THE DIABETES CONTROL LOOP: SENSING OF GLUCOSE

AND CONTROL OF INSULIN IN SITU USING ENGINEERED

                     SYSTE...
TABLE OF CONTENTS


                                                                                                      ...
iii

Table of Contents (Continued)

                                                                                      ...
LIST OF FIGURES


Figure                                                    Page

    8    FIGURE 1. DIAGRAM OF THE CLARK ...
Dummy page for page numbering, discard if printed.

Do not delete the section breaks at its beginning and end.
CHAPTER 1

I.INTRODUCTION


       One of the most common diseases of the endocrine system, diabetes, is a chronic

lifelo...
7

steadily growing and is quite high now due to the increased number of elderly

Americans, and a greater number of Ameri...
8

in the process. The oxygen electrode detects the decrease in oxygen partial pressure and

this is proportional to gluco...
9

substrate consumption, production of metabolites, detection of luminescence, and

electrochemical sampling of the elect...
10

               1.Biological Sensing Element (BSE)

       The BSE is used because a biological molecule is specific to...
11

surface of the sensor (Wallace, 1999). Also, efficient electron transfer must be possible

between the enzyme and the ...
12

       B.Inherently conducting polymer biosensor interface

       Inherently conducting polymers (ICP) are high condu...
13

enhancing the selectivity of the system. Optimization of the size of the electrode has

important effects on its trans...
14

                       b)Polymerization then attachment of BSE

       An alternative method used to attach the BSE to...
15




 Figure 3. Measurement Parameters for the Oxidation of Glucose Catalyzed by Glucose
                               ...
16

hydrophobic O2 permeable membrane. This sensor is very specific to O 2 concentrations

(Cammann, 1988).



           ...
17

               3.Redox glucose biosensor

       The sensing of products and reactants is not the only way to detect g...
18

acid. The sensitivity and specificity of this electrode make it a good candidate for an

implantable biosensor to cont...
19



        B.Implantable insulin delivery system requirements

        Since the glucose biosensor and the insulin deli...
20



       A.Closed and Open Loop insulin dispensing systems

       A glucose sensor response time and range of sensiti...
21

meal periods, and control would switch over to the open loop system only during meal

times.

         Another type of...
22

method, the interface between the transducer and biological sensing element is very

