Patent Publication Number: US-2005134858-A1

Title: Optical droplet inspecting system and inspecting method therefor

Description:
BACKGROUND OF THE INVENTION  
      1. Field of the Invention  
      The present invention relates to a biochip inspecting platform, and in particular to an optical droplet inspecting system and inspecting method therefor.  
      2. Description of Related Art  
      There are a number of ways for depositing reagents on a biochip, including a contact type minuscule drop way and a non-contact type squirt way, for example. A droplet of reagent just deposited on the surface of the biochip is shaped as a three-dimensional drop. It is a general practice to proceed with a droplet deposition inspecting action for the deposited reagent solutions prior to washing the biochip so as to detect whether or not all the reagent solutions are correctly spotted. Several currently known methods for inspecting droplet deposition are briefly described as follows.  
      Referring to  FIG. 1 , U.S. Pat. No. 6,232,072 discloses an optical droplet inspecting method, wherein an optical fiber bundle  2  generates an incident light  4 , irradiating droplets  8  and a photodetector  6  is used to receive signal light reflecting from or passing through the droplets  8  so as to inspect whether the droplet  8  is present. That is, the patent method uses changes in reflection angles resulting from light illumination onto the droplets to inspect whether or not the droplets  8  are correctly spotted. However, there is limited quantity of the droplets  8  for inspection at a time. Due to this incapability of large-scale inspection, inspection involves excessive time.  
      U.S. Pat. No. 6,558,623 also discloses an optical droplet inspecting method, wherein a light source and a photodetector are used to have a real-time inspection for the droplet deposition. The light source and the photodetector are arranged on the same side. Also, a reflection configuration is adopted to pick up the images of the droplets on a biochip. However, as the inspection has to be made simultaneously with the deposition, too much time is wasted. Production cost is thus too high for the current practice.  
      U.S. Pat. No. 5,601,980 discloses a droplet inspecting method by contact type deposition of droplets, wherein each of the droplets is inspected by a real-time optical manner when deposition is made. This method is not only a waste of time but is also inefficient. Although the teachings are capable of detecting the droplet deposition, only a small region such as a single droplet can be inspected at one time.  
      U.S. Pat. No. 6,587,579 discloses another droplet inspecting method; wherein an image set of a plurality of droplets adjacent to each other is obtained at a time to gradually build up the whole image of a biochip surface by a mapping algorithm. Thus, the overall droplet deposition can be determined. However, an apparatus having a powerful capability of calculation is necessary for forming the image of the biochip surface by using such a method. This method is time consuming, and not suitable for the processes of mass production.  
      There is accordingly a dire need for a method for speedily and efficiently inspecting the deposition state of quantities of droplets.  
     SUMMARY OF THE INVENTION  
      An object of the present invention is to provide an optical droplet inspecting system and inspecting method therefor so as to speedily detect reagent solutions deposited on a biochip and simultaneously proceed with quality control.  
      Another object of the present invention is to provide an optical droplet inspecting system and inspecting method therefor so as to provide a simple and efficient detecting mechanism and reduce the cost of mass production.  
      An optical droplet inspecting system provided according to an aspect of the present invention is adapted to inspect a target specimen having reagent solutions deposited, comprising a transporter for transporting the target specimen, a light source for illuminating the target specimen, and a photodetector mounted on one side of the transporter to detect the reagent solutions on the target specimen, wherein the target specimen on the transporter is mounted between the photodetector and the light source so that the reagent solutions on the target specimen are illuminated by means of the light source and detected by means of the photodetector to obtain a result of the detection.  
      An optical droplet inspecting system provided according to another aspect of the present invention is adapted to inspect a target specimen having reagent solutions deposited, comprising a transporter for transporting the target specimen, a light source for illumination, a light guide plate for receiving irradiating light to illuminate the target specimen, and a photodetector mounted on one side of the transporter to detect the reagent solutions on the target specimen, wherein the target specimen on the transporter is mounted between the photodetector and the light guide plate so that the reagent solutions on the target specimen are illuminated by means of the light guide plate and detected by means of the photodetector to obtain a result of the detection.  
      An inspecting method for optical droplet inspecting systems provided according to another aspect of the present invention comprises the steps of providing a target specimen having reagent solutions deposited, and simultaneously moving a light source and a photodetector relative to the target specimen to scan the target specimen, wherein the target specimen is mounted between the photodetector and the light source so that the target specimen is illuminated by means of the light source and then the reagent solutions on the target specimen are detected by means of the photodetector to obtain a result of the detection.  
