Skip to main content

Advertisement

SpringerLink
Log in

Clinically relevant experimental rodent models of diabetic foot ulcer

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Chronic wounds are a substantial clinical problem in diabetes and nearly 6% of diabetics suffer from foot disease including ulceration, infection, and tissue necrosis. Wound healing in diabetes is impaired and delayed and is augmented by diabetic complications. Wound healing involves complex cellular, molecular, and biochemical processes and animal models are the most suitable prototype to investigate and understand the underlying pathological changes in the process of wound healing. Animal models are also useful in evaluating the safety and efficacy of newer therapeutic agents and improving the clinical approaches for human patients with chronic ulcers. The wound healing strategies get more complicated in the presence of diabetes and its associated complication. Despite the advancement in methods of wound healing, the healing of the chronic diabetic foot ulcer (DFU) remains an important clinical problem resulting in costly and prolonged treatment and poses a risk for major amputation. Saying that it is important to elucidate the newer therapeutic targets and strategies via an in-depth understanding of the complicated cascade of the chronic DFU. A major challenge in translating lab findings to clinics is the lack of an optimal preclinical model capable of properly recapitulating human wounds. Both small and large animal models of wound healing involving rodents, rabbits, and pigs have been discussed. Mouse and rats as small animal models and pig as large animal models have been discussed in association with the diabetic wound but there are advantages and limitations for each model. In this review, we critically reviewed the pros and cons of experimental models of diabetic wound healing with a focus on type II diabetes rodent models.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Not applicable.

References

  1. Sen CK (2019) Human wounds and its burden: an updated compendium of estimates. Adv Wound Care (New Rochelle). 8(2):39–48. https://doi.org/10.1089/wound.2019.0946

    Article  PubMed  PubMed Central  Google Scholar 

  2. Raghav A, Khan ZA, Labala RK, Ahmad J, Noor S, Mishra BK (2018) Financial burden of diabetic foot ulcers to world: a progressive topic to discuss always. Ther Adv Endocrinol Metab. 9(1):29–31. https://doi.org/10.1177/2042018817744513

    Article  PubMed  Google Scholar 

  3. Frykberg RG, Banks J (2015) Challenges in the treatment of chronic wounds. Adv Wound Care (New Rochelle). 4(9):560–82. https://doi.org/10.1089/wound.2015.0635

    Article  PubMed  PubMed Central  Google Scholar 

  4. Elliot S, Wikramanayake TC, Jozic I, Tomic-Canic M (2018) A modeling conundrum: murine models for cutaneous wound healing. J Investig Dermatol 138(4):736–740

    Article  CAS  Google Scholar 

  5. Grada A, Mervis J, Falanga V (2018) Research techniques made simple: animal models of wound healing. J Investig Dermatol 138(10):2095-2105.e1

    Article  CAS  Google Scholar 

  6. Mustoe TA, O’shaughnessy K, Kloeters O (2006) Chronic wound pathogenesis and current treatment strategies: a unifying hypothesis. Plast Reconstr Surg 117(7S):35S-41S

    Article  CAS  Google Scholar 

  7. Mirzaei M, Rahmaninan M, Mirzaei M, Nadjarzadeh A, Dehghani Tafti AA (2020) Epidemiology of diabetes mellitus, pre-diabetes, undiagnosed and uncontrolled diabetes in Central Iran: results from Yazd health study. BMC Public Health 20(1):166. https://doi.org/10.1186/s12889-020-8267-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mekala KC, Bertoni AG (2020) Epidemiology of diabetes mellitus. Transplantation, bioengineering, and regeneration of the endocrine pancreas. Elsevier, New York, pp 49–58

    Book  Google Scholar 

  9. Deshpande AD, Harris-Hayes M, Schootman M (2008) (2008) Epidemiology of diabetes and diabetes-related complications. Phys Ther 88(11):1254–64. https://doi.org/10.2522/ptj.20080020

