Electrochemical sensing apparatus with in situ calibration

An in vivo electrochemical monitoring device is formed by a catheter-like member which terminates in a closed end having a wall with a fixed opening to admit fluid to be tested, such as blood in an artery. An electrochemical sensor, such as an ISFET device for monitoring the concentration of a particular ion in blood, is mounted inside the tube at a fixed location below the opening preferably a larger sensing chamber. an infusion channel in the tube is arranged to flood the sensor with a fluid of known chemical properties so that the sensor output can be calibrated. Under pressure the calibration fluid expels the test fluid out of the tube or chamber via the fixed opening. A method of constructing a suitable chamber on an ISFET wafer is also disclosed.

BACKGROUND OF THE INVENTION 
The invention relates generally to electrical sensor assemblies used in in 
vivo measurement of chemical parameters in a test fluid, such as blood in 
an artery, and in particular to calibration systems for chemically 
sensitive electrodes used in catheters, for example. 
Electrochemical sensing devices, such as ion sensitive field effect 
transistors (ISFETS) are finding numerous applications in measuring the 
chemical properties of fluids. One such application has been the use of an 
ISFET device in conjunction with an ion selective membrane for performing 
continuous in vivo measurement of the concentration of a particular ion in 
the blood. The sensor is mounted on a catheter which is fed into an artery 
via a conventional catheter introducer. While extremely sensitive to 
variations in ion concentration, the ISFET device, like other 
electrochemical sensors, suffers from drift which seriously undermines the 
accuracy of the readings. Frequent recalibration of the output device 
connected to the sensor essentially removes these inaccuracies. One method 
of calibration which has been used in the past is to draw a sample of 
blood, for example, from a separate arterial puncture or by means of a 
syringe connected to a side arm assembly of the catheter containing the 
sensor and actually measuring the electrochemical activity of the ion of 
interest using standard laboratory techniques. Alternatively, the sensor 
itself may be removed for in vitro calibration in a fluid of known exact 
ion concentration. The ideal system, however, would perform recalibration 
in vivo without laboratory analysis. 
One system which has been proposed for performing in vivo calibration of an 
electrochemical sensor is referred to in U.S. Pat. No. 4,016,866 to 
Lawton, involving a retractable sensing electrode carried by an insertion 
catheter. To perform measurements, the electrode is extended axially out 
of the insertion catheter. For recalibration, the sensing electrode is 
retracted into the insertion catheter to an infusion chamber where it is 
contacted with calibrating solution furnished by a drip line in which a 
reference electrode also contacts the calibrating solution. Following 
calibration the sensor is protracted to the exterior measurement position. 
The electrode must be accurately aligned with an opening in the end of the 
insertion catheter and the opening must be large enough to allow the 
electrode to freely pass through the opening in either direction. Thus the 
opening must be larger than the electrode. Moreover, the need for axial 
retractability requires a rather complicated mechanism involving sealing 
glands and guard tubes to maintain a sliding seal. The mechanical action 
of the sensor places certain constraints on the mounting arrangement of 
the sensor and generally increases the risk of mechanical damage to the 
sensor and electrical connections to the sensor. Because of the size of 
the opening in the insertion catheter, there is also a possibility of 
blood flowing into the catheter and mixing with the calibration liquid. 
SUMMARY OF THE INVENTION 
The general object of the invention is to provide a structural arrangement 
for an electrochemical sensor such as an ISFET device in a catheter-like 
tube in which the sensor remains at a fixed location in a chamber which 
functions both as a calibration chamber and as a test fluid chamber. In 
accordance with the invention, an in vivo electrochemical monitoring 
device is formed by a catheter-like member which terminates in a closed 
end having a wall with a fixed opening to admit fluid to be tested, such 
as blood in an artery. An electrochemical sensor, such as an ISFET device 
for monitoring the concentration of a particular ion in blood, is mounted 
inside the tube in a fixed location below the opening, preferably in a 
larger sensing chamber. An infusion channel in the tube is arranged to 
flood the sensor at its fixed location with a fluid of known chemical 
properties for calibration. Under pressure, the calibration fluid expels 
the test fluid out of the tube or chamber via the fixed opening. 
Maintaining a positive flow of calibration fluid at a controlled pressure 
keeps the test fluid out of contact with the sensor while bathing the 
sensor in the known ion concentration. 
According to a further aspect of the invention, a method of constructing a 
suitable chamber on an ISFET wafer includes applying a first layer of 
soluble material, covering the first layer with a second layer of another 
material, making a hole through the second layer and removing the first 
layer entirely by introducing solvent through the hole in the second layer 
.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
In the following examples the electrochemical sensor comprises an ISFET 
with a source and drain electrode and an Ag/AgCl reference electrode. In 
FIG. 1, a closed tubular catheter 10 made of flexible synthetic plastic 
material has a small opening 11 formed in the sidewall thereof which is 
sealed off on the inside of the catheter 10 by an ISFET device 9 which is 
bonded to the inner wall of the catheter by means of a suitable adhesive, 
for example. The catheter 10, over a limited circumferential extent, is 
double-walled to form an infusion channel 12 which leads to the opening 
11. The end portion 13 of the outer wall of the channel 12 extends part 
way over the opening 11 so as to constrict the opening 11 at the outer 
surface of the catheter 10. The compartment or chamber formed by the 
opening 11, end portion 13 of the wall and the ISFET 9 functions as a 
calibration compartment for the ISFET. When calibration liquid of a known 
chemical composition is forced through channel 12, the liquid, for example 
blood, present in the opening or chamber 11 will be expelled. Thus opening 
11 will become entirely filled with calibration liquid. While the supply 
of calibration liquid is being maintained under controlled pressure, the 
ISFET electrical output can be calibrated. When the flow of calibration 
liquid is stopped or reversed, the opening 11 functioning as a small 
compartment refills with blood and measurement can be continued. The 
calibration step can be automatically cycled if desired. 
