Liquid measurement instrument

A measurement instrument for analyzing a body fluid of a human body comprises a casing having a pair of liquid inlets and a pair of liquid outlets, and a sensor assembly slidably telescoped in the casing. The sensor assembly comprises a pair of liquid passages each aligned with a corresponding one the pair of liquid inlets and a corresponding one of the pair of liquid outlets at a specified position of the sensor assembly. One of the liquid passages is associated with a sensor for being a specific ingredient in the body fluid.

BACKGROUND OF THE INVENTION 
(a) Field of the Invention 
The present invention relates to a liquid measurement instrument for 
continuously analyzing particular ingredients in a liquid by using 
electrochemical analysis and, more particularly, to a liquid measurement 
instrument suitable for analyzing body fluid such as human blood or other 
fluids. 
(b) Description of the Related Art 
A liquid measurement (test) instrument is generally used for analyzing 
ingredients in body fluid such as human blood. Patent Publication 
JP-A-1(1989)-101968 describes a conventional test instrument wherein a 
chemical sensor is used for testing blood ingredients extracted or sampled 
from a living body. 
FIG. 1 shows the conventional test instrument as mentioned above, wherein a 
catheter 51 for sampling human blood is connected to the test instrument 
through a connector 54 attached to a first end of the test instrument by a 
tube 52. The test instrument comprises a chemical sensor 55, a first 3-way 
cock 56, a second 3-way cock 57, a pressure sensor 58, a flow control 
valve 59 connected by pipe 53 and arranged in this order from the 
connector 54 toward the second end of the test instrument to which a 
reservoir 61 for receiving therein a reference liquid 60 is connected. A 
pH sensor, a partial-pressure sensor for detecting PO.sub.2 or PCO.sub.2, 
an electrolyte sensor for detecting Na, K, Cl or Mg, a protein sensor, a 
blood sugar sensor or other sensor is used as the chemical sensor 55 
depending on the use of the test instrument. 
The first 3-way cock 56 is disposed between the chemical sensor 55 and the 
second 3-way cock 57, with a branch port of the first 3-way cock 56 being 
connected to a syringe 62. The first 3-way cock either connects the 
catheter 51 with the second 3-way cock 57, with the syringe 62 being 
disconnected, or connects the catheter 51 to the syringe 62. The second 
3-way cock 57 is disposed between the first 3-way cock 56 and the pressure 
sensor 58, with a branch port thereof being open to the drain. The second 
3-way cock either passes the reference liquid 60 to the chemical sensor 55 
or drains the reference liquid 60 from the chemical sensor 55. The flow 
control valve 59 codes a glass pole 59a having a small axial hole and an 
elastic tube 59c press-fit onto the glass pole 59a and slidably mounted on 
the pipe 53. When the elastic tube 59c is thrust in a direction normal to 
the axial direction, a space is provided between the inner wall of the 
elastic tube 59c and the external wall of the pipe 53, thereby bypassing 
the reference liquid 60 during a flashing operation. 
For flashing the pipe 53, after the catheter 51 is removed from a living 
body, the reservoir 61 is filled with the reference liquid 60, followed by 
thrusting the elastic tube 59c to form a bypass for introducing a 
comparatively large quantity of the reference liquid 60 into the pipe 53. 
After the reference liquid 60 is drained from the catheter 51 together 
with air bubbles to clean both the catheter 51 and the pipe 53, the 
catheter 51 is inserted in the blood vessel of the living body while both 
the catheter 51 and the pipe 53 are filled with the reference liquid. 
During this operation, both the 3-way cocks 56 and 57 are set for passing 
the reference liquid 60 to the catheter 51 through the pipe 53 as shown in 
FIG. 1. 
Then, the second 3-way cock 57 is switched for closing the pipe 53, as 
shown in FIG. 2, to calibrate the sensor by using the reference liquid 60 
and the chemical sensor 55. The calibration data is read through signal 
lines 64 extending from the chemical sensor 55 by a microcomputer not 
shown. 
Subsequently, the first 3-way cock 56 is switched so that the piston 62a in 
the syringe 62 is pulled out to introduce the reference liquid 60 into the 
syringe 62 and introduce blood 63 into the pipe 53 through the catheter 51 
by using a negative pressure, as shown in FIG. 3. The chemical sensor 55 
disposed for a particular ingredient detects the ingredient in blood 63 
and supplies data to the microcomputer. 
