Skip to main content

Advertisement

SpringerLink
Log in

Tomographic evaluation of the effect of simvastatin topical use on alveolar bone microarchitecture, pain and swelling after mandibular third molar extraction: a randomized controlled trial

  • Original Article
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript

Abstract

Objectives

To evaluate the effect of a collagen sponge containing simvastatin on socket healing in terms of bone microarchitecture through tomographic analysis, pain, and swelling after impacted third molar extraction.

Materials and methods

In this single-blind, split-mouth, randomized clinical trial, 29 patients undergoing impacted third molar extraction were allocated into two groups: (i) test group, a collagen sponge containing simvastatin was inserted within the sockets; and (ii) control group, in which sockets retained the clot. Bone volume (BV), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular spacing (Tb.Sp), and gray scale were evaluated using cone beam computed tomography (CBCT) acquired immediately postoperative and 3 months after surgery. Pain, swelling, and wound healing were evaluated using the 10-point visual analogue scale, three extra-oral reference measurements, and the Landry index.

Results

In total, 22 participants remained in the study; no loss-to-follow-up was related to the intervention. BV and BV/TV were significantly higher at 3 months postoperatively in the test group compared with the control group and were correlated with greater bone trabeculation. Pain, edema, and the Landry index revealed a greater inflammatory response in the test group during early repair. Simvastatin contributed to bone healing, with no adverse effects or postoperative complications.

Conclusions

The absorbable collagen sponge containing simvastatin improved BV, BV/TV, and trabecular bone, indicating the potential of this drug to induce the formation of autogenous bone.

Clinical relevance

Intraosseous statins represent a promising, low-cost, and easy-to-use alternative for alveolar ridge preservation and bone regeneration.

Trial registration

Brazilian Registry of Clinical Trials (REBEC), No. RBR-523N7R.

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

Similar content being viewed by others

References

  1. Noronha Oliveira M, Rau LH, Marodin A, Corrêa M, Corrêa LR, Aragones A, Magini RS (2017) Ridge preservation after maxillary third molar extraction using 30% porosity PLGA/HA/β-TCP scaffolds with and without simvastatin: a pilot randomized controlled clinical trial. Implant Dent 26:832–840. https://doi.org/10.1097/ID.0000000000000655

    Article  PubMed  Google Scholar 

  2. Moslemi N, Khoshkam V, Rafiei SC, Bahrami N, Aslroosta H (2018) Outcomes of alveolar ridge preservation with recombinant human bone morphogenetic protein-2: a systematic review. Implant Dent 27:351–362. https://doi.org/10.1097/ID.0000000000000722

    Article  PubMed  Google Scholar 

  3. Araújo MG, Silva CO, Misawa M (2000) Sukekava F (2015) Alveolar socket healing: what can we learn? Periodontol 68:122–134. https://doi.org/10.1111/prd.12082

    Article  Google Scholar 

  4. Gupta S, Del Fabbro M, Chang J (2019) The impact of simvastatin intervention on the healing of bone, soft tissue, and TMJ cartilage in dentistry: a systematic review and meta-analysis. Int J Implant Dent 5:17–27. https://doi.org/10.1186/s40729-019-0168-4

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wang Z, Li Y, Zhou F, Piao Z, Hao J (2016) Effects of statins on bone mineral density and fracture risk: a PRISMA-compliant systematic review and meta-analysis. Medicine 95:e3042–e3049. https://doi.org/10.1097/MD.0000000000003042

    Article  PubMed  PubMed Central  Google Scholar 

  6. Griffiths SL, Cartmell SH (2012) Use of statins for enhancing bone-tissue-engineered grafts. Eur J Plast Surg 35:151–157. https://doi.org/10.1007/s00238-007-0190-2

    Article  Google Scholar 

  7. Mundy G, Garrett R, Harris S, Chan J, Chen D, Rossini G, Boyce B, Zhao M, Gutierrez G (1999) Stimulation of bone formation in vitro and in rodents by statins. Science 286:1946–1949. https://doi.org/10.1126/science.286.5446.1946

