• Sustained TGF-β3 Delivery and Cartilage Regeneration via Schiff Base-Crosslinked Oxidized Gellan Gum/Silk Fibroin Injectable Hydrogel

  • Sunjae Park*,#, Soyoon Lee*,#, Hosoo Shin*, Nakyung Kim*, and Gilson Khang*, **,†

  • *Department of Bionanotechnology and Bio-Convergence Engineering, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do 54896, Korea
    **Department of Polymer Nano Science & Technology, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do 54896, Korea

  • 쉬프 염기 가교 산화 젤란검/실크 피브로인 주사형 하이드로젤을 통한 TGF-β3 지속 전달 및 연골 재생

  • 박선재*,# · 이소윤*,# · 신호수* · 김나경* · 강길선*, **,†

  • *전북대학교 바이오나노융합공학과, **전북대학교 고분자나노공학과

  • Reproduction, stored in a retrieval system, or transmitted in any form of any part of this publication is permitted only by written permission from the Polymer Society of Korea.

References
  • 1. Chen, X.; Tang, H.; Lin, J.; Zeng, R. Temporal Trends in the Disease Burden of Osteoarthritis from 1990 to 2019, and Projections Until 2030. PLoS One, 2023, 18, e0288561.
  •  
  • 2. Grote, C.; Reinhardt, D.; Zhang, M.; Wang, J. Regulatory Mechanisms and Clinical Manifestations of Musculoskeletal Aging. J. Orthop. Res. 2019, 37, 1475-1488.
  •  
  • 3. Mobasheri, A. Applications of Proteomics to Osteoarthritis, a Musculoskeletal Disease Characterized by Aging. Front. Phys. 2011, 2, 108.
  •  
  • 4. Emami, A.; Namdari, H.; Parvizpour, F.; Arabpour, Z. Challenges in Osteoarthritis Treatment. Tissue and Cell. 2023, 80, 101992.
  •  
  • 5. Ao, R., Liang, W.; Wang, Z.; Li, Q.; Pan, X.; Zhen, Y.; An, Y. Delivery Strategies of Growth Factors in Cartilage Tissue Engineering. Tissue Engineering Part B: Reviews, 2025, 31, 374-389.
  •  
  • 6. Karaarslan, N., Batmaz, A. G.; Yilmaz, I.; Ozbek, H.; Caliskan, T.; Yasar Sirin, D.; Kaplan, N.; Oznam, K.; Ates, O. Effect of Naproxen on Proliferation and Differentiation of Primary Cell Cultures Isolated from Human Cartilage Tissue. Exp. Therap. Med. 2018, 16, 1647-1654.
  •  
  • 7. Ratcliffee, A., Azzo, W.; Saed-nejad, F.; Lane, N.; Rosenwasser, M. P.; Mow, V. C. In vivo Effects of Naproxen on Composition, Proteoglycan Metabolism, and Matrix Metalloproteinase Activities in Canine Articular Cartilage. J. Orthop. Res. 1993, 11, 163-171.
  •  
  • 8. O'driscoll, S. W. Current Concepts Review-the Healing and Regeneration of Articular Cartilage. JBJS, 1998, 80, 1795-1812.
  •  
  • 9. Gomoll, A. H., Filardo, G.; De Girolamo, L.; Espregueira-mendes, J.; Marcacci, M.; Rodkey, W. G.; Steadman, J. R.; Zaffagnini, S.; Kon, E. Surgical Treatment for Early Osteoarthritis. Part I: Cartilage Repair Procedures. Knee Surgery, Sports Traumatol. Arthroscopy, 2012, 20, 450-466.
  •  
  • 10. Solchaga, L. A.; Goldberg, V. M.; Caplan, A. I. Cartilage Regeneration Using Principles of Tissue Engineering. Clinical Orthop. Related Res. 2001, 391, S161-S170.
  •  
  • 11. Liu, Y.; Shah, K. M.; Luo, J. Strategies for Articular Cartilage Repair and Regeneration. Front. Bioeng. Biotechnol. 2021, 9, 770655.
  •  
