A SEMINAR REPORT ON

SUGAR LEVEL DETECTION BY CONTACT LENS

In partial fulfillment of requirements for the degree of Bachelor of Technology in ELECTRONICS AND COMMUNICATION ENGINEERING

Submitted By: Ruchika Saxena 10EJTEC091 ECE Final Year

Guided By: Abhishek Karwa Assist. Prof. (Sr. Grade) ECE Department

DEPARTMENT OF ELECTRONICS & COMMUNICATION ENGINEERING JIET SCHOOL OF ENGINEERING & TECHNOLOGY FOR GIRLS, JODHPUR 2013-2014

JIET SCHOOL OF ENGINEERING &TECHNOLOGY FOR GIRLS,

JIET Universe, N.H. 65, New Pali Road, Mogra, Jodhpur-342002(Raj.)

Department of Electronics & Communication Engineering

CERTIFICATE
Certified that seminar work entitled SUGAR LEVEL DETECTION BY CONTACT LENS is a bonafide work carried out in the Eighth semester by Ruchika Saxena in partial fulfillment for the award of Bachelor of Technology in Electronics and Communication Engineering from Rajasthan Technical University during the academic year 2013-2014 who carried out the seminar work under the guidance and no part of this work has been submitted earlier for the award of any degree.

Prof. Abhishek Karwa Seminar Incharge

Prof. Abhishek Karwa Guide

Head of the Department Prof. Sanjay B.C. Gaur

Acknowledgement
I hereby acknowledge my sincere gratitude to all persons who have helped me in completing the seminar. We are grateful to Mr. Sanjay Gaur, Head of Department of Electronics and Communication Engineering, for his constant support. We are greatly indebted to our guide Mr. Abhishek Karwa and Miss Purneshwari Varshney, Department of Electronics and Communication Engineering, for their valuable guidance in this endeavor. We are thankful to all non-teaching staffs for their help in the seminar report. We express our gratitude to all other faculty members, seniors and our classmates who have constantly encouraged and helped us in completing this seminar successfully. We thank all persons who have directly or indirectly made their contribution in this seminar.

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INDEX
Contents Abstract Chapter 1: Introduction 1.1 Tear Glucose and Its Measures in Diabetes Patients 1.2 Contact Lens Sensor for Diabetes 1.3 Other embedded components 1.4 Topics discussed in the report Page No. 1 2 3 4 6 6

Chapter 2: Literature review 2.1 Study of IEEE paper - A 3-W CMOS Glucose Sensor for Wireless Contact-Lens Tear Glucose Monitoring. 2.1.1. Glucose sensor design and fabrication 2.1.2. System assembly 2.2. 2011 IEEE Global Humanitarian Technology Conference- Functional Contact Lenses for Remote Health Monitoring in Developing Countries. 2.2.1. Contact lens platform. 2.2.2 Lactate sensors. 2.3. Study of paper- Non-Invasive Blood Glucose Monitoring Systems 2.4. Study of paper Flexible glucose sensor utilizing multilayer PDMS process 2.5 Study of paper -Soft Contact-lens Sensor for Monitoring Tear Sugar as Novel Wearable Device of Body Sensor Network.

7 7 8 9 10 11 12 14 15 17

Chapter 3: Minimal or non-invasive methods used earlier for sugar level detection 19 3.1. Blood glucose meters 3.1.1. Size 3.1.2. Test strips 3.1.3. Coding 3.1.4. Volume of blood sample 3.1.5. Alternative site testing 3.1.6. Testing times 3.1.7. Display 3.2. Urine testing 3.3. A1C Test 3.3.1. Laboratory analysis 19 19 20 20 20 21 21 21 21 22 22

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3.3.2 Abnormal results 3.4. Fasting Plasma Glucose Test 3.5. Oral Glucose Tolerance Test Chapter 4: Technologies being used to detect sugar level 4.1. NIR spectroscopy 4.2. FIR spectroscopy 4.3. Radio wave impedance 4.4. Optical rotation of polarized light 4.5. Fluid extraction from skin 4.6. Interstitial fluid harvesting 4.7. Googles smart lens Chapter 5: Future scope of sugar level detecting contact lenses Conclusion References

23 23 23 24 24 25 26 27 28 30 31 32 34 35

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FIGURE INDEX
Contents Fig.1.1. A contact lens to detect sugar level in human body Fig.4.1. Schematic diagram of the glucose monitoring system Figure provided by Cygnus Therapeutic Systems. Fig.5.1. Conceptual diagram of an active contact-lens system for wireless health monitoring 33 Page no. 5 28

ABSTRACT
The ability to assess health status, disease onset and progression, and monitor treatment outcome through a non-invasive method is the main aim to be achieved in health care promotion and delivery and research. There are three prerequisites to reach this goal: specific biomarkers that indicates a healthy or diseased state; a non-invasive approach to detect and monitor the biomarkers; and the technologies to discriminate the biomarkers. The early disease diagnosis is crucial for patient survival and successful prognosis of the disease, so that sensitive and specific methods are required for that. A contact lens is being developed for measuring of sugar level in human body through the fluid present in the eye. To measure the blood glucose level at greater accuracy through tears, this remarkable device has microscopic chips, electronic sensor and hair thin antennas fixed between the layers of soft contact lens materials. It has the ability to calculate the wearers blood sugar once per second and there would be LED flash lights to alert them if they have crossed certain thresholds in glucose level. As this modernization device contains capacitor, controller and antenna, the collected information from the eye could be moved to the monitor to read and analyze the data.

CHAPTER-1
INTRODUCTION
A statistical analysis by the World Health Organization (WHO) indicates that more than 220 million people have to live with diabetes. Diabetes caused over 1.1 million deaths in 2005, and diabetes death is estimated to double by 2030. Early diagnosis and continuous management are vital to patients to ensure a healthy life and to avoid circulatory problems and other diseases caused by diabetes, such as kidney failure, heart disease, and blindness. Current practice for diabetes management relies on monitoring blood glucose. Patients have to prick their finger for a drop of blood multiple times a day, about 1800 times per year, to check glucose levels. Furthermore, the reports of blood-borne infection have been noted with these invasive glucose sensors [1]. For these reasons, new techniques have been employed to develop a minor invasive and/or noninvasive device for blood glucose monitoring, including infrared (IR) spectroscopy, fluorescence spectroscopy, Raman spectroscopy, optical polarization rotation measurement, photo-acoustic probes, and surface plasmon resonance [2]. However, results from these techniques need to be checked frequently against direct blood glucose measurements, that is, they cannot replace the direct measure of a blood glucose sensor. As an alternative, approaches to measure the concentration of glucose in an accessible body fluid, including urine, saliva, and tear fluid, has great potential for noninvasive diagnosis and management of diabetes. Compared to other body fluids, tears are more accessible than blood or interstitial fluid, more continuously obtainable, and less susceptible to dilution than urine. Tear fluid is the aqueous layer on the ocular surface, and has many functions as part of the optical system, such as lubricating the eye and nourishing the cornea. The average rate of tear product is in the range of 0.52.2 l/min; about 0.723.2 ml of tears are secreted per day. Tear fluid normally consists of over 20 components, including salt water, proteins, glucose, some small metallic ions, etc. Tear glucose has been studied since 1930[3]. At presently all existing methods of home blood glucose monitoring require obtaining a blood sample by pricking a fingertip with a needle. This method strongly discourages patients compliance and has the following serious drawbacks because the procedure is invasive.

