“Diabetes mellitus, commonly referred to as diabetes, is a big threat to human health globally. It is a disease characterized by high blood glucose levels (BGLs), which can cause severe damage to the eyes, kidneys, and nerves. In addition, it can also cause heart disease, strokes and even the need to remove limbs. Such complications can however be alleviated if controlled duly and effectively. Metabolites such as glucose are important indicators in diabetes management. The existing standard therapy for patients with insulin-dependent diabetes (type 1) and advanced patients with non-insulin-dependent diabetes (type 2) diabetics includes everyday insulin injections, and frequent fingerstick calibrations to monitor BGLs. Frequent injections and fingerstick calibrations are painful and has a high risk of infection as a result of exposure to the environment and the low immunity of diabetics, hence a more accurate, riskless and less painful method is highly desirable. Therefore, intense scholarly interest has been aroused concerning the detection, tracking, and control of metabolites using optical, electromagnetic or electrochemical sensors.”1
As scientists continue to break ground in combating Diabetes, biotechnology seems to be running parallel to the progress being made. A relatively new concept is garnering excitement, namely, a graphene patch with sensors that is worn (similar to a nicotine patch) to measure glucose levels found in perspiration, which is proven to be akin to blood glucose levels. Once measuring is complete, it proceeds to administer the proper dose of an anti-diabetic drug through microscopic needles.
“As sweat accumulates in the patch, the glucose it contains is monitored electrochemically on a graphene hybrid platform that also supports an array of other sensors (pH, humidity, mechanical strain). In response to the detected glucose, actuation of thermoresponsive polymeric microneedles is initiated, releasing an appropriate quantity of diabetes medication. The graphene hybrid device connects electrically to a portable electrochemical analyzer, which acts as a power supply and controller that wirelessly transmits data to a remote mobile device (such as a smartphone).”3
Scientists have cited the immediate rewards of this innovative approach to the management of Diabetes Mellitus, saying it is the ideal method long sought after because the inconveniences that come with traditional invasive methods to administer medications (such as needles).
The device utilizes several sheets of a synthetic fluoropolymer called Nafion to soak up sweat; the built-in sensors make the appropriate reading of glucose levels. The graphene patch is made with electrochemical materials (by doping the graphene with gold atoms) that provide the device functionality to detect glucose.
The chemical reaction that occurs within the glucose sensors is well known: Glucose oxidase is an enzyme that interacts with the soaked-up glucose from sweat resulting in hydrogen peroxide. Hydrogen peroxide then pulls electrical current from the gold atom imbibed graphene. This electrical response is correlated to the quantity of surrounding glucose.
“Sweat is one of the most accessible body fluids, where its primary biological role is for thermoregulation. Conveniently, for sampling purposes, eccrine glands that excrete sweat can be found all over the body, where they are particularly concentrated in multiple locations, for example in the hands, feet, lower back and underarm. Sweat has been exploited for diagnostic purposes, in particular for the detection of disease markers such as sodium, potassium, calcium, phosphate and glucose. It is also known that small-molecule drugs and their metabolites are present in sweat, thereby allowing the evaluation of drug efficacy. Sweat can be continuously accessed and its production can be stimulated on-demand at certain locations, for example by iontophoresis. By placing sensors in close contact with the skin, sweat samples can be processed rapidly without contamination. For many years, sweat has been used as a sampling medium of interest in sensing devices for confirming diseases, such as cystic fibrosis and for gaining other valuable information, relating to electrolyte balance, diet, injury, stress, medications and hydration. The hydration status of individuals has become a relatively new area of interest for monitoring human performance, resulting in an increase in wearable smart devices on the global market. Most analytes contained in sweat tend to vary significantly between basal and exercising states, as well as between individuals. The reported glucose level in sweat for healthy patients is between 0.06 and 0.11 mM and between 0.01 and 1 mM for diabetics. The fluctuations in analyte concentrations result in a broad pH range of sweat, typically between pH 4.0–6.8 during exercise, which can impact on the effectiveness of chemical-sensing or biosensing techniques chosen for disease diagnosis or monitoring.”4
Another built in attribute of this device is the versatility of the aforementioned sensors. They not only read glucose presence in sweat, but they also minimize possible measured reading errors by being able to detect pH as well as temperature levels. When worn by enlisted participants who wanted to try this new device, it was found that the readings it gave before and after meals was the same as glucose meters available commercially.