    Article  PubMed  Google Scholar 

  8. Gutierrez GE, Lalka D, Garrett IR, Rossini G, Mundy GR (2006) Transdermal application of lovastatin to rats causes profound increases in bone formation and plasma concentrations. Osteoporos Int 17:1033–1042. https://doi.org/10.1007/s00198-006-0079-0

    Article  PubMed  Google Scholar 

  9. Nyan M, Sato D, Oda M, Machida T, Kobayashi H, Nakamura T, Kasugai S (2007) Bone formation with the combination of simvastatin and calcium sulfate in critical-sized rat calvarial defect. J pharmacol sci 104:384–386. https://doi.org/10.1254/jphs.sc0070184

    Article  PubMed  Google Scholar 

  10. Ayukawa Y, Yasukawa E, Moriyama Y, Ogino Y, Wada H, Atsuta I, Koyano K (2009) Local application of statin promotes bone repair through the suppression of osteoclasts and the enhancement of osteoblasts at bone-healing sites in rats. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 107:336–342. https://doi.org/10.1016/j.tripleo.2008.07.013

    Article  PubMed  Google Scholar 

  11. Liu C, Wu Z, Sun HC (2009) The effect of simvastatin on mRNA expression of transforming growth factor-beta1, bone morphogenetic protein-2 and vascular endothelial growth factor in tooth extraction socket. Int J Oral Sci 1:90–98. https://doi.org/10.4248/ijos.08011

    Article  PubMed  PubMed Central  Google Scholar 

  12. Maciel-Oliveira N, Bradaschia-Correa V, Arana-Chavez VE (2011) Early alveolar bone regeneration in rats after topical administration of simvastatin. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 112:170–179. https://doi.org/10.1016/j.tripleo.2010.08.027

    Article  PubMed  Google Scholar 

  13. Liu S, Bertl K, Sun H, Liu ZH, Andrukhov O, Rausch-Fan X (2012) Effect of simvastatin on the osteogenetic behavior of alveolar osteoblasts and periodontal ligament cells. Hum cell 25:29–35. https://doi.org/10.1007/s13577-011-0028-x

    Article  PubMed  Google Scholar 

  14. Degala S, Bathija NA (2018) Evaluation of the efficacy of simvastatin in bone regeneration after surgical removal of bilaterally impacted third molars-a split-mouth randomized clinical trial. J Oral Maxillofac Surg 76:1847–1858. https://doi.org/10.1016/j.joms.2018.04.035

    Article  PubMed  Google Scholar 

  15. Saifi AM, Giraddi GB, Ahmed N (2017) Healing of extraction socket following local application of simvastatin: a split mouth prospective study. J Oral Biol Craniofac Res 7:106–112. https://doi.org/10.1016/j.jobcr.2017.04.001

    Article  PubMed  PubMed Central  Google Scholar 

  16. Chauhan AS, Maria A, Managutti A (2015) Efficacy of simvastatin in bone regeneration after surgical removal of mandibular third molars: a clinical pilot study. J Maxillofac Oral Surg 14:578–585. https://doi.org/10.1007/s12663-014-0697-6

    Article  PubMed  Google Scholar 

  17. Hopewell S, Clarke M, Moher D, Wager E, Middleton P, Altman DG, Schulz KF (2008) CONSORT for reporting randomized controlled trials in journal and conference abstracts: explanation and elaboration. PLoS Med 5:e20. https://doi.org/10.1371/journal.pmed.0050020

    Article  PubMed  PubMed Central  Google Scholar 

  18. Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DG (2010) CONSORT 2010 Explanation and elaboration: updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol 63:e1–e37. https://doi.org/10.1016/j.jclinepi.2010.03.004

    Article  PubMed  Google Scholar 

  19. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928. https://doi.org/10.1136/bmj.d5928

    Article  PubMed  PubMed Central  Google Scholar 

  20. Winter GB (1926) Impacted mandibular third molars. American Medical Book Co, St Louis

  21. Pell GJ, Gregory BT (1933) Impacted mandibular third molars: classification and modified techniques for removal. Dent Dig 39:330–338

