Skip to main content

Advertisement

Log in

Role of growth factors and cytokines in diabetic foot ulcer healing: A detailed review

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

The aim of the review is to examine the role of growth factors and cytokines in the management of Diabetic Foot Ulcers, such as platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and Insulin like growth factor (IGF). Taking this a step further, the role of Hypoxia-inducible factors (HIFs), Transforming growth factor beta 1 (TGF-β-1) and other growth factors have also been examined, with regard to the treatment of diabetic foot ulcers. The roles of these above-mentioned growth cytokines have been analyzed by studying various scholastic articles. The complete process of wound healing is implemented and regulated by numerous cytokines and human growth factors. The findings of the study indicate that wound healing of diabetic foot ulcers is a complex and extremely challenging biological and molecular process that involves coordinated efforts of multiple cell types. The therapeutic effects of various growth factors in the clinical management of wounds are chronic venous ulcers, pressure ulcers, and diabetic foot ulcers. It has been concluded that altercations of various cytokines are found in patients enduring diabetic foot ulcers. In a similar way, changes in the level of cytokines are also found in patients suffering from other diabetic complications such as diabetic nephropathy, retinopathy, and neuropathy. Subsequently, the diabetic wound healing process can be accelerated by regulating the levels of the cytokines.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2007;30:S4–S41.

    Article  CAS  Google Scholar 

  2. World Health Organization. Accessible at http://www.who.int/diabetes/en/, retrieved on 7 Nov 2018.

  3. Cho NH, Shaw JE, Karuranga S, Huang Y, da Rocha Fernandes JD, Ohlrogge AW, et al. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271–81.

    Article  CAS  PubMed  Google Scholar 

  4. Tuomilehto J, Lindström J, Eriksson JG. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343–50.

    Article  CAS  PubMed  Google Scholar 

  5. Pallela SR, Narahari P. A study to find the causes of diabetic foot infections in a selected community. International Surgery Journal. 2017;4(7):2153–56. https://doi.org/10.18203/2349-2902.isj20172576.

  6. American Diabetic Association. (2018). Accessible at: http://www.diabetes.org/diabetes-basics/statistics/. Retrieved on 11 Nov 2018.

  7. Park JW, Hwang SR, Yoon IS. Advanced growth factor delivery systems in wound management and skin regeneration. Molecules. 2017;22(8):1259.

    Article  CAS  PubMed Central  Google Scholar 

  8. Vlassara H, Uribarri J. Advanced glycation end products (AGE) and diabetes. Cause, effect, or both. Curr Diab Rep. 2014;14:453. https://doi.org/10.1007/s11892-013-0453-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Omanakuttan A, Nambiar J, Harris RM, Bose C, Pandurangan N, Varghese RK, et al. Anacardic acid inhibits the catalytic activity of matrix metalloproteinase-2 and matrix metalloproteinase-9. Molecular Pharmacology. 2012: Mol-112. https://doi.org/10.1124/mol.112.079020.

  10. Rupert P. Human acellular dermal wound matrix for complex diabetic wounds. J Wound Care. 2016;25:S17–21. https://doi.org/10.12968/jowc.2016.25.sup4.s17.

    Article  CAS  PubMed  Google Scholar 

  11. Crafts TD, Jensen AR, Blocher-Smith EC, Markel TA. Vascular endothelial growth factor: therapeutic possibilities and challenges for the treatment of ischemia. Cytokine. 2015;71:385–93. https://doi.org/10.1016/j.cyto.2014.08.005.

    Article  CAS  PubMed  Google Scholar 

  12. Barrientos S, Brem H, Stojadinovic O, Tomic-Canic M. Clinical application of growth factors and cytokines in wound healing. Wound Repair Regen. 2014;22:569–78. https://doi.org/10.1111/j.1524-475x.2008.00410.x.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Gowda S, Weinstein DA, Blalock TD. Topical application of recombinant platelet-derived growth factor increases the rate of healing and the level of proteins that regulate this response. Int Wound J. 2015;12:564–71. https://doi.org/10.1111/iwj.12165.

    Article  PubMed  Google Scholar 

  14. Heldin C-H, Rönnstrand L. The platelet-derived growth factor receptor. In: Moudgil VK, editor. Receptor phosphorylation. Boca Raton: CRC Press; 1988. p. 149–62.

