of scintillation detectors are always largest close to the borders of the scintillator, i. e. , the mosaic trigger detector may have somewhat lower detection efficiency and lower energy resolution, which negatively influences the background.
  • Na ⁇ (Tl) can be used for its good stopping power and the best energy resolution among scintillators.
  • An exemplary large area spatially resolving detector module uses a 8"x6" active area to permit imaging of the full surface of a typical sequencing gel.
  • An exemplary mosaic SR-detector uses four smaller SR-PMT's.
  • the detector assembly includes four spatially resolving detector modules, each consisting of a 4" x 3" Na ⁇ (Tl) crystal read out by a Hamamatsu square SR-PMT.
  • the square SR-PMT has an active area of 60 x 55 mm, wherein a spatial resolution of 2-3 mm is expected.
  • SR-PMT's Square rather than round 3" SR-PMT's are prefe ⁇ ed because they permit better coverage of the surface. Both the electronics and the imaging properties of square and round SR-PMT's are almost identical, and can use basically the same electronics and software. To economize the slots available in the control computer, all of the electronics for a single SR-PMT is preferably placed on a single card.
  • the large MPD-Imager uses multiplexing to diminish the number of electronics cards to economize space, facilitates handling of heat-load problem and diminish the cost of the device.
  • Use of a single Pentium 120 Mhz assumes that a single full length card contains the signal conditioning and coincidence circuitry for two detectors, i.e., four channels.
  • DSO 58 feamres two channels per card.
  • a prefe ⁇ ed DSO card 58 has 4 channels, each 50 MHZ. It is based on CMOS elements to considerably diminish heat dissipation. Four channels of DSO can then fit on a single full length card with the PCI bus.
  • Multiplexing electronics is prefe ⁇ ed with eight thresholds providing flags for software.
  • thresholds For each detector, mere is separate delay and coincidence circuitry, permitting both non- coincident and coincident counting.
  • a set of 40 flags (outputs from 8 thresholds for each SR- PMT, four coincidence signals and four thresholds for sum signals) are then transfened to the computer permitting on-line event reconstruction.
  • the signals from all SR-PMT's are summed and the outputs are input into the 3 DSO's. This permits pulse shape analysis using the present software. With the availability of a four channel DSO, only three cards are necessary to process the information from four SR-PMT's.
  • Software preferably permits "seamless" image reconstruction, taking into account the non-active area between detector units, and is consistent with use of computers based on the Intel P6 processor.
  • Multiplexing several SR-PMT based detectors and building a large-area detector requires faster pulse shape analysis. In single detector systems, DSO's with long transfer times (200 microseconds/pulse) are adequate.
  • the large MPD-Imager uses DSO's with a faster computer interface. To fully utilize this advantage requires fast drivers and accelerated pulse processing.
  • the logic of the pulse shape rejection is therefore optimized for the multiplexed systems by taking into consideration the additional information from all PMT's and changing the order of the tests. Further optimization of the pulse shape analysis code is achieved by utilizing the highly efficient native Pentium and P6 instructions.
  • the MPD-Imager includes software statistical analysis functions and routines for image enhancement and recognition. The latter are preferably based on such AI techniques as simulated neural networks and/or iterative use of memory matrices.
  • Large MPD-Imager based upon time delay techniques Some limitations of the large MPD-Imager relate to the SR-PMT's used « high radioactive background due to contamination of Hamamatsu tubes with K 40 and difficulty of calibration due a large dead zone between the four separate SR-PMT's.
  • Anger cameras are a popular class of large gamma detectors wherein the surface of a single large Na ⁇ (Tl) crystal is populated with many photomultipliers. When a photon is absorbed in the crystal, the light is shared between several PMT's. The center of gravity of the light pulse is established by finding the four PMT's with the largest signal and reconstructing the event from the ratio of their signal amplitudes.
  • Spatial resolution is limited by crystal thickness, light yield and the number of PMT's used.
  • the number of ADC's is the same as the number of PMT's, say twenty-four 2" PMT's. More complicated schemes are envisioned according to this aspect of the invention, in which a large number of thresholds are used but only eight ADC channels are necessary.
  • An Anger camera based MPD-Imager is prefe ⁇ ed, but the required electronics are complex and due to the large number of channels, pulse shape analysis is difficult to implement.
  • An alternative embodiment is a high performance spatially resolving gamma detector using a pulse delay technique and DSO to reconstruct the photon position, and the new scintillator material, yttrium aluminum perovskite activated with Ce (YAP(Ce)). It provides a high light yield (about 50% of Na ⁇ (Tl)) and is about five times faster than Na ⁇ (Tl). Also, multichannel, high speed and large memory DSO cards compatible with Intel Pentium or P6, e.g. , two channel, 150 MHz/channel with 32 kb of memory from Gage Inc., may be used. Low attenuation analog delay elements are readily available with delay times from a few tens of nanoseconds to a few microseconds.
  • the outputs of up to 10 PMT's can be digitized with a single channel of DSO.
  • two DSO cards encode the output of up to 40 PMT's and permit highly reliable, nominally 8 bit quantitation.
  • signal pulses have about a 50 nsec duration. This allows multiplexing signals from several PMT's onto a single DSO input through the use of constant delays.
  • Summing is prefe ⁇ ed for the 6 outputs from each of the 4 rows of PMT's delayed by 0, 100, 200, 300, 400 and 500 nsec, respectively.
  • This pulse train is then sent to a DSO input channel and to the trigger card (SCPC) which produces triggers for all DSO's in the system.
  • SCPC trigger card
  • For the second (coincidence) detector a Nal (Tl) crystal of the same size (12" x 8") is read out by four 3" PMT's. The outputs of these PMT's are summed and the sum signal used to establish whether the event is coincident. Additionally, this pulse is pulse shape analyzed to reject background. All thresholds, digital delays, and gains are under software control through the SCPC.
