Skip to main content

Effect of spirulina and chlorella alone and combined on the healing process of diabetic wounds: an experimental model of diabetic rats



Using chemical agents to cure diabetes mellitus and its complications may be accompanied by complications. New natural agents, such as spirulina and chlorella, could be used as alternative choices in this case.


65 male Wistar rats were allocated to 5 groups: A (healthy control), B (diabetic rats with a normal diet), C (diabetic rats supplemented with 50 g/kg/day spirulina), D (diabetic rats supplemented with 50 g/kg/day chlorella) and E (diabetic rats supplemented with 25 g/kg/day chlorella and 25 g/kg/day spirulina). After 21 days, wounds were inflicted on the back of rats. Assessment of blood sugar (BS), high-sensitivity C-reactive protein (hs-CRP), vascular endothelial growth factor (VEGF), granulation tissue formation, vascularization, epithelialization, and percentage of wound healing were determined along with macroscopic examinations.


The microscopic changes at days 3, 7, 14, and 21 showed significant evidence of improved angiogenesis, epithelial proliferation, and granulation tissue formation in the spirulina and chlorella treated rats compared with the controls (p˂0.05). Both spirulina and chlorella treatments of diabetic rats resulted in a significant reduction in BS and weight (p˂0.05), but VEGF and hs-CRP levels did not significantly change (p > 0.05). Percentage of wound healing was 100% on day 21 in all groups, except the control group B (97.8 ± 1.15%).


The results of this study showed that supplementation with spirulina and chlorella alone and combined could improve wound healing indices in diabetic rats and could therefore be recommended for the management of diabetic ulcer.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    WHO O. Diabetes [Available from:

  2. 2.

    Forouhi NG, Wareham NJ. Epidemiology of diabetes. Medicine. 2019;47(1):22–7.

    Article  Google Scholar 

  3. 3.

    Suthar M, Gupta S, Bukhari S, Ponemone V. Treatment of chronic non-healing ulcers using autologous platelet rich plasma: a case series. J Biomed Sci. 2017;24(1):16.

    Article  Google Scholar 

  4. 4.

    Greer N, Foman NA, MacDonald R, Dorrian J, Fitzgerald P, Rutks I, et al. Advanced wound care therapies for nonhealing diabetic, venous, and arterial ulcers: a systematic review. Ann Intern Med. 2013;159(8):532–42.

    Article  Google Scholar 

  5. 5.

    Cavanagh PR, Lipsky BA, Bradbury AW, Botek G. Treatment for diabetic foot ulcers. Lancet. 2005;366(9498):1725–35.

    Article  Google Scholar 

  6. 6.

    Sanaei N, Mohammadi R, Raisi A, Zarei L. Extract of Berula angustifolia (L.) Mertens enhances wound healing in Streptozotocin-induced diabetic rats. Wounds: Compend Clin Res Pract. 2018;30(8):242–8.

    Google Scholar 

  7. 7.

    Katz J, Bhattacharyya I, Farkhondeh-Kish F, Perez F, Caudle R, Heft M. Expression of the receptor of advanced glycation end products in gingival tissues of type 2 diabetes patients with chronic periodontal disease: a study utilizing immunohistochemistry and RT-PCR. J Clin Periodontol. 2005;32(1):40–4.

    CAS  Article  Google Scholar 

  8. 8.

    Layam A, Reddy CLK. Antidiabetic property of spirulina. Diabetol Croat. 2006;35(2):29–33.

    Google Scholar 

  9. 9.

    Morvan P, Vallee R. Effects of Chlorella extract on skin. Personal Care. 2007;2007:57–64.

    Google Scholar 

  10. 10.

    Nah WH, Koh IK, Ahn HS, Kim MJ, Kang H-G, Jun JH, et al. Effect of Spirulina maxima on spermatogenesis and steroidogenesis in streptozotocin-induced type I diabetic male rats. Food Chem. 2012;134(1):173–9.

    CAS  Article  Google Scholar 

  11. 11.

    Senthilkumar T, Sangeetha N, Ashokkumar N. Antihyperglycemic, antihyperlipidemic, and renoprotective effects of Chlorella pyrenoidosa in diabetic rats exposed to cadmium. Toxicol Mech Methods. 2012;22(8):617–24.

    CAS  Article  Google Scholar 

  12. 12.

    Moura LP, Puga GM, Beck WR, Teixeira IP, Ghezzi AC, Silva GA, et al. Exercise and spirulina control non-alcoholic hepatic steatosis and lipid profile in diabetic Wistar rats. Lipids Health Dis. 2011;10(1):77.

    Article  Google Scholar 

  13. 13.

