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Hydrogels with Dynamically Controllable Mechanics and Biochemistry for 3D Cell Culture Platforms

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Abstract

Many cell-matrix interaction studies have proved that dynamic changes in the extracellular matrix (ECM) are crucial to maintain cellular properties and behaviors. Thus, developing materials that can recapitulate the dynamic attributes of the ECM is highly desired for three-dimensional (3D) cell culture platforms. To this end, we sought to develop a hydrogel system that would enable dynamic and reversible turning of its mechanical and biochemical properties, thus facilitating the control of cell culture to imitate the natural ECM. Herein, a hydrogel with dynamic mechanics and a biochemistry based on an addition-fragmentation chain transfer (AFCT) reaction was constructed. Thiol-modified hyaluronic acid (HA) and allyl sulfide-modified ε-poly-L-lysine (EPL) were synthesized to form hydrogels, which were non-swellable and biocompatible. The reversible modulus of the hydrogel was first achieved through the AFCT reaction; the modulus can also be regulated stepwise by changing the dose of UVA irradiation. Dynamic patterning of fluorescent markers in the hydrogel was also realized. Therefore, this dynamically controllable hydrogel has great potential as a 3D cell culture platform for tissue engineering applications.

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References

  1. Lei, K. F.; Chang, C. H.; Chen, M. J. Paper/PMMA hybrid 3D cell culture microfluidic platform for the study of cellular crosstalk. ACS Appl. Mater. Interfaces 2017, 9, 13092–13101.

    Article  CAS  Google Scholar 

  2. Kim, J.; Hayward, R. C. Mimicking dynamic in vivo environments with stimuli-responsive materials for cell culture. Trends Biotechnol. 2012, 30, 426–439.

    Article  CAS  Google Scholar 

  3. Wu, Y.; Wang, L.; Guo, B.; Ma, P. X. Interwoven aligned conductive nanofiber yarn/hydrogel composite scaffolds for engineered 3D cardiac anisotropy. ACS Nano 2017, 11, 5646–5659.

    Article  CAS  Google Scholar 

  4. Ming, Z.; Fan, J.; Bao, C.; Xue, Y.; Lin, Q.; Zhu, L. Photogenerated aldehydes for protein patterns on hydrogels and guidance of cell behavior. Adv. Funct. Mater. 2018, 28, 1706918.

    Article  Google Scholar 

  5. Kocen, R.; Gasik, M.; Gantar, A.; Novak, S. Viscoelastic behaviour of hydrogel-based composites for tissue engineering under mechanical load. Biomed. Mater. 2017, 12, 025004.

    Article  Google Scholar 

  6. Cai, Z.; Huang, K.; Bao, C.; Wang, X.; Sun, X.; Xia, H.; Lin, Q.; Yang, Y.; Zhu, L. Precise construction of cell-instructive 3D microenvironments by photopatterning a biodegradable hydrogel. Chem. Mater. 2019, 31, 4710–4719.

    Article  CAS  Google Scholar 

  7. Truong, V. X.; Li, F.; Forsythe, J. S. Versatile bioorthogonal hydrogel platform by catalyst-free visible light initiated photodimerization of anthracene. ACS Macro Lett. 2017, 6, 657–662.

    Article  CAS  Google Scholar 

  8. Prasopthum, A.; Deng, Z.; Khan, I. M.; Yin, Z.; Guo, B.; Yang, J. Three dimensional printed degradable and conductive polymer scaffolds promote chondrogenic differentiation of chondroprogenitor cells. Biomater. Sci. 2020, 8, 4287–4298.

    Article  CAS  Google Scholar 

  9. Deng, C.; Wang, R.; Chen, W.; Meng, F. H.; Cheng, R.; Zhong, Z. Y. Design and synthesis of rapidly photo-crosslinkable bioactive biodegradable hydrogels. Acta Polymerica Sinica (in Chinese) 2013, 695–704.

    Google Scholar 

  10. Ma, X. B.; Yang, R.; Sekhar, K. P. C.; Chi, B. Injectable hyaluronic acid/poly(γ-glutamic acid) hydrogel with step-by-step tunable properties for soft tissue engineering. Chinese J. Polym. Sci. 2021, 39, 957–965.

    Article  CAS  Google Scholar 

  11. Liu, S. S.; Xiang, Z. H.; Ma, Z. F.; Wu, X. W.; Shi, Q.; Wong, S. C.; Yin, J. H. Surface patterning of self-healing P(MMA/nBA) copolymer for dynamic control cell behaviors. Chinese J. Polym. Sci. 2020, 38, 696–703.

    Article  CAS  Google Scholar 

  12. Lu, D.; Zhu, M.; Wu, S.; Lian, Q.; Wang, W.; Adlam, D.; Hoyland, J. A.; Saunders, B. R. Programmed multiresponsive hydrogel assemblies with light-tunable mechanical properties, actuation, and fluorescence. Adv. Funct. Mater. 2020, 30, 1909359.

