Effect of hyaluronic acid on alveolar ridge regeneration: a systematic review and meta-analysis assisted by the DeepSeek large language model

Relevance. Despite sustained research interest, the prevention of regressive changes associated with the absence of mechanical stimuli for bone remodeling and inflammatory alveolar ridge resorption continues to present a clinical challenge. Current alveolar ridge preservation protocols rely predominantly on xenogeneic and alloplastic biomaterials to support new mineralized tissue formation. However, the quality of the regenerated tissue remains suboptimal. High-molecular-weight hyaluronic acid has therefore been proposed as a bioactive adjunct because of its role in cell signaling, extracellular matrix formation, and the regulation of bone growth and mineralization. Objective: To evaluate the additional beneficial effect of exogenous hyaluronic acid combined with osteoconductive biomaterials on alveolar ridge defect repair.

Materials and methods. A targeted literature search based on predefined keywords and eligibility criteria was conducted for studies published between 2014 and 2025 in the PubMed/MEDLINE, CyberLeninka, and eLIBRARY databases. Study identification, screening, and selection were performed in accordance with PRISMA guidelines for systematic reviews and meta-analyses. The risk of bias in the four randomized controlled trials included in the review was assessed using the RoB 2.0 tool. Statistical analysis and data visualization were performed using the DeepSeek large language model (LLM), which generated Python code for the meta-analysis. Standardized mean differences (Cohen’s d) were calculated, pooled effect estimates were derived using a DerSimonian–Laird random-effects model, heterogeneity was assessed using I2, and forest and funnel plots were generated. All LLM-assisted outputs were verified at each stage of the analysis.

Results. The meta-analysis showed that exogenous hyaluronic acid had a statistically significant positive effect on new bone formation and significantly reduced the proportion of residual nonresorbed osteoconductive particles compared with the control group (p = 0.0035, 95% CI [0.275, 1.404] and p = 0.0001, 95% CI [−1.615, −0.547], respectively). In contrast, the percentage area of connective tissue structures/bone marrow spaces within alveolar ridge repair sites showed no significant effect of the bioactive polymer on new tissue modeling (p = 0.1881, 95% CI [−0.248, 1.263]). All assessed bone substitution outcome parameters showed a high degree of heterogeneity (I2 = 94.9%, 92.6%, and 96.7%, respectively). The main limitations of this meta-analysis include the small number of relevant studies, differences in study design, materials, and treatment protocols, wide variation in follow-up periods, and, more importantly, heterogeneity in the methods used to assess and interpret morphological outcomes, including histological and histomorphometric parameters.

Conclusion. High-molecular-weight hyaluronic acid exerts an additional beneficial effect on reparative remodeling of the alveolar ridge. The findings of this meta-analysis emphasize the importance of standardized outcome assessment protocols and the need for further studies to better define the outcomes of reconstructive procedures using more robust and objective evaluation measures.

1. Majidinia M, Sadeghpour A, Yousefi B. The roles of signaling pathways in bone repair and regeneration. J Cell Physiol. 2018;233(4):2937-2948. https://doi.org/10.1002/jcp.26042

2. Couso-Queiruga E, Stuhr S, Tattan M, Chambrone L, Avila-Ortiz G. Post-extraction dimensional changes: a systematic review and meta-analysis. J. Clin. Periodontol. 2021;48(1):126–144. https://doi.org/10.1111/jcpe.13390

3. Cardaropoli G, Araújo M, Lindhe J. Dynamics of bone tissue formation in tooth extraction sites. An experimental study in dogs. J. Clin. Periodontol. 2003;30(9):809–818. https://doi.org/10.1034/j.1600-051x.2003.00366.x

4. Bozo IY, Drobyshev AY, Redko NA, Komlev VS, Isaev AA, Deev RV. Bringing a Gene-Activated Bone Substitute Into Clinical Practice: From Bench to Bedside. Front Bioeng Biotechnol. 2021;9:599300. https://doi.org/10.3389/fbioe.2021.599300

