Tissue Engineering and Regenerative Medicine

, Volume 15, Issue 5, pp 513–520 | Cite as

Electrostatically Interactive Injectable Hydrogels for Drug Delivery

  • Ji Young Seo
  • Bong Lee
  • Tae Woong Kang
  • Jung Hyun Noh
  • Min Ju Kim
  • Yun Bae Ji
  • Hyeon Jin Ju
  • Byoung Hyun Min
  • Moon Suk KimEmail author
Review Article



Several injectable hydrogels have been developed extensively for a broad range of biomedical applications. Injectable hydrogels forming in situ through the change in external stimuli have the distinct properties of easy management and minimal invasiveness, and thus provide the advantage of bypassing surgical procedures for administration resulting in better patient compliance.


The injectable in situ-forming hydrogels can be formed irreversibly or reversibly under physiological stimuli. Among several external stimuli that induce formation of hydrogels in situ, in this review, we focused on the electrostatic interactions as the most simple and interesting stimulus.


Currently, numerous polyelectrolytes have been reported as potential electrostatically interactive in situ-forming hydrogels. In this review, a comprehensive overview of the rapidly developing electrostatically interactive in situ-forming hydrogels, which are produced by various anionic and cationic polyelectrolytes such as chitosan, celluloses, and alginates, has been outlined and summarized. Further, their biomedical applications have also been discussed.


The review concludes with perspectives on the future of electrostatically interactive in situ-forming hydrogels.


Electrostatic interactions In situ-forming hydrogels Injectable Drug delivery Regenerative medicine 



This work was supported by the Pukyong National University Research Abroad Fund in 2014 (C-D-2014-0713).

Compliance with ethical standards

Conflicts of interest

The authors have no financial conflicts of interest.

Ethical statement

There are no animal experiments carried out for this article.


