Despite the exciting design, it is difficult to measure glucose concentration in tears, because the amount of glucose present is very low: 0 to 64.8 mg/dL (3.59 mM) in healthy control subjects and may be as high as 84.6 mg/dL (4.69 mM) for diabetic subjects, and the tear glucose levels measured appear to be varied by the volume of the aqueous tear fraction collected.26 To achieve high-accurate measurement, the biosensor should be highly accessible by tear glucose, while having a minimal stimulation, which may decrease reflex tearing. Moreover, there is not much information on whether tear glucose levels vary from day to day, or are stable, as happens in blood. This brings up the issue of whether such lenses need to be calibrated every day and/or how often. Finally, hypoglycemia, which can be a severe and life-threatening aspect of diabetic management, often during sleep; a discussion of setting thresholds and alarms in extended-wear contact lenses; and the suitability of extended-wear contact lenses for diabetic subjects should be considered. These aspects are far from being resolved. Much larger studies are needed, which will be critical for regulatory approval and, indeed, the practicality of such a device.
One additional problem for these types of biodevices is the implementation of a suitable power source.48 Although integration with inductive links or radio-frequency circuits has been proposed, these solutions are not ideal and can be rather complicated, requiring inconvenient equipment. Integration of a biofuel cell (BFC) into the bionic contact lens could be an alternative power source.48 Thus, enzyme catalysts have been used to convert the chemical energy from biofuel (glucose) and biooxidant (oxygen) available in tear film into electrical energy.49,50 Biofuel cells appear to be a very attractive alternative power source for bionic contact lenses, because miniature devices can potentially be produced at a low cost and without complicated designs, especially when using enzymes immobilized directly on the electrode surfaces without using any mediators.50 For a glucose-sensing biodevice, use of glucose as a power source would be very problematic. In this sense, a more suitable fuel source present in tear fluid should be used. Thus, to avoid the oxidization of the glucose present in human lachrymal liquid, Falk et al.48 have designed a miniature membrane-less BFC using ascorbate instead of glucose to generate electrical power (Fig. 6). The electrical power production should thereby not alter the glucose level and influence the sensor performance. By means of a miniature membrane-less ascorbate/oxygen BFC, they have demonstrated that enough electrical power can be produced from human basal tears, without influencing the glucose profile of the lachrymal film. Considering the stability and power output of the BFC along with recent advances in modern ultralow power electronics and contact lens–based glucose biosensors, the BFC could be used as part of the design of bionic contact lenses and allow self-powered, noninvasive, continuous glucose monitoring to be realized.48 These biodevices hold great promise in the future as an aid for diabetic subjects and could help improve public health as well as reduce medical costs. Fabrication of BFCs incorporated into suitable flexible biocompatible polymeric materials is currently an ongoing investigation.
Although contact lens technology is one step closer to helping diabetic subjects better manage their condition, so far, practical applications have been slow to become real. Undoubtedly, it is difficult to solve some functional problems. Thus, these contact lenses should be comfortable to wear to avoid their impact on contact lens discomfort. Therefore, this aspect will be critical to determine whether such a lens would be wearable. Otherwise, vision will be impaired, making such a device cumbersome. Nevertheless, at the time of writing this article, an agreement between the Google research division and the Alcon eye care unit of the Swiss pharmaceutical company Novartis has been announced.51 They will license a smart lens technology for continuously measuring tear glucose levels in the diabetic patient by using a tiny wireless chip and miniaturized glucose sensor that are embedded between two layers of soft contact lens material. The lenses themselves are outfitted with tiny sensors and microchips (Fig. 7). According to the manufacturer, they will be so small they look like bits of glitter, whereas the embedded antenna will be thinner than a human hair. These contact lenses will be able to measure the level of glucose in the wearer’s tears and communicate the information to a mobile phone or computer.
In conclusion, it is clear that testing ocular glucose has great potential for noninvasive diagnosis of diabetes mellitus. Furthermore, monitoring glucose levels through the smart contact lenses could prove to be easier and more comprehensive than current techniques, which generally require diabetic subjects to prick their fingers for droplets of blood. Although numerous aspects must be improved, including more efficient interference rejection, better biocompatibility, and integrating sensors with readout and communication circuits, solutions to these problems should include the fabrication of a multifunctional contact lens to allow chemical analysis in the future.24
The authors have no funding or conflicts of interest to declare.
Received January 20, 2015; accepted April 15, 2015.
1. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014; 103: 137–49.
3. Townsend L. Basics of home glucose monitoring. MLO Med Lab Obs 2008; 40: 32–4.
4. Oliver NS, Toumazou C, Cass AE, Johnston DG. Glucose sensors: a review of current and emerging technology. Diabet Med 2009; 26: 197–210.
5. Zhang J, Hodge W, Hutnick C, Wang X. Noninvasive diagnostic devices for diabetes through measuring tear glucose
. J Diabetes Sci Technol 2011; 5: 166–72.