“The gold studs were added in order to be able to read the glucose levels. The material can also be employed for the fabrication of wearable patches for diabetes monitoring and feedback therapy. The fabricated stretchable device structures a serpentine bilayer of gold mesh and gold doped graphene and forming an efficient electrochemical interface for the stable transfer of electrical signals. The fabricated patch was mainly consisted of a heater, temperature, humidity, glucose, and pH sensors along with polymeric microneedles that can be thermally activated to deliver drugs transcutaneously. As an interesting fact of the fabricated is that the patch uses sweat to determine “sweat glucose,” which can be used to figure out blood glucose levels. They have used Metformin as an antidiabetic drug and showed that the patch can be thermally actuated to deliver Metformin and eventually can reduce the blood glucose levels in diabetic mice. These types of advances using nanomaterials and devices will provide some new opportunities for the treatment of chronic diseases like diabetes mellitus.”5
Demonstration of the wearable diabetes monitoring and therapy system in vivo
On the monitoring side of the patch, the sensors send the incoming signals for analysis, where analyzed information is then sent to a modern phone by wireless means.
“The detection of hyperglycaemia — through the glucose and pH sensors — is the cue to actuate drug delivery from the device. The polymeric microneedles, which contain metformin (a drug commonly used in the treatment of type 2 diabetes), are coated with a hydrophobic layer of tridecanoic acid. This layer protects the microneedles from moisture when inserted into the skin and prevents the premature release of the metformin. When an elevated glucose level is detected, the heater embedded in the patch is triggered, warming the microneedles.”6
The drug dispensing system is made of sophisticated 1-mm-long fluoropolymer needles imbibed with metformin (a diabetes-fighting pharmaceutical) that punctures the epidermis and disintegrates to deliver said drug. Also, the needles have a coating of tridecylic acid which is heated and subsequently melted by a mesh of gold graphene that rests atop the myriad of needles. The melted acid then disintegrates into the dermis and delivers the intended drug with it.
“Graphene biochemical sensors with solid-state Ag/AgCl counter electrodes show enhanced electrochemical activity, sensitivity and selectivity in detecting important biomarkers contained in human sweat. The GP-hybrid (graphene-hybrid) interconnections and physical sensors efficiently transmit the signal through the stretchable array and supplement electrochemical sensors, respectively. The orchestrated monitoring of biomarkers and physiological cues with sweat control and transcutaneous drug delivery achieves a closed-loop, point-of-care treatment for diabetes. The detection of RH (relative humidity) over a critical point due to sweat activates the glucose sensing, which is corrected by simultaneous measurement of pH and temperature. High glucose concentration recordings trigger the embedded heaters to dissolve PCM (phase-change material) and as a result, bioresorbable microneedles release Metformin as a feedback transdermal drug delivery to the glucose sensing. The use of intrinsically soft materials enhances the conformal integration of devices with the human skin and thus improves the effectiveness of biochemical sensors and drug delivery. The wireless connectivity further highlights the practical applicability of the current patch system. These advances using nanomaterials and devices provide new opportunities for the treatment of chronic diseases such as diabetes mellitus.”7
Conceptually, this new device is giving cause for excitement and hopefully, we see many more vanguard attempts at improving life with Diabetes.
(1) Conducting Polymers and Their Applications in Diabetes Management. Zhao, Y., Cao, L., Li, L., Cheng, W., Xu, L., Ping, X., Pan, L. & Shi, Y. Sensors. 2016. https://www.mdpi.com/1424-8220/16/11/1787/htm
(2, 7) A graphene-based electrochemical device with thermoresponsive microneedles for diabetes monitoring and therapy. Lee, H., Kyu Choi, T., Bum Lee, Y., Rim Cho, H., Ghaffari, R., Wang, L ., Jin Choi, H., Dong Chung, T., Lu, N., Hyeon, T., Hong Choi, S. & Kim, D-H. Nature Nanotechnology. 2016. https://www.nature.com/articles/nnano.2016.38
(3, 6) Managing diabetes through the skin. Richard Guy. Nature Nanotechnology. 2016. https://www.nature.com/articles/nnano.2016.53
(4) Glucose Sensing for Diabetes Monitoring: Recent Developments. Bruen, D., Delaney, C., Florea, L. & Diamond, D. Sensors. 2017. https://www.mdpi.com/1424-8220/17/8/1866/htm
(5) Stimuli-responsive polymers for treatment of diabetes mellitus. Patra, S., Madhuri, R. & Sharma, P.K. Advanced Nanocarrieres for Therapeutics. Volume 2. 2019. pg. 516, 518. https://books.google.co.ve/books?id=KOZ0DwAAQBAJ&pg=PA491&lpg=PA491&dq=Stimuli-responsive+polymers+for+treatment+of+diabetes+mellitus&source=bl&ots=PHkrUcuf9o&sig=ACfU3U02b-TplGQL3jcNMq2LRK9yHbPHWA&hl=es&sa=X&ved=2ahUKEwjvx9Lt5v3hAhWFm1kKHe2_BaQQ6AEwBHoECAkQAQ#v=onepage&q=Stimuli-responsive%20polymers%20for%20treatment%20of%20diabetes%20mellitus&f=false