SpringerLink
Log in

Role of crosslinkers for synthesizing biocompatible, biodegradable and mechanically strong hydrogels with desired release profile

  • Review Paper
  • Published:
Polymer Bulletin Aims and scope Submit manuscript

Abstract

Over the time, hydrogels have emerged as one of the most potential candidates for drug delivery and tissue engineering systems due to their swellable and porous nature. Fabrication process of hydrogel requires addition of crosslinkers. Various chemical (e.g., crosslinking by chemical reaction of complementary groups, polymer–polymer crosslinking, high energy irradiation and enzyme incorporation) and physical (e.g., charge interactions, crystallization and stereocomplex formation) approaches have been employed for crosslinking hydrogels. Majority of the conventionally employed crosslinkers are toxic in nature and unfavorable for use. Moreover, they have poor water solubility and low biodegradation rate. Various natural (e.g., vanillin, citric acid, gallic acid, ferulic acid and genipin) and synthetic (e.g., polymerizable polyphosphate, 1,2,3,4-butanetetracarboxylic dianhydride and 2-chloro-1-methylpyrinium iodide) novel crosslinking agents have been developed to overcome these limitations and to produce hydrogels with good mechanical properties. Furthermore, novel non-toxic crosslinkers are being introduced for modulating release characteristics and attaining controlled drug release profile of hydrogels made up of highly soluble and erodible polymers. Considering the drawbacks of conventional crosslinkers, there is a need to search for more biocompatible and biodegradable novel polymers to attain safe and efficient hydrogel formulations.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Chen G, Tang W, Wang X, Zhao X, Chen C, Zhu Z (2019) Applications of hydrogels with special physical properties in biomedicine. Polymers 11(9):1–17

    Article  Google Scholar 

  2. Arshad MS, Zahra AT, Zafar S, Zaman H, Akhtar A, Ayaz MM, Kucuk I, Maniruzzaman M, Chang M-W, Ahmad Z (2021) Antibiofilm effects of macrolide loaded microneedle patches: prospects in healing infected wounds. Pharm Res 38(1):165–177

    Article  CAS  PubMed  Google Scholar 

  3. Arshad MS, Zafar S, Zahra AT, Zaman MH, Akhtar A, Kucuk I, Farhan M, Chang M-W, Ahmad Z (2021) Fabrication and characterisation of self-applicating heparin sodium microneedle patches. J Drug Target 29(1):60–68

    Article  CAS  PubMed  Google Scholar 

  4. Khan S, Ullah A, Ullah K, Rehman N-u (2016) Insight into hydrogels. Des Monomers Polym 19(5):456–478

    Article  CAS  Google Scholar 

  5. Ahmed EM (2015) Hydrogel: Preparation, characterization, and applications: a review. J Adv Res 6(2):105–121

    Article  CAS  PubMed  Google Scholar 

  6. Akhtar MF, Hanif M, Ranjha NM (2016) Methods of synthesis of hydrogels… a review. Saudi Pharm J 24(5):554–559

    Article  PubMed  Google Scholar 

  7. Hoare TR, Kohane DS (2008) Hydrogels in drug delivery: progress and challenges. Polymer 49(8):1993–2007

    Article  CAS  Google Scholar 

  8. Parhi R (2017) Cross-linked hydrogel for pharmaceutical applications: a review. Adv Pharm Bull 7(4):515–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mondal S, Das S, Nandi AK (2020) A review on recent advances in polymer and peptide hydrogels. Soft Matter 16(6):1404–1454

    Article  CAS  PubMed  Google Scholar 

  10. Kevin J, D'Emilio E, Cranston ED, Geiger T, Nyström G (2020) Dual physically and chemically crosslinked regenerated cellulose–Gelatin composite hydrogels towards art restoration. Carbohydr Polym 234(1):115885

  11. Zhang X, Zhang R, Wu S, Sun Y, Yang H, Lin B (2020) Physically and chemically dual-crosslinked hydrogels with superior mechanical properties and self-healing behavior. New J Chem 44(23):9903–9911

    Article  CAS  Google Scholar 

  12. Hellio D, Djabourov M (2006) Physically and chemically crosslinked gelatin gels. Macromol Symp 241(1):23–27

    Article  CAS  Google Scholar 

  13. Bashir S, Hina M, Iqbal J, Rajpar A, Mujtaba M, Alghamdi N, Wageh S, Ramesh K, Ramesh S (2020) Fundamental concepts of hydrogels: synthesis, properties, and their applications. Polymers 12(11):1–60

