Stuart J. Updike

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.

Implanting the Glucose Enzyme Electrode: Problems, Progress, and Alternative Solutions

An implantable glucose sensor is needed before a reliable artificial pancreas can be realized. The principles and current status of one such device, the glucose enzyme electrode, is presented and discussed. While monitoring glucose this enzyme sensor consumes enough oxygen to become oxygen-limited. This problem has been solved by developing hydrophobic membranes that are more permeable to oxygen than to glucose. Two types of membranes with this property made from (1) cross-linked albumin and (2) sebacyl chloride (nylon) are described. Placing these membranes over the glucose enzyme electrode solves the problem of oxygen limitation. Furthermore, the addition of this type of membrane increases the linear response range of the electrode to glucose to include the entire clinical range of interest (0-400 mg/dl). Other problems in developing an implantable glucose sensor are discussed. Competing strategies to achieve an implantable artificial pancreas without using electronic or mechanical components are presented and evaluated.

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.

Pitfalls Using Doppler Ultrasound to Transduce Blood Flow

General testing procedures which will ascertain whether a Doppler ultrasonic blood flowmeter is correctly designed and operating properly are presented. A commercial Doppler ultrasonic blood flowmeter using the procedure is evaluated. Two pitfalls were encountered which prevented its proper operation. High-frequency response was inadequate, which introduced a nonlinearity into the input-output calibration curve. Low-frequency gain was too high, resulting in wall-motion artifacts. These problem areas are described in detail, and a remedy for each is suggested.

Pressure-flow relationships and pathological changes during renal preservation

The renal pedicle of one kidney from each of four dogs was ligated for one hour. The contralateral kidney served as a control. Both kidneys were removed and perfused using the “Belzer” technique. Pressure-flow relationships were determined and biopsy samples taken. The vasculature was then injected with silicone rubber. Perfusion resistance, vascular filling with silicone rubber and observations made by electron microscopy were compared.

Analogue computer model of a kidney during preservation

This report describes a model of the renal perfusion dynamic changes that occur during kidney preservation. The model utilises data from physiological experiments performed in this laboratory as well as from observations reported in the literature. Included in the model are the effects of cellular volume changes due to metabolic variations, vascular distensibility and a hypothesised tissue pressure effect observed under some conditions.

Renal perfusion dynamics during preservation.

A study of the relation between dynamic measurements of renal perfusion and the physiological state of the preserved kidney make it possible to predict posttransplant immediate function. This report describes the measurement of perfusion dynamic changes during preservation and the model utilized for comparing damaged and nondamaged kidneys.