GB2136561A - Monitoring the breakoff point of a droplet generation system - Google Patents
Monitoring the breakoff point of a droplet generation system Download PDFInfo
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- GB2136561A GB2136561A GB08303440A GB8303440A GB2136561A GB 2136561 A GB2136561 A GB 2136561A GB 08303440 A GB08303440 A GB 08303440A GB 8303440 A GB8303440 A GB 8303440A GB 2136561 A GB2136561 A GB 2136561A
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- 238000012544 monitoring process Methods 0.000 title description 3
- 230000008859 change Effects 0.000 claims abstract description 49
- 239000002245 particle Substances 0.000 claims abstract description 40
- 239000007788 liquid Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims description 16
- 230000007246 mechanism Effects 0.000 claims description 7
- 230000005855 radiation Effects 0.000 claims description 7
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 230000004044 response Effects 0.000 claims description 5
- 239000006194 liquid suspension Substances 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims 2
- 239000013078 crystal Substances 0.000 abstract description 11
- 210000004027 cell Anatomy 0.000 description 12
- 230000000694 effects Effects 0.000 description 5
- 238000012937 correction Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- 210000000601 blood cell Anatomy 0.000 description 2
- 239000003990 capacitor Substances 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
- G01N15/10—Investigating individual particles
- G01N15/14—Optical investigation techniques, e.g. flow cytometry
- G01N15/1404—Handling flow, e.g. hydrodynamic focusing
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
- G01N15/10—Investigating individual particles
- G01N15/14—Optical investigation techniques, e.g. flow cytometry
- G01N15/149—Optical investigation techniques, e.g. flow cytometry specially adapted for sorting particles, e.g. by their size or optical properties
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
- G01N15/10—Investigating individual particles
- G01N15/14—Optical investigation techniques, e.g. flow cytometry
- G01N15/1404—Handling flow, e.g. hydrodynamic focusing
- G01N2015/1406—Control of droplet point
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- Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Dispersion Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Investigating Or Analysing Materials By Optical Means (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
In a particle separator for sorting particles suspended in a liquid according to certain characteristics, a change in the droplet breakoff point of a liquid jet stream which is subjected to vibrations is detected. The vibrations, generated by piezo-electric crystal 24, produce, on the surface of the jet stream 16, undulations, the amplitude of which is monitored at a fixed point 21 on the jet stream prior to the breakoff point, producing a signal voltage which is proportional to the amplitude change and which may be used (1) to alert the operator that the point at which the jet stream is breaking up into droplets has changed, (2) to automatically control the intensity of the vibrations for restoring the amplitude of undulation at point 21, or (3) to automatically disable the sorting portion of the apparatus. The detecting means can be a photodiode 44 sensing the light of laser beam 20 scattered by jet stream 16. <IMAGE>
Description
SPECIFICATION
Method of and apparatus for detecting change in the breakoff point of a droplet generation system
This invention relates to apparatus for sorting minute particles in a fluid, and in particular to such apparatus wherein a liquid jet stream containing these particles is vibrated to produce undulations on the surface ofthe jet stream and subsequent breakup of the stream into droplets which are then sorted according to the particle characteristics and collected downstream.
Apparatus of the foregoing kind may be referred to as flow cytometric sorting systems and are used in the medical research and diagnostic field for the rapid analysis of blood cells and other biological cells. Systems for cell separation and sorting are described in U.S. patents 4,038,556; 3,963,606; 3,710,933 and 3,380,584 in SCIENCE, Vol. 198, pages 149-157, published October 1977, and in the references cited therein.
U.S. patent 4,038,556 discloses a method of and apparatus for the simultaneous optical measurement of several characteristics of each particle of a group of small particles while the particles are suspended in a liquid.
U.S. patent 3,963,606 discloses a particle separator for separating particles in a liquid according to certain characteristics including a device for adjusting an electrical delay to be equal to the time between the emergence of a particle from a jet forming aperture to the breakoff point.
U.S. patent 3,710,933 discloses an apparatus for automatically analyzing and sorting minute particles suspended in a liquid on the basis of certain preselected characteristics.
U.S. patent 3,380,584 discloses a particle separator in which electrical pulses cause an acoustic coupler driver to vibrate the fluid which contains the particles.
The SCIENCE article, Vol. 198. pages 149-157 discloses a flow cytometer. Fluorescence from biological cells within a fluid stream is measured at the intersection with a laser beam. Droplets containing cells of interest are sorted out of the fluid stream.
A major problem in using the cell sorter systems wherein a jet stream subjected to vibrations breaks off into droplets is ascertaining if a change has occurred in the point at which the jet stream is breaking into droplets. If the precise instant of breakoff with relation to the sense point changes, then the instrument ceases to be a cell sorter and becomes a water or saline solution sorter of unknown cell content. An even worse undesired result is that the unwanted particles are sorted when there is such a change in the breakoff point. Such a change is often due to changes in the mechanical coupling coefficients, such as air bubbles entering the flow chamber and partial plugs of the jet stream exit orifice.Optical sensitivities, such as the presence of undesired light, render impractical the use of an illuminating strobe source to observe the breakoff point on the jet stream while the system is taking data or sorting the cells. It is at this time of sorting that a monitor is most needed.
