Hydrogels: Stimuli Responsive to on-Demand Drug Delivery Systems

  • Arti VashistEmail author
  • Ajeet Kaushik
  • Rahul Dev Jayant
  • Atul Vashist
  • Anujit Ghosal
  • Madhavan NairEmail author


Hydrogels are the three dimensional crosslinked network of polymeric materials, which have the ability to respond and adapt to the surrounding environment inside the human body. Hydrogels are the upcoming class of biomaterials, which act as excellent drug delivery systems. These materials have important characteristic feature that they respond to various external stimuli like pH, light, temperature, magnetic field, electric field and pressure. Present chapter gives a broad overview of the recent hydrogels used for drug delivery using various external stimuli. Concluding remarks and viewpoints for the future development of stimuli responsive hydrogels are addressed.


pH responsive Hydrogels Stimuli responsive Drug delivery Thermosensitive hydrogels 



Authors acknowledge NIH grants: RO1DA027049, R21MH 101,025, RO1DA 034547, R01DA037838, and 1R01DA040537.

Conflict of Interest

Authors declare no conflict of interest.


  1. 1.
    Vashist A, Ahmad S. Hydrogels: smart materials for drug delivery. Orient J Chem. 2013;29:861–70.CrossRefGoogle Scholar
  2. 2.
    Vashist A, Vashist A, Gupta Y, Ahmad S. Recent advances in hydrogel based drug delivery systems for the human body. J Mater Chem B. 2014;2:147–66.CrossRefGoogle Scholar
  3. 3.
    Gupta P, Vermani K, Garg S. Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discov Today. 2002;7:569–79.CrossRefPubMedGoogle Scholar
  4. 4.
    Jing G, Wang L, Yu H, Amer WA, Zhang L. Recent progress on study of hybrid hydrogels for water treatment. Colloids Surf A Physicochem Eng Asp. 2013;416:86–94.CrossRefGoogle Scholar
  5. 5.
    Hoare TR, Kohane DS. Hydrogels in drug delivery: progress and challenges. Polymer. 2008;49:1993–2007.CrossRefGoogle Scholar
  6. 6.
    Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM. Polymeric systems for controlled drug release. Chem Rev. 1999;99:3181–98.CrossRefPubMedGoogle Scholar
  7. 7.
    Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat Mater. 2013;12:991–1003.CrossRefPubMedGoogle Scholar
  8. 8.
    Lin C-C, Metters AT. Hydrogels in controlled release formulations: network design and mathematical modeling. Adv Drug Deliv Rev. 2006;58:1379–408.CrossRefPubMedGoogle Scholar
  9. 9.
    Vashist A, Ahmad S. Hydrogels in tissue engineering: scope and applications. Curr Pharm Biotechnol. 2015;16:606–20.CrossRefPubMedGoogle Scholar
  10. 10.
    Wei Q, Xu M, Liao C, Wu Q, Liu M, Zhang Y, et al. Printable hybrid hydrogel by dual enzymatic polymerization with superactivity. Chem Sci. 2016;7:2748–52.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Li L, Shi Y, Pan L, Shi Y, Yu G. Rational design and applications of conducting polymer hydrogels as electrochemical biosensors. J Mater Chem B. 2015;3:2920–30.CrossRefGoogle Scholar
  12. 12.
    Merino S, Martín C, Kostarelos K, Prato M, Vázquez E. Nanocomposite hydrogels: 3D polymer–nanoparticle synergies for on-demand drug delivery. ACS Nano. 2015;9:4686–97.CrossRefPubMedGoogle Scholar
  13. 13.
    Tabujew I, Peneva K. Functionalization of cationic polymers for drug delivery applications. In: Samal SK, Dubruel P, editors. Cationic polymers in regenerative medicine. Cambridge: Royal Society of Chemistry; 2014.Google Scholar
  14. 14.
    Watkins KA, Chen R. pH-responsive, lysine-based hydrogels for the oral delivery of a wide size range of molecules. Int J Pharm. 2015;478:496–503.CrossRefPubMedGoogle Scholar
  15. 15.
    Li L, Gu J, Zhang J, Xie Z, Lu Y, Shen L, et al. Injectable and biodegradable pH-responsive hydrogels for localized and sustained treatment of human fibrosarcoma. ACS Appl Mater Interfaces. 2015;7:8033–40.CrossRefPubMedGoogle Scholar
  16. 16.
    Song HS, Kwon OS, Kim J-H, Conde J, Artzi N. 3D hydrogel scaffold doped with 2D graphene materials for biosensors and bioelectronics. Biosens Bioelectron. 2017;89:187–200.CrossRefPubMedGoogle Scholar
