Abstract:
A medical diagnostic device for measuring an analyte concentration or property of a biological fluid includes capillary flow channels to convey a sample of the fluid from an inlet to a branching point, and then to a measurement area and, alternatively, through a bypass channel to an overflow region. A first stop junction stops fluid flow after it enters the measurement area. The bypass channel has a capillary dimension in at least one direction. A second stop junction, in the bypass channel, has boundary region that has a dimension that is greater in that direction and forms an angle that points toward the branching point. With this construction, the second stop junction initially prevents flow to the overflow region, but permits the flow after the measurement area is filled. The device is particularly suited for measuring coagulation time of blood.

Description:
CROSS-REFERENCE TO PRIOR APPLICATION 
     This application relates to U.S. application Ser. Nos. 09/333,765, filed Jun. 15, 1999 , now U.S. Pat. No. 6,521,182, issued on Feb. 18, 2003; and 09/354,995, filed Jul. 16, 1999, now U.S. Pat. No. 6,084,660, issued on Jul. 4, 2000. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to a medical diagnostic device that includes an element for controlling fluid flow through the device; more particularly, to a device that facilitates fluid flow through a stop junction. 
     2. Description of the Related Art 
     A variety of medical diagnostic procedures involve tests on biological fluids, such as blood, urine, or saliva, to determine an analyte concentration in the fluid. The procedures measure a variety of physical parameters—mechanical, optical, electrical, etc.,—of the biological fluid. 
     Among the analytes of greatest interest is glucose, and dry phase reagent strips incorporating enzyme-based compositions are used extensively in clinical laboratories, physicians&#39; offices, hospitals, and homes to test samples of biological fluids for glucose concentration. In fact, reagent strips have become an everyday necessity for many of the nation&#39;s estimated 16 million people with diabetes. Since diabetes can cause dangerous anomalies in blood chemistry, it can contribute to vision loss, kidney failure, and other serious medical consequences. To minimize the risk of these consequences, most people with diabetes must test themselves periodically, then adjust their glucose concentration accordingly, for instance, through diet, exercise, and/or insulin injections. Some patients must test their blood glucose concentration as often as four times or more daily. 
     One type of glucose measurement system operates electrochemically, detecting the oxidation of blood glucose on a dry reagent strip. The reagent generally includes an enzyme, such as glucose oxidase or glucose dehydrogenase, and a redox mediator, such as ferrocene or ferricyanide. This type of measurement system is described in U.S. Pat. No. 4,224,125; issued on Sep. 23, 1980, to Nakamura et al.; and U.S. Pat. No. 4,545,382, issued on Oct. 8, 1985, to Higgins et al., incorporated herein by reference. 
     Hodges et al., WO 9718464 A1, published on May 22, 1997, discloses an electrochemical device for measuring blood glucose that includes two metallized polyethylene terephthalate (PET) layers sandwiching an adhesive-coated PET intermediate layer. The metallized layers constitute first and second electrodes, and a cutout in the adhesive-coated layer defines an electrochemical cell. The cell contains the reagent that reacts with the glucose in a blood sample. The device is elongated, and the sample is introduced at an inlet on one of the long sides. 
     The electrochemical devices for measuring blood glucose that are described in the patents cited above, as well as other medical diagnostic devices used for measuring analyte concentrations or characteristics of biological fluids, generally share a need to transport the fluid from a sample inlet to one or more other sections of the device. Typically, a sample flows through capillary channels between two spaced-apart surfaces. A number of patents, discussed below, disclose medical diagnostic devices and include descriptions of various methods to control the flow of the sample. 
     U.S. Pat. No. 4,254,083, issued on Mar. 3, 1981, to Columbus, discloses a device that includes a sample inlet configured to facilitate movement of a drop of fluid sample into the device, by causing a compound meniscus to form on the drop. (See also U.S. Pat. No. 5,997,817, issued on Dec. 7, 1999 to Crismore et al.) 
     U.S. Pat. No. 4,426,451, issued on Jan. 17, 1984 to Columbus, discloses a multi-zone fluidic device that has pressure-actuatable means for controlling the flow of fluid between the zones. His device makes use of pressure balances on a liquid meniscus at the interface between a first zone and a second zone that has a different cross section. When both the first and second zones are at atmospheric pressure, surface tension creates a back pressure that stops the liquid meniscus from proceeding from the first zone to the second. The configuration of this interface or “stop junction” is such that the liquid flows into the second zone only upon application of an externally generated pressure to the liquid in the first zone that is sufficient to push the meniscus into the second zone. 
