Abstract:
A sample is added to a chamber ( 12 ) in which magnetic particles (P) are provided. The sample includes a target component (T) and the chamber ( 12 ) has a detection surface ( 122 ). A magnetic force is exerted on the magnetic particles (P) to attract the magnetic particles (P) to the detection surface ( 122 ). The bound magnetic particles that captured the target component (T) in the magnetic particles (P) and the unbound magnetic particles that captured no target component (T) in the magnetic particles (P) are held at the detection surface ( 122 ). At least part of the sample is drained out of the chamber ( 12 ) and a new sample added to the chamber ( 12 ). The magnetic force exerted on the magnetic particles (P) is altered to release the unbound magnetic particles from the detection surface ( 122 ). An amount of the bound magnetic particles that are held at the detection surface ( 122 ) are measured. The target component (T) is preconcentrated by repeating the steps of magnetically binding the target component (T) from the newly added sample and washing the detection surface ( 122 ) from unbound magnetic particles.

Description:
CROSS-REFERENCE TO PRIOR APPLICATIONS 
     This application is the U.S. National Phase application under 35 U.S.C. §371 of International Application No. PCT/IB2013/058272, filed on Sep. 4, 2013, which claims the benefit of Chinese Patent Application No. PCT/CN2012/080969, filed on Sep. 4, 2012. These applications are hereby incorporated by reference herein. 
     FIELD OF THE INVENTION 
     The present invention relates to a sensor device. Moreover, the present invention relates to a method of sampling. 
     BACKGROUND OF THE INVENTION 
     A biosensor is an analytical device for the detection of an analyte that combines a biological component with a physicochemical detector. The biosensor is now being developed for a variety of applications, such as healthcare, food safety, etc. 
     One of the current biosensors, for example Magnotech platform, works as follows. When a sample is poured into a chamber, the magnetic beads in the chamber begin to capture the target molecules in the sample via antibodies (called ‘Target capture’). Then, a first magnetic field is applied to attract all of the magnetic beads to a detection surface, coated with antibodies, of the chamber (called ‘Magnetic attraction’), wherein magnetic beads capturing the target molecules (i.e., bound magnetic beads) are bound to the detection surface via antigen-antibody reaction, and magnetic beads capturing no target molecule (i.e., unbound magnetic beads) are held at the detection surface via magnetic force. Next, a second magnetic field is applied to pull the unbound magnetic beads away from the detection surface (called ‘Magnetic wash’). An optical method is then used to measure the amount of the bound magnetic beads at the detection surface and thereby the concentration of the target molecules in the sample. 
     The current biosensor can work with very small sample size, for example 100 μl, and have certain sensitivity for this sample size. However, this small sample size could be the limitation/disadvantage for applications such as food safety. First, the property of food sample determines that the sample size of 100 μl is less representative. Second, the sensitivity requirement in food safety is very high. Thus the small sample size may result in either false negative or longer enrichment time. 
     OBJECT AND SUMMARY OF THE INVENTION 
     Based on above concerns, in one aspect, one embodiment of the invention provides a sensor device. The sensor device comprises:
         a chamber in which magnetic particles are provided, the chamber having a detection surface and configured to receive a sample in which a target component is included;   a magnetic manipulator configured to exert a magnetic force on the magnetic particles to attract the magnetic particles to the detection surface, wherein bound magnetic particles that capture the target component in the magnetic particles are held at the detection surface, and unbound magnetic particles that capture no target component in the magnetic particles are held at the detection surface as well; then to alter the magnetic force exerted on the magnetic particles to release the unbound magnetic particles from the detection surface;   a sample replacing unit configured to replace at least part of the sample in the chamber with a new sample;   a sensor unit configured to measure the amount of the bound magnetic particles that are held at the detection surface;   a control unit coupled to the magnetic manipulator, the sample replacing unit and the sensor unit, wherein the control unit is configured to perform the following operations repeatedly until a given cycles is reached,
           control the magnetic manipulator to exert the magnetic force on the magnetic particles to attract the magnetic particles to the detection surface,   control the sample replacing unit to replace at least part of the sample in the chamber with the new sample,   control the magnetic manipulator to alter the magnetic force exerted on the magnetic particles to release the unbound magnetic particles from the detection surface;   
               

     and further configured to control the sensor unit to measure the amount of the bound magnetic particles that are bound to the detection surface when the given cycles is reached. 
