Skip to main content
Log in

A dual-cross-linked hydrogel based on hyaluronic acid/gelatin tethered via tannic acid: mechanical properties’ enhancement and stability control

  • Original Research
  • Published:
Iranian Polymer Journal Aims and scope Submit manuscript

Abstract

Extracellular matrix (ECM) as a network is mainly composed of glycosaminoglycans and proteins. Among these glycosaminoglycans and proteins that naturally occur in ECM, hyaluronic acid (HA) and gelatin attract more attentions. In this work, a chemically cross-linked HA/gelatin hydrogel (HG hydrogel) was firstly fabricated, and then, tannic acid (TA) was introduced as a physical cross-linker, to form a dual-cross-linked network (HG-TAx hydrogels). The strong hydrogen bonding between TA and HG hydrogel resulted in lower swelling ratio, decreasing from 220% (pristine HG hydrogels) to 7.5% (HG-TA25 hydrogels) and stronger mechanical properties increasing from 6 kPa (HG hydrogel) to 160 kPa (HG-TA25 hydrogel). The hydrogel stability in enzyme was significantly improved, attributing to the hyaluronidase inhibition activity of TA. The degradation time significantly increased along with the addition of TA (from 7 up to 21 days). Furthermore, the HG-TAx hydrogels exhibited good cleavage ability to reactive oxygen species (ROS) that could be generated in human tissues, and the antioxidant capacity increased up to 24.2 mg/mL of L-ascorbic acid standard. The improved mechanical properties, prolonged degradation time, and potential antioxidant ability of the HG-TAx hydrogels could pave the way for the design of biomaterials. Furthermore, TA has shown potential biological functions properties and brought the great potential of the HG-TAx hydrogels for implant applications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability statement

The raw/processed data required to reproduce these findings cannot be shared at this time as the data also form part of an ongoing study. However, they can be provided upon requested.

References

  1. Wu ZL, Gong JP (2011) Hydrogels with self-assembling ordered structures and their functions. NPG Asia Mater 3:57–64

    Google Scholar 

  2. Yang JZ, Zhang YS, Yue K, Khademhosseini A (2017) Cell-laden hydrogels for osteochondral and cartilage tissue engineering. Acta Biomater 57:1–25

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Naahidi S, Jafari M, Logan M, Wang YJ, Yuan YF, Bae H, Dixon B, Chen P (2017) Biocompatibility of hydrogel-based scaffolds for tissue engineering applications. Biotechnol Adv 35:530–544

    CAS  PubMed  Google Scholar 

  4. Ding XC, Wang YD (2017) Weak bond-based injectable and stimuli responsive hydrogels for biomedical applications. J Mater Chem B 5:887–906

    CAS  PubMed  Google Scholar 

  5. Lee HR, Kim CC, Sun JY (2018) Stretchable ionics—a promising candidate for upcoming wearable devices. Adv Mater 30:1704403. https://doi.org/10.1002/adma.201704403

    Article  CAS  Google Scholar 

  6. Khunmanee S, Jeong Y, Park H (2017) Crosslinking method of hyaluronic-based hydrogel for biomedical applications. J Tissue Eng 8:1–16

    CAS  Google Scholar 

  7. Vulpe R, Popa M, Picton L, Balan V, Dulong V, Butnaru M, Verestiuc L (2016) Crosslinked hydrogels based on biological macromolecules with potential use in skin tissue engineering. Int J Biol Macromol 84:174–181

    CAS  PubMed  Google Scholar 

  8. Qu J, Zhao X, Liang YP, Xu YM, Ma PX, Guo BL (2019) Degradable conductive injectable hydrogels as novel antibacterial, anti-oxidant wound dressings for wound healing. Chem Eng J 362:548–560

    CAS  Google Scholar 

  9. Liang YP, Zhao X, Hu TL, Chen BJ, Yin ZH, Ma PX, Guo BL (2019) Adhesive hemostatic conducting injectable composite hydrogels with sustained drug release and photothermal antibacterial activity to promote full-thickness skin regeneration during wound healing. Small 15:1900046. https://doi.org/10.1002/smll.201900046

    Article  CAS  Google Scholar 

  10. Wang G, Cao XD, Dong H, Zeng L, Yu CX, Chen XF (2018) A hyaluronic acid based injectable hydrogel formed via photo-crosslinking reaction and thermal-induced diels-alder reaction for cartilage tissue engineering. Polymers-Basel 10:949. https://doi.org/10.3390/polym10090949