5. Presnyakov E.V., Kurbonov K.R., Sorochanu I.P., Zhemkov N.I., Galbatsov D.F., Podluzhny P.S., et al. Regenerative osteogenesis at the interface of tissue–osteoplastic material. Morphology. 2023;161(4):33–42 (In Russ.). https://doi.org/10.17816/morph.629963

6. Perova M.D., Ananich A.Y., Verevkin A.A., Sevostyanov I.A., Melkonyan K.I., Samokhvalova I.D., et al. Intramembranous ossification in alveolar ridge defect repair using noninductive biomaterials: experimental study. Russian Journal of Dentistry. 2025;29 (4):327-337 (In Russ.). https://doi.org/10.17816/dent678800

7. West West DC, Hampson IN, Arnold F, Kumar S. Angiogenesis induced by degradation products of hyaluronic acid. Science. 1985;228(4705):1324-6. https://doi.org/10.1126/science.2408340

8. Eeckhout C, Ackerman J, Glibert M, Cosyn J. A randomized controlled trial evaluating hyaluronic acid gel as wound healing agent in alveolar ridge preservation. J. Clin. Periodontol. 2022;Mar;49(3):280-291. https://doi.org/10.1111/jcpe.13589

9. Abaza G, Abdel Gaber HK, Afifi NS, Adel-Khattab D. Injectable platelet rich fibrin versus hyaluronic acid with bovine derived xenograft for alveolar ridge preservation. A randomized controlled clinical trial with histomorphometric analysis. Clin. Implant. Dent. Relat. Res. 2024;26(1):88–102. https://doi.org/10.1111/cid.13289

10. James AW, LaChaud G, Shen J, Asatrian G, Nguyen V, Zhang X, et al. A Review of the clinical side effects of bone morphogenetic protein-2. Tissue Eng Part B Rev. 2016;22(4):284–297. https://doi.org/10.1089/ten.teb.2015.0357

11. Lopez-Pacheco A, Soto-Penaloza D, Gomez M, Penarrocha-Oltra D, Alarcon MA. Socket seal surgery techniques in the esthetic zone: A systematic review with meta-analysis and trial sequential analysis of randomized clinical trials. Int. J. Implant. Dent. 2021;7(1):13. https://doi.org/10.1186/s40729-021-00294-2

12. Retzepi M, Donos N. Guided Bone Regeneration: Biological Principle and Therapeutic Applications. Clin. Oral Implant. Res. 2010;21(6):567-76. https://doi.org/10.1111/j.1600-0501.2010.01922.x

13. Litwiniuk M, Krejner A, Speyrer MS, Gauto AR, Grzela T. Hyaluronic acid in inflammation and tissue regeneration. Wounds. 2016;28(3):78–88. Available from: https://pubmed.ncbi.nlm.nih.gov/26978861/ 14. Asparuhova MB, Chappuis V, Stahli A, Buser D, Sculean A. Role of hyaluronan in regulating self-renewal and osteogenic differentiation of mesenchymal stromal cells and pre-osteoblasts. Clin Oral Investig. 2020;24(11):3923–37. https://doi.org/10.1007/s00784-020-03259-8

14. Gurbuz E, Dursun E, Vatansever A, Caglayan F. Microcomputed tomographic analysis of bone microarchitecture after sinus augmentation with hyaluronic matrix: a case-control study. Oral Maxillofac Surg. 2022;26(3):431–7. https://doi.org/10.1007/s10006-021-01002-5

15. Tan WL, Wong TL, Wong MC, Lang NP. A systematic review of post-extractional alveolar hard and soft tissue dimensional changes in humans. Clin Oral Implants Res. 2012;23 (5):1–21. https://doi.org/10.1111/j.1600-0501.2011.02375.x

16. Jafer MA, Salem RM, Hakami FB, Ageeli RE, Alhazmi TA, Bhandi S, Patil S. Techniques for extraction socket regeneration for alveolar ridge preservation. J Contemp Dent Pract. 2022;23(2):245–50. Available from: https://pubmed.ncbi.nlm.nih.gov/35748457/