After the measurement is completed, the blood 63 is returned to the living 
body by thrusting the piston 62a of the syringe 62. Patent Publication 
JP-A-62(1987)-24139 describes an automated calibration of a test 
instrument with a simple configuration. 
Referring to FIG. 4, the test instrument described in JP-A-62(1987)-24139 
comprises a first reservoir 91 for receiving a carrier liquid 81, a second 
reservoir 101 for receiving a first reference liquid 82 comprising the 
carrier liquid and a calibrating substance and a third reservoir 111 for 
receiving a second reference liquid 83 comprising the carrier liquid and a 
disturbing substance. Tubes extending from the reservoirs 91, 101 and 111 
are connected to an 4-way cock 84 for controlling the direction of liquid 
flow. The 4-way cock 84 is driven by a servomotor and controlled by an 
encoder for selecting a desired liquid flow. One port of the 4-way cock 84 
is connected to a cell (reactor) 85 having a sensor 87 with a tube 121, 
and a pump 86 is provided for supplying the liquids from the reservoirs to 
the cell 85. 
FIG. 5 shows a partially cutout perspective view of the cell 85, wherein a 
sample liquid is supplied through an inlet port 132 and discharged hugh an 
outlet port 133. Since the outlet port 133 is disposed at a higher 
position than the inlet port 132, a specified amount of sample liquid 
stays within the cell 85, with the excess liquid or measured liquid 
overflowing through the outlet port 133 to a waste tank 88. The sensor 87 
comprises thee electrodes including an enzyme electrode 87a attached with 
a living catalyst such as enzyme, a disturbance electrode 87c for 
detecting a disturbance substance and a counter electrode 87b. The three 
electrodes 87a, 87b and 87c are connected to respective external 
electrodes by connectors 87d. On the top of the cell 85, an elastic cap 
131 is inserted in the central area, and a liquid inlet 131a is provided 
in the center of the elastic cap 131a for supplying sample liquid. The 
4-way valve 84 may be such that shown in FIG. 6 instead, wherein the 4-way 
valve 84 in FIG. 4 is implemented by three individual electromagnetic 
valves 84a. 
Utility Model Publication JM-A-7(1995)-56001 describes a sampling 
instrument such as shown in FIG. 7. The sampling instrument is dedicated 
for sampling and comprises a cell (housing) including a funnel area 153, 
having a sampling port 159 communicated to a suction port 151 with a valve 
157, for collecting a body fluid 161 from a living body. In operation, 
body fluid is first collected by vacuum and introduced to a storage space 
160 of the valve 157, then a handle 156 of the valve is operated to align 
the storage space 160 with an outlet port 165 for takeout of the body 
fluid. The takeout can be conducted without stopping the vacuum pump or 
removing a cover. 
FIG. 8 shows a modification of the sampling instrument of FIG. 7. The 
sampling instrument of FIG. 8 is similar to the sampling instrument of 
FIG. 7 except for a pair of storage spaces 160 provided in a valve 157 and 
a pair of outlet ports 165 in the modification. In operation, body fluid 
is introduced to one of the storage spaces 160 from the sampling port 159, 
then the handle 156 is operated to align the one of the storage spaces 160 
to one of the outlet ports 165 and to align the other of the storage 
spaces 160 with the sampling port 159. This enables to obtain a sampling 
operation and a takeout operation simultaneously for improvement of the 
throughput. 
The conventional measurement instruments as described above have the 
following problems. 
First, sampling is interrupted in the measurement instruments during 
cleaning the cell by a buffer solution after measurement and subsequent 
supplying a new buffer solution into the cell. The sampling is also 
interrupted by removing a sample liquid from the cell after measurement. 
Second, a large quantity of sample liquid must be sampled for measurement 
because a sensor is installed in a chamber, which results in a large 
quantity of dead volume. 
Third, an inaccurate measurement is caused by the precedent sampling liquid 
remaining within the cell after the cleaning thereof. 
Fourth, the sensor calibration is limited by the facts that the reference 
liquid cannot be supplied into the cell when both ports are closed for the 
sampling period and that the sensor must be cleaned by a buffer solution 
after removing the sample liquid. Especially, cleaning is difficult 
because of the column configuration of the cell. 
