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Reduction of measurement noise in a continuous glucose monitor by coating the sensor with a zwitterionic polymer


Continuous glucose monitors (CGMs), used by patients with diabetes mellitus, can autonomously track fluctuations in blood glucose over time. However, the signal produced by CGMs during the initial recording period following sensor implantation contains substantial noise, requiring frequent recalibration via finger-prick tests. Here, we show that coating the sensor with a zwitterionic polymer, found via a combinatorial chemistry approach, significantly reduces signal noise and improves CGM performance. We evaluated the polymer-coated sensors in mice as well as in healthy and diabetic non-human primates, and show that the sensors accurately record glucose levels without the need for recalibration. We also show that the coated sensors significantly abrogated immune responses, as indicated by histology, fluorescent whole-body imaging of inflammation-associated protease activity and gene expression of inflammation markers. The polymer coating may allow CGMs to become standalone measuring devices.

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Fig. 1: Illustration of CGM sensing in vivo.
Fig. 2: Zwitterionic polymer coating of Medtronic CGMs.
Fig. 3: Sensing performance in SKH1 mouse model.
Fig. 4: CGM biocompatibility in SKH1 mouse model is improved with the coating.
Fig. 5: Sensing performance of CGMs in NHP model.


  1. 1.

    Yach, D., Stuckler, D. & Brownell, K. D. Epidemiologic and economic consequences of the global epidemics of obesity and diabetes. Nat. Med. 12, 62–66 (2006).

    CAS  Article  Google Scholar 

  2. 2.

    Zimmet, P., Alberti, K. G. M. M. & Shaw, J. Global and societal implications of the diabetes epidemic. Nature 414, 782–787 (2001).

    CAS  Article  Google Scholar 

  3. 3.

    Gabir, M. M. et al. The1997 American Diabetes Association and 1999 World Health Organization criteria for hyperglycemia in the diagnosis and prediction of diabetes. Diabetes Care 23, 1108–1112 (2000).

    CAS  Article  Google Scholar 

  4. 4.

    Zhuo, X. et al. The lifetime cost of diabetes and its implications for diabetes prevention. Diabetes Care 37, 2557–2564 (2014).

    Article  Google Scholar 

  5. 5.

    Clar, C., Barnard, K., Cummins, E., Royle, P. & Waugh, N. Self-monitoring of blood glucose in type 2 diabetes: systematic review. Health Technol. Assess. (Rockv.) 14, 1–140 (2010).

    CAS  Google Scholar 

  6. 6.

    Kovatchev, B., Breton, M. & Clarke, W. Analytical methods for the retrieval and interpretation of continuous glucose monitoring data in diabetes. Methods Enzymol. 454, 69–86 (2009).

    CAS  Article  Google Scholar 

  7. 7.

    Boland, E. et al. Limitations of conventional methods of self-monitoring of blood glucose. Diabetes Care 24, 1858–1862 (2001).

    CAS  Article  Google Scholar 

  8. 8.

    Newman, J. D. & Turner, A. P. F. Home blood glucose biosensors: a commercial perspective. Biosens. Bioelectron. 20, 2435–2453 (2005).

    CAS  Article  Google Scholar 

  9. 9.

    Hovorka, R. Continuous glucose monitoring and closed-loop systems. Diabet. Med. 23, 1–12 (2006).

    CAS  Article  Google Scholar 

  10. 10.

    Shichiri, M., Yamasaki, Y., Kawamori, R., Hakui, N. & Abe, H. Wearable artificial endocrine pancreas with needle-type glucose sensor. Lancet 320, 1129–1131 (1982).

    Article  Google Scholar 

  11. 11.

    Hovorka, R. Closed-loop insulin delivery: from bench to clinical practice. Nat. Rev. Endocrinol. 7, 385–395 (2011).

    CAS  Article  Google Scholar 

  12. 12.

    Veiseh, O., Tang, B. C., Whitehead, K. A., Anderson, D. G. & Langer, R. Managing diabetes with nanomedicine: challenges and opportunities. Nat. Rev. Drug Discov. 14, 45–57 (2014).

    Article  Google Scholar 

  13. 13.

    Mastrototaro, J. J. The MiniMed continuous glucose monitoring system. Diabetes Technol. Ther. 2, 13–18 (2004).

    Article  Google Scholar 

  14. 14.

    Girardin, C. M., Huot, C., Gonthier, M. & Delvin, E. Continuous glucose monitoring: a review of biochemical perspectives and clinical use in type 1 diabetes. Clin. Biochem. 42, 136–142 (2009).