1.1 Tear Glucose and Its Measures in Diabetes Patients Since the 1930s, human models and animals have been studied to estimate the glucose level in tears and the correlation between tear glucose and blood glucose. The results indicate that the level of glucose in tears is often elevated in diabetes patients. Lewis and Stephens studied tear fluids of diabetic and nondiabetic subjects by using a commercialized blood test tool quantitatively and qualitatively, and concluded that tear fluid is a sample that can be used in the diagnosis of diabetes. Gasset et al. and Motoji et al. found a definite relationship between tear glucose and blood glucose and concluded that hyperglycemia could be detected by measuring tear glucose levels. Furthermore, Sen and Sarin compared the glucose levels in the tears and blood of both diabetic and nondiabetic subjects. Their study indicated that blood glucose was about two times higher in diabetic subjects than in nondiabetic subjects, whereas tear glucose was about five times higher in diabetic versus nondiabetic subjects. Dawn and Hill reported the correlation coefficient (r) between blood glucose and tear glucose was +0.53. Other studies indicate that diabetic and no diabetic tear glucose mean values were 6.34 0.7 mg/dl and 2.9 0.5 mg/dl, respectively.34 It should be noted that the discrepancy of the correlation coefficient (r) between blood glucose and tear glucose is caused by the different tear collection methods, e.g., filter paper or micro capillary[4]. Obviously, the development of an in situ ocular glucose sensor for diabetes control is heavily limited by the following factors: (1) it takes time to collect enough tear sample, i.e., at least 10 minutes is required to collect 10 l of tear sample by using glass capillaries; (2) the concentration of the glucose in tears is lower than that in blood; and (3) very few suitable devices are able to compete against commercial blood glucose testers to quantitatively measure tear glucose in a short period of time. A couple of methods have been developed to overcome the difficulties of in situ testing of tear glucose. Cot and colleagues developed a polarimetric glucose sensor for monitoring ocular glucose. It indicated that the time lag between blood glucose and anterior aqueous humor glucose concentrations was an average of five minutes. The other approach is related to the contact lens-based sensor, which has been receiving a lot of attention because the device is portable and disposable. It is likely that contact lens-based glucose sensors have great potential

to realize continuous and noninvasive diabetes control. Furthermore, hydrogel-based soft contact lenses are approved as safe daily wear lenses in diabetes patients.

1.2. Contact Lens Sensor for Diabetes These glasses work by embedding a tiny wireless transmitter and a miniature glucose sensor in between two layers of a soft contact lens. Prototypes currently undergoing testing are able to obtain measurements at a rate of one reading per second. And given this impressive temporal resolution, the system could potentially serve as a warning system for those with fluctuating blood glucose levels. Contact lenses have applications beyond vision correction. They are being considered by at least three research groups who are working with such sensors as an alternative tool to continuously and noninvasively monitor the level of glucose in tears [5].

Luminescent/fluorescent contact lens-based sensors are a feasible technique because there are no electrodes or electric circuits. The fluorescence emission intensity (F) is described as F = I0 (1 eabc).. (1) Where is the quantum efficiency, I0 the intensity of incident light, a molar absorptivity, b the path length of the cell, and c the molar concentration of the fluorophore, boronic acid and glucose. The first one uses the competition reaction; the bonding between the glucose and enzyme is stronger than that between the fluorescent molecules and enzyme. The second one uses the direct reaction of analyte and fluorescent molecules. The amount of glucose is measured by using Equation (1). A sensitive transducer is required to detect the tear glucose. Existing methods of fluorescent glucose sensing apply fluorescence resonance energy transfer (FRET). This method is based on the dual measure, i.e., the FRET and fluorescence intensity (I) measurements. FRET is a distance-dependent energy transfer from a fluorophore donor (D) to a fluorophore acceptor (A) in a nonradiative process [6]. Thus, a lens sensor should be able to monitor a wide range of glucose levels quickly and accurately; the fabrication of the lens sensor should be reproducible and the lens sensor should have an extended lifetime. In addition, the ideal sensor would be biocompatible and be able to keep the bio recognizer stable.

Fig: 1.1 a contact lens to detect sugar level in human body.

The advantages of the nanostructure-laden contact lens are (1) The porous nanostructure is able to bind to the desired bioassay for conjugating the glucose in tears. (2) The porous nanostructures act as an analyte reservoir, which helps to achieve the high loading of analyte for target sensing (e.g., glucose sensing). (3) The nanostructures embedded in the contact lens will not interfere with patient vision and will likely enhance oxygen permeability because of the porous structures. (4) The nanostructures are able to load high concentration of bioassay to secure better sensitivity. (5) The nanostructures keep the loaded fluorescent molecules from photo bleaching. Further efforts are needed to improve the resolution and sensitivity of the new device and to determine a physiologically relevant and baseline tear glucose concentration.

1.3 Other embedded components The contact lens used to measure the blood glucose level at greater accuracy through tears, has microscopic chips, electronic sensor and hair thin antennas fixed between the layers of soft contact lens materials. It has the ability to calculate the wearers blood sugar once per second and there would be LED flash lights to alert them if they have crossed certain thresholds in glucose level. As this modernization device contains capacitor, controller and antenna, the collected information from the eye could be moved to the monitor to read and analyze the data. Measures are taken to prevent the lens from overheating and other kinds of problem to offer this gadget as an innovative one for the diabetes sufferers [7]. The smart contact lenses from Google is based on the same technology and has to get approval from FDA before it hits the market and Google is looking for expert marketing partners for this technology gadget.

1.4 Topics discussed in the report The introduction part covered the theory of usage of contact lens for detection sugar level in human body which would be helpful in diabetes. The next chapter-2 literature review covers the various papers related to the topic. It discusses the basic idea of how contact lenses are being used for detection of sugar level and the various technologies involved in manufacturing and working of lens. The next chapter-3 discusses about the details of the technologies and tests that were used earlier for detection of sugar level that means the past technologies used. Chapter -4 is the present techniques used for sugar level detection which are mainly noninvasive methods. The next chapter discusses about the future scope of sugar level detection in human body. At the end we have conclusion which gives the details of sugar level detecting contact lens in brief.

CHAPTER-2
LITERATURE REVIEW
2.1. Study of IEEE paper - A 3-W CMOS Glucose Sensor for Wireless Contact-Lens Tear Glucose Monitoring

by Yu-Te Liao, Member, IEEE, Huanfen Yao, Andrew Lingley, Babak Parviz, Senior Member, IEEE, and Brian P. Otis, Senior Member, IEEE.

This paper presents a noninvasive wireless sensor platform for continuous health monitoring. The sensor system integrates a loop antenna, wireless sensor interface chip, and glucose sensor on a polymer substrate. The IC consists of power management, readout circuitry, wireless communication interface, LED driver, and energy storage capacitors in a 0.36-mm2 CMOS chip with no external components. The sensitivity of our glucose sensor is 0.18 A mm-2 mM 1

. The system is wirelessly powered and achieves a measured glucose range of 0.051 Mm with

a sensitivity of 400 Hz/mM while consuming 3 W from a regulated 1.2-V supply. Tear fluid is directly accessible on the eye and can be used as a chemical interface between a sensor and the human body. Tear fluid contains many biomarkers that are found in blood, such as glucose, cholesterol, sodium, and potassium. The glucose level in tear film is reported to be in the range of 0.10.6 millimoles per liter (mM), which is about ten times lower than the levels in blood. Conventional contact lenses are transparent polymers placed on the eye to correct faulty vision and can simultaneously serve as a platform to directly access tear fluid. Integrating biosensors on a contact lens would provide a noninvasive way for continuously sensing metabolites in tear fluid. Contact-lens-mounted biosensors have been developed to measure eyelid pressure, tear glucose, and intraocular pressure. These sensors use inconvenient wired readout interfaces [8]. The sensor directly accesses the tear fluid and thus can improve the sensitivity and reduce the sampling processes and potential of infection during operation. The proposed active contact lens system includes glucose sensor, antenna, communication interface, and readout circuitry on a polymer lens substrate. The on-lens glucose sensor system detects the tear glucose level and then wirelessly transmits the information to an external reader. This system could

potentially work as a point-of-care device in the future with the near-field communication feature of mobile phones. There are many challenges in the implementation of the on-lens sensor system. First, the system is extremely constrained by power and area. A standard contact lens has an area of about 1 cm and a total thickness of about 200 m. Component size in the design is severely restricted, roughly 0.6x0.6 Mm2 , which is determined by the curvature of the eye and our assembly process. Clearly, standard surface-mount components are too large for

integration onto a contact lens. In addition, volume limitations eliminate the possibility of large energy storage devices. Therefore, a biosensor on a contact lens must be powered wirelessly through external sources (e.g., RF power, inductive power, or optical power). Third, the active contact lens system requires the heterogeneous biocompatible integration of different devices/materials on a plastic substrate. Finally, possible issues of using the sensors on the eye may include RF-power-caused eye temperature increase, vision-blocking, and damage from on-lens device. The regulation of RF-power-caused temperature rises is still under study for human eyes. To reduce the intrusion and damage of devices, on-lens devices can be embedded into the lens. The devices on the contact lens are out of the focus of human eyes and are placed in the outer of a lens to further avoid vision blurring. This paper presents a fully integrated and wirelessly powered glucose sensor prototype embedded in a functional contact lens system.