  1. 1.
    Zhang Z. Injectable biomaterials for stem cell delivery and tissue regeneration. Expert Opin Biol Ther. 2016;17:49–62.CrossRefPubMedGoogle Scholar
  2. 2.
    Kim DY, Kwon DY, Kwon JS, Kim JH, Min BH, Kim MS. Stimuli-responsive injectable in situ-forming hydrogels for regenerative medicines. Polym Rev (Phila Pa). 2015;55:407–52.CrossRefGoogle Scholar
  3. 3.
    Yang J, Zhang YS, Yue K, Khademhosseini A. Cell-laden hydrogels for osteochondral and cartilage tissue engineering. Acta Biomater. 2017;57:1–25.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Luca A, Butnaru M, Maier SS, Knieling L, Bredetean O, Verestiuc L, et al. Atelocollagen-based hydrogels crosslinked with oxidised polysaccharides as cell encapsulation matrix for engineered bioactive stromal tissue. Tissue Eng Regen Med. 2017;14:539–56.CrossRefGoogle Scholar
  5. 5.
    Xia T, Liu W, Yang L. A review of gradient stiffness hydrogels used in tissue engineering and regenerative medicine. J Biomed Mater Res A. 2017;105:1799–812.CrossRefPubMedGoogle Scholar
  6. 6.
    Kim H, Jeong H, Han S, Beack S, Hwang BW, Shin M, et al. Hyaluronate and its derivatives for customized biomedical applications. Biomaterials. 2017;123:155–71.CrossRefPubMedGoogle Scholar
  7. 7.
    Vedadghavami A, Minooei F, Mohammadi MH, Khetani S, Rezaei Kolahchi A, Mashayekhan S, et al. Manufacturing of hydrogel biomaterials with controlled mechanical properties for tissue engineering applications. Acta Biomater. 2017;62:42–63.CrossRefPubMedGoogle Scholar
  8. 8.
    Das S, Zhou K, Ghosh D, Jha NN, Singh PK, Jacob RS, et al. Implantable amyloid hydrogels for promoting stem cell differentiation to neurons. NPG Asia Mater. 2016;8:e304.CrossRefGoogle Scholar
  9. 9.
    Jin GZ, Kim HW. Effects of type I collagen concentration in hydrogel on the growth and phenotypic expression of rat chondrocytes. Tissue Eng Regen Med. 2017;14:383–91.CrossRefGoogle Scholar
  10. 10.
    Bae JW, Choi JH, Lee Y, Park KD. Horseradish peroxidase-catalysed in situ-forming hydrogels for tissue-engineering applications. J Tissue Eng Regen Med. 2015;9:1225–32.CrossRefPubMedGoogle Scholar
  11. 11.
    Van Nieuwenhove I, Tytgat L, Ryx M, Blondeel P, Stillaert F, Thienpont H, et al. Soft tissue fillers for adipose tissue regeneration: From hydrogel development toward clinical applications. Acta Biomater. 2017;63:37–49.CrossRefPubMedGoogle Scholar
  12. 12.
    Saludas L, Pascual-Gil S, Prósper F, Garbayo E, Blanco-Prieto M. Hydrogel based approaches for cardiac tissue engineering. Int J Pharm. 2017;523:454–75.CrossRefPubMedGoogle Scholar
  13. 13.
    Song WY, Liu GM, Li J, Luo YG. Bone morphogenetic protein-2 sustained delivery by hydrogels with microspheres repairs rabbit mandibular defects. Tissue Eng Regen Med. 2016;13:750–61.CrossRefGoogle Scholar
  14. 14.
    Shi Z, Gao X, Ullah MW, Li S, Wang Q, Yang G. Electroconductive natural polymer-based hydrogels. Biomaterials. 2016;111:40–54.CrossRefPubMedGoogle Scholar
  15. 15.
    Zhao LZ, Zhou CH, Wang J, Tong DS, Yu WH, Wang H. Recent advances in clay mineral-containing nanocomposite hydrogels. Soft Matter. 2015;11:9229–46.CrossRefPubMedGoogle Scholar
  16. 16.
    Park SH, Kim DY, Panta P, Heo JY, Lee HY, Kim JH, et al. An intratumoral injectable, electrostatic, cross-linkable curcumin depot and synergistic enhancement of anticancer activity. NPG Asia Mater. 2017;9:e397.CrossRefGoogle Scholar
  17. 17.
    Lee JY, Kang YM, Kim ES, Kang ML, Lee B, Kim JH, et al. In vitro and in vivo release of albumin from an electrostatically crosslinked in situ-forming gel. J Mater Chem. 2010;20:3265–71.CrossRefGoogle Scholar
  18. 18.
    Shinya S, Fukamizo T. Interaction between chitosan and its related enzymes: a review. Int J Biol Macromol. 2017;104:1422–35.CrossRefPubMedGoogle Scholar
  19. 19.
