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Publication numberUS3705771 A
Publication typeGrant
Publication dateDec 12, 1972
Filing dateJan 14, 1970
Priority dateJan 14, 1970
Also published asDE2101358A1, DE2101358C2
Publication numberUS 3705771 A, US 3705771A, US-A-3705771, US3705771 A, US3705771A
InventorsMitchell Friedman, Louis A Kamentsky, Isaac Klinger
Original AssigneeBio Physics Systems Inc
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Photoanalysis apparatus
US 3705771 A
Abstract
A narrow beam of light is directed through an optical chamber to intersect a thin stream of small particles to be optically analyzed. At least two photoresponsive pick-up elements are positioned at different angular positions with respect to the beam to simultaneously detect different optical reactions of each particle to the beam illumination.
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Description  (OCR text may contain errors)

United States Patent Friedman et al. Dec. 12, 1972 [54] PHOTOANAL YSIS APPARATUS [56] References Cited [72] Inventors: HMitchell Lo Frigdman, storlgown UNITED STATES PATENTS e1 ts; uis Kame Isaac fi 2,816,479 12/1957 Sloan ..356/102 town Height; all ofN Y 2,875,666 3/1959 Parker et al ..356/39 UX 3,420,609 1/1969 Kozawa ..356/ 104 [73] Assignee: Bio/Physics Systems, Inc., Katonah, 3,504,183 3/ 1970 Salkowski et a1 .;.250/218 N.Y. Primary Examiner-Ronald L. Wibert [22] 1970 Assistant Examiner-Orville B. Chew, ll 21 App1.N0.: 2,750 y Ailes ABSTRACT [52] US. Cl. ..356/39, 250/218, 33556520): A narrow beam of H g is directed through an optic a1 5 I I t Cl G01 21 26 chamber to intersect a thin stream of small particles to Ill. I1 I be At least two photoresponsive [58] Field of Search ..250/2l8; 356/39, 102, 103, Pickup elements are positioned at diff t angular positions with respect to the beam to simultaneously detect difi'erent optical reactions of each particle to 7 the beam illumination.

'38Claims,7DrawingFigures P'ATENT nuEc 12 I972 3. 705, 771

sum 1 or 4 IIHI v ll s2 INVENTORS 5o\ MITCHELL FRIEDMAN I LOUIS A. KAMENTSKY ISAAC KLINGER ATTORNEY PATENTED DEC 12 I972 SHEET 2 OF 4 FIG.2

PATENTED DEC 12 m2 SHFEI (1P4 PHOTOANALYSIS APPARATUS The present invention. relates to photoanalysis apparatus, and more particularly to photoresponsive apparatus for detecting various characteristics of small particles such as blood cells.

There is a great need. for accurate analysis of the characteristics of groups of small particles such as in the analysis of air pollution and water pollution conditions. A particularly important field for such analysis is in medical, research and diagnosis. For this purpose, blood cells and other biological cells must be analyzed.

In the present invention the analysis of small particles is accomplished optically by entrainingthe particles in a very thin stream of liquid so that: the particles pass one by one in the stream through an optical scanning station. A photo-opticaldetecting device is arranged to detect the optical reaction of each. particle to illumination from a beam of light. This method has been shown to impart very important. information about the particles which have been scanned. Theinformation derived is. particularly valuable when special procedures are followed for preliminary preparation of the particles, such as the prior application. of. dyes which are taken up by the particles indifferent ways related to the differences in particles. which are to be detected. The particles having these differences may be differentially counted.

In accordance with one aspect of the. present.invention, it has been determined that inan apparatusof the above description, the value. of the; information which can be derived photo-optically is. tremendously increased if at least two differentoptical reactions of the. particles can be detected simultaneously by means of optical pick-up elements arranged atdifferentangular positions with respect to the direction of the beam of light directed at the particle.

-One of the most useful optical reactions to. theillumination is a measurementof the. optical absorptionof. the particles. The amount of optical absorption of the. particles may be directly related to theamount. of 'dye which has been taken into each particle in a preliminary conditioning step. Since the dye uptake by the particles may be different based upon different characteristics, the optical absorption may thus be used to; distinguish these characteristics. The. combined detection of absorption and another optical reaction, such as scatter, therefore provides a very usefulcombination of information about the particles under observation. For instance, in the analysisof biological cell samples, such as blood cells, it is recognized thatxdead cells-absorb the dye Trypan blue while live cells do not. Accordingly, it is possible to analyze a sample. of suchcellsby firstexposing the sample to such a dye and then. optically measuring both absorption and, scatter. The dead cells.

to provide a method and anapparatusin which at least two different optical reactionsof particles can be detected, and more specifically in which different conditions of individual cells, such as the differentiation of live and dead cells may be accomplished reliably and q kly- In photoanalysis apparatus. of the above description, it has been recognized that. the light scattering efiect produced by particles under observation varies accordingto different characteristics 'of the particles, including such factors as particle size, refractive index, and

the presence of refractive and absorbent substances in. the particles. Accordingly, the detection. of scattered light from the particles provides anextremely valuable method for determining the characteristics of the particles. Furthermore, the magnitude of the scatter radiation as a function of the angles or the ranges of angles over. which the scattering of light occurs provide distinctive information. In apparatus. heretofore availa- V ble, it has generally been possible to. detect light scattered by particles. under. observation only for a very small fixed range of scatter angles. This has been. accomplished: by projecting illumination to the particle by meansof alens'having a mask over the central portion thereof to createa cone of darkness beyond the particle positioned at. thev focal. point of the lens. The scatter illumination is detected within this cone of darkness. r

In accordance with another aspect. of the present invention, it is another'object. of the present invention to provide a photoanalysis apparatus. for optical. analysis of particles in which very accurate measurements of scatter illumination can bemade at any desired angle, or: over any desired. range of angles, without specific limitation to a particular cone of darkness.