important. It is possible to buil...
REFERENCES


 1. American Diabetes Association, Basic Diabetes Information, http:www.diabetes.org

 2. Cammann, K., 1988, ...
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THE DIABETES CONTROL LOOP

  1. 1. THE DIABETES CONTROL LOOP: SENSING OF GLUCOSE AND CONTROL OF INSULIN IN SITU USING ENGINEERED SYSTEMS A Paper Presented to the Graduate School of Clemson University by Daniel L. Maierhafer November 2001 Teacher: Dr. C.P. Leslie Grady
  2. 2. TABLE OF CONTENTS Page TITLE PAGE .................................................................................................... i LIST OF FIGURES........................................................................iv CHAPTER 1 THE DIABETES CONTROL LOOP: SENSING OF GLUCOSE AND CONTROL OF INSULIN IN SITU USING ENGINEERED SYSTEMS I 2 I. INTRODUCTION 6 3 II. HISTORY OF THE FIRST BIOSENSOR 7 4 III. BIOSENSORS 8 A. Common Biosensor Elements...................................................9 1. Biological Sensing Element (BSE)......................................10 2. Transducer............................................................................11 3. Target Analyte.....................................................................11 B. Inherently conducting polymer biosensor interface.................12 1. Electrode Materials and Manufacturing Methods................12 2. Attachment of the BSE to the electrode...............................13 C. Biosensors for Glucose Detection............................................14 1. Amperometric glucose biosensors.......................................15 2. Potentiometric pH glucose biosensor...................................16 3. Redox glucose biosensor......................................................17 5 IV. REQUIREMENTS FOR AN IMPLANTABLE DIABETES TREATMENT SYSTEM 18
  3. 3. iii Table of Contents (Continued) Page A. Implantable Glucose Biosensor Requirements........................18 B. Implantable insulin delivery system requirements..................19 6 V. INSULIN DISPENSING SYSTEMS 19 A. Closed and Open Loop insulin dispensing systems.................20 B. Mixed insulin dispensing system.............................................20 C. Other insulin dispensing systems.............................................21 7 VI. CONCLUSIONS 21 REFERENCES.............................................................................23
  4. 4. LIST OF FIGURES Figure Page 8 FIGURE 1. DIAGRAM OF THE CLARK GLUCOSE ENZYME- ELECTRODE 8 9 FIGURE 2. DIAGRAM OF GENERAL BIOSENSOR COMPONENTS 9 10 FIGURE 3. MEASUREMENT PARAMETERS FOR THE OXIDATION OF GLUCOSE CATALYZED BY GLUCOSE OXIDASE ENZYME. 15
  5. 5. Dummy page for page numbering, discard if printed. Do not delete the section breaks at its beginning and end.
  6. 6. CHAPTER 1 I.INTRODUCTION One of the most common diseases of the endocrine system, diabetes, is a chronic lifelong disease caused by a disruption of the carbohydrate metabolic pathway. Diabetes ranks as the third highest cause of death, directly after heart disease and cancer in industrialized nations. According to the International Diabetes Association in Brussels, Belgium, there are more than 100 million diabetics in the world, or 6% of the total adult population. As of today, diabetes cannot be cured, only controlled. If not well controlled it will affect the function and metabolism of tissues and organs. If neglected for a long enough period, organ complications will arise such as heart disease, renal disease, blindness, and paraplegia (Ping, 1997). The root cause of diabetes is the inability of the body to utilize or produce enough insulin. Insulin is a hormone that is needed to convert glucose into energy needed for daily life. Nobody knows what causes diabetes, but evidence points towards a combination of genetics, obesity, and lack of exercise (American Diabetes Association). There are two types of diabetes: In Type I diabetes, the pancreas does not produce any insulin. This type most often occurs in children and young adults. People with Type I diabetes must take daily insulin injections to stay alive. Five to ten percent of diabetics are Type I (American Diabetes Association). With Type II diabetes the body has a metabolic disorder resulting from its inability to make enough, or to properly use insulin. Ninety to ninety-five percent of diabetics are Type II. Unfortunately, the number of Type II diabetes cases has been
