Patent Publication Number: US-9404884-B2

Title: Biosensor device and related method

Description:
BACKGROUND 
     The semiconductor industry has experienced rapid growth due to improvements in the integration density of a variety of electronic components (e.g., transistors, diodes, resistors, capacitors, etc.). This improvement in integration density has come, in large part, from shrinking the semiconductor process node. A related aspect of the semiconductor industry similarly experiencing rapid growth is the microelectromechanical systems (MEMS) industry. MEMS devices are found in a variety of applications, ranging from automotive electronics to smartphones, and even biomedical devices. 
     Biomedical MEMS (BioMEMS) devices perform a variety of functions. A pH sensor is one type of BioMEMS device that electronically determines pH of a solution in contact with the pH sensor. The pH sensor may be used in disease detection, organ tissue monitoring, water contamination identification, or a myriad of other practical applications. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Aspects of the present disclosure are best understood from the following detailed description when read with the accompanying figures. It is noted that, in accordance with the standard practice in the industry, various features are not drawn to scale. In fact, the dimensions of the various features may be arbitrarily increased or reduced for clarity of discussion. 
         FIG. 1  is an illustration of a circuit arrangement of a biosensor in accordance with some embodiments. 
         FIG. 2  is an illustration of a circuit arrangement of a biosensor in accordance with some embodiments. 
         FIG. 3  is an illustration of a circuit arrangement of a biosensor in accordance with some embodiments. 
         FIG. 4  is an illustration of a timing diagram of a circuit arrangement of a biosensor in accordance with some embodiments. 
         FIG. 5  is an illustration of a circuit arrangement of a biosensor in accordance with some embodiments. 
         FIG. 6  is a truth table for a circuit arrangement of a biosensor in accordance with some embodiments. 
         FIG. 7  is a flow diagram illustrating a method for sensing a bio-reaction in accordance with some embodiments. 
         FIG. 8  is an illustration of an exemplary computer readable medium wherein processor-executable instructions configured to embody one or more of the provisions set forth herein may be comprised. 
     
    
    
     DETAILED DESCRIPTION 
     The following disclosure provides many different embodiments, or examples, for implementing different features of the provided subject matter. Specific examples of components and arrangements are described below to simplify the present disclosure. These are, of course, merely examples and are not intended to be limiting. For example, the formation of a first feature over or on a second feature in the description that follows may include embodiments in which the first and second features are formed in direct contact, and may also include embodiments in which additional features may be formed between the first and second features, such that the first and second features may not be in direct contact. In addition, the present disclosure may repeat reference numerals and/or letters in the various examples. This repetition is for the purpose of simplicity and clarity and does not in itself dictate a relationship between the various embodiments and/or configurations discussed. 
     Further, spatially relative terms, such as “beneath,” “below,” “lower,” “above,” “upper” and the like, may be used herein for ease of description to describe one element or feature&#39;s relationship to another element(s) or feature(s) as illustrated in the figures. The spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. The apparatus may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein may likewise be interpreted accordingly. 
     According to some embodiments, one or more circuit arrangements for a biosensor and one or more corresponding methods are provided. In some embodiments, a biosensor is able to directly indicate if a bio-reaction has taken place. In some embodiments, a circuit arrangement is able to mitigate low frequency noise and DC-offset of the biosensor. In some embodiments, the biosensor operates without a calibration phase, and thus does not need a memory cell or the like to store the biosensor&#39;s DC-bias or offset. 
     Turning now to  FIG. 1 , a diagram of a circuit arrangement  100  of a biosensor  10  in accordance with one or more embodiments is provided. In some embodiments, the circuit arrangement  100  includes at least one of an ion sensitive sensor  110   a,  a differentiator  120 , an AC signal level comparator  130 , a decision circuit  140 , a sampling clock  150 , a reset clock  152  or a latch clock  154 . In some embodiments, the circuit arrangement  100  is integrated into a single integrated circuit (IC). 
