Stimuli-responsive, smart, or intelligent polymers are materials that significantly change their physical or chemical properties when there is a small change in the surrounding environment due to either internal or external stimuli. In the last two decades or so, there has been tremendous growth in the strategies to develop various types of stimuli-responsive polymer (SRP) materials/systems that are suitable for various fields, including biomedical, material science, nanotechnology, biotechnology, surface and colloid sciences, biochemistry, and the environmental field. The wide acceptability of SRPs is due to their availability in different architectural forms such as scaffolds, aggregates, hydrogels, pickering emulsions, core-shell particles, nanogels, micelles, membranes, capsules, and layer-by-layer films. The present review focuses on different types of SRPs, such as physical, chemical, and biological, and various important applications, including controlled drug delivery (CDD), stabilization of colloidal dispersion, diagnostics (sensors and imaging), tissue engineering, regenerative medicines, and actuators. The applications of SRPs have immense potential in various fields, and the author hopes these polymers will add a new field of applications through new concepts.

stimuli-responsive polymer; scaffold; nanogel; actuator; artificial muscle; gripper

1. Parhi R. Drug delivery applications of chitin and chitosan: A review. Environmental Chemistry Letters 2020; 18(3): 577–594. doi: 10.1007/s10311-020-00963-5

2. Chen JK, Chang CJ. Fabrications and applications of stimulus-responsive polymer films and patterns on surfaces: A review. Materials 2014; 7(2): 805–875. doi: 10.3390/ma7020805

3. Cabane E, Zhang X, Langowska K, et al. Stimuli-responsive polymers and their applications in nanomedicine. Biointerphases 2012; 7(1). doi: 10.1007/s13758-011-0009-3

4. Chen Z, Huo J, Hao L, et al. Multiscale modeling and simulations of responsive polymers. Current Opinion in Chemical Engineering 2019; 23: 21–33. doi: 10.1016/j.coche.2019.02.004

5. Lee W, Kim D, Lee S, et al. Stimuli-responsive switchable organic-inorganic nanocomposite materials. Nano Today 2018; 23: 97–123. doi: 10.1016/j.nantod.2018.10.006

6. Alejo T, Uson L, Arruebo M. Reversible stimuli-responsive nanomaterials with on-off switching ability for biomedical applications. Journal of Controlled Release 2019; 314: 162–176. doi: 10.1016/j.jconrel.2019.10.036

7. Fleischmann E, Zentel R. Liquid‐crystalline ordering as a concept in materials science: From semiconductors to stimuli‐responsive devices. Angewandte Chemie International Edition 2013; 52(34): 8810–8827. doi: 10.1002/anie.201300371

8. Koçak G, Tuncer C, Bütün V. Stimuli-responsive polymers providing new opportunities for various applications. Hacettepe Journal of Biology and Chemistry 2020; 48(5): 527–574. doi: 10.15671/hjbc.811267

9. Qureshi D, Nayak SK, Maji S, et al. Environment sensitive hydrogels for drug delivery applications. European Polymer Journal 2019; 120: 109220. doi: 10.1016/j.eurpolymj.2019.109220

10. Roy D, Cambre JN, Sumerlin BS. Future perspectives and recent advances in stimuli-responsive materials. Progress in Polymer Science 2010; 35(1–2): 278–301. doi: 10.1016/j.progpolymsci.2009.10.008

11. Nawaz M, Sliman Y, Ercan I, et al. Magnetic and pH-responsive magnetic nanocarriers. In: Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications. Woodhead Publishing; 2019. pp. 37–85. doi: 10.1016/b978-0-08-101995-5.00002-7

12. Koçak G, Tuncer C, Bütün V. pH-responsive polymers. Polymer Chemistry 2017; 8(1): 144–176. doi: 10.1039/c6py01872f

13. Liu H, Lin S, Feng Y, et al. CO2-responsive polymer materials. Polymer Chemistry 2017; 8(1): 12–23. doi: 10.1039/c6py01101b

14. Xiang T, Lu T, Zhao WF, et al. Ionic strength- and thermo-responsive polyethersulfone composite membranes with enhanced antifouling properties. New Journal of Chemistry 2018; 42(7): 5323–5333. doi: 10.1039/c8nj00039e