6. Clark L Jr., Lyons C. Electrode systems for continuous monitoring in cardiovascular surgery. Ann N Y Acad Sci 1962; 102: 29–45.
7. Wilkins E, Wilkins MG. Implantable glucose sensor. J Biomed Eng 1983; 5: 309–15.
8. Pickup JC, Shaw GW, Claremont DJ. In vivo molecular sensing in diabetes mellitus
: an implantable glucose sensor with direct electron transfer. Diabetologia 1989; 32: 213–7.
9. Chu MX, Miyajima K, Takahashi D, Arakawa T, Sano K, Sawada S, Kudo H, Iwasaki Y, Akiyoshi K, Mochizuki M, Mitsubayashi K. Soft contact lens biosensor
for in situ monitoring of tear glucose
as non-invasive blood sugar assessment. Talanta 2011; 83: 960–5.
10. Tierney MJ, Jayalakshmi Y, Parris NA, Reidy MP, Uhegbu C, Vijayakumar P. Design of a biosensor
for continual, transdermal glucose monitoring. Clin Chem 1999; 45: 1681–3.
11. Yeh SJ, Hanna CF, Khalil OS. Monitoring blood glucose changes in cutaneous tissue by temperature-modulated localized reflectance measurements. Clin Chem 2003; 49: 924–34.
12. Heise HM, Marbach R, Koschinsky TH, Gries FA. Non-invasive blood glucose sensors based on near-infrared spectroscopy. Artif Organs 1994; 18: 439–47.
13. Lambert JL, Morookian JM, Sirk SJ, Borchert MS. Measurement of aqueous glucose in a model anterior chamber using Raman spectroscopy. J Raman Spectrosc 2002; 33: 524–9.
14. Coté GL, Fox MD, Northrop RB. Noninvasive optical polarimetric glucose sensing using a true phase measurement technique. IEEE Trans Biomed Eng 1992; 39: 752–6.
15. Cameron BD, Coté GL. Noninvasive glucose sensing utilizing a digital closed-loop polarimetric approach. IEEE Trans Biomed Eng 1997; 44: 1221–7.
16. MacKenzie HA, Ashton HS, Spiers S, Shen Y, Freeborn SS, Hannigan J, Lindberg J, Rae P. Advances in photoacoustic noninvasive glucose testing. Clin Chem 1999; 45: 1587–95.
17. Amarie D, Alileche A, Dragnea B, Glazier JA. Microfluidic devices integrating microcavity surface-plasmon-resonance sensors: glucose oxidase binding-activity detection. Anal Chem 2010; 82: 343–52.
18. Evans ND, Gnudi L, Rolinski OJ, Birch DJ, Pickup JC. Non-invasive glucose monitoring by NAD(P)H autofluorescence spectroscopy in fibroblasts and adipocytes: a model for skin glucose sensing. Diabetes Technol Ther 2003; 5: 807–16.
19. Meadows D, Schultz JS. Fiber-optic biosensor
based on fluorescence energy transfer. Talanta 1988; 35: 145–50.
20. Tolosa L, Malak H, Rao G, Lakowicz JR. Optical assay for glucose based on the luminescence decay time of the long wavelength dye Cy5. Sensor Actuat B-Chem 1997; 45: 93–9.
21. Michail D, Vancea P, Zolog N. Sur l’elimination lacrymale du glucose chez les diabetiques. C R Soc Biol Paris 1937; 125: 1095.
22. Lane JD, Krumholz DM, Sack RA, Morris C. Tear glucose
dynamics in diabetes mellitus
. Curr Eye Res 2006; 31: 895–901.
23. Badugu R, Lakowicz JR, Geddes CD. Wavelength-ratiometric probes for the selective detection of fluoride based on the 6-amino-quino-linium nucleus and boronic acid moiety. J Fluoresc 2004; 14: 693–703.
24. Yao H, Shum AJ, Cowan M, Lähdesmäki I, Parviz BA. A contact lens with embedded sensor for monitoring tear glucose
level. Biosens Bioelectron 2011; 26: 3290–6.
25. Sen DK, Sarin GS. Tear glucose
levels in normal people and in diabetic patients. Br J Ophthalmol 1980; 64: 693–5.
26. Baca JT, Finegold DN, Asher SA. Tear glucose
analysis for the noninvasive detection and monitoring of diabetes mellitus
. Ocul Surf 2007; 5: 280–93.
27. Bjerrum KB, Prause JU. Collection and concentration of tear proteins studied by SDS gel electrophoresis. Presentation of a new method with special reference to dry eye patients. Graefes Arch Clin Exp Ophthalmol 1994; 232: 402–5.
28. Martin D, Fatt I. The presence of a contact lens induces a very small change in the anterior corneal surface temperature. Acta Ophthalmol (Copenh) 1986; 64: 512–8.