    Article  PubMed  PubMed Central  Google Scholar 

  10. Oliver TI, Mutluoglu M. (2019) Diabetic foot ulcer

  11. Shofler D, Rai V, Mansager S, Cramer K, Agrawal DK (2021) Impact of resolving mediators in the immunopathology of diabetes and wound healing. Expert Rev Clin Immunol 17(6):681–90. https://doi.org/10.1080/1744666X.2021.1912598

    Article  CAS  PubMed  Google Scholar 

  12. Guo S, Dipietro LA (2010) Factors affecting wound healing. J Dent Res 89(3):219–29. https://doi.org/10.1177/0022034509359125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Suckow MA, Gobbett TA (2017) Peterson RG (2017) Wound healing delay in the ZDSD rat. In Vivo 31(1):55–60. https://doi.org/10.21873/invivo.11025

    Article  CAS  PubMed  Google Scholar 

  14. Chen L, Mirza R, Kwon Y, DiPietro LA, Koh TJ (2015) The murine excisional wound model: contraction revisited. Wound Repair Regen 23(6):874–877. https://doi.org/10.1111/wrr.12338

    Article  PubMed  PubMed Central  Google Scholar 

  15. Doeing DC, Borowicz JL, Crockett ET (2003) Gender dimorphism in differential peripheral blood leukocyte counts in mice using cardiac, tail, foot, and saphenous vein puncture methods. BMC Clin Pathol 3(1):3. https://doi.org/10.1186/1472-6890-3-3

    Article  PubMed  PubMed Central  Google Scholar 

  16. Mestas J, Hughes CC (2004) Of mice and not men: differences between mouse and human immunology. J Immunol 172(5):2731–8. https://doi.org/10.4049/jimmunol.172.5.2731

    Article  CAS  PubMed  Google Scholar 

  17. Tao L, Reese TA (2017) Making mouse models that reflect human immune responses. Trends Immunol 38(3):181–93. https://doi.org/10.1016/j.it.2016.12.007

    Article  CAS  PubMed  Google Scholar 

  18. Zschaler J, Schlorke D, Arnhold J (2014) Differences in innate immune response between man and mouse. Crit Rev Immunol 34(5):433–454

    PubMed  Google Scholar 

  19. Seaton M, Hocking A, Gibran NS (2015) Porcine models of cutaneous wound healing. ILAR J 56(1):127–38. https://doi.org/10.1093/ilar/ilv016

    Article  CAS  PubMed  Google Scholar 

  20. Pastar I, Liang L, Sawaya AP, Wikramanayake TC, Glinos GD, Drakulich S et al (2018) Preclinical models for wound-healing studies. In: Marques A, Reis R, Pirraco R, Cerqueria M (eds) Skin tissue models. Elsevier, New York, pp 223–53. https://doi.org/10.1016/B978-0-12-810545-0.00010-3

    Chapter  Google Scholar 

  21. Masson-Meyers DS, Andrade TA, Caetano GF, Guimaraes FR, Leite MN, Leite SN et al (2020) Experimental models and methods for cutaneous wound healing assessment. Int J Exp Pathol 101(1–2):21–37. https://doi.org/10.1111/iep.12346

    Article  PubMed  PubMed Central  Google Scholar 

  22. Rodier PM (1976) (1976) Critical periods for behavioral anomalies in mice. Environ Health Perspect 18:79–83. https://doi.org/10.1289/ehp.761879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Trøstrup H, Thomsen K, Calum H, Høiby N, Moser C. (2016) Animal models of chronic wound care: the application of biofilms in clinical research. Chronic Wound Care Manage Res. 3:123–32. http://creativecommons.org/licenses/by-nc/3.0/

  24. Wong VW, Sorkin M, Glotzbach JP, Longaker MT, Gurtner GC (2011) Surgical approaches to create murine models of human wound healing. J Biomed Biotechnol. https://doi.org/10.1155/2011/969618

    Article  PubMed  PubMed Central  Google Scholar 

  25. Sami DG, Heiba HH, Abdellatif A (2019) Wound healing models: a systematic review of animal and non-animal models. Wound Med 24(1):8–17. https://doi.org/10.1016/j.wndm.2018.12.001

