Biosensors & Bioelectronh
7 (1992) 587-592
Calibration in dogs of a subcutaneous miniaturized glucose sensor using a glucose meter for blood glucose determination V. Poitout, D. Moatti-Sirat 81G. Reach* INSERM U341, Service de Diabetologie, (Received 8 January
Hotel-Dieu,
75004 Paris, France
1991; revised version received 13 April 1992; accepted 23 June 1992)
Abstracti The feasibility of calibrating a glucose sensor by using a wearable glucose meter for blood glucose determination and moderate variations of blood glucose concentration was assessed. Six miniaturized glucose sensors were implanted in the subcutaneous tissue of conscious dogs, and the parameters used for the in vivo calibration of the sensor (sensitivity coefftcient and extrapolated current in the absence of glucose) were determined from values of blood glucose and sensor response obtained during glucose infusion. (1) Venous plasma glucose level and venous total blood glucose level were measured simultaneously on the same sample, using a Beckman analyser and a Glucometer II@, respectively. The regression between plasma glucose (x) and whole blood glucose Q was y = 1.12~ - 008 mM (n = 114 values, r = 096, p = 0@001).The error grid analysis indicated that the use of a Glucometer II for blood glucose determination was appropriate in dogs. (2) The in vivo sensitivity coefftcients were O-57 + 0 11 nA rnM_l when determined from plasma glucose, and 051 + @07 nA rnM_'when determined from whole blood glucose (f = l-53, p = 0.18, n.s.). The background currents were 0.88 + 0.57 nA when determined from plasma glucose, and @63 + 0 77 nA when determined from whole blood glucose (t = 0.82,~ = O-45, n.s.). (3) The regression equation of the estimation of the subcutaneous glucose level obtained from the two methods was y = l&lx + 0.56 mM (n = 171 values, r = 0.98,p = O@OOl).Thus, the calibration of a glucose sensor by using a home blood glucose meter and moderate variations of blood glucose concentration is feasible. Keywords: glucose sensor, calibration, analysis.
blood glucose monitoring,
disposable, subcutaneously implanted glucose sensor (Shichiri et aZ., 1982; Claremont et aZ., 1986; Fischer et al., 1987; Velho et al., 1987; Pickup et al., 1989; Koudelka et aZ., 1991). Briefly, glucose is oxidized by glucose oxidase layered on the surface of the electrode, and the generated
INTRODUCTION
In order to provide a continuous estimation of glucose concentration, amperometric, enzymatic sensors have been developed to be used as a *To whom correspondence
hydrogen
should be addressed.
0965-5663/92/$05.00 @ 1992 Elsevier Science Publishers
error grid
Ltd.
peroxide
is
monitored
yielding
a 587
current. The principle of sensor calibration is the transformation of this current into an estimation of the glucose ~o~~entra~u~ by using appropriate pammeters~ namely a se~si~~~ coefficient fin nAmM_‘) and a background current generated in the absence of glucose(in nA). In the past few years, we resolved the problem of sensor calibration by proposing a method based only on in viva measurements: under experimental conditions, blood glucose of the animals was modified by infusing glucose or insulin, and the resulting change in the current generated by the sensor was used to calculate for each individuaf experiment the ealibmtion pammet~~ rJelho et al., 1988,1989). Recently, we have developed in a collaborative programme with the University of Kansas (Professor G. S. Wilson) and the ~ni~rsi~ Paris - Val de Mame (Professor I.3.R, ~~venot) a rni~ia~~~ed glucose sensor, which has been shown to have appropriate irr v&o characteristics (Bindra e6aL, 1991),to work when implanted in the subcutaneous tissue of dogs (Poitout et al., 1991),and for extended periods in the subcutaneous tissue of rats (Moat&Sirat d al., 1992). In all these studies, ~alibra~on of the sensor by deponing glncose was performed concentration in plasma with a Beckman analyser, during increases in plasma glucose concentration reaching 12 mmol 1-t (Poitout Ed al., 1991; Moat&Sirat et aZ.,1992).The relevance of this approach could be questionable since ~libration must eventually be performed by the patient with a readily available glucose meter, and with moderate variations in blood glucose concentration. Thus this study was specifically undertaken to assess the feasibili~ of calibrating a glucose sensor under conditions which would be closer to the clinical use of a glucose sensing system. More specifically, we compared the results obtained from the same experiment by two methods of ~alibratiou of a glucose sensor subcutan~usly implanted in dogs, one using a Beckman analyser for plasma glucose determination, the other using a Glucometer II@for total blood glucose measurement. STEP
AND DEMURS
Glucose sensors allb al&rats This study was performed with rni~~a~~~ed glucose sensors whose preparation is described 588
TN3LI? 1 In vitro sensitivity coefficients (SC) and background currents &) detezmined before irnp~~~~o~. These parameters were determined itr physiok@a~ S&he sOlUtiOnby fecQrding the bad sewx cuneat f&) and rhe sensor response (SC) to stepwise increases in the glucose concentration Sensor no.
