Abstract:
A method for performing a blood assay includes the steps of positioning an optical biosensor in fluid communication with a blood vessel whereby blood from the blood vessel contacts the biosensor. The biosensor includes at least one material adapted to bind to an analyte. The method also includes the steps of detecting a change in at least one optical property of the biosensor resulting from binding of the at least one material with the analyte and transmitting a continuous signal representative of the change in at least one optical property of the biosensor to a display module to provide real time analysis by a clinician.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
       [0001]    The present application claims the benefit of U.S. Provisional Application Ser. No. 61/076,225 entitled “SYSTEM AND METHOD FOR OPTICAL CONTINUOUS DETECTION OF AN ANALYTE IN BLOODSTREAM” filed on Jun. 27, 2008 by Peter Meyer, the entire disclosure of which is incorporated by reference herein. 
     
    
     BACKGROUND 
       [0002]    1. Technical Field 
         [0003]    The present disclosure relates to a system and method for performing blood assays. In particular, the present disclosure is directed to in vivo optical biosensors configured to continuously monitor blood to detect the presence and/or concentration of an analyte of interest. 
         [0004]    2. Background of Related Art 
         [0005]    Various types of blood analyzers for detecting specific analytes of interest (e.g., proteins) are known in the art. A conventional blood analyzer utilizes a sensor to detect the presence of the analyte and optionally determines the concentration thereof. In vitro methods are usually utilized to obtain a blood sample from a blood vessel and subsequently provide the sample to the blood analyzer for analysis. 
         [0006]    Rapid diagnosis of a clinical condition is key to limiting severity of the illness. Conventional blood analyzers, which perform an in-vitro analysis on blood drawn from the patient at a single point in time, are appropriate when the concentration of the blood analyte of interest (e.g. viral infection) is approximately constant over the treatment time. However, known blood analyzers of the type aforementioned present a major drawback which detracts from their overall usefulness and effectiveness. In particular, the conventional blood analyzer is incapable of providing real or present time data of the analyte of interest present in the blood stream. In clinical situations where the concentration of an analyte of interest in the blood can be expected to change rapidly (e.g. myocardial infarction), conventional blood analyzers fail to detect the clinically meaningful rate of change in analyte concentration. Moreover, the conventional blood analyzer is limited in that it can only indicate the presence of the analyte at the moment when the sample of blood was drawn. In many applications, the amount of analyte present does not exhibit elevated concentrations in the bloodstream until several hours after the biological event. It is therefore possible to misdiagnose the patient because the blood used in the diagnostic assay was drawn before the analyte of interest had reached the threshold of clinical significance. 
         [0007]    One conventional solution involves performing multiple in vitro assays to periodically screen the blood for elevated concentration of the analyte. However, performing multiple assays is overly invasive to the patient. In addition, this solution is also imperfect since there is a possibility that occurrence of the biological event may be missed, or its detection delayed by as long as the time interval between successive blood draws. 
         [0008]    This particular problem is acutely prevalent in the field of monitoring of acute myocardial infarction patients. Biochemical markers associated with myocardial infarction (e.g., cardiac troponin) are detectable in the patient&#39;s blood stream about 3 to 8 hours from the onset of the condition. In the absence of other indications of the condition (e.g., electrocardiogram indicators, acute distress, etc.), a patient complaining of physical conditions associated with myocardial infarction (e.g., chest pain) is typically observed for up to 12 hours to rule out the infarction as the cause of the symptoms. Conventionally, cardiac marker assays are typically performed serially at 6-8 hour intervals in order to detect a recent infarction. Due to the relatively long time periods between assays, a true infarction patient with biological signs of infarction may, as a result, wait for many hours before the signs are detected. Consequently, there is a delay in providing therapy to the patient. 
         [0009]    Therefore it would be desirable to provide a blood analyzer that continuously detects the presence of an analyte in a bloodstream to allow for instantaneous and continuous detection of elevated analyte concentration. 
       SUMMARY 
       [0010]    The present disclosure relates to a system and method for performing in vivo blood assay to detect the presence and concentration of an analyte. The system includes an optical biosensor having an antibody material adapted to bind to the analyte of interest. The biosensor is in fluid communication with a blood vessel such that blood continuously contacts the biosensor and the analyte binds to the antibody material. Excitation light is supplied to the biosensor and passes therethrough. Certain properties of the emitted light are affected by the presence of analyte at or near the surface of the biosensor due to binding of the analyte to the antibody material. Changes in the emitted light are monitored and analyzed by a detector which then calculates the concentration of the analyte in the bloodstream. The calculations are then transmitted to a monitor for display. 