  7. 7. 7 steadily growing and is quite high now due to the increased number of elderly Americans, and a greater number of Americans that are obese and lead sedentary lifestyles (American Diabetes Association). Because diabetes is so widespread among the population, a large amount of research and engineering have been done to make sensors that can detect the concentration of glucose in the subject, and design devices that can help regulate the concentration of insulin in the body. This paper will explain how a general biosensor works, and then focus on the various schemes used to do glucose biosensing. Finally some developments of implantable insulin delivery systems will be covered to close the loop on the artificial insulin control system for diabetes. II.HISTORY OF THE FIRST BIOSENSOR The earliest known biosensor design for the detection of glucose was in 1962, when Clark and Lyons thought that it might be possible to use a membrane covered with an enzyme to transform glucose or urea into a substance that was detectable with an oxygen or pH electrode. This was accomplished in 1976 when Updike and Hicks were able to make such an enzyme electrode by polymerizing a gel that contained glucose oxidase and attaching that to an oxygen electrode (Canh, 1993). This type of biosensor is classified as an electroenzymatic sensor, because it uses the enzyme glucose oxidase to oxidize glucose to gluconoloactone, which is then hydrolyzed to gluconic acid. The reaction can be detected by either the disappearance of oxygen, or the appearance of the products (Cammann, 1988). When glucose and oxygen diffuse into the enzymatic membrane, glucose is oxidized to gluconic acid, reducing the partial pressure of oxygen
  8. 8. 8 in the process. The oxygen electrode detects the decrease in oxygen partial pressure and this is proportional to glucose concentration (Canh, 1993). The reaction proceeds according to the chemical formula in Equation 1: Equation 1: glu cos e + O2 + H 2 O cos e → gluconic acid + H 2 O2 glu  oxidase Figure 1 shows a diagram of this first enzyme catalyzed glucose biosensor (Hall, 1991). Figure 1. Diagram of the Clark glucose enzyme-electrode III.BIOSENSORS The term biosensor is very broad and encompasses the microscopic to the macroscopic size range, with measures from physical to chemical to electrical phenomena. Most biosensor developments have been in the field of medicine, the food industry, and environmental monitoring. For example, in the medical field, it has been found that the general metabolic status of a cell can be interrogated by oxygen or
  9. 9. 9 substrate consumption, production of metabolites, detection of luminescence, and electrochemical sampling of the electron transport chain. In the agricultural arena, biosensors are used to detect pollution in food and water samples and monitor livestock reproduction in situ via milk progesterone (Tothill, 2001). At an environmental monitoring site in Fort Detrick, Maryland, bluegill fish are used to continuously monitor for heavy metals and organic pollutants in the effluent of the groundwater treatment facility of a contaminated site (Van der Schalie, 2001). Even though the definition of a biosensor encompasses a lot of diversity, all biosensors consist of the same three elements. A.Common Biosensor Elements The distinguishing feature of the biosensor is that it is a transducer that incorporates a biological sensing element (BSE) to discriminate a target analyte. The biosensor consists of those three main parts: the BSE, the transducer, and the target analyte. These three pieces are shown in Figure 2 (Hall, 1991). Figure 2. Diagram of General Biosensor Components
  10. 10. 10 1.Biological Sensing Element (BSE) The BSE is used because a biological molecule is specific to a target analyte or small set of analytes. The BSE could possibly be an enzyme, microorganism, immunoagent, chemoreceptor, tissue, or organelle (Cahn, 1993). The detection of the target analyte is indirect, that is the analyte first reacts with the BSE, and this reaction produces a signal that is detectable by the transducer. The indirect mechanism allows selective detection of analytes that would otherwise be undetectable or hard to detect compared to a direct method using current technology. On the negative side, this makes a more complex sensor and therefore allows more opportunities for interference into the system than if the sensor used a direct method. For this reason, the union between the BSE and the tranducer is very important, because it plays a strong role in determining the signal to noise ratio, and the efficiency of signal conversion. Usually, the BSE is immobilized on the surface of the transducer so that the manufacturing process can control its thickness, and it will not wash away so it can be reused. Unfortunately, the kinetics of the immobilized BSE are different from the BSE in solution, and these kinetics change in the immobilized microenvironment. If mass transfer of the analyte is diffusion limited, the enzyme will not be utilized efficiently, and the output will be reduced. On the other hand, the linear dynamic range for enzyme assays is increased with a slow mass transfer. The interface must also be compatible with the operating environment. For example, if pH is to be monitored, the immobilized molecule should be resistant to the micro pH environment created by the reaction in the bio-linked immobilized layer (Hall, 1991). This is important when enzymatic reaction products like H+ or NH4+ are produced. These cations can cause in dramatic changes to the micro pH environment near the