  15. Kolumam G, Wu X, Lee WP. IL-22R ligands IL-20, IL-22, and IL-24 promote wound healing in diabetic db/db mice. PLoS One. 2017;12:e0170639. https://doi.org/10.1371/journal.pone.0170639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gardner JC, Wu H, Noel JG. Keratinocyte growth factor supports pulmonary innate immune defense through the maintenance of alveolar antimicrobial protein levels and macrophage function. Am J Phys Lung Cell Mol Phys. 2016;310:L868–79. https://doi.org/10.1152/ajplung.00363.2015.

    Article  Google Scholar 

  17. Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP, Brem H. The role of vascular endothelial growth factor in wound healing. J Surg Res. 2009;153:347–58. https://doi.org/10.1016/j.jss.2008.04.023.

    Article  CAS  PubMed  Google Scholar 

  18. Andersen LP, Holck S, Janulaityte-Günther D. Gastric inflammatory markers and interleukins in patients with functional dyspepsia, with and without helicobacter pylori infection. FEMS Immunol Med Microbiol. 2005;44:233–8. https://doi.org/10.1016/j.femsim.2004.10.022.

    Article  CAS  PubMed  Google Scholar 

  19. Avitabile OT, Madonna S. Interleukin-22 promotes wound repair in diabetes by improving keratinocyte pro-healing functions. J Invest Dermatol. 2015;135:2862–70. https://doi.org/10.1038/jid.2015.278.

    Article  CAS  PubMed  Google Scholar 

  20. Kolumam G, Wu X, Lee WP, Hackney JA, Zavala-Solorio J, Gandham V, et al. IL-22R ligands IL-20, IL-22, and IL-24 promote wound healing in diabetic db/db mice. PLoS One. 2017;12(1):e0170639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Braun AC. Bioresponsive delivery of anticatabolic and anabolic agents for muscle regeneration using bioinspired strategies. Available at https://opus.bibliothek.uni-wuerzburg.de/opus4-wuerzburg/frontdoor/deliver/index/docId/16904/file/Braun_Alexandra_Bioresponsive_delivery.pdf

  22. Costales J, Kolevzon A. The therapeutic potential of insulin-like growth factor-1 in central nervous system disorders. Neurosci Biobehav Rev. 2016;63:207–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Clemmons DR. Role of IGF binding proteins in regulating metabolism. Trends Endocrinol Metab. 2016;27:375–91. https://doi.org/10.1016/j.tem.2016.03.019.

    Article  CAS  PubMed  Google Scholar 

  24. Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014;6(1):a009191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol. 2003;14(5):1358–73.

    Article  CAS  PubMed  Google Scholar 

  26. Herder C, Brunner EJ, Rathmann W. Elevated levels of the anti-inflammatory interleukin-1 receptor antagonist precede the onset of type 2 diabetes. The Whitehall II study. Diabetes Care. 2009;32:421–3. https://doi.org/10.2337/dc08-1161.

    Article  PubMed  PubMed Central  Google Scholar 

  27. El Gazaerly H, Elbardisey DM, Eltokhy HM, Teaama D. Effect of transforming growth factor Beta 1 on wound healing in induced diabetic rats. Int J Health Sci. 2013;7(2):160–72.

    Article  Google Scholar 

  28. Chen S, Feng B, Thomas AA, Chakrabarti S. miR-146a regulates glucose induced upregulation of inflammatory cytokines extracellular matrix proteins in the retina and kidney in diabetes. PLoS One. 2017;12(3):e0173918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li Y, Zhang Y, Li X, Shi L, Tao W, Shi L, et al. Association study of polymorphisms in miRNAs with T2DM in a Chinese population. Int J Med Sci. 2015;12(11):875–80.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Xu J, Wu W, Zhang L. The role of microRNA-146a in the pathogenesis of the diabetic wound-healing impairment: correction with mesenchymal stem cell treatment. Diabetes. 2012;61:2906–12. https://doi.org/10.2337/db12-0145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mirza RE, Fang MM, Ennis WJ, Koh TJ. Blocking interleukin-1β induces a healing-associated wound macrophage phenotype and improves healing in type 2 diabetes. Diabetes. 2013;62(7):2579–87. https://doi.org/10.2337/db12-1450.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Robson MC, Payne WG. Growth factor therapy to aid wound healing. Basic and Clinical Dermatology. 2005;33:491.