The present invention provides:
Method for use in a droplet generation system wherein a liquid jet stream is produced and vibrations applied thereto in order to produce undulations on the surface of said stream and subsequent breakup of the jet stream into droplets which are collected downstream, and sensing the undulation on the surface of said jet stream at a point on said stream prior to the breakoff point of said stream into droplets, said method comprising the step of: controlling said vibrations as a function of the undulation at said point.
The present invention also provides:
Apparatus for analyzing and sorting particles suspended in a liquid, said apparatus including jet means for producing a jet stream from said liquid suspension, vibrating means for vibrating said jet stream to produce undulations on the surface of said stream and subsequent breakup of said stream into droplets for collection downstream, radiation means for impinging a beam of radiation upon said jet stream at a location thereon prior to the breakoff point of said droplets, and sensing means, coupled to said vibrating means, responsive to radiation scattered by said stream, for providing an output which is a function of the undulation at said location.
Such apparatus can be used to sense in a droplet generation system a change in the amplitude of the undulations at a fixed point on the surface of a liquid suspension jet stream prior to the droplet breakoff point, and to indicate that such a change has occurred.
It is also possible to automatically disable the sorting function in a particle analyzer and sorting system when there is a significant change in the droplet breakoff point.
Furthermore, it is possible to utilize the information derived from a change in the amplitude of undulation at a fixed point on the surface of a jet stream to restore the level of the amplitude of undulation at that fixed point to its original state.
In a preferred arrangement according to the invention a liquid jet stream containing minute particles in suspension is driven at the frequency at which it is desired to generate droplets normally 20 to 40 KC depending on the diameter of the jet exit orifice; for example, 32 KC frequency for a 76 micron jet exit orifice diameter and 40 KC frequency for a 50-60 micron jet exit orifice diameter. The jet is vibrated by introducing a small disturbance, as from a driven piezo-electric crystal, at the exit orifice of the jet stream. This disturbance is in the form of an undulation or a standing wave on the surface of the jet stream and this undulation grows as the jet advances and causes the breakoff of droplets downstream.The amplitude of the disturbance or undulation at any point along the jet stream is a function of the distance of that point from the point of droplet breakoff and this aspect is described in the report of
Richard G. Sweet, SEL-64-004, March 1964, of the
Stanford Laboratories of the Stanford University.
According to the invention, the amplitude of the undulation at a fixed point is monitored. A change in this amplitude at that fixed point indicates a change in the breakoff point. A laser beam, used as the illumination source in the optical cell sorting systems described in the foregoing U.S. patents, is utilized as a concentrated source of light rays in a preferred monitoring scheme of the invention. The laser beam strikes the jet stream at a fixed point and then the laser beam scatters to provide a lobe pattern of light that is in the same plane as the laser beam and is perpendicular to the jet stream. As is well known, this scattered laser light is modulated by the surface undulations on the jet. Heretofore, this modulation has been considered to be an indesirable phenomenon when cell light scatter is being measured and has usually been blocked out in the instrument.The preferred arrangement detects such modulation by positioning a photo diode in the plane of laser light scatter. The output of the photo diode is converted to a voltage which may be used (1) to alert the operator either visually or audibly that a change has occurred in the point at which the jet stream is breaking up into droplets, (2) to automatically control the intensity of the vibrations applied to the jet for restoring the amplitude of undulation at the point on the jet at which it is being monitored, or (3) to automatically disable the apparatus. Any one or any combination of the foregoing happenings can be utilized in the practice of the invention.
If desired, a secondary source of concentrated light rays other than the laser beam can be used to impinge on or interrogate the jet stream at a point closer to the droplet breakoff point where the undulations are larger and, therefore, where the signal obtained therefrom is larger. In this case, the photo diode would be judiciously positioned to receive the light scattered or reflected from the jet.
A preferred feature of the invention is the sorting disabling circuitry which includes a fast change detector responsive to a rectified output whose D.C.
level is proportional to the percentage modulation of the beam of concentrated light rays (laser beam, for example) as affected by the undulations on the surface of the jet stream. This detector controls a relay driver latching mechanism which acts to disable the sorting function of the particle analyzer whenever there is a significant change in the amplitude of undulation on the jet stream. This circuitry is provided with an operator reset device and an alarm which, if desired, can indicate the type of change based on the polarity of the output from the fast change detector.
Another preferred feature is an automatic gain control (AGC) loop system for varying the intensity ofthe vibrations applied by the piezo-electric crystal to the jet stream, for slow changes in the amplitude of modulation. The aforementioned rectified output serves as a control voltage for the AGC loop. This loop system varies the power which is applied to drive the piezo-electric crystal. As a result, fine, as distinguished from coarse, amplitude corrections on the surface of the jet stream is obtainable. An arm-disable control for the AGC system enable initial setting of the droplet breakoff point.