         [0011]    According to one aspect of the present disclosure, a medical analyzer to assay blood for an analyte is disclosed. The analyzer includes an optical biosensor adapted to be in fluid communication with a blood vessel whereby blood from the blood vessel contacts the biosensor. The biosensor includes at least one material adapted to bind to an analyte of the blood. The analyzer also includes an excitation source for supplying excitation light to the biosensor and a detector adapted to detect a change in emitted light by the biosensor resulting from the binding of the at least one material of the biosensor with the analyte of the blood. The detector is also adapted to generate a continuous signal representative of the change in the at least one optical property of the biosensor to provide real time analysis by a clinician. 
         [0012]    According to another aspect of the present disclosure, a medical analyzer to assay blood for an analyte is disclosed. The analyzer includes an optical biosensor adapted to be in fluid communication with a blood vessel whereby blood from the blood vessel contacts the biosensor. The biosensor includes at least one material adapted to bind to an analyte of the blood. The biosensor is adapted to transmit a change in at least one optical property of the biosensor resulting from the binding of the at least one material of the biosensor with the analyte of the blood. 
         [0013]    According to another aspect of the present disclosure, a medical analyzer to assay blood for an analyte is disclosed. The analyzer includes an optical biosensor adapted to be in fluid communication with a blood vessel whereby blood from the blood vessel contacts the biosensor. The biosensor includes at least one material adapted to bind to an analyte of the blood. The analyzer also includes an excitation source for supplying excitation light to the biosensor and a detector adapted to detect a change in emitted light by the biosensor resulting from the binding of the at least one material of the biosensor with the analyte of the blood. The detector is also adapted to generate signal representative of the second time derivative of the at least one optical property of the biosensor to provide a measurement of the rate of change in analyte concentration to a clinician for analysis. 
         [0014]    A method for performing a tissue assay is also contemplated according to the present disclosure. The method includes the steps of positioning a biosensor in fluid communication with tissue of the patient whereby the tissue contacts the biosensor. The biosensor includes a material adapted to bind to an analyte. The method also includes the steps of detecting a change in at least one optical property of the biosensor resulting from binding of the at least one material with the analyte and transmitting a continuous signal representative of the change in the at least one optical property of the biosensor to a display module to provide real time analysis by a clinician. 
         [0015]    A method for performing a blood assay is also contemplated according to the present disclosure. The method includes the steps of positioning an optical biosensor in fluid communication with a blood vessel of the patient whereby blood from the blood vessel contacts the biosensor. The biosensor includes a material adapted to bind to an analyte. The method also includes the steps of detecting a change in at least one optical property of the biosensor resulting from binding of the at least one material with the analyte and transmitting a continuous signal representative of the change in the at least one optical property of the biosensor to a display module to provide real time analysis by a clinician. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS  
         [0016]    Various embodiments of the present disclosure are described herein with reference to the drawings wherein: 
           [0017]      FIG. 1  is a view of a blood analyzer according to the present disclosure accessing a blood vessel; 
           [0018]      FIG. 2  is a cross-sectional view of the probe of the blood analyzer; 
           [0019]      FIG. 3  is a cross-sectional view of entry end of the probe of the blood analyzer illustrating the biosensor within the probe according to the present disclosure; 
           [0020]      FIGS. 4A-B  are diagrams of excitation and emitted light waveforms; 
           [0021]      FIG. 5  is a cross-sectional view of entry end of the probe of the blood analyzer illustrating the biosensor within the probe according to another embodiment of the present disclosure; and 
           [0022]      FIG. 6  is a flow diagram of a method for performing a blood assay according to the present disclosure. 
       
    
    
     DETAILED DESCRIPTION  
       [0023]    Particular embodiments of the present disclosure are described hereinbelow with reference to the accompanying drawings. In the following description, well-known functions or constructions are not described in detail to avoid obscuring the present disclosure in unnecessary detail. 
