Skip to main content

Advertisement

SpringerLink
Log in

Hyaluronic acid as adjunctive to non-surgical and surgical periodontal therapy: a systematic review and meta-analysis

  • Review
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

Objectives

To evaluate the potential added benefit of the topical application of hyaluronic acid (HA) on the clinical outcomes following non-surgical or surgical periodontal therapy.

Materials and methods

A systematic search was performed in Medline, Embase, Cochrane, Web of Science, Scopus and Grey literature databases. The literature search was preformed according to PRISMA guidelines. The Cochrane risk of bias tool was used in order to assess the methodology of the included trials. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) between the treatment and controls were estimated using the random-effect model for amount of bleeding on probing (BOP), probing depth (PD) reduction and clinical attachment level (CAL) gain. In order to minimize the bias and to perform meta-analysis, only randomized clinical studies (RCTs) were selected.

Results

Thirteen RCTs were included: 11 on non-surgical periodontal treatment and two on surgical periodontal treatment. Overall analysis of PD reduction, CAL gain and BOP reduction in non-surgical therapy with adjunctive HA presented WMD of − 0.36 mm (95% CI − 0.54 to − 0.19 mm; p < 0.0001), 0.73 mm (95% CI 0.28 to 1.17 mm; p < 0.0001) and − 15% (95% CI − 22 to − 8%; p < 0.001) respectively, favouring the application of HA. The overall analysis on PD and CAL gain in surgical therapy with adjunctive HA presented WMD of − 0.89 mm (95% CI − 1.42 to − 0.36 mm; p < 0.0001) for PD reduction and 0.85 mm (95% CI 0.08 to 1.62 mm; p < 0.0001) for CAL gain after 6–24 months favouring the treatment with HA. However, comparison presented considerable heterogeneity between the non-surgical studies and a high risk of bias in general.

Conclusions

Within their limits, the present data indicate that the topical application of HA may lead to additional clinical benefits when used as an adjunctive to non-surgical and surgical periodontal therapy. However, due to the high risk of bias and heterogeneity, there is a need for further well-designed RCTs to evaluate this material in various clinical scenarios.

Clinical relevance

The adjunctive use of HA may improve the clinical outcomes when used in conjunction with non-surgical and surgical periodontal therapy.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Fraser JR, Laurent TC, Laurent UB (1997) Hyaluronan: its nature, distribution, functions and turnover. J Intern Med 242(1):27–33

    Article  PubMed  Google Scholar 

  2. Ijuin C, Ohno S, Tanimoto K, Honda K, Tanne K (2001) Regulation of hyaluronan synthase gene expression in human periodontal ligament cells by tumour necrosis factor-alpha, interleukin-1beta and interferon-gamma. Arch Oral Biol 46(8):767–772

    Article  PubMed  Google Scholar 

  3. Laurent TC (1998) The chemistry, biology, and medical applications of hyaluronan and its derivatives, Wenner-Gren international series, vol 72. Portland Press, London

    Google Scholar 

  4. Carlson GA, Dragoo JL, Samimi B, Bruckner DA, Bernard GW, Hedrick M, Benhaim P (2004) Bacteriostatic properties of biomatrices against common orthopaedic pathogens. Biochem Biophys Res Commun 321(2):472–478. https://doi.org/10.1016/j.bbrc.2004.06.165

    Article  PubMed  Google Scholar 

  5. Pirnazar P, Wolinsky L, Nachnani S, Haake S, Pilloni A, Bernard GW (1999) Bacteriostatic effects of hyaluronic acid. J Periodontol 70(4):370–374. https://doi.org/10.1902/jop.1999.70.4.370

    Article  PubMed  Google Scholar 

  6. Kang JH, Kim YY, Chang JY, Kho HS (2011) Influences of hyaluronic acid on the anticandidal activities of lysozyme and the peroxidase system. Oral Dis 17(6):577–583. https://doi.org/10.1111/j.1601-0825.2011.01807.x

    Article  PubMed  Google Scholar 

  7. Sasaki T, Watanabe C (1995) Stimulation of osteoinduction in bone wound healing by high-molecular hyaluronic acid. Bone 16(1):9–15

    Article  PubMed  Google Scholar 

  8. Dahiya P, Kamal R (2013) Hyaluronic acid: a boon in periodontal therapy. N Am J Med Sci 5(5):309–315. https://doi.org/10.4103/1947-2714.112473

