Journal of Materials Science

, Volume 54, Issue 13, pp 10009–10023 | Cite as

Glucose-responsive nanostructured hydrogels with enhanced elastic and swelling properties

  • Tarig Elshaarani
  • Haojie YuEmail author
  • Li WangEmail author
  • Raja Summe Ullah
  • Shah Fahad
  • Kaleem Ur Rahman
  • Amin Khan
  • Ahsan Nazir
  • Muhammad Usman
  • Rizwan Ullah Khan
  • Fazal Haq
  • Ruixue Liang
  • Xiang Chen
  • Muhammad Haroon


Phenylboronic acids (PBAs) have gained considerable interest in recent years due to their recognition for diol-containing molecules such as glucose. Their response to the elevated glucose concentrations can be reported by measuring the change in the size or optical properties of polymers-bearing PBAs. In this context, fast response and good mechanical properties are crucial factors for constructing glucose-responsive sensors. Toward this goal, we have synthesized glucose-responsive nanostructured gels (NSGs) using 3-acrylamidophenylboronic acid and N-isopropylacrylamide. Herein, activated nanogels with controllable size were prepared and used as nano-cross-linkers. The prepared NSGs showed glucose-responsiveness in a remarkable concentration-dependent manner, exhibited high elasticity upon compression and slicing and resisted high level of deformation such as bending, twisting and stretching.



Financial support from the National Natural Science Foundation of China (21472168 and 21611530689) and the fundamental research funds for the central universities (2017FZA4023) are gratefully acknowledged.

Supplementary material

10853_2019_3505_MOESM1_ESM.docx (474 kb)
Supplementary material 1 (DOCX 474 kb)


