Iranian Journal of Basic Medical Sciences

Iranian Journal of Basic Medical Sciences

Immunomodulatory and anti-oxidant mechanisms of plant-derived bioactive scaffolds in diabetic wound healing: Molecular pathways and therapeutic implications

Articles in Press

Document Type : Review Article

Authors
Rania Hameed Hamad 1
Farag M. A. Altalbawy 2
Maher Abdulrazzaq Al-hakeem 3
Yasir Qasim Almajidi 3
Ozodbek Nematov 4
Ibrokhim Sapaev 5, 6, 7, 8
Safa hussien 9, 10
Aseel Smerat 11
Homeira Parizad 12
Narges Fereydouni 13, 14
1 Medical Laboratory Techniques Department, College of Health and Medical Techniques, University of Al maarif, Anbar, Iraq
2 Department of Chemistry, University College of Duba, University of Tabuk, Tabuk, Saudi Arabia
3 Department of Pharmaceutics, College of Pharmacy, Alnahrain University, Baghdad, Iraq
4 Jizzakh State Pedagogical University, Jizzakh, Uzbekistan
5 Department of Physics and Chemistry, “Tashkent Institute of Irrigation and Agricultural Mechanization Engineers” National Research University, Tashkent, Uzbekistan
6 University of Tashkent for Applied Science, Tashkent, Uzbekistan
7 School of Engineering, Central Asian University, Tashkent 111221, Uzbekistan
8 Western Caspian University, Baku, Azerbaijan
9 Department of Medical Analysis, Medical Laboratory Technique College, The Islamic University, Najaf, Iraq
10 Center of Research Impact and Outcome, Chitkara University, Rajpura 140417, Punjab, India
11 Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman 19328, Jordan
12 Central Laboratory of Shiraz University, Shiraz University, Shiraz, Iran
13 Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran
14 Clinical Research Development Unit, Valiasr Hospital, Fasa University of Medical Sciences, Fasa, Iran
10.22038/ijbms.2026.94549.20387
Abstract
Diabetic wound healing remains challenging due to persistent inflammation, oxidative stress, and impaired angiogenesis. Plant-derived bioactive scaffolds address multiple pathophysiological mechanisms simultaneously through inherent immunomodulatory and anti-oxidant properties. This review critically analyzes recent advances in plant-derived scaffolds for diabetic wound healing, focusing on molecular mechanisms. A systematic literature search was conducted in PubMed, Scopus, and Web of Science using terms such as “plant-derived scaffolds,” “decellularized scaffolds,” “diabetic wound healing,” “immunomodulation,” “anti-oxidant,” and “angiogenesis.” Studies published primarily between 2019 and 2026 that reported in vitro, in vivo, or ex vivo data on plant scaffold performance in diabetic wound models were prioritized; mechanistically relevant phytochemical studies were included where direct scaffold-level evidence was limited. The analysis emphasizes immunomodulatory, anti-oxidant, and angiogenic effects in experimental models. Plant-derived scaffolds from kelp, spinach, pomelo peel, walnut leaves, and mushrooms demonstrate therapeutic potential through multiple mechanisms. They promote macrophage polarization from pro-inflammatory M1 to regenerative M2 phenotypes, reduce reactive oxygen species via polyphenolic and flavonoid compounds, and enhance angiogenesis through VEGF up-regulation. Bioactive components, including fucoidan, gallic acid, carotenoids, and p-coumaric acid, reduce pro-inflammatory cytokines, enhance collagen deposition, and accelerate wound closure, exceeding 90% by day 14 in diabetic animal models, compared with approximately 70% in untreated controls. Plant-derived bioactive scaffolds represent a paradigm shift in diabetic wound management by simultaneously targeting inflammation, oxidative stress, and impaired regeneration through naturally occurring bioactive compounds while preserving extracellular matrix architecture.
Keywords
Anti-oxidant mechanisms
Bioactive compounds
Diabetic wound healing
Immunomodulation
Macrophage polarization
Plant-derived scaffolds
Subjects
1. Akkus G, Sert M. Diabetic foot ulcers: A devastating complication of diabetes mellitus continues non-stop in spite of new medical treatment modalities. World J Diabetes 2022; 13: 1106-1121.
