Hyaluronic acid as an active agent to accelerate bone regeneration aftertooth extraction: a literature review

  • Andyka Yasa I Putu Gede Department of Biomedicine, Faculty of Dentistry, Universitas Mahasaraswati, Denpasar, Bali
  • I Made Jawi Department of Pharmacology, Faculty of Medicine, Universitas Udayana, Denpasar, Bali
  • I Made Muliarta Department of Physiology, Faculty of Medicine, Universitas Udayana, Denpasar, Bali
Keywords: bone morphogenetic protein; growth factor; hyaluronic acid (HA); tooth extraction; dentistry;


Tooth extraction is a dental treatment that is performed frequently in dentistry. This procedure will stimulate a sophisticated healing process involving a variety
of biological factors although it takes a long time to complete. Three phases occur in this process i.e. the inflammatory phase, the proliferation phase, and the remodeling phase which aim to restore the tissue function. Several interventions can be used to accelerate bone formation after tooth extraction. Recently, hyaluronic acid (HA) has been commonly used in dentistry due to their essential physiological effects for the periodontal connective tissue, gingiva, and alveolar bone. Hyaluronic acidis a natural non-sulfate glycosaminoglycans compound that has high molecular weight consisting of D-glucuronic acid and N-acetylglucosamine. Hyaluronic acidis also a component of the extracellular matrix that plays an important role in morphogenesis and tissue healing. The mechanism of action of HA works in two ways, that is passive and active mechanism. The passive mechanism is depend on physical and chemical properties of HA that can change the molecular weight and concentration properties. The active mechanism of HA works by stimulating signal transduction pathway initiated by ligand binding with its receptors through autocrine or paracrine processes. The administration of HA can accelerate bone formation due to it can enhance bone morphogenetic protein (BMP) which belongs to the TGF- β superfamily that has high osteogenic capacity. The HA works through a passive mechanism that depends on its molecular weight and an active mechanism by
increasing BMP activity.


Hansson S, Halldin A. Alveolar ridge resorption after tooth extraction: a consequence of a fundamental principle of bone physiology. J Dent Biomech 2012; 3:1758736012456543.


Huumonen S, Haikola B, Oikarinen K, Soderholm A-L, Remes-Lyly T, Sipila T. Residual ridge resorption, lower denture stability and subjective complaints among edentulous individuals. J Oral Rehabil 2012; 39(5):384-90.

https://doi.org/ 10.1111/j.1365-2842.2011.02284.x

Tan WL, Wong TLT, Wong MCM, Lang NP. A systematic review of post-extractional alveolar hard and soft tissue dimensional changes in humans. Clin Oral Implant Res 2011; 23Suppl:1-21.


Araujo MG, Lindhe J. The edentulous ridge. In: Lang NP &Lindhe J editors. Clinical Periodontology and Implant Denstistry. New Jersy: Wiley Blackwell 2015.

Amato F, Mirabella D, Macca U, Tarnow DP. Implant site development by orthodontic forced extraction: a preliminary study. Int J Oral Maxillofac Implants 2012; 27(2):411-20.

Kubilius M, Kubilius R, Gleiznys A. The preservation of alveolar bone ridge during tooth extraction. Stomatologija 2012; 14(1):3-11.

Jamjoom A and Cohen RE. Grafts for ridge preservation. J Funct Biomater 2013; 6(3):834-48.


Fakhari A, Berkland C. Applications and emerging trends of hyaluronic acid in tissue engineering, as a dermal filler and in osteoarthritis treatment. Acta Biomater 2013; 9(7):7081-92.


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.


Alcântara CEP, Castro MAA, Noronha MS, Martins-Junior PA, Mendes RM, Caliari MV, et al. Hyaluronic acid accelerates bone repair in human dental sockets: a randomized triple-blind clinical trial. Braz Oral Res 2018; 84:1-10.


Zhao N, Wang X, Qin L, Zhai M, Yuan J, Chen J, et al. Effect of hyaluronic acid in bone formation and its applications in dentistry. J Biomed Mater Res A 2016; 104(6):1560-9.


Volpi N, Schiller J, Stern R, Soltés L. Role, metabolism, chemical modifications and applications of hyaluronan. Curr Med Chem 2009; 16:1718-45.


