Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
  • B01L3/5085—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates
  • B01L3/50855—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above for multiple samples, e.g. microtitration plates using modular assemblies of strips or of individual wells
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/508—Containers for the purpose of retaining a material to be analysed, e.g. test tubes rigid containers not provided for above
• • H—ELECTRICITY
  • H01—ELECTRIC ELEMENTS
  • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
  • H01J37/00—Discharge tubes with provision for introducing objects or material to be exposed to the discharge, e.g. for the purpose of examination or processing thereof
  • H01J37/02—Details
  • H01J37/20—Means for supporting or positioning the object or the material; Means for adjusting diaphragms or lenses associated with the support
• • H—ELECTRICITY
  • H01—ELECTRIC ELEMENTS
  • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
  • H01J37/00—Discharge tubes with provision for introducing objects or material to be exposed to the discharge, e.g. for the purpose of examination or processing thereof
  • H01J37/02—Details
  • H01J37/244—Detectors; Associated components or circuits therefor
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
  • B01L2200/06—Fluid handling related problems
  • B01L2200/0689—Sealing
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/04—Closures and closing means
  • B01L2300/041—Connecting closures to device or container
  • B01L2300/042—Caps; Plugs
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/06—Auxiliary integrated devices, integrated components
  • B01L2300/0627—Sensor or part of a sensor is integrated
  • B01L2300/0654—Lenses; Optical fibres
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L2300/00—Additional constructional details
  • B01L2300/08—Geometry, shape and general structure
  • B01L2300/0809—Geometry, shape and general structure rectangular shaped
  • B01L2300/0829—Multi-well plates; Microtitration plates
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N1/00—Sampling; Preparing specimens for investigation
  • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
  • G01N1/36—Embedding or analogous mounting of samples
• • H—ELECTRICITY
  • H01—ELECTRIC ELEMENTS
  • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
  • H01J2237/00—Discharge tubes exposing object to beam, e.g. for analysis treatment, etching, imaging
  • H01J2237/20—Positioning, supporting, modifying or maintaining the physical state of objects being observed or treated
  • H01J2237/2002—Controlling environment of sample
  • H01J2237/2003—Environmental cells
• • H—ELECTRICITY
  • H01—ELECTRIC ELEMENTS
  • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
  • H01J2237/00—Discharge tubes exposing object to beam, e.g. for analysis treatment, etching, imaging
  • H01J2237/20—Positioning, supporting, modifying or maintaining the physical state of objects being observed or treated
  • H01J2237/2005—Seal mechanisms
  • H01J2237/2006—Vacuum seals
• • H—ELECTRICITY
  • H01—ELECTRIC ELEMENTS
  • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
  • H01J2237/00—Discharge tubes exposing object to beam, e.g. for analysis treatment, etching, imaging
  • H01J2237/20—Positioning, supporting, modifying or maintaining the physical state of objects being observed or treated
  • H01J2237/201—Positioning, supporting, modifying or maintaining the physical state of objects being observed or treated for mounting multiple objects
• • H—ELECTRICITY
  • H01—ELECTRIC ELEMENTS
  • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
  • H01J2237/00—Discharge tubes exposing object to beam, e.g. for analysis treatment, etching, imaging
  • H01J2237/26—Electron or ion microscopes
  • H01J2237/2602—Details
  • H01J2237/2605—Details operating at elevated pressures, e.g. atmosphere
  • H01J2237/2608—Details operating at elevated pressures, e.g. atmosphere with environmental specimen chamber

Definitions

• Patent Application Serial No. 150055 filed on June 5, 2002, entitled "Automation Compatible Devices for Scanning Electron Microscopy Imaging of Samples in a Wet
• the present invention seeks to provide apparatus, systems and methodologies for enabling SEM inspection of fluid containing samples.
• Figs. 1A & IB are oppositely facing simplified exploded view pictorial illustrations of a disassembled SEM compatible sample container constructed and operative in accordance with a preferred embodiment of the present invention
• Figs. 2 A & 2B are oppositely facing simplified partially pictorial, partially sectional illustrations of a subassembly of the container of Figs. 1A & IB;
• Fig. 28 is a simplified illustration of a SEM based sample inspection system constructed and operative in accordance with a preferred embodiment of the present invention.