SUMMARY OF THE lNVENTION 
It is therefore an object of the present invention to provide a measurement 
instrument for analyzing an ingredient in a sample liquid, which is 
capable of iteratively measuring the ingredients in a small quantity of 
sample liquid and capable of enabling simple calibration of the sensor. 
The present invention provides a measurement instrument comprising a casing 
having a first liquid inlet and a first liquid outlet opposed to each 
other and a second liquid inlet and a second liquid outlet opposed to each 
other, a sensor assembly having a telescope member slidably telescoped in 
the casing between a first position and a second position, a liquid 
passage formed in the telescoped member, the liquid passage being aligned 
with the first liquid inlet and the first liquid outlet at the first 
position of the telescope member and aligned with the second liquid inlet 
and the second liquid outlet at the second position of the telescope 
member, at least one sensor supported by the telescope member and exposed 
in the liquid passage. 
In accordance with the measurement instrument of the present invention, 
structure of the instrument and switching operation thereof between 
calibration and measurement are simplified. 
The above and other objects, features and advantages of the present 
invention will be more apparent from the following description, referring 
to the accompanying drawings.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
Now, the present invention is more specifically described with reference to 
the accompanying drawings, wherein similar constituent elements are 
designated by the same or similar reference numerals. 
Referring to FIG. 9, a measurement instrument according to a first 
embodiment of the present invention comprises a measurement cell 30 
including a casing 31 having a shape of a hollow hexahedron and a sensor 
assembly 32 having a shape of substantially solid hexahedron and slidably 
telescoped in the casing 31, and a circuit block 40 including a measuring 
circuit 41, a data processor 42 and a display unit 43 and connected to the 
sensor assembly 32 via wires 23. 
The casing 31 has a reference liquid inlet 11 and a reference liquid outlet 
12 opposed to each other, and a sample liquid inlet 14 and a sample liquid 
outlet 13 opposed to each other. The sensor assembly 32 comprises a solid 
body (telescope member) 17 having therein a first passage 20a and a second 
passage 20b, which can be communicated with the liquid inlets 11 and 14 
and liquid outlets 12 and 13 of the casing 31, a pair of stoppers 19 
attached to both ends of the solid body 17 by way of screws 15, and a 
sensor 16 received in the solid body 17 and exposed in the first passage 
20a. The solid body 17 comprises a pair of block pieces coupled together 
via the screws 15 which attach the stoppers 19 to the solid body 17, as 
will be described later. The sensor 16 can be taken out or introduced in 
the solid body 17 by disassembling the solid body 17 using the screws 15. 
The sensor assembly 32 can be shifted in both directions of the axis of 
the solid body 17 with respect to the casing 31 and is shown at the left 
most position (first position) of the sensor assembly 32. 
The first and second passages 20a and 20b are communicated with the 
reference liquid inlet 11 and outlet 12 and sample liquid inlet 14 and 
outlet 13, respectively, at the first position of the sensor assembly 32, 
thereby forming liquid paths therethrough. The sensor 16 can measure a 
specific ingredient in the reference liquid at the first position of the 
sensor assembly 32, and the ingredient in the sample liquid at a second 
position at which the sensor assembly 32 is shifted in the right. In this 
embodiment, the passages 20a and 20b are shown as extending in the 
direction perpendicular to the sliding direction of the sensor assembly 
32. However, the direction of the passages 20a and 20b need not be 
perpendicular to the sliding direction of the sensor assembly 32. 
The sensor 16 is detachably mounted in the solid body 21, with the surface 
of the sensor 16 being flush with the inner surface of the first passage 
20a. The sensor surface may be disposed slightly depressed from the inner 
surface of the passage 20a. In this configuration, the liquid flows more 
smoothly in the passage. 
Materials for the ports of reference liquid inlet 11, reference liquid 
outlet 12, sample liquid inlet 14 and sample liquid outlet 13, sensor 
assembly 32 and casing 31 are not limited to any of the materials, and may 
be preferably plastic or ceramic-based materials in view of electric 
insulation, water and chemical resistance, and/or productivity of the 
instrument. 
