One-Pot Synthesis of Antibacterial and Antioxidant Self-Healing Bioadhesives Using Ugi Four-Component Reactions
Ronak Afshari
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA
Search for more papers by this authorArpita Roy
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA
Search for more papers by this authorSaumya Jain
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA
Search for more papers by this authorKaimana Lum
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA
Search for more papers by this authorJoyce Huang
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA
Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA
Search for more papers by this authorSam Denton
Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA
Search for more papers by this authorCorresponding Author
Nasim Annabi
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA
Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA
Correspondence:
Nasim Annabi ([email protected])
Search for more papers by this authorRonak Afshari
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA
Search for more papers by this authorArpita Roy
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA
Search for more papers by this authorSaumya Jain
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA
Search for more papers by this authorKaimana Lum
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA
Search for more papers by this authorJoyce Huang
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA
Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA
Search for more papers by this authorSam Denton
Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA
Search for more papers by this authorCorresponding Author
Nasim Annabi
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA
Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA
Correspondence:
Nasim Annabi ([email protected])
Search for more papers by this authorFunding: This work was supported by National Institutes of Health (Grant Nos. R01-EB023052 and R01-HL140618).
ABSTRACT
Bioadhesive materials are extensively utilized as alternatives to surgical sutures and wound dressings. Despite significant advancements in their synthesis, current bioadhesives suffer from inadequate mechanical stability, suboptimal wet tissue adhesion, and a lack of inherent antibacterial and antioxidant properties, while requiring multistep synthesis processes, complicating their production for biomedical applications. To address these limitations, we developed a new bioadhesive, named UgiGel, synthesized through a one-pot Ugi four-component reaction (Ugi-4CR). Our strategy utilized gelatin as the backbone, 4-formylphenylboronic acid (4-FPBA) as an aldehyde source for improved adhesion and antibacterial activity, gallic acid (GA) as a carboxylic acid source for improved antioxidant activity and wound healing, and cyclohexyl isocyanide (CyIso) to induce pseudopeptide structures. The internal crosslinking between GA and 4-FPBA via dynamic boronate ester bond formation, triggered by slight pH changes (7.4–7.8) and temperature elevation (25°C–40°C), resulted in the formation of viscoelastic and self-healing hydrogels with water as the only byproduct without the need for initiator/light activation. UgiGel showed higher adhesion to porcine skin tissue (139.8 ± 8.7 kPa) as compared to commercially available bioadhesives, Evicel (26.3 ± 2.6 kPa) and Coseal (19.3 ± 9.9 kPa). It also demonstrated effective antibacterial properties against both Gram-negative and Gram-positive bacteria, as well as antioxidant activity. Additionally, the in vitro studies using NIH-3T3 cells confirmed the biocompatibility of the UgiGel over 7 days of culture. Moreover, in vivo biocompatibility and biodegradation of UgiGel were confirmed via subcutaneous implantation in rats for up to 28 days. Our results demonstrated that UgiGel outperformed commercially available bioadhesives in terms of adhesion, self-healing, and antibacterial activity, without compromising biocompatibility or physical properties, representing a promising multifunctional bioadhesive for wound sealing and repair.
Conflicts of Interest
Dr. Nasim Annabi holds equity in GelMEDIX Inc. The remaining authors declare no conflicts of interest.
Open Research
Data Availability Statement
The data presented in this study are available on request from the corresponding author.