  • the computer decodes the multiplexed signals acquired by the DSO's and finds the coordinates of each detected event through analysis of the pulse amplitudes in all 24 PMT's.
  • the large MPD-Imager uses carefully selected PMT's based on radioactive background, detection efficiency, energy resolution, homogeneity over the photocathode surface, dark cu ⁇ ent, and long term stability.
  • Prefe ⁇ ed photomultipliers include either 1" or hexagonal 2" PMT's from EMI.
  • the prefe ⁇ ed configuration is a grid of 2" hexagonal PMT's with 2" center to center spacing, leading to a 6 x 4 a ⁇ ay of PMT's.
  • an a ⁇ ay of 8 x 5 PMT's is prefe ⁇ ed. Cost is much lower for 2" PMT's because the electronics are much simpler and only two DSO cards are needed.
  • the 1 " PMT provides slightly better spatial resolution and about a factor of 2 lower radioactive background.
  • the large MPD-Imager preferably uses dedicated data acquisition and processing software.
  • the signals from several PMT's are encoded using delay lines and multiplexed onto one DSO channel.
  • the acquisition software processes a succession of pulses using appropriate pulse-shape rejection and baseline restoration procedures. Although this task is simplified by the constant delay times between signals, additional consistency analysis of whether the pulses in the "train" are due to a single event, and even some deconvolution may be required.
  • a reliable and highly efficient process is prefe ⁇ ed for computing the coordinates of each event based on the data from multiple PMT's. Special provision is made for storing and processing much larger volumes of data, as well as for compensating for the inevitable non-uniformities in the large-area detector.
  • Sequential sample MPD device The ssMPD is a twelve sample, bench-top radiation counter that can be used to measure counts per minute and calculate disintegrations per minute emitted by multiphoton emission isotopes, including 125 I. In volumes of 0.05 to 2.0 mis contained in 12 mm x 75 mm or 13 mm x 100 mm sample mbes disintegrations are measured over the range of 1 to 10° dpms. The sample mbes are capped to avoid contaminating the detector chamber.
  • Tube holders 70 are mounted on horizontal mbe drive 71 running above the lead shield 72.
  • Two detectors 73 each comprising a scintillator 74, a PMT 75, and base electronics 76, are mounted facing separator 77.
  • Vertical mbe lift 78 lowers and raises each of the sample mbes (not shown) in mrn. The detector and mechanics are supported by frame 79 and the entire device is encompassed by enclosure 80.
  • the detector assembly is a twin detector system consisting of two scintillator crystals, each coupled to a high resolution planar photomultiplier.
  • the detector assembly is encased in a composite lead-tin-copper shield to minimize environmebntal background.
  • the sample holder acts as a separator to reduce crosstalk within the twin scintillator detector assembly.
  • the detector assembly is connected directly to a personal computer (PC) configured with ssMPD read-out electronics, control and data logger software for WindowsTM, and optionally, a printer.
  • PC personal computer
  • the software outputs, to a printer or a file, a general report header and, for each sample: sample number, sample position, count time, measured counts per minute, calculated disintegrations per minute, and statistical uncertainty.
  • the software supports data export to a variety of commercial data analysis and assay inte ⁇ retation software packages.
  • the specific regions of energy and the detection efficiency are established automatically during the calibration procedure.
  • the counting is performed with limited energy and pulse shape discrimination (i.e., with a higher background), and the absolute detection efficiency is unknown. If the absolute activity of non- 125 I samples is desired, the operator may acquire a calibrated source of the isotope in question and establish the detection efficiency of me ssMPD for this isotope.
  • the ssMPD system employs twin scintillator crystals with photomultiplier mbe (PMT) read-outs as a gamma- and X- ray emissions detector.
  • PMT photomultiplier mbe
  • the read-out electronics and software amplify and shape the signals from each PMT, analyze the pulse shapes and build a combined energy spectrum for subsequent pulse height analysis.
  • the external shielding of the ssMPD detector minimizes the effects of ambient radiation; therefore, the predominant component of the non-radioactive background is due to dark pulses in the PMTs.
  • the shape of these pulses is different than those produced by scintillation in the detector, allowing rejection of PMT dark pulses as well as a majority of electromagnetic and vibrational artifacts.
  • the background in the system is almost flat for energies in the 15-100 keV range and is very stable, independent of the activities in the vicinity of the detector (with the exception of hard gamma radiation capable of penetrating the ssMPD shielding).
  • the non-rejected counts in the appropriate energy region for the desired isotope are integrated to determine the count rate. Conversion of the count rate (counts per minute or cpm) into the acmal activity in the sample (decays per minute or dpm) requires knowledge of the detection efficiency (DE) of the counter for the specific radiolabel.
  • the DE for each of the two detectors is determined separately to improve the ssMPD's calibration and accuracy; to test system integrity; and to conect for sample holder misalignment by comparing the two estimates of the acmal activity of the calibration sample.
  • a direct indicator of the sensitivity (limit of detection) of the ssMPD is its background equivalent activity (BEA)--defined as the activity of a source that produces a count rate equal to the background in the detector. This figure of merit accounts for both the background and the detection efficiency of the ssMPD.
  • the background equivalent activity for the ssMPD is 2 picoCuries, or 1 attomole of 125 I, while maintaining comparable detection efficiency (DE 50%) and significantly lowering radioactive background (BKG 2cpm).
  • the ssMPD's background rejection techniques permit reliable quantitation from 1 to
  • Another benchtop embodiment uses a pick and place robot arm that picks a selected sample from a sample rack, places it in the sample holder, and removes and returns the sample when counting is complete.
  • the changing mechanics is coupled with the data processing equipment to allow for sample counting time to be optimized.