    Article  PubMed  PubMed Central  Google Scholar 

  9. de Brito BB, Mendes Brazao MA, de Campos ML, Casati MZ, Sallum EA, Sallum AW (2012) Association of hyaluronic acid with a collagen scaffold may improve bone healing in critical-size bone defects. Clin Oral Implants Res 23(8):938–942. https://doi.org/10.1111/j.1600-0501.2011.02234.x

    Article  Google Scholar 

  10. Kawano M, Ariyoshi W, Iwanaga K, Okinaga T, Habu M, Yoshioka I, Tominaga K, Nishihara T (2011) Mechanism involved in enhancement of osteoblast differentiation by hyaluronic acid. Biochem Biophys Res Commun 405(4):575–580. https://doi.org/10.1016/j.bbrc.2011.01.071

    Article  PubMed  Google Scholar 

  11. Mendes RM, Silva GA, Lima MF, Calliari MV, Almeida AP, Alves JB, Ferreira AJ (2008) Sodium hyaluronate accelerates the healing process in tooth sockets of rats. Arch Oral Biol 53(12):1155–1162. https://doi.org/10.1016/j.archoralbio.2008.07.001

    Article  PubMed  Google Scholar 

  12. Deed R, Rooney P, Kumar P, Norton JD, Smith J, Freemont AJ, Kumar S (1997) Early-response gene signalling is induced by angiogenic oligosaccharides of hyaluronan in endothelial cells. Inhibition by non-angiogenic, high-molecular-weight hyaluronan. Int J Cancer 71(2):251–256

    Article  PubMed  Google Scholar 

  13. Croce MA, Dyne K, Boraldi F, Quaglino D Jr, Cetta G, Tiozzo R, Pasquali Ronchetti I (2001) Hyaluronan affects protein and collagen synthesis by in vitro human skin fibroblasts. Tissue Cell 33(4):326–331. https://doi.org/10.1054/tice.2001.0180

    Article  PubMed  Google Scholar 

  14. Oryan A, Moshiri A, Meimandi Parizi AH, Raayat Jahromi A (2012) Repeated administration of exogenous sodium-hyaluronate improved tendon healing in an in vivo transection model. J Tissue Viability 21(3):88–102. https://doi.org/10.1016/j.jtv.2012.06.002

    Article  PubMed  Google Scholar 

  15. Tuncay I, Ozbek H, Atik B, Ozen S, Akpinar F (2002) Effects of hyaluronic acid on postoperative adhesion of tendo calcaneus surgery: an experimental study in rats. J Foot Ankle Surg 41(2):104–108

    Article  PubMed  Google Scholar 

  16. Chen WY, Abatangelo G (1999) Functions of hyaluronan in wound repair. 7(2):79–89

  17. Zanchetta P, Lagarde N, Uguen A, Marcorelles P (2012) Mixture of hyaluronic acid, chondroitin 6 sulphate and dermatan sulphate used to completely regenerate bone in rat critical size defect model. J Craniomaxillofac Surg 40(8):783–787. https://doi.org/10.1016/j.jcms.2012.02.011

    Article  PubMed  Google Scholar 

  18. Juhasz I, Zoltan P, Erdei I (2012) Treatment of partial thickness burns with Zn-hyaluronan: lessons of a clinical pilot study. Ann Burns Fire Disasters 25(2):82–85

    PubMed  PubMed Central  Google Scholar 

  19. Humbert P, Mikosinki J, Benchikhi H, Allaert FA (2013) Efficacy and safety of a gauze pad containing hyaluronic acid in treatment of leg ulcers of venous or mixed origin: a double-blind, randomised, controlled trial. Int Wound J 10(2):159–166. https://doi.org/10.1111/j.1742-481X.2012.00957.x

    Article  PubMed  Google Scholar 

  20. Bertolami CN, Messadi DV (1994) The role of proteoglycans in hard and soft tissue repair. Crit Rev Oral Biol Med 5(3–4):311–337

    Article  PubMed  Google Scholar 

  21. Pagnacco A, Vangelisti R, Erra C, Poma A (1997) Double blind clinical trial Vs. placebo of a new sodium hyaluronate-based gingival gel. Attual Ter In 15(1)

  22. Bansal J, Kedige SD, Anand S (2010) Hyaluronic acid: a promising mediator for periodontal regeneration. Indian J Dent Res 21(4):575–578. https://doi.org/10.4103/0970-9290.74232

    Article  PubMed  Google Scholar 

  23. Jentsch H, Pomowski R, Kundt G, Gocke R (2003) Treatment of gingivitis with hyaluronan. J Clin Periodontol 30(2):159–164