    Oliveira NM, Reis RL, Mano JF. The potential of liquid marbles for biomedical applications: a critical review. Adv Healthc Mater. 2017;6:1700192.CrossRefGoogle Scholar
  20. 20.
    Cho KH, Singh B, Maharjan S, Jang Y, Choi YJ, Cho CS. Local delivery of CTGF siRNA with poly(sorbitol-co-PEI) reduces scar contraction in cutaneous wound healing. Tissue Eng Regen Med. 2017;14:211–20.CrossRefGoogle Scholar
  21. 21.
    Borges J, Mano JF. Molecular interactions driving the layer-by-layer assembly of multilayers. Chem Rev. 2014;114:8883–942.CrossRefPubMedGoogle Scholar
  22. 22.
    Raftery R, O’Brien FJ, Cryan SA. Chitosan for gene delivery and orthopedic tissue engineering applications. Molecules. 2013;18:5611–47.CrossRefPubMedGoogle Scholar
  23. 23.
    Jho Y, Yoo HY, Lin Y, Han S, Hwang DS. Molecular and structural basis of low interfacial energy of complex coacervates in water. Adv Colloid Interface Sci. 2017;239:61–73.CrossRefPubMedGoogle Scholar
  24. 24.
    Elsaid N, Jackson TL, Elsaid Z, Alqathama A, Somavarapu S. PLGA microparticles entrapping chitosan-based nanoparticles for the ocular delivery of ranibizumab. Mol Pharm. 2016;13:2923–40.CrossRefPubMedGoogle Scholar
  25. 25.
    Duque Sánchez L, Brack N, Postma A, Pigram PJ, Meagher L. Surface modification of electrospun fibres for biomedical applications: a focus on radical polymerization methods. Biomaterials. 2016;106:24–45.CrossRefPubMedGoogle Scholar
  26. 26.
    Frost SJ, Mawad D, Higgins MJ, Ruprai H, Kuchel R, Tilley RD, et al. Gecko-inspired chitosan adhesive for tissue repair. NPG Asia Mater. 2016;8:e280.CrossRefGoogle Scholar
  27. 27.
    Sobhani A, Rafienia M, Ahmadian M, Naimi-Jamal MR. Fabrication and characterization of polyphosphazene/calcium phosphate scaffolds containing chitosan microspheres for sustained release of bone morphogenetic protein 2 in bone tissue engineering. Tissue Eng Regen Med. 2017;14:525–38.CrossRefGoogle Scholar
  28. 28.
    Zhou HY, Jiang LJ, Cao PP, Li JB, Chen XG. Glycerophosphate-based chitosan thermosensitive hydrogels and their biomedical applications. Carbohydr Polym. 2015;117:524–36.CrossRefPubMedGoogle Scholar
  29. 29.
    Tahrir FG, Ganji F, Ahooyi TM. Injectable thermosensitive chitosan/glycerophosphate-based hydrogels for tissue engineering and drug delivery applications: a review. Recent Pat Drug Deliv Formul. 2015;9:107–20.CrossRefPubMedGoogle Scholar
  30. 30.
    Shimojo AAM, Galdames SEM, Perez AGM, Ito TH, Luzo ACM, Santana MHA. In vitro performance of injectable chitosan-tripolyphosphate scaffolds combined with platelet-rich plasma. Tissue Eng Regen Med. 2016;13:21–30.CrossRefGoogle Scholar
  31. 31.
    Kim KS, Lee JH, Ahn HH, Lee JY, Lee B, Lee HB, et al. The osteogenic differentiation of rat muscle-derived stem cells in vivo within in situ-forming chitosan scaffolds. Biomaterials. 2008;29:4420–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Cho MH, Kim KS, Ahn HH, Kim MS, Kim SH, Khang G, et al. Chitosan gel as an in situ-forming scaffold for rat bone marrow mesenchymal stem cells in vivo. Tissue Eng Part A. 2008;14:1099–108.CrossRefPubMedGoogle Scholar
  33. 33.
    Junter GA, Thébault P, Lebrun L. Polysaccharide-based antibiofilm surfaces. Acta Biomater. 2016;30:13–25.CrossRefPubMedGoogle Scholar
  34. 34.
    Song L, Li L, He T, Wang N, Yang S, Yang X, et al. Peritoneal adhesion prevention with a biodegradable and injectable N,O-carboxymethyl chitosan-aldehyde hyaluronic acid hydrogel in a rat repeated-injury model. Sci Rep. 2016;6:37600.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Alvarez-Lorenzo C, Blanco-Fernandez B, Puga AM, Concheiro A. Crosslinked ionic polysaccharides for stimuli-sensitive drug delivery. Adv Drug Deliv Rev. 2013;65:1148–71.CrossRefPubMedGoogle Scholar
  36. 36.
    Abeer MM, Mohd Amin MC, Martin C. A review of bacterial cellulose-based drug delivery systems: their biochemistry, current approaches and future prospects. J Pharm Pharmacol. 2014;66:1047–61.PubMedGoogle Scholar