In carrying outthe above object, a structure is. employed inwhich there isproduced an extremely narrow beam. of illumination directed at the particles, and photosensing devices are arranged. at positions dis-- placed from the. beam to receiveillumination scattered at. predetermined angles from: the beam by the particles.

Another problem in photoanalysis apparatusof the above description has always been theeconomical production of a suitable optical chamber through which the particles to be examined are passed-and subjected tov illumination. It has been previously thoughtto be absolutely 'essentialto provide flatsides on thisoptical chamber in order. to avoid distortion of the. light beam: directed through the chamber: by the material of the side wallsof the chamber.

Accordingly, it is another. object of the present: invention to provide a very satisfactory and easily produced optical chamber'in a photoanalysis apparatus which is extremely. economical to produce because of the manner-in which provision ismade for satisfactory opticalpropertiesof'thesidewalls,

In carrying outtheabove object of the invention, a photoanalysis apparatusisprovided having; an optical chamber. in theformofa cylindrical tube.

Further. objectsand advantages of the. invention will be apparent'from the following description and the accompanying drawings.

In carrying outthe invention in one preferred from thereof, there is'provided an apparatus for simultaneous. optical measurement of several characteristics of each particlerof'a group. ofsmall particles suchas blood cellsv while. the particles are suspended in a liquid, including. a source of light, a housing comprised of a material. which transmits". light from the source. and defining an optical chamber. A means is provided for moving the particle suspending liquid through the housing in a thin stream to convey the particles in sequence through the stream one by one. Another means is provided for directing light from the light source into one side of the housing to intersect with the thin stream of particles in a narrow beam, and at least two photoresponsive pick-up elements are positioned outside of said housing at different angular positions with respect to the direction of the beam when measured from the intersection of the beam with the stream of particles, the photoresponsive pick-up elements being effective to simultaneously detect different optical reactions of each particle to illumination from the beam.

In the accompanying drawings:

FIG. 1 is a schematic top view, partly in section, of the most essential elements of a photoanalysis apparatus in accordance with the present invention.

FIG. 2 is a sectional side view of a portion of the apparatus shown in FIG. 1 and illustrating additional photo-optical pick-up elements for detecting scatter at additional angles.

FIG. 2A is a sectional side view corresponding to FIG. 2 and illustrating, on a reduced scale, an altemative arrangement of the apparatus including means for picking up and detecting fluorescence of the particles.

FIG. 3 is an enlarged sectional front view taken through a section at the center of the optical chamber of the apparatus of FIG. 1, and illustrating the intersection of the beam of light with the particles being measured.

FIG. 4 is a partial front view of a photoanalysis apparatus in accordance with the invention and having modified photoelectric pick-up elements for the detection of scattered illumination.

FIG. 5 is a top view, corresponding to FIG. 1, but illustrating a modification of the photoresponsive pickup elements in which separate signals are derived to indicate the intensity of scattered radiation and the angle of the scattered radiation.

An FIG. 6 is a top view of two optical chamber tube members for a photoanalysis apparatus in the course of production, in accordance with a preferred method of production.

Referring more particularly to FIG. 1, there is shown an optical chamber formed by a glass tube member 10 clamped between metal members 12, 14, which respectively include liquid tight annular seals 16 and 18. The liquid 19 containing the particles to be observed enters the apparatus through a tube 20 centrally disposed within member 12. Another liquid 23, which forms a sheath for the liquid 19 containing the particles enters the member 12 through an entrance opening 22. The liquids come together in the cone or funnel-shaped entrance portion 24 of the central bore 26 of the cylindrical member 10.

The velocity and volume of flow of the particle-bearing liquid 19 entering through tube 20 and the other liquid 23 entering through entrance 22 are such as to cause the stream of particle-bearing liquid to be narrowed down at the end of the tube 20, as shown at 28, into a very narrow stream 29 having a maximum dimension of the same order of magnitude as the maximum dimension of the particles being carried by the stream. For instance, this dimension may be in the order of a 25 micron stream diameter. The particles of greatest interest are oftensomewhat smaller than this, being in the range from 1 to 10 microns in diameter. The liquid 23 may be referred to hereinafter as the sheath flow liquid since it forms a liquid sheath abut the narrowed stream 29. In order to provide a smooth and non-turbulent flow of the sheath liquid 23, two or more radial inlet openings 22 may be provided to the central bore of the member 12. The funnel-shaped entrance portion 24 of the cylindrical member 10 a is preferably provided with a special exponential function shape, as described more fully below, particularly in connection with FIG. 6, in order to provide for smooth non-turbulent flow of the liquids at the critical position 28 where the particle-carrying liquid is narrowed down. Typically, the particle-carrying liquid may be an aqueous solution and the sheath liquid 23 may be water.

The stream 29 of particles is illuminated by a beam of light emitted by a light source 30 which preferably consists of a laser. One satisfactory laser,.for instance, is a heliumneon laser. The beam of light from the laser is reduced in diameter by a combination of spherical lenses 32 and 34. The resultant reduced diameter beam is collimated. This concentrated beam is narrowed by a lens 36 to provide a very narrow beam at the point 38 where the beam intersects with the stream 29 of particles under observation. For this purpose, the lens 36 is preferably a cylindrical lens having its cylinder axis arranged in a plane perpendicular to the axis of the chamber cylinder 10. Thus, the pattern of the illumination of the beam at the point 38 where it strikes the stream of particles is a very narrow ellipse which appears to be a thin line of light transverse to the stream of particles. This will be described more fully blow in connection with FIG. 3.

