Thermal Burn Wounds Produce Greater Scars Compared to Similarly Sized Excisional Wounds And Topical Amiloride Applied to Burn-Induced Scars Shows Scar Reduction

Main Article Content

Adrian E Rodrigues https://orcid.org/0000-0001-9308-1070
David Dolivo
Yingxing Li
Chun Hou
Lauren Sun
Thomas A. Mustoe
Seok Jong Hong
Robert D. Galiano

Keywords

burn, excision, scar, amiloride, celecoxib

Abstract

Background: Victims of severe traumatic injuries such as large surface area lacerations and thermal burns require substantial medical care that primarily promotes healing.  And although this care is essential, there is a lack of pharmacological treatments that reduce the resulting scars, consequently leaving many traumatic victims with profusely disfigured skin.


Methods: A rabbit-ear injury model was used to compare scar progression in adjacently paired contact thermal burns (n=24) and excisional wounds (n=16).  Once that model revealed significant differences in scar hypertrophy between these two types of injuries, a succeeding study involved solely inducing burns, with the resulting wounds undergoing scar elevation index (SEI) and gene expression analysis after unilateral topical treatment with either amiloride (n=12), celecoxib (n=11) or contralateral vehicle control (n=10 for each of the two control groups).  


Results: In the initial burn and excisional wound comparison study, thermal burns showed significantly larger scars, both in scar height measured at four timepoints (P<0.0001, <0.01, <0.05, and <0.05) and histologically by analyzing the SEI (P<0.05).  In the succeeding project, burn-induced scars treated with amiloride also demonstrated a significantly reduced histological SEI (P<0.05) compared to scars receiving vehicle control.  However, relative PTGS2, ACTA2 and COL1A1 expression was not significantly different in scar tissues treated with amiloride compared to those receiving vehicle control.  Also, no significant differences in SEI were determined in scars treated with celecoxib compared to vehicle control


Conclusions: Contact thermal burn injuries create profusive hypertrophic scars compared to similarly sized excisional wounds.  Topical application of amiloride to burn-induced scars reduce scar formation, yet this finding necessitates further studies to comprehend the mechanism behind its scar-reducing effect.

References

1. Smolle C, Cambiaso-Daniel J, Forbes AA, et al. Recent trends in burn epidemiology worldwide: A systematic review. Burns. Mar 2017;43(2):249-257.

2. Kraemer MD, Jones T, Deitch EA. Burn contractures: incidence, predisposing factors, and results of surgical therapy. J Burn Care Rehabil. May-Jun 1988;9(3):261-265.

3. Reinke JM, Sorg H. Wound Repair and Regeneration. European Surgical Research. 2012;49(1):35-43.

4. Nedelec B, Shankowsky H, Scott PG, Ghahary A, Tredget EE. Myofibroblasts and apoptosis in human hypertrophic scars: the effect of interferon-alpha2b. Surgery. Nov 2001;130(5):798-808.

5. Eishi K, Bae SJ, Ogawa F, Hamasaki Y, Shimizu K, Katayama I. Silicone gel sheets relieve pain and pruritus with clinical improvement of keloid: possible target of mast cells. J Dermatolog Treat. Dec 2003;14(4):248-252.

6. Xiao Y, Sun Y, Zhu B, et al. Risk factors for hypertrophic burn scar pain, pruritus, and paresthesia development. Wound Repair Regen. Mar 2018;26(2):172-181.

7. Van Loey NE, Van Son MJ. Psychopathology and psychological problems in patients with burn scars: epidemiology and management. Am J Clin Dermatol. 2003;4(4):245-272.

8. Rodrigues AE, Dolivo D, Li Y, Mustoe TA, Galiano RD, Hong SJ. Comparison of thermal burn-induced and excisional-induced scarring in animal models: a review of the literature. Adv Wound Care (New Rochelle). Nov 27 2021.

9. Friedrich EE, Niknam-Bienia S, Xie P, et al. Thermal injury model in the rabbit ear with quantifiable burn progression and hypertrophic scar. Wound Repair Regen. Apr 2017;25(2):327-337.

10. Blackstone BN, Kim JY, McFarland KL, et al. Scar formation following excisional and burn injuries in a red Duroc pig model. Wound Repair Regen. Aug 2017;25(4):618-631.

11. Teiwes J, Toto RD. Epithelial sodium channel inhibition in cardiovascular disease. A potential role for amiloride. Am J Hypertens. Jan 2007;20(1):109-117.

12. Xu W, Hong SJ, Zeitchek M, et al. Hydration Status Regulates Sodium Flux and Inflammatory Pathways through Epithelial Sodium Channel (ENaC) in the Skin. J Invest Dermatol. Mar 2015;135(3):796-806.

13. Grubauer G, Elias PM, Feingold KR. Transepidermal water loss: the signal for recovery of barrier structure and function. J Lipid Res. Mar 1989;30(3):323-333.

14. Gardien KLM, Baas DC, de Vet HCW, Middelkoop E. Transepidermal water loss measured with the Tewameter TM300 in burn scars. Burns. Nov 2016;42(7):1455-1462.

15. Jia SX, Xie P, Hong SJ, Galiano RD, Mustoe TA. Local Application of Statins Significantly Reduced Hypertrophic Scarring in a Rabbit Ear Model. Prs-Glob Open. Jun 2017;5(6).

16. Pathak R, Dash RP, Misra M, Nivsarkar M. Role of mucoadhesive polymers in enhancing delivery of nimodipine microemulsion to brain via intranasal route. Acta Pharm Sin B. Apr 2014;4(2):151-160.

17. Wilgus TA, Bergdall VK, Tober KL, et al. The impact of cyclooxygenase-2 mediated inflammation on scarless fetal wound healing. The American journal of pathology. 2004;165(3):753-761.

18. Zhou J, Zhao Y, Simonenko V, et al. Simultaneous silencing of TGF-β1 and COX-2 reduces human skin hypertrophic scar through activation of fibroblast apoptosis. Oncotarget. 2017-10-06 2017;8(46):80651-80665.

19. Wu J, Ma B, Yi S, et al. Gene expression of early hypertrophic scar tissue screened by means of cDNA microarrays. J Trauma. Dec 2004;57(6):1276-1286.

20. Jabeen S, Clough ECS, Thomlinson AM, Chadwick SL, Ferguson MWJ, Shah M. Partial thickness wound: Does mechanism of injury influence healing? Burns. May 2019;45(3):531-542.

21. Kirsner RS, Eaglstein WH. The wound healing process. Dermatol Clin. Oct 1993;11(4):629-640.

22. Brissett AE, Sherris DA. Scar Contractures, Hypertrophic Scars, and Keloids. Facial Plastic Surgery. 2001-01-01 2001;17(04):263-272.

23. Mari W, Alsabri SG, Tabal N, Younes S, Sherif A, Simman R. Novel Insights on Understanding of Keloid Scar: Article Review. J Am Coll Clin Wound Spec. Dec 2015;7(1-3):1-7.

24. Shumaker PR, Kwan JM, Landers JT, Uebelhoer NS. Functional improvements in traumatic scars and scar contractures using an ablative fractional laser protocol. J Trauma Acute Care. Aug 2012;73:S116-S121.