    Article  PubMed  Google Scholar 

  24. Pistorius A, Martin M, Willershausen B, Rockmann P (2005) The clinical application of hyaluronic acid in gingivitis therapy. Quintessence Int 36(7–8):531–538

    PubMed  Google Scholar 

  25. Bertl K, Bruckmann C, Isberg PE, Klinge B, Gotfredsen K, Stavropoulos A (2015) Hyaluronan in non-surgical and surgical periodontal therapy: a systematic review. J Clin Periodontol 42(3):236–246. https://doi.org/10.1111/jcpe.12371

    Article  PubMed  Google Scholar 

  26. Xu Y, Hofling K, Fimmers R, Frentzen M, Jervoe-Storm PM (2004) Clinical and microbiological effects of topical subgingival application of hyaluronic acid gel adjunctive to scaling and root planing in the treatment of chronic periodontitis. J Periodontol 75(8):1114–1118. https://doi.org/10.1902/jop.2004.75.8.1114

    Article  PubMed  Google Scholar 

  27. Briguglio F, Briguglio E, Briguglio R, Cafiero C, Isola G (2013) Treatment of infrabony periodontal defects using a resorbable biopolymer of hyaluronic acid: a randomized clinical trial. Quintessence Int 44(3):231–240. https://doi.org/10.3290/j.qi.a29054

    Article  PubMed  Google Scholar 

  28. Fawzy El-Sayed KM, Dahaba MA, Aboul-Ela S, Darhous MS (2012) Local application of hyaluronan gel in conjunction with periodontal surgery: a randomized controlled trial. Clin Oral Investig 16(4):1229–1236. https://doi.org/10.1007/s00784-011-0630-z

    Article  PubMed  Google Scholar 

  29. Vanden Bogaerde L (2009) Treatment of infrabony periodontal defects with esterified hyaluronic acid: clinical report of 19 consecutive lesions. Int J Periodontics Restorative Dent 29(3):315–323

    Google Scholar 

  30. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151(4):264–269 w264

    Article  PubMed  Google Scholar 

  31. Higgins JPT, Altman DG, Sterne JAC (2011) Chapter 8: assessing risk of bias in included studies. Cochrane handbook for systematic reviews of interventions Version 5.1.0 [updated March 2011]. Available from http://www.cochrane-handbook.org/

  32. Bevilacqua L, Eriani J, Serroni I, Liani G, Borelli V, Castronovo G, Di Lenarda R (2012) Effectiveness of adjunctive subgingival administration of amino acids and sodium hyaluronate gel on clinical and immunological parameters in the treatment of chronic periodontitis. Ann Stomatol 3(2):75–81

    Google Scholar 

  33. Chauhan A, Bains V, Gupta V, Singh G, Patil S (2013) Comparative analysis of hyaluronan gel and xanthan-based chlorhexidine gel, as adjunct to scaling and root planing with scaling and root planing alone in the treatment of chronic periodontitis: a preliminary study. Contemp Clin Dent 4(1):54–61. https://doi.org/10.4103/0976-237x.111619

    Article  PubMed  PubMed Central  Google Scholar 

  34. Eick S, Renatus A, Heinicke M, Pfister W, Stratul SI, Jentsch H (2013) Hyaluronic acid as an adjunct after scaling and root planing: a prospective randomized clinical trial. J Periodontol 84(7):941–949. https://doi.org/10.1902/jop.2012.120269

    Article  PubMed  Google Scholar 

  35. Engström PE, Shi XQ, Tronje G, Larsson A, Welander U, Frithiof L, Engstrom GN (2001) The effect of hyaluronan on bone and soft tissue and immune response in wound healing. J Periodontol 72(9):1192–1200. https://doi.org/10.1902/jop.2000.72.9.1192

    Article  PubMed  Google Scholar 

  36. Gontiya G, Galgali S (2012) Effect of hyaluronan on periodontitis: a clinical and histological study. J Indian Soc Periodontol 16(2):184–192. https://doi.org/10.4103/0972-124x.99260

    Article  PubMed  PubMed Central  Google Scholar 

  37. Johannsen A, Tellefsen M, Wikesjo U, Johannsen G (2009) Local delivery of hyaluronan as an adjunct to scaling and root planing in the treatment of chronic periodontitis. J Periodontol 80(9):1493–1497. https://doi.org/10.1902/jop.2009.090128

