|Year : 2010 | Volume
| Issue : 4 | Page : 575-578
|Hyaluronic acid: A promising mediator for periodontal regeneration
Jyoti Bansal, Suresh D Kedige, Samir Anand
Department of Periodontics and Oral Implantology, M.M. College of Dental Sciences & Research, M.M.University Mullana, Ambala, Haryana, India
Click here for correspondence address and email
|Date of Submission||17-Nov-2009|
|Date of Decision||02-Feb-2010|
|Date of Acceptance||06-Feb-2010|
|Date of Web Publication||24-Dec-2010|
| Abstract|| |
Hyaluronic acid (HA) is a natural-non sulphated high molecular weight glycosaminoglycan that forms a critical component of the extracellular matrix and contributes significantly to tissue hydrodynamics, cell migration and proliferation. The use of HA in the treatment of inflammatory process is established in medical areas such as orthopedics, dermatology and ophthalmology. In the field of dentistry, hyaluronate has shown anti-inflammatory, antiedematous and anti-bacterial effects for the treatment of gingivitis and periodontitis. Due to its potential role in modulation of wound healing, its administration to periodontal wound sites could achieve comparable beneficial effects in periodontal tissue regeneration and periodontal disease treatment.
Keywords: Hyaluronic acid, regeneration, periodontal wound healing
|How to cite this article:|
Bansal J, Kedige SD, Anand S. Hyaluronic acid: A promising mediator for periodontal regeneration. Indian J Dent Res 2010;21:575-8
Hyaluronic acid is also known as hyaluronan or hyaluronate. It is a high molecular weight polysaccharide (glycosaminoglycan) and plays a vital role in the functioning of extracellular matrices, including those of mineralized and non-mineralized periodontal tissues. It is a critical component of the extracellular matrix and contributes significantly to tissue hydrodynamics, cell migration and proliferation. Hyaluronan is also produced by fibroblasts in the presence of endotoxin; it plays an important anti-inflammatory role through the inhibition of tissue destruction and facilitates healing.  The use of HA in the treatment of inflammatory process is established in medical areas such as orthopedics, dermatology and ophthalmology. It has been used in radio-epithelitis,  osteoarthritis of the knee  and rheumatoid arthritis  and cataract surgery.  Rabasseda reviewed its wide use for the treatment of inflammatory conditions of the knee and temporomandibular joint, which has led to the study of its topical application in the treatment of periodontal diseases. 
|How to cite this URL:|
Bansal J, Kedige SD, Anand S. Hyaluronic acid: A promising mediator for periodontal regeneration. Indian J Dent Res [serial online] 2010 [cited 2019 Apr 23];21:575-8. Available from: http://www.ijdr.in/text.asp?2010/21/4/575/74232
In the field of dentistry, preliminary clinical trials have been conducted by Vangelisti and Pagnacco et al.  in 1997. Hyaluronate has shown anti-inflammatory, anti-edematous and anti-bacterial effects for the treatment of gingivitis and periodontitis. The anti-inflammatory effect may be due to the action of exogenous hyaluronan as a scavenger by draining prostaglandins, metalloproteinases and other bio-active molecules.  The antiedematous effect may also be related to the osmotic activity. Due to its acceleration in tissue healing properties, it could be used as an adjunct to mechanical therapy.  However, it is conceivable that Hyaluronan administration to periodontal wound sites could achieve comparable beneficial effects in periodontal tissue regeneration and periodontal disease treatment.  Hyaluronic acid has been studied as a metabolite or diagnostic marker of inflammation in the gingival crevicular fluid  as well as a significant factor in growth, development and repair of tissues. 
| Historical Background|| |
Hyaluronic acid was discovered in 1934 by Karl Meyer and his colleague John Palmer, scientists at Columbia University, New York, who isolated a chemical substance from the vitreous jelly of cow's eyes.  They proposed the name hyaluronic acid as it was derived from Greek word hyalos (glass) and contained two sugar molecules one of which was uronic acid.
