Joseph Y. Lucisano

APPLICATION OF CHRONIC INTRAVASCULAR BLOOD GLUCOSE SENSOR IN DOGS

An intravenous glucose sensor was implanted in six dogs for 1–15 wk. The glucose sensor is a flexible cylinder, ∼0.2 cm diam and 30 cm long, with a tip containing immobilized glucose oxidase and catalase coupled to a potentiostatic O2 sensor. The sensor and a similar O2 reference sensor were implanted in the superior vena cava near the entrance of the right atrium. The sensor response was conveyed externally either by a telemetry system implanted nearby, surgically accessed leads, or chronically maintained percutaneous leads. Summing over the six implants, there was a total implantation period of 333 days during which glucose sensors were functional on demand. The sensor response showed agreement with conventionally assayed blood samples after accounting for a response lag. Sensor response to glucose showed little change over the implant period. Biocompatibility, enzyme lifetime, O2 availability, O2 sensor stability, and biochemical interference were not limitations. Results demonstrated that this sensor can function effectively as an implant in dogs for a period of months and has the potential for long-term operation.

Function of an implanted tissue glucose sensor for more than 1 year in animals

An implanted tissue glucose sensor can provide stable readings of glucose concentrations for more than a year. Sweet Sensor The need for an automatic, long-term implanted glucose sensor for use in diabetes therapy has been acknowledged by the diabetes care community for several decades. However, it was previously unclear that a sensor-telemetry system could be developed that functions long enough (1 year or more) to justify implantation of such a device, and that the implant could avoid encapsulation by tissues and rejection by the body. Gough et al. describe long-term studies in animals of a continuous, totally implanted glucose sensor that wirelessly transmits glucose concentration values to an external receiver. When available for use in humans, the implant will allow people with diabetes to monitor tissue glucose continuously and report via telemetry to an external receiver that displays the blood glucose information or relays it to a caregiver. Control of blood sugar, or blood glucose, is essential for normal daily activities. For people not having diabetes, blood glucose levels remain remarkably constant during the day, except for a brief modest rise after eating followed by a rapid return to a baseline. However, for people with diabetes, blood glucose levels can remain significantly elevated for long periods after eating and are only occasionally found at the ideal baseline. Further, for people who must inject insulin to bring blood glucose back toward baseline levels after eating, there is the real possibility of blood glucose levels becoming too low. High blood glucose is linked to a number of metabolic problems and can cause serious long-term consequences such as kidney disease, blindness, heart disease, and other problems that can reduce the quality of life, whereas blood glucose levels that are too low are immediately dangerous and can lead to temporary mental impairment, loss of consciousness, and accidents. All treatments for diabetes (insulin, oral medications, and potential new treatments in the research pipeline) are intended in some way to reestablish normal control of blood glucose. People with diabetes should measure their blood glucose concentration many times during the day. The sensor system described by Gough et al. provides an alternative to the most common means for measurement of blood glucose, which involves blood collection by “fingersticking” and glucose detection by placing a drop of blood in a handheld device. This method is inconvenient and only minimally acceptable to most people with diabetes, and is rarely performed frequently enough to follow rapid blood glucose changes. The new sensor system would also be an alternative to other forms of continuous glucose monitoring used by some people with diabetes, in which sensors are inserted into subcutaneous tissues by introducer needles and remain for 3 to 7 days before being replaced. Gough et al. reported on long-term glucose monitoring with the sensor-telemetry system implanted in subcutaneous tissues of pigs. Monitoring was carried out while the pigs were initially nondiabetic (for 3 weeks in one animal and nearly 1 year in the other) and, after the pigs had been made diabetic by administration of a laboratory drug, the monitoring continued in each animal for an additional 6 months, with diabetes being managed by frequent insulin injections and diet. These studies show that by proper design of the sensor system, previous reservations can be overcome. The long-term animal results reported by Gough et al. provide a foundation for human trials, which may require several years. An implantable sensor capable of long-term monitoring of tissue glucose concentrations by wireless telemetry has been developed for eventual application in people with diabetes. The sensor telemetry system functioned continuously while implanted in subcutaneous tissues of two pigs for a total of 222 and 520 days, respectively, with each animal in both nondiabetic and diabetic states. The sensor detects glucose via an enzyme electrode that is based on differential electrochemical oxygen detection, which reduces the sensitivity of the sensor to encapsulation by the body, variations in local microvascular perfusion, limited availability of tissue oxygen, and inactivation of the enzymes. After an initial 2-week stabilization period, the implanted sensors maintained stability of calibration for extended periods. The lag between blood and tissue glucose concentrations was 11.8 ± 5.7 and 6.5 ± 13.3 minutes (mean ± standard deviation), respectively, for rising and falling blood glucose challenges. The lag resulted mainly from glucose mass transfer in the tissues, rather than the intrinsic response of the sensor, and showed no systematic change over implant test periods. These results represent a milestone in the translation of the sensor system to human applications.