By way of example only illustrative embodiments of the invention now will be described with reference to the accompanying drawings in which:
Figure 1 is a block diagram showing how the electrical elements of an embodiment of the invention are coupled to a known type of particle analyzer and sorter;
Figure 2 shows the electrical circuitry of the fast change detector, the relay driver latching mechanism and the alarm circuits of the diagram of Figure 1;
Figure 3 shows diagrammatically the electrical circuitry for converting the signal obtained from the photo diode to a rectified D.C. which is proportional to the modulation of the light rays by the surface undulations on the jet stream; and
Figures 4 to 8 illustrate in more detail the electrical circuitry of the blocks shown in Figure 3.
Throughout the figures of the drawings the same parts are designated by the same reference numerals.
The block diagram of Figure 1 is divided into two parts by a dot-dash line 10. System components to the left of the dot-dash line are those which normally exist in a known type particle analyzer and sorting system, sometimes referred to as a flow cytometric sorting system. One such known sorting system is found in the TPS and EPICS series of instruments manufactured and sold by Coulter Electronics, Inc. of
Hialeah, Florida 33010. Only those components of the particle analyzer and sorter have been shown which are necessary to explain the operation of the present apparatus. System components to the right of the dot-dash line 10 comprise parts of the present apparatus which have been added and couple to the known particle analyzer and sorter.It is to be noted that the automatic gain control (AGC) feature and the disabling feature involving a relay driver latching mechanism of the apparatus are inserted at two locations into the normal signal paths of the particle analyzer and sorting systems as will appear in more detail hereinafter.
The known particle analyzer and sorting system shown to the left of the dot-dash line 10 will now be briefly described. It includes a flow chamber 12 into which a saline solution (normally 13 p.s.i.g) is introduced under pressure and exits through a small orifice 14 (diameter ranges from 50 u to 200 u, depending upon the application of the system) to form a liquid jet stream 16. The sample (a suspension of minute particles, such as blood cells or biological cells) is introduced into the flow chamber 12 through a tube 18. Below the exit orifice 14 and above and prior to the breakoff point, the jet stream 16 is interrogated by a light source or radiation means 20 (normally a laser beam) and the response of the minute particle in the sample to the illumination (normally light scatter and fluorescence) is detected by the sensor system 22 also at a point prior to and above the breakoff point.
The flow chamber 12 is mounted to and supported by a piezo-electric crystal assemblage 24 which vibrates the chamber the chamber 12 at a high frequency. The exact frequency at which the chamber 12 vibrates is dependent on the selected diameter of the exit orifice 14 which frequency is normally 20-40 KC. These vibrations impart small disturbances, normally undulations, on the surface of the jet 16 which grow, due to well known surface tension effects, and eventually pinch the jet off at a breakoff point 26 into well defined droplets 28. The exact distance from the nozzle containing the orifice 14 to the breakoff point 26 is inversely proportional to the amplitude of the initial disturbance or undulation. The size of the disturbance is proportional to the amplitude of the signal voltage applied to the crystal 24, if the mechanical coupling coefficients of the system hold constant.Unfortunately, there are several factors which can cause changes in the mechanical coupling coefficients and these factors are difficult to eliminate. These include air bubbles entering the flow chamber 12 with the sample or with the saline solution and partial plugs of the exit orifice 14 due to debris, such as broken-up cells or fat.
The piezo-electric crystal is driven by a power amplifier 30 which normally derives its signal from a frequency generator 32 through a variable potentiometer 34 which is used to vary the amplitude of the signal applied to crystal 24 and therefore vary the nominal breakoff point 26. Potentiometer 34 serves as a coarse correction source to the drive of power amplifier 30 driving the crystal 24. Line 36 designates the normal path from the potentiometer 34 to the power amplifier in the absence of the components embodying the present invention. The system embodying the present invention has incorporated a switch 59 which is not present in the prior art systems, for a purpose described hereinafter.
Connected to the sensor 22 is the sort decision logic 38 in which the signals obtained from the detectors (not shown but forming part of the sensor system 22) are applied to a set of criteria to decide whether or not it is desired to capture the particle originating those signals. If capture is desired, that decision must be delayed, as by sort delay 40, while the particle travels from the sense point to the breakoff point. A sort pulse is then formed by sort pulse forming circuit 41 and amplified and applied, through power amplifier 43, to the jet stream as a voltage just as the droplets which will contain the desired particle breaks off from the jet. Because of this impressed voltage the droplets break off with a
net charge. The jet of droplets passes through an intense constant electric field which accelerates the charged droplets in the horizontal plane as they travel downwards.Thus charged droplets travel in a different path from the path of uncharged droplets
and fall into different capture vessels, thereby effect
ing a physical sorting of the particles. Atypical rate
of sorting for this process is 4,000 particles per second. Reference is made to U.S. patent 3,380,584 which discloses a way of impressing a voltage on a
downstream portion of the jet stream containing
particles to be charged for subsequent collection and to an article by Hulett, Bonner, Sweet and Herzen
berg, CLINICAL CHEMISTRY, Vol. 19, No. 8, 1973, which discloses impressing a voltage on an upstream portion of the jet stream for the same
purpose.
