Rathbun K. Rhodes

A telemetry-instrumentation system for monitoring multiple subcutaneously implanted glucose sensors

An implantable potentiostat-radiotelemetry system for in vivo sensing of glucose is described. An enzyme electrode sensor measures the oxidation current of hydrogen peroxide formed by the stoichiometric conversion of glucose substrate and oxygen cofactor in an immobilized glucose oxidase layer. The sensor current is converted to a frequency and transmitted at programmable intervals (4, 32, 256 s) to a remote receiver. Low power CMOS circuitry is employed and device operation for up to 1.5 years is predicted using two series connected 250 mAh lithium cells. Crystal controlled RF frequencies uniquely identify each sensor allowing over 10 sensors within the same 10 m radius. A custom interface card allows a PC to program the receiver and handle the transmitted sensor data using software written in Microsoft C and QuickBasic. Software control allows on-the-fly sensor addition or subtraction to the sensor group being monitored. Over 10 sensors can be tracked long-term using the longest transmit interval, or four sensors can be tracked during short-term infusion studies when the transmit interval is reduced to 4 s. The design, construction, operation, and performance of the system hardware and software are described and evaluated.<<ETX>>

Evaluation of a Subcutaneous Glucose Sensor out to 3 Months in a Dog Model

OBJECTIVE To advance the feasibility of an impiantatile long-term glucose sensor with bioprotective sensor membranes and test protocols using a somatostatin analog (octreotide). RESEARCH DESIGN AND METHODS Implantable sensors were constructed with one of eight bioprotective membranes and screened in vitro for stable response to glucose. Sensors were implanted subcutaneously into nondiabetic mongrel dogs and monitored at 4-min intervals via radiotelemetry. When implanted sensor responses showed evidence of tracking blood glucose after glucagon challenge (8–21 days postimplant), a glucose infusion protocolwas used to assess performance. Sensor data were collected every 4 s after octreotide inhibition of endogenous insulin release. Reference plasma glucose samples were taken every 4–10 min. RESULTS Preimplant in vitro testing of sensors verified linearity to 33.3 mM glucose and response times to 90% of equilibrium in 2–7 min. Ten implanted sensors tracked glucose for 20–114 days, during which 25 separate glucose infusion studies were conducted. The resulting regression data yielded a mean slope of 0.99 ± 0.06, an intercept of 0.24 ± 0.53 mM glucose, and a correlation coefficient 0.98 ± 0.01. Long-term sensor stability was not judged adequate for clinical application, although two sensors tracked within ±15% for 33 and 42 days. In vivo oxygen delivery was shown toaffect sensor performance. On expiant, two of eight tested bioprotective membranes were found to be biostable and to fully protect the sensors enzyme membrane. The foreign body capsule was adequately vascularized adjacent to the sensor up to 91 days postimplant. Sensor units eventually failed because of electronic problems (package leakage) or because of biodegradation or biofouling of test bioprotective membranes. CONCLUSION Further development of this type of sensor may provide diabetic patients with a better means of monitoring blood glucose.

Feasibility of Continuous Long-Term Glucose Monitoring from a Subcutaneous Glucose Sensor in Humans

The feasibility of continuous long-term glucose monitoring in humans has not yet been demonstrated. Enzyme-based electrochemical glucose sensors with telemetric output were subcutaneously implanted and evaluated in five human subjects with type I diabetes. Subject-worn radio-receiver data-loggers stored sensor outputs. Every 1-4 weeks the subjects glucose levels were manipulated through the full clinical range of interest using standard protocols. Reference blood glucose samples were obtained every 5-10 min and analyzed in our hospital clinical laboratory and/or on glucose meters. The sensor data were evaluated versus the reference data by linear least squares regression and by the Clarke Error Grid method. After surgical explantation and device inspection, the tissue-sensor interface was evaluated histologically. The remaining sensor-membranes were also recalibrated for comparison with preimplant performance. Four of the five glucose sensors tracked glucose in vivo. One sensor responded to manipulated glucose changes for 6.2 months with clinically useful performance (>/=90% of sensor glucose values within the A and B regions of the Clarke Error Grid). For this sensor, recalibration was required every 1-4 weeks. The other three transiently responding sensors had electronic problems associated with packaging failure. The remaining sensor never tracked glucose because of failure to form any sustained connection to adjacent subcutaneous tissue. Thus, stable, clinically useful sensor performance was demonstrated in one of five subjects with diabetes for a sustained interval of greater than 6 months. While this glucose sensor implant technology shows promise in humans, it needs to be made more reliable and robust with respect to device packaging and sensor-tissue connection.