Electrical photoresponsive pick-up elements are arranged around the outside of cylindrical chamber member 10 to detect different optical reactions of each particle to illumination from the beam through lens 36. For instance, an electrical photo-responsive pick-up element 40 is arranged in direct line with the beam to measure the absorption of illumination by each particle. The resultant electrical signals are connected to apparatus schematically shown at 46 for amplification and recording or display. In the absence of a particle at the intersection of the beam, or in the absence of any substantial absorption, the beam strikes the element 40 without any substantial diminution.

As illustrated in the drawing, the beam diverges to a certain extent after having been converged at the center of the chamber at 38. The effective divergence in a practical embodiment has been limited to approximately 1 on each side of the center line of the beam as measured from the particle scanning point 38 at the center of the chamber. Thus, photoresponsive pick-up elements 42 and 44 are arranged on opposite sides of the direct beam and can be used to measure illumination scattered out of the direct beam by the particles over a selected range of angles from 1 up to a predetermined angular limit. For instance, this range of angles may be from 1 to 9. As shown in the drawing, the photoresponsive pick-up elements 42 and 44 may be electrically connected in parallel so that electrical signals resulting from illumination scattered on either side of the beam will be detected and may be recorded by the electrical apparatus schematically illustrated at 46. Additional pairs of photoresponsive pick-up elements for detecting scattered light at other rangesof angles may be provided as shown at 47 and 48. For instance, this additional pair of pick-up elements may detect scatter over the scatter angle range from 9 to 22. The wider angle scatter sensors 47 and 48 may be'employed for the purpose of providing-a measurement of optical absorption of the particles as an alternative to the absorption measurement by pick-up element 40. It

is known that absorption of the incident beam will,

decrease the amount of light scattered by the particles. This decrease in scattered illumination is more pronounced for the wider angle scatter, than for the near forward scatter detected by sensors 42 and 44. Accordingly, it has been found to be advantageous to use the wider angle scatter measurements at 47 and 48 to detect absorption because noise signals due to light source intensity fluctuations and flow stream vibrations are much less for the scatter sensors than for the direct measurement absorption sensor 40 which is in the direct path of the beam.

Scattering of illumination from the particles in the reverse direction, called back-scattering, can also be detected by photoresponsive elements 50 and 52 arranged on the same side of the chamber as the light source 30 and connected in parallel to an electrical pick-up and recording apparatus 54. It will be understood that the electrical apparatus 54 may be combined with the apparatus 46, but it is shown separately here to simplify the drawing.

The apparatus 46 and 54 may include amplifiers, logic circuitry, digital counters, and electronic display devices. It is one of the important features of the invention that different optical reactions of each particleto illumination may be detected, processed, and recorded substantially simultaneously. The relationships between these different optical reactions may be processed by analog and digital circuitry, displayed, recorded, and plotted as a basis for making detailed determinations about the particles, differentially classifying the particles, or determining the frequency with which particular characteristics appear in successive particles. Because of the unique features of this invention, particle analysis and counting rates in the order of ten thousand particles per second may be achieved; It will be understood that this speed is well within the capacity of the electronic and digital portions of the system.

The photoresponsive pick-up elements, such as elements 42 and 44 for the detection of scatter, are illustrated in FIG. I as though-they were fixed with relation to the cylindrical chamber member 10. However, suitable means is provided for precisely changing the position of those pick-up elements in relation to the beam from source 30. This adjustment may be an adjustment from side to side and it may also be an adjustment to place the elements in greater orlesser proximity to the scanning position 38;. By moving the elements away from the scanning position, the inner margins of the elements may be precisely positioned with respect to the outer margins of the direct radiation beam directed to the absorption pick-up element 40. Thus, the elements 42 and 44 are capable, when so adjusted, or picking up scatter radiation over the narrowest possible angle outside of the direct radiation beam path.

FIG. 2 is a partial sectional side detail view of the apparatus of FIG. 1 including the cylindrical chamber member 10, the cylindrical lens 36, the absorption and scattering. pick-up elements 40, 44, and 48, and the back-scattering pick-up element 52. Asillustrated in FIG. 2, the cylindrical shape of the chamber member 10 causes a refractive effect upon the light beam supplied through the cylindrical lens 36 which causes the light beam to converge towards the center bore 26 of the chamber member 10. This effect is shown in an exaggerated form in FIG. 2. The diameter of the beam as it enters the cylindrical lens 36 is actually selected so as to be approximately equal to the diameter of the center bore. 26. This diameter is of the order of 250 microns. However, the convergence of the beam in the plane of FIG. 2 (perpendicular to the axis of the chamber member 10) is not a disadvantage since it serves to concentrate the beam in the central portion of the center bore-26 where the particle carrying stream is located. Since the particle carrying stream has a diameter of only about 25 microns, a considerable convergence of the beam is desirable. This provides relatively uniform illumination over the diameter of the particle-carrying stream, even though the original energy distribution from the laser beam is non-uniform. Furthermore, if the beam were not caused to converge upon the center bore 26, the outer portions of the beam would strike the interface between glass and liquid at the center bore 26 at an angle greater than the critical angle of refraction so that those outer portions of the beam would be reflected away from the center bore, and lost, without passing through the liquid.

FIG. 1 illustrated how pairs of photoresponsive pickup elements such as 42 and 44, and 47 and 48, can be arranged in' positions spaced away from the primary beam in directions parallel to the axis of the cylindrical chamber member 10 for'detecting small angles of scatteredillumination. However, as shown in FIG. 2, when larger angles of scatter are to be detected, the angular displacement of pick-up elements can be around the circumference of the cylindrical chamber member. Thus, as shown in FIG. 2, a pair of pick-up elements 56 and 58 may be circumferentially arranged to detect light scattered in a range at about 45 from the particle scanning point 38. Similarly, pick-up elements 60 and 62 may be provided to detect scatter in a range near degrees. It will be understood that these arrangements of pick-ups are by way of illustration only. Particular analyses will require the detection of scatter for particular ranges of angles. The important principle illustrated by FIGS. 1 and 2 is that light scattered by particles under analysis can be detected for any selected ranges of scatter angles from essentially 1 up to 179 with the analyzer configuration as illustrated.