The foregoing system is known in the art and no
claim is made herein to this prior art method of analyzing and sorting minute particles. Such apparatus is disclosed in the aforementioned U.S. patents and the references cited therein.
The present apparatus makes use of the relationship between the amplitude of undulation on the surface of the jet stream at any fixed point and the position of the droplet breakoff point to ascertain that there has been a change in the droplet breakoff point. As stated hereinabove, the amplitude of the undulations increases as the breakoff point is approached. An increase in amplitude of undulation at any given point along the jet is an indication that the breakoff point is closer while a decrease in the amplitude is an indication that the breakoff point is further away.The apparatus embodying the present invention monitors the position of the breakoff point to effect any one of the following three results: (1) to provide an indication, either visually, as by means of a meter, or audibly, by means of an alarm, of a change in the breakoff point, (2) to disable the sorting process and sound an alarm if there is a fast change in the breakoff point, or (3) to automatically and promptly restore the breakoff point, as by means of an automatic gain control loop, for small and slow changes in the breakoff point.
The system components to the right of the dotdash line 10 of the block diagram of Fig. 1 comprise parts of the present apparatus which couple to the known particle analyzer and sorter appearing at the left of dot-dash line 10, and include a photo diode or sensing means 44 which detects the light scattered by the jetstream 16 as a result of the impact thereon by the concentrated beam of intense light 20. This scattered light has two components: a D.C. compo next which is proportional to the size of the jet stream 16 at the sense point 21, the point on the jet stream 16 at which the beam of light strikes it, and the power of the intense light beam 20 (the laser).
The diode 44 is operated in the current mode, that is to say it is terminated in low impedance, thereby producing a linear optical power-to-current relationship and reducing the effects of diode capacitance for maximum electronic bandwidth. Photo diode 44 is coupled to an operational amplifier 46 which is operated as a transimpedance amplifier. Amplifier 46 converts the current from the diode 44 to a voltage linearly. The output from the transimpedance amplifier 46 splits into an A.C. path including
A.C. amplifier 48 and a D.C. path including D.C.
amplifier 50.
The A.C. path contains the basic information to be used in the practice of the invention, viz, the amplitude of the undulations on the jet stream.
Because the amplitude of the undulation signals generated at the photo diode detector 44 are low, this signal is given considerable gain by the A.C.
amplifier 48, of the order of 103. In order to improve the signal-to-noise ratio in this A.C. path the bandwidth of the A.C. amplifiers is limited to the range of frequencies of oscillation applied to the piezoelectric crystal 24.
Since the size of the jet 16 is held constant during a test run of sample particles and is rarely changed, the D.C. component is proportional to the size of the jet 16 and the power of the laser 20, then a change in the D.C. level in the path including D.C. amplifier 50 can be considered to be a change in laser power. The signal through the D.C. path controls the gain of a voltage controlled gain amplifier 52 in the output of the A.C. path, thereby enabling the A.C. path signal to be normalized as to laser power, as a result of which recalibration of the apparatus is eliminated each time the power of the laser 20 is changed.
Stated another way, the D.C. path removes the effect of a change in laser power from the measurement of the distance from the sensing point 21 to the breakoff point 26.
The A.C. signal from the voltage-controlled amplifier 52 is rectified by rectifier 54 (preferably a full-wave rectifier to obtain a smoother D.C. signal output therefrom) to provide a D.C. signal on lead 56 which is proportional to the amplitude of the undulations on the jet stream 16, and proportional to the distance from the sense point 21 to the breakoff point 26. The details of one suitable full wave rectifier which can be used is shown in Figure 8.
There are three ways for utilizing the D.C. voltage on lead 56. The simplest is to drive a percentage modulation meter 58 which provides a visual indication as to the position of the droplet breakoff point 26 on the jet stream 16. Properly calibrated, such a meter 58 can be used to set the breakoff point 26 by manually adjusting potentiometer 34 and using the normal path 36 in the known analyzer and sorter apparatus to bypass the AGC system hereinafter described. The meter 58 is connected so as to be operable at all times.
The rectified voltage on lead 56 (the output from rectifier 54) can also be set as a control voltage in an automatic gain control (AGC) loop which will provide fine, as distinguished from coarse, corrections to the voltage drive or power amplifier 30 which feeds the piezo-electric crystal transducer 24 over path 60, and therefore fine corrections in the drift in the breakoff point 26, assuming of course, that control of the normal path 36 is transferred by switching means 59 when the AGC feature of the apparatus is utilized. This AGC loop includes an AGC amplifier system 64 which is fed from the voltage on lead 56 over lead 66, and is similar in design to the circuitry of voltage controlled gain amplifier 52 as illustrated in Figure 7. A suitable double pole-single throw switch 59 is connected across leads 36 and 37.
Switch 59 serves to effectively deactivate the AGC loop from the system when it is desired to initially set up the analyzer and sorter for a specific droplet delay. Afterthe proper time delay has been set, the
AGC system 64 is armed or activated to maintain the desired breakoff point. Prior to activation of the AFC, the voltage output terminal V0 (lead 37) is adjusted to the same amplitude as that on the normal path 36, by means of potentiometer 67 as is indicated by the nuil detection meter 68, after which switch 59 can be thrown to transfer control of the power amplifier 30 to the AGC system.
