Journal of Angiotherapy
Angiogenesis, Inflammation & Therapeutics | Online ISSN  2207-872X
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Contents Vol 8 (11)

Advancements in Gelatin-Based Wound Dressings: Cross-Linking Techniques, Biocompatibility, and Biodegradability for Enhanced Angiogenesis and Healing

Ishita Singha1, Bani Kumar Jana1, Niva Rani Gogoi1, Hemanta Pathak1, Mohini Singh1, Bhaskar Mazumder1*

+ Author Affiliations

Journal of Angiotherapy 8 (11) 1-11 https://doi.org/10.25163/angiotherapy.81110011

Submitted: 09 September 2024 Revised: 28 November 2024  Published: 02 November 2024 

Abstract

Uncontrolled hemorrhage from wounds is a significant cause of morbidity, highlighting the need for rapid and effective hemostatic interventions. Wound dressings play a crucial role in managing blood loss and fluid exudation while supporting the dynamic wound-healing process. This process involves hemostasis, inflammation, proliferation, angiogenesis, and remodeling to restore the skin's barrier function. Among available options, dry absorbable local hemostats offer practical advantages by absorbing wound exudates and promoting healing. Gelatin sponges, known for their hemostatic properties, biocompatibility, and biodegradability, are excellent candidates for wound dressings. They effectively stop bleeding and support tissue repair. However, gelatin’s inherent sensitivity to environmental conditions limits its direct application. To address these challenges, cross-linking techniques are employed to improve mechanical strength, hydrolysis resistance, and stability while refining the pore morphology of gelatin sponges for enhanced biomedical applications. Various cross-linkers, such as aldehydes, carbodiimides, reducing sugars, genipin, and acyl azides, have been investigated for gelatin modification. While glutaraldehyde achieves effective cross-linking, its high cytotoxicity restricts its use in biocompatible products. Alternatives like 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and genipin offer reduced cytotoxicity, though genipin's cost poses a limitation. Reducing sugars, such as glucose and fructose, provide a promising, non-toxic, and cost-effective solution for commercial-scale production. Optimizing cross-linking methods is essential for developing safe, effective, and affordable gelatin-based wound dressings. Addressing cross-linker toxicity remains critical to advancing their clinical applicability.

Keywords: Gelatin, Hemostats, Cross-linkers, Sponge, Inflammation, Angiogenesis, Wound healing.

References

Agarwal, S., Wendorff, J. H., & Greiner, A. (2008). Use of electrospinning technique for biomedical applications. In Polymer (Vol. 49, Issue 26, pp. 5603–5621). Elsevier BV. https://doi.org/10.1016/j.polymer.2008.09.014

Bigi, A., Cojazzi, G., Panzavolta, S., Roveri, N., & Rubini, K. (2002). Stabilization of gelatin films by crosslinking with genipin. In Biomaterials (Vol. 23).

Bigi, A., Cojazzi, G., Panzavolta, S., Rubini, K., & Roveri, N. (2001). Mechanical and thermal properties of gelatin "lms at di!erent degrees of glutaraldehyde crosslinking. In Biomaterials (Vol. 22).

Boanini, E., Rubini, K., Panzavolta, S., & Bigi, A. (2010). Chemico-physical characterization of gelatin films modified with oxidized alginate. Acta Biomaterialia, 6(2), 383–388. https://doi.org/10.1016/j.actbio.2009.06.015

Byrd, A. L., Belkaid, Y., & Segre, J. A. (2018). The human skin microbiome. In Nature Reviews Microbiology (Vol. 16, Issue 3, pp. 143–155). Nature Publishing Group. https://doi.org/10.1038/nrmicro.2017.157

Chang, W. H., Chang, Y., Lai, P. H., & Sung, H. W. (2003). A genipin-crosslinked gelatin membrane as wound-dressing material: In vitro and in vivo studies. Journal of Biomaterials Science, Polymer Edition, 14(5), 481–495. https://doi.org/10.1163/156856203766652084

Choi, S. M., Singh, D., Kumar, A., Oh, T. H., Cho, Y. W., & Han, S. S. (2013). Porous three-dimensional PVA/gelatin sponge for skin tissue engineering. International Journal of Polymeric Materials and Polymeric Biomaterials, 62(7), 384–389. https://doi.org/10.1080/00914037.2012.710862

Chowrasia, P., Singh, M., Jana, B. K., Bora, P. L., Mahato, R. K., Kharbithai, R., Gogoi, N. R., Sarkar, T., Pal, P., & Mazumder, B. (2024). Current Drug Delivery Strategies to Design Orally Dissolving Formulations to Target Tuberculosis: A Futuristic Review. Drug Delivery Letters, 14(2), 109–134. https://doi.org/10.2174/0122103031267044231031044456

Chvapil, M. (n.d.). Considerations on manufacturing principles of a synthetic burn dressing: A review.