SC. (ti mM_‘)
10M)
elsewhere (Bindra d aL, 1991). fn vitm ~ham~e~~~s of the sensors are given in Table I, Experiments were carried out on two healthy female beagles. A 20 gauge catheter (?rasocan, Bureau, Boulo~e-BiIl~~~ou~ France) was used to insert the sensor through a skin fold of the dorsum. The sensor was left under the skin as the catheter was pulled out. The sensors were connected to an arn~~rne~~ unit (PRG-DEL, Solea Tacussef Electronique, Villeurb~ne~ France) and the signal recorded by a strip chart recorder [SE 120,Goerz Eleetro, Vienna, Aus~a) (pl = l), or connected to an experimental portable unit which applies a 650 mV potential between the electrodes and records the signal (n = 5). Venous plasma glucose level and venous total blood glucose level were measured ~ul~n~usly on the same sample every 5 min, using a Beckman analyser type 2 (Be&man, Fullerton, CA, USA) and a Glucometer II (Ames, Elkhart, IN, Uf3A)9 respectively. As a whole, six different sensors were investigated. In one experiment, two sensors were implanted simultaneously in the same animal,
When the sensor signal was stable (about 4 h after implantation), a glucose infusion was started with an initial rate of 6 mg kg-’ min-‘, to increase the plasma glucose ievel from 5.4 + 0.1 mM {?r= 5) to a 96 3~@7 mM plateau (n = 5, range = 667Il.33 mM). In some cases, an intravenous injection of 2-4 III of regular insulin was performed following the glucose infusion. The ~lib~ation parameters (sensitivity coefficient
Biosensors L Bioelectronics
Calibration of a subcutaneous miniaturized glucose sensor
(SC) and extrapolated current in the absence of glucose 00)) were determined by using the values, determined in the basal state and at the first hyperglycaemic plateau, of the current and of the blood glucose concentration, estimated either with the Beckman analyser or with a Glucometer II. Both the current and the plasma and/or blood glucose levels, which were chosen for the calibration, were stable for at least 5 min (see Fig. 2). Thus, only one set of values for the basal and the hyperglycaemic plateau were used. The subcutaneous glucose concentration (SCG) was calculated from the current and the in vivo parameters, according to the equation: SCG = (It - &,)/SC. Expression of results and statistics All results arc given as mean * s.e.m. The values of 1s and SC obtained from the two methods were compared using Student’s paired r-test. The values of glucose level and SCG obtained from the two methods were compared using regression analysis. Ap value of 005 or less was considered significant.
RESULTS AND DISCUSSION Figure 1 represents the correlation between the estimation of blood glucose with the Glucometer II and the results of the determination on the same sample in plasma with the Beckman analyser. The values were slightly higher in whole the regression equation being blood, y = 1.12~ - DO8mm01 1-l (n = 114 values, r = O%, p = 00001). These results are in contradiction to observed higher the usually glucose concentration in plasma than in whole blood (Report of a WHO Study Group, 1985). This discrepancy might be due to the difference between the two methods (calorimetric detection for the glucose meter versus oxygen consumption rate measurement for the Beckman analyser). Actually, our results are in agreement with those obtained by Aziz & Hsiang (1983) who compared glucose concentrations measured in human serum with a Beckman analyser and in veinous blood with a Glucometer II (an experimental design similar to ours). Error grid analysis (Clarke et aZ., 1987) indicated that 88% of the values were in zone A (accurate) and 12% in zone B (acceptable). These
PLASMA
GLUCOSE
(mM)
Fig. 1. Error grid analysis of 114 values of glucose measured in whole blood with the Glucometer II or in plasma with the Beckman analyser.