| Structure|| |
Hyaluronic acid (HA) is naturally occurring non sulphated glycosaminoglycan with high molecular weight of 4,000-20,000,000 daltons. HA structure consists of polyanionic disaccharide units of glucouronic acid and N-acetyl-glucosamine connected by alternating b1-3 and b1-4 bonds [Figure 1]. It is a linear polysaccharide of the extracellular matrix of connective tissue, synovial fluid, embryonic mesenchyma, vitreous humor, skin and many other organs and tissues of the body. Most cells of the body are capable of synthesizing hyaluronic acid and synthesis takes place in the cell membrane. Hyaluronan binds to many other extracellular matrix molecules, binds specifically to cell bodies through cell surface receptors, and has a unique mode of synthesis in which the molecule is extruded immediately into the extracellular space upon formation. 
| Properties|| |
Through its complex interactions with matrix components and cells, hyaluronan has multifaceted roles in biology utilizing both of its physicochemical and biological properties. These biological roles range from a purely structural function in the extracellular matrix to developmental regulation through effects of cellular behavior via control of the tissue macro- and microenvironments, as well as through direct receptor mediated effects on gene expression. Amongst extracellular matrix molecules, it has unique hygroscopic and viscoelastic properties. 
Hyaluronic acid is one of the most hygroscopic molecules known in nature. When HA is incorporated into aqueous solution, hydrogen bonding occurs between adjacent carboxyl and N-acetyl groups; this feature allows hyaluronic acid to maintain conformational stiffness and to retain water. One gram of hyaluronic acid can bind up to 6 L of water. As a physical background material, it has functions in space filling, lubrication, shock absorption, and protein exclusion. 
The viscoelastic properties of the material may slow the penetration of viruses and bacteria, a feature of particular interest in the treatment of periodontal diseases. Hyaluronan as a viscoelastic substance assists in periodontal regenerative procedures by maintaining spaces and protecting surfaces.  Through recognition of its hygroscopic and viscoelastic nature, hyaluronic acid can influence the cell function that modify the surrounding cellular and the extracellular micro and macro environments.
| Functions|| |
Hyaluronan has many structural and physiological functions within tissues, including extracellular and cellular interactions, growth factor interaction and in the regulation of osmotic pressure and tissue lubrication, which help maintain the structural and homeostatic integrity of tissues. 
Modulation of inflammation
Stimulation of cell migration, proliferation and differentiation
- In the initial stages of inflammation
- Enhanced inflammatory cell and extracellular matrix cell infiltration into the wound site
- Elevation in proinflammatory cytokine production by inflammatory cells and extracellular matrix cells.
- Organization and stabilization of granulation tissue matrix.
- Scavenges reactive oxygen species, such as superoxide radical (·O 2 ) and hydroxyl radical (·OH) thus preventing periodontal destruction.
- Inhibition of inflammatory cell-derived serine proteinases. 
The remarkable hydrophilicity of the hyaluronic acid makes the coagulum more receptive and thus more likely to undergo colonization by the cells committed to the reconstruction of the damaged tissue by migration, proliferation and differentiation of mesenchymal and basal keratinocytes. 
Effect on angiogenesis 
Low molecular weight hyaluronic acid has a marked angiogenic effect whereas, surprisingly, high molecular weight has the opposite effect.
Osteoconductive potential 
Hyaluronic acid accelerates the bone regeneration by means of chemotaxis, proliferation and successive differentiation of mesenchymal cells. Hyaluronic acid shares bone induction characteristics with osteogenic substances such as bone morphogenetic protein-2 and osteopontin.
Carrier function 
Hyaluronic acid may act as biomaterial scaffold for other molecules, such as BMP-2 and PDGF-BB, used in guided bone regeneration techniques and tissue engineering research.
Bacteriostatic effect 
Recent studies on regenerative surgical procedures indicate that reduction of bacterial burden at the wound site may improve the clinical outcome of regenerative therapy. The high concentration of medium and lower molecular weight hyaluronic acid has the greatest bacteriostatic effect, particularly on Aggregatibacter actinomycetemcomitans, Prevotella oris phylococcus aureus strains commonly found in oral gingival lesions and periodontal wounds. Clinical application of hyaluronic acid membranes, gels and sponges during surgical therapy may reduce the bacterial contamination of surgical wound site, thereby, lessening the risk of postsurgical infection and promoting more predictable regeneration.
| Clinical Applications in Periodontics|| |
Hyaluronan has been identified in all periodontal tissues in varying quantities, being more prominent in the nonmineralized tissues, such as gingiva and periodontal ligament, compared to mineralized tissues, such as cementum and alveolar bone. In addition, due to the high levels of hyaluronan in circulating blood serum, it is constantly present in gingival crevicular fluid (GCF) as a serum overload factor. 