    Google Scholar 

  22. da Costa Araújo FA, de Santana Santos T, de Morais HH, Laureano Filho JR, de Oliveira E Silva ED, Vasconcellos RJ (2012) Comparative analysis of preemptive analgesic effect of tramadol chlorhydrate and nimesulide following third molar surgery. J Craniomaxillofac Surg 40:e346–e349. https://doi.org/10.1016/j.jcms.2012.01.018

    Article  PubMed  Google Scholar 

  23. Almeida R, Lemos C, de Moraes S, Pellizzer EP, Vasconcelos BC (2019) Efficacy of corticosteroids versus placebo in impacted third molar surgery: systematic review and meta-analysis of randomized controlled trials. Int J Oral Maxillofac Surg 48:118–131. https://doi.org/10.1016/j.ijom.2018.05.023

    Article  PubMed  Google Scholar 

  24. Ragot JP, Monti T, Macciocchi A (1993) Controlled clinical investigation of acute analgesic activity of nimesulide in pain after oral surgery. Drugs 46:162–167. https://doi.org/10.2165/00003495-199300461-00039

    Article  PubMed  Google Scholar 

  25. de Melo DG, de Santana Santos T, Sehn FP, de Oliveira E Silva ED, Martins-Filho PR, Dourado AC (2015) Evaluation of inorganic bovine bone graft in periodontal defects after third molar surgery. Ann Maxillofac Surg 5:198–202. https://doi.org/10.4103/2231-0746.175765

    Article  PubMed  PubMed Central  Google Scholar 

  26. de Morais HH, Holanda Vasconcellos RJ, de Santana ST, Rocha NS, da Costa Araújo FA, de Carvalho RW (2013) Clinical study of hemodynamic changes comparing 4% articaine hydrochloride with 1:100,000 and 1:200,000 epinephrine. Oral Surg Oral Med Oral Pathol Oral Radiol 116:e14–e22. https://doi.org/10.1016/j.oooo.2011.10.043

    Article  PubMed  Google Scholar 

  27. Pauwels R, Faruangsaeng T, Charoenkarn T, Ngonphloy N, Panmekiate S (2015) Effect of exposure parameters and voxel size on bone structure analysis in CBCT. Dentomaxillofac Radiol 44:20150078. https://doi.org/10.1259/dmfr.20150078

    Article  PubMed  PubMed Central  Google Scholar 

  28. Mehrabi M, Allen JM, Roser SM (2007) Therapeutic agents in perioperative third molar surgical procedures. Oral Maxillofac Surg Clin North Am 19:69–vi. https://doi.org/10.1016/j.coms.2006.11.010

    Article  PubMed  Google Scholar 

  29. Alcântara CE, Falci SG, Oliveira-Ferreira F, Santos CR, Pinheiro ML (2014) Pre-emptive effect of dexamethasone and methylprednisolone on pain, swelling, and trismus after third molar surgery: a split-mouth randomized triple-blind clinical trial. Int J Oral Maxillofac Surg 43:93–98. https://doi.org/10.1016/j.ijom.2013.05.016

    Article  PubMed  Google Scholar 

  30. Ustün Y, Erdogan O, Esen E, Karsli ED (2003) Comparison of the effects of 2 doses of methylprednisolone on pain, swelling, and trismus after third molar surgery. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 96:535–539. https://doi.org/10.1016/S1079210403004645

    Article  PubMed  Google Scholar 

  31. Landry RG (1985) Effectiveness of benzydamine HCl in the treatment of periodontal post-surgical patients. Faculty of Dentistry. University of Toronto, Toronto

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

    Article  PubMed  Google Scholar 

  33. Chappuis V, Engel O, Reyes M, Shahim K, Nolte LP, Buser D (2013) Ridge alterations post-extraction in the esthetic zone: a 3D analysis with CBCT. J Dent Res 92:195S-201S. https://doi.org/10.1177/0022034513506713