Supporting Information
| Filename | Description |
|---|---|
| jbmb35584-sup-0001-Figures.docxWord 2007 document , 12.1 MB |
Figure S1. Comparison of gel formation with 4-FPBA and 3,4-dihydroxybenzaldehyde due to boronic acid groups and dynamic boronate ester bond crosslinking. (A) UgiGel formed with 4-FPBA (left vial, yellowish color) showed a robust and uniform gel after heating to 40°C for 1 min, while the gel prepared with 3,4-dihydroxybenzaldehyde (right vial, white color), lacking boronic groups, formed an aggregated precipitate with weak gel characteristics. (B) Even after 1 h, the gel formed with 3,4-dihydroxybenzaldehyde showed limited stability and remained precipitated. (C) After pH adjustment to the above pKa of 3,4-dihydroxybenzaldehyde (> 8.5), the gel formed with 3,4-dihydroxybenzaldehyde remained agglomerated after 48 s, confirming that boronate ester formation is essential for stable internal crosslinking. Figure S2. In vitro degradation and swelling behavior of UgiGel. (A) Degradation profile of UgiGel in DPBS at pH 7.4 and 37°C over 42 days, showing a gradual degradation up to approximately 75%. (B) Swelling behavior of UgiGel at pH 7.4 and 37°C, with the swelling ratio stabilizing after an initial increase to ~45% in the first 12 h and remaining constant up to 48 h (n = 3). Figure S3. In vitro antioxidant activity. % DPPH radical scavenging activity of UgiGel (n = 5). Figure S4. Quantification of cell infiltration for the in vivo subcutaneous implantation. (A) Cellular infiltration into the UgiGel hydrogel based on H&E images and (B) macrophage infiltration into tissue surrounding the hydrogel based on immunostaining images (marked by CD68 red dye) compared to 20% (w/v) GelMA bioadhesive as a control (n = 3). |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1K. Las Heras, M. Igartua, E. Santos-Vizcaino, and R. M. Hernandez, “Chronic Wounds: Current Status, Available Strategies and Emerging Therapeutic Solutions,” Journal of Controlled Release 328 (2020): 532–550.
- 2L. J. Borda, F. E. Macquhae, and R. S. Kirsner, “Wound Dressings: A Comprehensive Review,” Current Dermatology Reports 5, no. 4 (2016): 287–297.
- 3V. Brumberg, T. Astrelina, T. Malivanova, et al., “Modern Wound Dressings: Hydrogel Dressings,” Biomedicines 9, no. 9 (2021): 1235.
- 4S. Rathi, R. Saka, A. J. Domb, and W. Khan, “Protein-Based Bioadhesives and Bioglues,” Polymers for Advanced Technologies 30, no. 2 (2019): 217–234.
- 5G. M. Taboada, K. Yang, M. J. N. Pereira, et al., “Overcoming the Translational Barriers of Tissue Adhesives,” Nature Reviews Materials 5, no. 4 (2020): 310–329.
- 6R. Pinnaratip, M. S. A. Bhuiyan, K. Meyers, R. M. Rajachar, and B. P. Lee, “Multifunctional Biomedical Adhesives,” Advanced Healthcare Materials 8, no. 11 (2019): 1801568.
- 7A. A. P. Mansur, M. A. Rodrigues, N. S. V. Capanema, S. M. Carvalho, D. A. Gomes, and H. S. Mansur, “Functionalized Bioadhesion-Enhanced Carboxymethyl Cellulose/Polyvinyl Alcohol Hybrid Hydrogels for Chronic Wound Dressing Applications,” RSC Advances 13, no. 19 (2023): 13156–13168.
- 8L. Zhang, M. Liu, Y. Zhang, and R. Pei, “Recent Progress of Highly Adhesive Hydrogels as Wound Dressings,” Biomacromolecules 21, no. 10 (2020): 3966–3983.
- 9L. Zhao, Z. Shi, X. Sun, et al., “Natural Dual-Crosslinking Bioadhesive Hydrogel for Corneal Regeneration in Large-Size Defects,” Advanced Healthcare Materials 11, no. 21 (2022): 2201576.
- 10R. Song, X. Wang, M. Johnson, et al., “Enhanced Strength for Double Network Hydrogel Adhesive Through Cohesion-Adhesion Balance,” Advanced Functional Materials 34, no. 23 (2024): 2313322.
- 11Y. Liu, Y. Ouyang, L. Yu, et al., “Novel Approach for Enhancing Skin Allograft Survival by Bioadhesive Nanoparticles Loaded With Rapamycin,” International Journal of Pharmaceutics 651 (2024): 123742.
- 12Y. Zheng, K. Shariati, M. Ghovvati, et al., “Hemostatic Patch With Ultra-Strengthened Mechanical Properties for Efficient Adhesion to Wet Surfaces,” Biomaterials 301 (2023): 122240.
- 13S. Bashir, M. Hina, J. Iqbal, et al., “Fundamental Concepts of Hydrogels: Synthesis, Properties, and Their Applications,” Polymers 12, no. 11 (2020): 2702.
- 14M. Santos, T. Cernadas, P. Martins, et al., “Polyester-Based Photocrosslinkable Bioadhesives for Wound Closure and Tissue Regeneration Support,” Reactive and Functional Polymers 158 (2021): 104798.