     In this embodiment, the number of sample replacements (i.e. the given cycles) is predetermined and stored in the controller. During the operation of the sensor device, the controller will control the sample replacing unit to replace the sample in the chamber with a new sample until the given cycles is reached. As the sample in the chamber is replaced with a new sample by multiple times, the total sample volume for detection is increased and thus the sensitivity of the sensor device is improved. 
     Another embodiment of the invention provides a sensor device. The sensor device comprises:
         a chamber in which magnetic particles are provided, the chamber having a detection surface and configured to receive a sample in which a target component is included;   a magnetic manipulator configured to exert a magnetic force on the magnetic particles to attract the magnetic particles to the detection surface, wherein bound magnetic particles that capture the target component in the magnetic particles are held at the detection surface, and unbound magnetic particles that capture no target component in the magnetic particles are held at the detection surface as well; and then to alter the magnetic force exerted on the magnetic particles to release the unbound magnetic particles from the detection surface;   a sample replacing unit configured to replace at least part of the sample in the chamber with a new sample;   a sensor unit configured to measure the amount of the bound magnetic particles that are held at the detection surface;   a control unit coupled to the magnetic manipulator, the sample replacing unit and the sensor unit and configured to perform the following operations;
           i. control the magnetic manipulator to exert the magnetic force on the magnetic particles to attract the magnetic particles to the detection surface;   ii. control the magnetic manipulator to alter the magnetic force exerted on the magnetic particles to release the unbound magnetic particles from the detection surface;   iii. determine whether the amount of the bound magnetic particles that are held at the detection surface is above a predetermined threshold;
               if no, the control unit is further configured to perform the following operation,
                   control the magnetic manipulator to exert the magnetic force on the magnetic particles to attract the magnetic particles to the detection surface;   control the sample replacing unit to replace at least part of the sample in the chamber with the new sample;   control the magnetic manipulator to alter the magnetic force exerted on the magnetic particles to release the unbound magnetic particles from the detection surface;   
                   and then to perform the operation of i to iii.   
               
               

     In this embodiment, the number of sample replacements is determined based on the comparison of the measured amount of the bound magnetic particles and the predetermined threshold during the operation of the sensor device. Once the measured amount of the bound magnetic particles reaches the predetermined threshold, the sample replacing is ceased, which makes the detection of the sensor device more flexible. 
     In another aspect, one embodiment of the invention provides a method of sampling. The method comprises the steps of: 
     a. adding a sample to a chamber in which magnetic particles are provided, the sample including a target component and the chamber having a detection surface; 
     b. exerting a magnetic force on the magnetic particles to attract the magnetic particles to the detection surface, wherein bound magnetic particles that capture the target component in the magnetic particles are held at the detection surface, and unbound magnetic particles that capture no target component in the magnetic particles are held at the detection surface as well; 
     c. draining at least part of the sample out of the chamber and then adding a new sample to the chamber; 
     d. altering the magnetic force exerted on the magnetic particles to release the unbound magnetic particles from the detection surface; 
     e. repeating the steps b to d for a given cycles. 
     Another embodiment of the invention provides a method of sampling. The method comprises the steps of: 
     A. adding a sample to a chamber in which magnet particles are provided, the sample including a target component and the chamber having a detection surface; 
     B. exerting a magnetic force on the magnetic particles to attract the magnetic particles to the detection surface, wherein bound magnetic particles that capture the target component in the magnetic particles are held at the detection surface, and unbound magnetic particles that capture no target component in the magnetic particles are held at the detection surface as well; 
     C. altering the magnetic force exerted on the magnetic particles to release the unbound magnetic particles from the detection surface; 
     D. measuring the amount of the bound magnetic particles that are held at the detection surface; 
     E. determining whether the amount of the bound magnetic particles that are held at the detection surface is above a predetermined threshold;
         if no, performing the following steps of:
           exerting the magnetic force on the magnetic particles to attract the magnetic particles to the detection surface;   draining at least part of the sample out of the chamber and adding a new sample To the chamber;   altering the magnetic force exerted on the magnetic particles to release the unbound magnetic particles from the detection surface   going back to perform the steps B to E.   