  1. 1.
    Yu J, Zhang Y, Bomba H, Gu Z (2016) Stimuli-responsive delivery of therapeutics for diabetes treatment. Bioeng Trans Med 1(3):323–337CrossRefGoogle Scholar
  2. 2.
    Thérien-Aubin H, Wang Y, Nothdurft K, Prince E, Cho S, Kumacheva E (2016) Temperature-responsive nanofibrillar hydrogels for cell encapsulation. Biomacromolecules 17(10):3244–3251CrossRefGoogle Scholar
  3. 3.
    Kim YJ, Tachibana M, Umezu M, Matsunaga YT (2016) Bio-inspired smart hydrogel with temperature-dependent properties and enhanced cell attachment. J Mater Chem B 4(9):1740–1746CrossRefGoogle Scholar
  4. 4.
    Liu J, Yin Y (2015) Temperature responsive hydrogels: construction and applications. Polym Sci 1(13):1–6Google Scholar
  5. 5.
    Xiao Z, Wylie RAL, Brisson ERL, Connal LA (2016) pH-responsive fluorescent hydrogels using a new thioflavin T cross-linker. J Polym Sci Polym Chem 54(5):591–595CrossRefGoogle Scholar
  6. 6.
    Puranik AS, Pao LP, White VM, Peppas NA (2016) Synthesis and characterization of pH-responsive nanoscale hydrogels for oral delivery of hydrophobic therapeutics. Eur J Pharm Biopharm 108:196–213CrossRefGoogle Scholar
  7. 7.
    Carrick LM, Aggeli A, Boden N, Fisher J, Ingham E, Waigh TA (2007) Effect of ionic strength on the self-assembly, morphology and gelation of pH responsive β-sheet tape-forming peptides. Tetrahedron 63(31):7457–7467CrossRefGoogle Scholar
  8. 8.
    Takashi N, Yoshinori T, Akihito H, Hiroyasu Y, Akira H (2014) A metal-ion-responsive adhesive material via switching of molecular recognition properties. Nat Commun 5:4622–4631CrossRefGoogle Scholar
  9. 9.
    Huang YJ, Ouyang WJ, Wu X, Li Z, Fossey JS, James TD, Jiang YB (2013) Glucose sensing via aggregation and the use of “knock-out” binding to improve selectivity. J Am Chem Soc 135(5):1700–1703CrossRefGoogle Scholar
  10. 10.
    Yang T, Ji R, Deng XX, Du FS, Li ZC (2014) Glucose-responsive hydrogels based on dynamic covalent chemistry and inclusion complexation. Soft Matter 10(15):2671–2678CrossRefGoogle Scholar
  11. 11.
    Raja STK, Thiruselvi T, Mandal AB, Gnanamani A (2015) pH and redox sensitive albumin hydrogel: a self-derived biomaterial. Scientific Rep 5:15977CrossRefGoogle Scholar
  12. 12.
    Fan Y, Zhou W, Yasin A, Li H, Yang H (2015) Dual-responsive shape memory hydrogels with novel thermoplasticity based on a hydrophobically modified polyampholyte. Soft Matter 11(21):4218–4225CrossRefGoogle Scholar
  13. 13.
    Beebe DJ, Moore JS, Bauer JM, Yu Q, Liu RH, Devadoss CJ, Byung H (2000) Functional hydrogel structures for autonomous flow control inside microfluidic channels. Nature 404(6778):588–590CrossRefGoogle Scholar
  14. 14.
    Dong L, Agarwal AK, Beebe DJ, Jiang H (2006) Adaptive liquid microlenses activated by stimuli-responsive hydrogels. Nature 442(7102):551–554CrossRefGoogle Scholar
  15. 15.
    Qiu Y, Park K (2001) Environment-sensitive hydrogels for drug delivery. Adv Drug Deliv Rev 53(3):321–339CrossRefGoogle Scholar
  16. 16.
    Caldorera-Moore M, Peppas NA (2009) Micro- and nanotechnologies for intelligent and responsive biomaterial-based medical systems. Adv Drug Deliv Rev 61(15):1391–1401CrossRefGoogle Scholar
  17. 17.
    Yoo EH, Lee SY (2010) Glucose biosensors: an overview of use in clinical practice. Sensors 10(5):4558–4576CrossRefGoogle Scholar
  18. 18.
    Kissinger PT (2005) Biosensors-a perspective. Biosens Bioelectron 20(12):2512–2516CrossRefGoogle Scholar
  19. 19.
    Yu B, Wang C, Ju YM, West L, Harmon J, Moussy Y, Moussy F (2008) Use of hydrogel coating to improve the performance of implanted glucose sensors. Biosens Bioelectron 23(8):1278–1284CrossRefGoogle Scholar
  20. 20.
    Bahram M, Mohseni N, Moghtader M (2016) An introduction to hydrogels and some recent applications. In: Sutapa BM (ed) Emerging concepts in analysis and applications of hydrogels, pp 9–38. Intech, LondonGoogle Scholar