  • 12. Whitaker, M. J.; Quirk, R. A.; Howdle, S. M.; Shakesheff, K. M. Growth Factor Release from Tissue Engineering Scaffolds. J. Pharm. Pharmacol. 2001, 53, 1427-1437.
  •  
  • 13. Gugjoo, M. B.; Amarpal; Sharma, G. T.; Aithal, H. P.; Kinjavdekar, P. Cartilage Tissue Engineering: Role of Mesenchymal Stem Cells Along with Growth Factors & Scaffolds. Indian J. Med. Res. 2016, 144, 339-347.
  •  
  • 14. Rahmani, D.; Bakhshayesh, A.; Babaie, S.; Tayefi Nasrabadi, H.; Asadi, N.; Akbarzadeh, A.; Abedelahi, A. An Overview of Various Treatment Strategies, Especially Tissue Engineering for Damaged Articular Cartilage. Artificial Cells, Nanomedicine, and Biotechnol. 2020, 48, 1089-1104.
  •  
  • 15. Carletti, E.; Motta, A.; Migliaresi, C. Scaffolds for Tissue Engineering and 3D Cell Culture. 3D Cell Culture: Methods and Protocols, 2010, 17-39.
  •  
  • 16. Dutta, R. C.; Dutta, A. K. Cell-interactive 3D-scaffold; Advances and Applications. Biotechnol. Adv. 2009, 27, 334-339.
  •  
  • 17. Wang, W.; Caetano, G.; Ambler, W. S.; Blaker, J. J.; Frade, M. A.; Mandal, P.; Diver, C.; Bartolo, P. Enhancing the Hydrophilicity and Cell Attachment of 3D Printed PCL/graphene Scaffolds for Bone Tissue Engineering. Materials, 2016, 9, 992.
  •  
  • 18. Babaniamansour, P.; Salimi, M.; Dorkoosh, F.; Mohammadi, M. Magnetic Hydrogel for Cartilage Tissue Regeneration as Well as a Review on Advantages and Disadvantages of Different Cartilage Repair Strategies. BioMed Res. Int. 2022, 2022, 7230354.
  •  
  • 19. Gong, Y.; Wang, C.; Lai, R. C.; Su, K.; Zhang, F.; Wang, D.-A. An Improved Injectable Polysaccharide Hydrogel: Modified Gellan Gum for Long-term Cartilage Regeneration In Vitro. J. Mater. Chem. 2009, 19, 1968-1977.
  •  
  • 20. Bacelar, A. H.; Silva-correia, J.; Oliveira, J. M.; Reis, R. L. Recent Progress in Gellan Gum Hydrogels Provided by Functionalization Strategies. J. Mater. Chem. B, 2016, 4, 6164-6174.
  •  
  • 21. Xu, J.; Liu, Y.; Hsu, S.-H. Hydrogels Based on Schiff Base Linkages for Biomedical Applications. Molecules, 2019, 24, 3005.
  •  
  • 22. Cao, L.; Cao, B.; Lu, C.; Wang, G.; Yu, L.; Ding, J. An Injectable Hydrogel Formed by In Situ Cross-linking of Glycol Chitosan and Multi-benzaldehyde Functionalized PEG Analogues for Cartilage Tissue Engineering. J. Mater. Chem. B, 2015, 3, 1268-1280.
  •  
  • 23. Liu, J.; Li, J.; Yu, F.; Zhao, Y. X.; Mo, X. M.; Pan, J. F. In Situ Forming Hydrogel of Natural Polysaccharides Through Schiff Base Reaction for Soft Tissue Adhesive and Hemostasis. International J. Biological Macromol. 2020, 147, 653-666.
  •  
  • 24. Hifumi, H.; Ewing, A. V.; Kazarian, S. G. Atr-ftir Spectroscopic Imaging to Study the Drying and Dissolution of Pharmaceutical Polymer-based Films. Int. J. Pharm. 2016, 515, 57-68.
  •  
  • 25. Xu, X.; Li, B.; Kennedy, J. F.; Xie, B. J.; Huang, M. Characterization of Konjac Glucomannan–gellan Gum Blend Films and Their Suitability for Release of Nisin Incorporated Therein. Carbohyd. Polym. 2007, 70, 192-197.
  •  
  • 26. Chatterley, A. S.; Laity, P.; Holland, C.; Weidner, T.; Woutersen, S.; Giubertoni, G. Broadband Multidimensional Spectroscopy Identifies The Amide Ii Vibrations In Silkworm Films. Molecules, 2022, 27, 6275.