               

    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The above and other objects and features of the present invention will become more apparent from the following detailed description considered in connection with the accompanying drawings, in which: 
         FIG. 1  shows a block diagram of a sensor device according to one embodiment of the invention; 
         FIG. 2  shows an exemplary sensor device according to one embodiment of the invention; 
         FIG. 3  shows a schematic view of magnetic attraction of the sensor device according to one embodiment of the invention; 
         FIG. 4  shows a schematic view of magnetic wash of the sensor device according to one embodiment of the invention; 
         FIG. 5  shows a flow chart of a sampling and detection method implemented by the sensor device of  FIG. 2 ; and 
         FIG. 6  shows a flow chart of another sampling and detection method implemented by the sensor device of  FIG. 2 . 
       Throughout the above drawings, like reference numerals will be understood to refer to like, similar or corresponding features or functions. 
     
    
    
     DETAILED DESCRIPTION 
     Reference will now be made to embodiments of the invention, one or more examples of which are illustrated in the figures. The embodiments are provided by way of explanation of the invention, and are not meant as a limitation of the invention. For example, features illustrated or described as part of one embodiment may be used with another embodiment to yield still a further embodiment. It is intended that the invention encompass these and other modifications and variations as come within the scope and spirit of the invention. 
     The sensor device of the invention is applicable to a variety of detection scenarios, for example, the sensor device of the invention can be used to detect the concentration of target component in a sample. 
     The magnetic separation technology is applied in the sensor device of the invention to achieve the purpose of detection. In one example, the magnetic separation technology can be immunomagnetic separation which uses the mechanism of immune system. 
       FIG. 1  shows an exemplary sensor device  10  according to one embodiment of the invention. Referring to  FIG. 1 , the sensor device  10  comprises a chamber  12  for receiving a sample that includes a target component (e.g., antigens, for immunomagnetic separation). The chamber  12  may be an empty cavity, for example. Advantageously, the chamber  12  is made of a material that is substantially impervious to the sample. In the chamber  12 , a bunch of magnetic particles P are provided. The magnetic particle may for example be magnetized or magnetizable bead, which is capable of capturing the target component T in the sample. 
     The chamber  12  has a detection surface  122  that carries binding sites  124  (e.g., antibodies) to which those magnetic particles that capture the target component (e.g., antigens) can specifically bind to via antigen-antibody reaction. It shall be appreciated that there are also magnetic particles in the chamber  12  that cannot bind to the detection surface  122  because they did not capture the target component. The detection surface  122  may be the surface of a substrate, for example a silicon substrate in which microelectronic circuits are embedded, or a glass substrate in the case of optical measurement. 
     Still referring to  FIG. 1 , the sensor device  10  further comprises a magnetic manipulator  14  configured to exert a magnetic force on all of the magnetic particles in the chamber  12  so as to attract these magnetic particles to the detection surface  122  (called ‘Magnetic attraction’). In all these magnetic particles, the magnetic particles that capture the target component (hereinafter referred to as ‘bound magnetic particles’) are held at the detection surface  122 , for example via antigen-antibody reaction; and the remaining magnetic particles that do not capture the target component (hereinafter referred to as ‘unbound magnetic particles’) are held at the detection surface via magnetic force, as shown in  FIG. 3 . Moreover, the magnetic manipulator  14  is further configured to alter the magnetic force exerted on all of the magnetic particles so as to release the unbound magnetic particles from the detection surface  122  (called ‘Magnetic wash’), as shown in  FIG. 4 . 
     The magnetic manipulator  14  can be achieved by a variety of ways. In one example, the magnetic manipulator  14  may include a first magnet  142  disposed below the chamber  12  and adjacent to the detection surface  122  and a second magnet  144  disposed above the chamber  12 , as shown in  FIG. 2 . When the first magnet  142  is activated (i.e., switched on), a first magnetic field is generated so as to attract all of the magnetic particles to the detection surface  122 , and then when the first magnet  142  is deactivated (i.e., switched off) and the second magnet  144  is activated, a second magnetic field that is opposite to the first magnetic field is generated so as to pull the unbound magnetic particles away from the detection surface  122 . It is to be noted that the pulling force of the second magnetic field should be controlled to be smaller than the binding force of the bound magnetic particles at the detection surface  122  such that the bound magnetic particles can be retained on the detection surface  122  while the unbound magnetic particles are pulled away from the detection surface  122 . 