    Article  Google Scholar 

  26. Dorsett-Martin WA (2004) Rat models of skin wound healing: a review. Wound Repair Regen 12(6):591–599. https://doi.org/10.1111/j.1067-1927.2004.12601.x

    Article  PubMed  Google Scholar 

  27. Kim DJ, Mustoe T, Clark RA (2015) Cutaneous wound healing in aging small mammals: a systematic review. Wound Repair Regen. 23(3):318–39. https://doi.org/10.1111/wrr.12290

    Article  PubMed  Google Scholar 

  28. Slavkovsky R, Kohlerova R, Tkacova V, Jiroutova A, Tahmazoglu B, Velebny V et al (2011) Zucker diabetic fatty rat: a new model of impaired cutaneous wound repair with type II diabetes mellitus and obesity. Wound Repair Regen 19(4):515–525. https://doi.org/10.1111/j.1524-475X.2011.00703.x

    Article  PubMed  Google Scholar 

  29. Nascimento AP, Costa AM (2006) Overweight induced by high-fat diet delays rat cutaneous wound healing. Br J Nutr 96(6):1069–1077. https://doi.org/10.1017/bjn20061955

    Article  CAS  PubMed  Google Scholar 

  30. Huynh P, Phie J, Krishna SM, Golledge J (2020) Systematic review and meta-analysis of mouse models of diabetes-associated ulcers. BMJ Open Diabetes Res Care. https://doi.org/10.1136/bmjdrc-2019-000982

    Article  PubMed  PubMed Central  Google Scholar 

  31. King AJ (2012) (2012) The use of animal models in diabetes research. Br J Pharmacol 166(3):877–894. https://doi.org/10.1111/j.1476-5381.2012.01911.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fang RC, Kryger ZB, Buck DW II, De La Garza M, Galiano RD, Mustoe TA (2010) Limitations of the db/db mouse in translational wound healing research: Is the NONcNZO10 polygenic mouse model superior? Wound Repair Regen 18(6):605–13. https://doi.org/10.1111/j.1524-475X.2010.00634.x

    Article  PubMed  Google Scholar 

  33. Reinwald S, Peterson RG, Allen MR, Burr DB (2009) Skeletal changes associated with the onset of type 2 diabetes in the ZDF and ZDSD rodent models. Am J Physiol Endocrinol Metab 296(4):E765–E774. https://doi.org/10.1152/ajpendo.90937.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Velander P, Theopold C, Hirsch T, Bleiziffer O, Zuhaili B, Fossum M et al (2008) Impaired wound healing in an acute diabetic pig model and the effects of local hyperglycemia. Wound Repair Regen 16(2):288–93. https://doi.org/10.1111/j.1524-475X.2008.00367.x

    Article  PubMed  Google Scholar 

  35. Wang B, Charukeshi Chandrasekera P, Pippin J, J. (2014) Leptin-and leptin receptor-deficient rodent models: relevance for human type 2 diabetes. Curr Diabetes Rev 10(2):131–45. https://doi.org/10.2174/1573399810666140508121012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN (1988) Diet-induced type II diabetes in C57BL/6J mice. Diabetes 37(9):1163–7. https://doi.org/10.2337/diab.37.9.1163

    Article  CAS  PubMed  Google Scholar 

  37. Cheng KY, Lin ZH, Cheng YP, Chiu HY, Yeh NL, Wu TK et al (2018) Wound healing in streptozotocin-induced diabetic rats using atmospheric-pressure argon plasma jet. Sci Rep 8(1):12214. https://doi.org/10.1038/s41598-018-30597-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yu CO-L, Leung K-S, Fung K-P, Lam FF-Y, Ng ES-K, Lau K-M et al (2017) The characterization of a full-thickness excision open foot wound model in n5-streptozotocin (STZ)-induced type 2 diabetic rats that mimics diabetic foot ulcer in terms of reduced blood circulation, higher C-reactive protein, elevated inflammation, and reduced cell proliferation. Exp Anim 66(3):259–69. https://doi.org/10.1538/expanim.17-0016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang M, Lv X-Y, Li J, Xu Z-G, Chen L (2008) The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Exp Diabetes Res. https://doi.org/10.1155/2008/704045

