Patent Publication Number: US-2016246044-A1

Title: Handheld diagnostic system with chip-scale microscope and automated image capture mechanism

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a division of U.S. application Ser. No. 13/959,304, filed Aug. 5, 2013, which is incorporated by reference herein. 
    
    
     BACKGROUND 
     This relates generally to diagnostic systems and, more particularly, to handheld diagnostic systems with disposable sample holders and chip-scale microscopes. 
     Conventional diagnostic systems often require external wet chemistry (e.g., performed in a wet laboratory) and are typically only operated by trained personnel having professional expertise. Conventional diagnostic systems are also limited in their abilities to perform multiple tests simultaneously on a single sample. 
     Because of these factors, conventional diagnostic systems and microscopic imaging systems are typically non-portable, have high cost-per-test, and are unavailable or inconvenient for patients and care providers to use. 
     Moreover, microscopic imaging is traditionally limited to a very narrow depth of field that shrinks as the magnification increases. Scanning techniques are sometimes used to build a large depth of field image by combining multiple image frames at various focal lengths or to construct detailed images by stacking frames that have a focal plane at an angle to the sample surface. 
     Scanning techniques require precise control of the motion of the sample in order to accurately position the imaging frames. Typical systems achieve this level of control using step and repeat image capture and calibrated motions stages. Complex sample stage mechanisms and drive systems add significant weight, size, and cost to a system and can negatively affect its reliability and power requirements. 
     It would therefore be desirable to be able to provide improved diagnostic systems with microscopic imaging. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a diagram of an illustrative diagnostic system having a sample holder and an analysis module for capturing and analyzing magnified images of cells and other biological specimens in accordance with an embodiment of the present invention. 
         FIG. 2  is a diagram of an illustrative chip-scale microscope in accordance with an embodiment of the present invention. 
         FIG. 3  is a cross-sectional side view of an illustrative sample holder in accordance with an embodiment of the present invention. 
         FIG. 4  is a cross-sectional top view of an illustrative handheld diagnostic system having a sample holder and an analysis module with a chip-scale microscope in accordance with an embodiment of the present invention. 
         FIG. 5  is a diagram of an illustrative handheld diagnostic system that employs an automated image capture mechanism using a sensor and a series of reference markings on a sample holder in accordance with an embodiment of the present invention. 
         FIG. 6  is a diagram of an illustrative handheld diagnostic system that employs an automated image capture mechanism using a portion of an image sensor and a series of reference markings on a sample holder in accordance with an embodiment of the present invention. 
         FIG. 7  is a top view of an illustrative sample holder having a series of reference markings for triggering an automated image capture mechanism in a handheld diagnostic system of the type shown in  FIG. 5  in accordance with an embodiment of the present invention. 
         FIG. 8  is a top view of an illustrative sample holder having a series of reference markings for triggering an automated image capture mechanism in a handheld diagnostic system of the type shown in  FIG. 6  in accordance with an embodiment of the present invention. 
         FIG. 9  is a diagram of an illustrative diagnostic system having a sample holder for containing a sample, an analysis module having a chip-scale microscope for capturing magnified images of the sample, and an electronic device for obtaining sample analysis information from the analysis module in accordance with an embodiment of the present invention. 
         FIG. 10  is a flow chart of illustrative steps involved in operating a handheld diagnostic system of the type shown in  FIGS. 1-9  in accordance with an embodiment of the present invention. 
     
    
    
     DETAILED DESCRIPTION 
     Systems such as diagnostic systems may be provided with a disposable sample holder and a handheld, portable analysis module having a chip-scale microscope. The disposable sample holder may have internal flow control structures and mechanisms for moving fluids, samples, particles, reactants and/or reagents from one part of the system to another. The sample holder may have multiple test chambers for performing multiple tests simultaneously on a single sample. The sample holder may be configured to protect the sample from contamination, to protect the user from exposure to infectious agents, and to provide the ability to add reagents to the sample. The analysis module may have an opening that is configured to receive the sample holder. The chip-scale microscope may capture magnified images of the sample using the chip-scale microscope as the sample holder is inserted into the analysis module. 
     The handheld analysis module may be configured to connect with and provide sample analysis information to an electronic device such as a cellular telephone, a laptop, a tablet computer, or other portable computing device. The electronic device may display images captured by the analysis module, may perform additional image analysis, and/or may control specific functions within the analysis module. The analysis module and/or the electronic device may be configured to communicate sample analysis information from the analysis module over a communications network. 
     The chip-scale microscope may include an image sensor formed from complementary metal-oxide-semiconductor (CMOS) technology or other suitable image sensor integrated circuit technology. The chip-scale microscope may also include optics for focusing light from the sample onto the image sensor. An interchangeable illumination module in the analysis module may be used to illuminate the sample with a desired light source. 
     This type of diagnostic system may be used to analyze biological materials, bio-chemical materials, chemical materials, and/or other types of materials, and may be configured to perform spectral imaging operations such as narrow band imaging, multiple discrete band imaging, and fluorescence imaging (e.g., bio-fluorescence imaging as may be used in molecular analysis of biological samples). 
     The diagnostic system may be capable of performing medically viable diagnostics without requiring external wet chemistry or laboratory-trained personnel, may operate at low cost-per-test, and may be capable of operation in a variety of field environments (e.g., environments in which modern medical facilities are not available or are inconvenient). 