  •  
  • 27. Fabbrizzi, L. Beauty In Chemistry: Making Artistic Molecules With Schiff Bases. J. Organic Chem. 2020, 85, 12212-12226.
  •  
  • 28. Murphy, C. M.; O'brien, F. J. Understanding the Effect of Mean Pore Size on Cell Activity in Collagen-glycosaminoglycan Scaffolds. Cell. Adhesion Migration, 2010, 4, 377-381.
  •  
  • 29. Wong, R. S. H.; Ashton, M.; Dodou, K. Effect of Crosslinking Agent Concentration on the Properties of Unmedicated Hydrogels. Pharmaceutics, 2015, 7, 305-319.
  •  
  • 30. Maroudas, A. Biophysical Chemistry of Cartilaginous Tissues with Special Reference to Solute and Fluid Transport. Biorheology, 1975, 12, 233-248.
  •  
  • 31. Spiller, K. L.; Maher, S. A.; Lowman, A. M. Hydrogels for the Repair of Articular Cartilage Defects. Tissue Eng. Part B: Rev. 2011, 17, 281-299.
  •  
  • 32. Jin, H.‐J.; Park, J.; Karageorgiou, V.; Kim, U.-J.; Valluzzi, R.; Cebe, P.; Kaplan, D. L. Water‐stable Silk Films with Reduced β‐sheet Content. Adv. Funct. Mater. 2005, 15, 1241-1247.
  •  
  • 33. Zhang, X.; Xiao, L.; Ding, Z.; Lu, Q.; Kaplan, D. L. Engineered Tough Silk Hydrogels Through Assembling β-sheet Rich Nanofibers Based on a Solvent Replacement Strategy. ACS Nano, 2022, 16, 10209-10218.
  •  
  • 34. Hutmacher, D. W. Scaffolds in Tissue Engineering Bone and Cartilage. Biomaterials, 2000, 21, 2529-2543.
  •  
  • 35. Mason, J. M.; Breitbart, A. S.; Barcia, M.; Porti, D.; Pergolizzi, R. G.; Grande, D. A. Cartilage and Bone Regeneration Using Gene-enhanced Tissue Engineering. Clinical Orthopaedics and Related Research (1976-2007), 2000, 379, S171-S178.
  •  
  • 36. Bryant, S. J.; Anseth, K. S. Controlling the Spatial Distribution of ECM Components in Degradable PEG Hydrogels for Tissue Engineering Cartilage. J. Biomed. Mater. Res. Part A: An Official J. Soc. Biomater., Japanese Society for Biomaterials, and The Australian Society for Biomaterials and the Korean Society for Biomaterials, 2003, 64, 70-79.
  •  
  • 37. Williams, C. G.; Kim, T. K.; Taboas, A.; Malik, A.; Manson, P.; Elisseeff, J. In vitro Chondrogenesis of Bone Marrow-derived Mesenchymal Stem Cells in a Photopolymerizing Hydrogel. Tissue engineering, 2003, 9, 679-688.
  •  
  • 38. Lee, H.; Fisher, S.; Kallos, M. S.; Hunter, C. J. Optimizing Gelling Parameters of Gellan Gum for Fibrocartilage Tissue Engineering. J. Biomed. Mater. Res. Part B: Appl. Biomater. 2011, 98, 238-245.
  •  
  • 39. Brun-graeppi, A. K.; Andriola, S.; Richard, C.; Bessodes, M.; Scherman, D.; Merten, O.-W. Thermoresponsive Surfaces for Cell Culture and Enzyme-free Cell Detachment. Prog. Polym. Sci. 2010, 35, 1311-1324.
  •  
  • 40. Zhu, Z.; Ling, S.; Yeo, J.; Zhao, S.; Tozzi, L.; Buehler, M. J.; Omenetto, F.; Li, C.; Kaplan, D. L. High‐strength, Durable All‐silk Fibroin Hydrogels with Versatile Processability Toward Multifunctional Applications. Adv. Funct. Mater. 2018, 28, 1704757.
  •  