Preferably, the material for the liquid inlet or outlet of liquid passage 
may be an antibacterial substance or may be treated with such a substance. 
The materials for reference liquid inlet 11, reference liquid outlet 12, 
sample liquid inlet 14, sample liquid outlet 13, and passages 20a and 20b 
may have hydrophobic property for prevention of attachment of impurities 
or air bubbles in the liquid. 
The sensor 16 may be a chemical sensor of an amperometric or potentiometric 
detection type, such as for detecting an electrode active material or ions 
generated by catalytic reaction of an enzyme. Examples of enzyme sensors 
of amperometric type include sensors for detecting lactic acid, glucose, 
galactose, sucrose, ethanol, methanol, starch, uric acid, pyruvic acid, 
cholesterol, choline etc. Examples of sensors of potentiometric type 
include ion sensitive EFTs for detecting hydrogen-ion (pH), Na-ion, K-ion 
or Cl-ion concentration. 
The first and second passages 20a and 20b may have any sectional 
configuration and any length provided that a smooth supply, holding and 
flow of a liquid are assured. Preferably, the passages 20a and 20b may 
have a round section and straight length as shown in FIG. 9 for reducing 
void volume. For example, the length may be selected between 10 mm and 50 
mm and more preferably at about 30 mm and the diameter may be selected 
between 0.6 mm and 10 mm, and more preferably at about 2.0 mm. 
A spacing between the passages 20a and 20b may be selected in consideration 
of operability of the instrument and workability of the material. 
Referring to FIG. 10 showing the top plan view of the measurement cell 30, 
a sensor support 21 for supporting the sensor 16 is shown as extending 
from the sensor assembly 32 through the wall of the casing 31. The sensor 
support 21 also supports the wire 23 for the sensor 16. 
Referring to FIG. 11 showing the end view of the measurement cell 30, the 
stopper 19 is substantially of a square, but not limited to the shape 
illustrated. 
Referring to FIG. 12, the casing 31 has a rectangulr opening 24 for guiding 
the sensor support 21 during sliding movement of the sensor assembly 32. 
Referring to FIG. 13 showing an exploded view of the measurement cell 30, 
the solid body 17 of the sensor assembly 32 has two block pieces 17A and 
17B coupled together by screws 15 together with the stopper 19. The sensor 
support 21 extends from outside through the opening 24 into the solid body 
17 and is supported between the two block pieces 17A and 17B of the solid 
body 17. The two block pieces 17A and 17B are coupled, with a gasket (not 
shown) and sensor 16 being sandwiched therebetween. The liquid passages 
20a and 20b are formed in the block piece 17B, with an opening for the 
first passage 20a being exposed from the surface of the blockpiece 17B. 
Referring to FIGS. 14A and 14B, operation of the measurement instrument 
according to the present embodiment will be described. FIG. 14A shows an 
calibration operation, wherein the sensor assembly 32 is located at the 
first position to align the first passage 20a having the sensor 16 with 
the reference liquid inlet 11 and the reference liquid outlet 12, and 
align the second passage 20b with the sample liquid inlet 14 and the 
sample liquid outlet 13. The tip of a syringe 44 is inserted in the 
reference liquid inlet 11 for supplying a reference liquid 45. A pipette 
or any other instrument can be used instead of the syringe 44. Any amount 
of the reference liquid can be discharged smoothly from the reference 
liquid outlet 12 by gravity. The reference liquid outlet 12 can be 
directly connected to a waste tank with a tube for discharging the 
reference liquid. While sensor calibration is being conducted, a pump 46 
may be started by using the second passage 20b for preparation of the 
sampling. 
FIG. 14B shows a sampling and measurement operation, wherein the sensor 
assembly 32 is at the second position to align the first passage 20a with 
the sample liquid inlet 14 and the sample liquid outlet 13. A body fluid 
is sampled by the pump 46 from a human skin 47 through a body fluid 
sampling cell 48 and the sample liquid inlet 14 to the first passage 20a, 
wherein the sensor 16 detects a specific ingredient in the sample liquid. 
The sample liquid is drained from the first passage 20a after the 
measurement by the sensor 16 trough the sample liquid outlet 13 and a tube 
to the reservoir 49. The reservoir 49 functions for reducing load of the 
pump 46. 