Another way of monitoring the breakoff point 26 on the jet 16 is by means of a system including a fast change detector 70 to which the rectified voltage on lead 56 is fed. The output 80 of fast change detector 70 is zero if a D.C. signal is being applied (which is the case when the breakoff point 26 is constant) and changes from zero if a "fast" change in droplet breakoff point is encountered. The polarity of the change in the output 80 of the fast change detector 70 indicates whether the rectified signal level from rectifier 54 has increased or decreased. The output from detector 70 can drive an alarm circuit 72 to alert the operator of a change in the breakoff point. This same output can also drive a relay system composed of a driver latching mechanism 76, which, in turn, serves to automatically disable the sorting system, via leads 78 in the particle analyzer and sorter.
Operator reset 74 serves to manually reset the driver latching mechanism 76. The alarm 72 can be made to indicate the type of change in the breakoff point based on the polarity of the output from the detector 70.
Figure 2 diagramatically illustrates one form which the electrical circuitry of the fast change detector 70 may take, including the relay driving mechanism and the operator reset and the alarm. Figure 2 shows both the audible alarm 72 and a visual alarm 71. The change of the signal on lead 56 is coupled to the amplifier 70 by capacitor C1. This A.C. signal is amplified and applied to lead 80. If the signal on lead 56 is a constant D.C. value lead 80 will be near zero potential. Lead 80 is connected to two comparators 77 and 79 which are configured to sense variations in the signal on lead 80 in either polarity away from a zero potential. A slight guard band is used to allow for amplifier offset. When the signal on lead 80 changes, the appropriate comparator senses the change and switches. The switching is sensed and latched by the latch 81.The Q output of the latch 81 switches, disabling NAND gates in 78, thus interrupting the sort signals. The switching of the latch also activates both a visual alarm 71 and an audible alarm 72. The values of capacitor C1 and resistor R1 are selected for speed of change while R1 and R2 are selected for sensitivity to change.
Figure 4 illustrates the circuitry of the transimpedance pre-amplifier 46 of Figures 2 and 3. Figure 5 illustrates the circuitry of the A.C. amplifier 48 of
Figures 2 and 3. Figure 6 illustrates the circuitry of the D.C. amplifier 50 of Figures 2 and 3. Figure 7 illustrates the circuitry of the voltage controlled gain amplifier 52 of Figures 2 and 3. Figure 8 illustrates the circuitry of the full wave rectifier 58 of Figures 2 and 3.
The values of the components as well as the component parts illustrated in Figures 2 and 8 inclusive are merely illustrative and may be replaced by equivalent parts and circuitry to achieve the desired results.
Modifications can be made in the system embodying the invention without departing from the spirit and scope thereof. For example, since the A.C. path 48 contains the basic information constituting the amplitude of undulations on the jet stream, the D.C.
path 50 need not be used in a simplified form of an embodiment of the invention.
It is believed that this invention has been disclosed sufficiently for those skilled in the art to appreciate same and enable them to practice the invention, not only specifically as embodied herein, but in various forms as encompassed by the full scope of the invention as set forth in the claims appended hereto.
Claims (20)
1. Method for use in a droplet generation system wherein a liquid jet stream is produced and vibrations applied thereto in order to produce undulations on the surface of said stream and subsequent breakup of the jet stream into droplets which are collected downstream, and sensing the undulation on the surface of said jet stream at a point on said stream prior to the breakoff point of said stream into droplets, said method comprising the step of: controlling said vibrations as a function of the undulation at said point.
2. Method according to claim 1, wherein said point is fixed.
3. Method according to claim 1 which includes interrogating said stream by applying a concentrated beam of rays to said jet stream at any fixed
point on said stream prior to the breakoff point on said stream into droplets, and wherein said step of sensing includes deriving a D.C. signal from said
interrogation which is proportional to the amplitude of the undulations at said fixed point, and wherein said step of controlling said vibrations includes
controlling the intensity of said vibrations by said
D.C. signal in response to a deviation of said
amplitude from a predetermined level.
4. Method according to claim 1, wherein said
step of controlling said vibrations includes automatically controlling the intensity of the vibrations
applied to said stream in response to a change in
said amplitude of undulation at said fixed point in
such direction as to restore said amplitude of
undulation at said fixed point to its original state, to thereby prevent drift in said breakoff point.
5. Method according to claim 1, wherein said
step of automatically controlling the vibrations in
cludes automatically restoring the value of said
amplitude of undulation at said fixed point for
deviations below a predetermined level, and further
including the step of automatically disabling said
system when the deviations in amplitude of undula
tion at said fixed point exceed said level.
6. Method according to any one of claims 2 to 5,
wherein the vibrations are controlled as a function of
the amplitude of the undulation.