  21. 21.
    Wang Y, Huang F, Sun Y, Gao M, Chai Z (2017) Development of shell cross-linked nanoparticles based on boronic acid-related reactions for self-regulated insulin delivery. J Biomat Sci Polym Ed 28(1):93–106CrossRefGoogle Scholar
  22. 22.
    Gallei M, Rüttiger C (2018) Recent trends in metallopolymer design: redox-controlled surfaces, porous membranes, and switchable optical materials using ferrocene-containing polymers. Chem A Eur J 24(40):10006–10021CrossRefGoogle Scholar
  23. 23.
    Katz E (2017) Enzyme-based logic gates and networks with output signals analyzed by various methods. ChemPhysChem 18(13):1688–1713CrossRefGoogle Scholar
  24. 24.
    Sung D, Yang S (2014) Facile method for constructing an effective electron transfer mediating layer using ferrocene-containing multifunctional redox copolymer. Electrochim Acta 133:40–48CrossRefGoogle Scholar
  25. 25.
    Wang JY, Chen LC, Ho KC (2013) Synthesis of redox polymer nanobeads and nanocomposites for glucose biosensors. ACS Appl Mater Interfaces 5(16):7852–7861CrossRefGoogle Scholar
  26. 26.
    Feng X, Zhang K, Hempenius MA, Vancso GJ (2015) Organometallic polymers for electrode decoration in sensing applications. RSC Adv 5(129):106355–106376CrossRefGoogle Scholar
  27. 27.
    Li X, Zhou Y, Zheng Z, Yue X, Dai Z, Liu S, Tang Z (2009) Glucose biosensor based on nanocomposite films of CdTe quantum dots and glucose oxidase. Langmuir 25(11):6580–6586CrossRefGoogle Scholar
  28. 28.
    Yin R, Tong Z, Yang D, Nie J (2011) Glucose and pH dual-responsive concanavalin a based microhydrogels for insulin delivery. Int J Biol Macromol 49(5):1137–1142CrossRefGoogle Scholar
  29. 29.
    Wu Q, Wang L, Yu H, Wang J, Chen Z (2011) Organization of glucose-responsive systems and their properties. Chem Rev 111(12):7855–7875CrossRefGoogle Scholar
  30. 30.
    Gu Z, Aimetti AA, Wang Q et al (2013) Injectable nano-network for glucose-mediated insulin delivery. ACS Nano 7(5):4194–4201CrossRefGoogle Scholar
  31. 31.
    Guan Y, Zhang Y (2013) Boronic acid-containing hydrogels: synthesis and their applications. Chem Soc Rev 42(20):8106–8121CrossRefGoogle Scholar
  32. 32.
    Brooks WLA, Sumerlin BS (2016) Synthesis and applications of boronic acid-containing polymers: from materials to medicine. Chem Rev 116(3):1375–1397CrossRefGoogle Scholar
  33. 33.
    Fossey JS, D’Hooge F, van den Elsen JMH, Pereira M, Marta P, Pascu SI, Bull SD, Marken F, Jenkins A, Toby A, Jiang YB, James TD (2012) The development of boronic acids as sensors and separation tools. Chem Rec 12(5):464–478CrossRefGoogle Scholar
  34. 34.
    Yingyu Li SZ (2013) A simple method to fabricate fluorescent glucose sensor based on dye-complexed microgels. Sens Actuators B Chem 177:792–799CrossRefGoogle Scholar
  35. 35.
    Kim EY, Dryer SE (2011) Effects of insulin and high glucose on mobilization of slo1 BKCa channels in podocytes. J Cell Physiol 226(9):2307–2315CrossRefGoogle Scholar
  36. 36.
    Yetisen AK (2015) Holographic sensors. Springer, ChamCrossRefGoogle Scholar
  37. 37.
    Ruan JL, Chen C, Shen JH, Zhao XL, Qian SH, Zhu ZG (2017) A gelated colloidal crystal attached lens for noninvasive continuous monitoring of tear glucose. Polymers 9(4):125CrossRefGoogle Scholar
  38. 38.
    Tierney S, Volden S, Stokke BT (2009) Glucose sensors based on a responsive gel incorporated as a fabry-perot cavity on a fiber-optic readout platform. Biosens Bioelectron 24(7):2034–2039CrossRefGoogle Scholar
  39. 39.
    Shibata H, Heo YJ, Okitsu T, Matsunaga Y, Kawanishi T, Takeuchi S (2010) Injectable hydrogel microbeads for fluorescence-based in vivo continuous glucose monitoring. PNAS 107(42):17894–17898CrossRefGoogle Scholar
  40. 40.
    Wu W, Zhou T, Shen J, Zhou S (2009) Optical detection of glucose by CdS quantum dots immobilized in smart microgels. Chem Commun 29:4390–4392CrossRefGoogle Scholar
