3D-printed PNAGA thermosensitive hydrogelbased microrobots: An effective cancer therapy by temperature-triggered drug release

Yan Zhou, Min Ye, Hongyu Zhao, Xiaopu Wang

Article ID: 709
Vol 9, Issue 3, 2023, Article identifier:

VIEWS - 69 (Abstract) 46 (PDF) 12 (Supp.File) 14 (Supp. File (Video 1))


Hydrogels with temperature-responsive capabilities are increasingly utilized and researched owing to their prospective applications in the biomedical field. In this work, we developed thermosensitive poly-N-acryloyl glycinamide (PNAGA) hydrogels-based microrobots by using the advanced two-photon polymerization printing technology. N-acryloyl glycinamide (NAGA) concentration-dependent thermosensitive performance was presented and the underlying mechanism behind was discussed. Fast swelling behavior was achieved by PNAGA-100 at 45°C with a growth rate of 22.5%, which is the highest value among these PNAGA hydrogels. In addition, a drug release test of PNAGA-100-based thermosensitive hydrogels was conducted. Our microrobots demonstrate higher drug release amount at 45°C (close to body temperature) than at 25°C, indicating their great potential to be utilized in drug delivery in the human body. Furthermore, PNAGA-100-based thermosensitive microrobots are able to swim along the route as designed under the magnetic actuator after incubating with Fe@ZIF-8 crystals. Our biocompatible thermosensitive magnetic microrobots open up new options for biomedical applications and our work provides a robust pathway to the development of high-performance thermosensitive hydrogel-based microrobots.


3D printing; PNAGA thermosensitive hydrogel; Swelling; Drug release; Magnetic microrobot

Included Database


Aswathy SH, Narendrakumar U, Manjubala I, 2020, Commercial hydrogels for biomedical applications. Heliyon, 6(4):e03719. https://doi.org/10.1016/j.heliyon.2020.e03719

Gaharwar AK, Peppas NA, Khademhosseini A, 2014, Nanocomposite hydrogels for biomedical applications. Biotechnol Bioeng, 111(3):441–453. https://doi.org/10.1002/bit.25160

Kahn JS, Hu Y, Willner I, 2017, Stimuli-responsive DNA-based hydrogels: From basic principles to applications. Acc Chem Res, 50(4):680–690. https://doi.org/10.1021/acs.accounts.6b00542

Li Y, Yang HY, Lee DS, 2021, Advances in biodegradable and injectable hydrogels for biomedical applications. J Control Release, 330:151–160. https://doi.org/10.1016/j.jconrel.2020.12.008

Shi J, Yu L, Ding J, 2021, PEG-based thermosensitive and biodegradable hydrogels. Acta Biomater, 128:42–59. https://doi.org/10.1016/j.actbio.2021.04.009

Wahid F, Zhao X-J, Jia S-R, et al., 2020, Nanocomposite hydrogels as multifunctional systems for biomedical applications: Current state and perspectives. Compos B Eng, 200:108208. https://doi.org/10.1016/j.compositesb.2020.108208

Chen L, Duan G, Zhang C, et al., 2022, 3D printed hydrogel for soft thermo-responsive smart window. Int J of Extrem Manuf, 4(2):025302. https://doi.org/10.1088/2631-7990/ac5ae3

Boffito M, Sirianni P, Di Rienzo AM, et al., 2015, Thermosensitive block copolymer hydrogels based on poly(varepsilon-caprolactone) and polyethylene glycol for biomedical applications: State of the art and future perspectives. J Biomed Mater Res A, 103(3):1276–1290. https://doi.org/10.1002/jbm.a.35253

Bozoglan BK, Duman O, Tunc S, 2020, Preparation and characterization of thermosensitive chitosan/ carboxymethylcellulose/scleroglucan nanocomposite hydrogels. Int J Biol Macromol, 162:781–797. https://doi.org/10.1016/j.ijbiomac.2020.06.087

Fan R, Deng X, Zhou L, et al., 2014, Injectable thermosensitive hydrogel composite with surface-functionalized calcium phosphate as raw materials. Int J Nanomedicine, 9:615–626. https://doi.org/10.2147/IJN.S52689

Zhan Z, Chen L, Duan H, et al., 2021, 3D printed ultra-fast photothermal responsive shape memory hydrogel for microrobots. Int J Extrem Manuf, 4(1):015302. https://doi.org/10.1088/2631-7990/ac376b