15. Corpart JM, Candau F. Aqueous solution properties of ampholytic copolymers prepared in microemulsions. Macromolecules 1993; 26(6): 1333–1343. doi: 10.1021/ma00058a023

16. Casado N, Hernández G, Sardon H, et al. Current trends in redox polymers for energy and medicine. Progress in Polymer Science 2016; 52: 107–135. doi: 10.1016/j.progpolymsci.2015.08.003

17. Wang J, Zhang H, Wang F, et al. Enzyme-responsive polymers for drug delivery and molecular imaging. In: Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications. Woodhead Publishing. Elsevier Inc.; 2018. doi: 10.1016/b978-0-08-101997-9.00004-7

18. Sharifzadeh G, Hosseinkhani H. Biomolecule‐responsive hydrogels in medicine. Advanced Healthcare Materials 2017; 6(24). doi: 10.1002/adhm.201700801

19. Wang C, Wang J, Zhang X, et al. In situ formed reactive oxygen species–responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy. Science Translational Medicine 2018; 10(429). doi: 10.1126/scitranslmed.aan3682

20. Sanhai WR, Sakamoto JH, Canady R, et al. Seven challenges for nanomedicine. Nature Nanotechnology 2008; 3(5): 242–244. doi: 10.1038/nnano.2008.114

21. Lee JH. Injectable hydrogels delivering therapeutic agents for disease treatment and tissue engineering. Biomaterials Research 2018; 22(1). doi: 10.1186/s40824-018-0138-6

22. Ahmadi A, Hosseini-Nami S, Abed Z, et al. Recent advances in ultrasound-triggered drug delivery through lipid-based nanomaterials. Drug Discovery Today 2020; 25(12): 2182–2200. doi: 10.1016/j.drudis.2020.09.026

23. Massoumi B, Abbasian M, Jahanban‐Esfahlan R, et al. PEGylated hollow pH‐responsive polymeric nanocapsules for controlled drug delivery. Polymer International 2020; 69(5): 519–527. doi: 10.1002/pi.5987

24. Guo S, Gao Y, Wei M, et al. Controlled release kinetics from a surface modified microgel-based reservoir device. Journal of Materials Chemistry B 2015; 3(12): 2516–2521. doi: 10.1039/c4tb01964d

25. Gao Y, Wong KY, Ahiabu A, et al. Sequential and controlled release of small molecules from poly(N-isopropylacrylamide) microgel-based reservoir devices. Journal of Materials Chemistry B 2016; 4(30): 5144–5150. doi: 10.1039/c6tb00864j

26. Lee ES, Kim D, Youn YS, et al. A virus‐mimetic nanogel vehicle. Angewandte Chemie International Edition 2008; 47(13): 2418–2421. doi: 10.1002/anie.200704121

27. Zhu X, Sun Y, Chen D, et al. Mastocarcinoma therapy synergistically promoted by lysosome dependent apoptosis specifically evoked by 5-Fu@nanogel system with passive targeting and pH activatable dual function. Journal of Controlled Release 2017; 254: 107–118. doi: 10.1016/j.jconrel.2017.03.038

28. Dimde M, Neumann F, Reisbeck F, et al. Defined pH-sensitive nanogels as gene delivery platform for siRNA mediated in vitro gene silencing. Biomaterials Science 2017; 5(11): 2328–2336. doi: 10.1039/c7bm00729a

29. Parhi R, Suresh P, Patnaik S. Physical means of stratum corneum barrier manipulation to enhance transdermal drug delivery. Current Drug Delivery 2015; 12(2): 122–138. doi: 10.2174/1567201811666140515145329

30. Hardy JG, Larrañeta E, Donnelly RF, et al. Hydrogel-forming microneedle arrays made from light-responsive materials for on-demand transdermal drug delivery. Molecular Pharmaceutics 2016; 13(3): 907–914. doi: 10.1021/acs.molpharmaceut.5b00807