      An inspecting method for optical droplet inspecting systems provided according to another aspect of the present invention comprises the steps of providing a target specimen having reagent solutions deposited, and simultaneously moving a light source, a light guide plate and a photodetector relative to the target specimen to scan the target specimen, wherein the target specimen is mounted between the photodetector and the light guide plate so that the target specimen is illuminated with light from the light source by means of the light guide plate and then the reagent solutions on the target specimen are detected by means of the photodetector to obtain a result of the detection.  
      Other objects, advantages, and novel features of the invention will become more apparent from the following detailed description when taken in conjunction with the accompanying drawings. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       FIG. 1  is a schematic diagram of a conventional optical droplet inspecting method;  
       FIG. 2  is a schematic diagram of a systematic configuration of a first embodiment of an optical droplet inspecting system according to the present invention;  
       FIG. 3  is a schematic diagram of a systematic configuration of a second embodiment of an optical droplet inspecting system according to the present invention; and  
       FIG. 4  is a flowchart for illustration of an inspecting method for optical droplet inspecting systems according to the present invention. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
      An optical droplet inspecting system and inspecting method therefor according to the present invention is adapted to measure data on the position, shape, size and diameter of a droplet just deposited on the surface of a chip so as to achieve quality control of fabrication biochips.  
      Referring now to  FIG. 2 , a systematic configuration of the first embodiment according to the present invention is schematically shown, comprising a transporter  11 , a light source  12 , a photodetector  13 , a computer system  14 , a microarray  15 , and a light guide plate  16 , wherein the microarray  15  has regent solutions  151  deposited thereon by squirt.  
      In this embodiment, the transporter  11  preferably is an apparatus having a transparent conveyor  111 . Light emitting from the light source  12  is continuous. The light guide plate  16  is capable of converting the light continuously emitting from the light source  12  into linear light to be uniformly shined on the backside of the microarray  15  so as to be associated with the photodetector  13  for inspection by linear scan. The photodetector  13  is a digital camera, a CMOS (complementary metal-oxide semiconductor) sensor, or a Charge Coupled Device (CCD), and preferably, a line-scanning CCD. An optical droplet inspecting system and inspecting method therefor according to the present invention will be described, wherein the photodetector  13  preferably is a linear scanner used to continuously capture images in association with the operation of the light guide plate  16 . It is clear that as the embodiment needs no light guide plate  16  if the photodetector  13  is a CCD, the system is low in cost.  
      The said microarray  15  is mounted on the transparent conveyor  11  of the transporter  11 , being positioned between the photodetector  13  and the light guide plate  16 . That is, the photodetector  13  is mounted above the microarray  15  for capturing the images of reagent solutions  151  on the surface of the microarray  15  while the light guide plate  16  is mounted below the transparent conveyor  111  and the microarray  15 . Also, the light generated continuously by the light source  12  serves as a backlight light source so that the images captured by the photodetector  13  are clear. The reagent solutions contains biomolecules, which may be oligonucleotides, peptides or their derivatives.  
      The backlight light source adopted by the present invention is capable of providing the protuberant center of a droplet with a lens effect so that the image being captured appears as a dark ring with a bright center when light passes through the droplet, to allow for specific circumscription of the droplet and obtain precise data on the position, shape, size and diameter of the droplet. As a result, the deposition of each of the droplets can be verified with reference to the predetermined fabricating conditions.  
      The photodetector  13  is connected to the computer system  14  so that the images being captured are transmitted to the computer system  14  for analysis. The computer system  14  has quality control software installed and related database built-in to analyze the images so received. The images of the reagent solutions  151  captured by the photodetector  13  as well as the analysis of the images by the computer system will be described below.  
       FIG. 4  shows a flowchart for the inspection of the surface of the microarray  15  according to the present invention. Reference is made to  FIG. 4  together with the systematic configuration as shown in  FIG. 2 , the microarray  15  having reagent solutions deposited thereon is mounted on the transparent conveyor  111  of the transporter  11  at the beginning, wherein the quantity of the microarray  15  being mounted is not specifically defined in number (step S 201 ).  
