Impact of local hyaluronic acid on early gingival wound healing and heat shock protein 47

Authors

  • Gizem Ceren Yiğit Ondokuz Mayıs University. School of Dentistry. Department of Periodontology.
  • Feyza Otan Özden Ondokuz Mayıs University. School of Dentistry. Department of Periodontology.
  • Özgür Korhan Tunçel Ondokuz Mayıs University. School of Medicine. Department of Biochemistry.
  • Eser Çakmak Ondokuz Mayıs University. School of Medicine. Department of Biochemistry.
  • Fikret Yilmaz Ondokuz Mayıs University. School of Dentistry. Department of Restorative Dentistry.

DOI:

https://doi.org/10.1590/1678-7765-2026-0091

Keywords:

Hyaluronic acid, Heat shock protein 47, Wound healing, Gingiva

Abstract

Hyaluronic acid (HA) is important for tissue repair, especially in oral soft tissue healing. Objective:  This study aimed to evaluate the effect of HA on gingival healing and its relationship with heat shock protein 47 (HSP 47), which binds to procollagen. Methodology:  40 female Wistar albino rats were divided into two groups: a control (Group C) and an HA-treated group (Group H), each split into four subgroups for different time points (t1, t3, t7, t14 days). Excisional wounds were made in the palates of all rats. Group H received topical HA gel, whereas Group C received no treatment. HSP 47 levels were measured using enzyme-linked immunosorbent assay, and wound areas were analyzed with ImageJ. Results:  No significant difference in HSP 47 levels was observed between groups (p>0.05). However, wound areas in Group C were significantly larger than in Group H on day 3 (p=0.009). HSP 47 levels increased in both groups, with higher values on day 1 (p=0.043). Wound areas decreased over time in both groups, with significant reduction in Group H from days 1 to 3 (p=0.043). Conclusion:  Topical HA gel may accelerate early periodontal wound healing but failed to significantly affect HSP 47 levels.

Downloads

Download data is not yet available.

References

1- İşçimen A, Küçüktaş M. Wound healing and hyperbaric oxygen treatment. J Turk Acad Dermatol. 2008;2(3):82301r.

2- Pimentel SP, Barrella GE, Casarin RC, Cirano FR, Casati MZ, Foglio MA, et al. Protective effect of topical Cordia verbenacea in a rat periodontitis model: immune-inflammatory, antibacterial and morphometric assays. BMC Complement Altern Med. 2012;12:224. doi: 10.1186/1472-6882-12-224

» https://doi.org/10.1186/1472-6882-12-224

3- Chava VK, Vedula BD. Thermo-reversible green tea catechin gel for local application in chronic periodontitis: a 4-week clinical trial. J Periodontol. 2013;84(9):1290–6. doi: 10.1902/jop.2012.120425

» https://doi.org/10.1902/jop.2012.120425

4- Kreisler M, Christoffers AB, Willershausen B, d’Hoedt B. Effect of low-level GaAlAs laser irradiation on the proliferation rate of human periodontal ligament fibroblasts: an in vitro study. J Clin Periodontol. 2003;30(4):353-8. doi: 10.1034/j.1600-051x.2003.00001.x

» https://doi.org/10.1034/j.1600-051x.2003.00001.x

5- Casale M, Moffa A, Vella P, Sabatino L, Capuano F, Salvinelli B, et al. Hyaluronic acid: perspectives in dentistry. A systematic review. Int J Immunopathol Pharmacol. 2016;29(4):572-82. doi: 10.1177/0394632016652906

» https://doi.org/10.1177/0394632016652906

6- Burd DA, Greco RM, Regauer S, Longaker MT, Siebert JW, Garg HG. Hyaluronan and wound healing: a new perspective. Br J Plast Surg. 1991;44(8):579-84. doi: 10.1016/0007-1226(91)90093-y

» https://doi.org/10.1016/0007-1226(91)90093-y

7- Wight TN, Kinsella MG, Qwarnström EE. The role of proteoglycans in cell adhesion, migration and proliferation. Curr Opin Cell Biol. 1992;4(5):793-801. doi: 10.1016/0955-0674(92)90102-i

» https://doi.org/10.1016/0955-0674(92)90102-i

8- Brown JA. The role of hyaluronic acid in wound healing's proliferative phase. J Wound Care. 2004;13(2):48-51. doi: 10.12968/jowc.2004.13.2.26573

» https://doi.org/10.12968/jowc.2004.13.2.26573

9- Litwiniuk M, Krejner A, Speyrer MS, Gauto AR, Grzela T. Hyaluronic acid in inflammation and tissue regeneration. Wounds. 2016;28(3):78-88.