     The chip-scale microscope may be configured to capture spatially uniform imaging frames using an automated image capture mechanism. The automated image capture mechanism may be based on a sensor that detects when the next imaging frame should be captured. For example, the sample holder may include a series of uniformly spaced markings. When a user inserts the sample holder into the analysis module, the series of uniformly spaced markings may be detected by a sensor in the analysis module. Upon detecting one of the markings, a control signal may be issued to capture an imaging frame using the chip-scale microscope. This type of automated triggering ensures that the chip-scale microscope captures imaging frames at a uniform spatial distribution even when the sample is moving and even when the sample holder is inserted manually into the analysis module at variable speed. The sensor may be a photodiode that is separate from the image sensor in the chip-scale microscope or may formed from an edge of the image sensor itself in the chip-scale microscope. 
     A system of the type that may be used to image and otherwise evaluate cells and other samples such as biological specimens is shown in  FIG. 1 . As shown in  FIG. 1 , system  10  may include a sample holder such as sample holder  12  and an analysis module such as analysis module  14 . As indicated by arrow  36 , analysis module  14  may be configured to receive sample holder  12 . Analysis module  14  may be configured to image and analyze samples in different types of disposable sample holders such as sample holder  12 . 
     Sample holder  12  and analysis module  14  may be relatively small in size. For example, sample holder  12  may have a maximum lateral width of less than one inch, less than half of one inch, less than one quarter of one inch, less than four inches, or less than ten inches. Analysis module  14  may have a maximum lateral length of less than three inches, less than two inches, less than one inch, less than four inches, or less than ten inches. Sample holder  12  and analysis module  14  may each be small enough to fit in a user&#39;s hand, if desired. 
     Sample holder  12  may have a sample chamber such as sample chamber  16 , one or more reagent packs such as reagent pack  18 , flow control components such as flow control components  20 , and one or more test chambers such as test chambers  22 . 
     Sample chamber  16  may be configured to receive a sample from a user of system  10 . For example, a user may place a swab on which a sample has been collected into sample chamber  16 , or a user may place a sample on its own (e.g., a blood sample that has been collected with a lancet) into sample chamber  16 . The sample may be a biological sample including cells or other biological elements. If desired, system  10  may be used to analyze and capture high-magnification images of other types of samples (e.g., other biological specimen or other particles or materials). Arrangements in which system  10  is used to image cells are sometimes described herein as an example. 
     In some situations, it may be desirable to mix the sample with a reagent. Examples of reagents that may be introduced to the sample and allowed to interact with the sample include diluents (e.g., fluids such as ionic fluids), dyes (e.g., fluorescent dyes), or other chemical compounds, biological agents such as antigens, antibodies (e.g., antibodies with dye), phosphors, electrolytes, analyte-specific antibodies, etc. Reagent pack  18  may be used to contain reagents until they are introduced to the sample in sample chamber  16 . If desired, there may be one, two, or more than two reagent packs within a single sample holder. 
     Flow control components  20  may be used to control the flow of a sample within sample holder  12  without requiring electrical power. Flow control components  20  may, for example, include one or more compartments of chemicals configured to react with each other and produce gas which then forces the sample through a channel in the sample holder and distributes portions of the sample into respective test chambers  22  in sample holder  12 . For example, flow control components  20  may include a pack or compartment of acetic acid (vinegar) and a pack or compartment of sodium bicarbonate (baking soda). When combined, the sodium bicarbonate and acetic acid may produce carbon dioxide gas which then pushes the sample through the channel in a smooth, continuous, and predictable manner. This type of configuration is advantageous in that it does not require electrical power and also avoids the abrupt jerking of the sample which occurs when a pump is used to control the flow of a sample. However, if desired, other types of flow control structures such as one or more pumps may be used to move the sample from one location in sample holder  12  to another location in sample holder  12 . 
     Test chambers  22  may each be configured to receive a portion of the sample from sample chamber  16 . Each test chamber  22  may, for example, contain a different marker such as marker  98  configured to tag a specific chain of DNA, RNA, or protein. For example, markers  98  in test chambers  22  may be configured to locate and mark specific nucleic acids or proteins (e.g., nucleic acids or proteins associated with a bacterium, virus, poison, fungus, parasite, etc.) in the sample with specific colors (e.g., using stains, dyes, and/or fluorescent tagging). Each marker  98  in each test chamber  22  may be used to identify a different bacteria, virus, poison, fungus, or parasite in a single sample, thereby providing system  10  with the ability to perform multiple tests on a single sample simultaneously. There may be one, two, three, four, five, six, or more than six test chambers  22  within sample holder  12 . Illustrative examples of substances or structures that may be identified using system  10  include  S. aureus,  Coagulase-negative staphylococci (CNS),  E. faecalis, E. faecium  and other Enterococci,  E. coli, K. pneumoniae, P. aeruginosa, C. albicans, C. parapsilosis, C. tropicalis, C. glabrata, C. krusei, Listeria,  foot-and-mouth disease virus, Methicillin-resistant  Staphylococcus aureus  (MRSA), and malaria parasites such as  P. falciparum  and other malaria parasites. 
     In one suitable embodiment, markers  98  may be configured to tag structures within the sample using a process referred to as immunolabeling. In this type of configuration, markers  98  may include tagged conjugate antibodies that are configured to attach themselves to locations where the corresponding target antigen is found. The conjugate antibodies may be tagged with a fluorescent compound, gold beads, an epitope tag, or an enzyme that produces a colored compound. 