• Figs. 32A & 32B are oppositely facing simplified partially pictorial, partially sectional illustrations of a subassembly of the container of Figs. 31A & 3 IB;
• Figs. 33A & 33B are oppositely facing simplified exploded view pictorial illustrations of the SEM compatible sample container of Figs. 31A - 32B in a partially assembled state;
• Figs. 34A & 34B are oppositely facing simplified pictorial illustrations of the SEM compatible sample container of Figs. 31A - 33B in a fully assembled state;
• Fig. 56 is a simplified illustration of a SEM based sample inspection system constructed and operative in accordance with another preferred embodiment of the present invention.
• Figs. 61 A & 61B are oppositely facing simplified pictorial illustrations of the SEM compatible sample container of Figs. 58 A - 60B in a fully assembled state;
• Figs. 62A & 62B are oppositely facing simplified partially pictorial, partially sectional illustrations taken along lines LXIIA - LXIIA and LXIIB - LXIIB, respectively, in Figs. 60 A & 60B;
• Figs. 1A - 5B are oppositely facing simplified exploded view pictorial illustrations of a disassembled scanning electron microscope (SEM) compatible sample container constructed and operative in accordance with a preferred embodiment of the present invention.
• the SEM compatible sample container comprises first and second mutually threaded enclosure elements, respectively designated by reference numerals 100 and 102, arranged for enhanced ease and speed of closure.
• Enclosure elements 100 and 102 are preferably molded of plastic and coated with a conductive metal coating.
• a liquid sample enclosure defining ring 114 is adhered to electron beam permeable, fluid impermeable, membrane 110, preferably by an adhesive, such as Catalog No. NOA61, commercially available from Norland Products Inc. of Cranbury, NJ, U.S.A.
• Ring 114 is preferably formed of PMMA (polymethyl methacrylate), such as Catalog No. 692106001000, commercially available from Irpen of Barcelona, Spain, and preferably defines a liquid sample enclosure with a volume of approximately 20 microliters and a height of approximately 2 mm.
• ring 114 is configured to define a liquid sample enclosure 116 having inclined walls.
• Fig. 7D illustrates closing of the container containing the cells 140, seen in Fig. 7C, in a liquid medium 142.
• Fig. 7E shows the closed container, in the orientation of Fig. IB being inserted onto a stage 144 of a SEM 146. It is appreciated that there exist SEMs wherein the orientation of the container is opposite to that shown in Fig. 7E.
• Fig. 8B illustrates closing of the container containing the sample 160.
• Fig. 8C shows the closed container, in the orientation of Fig. IB, being inserted onto a stage 144 of a SEM 146. It is appreciated that there exist SEMs wherein the orientation of the container is opposite to that shown in Fig. 8C.
• Fig. 9 is a simplified pictorial and sectional illustration of SEM inspection of a sample using the SEM compatible sample container of Figs. 1A - 6C. As seen in Fig.
• An electron beam permeable, fluid impermeable, membrane subassembly 208 shown in detail in Figs. 12A and 12B, is seated inside enclosure element 200 against and over aperture 206, as shown in Figs. 13A & 13B and 15A & 15B.
• a sample dish comprising subassembly 208 suitably positioned in enclosure element 200 is designated by reference numeral 209, as shown in Figs. 13A-15B.
• an electron beam permeable, fluid impermeable, membrane 210 preferably a polyimide membrane, such as Catalog No. LWN00033, commercially available from Moxtek Inc.
• Grid 212 which is not shown to scale, is preferably Catalog No. BM 0090-01, commercially available from Buckbee-Mears of Cortland, N.Y., U.S.A., and the adhesive is preferably Catalog No. NOA61, commercially available from Norland Products Inc. of Cranbury, NJ, U.S.A.
• a liquid sample enclosure defining ring 214 is adhered to electron beam permeable, fluid impermeable, membrane 210, preferably by an adhesive, such as Catalog No NOA61, commercially available from Norland Products Inc. of Cranbury, NJ, U.S.A..