    Article  Google Scholar 

  14. Hennink WE, van Nostrum CF (2012) Novel crosslinking methods to design hydrogels. Adv Drug Deliv Rev 64(1):223–236

    Article  Google Scholar 

  15. Naeem F, Khan S, Jalil A, Ranjha NM, Riaz A, Haider MS, Sarwar S, Saher F, Afzal S (2017) pH responsive cross-linked polymeric matrices based on natural polymers: effect of process variables on swelling characterization and drug delivery properties. BioImpacts 7(3):177–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hu W, Wang Z, **ao Y, Zhang S, Wang J (2019) Advances in crosslinking strategies of biomedical hydrogels. Biomater Sci 7(3):843–855

    Article  CAS  PubMed  Google Scholar 

  17. Peppas NA, Berner RE Jr (1980) Proposed method of intracopdal injection and gelation of poly (vinyl alcohol) solution in vocal cords: polymer considerations. Biomaterials 1(3):158–162

    Article  CAS  PubMed  Google Scholar 

  18. Dai W, Barbari T (1999) Hydrogel membranes with mesh size asymmetry based on the gradient crosslinking of poly (vinyl alcohol). J Membr Sci 156(1):67–79

    Article  CAS  Google Scholar 

  19. Tabata Y, Ikada Y (1989) Synthesis of gelatin microspheres containing interferon. Pharm Res 6(5):422–427

    Article  CAS  PubMed  Google Scholar 

  20. Luo Y, Kirker KR, Prestwich GD (2000) Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery. J Control Release 69(1):169–184

    Article  CAS  PubMed  Google Scholar 

  21. Draye J-P, Delaey B, Van de Voorde A, Van Den Bulcke A, Bogdanov B, Schacht E (1998) In vitro release characteristics of bioactive molecules from dextran dialdehyde cross-linked gelatin hydrogel films. Biomaterials 19(1–3):99–107

    Article  PubMed  Google Scholar 

  22. Elbert D, Lutolf M, Pratt A, Halstenberg S, Hubbell J (2001) Protein release from PEG hydrogels that are similar to ideal Flory-Rehner Networks. Controlled Release Bioact Mater 28(1):987–988

    Google Scholar 

  23. de Nooy AE, Capitani D, Masci G, Crescenzi V (2000) Ionic polysaccharide hydrogels via the Passerini and Ugi multicomponent condensations: synthesis, behavior and solid-state NMR characterization. Biomacromol 1(2):259–267

    Article  Google Scholar 

  24. Ichi T, Watanabe J, Ooya T, Yui N (2001) Controllable erosion time and profile in poly (ethylene glycol) hydrogels by supramolecular structure of hydrolyzable polyrotaxane. Biomacromolecules 2(1):204–210

    Article  CAS  PubMed  Google Scholar 

  25. Tan H, Chu CR, Payne KA, Marra KG (2009) Injectable in situ forming biodegradable chitosan–hyaluronic acid based hydrogels for cartilage tissue engineering. Biomaterials 30(13):2499–2506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lee KY, Alsberg E, Mooney DJ (2001) Degradable and injectable poly (aldehyde guluronate) hydrogels for bone tissue engineering. J Biomed Mater Res 56(2):228–233

    Article  CAS  PubMed  Google Scholar 

  27. Elbert DL, Pratt AB, Lutolf MP, Halstenberg S, Hubbell JA (2001) Protein delivery from materials formed by self-selective conjugate addition reactions. J Control Release 76(1–2):11–25

    Article  CAS  PubMed  Google Scholar 

  28. Giammona G, Pitarresi G, Cavallaro G, Spadaro G (1999) New biodegradable hydrogels based on an acryloylated polyaspartamide cross-linked by gamma irradiation. J Biomater Sci Polym Ed 10(9):969–987

    Article  CAS  PubMed  Google Scholar 

  29. Hiemstra C, van der Aa LJ, Zhong Z, Dijkstra PJ, Feijen J (2007) Novel in situ forming, degradable dextran hydrogels by Michael addition chemistry: synthesis, rheology, and degradation. Macromolecules 40(4):1165–1173

