AccScience Publishing / IJB / Volume 9 / Issue 3 / DOI: 10.18063/ijb.709
RESEARCH ARTICLE

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

Yan Zhou1 Min Ye1 Hongyu Zhao1 Xiaopu Wang1*
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1 Shenzhen Institute of Artificial Intelligence and Robotics for Society (AIRS), The Chinese University of Hong Kong, Shenzhen, Guangdong 518129, China
Submitted: 8 November 2022 | Accepted: 22 December 2022 | Published: 15 March 2023
© 2023 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

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.

Keywords
3D printing
PNAGA thermosensitive hydrogel
Swelling
Drug release
Magnetic microrobot
References

1. 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 

2. 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 

3. 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

4. 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 

5. 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 

6. 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 

7. 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 

8. 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 

9. 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 

10. 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 

11. 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 

12. 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 

13. 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 

14. 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 

15. 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 

16. 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 

17. 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 

18. 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 

19. 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 

20. 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 

21. 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 

22. 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 

23. 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 

24. 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 

25. 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

26. 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 

27. 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 

28. 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
 
29. 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
 
30. 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 

31. 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 

32. 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 

33. 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 

34. 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 

35. 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
 
36. 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 

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

38. 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 

39. 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 

40. 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 

41. 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 

42. 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 

43. 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 

44. 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
 
45. 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

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International Journal of Bioprinting, Electronic ISSN: 2424-8002 Print ISSN: 2424-7723, Published by AccScience Publishing