• Figs. 18A, 18B and 18C are simplified sectional illustrations of liquid containing samples in contact with the electron beam permeable, fluid impermeable, membrane 210, sealing and insertion into a SEM respectively using the SEM compatible sample container of Figs. 11A - 16C.
• Figs. 18A - 18C exemplify a situation wherein at least a portion of a liquid containing sample 260 is in contact with the electron beam permeable, fluid impermeable, membrane 210 but is not adhered thereto.
• liquid containing samples may include various emulsions and suspensions such as milk, cosmetic creams, paints, inks, and pharmaceuticals in liquid form.
• Fig. 18C shows the closed container, in the orientation of Fig. 11B, being inserted onto a stage 244 of a SEM 246. It is appreciated that there exist SEMs wherein the orientation of the contamer is opposite to that shown in Fig. 18C.
• microscopy multi-sample holders 650 containing sample dishes 652 are used for conveying the microscopy multi-sample holders 650 containing sample dishes 652 throughout the system, it being appreciated that manual intervention may be employed at one or more stages as appropriate.
• automated positioning systems such as robotic arms, as shown, are used for conveying the microscopy multi-sample holders 670 throughout the system, it being appreciated that manual intervention may be employed at one or more stages as appropriate.
• a sample enclosure defining ring 1114 is adhered to electron beam permeable, fluid impermeable, membrane 1110, preferably by an adhesive, such as Catalog No. NOA61, commercially available from Norland Products Inc. of Cranbury, NJ, U.S.A.
• Ring 1114 is preferably formed of PMMA (polymethyl methacrylate), such as Catalog No. 692106001000, commercially available from Irpen of Barcelona, Spain, and preferably defines a sample enclosure with a volume of approximately 20 micro liters and a height of approximately 2 mm.
• ring 1114 is configured to define a sample enclosure 1116 having inclined walls.
• a first O-ring 1118 is preferably disposed between an interior surface
• Connecting element 1122 is preferably molded of plastic and coated with a conductive metal coating.
• a second O-ring 1123 is preferably disposed between connecting element 1122 and ring 1114 of subassembly 1108. O-rings 1118 and 1123 are operative, when enclosure elements 1100 and 1102 and connecting element 1122 are in tight threaded engagement, to obviate the need for the threaded engagement of elements 1100 and 1102 and connecting element 1122 to be a sealed engagement.
• the positioner 1128 and spring 1142 are operative to move a non-liquid sample up and against electron beam permeable, fluid impermeable, membrane 1110 when enclosure elements 1100 and 1102 and connecting element 1122 are in tight threaded engagement.
• Second enclosure element 1102 is preferably formed with a generally central stub 1150, which is arranged to be seated in a suitable recess (not shown) in a specimen stage of a scanning electron microscope. It is a particular feature of the present invention that the container, shown in Figs. 31A - 40, is sized and operative with conventional stub recesses in conventional scanning electron microscopes and does not require any modification thereof whatsoever. It is appreciated that various configurations and sizes of stubs may be provided so as to fit various scanning electron microscopes.
• the electron beam permeable, fluid impermeable, membrane 1110 and support grid 1112 bow outwardly to a greater extent than in the ambient environment of Fig. 38B and further that the electron beam permeable, fluid impermeable, membrane 1110 tends to be forced into and through the interstices of grid 1112 to a greater extent than occurs in the ambient environment of Fig. 38B.
• Fig. 38D shows the closed container 1170, in the orientation of Fig. 3 IB, being inserted onto stage 1164 of SEM 1166. It is appreciated that there exist SEMs wherein the orientation of the container is opposite to that shown in Fig. 38D.
• Fig. 39 is a simplified pictorial and sectional illustration of SEM inspection of a sample using the SEM compatible sample container of Figs. 31 A - 37. As seen in Fig.
• a diaphragm 1218 is preferably integrally formed of an O-ring portion
• the positioner 1228 and spring 1242 are operative to move a non-liquid sample up and against electron beam permeable, fluid impermeable, membrane 1210 when enclosure elements 1200 and 1202 and connecting element 1222 are in tight threaded engagement.