2.1.1. GLUCOSE SENSOR DESIGN AND FABRICATION Compared with traditional analytical techniques, electrochemical methods, based on oxidizing or reducing the target analytes, can achieve a real-time, quick-response, high-efficiency, and cost-effective analysis. The electrochemical reaction of an enzyme-based glucose sensor can be expressed as D-Glucose+ O2 H2O2 H2O2 + D-Gluconolactone. (2) 2H+ + O2 + 2e- . (3)

The basic electrochemical reaction for sensing glucose starts from catalyzing glucose to hydrogen peroxide (H2 O2 )using the enzyme glucose oxidase (GOD)[9]. H2O2 is further

oxidized at the electrode to release electrons, generating a current signal proportional to the glucose concentration. To make a stable electrochemical sensor, three electrodes are typically used: a working electrode (WE) where the target analytes are involved in an oxidation or reduction process, a counter electrode (CE) (also known as an auxiliary electrode) operating as a current drain to make an electron loop, and a reference electrode (RE) that provides a stable voltage potential for the whole system. In the proposed sensor, the working and counter electrodes are designed as concentric rings with widths of 50 and 75 m, respectively), which have a 50- m pitch to decrease the resistance and thus enhance the sensor sensitivity. The reference electrode is designed as a rectangular bar (1.6 mm 0.25 mm) close to the sensing area. The fabrication starts from a transparent polyethylene terephthalate (PET) polymer film (100- m thickness). Three metal layers, Ti, Pd, and Pt, are evaporated in sequence to achieve thicknesses of 10, 20, and 100 nm, respectively, to create electrodes. Then, the exposed Ti/Pd/Pt sensor surface is pretreated with a GOD/titania sol-gel membrane.

2.1.2. SYSTEM ASSEMBLY Here, they describe the on-lens integration of the sensor, IC, and antenna. First, they had cut 100-mm wafers from PET films and cleaned them with acetone, isopropyl alcohol, and deionized (DI) water. Then, a 6- m layer of positive photoresist (AZ4620) was spin-coated, soft baked, and patterned. Cr, Ni, and Au (20, 80, 350 nm) were evaporated and lifted off in acetone to create contacts for solder coating, an adhesion layer for the electroplated antenna, and low resistance connections from the chip to the sensor. After lift-off, SU-8 was deposited to restrict solder wetting. Next, a 40-nm seed layer of Au was deposited over the wafer, AZ4620 was used to pattern the antenna, and 5 m of Au was plated to reduce the antenna ohmic loss (improve the antenna efficiency) [10]. The seed layer was etched using Gold Etch TFA (Transene) mixed with DI water in a ratio of 5:1 (vol/vol). Then, a 25- m layer of SU-8 was used to mask the metal features and create an opening for the sensor. The wafer was dried with nitrogen gas, and then individual contact lenses with 1 cm in diameter were cut out using a CO laser cutter. The aluminum IC pads were nickel/gold plated using an electroless technique (CVinc.). Then, the chip and exposed solder pads on the contact lens were coated with a low

melting temperature solder. To accomplish this, indium-based solder (Indium Corporation, Indalloy 19, 60 C) was heated in a beaker while covered by 10-mL ethylene glycol (EG) and 60- L HCl. After the solder had melted completely, a pipette was used to solder coat all exposed pads on the IC and contact lens. The chip was then roughly aligned over the contact lens using tweezers in a petri dish of 25 mL of EG and 10- L HCl. The petri dish was heated on a hotplate until the solder reflowed, and the chip was aligned by solder capillary forces. The lens can be molded with heat and pressure to the curvature of the eye and then Parylene can be deposited (except the sensing area) for biocompatible encapsulation. In this paper, they demonstrate an on-lens sensing platform that allows wireless readout of glucose present in tear film. The proposed system contains an on-lens loop antenna for power and data transfer, low-power sensor interface readout IC, and glucose sensor to monitor tear glucose levels wirelessly. The system has a linear gain of 400 Hz/mM in the glucose range of 0.051 mM while consuming 3 W from a regulated on-chip 1.2-V supply. The system can be wirelessly powered from a distance of 15 cm. The readout architecture can also be used to connect an on-lens LED for immediate visual feedback to the contact lens wearer when interrogated by a simple continuous wave transmitter. The small chip area, high level of integration, and low power of our system provides a platform for application in multiple bio sensing tasks on contact lenses[11]. Their future work in this area includes addressing proteincaused desensitivity, sensor lifespan improvement, improvement of antenna-IC co-design, and clinical tests.

2.2. 2011 IEEE Global Humanitarian Technology Conference- Functional Contact Lenses for Remote Health Monitoring in Developing Countries By N. Thomas, I. Lhdesmki, A. Lingley, Y. Liao, J. Pandey, A. Afanasiev, B. Otis, T. Shen*, and B. A. Parviz Department of Electrical Engineering, College of Engineering *Department of Global Health & Department of Ophthalmology, School of Medicine University of Washington Seattle, WA USA They propose a system that makes use of the biological markers in tear fluid, and monitors the health status of a patient in a continuous, noninvasive manner. No blood drawing is necessary, which facilitates its application in areas with a lack of medical testing facilities or trained

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personnel. Furthermore, the system is powered wirelessly to allow for the most possible independence of the patient. The concept is based on the integration of biosensors, an optional display, electronic interconnects, energy harvesting devices, an antenna, and integrated circuits (ICs) for wireless data transmission on a polymer platform which can be comfortably worn as a contact lens. The system can ideally be used without extensive medical training. Health related data is transmitted to an external recording device where it can be stored, analyzed, and transferred to a remote health care professional. With the proliferation of cellular phones in developing countries, which are already effectively used for remote banking, telemedicine appears one option for the medical supervision of patients in rural areas. The contact lens system may operate on the existing cellular phone network, with a mobile phone as recording device for the storage, transfer, and display of data, allowing for real-time monitoring of patients and a direct feedback about necessary medical procedures by a health care professional. This paper summarizes recent progress in the development of the system by our group, especially focusing on the current advances in glucose and lactate sensing capabilities, and provides an outlook to future research activities [12].