    Article  CAS  Google Scholar 

  13. Guo, B.; Qu, J.; Zhao, X.; Zhang, M. Degradable conductive self-healing hydrogels based on dextran-graft-tetraaniline and N-carboxyethyl chitosan as injectable carriers for myoblast cell therapy and muscle regeneration. Acta Biomater. 2019, 84, 180–193.

    Article  CAS  Google Scholar 

  14. Uto, K.; Tsui, J. H.; DeForest, C. A.; Kim, D. H. Dynamically tunable cell culture platforms for tissue engineering and mechanobiology. Prog. Polym. Sci. 2017, 65, 53–82.

    Article  CAS  Google Scholar 

  15. Lu, D.; Zhu, M.; Wu, S.; Wang, W.; Lian, Q.; Saunders, B. R. Triply responsive coumarin-based microgels with remarkably large photo-switchable swelling. Polym. Chem. 2019, 10, 2516–2526.

    Article  CAS  Google Scholar 

  16. DeForest, C. A.; Tirrell, D. A. A photoreversible protein-patterning approach for guiding stem cell fate in three-dimensional gels. Nat. Mater. 2015, 14, 523–531.

    Article  CAS  Google Scholar 

  17. Blow, N. Cell culture: building a better matrix. Nat. Methods 2009, 6, 619–622.

    Article  CAS  Google Scholar 

  18. Shadish, J. A.; Benuska, G. M.; DeForest, C. A. Bioactive site-specifically modified proteins for 4D patterning of gel biomaterials. Nat. Mater. 2019, 18, 1005–1014.

    Article  CAS  Google Scholar 

  19. Rosales, A. M.; Anseth, K. S. The design of reversible hydrogels to capture extracellular matrix dynamics. Nat. Rev. Mater. 2016, 1, 15012.

    Article  CAS  Google Scholar 

  20. Brown, T. E.; Marozas, I. A.; Anseth, K. S. Amplified photodegradation of cell-laden hydrogels via an addition-fragmentation chain transfer reaction. Adv. Mater. 2017, 29, 1605001.

    Article  Google Scholar 

  21. Scott, T. F.; Schneider, A. D.; Cook, W. D.; Bowman, C. N. Photoinduced plasticity in cross-linked polymers. Science 2005, 308, 1615–1617.

    Article  CAS  Google Scholar 

  22. Grim, J. C.; Brown, T. E.; Aguado, B. A.; Chapnick, D. A.; Viert, A. L.; Liu, X.; Anseth, K. S. A Reversible and repeatable thiol-ene bioconjugation for dynamic patterning of signaling proteins in hydrogels. ACS Cent. Sci. 2018, 4, 909–916.

    Article  CAS  Google Scholar 

  23. Gandavarapu, N. R.; Azagarsamy, M. A.; Anseth, K. S. Photo-click living strategy for controlled, reversible exchange of biochemical ligands. Adv. Mater. 2014, 26, 2521–2526.

    Article  CAS  Google Scholar 

  24. Yavitt, F. M.; Brown, T. E.; Hushka, E. A.; Brown, M. E.; Gjorevski, N.; Dempsey, P. J.; Lutolf, M. P.; Anseth, K. S. The effect of thiol structure on allyl sulfide photodegradable hydrogels and their application as a degradable scaffold for organoid passaging. Adv. Mater. 2020, 32, 1905366.

    Article  CAS  Google Scholar 

  25. Hoang, T. T.; Smith, T. P.; Raines, R. T. A boronic acid conjugate of angiogenin that shows ROS-responsive neuroprotective activity. Angew. Chem. Int. Ed. 2017, 56, 2619–2622.

    Article  CAS  Google Scholar 

  26. Vercruysse, K. P.; Marecak, D. M.; Marecek, J. F.; Prestwich, G. D. Synthesis and in vitro degradation of new polyvalent hydrazide cross-linked hydrogels of hyaluronic acid. Bioconjugate Chem. 1997, 8, 686–694.

    Article  CAS  Google Scholar 

  27. Snow, A.; Foos, E. Conversion of alcohols to thiols via tosylate intermediates. Cheminform 2003, 38, 509–512.

    Google Scholar 

  28. Zhang, Y.; Heher, P.; Hilborn, J.; Redl, H.; Ossipov, D. A. Hyaluronic acid-fibrin interpenetrating double network hydrogel prepared in situ by orthogonal disulfide cross-linking reaction for biomedical applications. Acta Biomater. 2016, 38, 23–32.

    Article  CAS  Google Scholar 

  29. Hornof, M. D.; Kast, C. E.; Bernkop-Schnürch, A. In vitro evaluation of the viscoelastic properties of chitosan-thioglycolic acid conjugates. Eur. J. Pharm. Biopharm. 2003, 55, 185–190.

