Diabetes is a growing worldwide issue. In the United States alone, there are 25.8 million affected patients []. The annual cost of medical treatment (e.g. management and monitoring) and indirect expenses (such as disability and unemployment benefits) are $174 billion []. While there are several means for patients with diabetes mellitus to manage their condition, none of them are perfect.

The Biological Issue: Necessity of Sugar

In recent years, there has been a rise in the development of nanotechnology for drug delivery (refer to ‘Materials for Drug Delivery’ []). One area of clinical progress is in the field of diabetes management, particularly in how patients with diabetes monitor the levels of glucose in their blood.

Glucose, a type of sugar, is an essential energy source for the body. When you digest a meal, the sugar contents enter the bloodstream and get distributed to the cells. In addition, the pancreas produces the hormone insulin, signaling the body to store excess glucose as an energy reservoir. Patients with diabetes are either unable to produce insulin, or respond improperly to insulin production, and are therefore unable to regulate glucose levels in the blood []. This means that they frequently have elevated blood glucose levels, which can lead to numerous health problems. For example, diabetic retinopathy is characterized by damage to the retina, which is located towards the back of the eye and is surrounded by a meshwork of small blood vessels. The prolonged period of high blood sugar content in patients with diabetes causes damage to the blood vessels, leading to swelling of the retinal tissue and eventually, blurred vision for the patients []. To prevent or delay the onset of such health problems, patients with diabetes must learn how to regulate their blood glucose levels with the goal of keeping them within the recommended range of 80-120 milligrams of glucose per deciliter of blood volume [].

The Challenge: Fluctuations in Blood Glucose Levels

The typical management approach for patients is self-monitoring of glucose levels, meaning that many times each day they must prick their finger to collect a blood sample for testing, especially before and after meals or physical activity. Commonly, the blood sample is placed onto a test strip and read by a portable handheld glucose meter. If patients find that they have an abnormally high or low blood glucose level, they need to take action in order to correct the abnormality, or risk experiencing dangerous health effects. Hypoglycemia (low blood glucose levels) may cause dizziness, confusion, weakness, and sweating. It is treated by intake of glucose-rich food and/or injection of insulin. If untreated, hypoglycemia may result in seizures, coma and death due to an inadequate supply of glucose (and thus, energy source) reaching the cells in the brain. Hyperglycemia (high blood glucose levels) causes frequent urination and increased thirst, and is typically treated by exercising. If untreated, hyperglycemia may also result in a coma. A hyperglycemia-induced coma is a consequence of the cells being unable to absorb glucose from the blood, which in turn, causes the body to break down fats for energy. This process produces waste products that may accumulate to toxic levels in the body [5, 6].

The finger-prick sampling method is commonly used, but it is not without drawbacks. The major limitations are its associated physical pain and its intermittency. Unless a patient is constantly checking, he or she will be unaware of potentially dangerous deviations of their blood glucose levels from the desired range [].

Monitoring Glucose Levels with Nanosensor Tattoos

An ideal management method for patients with diabetes mellitus would be one that allows for continuous blood glucose monitoring, in order to avoid the problem of intermittency. In November 2010, scientists at Northeastern University’s Bouvé College of Health Sciences revealed results from a trial of a continuously-checking monitor tested in mice (to-date, the method has not yet been submitted for approval by the US Food and Drug Administration for use in humans). The research team, led by Associate Professor Dr. Heather Clark, developed a system that allows detection of blood glucose levels using a portable handheld device and a “nanosensor tattoo.” The idea is to inject patients right under the skin with a fluorescent nanosensor that changes the intensity of its fluorescence in response to changes in blood glucose levels (Figure 1a). Nanosensors would be on the scale of nanometers in size – for comparison, the width of human hair is approximately 80,000 nanometers []. The intensity of the fluorescence can then be measured by scanning the skin with a scanner that can be fitted to an iPhone case [].