All of the components illustrated in FIG. 2, with the exception of the cylindrical lens 36, are preferably mounted upon and movable with a support block schematically shown as a box 55 pivotally supported on a fixed mounting at 57. The support block 55 may be vertically adjusted by rotation about the pivot 57 by means of a thumb screw 59 engaging the lower edge of the block 55. Thumb screw 59 is threadedly engaged within a fixed support 61. The purpose for this vertical adjustment is to precisely position the chamber 10 with respect to the light supplied from the light source through the cylindrical lens 36. If the light beam is not vertically centered upon the center bore 26 of the chamber 10, so that the beam accurately intersects with the stream 29 of particle-carrying liquid, then the device may be inoperative. The accurate positioning of the chamber with respect to the beam is very important because an offset in the positioning of the chamber with respect to the beam causes undue loss of beam energy through excessive refraction of beam energy at the bore 26.

In the embodiment of the invention illustrated in FIGS. 1 and 2, there is unavoidably a certain amount of radiation which is reflected radially outwardly from the scanning point 38 in a narrow ring which is confined to a longitudinal dimension along the cylinder of the cylindrical chamber member generally corresponding to the width of the entering beam of illumination from source 30. Thus, the scatter detectors are always longitudinally displaced out of this ring of radiation and preferably arranged in pairs on opposite sides of the direct radiation position as shown by detectors 42 and 44 in FIG. 1. Similarly, in FIG. 2, the scatter detectors 56, 58, 60, and 62 each represent a pair of detectors preferably arranged on opposite sides of the ring of radiation.

The preferred photoresponsive pick-up elements to be employed in the present invention as thus fardescribed may consist of silicon barrier layer photo diodes. These devices are photo-voltaic devices commonly referred to as silicon solar cells. Suitable devices of this kind are available from many commercial sources.

FIG. 2A corresponds generally to FIG. 2, but illustrates alternative arrangements of the components, and also additionally illustrates an arrangement for picking up and detecting fluorescence of v the particles. The light from the light source is again supplied through the cylindrical lens 36 to the optical chamber 10, and absorption is detected by photo detector 40. In this embodiment of the invention, the scatter detector 44 includes an optical reflector which may consist of a mirror 44B, and a photoelectric device 44C arranged to receive the scatter radiation reflected by the optical reflector 4413. Since these two elements accomplish the same combined function as the scatter up element 44 of FIG. 2, the combination of the two elements 44B and 44C may be referred to collectively as a photoresponsive pick-up element. As explained above in connection with FIG. 1, the scatter pick-up element 44 is preferably paired with another scatter pick-up element 42, the combination of the two pick-up elements being effective to detect scatter on the two sides of the light beam passing through the scanning point. By means of the reflective arrangement shown and described in connection with FIG. 2A, it is possible to employ two separate reflectors on opposite sides of the beam, both reflectors directing scatter radiation to a single photoelectric device such as 44C. By this means, the scatter radiation signals from the two sides of the beam need not be electrically combined. They are, instead, optically combined by being directed by separate reflectors to the single photoelectric device.

The particular arrangement thus far described, with the reflector 44B, and a possible additional reflector, reflecting scatter signals to a single photoelectric device 44C may be employed in the embodiment previously shown and described in FIG. 2, and is not necessarily limited to combination with other features of FIG. 2A described immediately below.

One of the most useful categories of optical measurements available in the photoanalysis of particles is the measurement of fluorescence of the particles in response to the primary radiationby the light beam directed through the cylindrical lens 36. The particles may be stained with dyes so that when excited with light they are caused to emit fluorescent radiation at one or more wave lengths different from the wave length of the primary light beam. The intensity of fluorescent radiation at various wave lengths is an extremely useful indication of the propertiesand characteristics of the particles. Since the fluorescent radiation is emitted invirtually all directions from the particle, the fluorescent radiation is gathered by the reflectors 63 and 65 and generally directed, through a cylindrical lens 67, to a dichroic mirror 69. As is well known, the dichroic mirror 69 is designed to reflect radiation having a wave length shorter than a predetermined limit such as 5,500 angstroms and to transmit radiation having a longer wave length. The reflected radiation is directed through a filter element 71 to a first photo multiplier tube 73. The transmitted radiation is directed through a second optical filter 75 to a second photo multiplier tube 77. By means of the combination of the dichroic mirror 69 and the optical filters 71 and 75, each of the photo multiplier tubes 73 and 77 receives only that light at the wave length predetermined by the respective filters. If desired, additional dichronic mirrors may be provided to split up the fluorescent radiation into additional spectral components in order to obtain additional optical analysis information.

The reflective elements 63 and 65 generally extend axially along the tubular chamber member 10. However, these reflective elements are preferably split similarly to the scatter sensing devices as pictured in FIG. 1, so as to avoid reflecting andtransmitting the ring of radiation which is discussed immediately above. Avoiding the reflection and transmission of the ring of radiation is particularly important when dealing with radiation at the green end of the visible spectrum because it is difficult to provide eflicient optical filters 71 and 75 at that end of the spectrum. However, when dealing with fluorescence at the red end of the visible spectrum, efficient filtering is available and it is then preferably not to provide split reflective elements 63 and 65 and to gather the ring of radiation, which includes fluorescence signals at the desired wave length.