In the embodiment of FIG. 2, the catheter 14 has two lumina 15 and 16 
separated by a common partition 17. Adjacent to the end of catheter 14, a 
tapered opening 18 is formed in the catheter wall. Under the opening 18, 
the sensor 19 with ISFET 20 and Ag/AgCl reference electrode 21 with 
respective electrical leads 22 and 23, are mounted in partition 17. During 
measurement, channel 15, formed by the lumina in communication with 
opening 18, contains blood which is in contact with the sensor 19. By 
supplying calibration liquid through channel 15, the blood present therein 
is expelled and the sensor can be calibrated. When the supply of 
calibration liquid is discontinued, blood will again flow into channel 15 
and the unit will return to the measuring phase. The catheter end 24 may 
take the form of a loose cap which, after sensor 19 has been installed, 
can be placed in position on the partition and secured, for example, with 
adhesive. 
In FIGS. 4 and 5, an ISFET 31 is mounted in an opening in the wall of the 
catheter 41. ISFET 31 comprises source electrode 37, drain electrode 38 
and bulk contact 39, with leads 35. The ion-sensitive portion of the ISFET 
is housed in a chamber 34 formed by the ISFET and adjacent catheter wall, 
which also accommodates the Ag/AgCl reference electrode 36. An aperture 40 
is formed through the bulk of the ISFET terminating in chamber 34, to 
which infusion tube 33 is connected for supplying calibration liquid to 
the chamber. At the top the chamber 34 has an aperture 42 for incoming 
blood or outgoing calibration liquid. 
During the measuring phase, chamber 34 is entirely filled with blood. In 
order to switch over to calibration of the ion-sensitive electrode, a 
stream of calibration liquid is supplied to chamber 34 in excess of blood 
pressure. If desired, the pressure driving the calibration liquid may be 
adjusted automatically as a function of blood pressure. The blood present 
in chamber 34 is expelled through aperture 42. So long as adequate 
pressure is maintained, calibration liquid will flow in direction A, as 
indicated in FIG. 6, out of the opening 42. When, after the calibration, a 
reduced pressure, or at any rate no excess pressure, is established in 
chamber 34, the chamber will again be entirely filled with blood, and 
measurement can be resumed. Calibration and measurement can be performed 
automatically in pre-programmed repetition. 
Tube 33 is not an essential component. The calibration liquid can be 
supplied through catheter tube 41 provided that the leads 35 are suitably 
insulated. 
The chamber for the calibration compartment can be formed directly on an 
ISFET wafer using the same integrated circuit technology that is used for 
making the ISFET itself. A few additional steps are required for making 
the chamber. As shown in FIG. 7, the ion-sensitive portion (the gate) with 
the source electrode 51 and the drain electrode 52 of the ISFET 50 are 
covered with a temporary protective layer 53 of a material that can easily 
be dissolved or etched. Subsequently a layer 54, preferably of a 
conductive material, e.g., a metal or polysilicon, is applied on top of 
and around layer 53. Next a mask 55 having an opening 56 therein is laid 
on top of conductive layer 54, and through opening 56 an etching agent is 
supplied for etching an opening 57 in layer 54. Finally, a solvent for 
layer 53 is supplied through opening 57, and layer 53 is dissolved and 
removed, leaving an empty chamber. 
Although an insulating material may be selected for layer 54, the use of a 
conductor is preferred because the chamber formed therein functions as a 
Faraday cage. 
It is of advantage, after forming the chamber, to cover the unit of FIG. 7 
with a layer which promotes its biological compatability without unduly 
affecting its response period. A preferred material for this purpose is a 
hydrogel material. 
The chamber 34 of FIGS. 4-6 may be formed in the manner of FIG. 7 or by 
fixing a separately manufactured apertured chamber wall to the ISFET with 
adhesive, for example. 
The utility and applicability of the invention is not limited to ISFET 
devices. The possibility of neutralizing the effect of the drift phenomena 
by continual recalibration in a standard medium in a calibration/test 
chamber might also be beneficial with other types of electrochemical 
sensors. 
Among the many advantages of the invention is the use of a single location 
and single chamber for both measuring and calibrating the sensor whereby, 
without mechanical intervention, the contents of the chamber are solely 
determined by the pressure applied to the infusion channel, thus 
facilitating an automatic calibration cycle. The simple construction of 
the sensing apparatus according to the invention results in an 
inexpensively constructed reliable instrument. In addition, the Faraday 
cage effect of forming the calibration chamber in conductive material 
reduces the sensitivity of the instrument to external and internal (bio) 
sources of electrical interference. The constant access to infusion fluids 
enhances the biological compatability of the sensor by regularly washing 
it, for example, with heparinated liquid. In addition, the construction 
enables automatic testing of electrical sensitivity via a pulse on the 
reference electrode which is in a fixed electrolytic trough arrangement. 
The foregoing description and drawings are intended to be illustrative not 
restrictive, the scope of the invention being indicated by the appended 
claims.