    CAS  Article  Google Scholar 

  15. 15.

    Gifford, R. Continuous glucose monitoring: 40 years, what we’ve learned and what’s next. ChemPhysChem 14, 2032–2044 (2013).

    CAS  Article  Google Scholar 

  16. 16.

    Rodbard, D. Continuous glucose monitoring: a review of successes, challenges, and opportunities. Diabetes Technol. Ther. 18 (Suppl. 2), S23–S213 (2016).

  17. 17.

    Vaddiraju, S., Burgess, D. J., Tomazos, I., Jain, F. C. & Papadimitrakopoulos, F. Technologies for continuous glucose monitoring: current problems and future promises. J. Diabetes Sci. Technol. 4, 1540–1562 (2010).

    Article  Google Scholar 

  18. 18.

    Gerritsen, M. Problems associated with subcutaneously implanted glucose sensors. Diabetes Care 23, 143–145 (2000).

    CAS  Article  Google Scholar 

  19. 19.

    Nichols, S. P., Koh, A., Storm, W. L., Shin, J. H. & Schoenfisch, M. H. Biocompatible materials for continuous glucose monitoring devices. Chem. Rev. 113, 2528–2549 (2013).

    CAS  Article  Google Scholar 

  20. 20.

    Gerritsen, M., Jansen, J. A. & Lutterman, J. A. Performance of subcutaneously implanted glucose sensors for continuous monitoring. Neth. J. Med. 54, 167–179 (1999).

    CAS  Article  Google Scholar 

  21. 21.

    Novak, M. T., Yuan, F. & Reichert, W. M. Predicting glucose sensor behavior in blood using transport modeling: relative impacts of protein biofouling and cellular metabolic effects. J. Diabetes Sci. Technol. 7, 1547–1560 (2013).

    Article  Google Scholar 

  22. 22.

    Jadviscokova, T., Fajkusova, Z., Pallayova, M., Luza, J. & Kuzmina, G. Occurrence of adverse events due to continuous glucose monitoring. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech. Repub. 151, 263–266 (2007).

    Article  Google Scholar 

  23. 23.

    iPro2 User Guide (Medtronic MiniMed, 2017).

  24. 24.

    Boyne, M. S., Silver, D. M., Kaplan, J. & Saudek, C. D. Timing of changes in interstitial and venous blood glucose measured with a continuous subcutaneous glucose sensor. Diabetes 52, 2790–2794 (2003).

    CAS  Article  Google Scholar 

  25. 25.

    Ellison, J. M. et al. Rapid changes in postprandial blood glucose produce concentration differences at finger, forearm, and thigh sampling sites. Diabetes Care 25, 961–964 (2002).

    Article  Google Scholar 

  26. 26.

    Sylvain, H. F. et al. Accuracy of fingerstick glucose values in shock patients. Am. J. Crit. Care 4, 44–48 (1995).

    CAS  PubMed  Google Scholar 

  27. 27.

    McGarraugh, G. The chemistry of commercial continuous glucose monitors. Diabetes Technol. Ther. 11, S-17–S-24 (2009).

    CAS  Article  Google Scholar 

  28. 28.

    Wang, J. in Electrochemical Sensors, Biosensors and their Biomedical Applications (eds Zhang, X., Ju, H. & Wang, J.) 57–69 (Elsevier, New York, 2008).

  29. 29.

    Basu, A., Veettil, S., Dyer, R., Peyser, T. & Basu, R. Direct evidence of acetaminophen interference with subcutaneous glucose sensing in humans: a pilot study. Diabetes Technol. Ther. 18 (Suppl. 2), S243–S247 (2016).

  30. 30.

    Klueh, U., Frailey, J. T., Qiao, Y., Antar, O. & Kreutzer, D. L. Cell based metabolic barriers to glucose diffusion: macrophages and continuous glucose monitoring. Biomaterials 35, 3145–3153 (2014).

    CAS  Article  Google Scholar 

  31. 31.

    Klueh, U., Kaur, M., Qiao, Y. & Kreutzer, D. L. Critical role of tissue mast cells in controlling long-term glucose sensor function in vivo. Biomaterials 31, 4540–4551 (2010).

    CAS  Article  Google Scholar 

  32. 32.

    Onuki, Y., Bhardwaj, U., Papadimitrakopoulos, F. & Burgess, D. J. A review of the biocompatibility of implantable devices: current challenges to overcome foreign body response. J. Diabetes Sci. Technol. 2, 1003–1015 (2008).

    Article  Google Scholar 

  33. 33.

    Anderson, J. M. Biological responses to materials. Annu. Rev. Mater. Res. 31, 81–110 (2001).