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  • Physics & Mathematics (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Molecular Biology (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Measurement Of Radiation (AREA)
  • Light Receiving Elements (AREA)
  • Photometry And Measurement Of Optical Pulse Characteristics (AREA)

Abstract

Un détecteur multiphotonique à bruit de fond ultra-bas pour radio-isotopes (20) a un bruit de fond d'environ un coup par jour et peut détecter une attomole de matériau. Deux détecteurs photoniques de rayons gamma et de rayons X sont opposés l'un à l'autre, chacun comprenant de préférence un cristal de scintillation (22) et un tube de photomultiplication (26). Un séparateur (32) et un porte-échantillon (34) destiné à un échantillon (36) marqué par un radio-isotope tel que I125 sont placés en sandwich entre les détecteurs. Chacun de ceux-ci convertit les émissions provenant du radio-isotope en impulsions électriques de sortie dans une base (30), impulsions qui sont ensuite soumises à un traitement de signaux pour analyse de la forme des impulsions, discrimination entre évènements coïncidents et évènements non coïncidents, et quantification du radio-isotope. Les matériaux et les composants des détecteurs sont choisis de façon à minimiser le bruit de fond et sont protégés des rayonnements externes dans un blindage composite (55). Des détecteurs fonctionnant sur différents principes et des porte-échantillons de configurations différentes peuvent être utilisés. Le dispositif peut en outre être conçu pour résoudre et donner des images de séries d'échantillons bidimensionnels.
PCT/US1996/016968 1995-10-31 1996-10-31 Detecteur multiphotonique a bruit de fond ultra-bas WO1997016746A1 (fr)