  11. 11. 11 surface of the sensor (Wallace, 1999). Also, efficient electron transfer must be possible between the enzyme and the transducer if a redox enzyme is employed as the BSE (Hall, 1991). 2.Transducer The transducer converts the biochemical signal from the interaction between the BSE and the analyte into an electrical signal. There are four main categories of transducers used in biosensors: electromechanical (electrode), optical (optrode), mass (piezoelectric or SAW devices), and calorimetric (thermistor or heat sensitive devices). Electrochemical devices monitor current at a fixed voltage (amperometry), or monitor voltage at zero current (potentiometry). Optical methods measure light absorption, fluorescence, or the index of refraction of the analyte. Calorimetric devices measure the enthalpy change of the biochemical reaction. Piezoelectric transducers use the change in mass, viscosity, or density to modify the resonant frequency of an oscillating element (Tothill, 2001). Whatever the embodiment of the transducer, it should be very sensitive to the BSE output signal, should be easy to monitor, and should have low background noise (Canh, 1993). 3.Target Analyte The system is designed to detect the target analyte. Ideally, the BSE interacts exclusively with the target analyte, so compounds other than the analyte are ignored.
  12. 12. 12 B.Inherently conducting polymer biosensor interface Inherently conducting polymers (ICP) are high conductivity/weight ratio polymers that are being integrated with biological sensing elements in order to attach the BSE to a transducer. ICP’s have three useful characteristics: First, they are chemically compatible with many compounds found in nature. Second, inherently mild fabrication conditions during the polymerization of ICP are ideal for bonding enzymes, antibodies, or whole living cells. Third, since they are conductive, electron transfer from biomolecular events occurring in or on the polymer can easily be passed to the electronic interface (Wallace, 1999). 1.Electrode Materials and Manufacturing Methods Usually the ICP is mounted to a solid electrode like gold, platinum, or glassy carbon. However, disposable electrodes such as gold coated Mylar, carbon felt, and reticulated vitreous carbon (RVC) are becoming more popular. The RVC is particularly useful because it has electrochemical characteristics similar to glassy carbon yet it contains pores that allow it to be used as a flow through biosensor (Wallace, 1999). Attachment of the electrode material to the disposable electrode can be accomplished by screen-printing and sputter coating. To make a screen-printed electrode, a conducting component like carbon or silver is added to screen printing ink. The resulting disposable electrodes are inexpensive and easily fabricated. Sputter coating is another method that can be used to manufacture thin metallic layered disposable electrodes. A porous membrane can be sputter coated on both sides to produce a dual electrode biosensor. These two electrodes can each have a different potential. If the membrane is chosen correctly, transport of the analyte can be controlled, thereby
  13. 13. 13 enhancing the selectivity of the system. Optimization of the size of the electrode has important effects on its transport characteristics. If a dimension of the electrode becomes less than around 50 µm, the electrochemical transport characteristics of the electrode become more efficient (Wallace, 1999). 2.Attachment of the BSE to the electrode The BSE needs to be attached to the electrode firmly so that the biosensor can be reused, yet gently so the BSE is not denatured or destroyed. There are two main methods to accomplish this with ICP: direct electropolymerisation-deposition, and polymerisation then attachment of BSE. a)Direct electro-polymerization-deposition Electro-polymerisation, which is the electro-deposition of a conducting polymer onto an electrode surface, is an easy one-step process. The process is carried out in a solution of monomer and BSE. The BSE is given a negative charge, while the monomer is oxidized, allowed to combine with the BSE, and then polymerized. This method can be used if the BSE is an enzyme, antibody, or even a living cell. The deposition method can control voltage or current to change the thickness of the polymer on the transducer face. For the electrochemical biosensor, the controlled voltage method is commonly used because the integrity of the BSE can be maintained better during polymer formation, while for the ICP biosensor, the current is controlled which results in a more porous polymer coating (Wallace, 1999).