29. Malik BH, Coté GL. Modeling the corneal birefringence of the eye toward the development of a polarimetric glucose sensor. J Biomed Opt 2010; 15: 037012.
30. March W, Long B, Hofmann W, Keys D, McKenney C. Safety of contact lenses
in patients with diabetes. Diabetes Technol Ther 2004; 6: 49–52.
31. March WF. Glucose biosensors. In: Wise DL, ed. Bioinstrumentation: Research, Developments and Applications. Boston, MA: Butterworths; 1990; 31–46.
32. Alexeev VL, Das S, Finegold DN, Asher SA. Photonic crystal glucose-sensing material for noninvasive monitoring of glucose in tear fluid. Clin Chem 2004; 50: 2353–60.
33. Sekhon BS. Chemical biology: past, present and future. Current Chem Bio 2008; 2: 278–311.
34. Ben-Moshe M, Alexeev VL, Asher SA. Fast responsive crystalline colloidal array photonic crystal glucose sensors. Anal Chem 2006; 78: 5149–57.
35. Asher SA, Alexeev VL, Goponenko AV, Sharma AC, Lednev IK, Wilcox CS, Finegold DN. Photonic crystal carbohydrate sensors: low ionic strength sugar sensing. J Am Chem Soc 2003; 125: 3322–9.
36. March WF, Mueller A, Herbrechtsmeier P. Clinical trial of a noninvasive contact lens glucose sensor. Diabetes Technol Ther 2004; 6: 782–9.
37. Ballerstadt R, Schultz JS. Competitive-binding assay method based on fluorescence quenching of ligands held in close proximity by a multivalent receptor. Anal Chim Acta 1997; 345: 203–12.
38. Domschke AM. Continuous non-invasive ophthalmic glucose sensor for diabetics. Chimia (Aarau) 2010; 64: 43–4.
39. Mitsubayashi K, Dicks JM, Yokoyama K, Takeuchi T, Tamiya E, Karube I. A flexible biosensor
for glucose. Electroanalysis 1995; 7: 83–7.
40. Mitsubayashi K, Wakabayashi Y, Tanimoto S, Murotomi D, Endo T. Optical-transparent and flexible glucose sensor with ITO electrode. Biosens Bioelectron 2003; 19: 67–71.
41. Chu M, Kudo H, Shirai T, Miyajima K, Saito H, Morimoto N, Yano K, Iwasaki Y, Akiyoshi K, Mitsubayashi K. A soft and flexible biosensor
using a phospholipid polymer for continuous glucose monitoring. Biomed Microdevices 2009; 11: 837–42.
42. Iguchi S, Kudo H, Saito T, Ogawa M, Saito H, Otsuka K, Funakubo A, Mitsubayashi K. A flexible and wearable biosensor
for tear glucose
measurement. Biomed Microdevices 2007; 9: 603–9.
43. Kagie A, Bishop DK, Burdick J, La Belle JT, Dymond R, Felder R, Wang J. Flexible rolled thick-film miniaturized flow-cell for minimally invasive amperometric sensing. Electroanalysis 2008; 20: 1610–4.
44. Liao YT, Yao H, Lingley A, Parviz B, Otis BP. A 3-cmos glucose sensor for wireless contact-lens tear glucose
monitoring. IEEE J Solid-St Circ 2012; 47: 335–44.
45. Ho H, Saeedi E, Kim SS, Shen TT, Parviz BA. Contact lens with integrated inorganic semiconductor devices. Proceedings of the IEEE 21st International Conference on Micro Electro Mechanical Systems, 2008: MEMS 2008. Tucson, AZ, January 13-17, 2008. New York, NY: Institute of Electrical and Electronics Engineers (IEEE); 2008: 403–6.
46. Lingley AR, Ali M, Liao Y, Mirjalili R, Klonner M, Sopanen M, Suihkonen S, Shen T, Otis BP, Lipsanen H, Parviz BA. A single-pixel wireless contact lens display. J Micromech Microeng 2011; 21: 125014.
47. Hu Y, Jiang X, Zhang L, Fan J, Wu W. Construction of near-infrared photonic crystal glucose-sensing materials for ratiometric sensing of glucose in tears. Biosens Bioelectron 2013; 48: 94–9.
48. Falk M, Andoralov V, Silow M, Toscano MD, Shleev S. Miniature biofuel cell as a potential power source for glucose-sensing contact lenses
. Anal Chem 2013; 85: 6342–8.
49. Falk M, Andoralov V, Blum Z, Sotres J, Suyatin DB, Ruzgas T, Arnebrant T, Shleev S. Biofuel cell as a power source for electronic contact lenses
. Biosens Bioelectron 2012; 37: 38–45.
50. Falk M, Blum Z, Shleev S. Direct electron transfer based enzymatic fuel cells. Electrochim Acta 2012; 82: 191–202.