  41. 41.
    Kajisa T, Sakata T (2017) Glucose-responsive hydrogel electrode for biocompatible glucose transistor. Sci Technol Adv Mater 18(1):26–33CrossRefGoogle Scholar
  42. 42.
    Yetisen AK, Jiang N, Fallahi A, Montelongo Y, Ruiz-Esparza GU, Tamayol A, Zhang YS, Mahmood I, Yang SA, Kim KS, Butt H, Khademhosseini A, Yun SH (2017) Glucose-sensitive hydrogel optical fibers functionalized with phenylboronic acid. Adv Mater 29(15):1606380CrossRefGoogle Scholar
  43. 43.
    Heo YJ, Shibata H, Okitsu T, Kawanishi T, Takeuchi S (2011) Long-term in vivo glucose monitoring using fluorescent hydrogel fibers. PNAS 108(33):13399–13403CrossRefGoogle Scholar
  44. 44.
    Badugu R, Lakowicz JR, Geddes CD (2005) A glucose-sensing contact lens: from bench top to patient. Curr Opin Biotechnol 16(1):100–107CrossRefGoogle Scholar
  45. 45.
    Yan Z, Xue M, He Q, Lu W, Meng Z, Yan D, Qiu L, Zhou L, Yu Y (2016) A non-enzymatic urine glucose sensor with 2-D photonic crystal hydrogel. Anal Bioanall Chem 408(29):8317–8323CrossRefGoogle Scholar
  46. 46.
    Kataoka K, Miyazaki H, Bunya M, Okano T, Sakurai Y (1998) Totally synthetic polymer gels responding to external glucose concentration: their preparation and application to on − off regulation of insulin release. J Am Chem Soc 120(48):12694–12695CrossRefGoogle Scholar
  47. 47.
    Matsumoto A, Yoshida R, Kataoka K (2004) Glucose-responsive polymer gel bearing phenylborate derivative as a glucose-sensing moiety operating at the physiological pH. Biomacromol 5(3):1038–1045CrossRefGoogle Scholar
  48. 48.
    Ancla C, Lapeyre V, Gosse I, Catargi B, Ravaine V (2011) Designed glucose-responsive microgels with selective shrinking behavior. Langmuir 27(20):12693–12701CrossRefGoogle Scholar
  49. 49.
    Cheng R, Meng F, Deng C, Klok HA, Zhong Z (2013) Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery. Biomaterials 34(14):3647–3657CrossRefGoogle Scholar
  50. 50.
    Kharkar PM, Kiick KL, Kloxin AM (2013) Designing degradable hydrogels for orthogonal control of cell microenvironments. Chem Soc Rev 42(17):7335–7372CrossRefGoogle Scholar
  51. 51.
    Zhang SB, Chu LY, Xu D, Zhang J, Ju XJ, Rui X (2008) Poly(N-isopropylacrylamide)-based comb-type grafted hydrogel with rapid response to blood glucose concentration change at physiological temperature. Polym Adv Technol 19:937–943CrossRefGoogle Scholar
  52. 52.
    Yoshida R, Uchida K, Kaneko Y, Sakai K, Kikuchi A, Sakurai Y, Okano T (1995) Comb-type grafted hydrogels with rapid deswelling response to temperature changes. Nature 374(6519):240–242CrossRefGoogle Scholar
  53. 53.
    Xu XD, Zhang XZ, Yang J, Cheng SX, Zhuo RX, Huang YQ (2007) Strategy to introduce a pendent micellar structure into poly(N-isopropylacrylamide) hydrogels. Langmuir 23(8):4231–4236CrossRefGoogle Scholar
  54. 54.
    Sun JY, Zhao X, Illeperuma WRK, Chaudhuri O, Oh KH, Mooney DJ, Vlassak JJ, Suo Z (2012) Highly stretchable and tough hydrogels. Nature 489(7414):133–136CrossRefGoogle Scholar
  55. 55.
    Haraguchi K, Li HJ (2005) Control of the coil-to-globule transition and ultrahigh mechanical properties of pnipa in nanocomposite hydrogels. Angew Chem Int Ed 44(40):6500–6504CrossRefGoogle Scholar
  56. 56.
    Xia LW, Xie R, Ju XJ, Wang W, Chen Q, Chu LY (2013) Nano-structured smart hydrogels with rapid response and high elasticity. Nat Commun 4:2226CrossRefGoogle Scholar
  57. 57.
    Gao H, Wang N, Hu X, Nan W, Han Y, Liu W (2013) Double hydrogen-bonding ph-sensitive hydrogels retaining high-strengths over a wide pH range. Macromol Rapid Commun 34(1):63–68CrossRefGoogle Scholar
  58. 58.
    Zhang MJ, Wang W, Xie R, Ju XJ, Liu L, Gu YY (2013) Microfluidic fabrication of monodisperse microcapsules for glucose-response at physiological temperature. Soft Matter 9(16):4150–4159CrossRefGoogle Scholar
  59. 59.