    Article  PubMed  PubMed Central  Google Scholar 

  34. Spagnoli D, Choi C (2013) Extraction socket grafting and buccal wall regeneration with recombinant human bone morphogenetic protein-2 and acellular collagen sponge. Atlas Oral Maxillofac Surg Clin North Am 21:175–183. https://doi.org/10.1016/j.cxom.2013.05.003

    Article  PubMed  Google Scholar 

  35. Coomes AM, Mealey BL, Huynh-Ba G, Barboza-Arguello C, Moore WS, Cochran DL (2014) Buccal bone formation after flapless extraction: a randomized, controlled clinical trial comparing recombinant human bone morphogenetic protein 2/absorbable collagen carrier and collagen sponge alone. J Periodontol 85:525–535. https://doi.org/10.1902/jop.2013.130207

    Article  PubMed  Google Scholar 

  36. Morjaria KR, Wilson R, Palmer RM (2014) Bone healing after tooth extraction with or without an intervention: a systematic review of randomized controlled trials. Clin Implant Dent Relat Res 16:1–20. https://doi.org/10.1111/j.1708-8208.2012.00450.x

    Article  PubMed  Google Scholar 

  37. De Risi V, Clementini M, Vittorini G, Mannocci A, De Sanctis M (2015) Alveolar ridge preservation techniques: a systematic review and meta-analysis of histological and histomorphometrical data. Clin Oral Implants Res 26:50–68. https://doi.org/10.1111/clr.12288

    Article  PubMed  Google Scholar 

  38. Jambhekar S, Kernen F, Bidra AS (2015) Clinical and histologic outcomes of socket grafting after flapless tooth extraction: a systematic review of randomized controlled clinical trials. J Prosthet Dent 113:371–382. https://doi.org/10.1016/j.prosdent.2014.12.009

    Article  PubMed  Google Scholar 

  39. Sanz M, Dahlin C, Apatzidou D, Artzi Z, Bozic D, Calciolari E, De Bruyn H, Dommisch H, Donos N, Eickholz P, Ellingsen JE, Haugen HJ, Herrera D, Lambert F, Layrolle P, Montero E, Mustafa K, Omar O, Schliephake H (2019) Biomaterials and regenerative technologies used in bone regeneration in the craniomaxillofacial region: consensus report of group 2 of the 15th European Workshop on Periodontology on Bone Regeneration. J Clin Periodontol 46:82–91. https://doi.org/10.1111/jcpe.13123

    Article  PubMed  Google Scholar 

  40. Giannobile WV, Berglundh T, Al-Nawas B, Araujo M, Bartold PM, Bouchard P, Chapple I, Gruber R, Lundberg P, Sculean A, Lang NP, Lyngstadaas P, Kebschull M, Galindo-Moreno P, Schwartz Z, Shapira L, Stavropoulos A, Reseland J (2019) Biological factors involved in alveolar bone regeneration: consensus report of Working Group 1 of the 15th European Workshop on Periodontology on Bone Regeneration. J Clin Periodontol 46:6–11. https://doi.org/10.1111/jcpe.13130

    Article  PubMed  Google Scholar 

  41. Jepsen S, Schwarz F, Cordaro L, Derks J, Hämmerle CHF, Heitz-Mayfield LJ, Hernández-Alfaro F, Meijer HJA, Naenni N, Ortiz-Vigón A, Pjetursson B, Raghoebar GM, Renvert S, Rocchietta I, Roccuzzo M, Sanz-Sánchez I, Simion M, Tomasi C, Trombelli L, Urban I (2019) Regeneration of alveolar ridge defects. Consensus report of group 4 of the 15th. European Workshop on Periodontology on Bone Regeneration. J Clin Periodontol 46:277–286. https://doi.org/10.1111/jcpe.13121

    Article  PubMed  Google Scholar 

  42. Ritto FG, Pimentel T, Canellas J, Junger B, Cruz M, Medeiros PJ (2019) Randomized double-blind clinical trial evaluation of bone healing after third molar surgery with the use of leukocyte- and platelet-rich fibrin. Int J Oral Maxillofac Surg 48:1088–1093. https://doi.org/10.1016/j.ijom.2019.01.020