10- Asparuhova MB, Kiryak D, Eliezer M, Mihov D, Sculean A. Activity of two hyaluronan preparations on primary human oral fibroblasts. J Periodontal Res. 2019;54(1):33-45. doi: 10.1111/jre.12602

» https://doi.org/10.1111/jre.12602

11- Moseley R, Waddington RJ, Embery G. Hyaluronan and its potential role in periodontal healing. Dent Update. 2002;29(3):144-8. doi: 10.12968/denu.2002.29.3.144

» https://doi.org/10.12968/denu.2002.29.3.144

12- Voigt J, Driver VR. Hyaluronic acid derivatives and their healing effect on burns, epithelial surgical wounds, and chronic wounds: a systematic review and meta-analysis of randomized controlled trials. Wound Repair Regen. 2012;20(3):317-31. doi: 10.1111/j.1524-475X.2012.00777.x

» https://doi.org/10.1111/j.1524-475X.2012.00777.x

13- Ishida Y, Nagata K. Hsp47 as a collagen-specific molecular chaperone. Methods Enzymol. 2011;499:167-82. doi: 10.1016/B978-0-12-386471-0.00009-2

» https://doi.org/10.1016/B978-0-12-386471-0.00009-2

14- Satoh M, Hirayoshi K, Yokota S, Hosokawa N, Nagata K. Intracellular interaction of collagen-specific stress protein HSP47 with newly synthesized procollagen. J Cell Biol. 1996;133(2):469-83. doi: 10.1083/jcb.133.2.469

» https://doi.org/10.1083/jcb.133.2.469

15- Narayanan AS, Page RC. Connective tissues of the periodontium: a summary of current work. Coll Relat Res. 1983;3(1):33-64.

16- Guo Q, Tian Q, Tian X, Liu T. Effect of regulating the expression of HSP47 on collagen metabolism in scleral fibroblasts. Curr Eye Res. 2021;46(3):408-16. doi: 10.1080/02713683.2020.1805471

» https://doi.org/10.1080/02713683.2020.1805471

17- Nagata K. Hsp47: a collagen-specific molecular chaperone. Trends Biochem Sci. 1996;21(1):22-6. doi: 10.1016/0968-0004(96)80881-4

» https://doi.org/10.1016/0968-0004(96)80881-4

18- Toma AI, Fuller JM, Willett NJ, Goudy SL. Oral wound healing models and emerging regenerative therapies. Transl Res. 2021;236:17-34. doi: 10.1016/j.trsl.2021.06.003

» https://doi.org/10.1016/j.trsl.2021.06.003

19- Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265-75.

20- Molayem S, Pontes CC. Exploring the potential of plant-based remedies in periodontal treatment: a mini review. J Oral Med Dent Res. 2023;4(2):1-13. doi: 10.52793/JOMDR.2023.4(2)-36

» https://doi.org/10.52793/JOMDR.2023.4(2)-36

21- Turley EA. The role of a cell-associated hyaluronan-binding protein in fibroblast behaviour. Ciba Found Symp. 1989;143:121-33. doi: 10.1002/9780470513774.ch8

» https://doi.org/10.1002/9780470513774.ch8

22- Entwistle J, Hall CL, Turley EA. HA receptors: regulators of signalling to the cytoskeleton. J Cell Biochem. 1996;61(4):569–77. doi: 10.1002/(SICI)1097-4644(19960616)61:4<569::AID-JCB10>3.0.CO;2-B

» https://doi.org/10.1002/(SICI)1097-4644(19960616)61:4<569::AID-JCB10>3.0.CO;2-B

23- Shao Y, Lu GL, Shen ZJ, He HC. Reduction of intercellular adhesion molecule 1 may play a role in anti-inflammatory effect of hyaluronic acid in a rat model of severe non-bacterial cystitis. World J Urol. 2013;31(3):535-40. doi: 10.1007/s00345-012-0839-8

» https://doi.org/10.1007/s00345-012-0839-8

24- Noble PW, Lake FR, Henson PM, Riches DW. Hyaluronate activation of CD44 induces insulin-like growth factor-1 expression by a tumor necrosis factor-alpha-dependent mechanism in murine macrophages. J Clin Invest. 1993;91(6):2368-77. doi: 10.1172/JCI116469

» https://doi.org/10.1172/JCI116469

25- Hammad HM, Hammad MM, Abdelhadi IN, Khalifeh MS. Effects of topically applied agents on intra-oral wound healing in a rat model: a clinical and histomorphometric study. Int J Dent Hyg. 2011;9(1):9-16. doi: 10.1111/j.1601-5037.2009.00410.x