Cleaning of the surface of the sensor 16 and inside the passage 20a is not 
generally required in the present embodiment because the sampling and 
measurement can be performed continuously by passing the sample liquid 
through the liquid passage 20a. The liquid passage 20a is of a simple 
structure having a small void volume which passes the body fluid quickly 
for effecting self cleaning and rinsing functions. Measuremrent can be 
recorded simply after the indicator reading is stabilized. 
The body fluid sampling cell 48 has a wide opening to be attached onto the 
human skin 47 and a space for temporarily storing extracted body fluid for 
supplying the same to the liquid passage 20a. 
In the above embodiment, the measurement of a specific ingredient in a body 
fluid can be performed continuously, whereas the sensor calibration may be 
performed at any time for assuring the accuracy of the sensor 16. 
Sensor of any type may be selected and installed in the sensor assembly 32 
in the present embodiment depending on a target ingredient in the body 
fluid to be measure such as sweat, blood, suction effusion fluid, 
interstitial fluid, extracted fluid from skin or a mucous membrane. 
Referring to FIG. 15, a measurement instrument according to a second 
embodiment of the present invention is similar to the first embodiment 
except that a plurality of sensors 16 are disposed along the first passage 
20a in the direction of the liquid flow. The number of sensors 16 and 
their locations can be selected depending on the number of target 
ingredients and dimensions of the sensors 16 and the liquid passage 20a. 
The plurality of sensors 16 can measure a plurality of ingredients 
simultaneously and continuously. A reference liquid can be supplied from a 
syringe 44 corresponding to one of the sensors 16 to be calibrated. 
According to the first and the second embodiments of the present invention, 
target ingredients in a liquid can be continuously measured with accuracy. 
The measurement instrument has a sole structure which enables easy 
replacement of the sensor. 
EXAMPLES 
Several sample liquids are measured by using the measurement instruments of 
the present invention as follows: 
Example 1 
Liquid measurement instruments fabricated based on the structure of FIG. 9 
had a glucose sensor, a lactic acid sensor, a pH sensor and an uric acid 
sensor, respectively. The body fluid sampling cell of the liquid 
measurement instrument was attached to an upper arm of an adult (male, 31 
years old, weight 67 kg) for measuring glucose, lactic acid, pH or uric 
acid in the body fluid extracted at every 10 minutes in two hours (sample 
number n=12). The same ingredients were also measured by using a 
conventional diagnostic test instrument (Hitachi automated analyzer 70050) 
under a similar condition. The results of each ingredient were evaluated 
in correlation by using a regression analysis and shown in Table 1. 
TABLE 1 
______________________________________ 
Sensors used Correlation Coefficients (n = 12) 
______________________________________ 
Glucose sensor 
0.961 
Lactic acid sensor 0.945 
pH sensor 0.918 
Uric acid sensor 0.933 
______________________________________ 
Example 2 
Liquid measurement instruments fabricated based on the structure of FIG. 15 
included following combinations of sensors: 
(1) glucose and lactic acid sensors; 
(2) glucose, lactic acid and pH sensors; and 
(3) glucose, lactic acid, pH and uric acid sensors. 
The body fluid sampling cell of the liquid measurement instrument was 
attached to an upper arm of an adult (male, 31 years old, weight 67 kg) 
for measuring glucose, lactic acid, pH or uric acid in suction effusion 
fluid at every 10 minutes in two hours. The same ingredients were also 
measured by using a conventional diagnostic test instrument under a 
similar condition. The results of each ingredient were evaluated in 
correlation by using a regression analysis and shown in Table 2, wherein 
data obtained by a single glucose sensor in the measurement instrument of 
FIG. 9 is shown by reference. 
TABLE 2 
______________________________________ 
Sensors used Correlation Coefficients (n = 12) 
______________________________________ 
Glucose sensor 0.961 
Combination (1) Glucose 0.943 
Lactic acid 0.921 
Combination (2) Glucose 0.922 
Lactic acid 0.925 
pH 0.917 
Combination (3) Glucose 0.913 
Lactic acid 0.924 
pH 0.949 
Uric acid 0.935 
______________________________________ 
Example 3 
The solid body of the sensor assembly was fabricated from ABS plastic 
material, and the passages in the solid body were treated with respective 
hydrophobic materials which included paraffin, silicone and 
perfluorocarbon. The paraffin was heated up to 50.degree. C. for coating 
the passages, silicone was diluted to 50% with pure water for coating the 
passages, and perfluorocarbon (Fluorad FC-722 of Sumitomo 3M) was used 
intact for coating the passages. 