31. Chen S, Matsumoto H, Moro‐oka Y, et al. Microneedle‐array patch fabricated with enzyme‐free polymeric components capable of on‐demand insulin delivery. Advanced Functional Materials 2018; 29(7). doi: 10.1002/adfm.201807369

32. Yu J, Zhang Y, Ye Y, et al. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proceedings of the National Academy of Sciences 2015; 112(27): 8260–8265. doi: 10.1073/pnas.1505405112

33. Mir M, Permana AD, Ahmed N, et al. Enhancement in site-specific delivery of carvacrol for potential treatment of infected wounds using infection responsive nanoparticles loaded into dissolving microneedles: A proof of concept study. European Journal of Pharmaceutics and Biopharmaceutics 2020; 147: 57–68. doi: 10.1016/j.ejpb.2019.12.008

34. Qin S, Geng Y, Discher DE, et al. Temperature‐controlled assembly and release from polymer vesicles of poly(ethylene oxide)‐block‐ poly(N‐isopropylacrylamide). Advanced Materials 2006; 18(21): 2905–2909. doi: 10.1002/adma.200601019

35. Collins J, Bhaskaran A, Connal LA. Polymerosomes for drug delivery. Material Matters 2017; 12(1).

36. Wang X, Hu J, Liu G, et al. Reversibly switching bilayer permeability and release modules of photochromic polymersomes stabilized by cooperative noncovalent interactions. Journal of the American Chemical Society 2015; 137(48): 15262–15275. doi: 10.1021/jacs.5b10127

37. Chi X, Ji X, Xia D, et al. A dual-responsive supra-amphiphilic polypseudorotaxane constructed from a water-soluble pillar[7]arene and an azobenzene-containing random copolymer. Journal of the American Chemical Society 2015; 137(4): 1440–1443. doi: 10.1021/ja512978n

38. Wang Y, Luo Q, Zhu W, et al. Reduction/pH dual-responsive nano-prodrug micelles for controlled drug delivery. Polymer Chemistry 2016; 7(15): 2665–2673. doi: 10.1039/c6py00168h

39. Ye G, Jiang Y, Yang X, et al. Smart nanoparticles undergo phase transition for enhanced cellular uptake and subsequent intracellular drug release in a tumor microenvironment. ACS Applied Materials & Interfaces 2017; 10(1): 278–289. doi: 10.1021/acsami.7b15978

40. Qi X, Qin J, Fan Y, et al. Carboxymethyl chitosan-modified polyamidoamine dendrimer enables progressive drug targeting of tumors via pH-Sensitive charge inversion. Journal of Biomedical Nanotechnology 2016; 12(4): 667–678. doi: 10.1166/jbn.2016.2206

41. Nguyen TL, Nguyen TH, Nguyen CK, et al. Redox and pH responsive poly (amidoamine) dendrimer-heparin conjugates via disulfide linkages for letrozole delivery. BioMed Research International 2017; 2017: 1–7. doi: 10.1155/2017/8589212

42. Zhang C, Pan D, Li J, et al. Enzyme-responsive peptide dendrimer-gemcitabine conjugate as a controlled-release drug delivery vehicle with enhanced antitumor efficacy. Acta Biomaterialia 2017; 55: 153–162. doi: 10.1016/j.actbio.2017.02.047

43. Bijukumar D, Choonara YE, Murugan K, et al. Design of an inflammation-sensitive polyelectrolyte-based topical drug delivery system for arthritis. AAPS PharmSciTech 2015; 17(5): 1075–1085. doi: 10.1208/s12249-015-0434-6

44. Luo Z, Jiang L, Yang S, et al. Light‐induced redox‐responsive smart drug delivery system by using selenium‐containing polymer@MOF shell/core nanocomposite. Advanced Healthcare Materials 2019; 8(15). doi: 10.1002/adhm.201900406

45. Li Y, Zhao R, Hu F, et al. Laponite/lauric arginate stabilized AKD Pickering emulsions with shell-tunable hydrolytic resistance for use in sizing paper. Applied Clay Science 2021; 206: 106085. doi: 10.1016/j.clay.2021.106085

