US20040253742A1

US20040253742A1 - Automated imaging system and method

Info

Publication number: US20040253742A1
Application number: US10/769,461
Authority: US
Inventors: Rhett Affleck; Robert Levin; John Lillig; Robert Neeper
Original assignee: Discovery Partners International Inc
Current assignee: Discovery Partners International Inc
Priority date: 2003-01-31
Filing date: 2004-01-30
Publication date: 2004-12-16
Also published as: US20040218804A1; WO2004069984A2; WO2004071067A2; WO2004070653A2; WO2004069984A3; WO2004070653A3; US20040256963A1; WO2004071067A3; US20040260782A1; WO2004069409A3; US7596251B2; WO2004069409A2

Abstract

An imaging system for automation of sample monitoring includes an image capture device that cooperates with a lens assembly for imaging the samples. A translator positions the lens assembly and/or a sample plate mount for acquisition of the images. Some embodiments of the system include a light source configured to provide low temperature, flash illumination of a sample plate.

Description

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 60/444519, titled “AUTOMATED SAMPLE ANALYSIS SYSTEM AND METHOD,” filed on Jan. 31, 2003, having attorney Docket Number DPINTL.012PR, Provisional Patent Application No. 60/444585, titled “REMOTE CONTROL OF AUTOMATED LABS,” filed on Jan. 31, 2003, having attorney Docket Number DPINTL.014PR, U.S. Provisional Patent Application No. 60/444586, titled “AUTOMATED IMAGING SYSTEM AND METHOD,” filed on Jan. 31, 2003, having attorney Docket Number DPINTL.013PR and Provisional Patent Application No. 60/474989, titled “IMAGE ANALYSIS SYSTEM AND METHOD,” filed on May 30, 2003, having attorney Docket Number DPINTL.015PR, each of which is hereby incorporated by reference for all purposes.[0001]

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention is generally related to devices and methods for capturing and analyzing images of objects in a field of view. More particularly, the invention is directed to an imaging system and related methods for automating the detection and analysis of substances in samples using imaging techniques.

2. Description of the Related Technology

X-ray crystallography is used to determine the three-dimensional structure of macromolecules, e.g., proteins, nucleic acids, etc. This technique requires the growth of crystals of the target macromolecule. Typically, crystal growth of macromolecules is dependent on several environmental conditions, e.g., temperature, pH, salt, and ionic strength. Hence, growing crystals of macromolecules requires identifying the specific environmental conditions that will promote crystallization for any given macromolecule. Moreover, it is insufficient to find conditions that result in any type of crystal growth; rather, the objective is to determine those conditions that yield well-diffracting crystals, i.e., crystal configurations that provide the resolution desired to make the data useful. This may require performance of hundreds of screening experiments, varying the different conditions, for each macromolecule. In the screening experiments, samples under investigation are periodically evaluated to determine if suitable crystallization of the sample has taken place.

Heretofore, the conventional systems and methods for performing these tasks have been mostly manual, or at best involved only limited automation of some subsystems. In some systems, monitoring of samples involves an operator performing visual inspection of the samples under a microscope. In other systems, monitoring of the samples is accomplished by photographing samples stored in micro-titer plates. The images of the samples are captured using a camera in cooperation with a microscope and a light source.

Because crystallization is highly sensitive to temperature conditions, it is very important to provide lighting without adding energy to the sample. Known systems use incandescent or fluorescent light sources that remain on for the entire imaging process. To avoid heating the sample, these systems use heat absorbing filters. However, this approach nonetheless often results in the exposure of the sample to excessive heat, as well as in the reduction of illumination to the sample. Light emitting diodes are sometimes used to limit the amount of heat transferred to the sample, but the diodes provide light only at a single wavelength and in insufficient quantity. In these situations, expensive camera systems are often used to compensate for the diminished spectrum and quantity of light. Since a large depth of field is preferable in photographing the samples, it is sometimes necessary to use a small aperture in the lens. However, this requires compensation by providing additional light, which means further undesired heating of the sample.

Consequently, there is a need in the industry for devices and methods that enhance the automation of monitoring the crystallization of substances for use in crystallographic analysis.

SUMMARY OF THE INVENTION

The inventive systems and methods disclosed here have several aspects, no single one of which is solely responsible for the desirable attributes of the systems and methods. Without limiting the scope of the invention as expressed by the claims which follow, its more prominent features will now be discussed briefly.

In general terms, the invention concerns an imaging system and related methods for automating the task of monitoring crystallization of samples for use in crystallographic analysis. The imaging system receives sample plates at a plate mount. The system moves the plate into position so that a camera can take a picture of the sample through a microscope positioned over the sample. A light source provides illumination of the sample. Control circuitry and logic of the imaging system allows automatic monitoring of each well in a sample plate. The imaging system stores and analyzes the images captured by the camera to produce the best possible image of the sample. An operator, or a software module, may then analyze the images to characterize the crystal growth in the sample in any given well of the sample plate.

In one embodiment, an automated sample analysis system for incubating and analyzing multiple samples for, e.g., protein crystallization, includes an imaging system. A temperature controlled cabinet houses sample storage, transport, and imaging systems. The system is automated and can be controlled by software, preferably running on a processor external to the cabinet that can be reconfigured remotely. The system can include an array of storage shelves having multiple shelf columns arranged around a core. Each shelf can store a multi-well plate. The core houses a sample transport system that includes a multi-axis robot that rotates about a vertical axis to access the shelves in the shelf array. The transport system retrieves and replaces the multi-well plates in the shelves and can move plates from the shelves to the imaging system where each sample can be automatically imaged.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other aspects, features, and advantages of the invention will be better understood by referring to the following detailed description, which should be read in conjunction with the accompanying drawings, in which: [0012]
FIG. 1A is a high-level block diagram of an imaging system according to the invention. [0013]
FIG. 1B is high-level block diagram of another imaging system according to the invention. [0014]
FIG. 2 is a perspective view of an imaging system according to the invention. [0015]
FIG. 3 is a perspective view of the imaging system shown in FIG. 2, viewed from a different angle. [0016]
FIG. 4 is a perspective view of the imaging system shown in FIG. 2, viewed from yet a different angle. [0017]
FIG. 5 is a plan front view of the imaging system shown in FIG. 2. [0018]
FIG. 6 is a plan, right side view of the imaging system shown in FIG. 2. [0019]
FIGS. 7A and 7B are perspective views from different angles of a lens system as can be used with the imaging system shown in FIG. 2. [0020]
FIG. 8 is a perspective view from below of a photo-filter carriage that can be used with the imaging system shown in FIG. 2. [0021]
FIG. 9 is a perspective view of certain components as assembled in the imaging system shown in FIG. 2. [0022]
FIG. 10 is a plan front view of certain components as assembled in the imaging system shown in FIG. 2. [0023]
FIG. 11 is a plan, right side view of the components shown in FIG. 10. [0024]
FIG. 12 is a perspective view of a light source as can be used with the imaging system shown in FIG. 2. [0025]
FIG. 13 is a perspective view of a sample mount with the light source shown in FIG. 12, viewed from a different angle. [0026]
FIG. 14A is a plant top view of the light source shown in FIG. 12. [0027]
FIG. 14B is a cross-sectional view along the plane A-A of the light source shown in FIG. 14A. [0028]
FIG. 15 is a exploded, perspective view of certain components of the sample mount and the light source shown in FIG. 13. [0029]
FIG. 16 is a functional block diagram of an illumination duration control circuit as can be used with the light source shown in FIG. 12. [0030]
FIG. 17 is a functional block diagram of an automated sample analysis system in which the imaging system according to the invention can be used.[0031]