The reflector 63 is preferably arranged so that fluorescent radiation emitted through the lower surface of the chamber member 10 is reflected up to the upper reflector 65. The upper reflector 65 is preferably arranged so that all of the radiation directed to that reflector is ultimately reflected to and gathered by the left portion of that reflector and directed, through lens 67, down to the dichroic mirror 69.

When making fluorescence measurements, it has been found quite effective to employ for the light source 30 an argon laser which emits light in the blue part of the spectrum. Light of this wave length has been found to provide a high degree of fluorescence emission by biological particles which are often under observation. Since the particles fluorescence in the forward direction, it has been found to be quite desirable to provide a filter 79 which permits the passage only of the argon blue direct radiation to the scatter sensor 44B-44C, and to the absorption sensor 40.

It will be appreciated that the arrangement shown in FIG. 2A is particularly useful because it permits simultaneous detection of at least four different optical reactions of a particular particle simultaneously. Thus, absorption is detected at 40, scatter is detected at 44B44C, and two different wave lengths of fluorescent radiation are detected at photo multipliers 73 and 77. Metachromatic, or combinations of fluorescent dyes are available which, when used to stain cells, will fluoresce at two wave lengths with each fluorescent intensity proportional to a given cellular constituent.

FIG. 3 is an enlarged detail sectional front view of that portion of the apparatus of FIG. 1 where the light beam actually strikes the stream of particles at point 38 in the chamber 10. The stream of particles 29 is shown to contain actual entrained particles 64 which are transported one at a time through the elliptically shaped beam of light at 66. Because of the elliptical shape of the beam of light, the stream 29 carrying the particles 64 may vary in its position within the chamber without having the stream actually move out of the path of the beam. Thus, the beam always intercepts the entire stream of particles. On the other hand, the narrow elliptical shape of the beam, in which the width of the beam is of substantially the same order of magnitude as the diameter of the particles, means that each particle causes an optimum optical reaction with the beam. Furthermore, even if the particles are closely spaced together, it is virtually impossible for more than one particle to be acted upon by the beam at any particular instant.

FIG. 4 is a sectional front view illustrating a modification of the apparatus of FIG. 1 in which arcuate shaped pick-up elements 42A, 44A, and 46A, 48A are employed. This view is taken at a section corresponding to the section line indicated at 4-4 in FIG. 2, although it will be understood that the actual modified structure of FIG. 4 is not illustrated in FIG. 2. The scatter pick-up elements 42 and 44 and 46 and 48 of FIG. 1 are arranged to intercept scatter over selected ranges of angles simply by virtue of a displacement in position along the axis of the cylindrical chamber member 10. As illustrated in FIG. 2, for larger scatter angles, the measurements can be made by circumferential displacement of the pick-up elements about the cylindrical chamber. However, a combination of these techniques is possible in which a high efficiency is achieved by means of the semicircular pick-ups illustrated at 42A, 44A, and 46A, 48A in FIG. 4. Thus, the illumination scattered over a particular range of angles may be scattered anywhere within a possible cone of scatter radiation terminating in a substantially circular radiation area such as the area defined by the pick-up elements 46A and 48A. Thus, the semicircular pick-up elements are particularly efficient in intercepting substantially all of the scatter radiation over the range of scatter angles for which they are designed.

FIG. 5 is a top view corresponding to FIG. 1 and illustrating a modification of the apparatus of FIG. 1 employing special light position-sensing photo-detectors 68 and 70 which are capable of determining both the intensity and the angular position of scatter radiation. These are silicon barrier photo diodes of the type which are commercially available for instance from United Detector Technology of Santa Monica, California, the name of the product being designated as Light Position Sensing Photo-Detectors. The photo detectors 68 and 70 are driven by a direct current voltage source indicated at 72. The current from source 72 enters the detectors 68 and 70 at the center detector terminals 74 and 76. The current passes through either or both of the detectors and is emitted at the end terminals 78 and 80, or at the end terminals 82 and 84, the ratio of the current through the different end terminals of each detector device is determined by the position of the radiation striking the device. For instance, if the radiation strikes the device 70, and if the radiation position is closer to the terminal 84 than it is to the terminal 80, there will be a greater current from the terminal 84 than there is from the terminal 80. The currents from terminals 82 and 84 are returned to the source 72 through a load resistor 86 to ground and from ground through a load resistor 88. Similarly, the currents from terminals 78 and 80 are returned through a load resistor 90 to ground and thus through load resistor 88 to the source 72. The resistance values of load resistors 86 and 90 are preferably equal and the relative values of the load currents through those resistors are measured in terms of voltage drops in a differential amplifier 92 to provide a scatter angle signal fed to a detection and recording circuit 46A.

Similarly, the intensity of the scatter illumination is detected in terms of the voltage drop across the common load resistor 88 by an amplifier 94, the output of which is also supplied to the circuit 46A. Thus, the arrangement of FIG. 5 does not simply record scatter radiation in specified ranges of scatter angles, but rather it records the intensity of the scatter radiation and indicates the angle at which that radiation occurs. This provides a particularly valuable analysis tool where the significant range of scatter angle is not previously known.

In accordance with the present invention it has been determined that a new method may be followed, employing the apparatus described above, for rapidly analyzing samples of particles, and particularly biological samples of cells such as blood cells. As mentioned above, different conditions of biological cells may control the amount of dye which individual cells will pick up when the cell sample is exposed to a dye. For instance, when a mixture of live cells and dead cells is exposed to Trypan blue dye, the dead cells take up the dye to a significant extent, while the live cells do not.