     In another suitable embodiment, markers  98  may be configured to attach fluorophores to olignoucleotides complementary to the target RNA molecules (as an example). 
     Reagents and markers in sample holder  12  can be stored in active or in freeze-dried form. Substances stored in freeze-dried form may be activated with the addition of water and/or other reagents. 
     Sample holder  12  allows the chemistry required for sample processing and the sample itself to be sealed and safely contained once acquired and allows for the processing to be automated within a low-cost structure. If desired, sample holder  12  may be disposed with the sample when the sample analysis is complete or may be used to keep the sample in a safe, contained enclosure until further analysis can be performed in a fully-equipped laboratory. The chemistry, sample processing, and internal structure of a given sample holder may be customized depending on the type of test(s) or analysis being performed. Sample holders  12  may be provided with a common external mechanical structure so that analysis modules  14  are compatible with many different types of sample holders  12 , each of which is designed for performing a specific set of tests. Sample holder  12  may be produced inexpensively in high volume and may be disposed of after a single use (if desired). 
     Analysis module  14  may include chip-scale microscope  24 , illumination module  26 , sample holder receiving structures  28 , storage and processing circuitry  30 , input-output components  32 , and output ports  34 . 
     Chip-scale microscope  24  may include an image sensor for imaging samples within sample holder  12  and optics such as one or more lenses and/or mirrors for focusing light from the sample onto the image sensor. 
     Illumination module  26  may include one or more light sources (e.g., one or more light-emitting diodes, arc lamps, lasers, or other suitable type of light source) for illuminating the sample in sample holder  12 . Illumination module  26  may also include one or more optical structures such as mirrors, gratings, and/or condenser lenses for focusing light from the light source onto the sample. 
     Analysis module  14  may include a housing having sample holding receiving structures  28  for receiving sample holder  12 . Sample holder receiving structures  28  may include an opening into which sample holder  12  is inserted. The opening may be provided with guide rails or other alignment structures to facilitate insertion of sample holder  12  into analysis module  14 . If desired, sample holder receiving structures  28  may include structures for controlling the rate of insertion of sample holder  12  into analysis module  14 . For example, the opening into which sample holder  12  is inserted may include a pattern of gears or other structures configured to mate with a corresponding pattern of gears on an external surface of sample holder  12 . Such structures may be used to ensure that the rate at which sample holder  12  is guided into analysis module  14  is kept constant or within a given range (if desired). Chip-sale microscope  24  may capture images of the sample as sample holder  12  is being inserted into analysis module  14 . 
     Storage and processing circuitry  30  may include volatile memory (e.g., static or dynamic random-access memory), non-volatile memory (e.g., flash memory), microprocessors, integrated circuits, printed circuit boards, or other circuitry. Storage and processing circuitry  30  may be used for storing, processing, and analyzing image data captured using chip-scale microscope  24 , and/or for operating components such as illumination module  26  and input-output components  32 . 
     Storage and processing circuitry  30  may include communications circuitry such as circuitry coupled to output ports  34 . Storage and processing circuitry  30  may include wireless communications circuitry for conveying data such as image data, sample analysis information, diagnosis information, etc. to external equipment such as a computer, a handheld electronic device, a cellular telephone, a network router, a network antenna, etc. For example, wireless communications circuitry associated with circuitry  30  may be configured to transmit and/or receive data at WiFi® frequencies (e.g., 2.4 GHz and 5 GHz), Bluetooth® frequencies (e.g., 2.4 GHz), cellular telephone frequencies (e.g., 85-MHz, 900 MHz, 1800 MHz, 1900 MHz, and 2100 MHz), or other frequencies. 
     Output ports  34  may include one or more universal serial bus (USB) ports, serial ports, audio ports, video ports, etc. coupled to storage and processing circuitry  30 . 
     Data that may be transmitted using ports  34  or wireless communications circuitry associated with circuitry  30  may include identification data associated with a particular analysis module, identification data associated with a particular sample holder, identification data associated with a sample, geographic location data associated with the location of the analysis module, sample analysis information resulting from analysis of a sample within sample holder  12 , raw and/or processed imaging data obtained using chip-scale microscope  24 , and/or other information. Sample analysis information may, for example, include a medical diagnosis or an identification of which substances or structures were found to be present or absent in the sample. 
     Illustrative examples of procedures that may be performed using system  10  include whole blood cell analysis, cell counting, Complete Blood Count (CBC), nucleic acid amplification, PNA-FISH® bacterial testing, antigen and antibody infectious disease detection, and other tests. Because system  10  is handheld and portable, such tests may be performed in locations where laboratory facilities are unavailable or inconvenient for a user. 
     System  10  may provide a user with the ability to interact with analysis module  14 . User interactions may include inputting identification information (e.g., information identifying a sample, a sample donor, a geographic location, etc.) and obtaining output information (e.g., reading the result of an analysis performed using chip-scale microscope  24 ). To implement these interactions, analysis module  14  may have input-output components  32  such as keypads, virtual keypads, buttons, displays, or other suitable input-output components. Input-output components  32  may include circuitry coupled to one or more output ports such as output port  34  mounted in a housing structure. 