    Lin C-Y, Huang P-J, Chao C-Y. Chlorella protects against hydrogen peroxide-induced pancreatic β-cell damage. J Med Food. 2014;17(12):1273–80.

    Article  Google Scholar 

  14. 14.

    Aissaoui O, Amiali M, Bouzid N, Belkacemi K, Bitam A. Effect of Spirulina platensis ingestion on the abnormal biochemical and oxidative stress parameters in the pancreas and liver of alloxan-induced diabetic rats. Pharm Biol. 2017;55(1):1304–12.

    CAS  Article  Google Scholar 

  15. 15.

    Syarina PNA, Karthivashan G, Abas F, Arulselvan P, Fakurazi S. Wound healing potential of Spirulina platensis extracts on human dermal fibroblast cells. EXCLI J. 2015;14:385.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Kim Y-H, Hwang Y-K, Kim Y-Y, Ko S-M, Hwang J-M, Lee Y-W. Effect of chlorella growth factor on the proliferation of human skin keratinocyte. 대한의생명과학회지. 2002;8(4):229–34.

    Google Scholar 

  17. 17.

    Shih MF, Cherng JY. Protective effects of chlorella-derived peptide against UVC-induced cytotoxicity through inhibition of caspase-3 activity and reduction of the expression of phosphorylated FADD and cleaved PARP-1 in skin fibroblasts. Molecules. 2012;17(8):9116–28.

    CAS  Article  Google Scholar 

  18. 18.

    Gargouri M, Magné C, El Feki A. Hyperglycemia, oxidative stress, liver damage and dysfunction in alloxan-induced diabetic rat are prevented by Spirulina supplementation. Nutr Res. 2016;36(11):1255–68.

    CAS  Article  Google Scholar 

  19. 19.

    Rahati S, Eshraghian M, Ebrahimi A, Pishva H. Effect of spinach aqueous extract on wound healing in experimental model diabetic rats with streptozotocin. J Sci Food Agric. 2016;96(7):2337–43.

    CAS  Article  Google Scholar 

  20. 20.

    Gupta A, Kumar P. Assessment of the histological state of the healing wound. Plast Aesthet Res. 2015;2(2):239–42.

    Article  Google Scholar 

  21. 21.

    Gur CS, Erdogan DK, Onbasılar I, Atilla P, Cakar N, Gurhan ID. In vitro and in vivo investigations of the wound healing effect of crude Spirulina extract and C-phycocyanin. J Med Plants Res. 2013;7(8):425–33.

    Google Scholar 

  22. 22.

    Kim H-M, Lee E-H, Cho H-H, Moon Y-H. Inhibitory effect of mast cell-mediated immediate-type allergic reactions in rats by Spirulina. Biochem Pharmacol. 1998;55(7):1071–6.

    CAS  Article  Google Scholar 

  23. 23.

    Hidalgo-Lucas S, Bisson J-F, Duffaud A, Nejdi A, Guerin-Deremaux L, Baert B, et al. Benefits of oral and topical administration of ROQUETTE Chlorella sp. on skin inflammation and wound healing in mice. Antiinflamm Antiallergy Agents Med Chem. 2014;13(2):93–102.

    CAS  Article  Google Scholar 

  24. 24.

    Getie M, Gebre-Mariam T, Rietz R, Neubert R. Evaluation of the release profiles of flavonoids from topical formulations of the crude extract of the leaves of Dodonea viscosa (Sapindaceae). Die Pharmazie. 2002;57(5):320–2.

    CAS  PubMed  Google Scholar 

  25. 25.

    Scortichini M, Rossi MP. Preliminary in vitro evaluation of the antimicrobial activity of terpenes and terpenoids towards Erwinia amylovora (Burrill) Winslow et al. J Appl Bacteriol. 1991;71(2):109–12.

    CAS  Article  Google Scholar 

  26. 26.

    Syed S, Arasu A, Ponnuswamy I. The uses of Chlorella vulgaris as antimicrobial agent and as a diet: the presence of bio-active compounds which caters the vitamins, minerals in general. Int J Bio-Sci Bio-Technol. 2015;7(1):185–90.

    Article  Google Scholar 

  27. 27.

    Jung S-M, Min SK, Lee HC, Kwon YS, Jung MH, Shin HS. Spirulina-PCL nanofiber wound dressing to improve cutaneous wound healing by enhancing antioxidative mechanism. J Nanomater. 2016;2016:1–10.

    Google Scholar 

  28. 28.

    Ruthig DJ, Meckling-Gill KA. Both (n-3) and (n-6) fatty acids stimulate wound healing in the rat intestinal epithelial cell line, IEC-6. J Nutr. 1999;129(10):1791–8.