In a specific example of the practice of this method, the method may be employed to determine the feasibility of an organ transplant from one individual to another by checking for compatibility of blood cells. For such a compatibility test, lymphocytes may be extracted from the blood of a donor to be matched with the sera of potential recipients. To effect this match the lymphocytes are diluted in 0.85 percent sodium chloride solution or an appropriate nutrient medium to a concentration of 5 million cells per milliliter and added to the diluted serum of the potential donor. The

mixture is then incubated at atemperature in the range from 35 to 40 C. for approximately 45 minutes. The incubation is then stopped by placing the samples on ice. Immediately before examination a freshly prepared Trypan blue aqueous solution containing 0.24 percent Trypan blue and 0.85 percent sodium chloride is added to the sample in a volume equal to 50 percent of the sample volume so as to increase the sample volume by about 50 percent. The final suspension should have a cell concentration in the range of 1 million cells, or less, per milliliter of solution to provide reasonable assurance that the cells will pass through the apparatus one at a time. The sample is then caused to pass through the apparatus as described above in connection with FIG. 1, and the optical absorption of the cells is detected concurrently with the optical scatter over a range from about one degree to about 30 away from the axis of the beam. The stained cells, which provide a large absorption signal, are indicated as dead, and the unstained cells, which provide a high scatter signal, and a low absorption signal are indicated as live. A high count of dead cells in this compatibility analysis indicates a lack of compatibility between donor and recipient for the purpose of transplants.

For this analysis, a helium neon laser emitting illumination at 6,300 angstroms may be employed. Other dyes may be alternatively used for this live-dead cell analysis method. For instance, nigrosine dyes are useful for this purpose.

FIG. 6 illustrates an essential step in the preferred method of the production of the optical chamber member 10 of the apparatus of the present invention. In practicing this method, a piece of glass tubing having inside and outside diameters of the desired size for the finished optical measurement portion of the tubular optical chamber is cut to a length which is somewhat greater than twice the desired length of the finished optical chamber. The tubing must be substantially free of any cracks, scratches or blemishes. The glass tubing is then heated uniformly around the central portion of the axial length thereof to the softening temperature of the glass. This may be simply accomplished by rotating the tubing while the central portion of the tubing is held in a gas flame.

Next, the central bore of the tubing is placed under pressure. This causes enlargement, or blowing out, of the central bore of the tubing at the heated central portion thereof, as shown at 96 in FIG. 6.

When the proper degree of enlargement has been achieved, the pressure is released and the tubing is allowed to cool and harden. It is then cut apart through the centerline as indicated at 98. The two resultant separate pieces 10A and 10B can each be used as optical chambers in an apparatus such as previously described in connection with FIG. 1 after the next step. As the final step, in order to provide a liquid-tight seal at the ends of each chamber, both ends of each of the glass parts 10A and 10B are preferably ground flat and mutually parallel to eliminate the slight inaccuracies of the glass cutting procedure.

There are a number of useful variations in the process described just above. For instance, the central bore of the tubing may be placed under pressure while the tubing is being heated so that the enlargement of the tubing occurs at the earliest possible moment when the heating has progressed sufficiently to soften the glass. Also, it has been found to be quitepractical and desirable to perform the heating and pressurizing steps at spaced axial positions along an extended length of glass tubing. All of the tube cutting operations are then done after the enlargements have been formed, cutting at each enlargement and midway between adjacent enlargements to thereby obtain a yield of two optical chambers for each tubing enlargement.

It has been found that the above method of production of the optical chambers is very simple and inexpensive and also satisfactory. It has been determined that the changes in the diameter in the resultant enlarged funnel-shaped end 24 of the central bore 26 is substantially an exponential function. That is, the change in the diameter of the central bore is substantially an exponential function of the displacement along the axis of the tube at which the diameter is measured. This provides a graded change in the bore diameter which is very valuable and useful in promoting smooth and nonturbulent liquid flow in the critical bore narrowing region where the sheath liquid is reducing the diameter of the particle carrying liquid stream.

While this invention has been shown and described in connection with particular preferred embodiments, various alterations and modifications will occur to those skilled in the art. Accordingly, the .following claims are intended to define the valid scope of this invention over the prior art, and to cover all changes and modifications falling within the true spirit and valid scope of this invention.

We claim:

1. Apparatus for simultaneous optical measurement of several characteristics of each particle of a group of small particles such as blood cells while the particles are suspended in a liquid,

comprising a source of light,

a housing comprised of a material which transmits light from said source and defining an optical chamber,

means for moving the particle suspending liquid through said housing in a thin narrow stream to convey the particles in sequence through the stream one by one,

means for directing light from said light source into one side of said housing to intersect with the thin stream of particles in a narrow beam substantially converging at the intersection with the stream of particles and operable to intercept the entire particle stream,

and at least two photoresponsive pick-upelements positioned outside of said housing at difierent angular positions with respect to the direction of said beam when measured from the intersection of the beam with the stream of particles,

said photoresponsive pick-up elements being effective to simultaneously detect different optical reactions of each particle to illumination from the beam.

2. Apparatus as claimed in claim 1 wherein one of said photoresponsive pick-up elements is positioned in alignment with the light beam on the side of said housing opposite to said light source to receive the un-scattered illumination from the light beam to thereby detect the amount of light absorbed by each particle being measured.

3. Apparatus as claimed in claim 1 wherein said photoresponsive pick-up elements are respectively angularly positioned to intercept light at different ranges of angles with respect to the direction of the light beam for the detection of the relative intensities of light scattered by each particle at said respective ranges of angles.

4. Apparatus as claimed in claim 1 wherein the maximum value of each transverse dimension of the thin stream of particle-suspending liquid is of the same order of magnitude as the maximum dimensions of said particles.

5. Apparatus as claimed in claim 1 wherein said means for directing light from said light source is operable to direct the light in said narrow beam such that the angle between the directions of the outermost portions of the beam does not exceed a very small predetermined value.