     U.S. Pat. No. 4,868,129, issued on Sep. 19, 1989 to Gibbons et al., discloses that the back pressure in a stop junction can be overcome by hydrostatic pressure on the liquid in the first zone, for example by having a column of fluid in the first zone. 
     U.S. Pat. No. 5,230,866, issued on Jul. 27, 1993 to Shartle et al., discloses a fluidic device with multiple stop junctions in which the surface tension-induced back pressure at the stop junction is augmented; for example, by trapping and compressing gas in the second zone. The compressed gas can then be vented before applying additional hydrostatic pressure to the first zone to cause fluid to flow into the second zone. By varying the back pressure of multiple stop junctions in parallel, “rupture junctions” can be formed, having lower maximum back pressure. 
     U.S. Pat. No. 5,472,603, issued on Dec. 5, 1995 to Schembri (see also U.S. Pat. No. 5,627,041), discloses using centrifugal force to overcome the back pressure in a stop junction. When flow stops, the first zone is at atmospheric pressure plus a centrifugally generated pressure that is less than the pressure required to overcome the back pressure. The second zone is at atmospheric pressure. To resume flow, additional centrifugal pressure is applied to the first zone, overcoming the meniscus back pressure. The second zone remains at atmospheric pressure. 
     U.S. Pat. No. 6,011,307, issued on Dec. 14, 1999, to Naka et al., published on Oct. 29, 1997, discloses a device and method for analyzing a sample that includes drawing the sample into the device by suction, then reacting the sample with a reagent in an analytical section. Analysis is done by optical or electrochemical means. In alternate embodiments, there are multiple analytical sections and/or a bypass channel. The flow among these sections is balanced without using stop junctions. 
     U.S. Pat. No. 5,700,695, issued on Dec. 23, 1997 to Yassinzadeh et al., discloses an apparatus for collecting and manipulating a biological fluid that uses a “thermal pressure chamber” to provide the driving force for moving the sample through the apparatus. 
     U.S. Pat. No. 5,736,404, issued on Apr. 7, 1998, to Yassinzadeh et al., discloses a method for determining the coagulation time of a blood sample that involves causing an end of the sample to oscillate within a passageway. The oscillating motion is caused by alternately increasing and decreasing the pressure on the sample. 
     None of the references discussed above suggest a device in which a flow channel has a stop junction that is angular in the flow direction. 
     SUMMARY OF THE INVENTION 
     This invention provides a medical device for measuring an analyte concentration or property of a biological fluid. This embodiment of the device comprises 
     a) a sample inlet for introducing a sample of the biological fluid into the device; 
     b) a first capillary channel for conveying the sample from the inlet to a branching point; 
     c) a capillary connecting channel for conveying a first part of the sample from the branching point through a measurement area, in which is measured a physical parameter of the sample that is related to the analyte concentration or property of the fluid, and to a first stop junction; 
     d) a capillary bypass channel for conveying a second part of the sample in a first direction from a first region, proximate to the branching point, to an overflow region, distal to the branching point, the first region having a capillary dimension in a second direction substantially perpendicular to the first direction; 
     e) a second stop junction in the bypass channel, comprising a boundary region that
         i) separates the first and overflow regions,   ii) has a second predetermined dimension in the second direction that is greater than the capillary dimension, and   iii) forms an angle that points toward the first region, whereby any excess sample that enters the sample inlet will pass through the second stop junction into the overflow region.       

     Devices of the present invention provide, in a capillary flow channel of the device, a stop junction that is angular in the flow direction. Such a stop junction can be designed with readily-controlled break-through pressure. Note that in the present specification and the figures, capillaries are shown bounded by parallel plates. In that case, the “second direction”. which has the capillary dimension, is uniquely determined. Alternatively, capillaries of the invention could be cylindrical. In that case, the second direction is radial, in a planar circle, or disk, that is perpendicular to the direction of fluid flow. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  depicts the operation of a stop junction in a medical device. 
         FIGS. 2-5  depict the flow of a fluid in part of a device of this invention. 
         FIG. 6  is an exploded perspective view of a device of this invention. 
         FIG. 7  is a plan view of the device of FIG.  6 . 
         FIGS. 7A ,  7 B, and  7 C depict sample filling the device of FIG.  6 . 