  17. 17.
    Campbell S, Maitland D, Hoare T. Enhanced pulsatile drug release from injectable magnetic hydrogels with embedded thermosensitive microgels. ACS Macro Lett. 2015;4:312–6.CrossRefGoogle Scholar
  18. 18.
    Li Y, Huang G, Zhang X, Li B, Chen Y, Lu T, et al. Magnetic hydrogels and their potential biomedical applications. Adv Funct Mater. 2013;23:660–72.CrossRefGoogle Scholar
  19. 19.
    Sapir Y, Cohen S, Friedman G, Polyak B. The promotion of in vitro vessel-like organization of endothelial cells in magnetically responsive alginate scaffolds. Biomaterials. 2012;33:4100–9.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Zhang Y, Yang B, Zhang X, Xu L, Tao L, Li S, et al. A magnetic self-healing hydrogel. Chem Commun. 2012;48:9305–7.CrossRefGoogle Scholar
  21. 21.
    Liu T-Y, Hu S-H, Liu T-Y, Liu D-M, Chen S-Y. Magnetic-sensitive behavior of intelligent ferrogels for controlled release of drug. Langmuir. 2006;22:5974–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Szabo D, Szeghy G, Zrinyi M. Shape transition of magnetic field sensitive polymer gels. Macromolecules. 1998;31:6541–8.CrossRefGoogle Scholar
  23. 23.
    Snyder R, Nguyen V, Ramanujan R. Design parameters for magneto-elastic soft actuators. Smart Mater Struct. 2010;19:055017.CrossRefGoogle Scholar
  24. 24.
    Fuhrer R, Athanassiou EK, Luechinger NA, Stark WJ. Crosslinking metal nanoparticles into the polymer backbone of hydrogels enables preparation of soft, magnetic field-driven actuators with muscle-like flexibility. Small. 2009;5:383–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Liu T-Y, Hu S-H, Liu D-M, Chen S-Y, Chen I-W. Biomedical nanoparticle carriers with combined thermal and magnetic responses. Nano Today. 2009;4:52–65.CrossRefGoogle Scholar
  26. 26.
    Kost J, Wolfrum J, Langer R. Magnetically enhanced insulin release in diabetic rats. J Biomed Mater Res. 1987;21:1367–73.CrossRefPubMedGoogle Scholar
  27. 27.
    Ang K, Venkatraman S, Ramanujan R. Magnetic PNIPA hydrogels for hyperthermia applications in cancer therapy. Mater Sci Eng C. 2007;27:347–51.CrossRefGoogle Scholar
  28. 28.
    Le Renard P-E, Jordan O, Faes A, Petri-Fink A, Hofmann H, Ruefenacht D, et al. The in vivo performance of magnetic particle-loaded injectable, in situ gelling, carriers for the delivery of local hyperthermia. Biomaterials. 2010;31:691–705.CrossRefPubMedGoogle Scholar
  29. 29.
    McKenzie M, Betts D, Suh A, Bui K, Kim LD, Cho H. Hydrogel-based drug delivery systems for poorly water-soluble drugs. Molecules. 2015;20:20397–408.CrossRefPubMedGoogle Scholar
  30. 30.
    Nguyen MK, Lee DS. Injectable biodegradable hydrogels. Macromol Biosci. 2010;10:563–79.CrossRefPubMedGoogle Scholar
  31. 31.
    Wu Q, Wang N, He T, Shang J, Li L, Song L, et al. Thermosensitive hydrogel containing dexamethasone micelles for preventing postsurgical adhesion in a repeated-injury model. Sci Rep. 2015;5:13553.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Fusco S, Borzacchiello A, Netti P. Perspectives on: PEO-PPO-PEO triblock copolymers and their biomedical applications. J Bioact Compat Polym. 2006;21:149–64.CrossRefGoogle Scholar
  33. 33.
    Jeong B, Bae YH, Kim SW. In situ gelation of PEG-PLGA-PEG triblock copolymer aqueous solutions and degradation thereof. J Biomed Mater Res. 2000;50:171–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Yan S, Zhang X, Zhang K, Di H, Feng L, Li G, et al. Injectable in situ forming poly (l-glutamic acid) hydrogels for cartilage tissue engineering. J Mater Chem B. 2016;4:947–61.CrossRefGoogle Scholar
  35. 35.
    Tahrir FG, Ganji F, Ahooyi TM. Injectable Thermosensitive chitosan/Glycerophosphate-based hydrogels for tissue engineering and drug delivery applications: a review. Recent Pat Drug Deliv Formul. 2015;9:107–20.CrossRefPubMedGoogle Scholar
  36. 36.
    Cho J, Heuzey M-C, Bégin A, Carreau PJ. Physical gelation of chitosan in the presence of β-glycerophosphate: the effect of temperature. Biomacromolecules. 2005;6:3267–75.CrossRefPubMedGoogle Scholar