Permeability of subcutaneous tissues surrounding long-term implants to oxygen.

Certain types of implanted medical devices depend on oxygen supplied from surrounding tissues for their function. However, there is a concern that the tissue associated with the foreign body response to implants may become impermeable to oxygen over the long term and render the implant nonfunctional. We report oxygen flux recordings from electrochemical oxygen sensor devices with wireless telemetry implanted in subcutaneous porcine tissues. The devices remained implanted for up to 13 weeks and were removed with adjacent tissues at specified times for histologic examination. There are four main observations: (1) In the first few weeks after implantation, the oxygen flux to the sensors, or current density, declined to a sustained mean value, having unsynchronized cyclic variations around the mean; (2) The oxygen mass transfer resistance of the sensor membrane was negligible compared to that of the tissue, allowing for a sensitive estimate of the tissue permeability; (3) The effective diffusion coefficient of oxygen in tissues was found to be approximately one order of magnitude lower than in water; and (4) Quantitative histologic analysis of the tissues showed a mild foreign body response to the PDMS sensor membrane material, with capillaries positioned close to the implant surface. Continuous recordings of oxygen flux indicate that the tissue permeability changes predictably with time, and suggest that oxygen delivery can be sustained over the long term.

Glucose Monitoring in Individuals With Diabetes Using a Long-Term Implanted Sensor/Telemetry System and Model

Objective: The use of a fully implanted first-generation prototype sensor/telemetry system is described for long-term monitoring of subcutaneous tissue glucose in a small cohort of people with diabetes. Methods: Sensors are based on a membrane containing immobilized glucose oxidase and catalase coupled to oxygen electrodes and a telemetry system, integrated as an implant. The devices remained implanted for up to 180 days, with signals transmitted every 2 min to external receivers. Results: The data include signal recordings from glucose clamps and spontaneous glucose excursions, matched, respectively, to reference blood glucose and finger-stick values. The sensor signals indicate dynamic tissue glucose, for which there is no independent standard, and a model describing the relationship between blood glucose and the signal is, therefore, included. The values of all model parameters have been estimated, including the permeability of adjacent tissues to glucose, and equated to conventional mass transfer parameters. As a group, the sensor calibration varied randomly at an average rate of −2.6%/week. Statistical correlation indicated strong association between the sensor signals and reference glucose values. Conclusion: Continuous long-term glucose monitoring in individuals with diabetes is feasible with this system. Significance: All therapies for diabetes are based on glucose control, and therefore, require glucose monitoring. This fully implanted long-term sensor/telemetry system may facilitate a new era of management of the disease.

Adoption Barriers for Continuous Glucose Monitoring and Their Potential Reduction With a Fully Implanted System: Results From Patient Preference Surveys

IN BRIEF A patient-centered approach to device design can provide important advantages in optimizing diabetes care technology for broadened adoption and improved adherence. Results from two surveys of people with diabetes and the parents of children with diabetes (n = 1,348) regarding continuous glucose monitoring (CGM) devices reveal the importance of the concept of “user burden” in patients’ and caregivers’ evaluations of the acceptability of available devices. Survey respondents’ strongly favorable reactions to a proposed 1-year, fully implanted CGM device with no skin-attached components further confirm that minimizing system obtrusiveness will likely be of significant value in reducing hurdles to CGM device use and adherence.