    Article  CAS  Google Scholar 

  30. Bulpitt P, Aeschlimann D (1999) New strategy for chemical modification of hyaluronic acid: preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels. J Biomed Mater Res 47(2):152–169

    Article  CAS  PubMed  Google Scholar 

  31. Ito T, Yeo Y, Highley CB, Bellas E, Benitez CA, Kohane DS (2007) The prevention of peritoneal adhesions by in situ cross-linking hydrogels of hyaluronic acid and cellulose derivatives. Biomaterials 28(6):975–983

    Article  CAS  PubMed  Google Scholar 

  32. Moerkerke R, Meeussen F, Koningsveld R, Berghmans H, Mondelaers W, Schacht E, Dušek K, Šolc K (1998) Phase transitions in swollen networks. 3. Swelling behavior of radiation cross-linked poly (vinyl methyl ether) in water. Macromolecules 31(7):2223–2229

  33. Arndt K-F, Schmidt T, Reichelt R (2001) Thermo-sensitive poly (methyl vinyl ether) micro-gel formed by high energy radiation. Polymer 42(16):6785–6791

    Article  CAS  Google Scholar 

  34. Jeong J-O, Park J-S, Kim EJ, Jeong S-I, Lee JY, Lim Y-M (2020) Preparation of radiation cross-linked poly (Acrylic acid) hydrogel containing metronidazole with enhanced antibacterial activity. Int J Mol Sci 21(1):1–14

    Google Scholar 

  35. Jeong J-O, Park J-S, Kim Y-A, Yang S-J, Jeong S-I, Lee J-Y, Lim Y-M (2020) Gamma ray-induced polymerization and cross-linking for optimization of PPy/PVP hydrogel as biomaterial. Polymers 12(1):1–11

    Article  Google Scholar 

  36. Mitsui H, Hosoi F, Kagiya T (1973) γ-radiation-induced cross-linking of polyethylene. Polym J 4(1):79–86

    Article  CAS  Google Scholar 

  37. Rimdusit S, Somsaeng K, Kewsuwan P, Jubsilp C, Tiptipakorn S (2012) Comparison of gamma radiation crosslinking and chemical crosslinking on properties of methylcellulose hydrogel. Eng J 16(4):15–28

    Article  Google Scholar 

  38. Tavakol M, Dehshiri S, Vasheghani-Farahani E (2016) Electron beam irradiation crosslinked hydrogels based on tyramine conjugated gum tragacanth. Carbohydr Polym 152(1):504–509

    Article  CAS  PubMed  Google Scholar 

  39. Moghaddam RH, Dadfarnia S, Shabani AMH, Moghaddam ZH, Tavakol M (2019) Electron beam irradiation synthesis of porous and non-porous pectin based hydrogels for a tetracycline drug delivery system. Mater Sci Eng C 102(1):391–404

    Article  Google Scholar 

  40. Călina I, Demeter M, Scărișoreanu A, Sătulu V, Mitu B (2020) One step e-beam radiation cross-linking of quaternary hydrogels dressings based on chitosan-poly (vinyl-pyrrolidone)-poly (ethylene glycol)-poly (acrylic acid). Int J Mol Sci 21(23):1–24

    Article  Google Scholar 

  41. Suliwarno A (2014) Hydrogel based on crosslinked methylcellulose prepared by electron beam irradiation for wound dressing application. Indones J Chem 14(3):262–268

    Article  CAS  Google Scholar 

  42. Ono K, Saito Y, Yura H, Ishikawa K, Kurita A, Akaike T, Ishihara M (2000) Photocrosslinkable chitosan as a biological adhesive. J Biomed Mater Res 49(2):289–295

    Article  CAS  PubMed  Google Scholar 

  43. Xu Q, McMichael P, Creagh-Flynn J, Zhou D, Gao Y, Li X, Wang X, Wang W (2018) Double-cross-linked hydrogel strengthened by UV irradiation from a hyperbranched PEG-based trifunctional polymer. ACS Macro Lett 7(5):509–513

    Article  CAS  PubMed  Google Scholar 

  44. Shamekhi M, Jafari S, Khonakdar H, Ehsani M (2010) Preparation and characterisation of UV irradiation cross-linked LDPE/EVA blends. Plast Rubber Compos 39(10):431–436