results extend to the dog the validation of the Glucometer II for blood glucose determination. Figure 2 shows an individual experiment indicating the changes in glucose concentration determined in plasma with the Beckman analyser or in whole blood with the Glucometer II (upper curve), changes in the current (middle curve), and the estimations of SCG calculated by taking into account the basal value and the first hyperglycaemic plateau, as determined either in plasma or in whole blood (lower curve). Obviously, the two estimations were essentially identical. This is further shown in Fig. 3, which represents the correlation between the estimations of glucose concentration in the subcutaneous tissue, as performed from the two sets of values of in vivo parameters. All the data collected over the live experiments are represented, yielding a regression equation y = 1.04x + 0.56 mmol 1-l (n = 171 values, r = 0.98,~ = 0~0001). Table 2 indicates that there was no significant difference in the individual values of the calibration parameters observed in five experiments, when they were determined with the two calibration methods (SCs: t = 1.53, p = O-18, n.s.; background currents: t = 0.82,~ = 0.45, n.s.). Note that the in vivo sensitivity was lower than that observed in vitro, a common phenomenon observed by all investigators in the field (Rebrin et al., 1992; Moatti-Sirat et aZ., 1992).
V; Poitout, D. Moam’-Sirat, G. Reach
Biosensors t Bioelectronics
0 -10
0
10
20
30
40
50
60
70
TIME
o!, -10
,I
I,
0
IO
20
30
I,
40
00
,,
50
60
TIME
20
100
110120
130 140
100
110120
130140
l!sO160
(min)
70
,,
,111
20
90
,,
150
160
(mln)
TIME (mln)
Fig. 2. Results of an experiment showing the variations in bloodglucose as determined with the GlucometerII(open squares) and with the Beckman analyser (closed squares) (upper curve), the current generated by the sensor (middle curve), and the estimation of SCG as determinedfim the two methods (lower curve).
We conclude that calibrating a glucose sensor by using a home blood glucose monitoring system is feasible, and should not be hindered by the slight difference between the whole blood and plasma glucose concentrations. However, it must be stressed that this calibration procedure is basically performed a posterior-i. A method for calibrating the sensor in real time remains to be developed.
ACKNOWLEDGEMENTS The sensors used in this study were prepared by T. Cart+, Laboratoire de Bidlectrochimie et d’Analyse du Milieu, Universite Paris-Val de Mame, Professeur D. R. Thevenot. We express our gratitude to Y. Zhang and G. S. Wilson, Chemistry Department, University of Kansas, for fruitful comments. This work was supported by
C~ibr~~n
Bi~e~so~ & B~i~~ni~
of a subcatun~us rni~i~~~
&eose sensor
TABLE 2 In vivo sensitivity coefftcients and background currents as determined from the plasma glucose measured with the Beckman analyser or from the whole blood glucose measured with the Glucometer II Experiment
Sensitivity
no.
Coefflicient
Beckman
(IL&
ItIM-‘)
Beckman
Glucometer
044 047 035 035 1.01 0.76 069 081 035 o-34 0.5 046 057 f Qll O-51 f O-07 n.s. lp = 02, f-test)
1 2 3 4 5 6 Mean -I s.e.m.
Background
current (nA) Glucometer
0.21 -0.29 2.49 2,49 067 1.7 -0.87 -1.96 268 2.58 o-14 -0+72 088 * o-57 0.63 + 0.77 ns. (p = 02, t-test)
Bindra, D. S., Zhang, Y., Wilson, G. S., Sternberg, R, Thevenot, D. R, Moatti, D. & Reach, G. (1991). Design and invitro studies of a needle type glucose sensor for subcu~neous monitoring. Anal. Chem., 63, 1692-6.
0
1
2
3
4
5
6
7
a
3
10 11 12 13 14 15
Subcutrnwwr
glucor ostimatod from the plasma g&a60 (mM)
Fig 3. Correlation between the estimation of 171 SCGs as ~~~~rn plasma glucose rn~~ with the Beckman anaiyser or from whole blood glucose measured with the GlucometerZZ. In th&figure, ail the values obtained within Jive experiments (six sensors investigated) are represented.
the National Institutes of Health (Grant DK 307 18 to Pr G. S. Wilson), Institut National de la Santi et de la Recherche Mkdicale (Grant CRE 89-90-14), and Aide aux Jeunes Diab~tiques (Grant to V.P.). REFERENCES Aziz, S. & Hsiang, Y.-H. (1983). Comparative study of home blood glucose monitoring devices: Visidex, Chemstrip bG, Glucometer, and Accu-Chek bG. Diabetes Care, 6,529-32.
