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A miniaturized transcutaneous system for continuous glucose monitoring

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Abstract

Implantable sensors for continuous glucose monitoring hold great potential for optimal diabetes management. This is often undermined by a variety of issues associated with: (1) negative tissue response; (2) poor sensor performance; and (3) lack of device miniaturization needed to reduce implantation trauma. Herein, we report our initial results towards constructing an implantable device that simultaneously address all three aforementioned issues. In terms of device miniaturization, a highly miniaturized CMOS (complementary metal-oxide-semiconductor) potentiostat and signal processing unit was employed (with a combined area of 0.665 mm2). The signal processing unit converts the current generated by a transcutaneous, Clark-type amperometric sensor to output frequency in a linear fashion. The Clark-type amperometric sensor employs stratification of five functional layers to attain a well-balanced mass transfer which in turn yields a linear sensor response from 0 to 25 mM of glucose concentration, well beyond the physiologically observed (2 to 22 mM) range. In addition, it is coated with a thick polyvinyl alcohol (PVA) hydrogel with embedded poly(lactic-co-glycolic acid) (PLGA) microspheres intended to provide continuous, localized delivery of dexamethasone to suppress inflammation and fibrosis. In vivo evaluation in rat model has shown that the transcutaneous sensor system reproducibly tracks repeated glycemic events. Clarke’s error grid analysis on the as—obtained glycemic data has indicated that all of the measured glucose readings fell in the desired Zones A & B and none fell in the erroneous Zones C, D and E. Such reproducible operation of the transcutaneous sensor system, together with low power (140 μW) consumption and capability for current-to-frequency conversion renders this a versatile platform for continuous glucose monitoring and other biomedical sensing devices.

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References

  • M.M. Ahmadi, G.A. Jullien, A wireless-implantable microsystem for continuous blood glucose monitoring. IEEE Trans Biomed Circ Syst 3(3), 169–180 (2009)

    Article  Google Scholar 

  • U. Bhardwaj, R. Sura et al., Controlling acute inflammation with fast-releasing dexamethasone-PLGA microsphere/PVA hydrogel composites for implantable devices. J Diabetes Sci Technol 1(1), 8–17 (2007)

    Google Scholar 

  • U. Bhardwaj, R. Sura et al., PLGA/PVA hydrogel composites for long-term inflammation control following s.c. implantation. Int J Pharm 384(1–2), 78–86 (2010)

    Article  Google Scholar 

  • L. Bolomey, E. Meurville et al., Implantable ultra-low power DSP-based system for a miniature chemico-rheological biosensor. Proc Eurosensors XXIII Conf 1(1), 1235–1238 (2009)

    Google Scholar 

  • M.S. Boyne, D.M. Silver et al., Timing of changes in interstitial and venous blood glucose measured with a continuous subcutaneous glucose sensor. Diabetes 52(11), 2790–2794 (2003)

    Article  Google Scholar 

  • C. Choleau, J.C. Klein et al., Calibration of a subcutaneous amperometric glucose sensor implanted for 7 days in diabetic patients: Part 2. Superiority of the one-point calibration method. Biosens Bioelectron 17(8), 647–654 (2002)

    Article  Google Scholar 

  • X. Chu, D. Duan et al., Amperometric glucose biosensor based on electrodeposition of platinum nanoparticles onto covalently immobilized carbon nanotube electrode. Talanta 71(5), 2040–2047 (2007)

    Article  Google Scholar 

  • Y. Degani, A. Heller, Direct electrical communication between chemically modified enzymes and metal electrodes. 1. Electron transfer from glucose oxidase to metal electrodes via electron relays, bound covalently to the enzyme. J Phys Chem 91(6), 1285–1289 (1987)

    Article  Google Scholar 

  • S. Dong, B. Wang et al., Amperometric glucose sensor with ferrocene as an electron transfer mediator. Biosens Bioelectron 7(3), 215–222 (1992)

    Article  MathSciNet  Google Scholar 

  • A.M.K. Enejder, T.G. Scecina et al., Raman spectroscopy for noninvasive glucose measurements. J Biomed Opt 10(3), 1–9 (2005)