    Article  CAS  Google Scholar 

  45. Teixeira RS, Correa RJ, Belvino A, Nascimento RS (2013) UV Irradiation-induced crosslinking of aqueous solution of poly (ethylene oxide) with benzophenone as initiator. J Appl Polym Sci 130(4):2458–2467

    Article  CAS  Google Scholar 

  46. Cook JP, Goodall GW, Khutoryanskaya OV, Khutoryanskiy VV (2012) Microwave-assisted hydrogel synthesis: a new method for crosslinking polymers in aqueous solutions. Macromol Rapid Commun 33(4):332–336

    Article  CAS  PubMed  Google Scholar 

  47. Larraneta E, Lutton RE, Brady AJ, Vicente-Pérez EM, Woolfson AD, Thakur RRS, Donnelly RF (2015) Microwave-assisted preparation of hydrogel-forming microneedle arrays for transdermal drug delivery applications. Macromol Mater Eng 300(6):586–595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Radwan-Pragłowska J, Piątkowski M, Janus Ł, Bogdał D, Matysek D, Čablik V (2019) Microwave-assisted synthesis and characterization of antibacterial O-crosslinked chitosan hydrogels doped with TiO2 nanoparticles for skin regeneration. Int J Polym Mater Polym Biomater 68(15):881–890

    Article  Google Scholar 

  49. Sperinde JJ, Griffith LG (1997) Synthesis and characterization of enzymatically-cross-linked poly (ethylene glycol) hydrogels. Macromolecules 30(18):5255–5264

    Article  CAS  Google Scholar 

  50. Yung C, Wu L, Tullman J, Payne G, Bentley W, Barbari T (2007) Transglutaminase crosslinked gelatin as a tissue engineering scaffold. J Biomed Mater Res A 83(4):1039–1046

    Article  CAS  PubMed  Google Scholar 

  51. Kim K, Park S, Yang J-A, Jeon J-H, Bhang S, Kim B-S, Hahn S (2011) Injectable hyaluronic acid–tyramine hydrogels for the treatment of rheumatoid arthritis. Acta Biomater 7(2):666–674

    Article  CAS  PubMed  Google Scholar 

  52. Wu J, Su Z-G, Ma G-H (2006) A thermo-and pH-sensitive hydrogel composed of quaternized chitosan/glycerophosphate. Int J Pharm 315(1–2):1–11

    Article  CAS  PubMed  Google Scholar 

  53. Gacesa P (1988) Alginates. Carbohydr Polym 8(3):161–182

    Article  CAS  Google Scholar 

  54. Gombotz WR, Wee S (1998) Protein release from alginate matrices. Adv Drug Deliv Rev 31(3):267–285

    Article  CAS  PubMed  Google Scholar 

  55. Goosen MF, O’Shea GM, Gharapetian HM, Chou S, Sun AM (1985) Optimization of microencapsulation parameters: semipermeable microcapsules as a bioartificial pancreas. Biotechnol Bioeng 27(2):146–150

    Article  CAS  PubMed  Google Scholar 

  56. Polk A, Amsden B, De Yao K, Peng T, Goosen M (1994) Controlled release of albumin from chitosan-alginate microcapsules. J Pharm Sci 83(2):178–185

    Article  CAS  PubMed  Google Scholar 

  57. Liu L-S, Liu S-Q, Ng SY, Froix M, Ohno T, Heller J (1997) Controlled release of interleukin-2 for tumour immunotherapy using alginate/chitosan porous microspheres. J Control Release 43(1):65–74

    Article  CAS  Google Scholar 

  58. Andrianov AK, Payne LG, Visscher KB, Allcock HR, Langer R (1994) Hydrolytic degradation of ionically cross-linked polyphosphazene microspheres. J Appl Polym Sci 53(12):1573–1578

    Article  CAS  Google Scholar 

  59. Chenite A, Chaput C, Wang D, Combes C, Buschmann M, Hoemann C, Leroux J, Atkinson B, Binette F, Selmani A (2000) Novel injectable neutral solutions of chitosan form biodegradable gels in situ. Biomaterials 21(21):2155–2161

    Article  CAS  PubMed  Google Scholar 

  60. Hossain KS, Miyanaga K, Maeda H, Nemoto N (2001) Sol− gel transition behavior of pure ι-carrageenan in both salt-free and added salt states. Biomacromolecules 2(2):442–449