17. Kyyak S, Blatt S, Wiesmann N, Smeets R, Kaemmerer PW. Hyaluronic Acid with Bone Substitutes Enhance Angiogenesis In Vivo. Materials (Basel). 2022;15(11):3839. https://doi.org/10.3390/ma15113839

18. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. https://doi.org/10.1136/bmj.n71

19. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. https://doi.org/10.1136/bmj.d5928

20. Viana J, Machado V, Proença, L, Chambrone L, Mendes JJ, Botelho J. Comparative assessment of Cochrane’s RоB and RоB2 in dentistry trials: a meta-research study. Syst Rev. 2025;14:154. https://doi.org/10.1186/s13643-025-02901-4

21. Arpağ OF, Damlar I, Altan A, Tatli U, Gunay A. To what extent does hyaluronic acid affect healing of xenografts? A histomorphometric study in rabbits. J Appl Oral Sci. 2018;26:e20170004. https://doi.org/10.1590/1678-7757-2017-0004

22. Abaza G, Gaber HKA, Afifi NS, Adel-Khattab D. Injectable platelet rich fibrin versus hyaluronic acid with bovine derived xenograft for alveolar ridge preservation. A randomized controlled clinical trial with histomorphometric analysis. Clin. Implant. Dent. Relat. Res. 2024;26(1):88-102. https://doi.org/10.1111/cid.13289

23. Stiller M, Kluk E, Bohner M, Lopez-Heredia MA, Muller-Mai C, Knab C. Performance of β-tricalcium phosphate granules and putty, bone grafting materials after bilateral sinus floor augmentation in humans. Biomaterials. 2014;35(10):3154-63. https://doi.org/10.1016/j.biomaterials.2013.12.068

24. Velasco-Ortega E, Valente NA, Iezzi G, Petrini M, Derchi G, Barone A. Maxillary sinus augmentation with three different biomaterials: Histological, histomorphometric, clinical, and patient-reported outcomes from a randomized controlled trial. Clin. Implant. Dent. Relat. Res. 2021;23(1):86-95. https://doi.org/10.1111/cid.12964

25. Zhu H, Mitsuhashi N, Klein A, Barsky LW, Weinberg K, Barr ML, et al. The role of the hyaluronan receptor CD44 in mesenchymal stem cell migration in the extracellular matrix. Stem Cells. 2006;24(4):928-35. https://doi.org/10.10.1634/stemcells.2005-0186

26. Lorenzi C, Leggeri A, Cammarota I, Carosi P, Mazzetti V, Arcuri C. Hyaluronic Acid in Bone Regeneration: Systematic Review and Meta-Analysis. Dent. J (Basel). 2024;12(8):263. https://doi.org/10.3390/dj12080263

27. Engstrom PE, Shi XQ, Tronje G, Larsson A, Welander U, Frithiof L, et al. The effect of hyaluronan on bone and soft tissue and immune response in wound healing. J. Periodontol. 2001;72(9):1192-200. https://doi.org/10.1902/jop.2000.72.9.1192

28. Husseini B, Friedmann A,Wak R, Ghosn N, Khoury G, El Ghoul T, et al. Clinical and radiographic assessment of cross-linked hyaluronic acid addition in demineralized bovine bone based alveolar ridge preservation: A human randomized split-mouth pilot study. J. Stomatol. Oral Maxillofac. Surg. 2023;124(4):101426. https://doi.org/10.1016/j.jormas.2023.101426

29. Alcântara CEP, Castro MAA., Noronha MS, MartinsJunior 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;32:e84. https://doi.org/10.1590/1807-3107bor-2018.vol32.0084

30. Dempster DW, Compston JE, Drezner MK, Glorieux FH, Kanis JA, Malluche H, et al. Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 2013;28(1):2–17. https://doi.org/10.1002/jbmr.1805