Cortesi, R., Nastruzzi, C., & Davis, S. S. (1998). Sugar cross-linked gelatin for controlled release: microspheres and disks. In Biomaterials (Vol. 19).

de Clercq, K., Schelfhout, C., Bracke, M., de Wever, O., van Bockstal, M., Ceelen, W., Remon, J. P., & Vervaet, C. (2016). Genipin-crosslinked gelatin microspheres as a strategy to prevent postsurgical peritoneal adhesions: In vitro and in vivo characterization. Biomaterials, 96, 33–46. https://doi.org/10.1016/j.biomaterials.2016.04.012

de la Torre, R. A., Bachman, S. L., Wheeler, A. A., Bartow, K. N., & Scott, J. S. (2007). Hemostasis and hemostatic agents in minimally invasive surgery. In Surgery (Vol. 142, Issue 4 Suppl). https://doi.org/10.1016/j.surg.2007.06.023

Du, J. P., Fan, Y., Hao, D. J., Huang, Y. F., Zhang, J. N., & Yuan, L. H. (2018). Application of Gelatin Sponge Impregnated with a Mixture of 3 Drugs to Intraoperative Nerve Root Block to Promote Early Postoperative Recovery of Lumbar Disc Herniation. World Neurosurgery, 114, e1168–e1173. https://doi.org/10.1016/j.wneu.2018.03.170

Fan, X., Li, M., Yang, Q., Wan, G., Li, Y., Li, N., & Tang, K. (2021). Morphology-controllable cellulose/chitosan sponge for deep wound hemostasis with surfactant and pore-foaming agent. Materials Science and Engineering C, 118. https://doi.org/10.1016/j.msec.2020.111408

Fereshteh, Z. (2018). Freeze-drying technologies for 3D scaffold engineering. In Functional 3D Tissue Engineering Scaffolds: Materials, Technologies, and Applications (pp. 151–174). Elsevier. https://doi.org/10.1016/B978-0-08-100979-6.00007-0

Furuike, T., Chaochai, T., Okubo, T., Mori, T., & Tamura, H. (2016). Fabrication of nonwoven fabrics consisting of gelatin nanofibers cross-linked by glutaraldehyde or N-acetyl-D-glucosamine by aqueous method. International Journal of Biological Macromolecules, 93, 1530–1538. https://doi.org/10.1016/j.ijbiomac.2016.03.053

Gomes, S. R., Rodrigues, G., Martins, G. G., Henriques, C. M. R., & Silva, J. C. (2013). In vitro evaluation of crosslinked electrospun fish gelatin scaffolds. Materials Science and Engineering C, 33(3), 1219–1227. https://doi.org/10.1016/j.msec.2012.12.014

Harris, L. D., Kim, B.-S., & Mooney, D. J. (1998). Open pore biodegradable matrices formed with gas foaming.

Hou, Q., Grijpma, D. W., & Feijen, J. (2003). Porous polymeric structures for tissue engineering prepared by a coagulation, compression moulding and salt leaching technique. Biomaterials, 24(11), 1937–1947. https://doi.org/10.1016/S0142-9612(02)00562-8

Howell-Jones, R. S., Wilson, M. J., Hill, K. E., Howard, A. J., Price, P. E., & Thomas, D. W. (2005). A review of the microbiology, antibiotic usage and resistance in chronic skin wounds. In Journal of Antimicrobial Chemotherapy (Vol. 55, Issue 2, pp. 143–149). https://doi.org/10.1093/jac/dkh513

Hu, S., Bi, S., Yan, D., Zhou, Z., Sun, G., Cheng, X., & Chen, X. (2018). Preparation of composite hydroxybutyl chitosan sponge and its role in promoting wound healing. Carbohydrate Polymers, 184, 154–163. https://doi.org/10.1016/j.carbpol.2017.12.033

Imani, R., Rafienia, M., & Emami, S. H. (2013). Synthesis and characterization of glutaraldehyde-based crosslinked gelatin as a local hemostat sponge in surgery: an in vitro study. Bio-Medical Materials and Engineering, 23(3), 211–224. https://doi.org/10.3233/bme-130745

Jana, B. K., Singh, M., Dutta, R. S., & Mazumder, B. (2024). Current Drug Delivery Strategies for Buccal Cavity Ailments using Mouth Dissolving Wafer Technology: A Comprehensive Review on the Present State of the Art. Current Drug Delivery, 21(3), 339–359. https://doi.org/10.2174/1567201820666221128152010

Jayakrishnan, A., & Jameela, S. R. (1996). Glutaraldehyde as a fixative in bioprostheses and drug delivery matrices. In Biomaterids (Vol. 17).