    Article  CAS  PubMed Central  Google Scholar 

  11. Stern R, Kogan G, Jedrzejas MJ, Soltes L (2007) The many ways to cleave hyaluronan. Biotechnol Adv 25:537–557

    CAS  PubMed  Google Scholar 

  12. Rinaudo M, Lardy B, Grange L, Conrozier T (2014) Effect of mannitol on hyaluronic acid stability in two in vitro models of oxidative stress. Polymers-Basel 6:1948–1957

    Google Scholar 

  13. Lu LY, Yuan SL, Wang J, Shen Y, Deng SW, Xie LY, Yang QX (2018) The formation mechanism of hydrogels. Curr Stem Cell Res T 13:490–496

    CAS  Google Scholar 

  14. Trombino S, Servidio C, Curcio F, Cassano R (2019) Strategies for hyaluronic acid-based hydrogel design in drug delivery. Pharmaceutics 11:407. https://doi.org/10.3390/pharmaceutics11080407

    Article  CAS  PubMed Central  Google Scholar 

  15. Lee JH (2018) Injectable hydrogels delivering therapeutic agents for disease treatment and tissue engineering. Biomater Res 22:27. https://doi.org/10.1186/s40824-018-0138-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Haque MA, Kurokawa T, Gong JP (2012) Super tough double network hydrogels and their application as biomaterials. Polymer 53:1805–1822

    CAS  Google Scholar 

  17. Zhao D, Huang JC, Zhong Y, Li K, Zhang LN, Cai J (2016) High-strength and high-toughness double-cross-linked cellulose hydrogels: a new strategy using sequential chemical and physical cross-linking. Adv Funct Mater 26:6279–6287

    CAS  Google Scholar 

  18. Deng Y, Huang M, Sun D, Hou Y, Li YB, Dong TS, Wang XH, Zhang L, Yang WZ (2018) Dual physically cross-linked kappa-carrageenan-based double network hydrogels with superior self-healing performance for biomedical application. ACS Appl Mater Inter 10:37544–37554

    CAS  Google Scholar 

  19. Gu S, Cheng GR, Yang TY, Ren XY, Gao GH (2017) Mechanical and rheological behavior of hybrid cross-linked polyacrylamide/cationic micelle hydrogels. Macromol Mater Eng 302:1700402. https://doi.org/10.1002/mame.201700402

    Article  CAS  Google Scholar 

  20. Liu X, Duan LJ, Gao GH (2017) Rapidly self-recoverable and fatigue-resistant hydrogels toughened by chemical crosslinking and hydrophobic association. Eur Polym J 89:185–194

    CAS  Google Scholar 

  21. Qin ZH, Niu R, Tang CJ, Xia J, Ji F, Dong DY, Zhang HT, Zhang S, Li JJ, Yao FL (2018) A dual-crosslinked strategy to construct physical hydrogels with high strength, toughness, good mechanical recoverability, and shape-memory ability. Macromol Mater Eng 303:1700396. https://doi.org/10.1002/mame.201700396

    Article  CAS  Google Scholar 

  22. Baruah P, Duarah R, Karak N (2016) Tannic acid-based tough hyperbranched epoxy thermoset as an advanced environmentally sustainable high-performing material. Iran Polym J 25:849–861

    CAS  Google Scholar 

  23. Ninan N, Forget A, Shastri VP, Voelcker NH, Blencowe A (2016) Antibacterial and anti-inflammatory pH-responsive tannic acid-carboxylated agarose composite hydrogels for wound healing. ACS Appl Mater Inter 8:28511–28521

    CAS  Google Scholar 

  24. Zheng LY, Shi JM, Chi YH (2018) Tannic acid physically cross-linked responsive hydrogel. Macromol Chem Phys 219:1800234. https://doi.org/10.1002/macp.201800234

    Article  CAS  Google Scholar 

  25. Collins J, Nadgorny M, Xiao ZY, Connal LA (2017) Doubly dynamic self-healing materials based on oxime click chemistry and boronic acids. Macromol Rapid Comm 38:1600760. https://doi.org/10.1002/marc.201600760

    Article  CAS  Google Scholar 

  26. Zhao QX, Mu SD, Long YR, Zhou J, Chen WY, Astruc D, Gaidau C, Gu HB (2019) Tannin-tethered gelatin hydrogels with considerable self-healing and adhesive performances. Macromol Mater Eng 304:1800664. https://doi.org/10.1002/mame.201800664

    Article  CAS  Google Scholar 

  27. Wang R, Wang XX, Zhan YJ, Xu Z, Xu ZQ, Feng XH, Li S, Xu H (2019) A dual network hydrogel sunscreen based on poly-gamma-glutamic acid/tannic acid demonstrates excellent anti-UV, self-recovery, and skin-integration capacities. ACS Appl Mater Inter 11:37502–37512