  33. Arfianti E, Barn V, Pok S, Larter CZ, Teoh NC, Farrell. Diabetes augments obesity in accelerating liver tumor development: role of oxidative stress-induced JNK signaling and DNA damage response. J Hepatol. 2017;66:S78–9. https://doi.org/10.1016/s0168-8278(17)30420-8.

    Article  Google Scholar 

  34. Botusan IR, Sunkari VG, Savu O. Stabilization of HIF-1α is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci. 2008;105:19426–31. https://doi.org/10.1073/pnas.0805230105.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mueller CG, Hess E. Emerging functions of RANKL in lymphoid tissues. Front Immunol. 2012;3:261. https://doi.org/10.3389/fimmu.2012.00261.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lampropoulou IT, Stangou M, Papagianni A, Didangelos T, Iliadis F, Efstratiadis G. TNF-α and microalbuminuria in patients with type 2 diabetes mellitus. J Diabetes Res. 2014;2014:1–7.

    Article  Google Scholar 

  37. Sugimoto M, Furuta T, Shirai N. Different effects of polymorphisms of tumor necrosis factor-alpha and interleukin-1 beta on development of peptic ulcer and gastric cancer. J Gastroenterol Hepatol. 2007;22:51–9. https://doi.org/10.1111/j.1440-1746.2006.04442.x.

    Article  CAS  PubMed  Google Scholar 

  38. Liu L, Chen B, Zhang X, Tan L, Wang DW. Increased Cathepsin D correlates with clinical parameters in newly diagnosed type 2 diabetes. Dis Markers. 2017;2017:1–6.

    Google Scholar 

  39. Nowak C, Sundström J, Gustafsson S. Protein biomarkers for insulin resistance and type 2 diabetes risk in two large community cohorts. Diabetes. 2016;65:276–84.

    CAS  PubMed  Google Scholar 

  40. Necchi V, Sommi P, Vanoli A, Fiocca R, Ricci V, Solcia E. Natural history of helicobacter pylori VacA toxin in human gastric epithelium in vivo. Vacuoles and beyond. Sci Rep. 2017;7(1):14526. https://doi.org/10.1038/s41598-017-15204-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ayuk SM, Abrahamse H, Houreld NN. The role of matrix metalloproteinases in diabetic wound healing in relation to photobiomodulation. J Diabetes Res. 2016;2016:1–9.

    Article  CAS  Google Scholar 

  42. Serra R, Gallelli L, Grande R. Hemorrhoids and matrix metalloproteinases: a multicenter study on the predictive role of biomarkers. Surgery. 2016;159:487–94. https://doi.org/10.1016/j.surg.2015.07.003.

    Article  PubMed  Google Scholar 

  43. Singh K, Agrawal NK, Gupta SK, Mohan G, Chaturvedi S, Singh K. Decreased expression of heat shock proteins may lead to compromised wound healing in type 2 diabetes mellitus patients. J Diabetes Complicat. 2015;29:578–88. https://doi.org/10.1016/j.jdiacomp.2015.01.007.

    Article  Google Scholar 

  44. Gruden G, Bruno G, Chaturvedi N. Prospective complications study group. Serum heat shock protein 27 and diabetes complications in the EURODIAB prospective complications study. A novel circulating marker for diabetic neuropathy. Diabetes. 2008;57:1966–70. https://doi.org/10.2337/db08-0009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nakhjavani M, Morteza A, Khajeali L. Increased serum HSP70 levels are associated with the duration of diabetes. Cell Stress Chaperones. 2010;15:959–64. https://doi.org/10.1007/s12192-010-0204-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zubair M, Ahmad J. Plasma heat shock proteins (HSPs) 70 and 47 levels in diabetic foot and its possible correlation with clinical variables in a north Indian tertiary care hospital. Diabetes & Metabolic Syndrome Clinical Research & Reviews. 2015;9:237–43. https://doi.org/10.1016/j.dsx.2015.02.015.

    Article  Google Scholar 

  47. Tsukimi Y, Nakai H, Itoh S, Amagase K, Okabe S. Involvement of heat shock proteins in the healing of acetic acid-induced gastric ulcers in rats. J Physiol Pharmacol. 2001;52:3. https://doi.org/10.1007/978-94-011-5390-4_28.

    Article  Google Scholar 

  48. Dreifke MB, Jayasuriya AA, Jayasuriya AC. Current wound healing procedures and potential care. Mater Sci Eng C. 2015;48:651–62. https://doi.org/10.1016/j.msec.2014.12.068.