  • 41. Jiang, C.; Wang, X.; Gunawidjaja, R.; Lin, Y.-h.; Gupta, M. K.; Kaplan, D. L.; Naik, R. R.; Tsukruk, V. V. Mechanical Properties of Robust Ultrathin Silk Fibroin Films. Advanced Functional Materials, 2007, 17, 2229-2237.
  •  
  • 42. Gil, E. S.; Hudson, S. M. Effect of Silk Fibroin Interpenetrating Networks on Swelling/deswelling Kinetics and Rheological Properties of Poly(N-isopropylacrylamide) Hydrogels. Biomacromolecules, 2007, 8, 258-264.
  •  
  • 43. Tanaka, F. Thermoreversible Gelation of Associating Polymers. Phys. A: Statistical Mechanics and Its Appl. 1998, 257, 245-255.
  •  
  • 44. Loebel, C.; Rodell, C. B.; Chen, M. H.; Burdick, J. A. Shear-thinning and Self-healing Hydrogels as Injectable Therapeutics and for 3D-printing. Nat. Protocols, 2017, 12, 1521-1541.
  •  
  • 45. Schlichting, K.; Schell, H.; Kleemann, R. U.; Schill, A.; Weiler, A.; Duda, G. N.; Epari, D. R. Influence of Scaffold Stiffness on Subchondral Bone and Subsequent Cartilage Regeneration in an Ovine Model of Osteochondral Defect Healing. Am. J. Sports Med. 2008, 36, 2379-2391.
  •  
  • 46. Guvendiren, M.; Lu, H. D.; Burdick, J. A. Shear-thinning Hydrogels For Biomedical Applications. Soft Matter, 2012, 8, 260-272.
  •  
  • 47. Gong, J. P. Why are Double Network Hydrogels So Tough?. Soft Matter, 2010, 6, 2583-2590.
  •  
  • 48. Sun, J.-Y.; Zhao, X.; Illeperuma, W. R. K.; Chaudhuri, O.; Oh, K. H.; Mooney, D. J.; Vlassak, J. J.; Suo, Z. Highly Stretchable and Tough Hydrogels. Nature, 2012, 489, 133-136.
  •  
  • 49. Vasita, R.; Katti, D. S. Growth Factor-delivery Systems For Tissue Engineering: A Materials Perspective. Exp. Review Med. Devices, 2006, 3, 29-47.
  •  
  • 50. Ren, X.; Zhao, M.; Lash, B.; Martino, M. M.; Julier, Z. Growth Factor Engineering Strategies for Regenerative Medicine Applications. Front. Bioeng. Biotechnol. 2020, 7, 469.
  •  
  • 51. Schug, K. A.; Lindner, W. Noncovalent Binding Between Guanidinium and Anionic Groups: Focus on Biological-and Synthetic-based Arginine/guanidinium Interactions with Phosph[on]ate and sulf[on]ate Residues. Chem. Reviews, 2005, 105, 67-114.
  •  
  • 52. Pellaud, J.; Schote, U.; Arvinte, T.; Seelig, J. Conformation and Self-association of Human Recombinant Transforming Growth Factor-β3 in Aqueous Solutions. J. Biological. Chem. 1999, 274, 7699-7704.
  •  
  • 53. Tae, G.; Scatena, M.; Stayton, P. S.; Hoffman, A. S. Peg-cross-linked Heparin is an Affinity Hydrogel for Sustained Release of Vascular Endothelial Growth Factor. J. Biomater. Sci., Polym. Edition, 2006, 17, 187-197.
  •  
  • 54. Sawatjui, N.; Damrongrungruang, T.; Leeanansaksiri, W.; Jearanaikoon, P.; Hongeng, S.; Limpaiboon, T. Silk Fibroin/gelatin–chondroitin Sulfate–hyaluronic Acid Effectively Enhances In Vitro Chondrogenesis of Bone Marrow Mesenchymal Stem Cells. Mater. Sci. Eng. C, 2015, 52, 90-96.
  •  
  • 55. Madappura, A. P.; Madduri, S. A Comprehensive Review of Silk-fibroin Hydrogels for Cell and Drug Delivery Applications in Tissue Engineering and Regenerative Medicine. Computational and Struct. Biotechnol. J., 2023, 21, 4868-4886.
  •  