Claremont, D. J., Sambrook I. E., Penton, C. & Pickup, J. C. (1986). Subcutaneous implantation of a ferrocene mediated glucose sensor in pigs. Diabetologia 29, 817-21. Clarke, W. L., Cox, D., Gander-Frederick, L. A, Carter, W. & Pohl, S. L. (1987). Evaluating clinical accuracy of systems for self-moni~~ng of blood glucose. Diabetes Care, 5, 622-7. Fischer, U., Ertle, R, Abel, P., Rebrin, K, Brunstein, E., Hahn von Dorsche, H. & Freyse, E. J. (1987). Assessment of subcutaneous glucose concentration: Validation of the wick technique as a reference for implanted electrochemical sensors in normal and diabetic dogs. Diabetologia, 30, 940-5. Koudelka, M., Rohner-Jeanrenaud, F., Terrattaz, J., ~bbioni-Hatch, E., de Rooij, N. F. & Jeanrenaud, B. In-vivo behaviour of hypodermically implanted microfabricated glucose sensors. Biosensors and Bioelectronics, 6, 31-6. Moat&Sirat, D., Capron, F., Poitout, V., Reach, G., Bindra, D. S., Zhang, Y., Wilson, G. S. &Thtvenot, D. R. (1992). Towards continuous glucose monitoring: In vivo evaluation of a miniaturized glucose sensor implanted for several days in rat subc~~n~us tissue. Diabetoio~‘a, 35, 224-30. Pickup, J. C., Shaw, G. W. & Claremont, D. J. (1989). In vivo molecular sensing in diabetes mellitus: An implantable glucose sensor with direct electron transfer. Diubetologia, 32, 213-17. Poitout, V., Moatti, D., Velho, G., Reach, G., Sternberg, R, Tbevenot, D. R, Bindra, D., Zhang, Y. & Wilson, G. S. (1991). In vitro and in vivo evaluation in dogs of a minia~~zed glucose sensor. Trans. Am. &x. Artif. Znt. OQ., 37, M298-M3OO. 591
K Poitout, D. Aloam’-Sirat, G. Reach Rebrin, K, Fischer, U., Hahn von Dorsche, H., von Woetke, T., Abel, P. & Brunstein, E. (1992). Subcutaneous glucose monitoring by means of electrochemical sensors: Fiction or reality2 1 Biomed Eng.., 14, 33-40. Report of a WHO Study Group (1985). DiabetesMellitus. Technical report series 727, WHO, Geneva. Shichiri, M., Yamasaki, Y., Rawamori, R & Abe, H. (1982). Wearable artificial pancreas with needle type glucose sensor. L.ancef ii, 1129-31. Velho, G., Reach, G. & Thevenot, D. (1987). The design and development of in vivo glucose sensors for an
Biosensors h Bioel~tmnics artiticial endocrine pancreas. In Biosensors: Fundamentals andApplications, ed. k P. F. Turner, I. Karube & G. S. Wilson. Elsevier, Barking, UK, pp. 390408. Velho, G., Froguel, Ph., Thevenot, D. R & Reach, G. (1988). In vivo calibration of a subcutaneous glucose sensor for determination of subcutaneous glucose kinetics. Diab. Nutr. Metab., 1,227-33. Velho, G., Froguel, Ph., Thevenof D. R & Reach, G. (1989). Strategies for calibrating a subcutaneous glucose sensor. Biochim. Biomed Acta, 48, 957&I.