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EP96941945A EP0866986A1 (fr) 1995-10-31 1996-10-31 Detecteur multiphotonique a bruit de fond ultra-bas
JP9517408A JPH11514742A (ja) 1995-10-31 1996-10-31 超低バックグラウンド多光子検出器
KR1019980703222A KR19990067259A (ko) 1995-10-31 1996-10-31 극저의 광레벨 다중 광자 검출기
AU11154/97A AU700518B2 (en) 1995-10-31 1996-10-31 Ultralow background multiple photon detector
BR9611171-2A BR9611171A (pt) 1995-10-31 1996-10-31 Detector de multi fótons de fundo ultra baixo

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US710895P 1995-10-31 1995-10-31
US60/007,108 1995-10-31
US08/669,970 1996-06-25
US08/669,970 US5866907A (en) 1993-10-12 1996-06-25 Ultralow background multiple photon detector

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WO1998002750A1 (fr) * 1996-07-12 1998-01-22 Biotraces, Inc. Chromatographie amelioree a base de detection de multiphotons
WO2002046791A1 (fr) * 2000-12-04 2002-06-13 University Of Leicester Dispositifs pour produire des images d'emissions de radionucleides
WO2007005442A2 (fr) 2005-07-01 2007-01-11 Warburton William K Detection de rayonnements coincidents dans un transducteur unique par analyse de forme d'impulsion
CN104570035A (zh) * 2014-12-26 2015-04-29 北京放射性核素实验室 一种放射性气体核素β射线自吸收校正方法
CN106443807A (zh) * 2016-12-27 2017-02-22 成都理工大学 一种放射源搜寻装置和搜寻方法
CN106768401A (zh) * 2017-03-24 2017-05-31 中国工程物理研究院应用电子学研究所 一种微能量脉冲激光光子数测量装置及方法
WO2018186785A1 (fr) 2017-04-06 2018-10-11 Prismatic Sensors Ab Système de détecteur de rayons x à comptage de photons ayant un système adaptatif anti-coïncidence
CN109725342A (zh) * 2019-01-01 2019-05-07 中国人民解放军63653部队 一种用于现场低能γ射线测量的散射抑制探测结构
WO2019050862A3 (fr) * 2017-09-06 2019-05-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Étalonneur de micro-dose
CN110062896A (zh) * 2016-12-16 2019-07-26 森斯奈特公司 用于测量辐射的装置
CN110501740A (zh) * 2019-08-23 2019-11-26 南京核安核能科技有限公司 一种本底数字化反康反宇宙射线谱仪HPGe探测器探测方法
CN110515115A (zh) * 2018-05-22 2019-11-29 中国辐射防护研究院 一种用于伽马谱峰面积求解的评估方法
CN110780331A (zh) * 2019-11-06 2020-02-11 中国原子能科学研究院 一种非破坏性快速分析溶液中微痕钚的测量装置
EP3132285B1 (fr) * 2014-04-18 2020-04-22 PerkinElmer Health Sciences, Inc. Système de compensation d'efficacité de protection
CN113031050A (zh) * 2021-03-18 2021-06-25 捷创核仪(北京)科技有限公司 高稳定度超低本底γ谱仪系统
CN113534232A (zh) * 2020-04-16 2021-10-22 中国科学院国家空间科学中心 一种同步测量电离层中性分子与带电粒子的装置及方法
CN115043604A (zh) * 2022-07-15 2022-09-13 中国建筑材料科学研究总院有限公司 一种低本底水泥的制备方法及低本底水泥
CN116859438A (zh) * 2023-06-29 2023-10-10 黑龙江省原子能研究院 一种瞬时弱辐射信号探测装置及其方法
CN116859438B (zh) * 2023-06-29 2024-06-11 黑龙江省原子能研究院 一种瞬时弱辐射信号探测装置及其方法

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JP5836465B1 (ja) * 2014-10-20 2015-12-24 株式会社日立パワーソリューションズ 放射線計測装置および放射線計測方法

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Cited By (27)

