Ultra-miniaturization of a planar amperometric sensor targeting continuous intradermal glucose monitoring.

An ultra-miniaturized electrochemical biosensor for continuous glucose monitoring (CGM) is presented. The aim of this work is to demonstrate the possibility of an overall reduction in sensor size to allow minimally invasive glucose monitoring in the interstitial fluid in the dermal region, in contrast to larger state-of-the-art systems, which are necessarily placed in the subcutaneous layer. Moreover, the reduction in size might be a key factor to improve the stability and reliability of transdermal sensors, due to the reduction of the detrimental foreign body reaction and of consequent potential failures. These advantages are combined with lower invasiveness and discomfort for patients. The realized device consists of a microfabricated three-electrode enzymatic sensor with a total surface area of the sensing portion of less than 0.04mm2, making it the smallest fully integrated planar amperometric glucose sensor area reported to date. The working electrode and counter electrode consist of platinum and are functionalized by drop casting of three polymeric membranes. The on-chip iridium oxide (IrOx) pseudo-reference electrode provides the required stability for measurements under physiological conditions. The device is able to dynamically and linearly measure glucose concentrations in-vitro over the relevant physiological range, while showing sufficient selectivity to known interfering species present in the interstitial fluid, with resolution and sensitivity (1.51nA/mM) comparable to that of state-of-art commercial CGM systems. This work can therefore enable less invasive and improved CGM in patients affected by diabetes.

[1]  C. Choi,et al.  Glucose sensor using a microfabricated electrode and electropolymerized bilayer films. , 2002, Biosensors & bioelectronics.

[2]  B. Fritsch,et al.  Polymer-based, flexible glutamate and lactate microsensors for in vivo applications. , 2014, Biosensors & bioelectronics.

[3]  Yanfeng Liu,et al.  A study of human skin and surface temperatures in stable and unstable thermal environments , 2013 .

[4]  Santhisagar Vaddiraju,et al.  Emerging synergy between nanotechnology and implantable biosensors: a review. , 2010, Biosensors & bioelectronics.

[5]  Isao Karube,et al.  Problems associated with the thin-film Ag/AgCl reference electrode and a novel structure with improved durability , 1998 .

[6]  P J Stout,et al.  Comparison of glucose levels in dermal interstitial fluid and finger capillary blood. , 2001, Diabetes technology & therapeutics.

[7]  Hua Dong,et al.  Implantable electrochemical sensors for biomedical and clinical applications: progress, problems, and future possibilities. , 2007, Current medicinal chemistry.

[8]  Nicolaas F. de Rooij,et al.  Microsystem technologies for implantable applications , 2007 .

[9]  Yingchun Fu,et al.  Recent advances in electrochemical glucose biosensors: a review , 2013 .

[10]  Sejin Park,et al.  Electrochemical non-enzymatic glucose sensors. , 2006, Analytica chimica acta.

[11]  Yan Wang,et al.  Design and Fabrication of a High-Performance Electrochemical Glucose Sensor , 2011, Journal of diabetes science and technology.

[12]  W Thomas,et al.  Glucose measurement in patients with diabetes mellitus with dermal interstitial fluid. , 1997, The Journal of laboratory and clinical medicine.

[13]  John L. Crassidis,et al.  Sensors and actuators , 2005, Conference on Electron Devices, 2005 Spanish.

[14]  A Heller,et al.  Design and optimization of a selective subcutaneously implantable glucose electrode based on "wired" glucose oxidase. , 1995, Analytical chemistry.

[15]  K. Juodkazis,et al.  Iridium Anodic Oxidation to Ir(III) and Ir(IV) Hydrous Oxides , 2005 .

[16]  Barbara Enderle,et al.  Multiparametric, Flexible Microsensor Platform for Metabolic Monitoring \(In~Vivo\) , 2014, IEEE Sensors Journal.

[17]  Y. Marunaka Roles of interstitial fluid pH in diabetes mellitus: Glycolysis and mitochondrial function. , 2015, World journal of diabetes.

[18]  Adam Heller,et al.  Electrochemical glucose sensors and their applications in diabetes management. , 2008, Chemical reviews.

[19]  D. J. Harrison,et al.  Characterization of perfluorosulfonic acid polymer coated enzyme electrodes and a miniaturized integrated potentiostat for glucose analysis in whole blood. , 1988, Analytical chemistry.

[20]  Mei-Ling Li,et al.  The efficacy of viral capsid inhibitors in human enterovirus infection and associated diseases. , 2007, Current medicinal chemistry.

[21]  Ellis Meng,et al.  Chronically Implanted Pressure Sensors: Challenges and State of the Field , 2014, Sensors.

[22]  S. D. Collins,et al.  Microneedle array for transdermal biological fluid extraction and in situ analysis , 2004 .

[23]  D. J. Harrison,et al.  A biocompatible enzyme electrode for continuous in vivo glucose monitoring in whole blood , 1990 .

[24]  Richard G. Compton,et al.  Electrochemical Non-enzymatic Glucose Sensors: A Perspective and an Evaluation , 2010, International Journal of Electrochemical Science.

[25]  M. Jamal Deen,et al.  Microfabricated Reference Electrodes and their Biosensing Applications , 2010, Sensors.