Natural hyaluronic acid is an extremely hydrophilic polymer; it exists as a viscous gel and does not per se have the structural features required for use as a surgical product. An ester of hyaluronic acid synthesized by esterification of a carboxyl group with benzyl alcohol is less water soluble and thus more stable. Because of its unique molecular structure, hyaluronic acid can be assembled into various molecular weights and lyophilized or esterified into a variety of different structural configurations such as sponges and membranes. The rate of biodegradation of these materials can be manipulated by altering their degree of lyophilization or esterification. Thus, hyaluronic acid may be of benefit as a resorbable grafting material in regenerative surgical procedures. 
A study by Yi Xu et al.  concluded that there was no clinical or microbiological improvement achieved by the adjunctive use of Hyaluronan 0.2% gel when compared to mechanical debridement. However in this study Hyaluronan 0.2% gel was applied only once a week for six weeks, a total of seven applications over a six-week period, compared to the recommended application level of three times daily for at least four to eight weeks. The absence of observed clinical improvements, contrary to other published studies, may indicate that the Hyaluronan levels used in this study were well below the optimum levels required to achieve a significant clinical improvement.
Vanden Bogaerde  in a recent clinical report evaluated the clinical efficacy of esterified hyaluronic acid in the treatment of infrabony periodontal defects. The author concluded that application of hyaluronic acid seems a promising method for the treatment of infrabony defects by inducing a significant reduction in pocket depth and promoting gain in clinical attachment.
Hyaluronic acid has a multifunctional role in periodontics
- Topical application of subgingival hyaluronic acid gel can be used as an antimicrobial agent as an adjunct to scaling and root planing. ,,
- Bone regeneration in periodontal bony defects. 
- Guided Bone Regeneration. 
- Non surgical treatment of peri-implant pockets. 
- Peri-implant maintenance of immediate function implants. 
- As autologous cell hyaluronic acid graft gingival augmentation in mucogingival surgery. 
- As a carrier for newer molecules in various regenerative procedures. 
- As a biomaterial scaffold in tissue engineering research.
Hyaluronic acid is biocompatiable and intrinsically safe to use, with no evidence of cytotoxicity has been found.  Hyaluronic acid gel, injections or oral (by mouth), should not be used in patients with allergies.
Hyaluronic acid side effects although not severe include bruising, swelling, redness, pain, itching and tenderness at the injection site.
Hyaloss® matrix,  trade names of products composed entirely of an ester of hyaluronic acid with benzyl alcohol (HYAFF™), a concentration ranging of from 20 to 60 mg/ml. Hyaloss matrix is a product manufactured as a solid in the form of fibers that forms a gel when hydrated, releasing pure hyaluronic acid for about 10 days. It is highly multipurpose because at room temperature it can form a biodegradable, biocompatible gel that can be adapted by the operator to the desired consistency, by regulating the blood and saline volume.
Gengigel® (Ricerfarma S.r.l., Milano, Italy) contains high molecular weight fractions of Hyaluronic acid in gel formulation with 0.2% concentration for its effect in the treatment of plaque-induced gingivitis as an adjunct to scaling and root planing. The adjunctive use of Hyaluronan with 0.8% after thorough mechanical debridement potentially has major clinical benefits in terms of improved healing after non-surgical therapy. 
Gengigel® is available in different presentations to aid treatment efficacy and patient compliance over the longer term. It is available as tubes and applicators for use within the surgery, mouthwash and oral sprays for patients to continue treatment at home. Gengigel as a product for oral use has been evaluated by skin irritation test, sensitizing potentiality and percutaneous absorption test and has been proved to be a safe non irritant product.