Enzymatic glucose sensors. Improved long-term performance in vitro and in vivo.

We studied the long-term in vitro and in vivo performance of enzyme electrode glucose sensors. Single commercially produced enzyme-active membranes remained functional for estimating glucose in vitro for 14-36 months. These membranes were implanted subcutaneously in rats for 1 year and, upon explanation, remained functional for measuring glucose in vitro. Sensors with these membranes plus an additional outer membrane with lower glucose permeability allowed glucose monitoring in the low oxygen tension of subcutaneous tissue. These sensors were surgically implanted in three nondiabetic dogs. Each sensor implant was coupled to a radio transmitter to allow continuous long-term glucose monitoring in these awake unrestrained dogs. In vivo sensor performance was evaluated by intravenous glucose infusion, with reference blood glucose determinations made in the clinical laboratory. These subcutaneously implanted sensors tracked changes in plasma glucose for up to 12 weeks. The in vivo initial response for three sensor implants was approximately 35 sec (n=8). Sensor peak response to glucose after bolus infusion ranged from 3 to 14 min. Stability of sensor sensitivity within ± 15% for more than 1 month was demonstrated in two of the dogs. Sensor lifetime was limited not by loss of enzyme activity, but by biodegradation of the outermost polyurethane membrane. The findings suggest that long-term continuous monitoring of blood glucose using a subcutaneously implanted enzyme electrode sensor may be possible.

Laboratory Evaluation of New Reusable Blood Glucose Sensor

An enzyme-electrode sensor designed specifically for pocket-portable self-monitoring of blood glucose is described. The sensing device in this instrument is unique because it is reusable for at least 30 days, at which time it is easily replaced by placing a new enzyme-membrane cartridge over the electrode. As little as 7 μl of undiluted whole blood, plasma, or serum is applied directly to the sensor, and glucose is automatically determined in 30 s. No manual timing or wiping step is required after sample application. On eight production instruments, plasma glucose concentration was determined (n = 20) at 57, 125, 246, and 347 mg/dl. The average coefficient of variation for the 80 determinations for each instrument ranged from 2 to 5%, averaging 3.7%. The instrument is inherently linear, independent of hematocrit, and without oxygen limitation when dissolved oxygen concentration is >35 mmHg. No interferences were found from plasma constituents, heparin, or acetaminophen.

Development of Low-Drift pH Electrodes Based on Neutral Carrier in PVC Overlayered Metallizations

The majority of work on pH ISFETs has been done with devices whose gate has been overlayered with solid-state insulators formed by either vacuum deposition or chemical vapor deposition (silicon dioxide and nitride, oxides of aluminum, iridium, or tantalum). Historically, these layers have. shown problems of drift, redox sensitivity, degradation of response, and shortened lifetime. The recent introduction of improved pH neutral carriers has provided another possible approach. When these carriers are incorporated into a PVC matrix, and used in symmetrical solution contact configuration, they form electrodes which are highly selective, maintain sensitivity, show low drift, and provide long lifetime. This work describes the results for a-suitable metallization/membrane configuration which maintains these desirable characteristics, the degree to which the resultant system has been miniaturized, and its prospects for usage as part of an ISFET device.