- 15R. Afshari and A. Shaabani, “Materials Functionalization With Multicomponent Reactions: State of the Art,” ACS Combinatorial Science 20, no. 9 (2018): 499–528.
- 16T. Zarganes-Tzitzikas, A. L. Chandgude, and A. Dömling, “Multicomponent Reactions, Union of MCRs and Beyond,” Chemical Record 15, no. 5 (2015): 981–996.
- 17A. Dömling, W. Wang, and K. Wang, “Chemistry and Biology of Multicomponent Reactions,” Chemical Review 112, no. 6 (2012): 3083–3135.
- 18A. Dömling, “Recent Developments in Isocyanide Based Multicomponent Reactions in Applied Chemistry,” Chemical Reviews 106, no. 1 (2006): 17–89.
- 19S. E. Hooshmand and W. Zhang, “Ugi Four-Component Reactions Using Alternative Reactants,” Molecules 28, no. 4 (2023): 1642.
- 20A. Sehlinger, P. K. Dannecker, O. Kreye, and M. A. R. Meier, “Diversely Substituted Polyamides: Macromolecular Design Using the Ugi Four-Component Reaction,” Macromolecules 47, no. 9 (2014): 2774–2783.
- 21I. Ugi, B. Werner, and A. Dömling, “The Chemistry of Isocyanides, Their Multi Component Reactions and Their Libraries,” Molecules 8, no. 1 (2003): 53–66.
- 22B. Yang, Y. Zhao, X. Ren, et al., “The Power of One-Pot: A Hexa-Component System Containing π–π Stacking, Ugi Reaction and RAFT Polymerization for Simple Polymer Conjugation on Carbon Nanotubes,” Polymer Chemistry 6, no. 4 (2014): 509–513.
10.1039/C4PY01323A Google Scholar
- 23A. Shaabani and R. Afshari, “Synthesis of Carboxamide-Functionalized Multiwall Carbon Nanotubes via Ugi Multicomponent Reaction: Water-Dispersible Peptidomimetic Nanohybrid as Controlled Drug Delivery Vehicle,” ChemistrySelect 2, no. 18 (2017): 5218–5225.
- 24A. Rezaei, O. Akhavan, E. Hashemi, and M. Shamsara, “Toward Chemical Perfection of Graphene-Based Gene Carrier via Ugi Multicomponent Assembly Process,” Biomacromolecules 17, no. 9 (2016): 2963–2971.
- 25R. Afshari, V. Ghasemi, S. Shaabani, A. Shaabani, Z. Aladaghlo, and A. R. Fakhari, “Post-modification of Phthalocyanines via Isocyanide-Based Multicomponent Reactions: Highly Dispersible Peptidomimetic Metallophthalocyanines as Potent Photosensitizers,” Dyes and Pigments 166 (2019): 49–59.
- 26L. Reguera, Y. Méndez, A. R. Humpierre, O. Valdés, and D. G. Rivera, “Multicomponent Reactions in Ligation and Bioconjugation Chemistry,” Account of Chemical Research 51, no. 6 (2018): 1475–1486.
- 27H. Yazdani, S. E. Hooshmand, and M. H. Stenzel, “Fusion of Cellulose and Multicomponent Reactions: Benign by Design,” ACS Sustainable Chemistry & Engineering 10, no. 14 (2022): 4359–4373.
- 28Y. Zeng, C. Zhu, L. Tao, Y. Zeng, L. Tao, and C. Zhu, “Stimuli-Responsive Multifunctional Phenylboronic Acid Polymers Via Multicomponent Reactions: From Synthesis to Application,” Macromolecular Rapid Communications 42, no. 18 (2021): 2100022.
- 29Y. Zeng, Y. Li, G. Liu, Y. Wei, Y. Wu, and L. Tao, “Antibacterial Self-Healing Hydrogel via the Ugi Reaction,” ACS Applied Polymer Materials 2, no. 2 (2020): 404–410.
- 30W. Zhang, P. Tang, M. A. Abubaker, G.-H. Hu, and F.-E. Chen, “Advances of Ugi Reaction in Natural Product Synthesis,” Green Synthesis and Catalysis (2024), https://doi.org/10.1016/j.gresc.2024.08.004.