    Article  CAS  Google Scholar 

  49. Velnar T, Bailey T, Smrkolj V. The wound healing process: an overview of the cellular and molecular mechanisms. J Int Med Res. 2009;37:1528–42. https://doi.org/10.1177/147323000903700531.

    Article  CAS  PubMed  Google Scholar 

  50. Thiruvoth FM, Mohapatra DP, Sivakumar DK, Chittoria RK, Nandhagopal V. Current concepts in the physiology of adult wound healing. Plast Aesthet Res. 2015;2:250–6. https://doi.org/10.4103/2347-9264.158851.

    Article  Google Scholar 

  51. Foy Y, Li J, Kirsner R, Eaglstein W. Analysis of fibroblast defects in extracellular matrix. J Am Acad Dermatol. 2004;50(3):P168.

  52. Jhamb S, Vangaveti VN, Malabu UH. Genetic and molecular basis of diabetic foot ulcers: a clinical review. J Tissue Viability. 2016;25(4):229–36.

    Article  PubMed  Google Scholar 

  53. Lai JY, Borson ND, Strausbauch MA, Pittelkow MR. Mitosis increases levels of secretory leukocyte protease inhibitor in keratinocytes. Biochem Biophys Res Commun. 2004;316:407–10. https://doi.org/10.1016/j.bbrc.2004.02.065.

    Article  CAS  PubMed  Google Scholar 

  54. Ching YH, Sutton TL, Pierpont YN, Robson MC, Payne WG. The use of growth factors and other humoral agents to accelerate and enhance burn wound healing. Eplasty. 2011;11.

  55. Larouche J, Sheoran S, Maruyama K, Martino MM. Immune regulation of skin wound healing: mechanisms and novel therapeutic targets. Adv Wound Care. 2018;7:209–31. https://doi.org/10.1089/wound.2017.0761.

    Article  Google Scholar 

  56. Bakker AD, Schrooten J, Van Cleynenbreugel T, Vanlauwe J, Luyten J, Schepers E, Dubruel P, Schacht E, Lammens J, Luyten FP. Quantitative screening of engineered implants in a long bone defect model in rabbits. Tissue Eng Part C: Methods. 2008;14(3):251–60. https://doi.org/10.1089/ten.tec.2008.0022.

  57. Pauli A, Valen E, Schier AF. Identifying (non-) coding RNAs and small peptides. Challenges and opportunities. Bioessays. 2015;37:103–12. https://doi.org/10.1002/bies.201400103.

    Article  CAS  PubMed  Google Scholar 

  58. Margolis DJ, Hampton M, Hoffstad O. NOS1AP genetic variation is associated with impaired healing of diabetic foot ulcers and diminished response to healing of circulating stem/progenitor cells. Wound Repair Regen. 2017;25:733–6.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Viswanathan V, Dhamodharan U, Srinivasan V, Rajaram R, Aravindhan V. Single nucleotide polymorphisms in cytokine/chemokine genes are associated with severe infection, ulcer grade and amputation in diabetic foot ulcer. Int J Biol Macromol. 2018;118:1995–2000.

    Article  CAS  PubMed  Google Scholar 

  60. Lindley LE, Stojadinovic O, Pastar I, Tomic-Canic M. Biology and biomarkers for wound healing. Plast Reconstr Surg. 2016;138:18S–28S. https://doi.org/10.1097/prs.0000000000002682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Stojadinovic O, Brem H, Vouthounis C. Molecular pathogenesis of chronic wounds: the role of β-catenin and c-myc in the inhibition of epithelialization and wound healing. Am J Pathol. 2005;167:59–69. https://doi.org/10.1016/s0002-9440(10)62953-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Investig. 2007;117(5):1219–22.

  63. Johnson T, Gómez B, McIntyre M, Dubick M, Christy R, Nicholson S, Burmeister D. The cutaneous microbiome and wounds: New molecular targets to promote wound healing. Int J Mol Sci. 2018;19(9):2699.

    Article  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

The author is very thankful to all the associated personnel in any reference that contributed in/for the purpose of this research.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mohammad Zubair.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Not applicable.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zubair, M., Ahmad, J. Role of growth factors and cytokines in diabetic foot ulcer healing: A detailed review. Rev Endocr Metab Disord 20, 207–217 (2019). https://doi.org/10.1007/s11154-019-09492-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-019-09492-1

Keywords

Navigation