    Article  PubMed  Google Scholar 

  38. Koshal A, Bolt R, Galgut P (2012) A comparison in postoperative healing of sites receiving non-surgical debridement augmented with and without a single application of hyaluronan 0.8% gel. Dental Tribune MEA 10(5):8-9-13

    Google Scholar 

  39. Polepalle T, Srinivas M, Swamy N, Aluru S, Chakrapani S, Chowdary B (2015) Local delivery of hyaluronan 0.8% as an adjunct to scaling and root planing in the treatment of chronic periodontitis: a clinical and microbiological study. J Indian Soc Periodontol 19(1):37–42. https://doi.org/10.4103/0972-124x.145807

    Article  PubMed  PubMed Central  Google Scholar 

  40. Rajan P, Baramappa R, Rao NM, Pavaluri AK, P I, Rahaman SMU (2014) Hyaluronic acid as an adjunct to scaling and root Planing in chronic periodontitis. A randomized clinical trial. J Clin Diagn Res 8(12):ZC11–ZC14. https://doi.org/10.7860/JCDR/2014/8848.5237

    Article  PubMed  PubMed Central  Google Scholar 

  41. Wan P (2004) A clinical trial of local delivery of hyaluronic acid gel as an adjunct to non-surgical treatment of chronic periodontitis. The University of Hong Kong, Pokfulam

    Book  Google Scholar 

  42. Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, Carpenter J, Rucker G, Harbord RM, Schmid CH, Tetzlaff J, Deeks JJ, Peters J, Macaskill P, Schwarzer G, Duval S, Altman DG, Moher D, Higgins JP (2011) Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ 343:d4002. https://doi.org/10.1136/bmj.d4002

    Article  PubMed  Google Scholar 

  43. Smiley CJ, Tracy SL, Abt E, Michalowicz BS, John MT, Gunsolley J, Cobb CM, Rossmann J, Harrel SK, Forrest JL, Hujoel PP, Noraian KW, Greenwell H, Frantsve-Hawley J, Estrich C (1939) Hanson N (2015) evidence-based clinical practice guideline on the nonsurgical treatment of chronic periodontitis by means of scaling and root planing with or without adjuncts. J Am Dent Assoc 146(7):525–535. https://doi.org/10.1016/j.adaj.2015.01.026

    Article  Google Scholar 

  44. Asparuhova MB, Kiryak D, Eliezer M, Mihov D, Sculean A (2018) Activity of two hyaluronan preparations on primary human oral fibroblasts. J Periodontal Res 54:33–45. https://doi.org/10.1111/jre.12602

    Article  PubMed  PubMed Central  Google Scholar 

  45. Papapanou PN, Wennstrom JL (1991) The angular bony defect as indicator of further alveolar bone loss. J Clin Periodontol 18(5):317–322

    Article  PubMed  Google Scholar 

  46. Ballini A, Cantore S, Capodiferro S, Grassi R (2009) Esterified hyaluronic acid and autologous bone in the surgical correction of the infra-bone defects. Int J Med Sci:6–71. https://doi.org/10.7150/ijms.6.65

  47. Aslan M, Simsek G, Dayi E (2006) The effect of hyaluronic acid-supplemented bone graft in bone healing: experimental study in rabbits. J Biomater Appl 20(3):209–220. https://doi.org/10.1177/0885328206051047

    Article  PubMed  Google Scholar 

  48. Kim JJ, Song HY, Ben Amara H, Kyung-Rim K, Koo KT (2016) Hyaluronic acid improves bone formation in extraction sockets with chronic pathology: a pilot study in dogs. J Periodontol 87:1–13. https://doi.org/10.1902/jop.2016.150707

    Article  Google Scholar 

  49. Aya KL, Stern R (2014) Hyaluronan in wound healing: rediscovering a major player. Wound Repair Regen 22(5):579–593. https://doi.org/10.1111/wrr.12214

    Article  PubMed  Google Scholar 

  50. Salbach J, Rachner TD, Rauner M, Hempel U, Anderegg U, Franz S, Simon JC, Hofbauer LC (2012) Regenerative potential of glycosaminoglycans for skin and bone. J Mol Med (Berl) 90(6):625–635. https://doi.org/10.1007/s00109-011-0843-2

    Article  Google Scholar 

  51. Takeda K, Sakai N, Shiba H, Nagahara T, Fujita T, Kajiya M, Iwata T, Matsuda S, Kawahara K, Kawaguchi H, Kurihara H (2011) Characteristics of high-molecular-weight hyaluronic acid as a brain-derived neurotrophic factor scaffold in periodontal tissue regeneration. Tissue Eng A 17(7–8):955–967. https://doi.org/10.1089/ten.TEA.2010.0070