         [0024]    Referring now to  FIGS. 1-3 , blood analyzer  10  in accordance with the principles of the present disclosure is illustrated. Generally, blood analyzer  10  includes an access member or a probe  12  and a monitor  14  in electrical communication with the probe  12 . The probe  12  has a proximal end  16  and a distal end  18 . The probe  12  may be any tubular structure (e.g., a catheter or a cannula) having a housing  20  and a lumen  22  defined therein and one or more ports  24  at the distal end  18  thereof adapted to provide fluid access to the lumen  22 . The distal end  18  of the probe  12  is inserted into a blood vessel “V” to allow for the blood to flow into the lumen as illustrated by directional arrows  26 . It is envisioned that the distal end  18  may be configured for penetration and insertion into the blood vessel “V.” Alternatively, a tissue-penetrating device may be utilized to create an orifice in the blood vessel “V” into which the probe  12  is later inserted. The blood flows into and through the lumen  22  through the ports  24 . Specifically, a portion of the venous circulation is diverted from the vessel “V”, passes through the probe  12  and is returned to the venous circulation. An exemplary probe for use with evanescent wave sensors is disclosed in U.S. Pat. Nos. 5,340,715 and Nos. 5,156,976, the entire contents of which is incorporated by reference herein. 
         [0025]    Probe  12  includes an optical biosensor  28  disposed within the lumen  22  which is in fluid communication with the blood flowing through the blood vessel “V.” This allows for the blood analyzer  10  to continuously monitor the blood stream for analyte  30  of interest. The biosensor  28  may be an optical sphere-shaped microresonator  29  as shown in  FIG. 3  or a prism as shown in  FIG. 5 . The sphere-shaped microresonator  29  may have a diameter ranging from about 200 to 400 micrometers, preferably about 300 micrometers and may be formed from glass or similar material. The biosensor  28  is configured to resonate in response to excitation light of a predetermined frequency. 
         [0026]    The optical microresonator  29  includes a capture agent  32  disposed on the surface thereof. The capture agent  32  may be, for example, specific antibodies adapted to bind to an analyte  30  of interest. Analytes of interest include cardiac troponin, myoglobin, creatinine kinase, creatine kinase isozyme MB, albumin, myeloperoxidase, C-reactive protein, ischemia-modified albumin or fatty acid binding protein and the like. The capture agent  32  may be bound to the surface of the optical microresonator  29  using any number of conventional deposition techniques, such as covalent bonding, physical absorption, or cross-linking to a suitable carrier matrix. 
         [0027]    During operation, the microresonator  29  is in fluid communication with the blood. If analyte  30  is present in the blood, the analyte  30  binds to the capture agent  32  to form a bound complex  34 . As the capture agent  32  continuously binds to the analyte  30  to form the complex  34 , the amount of analyte  30  at or near the surface of the microresonator  29  increases. This, in effect, alters properties of the evanescent field surrounding the microresonator  29  and the light emitted therefrom. The concentration of analyte  30  is capable of being measured by measuring changes in optical properties of the microresonator  29  as discussed hereinbelow. 
         [0028]    Prior to commencement of the analysis, the probe  12  is inserted into the blood vessel such that the microresonator  29  is in fluid communication with the blood. The monitor  14  is calibrated. The optical microresonator  29  is optically coupled to an excitation source  36  and a detector  38  via an excitation source waveguide  40  and a detector waveguide  42 , respectively. The waveguides  40  and  42  may be optical fibers which are evanescently coupled to the microresonator  29 . The optical fibers may be eroded at the distal ends thereof which are coupled to the microresonator  29  by removing reflective cladding from the fibers. 
         [0029]    The excitation source  36  supplies an excitation light, shown as an excitation light waveform  41 , to the optical microresonator  29  through the excitation source waveguide  40  to excite the biosensor  30  and thereby create an evanescent field around the biosensor  30 . The excitation light is supplied to the microresonator  29  at an eigenfrequency, a frequency which induces optical resonance of the microresonator  29 . In response to the excitation light, the microresonator  29  emits light, shown as an emitted light waveform  43 , which is transmitted through the detector waveguide  42  to the detector  38 . Measuring intensity of the emitted light (e.g., light returning from the microresonator  29 ) allows for the determination of the amount of antigen bound to the microresonator  29 . 
         [0030]    In a first embodiment, the light supplied by the excitation source  36  is of fixed wavelength and the intensity of the light source is modulated. In this embodiment, the phase lag between the emitted light waveform  43  and the excitation light waveform  41  is solely due to the surface properties of the microresonator  29 . This allows for measurement of the phase lag ρ (e.g., difference) between the emitted light waveform  43  and the excitation light waveform  41  as shown in  FIG. 4A . The phase lag is then used to determine the amount of bound antigen. 