2. Wang R, Gu S, Kim YH, Lee A, Lin H, Jiang D. Diabetic wound repair: From mechanism to therapeutic opportunities. MedComm (2020) 2025; 6: e70406.
3. Astaneh ME, Fereydouni N. Nanocurcumin-enhanced zein nanofibers: Advancing macrophage polarization and accelerating wound healing. Regen Ther 2025; 28: 51-62.
4. Dai Y, Chen Y. Targeting persistently activated inflammatory microenvironment to promote chronic wound healing. Front Immunol 2025; 16: 1708358.
5. Qin Y, Qian C, Li W, Wang Q, Sheng Q, Chen Z, et al. Oxidative stress: Molecular mechanisms, diseases, and therapeutic targets. MedComm (2020) 2026; 7: e70600. 
6. Huang K, Mi B, Xiong Y, Fu Z, Zhou W, Liu W, et al. Angiogenesis during diabetic wound repair: From mechanism to therapy opportunity. Burns Trauma 2025; 13: tkae052.
7. Chen J, Qin S, Xing Z, Peng C, Li D. Targeting angiogenesis in diabetic wound healing: New insight from chemical architecture to functional outcomes. J Pharm Anal 2025; 11: 101475.
8. Dudley AC, Griffioen AW. Pathological angiogenesis: Mechanisms and therapeutic strategies. Angiogenesis 2023; 26: 313-347.
9. Ramsamooj A, Gorbenko N, Olivares C, John S, Merna N. Improving the biocompatibility of plant-derived scaffolds for tissue engineering using heat treatment. J Funct Biomater 2025; 16: 380.
10. Almajidi YQ, Al-hakeem MA, Maashi MS, Kareem AK, Kadhim M, Waad I, et al. Chitosan-based hydrogels loaded with repaglinide and difluorinated curcumin: Impact on structural integrity, drug release, and antibacterial activity. Naunyn-Schmiedeberg’s Arch Pharmacol 2025; 399: 5499-5514.
11. Hsu C-Y, Azzam ER, Merza M, Maashi MS, Hjazi A, M.M R, et al. Therapeutic potential of repaglinide-embedded chitosan hydrogel in promoting wound healing. Regen Ther 2025; 29: 551-562.
12. Chen X, Chen C, Fu X. Dendrobium officinale polysaccharide alleviates type 2 diabetes mellitus by restoring gut microbiota and repairing intestinal barrier via the LPS/TLR4/TRIF/NF-kB axis. J Agric Food Chem 2023; 71: 11929-11940.
13. Sabarudin NS, Ab Ghani N, Ahmat N, Harlin EW, Hao LQ, Handajani J, et al. Harnessing plant bioactive compounds in biomaterial scaffolds for advanced wound healing: A comprehensive review. Biomedicines 2025; 13: 2414.
14. Wang XF, Chen X, Tang Y, Wu JM, Qin DL, Yu L, et al. The therapeutic potential of plant polysaccharides in metabolic diseases. Pharmaceuticals (Basel) 2022; 15: 1329.
15. Bock N, Delbianco M, Eder M, Weinkamer R, Amini S, Bidan CM, et al. A materials science approach to extracellular matrices. Prog Mater Sci 2025; 149: 101391.
16. Zheng Y, Wang J, Wang J, Li Y, Jiang Z. Insect cuticle: A source of inspiration for biomimetic Interface material design. Colloid Interface Sci Commun 2025; 64: 100818.
17. Allu I, Sahi AK, Koppadi M, Gundu S, Sionkowska A. Decellularization techniques for tissue engineering: Towards replicating native extracellular matrix architecture in liver regeneration. J Funct Biomater 2023; 14: 518.
18. Jin C, Zhang X, Jin Y, Chien PN, Heo CY. Acellular extracellular matrix scaffolds in regenerative medicine: Advances in decellularization and clinical applications. J Funct Biomater 2025; 16: 383.
19. Riaz S, Waheed H, Ahmad F, Khan MI, Shanableh A. Natural and synthetic biomaterials, structural matrices-based wound dressings: Key properties, material correlation, and adaptability. Regenesis Repair Rehabil 2025; 1: 47-65.