2.2.1 THE CONTACT LENS PLATFORM Biosensors can measure biological markers in the tear fluid in which the contact lens will be embedded. The optional display will be composed of light emitting diodes (LEDs) and micro lenses, and may be utilized to give the patient direct feedback about his/her health status. All components are wired by metallic interconnects on the surface of the polymer substrate forming the contact lens. Photovoltaic cells are considered one option to provide part of the electrical energy necessary to power devices in the system. ICs and a loop antenna allow for the transmission of data in between the contact lens and an external system (mobile phone), while providing wireless power transfer to supply energy to the system. The single components of the system are either directly fabricated or assembled on a flexible poly (ethylene terephthalate) (PET) polymer substrate. PET was chosen due to its chemical resistance, transparency and thermal stability, which allow for an employment of common micro fabrication techniques with minimal alterations. The metallic interconnects, for example,

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are deposited via electron beam evaporation. After assembly, the previously flat substrate is heated and molded into its final shape. Two sensor configurations, each continuously monitoring either the glucose (and thereby diabetes) or lactate (and thereby cardiovascular stress) level in the tear fluid, are currently under development. Glucose levels in the tear fluid are suggested to be proportional to those in blood [13]. We employ an enzymatic, amperometric sensor measuring the current produced by hydrogen peroxide released during the catalytic action of the enzyme glucose oxidase (GOx) on glucose. The LEDs were fabricated on a GaAs wafer using common micro fabrication techniques and released from the substrate. Micro fabricated wells on PET aided the self-assembly of the devices on the substrate with pre-fabricated interconnects. A molten alloy assured fastening of the diodes and their electrical contact with the metallic interconnects. A similar process is used for the integration of ICs on the polymer substrate [14].

2.2.2 LACTATE SENSORS To add further functionality to the contact lens platform, they have been exploring a second biosensor based on the catalytic action of an enzyme. The sensor determines the presence of lactate in a solution. Lactate levels in the body are known to increase shortly before a cardiovascular emergency such as a stroke. The epithelium allows for an unobstructed transport of lactate and pyruvate between blood and tear fluid [5]. Physiological lactate levels in the blood range from 0.5 mM to 0.8 mM, whereas lactate levels in the tear fluid range from 1 to 5 mM [15]. Hence, sensing of the lactate levels in tear fluid may be more sensitive than monitoring blood lactate levels. The approach is based on an amperometric sensor utilizing three electrodes: a working electrode (WE), a counter electrode (CE), and a reference electrode (RE). The sensor current is generated at the WE by the application of a suitable potential. The CE provides a path for the current to flow. The RE supplies a stable reference potential that the WE potential can be measured against. The sensor utilizes the generation of hydrogen peroxide facilitated by the catalytic action of the enzyme lactate oxidase (LOx) on sodium-L-lactate.

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L- Lactate + O2 pyruvate +H2O2... (4) H2O2 O2+2H++2e-........................ (5) Subsequently, hydrogen peroxide is oxidized at the working Electrode Generating an electric current proportional to the amount of lactate in the solution. The rapid expansion of the cellular phone network in the developing world, even in places where most of the basic infrastructure is absent, has provided the ability to connect and wirelessly monitor remote areas in a very large scale. In order to take advantage of this connectivity in remote health monitoring and general healthcare, devices are needed to cover the last yard and interface the mobile phone to the human body to collect biologically relevant data. We propose functional contact lenses, complete with biosensor and radios, as such last yard devices. A disposable contact lens with integrated biosensors can be comfortably worn throughout the day. The contact lens can sample and analyze the tear film. The composition of the tear film is a proxy of the wearers health status in many instances. The contact lens can send the data wirelessly to a mobile phone worn by the user and the mobile phone in turn can send the data to a healthcare professional or a remote datacenter. Building such contact lenses and deploying them in conjunction with the cellular network may provide a radically new approach in large scale health status monitoring. Building such a system faces both technical and deployment hurdles. People unfamiliar with technology and contact lenses must be trained in putting on and taking off contact lenses and the utility, at least initially, will be limited to the users that carry their mobile phones. In addition, building contact lenses with the proper functionality is a major engineering challenge. The group has pioneered the construction of such contact lenses and demonstrated the integration of antennas, micro-scale light sensors, glucose sensors, lactate sensors, and small radios on contact lenses. By taking advantage of technologies that have been independently developing in the semiconductor industry for consumer electronics, we aim to reduce the cost of the contact lenses to levels suitable for large-scale deployment and adoption. Although much work remains to be done, the successful development work to this date points towards a potentially game-changing health monitoring platform.

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2.3. Study of paper Non-Invasive Blood Glucose Monitoring Systems By Zac Canders ELE 482: Biomedical Seminar 3 University of Rhode Island February 14 2005 This paper represented noninvasive methods of measuring glucose level in human body. Diabetes is a group of diseases characterized by a lack of the hormone insulin, which results in abnormally high levels of glucose in the blood. The three main types of diabetes are type 1, type 2, and gestational. For diabetics either the pancreas produces too little or no insulin or the cells do not respond to the insulin that is produced. This causes a build-up of glucose in the blood, which passes into the urine where it is eventually eliminated. Traditionally, diabetics have to closely monitor their blood glucose level by pricking a finger and placing a drop of blood on reagent strip which is then evaluated by a glucose monitor. Current research is focusing on continuous and non-invasive monitoring of physiological glucose, due to the dangers and inconveniencies of traditional monitoring systems. Current commercially available non-invasive systems: 1. Glucowatch: A low electric current pulls glucose through the skin. Glucose is accumulated in two gel collection discs in the AutoSensor. The AutoSensor measures the glucose and a reading is displayed. 2. Diasensor: An infrared beam shines on the skin and is able to painlessly measure sugar in the blood. Current Research has found that by shining light through human interstitial fluids at translucent dermal positions such as ocular aqueous humor in the eyes, information about the glucose levels. Using daily, disposable contact lenses embedded with newly developed boronic acid containing fluorophores it is possible to create glucose level sensing contact lenses [16]. By doping strategically designed fluorescent probes into commercially available contact lenses. The probes are completely compatible with the new lenses and can readily detect glucose changes up to several mM glucose. The lenses have a 90% response time of about 10 min, allowing the continuous and noninvasive monitoring of ocular glucose. A significant improvement over blood sampling between 4 and 6 times daily.

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It is believed that the doped contact lens approach and findings are a notable step forward towards the continuous and non-invasive monitoring of physiological glucose.

2.4. Study of paper Flexible glucose sensor utilizing multilayer PDMS process By Jasbir N. Patel*, Bonnie L. Gray*, Bozena Kaminska* and Byron D. Gates School of Engineering Science, Simon Fraser University, Burnaby, BC, CANADA. Department of Chemistry, Simon Fraser University, Burnaby, BC, CANADA. In this paper, a flexible glucose sensor with gold electrodes sandwiched between two polydimethyle siloxane (PDMS) layers is presented. PDMS is used as a flexible and biocompatible sensor substrate material. Furthermore, PDMS is optically transparent and haemocompatible which is very important for implantable sensors. The novel self-registration fabrication process gives accurate alignment to all the layers of the glucose sensor and it is easy to fabricate without any manual interaction or alignment. Furthermore, cross-linked SU-8 (a negative photoresist) is used first time as a lift-off layer to pattern metal on the PDMS surface. The bottom PDMS layer of the sensor is ~500 m thick and the top PDMS layer is ~120 m. Each sensor chip is 5.5 mm X 10.5 mm in size with 2 mm X 3 mm for the actual sensor area. Resistance of the successfully fabricated gold electrodes is measured between 3 to 6 m. The drift of the sensors are measured using high purity water followed by the linearity test using hydrogen peroxide (H2O2).However, this method gives only rough glucose concentrations instead of the exact measure of blood glucose. Glucose detection using the affinity principle detects a change in the physical properties of a sensitive cantilever, usually a change in the resonant frequency due to mass loading [17]. The oldest electro-enzymatic detection principle, developed by Clark in the 1960s, is still of interest to many researchers because of its high selectivity to glucose. The stage of proof of concept for such a device has passed, and currently efforts are aimed at improving the performance of electro-enzymatic sensors. First among the problems with an enzymatic glucose sensor is the unpredictability of the Ag/AgCl electrode fabrication and drift in current. Moreover, platinum is widely used as an active electrode but is quite an expensive material for large scale production of the glucose sensors. Finally, flexibility and optical transparency is crucial for sensors that may be worn or implanted, such as within contact lenses in the eyes for detecting glucose in tears. However, a

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fully transparent sensor must be fabricated using optically transparent electrodes (e.g. ITO) and such a transparent sensor should be designed using a flexible material such as PDMS. The only design that is both optically transparent and mechanically flexible has been proposed by Mitsubayashi. However, this design uses platinum or indium tin oxide (ITO) and silver/silver chloride electrodes. In order to address some of the problems discussed above, a PDMS based flexible glucose sensor with optically transparent substrate is presented here. Gold as an electrode (both the active and the reference electrodes) material is presented for the first time. A simple fabrication process flow without any manual interaction is also presented [18]. This hybrid polymer fabrication process uses SU-8 as a lift-off material for metallization on the PDMS surface.