     In some embodiments, the ion sensitive sensor  110   a  is configured to senses a parameter, such as a pH, of a solution, and output a signal, such as a current or voltage. In some embodiments, the ion selective sensor  110   a  comprises at least one of an ion-sensitive field effect transistor (ISFET), a nanowire or a nanopore. In some embodiments, the ion sensitive sensor  110   a  includes a converter. In some embodiments, the converter is at least one of a current-to-voltage converter, a voltage-to-current converter, a voltage-to-voltage converter or a capacitance-to-voltage converter. In some embodiments, the converter converts an input signal, such as a current, voltage or capacitance, to a current or voltage. 
     In some embodiments, the ion sensitive sensor  110   a  is one of an array of ion sensitive sensors  110   a - 110   i,  as illustrated in  FIG. 2 . In some embodiments, at least one of the ion sensitive sensors  110   a - 110   i  is connected to a multiplexer  190 . In some embodiments, the multiplexer  190  is configured to select at least one of the ion sensitive sensors  110   a - 110   i  from the array of ion sensitive sensors. In some embodiments, at least one of the ion sensitive sensors  110   a - 110   i  outputs at least one of a first signal out (Sout) or a second Sout. In some embodiments, at least one of the first Sout or the second Sout is at least one of a voltage signal or a current signal. In some embodiments, the first Sout is sensed at a first time and the second Sout is sensed at a second time. In some embodiments, the first Sout and the second Sout are output by the same ion sensitive sensor. In some embodiments, the first Sout and the second Sout are output by different ion sensitive sensors. 
     In some embodiments, the differentiator  120  is electrically connected to at least one of the ion sensitive sensors  110   a - 110   i.  In some embodiments, at least one of the ion sensitive sensors  110   a - 110   i  outputs at least one of the first Sout or the second Sout to the differentiator  120 . In some embodiments, the differentiator  120  differentiates the first Sout inputted at the first time from the second Sout imputed at the second time. In some embodiments, the differentiator  120  is designed such that an output of the differentiator  120  is approximately directly proportional to a rate of change from the first Sout to the second Sout. In some embodiments, the differentiator  120  differentiates at least one of the first Sout or the second Sout by at least one of a differential voltage or electrical potential (potential), such that in some embodiments at least one of the first Sout is compared to a reference voltage or a common mode voltage (Vcm), such as  156  in  FIG. 3 , or the second Sout is compared to the reference voltage or the Vcm, such as  156  in  FIG. 3 . In some embodiments, when the first Sout and the second Sout are at the same potential, the output from the differentiator  120  for the first Sout and the output from the differentiator  120  for the second Sout are equal, such that a differential voltage between the outputs is zero. In some embodiments, when the first Sout and the second Sout have different potentials, the output from the differentiator  120  for the first Sout and the output from the differentiator  120  for the second Sout will differ, such that the differential voltage between the outputs is not zero. In some embodiments, the differentiator  120  amplifies the difference between the output for the first Sout and the output for the second Sout. 
     In some embodiments, the differentiator  120  is at least one of an active differentiator or a passive differentiator. In some embodiments, as illustrated in  FIG. 3 , the differentiator  120  includes at least one of a first capacitor  302 , a second capacitor  304 , a first switch  306 , a second switch  308  or an amplifier  310 . In some embodiments, the differentiator  120  is configurable to have at least one of a sampling phase or a reset phase. Referring to  FIG. 1 ,  FIG. 2  and  FIG. 3 , in some embodiments, the sampling phase is controlled by the sampling clock  150  and the reset phase is controlled by the reset clock  152 . In some embodiments, at least one of the sampling clock  150  is connected to the first switch  306  or the reset clock  152  is connected to the second switch  308 . 
     In some embodiments, the sampling clock  150  is configured to control the sampling of at least one of the first Sout or the second Sout by the differentiator  120 . In some embodiments, the sampling clock  150  will cause the first switch  306  to close initiating the sampling phase. In some embodiments, when the first switch  306  is closed, at least one of the first Sout or the second Sout will flow into at least one of the first capacitor  302 , the second capacitor  304  or the amplifier  310 . In some embodiments, the Vcm  156  is imputed into the amplifier  310  during the sampling phase, such that the Vcm  156  is compared to at least one of the first Sout or the second Sout. 