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WO1998002750A1 (fr) * 1996-07-12 1998-01-22 Biotraces, Inc. Chromatographie amelioree a base de detection de multiphotons
WO2002046791A1 (fr) * 2000-12-04 2002-06-13 University Of Leicester Dispositifs pour produire des images d'emissions de radionucleides
US7173251B2 (en) 2000-12-04 2007-02-06 University Of Leicester Devices for imaging radionuclide emissions
WO2007005442A2 (fr) 2005-07-01 2007-01-11 Warburton William K Detection de rayonnements coincidents dans un transducteur unique par analyse de forme d'impulsion
EP1899747A4 (fr) * 2005-07-01 2016-12-07 Warburton William K Detection de rayonnements coincidents dans un transducteur unique par analyse de forme d'impulsion
EP3132285B1 (fr) * 2014-04-18 2020-04-22 PerkinElmer Health Sciences, Inc. Système de compensation d'efficacité de protection
CN104570035A (zh) * 2014-12-26 2015-04-29 北京放射性核素实验室 一种放射性气体核素β射线自吸收校正方法
CN104570035B (zh) * 2014-12-26 2017-04-12 北京放射性核素实验室 一种放射性气体核素β射线自吸收校正方法
CN110062896A (zh) * 2016-12-16 2019-07-26 森斯奈特公司 用于测量辐射的装置
CN106443807A (zh) * 2016-12-27 2017-02-22 成都理工大学 一种放射源搜寻装置和搜寻方法
CN106768401A (zh) * 2017-03-24 2017-05-31 中国工程物理研究院应用电子学研究所 一种微能量脉冲激光光子数测量装置及方法
CN106768401B (zh) * 2017-03-24 2023-03-21 中国工程物理研究院应用电子学研究所 一种微能量脉冲激光光子数测量装置及方法
WO2018186785A1 (fr) 2017-04-06 2018-10-11 Prismatic Sensors Ab Système de détecteur de rayons x à comptage de photons ayant un système adaptatif anti-coïncidence
WO2019050862A3 (fr) * 2017-09-06 2019-05-09 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Étalonneur de micro-dose
US11614548B2 (en) 2017-09-06 2023-03-28 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Radioactive source calibration
US11029418B2 (en) 2017-09-06 2021-06-08 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Micro-dose calibrator
CN110515115A (zh) * 2018-05-22 2019-11-29 中国辐射防护研究院 一种用于伽马谱峰面积求解的评估方法
CN110515115B (zh) * 2018-05-22 2022-11-25 中国辐射防护研究院 一种用于伽马谱峰面积求解的评估方法
CN109725342A (zh) * 2019-01-01 2019-05-07 中国人民解放军63653部队 一种用于现场低能γ射线测量的散射抑制探测结构
CN110501740A (zh) * 2019-08-23 2019-11-26 南京核安核能科技有限公司 一种本底数字化反康反宇宙射线谱仪HPGe探测器探测方法
CN110780331A (zh) * 2019-11-06 2020-02-11 中国原子能科学研究院 一种非破坏性快速分析溶液中微痕钚的测量装置
CN113534232A (zh) * 2020-04-16 2021-10-22 中国科学院国家空间科学中心 一种同步测量电离层中性分子与带电粒子的装置及方法
CN113534232B (zh) * 2020-04-16 2024-04-09 中国科学院国家空间科学中心 一种同步测量电离层中性分子与带电粒子的装置及方法
CN113031050A (zh) * 2021-03-18 2021-06-25 捷创核仪(北京)科技有限公司 高稳定度超低本底γ谱仪系统
CN115043604A (zh) * 2022-07-15 2022-09-13 中国建筑材料科学研究总院有限公司 一种低本底水泥的制备方法及低本底水泥
CN116859438A (zh) * 2023-06-29 2023-10-10 黑龙江省原子能研究院 一种瞬时弱辐射信号探测装置及其方法
CN116859438B (zh) * 2023-06-29 2024-06-11 黑龙江省原子能研究院 一种瞬时弱辐射信号探测装置及其方法

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AU700518B2 (en) 1999-01-07
CA2236295A1 (fr) 1997-05-09
BR9611171A (pt) 2001-10-23
MX9803468A (es) 1998-11-29
JPH11514742A (ja) 1999-12-14
EP0866986A1 (fr) 1998-09-30
PL326564A1 (en) 1998-09-28

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