20. Boleti APA, Jacobowski AC, Frihling BEF, Cruz MV, Santos K, Migliolo L, et al. Wound healing: Molecular mechanisms, antimicrobial peptides, and emerging technologies in regenerative medicine. Pharmaceuticals (Basel) 2025; 18: 1525.
21. Ye J, Xie C, Wang C, Huang J, Yin Z, Heng BC, et al. Promoting musculoskeletal system soft tissue regeneration by biomaterial-mediated modulation of macrophage polarization. Bioact Mater 2021; 6: 4096-4109.
22. Gangwar V, Garg A, Lomore K, Korla K, Bhat SS, Rao RP, et al. Immunomodulatory effects of a concoction of natural bioactive compounds-mechanistic insights. Biomedicines 2021; 9: 1522.
23. Ngo V, Duennwald ML. Nrf2 and oxidative stress: A general overview of mechanisms and implications in human disease. Antioxidants 2022; 11: 2345. 
24. El-Beltagi HS, Mohamed AA, Mohamed HI, Ramadan KMA, Barqawi AA, Mansour AT. Phytochemical and potential properties of seaweeds and their recent applications: A review. Mar Drugs 2022; 20: 342. 
25. Salehi M, Rashidinejad A. Multifaceted roles of plant-derived bioactive polysaccharides: A review of their biological functions, delivery, bioavailability, and applications within the food and pharmaceutical sectors. Int J Biol Macromol 2025; 290: 138855. 
26. Zhao M, Huang J, Yang H, Yang R, Guo S, Liu Z, et al. Engineered aggregation-induced emission luminogens-based framework with CO-releasing property for accelerating diabetic wound healing. Chem Eng J 2025; 524: 168981.
27. Andleeb A, Dikici S, Waris TS, Bashir MM, Akhter S, Chaudhry AA, et al. Developing affordable and accessible pro-angiogenic wound dressings; incorporation of 2 deoxy D-ribose (2dDR) into cotton fibres and wax-coated cotton fibres. J Tissue Eng Regen Med 2020; 14: 973-988.
28. Cheng S, Yang J, Song J, Cao X, Zhou B, Yang L, et al. A motion-responsive injectable lubricative hydrogel for efficient Achilles tendon adhesion prevention. Mater Today Bio 2025; 30: 101458.
29. Patil SB, Patil PP, Gore SD, Patil SC, Koli R. Nanoparticle-enabled herbal therapeutics for wound healing: bridging traditional medicine and modern nanotechnology. Nano Trends 2026; 13: 100170.
30.Moldovan C-A-D, Salagean A-A, Slevin M. Multiplexing 3D natural scaffolds to optimize the repair and regeneration of chronic diabetic wounds. Gels 2025; 11: 430.
31. Kumar V, Naik IS, Das B, Singh A, Nayak P, Mohapatra C, et al. Nanoparticles in plant system: A comprehensive review on their role in diverse stress management and phytohormone signaling. Plant Stress 2025; 18: 101000.
32. Ren R-Y, Zhao T-G, Li L-X, Tang X-Y, Li J-L, Jiang F, et al. Immunomodulatory all-natural kelp decellularized scaffold prepared using deep eutectic solvent with angiogenic properties for accelerating diabetic wound healing. ACS Biomater Sci Eng 2025; 11: 2306-2320.
33. Ksouri R, Aksel H, Saghrouchni H, Saygideger Y. Biocompatible and safe decellularized spinach with antibacterial and wound healing activity. J Biomed Mater Res B Appl Biomater 2024; 112: e35489.
34. Dikici S, Çavdaroglu Ç. Development of pro-angiogenic wound dressings from 2-deoxy-D-ribose (2dDR)-loaded decellularized plant leaves. J Mater Sci 2023; 58: 16428–16444.
35. Yang J, Huang Z, Tan J, Pan J, Chen S, Wan W. Copper ion/gallic acid MOFs-laden adhesive pomelo peel sponge effectively treats biofilm-infected skin wounds and improves healing quality. Bioact Mater 2024; 32: 260-276.
36. Arin A, Rahaman MS, Farwa U, Lee B-T. Faster and protective wound healing mechanistic of para-coumaric acid loaded liver ECM scaffold cross-linked with acellular marine kelp. Adv Funct Mater 2023; 33: 2212325.