    CAS  Google Scholar 

  28. Nichol JW, Koshy ST, Bae H, Hwang CM, Yamanlar S, Khademhosseini A (2010) Cell-laden microengineered gelatin methacrylate hydrogels. Biomaterials 31:5536–5544

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Wu S, Deng L, Hsia HS, Xu K, He Y, Huang QR, Peng Y, Zhou ZH, Peng C (2017) Evaluation of gelatin-hyaluronic acid composite hydrogels for accelerating wound healing. J Biomater Appl 31:1380–1390. https://doi.org/10.1177/0885328217702526

    Article  CAS  PubMed  Google Scholar 

  30. Fairbanks BD, Schwartz MP, Bowman CN, Anseth KS (2009) Photoinitiated polymerization of PEG-diacrylate with lithium phenyl-2,4,6-trimethylbenzoylphosphinate: polymerization rate and cytocompatibility. Biomaterials 30:6702–6707

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Yu S, Duan YY, Zuo XG, Chen XY, Mao ZW, Gao CY (2018) Mediating the invasion of smooth muscle cells into a cell-responsive hydrogel under the existence of immune cells. Biomaterials 180:193–205

    CAS  PubMed  Google Scholar 

  32. Shin SR, Aghaei-Ghareh-Bolagh B, Dang TT, Topkaya SN, Gao XG, Yang SY, Jung SM, Oh JH, Dokmeci MR, Tang XW, Khademhosseini A (2013) Cell-laden microengineered and mechanically tunable hybrid hydrogels of gelatin and graphene oxide. Adv Mater 25:6385–6391

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C (1999) Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radical Bio Med 26:1231–1237

    CAS  Google Scholar 

  34. Yu S, Gao Y, Mei X, Ren TC, Liang S, Mao ZW, Gao CY (2016) Preparation of an Arg-Glu-Asp-Val peptide density gradient on hyaluronic acid-coated poly(epsilon-caprolactone) film and its influence on the selective adhesion and directional migration of endothelial cells. ACS Appl Mater Inter 8:29280–29288

    CAS  Google Scholar 

  35. Oudshoorn MHM, Rissmann R, Bouwstra JA, Hennink WE (2007) Synthesis of methacrylated hyaluronic acid with tailored degree of substitution. Polymer 48:1915–1920

    CAS  Google Scholar 

  36. Ovsianikov A, Deiwick A, Van Vlierberghe S, Dubruel P, Moller L, Drager G, Chichkov B (2011) Laser fabrication of three-dimensional CAD scaffolds from photosensitive gelatin for applications in tissue engineering. Biomacromol 12:851–858

    CAS  Google Scholar 

  37. Lee J, Yeo M, Kim W, Koo Y, Kim GH (2018) Development of a tannic acid cross-linking process for obtaining 3D porous cell-laden collagen structure. Int J Biol Macromol 110:497–503

    CAS  PubMed  Google Scholar 

  38. Ninan N, Muthiah M, Park I-K, Elain A, Thomas S, Grohens Y (2013) Pectin/carboxymethyl cellulose/microfibrillated cellulose composite scaffolds for tissue engineering. Carbohyd Polym 98:877–885

    CAS  Google Scholar 

  39. Zhao X, Lang Q, Yildirimer L, Lin ZY, Cui WG, Annabi N, Ng KW, Dokmeci MR, Ghaemmaghami AM, Khademhosseini A (2016) Photocrosslinkable gelatin hydrogel for epidermal tissue engineering. Adv Healthc Mater 5:108–118

    CAS  PubMed  Google Scholar 

  40. Jing X, Mi H-Y, Napiwocki BN, Peng X-F, Turng L-S (2017) Mussel-inspired electroactive chitosan/graphene oxide composite hydrogel with rapid self-healing and recovery behavior for tissue engineering. Carbon 125:557–570

    CAS  Google Scholar 

  41. Nam HG, Nam MG, Yoo PJ, Kim J-H (2019) Hydrogen bonding-based strongly adhesive coacervate hydrogels synthesized using poly(N-vinylpyrrolidone) and tannic acid. Soft Matter 15:785–791

    CAS  PubMed  Google Scholar 

  42. Roberts MC, Hanson MC, Massey AP, Karren EA, Kiser PF (2007) Dynamically restructuring hydrogel networks formed with reversible covalent crosslinks. Adv Mater 19:2503–2507

    CAS  Google Scholar 

  43. Lam J, Truong NF, Segura T (2014) Design of cell-matrix interactions in hyaluronic acid hydrogel scaffolds. Acta Biomater 10:1571–1580