    Article  Google Scholar 

  • A. Errachid, A. Ivorra et al., New technology for multi-sensor silicon needles for biomedical applications. Sensors and Actuators, B: Chem 78(1–3), 279–284 (2001)

    Article  Google Scholar 

  • A. Ersöz, A. Denizli et al., Molecularly imprinted ligand-exchange recognition assay of glucose by quartz crystal microbalance. Biosens Bioelectron 20(11), 2197–2202 (2005)

    Article  Google Scholar 

  • M. Frost, M.E. Meyerhoff, In vivo chemical sensors: Tackling biocompatibility. Anal Chem 78(21), 7370–7377 (2006)

    Article  Google Scholar 

  • I. Galeska, T.K. Kim et al., Controlled release of dexamethasone from PLGA microspheres embedded within polyacid-containing PVA hydrogels. AAPS J 7(1), E231–E240 (2005)

    Article  Google Scholar 

  • R.J. Geise, J.M. Adams et al., Electropolymerized films to prevent interferences and electrode fouling in biosensors. Biosens Bioelectron 6(2), 151–160 (1991)

    Article  Google Scholar 

  • R. Gifford, J.J. Kehoe et al., Protein interactions with subcutaneously implanted biosensors. Biomaterials 27(12), 2587–2598 (2006)

    Article  Google Scholar 

  • M.R. Haider, S.K. Islam et al., A low-power signal processing unit for in vivo monitoring and transmission of sensor signals. Sensors Transducers 84(10), 1625–1632 (2007)

    Google Scholar 

  • K.L. Helton, B.D. Ratner et al., Biomechanics of the sensor -tissue interface-effects of motion, pressure, and design on sensor performance and the foreign body response-part II: examples and applications. J Diabetes Sci Technol 5(3), 647–656 (2011)

    Google Scholar 

  • T. Hickey, D. Kreutzer et al., Dexamethasone/PLGA microspheres for continuous delivery of an anti-inflammatory drug for implantable medical devices. Biomaterials 23(7), 1649–1656 (2002a)

    Article  Google Scholar 

  • T. Hickey, D. Kreutzer et al., In vivo evaluation of a dexamethasone/PLGA microsphere system designed to suppress the inflammatory tissue response to implantable medical devices. J Biomed Mater Res 61(2), 180–187 (2002b)

    Article  Google Scholar 

  • J.L. House, E.M. Anderson et al., Immobilization techniques to avoid enzyme loss from oxidase-based biosensors: a one-year study. J Diabetes Sci Technol 1(1), 18–22 (2007)

    Google Scholar 

  • F. Jain, H. Grantham et al., Implantable Biosensor and Methods of Use Thereof, 2008, Patent Pending. US Patent Application No. 20080154101 (2008)

  • K.W. Johnson, J.J. Mastrototaro et al., In vivo evaluation of an electroenzymatic glucose sensor implanted in subcutaneous tissue. Biosens Bioelectron 7(10), 709–714 (1992)

    Article  Google Scholar 

  • F. Khan, T.E. Saxl et al., Fluorescence intensity- and lifetime-based glucose sensing using an engineered high-Kd mutant of glucose/galactose-binding protein. Anal Biochem 399(1), 39–43 (2010)

    Article  Google Scholar 

  • B.P. Kovatchev, D. Shields et al., Graphical and numerical evaluation of continuous glucose sensing time lag. Diabetes Technol Ther 11(3), 139–143 (2009)

    Article  Google Scholar 

  • P.H. Kvist, T. Iburg et al., Biocompatibility of an enzyme-based, electrochemical glucose sensor for short-term implantation in the subcutis. Diabetes Technol Ther 8(5), 546–559 (2006)

    Article  Google Scholar 

  • O. Lyandres, J.M. Yuen et al., Progress toward an in vivo surface-enhanced Raman spectroscopy glucose sensor. Diabetes Technol Ther 10(4), 257–265 (2008)

    Article  Google Scholar 

  • H.A. MacKenzie, H.S. Ashton et al., Advances in photoacoustic noninvasive glucose testing. Clin Chem 45(9), 1587–1595 (1999)