     In another example, the magnetic manipulator  14  may only include the first magnet  142 . When the first magnet  142  is activated, the first magnetic field is generated so as to attract all of the magnetic particles to the detection surface  122 , and then when the first magnet  142  is deactivated, the first magnetic field is switched off and thereby the unbound magnetic particles are released from the detection surface  122 . 
     Still referring to  FIG. 1 , the sensor device  10  further comprises a sample replacing unit  16  configured to replace at least part of the sample in the chamber  12  with a new sample that includes a target component. 
     The sample replacing unit  16  may take on various configurations, but generally includes an outflow valve  162  and an inflow valve  164  disposed at the chamber  12 , as shown in  FIG. 2 . Advantageously, the outflow valve  162  is disposed at a lower position of the chamber  12 , for example at the bottom of the chamber  12 , such that at least part of the sample can be drained out of the chamber  12  by gravity when the outflow valve  162  is controlled to be open. Alternatively, a pump may also be used to pump at least part of the sample out of the chamber  12 . 
     The inflow valve  164  may for example be in fluid communication with a container that contains plenty of new sample. When the outflow valve  162  is controlled to be closed and the inflow valve  164  is controlled to be open, the new sample in the container flows into the chamber  12 . 
     Still referring to  FIG. 1 , the sensor device  10  further comprises a sensor unit  18  configured to measure the amount of the bound magnetic particles at the detection surface  122 . Advantageously, the sensor unit  18  is disposed below the detection surface  122  of the chamber  12 . The sensor unit  18  may be any suitable sensor to detect the presence of magnetic particles at the detection surface  122 . For example, the sensor unit  18  may detect the presence of the bound magnetic particles via magnetic methods, optical methods, sonic methods, electrical methods, the combination thereof, etc. 
     Advantageously, the sensor device  10  may further comprise a mixing unit  13  configured to mix the magnetic particles and the target component when the sample/new sample is added into the chamber  12 . In an example, the first magnet  142  and the second magnet  144  can be served as the mixing unit  13 . To be specific, the first magnet  142  and the second magnet  144  are controlled to be switched on alternately to generate an alternate magnetic field, such that the good mixing of the magnetic particles and the target component can be achieved. 
     Still referring to  FIG. 1 , the sensor device  10  further comprise a controller  15  coupled to the magnetic manipulator  14 , the mixing unit  13 , the sample replacing unit  16  and the sensor unit  18 , and configured to control the activities of these units. The controller  15  may be an MCU (Micro Control Unit), for example. 
     Based on different control strategies of the controller  15 , the sensor device  10  can operate in different ways. Hereinafter, different operations of the sensor device  10  will be described respectively in connection with the configuration of the sensor device  10  described above and with reference to  FIGS. 5 and 6 . 
     In one embodiment, referring to  FIG. 5 , first, in Step  31 , the sample is added to the chamber  12 . 
     Then, in Step  32 , the controller  15  controls the first magnet  142  and the second magnet  144  to be switched on alternately to generate an alternate magnetic field. Advantageously, the alternate magnetic field lasts for a predetermined duration, thus facilitating the good mixing of the magnetic particles and the target component in the sample. The predetermined duration may be preset according to the type of the sample, the amount of target component in the sample, etc. After the mixing, part of the magnetic particles capture the target component in the sample (i.e., bound magnetic particles), and the others do not capture the target component (i.e., unbound magnetic particles). 
     Next, in Step  33 , the controller  15  controls the first magnet  142  to generate the first magnet field so as to attract all of the magnetic particles to the detection surface  122 . For all of the magnetic particles that are attracted to the detection surface  122 , the bound magnetic particles will be held at the detection surface  122 , for example via antigen-antibody reaction; and the unbound magnetic particles will be held at the detection surface  122  via magnetic force. 
     Then, in Step  34 , the controller  15  controls the outflow valve  162  to be open to drain at least part of the sample out of the chamber  12 , and then controls the outflow valve  162  to be closed and the inflow valve  162  to be open to allow the new sample to flow into the chamber  12 . 
     Further, in Step  35 , the controller  15  controls the first magnet  142  to be switched off and the second magnet  144  to be switched on to generate the second magnetic field so as to pull the unbound magnetic particles away from the detection surface  122 . 
     Next, in Step  36 , the controller  15  determines whether a given cycles is reached. The given cycles may be preset according to the type of the sample, the sensitivity of the sensor unit  18 , etc. 