         FIG. 8  is a plan view of a preferred embodiment of this invention, which includes three measurement areas. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     When fluid flows through a channel, a discontinuity in channel cross section can form a “stop junction,” which can stop the fluid flow, as described in U.S. Pat. Nos. 4,426,451; 5,230,866; and 5,912,134, incorporated herein by reference. The stop junction results from surface tension that creates a back pressure that stops the fluid meniscus from proceeding through the discontinuity. The stop junction is weakened, and flow thereby enhanced, when the leading edge of the meniscus encounters the vertex of an acute angle and is then stretched along the arms of the angle. This may be described as the angle “pointing” in a direction opposite to the direction of fluid flow. 
     This invention relates to a medical diagnostic device that has a flow channel with a stop junction. The stop junction is angular in the direction of flow, which permits fluid in the channel to break through the stop junction when there is a predetermined pressure difference across the stop junction. The advantages of such a controlled break-through stop junction are apparent from the description that follows. 
       FIG. 1  depicts part of a medical diagnostic strip  10  that is a multilayer sandwich. Top layer  12  and bottom layer  14  sandwich intermediate layer  16 . A cutout in intermediate layer  16  forms channel  18 . Lines  20  and  20 A are scored into the bottom surface of layer  12  and form in channel  18  stop junctions  21  and  21 A, respectively. Thus, sample S, introduced into channel  18  at sample inlet  22 , stops when it reaches stop junction  21 . 
       FIGS. 2 and 3  depict the part of a medical diagnostic strip of  FIG. 1  in which stop junctions  21  and  21 A have been modified by adding serrations  24  and  24 A, respectively. Serration  24  forms an acute angle A that “points” toward sample inlet  22 .  FIGS. 2 and 3  depict sample S just before and just after it breaks through stop junction  21 , respectively. Note that the breakthrough occurs first at the vertex that points opposite to the direction of fluid flow. The effectiveness of the serration in enhancing flow through a stop junction in a capillary channel depends on the angle and the length of the legs that form the angle. The smaller the angle and the longer the legs, the greater the effectiveness of the serration. Thus, if the angle is small and the legs long, only a small hydraulic pressure differential across the scored region will cause the sample to flow through it. Preferably, angle A is less than about 90° and its axis of symmetry is aligned with the direction of flow in the channel. 
     Stop junction  21 A has an angle that points toward end  26  of channel  18  that is opposite inlet  22 , and it would have reduced resistance to the flow of sample that entered end  26 .  FIGS. 4 and 5  depict the flow of sample through channel  18  after it has broken through stop junction  21 . In  FIG. 4 , the sample is stopped at stop junction  21 A. In  FIG. 5 , sample has passed through stop junction  21 A at its two ends. The breakthroughs occur there, because although the angles at the two ends are greater than 90°, they are smaller than the angle (i.e., the supplement of. the angle that points toward  26 ) at the center of serration  24 A. A short time after the sample reaches the position shown in  FIG. 5 , the sample will pass through stop junction  21 A across the entire width of channel  18 . 
       FIG. 6  is an exploded perspective view of an embodiment of the present invention. The diagnostic device  30  has a top layer  32  and bottom layer  34  sandwiching intermediate layer  36 . Elements of the device are formed by the layers, together with cutouts them. Depicted in  FIG. 6  are sample inlet  38 , formed by coaligned holes in intermediate layer  66  and top layer  32 ; first capillary channel  40 , for conveying sample from sample inlet  38  to branching point  42 ; and capillary connecting channel  44 , for conveying sample through measurement area  46  to a first stop junction  48 . Stop junction  48  is formed by the intersection of the capillary neck, at the end of measurement area  46 , and the coinciding holes  48 A,  48 B, and  48 C in intermediate layer  36 , top layer  32 , and bottom layer  34 , respectively. Holes  48 A,  48 B, and  48 C are conveniently punched in a single operation when the layers are together. In a less-preferred embodiment, only two holes are needed. Thus  48 B or  48 C could be omitted. 
     Measurement area  46  preferably contains a reagent  50 . Cutout  58  is part of a bladder that includes the adjoining regions of top layer  32  and bottom layer  34 . Capillary bypass channel  52  provides an alternate path from branching point  42  to overflow region  54 . A stop junction  56  in bypass channel  52  impedes flow into overflow region  54 . Stop junction  56  is formed by the intersection of capillary bypass channel  52  and the coinciding holes  56 A,  56 B, and  56 C in intermediate layer  36 , top layer  32 , and bottom layer  34 , respectively. (Either hole  56 B or  56 C can be omitted). Note that stop junctions  48  and  56  also require seals  48 D,  48 E, and  56 D,  56 E, respectively. 