2.4.1. DESIGN The flexible electro-enzymatic sensor is fabricated using PDMS as a sensor material. PDMS is widely used for microfluidic and biomedical applications because of its ease of fabrication and biocompatibility. PDMS is used as a sensor substrate which is optically transparent and flexible. In addition, both the active and the reference electrodes of the flexible sensor are fabricated using only gold. Gold, similar to platinum, is also a biocompatible material. The sensor design avoids any manual assembly or alignment steps. In order to test and characterize different properties of the flexible electro-enzymatic glucose sensor, we designed a flexible sensor with sandwiched gold electrodes between two PDMS layers. The bottom layer of the sensor is a 500m thick rectangular PDMS layer. This bottom layer is little larger than the area occupied by the electrodes. The top sensor layer is designed using a 100 to 200 m thick PDMS layer with contact pad openings and electrode openings. The electrode opening is provided only in the sensing area. Two separate openings are designed so that any of the gold electrodes can be used as an active electrode by immobilizing the enzyme on them. And, as mentioned previously, both gold electrodes are sandwiched between the two PDMS layers. All the sensor designs consist of three sections: a sensing area, a connecting conductor, and a contact pad. Each sensor die is 5.5 mm x 10.5 mm in size and is fabricated with gold electrodes sandwiched between two layers of PDMS. A flexible polymer based electro-enzymatic glucose sensor using a new two layer PDMS fabrication process, SU-8 as a lift off layer, and gold electrodes is presented for the first time.

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The new fabrication process for flexible sensors with transparent hybrid polymer fabrication technique using PDMS and SU-8 is successfully demonstrated. The total thickness of the fabricated sensors is measured 700 m. The actual sensor size in all the designs is 2mm x 3mm. Both active and reference gold electrodes are successfully tested. The PDMS polymer based glucose sensor is economical to fabricate, with the use of gold electrodes making the fabrication process very simple to perform in any basic micro-fabrication facility. Post fabrication tests such as electrical conductivity, profilometry, and H2O2 concentration response are utilized to characterize the process and working sensors. Optical imaging and electrical conductivity tests show for the first time successful fabrication of the electro-enzymatic sensor using the novel materials in the dual layer PDMS process with sandwiched gold electrodes. A linearity measurement is successfully done on working sensors, showing a linear response for sensors [19].

2.5. Study of paper Soft Contact-lens Sensor for Monitoring Tear Sugar as Novel Wearable Device of Body Sensor Network By M.K. Chu, K. Mitsubayashi, Dept. of Advanced Sci. & Tech. for Biomedical Sensors, Tokyo Medical and Dental University Tokyo, Japan K. Miyajima, T. Arakawa, H. Kudo, K. Mitsubayashi, Dept. of Biomedical Devices and Instrumentation, Tokyo Medical and Dental University Tokyo, Japan In this paper a soft contact-lens amperometric glucose sensor as novel wearable device of body sensor network was fabricated and tested. Also, the sensor was utilized to tear glucose monitoring. The sensor was constructed by immobilizing GOD onto a flexible oxygen electrode, which was fabricated using Soft-MEMS techniques onto a functional polymer membrane. In purpose of bioinstrumentation, adhesive agents were not used for constructing the flexible biosensor. Linear relationship between glucose concentration and output current was obtained in a range of 0.039 0.537 mmol/l. Current dependences on pH and temperature was also evaluated. The current was largest at pH 7.0 and the current increased when temperature increased. This indicates that the output current depends on enzyme activity. Based on the basic characteristics investigation, the glucose sensor was applied to measurement of glucose in tear fluids on an eye site of a Japan white rabbit. The change of tear glucose level induced by oral-administration of glucose was monitored as a current change of the sensor

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attached on the eye site. In this investigation, the tear glucose level varied from 0.2 mmol/l to 0.5 mmol/l. Although there was a delay of several tens of minutes towards blood sugar level, it is considered to be possible that noninvasive continuous glucose monitoring can be realized using the flexible biosensor [20]. In this paper, details of the design, fabrication and evaluation of the flexible biosensor are presented. Also, the result of continuous and non-invasive tear glucose monitoring using the flexible biosensor is reported. The monitoring test on eye site was carried out within two steps. At first, the sensor output during steady state was monitored and the stability of the output current was investigated. After that, the change of tear glucose level induced by oral glucose load was measured using the glucose sensors. Owing to unique features of flexibility, biocompatibility and thinner structure, continuous tear glucose monitoring was carried out. The sensor was sufficiently stable and sensitive when it is attached on rabbit eye. Thus, change of tear glucose level induced by oral administration of glucose was measured using the biosensor. Blood sugar level was also measured by a commercially produced monitoring kit as a controlled study. As a result, the tear glucose level was increased from 0.2 to 0.5 mmol/l. Although the change of tear glucose level delayed in tens of minutes from that of blood sugar level, it is considered to be possible that non-invasive continuous glucose monitoring can be realized using the glucose sensor.

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CHAPTER-3
MINIMAL OR NON INVASIVE METHODS USED EARLIER FOR SUGAR LEVEL DETECTION
Earlier the methods used for sugar level detection usually involved finger pricking or through blood analysis. The methods used were generally painful and time consuming. These methods were generally used earlier:-

3.1. Blood glucose meters A glucose meter (or glucometer) is a medical device for determining the approximate concentration of glucose in the blood. It can also be a strip of glucose paper dipped into a substance and measured to the glucose chart. It is a key element of home blood glucose monitoring (HBGM) by people with diabetes mellitus or hypoglycemia. A small drop of blood, obtained by pricking the skin with a lancet, is placed on a disposable test strip that the meter reads and uses to calculate the blood glucose level. The meter then displays the level in mg/dl or mmol/l. Since approximately 1980, a primary goal of the management of type 1 diabetes and type 2 diabetes mellitus has been achieving closer-to-normal levels of glucose in the blood for as much of the time as possible, guided by HBGM several times a day. The benefits include a reduction in the occurrence rate and severity of long-term complications from hyperglycemia as well as a reduction in the short-term, potentially life-threatening complications

of hypoglycemia [21]. There are several key characteristics of glucose meters which may differ from model to model:

3.1.1. Size: The average size is now approximately the size of the palm of the hand. They are batterypowered. The size is usually kept small for convenience of the user.

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3.1.2. Test strips

The strips used with meters are nearly always provided in batches of 50, but check with your healthcare team before choosing a meter. If you purchase testing strips from abroad.

Meters for people with visual impairments Finger-pricking devices and lancets: Finger-pricking devices are automatic devices that pierce the skin so that a drop of blood can be extracted for testing. They insert a lancet (a very short, fine needle) into the skin using a spring mechanism. The depth at which the needle is inserted can be adjusted depending on the thickness of the skin. Lancets are available in different sizes, or gauges. A higher-gauge lancet is generally less painful; however, you may not get enough blood to test with the higher-gauge needles. Lancets are designed to be used only once. If they are used more than once they become blunt and painful to use.