         [0031]    In an alternate embodiment, the light from the excitation source  36  is pulsed, and the so-called “ring down time,” which is a characteristic time constant of the microresonator is measured to characterize the surface properties of the microresonator  29 . The ring down time, which is different for each specific analyte, is the time it takes for the intensity of the excitation light waveform  41  to decrease to a predetermined value (e.g., from 100% to 10%) of the emitted light waveform  43  as shown in  FIG. 4B . In either embodiment, the detector  38  transmits a signal to the monitor  14  that is indicative of the amount of antigen bound to the microresonator  29 . 
         [0032]    Throughout this document, the term “continuous” is used to refer to measurements which may be made continuously, or discretely at relatively short time intervals, which are sufficiently brief to result in essentially or approximately continuous measurement. In the aforementioned embodiment, the excitation waveform  41 , and therefore the signal to the monitor  14  indicative of the amount of antigen bound to the microresonator, is pulsed rather than continuous. However, in this and similar embodiments, the pulse rate is selected such that the clinically meaningful output to the clinician is essentially continuous. For example, if, for a given pathological condition, the concentration of an analyte of interest is expected to rise to a clinical detection threshold in 1 hour, the collection of one measurement per minute may be sufficient to provide a continuous or approximately continuous clinical measurement. 
         [0033]    The excitation source  36  and the detector  38  are coupled to the monitor  14  via two or more wires, excitation wires  44 ,  46  and emission wires  48 ,  50 , respectively, to the monitor  14 . The probe  12  at its proximal end  16  includes a cable  18  which encloses the wires  44 ,  46 ,  48 ,  50 . The monitor  14  includes input controls and a display (not explicitly shown). During operation, the excitation source  36  supplies excitation light to the microresonator  29 . As analyte  30  binds to the capture agent  32  and complex  34  is formed, the properties of the emitted light waveform change, including changes in intensity, ring down time constant, and phase lag between the excitation light waveform  41  and the emitted light waveform  43 . These variables of the emitted light are recorded by the detector  38  which then analyzes the results and determines the amount of the bound analyte. 
         [0034]    The detector  38  includes programmable instructions (e.g., algorithm) adapted to calculate the concentration of the analyte  30  as a function of the change in the emitted light. The detector  38  converts the changes in the emitted light measured by the detector  38  and determines presence, concentration and/or change in concentration of the analyte  30 . A change in the evanescent field or the emitted light of the microresonator  29  signifies that the analyte  30  has been captured by the capture agent  32  to form the complex  34 . The detector  38  transmits the calculations and/or signals corresponding to changes in the evanescent field and/or emitted light of the biosensor  28  to the monitor  14 . The monitor  14  then formats the data relating to the concentration of the analyte  30  for output on the display. This step may include displaying that the analyte  30  is present in the blood stream (e.g., displaying text “analyte detected.”). 
         [0035]    It is further contemplated that the detector  38  is configured to calculate a time derivative of the change in concentration of the analyte  30 . In particular, the rate of change of the light properties of the microresonator  29  allows for determination of the concentration of the analyte  30 . Taking a second time derivative of the light properties of the microresonator  29  allows for calculation of the rate of change in the concentration of the analyte  30 . It is within the purview of those skilled in the art to provide programmable instructions to the detector to enable calculation of derivatives. The data relating to the concentration of the analyte  30  in the bloodstream allows for a more detailed analysis of the test results. In particular, as opposed to simply outputting whether the analyte  30  is present in the bloodstream, knowing the concentration of the analyte  30  and the rate at which the analyte  30  is being generated provides health professionals with a tool to determine the severity of the condition (e.g., myocardial infarction). The detected concentration or the change in concentration of the analyte  30  may be outputted as grams per liter of blood (e.g., μg/L). 
         [0036]    The microresonator  29  may operate continuously, wherein the excitation source  36  continuously supplies excitation light to the microresonator  29  and the detector  38  continuously receives the emitted light. In some embodiments, the excitation source  36  pulses the excitation light and the detector  38  measures the so called “ring down time,” the characteristic time constant of the microresonator  29  associated with surface properties thereof. 
         [0037]    The microresonator  29  ceases to function when all of the antibodies are bound to the analyte  30  and no more analyte  30  can be bound thereto. Therefore, the duration of the functionality of the microresonator  29  varies with the concentration of the analyte  30  in the patient&#39;s blood. 