    Article  CAS  PubMed  Google Scholar 

  61. Janes KA, Fresneau MP, Marazuela A, Fabra A, MaJ A (2001) Chitosan nanoparticles as delivery systems for doxorubicin. J Control Release 73(2–3):255–267

    Article  CAS  PubMed  Google Scholar 

  62. Yokoyama F, Masada I, Shimamura K, Ikawa T, Monobe K (1986) Morphology and structure of highly elastic poly (vinyl alcohol) hydrogel prepared by repeated freezing-and-melting. Colloid Polym Sci 264(7):595–601

    Article  CAS  Google Scholar 

  63. Stenekes R, Talsma H, Hennink W (2001) Formation of dextran hydrogels by crystallization. Biomaterials 22(13):1891–1898

    Article  CAS  PubMed  Google Scholar 

  64. Zhang Y, Song M, Diao Y, Li B, Shi L, Ran R (2016) Preparation and properties of polyacrylamide/polyvinyl alcohol physical double network hydrogel. RSC Adv 6(113):112468–112476

    Article  CAS  Google Scholar 

  65. Lim DW, Park TG (2000) Stereocomplex formation between enantiomeric PLA–PEG–PLA triblock copolymers: Characterization and use as protein-delivery microparticulate carriers. J Appl Polym Sci 75(13):1615–1623

    Article  CAS  Google Scholar 

  66. Tsuji H (2005) Poly (lactide) stereocomplexes: Formation, structure, properties, degradation, and applications. Macromol Biosci 5(7):569–597

    Article  CAS  PubMed  Google Scholar 

  67. Lim DW, Choi SH, Park TG (2000) A new class of biodegradable hydrogels stereocomplexed by enantiomeric oligo (lactide) side chains of poly (HEMA-g-OLA) s. Macromol Rapid Commun 21(8):464–471

    Article  CAS  Google Scholar 

  68. De Jong S, van Dijk-Wolthuis W, Kettenes-Van Den Bosch J, Schuyl P, Hennink W (1998) Monodisperse enantiomeric lactic acid oligomers: preparation, characterization, and stereocomplex formation. Macromolecules 31(19):6397–6402

    Article  Google Scholar 

  69. De Jong S, De Smedt S, Wahls M, Demeester J, Kettenes-van Den Bosch J, Hennink W (2000) Novel self-assembled hydrogels by stereocomplex formation in aqueous solution of enantiomeric lactic acid oligomers grafted to dextran. Macromolecules 33(10):3680–3686

    Article  Google Scholar 

  70. De Jong S, De Smedt S, Demeester J, Van Nostrum C, Kettenes-Van Den Bosch J, Hennink W (2001) Biodegradable hydrogels based on stereocomplex formation between lactic acid oligomers grafted to dextran. J Control Release 72(1–3):47–56

    Article  PubMed  Google Scholar 

  71. Tokareva MI, Ivantsova MN, Mironov MA (2017) Heterocycles of natural origin as non-toxic reagents for cross-linking of proteins and polysaccharides. Chem Heterocycl Compd 53(1):21–35

    Article  CAS  Google Scholar 

  72. Akakuru O, Isiuku B (2017) Chitosan hydrogels and their glutaraldehyde-crosslinked counterparts as potential drug release and tissue engineering systems-synthesis, characterization, swelling kinetics and mechanism. J Phys Chem Biophys 7(3):1–7

    Google Scholar 

  73. Tian Z, Liu W, Li G (2016) The microstructure and stability of collagen hydrogel cross-linked by glutaraldehyde. Polym Degrad Stab 130(1):264–270

    Article  CAS  Google Scholar 

  74. Yu S, Zhang X, Tan G, Tian L, Liu D, Liu Y, Yang X, Pan W (2017) A novel pH-induced thermosensitive hydrogel composed of carboxymethyl chitosan and poloxamer cross-linked by glutaraldehyde for ophthalmic drug delivery. Carbohydr polym 155(1):208–217

    Article  CAS  PubMed  Google Scholar 

  75. Martínez-Mejía G, Vázquez-Torres NA, Castell-Rodríguez A, del Río JM, Corea M, Jiménez-Juárez R (2019) Synthesis of new chitosan-glutaraldehyde scaffolds for tissue engineering using Schiff reactions. Colloids Surf A Physicochem Eng Asp 579(1):123658