37. Kabra R, Poonia N, Subudhi RN, Singh T, Joshi G, Sharma R, et al. Innovative strategies for the management of diabetic wounds: A step toward faster recovery. J Drug Deliv Sci Technol 2026; 115: 107824.
38. Ji Y, Li X, Yao X, Sun J, Yi J, Shen Y, et al. Macrophage polarization: Molecular mechanisms, disease implications, and targeted therapeutic strategies. Front Immunol 2025; 16: 1732718.
39. Adhikary K, Sarkar R, Maity S, Sadhukhan I, Sarkar R, Ganguly K, et al. Immunomodulation of macrophages in diabetic wound individuals by structurally diverse bioactive phytochemicals. Pharmaceuticals (Basel) 2024; 17: 1294. 
40. Huang W, Huang S, Linghu X, Chen W-C, Wang Y, Li J, et al. 3D-Printed mesoporous bioglass/polycaprolactone scaffolds induce macrophage polarization toward M2 phenotype and immunomodulates osteogenic differentiation of BMSCs. Int J Bioprint 2024; 10: 3551.
41. Mamun AA, Shao C, Geng P, Wang S, Xiao J. Polyphenols targeting NF-κB pathway in neurological disorders: What we know so far? Int J Biol Sci 2024; 20: 1332-1355.
42. Chauhan A, Islam AU, Prakash H, Singh S. Phytochemicals targeting NF-κB signaling: Potential anti-cancer interventions. J Pharm Anal 2022; 12: 394-405.
43. Kian M, Hashemi SS, Derakhshanfar A, Darya GH, Shahhossein Z, Saharkhiz MJ. Decellularized Persian walnut leaf (Juglans regia) as a potential wound dressing scaffold: An experimental study. Front Bioeng Biotechnol 2025; 13: 1524956.
44. Zhang C, Fan S, Zhang J, Yang G, Cai C, Chen S, et al. A multifunctional trap-capture-kill antibacterial system for enhanced wound healing via modified decellularized mushroom aerogels. Bioact Mater 2025; 50: 232-245.
45. Salazar J, Pirela D, Nava M, Castro A, Angarita L, Parra H, et al. Specialized proresolving lipid mediators: A potential therapeutic target for atherosclerosis. Int J Mol Sci 2022; 23: 3133.
46. Skenderidou I, Leontopoulos S, Skenderidis P. Functional food ingredients enhancing immune health: A systematic review. Int J Mol Sci 2025; 26: 8408.
47. Wang Z, Lin X, Shi Y, Yan H, Shang Y, Ren H. Decellularized extracellular matrix: Advanced bioplatforms for functional tissue restoration via innovative decellularization techniques. Biomed Technol 2026; 13: 100131.
48. Elbouzidi A, Haddou M, Baraich A, Taibi M, El Hachlafi N, Pareek A, et al. Biochemical insights into specialized plant metabolites: Advancing cosmeceutical applications for skin benefits. J Agric Food Res 2025; 19: 101651. 
49. Wang W, Cai T, Shao C, Xiao Y, Xiang Y, Jiang Y. MXene‐based responsive hydrogels and applications in wound healing. ChemistrySelect 2024; 9: e202402073.
50. Liu S, Liu J, Wang Y, Deng F, Deng Z. Oxidative stress: Signaling pathways, biological functions, and disease. MedComm (2020) 2025; 6: e70268.
51. Yan S, Bhawal R, Yin Z, Thannhauser TW, Zhang S. Recent advances in proteomics and metabolomics in plants. Mol Hortic 2022; 2: 17.
52. Xiang J, Zhang J, Zheng R, Li X, Li M. NIDM: Network impulsive dynamics on multiplex biological network for disease-gene prediction. Brief Bioinform 2021; 22: bbab080. 
53. Son B. Regulation of tissue regeneration by immune microenvironment–fibroblast interactions. Int J Mol Sci 2025; 26: 11950.
54. Hong L, Li M, Fan Y. Oxidative stress and programmed cell death in diabetic wounds: A comprehensive review. Sci Prog 2025; 108: 368504251370676.