7. Apparatus for analyzing and sorting particles
suspended in a liquid, said apparatus including jet
means for producing a jet stream from said liquid
suspension, vibrating means for vibrating said jet
stream to produce undulations on the surface of said
stream and subsequent breakup of said stream into
droplets for collection downstream, radiation means
for impinging a beam of radiation upon said jet
stream at a location thereon prior to the breakoff
point of said droplets, and sensing means, coupled
to said vibrating means, responsive to radiation
scattered by said stream ,for providing an output
which is a function of the undulation at said location.
8. Apparatus according to claim 7 where said
location is fixed.
9. Apparatus according to claim 7 or 8 wherein said output is a function of the amplitude of the undulation.
10. Apparatus according to claim 8 or 9, further including coupling means, connected to said sensing means, for providing a signal indicating a change in the amplitude of undulation at said fixed location; whereby said change in the amplitude of undulation correlates to a change in position of the breakoff point of said droplets.
11. Apparatus according to claim 10, wherein said sensing means includes a photo diode, operating, in use, in the current mode, so positioned as to receive and detect the rays scattered by said jet stream as a result of impingement by said beam, wherein said coupling means includes rectifier means coupled to the output of said photo diode for producing a voltage which is proportional to the amplitude of the undulations on the jet stream at said fixed location, and further including means coupled to the output of said rectifier means and responsive to the rectified output thereof for indicating a change in the amplitude of undulation at said fixed location and particle sensing means operating art a point prior to the breakoff point.
12. Apparatus according to claim 11, further including an automatic gain control circuit having an input coupled to the output of said rectifier means and having an output coupled to said vibrating means for altering the intensity of vibrations applied to said jet stream in response to a change in the level of said amplitude of undulation at said fixed location in such direction as to restore said amplitude of undulation at said fixed location to its original state and thereby correct for a change in the breakoff point of said jet stream.
13.Apparatus according to claim 7,8 or 9 further including a trans-impedance operational preamplifier means coupled to said sensing means, an
A.C. path means including an A.C. amplifier means coupled to the output of said pre-amplifier means, a rectifier means coupled to the output of said A.C.
amplifier means for rectifying the signal obtained therefrom, and means coupled to and responsive to the output of said rectifier means for alerting the operator of a change in said breakoff point.
14. Apparatus according to claim 10, wherein said sensing means includes a photo diode so positioned as to receive and detect the rays scattered by said jet stream as a result of impingement by said beam, wherein said coupling means includes rectifier means coupled to the output of said photo diode for producing a voltage which is proportional to the amplitude of the undulations on the jet stream at said fixed location, and further including means coupled to the output of said rectifier means and
responsive to the rectified output thereof for indicating a change in the amplitude of undulation at said fixed location, an automatic gain control circuit having an input coupled to the output of said rectifier means and having an output coupled to said vibrating means for altering the intensity of vibrations
applied to said jet stream in response to a change in the level of said amplitude of undulation at said fixed
location in such direction as to restore said amplitude of undulation at said fixed location to its original state and thereby correct for a change in the breakoff point of said jet stream, disabling means coupled and responsive to the output of said rectifier means for disabling the sorting function of said apparatus, said disabling means including a fast change detector means and a driver latching device coupled to the output of said detector means.
15. Apparatus according to claim 13, further including a D.C. path means having a D.C. amplifier means also coupled to the output of said preamplifier means, a voltage-controlled gain amplifier means coupled to the outputs of both said A.C. and
D.C. amplifier means in such manner that the output from the D.C. amplifier means controls the gain of said voltage-controlled gain amplifier means, and a connection from said rectifier means to said gain amplifier means, whereby said rectifier means rectifies the A.C. signal obtained therefrom and produces a voltage which is proportional to the amplitude of the undulations on the jet stream at said fixed location.
16. A method for use in a droplet generation system, the method being substantially as herein described with reference to, and as illustrated by, the accompanying drawings.
17. Apparatus for analyzing and sorting particles suspended in a liquid, the apparatus being substantially as herein described with reference to, and as illustrated by, Figure 1 of the accompanying drawings.
18. Apparatus according to claim 17 having a fast change detector, relay driver latching mechanism and alarm circuits substantially as herein described with reference to, and as illustrated by Figure 2 of the accompanying drawings.
19. Apparatus according to claim 17 or 18 having signal conversion circuitry substantially as herein described with reference to, and as illustrated by,
Figure 3 of the accompanying drawings.