DETAILED DESCRIPTION Of CERTAIN INVENTIVE EMBODIMENTS

Embodiments of the invention will now be described with reference to the accompanying figures, wherein like numerals refer to like elements throughout. The terminology used in the description presented herein is not intended to be interpreted in any limited or restrictive manner, simply because it is being utilized in conjunction with a detailed description of certain specific embodiments of the invention. Furthermore, embodiments of the invention may include several novel features, no single one of which is solely responsible for its desirable attributes or which is essential to practicing the inventions herein described. [0032]
The imaging system disclosed here is an automated assembly that positions a sample plate and obtains images of samples stored in the wells of the plate. In some embodiments, the imaging system stores the images in a digital storage device for further analysis. [0033]
FIG. 1A is a high-level block diagram of an [0034] imaging system 100. In this embodiment, the imaging system 100 has an assembly 105 that is controlled by controllers and logic 110. The assembly 105 includes a stage 115 that holds and transports target samples to be imaged by an image capture device 120. The imaging system 100 employs an optics assembly 125 to enhance the view of the target samples before the image capture device 120 obtains the images of the samples. An illuminator 130 is configured as part of the assembly 105 to direct light at the samples held in the stage 115.
The [0035] assembly 105 also includes a translator 135 that provides the structural support members and actuators to move any one combination of the stage 115, image capture device 120, optics 125, or illuminator 130. The translator 135 may be configured to move the combination of components in one, two, or three dimensions. As will be discussed in detail below, in some embodiments the stage 115 remains stationary while the translator 135 moves the image capture device 120 and optics 125 to a desired well position in a sample plate held by the stage 115. In other embodiments of the imaging system 100, the translator 135 moves the stage 115 in a first axis and the image capture device 120 and optics 125 in a second axis which is substantially perpendicular to the first axis.
The controllers and [0036] logic 110 of the imaging system 100 provide instructions to and coordinate the activities of the components of the assembly 105. The controllers may include a microprocessor, controller, microcontroller, or any other computing device. The logic includes the instructions to cause the controller to perform the tasks or processing described here.
FIG. 1B is high-level block diagram of an [0037] imaging system 150. The imaging system 150 includes an assembly 155 in communication with controllers and logic 160. The assembly 155 may also be in communication with a data storage device 190, which itself may be configured for communication with the controllers and logic 160. The controllers and logic 160 control and coordinate the activities of the components of the assembly 155.
In this embodiment, the [0038] assembly 155 includes a sample plate mount 165 suitably configured to receive micro-titer plates of various configurations and sizes. Alternatively, the sample plate mount 165 can be configured to receive any sample matrix that carries samples, regardless of whether the samples are stored in individuals sample wells, rest on the surface of the sample matrix (e.g., as droplets), or are embedded in the sample matrix. A source of flash lighting 180 is arranged to direct light bursts to the samples stored in the micro-titer plate carried by the sample plate mount 165. An inventive system and method of providing the flash lighting 180 will be discussed with reference to FIG. 16.
The [0039] assembly 155 includes a compound lens 175 that cooperates with a digital camera 170 to acquire images of the samples in the sample plate. The compound lens 175 may consist, for example, of an objective lens, a zoom lens, and additional optics chosen to provide the digital camera 170 with the desired image from the light from the samples. In one embodiment, as will be discussed further below, the compound lens 175 may be motorized (i.e., provided with one or more actuators) so that the controllers and logic 160 can automatically focus the scene, zoom on the scene, and set the aperture.
In this embodiment, the [0040] assembly 155 includes an x-y translator that moves either the sample plate mount 165 or the compound lens 175, or both. Of course, if the digital camera 170 is coupled to the compound lens 175, the x-y translator moves both the digital camera 170 and the compound lens 175. In some embodiments, the x-y translator 185 is configured to move the sample plate mount 165 in two axis, e.g., x and y coordinates. Alternatively, the x-y translator 185 moves the compound lens 175 in two axis, while the sample plate mount 165 remains stationary. In yet another embodiment, the x-y translator consists of multiple and separate actuators that move independently from one another the sample mount 165 or the compound lens 175.
It should be noted that the [0041] assembly 155, the controllers and logic 160, and the data storage 190 are depicted as separate components for schematic purposes only. That is, in some embodiments of the imaging system 150 it is advantageous to, for example, integrate the data storage device 190 into the assembly 155 and to include the controllers and logic 160 as part of one or more of the components shown as being part of the assembly 155. Similarly, the sample mount 165, digital camera 170, compound lens 175, flash lighting 180, and x-y translator 185 need not all be configured as part of a single assembly 155 as shown.
Exemplary ways of using and constructing embodiments of the [0042] imaging system 100 or 150 will be described in detail below with reference to FIGS. 2-16, which depict a specific embodiment of the imaging system. Of course, since there are multiple ways to implement the imaging system, the following description of the specific embodiment should not be taken to limit the full scope of the inventive imaging system.
Illustrative Embodiment [0043]
With reference to FIGS. 2-6 and [0044] 9-11, perspective and plan views of an imaging system 200 according to the invention are illustrated. The imaging system 200 includes a sample plate mount 210 that receives a sample plate 212. An x-translator having an actuator 218 (see FIG. 4) is coupled to the sample plate mount 210 to move the sample plate mount 210 into position above a light source 216 and below a lens assembly 230. A digital camera 214 is coupled to the lens assembly 230 to capture images of the wells in the sample plate 212. A y-translator having an actuator 220 (see FIG. 3) is coupled to the lens assembly 230 to move the lens assembly 230 into position over a desired well of the sample plate 212.
Support Platform [0045]
The [0046] digital camera 214, lens assembly 230, sample plate mount 210, light source 216, x-translator 218, and y-translator 220 are mounted on a platform 240 (see FIG. 2). The platform 240 generally consists of several structural members, brackets, or walls, e.g., base 242, side wall 244, front wall 250, bracket 252, bracket 246, post 248, and support member 254. The light source 216 can be fastened to the base 242. Rails 256 and 258, which support the lens assembly 230 are fastened to the wall 250 of the platform 240 and to the support member 254. The sample plate mount 210 is supported by a rail 262 and an outport guide 253 of the support member 254. The rail 262 is supported through attachment to the side wall 244 and the post 248. Of course, there are multiple, equivalent alternatives to providing support for and configuring the lens assembly 230, sample plate mount 210, light source 216, and x-, y- translators 218 and 220 on the platform 240.