  76. Zhao Y, He M, Zhao L, Wang S, Li Y, Gan L, Li M, Xu L, Chang PR, Anderson DP (2016) Epichlorohydrin-cross-linked hydroxyethyl cellulose/soy protein isolate composite films as biocompatible and biodegradable implants for tissue engineering. ACS Appl Mater Interfaces 8(4):2781–2795

    Article  CAS  PubMed  Google Scholar 

  77. Huber T, Feast S, Dimartino S, Cen W, Fee C (2019) Analysis of the effect of processing conditions on physical properties of thermally set cellulose hydrogels. Materials 12(7):1–20

    Article  Google Scholar 

  78. Imren D, Gümüşderelioğlu M, Güner A (2006) Synthesis and characterization of dextran hydrogels prepared with chlor-and nitrogen-containing crosslinkers. J Appl Polym Sci 102(5):4213–4221

    Article  CAS  Google Scholar 

  79. Buhus G, Peptu C, Popa M, Desbrieres J (2009) Controlled release of water soluble antibiotics by carboxymethylcellulose-and gelatin-based hydrogels crosslinked with epichlorohydrin. Cellul Chem Technol 43(4):141–151

    CAS  Google Scholar 

  80. Singh A, Narvi S, Dutta P, Pandey N (2006) External stimuli response on a novel chitosan hydrogel crosslinked with formaldehyde. Bull Mater Sci 29(3):233–238

    Article  CAS  Google Scholar 

  81. Dimida S, Barca A, Cancelli N, De Benedictis V, Raucci MG (2017) Demitri C (2017) Effects of genipin concentration on cross-linked chitosan scaffolds for bone tissue engineering: structural characterization and evidence of biocompatibility features. Int J Polym Sci 1:1–8

    Article  Google Scholar 

  82. Heimbuck AM, Priddy-Arrington TR, Padgett ML, Llamas CB, Barnett HH, Bunnell BA, Caldorera-Moore ME (2019) Development of responsive chitosan–genipin hydrogels for the treatment of wounds. ACS Appl Biol Mater 2(7):2879–2888

    Article  CAS  Google Scholar 

  83. Heris HK, Latifi N, Vali H, Li N, Mongeau L (2015) Investigation of chitosan-glycol/glyoxal as an injectable biomaterial for vocal fold tissue engineering. Procedia Eng 110(1):143–150

    Article  CAS  Google Scholar 

  84. Bhumkar DR, Pokharkar VB (2006) Studies on effect of pH on cross-linking of chitosan with sodium tripolyphosphate: a technical note. AAPS PharmSciTech 7(2):E138–E143

    Article  PubMed Central  Google Scholar 

  85. Mi F-L, Sung H-W, Shyu S-S, Su C-C, Peng C-K (2003) Synthesis and characterization of biodegradable TPP/genipin co-crosslinked chitosan gel beads. Polymer 44(21):6521–6530

    Article  CAS  Google Scholar 

  86. Jimtaisong A, Saewan N (2018) Plant-derived polyphenols as potential cross-linking agents for methylcellulose-chitosan biocomposites. Solid State Phenom 283(1):140–146

    Article  Google Scholar 

  87. Iwasaki Y, Nakagawa C, Ohtomi M, Ishihara K, Akiyoshi K (2004) Novel biodegradable polyphosphate cross-linker for making biocompatible hydrogel. Biomacromolecules 5(3):1110–1115

    Article  CAS  PubMed  Google Scholar 

  88. Poursamar SA, Lehner AN, Azami M, Ebrahimi-Barough S, Samadikuchaksaraei A, Antunes APM (2016) The effects of crosslinkers on physical, mechanical, and cytotoxic properties of gelatin sponge prepared via in-situ gas foaming method as a tissue engineering scaffold. Mater Sci Eng C 63(1):1–9

    Article  CAS  Google Scholar 

  89. Pluda S, Pavan M, Galesso D, Guarise C (2016) Hyaluronic acid auto-crosslinked polymer (ACP): Reaction monitoring, process investigation and hyaluronidase stability. Carbohydr Res 433(1):47–53

    Article  CAS  PubMed  Google Scholar 

  90. Garnica-Palafox I, Sánchez-Arévalo F (2016) Influence of natural and synthetic crosslinking reagents on the structural and mechanical properties of chitosan-based hybrid hydrogels. Carbohydr polym 151(1):1073–1081