    CAS  Article  Google Scholar 

  34. 34.

    Moussy, F. Implantable glucose sensor: progress and problems. In Proceedings of IEEE Sensors 270–273 (IEEE, 2002).

  35. 35.

    Meyers, S. R. & Grinstaff, M. W. Biocompatible and bioactive surface modifications for prolonged in vivo efficacy. Chem. Rev. 112, 1615–1632 (2012).

    CAS  Article  Google Scholar 

  36. 36.

    Vallejo-Heligon, S. G., Brown, N. L., Reichert, W. M. & Klitzman, B. Porous, dexamethasone-loaded polyurethane coatings extend performance window of implantable glucose sensors in vivo. Acta Biomater. 30, 106–115 (2016).

    CAS  Article  Google Scholar 

  37. 37.

    Klueh, U., Kaur, M., Montrose, D. C. & Kreutzer, D. L. Inflammation and glucose sensors: use of dexamethasone to extend glucose sensor function and life span in vivo. J. Diabetes Sci. Technol. 1, 496–504 (2007).

    Article  Google Scholar 

  38. 38.

    Vaisocherová, H. et al. Ultralow fouling and functionalizable surface chemistry based on a zwitterionic polymer enabling sensitive and specific protein detection in undiluted blood plasma. Anal. Chem. 80, 7894–7901 (2008).

    Article  Google Scholar 

  39. 39.

    Zhang, L. et al. Zwitterionic hydrogels implanted in mice resist the foreign-body reaction. Nat. Biotechnol. 31, 553–556 (2013).

    CAS  Article  Google Scholar 

  40. 40.

    Zhao, J. et al. Improved biocompatibility and antifouling property of polypropylene non-woven fabric membrane by surface grafting zwitterionic polymer. J. Memb. Sci. 369, 5–12 (2011).

    CAS  Article  Google Scholar 

  41. 41.

    Klueh, U., Antar, O., Qiao, Y. & Kreutzer, D. L. Role of vascular networks in extending glucose sensor function: impact of angiogenesis and lymphangiogenesis on continuous glucose monitoring in vivo. J. Biomed. Mater. Res. Part A 102, 3512–3522 (2014).

    Article  Google Scholar 

  42. 42.

    Englert, K. et al. Skin and adhesive issues with continuous glucose monitors: a sticky situation. J. Diabetes Sci. Technol. 8, 745–751 (2014).

    Article  Google Scholar 

  43. 43.

    Abbott Laboratories. FreeStyle Libre, flash glucose monitoring system. Abbott Libre (2018).

  44. 44.

    Bailey, T., Bode, B. W., Christiansen, M. P., Klaff, L. J. & Alva, S. The performance and usability of a factory-calibrated flash glucose monitoring system. Diabetes Technol. Ther. 17, 787–794 (2015).

    CAS  Article  Google Scholar 

  45. 45.

    Hoss, U. & Budiman, E. S. Factory-calibrated continuous glucose sensors: the science behind the technology. Diabetes Technol. Ther. 19, S-44–S-50 (2017).

    Article  Google Scholar 

  46. 46.

    Bequette, B. W. Continuous glucose monitoring: real-time algorithms for calibration, filtering, and alarms. J. Diabetes Sci. Technol. 4, 404–18 (2010).

    Article  Google Scholar 

  47. 47.

    Doloff, J. C. et al. Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates. Nat. Mater. 16, 671–680 (2017).

    CAS  Article  Google Scholar 

  48. 48.

    Prichard, H. L., Schroeder, T., Reichert, W. M. & Klitzman, B. Bioluminescence imaging of glucose in tissue surrounding polyurethane and glucose sensor implants. J. Diabetes Sci. Technol. 4, 1055–1062 (2010).

    Article  Google Scholar 

  49. 49.

    Yang, W., Xue, H., Carr, L. R., Wang, J. & Jiang, S. Zwitterionic poly(carboxybetaine) hydrogels for glucose biosensors in complex media. Biosens. Bioelectron. 26, 2454–2459 (2011).

    CAS  Article  Google Scholar 

  50. 50.

    Yang, W. et al. The effect of lightly crosslinked poly(carboxybetaine) hydrogel coating on the performance of sensors in whole blood. Biomaterials 33, 7945–7951 (2012).

    CAS  Article  Google Scholar 

  51. 51.

    Reid, B. et al. PEG hydrogel degradation and the role of the surrounding tissue environment. J. Tissue Eng. Regen. Med. 9, 315–318 (2015).

    CAS  Article  Google Scholar 

  52. 52.