The [0047] platform 240 may be constructed of any of several suitable materials, including but not limited to, aluminum, steel, or plastics. Because in some applications it is critical to keep vibration of the platform 240 to a minimum, materials that provide rigidity to the platform 240 are preferred in such applications. With regard to the rails 256, 258, and 262, these are preferably manufactured with very smooth surfaces to carry the lens assembly 230 or the sample plate mount 210 in a smooth fashion, thereby avoiding vibrations. As illustrated in FIGS. 3 and 9, supporting the lens assembly 230 may be done by coupling the linear plain bearings 264 and 266 to the rails 256 and 258. A similar coupling using a “bushing” 267 (see FIG. 10) may be employed to fasten the sample plate mount 210 to the rail 262. Bearings 264, 266, and 267 are chosen to provide smooth bearing surfaces for smooth translation of the load, e.g., the lens assembly 230 or the sample plate mount 210.
Sample Plate Mount [0048]
The [0049] sample plate mount 210 may be constructed from any rigid material, e.g., steel, aluminum, or plastics. Preferably the sample plate mount 210 is configured to accommodate, either directly or through the use of adapters, various standard sizes of micro-titer plates. Micro-titer plates that maybe used with the sample plate mount 210 include, but are not limited to, crystallography plates manufactured by Linbro, Douglas, Greiner, and Corning. As will be described further below, the sample plate mount 210 is coupled to an actuator 218 for moving the sample plate mount 210 in one axis.
Translators [0050]
The [0051] imaging system 200 includes two independent translators. Typically, the sample plate mount 210 and the lens assembly 230 move on a plane that is substantially parallel to a plane defined by the sample plate 212 carried by the sample plate mount 210. In one embodiment, the controllers and logic 110 or 160 can control x-, y-translators to position the sample plate mount 210 and the lens assembly 230 at the coordinates of a specific well of the sample plate 212.
An x-axis translator for moving the [0052] sample plate mount 210 consists of an actuator 218 (see FIG. 4) that rotates a threaded rod 219 (or “lead screw”) about its axis in clockwise or counter-clockwise directions. In the embodiment shown in FIGS. 3, 4, and 10, the actuator 218 is coupled to the rod 219 via a belt (not shown) and pulleys 221 and 221′. The sample plate 210 mount is fastened to a “bushing” 267 (see FIG. 10) that rides on the rail 262. The sample plate mount 210 is also supported by the outport guide 253 (see FIGS. 6 and 11) of the support member 254. The “bushing” 267 is additionally coupled in a known manner to the rod 219. When the actuator 218 turns in one direction, its power is transmitted via the belt and pulleys 221 and 221′ to the rod 219, which then moves the “bushing” 267 and, thereby, moves the sample plate mount 210 in a linear direction.
A y-axis translator for moving the [0053] lens assembly 230 consists of an actuator 220 (see FIG. 3) that rotates a threaded rod 260 about its axis in clockwise or counter-clockwise directions. In the embodiment shown in FIGS. 3, 6, and 9, for example, the actuator 220 is coupled to the rod 260 through a slotted disc coupling (not shown). The lens assembly 230 is coupled to bearings 264 and 266 that respectively ride on rails 256 and 258. The bearings 264 and 266 are coupled to the rod 260 through plate 255 and the bracket 257 (see FIG. 6) in a known manner. When the actuator 220 turns in one direction, its power is transmitted via the slotted disc coupling to the rod 260, which then moves the bearings 264 and 266 and, thereby, moves the lens assembly in a linear direction.
The [0054] actuators 218 and 220 may be direct current gear motors or 3-phase servo motors, for example. Of course, the type of motors employed as the actuators 218 or 220 will depend on, among other things, the weight of the sample plate mount 210 plus sample plate 212 or the lens assembly 230 and the digital camera 214. Another factor in determining the type of motor is the desired speed. In one embodiment, actuators 218 and 220 having a positioning precision of 10-microns are used. Suitable motors may be obtained from PITMANN of Harleysville, Pa.
In the embodiment of the x-, y-translators described above, each translator mechanism independently translates along an axis of motion each of the [0055] sample plate mount 210 and the lens assembly 230. However, it should be noted that in other embodiments of the imaging system 200, it may be desirable to maintain the lens assembly stationary and only move the sample plate mount 210, which would then have one or more translators to position the sample plate mount 210 anywhere in an x-y coordinate area. Similarly, the imaging system 200 may be configured so that an x-y translator (or set of x-, y-translators) moves the lens assembly in the x-y coordinate area, while the sample plate mount 210 remains stationary over the light source 216. In one embodiment, the x-, y-translators employ optical sensors 285 and 287 (see FIG. 5) as to sense the start or end positions (“home positions”) of the lens assembly 230 or the sample plate mount 210.
In yet another embodiment, the [0056] imaging system 200 may also include a z-axis translator (not shown) to lift or lower the sample plate mount 210, lens assembly 230, or light source 216. The z-axis translator may consist of, for example, an actuator, a lead screw, one or more rails, and appropriate bearings and fasteners.
The [0057] actuators 218 and 220 may be governed by a controller (not shown). Suitable controllers may be obtained from J R Kerr Automation Engineering of Flagstaff, Ariz. The controller may be configured to interpret high level commands from a computing device. In one embodiment, when a specific axis is addressed, the controller causes the actuator 220, for example, to move and keeps count of the travel distance and final location. The controller can be programmed to move the actuator 220 at varying speed, torque, and acceleration.
Image Capture Device [0058]
In some embodiments of the [0059] imaging system 200, the image capture device can be a film camera, a digital camera, a CMOS camera, a charge coupled device (CCD), and the like, or some other apparatus for capturing an image of an object. The embodiments of the imaging system 200 described here employ a digital camera 214. A suitable digital camera 214 is, for example, a CMOS digital camera. However, it should be apparent that several digital photography devices could also be employed. The CMOS camera 214 is preferred because it provides random access to the image data and is relatively low cost. In conventional imaging systems for crystallography, a CMOS camera is typically not used because in those systems the level of light is insufficient for this type of camera. In contrast, the imaging system 200 is configured to provide the level of light necessary to allow use of a CMOS camera.
The [0060] digital camera 214 can be a CMOS camera having a pixel resolution of 1280×1024 pixels, Bayer color filter, a pixel size of 7.5×7.5 microns, and a data interface governed by the IEEE 1394 standard (commonly known as “Firewire”). The digital camera 124 may be fully digital and not require a frame grabber. The digital camera 124 may also have a centered pixel area, e.g. a 1024×1024 or 800×600 pixel subset of the array, which enhances the image quality since the edges of the array where optical distortions increase are avoided. In one embodiment, the digital camera 214 is connected separately to a host computer (not shown) via a Firewire data interface. This allows for rapid transfer of large amounts of image data, e.g., five images per second.
Lens Assembly [0061]
One embodiment of the [0062] lens assembly 230 includes an objective lens 231, a zoom lens 233, and an adapter 235. These optical components are chosen to provide suitable field of view, magnification, and image quality. The objective lens 231, zoom lens 233, and adapter 235 may be purchased from, for example, Navitar Inc. of Rochester, N. Y.
In one embodiment, the [0063] zoom lens 233 may be the “12X UltraZoom” zoom lens manufactured by Navitar. The zoom lens 233 may provide a 12:1 zoom factor, a focus range of about 12-mm, and an aperture of about 0.14. The zoom lens 233 preferably includes adapters for mounting the objective lens 231. The zoom lens 233 may have actuators 233A, 233B, and 233C for providing, respectively, automatic aperture adjustment, autozoom, and autofocus functionality. In one embodiment, actuators 233B and 233C have gear reductions of 262:1. Of course, the gear reduction ratio is chosen to suit the particular application. For example, a 5752:1 gear ratio for the focus actuator 233C may be too slow for some applications of the imaging system 200. The actuators 233A, 233B, and 233C may be obtained from Navitar or from MicroMo Electronics, Inc. of Clearwater, Fla.