  14. 14. 14 b)Polymerization then attachment of BSE An alternative method used to attach the BSE to the electrode is polymerization, followed by adsorption or ion exchange of the BSE to the ICP. First, bulky anions like paratoluene-sulphonate are used in the polymer fabrication. Then these bulky ions are exchanged with smaller Cl- ions before the glucose oxidase enzyme is immobilized (Wallace, 1999). C.Biosensors for Glucose Detection It is relatively easy to detect glucose because it can be oxidized directly or indirectly through enzymatic action yielding products ideal for electrochemical sensing (Cammann, 1988). The difficult task is to tune the glucose sensor to the characteristics of the human body. The response time of the glucose sensing system in an insulin delivery device has been an area of consternation, because even a “perfect” glucose sensor with zero response time is not sufficient to ensure correct timing of insulin delivery with meals (Kraegen, 1988). Glucose biosensor technology is dominated by four sensing methods, two electrochemical, one Redox, and one pH, depending where in the reaction the sensing is occurring. Figure 3 shows the four most common methods used in glucose detection (Hall, 1991).
  15. 15. 15 Figure 3. Measurement Parameters for the Oxidation of Glucose Catalyzed by Glucose Oxidase Enzyme. 1.Amperometric glucose biosensors As described earlier, the disappearance in the partial pressure of the oxygen can be detected, as well as the appearance of reaction products like H2O2. One type of amperometric sensor detects the concentration of H2O2. This sensor utilizes an outer cuprophan membrane with immobilized glucose oxidase enzyme on the inner surface. The cuprophan blocks interferences such as urate, ascorbate, and bilirubin. The inner layers consist of acetate followed by a platinum or gold anode. The other type of amperometric sensor measures the decrease in the partial pressure of O2. This sensor uses a layer of immobilized glucose oxidase in front of a
  16. 16. 16 hydrophobic O2 permeable membrane. This sensor is very specific to O 2 concentrations (Cammann, 1988). 2.Potentiometric pH glucose biosensor Amperometric measurement of H2O2 has a minor problem. Any buildup or other reactive oxidizable compound that collects on the electrode will change the signal. During testing of the glucose sensor, the influence of material buildup can be simulated by the addition of layers of dialysis foil between the electrode and BSE (Honold, 1988). The potentiometric pH glucose biosensor works by the detection of the reaction product, gluconic acid. The formation of gluconic acid will cause a change in pH with an enzyme coated conventional glass electrode, or a modern ion selective field effect transistor. A reference sensor, without enzyme, can be used to null out pH changes of the analyte (Honold, 1988). A pH sensitive electrode does not destroy the analyte, gluconic acid, and therefore does not change the concentration of analyte in solution. An amperometric probe destroys the analyte, H2O2, thus changes the concentration and forms a depletion layer at the electrode. If increasing layers of dialysis foil (to simulate buildup) are added, the amperometric probe shows in increase in analyte concentration error and time delay error, whereas the pH electrode will only show an increase in time delay error due to the increased time of diffusion through the dialysis foil (Honold, 1988).
  17. 17. 17 3.Redox glucose biosensor The sensing of products and reactants is not the only way to detect glucose. Because the transducer is usually an electrical device, a Redox sensor can be used because it passes a current or voltage to the transducer. Research has been done on a type of Redox biosensor that uses a bifunctional crosslinking reagent to attach a multi-layered assembly of glucose oxidase on a gold electrode. This method makes it possible to control the number of layers in an enzyme assembly, which in turn controls the sensitivity of the electrodes. The electroactive materials ferrocyanide, water-soluble ferrocene derivatives, and quinones can be used to transport electrons from the enzyme active site to the electrode. The enzyme and the electroactive materials are bound together to electrically connect the enzyme active site to the electrode. These electron relay units shorten the electron transfer distance and make a better electrical connection between the Redox center and the electrode. The enzyme works in the presence of glucose to create an electrocatalytic anodic current where the glucose concentration affects the amperometric response (Willner, 2001). In one experimental glucose biosensor, the best electrical connection between the Redox protein and the support electrode was achieved by aligning the Redox protein on the electron-relay wires of the electrode. The protein was aligned to the relay wires by the surface reconstitution of apo-glucose oxidase on a monolayer of pyrroloquinoline quinone-FAD. Using this scheme the electron transport was made extremely efficient. The calculated electron transport turnover rate is 900/s at 35 °C. This exceeds even the electron transfer rate between the enzyme and oxygen, its native electron acceptor. The resulting biocatalyst is insensitive to oxygen and other interferants like uric or ascorbic