    Article  CAS  PubMed  Google Scholar 

  91. Kono H, Fujita S (2012) Biodegradable superabsorbent hydrogels derived from cellulose by esterification crosslinking with 1, 2, 3, 4-butanetetracarboxylic dianhydride. Carbohydr Polym 87(4):2582–2588

    Article  CAS  Google Scholar 

  92. Erikci S, Mundinger P, Boehm H (2020) Small physical cross-linker facilitates hyaluronan hydrogels. Molecules 25(18):1–13

    Article  Google Scholar 

  93. Homenick CM, de Silveira G, Sheardown H, Adronov A (2011) Pluronics as crosslinking agents for collagen: ovel amphiphilic hydrogels. Polym Int 60(3):458–465

    Article  CAS  Google Scholar 

  94. Kasák P, Kroneková Z, Krupa I, Lacík I (2011) Zwitterionic hydrogels crosslinked with novel zwitterionic crosslinkers: Synthesis and characterization. Polymer 52(14):3011–3020

    Article  Google Scholar 

  95. Hu X, Lu L, Xu C, Li X (2015) Mechanically tough biomacromolecular IPN hydrogel fibers by enzymatic and ionic crosslinking. Int J Biol Macromol 72(1):403–409

    Article  CAS  PubMed  Google Scholar 

  96. Zhang H, Huang X, Jiang J, Shang S, Song Z (2017) Hydrogels with high mechanical strength cross-linked by a rosin-based crosslinking agent. RSC Adv 7(67):42541–42548

    Article  CAS  Google Scholar 

  97. Li L, Zhao J, Sun Y, Yu F, Ma J (2019) Ionically cross-linked sodium alginate/ĸ-carrageenan double-network gel beads with low-swelling, enhanced mechanical properties, and excellent adsorption performance. Chem Eng J 372(1):1091–1103

    Article  CAS  Google Scholar 

  98. Li X, Qin H, Zhang X, Guo Z (2019) Triple-network hydrogels with high strength, low friction and self-healing by chemical-physical crosslinking. J Colloid Interface Sci 556(1):549–556

    Article  CAS  PubMed  Google Scholar 

  99. Subramanian K, Vijayakumar V (2013) Evaluation of isophorone diisocyanate crosslinked gelatin as a carrier for controlled delivery of drugs. Polym Bull 70(3):733–753

    Article  CAS  Google Scholar 

  100. Sarıyer S, Duranoğlu D, Doğan Ö, Küçük İ (2020) pH-responsive double network alginate/kappa-carrageenan hydrogel beads for controlled protein release: Effect of pH and crosslinking agent. J Drug Deliv Sci Technol 56(1):101551

  101. Song Y, Nagai N, Saijo S, Kaji H, Nishizawa M, Abe T (2018) In situ formation of injectable chitosan–gelatin hydrogels through double crosslinking for sustained intraocular drug delivery. Mater Sci Eng C 88(1):1–12

    CAS  Google Scholar 

  102. Mahdavinia GR, Karimi MH, Soltaniniya M, Massoumi B (2019) In vitro evaluation of sustained ciprofloxacin release from κ-carrageenan-crosslinked chitosan/hydroxyapatite hydrogel nanocomposites. Int J Biol Macromol 126(1):443–453

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan

    Saman Zafar, Muhammad Hanif & Muhammad Azeem

  2. Hamdard Institute of Pharmaceutical Sciences, Hamdard University Islamabad Campus, Islamabad, Pakistan

    Muhammad Azeem

  3. Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, Pakistan

    Khalid Mahmood

  4. School of Pharmacy, Hajvery University, Lahore, Pakistan

    Sonia Ashfaq Gondal

Authors
  1. Saman Zafar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Muhammad Hanif
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Muhammad Azeem
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Khalid Mahmood
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sonia Ashfaq Gondal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Muhammad Hanif.

Additional information

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zafar, S., Hanif, M., Azeem, M. et al. Role of crosslinkers for synthesizing biocompatible, biodegradable and mechanically strong hydrogels with desired release profile. Polym. Bull. 79, 9199–9219 (2022). https://doi.org/10.1007/s00289-021-03956-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00289-021-03956-8

Keywords

Search

Navigation