  37. 37.
    Cho J, Heuzey M-C, Bégin A, Carreau PJ. Chitosan and glycerophosphate concentration dependence of solution behaviour and gel point using small amplitude oscillatory rheometry. Food Hydrocoll. 2006;20:936–45.CrossRefGoogle Scholar
  38. 38.
    Zhou HY, Jiang LJ, Cao PP, Li JB, Chen XG. Glycerophosphate-based chitosan thermosensitive hydrogels and their biomedical applications. Carbohydr Polym. 2015;117:524–36.CrossRefPubMedGoogle Scholar
  39. 39.
    Crompton K, Goud J, Bellamkonda R, Gengenbach T, Finkelstein D, Horne M, et al. Polylysine-functionalised thermoresponsive chitosan hydrogel for neural tissue engineering. Biomaterials. 2007;28:441–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Elad D, Wolf M, Keck T. Air-conditioning in the human nasal cavity. Respir Physiol Neurobiol. 2008;163:121–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Mygind N, Dahl R. Anatomy, physiology and function of the nasal cavities in health and disease. Adv Drug Deliv Rev. 1998;29:3–12.CrossRefPubMedGoogle Scholar
  42. 42.
    Nazar H, Fatouros DG, van der Merwe SM, Bouropoulos N, Avgouropoulos G, Tsibouklis J, et al. Thermosensitive hydrogels for nasal drug delivery: the formulation and characterisation of systems based on N-trimethyl chitosan chloride. Eur J Pharm Biopharm. 2011;77:225–32.CrossRefPubMedGoogle Scholar
  43. 43.
    Gou M, Li X, Dai M, Gong C, Wang X, Xie Y, et al. A novel injectable local hydrophobic drug delivery system: biodegradable nanoparticles in thermo-sensitive hydrogel. Int J Pharm. 2008;359:228–33.CrossRefPubMedGoogle Scholar
  44. 44.
    Di J, Yao S, Ye Y, Cui Z, Yu J, Ghosh TK, et al. Stretch-triggered drug delivery from wearable elastomer films containing therapeutic depots. ACS Nano. 2015;9:9407–15.CrossRefPubMedGoogle Scholar
  45. 45.
    Lee K, Cussler E, Marchetti M, McHugh M. Pressure-dependent phase transitions in hydrogels. Chem Eng Sci. 1990;45:766–7.CrossRefGoogle Scholar
  46. 46.
    Zhong X, Wang Y-X, Wang S-C. Pressure dependence of the volume phase-transition of temperature-sensitive gels. Chem Eng Sci. 1996;51:3235–9.CrossRefGoogle Scholar
  47. 47.
    Rosenthal A, Barry JJ, Sahatjian R. Triggered release hydrogel drug delivery system. Google Patents, 2003.Google Scholar
  48. 48.
    Yuk SH, Cho SH, Lee HB. Electric current-sensitive drug delivery systems using sodium alginate/polyacrylic acid composites. Pharm Res. 1992;09:955–7.CrossRefGoogle Scholar
  49. 49.
    Kwon IC, Bae YH, Kim SW. Electrically credible polymer gel for controlled release of drugs. Nature. 1991;354:291.CrossRefPubMedGoogle Scholar
  50. 50.
    Delgado-Charro MB, Guy RH. Transdermal iontophoresis for controlled drug delivery and non-invasive monitoring. STP Pharma Sci. 2001;11:404–14.Google Scholar
  51. 51.
    Vanbever R, Preat V. In vivo efficacy and safety of skin electroporation. Adv Drug Deliv Rev. 1999;35:77–88.CrossRefPubMedGoogle Scholar
  52. 52.
    Murdan S. Electro-responsive drug delivery from hydrogels. J Control Release. 2003;92:1–17.CrossRefPubMedGoogle Scholar
  53. 53.
    Tanaka T, Nishio I, Sun S-T, Ueno-Nishio S. Collapse of gels in an electric field. Science. 1982;218:467–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Tomer R, Dimitrijevic D, Florence AT. Electrically controlled release of macromolecules from cross-linked hyaluronic acid hydrogels. J Control Release. 1995;33:405–13.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Center for Personalized Nanomedicine, Institute of Neuro immune PharmacologyDepartment of Immunology, Herbert Wertheim College of Medicine, Florida International UniversityMiamiUSA
  2. 2.Department of BiotechnologyAll India Institute Medical SciencesNew DelhiIndia
  3. 3.Department of Chemistry, School of Basic and Applied SciencesGalgotias University, Gautam Buddh NagarUttar PradeshIndia
  4. 4.School of BiotechnologyJawaharlal Nehru UniversityNew DelhiIndia

Personalised recommendations