         [0038]      FIG. 5  shows another embodiment of the biosensor  28  which employs principles of surface plasmon resonance. In this embodiment, the biosensor  28  includes an optical prism  52  having a first side  53 , a base  54  and a second side  55 . A metallic layer  56  is disposed on the base  54 . The metallic layer  56  is formed from metals such as gold, copper, silver and/or combination thereof. It is also envisioned that a dielectric material may be used as substitute for the metallic layer  56 . The metallic layer  56  includes the capture agent  32  disposed on the unattached surface thereof. 
         [0039]    The prism  52  is optically coupled to the excitation source  36  and the detector  38 . The excitation source  36  supplies a monochromatic light at incident angles through the side  53  sufficient to produce internal reflectance. Due to surface plasmon resonance, the excitation light is partially reflected through the side  55  and partially propagated through the metallic layer  56 . The resulting electromagnetic evanescent wave traveling along the metal layer is altered by binding of analyte  30  to the metallic layer  56 . The intensity of the reflected light is thereby altered by energy transfer between the evanescent wave and surface plasmons. The excitation source  36  modulates the angle of incidence to identify surface plasmon resonance angle, where the intensity of the reflected light experiences a local minimum. 
         [0040]    The detector  38  receives the reflected light from the side  53 , measures the intensity of the reflected light and determines the surface plasmon resonance angle. The detector  38  then transmits a signal to the monitor  14  indicative of the amount of analyte  30  bound to the prism  52 . The monitor  14  then calculates concentration, rate of change in concentration of the analyte  30 . 
         [0041]    A method for performing a blood assay is illustrated in  FIG. 6 . In step  100 , the biosensor  28  is positioned in fluid communication with the blood. This may be accomplished by positioning the biosensor  28  within an access member (e.g., probe  12 ) which is then inserted into the blood vessel “V”. As discussed above, when the probe  12  is inserted into the blood vessel, the blood flows into the lumen  22  thereby positioning the biosensor  28  in fluid communication with the blood. Alternatively, it is envisioned that blood may be withdrawn through a first lumen of the probe  12  to an external location, passed over the biosensor  28  at the ex vivo location and returned through a second lumen of the probe  12  to the patient. 
         [0042]    In step  102 , the excitation source  36  transmits excitation light to the biosensor  28 , either the microresonator  29  or the prism  52 . In step  104 , the concentration and change in concentration of the analyte  30  is determined by the detector  38 . The detector  38  measures the light returning from the biosensor  28  and determines, based on intensity, ring down time constant, and phase lag of the emitted light, the change in concentration of the analyte  30 . As discussed above, the concentration of the analyte  30  is attributed to the binding of the analyte  30  to the capture agent  32  disposed on the surface of the biosensor  28 . In particular, the detector  38  calculates the concentration by measuring the optical properties of the biosensor  28 . The concentration of the analyte  30  is determined by calculating the rate of change of the optical properties of the biosensor  28 . The rate of change of concentration of the analyte  30  is calculated by taking a second time derivative of optical properties of the biosensor  28 . 
         [0043]    In step  106 , the detector  38  transmits the signal relating to the concentration of the analyte  30  to the display of the monitor  14  to provide a clinician with continuous analysis of the level of the analyte  30 . The signal may include, but is not limited to, an indicator that analyte  30  is present, an indicator of the concentration of the analyte  30 , an indicator of the change in concentration of the analyte  30 , and an indicator of the rate of change in concentration of the analyte  30 . The clinician then compares the concentration of the analyte to a first predetermined clinical threshold to determine if a particular treatment is warranted. 
         [0044]    Further, the monitor  14  is also adapted to display the rate of change in the analyte concentration. The clinician compares the rate of change in analyte concentration to a second predetermined clinical threshold to determine if a particular treatment is warranted. The monitor  14  may optionally include automatic alarms to alert the clinician that the analyte concentration has exceeded one or more threshold values. 
         [0045]    While several embodiments of the disclosure have been shown in the drawings and/or discussed herein, it is not intended that the disclosure be limited thereto, as it is intended that the disclosure be as broad in scope as the art will allow and that the specification be read likewise. For example, it is envisioned that the biosensor and/or monitor could evaluate or perform an assay on other body fluid, tissues, enzymes etc. Therefore, the above description should not be construed as limiting, but merely as exemplifications of particular embodiments. Those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.