10.1016/j.gresc.2024.08.004 Google Scholar
- 31A. Shaabani and R. Afshari, “Magnetic Ugi-Functionalized Graphene Oxide Complexed With Copper Nanoparticles: Efficient Catalyst toward Ullman Coupling Reaction in Deep Eutectic Solvents,” Journal of Colloid and Interface Science 510 (2018): 384–394.
- 32C. Jumelle, E. S. Sani, Y. Taketani, et al., “Growth Factor-Eluting Hydrogels for Management of Corneal Defects,” Materials Science and Engineering: C 120 (2021): 111790.
- 33C. Jumelle, A. Yung, E. S. Sani, et al., “Development and Characterization of a Hydrogel-Based Adhesive Patch for Sealing Open-Globe Injuries,” Acta Biomaterialia 137 (2022): 53–63.
- 34Y. Zhu, Q. Luo, H. Zhang, et al., “A Shear-Thinning Electrostatic Hydrogel With Antibacterial Activity by Nanoengineering of Polyelectrolytes,” Biomaterials Science 8, no. 5 (2020): 1394–1404.
- 35H. Montazerian, A. Hassani Najafabadi, E. Davoodi, et al., “Poly-Catecholic Functionalization of Biomolecules for Rapid Gelation, Robust Injectable Bioadhesion, and Near-Infrared Responsiveness,” Advanced Healthcare Materials 12, no. 17 (2023): 2203404.
- 36N. Annabi, D. Rana, E. Shirzaei Sani, et al., “Engineering a Sprayable and Elastic Hydrogel Adhesive With Antimicrobial Properties for Wound Healing,” Biomaterials 139 (2017): 229–243.
- 37A. Roy, P. Guha Ray, A. Bose, S. Dhara, and S. Pal, “PH-Responsive Copolymeric Network Gel Using Methacrylated β-Cyclodextrin for Controlled Codelivery of Hydrophilic and Hydrophobic Drugs,” ACS Applied Bio Materials 5, no. 7 (2022): 3530–3543.
- 38A. Roy, P. Guha Ray, K. Manna, C. Banerjee, S. Dhara, and S. Pal, “Poly(N-Vinyl Imidazole) Cross-Linked β-Cyclodextrin Hydrogel for Rapid Hemostasis in Severe Renal Arterial Hemorrhagic Model,” Biomacromolecules 22, no. 12 (2021): 5256–5269.
- 39N. Annabi, S. M. Mithieux, P. Zorlutuna, G. Camci-Unal, A. S. Weiss, and A. Khademhosseini, “Engineered Cell-Laden Human Protein-Based Elastomer,” Biomaterials 34, no. 22 (2013): 5496–5505.
- 40N. Annabi, K. Tsang, S. M. Mithieux, et al., “Highly Elastic Micropatterned Hydrogel for Engineering Functional Cardiac Tissue,” Advanced Functional Materials 23, no. 39 (2013): 4950–4959.
- 41N. Annabi, Y. N. Zhang, A. Assmann, et al., “Engineering a Highly Elastic Human Protein-Based Sealant for Surgical Applications,” Science Translational Medicine 9, no. 410 (2017): aai7466.
- 42M. Zhu, W. Li, X. Dong, et al., “In Vivo Engineered Extracellular Matrix Scaffolds With Instructive Niches for Oriented Tissue Regeneration,” Nature Communication 10, no. 1 (2019): 4620.
- 43Y. Mao, Y. Zhang, Y. Wang, T. Zhou, B. Ma, and P. Zhou, “A Multifunctional Nanocomposite Hydrogel With Controllable Release Behavior Enhances Bone Regeneration. Regenerative,” Biomaterials 10 (2023): rbad046.
- 44A. Roy, S. Zenker, S. Jain, et al., “A Highly Stretchable, Conductive, and Transparent Bioadhesive Hydrogel as a Flexible Sensor for Enhanced Real-Time Human Health Monitoring,” Advanced Materials 36, no. 35 (2024): 2404225.
- 45A. Assmann, A. Vegh, M. Ghasemi-Rad, et al., “A Highly Adhesive and Naturally Derived Sealant,” Biomaterials 140 (2017): 115–127.
- 46A. M. Rahimi, M. Cai, and S. Hoyer-Fender, “Heterogeneity of the NIH3T3 Fibroblast Cell Line,” Cells 11, no. 17 (2022): 2677.