     If the given cycles is not reached, the controller  15  continues to perform Steps  32  to  36 . If the given cycles is reached, in Step  37 , the controller  15  controls the sensor unit  18  to measure the amount of the bound magnetic particles at the detection surface  122 . Based on the measured amount of the bound magnetic particles at the detection surface  122 , the concentration of the target component in the sample can be obtained. 
     In this embodiment, the number of sample replacements (i.e., the given cycles) is predetermined and stored in the controller  15 . During the operation of the sensor device  10 , the controller  15  controls the sample replacing unit  16  to replace the sample in the chamber  12  with a new sample until the given cycles is reached. As the sample in the chamber  12  is replaced with a new sample by multiple times, the total sample volume for detection is increased and thus the sensitivity of sensor device  10  is improved. 
     In another embodiment, referring to  FIG. 6 , first, in Step  41 , the sample is added to the chamber  12 . 
     Then, in Step  42 , the controller  15  controls the first magnet  142  and the second magnet  144  to be switched on alternately to generate an alternate magnetic field. Advantageously, the alternate magnetic field lasts for a predetermined duration, thus facilitating the good mixing of the magnetic particles and the target component in the sample. The predetermined duration may be preset according to the type of the sample, the amount of target component in the sample, etc. After the mixing, part of the magnetic particles capture the target component in the sample (i.e., bound magnetic particles), and the others do not capture the target component (i.e., unbound magnetic particles). 
     Next, in Step  43 , the controller  15  controls the first magnet  142  to generate the first magnet field so as to attract all of the magnetic particles to the detection surface  122 . For all of the magnetic particles that are attracted to the detection surface  122 , the bound magnetic particles will be held at the detection surface  122 , for example via antigen-antibody reaction; and the unbound magnetic particles will be held at the detection surface  122  via magnetic force. 
     Further, in Step  44 , the controller  15  controls the first magnet  142  to be switched off and the second magnet  144  to be switched on to generate the second magnetic field so as to pull the unbound magnetic particles away from the detection surface  122 . 
     Then, in Step  45 , the controller  15  controls the sensor unit  18  to measure the amount of the bound magnetic particles at the detection surface  122 . 
     Next, in Step  46 , the controller  15  determines whether the amount of the bound magnetic particles at the detection surface  122  is above a predetermined threshold. The predetermined threshold may be determined based on the property of the sample and/or the sensor unit  18 . For example, the predetermined threshold can be the quantification limit of the target component. 
     If the amount of the bound magnetic particles at the detection surface  122  is above the predetermined threshold, then this amount of the bound magnetic particles can be used to obtain the concentration of the target component in the sample. 
     If the amount of the bound magnetic particles at the detection surface  122  is lower than the predetermined threshold, the controller  15  continues to perform the following Steps  47  to  49 . 
     In Step  47 , the controller  15  further controls the first magnet  142  to generate the first magnet field so as to attract all of the magnetic particles to the detection surface  122 . 
     Then, in Step  48 , the controller  15  further controls the outflow valve  162  to be open to drain at least part of the sample out of the chamber  12 , and then controls the outflow valve  162  to be closed and the inflow valve  162  to be open to allow the new sample to flow into the chamber  12 . 
     Next, in Step  49 , the controller  15  further controls the first magnet  142  to be switched off and the second magnet  144  to be switched on to generate the second magnetic field so as to pull the unbound magnetic particles away from the detection surface  122 . 
     Then, the controller  15  continues to perform Steps  42  to  46 . 
     In this embodiment, the number of sample replacements is determined based on the comparison of the measured amount of the bound magnetic particles and the predetermined threshold during the operation of the sensor device  10 . Once the measured amount of the bound magnetic particles reaches the predetermined threshold, the sample replacement is ceased, which makes the detection of the sensor device  10  more flexible. 
     It should be noted that the above described embodiments are given for describing rather than limiting the invention, and it is to be understood that modifications and variations may be resorted to without departing from the spirit and scope of the invention as those skilled in the art readily understand. Such modifications and variations are considered to be within the scope of the invention and the appended claims. The protection scope of the invention is defined by the accompanying claims. In addition, any of the reference numerals in the claims should not be interpreted as a limitation to the claims. Use of the verb “comprise” and its conjugations does not exclude the presence of elements or steps other than those stated in a claim. The indefinite article “a” or “an” preceding an element or step does not exclude the presence of a plurality of such elements or steps.