Huang H, Qi X, Chen Y, et al., 2019, Thermo-sensitive hydrogels for delivering biotherapeutic molecules: A review. Saudi Pharm J, 27(7):990–999. https://doi.org/10.1016/j.jsps.2019.08.001

Yuan M, Bi B, Huang J, et al., 2018, Thermosensitive and photocrosslinkable hydroxypropyl chitin-based hydrogels for biomedical applications. Carbohydr Polym, 192:10–18. https://doi.org/10.1016/j.carbpol.2018.03.031

Zhang Y, Yu J, Ren K, et al., 2019, Thermosensitive hydrogels as scaffolds for cartilage tissue engineering. Biomacromolecules, 20(4):1478–1492. https://doi.org/10.1021/acs.biomac.9b00043

He W, Ma Y, Gao X, et al., 2020, Application of poly(N-isopropylacrylamide) as thermosensitive smart materials. J Phys Conf Ser, 1676(1):012063. https://doi.org/10.1088/1742-6596/1676/1/012063

Li J, Ma Q, Xu Y, et al., 2020, Highly bidirectional bendable actuator engineered by LCST-UCST bilayer hydrogel with enhanced interface. ACS Appl Mater Interfaces, 12(49):55290–55298. https://doi.org/10.1021/acsami.0c17085

Li S, Wang W, Li W, et al., 2021, Fabrication of thermoresponsive hydrogel scaffolds with engineered microscale vasculatures. Adv Funct Mater, 31(27):2102685. https://doi.org/10.1002/adfm.202102685

Tang L, Wang L, Yang X, et al., 2021, Poly(N-isopropylacrylamide)-based smart hydrogels: Design, properties and applications. Prog Mater Sci, 115:100702. https://doi.org/10.1016/j.pmatsci.2020.100702

Xiao XC, 2007, Effect of the initiator on thermosensitive rate of poly(N-isopropylacrylamide) hydrogels. Express Polym Lett, 1(4):232–235. https://doi.org/10.3144/expresspolymlett.2007.35

Fu W, Zhao B, 2016, Thermoreversible physically crosslinked hydrogels from UCST-type thermosensitive ABA linear triblock copolymers. Polym Chem, 7(45):6980–6991. https://doi.org/10.1039/c6py01517d

Hua L, Xie M, Jian Y, et al., 2019, Multiple-responsive and amphibious hydrogel actuator based on asymmetric UCST-type volume phase transition. ACS Appl Mater Interfaces, 11(46):43641–43648. https://doi.org/10.1021/acsami.9b17159

Xia M, Cheng Y, Meng Z, et al., 2015, A novel nanocomposite hydrogel with precisely tunable UCST and LCST. Macromol Rapid Commun, 36(5):477–482. https://doi.org/10.1002/marc.201400665

Yu J, Wang K, Fan C, et al., 2021, An ultrasoft self-fused supramolecular polymer hydrogel for completely preventing postoperative tissue adhesion. Adv Mater, 33(16):e2008395. https://doi.org/10.1002/adma.202008395

Xue X, Thiagarajan L, Braim S, et al., 2017, Upper critical solution temperature thermo-responsive polymer brushes and a mechanism for controlled cell attachment. J Mater Chem B, 5(25):4926–4933. https://doi.org/10.1039/c7tb00052a

Ge S, Li J, Geng J, et al., 2021, Adjustable dual temperature-sensitive hydrogel based on a self-assembly cross-linking strategy with highly stretchable and healable properties. Mater Horiz, 8(4):1189–1198. https://doi.org/10.1039/d0mh01762k

Wu Y, Wang H, Gao F, et al., 2018, An injectable supramolecular polymer nanocomposite hydrogel for prevention of breast cancer recurrence with theranostic and mammoplastic functions. Adv Funct Mater, 28(21):1801000. https://doi.org/10.1002/adfm.201801000

Xu Z, Liu W, 2018, Poly(N-acryloyl glycinamide): A fascinating polymer that exhibits a range of properties from UCST to high-strength hydrogels. Chem Commun(Camb), 54(75):10540–10553. https://doi.org/10.1039/c8cc04614j

Boustta M, Vert M, 2020, Hyaluronic acid-poly(N-acryloyl glycinamide) copolymers as sources of degradable thermoresponsive hydrogels for therapy. Gels, 6(4):E42. https://doi.org/10.3390/gels6040042