- 47R. Afshari, S. Emad Hooshmand, M. Atharnezhad, and A. Shaabani, “An Insight into the Novel Covalent Functionalization of Multi-Wall Carbon Nanotubes With Pseudopeptide Backbones for Palladium Nanoparticles Immobilization: A Versatile Catalyst towards Diverse Cross-Coupling Reactions in Bio-Based Solvents,” Polyhedron 175 (2020): 114238.
- 48H. Montazerian, A. Baidya, R. Haghniaz, et al., “Stretchable and Bioadhesive Gelatin Methacryloyl-Based Hydrogels Enabled by In Situ Dopamine Polymerization,” ACS Applied Materials & Interfaces 13, no. 34 (2021): 40290–40301.
- 49J. I. Kang and K. M. Park, “Advances in Gelatin-Based Hydrogels for Wound Management,” Journal of Materials Chemistry B 9, no. 6 (2021): 1503–1520.
- 50A. Nouri, N. Salehi-Vanani, and E. Heidarian, “Antioxidant, Anti-Inflammatory and Protective Potential of Gallic Acid against Paraquat-Induced Liver Toxicity in Male Rats,” Avicenna Journal of Phytomedicine 11, no. 6 (2021): 633.
- 51N. A. Al Zahrani, R. M. El-Shishtawy, and A. M. Asiri, “Recent Developments of Gallic Acid Derivatives and Their Hybrids in Medicinal Chemistry: A Review,” European Journal of Medicinal Chemistry 204 (2020): 112609.
- 52D. J. Yang, S. H. Moh, D. H. Son, et al., “Gallic Acid Promotes Wound Healing in Normal and Hyperglucidic Conditions,” Molecules 21, no. 7 (2016): 899.
- 53H. M. U. Abid, M. Hanif, K. Mahmood, M. Aziz, G. Abbas, and H. Latif, “Wound-Healing and Antibacterial Activity of the Quercetin-4-Formyl Phenyl Boronic Acid Complex against Bacterial Pathogens of Diabetic Foot Ulcer,” ACS Omega 7, no. 28 (2022): 24415–24422.
- 54A. Zhang, Y. Liu, D. Qin, M. Sun, T. Wang, and X. Chen, “Research Status of Self-Healing Hydrogel for Wound Management: A Review,” International Journal of Biological Macromolecules 164 (2020): 2108–2123.
- 55P. Yang, Z. Li, B. Fang, and L. Liu, “Self-Healing Hydrogels Based on Biological Macromolecules in Wound Healing: A Review,” International Journal of Biological Macromolecules 253 (2023): 127612.
- 56Y. Chen, W. Qian, R. Chen, et al., “One-Pot Preparation of Autonomously Self-Healable Elastomeric Hydrogel From Boric Acid and Random Copolymer Bearing Hydroxyl Groups,” ACS Macro Letters 6, no. 10 (2017): 1129–1133.
- 57K. G. M. Brown and M. J. Solomon, “Topical Haemostatic Agents in Surgery,” British Journal of Surgery 111, no. 1 (2024): znad361.
10.1093/bjs/znad361 Google Scholar
- 58R. Dong and B. Guo, “Smart Wound Dressings for Wound Healing,” Nano Today 41 (2021): 101290.
- 59S. L. Percival, S. McCarty, J. A. Hunt, and E. J. Woods, “The Effects of PH on Wound Healing, Biofilms, and Antimicrobial Efficacy,” Wound Repair and Regeneration 22, no. 2 (2014): 174–186.
- 60 A. Rudawska, ed., Adhesives – Applications and Properties (InTech, 2016).
10.5772/62603 Google Scholar
- 61H. Cheng, K. Yue, M. Kazemzadeh-Narbat, et al., “Mussel-Inspired Multifunctional Hydrogel Coating for Prevention of Infections and Enhanced Osteogenesis,” ACS Applied Materials Interfaces 9, no. 13 (2017): 11428–11439.
- 62A. Basit, H. Yu, L. Wang, et al., “Recent Advances in Wet Surface Tissue Adhesive Hydrogels for Wound Treatment,” European Polymer Journal 216 (2024): 113260.