    CAS  Article  Google Scholar 

  29. 29.

    Yamagishi S, Nakamura K, Inoue H. Therapeutic potentials of unicellular green alga Chlorella in advanced glycation end product (AGE)-related disorders. Med Hypotheses. 2005;65(5):953–5.

    CAS  Article  Google Scholar 

  30. 30.

    Gargouri M, Ghorbel-Koubaa F, Bonenfant-Magné M, Magné C, Dauvergne X, Ksouri R, et al. Spirulina or dandelion-enriched diet of mothers alleviates lead-induced damages in brain and cerebellum of newborn rats. Food Chem Toxicol. 2012;50(7):2303–10.

    CAS  Article  Google Scholar 

  31. 31.

    Cherng J-Y, Shih M-F. Improving glycogenesis in Streptozocin (STZ) diabetic mice after administration of green algae Chlorella. Life Sci. 2006;78(11):1181–6.

    CAS  Article  Google Scholar 

  32. 32.

    Jong-Yuh C, Mei-Fen S. Potential hypoglycemic effects of Chlorella in streptozotocin-induced diabetic mice. Life Sci. 2005;77(9):980–90.

    CAS  Article  Google Scholar 

  33. 33.

    Hoseini SM, Khosravi-Darani K, Mozafari MR. Nutritional and medical applications of spirulina microalgae. Mini-Rev Med Chem. 2013;13(8):1231–7.

    CAS  Article  Google Scholar 

  34. 34.

    EL-Sabagh MR, Eldaim MAA, Mahboub D, Abdel-Daim M. Effects of Spirulina platensis algae on growth performance, antioxidative status and blood metabolites in fattening lambs. J Agric Sci. 2014;6(3):92.

    Google Scholar 

  35. 35.

    Cheong SH, Kim MY, Sok D-E, Hwang S-Y, Kim JH, Kim HR, et al. Spirulina prevents atherosclerosis by reducing hypercholesterolemia in rabbits fed a high-cholesterol diet. J Nutr Sci Vitaminol. 2010;56(1):34–40.

    CAS  Article  Google Scholar 

  36. 36.

    Joventino IP, Alves HG, Neves LC, Pinheiro-Joventino F, Leal LKA, Neves SA, et al. The microalga Spirulina platensis presents anti-inflammatory action as well as hypoglycemic and hypolipidemic properties in diabetic rats. J Complement Integ Med. 2012;9(1).

  37. 37.

    Lee HS, Park HJ, Kim MK. Effect of Chlorella vulgaris on lipid metabolism in Wistar rats fed high fat diet. Nutr Res Pract. 2008;2(4):204–10.

    CAS  Article  Google Scholar 

  38. 38.

    Yousefi R, Mottaghi A, Saidpour A. Spirulina platensis effectively ameliorates anthropometric measurements and obesity-related metabolic disorders in obese or overweight healthy individuals: a randomized controlled trial. Complement Ther Med. 2018;40:106–12.

    Article  Google Scholar 

  39. 39.

    Pang Y, Zhang Y, Huang L, Xu L, Wang K, Wang D, et al. Effects and mechanisms of total flavonoids from Blumea balsamifera (L.) DC. on skin wound in rats. Int J Mol Sci. 2017;18(12):2766.

    Article  Google Scholar 

Download references


We would like to express our appreciation towards distinguished personnel of the Center for Experimental Studies of the Institute of Nutritional Research and Food Industry, Shahid Beheshti University of Medical Sciences. We also thank the Vice Chancellor for Research of Iran University of Medical Sciences for funding this research (grant number 31474).

Author information




Naeim Mehdinezhad, Naheed Aryaeian, and Mohammadreza Vafa designed this research, Atoosa Saeedpour and Naeim Mehdinezhad conducted research, Reza Fahimi provided essential materials and visualization, Abdolali Ebrahimi and Tofigh Mobaderi performed statistical analysis, Zohreh Sajadi Hezaveh did the original draft preparation, and Naheed Aryaeian had primary responsibility for final content. All authors have revised and approved the final manuscript.

Corresponding author

Correspondence to Naheed Aryaeian.

Ethics declarations

Competing interests


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

Verify currency and authenticity via CrossMark

Cite this article

Mehdinezhad, N., Aryaeian, N., Vafa, M. et al. Effect of spirulina and chlorella alone and combined on the healing process of diabetic wounds: an experimental model of diabetic rats. J Diabetes Metab Disord 20, 161–169 (2021).

Download citation


  • Diabetic ulcer
  • Diabetic wound
  • Rat
  • Spirulina
  • Chlorella