Jevotovsky, D. S., Thirukumaran, C. P., & Rubery, P. T. (2018). Friday, September 28, 2018 3:00 PM–4:00 PM abstracts: optimizing lumbar disc surgery. The Spine Journal, 18(8), S105–S106. https://doi.org/10.1016/j.spinee.2018.06.478

Kabiri, M., Emami, S. H., Rafinia, M., & Tahriri, M. (2011). Preparation and characterization of absorbable hemostat crosslinked gelatin sponges for surgical applications. Current Applied Physics, 11(3), 457–461. https://doi.org/10.1016/j.cap.2010.08.031

Khadidja, L., Asma, C., Mahmoud, B., & Meriem, E. (2017). Alginate/gelatin crosslinked system through Maillard reaction: preparation, characterization and biological properties. Polymer Bulletin, 74(12), 4899–4919. https://doi.org/10.1007/s00289-017-1997-z

Kheirabadi, B. S., MacE, J. E., Terrazas, I. B., Fedyk, C. G., Estep, J. S., Dubick, M. A., & Blackbourne, L. H. (2010). Safety evaluation of new hemostatic agents, smectite granules, and kaolin-coated gauze in a vascular injury wound model in swine. Journal of Trauma - Injury, Infection and Critical Care, 68(2), 269–277. https://doi.org/10.1097/TA.0b013e3181c97ef1

Kirdponpattara, S., Phisalaphong, M., & Kongruang, S. (2017). Gelatin-bacterial cellulose composite sponges thermally cross-linked with glucose for tissue engineering applications. Carbohydrate Polymers, 177, 361–368. https://doi.org/10.1016/j.carbpol.2017.08.094

Ko, C. L., Tien, Y. C., Wang, J. C., & Chen, W. C. (2012). Characterization of controlled highly porous hyaluronan/gelatin cross-linking sponges for tissue engineering. Journal of the Mechanical Behavior of Biomedical Materials, 14, 227–238. https://doi.org/10.1016/j.jmbbm.2012.06.019

Lee, S. B., Kim, Y. H., Chong, M. S., Hong, S. H., & Lee, Y. M. (2005). Study of gelatin-containing artificial skin V: Fabrication of gelatin scaffolds using a salt-leaching method. Biomaterials, 26(14), 1961–1968. https://doi.org/10.1016/j.biomaterials.2004.06.032

Li, Q., Lu, F., Zhou, G., Yu, K., Lu, B., Xiao, Y., Dai, F., Wu, D., & Lan, G. (2017). Silver Inlaid with Gold Nanoparticle/Chitosan Wound Dressing Enhances Antibacterial Activity and Porosity, and Promotes Wound Healing. Biomacromolecules, 18(11), 3766–3775. https://doi.org/10.1021/acs.biomac.7b01180

Liang, H.-C., Chang, W.-H., Liang, H.-F., Lee, M.-H., & Sung, H.-W. (2004). Crosslinking Structures of Gelatin Hydrogels Crosslinked with Genipin or a Water-Soluble Carbodiimide.

Mahabub Hasan, M., Mashud Alam, A., & Lecturer, S. (2014). Application of electrospinning techniques for the production of tissue engineering scaffolds: a review. Khandakar Abu Nayem (Vol. 10, Issue 15).

Masutani, E. M., Kinoshita, C. K., Tanaka, T. T., Ellison, A. K. D., & Yoza, B. A. (2014). Increasing thermal stability of gelatin by UV-induced cross-linking with glucose. International Journal of Biomaterials, 2014. https://doi.org/10.1155/2014/979636

Mekhail, M., Jahan, K., & Tabrizian, M. (2014). Genipin-crosslinked chitosan/poly-l-lysine gels promote fibroblast adhesion and proliferation. Carbohydrate Polymers, 108(1), 91–98. https://doi.org/10.1016/j.carbpol.2014.03.021

Mikes, A. G., Sarakinos, G., Leite, S. M., Vacant, J. P., & Langer, R. (n.d.). Laminated three-dimensional biodegradable foams for use in tissue engineering.