- 63Y. Lu, X. Xu, and J. Li, “Recent Advances in Adhesive Materials Used in the Biomedical Field: Adhesive Properties, Mechanism, and Applications,” Journal of Materials Chemistry B 11, no. 15 (2023): 3338–3355.
- 64N. Zandi, B. Dolatyar, R. Lotfi, et al., “Biomimetic Nanoengineered Scaffold for Enhanced Full-Thickness Cutaneous Wound Healing,” Acta Biomaterialia 124 (2021): 191–204.
- 65A. Gefen, P. Alves, D. Beeckman, et al., “How Should Clinical Wound Care and Management Translate to Effective Engineering Standard Testing Requirements From Foam Dressings? Mapping the Existing Gaps and Needs,” Advances in Wound Care (New Rochelle) 13, no. 1 (2024): 34.
- 66A. S. Moffarah, M. Mohajer Al, B. L. Hurwitz, and D. G. Armstrong, “ Skin and Soft Tissue Infections,” in Diagnostic Microbiology of the Immunocompromised Host (Wiley, 2016), 691–708.
10.1128/9781555819040.ch26 Google Scholar
- 67S. Gao, Y. Zhang, R. Zhou, et al., “Boronic Acid-Assisted Detection of Bacterial Pathogens: Applications and Perspectives,” Coordination Chemistry Reviews 518 (2024): 216082.
- 68J. Chen, J. He, Y. Yang, et al., “Antibacterial Adhesive Self-Healing Hydrogels to Promote Diabetic Wound Healing,” Acta Biomaterialia 146 (2022): 119–130.
- 69X. He, Z. Li, J. Li, et al., “Ultrastretchable, Adhesive, and Antibacterial Hydrogel With Robust Spinnability for Manufacturing Strong Hydrogel Micro/Nanofibers,” Small 17, no. 49 (2021): e2103521.
10.1002/smll.202103521 Google Scholar
- 70C. Mao, Y. Xiang, X. Liu, et al., “Photo-Inspired Antibacterial Activity and Wound Healing Acceleration by Hydrogel Embedded With Ag/Ag@AgCl/ZnO Nanostructures,” ACS Nano 11, no. 9 (2017): 9010–9021.
- 71K. Gwon, I. Han, S. Lee, Y. Kim, and D. N. Lee, “Novel Metal–Organic Framework-Based Photocrosslinked Hydrogel System for Efficient Antibacterial Applications,” ACS Applied Materials Interfaces 12, no. 18 (2020): 20234–20242.
- 72Z. Xu, S. Han, Z. Gu, and J. Wu, “Advances and Impact of Antioxidant Hydrogel in Chronic Wound Healing,” Advanced Healthcare Materials 9, no. 5 (2020): 1901502.
- 73G. Wang, F. Yang, W. Zhou, N. Xiao, M. Luo, and Z. Tang, “The Initiation of Oxidative Stress and Therapeutic Strategies in Wound Healing,” Biomedicine & Pharmacotherapy 157 (2023): 114004.
- 74P. S. Kaparekar, S. Pathmanapan, and S. K. Anandasadagopan, “Polymeric Scaffold of Gallic Acid Loaded Chitosan Nanoparticles Infused With Collagen-Fibrin for Wound Dressing Application,” International Journal of Biological Macromolecules 165 (2020): 930–947.
- 75Y. Liang, J. He, and B. Guo, “Functional Hydrogels as Wound Dressing to Enhance Wound Healing,” ACS Nano 15, no. 8 (2021): 12687–12722.
- 76S. Suzuki and Y. Ikada, “Sealing Effects of Cross-Linked Gelatin,” Journal of Biomaterials Applications 27, no. 7 (2013): 801–810.
- 77X. Cao, X. Wu, Y. Zhang, X. Qian, W. Sun, and Y. Zhao, “Emerging Biomedical Technologies for Scarless Wound Healing,” Bioactive Materials 42 (2024): 449–477.
- 78J. Chen, X. Zhou, W. Sun, et al., “Vascular Derived ECM Improves Therapeutic Index of BMP-2 and Drives Vascularized Bone Regeneration,” Small 18, no. 36 (2022): 2107991.
- 79S. Baghdasarian, B. Saleh, A. Baidya, et al., “Engineering a Naturally Derived Hemostatic Sealant for Sealing Internal Organs,” Materials Today Bio 13 (2022): 100199.