  37. 37.
    Yang Y, Liu X, Li Y, Wang Y, Bao C, Chen Y, et al. A postoperative anti-adhesion barrier based on photoinduced imine-crosslinking hydrogel with tissue-adhesive ability. Acta Biomater. 2017;62:199–209.CrossRefPubMedGoogle Scholar
  38. 38.
    Kim MS, Kim JH, Min BH, Chun HJ, Han DK, Lee HB. Polymeric scaffolds for regenerative medicine. Polym Rev (Phila Pa). 2011;51:23–52.CrossRefGoogle Scholar
  39. 39.
    Udoetok IA, Wilson LD, Headley JV. Quaternized cellulose hydrogels as sorbent materials and pickering emulsion stabilizing agents. Materials (Basel). 2016;9:E645.CrossRefGoogle Scholar
  40. 40.
    Wu Y, Wang L, Qing Y, Yan N, Tian C, Huang Y. A green route to prepare fluorescent and absorbent nano-hybrid hydrogel for water detection. Sci Rep. 2017;7:4380.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Wang W, Zhang X, Teng A, Liu A. Mechanical reinforcement of gelatin hydrogel with nanofiber cellulose as a function of percolation concentration. Int J Biol Macromol. 2017;103:226–33.CrossRefPubMedGoogle Scholar
  42. 42.
    Dolan GK, Yakubov GE, Bonilla MR, Lopez-Sanchez P, Stokes JR. Friction, lubrication, and in situ mechanics of poroelastic cellulose hydrogels. Soft Matter. 2017;13:3592–601.CrossRefPubMedGoogle Scholar
  43. 43.
    Kim KS, Kang YM, Lee JY, Kim ES, Kim CH, Min BH, et al. Injectable CMC/PEI gel as an in vivo scaffold for demineralized bone matrix. Biomed Mater Eng. 2009;19:381–90.PubMedGoogle Scholar
  44. 44.
    Nguyen MK, Alsberg E. Bioactive factor delivery strategies from engineered polymer hydrogels for therapeutic medicine. Prog Polym Sci. 2014;39:1235–65.CrossRefGoogle Scholar
  45. 45.
    Giri TK, Thakur D, Alexander A, Ajazuddin, Badwaik H, Tripathi DK. Alginate based hydrogel as a potential biopolymeric carrier for drug delivery and cell delivery systems: present status and applications. Curr Drug Deliv. 2012;9:539–55.CrossRefPubMedGoogle Scholar
  46. 46.
    Mun CH, Hwang JY, Lee SH. Microfluidic spinning of the fibrous alginate scaffolds for modulation of the degradation profile. Tissue Eng Regen Med. 2016;13:140–8.CrossRefGoogle Scholar
  47. 47.
    Williams PA, Campbell KT, Silva EA. Alginate hydrogels of varied molecular weight distribution enable sustained release of sphingosine-1-phosphate and promote angiogenesis. J Biomed Mater Res A. 2018;106:138–46.CrossRefPubMedGoogle Scholar
  48. 48.
    Bauer A, Gu L, Kwee B, Li WA, Dellacherie M, Celiz AD, et al. Hydrogel substrate stress-relaxation regulates the spreading and proliferation of mouse myoblasts. Acta Biomater. 2017;62:82–90.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Mahapatra C, Jin GZ, Kim HW. Alginate-hyaluronic acid-collagen composite hydrogel favorable for the culture of chondrocytes and their phenotype maintenance. Tissue Eng Regan Med. 2016;13:538–46.CrossRefGoogle Scholar
  50. 50.
    Chen Y, Yan X, Zhao J, Feng H, Li P, Tong Z, et al. Preparation of the chitosan/poly(glutamic acid)/alginate polyelectrolyte complexing hydrogel and study on its drug releasing property. Carbohydr Polym. 2018;191:8–16.CrossRefPubMedGoogle Scholar
  51. 51.
    Wei Z, Zhao J, Chen YM, Zhang P, Zhang Q. Self-healing polysaccharide-based hydrogels as injectable carriers for neural stem cells. Sci Rep. 2016;6:37841.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Lym JS, Nguyen QV, Ahn da W, Huynh CT, Jae HJ, Kim YI, et al. Sulfamethazine-based pH-sensitive hydrogels with potential application for transcatheter arterial chemoembolization therapy. Acta Biomater. 2016;41:253–63.CrossRefPubMedGoogle Scholar
  53. 53.