20. Apparatus according to claim 19 wherein the signal conversion circuitry is substantially as herein described with reference to, and as illustrated by,
Figures 4 to 8 of the accompanying drawings.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HK19987A HK19987A (en) | 1983-02-08 | 1987-03-05 | Method of and apparatus for detecting change in the breakoff point of a droplet generation system |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833307789 DE3307789A1 (en) | 1983-03-04 | 1983-03-04 | METHOD AND DEVICE FOR DISPLAYING A CHANGE IN THE DECOMPOSITION POINT IN A DROP PRODUCTION SYSTEM |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8303440D0 GB8303440D0 (en) | 1983-03-16 |
| GB2136561A true GB2136561A (en) | 1984-09-19 |
| GB2136561B GB2136561B (en) | 1986-06-25 |
Family
ID=6192580
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08303440A Expired GB2136561B (en) | 1983-02-08 | 1983-02-08 | Monitoring the breakoff point of a droplet generation system |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS59159046A (en) |
| AU (1) | AU563027B2 (en) |
| CA (1) | CA1206559A (en) |
| CH (1) | CH654925A5 (en) |
| DE (1) | DE3307789A1 (en) |
| FR (1) | FR2542110B1 (en) |
| GB (1) | GB2136561B (en) |
| NL (1) | NL8300783A (en) |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001073381A2 (en) * | 2000-03-28 | 2001-10-04 | Matsushita Electric Works, Ltd. | Particle sensor |
| US7713687B2 (en) | 2000-11-29 | 2010-05-11 | Xy, Inc. | System to separate frozen-thawed spermatozoa into x-chromosome bearing and y-chromosome bearing populations |
| US7723116B2 (en) | 2003-05-15 | 2010-05-25 | Xy, Inc. | Apparatus, methods and processes for sorting particles and for providing sex-sorted animal sperm |
| US7758811B2 (en) | 2003-03-28 | 2010-07-20 | Inguran, Llc | System for analyzing particles using multiple flow cytometry units |
| US7820425B2 (en) | 1999-11-24 | 2010-10-26 | Xy, Llc | Method of cryopreserving selected sperm cells |
| US7833147B2 (en) | 2004-07-22 | 2010-11-16 | Inguran, LLC. | Process for enriching a population of sperm cells |
| US7838210B2 (en) | 2004-03-29 | 2010-11-23 | Inguran, LLC. | Sperm suspensions for sorting into X or Y chromosome-bearing enriched populations |
| US7855078B2 (en) | 2002-08-15 | 2010-12-21 | Xy, Llc | High resolution flow cytometer |
| US7929137B2 (en) | 1997-01-31 | 2011-04-19 | Xy, Llc | Optical apparatus |
| US8137967B2 (en) | 2000-11-29 | 2012-03-20 | Xy, Llc | In-vitro fertilization systems with spermatozoa separated into X-chromosome and Y-chromosome bearing populations |
| US8486618B2 (en) | 2002-08-01 | 2013-07-16 | Xy, Llc | Heterogeneous inseminate system |
| US8497063B2 (en) | 2002-08-01 | 2013-07-30 | Xy, Llc | Sex selected equine embryo production system |
| US9365822B2 (en) | 1997-12-31 | 2016-06-14 | Xy, Llc | System and method for sorting cells |
| US11230695B2 (en) | 2002-09-13 | 2022-01-25 | Xy, Llc | Sperm cell processing and preservation systems |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3512090C1 (en) * | 1985-04-03 | 1986-10-02 | Eltro GmbH, Gesellschaft für Strahlungstechnik, 6900 Heidelberg | Circuit arrangement for the preparation of signal amplitudes of very different sizes which are to be processed at the same time |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3380584A (en) * | 1965-06-04 | 1968-04-30 | Atomic Energy Commission Usa | Particle separator |
| BE793185A (en) * | 1971-12-23 | 1973-04-16 | Atomic Energy Commission | APPARATUS FOR QUICKLY ANALYZING AND SORTING PARTICLES SUCH AS BIOLOGICAL CELLS |
| US3963606A (en) * | 1974-06-03 | 1976-06-15 | Coulter Electronics, Inc. | Semi-automatic adjusting delay for an electronic particle separator |
| NL180704C (en) * | 1976-06-14 | Coulter Electronics | DEVICE FOR SIMULTANEOUS OPTICAL MEASUREMENT OF CHARACTERISTICS OF PARTICLES CONTAINING IN SUSPENSION. | |
| US4047183A (en) * | 1976-11-04 | 1977-09-06 | International Business Machines Corporation | Method and apparatus for controlling the formation and shape of droplets in an ink jet stream |
| US4318480A (en) * | 1979-08-20 | 1982-03-09 | Ortho Diagnostics, Inc. | Method and apparatus for positioning the point of droplet formation in the jetting fluid of an electrostatic sorting device |
-
1983
- 1983-02-07 CA CA000421053A patent/CA1206559A/en not_active Expired
- 1983-02-08 GB GB08303440A patent/GB2136561B/en not_active Expired
- 1983-02-08 AU AU11244/83A patent/AU563027B2/en not_active Ceased
- 1983-03-02 JP JP58033000A patent/JPS59159046A/en active Granted
- 1983-03-03 NL NL8300783A patent/NL8300783A/en not_active Application Discontinuation