• Cell growth platform 1274 is removably mounted onto a suitably configured positioner 1276, which corresponds to positioner 1228 in the embodiment of Figs. 41A - 47.
• the cells are grown onto cell growth platform 1274 while platform 1274 is not mounted onto positioner 1276.
• the mounting of platform 1274 onto positioner 1276 typically occurs just before SEM inspection takes place.
• Fig. 48B shows the container of Fig. 48A immediately following full threaded engagement between enclosure elements 1200 and 1202 and connecting element 1222 producing sealing of the cell sample enclosure, here designated by reference numeral 1278, from the ambient. It is noted that the sample containing cells 1272 is in close contact with the electron beam permeable, fluid impermeable, membrane 1210 due to the force exerted by the positioner 1276.
• Fig. 50 schematically illustrates some details of the electron beam interaction with the sample 1284 in container 1280 in accordance with a preferred embodiment of the present invention.
• the present invention enables high contrast imaging of features which are distinguished from each other by their average atomic number, as illustrated in Fig. 50.
• nucleoli 1290 having a relatively high average atomic number, backscatter electrons more than the surrounding nucleoplasm 1292.
• imaging of the interior of the sample to a depth of up to approximately 2 microns is achievable for electrons having an energy level of less than 50KeV, as seen in Fig. 50, wherein nucleoli 1290 disposed below electron beam permeable, fluid impermeable, membrane 1210 are imaged.
• sealing cover 1404 is provided on the underside thereof with an array of O-rings 1426, shown in Fig 51C, sealed thereto and arranged so as to sealingly engage a top rim surface of each of sample dishes 1425, when the sealing cover 1404 is in place, preferably in removable snap-fit engagement with base 1400.
• sealing cover 1454 is provided on the underside of sealing cover 1454.
• the individual diaphragms 1477 are arranged so as to sealingly engage a top rim surface of each of sample dishes 1475, when the sealing cover 1454 is in place, preferably in removable snap-fit engagement with base 1450.
• Figs. 54A and 54B are simplified illustrations of a microscopy multi-sample holder defining a plurality of SEM compatible sample containers in accordance with a preferred embodiment of the present invention.
• the microscopy multi-sample holder preferably comprises a base 1550 and a sealing cover 1554.
• the base 1550 is preferably injection molded of a plastic material and defines an array of sample containers 1556.
• Each sample container 1556 preferably includes an aperture 1558 through which SEM microscopy may take place.
• a liquid sample enclosure defining ring 2114 is adhered to electron beam permeable, fluid impermeable, membrane 2110, preferably by an adhesive, such as Catalog No. NOA61, commercially available from Norland Products Inc. of Cranbury, NJ, U.S.A.
• Ring 2114 is preferably formed of PMMA (polymethyl methacrylate), such as Catalog No. 692106001000, commercially available from Irpen of Barcelona, Spain, and preferably defines a liquid sample enclosure with a volume of approximately 20 microliters and a height of approximately 2 mm.
• ring 2114 is configured to define a liquid sample enclosure 2116 having inclined walls.
• Second enclosure element 2102 preferably is formed with a generally central stub 2122, having a throughgoing bore 2123, which stub is arranged to be seated in a suitable recess (not shown) in a specimen stage of a scanning electron microscope.
• Enclosure elements 2100 and 2102 are preferably also provided with respective radially extending positioning and retaining protrusions 2124 and 2125, to enable the container to be readily seated in a suitable multi-container holder and also to assist users in threadably opening and closing the enclosure elements 2100 and 2102.
• Figs. 63 A, 63B & 63 C are three sectional illustrations showing the operative orientation of the SEM compatible sample container of Figs. 58A - 62B at three stages of operation.
• Fig. 63 A shows the container of Figs. 58A - 62B containing a liquid sample 2130 and arranged in the orientation shown in Fig. 58B, prior to threaded closure of enclosure elements 2100 and 2102. It is noted that the liquid sample does not flow out of the liquid sample enclosure 2116 due to surface tension.