    Li X, Liu L, Wang X, Ok YS, Elliott JAW, Chang SX, et al. Flexible and self-healing aqueous supercapacitors for low temperature applications: polyampholyte gel electrolytes with biochar electrodes. Sci Rep. 2017;7:1685.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Shim SW, Kwon DY, Park JH, Kim JH, Chun HJ, Koh YJ, et al. Preparation of zwitterionic sulfobetaine end-functionalized poly(ethylene glycol)-b-poly(caprolactone) diblock copolymers and examination of their thermogelling properties. J Polym Sci A Ploym Chem. 2014;52:2185–91.CrossRefGoogle Scholar
  55. 55.
    Jung BK, Oh E, Hong J, Lee Y, Park KD, Yun CO. A hydrogel matrix prolongs persistence and promotes specific localization of an oncolytic adenovirus in a tumor by restricting nonspecific shedding and an antiviral immune response. Biomaterials. 2017;147:26–38.CrossRefPubMedGoogle Scholar
  56. 56.
    Kim DY, Kwon DY, Kwon JS, Park JH, Park SH, Oh HJ, et al. Synergistic anti-tumor activity through combinational intratumoral injection of an in situ injectable drug depot. Biomaterials. 2016;85:232–45.CrossRefPubMedGoogle Scholar
  57. 57.
    Wang C, Wang X, Dong K, Luo J, Zhang Q, Cheng Y. Injectable and responsively degradable hydrogel for personalized photothermal therapy. Biomaterials. 2016;104:129–37.CrossRefPubMedGoogle Scholar
  58. 58.
    Kanazawa T, Tamano K, Sogabe K, Endo T, Ibaraki H, Takashima Y, et al. Intra-articular retention and anti-arthritic effects in collagen-induced arthritis model mice by injectable small interfering RNA containing hydrogel. Biol Pharm Bull. 2017;40:1929–33.CrossRefPubMedGoogle Scholar
  59. 59.
    Cheng OT, Souzdalnitski D, Vrooman B, Cheng J. Evidence-based knee injections for the management of arthritis. Pain Med. 2012;13:740–53.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Park JH, Park SH, Lee HY, Lee JW, Lee BK, Lee BY, et al. An injectable, electrostatically interacting drug depot for the treatment of rheumatoid arthritis. Biomaterials. 2018;154:86–98.CrossRefPubMedGoogle Scholar
  61. 61.
    Kim K, Park JH, Park SH, Lee HY, Kim JH, Kim MS. An injectable, click-cross-linked small intestinal submucosa drug depot for the treatment of rheumatoid arthritis. Adv Healthc Mater. 2016;5:3105–17.CrossRefPubMedGoogle Scholar
  62. 62.
    Wang P, Zhuo X, Chu W, Tang X. Exenatide-loaded microsphere/thermosensitive hydrogel long-acting delivery system with high drug bioactivity. Int J Pharm. 2017;528:62–75.CrossRefPubMedGoogle Scholar
  63. 63.
    Zhao F, Wu D, Yao D, Guo R, Wang W, Dong A, et al. An injectable particle-hydrogel hybrid system for glucose-regulatory insulin delivery. Acta Biomater. 2017;64:334–45.CrossRefPubMedGoogle Scholar
  64. 64.
    Shen YI, Cho H, Papa AE, Burke JA, Chan XY, Duh EJ, et al. Engineered human vascularized constructs accelerate diabetic wound healing. Biomaterials. 2016;102:107–19.CrossRefPubMedGoogle Scholar
  65. 65.
    Tendulkar S, Mirmalek-Sani SH, Childers C, Saul J, Opara EC, Ramasubramanian MK. A three-dimensional microfluidic approach to scaling up microencapsulation of cells. Biomed Microdevices. 2012;14:461–9.CrossRefPubMedGoogle Scholar
  66. 66.
    Tong X, Yang F. Recent progress in developing injectable matrices for enhancing cell delivery and tissue regeneration. Adv Healthc Mater. 2018;7:e1701065.CrossRefPubMedGoogle Scholar
  67. 67.
    Lee BH, Shirahama H, Kim MH, Lee JH, Cho NJ, Tan LP. Colloidal templating of highly ordered gelatin methacryloyl-based hydrogel platforms for three-dimensional tissue analogues. NPG Asia Mater. 2017;9:e412.CrossRefGoogle Scholar

Copyright information

© The Korean Tissue Engineering and Regenerative Medicine Society and Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Molecular Science and TechnologyAjou UniversitySuwonRepublic of Korea
  2. 2.Department of Polymer EngineeringPukyong National UniversityBusanRepublic of Korea
  3. 3.Cell Therapy CenterAjou University Medical CenterSuwonRepublic of Korea

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