  18. 18. 18 acid. The sensitivity and specificity of this electrode make it a good candidate for an implantable biosensor to continuously monitor blood glucose levels (Willner, 2001). IV.REQUIREMENTS FOR AN IMPLANTABLE DIABETES TREATMENT SYSTEM An implantable biosensor should be minimally invasive to the host and not disrupt any of the normal functions of the human body. The ultimate goal of an implantable system is to simulate the function of a healthy pancreatic β cell (Kraegen, 1988). There has been research both on glucose biosensors and insulin delivery systems. A.Implantable Glucose Biosensor Requirements The 1988 International Symposium of Implantable Glucose Sensors in Reisensburg, Germany defined some specifications that designers of implantable glucose biosensors should follow. It is mentioned that a good glucose biosensor is the missing piece in portable diabetes treatment therapy. Some of the analytical requirements for an implantable glucose biosensor include: dynamic measurement range of 1-100 mM in undiluted blood, response time of less than 10 minutes based on the rate of the appearance of glucose in blood after meals, accuracy of 10% from true glucose content, no direct zeroing required, calibration cycle of greater than one week to eliminate daily needle invasion, and a low temperature response of less than 5% / °C (Cammann, 1988). The physical requirements include: small size that is round and flat with nonthrombogenic (blood clotting) surfaces, greater than a one year lifetime, noninvasive battery recharging, and no reagents used in the system (Cammann, 1988).
  19. 19. 19 B.Implantable insulin delivery system requirements Since the glucose biosensor and the insulin delivery system will most likely be contained in the same package, all of the above glucose biosensor physical requirements apply to the insulin delivery system. There are two additional requirements for the insulin delivery system: • During normal digestion, there is a time lag of 10-20 minutes from the beginning of food ingestion to the rise in blood glucose level. The rise in insulin delivery above normal levels should occur within this time (Kraegan, 1988). • Modeling with an empirical time constant of 45 minutes from ingestion to insulin action in the body determined that a sample of glucose taken once every one to three hours would be sufficient to develop a glucose concentration versus time profile. However, if the subject were an ambulatory diabetic, a faster sensor with a 20-30 minute response time would be desirable (Kraegan, 1988). V.INSULIN DISPENSING SYSTEMS Research groups are using three types of insulin delivery systems: closed loop, open loop, and a mixture of the two. The closed loop uses glucose monitoring to determine the amount of insulin to dispense in real time. The open loop system dispenses insulin at a preprogrammed rate profile from the start of a meal, and at a constant rate at all other times.
  20. 20. 20 A.Closed and Open Loop insulin dispensing systems A glucose sensor response time and range of sensitivity in a closed loop system is most important during mealtime. The glucose levels increase 10-20 minutes after the start of meal consumption. However, the body requirement for insulin injection is non- linear. The closed loop system can be optimized by delivering insulin just prior, or at the start of a meal, as well as delivering it as a function of the rising blood glucose level (Kraegen, 1988). This was found when a closed loop system was tested which had an inherent time lag from the start of the meal to the start of insulin delivery due to an integral term in the control loop. The same test was run on an open loop system that started to dispense insulin immediately from the start of the meal. The closed loop system severely overcompensated for insulin levels. The area under the glucose curve for the closed loop system was about twice that of the open loop system. Because of the delay in the closed loop system, and the failure to dispense insulin at the start of the meal, the open loop system did a better job of regulating blood glucose levels in this test (Kraegen, 1988). The closed loop system is still useful. Excellent results have been obtained with regulation of insulin levels between meals and overnight using a closed loop blood glucose sensor (Kraegen, 1988). B.Mixed insulin dispensing system Currently, the most promising type of system is one that uses both a closed and an open loop control system. The closed loop would strictly control the system during non-