    Google Scholar 

  • C.D. Malchoff, K. Shoukri et al., A novel noninvasive blood glucose monitor. Diabetes Care 25(12), 2268–2275 (2002)

    Article  Google Scholar 

  • C. Malitesta, F. Palmisano et al., Glucose fast-response amperometric sensor based on glucose oxidase immobilized in an electropolymerized poly(o-phenylenediamine) film. Anal Chem 62(24), 2735–2740 (1990)

    Article  Google Scholar 

  • S.M. Martin, F.H. Gebara et al., A fully differential potentiostat. Sensors J, IEEE 9(2), 135–142 (2009)

    Article  Google Scholar 

  • B.D. McKean, D.A. Gough, A telemetry-instrumentation system for chronically implanted glucose and oxygen sensors. IEEE Trans Biomed Eng 35(7), 526–532 (1988)

    Article  Google Scholar 

  • J.M. Morais, F. Papadimitrakopoulos et al., Biomaterials/tissue interactions: possible solutions to overcome foreign body response. AAPS J 12(2), 188–196 (2010)

    Article  Google Scholar 

  • L.W. Norton, H.E. Koschwanez et al., Vascular endothelial growth factor and dexamethasone release from nonfouling sensor coatings affect the foreign body response. J Biomed Mater Res A 81(4), 858–869 (2007)

    Google Scholar 

  • A. Pasic, H. Koehler et al., Fiber-optic flow-through sensor for online monitoring of glucose. Anal Bioanal Chem 386(5), 1293–1302 (2006)

    Article  Google Scholar 

  • S.D. Patil, F. Papadimitrakopoulos et al., Dexamethasone-loaded poly(lactic-co-glycolic) acid microspheres/poly(vinyl alcohol) hydrogel composite coatings for inflammation control. Diabetes Technol Ther 6(6), 887–897 (2004)

    Article  Google Scholar 

  • S.D. Patil, F. Papadimitrakopoulos et al., Concurrent delivery of dexamethasone and VEGF for localized inflammation control and angiogenesis. J Control Release 117(1), 68–79 (2007)

    Article  Google Scholar 

  • J.C. Pickup, F. Hussain et al., Fluorescence-based glucose sensors. Biosens Bioelectron 20(12), 2555–2565 (2005)

    Article  Google Scholar 

  • A. Rawat, D.J. Burgess, Effect of physical ageing on the performance of dexamethasone loaded PLGA microspheres. Int J Pharm 415(1–2), 164–168 (2011)

    Article  Google Scholar 

  • P.A. Serra, G. Rocchitta et al., Design and construction of a low cost single-supply embedded telemetry system for amperometric biosensor applications. Sensors Actuators B: Chem 122(1), 118–126 (2007)

    Article  Google Scholar 

  • M.C. Shults, R.K. Rhodes et al., A telemetry-instrumentation system for monitoring multiple subcutaneously implanted glucose sensors. IEEE Trans Biomed Eng 41(10), 937–942 (1994)

    Article  Google Scholar 

  • R. Tipnis, S. Vaddiraju et al., Layer-by-layer assembled semipermeable membrane for amperometric glucose sensors. J Diabetes Sci Technol 1(2), 193–200 (2007)

    Google Scholar 

  • J. Trzebinski, A.R.-B. Moniz et al., Hydrogel membrane improves batch-to-batch reproducibility of an enzymatic glucose biosensor. Electroanalysis 23(12), 2789–2795 (2011)

    Article  Google Scholar 

  • S. Vaddiraju, D.J. Burgess et al., The role of H2O2 outer diffusion on the performance of implantable glucose sensors. Biosens Bioelectron 24(6), 1557–1562 (2009a)

    Article  Google Scholar 

  • S. Vaddiraju, S.H., D.J. Burgess, F.C. Jain, F. Papadimitrakopoulos, “Enhanced glucose sensor linearity using poly(vinyl alcohol) hydrogels.” J. Diabetes Sci. Technol. (4), 863–874 (2009b)

  • S. Vaddiraju, D.J. Burgess et al., Technologies for continuous glucose monitoring: current problems and future promises. J Diabetes Sci Technol 4(6), 1540–1562 (2010a)