7 (1992) 587-592
Calibration in dogs of a subcutaneous miniaturized glucose sensor using a glucose meter for blood glucose determination V. Poitout, D. Moatti-Sirat 81G. Reach* INSERM U341, Service de Diabetologie, (Received 8 January
Hotel-Dieu,
75004 Paris, France
1991; revised version received 13 April 1992; accepted 23 June 1992)
Abstracti The feasibility of calibrating a glucose sensor by using a wearable glucose meter for blood glucose determination and moderate variations of blood glucose concentration was assessed. Six miniaturized glucose sensors were implanted in the subcutaneous tissue of conscious dogs, and the parameters used for the in vivo calibration of the sensor (sensitivity coefftcient and extrapolated current in the absence of glucose) were determined from values of blood glucose and sensor response obtained during glucose infusion. (1) Venous plasma glucose level and venous total blood glucose level were measured simultaneously on the same sample, using a Beckman analyser and a Glucometer II@, respectively. The regression between plasma glucose (x) and whole blood glucose Q was y = 1.12~ - 008 mM (n = 114 values, r = 096, p = 0@001).The error grid analysis indicated that the use of a Glucometer II for blood glucose determination was appropriate in dogs. (2) The in vivo sensitivity coefftcients were O-57 + 0 11 nA rnM_l when determined from plasma glucose, and 051 + @07 nA rnM_'when determined from whole blood glucose (f = l-53, p = 0.18, n.s.). The background currents were 0.88 + 0.57 nA when determined from plasma glucose, and @63 + 0 77 nA when determined from whole blood glucose (t = 0.82,~ = O-45, n.s.). (3) The regression equation of the estimation of the subcutaneous glucose level obtained from the two methods was y = l&lx + 0.56 mM (n = 171 values, r = 0.98,p = O@OOl).Thus, the calibration of a glucose sensor by using a home blood glucose meter and moderate variations of blood glucose concentration is feasible. Keywords: glucose sensor, calibration, analysis.
blood glucose monitoring,
disposable, subcutaneously implanted glucose sensor (Shichiri et aZ., 1982; Claremont et aZ., 1986; Fischer et al., 1987; Velho et al., 1987; Pickup et al., 1989; Koudelka et aZ., 1991). Briefly, glucose is oxidized by glucose oxidase layered on the surface of the electrode, and the generated
INTRODUCTION
In order to provide a continuous estimation of glucose concentration, amperometric, enzymatic sensors have been developed to be used as a *To whom correspondence
hydrogen
should be addressed.
0965-5663/92/$05.00 @ 1992 Elsevier Science Publishers
error grid
Ltd.
peroxide
is
monitored
yielding
a 587
current. The principle of sensor calibration is the transformation of this current into an estimation of the glucose ~o~~entra~u~ by using appropriate pammeters~ namely a se~si~~~ coefficient fin nAmM_‘) and a background current generated in the absence of glucose(in nA). In the past few years, we resolved the problem of sensor calibration by proposing a method based only on in viva measurements: under experimental conditions, blood glucose of the animals was modified by infusing glucose or insulin, and the resulting change in the current generated by the sensor was used to calculate for each individuaf experiment the ealibmtion pammet~~ rJelho et al., 1988,1989). Recently, we have developed in a collaborative programme with the University of Kansas (Professor G. S. Wilson) and the ~ni~rsi~ Paris - Val de Mame (Professor I.3.R, ~~venot) a rni~ia~~~ed glucose sensor, which has been shown to have appropriate irr v&o characteristics (Bindra e6aL, 1991),to work when implanted in the subcutaneous tissue of dogs (Poitout et al., 1991),and for extended periods in the subcutaneous tissue of rats (Moat&Sirat d al., 1992). In all these studies, ~alibra~on of the sensor by deponing glncose was performed concentration in plasma with a Beckman analyser, during increases in plasma glucose concentration reaching 12 mmol 1-t (Poitout Ed al., 1991; Moat&Sirat et aZ.,1992).The relevance of this approach could be questionable since ~libration must eventually be performed by the patient with a readily available glucose meter, and with moderate variations in blood glucose concentration. Thus this study was specifically undertaken to assess the feasibili~ of calibrating a glucose sensor under conditions which would be closer to the clinical use of a glucose sensing system. More specifically, we compared the results obtained from the same experiment by two methods of ~alibratiou of a glucose sensor subcutan~usly implanted in dogs, one using a Beckman analyser for plasma glucose determination, the other using a Glucometer II@for total blood glucose measurement. STEP
AND DEMURS
Glucose sensors allb al&rats This study was performed with rni~~a~~~ed glucose sensors whose preparation is described 588
TN3LI? 1 In vitro sensitivity coefficients (SC) and background currents &) detezmined before irnp~~~~o~. These parameters were determined itr physiok@a~ S&he sOlUtiOnby fecQrding the bad sewx cuneat f&) and rhe sensor response (SC) to stepwise increases in the glucose concentration Sensor no.