    Article  Google Scholar 

  52. Laugisch O, Cosgarea R, Nikou G, Nikolidakis D, Donos N, Salvi GE, Stavropoulos A, Jepsen S, Sculean A (2019) Histologic evidence of periodontal regeneration in furcation defects: a systematic review. Clin Oral Investig 23(7):2861–2906. https://doi.org/10.1007/s00784-019-02964-3

    Article  PubMed  Google Scholar 

Download references

Funding

The work was supported by the authors’ own institutions.

Author information

Author notes

  1. Meizi Eliezer and Jean-Claude Imber contributed equally to this work.

Authors and Affiliations

  1. Department of Periodontology, University of Bern, Bern, Switzerland

    Meizi Eliezer, Jean-Claude Imber & Anton Sculean

  2. Department of Periodontology and Operative Dentistry, University of Mainz, Mainz, Germany

    Jean-Claude Imber

  3. Department of Orthodontics and Dentofacial Orthopedics, University of Bern, Bern, Switzerland

    Nikolas Pandis

  4. Medical University of South Carolina, James B. Edwards College of Dental Medicine, Charleston, South Carolina, USA

    Sorin Teich

Authors
  1. Meizi Eliezer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jean-Claude Imber
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anton Sculean
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nikolas Pandis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sorin Teich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anton Sculean.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

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

Informed consent

For this type of study (e.g. systematic review and meta-analysis), formal consent is not required.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Appendix 1 Full searching strategy

Appendix 1 Full searching strategy

((“periodontics” [MeSH Terms] OR “periodontics” [All Fields] OR “periodontology” [All Fields]) OR (“periodontitis” [MeSH Terms] OR “periodontitis” [All Fields]) OR (“periodontal diseases” [MeSH Terms] OR “periodontal” [All Fields] AND “diseases” [All Fields]) OR “periodontal diseases” [All Fields] OR (“periodontal” [All Fields] AND “disease” [All Fields]) OR (“periodontal disease” [All Fields] OR “periodontal pocket” [MeSH Terms]) OR (“periodontal” [All Fields] AND “pocket” [All Fields]) OR (“periodontal pocket” [All Fields]) OR (furcation [All Fields] AND (“therapy” [Subheading] OR “therapy” [All Fields] OR “therapeutics” [MeSH Terms] OR “therapeutics” [All Fields])) OR (intrabony [All Fields] AND defect [All Fields]) OR (infrabony [All Fields] AND defect [All Fields]) OR (intraosseous [All Fields] AND defect [All Fields]) OR (periodontal [All Fields] AND (“surgery” [Subheading] OR “surgery” [All Fields] OR “surgical procedures, operative” [MeSH Terms] OR (“surgical” [All Fields] AND “procedures” [All Fields] AND “operative” [All Fields]) OR “operative surgical procedures” [All Fields] OR “surgery” [All Fields] OR “general surgery” [MeSH Terms] OR (“general” [All Fields] AND “surgery” [All Fields]) OR “general surgery” [All Fields])) OR (periodontal [All Fields] AND (“therapy” [Subheading] OR “therapy” [All Fields] OR “therapeutics” [MeSH Terms] OR “therapeutics” [All Fields])) OR (periodontal [All Fields] AND (“regeneration” [MeSH Terms] OR “regeneration” [All Fields]))) AND (hyaluron [All Fields] OR (“hyaluronic acid” [MeSH Terms] OR (“hyaluronic” [All Fields] AND “acid” [All Fields]) OR “hyaluronic acid” [All Fields]) OR (“hyaluronic acid” [MeSH Terms] OR (“hyaluronic” [All Fields] AND “acid” [All Fields]) OR “hyaluronic acid” [All Fields] OR “hyaluronan” [All Fields]) OR (“hyaluronic acid” [MeSH Terms] OR (“hyaluronic” [All Fields] AND “acid” [All Fields]) OR “hyaluronic acid” [All Fields] OR “hyaluronate” [All Fields]))

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eliezer, M., Imber, JC., Sculean, A. et al. Hyaluronic acid as adjunctive to non-surgical and surgical periodontal therapy: a systematic review and meta-analysis. Clin Oral Invest 23, 3423–3435 (2019). https://doi.org/10.1007/s00784-019-03012-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-019-03012-w

Keywords

Search

Navigation