  • 56. Steward, A. J.; Kelly, D. J. Mechanical Regulation of Mesenchymal Stem Cell Differentiation. J. Anatomy, 2015, 227, 717-731.
  •  
  • 57. Müller, P.; Langenbach, A.; Kaminski, A.; Rychly, J. Modulating the Actin Cytoskeleton Affects Mechanically Induced Signal Transduction And Differentiation in Mesenchymal Stem Cells. PloS One, 2013, 8, e71283.
  •  
  • 58. Lefebvre, V.; Huang, W.; Harley, V. R.; Goodfellow, P. N.; De Crombrugghe, B. SOX9 is a Potent Activator of the Chondrocyte-specific Enhancer of the Proα1 (II) Collagen Gene. Molecul. Cellular Biology, 1997, 17, 2336-2346.
  •  
  • 59. Ng, L.-J.; Wheatley, S.; Muscat, G. E.; Conway-campbell, J.; Bowles, J.; Wright, E.; Bell, D. M.; Tam, P. P.; Cheah, K. S.; Koopman, P. SOX9 Binds Dna, Activates Transcription, and Coexpresses With Type II Collagen During Chondrogenesis in the Mouse. Developmental Biology, 1997, 183, 108-121.
  •  
  • 60. Hattori, T.; Muller, C.; Gebhard, S.; Bauer, E.; Pausch, F.; Schlund, B.; Bosl, M. R.; Hess, A.; Surmann-schmitt, C.; Von Der Mark, H.; De Crombrugghe, B.; Von Der Mark, K. SOX9 is a Major Negative Regulator of Cartilage Vascularization, Bone Marrow Formation and Endochondral Ossification. Development, 2010, 137, 901-911.
  •  
  • 61. Matsusaki, M.; Sakaguchi, H.; Serizawa, T.; Akashi, M. Controlled Release of Vascular Endothelial Growth Factor From Alginate Hydrogels Nano-coated With Polyelectrolyte Multilayer Films. J. Biomat. Sci. Polym. Ed. 2007, 18, 775-783.
  •  
  • 62. Ferretti, M.; Marra, K. G.; Kobayashi, K.; Defail, A. J.; Chu, C. R. Controlled In Vivo Degradation of Genipin Crosslinked Polyethylene Glycol Hydrogels Within Osteochondral Defects. Tissue Eng. 2006, 12, 2657-2663.
  •  
  • 63. Moioli, Eduardo K.; Mao, J. J. Chondrogenesis Of Mesenchymal Stem Cells by Controlled Delivery of Transforming Growth Factor-ß3. In: 2006 International Conference of the Ieee Engineering in Medicine and Biology Society. IEEE, 2006,2647-2650.
  •  
  • 64. Singh, A.; Elisseeff, J. Biomaterials For Stem Cell Differentiation. J. Mater. Chem. 2010, 20, 8832-8847.
  •  
  • 65. Lee, J. H.; Kim, P. Y.; Pyun, Y. C.; Park, J.; Kang, T. W.; Seo, J. S.; Lee, D. H.; Khang, G. Cartilage Regeneration Using Transforming Growth Factor-beta 3-loaded Injectable Crosslinked Hyaluronic Acid Hydrogel. Biomaterials Science, 2024, 12, 479-494.
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  • Polymer(Korea) 폴리머
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    ISSN 2234-8077(Online)
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This Article

  • 2026; 50(4): 524-534

    Published online Jul 25, 2026

  • 10.7317/pk.2026.50.4.524
  • Received on Feb 10, 2026
  • Revised on Apr 11, 2026
  • Accepted on Apr 13, 2026

Correspondence to

  • Gilson Khang

  • *Department of Bionanotechnology and Bio-Convergence Engineering, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do 54896, Korea
    **Department of Polymer Nano Science & Technology, Jeonbuk National University, 567 Baekje-daero, Deokjin-gu, Jeonju-si, Jeollabuk-do 54896, Korea

  • E-mail: gskhang@jbnu.ac.kr