     An illustrative configuration for chip-scale microscope  24  is shown in  FIG. 2 . As shown in  FIG. 2 , chip-scale microscope  24  may include optics such as optics  38  and an image sensor (sometimes referred to as an imager) such as image sensor  40 . Image sensor  40  may include an array of image pixels such as pixel array  42  and image sensor circuitry such as image sensor circuitry  44 . Image sensor circuitry  44  may include row control circuitry, column readout circuitry, analog-to-digital conversion circuitry, and other circuitry associated with capturing raw data using image pixel array  42  of image sensor  40 . Circuitry  30  of  FIG. 1  may, for example, be used to control imaging functions performed using chip-scale microscope  24 . 
     Optics  38  (sometimes referred to as microscope objective  38 ) may include optical elements for gathering light from the sample in sample holder  12  and focusing the light onto pixel array  42  of image sensor  40 . Optics  38  may include one or more objective lenses, one or more mirrors, one or more layers of glass, and/or other optical structures for focusing light from the sample onto image sensor  40 . Optics  38  may, for example, be interposed between the sample (when sample holder  12  is inserted into analysis module  14 ) and image sensor  40 . Optics  38  may be characterized by a magnification of 1000×, 400×, 200×, or other suitable magnification; may be characterized by a numerical aperture of less than 0.5, less than 1.0, less than 1.5, or greater than 1.5; and may be characterized by a working distance of 5 mm, greater than 5 mm, less than 5 mm, less than 10 mm, or greater than 10 mm. Chip-scale microscope  24  may be configured to achieve a depth of field of about 125 microns, about 130 microns, about 120 microns, about 100 microns, less than 100 microns, greater than 100 microns, or greater than 120 microns. 
     Microscope objective  38  may, if desired, operate with an air medium, thereby eliminating the need for an immersion liquid between the front lens element and the sample. Chip-scale microscope  24  may be equipped to obtain volumetric data using the automatic focus functionality of image sensor  40  without requiring an automated stage. 
     A cross-sectional top view of sample holder  12  is shown in  FIG. 3 . As shown in  FIG. 3 , sample holder  12  may include a first portion such as sample-receiving portion  62 , and a second portion such as sample imaging portion  64 . 
     Sample-receiving portion  62  may include reagent pack  18 , flow control components  20 , and sample chamber  16 . As described in connection with  FIG. 1 , reagent pack  18  may be used to contain reagents until they are introduced to the sample in sample chamber  16 . Initially, reagent pack  18  may be sealed from sample chamber  16 . Upon breaking the seal, reagents in reagent pack  18  may be allowed to interact with a sample such as sample  80  in sample chamber  16  via path  66 . 
     Flow control components  20  may provide a sample distribution mechanism for distributing portions of sample  80  in sample chamber  16  to respective test chambers  22 . Flow control components  20  may be implemented as a gas generating component having two adjacent chambers  48  and  50 . Chamber  48  may contain a first reactant such as liquid reactant  48 A (e.g., acetic acid). Chamber  50  may contain a second reactant such as solid or powder reactant  50 A (e.g., sodium bicarbonate). First and second reactants  48 A and  50 A may be selected to be stable chemicals (e.g., acetic acid (vinegar) and sodium bicarbonate (baking soda), respectively) that generate a gas such as carbon dioxide when mixed. 
     Chambers  48  and  50  may initially be separated by structural member  70  (e.g., a plastic seal). When seal  70  is punctured or otherwise broken, chemical reactants  48 A and  50 A may be allowed to interact and a chemical reaction may occur, leading to the release of a significant volume of gas (e.g., carbon dioxide). The gas produced may provide pressure to chamber  16  via path  68 , which may in turn move sample  80  in sample chamber  16  through channel  52  in direction  82 . Portions of sample  80  may be distributed to respective test chambers  22  in sample imaging portion  64 . If desired, a particle filter such as particle filter  54  may be configured to filter sample  80  to prevent certain substances or structures from passing through channel  52  to sample imaging portion  64 . 
     Each test chamber  22  may be coupled to vent line  56 . Vent line  56  may allow air to escape via exit port  58  and may be used in regulating the flow of air and the movement of sample  80 , if desired. 
     If desired, other sample distribution mechanisms may be employed to distribute sample  80  in sample chamber  16  to test chambers  22 . The use of sodium bicarbonate and acetic acid is merely. 
     Sample-receiving portion  62  may have a clamshell shape with first and second portions  62 A and  62 B connected by a bendable joint such as bendable joint  60 . With this type of configuration, sample-receiving portion  62  of sample holder  12  may be configurable in open and closed positions. In the open configuration (as shown in  FIG. 3 ), compartments within sample-receiving portion  62  may be sealed. For example, reagent pack  18  may be sealed and compartments  48  and  50  may be sealed and separated from each other. While sample-receiving portion  62  is open, a user may place a sample into sample chamber  16  and may then close sample-receiving portion  62  by bending sample-receiving portion  62  at bendable portion  60 . Upon closing sample-receiving portion  62 , a protrusion such as protrusion  46  (e.g., a structure having one or more sharp edges) within portion  62  may puncture reagent pack  18  and seal  70 , thereby allowing reagents in reagent pack  18  to interact with the sample in sample chamber  16  while also allowing reactants  48 A and  50 A in compartments  48  and  50  to interact with each other. Sample  80  is mixed with reagents in reagent pack  18  and is moved through channel  52  to test chambers  22 . With this type of configuration, the appropriate chemistry and sample processing may automatically occur within sample holder  12  by merely closing sample-receiving portion  62  after placing sample  80  in sample chamber  16 . 