6. Apparatus as claimed in claim 1 wherein said different optical reactions of said particles to illumination from the beam are recorded and used as different parameters in combination in determining the characteristics of the particles.

7. Apparatus as claimed in claim 1 wherein at least one of said photoresponsive pick-up elements comprises the combination of an optical reflector positioned at a predetermined angular position with respect to the direction of said beam to intercept and reflect the desired optical reaction of each particle and a photoelectric device positioned to receive said optical reaction reflected by said reflector.

8. Apparatus as claimed in claim 7 wherein two optical reflectors are positioned on opposite sides of said beam to intercept and reflect the desired optical reaction of each particle to a single photoelectric device positioned to receive the optical reactions reflected by said reflectors.

9. An apparatus for rapid optical measurementof the characteristics of small particles such as blood cells while the particles are suspended in a liquid,

comprising a source of light,

a cylindrical tube member defining an optical chamber,

said tube member being comprised of a material which transmits light from said source,

means for directing said light into one side of said tube member in a beam substantially converging at the center of said optical chamber when viewed in a direction perpendicular to the axis of said tube member defining said chamber,

means for moving the particle suspending liquid through said tube member in a thin stream to cause the particles therein to pass in sequence through said light beam one by one,

and at least one photoresponsive pick-up element for detecting light scattered by said particles positioned on the side of said tube member opposite to said light source and displaced away from the direct path of said light beam through said tube member in a direction parallel to the axis of said tube member.

10. Apparatus as claimed in claim 9 wherein said photoresponsive pick-up element is positioned outside of said housing and in a position which is displaced away from the point of intersection of the light beam with the thin stream of particles in a direction substantially perpendicular to the direction of the light beam.

1.1. Apparatus as claimed in claim 9 wherein said cylindrical tube member defining said optical chamber is in the form of a circular cylinder.

12. Apparatus as claimed in claim 10 wherein there is provided a second photoresponsive pick-up element positioned and arranged in direct alignment with the light beam on the side of said housing opposite to said light source to receive the unscattered illumination from the light beam to thereby detect the amount of light absorbed by the particles being measured.

13. An apparatus as claimed in claim 9 wherein said tube member is mounted for movement about a pivot axis substantially parallel to said tube axis and displaced away from the tube axis in a direction substantially parallel to the direction of said beam,

an adjustable positioning means for adjusting said tube member by rotation about said mounting axis to center said tube memberin said beam of light.

14. Apparatus as claimed in claim 9 wherein said means. for moving the particle suspending liquid through said tube member in a thin stream includes means for providing a sheath of liquid flowing in an annular configuration through said tube member and surrounding said thin stream to thereby confine the thin stream of particle suspending liquid to a dimension smallerv than the interior diameter of said tube member.

15. Apparatus as claimed in claim 14 wherein said tube member includes a substantially uniform constricted central bore,

said central bore being widened substantially at the inlet end thereof,

the shape of the widening of the inlet endof said bore being such that the change in diameter is substantially an exponential function of the displacement along the axis of said tube in the widening end portion thereof.

16. An apparatus for rapid optical measurement of the characteristics of small particles such as blood cells whilethe particles are suspended in a liquid comprising a housing defining an optical chamber,

a source of light,

said housing member being comprised of a material which transmits light from said source,

means for moving the particle suspending liquid through said housing member in a thin narrow stream to thereby convey the particles in sequence through the light beam one by one,

means for directing light from said light source into one side of said housing to intersect with the thin stream. carrying the particles therein,

said means for directing said light being operable in cooperation with said side of said housing to converge said light beam into 'a substantially elliptical shape in a plane transverse to the light beam and at the point of intersection with the position of the thinstream of particles,

the major axis of the elliptical shape of said beam being substantially perpendicular to the direction of the stream of particles and the dimension of said beam at said major axis being substantially greater than the transverse dimension of said particle stream,

and at least one photoresponsive pick-up element for detecting light scattered by said particles and displaced away from the direct path of said light beam in a direction substantially parallel to the direction of the thin stream of particles.

17. Apparatus as claimed in claim 16 wherein said photoresponsive pick-up element is positioned on the side of said housing opposite to said light source.

18. Apparatus as claimed in claim 17 wherein there is provided a second photoresponsive pick-up element positioned and arranged in direct alignment with the light beam on the side of said housing opposite to said light source to receive the unscattered illumination from the light beam to thereby detect the amount of light absorbed by the particles being measured.

15!. Apparatus as claimed in claim 17 wherein there is provided a second photoresponsive pick-up element which is positioned on the same side of said housing as said light source for the detection of light back-scattered from the particles being measured concurrently with the detection of for ward scattering by said first-mentioned photoresponsive pick-up element,

said second photoresponsive pick-up element being displaced away from the direct path of said light beam in a direction substantially parallel to the direction of the thin stream of particles.

20. Apparatus as claimed in claim 16 wherein said photoresponsive pick-up element is positioned on the same side of said housing as said light source for the detection of light back-scattered from the particles being measured.

21. Apparatus as claimed in claim 20 wherein there is provided a second photoresponsive pick-up element positioned and arranged in direct alignment with the light beam on the side of said housing opposite to said light source to receive the unscattered illumination from the light beam to thereby detect the amount of light absorbed by the particles being measured.

22. Apparatus as claimed in claim 16 wherein said means for directing said light is operable to form said light beam into said substantially elliptical shape in which the length of the minor axis is of the same order of magnitude as the maximum dimension of the particles to be observed and the major axis of the elliptical beam shape is substantially greater than the maximum dimension of the particles to be observed to thereby accommodate for variations in the path of movement of said particles with relation to the light beam as the particles move through the light beam.

23. Apparatus as claimed in claim 22 wherein said means for directing said light comprises a substantially cylindrical lens device.