     In some embodiments, the reset clock  152  is configured to reset the differentiator  120 . In some embodiments, the reset clock  152  is configured to cause the second switch  308  to close initiating the reset phase. In some embodiments, the reset clock  152  resets the differentiator  120  between a first sampling phase and a second sampling phase. In some embodiments, at least one of the first Sout or the second Sout is stored in the first capacitor  302  during the reset phase. In some embodiments, the charge at the second capacitor  304  is reset to zero during the reset phase. In some embodiments, the reset clock  152  resets the differentiator  120  to the Vcm  156  during the reset phase. In some embodiments, the differentiator  120  will output Vcm  156  during the reset phase. 
     In some embodiments, the differentiator  120  outputs a differentiator output signal (Diff-out). In some embodiments, the Diff-out is outputted during at least one of the sampling phase or the reset phase. In some embodiments, the Diff-out is directly proportional to the rate of change of the signals inputted into the differentiator  120  during the sampling phase. In some embodiments, the Diff-out is a function of the difference between the first Sout and the Vcm  156  at the first time and the difference between the second Sout and the Vcm  156  at the second time. In some embodiments, the Diff-out reflects a gain of the differentiator  120  where the gain is, according to some embodiments, a function of the Vcm  156  and a charge of the first capacitor  302  divided by a charge of the second capacitor  304 . In some embodiments, Diff-out is an AC signal. 
     Turning to  FIG. 4 , a timing diagram  200  for the differentiator  120  is provided. Referring to  FIG. 1 ,  FIG. 2 ,  FIG. 3  and  FIG. 4 , in some embodiments, the sampling clock  150  will cause the first switch  306  to close initiating the first sampling phase. In some embodiments, during the first sampling phase, the first Sout (Sout( 1 )) will flow into the differentiator  120 . In some embodiments, Diff-out( 1 ) will be outputted. In some embodiments, the reset clock  152  will cause the second switch  308  to close initiating the reset phase. In some embodiments, the reset phase will reset the differentiator  120  to Vcm  156 . In some embodiments, during the reset phase the Diff-out will be equal to Vcm  156 . In some embodiments, at least one of the sampling clock  150  or the reset clock  152  will cause at least one of the first switch  306  to close or the second switch  308  to open, therein initiating the second sampling phase. In some embodiments, during the second sampling phase, the second Sout (Sout( 2 )) will flow into the differentiator  120 . In some embodiments, a Diff-out( 2 ) will be outputted. In some embodiments, the Diff-out( 2 ) is directly proportional to the rate of change from Sout( 1 ) to Sout( 2 ). In some embodiments, additional signals, such as Sout( 3 ) through Sout( 9 ), are sampled by the differentiator  120  in the same manner described above. 
     As illustrated in  FIG. 5 , the AC signal level comparator  130  is electrically connected to the differentiator  120 , according to some embodiments. In some embodiments, the AC signal level comparator  130  includes at least one of a first comparator  402 , a second comparator  404  or a reference generator  406 . In some embodiments, the Diff-out is inputted into at least one of the first comparator  402  or the second comparator  404 . In some embodiments, at least one of the first comparator  402  or the second comparator  404  is configured to detect at least one of a positive or a negative AC signal. In some embodiments, at least one of a first threshold voltage (vth 1 ) or a second threshold voltage (vth 2 ) is inputted into at least one of the first comparator  402  or the second comparator  404 . In some embodiments, at least one of the first comparator  402  or the second comparator  404  compares at least one of the Diff-outs to at least one of vth 1  or vth 2 . In some embodiments, the AC signal level comparator  130  includes at least one of a third comparator, a fourth comparator or additional comparators (not illustrated). 
     In some embodiments, the reference generator  406  is configured to generate at least one of vth 1  or vth 2 . In some embodiments, at least one of vth 1  or vth 2  is set by a first tuning signal (Tune vth 1 ) or a second tuning signal (Tune vth 2 ). In some embodiments, at least one of Tune vth 1  or Tune vth 2  is a digital signal. In some embodiments, at least one of vth 1  or vth 2  is at least one of a positive threshold level or a negative threshold level. In some embodiments, the positive threshold level is between about 0.01 v to about 1 v. In some embodiments, the negative threshold level is between about −0.01 v to about −1 v. 
     In some embodiments, at least one of the first comparator  402  or the second comparator  404  outputs at least one of a first comparator output (cmp 1 ) or a second comparator output (cmp 2 ). In some embodiments, at least one of cmp 1  or cmp 2  is a function of whether Diff-out is greater or less than at least one of vth 1  or the vth 2 . In some embodiments, at least one of cmp 1  or cmp 2  is inverted by an inverter  408 . 