     If desired, sample chamber  16  may include a permeable or semi-permeable cover such as a neoprene membrane through which a needle may be inserted (as an example). 
     As described in connection with  FIG. 1 , each test chamber  22  in sample holder  12  may contain a different marker for tagging a specific substance (e.g., via staining, dying, fluorescent tagging, etc.). As an example, one test chamber  22  may contain a marker for tagging foot-and-mouth disease virus, while another test chamber  22  may contain a marker for tagging Methicillin-resistant Staphylococcus aureus (MRSA). Because the sample is automatically distributed to chambers  22  by closing sample-receiving portion  62 , the sample may automatically be tagged by different markers in chambers  22 , without requiring external wet chemistry or laboratory-trained personnel. Moreover, by simultaneously tagging different portions of a single sample in sample holder  12  with different markers, different types of tests (e.g., tests for different types of bacteria, viruses, fungi, parasites, etc.) may be performed simultaneously on a single sample. 
     Sample holder  12  may be formed from plastic, glass, metal, carbon fiber and/or other fiber composites, ceramic, glass, wood, other materials, or combinations of any two or more of these materials. Sample imaging portion  64  may be designed for microscopic imaging (e.g., may be partially or fully transparent so that sample  80  in test chambers  22  may be illuminated for microscopic imaging). 
       FIG. 4  is a cross-sectional top view of system  10  in which sample holder  12  has been inserted into analysis module  14 . As shown in  FIG. 4 , analysis module  14  may include a housing such as housing  84  having an opening such as opening  86 . Opening  86  may have a shape that corresponds to the shape of sample imaging portion  64  of sample holder  12  so that sample imaging portion  64  of sample holder  12  may be inserted into analysis module  14 . Sample holder  12  may be engaged with analysis module  14  by inserting sample imaging portion  64  of sample holder  12  into opening  86  in direction  88 . 
     As shown in  FIG. 4 , output port  34  may be implemented as a USB connector for coupling module  14  to external equipment such as a computer, cell phone, laptop computer, tablet computer, etc. In addition to providing a means for communicating sample analysis information and/or sample imaging data from analysis module  14  to external electronic devices, output port  34  may also be configured to provide power to components within analysis module  14 . For example, port  34  may include a power supply for providing power to illumination module  26 , image sensor  40 , and storage and processing circuitry  30 . This is, however, merely illustrative. If desired, electrical components in analysis module  14  may receive power from an external power source. 
     Storage and processing circuitry  30  may be implemented using a printed circuit substrate such as printed circuit substrate  76 , integrated circuits or other electrical components such as electrical components  78 , and/or other circuitry in analysis module  14 . Image sensor  40  may he coupled to printed circuit board  76  using an array of solder balls (e.g., a ball grid array) or may be coupled to printed circuit board  76  using other mounting techniques. Printed circuit board  76  may include metal traces  90  for electrically coupling image sensor  40  to other circuitry such as integrated circuit  78 . 
     Lighting components  26  may be mounted in analysis module  14  so that light from lighting sources  74  passes through test chambers  22  of sample holder  12  during sample analysis operations. As described in connection with  FIG. 1 , illumination module  26  may include one or more light sources such as light sources  74  (e.g., one or more light-emitting diodes, arc lamps, lasers, or other suitable type of light source) for illuminating sample  80  in sample holder  12 . Light sources  74  may be white light sources or may be configured to emit different colors of light. For example, light source  74  may be white light sources that are provided with different colored filters. 
     Illumination module  26  may include one or more optical structures such as lenses  92 L mirror  92 M for focusing light  94  from light source  74  onto sample  80 . In response to control signals from control circuitry  30 , light sources  74  may produce light  94  of a desired color and intensity. Light  94  may be directed through sample holder  12  (when sample holder  12  is inserted into analysis module  14 ) towards image sensor  40 . 
     Illumination module  26  may be interchangeable so that different types of microscopy may be performed. For example, a first illumination module may be used to perform fluorescence microscopy using chip-scale microscope  24 , and a second illumination module may be used to perform bright field microscopy using chip-scale microscope  24 . When it is desired to change the type of microscopy being performed, the first illumination module may be removed from analysis module  14  and the second illumination module may be installed in its place (or vice versa). 
     Light  94  may pass through sample  80  and may be focused onto image sensor  40  using optics  38 . As described in connection with  FIG. 2 , optics  38  may include one or more objective lenses, one or more mirrors, one or more layers of glass, and/or other optical structures for focusing light from sample  80  onto image sensor  40 . If desired, one or more optical filters such as optical filter  96  may be interposed between optics  38  and image sensor  40 . Like illumination module  26 , optical filters in analysis module  14  such as optical filter  96  may be interchangeable so that different types of microscopy may be performed. Illustrative types of filters that may be used in analysis module  14  include longpass filters, colored and/or neutral density filters, absorptive filters, interference filters, dichroic filters, polarization filters, other suitable types of filters, or a combination of any two or more of these types of filters. 