    Article  PubMed  PubMed Central  Google Scholar 

  40. Liu Z, Li W, Li X, Zhang M, Chen L, Zheng Y-N et al (2013) Antidiabetic effects of malonyl ginsenosides from Panax ginseng on type 2 diabetic rats induced by high-fat diet and streptozotocin. J Ethnopharmacol 145(1):233–40. https://doi.org/10.1016/j.jep.2012.10.058

    Article  CAS  PubMed  Google Scholar 

  41. Qian C, Zhu C, Yu W, Jiang X, Zhang F (2015) High-fat diet/low-dose streptozotocin-induced type 2 diabetes in rats impacts osteogenesis and Wnt signaling in bone marrow stromal cells. PLoS ONE. https://doi.org/10.1371/journal.pone.0136390

    Article  PubMed  PubMed Central  Google Scholar 

  42. Premilovac D, Gasperini RJ, Sawyer S, West A, Keske MA, Taylor BV et al (2017) A new method for targeted and sustained induction of type 2 diabetes in rodents. Sci Rep 7(1):14158. https://doi.org/10.1038/s41598-017-14114-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Barrière DA, Noll C, Roussy G, Lizotte F, Kessai A, Kirby K et al (2018) Combination of high-fat/high-fructose diet and low-dose streptozotocin to model long-term type-2 diabetes complications. Sci. Rep 8(1):424. https://doi.org/10.1038/s41598-017-18896-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Greenhalgh DG, Warden GD, Tissue V (2001) Wound care models. Surgical research. Academic Press, London, pp 379–91. International Standard Book Number 0-12-655330-0

  45. Falanga V, Schrayer D, Cha J, Butmarc J, Carson P, Roberts AB et al (2004) Full-thickness wounding of the mouse tail as a model for delayed wound healing: accelerated wound closure in Smad3 knock-out mice. Wound Repair Regen 12(3):320–6. https://doi.org/10.1111/j.1067-1927.2004.012316.x

    Article  PubMed  Google Scholar 

  46. Wang X, Ge J, Tredget EE, Wu Y (2013) The mouse excisional wound splinting model, including applications for stem cell transplantation. Nat Protoc 8(2):302–9. https://doi.org/10.1038/nprot.2013.002

    Article  CAS  PubMed  Google Scholar 

  47. Galiano RD, Michaels JT, DObryansky MV, Levine JP, Gurtner GC (2004) Quantitative and reproducible murine model of excisional wound healing. Wound Repair Regen 12(4):485–92. https://doi.org/10.1111/j.1067-1927.2004.12404.x

    Article  PubMed  Google Scholar 

  48. Enoch S, Leaper DJ (2008) Basic science of wound healing. Surg Infect (Larchmt) 26(2):31–37. https://doi.org/10.1016/j.mpsur.2007.11.005

    Article  Google Scholar 

  49. Wallace HA, Basehore BM, Zito PM (2017) Wound healing phases

  50. Sorg H, Tilkorn DJ, Hager S, Hauser J, Mirastschijski U (2017) Skin wound healing: an update on the current knowledge and concepts. Eur Surg Res 58(1–2):81–94. https://doi.org/10.1159/000454919

    Article  PubMed  Google Scholar 

  51. Ellis S, Lin EJ, Tartar D (2018) Immunology of wound healing. Curr Dermatol Rep 7(4):350–8. https://doi.org/10.1007/s13671-018-0234-9

    Article  PubMed  PubMed Central  Google Scholar 

  52. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M (2008) Growth factors and cytokines in wound healing. Wound Repair Regen 16(5):585–601. https://doi.org/10.1111/j.1524-475X.2008.00410.x