| References|| |
|1.||Moseley R, Waddington RJ, Embery G. Hyaluronan and its potential role in periodontal healing. Dent Update 2002;29:144-8. |
|2.||Liguori V, Guillemin C, Pesce GF, Mirimanoff RO, Bernier J. Double-blind, randomized clinical study comparing hyaluronic acid cream to placebo in patients treated with radiotherapy. Radiother Oncol 1997;42:155-61. |
|3.||Adams ME, Atkinson MH, Lussier AJ, Schulz JI, Siminovitch KA, Wade JP, et al. The role of viscosupplementation with hylan G-F 20 (Synvisc) in the treatment of osteoarthritis of the knee: A Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone. Osteoarthritis Cartilage 1995;3:213-25. |
|4.||Matsuno H, Yudoh K, Kondo M, Goto M, Kimura T. Biochemical effect of intra-articular injections of high molecular weight hyaluronate in rheumatoid arthritis patients. Inflamm Res 1999;48:154-9. |
|5.||Neumayer T, Prinz A, Findl O. Effect of a new cohesive ophthalmic viscosurgical device on corneal protection and intraocular pressure in small-incision cataract surgery. J Cataract Refract Surg 2008;34:1362-6. |
|6.||Rabasseda X. The role of hyaluronic acid in the management of periodontal disease. Drugs Today 2000;36:1-20. |
|7.||Pagnacco A, Vangelisti R, Erra C, Poma A. Double-blind clinical trial versus placebo of a new sodium-hyaluronate- based gingival gel (in Italian). Attualitΰ Terapeutica Inter- nazionale 1997;15:1-7 |
|8.||Laurent TC, Laurent UB, Fraser JR. Functions of hyaluronan. Ann Rheum Dis 1995;54:429-32. |
|9.||Jentsch H, Pomowski R, Kundt G, Göcke R. Treatment of gingivitis with hyaluronan. J Clin Periodontol 2003;30:159-64. |
|10.||Embery G, Oliver WM, Stanbury JB, Purvis JA. The electrophoretic detection of acidic glycosaminoglycans in human gingival sulcus fluid. Arch Oral Biol 1982;27:177-9. |
|11.||Pogrel MA, Lowe MA, Stern R. Hyaluronan (hyaluronic acid) in human saliva. Arch Oral Biol 1996;41:667-71. |
|12.||Vedamurthy M. Soft tissue augmentation - Use of hyaluronic acid as dermal filler. Indian J Dermatol Venereol Leprol 2004;70:383-7. |
|13.||Rahemtulla F. Proteoglycans of oral tissues. Crit Rev Oral Biol Med 1992;3:3-67. |
|14.||Stern R, Asari AA, Sugahara KN. Hyaluronan fragments: an information-rich system. Eur J Cell Biol 2006;85:699-715. |
|15.||Sutherland IW. Novel and established applications of microbial polysaccharides. Trends Biotechnol 1998;16:41-6. |
|16.||Laurent TC (ed.). In: The Chemistry, Biology and Medical Applications of Hyaluronan and its Derivatives. Wenner-Gren International Series, volume 72. Portland Press, London; 1998. |
|17.||Weigel PH, Frost SJ, McGary CT, LeBoeuf RD. The role of hyaluronic acid in inflammation and wound healing. Int J Tissue React 1988;10:355-65. |
|18.||Toole BP. Hyaluronan in morphogenesis. Semin Cell Dev Biol 2001;12:79-87. |
|19.||Deed R, Rooney P, Kumar P, Norton JD, Smith J, Freemont AJ, et al. 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 1997;71:251-6. |
|20.||Mendes RM, Silva GA, Lima MF, Calliari MV, Almeida AP, Alves JB, et al. Sodium hyaluronate accelerates the healing process in tooth sockets of rats. Arch Oral Biol 2008;53:1155-62. |
|21.||Hunt DR, Jovanovic SA, Wikesjö UM, Wozney JM, Bernard GW. Hyaluronan supports recombinant human bone morphogenetic protein-2 induced bone reconstruction of advanced alveolar ridge defects in dogs. A pilot study. J Periodontol 2001;72:651-8. |
|22.||Pirnazar P, Wolinsky L, Nachnani S, Haake S, Pilloni A, Bernard GW. Bacteriostatic effects of hyaluronic acid. J Periodontol 1999;70:370-4. |
|23.||Embery G, Waddington RJ, Hall RC, Last KS. Connective tissue elements as diagnostic aids in periodontology. Periodontol 2000 2000;24:193-214. |
|24.||Vanden Bogaerde L. Treatment of infrabony periodontal defects with esterified hyaluronic acid: clinical report of 19 consecutive lesions. Int J Periodontics Restorative Dent 2009;29:315-23. |