     After a user injects or otherwise places a sample into test chamber  16  ( FIG. 3 ) and closes sample-receiving portion  62 , flow control components  20  may automatically be activated to distribute portions of sample  80  into respective test chambers  22  (as shown in  FIG. 4 ). The user may then insert sample holder  12  into analysis module  14  by sliding sample imaging portion  64  of sample holder  12  into opening  86  of analysis module  14  in direction  88 . As sample imaging portion  64  of sample holder  12  moves in direction  88  within cavity  86 , each test chamber  22  may pass through light  94  and over image sensor  40 . In the configuration shown in  FIG. 4 , for example, sample  80  in the rightmost chamber  22  will be the first to pass through light  94  over image sensor  40  and will therefore be the first specimen to be imaged with image sensor  40 . As the user continues to push sample holder  12  into analysis module  14 , sample  80  in the second chamber  22  from the right will pass through light  94  over image sensor  40  and will therefore be the second specimen to be imaged with image sensor  40 . In this way, light  94  may successively illuminate sample  80  in each test chamber  22 , and images may be successively captured of sample  80  in each chamber  22  as each chamber  22  is moved across the field of view of chip-scale microscope  24 . Analysis module  14  may include circuitry for automatically triggering each image capture operation as test chambers  22  move across image sensor  40 . 
     Sample imaging portion  64  of sample holder  12  may have uniformly spaced reference markings distributed along the length of sample imaging portion  64  (i.e., along the portion of sample holder  12  that is inserted into analysis module  14 ). Reference markings in sample holder  12  may be detected by a sensor in analysis module  14  and may be configured to trigger an automated image capture mechanism whereby chip-scale microscope  24  captures imaging frames at a uniform spatial distribution.  FIG. 5  is a diagram of a portion of system  10  showing how system  10  may include a sensor for detecting reference markings on sample holder  12  for automatically triggering image capture operations as sample holder  12  is inserted into analysis module  14 . 
     As shown in  FIG. 5 , sample holder  12  may have reference markings such as reference markings  122 . There may be five, ten, fifteen, twenty, more than twenty, or less than twenty reference markings  122  on sample holder  12 . Reference markings  122  may be separated from each other by a distance D. Analysis module  14  may include a sensor such as sensor  126  and a light source such as light source  124 . Light source  124  (e.g., a light-emitting diode light source or other type of light source) may, for example, be foam ed as part of illumination module  26  or may be separate from illumination module  26 . Sensor  126  and light source  124  may be aligned such that sensor  126  is configured to receive light  128  emitted by light source  124 . Sensor  126  may include one or more photodiodes or other suitable type of light sensor. 
     Sensor  126  may be coupled to a trigger generator such as trigger generator  130  and control circuitry such as control circuitry  132 . Control circuitry  132  and trigger generator  130  may, for example, form part of storage and processing circuitry  30  ( FIG. 4 ). Control circuitry  132  may be coupled to image sensor  40  and may be configured to issue control signals to image sensor  40  based on signals received from sensor  126  via trigger generator  130 . 
     As a user inserts sample holder  12  into analysis module  14  (e.g., in direction  88 ), sensor  126  may be configured to detect when reference markings  122  pass through light  128 . Upon detecting one of reference markings  122 , trigger generator  130  may generate a trigger signal for control circuitry  132 , which may in turn issue control signals to image sensor  40  to capture an imaging frame. Thus, each time a reference marking  122  in sample holder  12  passes over sensor  126  in analysis module  14 , image sensor  40  may capture an image of sample  80  in sample holder  12 . This automated image capture mechanism ensures that imaging frames are captured at a uniform spatial distribution even when the sample is moving and even when the sample holder is inserted manually into the analysis module at variable speeds. 
     The distance D between reference markings  122  may be any suitable distance (e.g., 1 mm, 2 mm, 3 mm, 5 mm, less than 5 mm, or more than 5 mm). If desired, multiple imaging frames may be captured of each portion of sample  80  in each respective test chamber  22 . Capturing multiple imaging frames of sample  80  at uniform spatial distribution may allow processing circuitry (e.g., processing circuitry  30 ) to build a large depth of field image of sample  80  by combining multiple imaging frames at different focal lengths; to construct a detailed image of sample  80  by stacking frames that have a focal plane at an angle to the sample surface, thereby providing a focal region that is larger than a single frame focal region; and to build images of large samples by stitching together multiple imaging frames that have a uniform spatial distribution. 
     Sensor  126  need not be separate from image sensor  40 . If desired, a portion of pixel array  42  ( FIG. 2 ) of image sensor  40  may be used to detect reference markings  122 . A diagram illustrating how sensor  126  may be formed from a portion of image sensor  40  is shown in  FIG. 6 . As shown in  FIG. 6 , sensor  126  may be located on an edge of image sensor  40  and may be formed from a portion of pixel array  42  (e.g., one or more rows or columns of pixels in pixel array  42 , one or more individual pixels or groups of pixels in pixel array  42 , etc.). 
     Sensor  126  may be configured to detect when reference markings  122  pass through light  94  emitted by illumination module  26 . Upon detecting one of reference markings  122 , trigger generator  130  may generate a trigger signal for control circuitry  132 , which may in turn issue control signals to image sensor  40  to capture an imaging frame. Thus, each time a reference marking  122  in sample holder  12  passes over sensor  126  at the edge of image sensor  40  in analysis module  14 , image sensor  40  may capture an image of sample  80  in sample holder  12 . This automated image capture mechanism ensures that imaging frames are captured at a uniform spatial distribution even when the sample is moving and even when the sample holder is inserted manually into the analysis module at variable speeds. 
