Implantable glucose sensor

Details Implantable glucose sensor Implantable glucose sensor

2002-01-28

2004-11-09

Lankford, Jr., Leon B. (Department: 1651)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

C435S180000, C435S182000, C435S176000, C435S188000, C435S189000, C600S347000, C600S377000, C600S300000

Reexamination Certificate

active

06815186

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns the field of electrochemical devices for detection and measurement purposes and more specifically an enzyme emulsion for use in an implantable miniature polarographic glucose sensor.
2. Description of Related Art
There is currently a considerable need for a glucose sensor that can be readily implanted into a human where it will function for a prolonged time period. The primary impetus for such a device is diabetes, a potentially devastating complex disorder of glucose metabolism, currently controllable through insulin injections, is increasing worldwide. In the United States it is estimated that over ten million persons have diabetes. The monetary cost to society is in the many billions of dollars reflecting treatment expense and loss of productivity while the human cost in impaired function, progression to blindness, limb amputations, kidney failure and heart and vascular disease is immeasurable.
It has been known for well over seventy years that this disease primarily results from inadequate secretion of the hormone insulin by the islet or Beta cells of the pancreas. When uncontrolled, this disease often leads to serious metabolic imbalances-elevated glucose levels lead to ketosis and to damaging alterations in blood pH while inadequate glucose levels lead to lethargy and coma. Diet and daily injections of insulin are now used in an attempt to control life-threatening swings in blood glucose. It is now well established that the damage is caused by excessive glucose and not directly by lack of insulin. Glucose combines with hundreds of proteins essential for normal metabolism and in that way damages the cellular machinery of the body.
Control of diabetes by insulin injection generally results in much wider swings in blood glucose level than are common in a normal individual. Occasional insulin injections (up to several per day) are unable to duplicate the strict control of blood glucose afforded by a properly functioning pancreas which continually meters out just enough insulin to maintain a stable and relatively normal blood glucose level. Extremes in blood glucose level need be avoided. Yet despite avoiding extremes in blood glucose level insulin-dependent diabetics suffer a host of other maladies, mentioned above, that decrease both the quality and length of life. Diabetics experience frequent vascular disease that often results in amputation of limbs as impaired circulation prevents adequate blood flow. Abnormal vascular growth within the eye may result in intraocular bleeding and retinal damage with progressive loss of vision. Nerve degeneration may lead to loss of sensation and other related problems.
To control the blood level of glucose by injection of insulin requires the analysis of six to eight samples of blood each day. This is usually performed by puncturing the finger tip with a small lancet and analyzing blood glucose level with a photometric “home glucose monitor.” This is, of course, not a pleasant experience and requires considerable skill as well as motivation. As home glucose tests have became common, more and more data have became available demonstrating the relatively poor control of blood glucose afforded by periodic insulin injections. At the same time, a growing number of clinical studies demonstrated that strict control of blood glucose reduces many if not all of the diabetes-related diseases mentioned above. Many scientists and physicians now believe that greatly improved blood glucose control can largely eliminate the mortality and morbidity associated with diabetes.
The ultimate goal of diabetes treatment is a replacement for the patient's non-functioning pancreatic islet cells. Some scientists are seeking ways to transplant functioning islet cells into diabetic patients to provide a naturally controlled source of insulin. Other scientists are working on automatic insulin injection systems that deliver exogenously supplied insulin as needed to maintain precise blood glucose control. Most probably both of these “cures” will be needed. Although transplanted islet cells would seem to be the optimal solution, at this time anti-rejection drugs required for transplants have almost as many negative side effects as diabetes itself. In any case, a self-regulating artificial insulin source is needed to limit the damage caused by diabetes until islet transplantation is perfected. Even when transplantation is widely available, a self regulating insulin source will be needed for patient maintenance prior to transplantation, and, perhaps, for some post-transplantation support.
Many types of regulated injection systems, both implantable and external, are already available. The key problem continues to be the requirement for an accurate glucose sensor to control these injection systems. The need to continually monitor glucose levels to permit a constantly metered dispensing of insulin generally eliminates methods relying on blood samples. It is clear that an implantable glucose sensor that measures in vivo glucose levels is the real answer.
Previous to modem instrumentation the analysis for blood glucose required a venipuncture with the collection of several milliliters of blood, precipitation, filtration, treatment with a colorimetric glucose reagent and spectrophotometric determination of glucose. The invention of the first “enzyme electrode” and glucose sensor by the present inventor in the 1960's led to the production of the first commercially successful blood glucose analyzer. The Clark glucose sensor consisted of a platinum anode, a layer of glucose oxygen oxioreductase (glucose oxidase) and a cellophane or cellulose acetate membrane. A silver “reference” electrode was also incorporated into the sensor. Only 0.01 ml of blood was required and the final analysis was complete in about one minute. Since then literally billions of blood samples have been analyzed by this type of instrument.
The inventor's polarographic glucose method just mentioned is explained in U.S. Pat. No. 3,539,455. The chemical reaction most commonly used by such enzyme-coupled polarographic glucose sensors is glucose oxidase mediated catalytic oxidation of glucose by atmospheric oxygen to produce gluconolactone and hydrogen peroxide (equation 1):
C
6
H
12
O
6
+O
2
+H
2
O→C
6
H
12
O
7
+H
2
O
2
  (1)
In the presence of excess oxygen, the quantity of hydrogen peroxide produced will be a direct measure of the glucose concentration. The hydrogen peroxide is measured by being reoxidized by an electrode (anode) maintained at an appropriate positive potential (equation 2):
H
2
O
2
−2
e
−
→O
2
+2H
+
  (2)
The glucose detection process, then, is dependent upon the measurement of electrons removed from hydrogen peroxide in equation (2). The electrode is normally formed from a noble metal such as gold or platinum. The latter preferred metal although carbon, pyrolytic or glassy, graphite and other electrically conducting materials are sometimes used.
As is well known to those of ordinary skill in the art, other specific hydrogen peroxide producing oxidase enzymes can be used to produce sensors for other substances such as cholesterol (cholesterol oxidase), amino acids (amino acid oxidase), alcohol (alcohol oxidase), lactic acid (lactate oxidase), and galactose (galactose oxidase), to name only a few.
The success of this kind of enzyme-based sensor suggested to many that a similar sensor might be implanted with a simple power source and a means for transmitting the glucose data to the outside of the body. Such a continuously reading device would not only eliminate the pain of repeatedly puncturing the finger but would also supply a constant reading of the glucose level. It is known that the glucose level in many locations in the body closely mirror the blood glucose level. Numerous attempts have been made to make such a device available to diabetics. However, experimental devices did not function a sufficiently long period of time. Thes

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