    Bratlie, K. M. et al. Rapid biocompatibility analysis of materials via in vivo fluorescence imaging of mouse models. PLoS ONE 5, e10032 (2010).

    Article  Google Scholar 

  53. 53.

    Vegas, A. J. et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat. Biotechnol. 34, 345–352 (2016).

    CAS  Article  Google Scholar 

  54. 54.

    Yesilyurt, V. et al. A facile and versatile method to endow biomaterial devices with zwitterionic surface coatings. Adv. Healthc. Mater. 6, 1601091 (2017).

    Article  Google Scholar 

  55. 55.

    Lee, H., Dellatore, S. M., Miller, W. M. & Messersmith, P. B. Mussel-inspired surface chemistry for multifunctional coatings. Science 318, 426–430 (2007).

    CAS  Article  Google Scholar 

  56. 56.

    Lee, H., Rho, J. & Messersmith, P. B. Facile conjugation of biomolecules onto surfaces via mussel adhesive protein inspired coatings. Adv. Mater. 21, 431–434 (2009).

    CAS  Article  Google Scholar 

  57. 57.

    Kang, S. M. et al. One-step multipurpose surface functionalization by adhesive catecholamine. Adv. Funct. Mater. 22, 2949–2955 (2012).

    CAS  Article  Google Scholar 

  58. 58.

    Facchinetti, A., Sparacino, G. & Cobelli, C. Signal processing algorithms implementing the ‘smart sensor’ concept to improve continuous glucose monitoring in diabetes. J. Diabetes Sci. Technol. 7, 1308–1318 (2013).

    Article  Google Scholar 

  59. 59.

    Vallejo-Heligon, S. G., Klitzman, B. & Reichert, W. M. Characterization of porous, dexamethasone-releasing polyurethane coatings for glucose sensors. Acta Biomater. 10, 4629–4638 (2014).

    CAS  Article  Google Scholar 

  60. 60.

    Salesov, E., Zini, E., Riederer, A., Lutz, T. A. & Reusch, C. E. Comparison of the pharmacodynamics of protamine zinc insulin and insulin degludec and validation of the continuous glucose monitoring system iPro2 in healthy cats. Res. Vet. Sci. 118, 79–85 (2018).

    CAS  Article  Google Scholar 

  61. 61.

    Chen, X., Lawrence, J., Parelkar, S. & Emrick, T. Novel zwitterionic copolymers with dihydrolipoic acid: synthesis and preparation of nonfouling nanorods. Macromolecules 46, 119–127 (2013).

    CAS  Article  Google Scholar 

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This work was supported by the Leona M. and Harry B. Helmsley Charitable Trust Foundation (2015PG-T1D063), Juvenile Diabetes Research Foundation (JDRF) (Grant 17-2007-1063) and National Institutes of Health (Grants EB000244, EB000351, DE013023 and CA151884), and through a generous gift from the Tayebati Family Foundation. J.C.D. was supported by JDRF postdoctoral fellowship (Grant 3-PDF-2015-91-A-N). J.O. is supported by the National Institutes of Health (NIH/NIDDK) R01DK091526 and the Chicago Diabetes Project. X.X. was supported by the 100 Talents Program of Sun Yat-Sen University (76120-18821104) and 1000 Talents Youth Program of China and acknowledges financial support from the National Natural Science Foundation of China (Grant No.51705543, 61771498 and 31530023) and Science and Technology Program of Guangzhou, China (Grant No. 20180310097). In addition, of extreme importance, the authors thank the Histology and Whole Animal Imaging cores for use of resources (Swanson Biotechnology Center, David H. Koch Institute for Integrative Cancer Research at MIT).

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X.X., J.C.D., V.Y., A.S. and D.G.A. designed experiments, analysed data and wrote the manuscript. X.X., J.C.D., V.Y., A.S., J.J.M., M.O., S.F., D.I., S.G., I.J., J.L., W.W., A.B. and K.A.W. performed experiments. X.X., J.C.D., V.Y., A.S., H.H.T., J.T., H.-j.C. and B.Y. performed statistical analyses of datasets and aided in the preparation of displays communicating datasets. R.L. and D.G.A. provided conceptual advice. R.L. and D.GA. supervised the study. All authors discussed the results and assisted in the preparation of the manuscript.

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Correspondence to Daniel G. Anderson.

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Xie, X., Doloff, J.C., Yesilyurt, V. et al. Reduction of measurement noise in a continuous glucose monitor by coating the sensor with a zwitterionic polymer. Nat Biomed Eng 2, 894–906 (2018).

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