[26]  Mark R Prausnitz,et al.  Minimally invasive extraction of dermal interstitial fluid for glucose monitoring using microneedles. , 2005, Diabetes technology & therapeutics.

[27]  Ronald Brazg,et al.  A continuous glucose sensor based on wired enzyme technology -- results from a 3-day trial in patients with type 1 diabetes. , 2003, Diabetes technology & therapeutics.

[28]  Kun Hwang,et al.  Thickness of skin and subcutaneous tissue of the free flap donor sites: A histologic study , 2016, Microsurgery.

[29]  R. Hovorka Continuous glucose monitoring and closed‐loop systems , 2006, Diabetic medicine : a journal of the British Diabetic Association.

[30]  Megan C Frost,et al.  Implantable chemical sensors for real-time clinical monitoring: progress and challenges. , 2002, Current opinion in chemical biology.

[31]  J. Tamada,et al.  Rates of glucose change measured by blood glucose meter and the GlucoWatch Biographer during day, night, and around mealtimes. , 2004, Diabetes care.

[32]  S. K. Vashist Non-invasive glucose monitoring technology in diabetes management: a review. , 2012, Analytica chimica acta.

[33]  Marc Madou,et al.  A pH Electrode Based on Melt-Oxidized Iridium Oxide , 2001 .

[34]  Tian C Zhang,et al.  Fabrication of anodically electrodeposited iridium oxide film pH microelectrodes for microenvironmental studies. , 2002, Analytical chemistry.

[35]  N A W van Riel,et al.  Modeling glucose and water dynamics in human skin. , 2008, Diabetes technology & therapeutics.

[36]  Vanessa M. Tolosa,et al.  Electrochemically deposited iridium oxide reference electrode integrated with an electroenzymatic glutamate sensor on a multi-electrode array microprobe. , 2013, Biosensors & bioelectronics.

[37]  N. Oliver,et al.  Use of microneedle array devices for continuous glucose monitoring: a review. , 2013, Diabetes technology & therapeutics.

[38]  Benoit Gosselin,et al.  Recent Advances in Neural Recording Microsystems , 2011, Sensors.

[39]  Mark R Prausnitz,et al.  Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force. , 2004, Journal of biomechanics.

[40]  Carlos Eduardo Ferrante do Amaral,et al.  Current development in non-invasive glucose monitoring. , 2008, Medical engineering & physics.

[41]  Zhixiong Cai,et al.  Advances in enzyme-free electrochemical sensors for hydrogen peroxide, glucose, and uric acid , 2014, Microchimica Acta.

[42]  Barbara K Bailes,et al.  Diabetes mellitus and its chronic complications. , 2002, AORN journal.

[43]  Chong H Ahn,et al.  Toward real-time continuous brain glucose and oxygen monitoring with a smart catheter. , 2009, Biosensors & bioelectronics.

[44]  Mark R Prausnitz,et al.  Microneedles for transdermal drug delivery. , 2004, Advanced drug delivery reviews.

[45]  Yan Wang,et al.  Foreign Body Reaction to Implantable Biosensors , 2015, Journal of diabetes science and technology.

[46]  N. F. Rooij,et al.  Planar Amperometric Enzyme-Based Glucose Microelectrode , 1989 .

[47]  Changhyun Pang,et al.  Recent advances in flexible sensors for wearable and implantable devices , 2013 .

[48]  Joseph Wang,et al.  CHAPTER 3 – Electrochemical glucose biosensors , 2008 .

[49]  Jiri Janata,et al.  Principles of Chemical Sensors , 1989 .

[50]  Santhisagar Vaddiraju,et al.  Technologies for Continuous Glucose Monitoring: Current Problems and Future Promises , 2010, Journal of diabetes science and technology.

[51]  D. Jed Harrison,et al.  Permeability of glucose and other neutral species through recast perfluorosulfonated ionomer films , 1992 .

[52]  R. Gifford,et al.  Continuous glucose monitoring: 40 years, what we've learned and what's next. , 2013, Chemphyschem : a European journal of chemical physics and physical chemistry.

[53]  Ingelin Clausen,et al.  Development of Clinically Relevant Implantable Pressure Sensors: Perspectives and Challenges , 2014, Sensors.

[54]  Chang Auck Choi,et al.  An iridium oxide reference electrode for use in microfabricated biosensors and biochips. , 2004, Lab on a chip.

[55]  Sang Beom Jun,et al.  Application of a new Cl-plasma-treated Ag/AgCl reference electrode to micromachined glucose sensor , 2003 .

[56]  W. Cascio,et al.  Electrodeposited iridium oxide pH electrode for measurement of extracellular myocardial acidosis during acute ischemia. , 1998, Analytical chemistry.

[57]  Adam Heller,et al.  Electrochemistry in diabetes management. , 2010, Accounts of chemical research.

[58]  D. J. Harrison,et al.  Preliminary in vivo biocompatibility studies on perfluorosulphonic acid polymer membranes for biosensor applications. , 1991, Biomaterials.

[59]  Sandeep Kumar Vashist,et al.  Technology behind commercial devices for blood glucose monitoring in diabetes management: a review. , 2011, Analytica chimica acta.