• the electron beam permeable, fluid impermeable, membrane 2110 is seen in Fig. 63 A to be generally planar.
• Fig. 63B shows the container of Fig.
• the electron beam 2172 generated by the SEM, passes through electron beam permeable, fluid impermeable, membrane 2110 and impinges on sample 2174 within container 2170.
• Backscattered electrons from sample 2174 pass through electron beam permeable, fluid impermeable, membrane 2110 and are detected by a detector 2176, forming part of the SEM.
• One or more additional detectors such as a secondary electron detector 2178, may also be provided.
• An X-ray detector (not shown) may also be provided for detecting X-ray radiation emitted by the sample 2174 due to electron beam excitation thereof.
• Fig. 67 schematically illustrates some details of the electron beam and photon interaction with the sample 2174 in container 2170 in accordance with a preferred embodiment of the present invention. It is noted that the present invention enables high contrast imaging of features which are distinguished from each other by their average atomic number or, alternatively, by their average photon yield due to excitation by electrons, as illustrated in Fig. 67. In Fig. 67 it is seen that nucleoli 2190, having a relatively high average atomic number, backscatter electrons more than the surrounding nucleoplasm 2192.
• First enclosure element 2200 preferably defines a liquid sample enclosure and has a base surface 2204 having a generally central aperture 2206.
• An electron beam permeable, fluid impermeable, membrane subassembly 2208 shown in detail in Figs. 69 A and 69B, is seated inside enclos re element 2200 against and over aperture 2206, as shown in Figs. 70A & 70B and 72A & 72B.
• a sample dish comprising subassembly 2208 suitably positioned in enclos re element 2200 is designated by reference numeral 2209, as shown in Figs. 70A-72B.
• second light guide 2286 is preferably formed in an L-shaped curve and preferably comprises a multiplicity of optic fibers disposed along the L-shaped light guide 2286 at an angle that ensures internal reflection of photons 2280 throughout the length of second light guide 2286.
• Base 2400 Adjacent to each aperture 2408 there is preferably formed a pair of mutually aligned pairs of upstanding mutually spaced protrusions 2410 arranged to receive protrusions 2424 on sample dishes 2425.
• Sample dishes 2425 may be generally identical to sample dishes 2109, shown in Figs. 60A -62B, but do not require any threading or other attachment mechanism.
• Base 2400 preferably also defines a plurality of liquid reservoirs 2412 which are adapted to hold liquid used to maintain a desired level of humidity in the interior of the microscopy multi-sample holder.
• the electron beam 3020 impinges on sample 3002 on the underside thereof, thereby inspecting a sample region lying against electron beam permeable, fluid impermeable membrane 3020.
• the electron gun assembly 3010 defines an electron gun assembly internal volume 3032. Internal volume 3032 is sealed by walls of the electron gun assembly 3010 and the container 3000 so as to maintain an evacuated environment within internal volume 3032, typically at a vacuum of 10 "2 - 10 " millibars, during SEM inspection.

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• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Analytical Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Hematology (AREA)
• Clinical Laboratory Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Analysing Materials By The Use Of Radiation (AREA)
• Sampling And Sample Adjustment (AREA)
• Investigating Or Analysing Biological Materials (AREA)

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• 2003
  • 2003-06-01 AU AU2003231893A patent/AU2003231893A1/en not_active Abandoned
  • 2003-06-01 AU AU2003228092A patent/AU2003228092A1/en not_active Abandoned
  • 2003-06-01 JP JP2004511867A patent/JP2005529341A/ja active Pending
  • 2003-06-01 WO PCT/IL2003/000457 patent/WO2003104848A2/en not_active Ceased
  • 2003-06-01 WO PCT/IL2003/000454 patent/WO2003104846A2/en not_active Ceased
  • 2003-06-01 EP EP03725574A patent/EP1509761A2/en not_active Withdrawn
  • 2003-06-01 US US10/516,411 patent/US7230242B2/en not_active Expired - Fee Related
• 2007
  • 2007-05-11 US US11/798,231 patent/US7573031B2/en not_active Expired - Fee Related

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