3.1.3. Coding: Since test strips may vary from batch to batch, some models require the user to manually enter in a code found on the vial of test strips or on a chip that comes with the test strip. By entering the coding or chip into the glucose meter, the meter will be calibrated to that batch of test strips. However, if this process is carried out incorrectly, the meter reading can be up to 4 mmol/L (72 mg/dL) inaccurate. The implications of an incorrectly coded meter can be serious for patients actively managing their diabetes. This may place patients at increased risk of hypoglycemia. Alternatively, some test strips contain the code information in the strip; others have a microchip in the vial of strips that can be inserted into the meter. These last two methods reduce the possibility of user error. One manufacturer has standardized their test strips around a single code number, so that, once set, there is no need to further change the code in their older meters, and in some of their newer meters, there is no way to change the code.

3.1.4. Volume of blood sample: The size of the drop of blood needed by different models varies from 0.3 to 1 l. (Older models required larger blood samples, usually defined as a "hanging drop" from the fingertip.) Smaller volume requirements reduce the frequency of unproductive pricks.

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3.1.5. Alternative site testing: Smaller drop volumes have enabled "alternate site testing" pricking the forearms or other less sensitive areas instead of the fingertips. Although less uncomfortable, readings obtained from forearm blood lag behind fingertip blood in reflecting rapidly changing glucose levels in the rest of the body.

3.1.6. Testing times: The times it takes to read a test strip may range from 3 to 60 seconds for different models.

3.1.7. Display: The glucose value in mg/dl or mmol/l is displayed on a digital display. The preferred measurement unit varies by country: mg/dl is preferred in the U.S., France, Japan, Israel, and India. Mmol/l are used in Canada, Australia, China and the UK. Germany is the only country where medical professionals routinely operate in both units of measure. (To convert mmol/l to mg/dl, multiply by 18. To convert mg/dl to mmol/l, divide by 18.) Many meters can display either unit of measure; there have been a couple of published instances in which someone with diabetes has been misled into the wrong action by assuming that a reading in mmol/l was really a very low reading in mg/dl, or the converse. In general, if a value is presented with a decimal point, it is in mmol/l, without a decimal it is most likely mg/dl.

3.2. Urine testing Urine testing involves holding a test strip under a stream of urine for a few seconds and comparing the color change on the strip, after a set amount of time, with the chart on the strip container. If you have been advised to test your urine for glucose it is best to test it in the morning before your breakfast. Empty your bladder when you get up, then test a sample passed 30 minutes later. Tests done at this time should be negative. You can also test two to three hours after a meal, when your blood glucose will have been at its highest.

Urine testing gives a less accurate picture of your blood glucose than blood testing, but your doctor may still feel that it is suitable for you. It is less accurate because there is usually no glucose in your urine unless the glucose levels have risen to 10mmol/l or above, which is considered quite high.

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Also, it does not give you an indication of what your blood glucose level is at the time you test, because the urine you are testing may have been produced several hours before you test.

Urine tests also cannot tell you if your blood glucose is too low which is important for people on insulin or certain tablets.

Some people get glucose in their urine at lower levels. They are said to have a 'low renal threshold' for glucose. Older people may develop a high renal threshold, when glucose does not appear in the urine until the level in the blood is much higher than 10mmol/l. High or low renal thresholds will cause confusion if you are monitoring your diabetes with urine tests.

Because urine testing involves comparing a color change on the urine testing strip, it is not suitable if you are visually impaired [22].

3.3. A1C Test The A1C test is used to detect type 2 diabetes and prediabetes but is not recommended for diagnosis of type 1 diabetes or gestational diabetes. The A1C test is a blood test that reflects the average of a persons blood glucose levels over the past 3 months and does not show daily fluctuations. The A1C test is more convenient for patients than the traditional glucose tests because it does not require fasting and can be performed at any time of the day. The A1C test result is reported as a percentage. The higher the percentage, the higher a persons blood glucose levels have been. A normal A1C level is below 5.7 percent. An A1C of 5.7 to 6.4 percent indicates prediabetes. People diagnosed with prediabetes may be retested in 1 year. People with an A1C below 5.7 percent may still be at risk for diabetes, depending on the presence of other characteristics that put them at risk, also known as risk factors. People with an A1C above 6.0 percent should be considered at very high risk of developing diabetes. A level of 6.5 percent or above means a person has diabetes. 3.3.1. Laboratory analysis: When the A1C test is used for diagnosis, the blood sample must be sent to a laboratory using a method that is certified by the NGSP to ensure the results are standardized. Blood samples

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analyzed in a health care providers office, known as point-of-care tests, are not standardized for diagnosing diabetes. 3.3.2 Abnormal results: The A1C test can be unreliable for diagnosing or monitoring diabetes in people with certain conditions known to interfere with the results. Interference should be suspected when A1C results seem very different from the results of a blood glucose test. However, not all of the A1C tests are unreliable for people with these diseases. False A1C test results may also occur in people with other problems that affect their blood or hemoglobin such as chronic kidney disease, liver disease, or anemia [23]. 3.4. Fasting Plasma Glucose Test The FPG test is used to detect diabetes and prediabetes. The FPG test has been the most common test used for diagnosing diabetes because it is more convenient than the OGTT and less expensive. The FPG test measures blood glucose in a person who has fasted for at least 8 hours and is most reliable when given in the morning. People with a fasting glucose level of 100 to 125 mg/dL have impaired fasting glucose (IFG), or prediabetes. A level of 126 mg/dL or above, confirmed by repeating the test on another day, means a person has diabetes. 3.5. Oral Glucose Tolerance Test The OGTT can be used to diagnose diabetes, prediabetes, and gestational diabetes. When used to test for diabetes or prediabetes, the OGTT measures blood glucose after a person fasts for at least 8 hours and 2 hours after the person drinks a liquid containing 75 grams of glucose dissolved in water. If the 2-hour blood glucose level is between 140 and 199 mg/dL, the person has a type of prediabetes called impaired glucose tolerance (IGT). If confirmed by a second test, a 2-hour glucose level of 200 mg/dL or above means a person has diabetes [24].

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CHAPTER-4
TECHNOLOGIES BEING USED TO DETECT SUGAR LEVEL
Diabetic patients are generally advised to check their blood glucose level 5 to 7 times per day. Since the all current existing conventional methods of home blood glucose tests are painful, intimidating, laborious, and expensive, since they require obtaining a blood sample by pricking a fingertip with a needle or lancet. Thus it was necessary to develop a non-invasive blood glucose method which could provide fast, painless, and convenient glucose monitoring to diabetic patients. Existing methods and the high monthly expense of testing strips would be avoided. In addition, patient acceptance would be very high because of the non-invasive nature and the simple and safe use of the procedure. Therefore, our optical glucose sensing technique using the optical rotatory effect of glucose have many advantages over currently existing invasive and noninvasive methods, since the method is based on shining a brief pulse of light into the front of the eye The optical glucose sensing method introduced in this study can be miniaturized using current integrated optics, electronics, and advanced micro fabrication technologies and has the potential to provide a low cost, fast, and compact noninvasive glucose sensor for the diabetic patients within near future [25]. Innovative methods for noninvasive blood glucose monitoring are being developed. Noninvasive blood glucose measurements are based on one of two types of technology: 1) radiation 2) fluid extraction

4.1. NIR spectroscopy NIR spectroscopy is the only noninvasive blood glucose monitoring technology ever reviewed by a public Food and Drug Administration (FDA) panel for marketing approval. Although approval was not granted, press coverage of the hearing in 1996 resulted in heightened public awareness of the competition to produce a noninvasive blood glucose monitoring system and of NIR spectroscopy as a technology that might make such monitoring possible. The term "nearinfrared light" refers to the use of an external light source with wavelengths in the infrared spectrum near the wavelengths of visible light. An NIR source can pass through or be reflected by a body part. Glucose and other body constituents absorb a small amount of the light at each