The sensor is synthesized to have a stabilized infrastructure in a cellular environment such that ongoing cellular processes do not interfere with the chemistry of glucose detection. In addition, the materials of the sensor were selected for their effectiveness in extracting glucose molecules from nearby blood vessels into the nanosensor. The main components of the sensor are glucose recognition elements and a fluorescent reporter molecule. A reporter molecule is characterized by its ability to provide a read-out for a particular cellular event, in this case, its formation in a complex with glucose recognition elements. The glucose recognition elements have the ability to bind either the reporter molecule or glucose molecules, a process that is completely reversible. Depending on whether glucose or the reporter molecule is bound, the fluorescence intensity of the tattoo sensor changes. In the absence of glucose, the glucose recognition elements will bind to the reporter molecules and form fluorescent complexes, whereas in the presence of glucose, they will bind to glucose molecules instead of the reporter molecule, and no fluorescent complexes will form. So, low blood glucose is indicated by high intensity of fluorescence, and high blood glucose will be indicated by low intensity of fluorescence. The measurements made using the tattoo sensor in the Northeastern team’s mouse trial were comparable to those taken using a glucose meter [10-12].

Figure 1. Mechanism of continuous glucose monitoring of nanosensor tattoo. (A) Sensors are designed to change fluorescence intensity to correspond to glucose concentration. (B) Nanosensors is synthesized to contain glucose recognition elements and reporter molecules. In the absence of glucose, the binding of the glucose recognition elements with the reporter molecules result in the formation of fluorescent complexes. In the presence of glucose, the glucose recognition elements bind glucose, which displaces them from a complex with the reporter molecules, and thus, leads to a decrease in fluorescence intensity. Image modified from [].

Looking Toward the Future

Since the nanosensor has only been tested in mouse models, there remains a tremendous amount of work that needs to be done before such a device becomes available in the clinic. Some initial issues that need to be addressed include the possibility of the body mounting an immune response against the nanosensor. In addition, there may be a lag time in measuring blood glucose levels since the skin implantation does not directly sample the blood. Lastly, there needs to be clinical evidence that this nanosensor is just as efficient, if not more efficient, than other monitoring methods currently available to diabetes patients []. Despite these challenges, the nanosensor tattoo is an important step in the development of tools for continuous glucose monitoring, which could, in turn, improve the quality of life for patients with diabetes mellitus.

Jessica W. Chen is a PhD student in the Biological and Biomedical Sciences Program at Harvard University.

References:

[] 2011. “National Diabetes Statistics, 2011.” National Diabetes Information Clearinghouse. http://diabetes.niddk.nih.gov/dm/pubs/statistics/

[] Akin J, 2011. “Materials for Drug Delivery.” Harvard University Science in the News Flash Newsletter. http://sitn.hms.harvard.edu/flash/2011/materials-for-drug-delivery/

[] Rother KI, 2007. Diabetes Treatment – Bridging the Divide. NEJM 356 (15): 1499-1501.

[] 2009. “Diabetic Retinopathy.” Eyemaginations, Inc. http://www.aoa.org/patients-and-public/eye-and-vision-problems/glossary-of-eye-and-vision-conditions/diabetic-retinopathy

[] 2008. “Diabetes.” National Diabetes Information Clearinghouse. http://diabetes.niddk.nih.gov/dm/a-z.aspx

[] Pickup JC, Zhi ZL, Khan F, Saxl T, Birch DJS, 2008. Nanomedicine and its potential in diabetes research and practice. Diabetes Metab Res Rev 24: 604-610.

[] Langer, Robert. “Case Studies.” HST 150 – Principles of Pharmacology. Harvard Medical School. Boston, 05 January 2012.

[] “Size of the Nanoscale.” National Nanotechnology Initiative. http://www.nano.gov/nanotech-101/what/nano-size/

[] 2010. “Tattoos that Improve Health.” News @ Northeastern. http://www.northeastern.edu/news/2010/11/heather_clark/

[] Balaconis MK, Billingsley K, Dubach JM, Cash KJ, Clark HA, 2011. The Design and Development of Fluorescent Nano-Optodes for in Vivo Glucose Monitoring. J Diabetes Sci Technol 5(1): 68-75.

[] Billingsley K, Balaconis MK, Dubach JM, Zhang N, Lim E, Francis KP, Clark HA, 2010. Fluorescent Nano-Optodes for Glucose Detection. Anal Chem 82(9): 3707-3713.

[] Cash KJ and Clark HA, 2010. Nanosensors and nanomaterials for monitoring glucose in diabetes. Trends in Molecular Medicine 16(12): 584-593.