Fallacara A, Baldini E, Manfredini S, Vertuani S. Hyaluronic acid in the third millennium. Polymers (Basel) 2018; 10(7):1-36.


Vigetti D, Karousou E, Viola M, Deleonibus S, De Luca G, Passi A. Hyaluronan: biosynthesis and signaling. Biochim Biophys Acta 201; 1840:2452-9.


Park D, Kim Y, Kim H, Kim K, Lee YS, Choe J. Hyaluronic acid promotes angiogenesis by inducing RHAMM-TGFβ receptor interaction via CD44-PKCδ. Mol Cells 2012; 33(6):563-74.


Putra RH, Astuti ER, Devijanti R. Transforming growth factor beta 1 expression and inflammatory cells in tooth extraction socket after X-ray irradiation. Majalah Kedokteran Gigi 2016; 49(2):87-92.


Wu R-L, Sedlmeier G, Kyjacova L, Schamaus A, Philip J, Thiele W, et al. Hyaluronic acid-CD44 interactions promote BMP4/7-dependent Id1/3 expression in melanoma cells. Sci Rep 2018; 8:14913.


Girish KS, Kemparaju K. The magic glue hyaluronan and its eraser hyaluronidase: a biological overview. Life Sci 2007; 80:1921-43.


Necas J, Bartosikova L, Brauner P, Kolar J. Hyaluronic acid (hyaluronan): a review. Vet Med 2008; 53:397-411.


Hamilton SR, Veiseh M, Tolg C, Tirona R, Richardson J, Brown R, et al. Pharmacokinetics and pharmacodynamics of hyaluronan infused into healthy human volunteers. Open Drug Met J 2009; 3:43-55.


Huang H, Feng J, Wismeijer D, Wu G, Hunziker EB. Hyaluronic acid promotes the osteogenesis of BMP-2 in an absorbable collagen sponge. Polymers (Basel) 2017; 9:2-13.


Bartold M, Gronthos S, Haynes D, Ivanovski S. Mesenchymal stem cells and biologic factor leading to bone formation. J Clin Periodontol 2019; 46:12-32.


Bastian O, Pillay J, Alblas J, Leenen L, Koenderman L, Blokhuis T. Systemic inflammation and fracture healing. J Leukoc Biol 2011; 89:669-73.


Nickel J, Ten Dijke P, Mueller TD. TGF-beta family co-receptor function and signaling. Acta Biochim Biophys Sin (Shanghai) 2018; 50:12-36.


Godwina J, Kuraitis D, Rosenthal. Extracellular matrix considerations for scar-free repair and regeneration: Insights from regenerative diversity among vertebrates. Int J Biochem Cell Biol 2014; 56:47-5.


Knopf-Marques H, Pravda M, Wolfova L, Velebny V, Schaaf P, Vrana NE, et al. Hyaluronic acid and its derivatives in coating and delivery systems: applications in tissue engineering, regenerative medicine and immunomodulation. Adv Health Mater 2016; 5(22):2841-55.


Turley EA, Noble PW, Bourguignon LY. Signalling properties of hyaluronan receptors. J Biol Chem 2002; 277(7):4589-92.


Ebid R, Lichtnekert J, Anders HJ. Hyaluronan is not a ligand but a regulator of toll-like receptor signalling in mesangial cells: Role of extracellular matrix in innate immunity. ISRN Nephrol 2014; 714081:1-11.


Hassumi JS, Mulinari-Santos G, Fabris ALDS, Jacob RGM, Gonçalves A, Rossi AC, et al. Alveolar bone healing in rats: micro-CT, immunohistochemical and molecular analysis. J Appl Oral Sci 2018; 26:e20170326.


Kawano M, Ariyoshi W, Iwanaga K, Okinaga T, Habu M, Yoshioka I, et al. Mechanism involved in enhancement of osteoblast differentiation by hyaluronic acid. Biochem Biophys Res Commun 2011; 405:575-80.


Miyazono K. Transforming growth factor-β signalling in epithelial mesenchymal transition and progression of cancer. Proc Jpn Acad 2009; 85:314-23.