  21. 21. 21 meal periods, and control would switch over to the open loop system only during meal times. Another type of system undergoing research is one that normally utilizes an open loop system, but switches over to closed loop insulin control for a short period three times per day. C.Other insulin dispensing systems Research has also been done with a non-electronic type of control system. The CO2 fermentation product of 10 mg of freeze-dried yeast provided the pressure to pump insulin from a syringe in one experiment. The yeast was mixed with various concentrations of glucose and the resulting CO2 pushed a piston in a syringe that in turn was used to dispense a proportional amount of insulin. The authors claim that blood can be used in lieu of the glucose solution (Groning, 1997). VI.CONCLUSIONS Even though there are many different types of biosensors, they all operate with the same general components. There is a lot of research happening for glucose biosensors right now in the medical field for an automatic insulin dispensing system for people with diabetes. The glucose oxidase enzymatically catalyzed reaction is well understood. For glucose sensing in a live body, a potentiometric sensing method is better than an amperometric method because errors associated with the buildup of material on the sensor does not skew the output as much due to the lack of an analyte depletion region in the potentiometric sensor. Because the biosensor operates by an indirect
  22. 22. 22 method, the interface between the transducer and biological sensing element is very important. It is possible to build glucose biosensors that use an inherently conducting polymer interface to transfer electrons more efficiently than oxygen, the native electron acceptor. Much research is being done on glucose biosensors due to the need for an accurate and low maintenance glucose-sensing element for an insulin delivery system for people with diabetes. A closed loop insulin delivery system does a good job of controlling insulin levels during normal static conditions, however, during meal time the open loop insulin delivery system does a better job due its the pre-programmed insulin profile. The best type of system now is one that uses the best of both systems. This system utilizes open loop for mealtime, and closed loop for non-mealtime. Scientists are close in understanding the glucose-insulin response of the pancreas. The only questions left are the insulin timing during mealtime, and the insulin profile. It can be expected that in the future, a better sensor and control system package will be designed that will allow Type I diabetics more freedom so they do not have to inject insulin into their bodies subcutaneously, but instead opt to have an outpatient surgery to have a subcutaneous system installed and maintained once per year.
  23. 23. REFERENCES 1. American Diabetes Association, Basic Diabetes Information, http:www.diabetes.org 2. Cammann, K., 1988, “Implantable Electrochemical Glucose Sensors – State of the Art”, pp. 4-8. in Implantable Glucose Sensors – The State of the Art, Pfeiffer, E.F., Reaven, G.M., Hetzel, W.D., Hoffman, A.R., ed., Thieme Medical Publishers, Inc. New York. 3. Canh, Tran M., 1993, Biosensors, Chapman & Hall, London, ISBN #0412481901. 4. Groning, R., 1997, “Computer-controlled drug release from small-sized dosage forms”, Journal of Controlled Release, V48, 185-193. 5. Hall, Elizabeth A.H., 1991, Biosensors, Prentice-Hall, Englewood Cliffs, New Jersey, ISBN #0-13-084526-4. 6. Honold, F., Cammann, K., 1988, “Potentiometric Glucose Sensors”, pp. 47-49. in Implantable Glucose Sensors – The State of the Art, Pfeiffer, E.F., Reaven, G.M., Hetzel, W.D., Hoffman, A.R., ed., Thieme Medical Publishers, Inc. New York. 7. Kraegen, E.W., Chisholm, D.J., 1988, “Closure of the Loop by Glucose Sensing, Physiological and Practical Considerations”, pp. 1-4. in Implantable Glucose Sensors – The State of the Art, Pfeiffer, E.F., Reaven, G.M., Hetzel, W.D., Hoffman, A.R., ed., Thieme Medical Publishers, Inc. New York. 8. Ping, W., Yi, T., Haibao, X., Farong, S., 1997, “A novel method for diabetes diagnosis based on electronic nose”, Biosensors and Bioelectronics, V12, N9-10, 1031-1036. 9. Tothill, I.E., February 2001, “Biosensors developments and potential applications in the agricultural diagnosis sector”, Computers and Electronics in Agriculture, V30, N1, 205-218. 10. Van der Schalie, W.H., Shedd, T.R., Knechtges, P.L., Widder, M.W. September 2001, “Using higher organisms in biological early warning systems for real-time toxicity detection”, Biosensors and Bioelectronics, V16, N7, 457-465. 11. Wallace, G.G., Smyth, M., Zhao, H., April 1999, “Conducting electroactive polymer- based biosensors”, Trends in Analytical Chemistry, V18, N4, 245-251. 12. Willner, I., Willner, B., June 2001, “Biomaterials integrated with electronic elements: en route to bioelectronics”, Trends in Biotechnology, V19, N6, 222-230.

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