The [0064] objective lens 231 may be, for example, a 5X Mitutoyo Infinity Corrected Long Working Distance Microscope Objective (model M Plan Apo 5) microscope accessory. The objective lens 231 is coupled to the zoom lens 233. Since the light source 216 delivers sufficient light to the sample plate 212, the lens assembly 230 is configured to allow for setting a small aperture in order to increase the depth of field. The objective lens 231 preferably provides a working distance that allows adequate room beneath the lens assembly 230 to manipulate a sample plate 212 and provide a photo-filter carriage 237 in the image path. In one embodiment, the working distance of the objective lens 231 is about 34-mm.
The [0065] adapter 235 serves to allow use of the digital camera 214. The adapter 235 may be, for example, a 1X Adapter model number 1-6015 sold by Navitar. Of course, different combinations of objective lenses 231 and adapters 235 may be used, e.g., a 2X Adapter and 2X Objective combination. The combination of 1X Adapter and 5X Objective provides a suitable image for most applications of the imaging system 200. In some embodiments, it is desirable to use a 0.67X Adapter 235 with a 10X Objective 231, for example, to provide a higher image resolution.
The optical components of the [0066] lens assembly 230 can be provided with actuators for remote and automatic control. To allow software control of the optical components, controllers and control logic (not shown) can control the actuators 233A, 233B, 233C, and 233D. The actuators (e.g., dc motors) may be coupled to the aperture of the, magnification and focus of the zoom lens 233, as well as the photo-filter carriage 237. In some embodiments, the actuators 233A, 233B, 233C, and 233D are preferably provided with encoders to provide position information to the controllers. In one embodiment, the actuators on the lens assembly 230 are 17-mm direct current motors with 100:1 gear reducers. These motors may be obtained from PITMANN® of Harleysville, Pa.
The [0067] lens assembly 230 may also include a photo-filter carriage 237 that is configured to hold optical filters (not shown). For example, the photo-filter carriage 237 can hold polarization plates or color light filtering plates. FIG. 8 illustrates one embodiment of a photo-filter carriage 237 that may be used with the imaging system 200. The photo-filter carriage 237 includes a filter wheel 237A for receiving one or more photo-filters (not shown) in openings 237B. The photo-filters may be held in place in the filter wheel 237A in a variety of ways. For example, in the embodiment illustrated in FIG. 8, caps 237C in cooperation with suitable fasteners hold the photo-filters in place. The filter wheel 237A may be coupled to an actuator 233D for remote and automatic control of the filter wheel 237A. The actuator 233D and the filter wheel 237A may be fastened, in a conventional manner, to a clamp 237D that is coupled to, for example, the objective lens 231 or the zoom lens 233 (see FIGS. 1 and 9). In one embodiment, a polarization filter is coupled to a filter wheel so that the polarization filter covers about 90 degrees of the wheel. In this embodiment, the polarization filter can be rotated so that the applied polarization varies between zero and ninety degrees. Thus, the use of the polarization filter with a polarized light source can provide analysis of the effect of samples on polarized light. For example, when a polarized light source and the polarization filter are cross-polarized then minimal light should get to the objective lens 231, unless the sample re-orients the polarized light, such as can happen when the light passes through crystals.
The [0068] digital camera 214 in combination with the lens assembly 230 provides a broad depth of field to allow imaging of objects such as protein crystals at varying depths within a sample droplet stored in a sample well of a sample plate 212. In one embodiment, the lens assembly 230 has a 12:1 zoom lens and, in cooperation with the digital camera 214, can provide a 1 micron optical resolution. In some embodiments, the lens assembly 230 and the digital camera 214 may be integrated as a single assembly.
Light Source [0069]
The [0070] light source 216 will now be described with reference to FIGS. 12-15. FIG. 12 shows a perspective view of the light source 216. Since the crystallization of substances is often highly sensitive to temperature changes, the light source 216 is preferably configured to minimize the amount of heat transferred to the sample plate 212, e.g., by isolating and removing heat generated by the electronics 1408 and illuminators 1402 (see FIG. 14B).
Housing [0071]
With reference to FIGS. 12, 14B and [0072] 15, the light source 216 includes a housing 1202 adapted to store one or more illuminators 1402 (see FIGS. 14B and 15), cooling elements 1404, heat reflecting glass 1406, light diffuser plate 1206, and corresponding electronics 1405 and 1408. In one embodiment, the housing 1202 consists of a plurality of walls that serve as structural support for the internal components and that substantially isolate the internal components from the external environment. The housing 1202 can be constructed of a variety of materials including, but not limited to, stainless steel, aluminum, and hard plastics. A material with a low coefficient of heat transfer is preferred so as to substantially keep heat generated within the housing 1202 from reaching the outside through the walls of the housing 1202. However, depending on the application, use of metals is appropriate when cooling elements 1404 are provided. In some embodiments, one or more of the internal surfaces of the walls of the housing 1202 may be coated with a suitable material that absorbs or reflects various types of radiation and prevents them from reaching the outside of the housing 1202.
In the embodiment of the [0073] light source 216 shown in FIGS. 12-14B, the top wall 1204A of the housing 1202 has an opening to receive and support a light diffuser plate 1206. The plate 1206 serves to diffuse light from the illuminators 1402 onto the sample plate 212. The plate 1206 may be, for example, a sheet of translucent plastic. In one embodiment, inside the housing 1202 and adjacent and below the plate 1206, a heat reflecting glass (“hot mirror”) 1406 (see FIG. 14B) is provided. The heat reflecting glass 1406 prevents most infra-red energy from exiting the housing 1202.
The [0074] wall 1204B of the housing 1202 may be provided with a plurality of orifices 1208 that allows a cooling element 1404, such as fan, to draw air into the housing 1202 for cooling the internal components. A wall 1204C (see FIG. 14B) of the housing 1202 can be fitted with an opening 1410 for receiving a duct that guides forced air out of the housing 1202. A wall 1204D (see FIG. 13) of the housing 1202 can be fitted with a power plug 1208 communications port 1302. The housing 1202 is preferably adapted to isolate an operator of the imaging system 200 from high voltages that may be used to fire the illuminators 1402.
Of course, the [0075] housing 1202 may be configured in a variety of ways not limited to that detailed above. For example, the ventilation openings 1208 on wall 1204B may be replaced by one or more fans built into the wall 1204B or the wall 1204E. Moreover, depending on the specific location of the light source 216 in any given application of the imaging system 200, the ventilation openings 1208 may be located on the bottom wall (not shown) of the housing 1202, for example.
Illuminators [0076]
With reference to FIGS. 14B and 15, the [0077] light source 216 includes one or more illuminators 1402 that generate light rays. The illuminators 1402 may be, for example, incandescent bulbs, light emitting diodes, or fluorescent tubes of various types including, but not limited to, mercury- or neon-based fluorescent tubes. In one embodiment, the illuminators 1402 are two xenon tubes. Xenon tubes are well known in the relevant technology and are readily available. The xenon tubes 1402 can include borosilicate glass that absorbs ultra-violate radiation. Xenon tubes are preferred because they produce sufficient light to allow use of a CMOS camera 214 in the imaging system 200. Xenon tubes are also preferred since they provide a broad spectrum of light rays, which enables use of color to enhance detection of crystal growth in the wells of the sample plate 212.
