Stimuli-Responsive Insulin Delivery Devices


The development of new diabetes treatment strategies has garnered much interest given that conventional management therapies for type 1 diabetes fail to provide optimal glycemic control while creating a high burden of self-care to patients. Stimuli-responsive, “closed-loop” systems are particularly attractive due to their ability to mimic dynamic ß cell function by releasing insulin in response to fluctuating glucose levels in real-time and with minimal patient discomfort. In this short review, we focus on stimuli-responsive, reservoir-based insulin delivery devices. We explore and evaluate systems that are either physiologically or externally triggered. While obstacles remain before such technologies can be translated to clinical settings, further optimization of delivery systems forebodes that these technologies will have a tremendous impact on type 1 diabetes treatment.

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  1. 1.

    Federation ID. International diabetes federation 2020 [Available from:

  2. 2.

    Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383(9911):69–82.

    Article  PubMed Central  Google Scholar 

  3. 3.

    Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, Di Angelantonio E, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215–22.

    CAS  Article  PubMed Central  Google Scholar 

  4. 4.

    Ravaine V, Ancla C, Catargi B. Chemically controlled closed-loop insulin delivery. J Control Release. 2008;132(1):2–11.

    CAS  Article  PubMed Central  Google Scholar 

  5. 5.

    Nijhoff MF, de Koning EJP. Artificial pancreas or novel Beta-cell replacement therapies: a race for optimal glycemic control? Curr Diab Rep. 2018;18(11):110.

    Article  PubMed Central  Google Scholar 

  6. 6.

    Lachin J, Mcgee P, Palmer J, Grp DER, Grp DER. Impact of C-peptide preservation on metabolic and clinical outcomes in the diabetes control and complications trial. Diabetes. 2014;63(2):739–48.

    CAS  Article  PubMed Central  Google Scholar 

  7. 7.

    Shapiro A, Lakey J, Ryan E, Korbutt G, Toth E, Warnock G, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343(4):230–8.

    CAS  Article  PubMed Central  Google Scholar 

  8. 8.

    Ernst A, Bowers D, Wang L, Shariati K, Plesser M, Brown N, et al. Nanotechnology in cell replacement therapies for type 1 diabetes. Adv Drug Deliv Rev. 2019;139:116–38.

    CAS  Article  PubMed Central  Google Scholar 

  9. 9.

    Mo R, Jiang T, Di J, Tai W, Gu Z. Emerging micro- and nanotechnology based synthetic approaches for insulin delivery. Chem Soc Rev. 2014;43(10):3595–629.

    CAS  Article  PubMed Central  Google Scholar 

  10. 10.

    Wang J, Wang Z, Yu J, Kahkoska AR, Buse JB, Gu Z. Glucose-Responsive Insulin and Delivery Systems: Innovation and Translation. Adv Mater. 2019:e1902004.

  11. 11.

    Langer R. Advances in drug delivery. Cancer Res. 2017;77.

  12. 12.

    Yu J, Zhang Y, Yan J, Kahkoska AR, Gu Z. Advances in bioresponsive closed-loop drug delivery systems. Int J Pharm. 2018;544(2):350–7.

    CAS  Article  PubMed Central  Google Scholar 

  13. 13.

    Wilson R, Turner A. Glucose-oxidase - an ideal enzyme. Biosens Bioelectron. 1992;7(3):165–85.

    CAS  Article  Google Scholar 

  14. 14.

    Bankar S, Bule M, Singhal R, Ananthanarayan L. Glucose oxidase - an overview. Biotechnol Adv. 2009;27(4):489–501.

    CAS  Article  PubMed Central  Google Scholar 

  15. 15.

    Gordijo C, Koulajian K, Shuhendler A, Bonifacio L, Huang H, Chiang S, et al. Nanotechnology-enabled closed loop insulin delivery device: in vitro and in vivo evaluation of glucose-regulated insulin release for diabetes control. Adv Funct Mater. 2011;21(1):73–82.

    CAS  Article  Google Scholar 

  16. 16.

    Gordijo C, Shuhendler A, Wu X. Glucose-responsive bioinorganic Nanohybrid membrane for self-regulated insulin release. Adv Funct Mater. 2010;20(9):1404–12.

    CAS  Article  Google Scholar 

  17. 17.

    Chu M, Chen J, Gordijo C, Chiang S, Ivovic A, Koulajian K, et al. In vitro and in vivo testing of glucose-responsive insulin-delivery microdevices in diabetic rats. Lab Chip. 2012;12(14):2533–9.

    CAS  Article  PubMed Central  Google Scholar 

  18. 18.

    Diez P, de Avila B, Ramirez-Herrera D, Villalonga R, Wang J. Biomedical nanomotors: efficient glucose-mediated insulin release. Nanoscale. 2017;9(38):14307–11.

    CAS  Article  PubMed Central  Google Scholar 

  19. 19.

    Ortiz-Prado E, Dunn JF, Vasconez J, Castillo D, Viscor G. Partial pressure of oxygen in the human body: a general review. Am J Blood Res. 2019;9(1):1–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Klumb L, Horbett T. Design of insulin delivery devices based on glucose sensitive membranes. J Control Release. 1992;18(1):59–80.

    CAS  Article  Google Scholar 

  21. 21.

    Yin R, Bai M, He J, Nie J, Zhang W. Concanavalin A-sugar affinity based system: binding interactions, principle of glucose-responsiveness, and modulated insulin release for diabetes care. Int J Biol Macromol. 2019;124:724–32.

    CAS  Article  PubMed Central  Google Scholar 

  22. 22.

    Wu S, Huang X, Du X. Glucose- and pH-responsive controlled release of cargo from protein-gated carbohydrate-functionalized Mesoporous silica Nanocontainers. Angewandte Chemie-International Edition. 2013;52(21):5580–4.