|25.||Xu Y, Höfling K, Fimmers R, Frentzen M, Jervoe-Storm PM. 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 2004;75:1114-8. |
|26.||Johannsen A, Tellefsen M, Wikesjö U, Johannsen G. Local delivery of hyaluronan as an adjunct to scaling and root planing in the treatment of chronic periodontitis. J Periodontol 2009;80:1493-7. |
|27.||Pistorius A, Martin M, Willershausen B, Rockmann P. The clinical application of hyaluronic acid in gingivitis therapy. Quintessence Int 2005;36:531-8. |
|28.||Park JK, Yeom J, Oh EJ, Reddy M, Kim JY, Cho DW, et al. Guided bone regeneration by poly (lactic-co-glycolic acid) grafted hyaluronic acid bi-layer films for periodontal barrier applications. Acta Biomater 2009;5:3394-403. |
|29.||De Araújo Nobre M,Carvalho R, Malo P. Non surgical treatment of peri-implant pockets: an exploratory study comparing 0.2% chlorhexidine and 0.8% hyaluronic acid. Can J Dent Hygiene 2009;43:25-30. |
|30.||De Araújo Nobre M, Cintra N, Maló P. Peri-implant maintenance of immediate function implants: a pilot study comparing hyaluronic acid and chlorhexidine.Int J Dent Hyg 2007;5:87-94. |
|31.||Prato GP, Rotundo R, Magnani C, Soranzo C, Muzzi L, Cairo F. An autologous cell hyaluronic acid graft technique for gingival augmentation: A case series. J Periodontol 2003;74:262-7. |
|32.||Ballini A, Cantore S, Capodiferro S, Grassi FR. Esterified hyaluronic acid and autologous bone in the surgical correction of the infra-bone defects. Int J Med Sci 2009;6:65-71. |
|33.||Campoccia D, Doherty P, Radice M, Brun P, Abatangelo G, Williams DF. Semisynthetic resorbable materials from hyaluronan esterification. Biomaterials 1998;19:2101-27. |
|34.||Benedetti L, Cortivo R, Berti T, Berti A, Pea F, Mazzo M, et al. Biocompatibility and biodegradation of different hyaluronan derivatives (HYAFF) implanted in rats. Biomaterials 1993;14:1154-60. |
|35.||Koshal A, Patel P, Robert B, Galgut Peter N. A comparison in postoperative healing of sites receiving non-surgical debridement augmented with and without a single application of hyaluronan 0.8% gel. Prev Dent 2007;2:34-8. |
Suresh D Kedige
Department of Periodontics and Oral Implantology, M.M. College of Dental Sciences & Research, M.M.University Mullana, Ambala, Haryana
Source of Support: None, Conflict of Interest: None
|This article has been cited by|
||Hyaluronan in non-surgical and surgical periodontal therapy: a systematic review
| ||Kristina Bertl,Corinna Bruckmann,Per-Erik Isberg,Björn Klinge,Klaus Gotfredsen,Andreas Stavropoulos |
| ||Journal of Clinical Periodontology. 2015; 42(3): 236 |
|[Pubmed] | [DOI]|
||Surface-modified silicone T-tubes for prevention of tracheal stenosis in a rabbit model
| ||Jeong-Seok Choi,Jae-Yol Lim,In Suh Park,Si Yoong Seo,Yoon Ki Joung,Dong Keun Han,Young-Mo Kim |
| ||The Laryngoscope. 2014; : n/a |
|[Pubmed] | [DOI]|
||Acemannan sponges stimulate alveolar bone, cementum and periodontal ligament regeneration in a canine class II furcation defect model
| ||P. Chantarawaratit,P. Sangvanich,W. Banlunara,K. Soontornvipart,P. Thunyakitpisal |
| ||Journal of Periodontal Research. 2013; : n/a |
|[Pubmed] | [DOI]|
||hyaluronic acid as a treatment option for pressure ulcers
| ||ramos-torrecillas, j. and de luna-bertos, e. and díaz-rodríguez, l. and garcía-martínez, o. and rodríguez-pérez, l. and ruiz, c. |
| ||wounds. 2013; 25(12): 328-332 |
||biotechnological value of the hyaluronic acid in periodontal treatment
| ||cristina, g.m. and stana, p. and maniu, g. and traian, d.h. and silvia, d.a. |
| ||romanian biotechnological letters. 2013; 18(4): 8551-8558 |
| Article Access Statistics|
| Viewed||16986 |
| Printed||735 |
| Emailed||26 |
| PDF Downloaded||665 |
| Comments ||[Add] |
| Cited by others ||5 |