Murphy, W. L., Dennis, R. G., Kileny, J. L., & Mooney, D. J. (2002). Salt Fusion: An Approach to Improve Pore Interconnectivity within Tissue Engineering Scaffolds. In TISSUE ENGINEERING (Vol. 8, Issue 1).

Muzzarelli, R. A. A. (2009). Genipin-crosslinked chitosan hydrogels as biomedical and pharmaceutical aids. In Carbohydrate Polymers (Vol. 77, Issue 1, pp. 1–9). https://doi.org/10.1016/j.carbpol.2009.01.016

Nagahama, Y., Li, L., Takeda, M., Mitsuhara, T., Kurisu, K., Howard, M. A., Hitchon, P. W., & Yamaguchi, S. (2019). Localized controlled fibrin glue application with gelatin sponge for hemostasis and dural defect repair: Technical note. Interdisciplinary Neurosurgery: Advanced Techniques and Case Management, 18. https://doi.org/10.1016/j.inat.2019.100476

Naimark, W. A., Pereira, C. A., Tsang, K., & Lee, J. M. (1995). HMDC crosslinking of bovine pericardial tissue: a potential role of the solvent environment in the design of bioprosthetic materials. In JOURNAL OF MATERIALS SCIENCE: MATERIALS IN MEDICINE (Vol. 6).

Nakajima, N., & Ikada, Y. (1995). Mechanism of Amide Formation by Carbodiimide for Bioconjugation in Aqueous Media. In Bioconjugate Chem (Vol. 6).

Nguyen, D. T., Orgill, D. P., & Murphy, G. F. (2009). The pathophysiologic basis for wound healing and cutaneous regeneration. In Biomaterials for Treating Skin Loss: A volume in Woodhead Publishing Series in Biomaterials (pp. 25–57). Elsevier Ltd. https://doi.org/10.1533/9781845695545.1.25

Nickerson, M. T., Patel, J., Heyd, D. v., Rousseau, D., & Paulson, A. T. (2006). Kinetic and mechanistic considerations in the gelation of genipin-crosslinked gelatin. International Journal of Biological Macromolecules, 39(4–5), 298–302. https://doi.org/10.1016/j.ijbiomac.2006.04.010

Panzavolta, S., Gioffrè, M., Focarete, M. L., Gualandi, C., Foroni, L., & Bigi, A. (2011). Electrospun gelatin nanofibers: Optimization of genipin cross-linking to preserve fiber morphology after exposure to water. Acta Biomaterialia, 7(4), 1702–1709. https://doi.org/10.1016/j.actbio.2010.11.021

Powell, H. M., & Boyce, S. T. (2006). EDC cross-linking improves skin substitute strength and stability. Biomaterials, 27(34), 5821–5827. https://doi.org/10.1016/j.biomaterials.2006.07.030

Protein fructosylation: fructose and the Maillard reaction. (1993). https://academic.oup.com/ajcn/article-abstract/58/5/779S/4732308

Ratanavaraporn, J., Rangkupan, R., Jeeratawatchai, H., Kanokpanont, S., & Damrongsakkul, S. (2010). Influences of physical and chemical crosslinking techniques on electrospun type A and B gelatin fiber mats. International Journal of Biological Macromolecules, 47(4), 431–438. https://doi.org/10.1016/j.ijbiomac.2010.06.008

Rault, I., Frei, V., & Herbage, D. (1996). Evaluation of different chemical methods for cross-linking collagen gel, films and sponges. In JOURNAL OF MATERIALS SCIENCE: MATERIALS IN MEDICINE.

Seon Choi, Y., Ran Hong, S., Moo Lee, Y., Won Song, K., Hyang Park, M., & Soo Nam, Y. (1999a). Studies on Gelatin-Containing Artificial Skin: II. Preparation and Characterization of Cross-Linked Gelatin-Hyaluronate Sponge.

Seon Choi, Y., Ran Hong, S., Moo Lee, Y., Won Song, K., Hyang Park, M., & Soo Nam, Y. (1999b). Study on gelatin-containing artificial skin: I. Preparation and characteristics of novel gelatin-alginate sponge. In Biomaterials (Vol. 20).