The measurement instrument based on the structure shown in FIG. 9 had the 
central solid bodies of the sensor assembly as mentioned above and a 
lactic acid sensor for evaluating the effectiveness of hydrophobic 
coatings in the passages. The results are shown in Table 3, wherein time 
length for obtaining readings of the measurements are listed in connection 
with the treatments. 
TABLE 3 
______________________________________ 
Hydrophobic Coating 
Time (sec.) 
______________________________________ 
No treatment 192 
Paraffin 144 
Silicone 77 
Perfluorocarbon 74 
______________________________________ 
Example 4 
The measurement instruments each having a lactic acid sensor were 
fabricated based on the common structure of FIG. 9. The instruments had 
different positions of the lactic acid sensors, as shown in FIGS. 16A, 16B 
and 16C for evaluating the effectiveness of the positions of the sensors 
with respect to the inner surface of the liquid passage 20a. A sample 
liquid having a known lactic acid concentration was supplied at a flow 
rate of 0.1 milliliter/minute (ml/min.) in the passage. Each passage had a 
round section of 2.0 mm diameter and 30 mm length. The dimensions of the 
sensor were 1.2.times.10.times.0.05 mm, whereas the step "A" in FIG. 16A 
and the step "B" in FIG. 16C were 0.05 mm. Table 4 shows the results of 
correlations which are listed in connection with the configurations of the 
passages. 
TABLE 4 
______________________________________ 
Sensor Configurations 
Correlation Coefficients (n = 12) 
______________________________________ 
FIG. 16A 0.923 
FIG. 16B 0.898 
FIG. 16C 0.651 
______________________________________ 
Example 5 
Time length required for replacing sample liquid was evaluated in the 
structure shown in FIGS. 16A, 16B and 16C by introducing a sample liquid 
having known lactic acid concentrations in the passages with flow rate of 
0.1 ml/min. Time lengths were measured until a stabilized readings were 
observed after the sample liquid was changed. Table 5 shows an average 
time length and the standard deviation thereof listed in connection with 
the configurations of the passages. 
TABLE 5 
______________________________________ 
Sensor Configurations Time length 
______________________________________ 
FIG. 16A 8 .+-. 1 sec. 
FIG. 16B 11 .+-. 1.5 sec. 
FIG. 16C 36 .+-. 4 sec. 
______________________________________ 
Example 6 
Liquid measurement instruments similar to Example 4 were fabricated each 
having a glucose sensor, for evaluating air bubbles or impurities (such as 
protein) on the passage wall. The body fluid sampling cell of the 
measurement instrument was attached to an upper arm of an adult (male, 31 
years old, weight 67 kg) for measuring glucose in suction effusion fluid 
every 10 minutes in two hours. Number of air bubbles and number of 
impurities attached to the passage wall were counted, the results of which 
are shown in Table 6. 
TABLE 6 
______________________________________ 
Sensor Configurations 
Impurities 
Air bubbles 
______________________________________ 
FIG. 16A 1 0 
FIG. 16B 11 20 
FIG. 16C 100 or more 36 
______________________________________ 
The measurement instruments of the embodiments as described above achieve 
an advantage in that a real time measurement can be obtained due to the 
simple operation of switching between calibration and measurement of the 
instrument, which can be obtained by simply shifting the sensor assembly 
with respect to the casing. 
The measurement instruments further achieve advantages of continuous 
measurement substantially without cleaning the liquid passage because of 
the simple structure of the liquid passage, accurate measurement which can 
be obtained by the facts that the sample liquid is not diluted and that 
the liquid passage has a simple structure, easy replacement of the sensor, 
minute amount of sample liquid required for measurement, a low cost of the 
instrument due to less number of constituent elements, and easy 
calibration which can be conducted at any time simply by shifting the 
sensor assembly. 
Since the above embodiments are described only for examples, the present 
invention is not limited to the above embodiments and various 
modifications or alterations can be easily made therefrom by those skilled 
in the art without departing from the scope of the present invention.