       FIG. 7  is a top plan view of the device of FIG.  6 . The device depicted in  FIGS. 6 and 7  is particularly well suited for measuring blood-clotting time—“prothrombin time” or “PT time”—and details regarding such a device appear below. The modifications needed to adapt the device for other medical diagnostic applications require no more than routine experimentation. In operation, sample is applied to sample port  38  after bladder  58  has been compressed. Clearly, the region of top layer  32  and/or bottom layer  34  that adjoins the cutout for bladder  58  must be resilient, to permit bladder  58  to be compressed. When the bladder is released, suction draws sample through first capillary channel  40  to branching point  42  and through capillary connecting channel  44  to measurement area  46 . In order to ensure that measurement area  46  can be filled with sample, the volume of bladder  58  is preferably at least about equal to the combined volume of first channel  40 , connecting channel  44 , capillary bypass channel  52 , and measurement area  46 . If the measurement method is optical, and the measurement area  46  is to be illuminated from below, bottom layer  34  must be transparent where it adjoins measurement area  46 . For a PT test, reagent  50  contains thromboplastin that is free of bulking reagents normally found in lyophilized reagents. 
     As shown in  FIGS. 6 and 7 , sample is drawn into the device by suction, caused by decompression of bladder  88 . When the sample reaches stop junction  48 , sample flow stops. For PT measurements, it is important to stop the flow of sample as it reaches that point to permit reproducible “rouleaux formation”—the stacking of red blood cells—which is an important step in monitoring blood clotting using the present invention. 
     The function and operation of the bypass channel can be understood by referring to  FIGS. 7A ,  7 B, and  7 C which depict a time sequence during which a sample is drawn into device  30  for the measurement. 
       FIG. 7A  depicts the situation after a user has applied a sample to the strip, while bladder  58  is compressed. This can be accomplished by applying one or more drops of blood. 
       FIG. 7B  depicts the situation after the bladder is decompressed. The resulting reduced pressure in the first channel  40  and connecting channel  44  draws the sample initially into the measurement area  46 . When the sample reaches stop junction  48 , the sample encounters a back pressure that causes it to stop and causes additional sample to be drawn into the bypass channel toward stop junction  56 . Note that stop junction  56  is “weaker” than stop junction  48 , because it has an angle A that points toward branching point  42 . (See FIGS.  1 - 5 ). Thus weak stop junction  56  performs two functions. It first impedes the flow of sample into overflow region  54 , thus permitting measurement area  46  to fill rapidly. Second, it permits any excess sample to flow through it (after measurement area  46  is full) to relieve any pressure difference remaining on the two sides of stop junction  48 . Such a pressure difference could cause sample to “leak” through stop junction  48 , causing movement of sample through the measurement area, which is undesirable, for the reason discussed earlier. 
       FIG. 7C  depicts the situation when an equilibrium has been established among the pressures on the sample surfaces—atmospheric pressure on the sample in inlet  38  and the pressure on the free surfaces in overflow region  54  and stop junction  48 . 
       FIG. 8  depicts a preferred embodiment of the present device that includes three measurement areas. For a PT test, measurement area  146  contains thromboplastin. Preferably, measurement areas  146 A and  146 B contain controls, more preferably, the controls described below. Area  146 A contains thromboplastin, bovine eluate,. and recombinant Factor VIIa. The composition is selected to normalize the clotting time of a blood sample by counteracting the effect of an anticoagulant, such as warfarin. Measurement area  146 B contains thromboplastin and bovine eluate alone, to partially overcome the effect of an anticoagulent. Thus, three measurements are made on the strip. PT time of the sample, the measurement of primary interest, is measured on area  146 . However, that measurement is validated only when measurements on areas  146 A and  146 B yield results within a predetermined range. If either or both of these control measurements are outside the range, then a retest is indicated. Extended stop junction  148  stops flow in all three measurement areas. Stop junction  156 , in bypass channel  152 , functions as described above. 
     Additional details on this embodiment of the invention appear in copending U.S. patent application Ser. No. 09/333,765, filed on Jun. 15, 1999, and incorporated herein by reference.