     A top view of the arrangement of  FIG. 5  is shown in  FIG. 7 . As shown in  FIG. 7 , reference markings  122  may pass through field of view  126 ′ of sensor  126  as sample holder  12  is moved in direction  88 . In response to one of tick marks  122 T of reference markings  122  passing through field of view  126 ′, control circuitry  132  may issue a control signal to image sensor  40  to capture an imaging frame. Region  40 ′ indicates the field of view of image sensor  40  during an image capture. As a user inserts sample holder  12  into analysis module  14 , tick marks  122 T will each successively pass over sensor  126 , and chip-scale microscope  24  will capture a corresponding series of imaging frames as test chambers  22  move across imaging frame region  40 ′ from edge  134  to edge  136 . 
     The rightmost edge of each imaging frame region  40 ′ may be separated from the rightmost edge of the adjacent imaging frame region by a distance D (i.e., a distance corresponding to the separation between tick marks  122 T). If desired, tick marks  122 T may be spaced such that a region of overlap exists between adjacent imaging frames so that the images can be integrated as tiles to generate a larger field of view than chip-scale microscope  24  can achieve in a single imaging frame. 
     A top view of the arrangement of  FIG. 6  is shown in  FIG. 8 . In this type of configuration, sensor  126  is formed from a portion of pixel array  42  ( FIG. 2 ). In other words, a first portion of pixel array  42  is used to detect reference markings  122 , while a second portion of pixel array  42  is used to capture images of sample  80  in sample holder  12 . Region  126 ′ indicates the field of view of sensor  126  at the edge of image sensor  40  and region  40 ′ indicates the field of view of the portion of image sensor  40 ′ that is used to capture images of sample  80 . As shown in  FIG. 8 , reference markings  122  may pass through field of view  126 ′ of sensor  126  as sample holder  12  is moved in direction  88 . In response to one of tick marks  122 T of reference markings  122  passing through field of view  126 ′, control circuitry  132  may issue a control signal to image sensor  40  to capture an imaging frame. As a user inserts sample holder  12  into analysis module  14 , tick marks  122 T will each successively pass over sensor  126 , and chip-scale microscope  24  will capture a corresponding series of imaging frames as test chambers  22  move across imaging frame region  40 ′ from edge  134  to edge  136 . 
     The rightmost edge of each imaging frame region  40 ′ may be separated from the rightmost edge of the adjacent imaging frame region by a distance D (i.e., a distance corresponding to the separation between tick marks  122 T). If desired, tick marks  122 T may be spaced such that a region of overlap exists between adjacent imaging frames so that the images can be integrated as tiles to generate a larger field of view than chip-scale microscope  24  can achieve in a single imaging frame. 
     In the illustrative examples of  FIGS. 7 and 8 , tick marks  122 T are formed along a line that is parallel to the length of sample imaging portion  64  of sample holder  12  (i.e., along the x-axis as shown in  FIG. 7 ). This arrangement is merely illustrative. If desired, tick marks  122 T may be formed along multiple axes such as both the x-axis and y-axis. Using a multiple-axes tracking system may be used to compensate for sample motion in multiple directions. Motion along each axis may be sensed independently by sensor  126  by using a unique color for each axial marking or by using other suitable identifying characteristic. 
       FIG. 9  is a diagram showing how a handheld diagnostic system such as system  10  may be configured to communicate with computing equipment such as computing equipment  102 . Computing equipment  102  may be a portable electronic device (e.g., a mobile phone, a personal digital assistant, a laptop computer, a tablet computer, or other computing equipment). Computing equipment  102  may include a display such as display  104  for presenting visual information to a user based on data received from system  10 . For example, display  104  may be used in displaying images of samples acquired by system  10  (sometimes referred to as sample image data) and/or may be used in displaying sample analysis information (e.g., may present a list of bacteria, viruses, poisons, fungi, or parasites which were found present in the sample). 
     Computing equipment  102  may have a user input interface for gathering input from a user and for supplying output to a user. The user input interface may include user input devices such as keyboard, keypads, mice, trackballs, track pads, etc. If desired, display  104  may be touch-sensitive (i.e., display  104  may be a touch screen) and may be used to gather user input from a user. Computing equipment  102  may also include equipment for supplying output such as speakers for providing audio output, status indicator lights for providing visible output, etc. 
     Computing equipment  102  may include a data port such as data port  110 . Data port  110  may be connected to analysis module  14  using a cable such as cable  112 . On one end, cable  112  may have a connector such as connector  114  configured to mate with output port  34  of analysis module  14  ( FIG. 4 ). On an opposing end, cable  112  may have a connector such as connector  116  configured to mate with data port  110  of computing equipment  102 . Sample image data and/or sample analysis information may be conveyed from analysis module  14  to computing equipment  102  via cable  112 . This is, however, merely illustrative. If desired, information may be conveyed from sample analysis module  14  to computing equipment  102  over a wireless network. As another example, data port  110  may be a Universal Serial Bus (USB) port and may be configured to receive output port  34  of analysis module  14  directly (without requiring cable  112 ). 