Siimon, K., Reemann, P., Põder, A., Pook, M., Kangur, T., Kingo, K., Jaks, V., Mäeorg, U., & Järvekülg, M. (2014). Effect of glucose content on thermally cross-linked fibrous gelatin scaffolds for tissue engineering. Materials Science and Engineering C, 42, 538–545. https://doi.org/10.1016/j.msec.2014.05.075

Singh, S., Young, A., & McNaught, C. E. (2017). The physiology of wound healing. In Surgery (United Kingdom) (Vol. 35, Issue 9, pp. 473–477). Elsevier Ltd. https://doi.org/10.1016/j.mpsur.2017.06.004

Speer, D. P., Chvapil, M., Eskelson, C. D., & Ulreich, J. (n.d.). Biological effects of residual glutaraldehyde in glutaraldehyde-tanned collagen biomaterials.

Tai, H., Mather, M. L., Howard, D., Wang, W., White, L. J., Crowe, J. A., Morgan, S. P., Chandra, A., Williams, D. J., Howdle, S. M., & Shakesheff, K. M. (2007). Control of pore size and structure of tissue engineering scaffolds produced by supercritical fluid processing. European Cells and Materials, 14, 64–76. https://doi.org/10.22203/ecm.v014a07

Tomihata, K., Agr, M., & Ikada, Y. (1996). Cross-Linking of Gelatin with Carbodiimides. In TISSUE ENGINEERING (Vol. 2, Issue 4). Mary Ann Liebert, Inc.

Tomihata, K., Burczak, K., Shiraki, K., & Ikada, Y. (1993). Cross-Linking and Biodegradation of Native and Denatured Collagen (pp. 275–286). https://doi.org/10.1021/bk-1994-0540.ch024

Tomizawa, Y. (2005). Clinical benefits and risk analysis of topical hemostats: A review. In Journal of Artificial Organs (Vol. 8, Issue 3, pp. 137–142). https://doi.org/10.1007/s10047-005-0296-x

Ulubayram, K., Aksu, E., Gurhan, S. I. D., Serbetci, K., & Hasirci, N. (2002). Cytotoxicity evaluation of gelatin sponges prepared with different cross-linking agents. In Journal of Biomaterials Science, Polymer Edition (Vol. 13, Issue 11, pp. 1203–1219). https://doi.org/10.1163/156856202320892966

Ulubayram, K., Cakar, A. N., Korkusuz, P., Ertan, C., & Hasirci, N. (2001). EGF containing gelatin-based wound dressings. In Biomaterials (Vol. 22).

Ulubayram, K., Eroglu, I., & Hasirci, N. (2002). Gelatin microspheres and sponges for delivery of macromolecules. Journal of Biomaterials Applications, 16(3), 227–241. https://doi.org/10.1177/0885328202016003178

Wang, T., Zhu, X. K., Xue, X. T., & Wu, D. Y. (2012). Hydrogel sheets of chitosan, honey and gelatin as burn wound dressings. Carbohydrate Polymers, 88(1), 75–83. https://doi.org/10.1016/j.carbpol.2011.11.069

Wang, X., Guo, J., Zhang, Q., Zhu, S., Liu, L., Jiang, X., Wei, D. H., Liu, R. S., & Li, L. (2020). Gelatin sponge functionalized with gold/silver clusters for antibacterial application. Nanotechnology, 31(13). https://doi.org/10.1088/1361-6528/ab59eb

Yang, G., Xiao, Z., Long, H., Ma, K., Zhang, J., Ren, X., & Zhang, J. (2018). Assessment of the characteristics and biocompatibility of gelatin sponge scaffolds prepared by various crosslinking methods. Scientific Reports, 8(1). https://doi.org/10.1038/s41598-018-20006-y

Yeh, M. K., Liang, Y. M., Hu, C. S., Cheng, K. M., Hung, Y. W., Young, J. J., & Hong, P. da. (2012). Studies on a novel gelatin sponge: Preparation and characterization of cross-linked gelatin scaffolds using 2-chloro-1-methylpyridinium iodide as a zero-length cross-linker. Journal of Biomaterials Science, Polymer Edition, 23(7), 973–990. https://doi.org/10.1163/092050611X568430

Young, A., & McNaught, C. E. (2011). The physiology of wound healing. In Surgery (Vol. 29, Issue 10, pp. 475–479). Elsevier Ltd. https://doi.org/10.1016/j.mpsur.2011.06.011

Zeugolis, D. I., Khew, S. T., Yew, E. S. Y., Ekaputra, A. K., Tong, Y. W., Yung, L. Y. L., Hutmacher, D. W., Sheppard, C., & Raghunath, M. (2008). Electro-spinning of pure collagen nano-fibres - Just an expensive way to make gelatin? Biomaterials, 29(15), 2293–2305. https://doi.org/10.1016/j.biomaterials.2008.02.009

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