55. Ashok A, Andrabi SS, Mansoor S, Kuang Y, Kwon BK, Labhasetwar V. Antioxidant therapy in oxidative stress-induced neurodegenerative diseases: Role of nanoparticle-based drug delivery systems in clinical translation. Antioxidants (Basel) 2022; 11: 408.
56. Begum R, Howlader S, Mamun-Or-Rashid ANM, Rafiquzzaman SM, Ashraf GM, Albadrani GM, et al. Antioxidant and signal-modulating effects of brown seaweed-derived compounds against oxidative stress-associated pathology. Oxid Med Cell Longev 2021; 2021: 9974890.
57. Li Y, Zhao W, Wang L, Chen Y, Zhang H, Wang T, et al. Protective effects of fucoidan against hydrogen peroxide-induced oxidative damage in porcine intestinal epithelial cells. Animals (Basel) 2019; 9: 1108.
58. Lewandowska H, Chen Z, Marszałek K, Lewandowski W, Świsłocka R. Effective antioxidants as plausible ligands in chromium (III) supplementation: How complexation modulates catechol-based polyphenols. Molecules 2025; 30: 4467.
59. Dikici S. Enhancing wound regeneration potential of fibroblasts using ascorbic acid-loaded decellularized baby spinach leaves. Polym Bull 2024; 81: 9995-10016. 
60. Truong TT, Singh AA, Tak S, Na S, Choi J, Oh J, et al. Plant-derived antioxidants as modulators of redox signaling and epigenetic reprogramming in cancer. Cells 2025; 14: 1948.
61. Guillard J, Schwörer S. Metabolic control of collagen synthesis. Matrix Biol 2024; 133: 43-56.
62. Altanam SY, Darwish N, Bakillah A. Exploring the interplay of antioxidants, inflammation, and oxidative stress: mechanisms, therapeutic potential, and clinical implications. Diseases 2025; 13: 309.
63.Nailwal N, Bhatia N, Ali A, Ansari A, Raheja R, Godad A, et al. Chapter 4 - Antioxidants obtained from marine sources. In: Kim S-K, Shin K-H, Venkatesan J, editors. Marine Antioxidants: Academic Press; 2023. p. 45-56.
64. Zaman W, Amin A. Mechanistic insight into phenolic compounds in mitigating diabetic complications induced by advanced glycation end products. Curr Issues Mol Biol 2025; 47: 841. 
65. Morales NP, Sirijaroonwong S, Yamanont P, Phisalaphong C. Electron paramagnetic resonance study of the free radical scavenging capacity of curcumin and its demethoxy and hydrogenated derivatives. Biol Pharm Bull 2015; 38: 1478-1483. 
66. Egbujor MC, Buttari B, Profumo E, Telkoparan-Akillilar P, Saso L. An overview of NRF2-activating compounds bearing α,β-unsaturated moiety and their antioxidant effects. Int J Mol Sci 2022; 23: 8466.
67. Zivari-Ghader T, Rashidi M-R, Mehrali M. Biological macromolecule-based hydrogels with antibacterial and antioxidant activities for wound dressing: A review. Int J Biol Macromol 2024; 279: 134578.
68. Roy B. Pathophysiological mechanisms of diabetes-induced macrovascular and microvascular complications: the role of oxidative stress. Med Sci 2025; 13: 87. 
69. Guo YL, Niu WJ, Jiao HR, Li YP, Xu C, Zhou X, et al. Crosstalk between oxidative stress and inflammatory pathways: Natural therapeutic approaches for diabetic wound healing. World J Diabetes 2025; 16: 111400.
70. Carmichael E, Reme A-IS, Bosco PJ, Ortiz YY, Ramos DA, Gomez K, et al. Biological regulation of HIF-1α and its role in therapeutic angiogenesis for treatment of ischemic cardiovascular disease. Int J Mol Sci 2025; 26: 11236.
71. Lin Y, Jiang Y, Xian H, Cai X, Wang T. Expression and correlation of the Pi3k/Akt pathway and VEGF in oral submucous fibrosis. Cell Prolif 2023; 56: e13491.
72. Sabarudin NS, Ab Ghani N, Ahmat N, Harlin EW, Hao LQ, Handajani J, et al. Harnessing plant bioactive compounds in biomaterial scaffolds for advanced wound healing: A comprehensive review. Biomedicines 2025; 13: 2414.