    Article  PubMed  Google Scholar 

  53. Ridiandries A, Tan JTM, Bursill CA (2018) The role of chemokines in wound healing. Int J Mol Sci. https://doi.org/10.3390/ijms19103217

    Article  PubMed  PubMed Central  Google Scholar 

  54. Behm B, Babilas P, Landthaler M, Schreml S (2012) Cytokines, chemokines and growth factors in wound healing. J Eur Acad Dermatol Venereol 26(7):812–20. https://doi.org/10.1111/j.1468-3083.2011.04415.x

    Article  CAS  PubMed  Google Scholar 

  55. Xiao T, Yan Z, Xiao S, Xia Y (2020) Proinflammatory cytokines regulate epidermal stem cells in wound epithelialization. Stem Cell Res Ther 11(1):232. https://doi.org/10.1186/s13287-020-01755-y

    Article  PubMed  PubMed Central  Google Scholar 

  56. Kyaw B, Jaerbrink K, Martinengo L, Car J, Harding K, Schmidtchen A (2017) Need for improved definition of “chronic wounds” in clinical studies. Acta Dermato-Venereol 98(1):157–8. https://doi.org/10.2340/00015555-2786

    Article  Google Scholar 

  57. Iqbal A, Jan A, Wajid MA, Tariq S (2017) Management of chronic non-healing wounds by hirudotherapy. World J Plast Surg 6(1):9–17

    PubMed  PubMed Central  Google Scholar 

  58. Boulton AJ, Kirsner RS, Vileikyte L (2004) Neuropathic diabetic foot ulcers. N Engl J Med 351(1):48–55. https://doi.org/10.1056/NEJMcp032966

    Article  CAS  PubMed  Google Scholar 

  59. Zhang Z, Liu P, Yang B, Li J, Wang W, Yang H et al (2021) Necrotizing fasciitis caused by diabetic foot. Int J Infect Dis 103:3–5. https://doi.org/10.1016/j.ijid.2020.11.132

    Article  PubMed  Google Scholar 

  60. Lyder CH, Ayello EA (2008) Pressure ulcers: a patient safety issue. Patient safety and quality: an evidence-based handbook for nurses. https://www.ncbi.nlm.nih.gov/books/NBK2631/?report=reader

  61. Yarkony GM (1994) Pressure ulcers: a review. Arch Phys Med Rehabil 75(8):908–917. https://doi.org/10.1016/0003-9993(94)90117-1

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

As the corresponding author, I declare that this manuscript is original; that the article does not infringe upon any copyright or other proprietary rights of any third party; that neither the text nor the data have been reported or published previously.

Funding

VR is supported by an intramural Grant IMR Rai 12397B from the Western University of Health Sciences, Pomona, California. RM is supported by an intramural seed Grant IMR 12402F from the Western University of Health Sciences, Pomona, California. The research work of DKA is supported by the R01 HL144125 and R01 HL147662 grants from the National Institutes of Health, USA. The content of this critical review is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Translational Research, Western University of Health Sciences, 309 E. Second Street, Pomona, CA, 91766-1854, USA

    Vikrant Rai & Devendra K. Agrawal

  2. Western University College of Podiatric Medicine, Pomona, CA, 91766, USA

    Rebecca Moellmer

Authors
  1. Vikrant Rai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rebecca Moellmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Devendra K. Agrawal
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

VR wrote the initial draft; RM and DKA critically edited and reviewed the manuscript; VR, RM, DKA finalized the manuscript.

Corresponding author

Correspondence to Vikrant Rai.

Ethics declarations

Conflict of interest

All the authors have no conflict of interest and have read the journal’s authorship statement.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publish

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

Rai, V., Moellmer, R. & Agrawal, D.K. Clinically relevant experimental rodent models of diabetic foot ulcer. Mol Cell Biochem 477, 1239–1247 (2022). https://doi.org/10.1007/s11010-022-04372-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-022-04372-w

Keywords

Search

Navigation