    Pelton RH, Chibante P (1986) Preparation of aqueous latices with N-isopropylacrylamide. Colloid Surf 20(3):247–256CrossRefGoogle Scholar
  60. 60.
    McPhee W, Tam KC, Pelton R (1993) Poly(N-isopropylacrylamide) latices prepared with sodium dodecyl sulfate. J Colloid Interface Sci 156(1):24–30CrossRefGoogle Scholar
  61. 61.
    Wolff HJM, Kather M, Breisig H, Richtering W, Pich A, Wessling M (2018) From batch to continuous precipitation polymerization of thermoresponsive microgels. ACS Appl Mater Interfaces 10(29):24799–24806CrossRefGoogle Scholar
  62. 62.
    Guillermo A, Cohen Addad JP, Bazile JP, Duracher D, Elaissari A, Pichot C (2000) NMR investigations into heterogeneous structures of thermosensitive microgel particles. J Polym Sci Part B Polym Phys 38(6):889–898CrossRefGoogle Scholar
  63. 63.
    Zhang S, Shi Z, Xu H, Ma X, Yin J, Tian M (2016) Revisiting the mechanism of redox-polymerization to build the hydrogel with excellent properties using a novel initiator. Soft Matter 12(9):2575–2582CrossRefGoogle Scholar
  64. 64.
    Feng XD, Guo XQ, Qiu KY (1988) Study of the initiation mechanism of the vinyl polymerization with the system persulfate/N, N, N′, N′-tetramethylethylenediamine. Die Makromol Chem 189(1):77–83CrossRefGoogle Scholar
  65. 65.
    Cheng CJ, Chu LY, Zhang J, Wang HD, Wei G (2008) Effect of freeze-drying and rehydrating treatment on the thermo-responsive characteristics of poly(N-isopropylacrylamide) microspheres. Colloid Polym Sci 286(5):571–577CrossRefGoogle Scholar
  66. 66.
    Kang HW, Tabata Y, Ikada Y (1999) Fabrication of porous gelatin scaffolds for tissue engineering. Biomaterials 20(14):1339–1344CrossRefGoogle Scholar
  67. 67.
    Tenório-Neto ET, Lima DdS, Guilherme MR, Lima-Tenório MK, Scariot DB, Nakamura CV, Kunita MH, Rubira AF (2017) Synthesis and drug release profile of a dual-responsive poly(ethylene glycol) hydrogel nanocomposite. RSC Adv 7(44):27637–27644CrossRefGoogle Scholar
  68. 68.
    Fujishige S, Kubota K, Ando I (1989) Phase transition of aqueous solutions of poly(N-isopropylacrylamide) and poly(N-isopropylmethacrylamide). J Phys Chem 93(8):3311–3313CrossRefGoogle Scholar
  69. 69.
    Tanaka T (1986) Kinetics of phase transition in polymer gels. Phys A 140(1):261–268CrossRefGoogle Scholar
  70. 70.
    Chiessi E, Lonardi A, Paradossi G (2010) Toward modeling thermoresponsive polymer networks: a molecular dynamics simulation study of N-isopropyl acrylamide co-oligomers. J Phys Chem B 114(25):8301–8312CrossRefGoogle Scholar
  71. 71.
    Oliveira TEd, Mukherji D, Kremer K, Netz PA (2017) Effects of stereochemistry and copolymerization on the lcst of pnipam. J Chem Phys 146(3):034904CrossRefGoogle Scholar
  72. 72.
    Xu H, Meng F, Zhong Z (2009) Reversibly crosslinked temperature-responsive nano-sized polymersomes: synthesis and triggered drug release. J Mater Chem 19(24):4183–4190CrossRefGoogle Scholar
  73. 73.
    Brooks WLA, Vancoillie G, Kabb CP, Hoogenboom R, Sumerlin BS (2017) Triple responsive block copolymers combining pH-responsive, thermoresponsive, and glucose-responsive behaviors. J Polym Sci Pol Chem 55(14):2309–2317CrossRefGoogle Scholar
  74. 74.
    Morawetz H (1974) Pure Appl Chem 38:267–277CrossRefGoogle Scholar
  75. 75.
    Sawant S, Morawetz H (1984) Microstructure, neighboring group inhibition, and electrostatic effects in the base-catalyzed degradation of polyacrylamide. Macromolecules 17(11):2427–2431CrossRefGoogle Scholar
  76. 76.
    Xing S, Guan Y, Zhang Y (2011) Kinetics of glucose-induced swelling of p(nipam-aapba) microgels. Macromolecules 44(11):4479–4486CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.State Key Laboratory of Chemical Engineering, College of Chemical and Biological EngineeringZhejiang UniversityHangzhouPeople’s Republic of China

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