73. Xue H, Zhang Z, Lin Z, Su J, Panayi AC, Xiong Y, et al. Enhanced tissue regeneration through immunomodulation of angiogenesis and osteogenesis with a multifaceted nanohybrid modified bioactive scaffold. Bioact Mater 2022; 18: 552-568.
74. Lu H, Cui M, Wang Y, Du X, Zhou X, Fang Y, et al. Protein-based functional hydrogel improves cutaneous nerve repair and diabetic wound healing. Nano Res 2025; 18: 94907012.
75. Moldovan CA, Salagean AA, Slevin M. Multiplexing 3D natural scaffolds to optimize the repair and regeneration of chronic diabetic wounds. Gels 2025; 11: 430.
76. Singh PK, Gangwar AK, Khangembam SD, Verma RK, Yadav VK, Goyal RP, et al. Ficus benjamina leaves derived cellulose scaffolds for regeneration of full thickness skin wound in new zealand white rabbits. Trends Biomater Artif Organs 2024; 38: 134-146. 
77. Singh P, Maparu AK, Mishra M, Rai B, Sivakumar S. In vitro evaluation of decellularized floral scaffold with surface nanotopography for skin tissue engineering. Mater Today Commun 2024; 41: 111056.
78. Hoffmann A, Cheng G, Baltimore D. NF-κB: Master regulator of cellular responses in health and disease. Immun Inflamm 2025; 1: 2.
79. Behl T, Rana T, Alotaibi GH, Shamsuzzaman M, Naqvi M, Sehgal A, et al. Polyphenols inhibiting MAPK signalling pathway mediated oxidative stress and inflammation in depression. Biomed Pharmacother 2022; 146: 112545.
80. Radzka J, Łapińska Z, Szwedowicz U, Gajewska-Naryniecka A, Gizak A, Kulbacka J. Alternations of NF-κB signaling by natural compounds in muscle-derived cancers. Int J Mol Sci 2023; 24: 11900.
81. Koga Y, Tsurumaki H, Aoki-Saito H, Sato M, Yatomi M, Takehara K, et al. Roles of cyclic AMP response element binding activation in the ERK1/2 and p38 MAPK signalling pathway in central nervous system, cardiovascular system, osteoclast differentiation and mucin and cytokine production. Int J Mol Sci 2019; 20: 1346.
82. Liu J, Han X, Zhang T, Tian K, Li Z, Luo F. Reactive oxygen species (ROS) scavenging biomaterials for anti-inflammatory diseases: From mechanism to therapy. J Hematol Oncol 2023; 16: 116. 
83. He Y, Sun MM, Zhang GG, Yang J, Chen KS, Xu WW, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther 2021; 6: 425. 
84. Glaviano A, Foo ASC, Lam HY, Yap KCH, Jacot W, Jones RH, et al. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Molecular Cancer 2023; 22: 138. 
85. Liu H, Hu Y, Ji W, Wang S, Zhu Y, Lin Q, et al. Sustained activation of Nrf2 antioxidant pathway by flexible liposome based on low phase transition temperature to delay skin aging. Adv Healthc Mater 2026; 15: e01696.
86. Margheri F, Anceschi C, Frediani E, Marzoppi A, Vasarri M, Degl’Innocenti D, et al. Posidonia oceanica extract inhibits VEGF-induced angiogenic and oxidative responses in human endothelial colony-forming cells. J Xenobiot 2025; 15: 153.
87. Miranda MR, Montano C, Golino V, de Chiara M, Del Prete C, Pepe G, et al. Integrated proteomics highlights functional activation induced by advanced-platelet rich fibrin plus (A-PRF +) in primary equine fibroblasts. Sci Rep 2025; 15: 18021. 
88. Liu W, Jiang H, Yang D, Xie Y. The role of cell metabolism in skin wound healing. Research (Wash D C) 2025; 8: 1000. 
89. Yang C, Zhou Y, Wang X, Zhou Y. Sustainable high thermal conductivity composites from biomass: bio-based polyimide/microencapsulated CNTs for green thermal management. ACS Appl Polym Mater 2026; 8: 2762-2775. 
Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 26 September 2026