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wavelength. Spectroscopy, an established technology used to measure energy containing many wavelengths, detects the amount of NIR absorbed at each wavelength by comparing a reference beam with the detection beam that has passed through or is reflected by the body. With spectroscopy, a data processing technique known as chemometrics or multivariate analysis simultaneously analyzes the amount of light absorption at selected wavelengths for each blood glucose level. A polynomial formula is generated that converts the sum of the relative contributions of absorption at the selected wavelengths to the blood glucose concentration. This technology is used in oximetry to measure the oxygen saturation of blood. The major problem with using NIR spectroscopy for blood glucose monitoring is the necessity for frequent recalibration. NIR spectroscopy does not measure one signal specific for glucose, but rather many signals that are neither specific for glucose nor linked to glucose levels in a linear fashion. Glucose is responsible for <0.1% of NIR absorbed by the body. Water, fat, skin, muscle, and bone account for the vast majority of NIR absorption. Perturbations in the amounts of these substances can alter NIR absorption and thus invalidate the calibration formula for correlating light absorption with blood glucose concentrations that was generated during the calibration process. Other situations that could also require recalibration include: 1) Use of medications that absorb NIR, 2) Alterations in blood levels of hemoglobin or other proteins that absorb NIR, 3) Alterations in body temperature, and 4) Alterations in state of hydration or nutrition. Studies of glucose measurement in vivo using NIR spectroscopy have been disappointing. 4.2. FIR spectroscopy A second technology for noninvasive blood glucose monitoring spectroscopically measures absorption of FIR contained in natural thermal emissions or body heat. FIR spectroscopy is the only type of radiation technology that does not require an external energy source. The term "thermal emissions" refers to deep layers of the human body emitting thermal radiation or body heat with wavelengths in the FAR spectrum far from the wavelengths of visible light. The peak wavelengths of thermal energy emitted by a 37 human body are 5,000-12,000 nm, in the FIR

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range of the electromagnetic spectrum. Among these wavelengths, glucose strongly absorbs energy in a band (the FIR "glucose band") around 9,400 nm. When FIR passes out of the body, glucose in the blood absorbs part of the radiation. Absorption of thermal energy in the FIR glucose band by blood glucose in tissue is related in a linear fashion to blood glucose concentration. Thermal energy absorption of FIR in the glucose band by blood glucose can be spectroscopically determined by comparing measured and predicted amounts of thermal energy at the skin surface. The predicted amount of thermal energy radiated can be calculated by the Planck distribution function [26]. Simultaneous measurement of thermal energy absorption outside the FIR glucose band determines the reference intensity, which is a necessary variable for calculating the blood glucose concentration. The percentage of thermal energy absorption can be arithmetically converted to a blood glucose concentration. No in vivo data has been published about the accuracy of this method for measuring blood glucose. This technology is used in tympanic thermometry to measure body temperature. FIR spectroscopy for blood glucose monitoring has two problems. First, the signal size of human thermal emissions is very small. Second, the prototype device incorporates cryogenically cooled infrared detectors. Replenishment of the cryogenic fluid, currently liquid nitrogen, is inconvenient. 4.3. Radio wave impedance A third technology for noninvasive blood glucose monitoring measures the impedance of radio waves. The components of a device using this technology will be inexpensive because they will be off-the-shelf and not custom miniaturized versions of bench-top equipment. Impedance is the total opposition to an alternating current flowing through a material. Impedance is proportional to the differences in both amplitude and phase of a detection beam compared to a reference beam. When a radio wave beam is applied to an aqueous solution, a nonionic solute such as glucose interacts with the energy to attenuate the amplitude and shift the phase of the beam, resulting in increased impedance proportionate to the solute concentration. In blood, glucose is the nonionic solute present at the highest molar concentration. With the use of a conversion factor, the concentration of glucose in blood can be calculated from a measurement of the impedance to radio wave energy of a body appendage such as a

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fingertip. No in vivo data has been published about the accuracy of this method for measuring blood glucose. This technology is used to measure the moisture content of agricultural crops. Radio wave impedance technology for blood glucose monitoring has two problems. First, impedance is also affected by factors other than glucose, which must be accounted for to determine the relationship between impedance and blood glucose concentration. These factors include concentration of electrolytes in the blood, finger width, and body temperature. Second, an inexpensive disposable finger clip may be necessary to conduct the radio waves. The recurring costs of any disposable attachment could be a psychological deterrent to frequent use of a monitor. 4.4. Optical rotation of polarized light A fourth technology for noninvasive blood glucose monitoring measures the optical rotation of polarized light. This process is known as polarimetry. When polarized light passes through a fluid that contains glucose, the plane of polarization rotates proportionate to the glucose concentration. A beam of infrared polarized light can be passed through a body compartment, and the amount of optical rotation can then be measured. This method would be used to measure the glucose content of the aqueous humor of the eye. In rabbits the aqueous humor glucose concentration has been demonstrated to correlate with the blood glucose concentration. In polarimetry, a beam splitter divides a polarized light beam into a reference beam and a detection beam that passes through the body. The beams are then compared to determine the amount of phase shift produced by passage through the body. A blood glucose level is calculated by applying a conversion factor to the phase shift. No in vivo data has been published on the accuracy of such a method for measuring blood glucose. This technology is used industrially to measure the concentration of sugar in foods and dextrose in intravenous solutions [27]. There are two problems with polarimetry for blood glucose measurement. First, the signal size is small. The angle of rotation for a 1 cm thick tissue compartment would be <0.00004 per 1 mg/dl increment in glucose concentration. Second, there is a potential lag time between blood and aqueous humor glucose concentrations during periods of rapidly shifting blood glucose concentrations.

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Fig 4.1: Schematic diagram of the glucose monitoring system. Figure provided by Cygnus Therapeutic Systems.

4.5. Fluid extraction from skin A fifth technology for noninvasive blood glucose monitoring extracts and measures tissue fluid from skin. This technology, also known as reverse iontophoresis, is accurate and produces multiple measurements over a 24-h period. A device using this technology would measure trends in blood glucose concentrations and could be programmed to control an insulin delivery system, which would create an artificial pancreas. Fluid extraction from skin is the only noninvasive blood glucose monitoring technology capable of measuring blood glucose levels continuously without patient effort. Reverse iontophoresis involves creation of an electrical current applied to the skin. The current pulls out salt, which carries water, which in turn carries glucose. Thus, glucose is extracted from the skin, where it can be absorbed and its concentration measured. The glucose concentration of this extracted fluid is proportionate to that of blood. Iontophoresis, from which reverse iontophoresis derives, is an effective drugdelivery technology. There are several problems with fluid extraction from skin as a method for blood glucose measurement.

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1. There is a lag time of at least 20 min from the beginning of a fluid extraction cycle until a blood glucose level can be reported. If the blood glucose level is falling rapidly, severe hypoglycemia may not be ascertained and a patient might fail to take corrective action. Delayed recognition of a rapidly rising blood glucose level is less dangerous. The time required to complete a measurement makes the technology unsuitable for a physician's office or hospital, where rapid screening of blood glucose levels is desired. 2. The technology necessary to measure extracted fluid glucose levels must be very accurate because the glucose concentration in this fluid is 1/1,000 that of blood glucose and the fluid glucose level is converted to blood glucose with a conversion factor. 3. The prototype device requires recalibration at least weekly and cannot be shared by a second person without a 60-min equilibration period followed by recalibration. 4. There may be a few minutes of mild discomfort or formication on first applying such a device to the skin, but these symptoms should then resolve. 5. The device has not been tested in patients with diabetic thick skin or during exerciseinduced sweating, where the fluid extraction rate could be altered. 6. Wrist skin could be adversely affected by prolonged reverse iontophoresis. 7. The prototype device is currently too large for commercial use and must be miniaturized. A noninvasive blood glucose monitoring system is being developed that will resemble a wristwatch. The device will consist of: 1) A display unit that shows the time and the blood glucose level; 2) A glucose pad, which is a disposable pad in which extracted fluid glucose triggers an electrochemical reaction and that must be replaced every 24 h; 3) A pair of electrodes that transmit current to the skin; 4) A biosensor that measures electron emissions; and 5) A computer that stores data. This system will extract fluid from skin using reverse iontophoresis. A blood glucose level could be reported as often as three times per hour. A programmable alarm will sound if high or low panic values are exceeded. The device will be powered by a single AAA battery. A prototype of the reverse iontophoresis system has been reported to