Yang D, Eronen H, Tenhu H, et al., 2021, Phase transition behavior and catalytic activity of poly(N-acryloylglycinamide-co-methacrylic acid) microgels. Langmuir, 37(8):2639–2648. https://doi.org/10.1021/acs.langmuir.0c03264

Bunea A-I, del Castillo Iniesta N, Droumpali A, et al., 2021, Micro 3D printing by two-photon polymerization: Configurations and parameters for the nanoscribe system. Micro, 1:164–180. https://doi.org/10.3390/micro1020013

Faraji Rad Z, Prewett PD, Davies GJ, 2021, High-resolution two-photon polymerization: The most versatile technique for the fabrication of microneedle arrays. Microsyst Nanoeng, 7:71. https://doi.org/10.1038/s41378-021-00298-3

Koskela JE, Turunen S, Ylä-Outinen L, et al., 2012, Two-photon microfabrication of poly(ethylene glycol) diacrylate and a novel biodegradable photopolymer-comparison of processability for biomedical applications. Polym Adv Technol, 23(6):992–1001. https://doi.org/10.1002/pat.2002

Petcu EB, Midha R, McColl E, et al., 2018, 3D printing strategies for peripheral nerve regeneration. Biofabrication, 10(3):032001. https://doi.org/10.1088/1758-5090/aaaf50

Tao J, He Y, Wang S, et al., 2019, 3D-printed nerve conduit with vascular networks to promote peripheral nerve regeneration. Med Hypotheses, 133:109395. https://doi.org/10.1016/j.mehy.2019.109395

Weisgrab G, Guillaume O, Guo Z, et al., 2020, 3D printing of large-scale and highly porous biodegradable tissue engineering scaffolds from poly(trimethylene-carbonate) using two-photon-polymerization. Biofabrication, 12(4):045036. https://doi.org/10.1088/1758-5090/abb539

Lee SJ, Esworthy T, Stake S, et al., 2018, Advances in 3D bioprinting for neural tissue engineering. Adv Biosyst, 2:1700213. https://doi.org/10.1002/adbi.201700213

Lee JW, 2015, 3D nanoprinting technologies for tissue engineering applications. J Nanomater, 2015:1–14. https://doi.org/10.1155/2015/213521

Terzopoulou A, Wang X, Chen XZ, et al., 2020, Biodegradable metal-organic framework-based microrobots (MOFBOTs). Adv Healthc Mater, 9:e2001031. https://doi.org/10.1002/adhm.202001031

Wang X, Qin X-H, Hu C, et al., 2018, 3D printed enzymatically biodegradable soft helical microswimmers. Adv Funct Mater, 28:1804107. https://doi.org/10.1002/adfm.201804107

Jiang Z, Tan ML, Taheri M, et al., 2020, Strong, self-healable, and recyclable visible-light-responsive hydrogel actuators. Angew Chem Int Ed Engl, 59(18):7049–7056. https://doi.org/10.1002/anie.201916058

Song X, Zhang Z, Zhu J, et al., 2020, Thermoresponsive hydrogel induced by dual supramolecular assemblies and its controlled release property for enhanced anticancer drug delivery. Biomacromolecules, 21(4):1516–1527. https://doi.org/10.1021/acs.biomac.0c00077

Peng X, Liu T, Jiao C, et al., 2017, Complex shape deformations of homogeneous poly(N-isopropylacrylamide)/graphene oxide hydrogels programmed by local NIR irradiation. J Mater Chem B, 5(39):7997–8003. https://doi.org/10.1039/c7tb02119d

Bian Q, Fu L, Li H, 2022, Engineering shape memory and morphing protein hydrogels based on protein unfolding and folding. Nat Commun, 13(1):137. https://doi.org/10.1038/s41467-021-27744-0

Xu Z, Fan C, Zhang Q, et al., 2021, A self‐thickening and self‐strengthening strategy for 3D printing high‐strength and antiswelling supramolecular polymer hydrogels as meniscus substitutes. Adv Funct Mater, 31(18):2100462. https://doi.org/10.1002/adfm.202100462

Wang X, Chen XZ, Alcantara CCJ, et al., 2019, MOFBOTS: Metal-organic-framework-based biomedical microrobots. Adv Mater, 31:e1901592. https://doi.org/10.1002/adma.201901592

DOI: http://dx.doi.org/10.18063/ijb.709


  • There are currently no refbacks.

Copyright (c) 2023 Author(s).

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.