The actual dimensions of the [0078] illuminators 1402 are chosen to suit the specific application. For example, in the imaging system 200 the xenon tubes 1402 are long enough to cover one dimension of the sample plate 212 so that it is not necessary to move the light source 216 when the lens assembly 230 or sample plate mount 210 are repositioned. As shown in FIG. 14B, the illuminators 1402 may be supported on a board 1405, which may also support electronics for control of the illuminators 1402.
Off-axis Lighting [0079]
In one embodiment, two [0080] illuminators 1402 are positioned to provide both on-axis and off-axis lighting of the wells in the sample plate 212. As used here, the imaging axis of the lens assembly means the principal axes of the lens assembly. For example, first and second xenon tubes 1402 can be positioned, respectively, a first and second distance from the imaging axis of the lens assembly 230. Typically, the first and second distances are substantially equal in length, and the first xenon tube is positioned opposite the imaging axis from the second xenon tube.
In one embodiment, the [0081] xenon tubes 1402 are mounted about an inch on either side of the area directly under the lens assembly 230. This configuration allows the use of an indirect lighting effect when only one xenon tube is fired. That is, when two xenon tubes are positioned off the imaging axis, the controllers and logic 110 or 160 can control the tubes to provide on-axis or off-axis illumination of the sample plate 212. One xenon tube can be fired to provide off-axis illumination of the sample plate 212. When the two xenon tubes are fired simultaneously a more conventional backlit scene is obtained. In some applications, off-axis illumination is preferred because it produces shadows on small objects in a sample droplet stored in a well of the sample plate 212. The shadows caused by off-axis lighting enhance the ability of the controllers and logic 110 or 160, or an operator, to detect objects in the sample.
In one embodiment, for example the [0082] imaging system 150 shown in FIG. 1B, the controllers and logic 160 control the assembly 155 to capture two images of a droplet in a well plate of the sample plate 212. The imaging system 150 captures one image with the light source 216 lighting the sample with a first xenon tube. The imaging system 150 captures a second image with the light source 216 lighting the sample with the second xenon tube. The controllers and logic 160 can then combine the data from both images and perform an analysis based on the combined data. This results in enhanced characterization of the sample since the combination of the images typically provides more information about crystallization of the sample than a single image acquired with standard back lighting of the scene.
Filters [0083]
In one embodiment, a source filter [0084] 270 (FIG. 2) may be inserted in a filter slot 272 so that the filter 270 is interposed between the light source 216 and the sample plate 212. The various filters 270 may be inserted and removed from the filter slot 272 by a plate handler. Thus, the filter 270 may be automatically removed, or exchanged with another filter, by the imaging system 200. The source filter 270 may be any type of filter, such as a wavelength specific filter (e.g. red, blue, yellow, etc.) or a polarization filter.
Flash Mode [0085]
In one embodiment of the [0086] imaging system 200, the light source 216 includes one or more illuminators 1402 (e.g., fluorescent tubes) adapted to provide flash lighting. That is the illuminators 1402 are controlled to illuminate only momentarily the sample plate 212 as the digital camera 214 captures an image of a well in the sample plate 212. This arrangement provides benefits over known devices in which illuminators remain in the on-position throughout the entire time that the sample plate 212 is handled by an imaging system. In the imaging system 200, since the illuminators 1402 are turned on for only a fraction of a second per image, very little heat radiation is transferred to the wells of the sample plate 212. Hence, one benefit of this configuration is that the imaging system 200 can provide high illumination levels for the camera 214 while minimizing energy or radiation transfer to the samples in the sample plate 210. An exemplary control circuit 1600 that provides controlled flash lighting is described below with reference to FIG. 16.
Flash Lighting Circuitry [0087]
FIG. 16 is a functional block diagram of an illumination duration (“flash”) [0088] control circuit 1600 for an illuminator 1402. Although only one illuminator 1402 and control circuit 1600 is shown, multiple illuminators 1402 can be used and independently controlled using additional control circuits 1600. The illuminator 1402 can be, for example, a xenon tube having a length greater than the maximum width of the sample plate 212 to be used in the imaging system 100, 150, or 200. By having such a dimension, the illuminator 1402 can be located underneath and along one axis of the sample plate 212 to illuminate all the wells in one row or column of the sample plate 212 without repositioning the illuminator 1402.
A first end of the [0089] illuminator 1402 is connected to a first capacitor 1602 and a first resistor 1604. The opposite end of the first resistor 1604 is connected to a power supply 1606. The power supply 1606 may be controlled by a dedicated RS232 line, for example. The opposite or second end of the first capacitor 1602 that is not connected to the illuminator 1402 is connected to ground or a voltage common.
The second end of the [0090] illuminator 1402 is connected to the anode of a first silicon controlled rectifier (“SCR”) 1607 and a first terminal of a second capacitor 1608, respectively. An SCR is a solid state switching device that can provide fast, variable proportional control of electric power. A resistor 1620 is connected between the first terminal of the second capacitor and the cathode of a second SCR 1610. The second terminal of the second capacitor 1608 is connected to an anode of the second SCR 1610. The cathode of the first SCR 1607 is connected to the ground or voltage common potential. The cathode of the second SCR 1610 is connected to the cathode of the first SCR 1607 and is similarly connected to ground or the voltage common potential. The anode of the second SCR 1610 is also connected to a second resistor 1614 that connects the anode of the second SCR 1610 to the power supply 1606.
A [0091] trigger 1612 of the illuminator 1402 is connected to the gate of the first SCR 1607 so that both can be triggered simultaneously. This common connection controls the trigger 1612 of the illuminator 1402 and the start of illumination. The gate of the second SCR 1610 controls a stop or end of illumination.
The duration of illumination provided by the [0092] illuminator 1402 can be controlled as follows. Initially, the first and second SCRs 1607 and 1610, respectively, are not conducting. The first capacitor 1602 is charged up to the level of the voltage of the power supply 1606 using the first resistor 1604. The power supply 1606 can, for example, charge the first capacitor to 300 volts or more.
The size of the [0093] first capacitor 1602 relates to the amount of energy that can be transferred to the illuminator 1402. The illuminator 1402 provides an illumination based in part on the amount of energy provided by the first capacitor 1602. The first capacitor 1602 can be one capacitor or a bank of capacitors. The first capacitor 1602 can be, for example, a 600 μF capacitor.
The size of the [0094] resistors 1620 and 1614 are determined in part by the desired voltage rise time on the second capacitor 1608. Smaller resistors 1620 and 1614 allow the second capacitor 1608 to charge quickly. However, the second SCR 1610 can inadvertently trigger if the voltage impulse at its anode is too great. Thus, the value of the resistors 1620 and 1614 are typically chosen to allow the second capacitor 1608 to recharge before the next image flash trigger, but not to recharge so quickly as to inadvertently trigger conduction in the second SCR 1610.
The [0095] resistor 1620 provides an electrical path from the anode of the first SCR 1607 to ground or voltage common to allow the second capacitor 1608 to charge.