      The transporter  11  is then controlled to move the transparent conveyor  111  rightward so that the backlight light source and the photodetector  13  are simultaneously moved relative to the microarray  15  in order for the photodetector  13  to scan the reagent solutions  151  on the surface of the microarray  15  (step S 202 ). Thus, the photodetector  13  will capture the images of the reagent solutions on the surface of the microarray  15  at a time, the images being transmitted to the computer system  14  for analysis (step S 203 ).  
      The computer system  14  analyzes the detected images in accordance with the build-in database as well as the pre-installed analytic software. The computer system  14  initially compares the detected images with a predetermined image (for example, a perfectly deposited droplet image) to determine whether or not the deposited reagent solutions are correctly spotted. If a large quantity of the reagent solutions  151  (for example, twenty reagent solutions in quantity) is failed to be correctly spotted, the computer system  14  indicates a message of re-deposition or serious error (step S 204 ); and simultaneously, the computer system  14  will gather statistics as to the quantity of irregular reagent solutions  151  to serve as reference parameters of an apparatus (not shown) for adjusting the deposition of the reagent solutions  151 .  
      Then, the computer system  14  analyzes the diameter of the deposited reagent solutions  151  by comparing the diameter of the reagent solutions  151  with the predetermined droplet diameter stored in the database to verify whether the reagent solutions are properly deposited by the apparatus. If the reagent solutions  151  have a diameter significantly more or less than the predetermined droplet diameter and a significant quantity of such reagent solutions  151  (for example, twenty reagent solutions in number) occurs, the computer system  14  indicates a message of re-deposition or serious error (step S 205 ).  
      Finally, the computer system  14  measures the area of the deposited reagent solutions  151  on the surface of the microarray  15  by comparing the area of the reagent solutions  151  with the predetermined area of a droplet stored in the database to verify whether the reagent solutions are properly deposited by the apparatus. If the area of reagent solutions  151  is significantly more or less than the predetermined area of a droplet and a significant quantity of such reagent solutions  151  (for example, twenty reagent solutions in quantity) occurs, the computer system  14  indicates a message of re-deposition or serious error. The computer system  14  also gathers statistics as to the diameter and area as a result of the analyses to obtain a plurality of parameters for adjusting the depositing apparatus. Accordingly such, all of the droplets to be deposited next can be made successfully at a time to optimize the deposition of these reagent solutions and increase deposition efficiency (step S 206 ).  
      Hence, the computer system  14  analyzes the state of these reagent solutions  151  by comparing them with the predetermined value stored therein or the build-in database. Because the deposition of these reagent solutions  151  will affect the contact of the reagents in the reagent solutions  151  with the microarray  15 , the deposition of the reagent solutions  151  can be verified in accordance with an inspecting method of the present invention before washing the microarray  15  to complete the fabricating processes for a biochip (step S 207 ).  
      Turning now to  FIG. 3 , a systematic configuration of the second embodiment according to the present invention is schematically shown. This embodiment further comprises a displacement device  17 , in addition to the transporter  11 , the light source  12 , the photodetector  13 , the computer system  14 , the microarray  15  and the light guide plate  16 . The displacement device  17  is used to move the photodetector  13 , the light source  12  and the light guide plate  16 . The main differences between this embodiment and the first embodiment of the present invention reside in the transporter  11  being fixed to solely support the microarray  15 , and the relative position among the photodetector  13 , the light source  12  and the light guide plate  16  which remains unchanged so that the photodetector  13  is capable of scanning the reagent solutions  151  on the surface of the microarray  15  and the subsequent processes. Because the operating principle of the second embodiment of the present invention is similar to that of the first embodiment of the present invention and the flowchart for the inspection of the surface of the biochip  15  is similar to that of  FIG. 3 , this embodiment will not be depicted.  
      It is inferable from the above description that the present invention adopts a backlight-type optical scanning mechanism composed of a light source and a photodetector to inspect reagent solutions over a microarray and obtain a droplet image having an optimal resolution. The inspection according to the present invention proceeds in sequence, that is, the surface of at least one microarray is surveyed again after depositing the reagent solutions, and then images of the droplets are analyzed in accordance with predetermined values stored in the computer system or the build-in database of the computer system to verify the state of these reagent solutions, and then, a process for quality control (such as re-deposition and defect marking) is made in accordance with the result of such analyses to conduct real-time quality control. Thus, a simple and efficient inspecting mechanism is provided to achieve minimal fabrication cost.  
      Although the present invention has been explained in relation to its preferred embodiments, it is to be understood that many other possible modifications and variations can be made without departing from the spirit and scope of the invention as hereinafter claimed.