Multidimensional gradient hydrogel and its application in sustained release


We prepared two types of multidimensional gradient hydrogels by simple electrophoresis using spherical graphite electrode. To explore their application in controlled drug release, rhodamine B (RB) and sodium salicylate (SS) were used as oppositely charged drug models respectively to in situ loading into the hydrogels by electrostatic interaction with the charged components accordingly. In both cases, the model drugs and the charged components of the hydrogels were gradiently distributed with the drug concentration increased from the gel surface to the gel core. For the crosslinking gradient hydrogel prepared at 2 V, the network size near the gel surface is about 3 times that of the gel core, and the release rate is 0.85 times of that of the non-gradient hydrogel. For the polymer chain gradient hydrogel prepared at 2.5 V, the relative content of polymer chain near the core of the gel is 2.5 times that of the gel surface, and the release rate is 0.71 times of the non-gradient hydrogel.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  1. 1.

    T-a A, Matsusaki M, Kaneko T, Akashi M (2008) Fabrication of temperature-responsive bending hydrogels with a nanostructured gradient. Adv Mater 20(11):2080–2083.

    CAS  Article  Google Scholar 

  2. 2.

    DeLong SA, Moon JJ, West JL (2005) Covalently immobilized gradients of bFGF on hydrogel scaffolds for directed cell migration. Biomaterials 26(16):3227–3234.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Hong B, Xue P, Wu Y, Bao J, Chuah YJ, Kang Y (2016) A concentration gradient generator on a paper-based microfluidic chip coupled with cell culture microarray for high-throughput drug screening. Biomed Microdevices 18(1):21.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Reynolds PM, Pedersen RH, Riehle MO, Gadegaard N (2012) A dual gradient assay for the parametric analysis of cell-surface interactions. Small 8(16):2541–2547.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Ostrovidov S, Annabi N, Seidi A, Ramalingam M, Dehghani F, Kaji H, Khademhosseini A (2012) Controlled release of drugs from gradient hydrogels for high-throughput analysis of cell-drug interactions. Anal Chem 84(3):1302–1309.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    He J, Du Y, Villa-Uribe JL, Hwang C, Li D, Khademhosseini A (2010) Rapid generation of biologically relevant hydrogels containing long-range chemical gradients. Adv Funct Mater 20(1):131–137.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Guarnieri D, De Capua A, Ventre M, Borzacchiello A, Pedone C, Marasco D, Ruvo M, Netti PA (2010) Covalently immobilized RGD gradient on PEG hydrogel scaffold influences cell migration parameters. Acta Biomater 6(7):2532–2539.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Guvendiren M, Yang S, Burdick JA (2009) Swelling-induced surface patterns in hydrogels with gradient crosslinking density. Adv Funct Mater 19(19):3038–3045.

    CAS  Article  Google Scholar 

  9. 9.

    Peret BJ, Murphy WL (2008) Controllable soluble protein concentration gradients in hydrogel networks. Adv Funct Mater 18(21):3410–3417.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Gao F, Xu Z, Liang Q, Liu B, Li H, Wu Y, Zhang Y, Lin Z, Wu M, Ruan C, Liu W (2018) Direct 3D printing of high strength biohybrid gradient hydrogel scaffolds for efficient repair of osteochondral defect. Adv Funct Mater 28(13):1706644.

    CAS  Article  Google Scholar 

  11. 11.

    Shu Y, Chan HN, Guan D, Wu H, Ma L (2017) A simple fabricated thickness-based stiffness gradient for cell studies. Sci Bull 62(3):222–228.

    CAS  Article  Google Scholar 

  12. 12.

    Kim TH, An DB, Oh SH, Kang MK, Song HH, Lee JH (2015) Creating stiffness gradient polyvinyl alcohol hydrogel using a simple gradual freezing-thawing method to investigate stem cell differentiation behaviors. Biomaterials 40:51–60.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Bui TQ, Cao VD, Do NBD, Christoffersen TE, Wang W, Kjoniksen AL (2018) Salinity gradient energy from expansion and contraction of poly(allylamine hydrochloride) hydrogels. ACS Appl Mater Interfaces 10(26):22218–22225.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Tan Y, Wang D, Xu H, Yang Y, Wang XL, Tian F, Xu P, An W, Zhao X, Xu S (2018) Rapid recovery hydrogel actuators in air with bionic large-ranged gradient structure. ACS Appl Mater Interfaces 10(46):40125–40131.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    T-a A, Akashi M (2009) Hydrogel logic gates using gradient semi-IPNs. Chem Commun 24:3548–3550.

    CAS  Article  Google Scholar 

  16. 16.

    Yang Y, Tian F, Wang X, Xu P, An W, Hu Y, Xu S (2019) Biomimetic color-changing hierarchical and gradient hydrogel actuators based on salt-induced microphase separation. ACS Appl Mater Interfaces 11(51):48428–48436.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Tan Y, Wu R, Li H, Ren W, Du J, Xu S, Wang J (2015) Electric field-induced gradient strength in nanocomposite hydrogel through gradient crosslinking of clay. J Mater Chem B 3(21):4426–4430.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Li Z, Su Y, Xie B, Wang H, Wen T, He C, Shen H, Wu D, Wang D (2013) A tough hydrogel–hydroxyapatite bone-like composite fabricated in situ by the electrophoresis approach. J Mater Chem B 1(12):1755–1764.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Tan Y, Wang D, Xu H, Yang Y, An W, Yu L, Xiao Z, Xu S (2018) A fast, reversible, and robust gradient nanocomposite hydrogel actuator with water-promoted thermal response. Macromol Rapid Commun 39(8):e1700863.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Tan Y, Xu S, Wu R, Du J, Sang J, Wang J (2017) A gradient Laponite-crosslinked nanocomposite hydrogel with anisotropic stress and thermo-response. Appl Clay Sci 148:77–82.