    Google Scholar 

  • S. Vaddiraju, I. Tomazos et al., Emerging synergy between nanotechnology and implantable biosensors: a review. Biosens Bioelectron 25(7), 1553–1565 (2010b)

    Article  Google Scholar 

  • P. Valdastri, E. Susilo et al., Wireless implantable electronic platform for blood glucose level monitoring. Proc Eurosensors XXIII Conf 1(1), 1255–1258 (2009)

    Google Scholar 

  • S. Vaddiraju, A. Legassey et al., Design and fabrication of a high-performance electrochemical glucose sensor. J Diabetes Sci Technol 5(5), 1044–1051 (2011)

    Google Scholar 

  • B.E. Watt, A.T. Proudfoot et al., Hydrogen peroxide poisoning. Toxicol Rev 23(1), 51–57 (2004)

    Article  Google Scholar 

  • R. Weiss, Y. Yegorchikov et al., Noninvasive continuous glucose monitoring using photoacoustic technology —Results from the first 62 subjects. Diabetes Technol Ther 9(1), 68–74 (2007)

    Article  Google Scholar 

  • E. Wilkins, P. Atanasov et al., Integrated implantable device for long-term glucose monitoring. Biosens Bioelectron 10(5), 485–494 (1995)

    Article  Google Scholar 

  • G.S. Wilson, R. Gifford, Biosensors for real-time in vivo measurements. Biosens Bioelectron 20(12), 2388–2403 (2005)

    Article  Google Scholar 

  • N. Wisniewski, M. Reichert, Methods for reducing biosensor membrane biofouling. Colloids Surf B Biointerfaces 18(3–4), 197–219 (2000)

    Article  Google Scholar 

  • H. Yang, T.D. Chung et al., Glucose sensor using a microfabricated electrode and electropolymerized bilayer films. Biosens Bioelectron 17(3), 251–259 (2002)

    Article  Google Scholar 

  • M. Zhang, M. R. Haider et al., “A low power sensor signal processing circuit for implantable biosensor applications.” Smart Mater. Struct. 16(Journal Article), 525–530 (2007)

    Google Scholar 

Download references

Acknowledgements

Financial support for this study was obtained from US Army Medical Research Grants (W81XWH-09-1-0711 and W81XWH-07-10688), NIH grants (1-R21-HL090458-01, ES013557, R43EB011886 and 9R01EB014586) and NSF/SBIR grants (1046902 and 1230148).

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Authors and Affiliations

  1. Electrical & Computer Engineering, University of Connecticut, Storrs, CT, 06269, USA

    Robert A. Croce Jr, Jun Kondo & Faquir C. Jain

  2. Biorasis Inc., Technology Incubation Program, University of Connecticut, Storrs, CT, 06269, USA

    SanthiSagar Vaddiraju

  3. Nanomaterials Optoelectronics Laboratory, Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, CT, 06269, USA

    SanthiSagar Vaddiraju & Fotios Papadimitrakopoulos

  4. Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, 06269, USA

    Yan Wang & Diane J. Burgess

  5. University of Tennesse, Knoxville, TN, USA

    Liang Zuo, Kai Zhu & Syed K. Islam

  6. Department of Chemistry, University of Connecticut, Storrs, CT, 06269, USA

    Fotios Papadimitrakopoulos

Authors
  1. Robert A. Croce Jr
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  2. SanthiSagar Vaddiraju
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  3. Jun Kondo
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  4. Yan Wang
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  5. Liang Zuo
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  6. Kai Zhu
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  7. Syed K. Islam
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  8. Diane J. Burgess
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  9. Fotios Papadimitrakopoulos
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  10. Faquir C. Jain
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Corresponding authors

Correspondence to Fotios Papadimitrakopoulos or Faquir C. Jain.

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Robert A. Croce Jr and SanthiSagar Vaddiraju are authors who contributed equally to this manuscript

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Croce, R.A., Vaddiraju, S., Kondo, J. et al. A miniaturized transcutaneous system for continuous glucose monitoring. Biomed Microdevices 15, 151–160 (2013). https://doi.org/10.1007/s10544-012-9708-x

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