    Article  CAS  Google Scholar 

  30. Ni, M.; Peng, H.; Liao, Y.; Yang, Z.; Xue, Z.; Xie, X. 3D image storage in photopolymer/ZnS nanocomposites tailored by “photoinitibitor”. Macromolecules 2015, 48, 2958–2966.

    Article  CAS  Google Scholar 

  31. Rong, Y.; Zhang, Z.; He, C.; Chen, X. Bioactive polypeptide hydrogels modified with RGD and N-cadherin mimetic peptide promote chondrogenic differentiation of bone marrow mesenchymal stem cells. Sci. China Chem. 2020, 63, 1100–1111.

    Article  CAS  Google Scholar 

  32. Chircov, C.; Grumezescu, A.; Bejenaru, L. Hyaluronic acid-based scaffolds for tissue engineering. Rom. J. of Morphol. Embryo. 2018, 59, 71–76.

    Google Scholar 

  33. Xi, Y.; Ge, J.; Guo, Y.; Lei, B.; Ma, P. X. Biomimetic elastomeric polypeptide-based nanofibrous matrix for overcoming multidrug-resistant bacteria and enhancing full-thickness wound healing/skin regeneration. ACS Nano 2018, 12, 10772–10784.

    Article  CAS  Google Scholar 

  34. Zou, Y. J.; He, S. S.; Du, J. Z. ε-Poly(L-lysine)-based hydrogels with fast-acting and prolonged antibacterial activities. Chinese J. Polym. Sci. 2018, 36, 1239–1250.

    Article  CAS  Google Scholar 

  35. Lee, I. C.; Wu, Y. C.; Cheng, E. M.; Yang, W. T. Biomimetic niche for neural stem cell differentiation using poly-L-lysine/hyaluronic acid multilayer films. J. Biomater. Appl. 2014, 29, 1418–1427.

    Article  Google Scholar 

  36. Bermejo-Velasco, D.; Azémar, A.; Oommen, O. P.; Hilborn, J.; Varghese, O. P. Modulating thiol pKa promotes disulfide formation at physiological pH: an elegant strategy to design disulfide cross-linked hyaluronic acid hydrogels. Biomacromolecules 2019, 20, 1412–1420.

    Article  CAS  Google Scholar 

  37. Elbini Dhouib, I.; Jallouli, M.; Annabi, A.; Gharbi, N.; Elfazaa, S.; Lasram, M. M. A mini review on N-acetylcysteine: an old drug with new approaches. Life Sci. 2016, 151, 359–363.

    Article  CAS  Google Scholar 

  38. Ma, Y.; Lin, M.; Huang, G.; Li, Y.; Wang, S.; Bai, G.; Lu, T. J.; Xu, F. 3D spatiotemporal mechanical microenvironment: a hydrogel-based platform for guiding stem cell fate. Adv. Mater. 2018, 30, 1705911.

    Article  Google Scholar 

  39. Truong, V. X.; Tsang, K. M.; Simon, G. P.; Boyd, R. L.; Evans, R. A.; Thissen, H.; Forsythe, J. S. Photodegradable gelatin-based hydrogels prepared by bioorthogonal click chemistry for cell encapsulation and release. Biomacromolecules 2015, 16, 2246–2253.

    Article  CAS  Google Scholar 

  40. Song, G.; Ju, Y.; Shen, X.; Luo, Q.; Shi, Y.; Qin, J. Mechanical stretch promotes proliferation of rat bone marrow mesenchymal stem cells. Colloid. Surface. B 2007, 58, 271–277.

    Article  CAS  Google Scholar 

  41. http://www.nih3t3.com/.

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Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (Nos. 21803069 and 21975249).

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Authors and Affiliations

  1. State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China

    Hai-Yang Wu, Lei Yang, Jiang-Shan Tu, Jin-Ge Li, Hong-Ying Lv & Xiao-Niu Yang

  2. School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China

    Hai-Yang Wu, Lei Yang, Jiang-Shan Tu, Jin-Ge Li & Xiao-Niu Yang

  3. Polymer Composite Engineering Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China

    Hai-Yang Wu, Lei Yang, Jiang-Shan Tu, Jin-Ge Li, Hong-Ying Lv & Xiao-Niu Yang

  4. Huangpu Institute of Advanced Materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Guangzhou, 510530, China

    Jie Wang

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  1. Hai-Yang Wu
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Correspondence to Hong-Ying Lv or Xiao-Niu Yang.

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Wu, HY., Yang, L., Tu, JS. et al. Hydrogels with Dynamically Controllable Mechanics and Biochemistry for 3D Cell Culture Platforms. Chin J Polym Sci 40, 38–46 (2022). https://doi.org/10.1007/s10118-021-2639-3

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  • DOI: https://doi.org/10.1007/s10118-021-2639-3

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