    CAS  Article  Google Scholar 

  21. 21.

    Annabi N, Tamayol A, Uquillas JA, Akbari M, Bertassoni LE, Cha C, Camci-Unal G, Dokmeci MR, Peppas NA, Khademhosseini A (2014) 25th anniversary article: rational design and applications of hydrogels in regenerative medicine. Adv Mater 26(1):85–124.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Fan X, Wang T, Miao W (2018) The preparation of pH-sensitive hydrogel based on host-guest and electrostatic interactions and its drug release studies in vitro. J Polym Res 25(10):215.

    CAS  Article  Google Scholar 

  23. 23.

    Macdonald ML, Samuel RE, Shah NJ, Padera RF, Beben YM, Hammond PT (2011) Tissue integration of growth factor-eluting layer-by-layer polyelectrolyte multilayer coated implants. Biomaterials 32(5):1446–1453.

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Shah NJ, Hyder MN, Quadir MA, Dorval Courchesne NM, Seeherman HJ, Nevins M, Spector M, Hammond PT (2014) Adaptive growth factor delivery from a polyelectrolyte coating promotes synergistic bone tissue repair and reconstruction. Proc Natl Acad Sci U S A 111(35):12847–12852.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Peng CC, Burke MT, Chauhan A (2012) Transport of topical anesthetics in vitamin E loaded silicone hydrogel contact lenses. Langmuir 28(2):1478–1487.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Silva EA, Mooney DJ (2010) Effects of VEGF temporal and spatial presentation on angiogenesis. Biomaterials 31(6):1235–1241.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Freudenberg U, Zieris A, Chwalek K, Tsurkan MV, Maitz MF, Atallah P, Levental KR, Eming SA, Werner C (2015) Heparin desulfation modulates VEGF release and angiogenesis in diabetic wounds. J Control Release 220(Pt A):79–88.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Teng SH, Lee EJ, Wang P, Jun SH, Han CM, Kim HE (2008) Functionally gradient chitosan/hydroxyapatite composite scaffolds for controlled drug release. J Biomed Mater Res Part B 90B(1):275–282.

    CAS  Article  Google Scholar 

  29. 29.

    Liu Z, Xiao L, Xu B, Zhang Y, Mak AF, Li Y, Man WY, Yang M (2012) Covalently immobilized biomolecule gradient on hydrogel surface using a gradient generating microfluidic device for a quantitative mesenchymal stem cell study. Biomicrofluidics 6(2):24111–2411112.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Karpiak JV, Ner Y, Almutairi A (2012) Density gradient multilayer polymerization for creating complex tissue. Adv Mater 24(11):1466–1470.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Yang Y, Tan Y, Wang X, An W, Xu S, Liao W, Wang Y (2018) Photothermal nanocomposite hydrogel actuator with electric-field-induced gradient and oriented structure. ACS Appl Mater Interfaces 10(9):7688–7692.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Wang D, Tan Y, Yu L, Xiao Z, Du J, Ling J, Li N, Wang J, Xu S, Huang J (2019) Tuning morphology and mechanical property of polyacrylamide/laponite/titania dual nanocomposite hydrogels by titania. Polym Compos 40(S1):E466–E475.

    CAS  Article  Google Scholar 

  33. 33.

    Zhen H, Xin S, Ran QP, Liu JP (2013) Sythesis and characterization of cationic polyacrylamide aqueous dispersion. Acta Polym Sin 013:1013–1019.

    CAS  Article  Google Scholar 

  34. 34.

    Wei C, Dong X, Zhang Y, Liang J, Yang A, Zhu D, Liu T, Kong D, Lv F (2018) Simultaneous fluorescence imaging monitoring of the programmed release of dual drugs from a hydrogel-carbon nanotube delivery system. Sensors Actuators B Chem 273:264–275.

    CAS  Article  Google Scholar 

  35. 35.

    Thananukul K, Jarruwale P, Suttenun N, Thordason P, Punyamoonwongsa P (2015) Silk semi-interpenetrating network hydrogels for biomedical applications. Macromol Symp 354(1):251–257.

    CAS  Article  Google Scholar 

Download references


The work was supported by the Sichuan Science and Technology Program (No. 2018HH0024) and National Natural Science Foundation of China (No. 51773132).

Author information



Corresponding author

Correspondence to Shimei Xu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material


(DOCX 1882 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Xu, P., Tan, Y., Wang, X. et al. Multidimensional gradient hydrogel and its application in sustained release. Colloid Polym Sci (2020).

Download citation


  • Multidimensional gradient hydrogel
  • Controlled release
  • Electrophoresis
  • Drug concentration gradient