     Computing equipment  102  may be used to analyze sample image data and/or sample analysis information (e.g., to produce images of the sample from raw image data, to produce enhanced images of the sample, to analyze images of the sample to produce sample evaluation information or diagnosis information, etc.). Computing equipment  102  may, if desired, transmit data from system  10  to computing and data processing equipment  118  via communications network  106 . Communications network  106  may include wired and wireless local area networks and wide area networks (e.g., the internet). 
     Computing equipment  102  may be connected to network  106  using a link such as link  108  (e.g., a wired link that uses a modem or wireless link such as a local wireless link), and computing and data processing equipment  118  may be connected to network 106  using a link such as link  120  (e.g., a wired link that uses a modem or wireless link such as a local wireless link). Computing and data processing equipment  118  may be a remote mainframe computer, may be a cloud computing network (i.e., a network of computers on which software can be run from computing equipment  102 ) or other computing equipment. If desired, computing and data processing equipment  118  may be used to perform advanced analysis on sample image data and/or sample analysis information from system  10  (e.g., advanced analysis that requires more computing power than computing equipment  102  is capable of). 
       FIG. 10  is a flow chart of illustrative steps involved in using a system such as system  10  of  FIGS. 1-9  in acquiring images of cells or other samples. 
     At step  202 , a sample may be injected into a sample chamber in a sample holder such as sample chamber  16  in sample holder  12 . 
     At step  204 , the sample holder may be closed to automatically activate the sample distribution mechanism and thereby distribute portions of the sample from the sample chamber to respective test chambers in the sample holder. The sample distribution mechanism may be controlled by flow control components such as flow control components  20  of  FIG. 3 . 
     At step  206 , a user may insert the sample holder into an analysis module such as analysis module  14  of  FIG. 4  by inserting sample imaging portion  64  of sample holder  12  into opening  86  of analysis module  14 . 
     At step  208 , sensor  126  may detect reference markings  122  as they pass through its field of view during insertion of sample holder  12  into analysis module  14 . In configurations where sensor  126  is separate from image sensor  40 , a light source such as light source  124  may emit light towards sensor  126 . Sensor  126  may detect each tick mark  122 T by detecting a change in received light as the tick mark passes through the light emitted by light source  124 . In configurations where sensor  126  is formed from a portion of image sensor  40  (e.g., from a portion of pixel array  42 ), sensor  126  may detect each tick mark  122 T by detecting a change in received light as the tick mark passes through the light emitted by illumination module  26 . 
     At step  210 , trigger generator  130  may generate trigger signals for control circuitry  132  in response to sensor  126  detecting tick marks  122 T. In response to each trigger signal, control circuitry  132  may issue control signals to chip-scale microscope  24  to capture an imaging frame. Multiple imaging frames may be captured of sample  80 . Because imaging frame capture operations are triggered based on the detected reference markings, the imaging frames may have a uniform spatial distribution regardless of whether or not the user inserts sample holder  12  into analysis module  14  at a uniform speed. If desired, adjacent imaging frames may have some overlap with each other so that the imaging frames may be integrated as tiles to generate a large field of view image. 
     Various embodiments have been described illustrating a handheld diagnostic system for imaging and analyzing cells and other substances. The handheld diagnostic system may include a disposable sample holder for collecting a sample, safely containing the sample, and for presenting the sample to an analysis module having a chip-scale microscope. 
     The sample holder may include fluid control components for automatically distributing portions of the sample to respective test chambers in the sample holder for imaging. The test chambers may include markers (e.g., dyes, stains, fluorescence markers, etc.) configured to mark or otherwise identify specific nucleic acids or proteins in the sample if present in the sample. The test chambers may be located in a transparent portion of the sample holder. 
     The analysis module may have a housing with an opening. The opening may be configured to receive the transparent portion of the sample holder. While a user inserts the transparent portion of the sample holder into the opening of the analysis module, the chip-scale microscope may capture images of the sample in each test chamber as each test chamber passes through the field of view of the chip-scale microscope. 
     The analysis module may include an interchangeable illumination module for illuminating the sample and a chip-scale microscope for capturing images of the sample. The chip-scale microscope may include an image sensor having an array of image pixels configured to gather pixel data from the sample. The chip-scale microscope may also include optics such as one or more objective lenses for gathering light from the sample and focusing the light onto the image sensor. 
     The analysis module may include storage and processing circuitry for processing pixel data and, if desired, analyzing the processed pixel data to produce sample analysis information. The pixel data and/or the sample analysis information may be transmitted to external computing equipment such as a portable electronic device for further analysis and/or for displaying sample analysis information for a user based on the sample images acquired using the chip-scale microscope. 
     The chip-scale microscope may be configured to capture spatially uniform imaging frames using an automated image capture mechanism. The automated image capture mechanism may be based on a sensor that detects when the next imaging frame should be captured. For example, the sample holder may include a series of uniformly spaced markings. When a user inserts the sample holder into the analysis module, the series of uniformly spaced markings may be detected by a sensor in the analysis module. Upon detecting one of the markings, a control signal may be issued to capture an imaging frame using the chip-scale microscope. This type of automated triggering ensures that the chip-scale microscope captures imaging frames at uniform spatial distribution even when the sample is moving and even when the sample holder is inserted manually into the analysis module at variable speed. The sensor may be a photodiode that is separate from the image sensor in the chip-scale microscope or may formed from one or more image pixels at an edge of the image sensor in the chip-scale microscope. 
     The foregoing is merely illustrative of the principles of this invention which can be practiced in other embodiments.