SC. (ti mM_‘)
10M)
elsewhere (Bindra d aL, 1991). fn vitm ~ham~e~~~s of the sensors are given in Table I, Experiments were carried out on two healthy female beagles. A 20 gauge catheter (?rasocan, Bureau, Boulo~e-BiIl~~~ou~ France) was used to insert the sensor through a skin fold of the dorsum. The sensor was left under the skin as the catheter was pulled out. The sensors were connected to an arn~~rne~~ unit (PRG-DEL, Solea Tacussef Electronique, Villeurb~ne~ France) and the signal recorded by a strip chart recorder [SE 120,Goerz Eleetro, Vienna, Aus~a) (pl = l), or connected to an experimental portable unit which applies a 650 mV potential between the electrodes and records the signal (n = 5). Venous plasma glucose level and venous total blood glucose level were measured ~ul~n~usly on the same sample every 5 min, using a Beckman analyser type 2 (Be&man, Fullerton, CA, USA) and a Glucometer II (Ames, Elkhart, IN, Uf3A)9 respectively. As a whole, six different sensors were investigated. In one experiment, two sensors were implanted simultaneously in the same animal,
When the sensor signal was stable (about 4 h after implantation), a glucose infusion was started with an initial rate of 6 mg kg-’ min-‘, to increase the plasma glucose ievel from 5.4 + 0.1 mM {?r= 5) to a 96 3~@7 mM plateau (n = 5, range = 667Il.33 mM). In some cases, an intravenous injection of 2-4 III of regular insulin was performed following the glucose infusion. The ~lib~ation parameters (sensitivity coefficient
Biosensors L Bioelectronics
Calibration of a subcutaneous miniaturized glucose sensor
(SC) and extrapolated current in the absence of glucose 00)) were determined by using the values, determined in the basal state and at the first hyperglycaemic plateau, of the current and of the blood glucose concentration, estimated either with the Beckman analyser or with a Glucometer II. Both the current and the plasma and/or blood glucose levels, which were chosen for the calibration, were stable for at least 5 min (see Fig. 2). Thus, only one set of values for the basal and the hyperglycaemic plateau were used. The subcutaneous glucose concentration (SCG) was calculated from the current and the in vivo parameters, according to the equation: SCG = (It - &,)/SC. Expression of results and statistics All results arc given as mean * s.e.m. The values of 1s and SC obtained from the two methods were compared using Student’s paired r-test. The values of glucose level and SCG obtained from the two methods were compared using regression analysis. Ap value of 005 or less was considered significant.
RESULTS AND DISCUSSION Figure 1 represents the correlation between the estimation of blood glucose with the Glucometer II and the results of the determination on the same sample in plasma with the Beckman analyser. The values were slightly higher in whole the regression equation being blood, y = 1.12~ - DO8mm01 1-l (n = 114 values, r = O%, p = 00001). These results are in contradiction to observed higher the usually glucose concentration in plasma than in whole blood (Report of a WHO Study Group, 1985). This discrepancy might be due to the difference between the two methods (calorimetric detection for the glucose meter versus oxygen consumption rate measurement for the Beckman analyser). Actually, our results are in agreement with those obtained by Aziz & Hsiang (1983) who compared glucose concentrations measured in human serum with a Beckman analyser and in veinous blood with a Glucometer II (an experimental design similar to ours). Error grid analysis (Clarke et aZ., 1987) indicated that 88% of the values were in zone A (accurate) and 12% in zone B (acceptable). These
PLASMA
GLUCOSE
(mM)
Fig. 1. Error grid analysis of 114 values of glucose measured in whole blood with the Glucometer II or in plasma with the Beckman analyser.