» https://doi.org/10.1111/j.1601-5037.2009.00410.x

26- Bulut T, Ercan N. The effect of polyvinylpyrrolidone-sodium hyaluronate gel on palatal wound healing: a randomized controlled clinical trial. BMC Oral Health. 2025;25(1):1305. doi: 10.1186/s12903-025-06677-w

» https://doi.org/10.1186/s12903-025-06677-w

27- Abatangelo G, Martelli M, Vecchia P. Healing of hyaluronic acid-enriched wounds: histological observations. J Surg Res. 1983;35(5):410-6. doi: 10.1016/0022-4804(83)90030-6

» https://doi.org/10.1016/0022-4804(83)90030-6

28- Kikuchi T, Sakuta T, Yamaguchi T. Effects of hyaluronan on cell proliferation and proteoglycan synthesis in rabbit ligamental cells. Int J Tissue React. 1996;18(4-6):87-95.

29- Kaya G, Rodriguez I, Jorcano JL, Vassalli P, Stamenkovic I. Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation. Genes Dev. 1997;11(8):996-1007. doi: 10.1101/gad.11.8.996

» https://doi.org/10.1101/gad.11.8.996

30- Oka T, Ohta K, Kanazawa T, Nakamura K. Interaction between macrophages and fibroblasts during wound healing of burn injuries in rats. Kurume Med J. 2016;62(3-4):59-66. doi: 10.2739/kurumemedj.MS00003

» https://doi.org/10.2739/kurumemedj.MS00003

31- Mimura H, Takaya T, Matsuda S, Nakano K, Muraoka R, Tomida M, et al. Functional role of HSP47 in the periodontal ligament subjected to occlusal overload in mice. Int J Med Sci. 2016;13(4):248-54. doi: 10.7150/ijms.14129

» https://doi.org/10.7150/ijms.14129

32- Sawabe M, Aoki A, Komaki M, Iwasaki K, Ogita M, Izumi Y. Gingival tissue healing following Er:YAG laser ablation compared to electrosurgery in rats. Lasers Med Sci. 2015;30(2):875-83. doi: 10.1007/s10103-013-1478-z

» https://doi.org/10.1007/s10103-013-1478-z

33- Yamasaki A, Tamamura K, Sakurai Y, Okuyama N, Yusa J, Ito H. Remodeling of the rat gingiva induced by CO2 laser coagulation mode. Lasers Surg Med. 2008;40(10):695-703. doi: 10.1002/lsm.20712

» https://doi.org/10.1002/lsm.20712

34- Vasques MT, Alves MA, Benetti C, Aranha AC, Zezell DM, Corrêa L. Temperature measurement and Hsp47 immunoexpression in oral ulcers irradiated with defocused high-energy diode laser. J Photochem Photobiol B. 2013;118:42-8. doi: 10.1016/j.jphotobiol.2012.10.014

» https://doi.org/10.1016/j.jphotobiol.2012.10.014

35- Schimizzi AL, Massie JB, Murphy M, Perry A, Kim CW, Garfin SR, et al. High-molecular-weight hyaluronan inhibits macrophage proliferation and cytokine release in the early wound of a preclinical postlaminectomy rat model. Spine J. 2006;6(5):550-6. doi: 10.1016/j.spinee.2005.12.005

» https://doi.org/10.1016/j.spinee.2005.12.005

36- Lee JH, Lee KE, Kang SW, Park SH, Chae YK, Lee MH, et al. Effect of orodispersible hyaluronic acid film on palatal mucosa wound healing. Oral Dis. 2024;30(2):518-27. doi: 10.1111/odi.14517

» https://doi.org/10.1111/odi.14517

37- King SR, Hickerson WL, Proctor KG. Beneficial actions of exogenous hyaluronic acid on wound healing. Surgery. 1991;109(1):76-84.

38- Razzaque MS, Taguchi T. The possible role of colligin/HSP47, a collagen-binding protein, in the pathogenesis of human and experimental fibrotic diseases. Histol Histopathol. 1999;14(4):1199-212. doi: 10.14670/HH-14.1199

» https://doi.org/10.14670/HH-14.1199

Downloads

Published

2026-07-27

Issue

Section

Original Articles

How to Cite

Yiğit, G. C., Özden, F. O., Tunçel, Özgür K., Çakmak, E., & Yilmaz, F. (2026). Impact of local hyaluronic acid on early gingival wound healing and heat shock protein 47. Journal of Applied Oral Science, 34, e20260091. https://doi.org/10.1590/1678-7765-2026-0091