    CAS  Article  PubMed Central  Google Scholar 

  23. 23.

    Powell AE, Leon MA. Reversible interaction of human lymphocytes with the mitogen concanavalin a. Exp Cell Res. 1970;62(2):315–25.

    CAS  Article  PubMed Central  Google Scholar 

  24. 24.

    Kataoka K, Hisamitsu I, Sayama N, Okano T, Sakurai Y. Novel sensing system for glucose based on the complex formation between phenylborate and fluorescent diol compounds. J Biochem. 1995;117(6):1145–7.

    CAS  Article  PubMed Central  Google Scholar 

  25. 25.

    Matsumoto A, Tanaka M, Matsumoto H, Ochi K, Moro-oka Y, Kuwata H, et al. Synthetic "smart gel" provides glucose-responsive insulin delivery in diabetic mice. Science Advances. 2017;3(11).

  26. 26.

    Matsumoto A, Ishii T, Nishida J, Matsumoto H, Kataoka K, Miyahara Y. A synthetic approach toward a self-regulated insulin delivery system. Angewandte Chemie-International Edition. 2012;51(9):2124–8.

    CAS  Article  PubMed Central  Google Scholar 

  27. 27.

    Matsumoto A, Ikeda S, Harada A, Kataoka K. Glucose-responsive polymer bearing a novel phenylborate derivative as a glucose-sensing moiety operating at physiological pH conditions. Biomacromolecules. 2003;4(5):1410–6.

    CAS  Article  PubMed Central  Google Scholar 

  28. 28.

    Blum A, Kammeyer J, Rush A, Callmann C, Hahn M, Gianneschi N. Stimuli-responsive Nanomaterials for biomedical applications. J Am Chem Soc. 2015;137(6):2140–54.

    CAS  Article  PubMed Central  Google Scholar 

  29. 29.

    Prausnitz M, Langer R. Transdermal drug delivery. Nat Biotechnol. 2008;26(11):1261–8.

    CAS  Article  PubMed Central  Google Scholar 

  30. 30.

    Sirsi S, Borden M. State-of-the-art materials for ultrasound-triggered drug delivery. Adv Drug Deliv Rev. 2014;72:3–14.

    CAS  Article  PubMed Central  Google Scholar 

  31. 31.

    Smith N, Lee S, Maione E, Roy R, McElligott S, Shung K. Ultrasound-mediated transdermal transport of insulin in vitro through human skin using novel transducer designs. Ultrasound Med Biol. 2003;29(2):311–7.

    Article  PubMed Central  Google Scholar 

  32. 32.

    Smith N, Lee S, Shung K. Ultrasound-mediated transdermal in vivo transport of insulin with low-profile cymbal arrays. Ultrasound Med Biol. 2003;29(8):1205–10.

    Article  PubMed Central  Google Scholar 

  33. 33.

    Lee S, Snyder B, Newnham RE, Smith NB. Noninvasive ultrasonic transdermal insulin delivery in rabbits using the light-weight cymbal array. Diabetes Technol Ther. 2004;6(6):808–15.

    CAS  Article  PubMed Central  Google Scholar 

  34. 34.

    Park EJ, Werner J, Smith NB. Ultrasound mediated transdermal insulin delivery in pigs using a lightweight transducer. Pharm Res. 2007;24(7):1396–401.

    CAS  Article  PubMed Central  Google Scholar 

  35. 35.

    Park E-J, Werner J, Jaiswal D, Smith NB, editors. Closed-Loop controlled noninvasive ultrasonic glucose sensing and insulin delivery. American Institute of Physics; 2010.

  36. 36.

    Jabbari N, Asghari MH, Ahmadian H, Mikaili P. Developing a commercial air ultrasonic ceramic transducer to transdermal insulin delivery. J Med Signals Sens. 2015;5(2):117–22.

    Article  PubMed Central  Google Scholar 

  37. 37.

    Timko BP, Arruebo M, Shankarappa SA, McAlvin JB, Okonkwo OS, Mizrahi B, et al. Near-infrared-actuated devices for remotely controlled drug delivery. Proc Natl Acad Sci U S A. 2014;111(4):1349–54.

    CAS  Article  PubMed Central  Google Scholar 

  38. 38.

    Zhang Y, Yu J, Kahkoska AR, Wang J, Buse JB, Gu Z. Advances in transdermal insulin delivery. Adv Drug Deliv Rev. 2019;139:51–70.

    CAS  Article  PubMed Central  Google Scholar 

  39. 39.

    Roxhed N, Samel B, Nordquist L, Griss P, Stemme G. Painless drug delivery through microneedle-based transdermal patches featuring active infusion. IEEE Trans Biomed Eng. 2008;55(3):1063–71.

    Article  PubMed Central  Google Scholar 

  40. 40.

    Kochba E, Levin Y, Raz I, Cahn A. Improved insulin pharmacokinetics using a novel microneedle device for intradermal delivery in patients with type 2 diabetes. Diabetes Technol Ther. 2016;18(9):525–31.

    CAS  Article  PubMed Central  Google Scholar 

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This work was partially supported by the National Science Foundation (SNM-1530522), Juvenile Diabetes Research Foundation (JDRF), the Hartwell Foundation, the National Institutes of Health (NIH, 1R01DK105967-01A1) and the Novo Nordisk Company. The authors declare no conflict of interest.

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Correspondence to Minglin Ma.

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Fuchs, S., Shariati, K. & Ma, M. Stimuli-Responsive Insulin Delivery Devices. Pharm Res 37, 202 (2020).

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Key words

  • closed-loop devices
  • drug delivery
  • stimuli-responsive
  • type 1 diabetes