The [0096] illuminator 1402 is ready to trigger once the first capacitor 1602 is charged. The second capacitor 1608 is charged by the power supply 1606 through the second resistor 1614 concurrent with the charging of the first capacitor 1602. The second capacitor 1608 is chosen to be large enough to generate a current potential that shuts off the first SCR 1607 and, thus, to terminate illumination by the illuminator 1402. The second capacitor 1608 can be a single capacitor or can be a bank of capacitors. The second capacitor 1608 can be, for example, a 20 μF capacitor.
After the first and [0097] second capacitors 1602 and 1608 have been charged, the duration of illumination can be controlled. The illuminator 1402 initially illuminates when the trigger signal is provided to the control of the illuminator 1402 and the gate of the first SCR 1607. The illuminator 1402 can include a triggering circuit that triggers the illuminator 1402 in response to a logic signal. If the illuminator 1402 does not include this circuit, an external triggering circuit can be included.
The [0098] first SCR 1607 conducts in response to the trigger signal. The first SCR 1607 then continues to conduct even in the absence of a gate signal. The first SCR 1607 can be shut off by interrupting the current through the SCR or by reducing the voltage drop across the first SCR 1607 to below the forward voltage of the device.
The [0099] second SCR 1610 is controlled by a stop signal generator 1616 to connect the second capacitor 1608 in parallel with the first SCR 1607. However, the second capacitor 1608 is charged in opposite polarity to the voltage drop across the first SCR 1607. Thus, when the second SCR 1610 initially conducts, the voltage from the second capacitor 1608 is placed in opposite polarity across the first SCR 1607 thereby shutting off the first SCR 1607.
After the [0100] first SCR 1607 is triggered by a gate signal and begins to conduct, the second end of the illuminator 1402 and the first terminal of the second capacitor 1608 are pulled to ground via the first SCR 1607. The illuminator 1402 then illuminates in response to the current flowing through the illuminator 1402. The second SCR 1610 controls turn-off of the illuminator 1402. The second SCR 1610 begins to conduct when a stop signal is applied to the gate of the second SCR 1610. This pulls the second terminal of the second capacitor 1608 to ground. Because a capacitor resists instantaneous voltage changes, the voltage across the second capacitor 1608 momentarily causes the voltage at the anode of the first SCR 1607 to be pushed below the ground or voltage common potential. A negative voltage at the anode of the first SCR 1607 results in a loss of current flowing through the first SCR 1607, which results in shut down of the first SCR 1607. The second capacitor 1608 discharges almost immediately. The illuminator 1402 shuts off when the first SCR 1607 turns off because there is no longer a current path through the illuminator 1402.
Thus, a microprocessor, controller, or microcontroller can be programmed to control the [0101] trigger 1612 and stop signal generator 1616. The processor controls the trigger signal to initiate illumination with the illuminator 1402. The processor then controls the stop signal to control termination of the illuminator 1402. The processor can thus control the trigger and stop signals to control the duration of the illumination. The processor can control the duration of the illumination (a “flash”) in predetermined intervals or can control the duration of the illumination over a range of time. For example, the processor can control the duration of the flash in microsecond steps across an interval of approximately 20 μS - 600 μS. Alternatively, the processor can control the lower range of the duration of the flash to be 0, 20, 40, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, or 550 μS. In another alternative, the processor can control the upper range of the duration of the flash to be 40, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550 or 600 μS. In one embodiment, the digital camera 214 issues the signal to turn on the illuminator 1402 so that the “flash” will be in synchronization with the electronic shutter of the digital camera 214.
The [0102] power supply 1606 can be a controllable high voltage power supply. The microprocessor, controller, or microcontroller can also control the output voltage of the power supply 1606 to further control the illumination provided by the illuminator 1402. For example, the microprocessor can control the output voltage of the power supply 1606 to vary the illumination provided by the illuminator 1402 for the same illumination duration. Thus, for a given illumination duration, the microprocessor can control the power supply 1606 to a lower output voltage to minimize the illumination. Similarly, for the same illumination duration, the microprocessor can control the power supply 1606 to a higher output voltage, thereby increasing the illumination.
The microprocessor can control the output voltage of the [0103] power supply 1606 over a range of, for example, 180-300 volts. The illuminator 1402 may not consistently illuminate for voltages below 180 volts when the illuminator 1402 is a xenon flash tube. The microprocessor can control the output voltage of the power supply 1606 using a digital control word. Thus, the microcontroller can control the output voltage of the power supply 1606 in steps determined in part by the number of bits in the control word and the tunable range of the power supply 1606. The microcontroller can, for example provide a 10-bit control word, an 8-bit control word, a 6-bit control word, a 4-bit control word, or a 2-bit control word. Alternatively, the power supply 1606 output voltage can be continuously variable over a predetermined range.
Thus, the microcontroller can control a level of illumination by controlling the illumination duration, the [0104] power supply 1606 output voltage, or a combination of the two. The microprocessor's ability to control the combination of the two permits a wider range of brightness outputs than if only one parameter were controllable. The microprocessors ability to control both illumination duration and power supply 1606 output voltage is advantageous for different lens zoom conditions. When magnification is low, such as when the lens is zoomed out, a relatively small amount of light is required. When magnification is high, a relatively large amount of light is required to capture an image. Use of filters and varying apertures may also be used to adjust the amount of light from the light source.
Operation [0105]
The [0106] imaging system 200 includes software modules that control and direct the lens assembly 230 to perform the following functions. In one embodiment, the imaging system 200 is configured to automatically control the brightness of the image. For example, after the camera 214 captures an image of a well of the sample plate 212, the software determines whether the brightness is within predetermined thresholds. If the brightness does not fall within the thresholds, the controllers and logic of the imaging system 200 iteratively adjust the illumination intensity of the illuminators 1402 to adjust the brightness of the images until the brightness falls within the thresholds. In some embodiments, the brightness of the image may be evaluated based on a predetermined region (or set of pixels) of the image captured.
The [0107] imaging system 200 can also be configured with software to automatically focus the image. An exemplary autofocus routine is as follows. Once the lens assembly 230 is positioned over a sample of the sample plate 210, the objective lens 231 is moved along its imaging axis to a predetermined starting position. The camera 214 then acquires an image of the sample and/or well at that focus position. In one embodiment, the software obtains a “focus score.” This may be done, for example, by examining the brightness values of a set of pixels (e.g., a 500×3 pixel area) in the captured image, applying a low pass filter, and computing the sum of the squares of the differences in brightness of adjacent pixels for the set of pixels. The position and focus score data points are stored in an array. The objective lens 231 is moved to the next predetermined incremental position on its imaging axis, and the process of acquiring an image, computing the focus score, and storing the position and focus score values is repeated. This process continues until the objective lens 231 has been moved to all the predetermined or desired positions, e.g., until it reaches a predetermined end position by incrementally moving in a predetermined step size from the starting position. In one embodiment, the step size depends at least in part upon a predetermined maximum number of images to be acquired during the autofocus routine.