     In some embodiments, the decision circuit  140  is electrically connected to the AC signal level comparator  130 . In some embodiments, the decision circuit  140  is a logic circuit. In some embodiments, the decision circuit  140  includes at least one of a nand gate  410  or a latch  412 . In some embodiments, at least one of cmp 1  or cmp 2  is imputed into the nand gate  410 . In some embodiments, a nand output (No) is inputted into the latch  412 . In some embodiments, the latch  412  is configured to output a one bit signal (Do) to indicate whether or not there is a bio-reaction. In some embodiments, the latch clock  154  is connected to the latch  412 . In some embodiments, the latch  412  comprises a DQ flip-flop. In some embodiments, the latch clock  154  is synchronized with the sampling clock  150 . In some embodiments, the latch  142  is configured to latch the result through the latch clock  154 . In some embodiments, the decision circuit  140  includes additional nand gates (not illustrated) connected to at least one of the additional comparator(s) (not illustrated). 
     In some embodiments, the decision circuit  140  is associated with or operates according to a truth table  500 , illustrated in  FIG. 6 . In some embodiments, if the Diff-out is greater than vth 1  then the first comparator  402  and the second comparator  404  will both output  1  and the decision circuit  140  will output  1  indicative that a bio-reaction was sensed. In some embodiments, if the Diff-out is less than vth 1  but greater than vth 2  then the first comparator  402  will output  0  and the second comparator  404  will output  1  and the decision circuit  140  will output  0  indicative that no bio-reaction was sensed. In some embodiments, if the output of the differentiator  120  is less than vth 2  then the first comparator  402  and the second comparator  404  will output  0  and the decision circuit  140  will output  1  indicative of a bio-reaction being sensed. In some embodiments, an output from each of the ion sensitive sensors  110   a - 110   i  is used to directly indicate whether there is a bio-reaction or not using at least one of the differentiator  120 , AC signal level comparator  130  or decision circuit  140 . 
     In some embodiments, at least one of low frequency noise, long-term drift, ion diffusion, or pixel-to-pixel crosstalk associated with an ion sensitive sensor  110  is mitigated by implementing at least one of the differentiator  120 , AC signal level comparator  130  or decision circuit  140 . In some embodiments, low frequency noise is mitigated without the need for a memory cell or a quantizer. 
     Referring to  FIG. 7 , illustrated is a flow diagram of a method  600  for sensing a bio-reaction according to some embodiments. In some embodiments, additional processes are provided at least one of before, during, or after the method  600  of  FIG. 7 . At  602 , a biological material is brought into contact with a biosensor, such as biosensor  10 . In some embodiments, the biological material is brought into contact with an ion sensitive sensor, such as  110   a,  of the biosensor  10 . In some embodiments, the biological material contacts a gate of an ISFET. In some embodiments, the biological material is provided in a liquid form. At  604 , a response of the biosensor to the biological material is sensed. In some embodiments, the biological material contacting the gate of the ISFET changes the threshold voltage of the ISFET, and alters an output current or voltage of the ISFET. At  606 , a signal indicative of a response is detected. In some embodiments, the signal is at least one of a voltage signal or a current signal. In some embodiments, the signal is an AC signal. At  608 , the signal is differentiated. In some embodiments, a difference between a first signal and a second signal is adjusted by a gain in differentiating the signal. At  610 , the signal is compared to a first reference signal. In some embodiments, the signal is compared to a second reference signal. In some embodiments, at least one of the first reference signal or the second reference signal is a threshold voltage. In some embodiments, at least one of the first reference signal or the second reference signal is tuned to a desired threshold voltage. At  612 , a determination is made as to whether a bio-reaction occurred based upon the comparison. In some embodiments, a decision circuit  140  is used to determine if there is a bio-reaction. In some embodiments, the decision circuit  140  directly shows if there is a bio-reaction or not. 