24. Apparatus as claimed in claim 16 wherein said housing comprises a cylindrical tube member and the direction of the thin stream of particle suspending liquid is in an axial direction through the interior of said tube member.

25. Apparatus as claimed in claim 24 wherein said means for moving the particle suspending liquid through said tube member in a thin stream includes means for providing a sheath of liquid flowing in an annular configuration through said tube member and surrounding said thin stream to thereby confine the thin stream of particle suspending liquid to a dimension smaller than the interior diameter of said tube member.

26. Apparatus as claimed in claim 25 wherein the interior of said tube member is flared outwardly at the entrance end thereof to provide a funneling effect to reduce the diameter of the entering flow of the stream of particle suspending liquid and the sheath liquid.

27. Apparatus as claimed in claim 24 wherein said light source is. a source of monochromatic coherent light.

28. Apparatus as claimed in claim 27 wherein said light source is a laser.

29. Apparatus as claimed in claim 28 wherein said laser is a helium-neon laser.

30. Apparatus as claimed in claim 28 wherein said laser is an argon laser.

31. Apparatus as claimed in claim 28 wherein said means for directing said light includes a combination of lenses providing an optical telescope to concentrate the beam of light from said laser into a beam of reduced cross-section.

32. Apparatus as claimed in claim 16 wherein said photoresponsive pick-up element is positioned and arranged to detect light scattered by the particles over a predetermined narrow range of angles as measured away from the direction of the light beam at the point of intersection with the position of the thin stream of particles in a plane parallel to the direction of the light beam and transverse to the major axis of the elliptical shape of the light beam.

33. Apparatus as claimed in claim 32 wherein there are provided at least two photoresponsive pickup elements for detecting light scattered by the particles over said predetermined range of angles, said photoresponsive pick-up elements being symmetrically arranged on opposite sides of the light beam to intercept light scattered by the particles over the same range of angles on both sides of the light beam.

34. Apparatus as claimed in claim 33 wherein said photoresponsive pick-up elements are positioned on the side of said housing opposite to said light source,

and wherein there is provided an additional photoresponsive pick-up element positioned and arranged in direct alignment with the light beam on the side of said housing opposite to said light source to receive the illumination from the light beam passing between said scattered light photoresponsive pick-up elements to thereby detect the amount of light absorbed by the particles being measured.

35. Apparatus as claimed in claim 34 wherein said photoresponsive pick-up elements are operable to provide electrical signal changes in response to the reception of optical radiation,

and wherein there is provided means for receiving and registering said electrical signal changes.

36. Apparatus as claimed in claim 33 wherein there are provided a plurality of pairs of scattered light photoresponsive pick-up elements symmetrically arranged on opposite sides of the light beam to detect light scattered over different exclusive ranges of angles for each pair,

each pair of photoresponsive pick-up elements being electrically connected together to provide a combined electrical signal,

and the members of each pair being arranged to intercept light scattered over the same range of angles on the opposite sides of the light beam.

37. Apparatus as claimed in claim 16 wherein said photoresponsive pick-up element comprises a radiation position sensing device providing one electrical output signal corresponding to the position of a spot of light on the surface thereof and another electrical signal corresponding to the intensity of the light spot,

said device having the position sensing axis thereof arranged in a plane substantially perpendicular to the major axis of the light beam and parallel to the direction of light transmission in the light beam so that the position sensing signal of said device in response to scattered light provides an indication of the angle of the peak of the distributed radiation scattered from each particle.

38. In an apparatus for optical measurement of the characteristics of small particles such as blood cells while the particles are suspended in a liquid,

a cylindrical tube defining an optical chamber member and comprised of a material which transmits light at the wave length at which the optical measurement is to'be carried out,

said chamber member having a substantially uniform cylindrical bore of restricted cross-section extending from an inlet end to an outlet end through a substantial portion of the length thereof,

said cylindrical bore being flared outwardly at the inlet end thereof to form a funnel-like configuration,

an inlet mounting member engaging said chamber member at the inlet end thereof,

an outlet mounting member engaging said chamber member at the outlet end thereof,

said inlet and outlet mounting members being arranged to clamp said tube member therebetween,

and each of said mounting members including a sealing ring engaging with the respective end surfaces of said chamber member to establish a liquid tight seal therewith,

said inlet mounting member including an axially extending flange at the surface thereof arranged to protrude into the enlarged funnel-shaped opening of said central bore of said tubemember to center said tube member with respect to said mounting members,

said inlet mounting member including a central tube for the transmission of particle carrying liquid into the center bore of said chamber member,

said inlet mounting member also including an annular inlet opening surrounding said central tube for 521%? 2%?filfi3fl8illl? ii hi s iifi frif said particle carrying liquid.

B s d December 12, 1972 Patent No.

lnv' n fl Mitchell Friedman,

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

C olumn 3, line 43, "Al 1 should read And-.

ld read -'-below- Column 4, line 32%;, "blOw" shou should read --absorption Column 5, line 9, "absorptlon line 65, "or" should read -of--, Column 7 line 45, "up" should read -pickup.. Column 8, line 34, "dichronic should read -dichroic-;

line 51, "preferably" should read *--preferable-.

" should read fluoresce-.

Column 9, line 1, "fluorescence Signed and sealed this 29th day of. May 1973 ROBERT GOTTSCHALK Commissioner of Patents (SEAL) Attest;

EDWARD M.FLETCHER,JR. Attesting Officer

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Classifications
U.S. Classification356/39, 356/343, 250/576, 356/342, 250/461.2
International ClassificationG01N15/14
Cooperative ClassificationG01N2021/4709, G01N2015/1413, G01N2021/4711, G01N15/1434, G01N2021/4707
European ClassificationG01N15/14F