results extend to the dog the validation of the Glucometer II for blood glucose determination. Figure 2 shows an individual experiment indicating the changes in glucose concentration determined in plasma with the Beckman analyser or in whole blood with the Glucometer II (upper curve), changes in the current (middle curve), and the estimations of SCG calculated by taking into account the basal value and the first hyperglycaemic plateau, as determined either in plasma or in whole blood (lower curve). Obviously, the two estimations were essentially identical. This is further shown in Fig. 3, which represents the correlation between the estimations of glucose concentration in the subcutaneous tissue, as performed from the two sets of values of in vivo parameters. All the data collected over the live experiments are represented, yielding a regression equation y = 1.04x + 0.56 mmol 1-l (n = 171 values, r = 0.98,~ = 0~0001). Table 2 indicates that there was no significant difference in the individual values of the calibration parameters observed in five experiments, when they were determined with the two calibration methods (SCs: t = 1.53, p = O-18, n.s.; background currents: t = 0.82,~ = 0.45, n.s.). Note that the in vivo sensitivity was lower than that observed in vitro, a common phenomenon observed by all investigators in the field (Rebrin et al., 1992; Moatti-Sirat et aZ., 1992).
V; Poitout, D. Moam’-Sirat, G. Reach
Biosensors t Bioelectronics
0 -10
0
10
20
30
40
50
60
70
TIME
o!, -10
,I
I,
0
IO
20
30
I,
40
00
,,
50
60
TIME
20
100
110120
130 140
100
110120
130140
l!sO160
(min)
70
,,
,111
20
90
,,
150
160
(mln)
TIME (mln)
Fig. 2. Results of an experiment showing the variations in bloodglucose as determined with the GlucometerII(open squares) and with the Beckman analyser (closed squares) (upper curve), the current generated by the sensor (middle curve), and the estimation of SCG as determinedfim the two methods (lower curve).
We conclude that calibrating a glucose sensor by using a home blood glucose monitoring system is feasible, and should not be hindered by the slight difference between the whole blood and plasma glucose concentrations. However, it must be stressed that this calibration procedure is basically performed a posterior-i. A method for calibrating the sensor in real time remains to be developed.
ACKNOWLEDGEMENTS The sensors used in this study were prepared by T. Cart+, Laboratoire de Bidlectrochimie et d’Analyse du Milieu, Universite Paris-Val de Mame, Professeur D. R. Thevenot. We express our gratitude to Y. Zhang and G. S. Wilson, Chemistry Department, University of Kansas, for fruitful comments. This work was supported by
C~ibr~~n
Bi~e~so~ & B~i~~ni~
of a subcatun~us rni~i~~~
&eose sensor
TABLE 2 In vivo sensitivity coefftcients and background currents as determined from the plasma glucose measured with the Beckman analyser or from the whole blood glucose measured with the Glucometer II Experiment
Sensitivity
no.
Coefflicient
Beckman
(IL&
ItIM-‘)
Beckman
Glucometer
044 047 035 035 1.01 0.76 069 081 035 o-34 0.5 046 057 f Qll O-51 f O-07 n.s. lp = 02, f-test)
1 2 3 4 5 6 Mean -I s.e.m.
Background
current (nA) Glucometer
0.21 -0.29 2.49 2,49 067 1.7 -0.87 -1.96 268 2.58 o-14 -0+72 088 * o-57 0.63 + 0.77 ns. (p = 02, t-test)
Bindra, D. S., Zhang, Y., Wilson, G. S., Sternberg, R, Thevenot, D. R, Moatti, D. & Reach, G. (1991). Design and invitro studies of a needle type glucose sensor for subcu~neous monitoring. Anal. Chem., 63, 1692-6.
0
1
2
3
4
5
6
7
a
3
10 11 12 13 14 15
Subcutrnwwr
glucor ostimatod from the plasma g&a60 (mM)
Fig 3. Correlation between the estimation of 171 SCGs as ~~~~rn plasma glucose rn~~ with the Beckman anaiyser or from whole blood glucose measured with the GlucometerZZ. In th&figure, ail the values obtained within Jive experiments (six sensors investigated) are represented.
the National Institutes of Health (Grant DK 307 18 to Pr G. S. Wilson), Institut National de la Santi et de la Recherche Mkdicale (Grant CRE 89-90-14), and Aide aux Jeunes Diab~tiques (Grant to V.P.). REFERENCES Aziz, S. & Hsiang, Y.-H. (1983). Comparative study of home blood glucose monitoring devices: Visidex, Chemstrip bG, Glucometer, and Accu-Chek bG. Diabetes Care, 6,529-32.
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