    CAS  PubMed  Google Scholar 

  44. Arimura H, Ouchi T, Kishida A, Ohya Y (2005) Preparation of a hyaluronic acid hydrogel through polyion complex formation using cationic polylactide-based microspheres as a biodegradable cross-linking agent. J Biomat Sci-Polym E 16:1347–1358

    CAS  Google Scholar 

  45. Han L, Xu JL, Lu X, Gan DL, Wang ZX, Wang KF, Zhang HP, Yuan HP, Weng J (2017) Biohybrid methacrylated gelatin/polyacrylamide hydrogels for cartilage repair. J Mater Chem B 5:731–741

    CAS  PubMed  Google Scholar 

  46. Li XM, Zhang J, Kawazoe N, Chen GP (2017) Fabrication of highly crosslinked gelatin hydrogel and its influence on chondrocyte proliferation and phenotype. Polymers-Basel 9:309

    PubMed Central  Google Scholar 

  47. Poveda-Reyes S, Moulisova V, Sanmartin-Masia E, Quintanilla-Sierra L, Salmeron-Sanchez M, Ferrer GG (2016) Gelatin-hyaluronic acid hydrogels with tuned stiffness to counterbalance cellular forces and promote cell differentiation. Macromol Biosci 16:1311–1324

    CAS  PubMed  Google Scholar 

  48. Spearman BS, Agrawal NK, Rubiano A, Simmons CS, Mobini S, Schmidt CE (2020) Tunable methacrylated hyaluronic acid-based hydrogels as scaffolds for soft tissue engineering applications. J Biomed Mater Res A 108:279–291

    CAS  PubMed  Google Scholar 

  49. Guo JS, Sun W, Kim JP, Lu XL, Li QY, Lin M, Mrowczynski O, Rizk EB, Cheng JG, Qian GY, Yang J (2018) Development of tannin-inspired antimicrobial bioadhesives. Acta Biomater 72:35–44

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Zou Y, Guo J, Yin S-W, Wang J-M, Yang XQ (2015) Pickering emulsion gels prepared by hydrogen-bonded zein/tannic acid complex colloidal particles. J Agric Food Chem 63:7405–7414

    CAS  PubMed  Google Scholar 

  51. Lee H-Y, Hwang C-H, Kim H-E, Jeong S-H (2018) Enhancement of bio-stability and mechanical properties of hyaluronic acid hydrogels by tannic acid treatment. Carbohyd Polym 186:290–298

    CAS  Google Scholar 

  52. Natarajan V, Krithica N, Madhan B, Sehgal PK (2013) Preparation and properties of tannic acid cross-linked collagen scaffold and its application in wound healing. J Biomed Mater Res B 101:560–567

    Google Scholar 

  53. Shumate GT, Chopra R, Jones D, Messina DJ, Hee CK (2018) In vivo degradation of crosslinked hyaluronic acid fillers by exogenous hyaluronidases. Dermatol Surg 44:1075–1083

    CAS  PubMed  Google Scholar 

  54. Balogh GT, Illes J, Szekely Z, Forrai E, Gere A (2003) Effect of different metal ions on the oxidative damage and antioxidant capacity of hyaluronic acid. Arch Biochem Biophys 410:76–82

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was financially supported by the Special Fund Project for Guangdong Academy of Sciences to Build First-Class Research Institutions in China (2020GDASYL-20200103039, 2019GDASYL-0105009, 2019GDASYL-0501003, 2019GDASYL-0105008, 2019GDASYL-0402002, and 2017GDASCX-0103), Guangdong Basic and Applied Basic Research Foundation (2019A1515110207), Science and Technology Program of Guangzhou (202002030381), and Science and Technology Planning Project of Guangdong Province of China (2017A070701019).

Author information

Authors and Affiliations

Authors

Contributions

SY conceptualization, methodology, analysis, and writing original draft and reviewing. YJ preparing samples and characterization, and reviewing and editing biological part. CG editing. DL material characterization. ZG material characterization. DP reviewing and editing. QL validation and reviewing.

Corresponding authors

Correspondence to Shan Yu or Qunfeng Liu.

Ethics declarations

Conflict of interest

The authors declared that they have no conflicts of interest to this work. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 317 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, S., Ji, Y., Guo, C. et al. A dual-cross-linked hydrogel based on hyaluronic acid/gelatin tethered via tannic acid: mechanical properties’ enhancement and stability control. Iran Polym J 30, 307–317 (2021). https://doi.org/10.1007/s13726-020-00891-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13726-020-00891-9

Keywords

Navigation