46. Ee Low L, Tan LTH, Goh BH, et al. Magnetic cellulose nanocrystal stabilized Pickering emulsions for enhanced bioactive release and human colon cancer therapy. International Journal of Biological Macromolecules 2019; 127: 76–84. doi: 10.1016/j.ijbiomac.2019.01.037

47. Sun N, Li Q, Luo D, et al. Dual-responsive pickering emulsion stabilized by Fe3O4 nanoparticles hydrophobized in situ with an electrochemical active molecule. Colloids and Surfaces A: Physicochemical and Engineering Aspects 2021; 608: 125588. doi: 10.1016/j.colsurfa.2020.125588

48. Islam MR, Gao Y, Li X, et al. Stimuli-responsive polymeric materials for human health applications. Chinese Science Bulletin 2014; 59(32): 4237–4255. doi: 10.1007/s11434-014-0545-6

49. Bratek-Skicki A. Towards a new class of stimuli-responsive polymer-based materials – Recent advances and challenges. Applied Surface Science Advances 2021; 4: 100068. doi: 10.1016/j.apsadv.2021.100068

50. Bhalla N, Jolly P, Formisano N, Estrela P. Introduction to biosensors. Essays in Biochemistry 2016; 60(1): 1–8. doi: 10.1042/EBC20150001

51. Zhang T, Liu GQ, Leong WH, et al. Hybrid nanodiamond quantum sensors enabled by volume phase transitions of hydrogels. Nature Communications 2018; 9(1). doi: 10.1038/s41467-018-05673-9

52. Yuan W, Wang C, Lei S, et al. Ultraviolet light-, temperature- and pH-responsive fluorescent sensors based on cellulose nanocrystals. Polymer Chemistry 2018; 9(22): 3098–3107. doi: 10.1039/c8py00613j

53. Jia Z, Müller M, Schönherr H. Towards multiplexed bacteria detection by enzyme responsive hydrogels. Macromolecular Symposia 2018; 379(1). doi: 10.1002/masy.201600178

54. Leu HY, Farhoudi N, Reiche C, et al. Low-cost microfluidic sensors with smart hydrogel patterned arrays using electronic resistive channel sensing for readout. Gels 2018; 4(4): 84. doi: 10.3390/gels4040084

55. Chatterjee S, Hui CL. Review of stimuli-responsive polymers in drug delivery and textile application. Molecules 2019; 24(14): 2547. doi: 10.3390/molecules24142547

56. Das SS, Bharadwaj P, Bilal M, et al. Stimuli-responsive polymeric nanocarriers for drug delivery, imaging, and theragnosis. Polymers 2020; 12(6): 1397. doi: 10.3390/polym12061397

57. Yang X, An J, Luo Z, et al. A cyanine-based polymeric nanoplatform with microenvironment-driven cascaded responsiveness for imaging-guided chemo-photothermal combination anticancer therapy. Journal of Materials Chemistry B 2020; 8(10): 2115–2122. doi: 10.1039/c9tb02890k

58. Sun C, Li B, Zhao M, et al. J-aggregates of cyanine dye for NIR-II in vivo dynamic vascular imaging beyond 1500 nm. Journal of the American Chemical Society 2019; 141(49): 19221–19225. doi: 10.1021/jacs.9b10043

59. Yang H, Deng L, Li T, et al. Multifunctional PLGA nanobubbles as theranostic agents: Combining doxorubicin and P-gp siRNA co-delivery into human breast cancer cells and ultrasound cellular imaging. Journal of Biomedical Nanotechnology 2015; 11(12): 2124–2136. doi: 10.1166/jbn.2015.2168

60. Prabhakar A, Banerjee R. Nanobubble liposome complexes for diagnostic imaging and ultrasound-triggered drug delivery in cancers: A theranostic approach. ACS Omega 2019; 4(13): 15567–15580. doi: 10.1021/acsomega.9b01924

61. Shang M, Wang K, Guo L, et al. Development of novel ST68/PLA-PEG stabilized ultrasound nanobubbles for potential tumor imaging and theranostic. Ultrasonics 2019; 99: 105947. doi: 10.1016/j.ultras.2019.105947