     Still another embodiment involves a computer-readable medium comprising processor-executable instructions configured to implement one or more of the techniques presented herein. An example embodiment of a computer-readable medium or a computer-readable device is illustrated in  FIG. 8 , wherein the implementation  800  comprises a computer-readable medium  808 , such as a CD-R, DVD-R, flash drive, a platter of a hard disk drive, etc., on which is encoded computer-readable data  806 . This computer-readable data  806 , such as binary data comprising at least one of a zero or a one, in turn comprises a set of computer instructions  804  configured to operate according to one or more of the principles set forth herein. In some embodiments, the processor-executable computer instructions  804  are configured to perform a method  802 , such as at least some of the exemplary method  600  of  FIG. 7 , for example. Many such computer-readable media are configured to operate in accordance with the techniques presented herein. 
     According to some aspects of the instant disclosure, a circuit arrangement is provided. The circuit arrangement comprises an ion sensitive sensor, a differentiator electrically connected to the ion sensitive sensor, an AC signal level comparator electrically connected to the differentiator and a decision circuit electrically connected to the AC signal level comparator. 
     According to some aspects of the instant disclosure, a circuit arrangement is provided. The circuit arrangement comprises an ion sensitive sensor, a differentiator electrically connected to the ion sensitive sensor, an AC signal level comparator electrically connected to the differentiator and a decision circuit electrically connected to the AC signal level comparator. The AC signal level comparator comprising a first comparator. The decision circuit comprising a nand gate. 
     According to some aspects of the instant disclosure, a method is provided. The method comprising contacting a biosensor with a biological material, sensing a response of the biosensor to the biological material by a ion sensitive sensor, detecting a signal indicative of the response, differentiating the signal, comparing the signal to a reference signal and determining if there is a bio-reaction based upon the comparison. 
     The foregoing outlines features of several embodiments so that those skilled in the art may better understand the aspects of the present disclosure. Those skilled in the art should appreciate that they may readily use the present disclosure as a basis for designing or modifying other processes and structures for carrying out the same purposes and/or achieving the same advantages of the embodiments introduced herein. Those skilled in the art should also realize that such equivalent constructions do not depart from the spirit and scope of the present disclosure, and that they may make various changes, substitutions, and alterations herein without departing from the spirit and scope of the present disclosure. 
     Various operations of embodiments are provided herein. The order in which some or all of the operations are described should not be construed as to imply that these operations are necessarily order dependent. Alternative ordering will be appreciated given the benefit of this description. Further, it will be understood that not all operations are necessarily present in each embodiment provided herein. Also, it will be understood that not all operations are necessary in some embodiments. 
     Further, unless specified otherwise, “first,” “second,” or the like are not intended to imply a temporal aspect, a spatial aspect, an ordering, etc. Rather, such terms are merely used as identifiers, names, etc. for features, elements, items, etc. For example, a first channel and a second channel generally correspond to channel A and channel B or two different or two identical channels or the same channel. 
     It will be appreciated that layers, features, elements, etc. depicted herein are illustrated with particular dimensions relative to one another, such as structural dimensions or orientations, for purposes of simplicity and ease of understanding and that actual dimensions of the same differ substantially from that illustrated herein, in some embodiments. 
     Moreover, “exemplary” is used herein to mean serving as an example, instance, illustration, etc., and not necessarily as advantageous. As used in this application, “or” is intended to mean an inclusive “or” rather than an exclusive “or”. In addition, “a” and “an” as used in this application are generally be construed to mean “one or more” unless specified otherwise or clear from context to be directed to a singular form. Also, at least one of A and B or the like generally means A or B or both A and B. Furthermore, to the extent that “includes”, “having”, “has”, “with”, or variants thereof are used in either the detailed description or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising”. 
     Also, although the disclosure has been shown and described with respect to one or more implementations, equivalent alterations and modifications will occur to others skilled in the art based upon a reading and understanding of this specification and the annexed drawings. The disclosure includes all such modifications and alterations and is limited only by the scope of the following claims. In particular regard to the various functions performed by the above described components (e.g., elements, resources, etc.), the terms used to describe such components are intended to correspond, unless otherwise indicated, to any component which performs the specified function of the described component (e.g., that is functionally equivalent), even though not structurally equivalent to the disclosed structure. In addition, while a particular feature of the disclosure may have been disclosed with respect to only one of several implementations, such feature may be combined with one or more other features of the other implementations as may be desired and advantageous for any given or particular application.