Next, the software searches the lens position/focus score array to identify the lens position with the best focus score. In one embodiment, the software then proceeds to compute the lens positions that are midway from the best focus score position to positions adjacent to it in the array. That is, the software examines the array of positions already imaged, finds the nearest position greater than the lens position associated with the best focus score, and calculates a “midpoint” position between them. A similar process is performed with regard to the nearest lens position that is less than the best focus score position. The software then acquires images at the midpoint positions and obtains corresponding focus scores. The software once again evaluates the array to identify the image with the best focus score, using a step size that is, say, one-half of the initial step size. These tasks are repeated until, for example, a maximum number of images acquired during autofocus, or a minimum step size, has been reached. [0108]
In some embodiments, the [0109] imaging system 200 performs the processes of autofocusing and automatically adjusting the brightness, as described above, for each sample of a sample plate 212 received by the imaging system 200. After the desired brightness and focus are set, the imaging system 200 then captures an image and stores it in, for example, the data storage 190. In one embodiment, the automatically determined brightness and focus are also stored for each sample. In another embodiment, the software of the imaging system 200 calculates and stores a value associated with the mean of the brightness and focus positions for the aggregate of samples of the first plate. This value is then associated with each of the position/focus score data points in the array. Subsequent plates are examined using the mean brightness and focus as initial imaging values.
The [0110] imaging system 200 may also include additional functionality related to automatically finding the edges of a droplet in a well of a sample plate 212. In one embodiment, after the edges of the drop have been found, the imaging system 200 finds the centroid of the droplet and moves the lens assembly 230 to the centroid. The imaging system 200 then determines the magnification required to image substantially only that area corresponding to the droplet, adjusts the zoom, and acquires the image.
In another embodiment, the [0111] imaging system 200 may be configured to perform automatic adjustment of aperture. In this embodiment, the imaging system 200 receives settings for either maximum image resolution or maximum depth of field. The imaging system 200 then determines the corresponding aperture by, for example, looking at one or more tables having values correlating aperture with maximum resolution and/or maximum depth of field. Of course, magnification data may be part of these tables.
In yet another embodiment, the [0112] imaging system 200 may be configured to perform automatic zoom of a substance in a sample stored in a well of the sample plate 212. In one embodiment, for example, the imaging system identifies a “crystal-like object” in the sample, calculates its centroid, moves the lens assembly 230 and digital camera 214 to the centroid, adjusts the zoom level, and captures an image of the “crystal-like object.” In another embodiment, the imaging system 200 can be configured to capture an image of a sample or a crystal-like object, perform image analysis of the image, adjust imaging parameters (e.g., focus, aperture, zoom, illumination filtering, image filtering, brightness, etc.) and retake an image of the sample or crystal-like object. The imaging system 200 can perform this process iteratively until predetermined thresholds (e.g., contrast, edge detection, etc.) are met.
Thus, in one embodiment of the [0113] imaging system 200, the imaging system receives a sample plate 212 and for each sample performs the following functions including, automatic adjustment of brightness and aperture, autofocus, automatic detection of the sample droplet, and acquisition and storage of images. The imaging system 200 stores the aperture, brightness, focus position, drop position and/or size. The imaging system 200 may then use mean values of these factors as initial imaging settings for subsequent plates.
To increase the amount of data available for analysis of the sample, or crystal detection, in some embodiments an illumination source filter [0114] 270 (FIG. 2) may be inserted in the filter slot 272 so that the filter 270 is interposed between the light source 216 and the sample plate 212. In one embodiment the various filters 270 may be inserted and removed from the filter slot 272 by a plate handler. Thus, the filter 270 may be automatically removed or exchanged by the imaging system 200. Alternatively, or additionally, an image filter (such as those that may be placed in the photo-filter carriage 237) may be interposed between the sample droplet in the sample plate 212 and the objective lens 231. In one embodiment, the image filter includes a polarization filter that provides a variable amount of polarization on the light incident on the objective lens 231. The use of these filters can be automatically controlled by imaging software routines and/or determined by operator defined variables.
The motorized control of aperture, focus, and zoom of the [0115] lens assembly 230 in conjunction with remote control of the light source 216 (e.g., brightness and direction of illumination) allows dynamic optimization of contrast, field of view, depth of field, and resolution.
Imaging System Integrated With Automated Sample Analysis System [0116]
FIG. 17 depicts a functional block diagram of an automated [0117] sample analysis system 1700 having an imaging system 100, 150, or 200. The system 1700 includes controllers and logic 1760 for controlling various subsystems housed in a cabinet 1702. The system 1700 can further include a shelf access door 1712 for allowing access to a removable shelf system 1720 and/or a stationary shelf system 1722. In one embodiment, a removable shelf access door 1710 can be provided. The system 1700 can include a transport assembly 1730 that can consist of a plate handler 1732, an elevator assembly 1734, and a rotatable platform 1736. The system 1700 can further include an environmental control subsystem 1765 that employs a refrigeration unit 1762 and/or a heater 1764.
In one embodiment, the [0118] system 1700 also includes an imaging system 200 as has been described in above. The imaging system 200, having subcomponents 210, 214, 216, 218, 220, and 230, which are fully detailed above with reference to FIGS. 2-16, can be housed in the cabinet 1702. This arrangement ensures that the samples in the sample plates remain at all times within the confines of a controlled environment. That is, once a sample plate is stored in the cabinet 1702, it is unnecessary to expose the sample plate to the environment external to the cabinet since the system 1700 is capable of automatically (i.e., without operator intervention) carry out the imaging of the sample within the cabinet 1702.
Embodiments of an automated [0119] sample analysis system 1700 having an imaging system in accordance with the invention are described in the related United States Provisional Patent Application entitled “AUTOMATED SAMPLE ANALYSIS SYSTEM AND METHOD,” having attorney Docket Number DPINTL.012PR, which is referenced above.
While the above detailed description has shown, described, and pointed out novel features of the invention as applied to various embodiments, it will be understood that various omissions, substitutions, and changes in the form and details of the device or process illustrated may be made by those skilled in the art without departing from the spirit of the invention. The scope of the invention is indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope. [0120]