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produce clinically acceptable results for 95% of its measurements. Such accuracy is comparable to that of currently available blood glucose monitors. 4.6. Interstitial fluid harvesting A sixth technology for noninvasive blood glucose monitoring involves transcutaneous harvesting and measurement of interstitial fluid from skin. Prototype devices using this technology are accurate and are handheld. Various methods can be used to extract and measure interstitial fluid. Unlike the aforementioned five noninvasive technologies, which produce neither skin trauma nor pain, transcutaneous harvesting of interstitial fluid may be accomplished with nearly no skin trauma and with minimal sensation. This technology is therefore classified not as noninvasive, but rather as nearly noninvasive. Transcutaneous harvesting of interstitial fluid produces no significant breaks in the skin surface, in contrast to minimally invasive technology, which involves insertion of an indwelling subcutaneous glucose sensor. There is such similarity between transcutaneous interstitial fluid harvesting technology and noninvasive technologies that this nearly noninvasive technology is being included in the present review of noninvasive monitoring. The process of collecting interstitial fluid, compared to blood, is less inconvenient in terms of 1) Pain, 2) Skin trauma, 3) Site restriction (sampling is not limited to the fingertips), and 4) Risk of contamination by a pathogenic agent into or from the circulation. Furthermore, it is simpler to assay glucose in interstitial fluid than in blood because with interstitial fluid an erythrocyte sequestration step is not necessary Interstitial fluid harvesting involves extraction of fluid from the skin followed by direct measurement of the fluid glucose concentration. In the literature, if there is a rapid shift in the serum glucose level, then the equilibration process between blood and the interstitium results in a 5- to 15-min lag before the interstitial fluid glucose concentration also changes. There are two problems with interstitial fluid technology for blood glucose monitoring. 1. Most interstitial fluid systems use disposable assay systems intended for one-time use. The expense of these disposables could impede frequent use of the monitor.

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2. And because of the potential lag time, as with extracted skin fluid technology, some treatment decisions may be based on inaccurate measurements if blood glucose levels are shifting rapidly. 4.7 GOOGLES SMART LENS Google manufactured a contact lens thats built to measure glucose levels in tears using a tiny wireless chip and miniaturized glucose sensor that are embedded between two layers of soft contact lens material. They are testing prototypes that can generate a reading once per second. They also investigated the potential for this to serve as an early warning for the wearer, so they are exploring integrating tiny LED lights that could light up to indicate that glucose levels have crossed above or below certain thresholds. Its still early days for this technology, but they have completed multiple clinical research studies which are helping to refine the prototype [28]. Google X came up with the idea of contact lenses with embedded chips and sensors so small they look like bits of glitter, and an antenna thinner than a human hair. They hope this kind of innovation would help with certain health situations, like people with Diabetes who would love an alternative to pricking their finger every day. They werent the first to think of this concept. For years, physicians and medical researchers have tried to think about ways to measure glucose through the fluid in the eye but struggled to decide how best to capture and analyze those tears. Companies such as EyeSense have even developed their own products to embed sensors in the eye to measure these levels, while companies like Freedom Meditech have explored measuring glucose levels through the eye by using light. The soft prototype contact lens house a sensor that measures the glucose levels in tears. A tiny pinhole in the lens lets tear fluid seep over the glucose monitor to get regular readings. Right now, it registers a level reading once every second. The lens also has a tiny antenna, capacitor and controller that allow the information gathered from the lens to move from the eye to a monitor where that data can be read and analyzed. It will draw its power from that device and communicate with it using a wireless technology known as RFID.

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CHAPTER-5
FUTURE SCOPE FOR THE SUGAR LEVEL DETECTING CONTACT LENSES
Diabetes must prick their fingers several times a day to test their blood sugar level. Though the pain is minor, the chore interferes with daily life. They never really escape it, says Paul Barone, a postdoctoral researcher in MITs Department of Chemical Engineering. Barone and Professor Michael Strano are working on a new type of blood glucose monitor that could not only eliminate the need for finger pricks but also offer more accurate readings. Strano and Barones sensing system consists of a tattoo of nanoparticles designed to detect glucose, injected below the skin. A device similar to a wristwatch would be worn over the tattoo, displaying the patients glucose levels. Most existing continuous glucose sensors work via an injection of an enzyme called glucose oxidase, which breaks down glucose. An electrode placed on the skin interacts with a byproduct of that reaction, hydrogen peroxide, allowing glucose levels to be indirectly measured. However, none of those sensors have been approved for use longer than seven days at a time. The technology behind the MIT sensor, described in a December 2009 issue of ACS Nano, is fundamentally different from existing sensors, says Strano. The sensor is based on carbon nanotubes wrapped in a polymer that is sensitive to glucose concentrations. When this sensor encounters glucose, the nanotubes fluoresce, which can be detected by shining near-infrared light on them. Measuring the amount of fluorescence reveals the concentration of glucose. The researchers plan to create an ink of these nanoparticles suspended in a saline solution that could be injected under the skin like a tattoo. The tattoo would last for a specified length of time, probably six months, before needing to be refreshed [29].To get glucose readings, the patient would wear a monitor that shines near-infrared light on the tattoo and detects the resulting fluorescence. One advantage of this type of sensor is that, unlike some fluorescent molecules, carbon nanotubes arent destroyed by light exposure. Because of this, the sensor can give continuous readings. Development of the nanoparticles and the wearable monitor is being funded by MITs Deshpande Center for Technological Innovation.

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Barone and Strano are now working to improve the accuracy of their sensor. Any glucose monitor must pass a test known as the Clarke Error Grid, the gold standard for glucose-sensor accuracy. The test, which compares sensor results to results from a lab-based glucose meter, needs to be very stringent, since mistakes in glucose detection can be fatal. Biological devices are being developed which can detect sugar level through saliva. The technique could eliminate the need for diabetics to draw blood to check their glucose levels. The biochip uses plasmonic interferometers and could be used to measure a range of biological and environmental substances. Contact lenses which can detect the sugar levels in a human body and automatically transmit it to a storing device or medical centers for further processing are being worked upon [30].

Fig.5.1. Conceptual diagram of an active contact-lens system for wireless health monitoring.

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CONCLUSION
Diabetes has become a global epidemic during the last two decades. It is increasing at an alarming pace of 7.8 million new diabetics each year and is taking an unsustainable economic toll, amounting to 11.6% of the total healthcare expenditure [31]. The ongoing research efforts to find the cure for diabetes by developing an artificial pancreas or by islet cell transplantation will take a lot of time based on the challenges involved and only a very limited scope for success. The current use of intensive insulin treatment is inadequate, as it leads to a marked increase in episodes of severe hypoglycemia. Moreover, insulin treatment is not expected to dramatically reduce the formation of Amadori products, which have a major impact on secondary health problems. Therefore, more frequent glucose monitoring is the only way to effectively manage diabetes by sustaining the physiological blood glucose level. The need for new glucose sensors in diabetes is now greater than ever. Although development of an acceptable, continuous & automatic glucose sensor has proven to be a substantial challenge, progress over the past several decades has defined sensor performance requirement & has focused development efforts on a limited group promising candidates. The advent of new glucose sensing technologies could facilitate fundamentally new approaches to the therapy of diabetes.

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