62. Vijayan VM, Muthu J. Polymeric nanocarriers for cancer theranostics. Polymers for Advanced Technologies 2017; 28(12): 1572–1582. doi: 10.1002/pat.4070

63. Hu H. Recent advances of bioresponsive nano-sized contrast agents for ultra-high-field magnetic resonance imaging. Frontiers in Chemistry 2020; 8. doi: 10.3389/fchem.2020.00203

64. Bain J, Legge CJ, Beattie DL, et al. A biomimetic magnetosome: Formation of iron oxide within carboxylic acid terminated polymersomes. Nanoscale 2019; 11(24): 11617–11625. doi: 10.1039/c9nr00498j

65. Aouidat F, Boumati S, Khan M, et al. Design and synthesis of gold-gadolinium-core-shell nanoparticles as contrast agent: A smart way to future nanomaterials for nanomedicine applications. International Journal of Nanomedicine 2019; 14: 9309–9324. doi: 10.2147/ijn.s224805

66. Pant K, Sedláček O, Nadar RA, et al. Radiolabelled polymeric materials for imaging and treatment of cancer: Quo vadis? Advanced Healthcare Materials 2017; 6(6). doi: 10.1002/adhm.201601115

67. Sun J, Sun L, Li J, et al. A multi-functional polymeric carrier for simultaneous positron emission tomography imaging and combination therapy. Acta Biomaterialia 2018; 75: 312–322. doi: 10.1016/j.actbio.2018.06.010

68. Sun N, Zhao L, Zhu J, et al. 131I-labeled polyethylenimine-entrapped gold nanoparticles for targeted tumor SPECT/CT imaging and radionuclide therapy. International Journal of Nanomedicine 2019; 14: 4367–4381. doi: 10.2147/ijn.s203259

69. Zhang J, Yang C, Zhang R, et al. Biocompatible D–A semiconducting polymer nanoparticle with light‐harvesting unit for highly effective photoacoustic imaging guided photothermal therapy. Advanced Functional Materials 2017; 27(13). doi: 10.1002/adfm.201605094

70. Lyu Y, Fang Y, Miao Q, et al. Intraparticle molecular orbital engineering of semiconducting polymer nanoparticles as amplified theranostics for in vivo photoacoustic imaging and photothermal therapy. ACS Nano 2016; 10(4): 4472–4481. doi: 10.1021/acsnano.6b00168

71. Parhi R. Applications of chitosan composites in pharmaceutical and food sectors. In: Al-Ahmed A, Inamuddin (editors). Advanced Applications of Polysaccharides and Their Composites. Research Forum LLC.; 2020. pp. 86–135.

72. Lavrador P, Gaspar VM, Mano JF. Stimuli-responsive nanocarriers for delivery of bone therapeutics – Barriers and progresses. Journal of Controlled Release 2018; 273: 51–67. doi: 10.1016/j.jconrel.2018.01.021

73. Levingstone T, Ali B, Kearney C, et al. Hydroxyapatite sonosensitization of ultrasound‐triggered, thermally responsive hydrogels: An on‐demand delivery system for bone repair applications. Journal of Biomedical Materials Research Part B: Applied Biomaterials 2021; 109(10): 1622–1633. doi: 10.1002/jbm.b.34820

74. Ding Y, Hao Y, Yuan Z, et al. A dual-functional implant with an enzyme-responsive effect for bacterial infection therapy and tissue regeneration. Biomaterials Science 2020; 8(7): 1840–1854. doi: 10.1039/c9bm01924c

75. Li X, Bian S, Zhao M, et al. Stimuli-responsive biphenyl-tripeptide supramolecular hydrogels as biomimetic extracellular matrix scaffolds for cartilage tissue engineering. Acta Biomaterialia 2021; 131: 128–137. doi: 10.1016/j.actbio.2021.07.007

76. Liang X, Wang X, Xu Q, et al. Rubbery chitosan/carrageenan hydrogels constructed through an electroneutrality system and their potential application as cartilage scaffolds. Biomacromolecules 2018; 19(2): 340–352. doi: 10.1021/acs.biomac.7b01456