Claims

What is claimed is:

1. An automated imaging system comprising:

an imaging device configured to automatically capture an image of a sample;

a lens coupled to the imaging device; and

an automated lens translator configured to move the lens along a first axis substantially parallel to the sample.

2. The imaging system of claim 1, further comprising an automated well plate translator configured to selectively position a well plate along a second axis substantially perpendicular to the first axis.

3. The imaging system of claim 1, wherein the lens comprises a motorized aperture.

4. The imaging system of claim 1, wherein the imaging device comprises at least one of an automated focus, zoom, and filter wheel.

5. The imaging system of claim 1, further comprising a polarization filter disposed between the imaging device and the sample.

6. The imaging system of claim 1, wherein the filter wheel rotates so that the polarization filter rotates between the imaging device and the sample to provide varying polarization angles.

7. The imaging system of claim 1, the filter wheel rotates so as to provide at least 90 degrees variance of rotational angles of the filter.

8. An imaging system for obtaining images of a sample, the imaging system comprising a first illuminator placed off an imaging axis of the imaging system, whereby the illuminator illuminates the sample from below and at an angle relative to the imaging axis.

9. The imaging system of claim 8, comprising a second illuminator positioned away from the imaging axis, wherein the second illuminator is positioned substantially opposite the imaging axis from the first illuminator.

10. A method of automatically imaging at least one sample in a well plate, the method comprising:

moving the well plate along a first axis to a position x;

moving an imaging device along a second axis substantially perpendicular to the first axis to a position y; and

capturing an image of at least one sample of the well plate, wherein the sample is substantially positioned at coordinates (x,y).

11. An automated sample analysis system comprising:

a temperature controlled cabinet;

a plurality of shelves within the cabinet, each shelf configured to store a sample carrier;

a transport assembly, within the cabinet, configured to retrieve the sample carrier from one of the shelves and to transport the sample carrier to a destination; and

an imaging system configured to receive the sample carrier from the transport assembly and to image at least one sample of the sample carrier.

12. The automated sample analysis system of claim 11, wherein the transport assembly is configured to transport a source filter from a storage location to a position between a light source and the imaging system.

13. The automated sample analysis system of claim 11, wherein the source filter comprises a polarizing filter.

14. A method of imaging at least one well in a well plate, the method comprising;

storing the well plate on a shelf at a selected environment;

retrieving the well plate from the shelf using an automated well plate transport assembly;

transporting, at the selected environment, the well plate to an imaging system using the automated well plate transport assembly;

autonomously imaging, at the selected environment, at least one well in the well plate using the imaging system;

transporting the well plate from the imaging system to the shelf using the automated well plate transport assembly; and

repositioning the well plate in the shelf.

15. A method of adjusting a light intensity in an automated crystallization imaging system, the method comprising:

charging a first capacitor;

connecting the first capacitor to an illuminator to generate flash illumination; and

controlling a period of time the first capacitor is connected to the illuminator to adjust the illumination from the illuminator.

16. The method of claim 15, wherein connecting the first capacitor to the illuminator comprises activating an SCR connecting the first capacitor to the illuminator.

17. The method of claim 15, wherein controlling the period of time the first capacitor is connected to the illuminator comprises momentarily interrupting a current flow through the SCR using a second capacitor.