- 1983-03-03 FR FR8303501A patent/FR2542110B1/en not_active Expired
- 1983-03-03 CH CH1159/83A patent/CH654925A5/en not_active IP Right Cessation
- 1983-03-04 DE DE19833307789 patent/DE3307789A1/en active Granted
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| US7929137B2 (en) | 1997-01-31 | 2011-04-19 | Xy, Llc | Optical apparatus |
| US9365822B2 (en) | 1997-12-31 | 2016-06-14 | Xy, Llc | System and method for sorting cells |
| US9422523B2 (en) | 1997-12-31 | 2016-08-23 | Xy, Llc | System and method for sorting cells |
| US7820425B2 (en) | 1999-11-24 | 2010-10-26 | Xy, Llc | Method of cryopreserving selected sperm cells |
| WO2001073381A2 (en) * | 2000-03-28 | 2001-10-04 | Matsushita Electric Works, Ltd. | Particle sensor |
| WO2001073381A3 (en) * | 2000-03-28 | 2002-02-07 | Matsushita Electric Works Ltd | Particle sensor |
| AU760689B2 (en) * | 2000-03-28 | 2003-05-22 | Matsushita Electric Works Ltd. | Particle sensor |
| US6611611B2 (en) | 2000-03-28 | 2003-08-26 | Matsushita Electric Works, Ltd. | Particle sensor |
| US7713687B2 (en) | 2000-11-29 | 2010-05-11 | Xy, Inc. | System to separate frozen-thawed spermatozoa into x-chromosome bearing and y-chromosome bearing populations |
| US7771921B2 (en) | 2000-11-29 | 2010-08-10 | Xy, Llc | Separation systems of frozen-thawed spermatozoa into X-chromosome bearing and Y-chromosome bearing populations |
| US9879221B2 (en) | 2000-11-29 | 2018-01-30 | Xy, Llc | Method of in-vitro fertilization with spermatozoa separated into X-chromosome and Y-chromosome bearing populations |
| US8652769B2 (en) | 2000-11-29 | 2014-02-18 | Xy, Llc | Methods for separating frozen-thawed spermatozoa into X-chromosome bearing and Y-chromosome bearing populations |
| US8137967B2 (en) | 2000-11-29 | 2012-03-20 | Xy, Llc | In-vitro fertilization systems with spermatozoa separated into X-chromosome and Y-chromosome bearing populations |
| US8497063B2 (en) | 2002-08-01 | 2013-07-30 | Xy, Llc | Sex selected equine embryo production system |
| US8486618B2 (en) | 2002-08-01 | 2013-07-16 | Xy, Llc | Heterogeneous inseminate system |
| US7855078B2 (en) | 2002-08-15 | 2010-12-21 | Xy, Llc | High resolution flow cytometer |
| US11230695B2 (en) | 2002-09-13 | 2022-01-25 | Xy, Llc | Sperm cell processing and preservation systems |
| US11261424B2 (en) | 2002-09-13 | 2022-03-01 | Xy, Llc | Sperm cell processing systems |
| US7799569B2 (en) | 2003-03-28 | 2010-09-21 | Inguran, Llc | Process for evaluating staining conditions of cells for sorting |
| US11104880B2 (en) | 2003-03-28 | 2021-08-31 | Inguran, Llc | Photo-damage system for sorting particles |
| US8664006B2 (en) | 2003-03-28 | 2014-03-04 | Inguran, Llc | Flow cytometer apparatus and method |
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| US8748183B2 (en) | 2003-03-28 | 2014-06-10 | Inguran, Llc | Method and apparatus for calibrating a flow cytometer |
| US9040304B2 (en) | 2003-03-28 | 2015-05-26 | Inguran, Llc | Multi-channel system and methods for sorting particles |
| US7943384B2 (en) | 2003-03-28 | 2011-05-17 | Inguran Llc | Apparatus and methods for sorting particles |
| US9377390B2 (en) | 2003-03-28 | 2016-06-28 | Inguran, Llc | Apparatus, methods and processes for sorting particles and for providing sex-sorted animal sperm |
| US7758811B2 (en) | 2003-03-28 | 2010-07-20 | Inguran, Llc | System for analyzing particles using multiple flow cytometry units |
| US10100278B2 (en) | 2003-03-28 | 2018-10-16 | Inguran, Llc | Multi-channel system and methods for sorting particles |
| US7723116B2 (en) | 2003-05-15 | 2010-05-25 | Xy, Inc. | Apparatus, methods and processes for sorting particles and for providing sex-sorted animal sperm |
| US7892725B2 (en) | 2004-03-29 | 2011-02-22 | Inguran, Llc | Process for storing a sperm dispersion |
| US7838210B2 (en) | 2004-03-29 | 2010-11-23 | Inguran, LLC. | Sperm suspensions for sorting into X or Y chromosome-bearing enriched populations |
| US7833147B2 (en) | 2004-07-22 | 2010-11-16 | Inguran, LLC. | Process for enriching a population of sperm cells |
Also Published As
| Publication number | Publication date |
|---|---|
| CH654925A5 (en) | 1986-03-14 |
| DE3307789C2 (en) | 1991-09-19 |
| FR2542110B1 (en) | 1988-11-04 |
| JPS59159046A (en) | 1984-09-08 |
| FR2542110A1 (en) | 1984-09-07 |
| DE3307789A1 (en) | 1984-09-06 |
| GB2136561B (en) | 1986-06-25 |
| GB8303440D0 (en) | 1983-03-16 |
| AU1124483A (en) | 1984-08-16 |
| JPH0324626B2 (en) | 1991-04-03 |
| NL8300783A (en) | 1984-10-01 |
| AU563027B2 (en) | 1987-06-25 |
| CA1206559A (en) | 1986-06-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19940208 |