77. Aust L, Devlin B, Foster SJ, et al. Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy 2004; 6(1): 7–14. doi: 10.1080/14653240310004539

78. Li Z, Zhu D, Hui Q, et al. Injection of ROS‐responsive hydrogel loaded with basic fibroblast growth factor into the pericardial cavity for heart repair. Advanced Functional Materials 2021; 31(15). doi: 10.1002/adfm.202004377

79. Malki M, Shapira A, Dvir T. Chondroitin sulfate-AuNRs electroactive scaffolds for on-demand release of biofactors. Journal of Nanobiotechnology 2022; 20(1). doi: 10.1186/s12951-022-01261-8

80. Kim IY, Seo SJ, Moon HS, et al. Chitosan and its derivatives for tissue engineering applications. Biotechnology Advances 2008; 26(1): 1–21. doi: 10.1016/j.biotechadv.2007.07.009

81. Xu C, Guan S, Wang S, et al. Biodegradable and electroconductive poly(3,4-ethylenedioxythiophene)/carboxymethyl chitosan hydrogels for neural tissue engineering. Materials Science and Engineering: C 2018; 84: 32–43. doi: 10.1016/j.msec.2017.11.032

82. Dong M, Shi B, Liu D, et al. Conductive hydrogel for a photothermal-responsive stretchable artificial nerve and coalescing with a damaged peripheral nerve. ACS Nano 2020; 14(12): 16565–16575. doi: 10.1021/acsnano.0c05197

83. Tavakoli S, Klar AS. Bioengineered skin substitutes: Advances and future trends. Applied Sciences 2021; 11(4): 1493. doi: 10.3390/app11041493

84. Palem RR, Rao KM, Shimoga G, et al. Physicochemical characterization, drug release, and biocompatibility evaluation of carboxymethyl cellulose-based hydrogels reinforced with sepiolite nanoclay. International Journal of Biological Macromolecules 2021; 178: 464–476. doi: 10.1016/j.ijbiomac.2021.02.195

85. Zhang K, Lv H, Zheng Y, et al. Nanofibrous hydrogels embedded with phase-change materials: Temperature-responsive dressings for accelerating skin wound healing. Composites Communications 2021; 25: 100752. doi: 10.1016/j.coco.2021.100752

86. Wei M, Gao Y, Li X, et al. Stimuli-responsive polymers and their applications. Polymer Chemistry 2017; 8(1): 127–143. doi: 10.1039/c6py01585a

87. Yasa IC, Tabak AF, Yasa O, et al. 3D‐printed microrobotic transporters with recapitulated stem cell niche for programmable and active cell delivery. Advanced Functional Materials 2019; 29(17). doi: 10.1002/adfm.201808992

88. Hu X, Yasa IC, Ren Z, et al. Magnetic soft micromachines made of linked microactuator networks. Science Advances 2021; 7(23). doi: 10.1126/sciadv.abe8436

89. El-Husseiny HM, Mady EA, Hamabe L, et al. Smart/stimuli-responsive hydrogels: Cutting-edge platforms for tissue engineering and other biomedical applications. Materials Today Bio 2022; 13: 100186. doi: 10.1016/j.mtbio.2021.100186

90. Jiang Y, Hu C, Cheng H, et al. Spontaneous, straightforward fabrication of partially reduced graphene oxide–polypyrrole composite films for versatile actuators. ACS Nano 2016; 10(4): 4735–4741. doi: 10.1021/acsnano.6b01233

91. Li X, Serpe MJ. Understanding the shape memory behavior of self‐bending materials and their use as sensors. Advanced Functional Materials 2016; 26(19): 3282–3290. doi: 10.1002/adfm.201505391

92. Breger JC, Yoon C, Xiao R, et al. Self-folding thermo-magnetically responsive soft microgrippers. ACS Applied Materials & Interfaces 2015; 7(5): 3398–3405. doi: 10.1021/am508621s

93. Molla MR, Rangadurai P, Antony L, et al. Dynamic actuation of glassy polymersomes through isomerization of a single azobenzene unit at the block copolymer interface. Nature Chemistry 2018; 10(6): 659–666. doi: 10.1038/s41557-018-0027-6