    Article  PubMed  Google Scholar 

  43. Panmekiate S, Ngonphloy N, Charoenkarn T, Faruangsaeng T, Pauwels R (2015) Comparison of mandibular bone microarchitecture between micro-CT and CBCT images. Dentomaxillofac Radiol 44:20140322. https://doi.org/10.1259/dmfr.20140322

    Article  PubMed  PubMed Central  Google Scholar 

  44. Pauwels R, Jacobs R, Singer SR, Mupparapu M (2015) CBCT-based bone quality assessment: are Hounsfield units applicable? Dentomaxillofac Radiol 44:20140238. https://doi.org/10.1259/dmfr.20140238

    Article  PubMed  Google Scholar 

  45. Nyan M, Sato D, Kihara H, Machida T, Ohya K, Kasugai S (2009) Effects of the combination with alpha-tricalcium phosphate and simvastatin on bone regeneration. Clin Oral implants Res 20:280–287. https://doi.org/10.1111/j.1600-0501.2008.01639.x

    Article  PubMed  Google Scholar 

  46. Tai IC, Fu YC, Wang CK, Chang JK, Ho ML (2013) Local delivery of controlled-release simvastatin/PLGA/HAp microspheres enhances bone repair. Int J Nanomedicine 8:3895–3904. https://doi.org/10.2147/IJN.S48694

    Article  PubMed  PubMed Central  Google Scholar 

  47. Tanigo T, Takaoka R, Tabata Y (2010) Sustained release of water-insoluble simvastatin from biodegradable hydrogel augments bone regeneration. J Control Release 143:201–206. https://doi.org/10.1016/j.jconrel.2009.12.027

    Article  PubMed  Google Scholar 

  48. Moraschini V, Barboza E (2016) Quality assessment of systematic reviews on alveolar socket preservation. Int J Oral and maxillofac Surg 45:1126–1134. https://doi.org/10.1016/j.ijom.2016.03.010

    Article  Google Scholar 

  49. Mukozawa A, Ueki K, Marukawa K, Okabe K, Moroi A, Nakagawa K (2011) Bone healing of critical-sized nasal defects in rabbits by statins in two different carriers. Clin Oral Implants Res 22:1327–1335. https://doi.org/10.1111/j.1600-0501.2010.02135.x

    Article  PubMed  Google Scholar 

  50. Duong M, Mealey BL, Walker C, Al-Harthi S, Prihoda TJ, Huynh-Ba G (2020) Evaluation of healing at molar extraction sites with and without ridge preservation: a three-arm histologic analysis. J Periodontol 91:74–82. https://doi.org/10.1002/JPER.19-0237

    Article  PubMed  Google Scholar 

  51. Kim YK, Yun PY, Lee HJ, Ahn JY, Kim SG (2011) Ridge preservation of the molar extraction socket using collagen sponge and xenogeneic bone grafts. Implant Dent 20:267–272. https://doi.org/10.1097/ID.0b013e3182166afc

    Article  PubMed  Google Scholar 

  52. Pauly S, Back DA, Kaeppler K, Haas NP, Schmidmaier G, Wildemann B (2012) Influence of Statins locally applied from orthopedic implants on osseous integration. BMC Musculoskelet Disord 13:208–215. https://doi.org/10.1186/1471-2474-13-208

    Article  PubMed  PubMed Central  Google Scholar 

  53. Yaghobee S, Panjnoush M, Rafiei SC, Shakib PA, Mahmoodi S, Rasouli-ghahroudi AAR, Poursafar F (2020) Effect of simvastatin on bone regeneration: a histologic and histomorphometric analysis. J Oral Maxillofac Surg 78:927–934. https://doi.org/10.1016/j.joms.2020.01.016

    Article  PubMed  Google Scholar 

  54. Sezavar M, Bohlouli B, Farhadi S, Tabatabaee S, Latifi R (2018) Simvastatin effects on dental socket quality: a comparative study. Contemp Clin Dent 9:55–59. https://doi.org/10.4103/ccd.ccd_719_17

    Article  PubMed  PubMed Central  Google Scholar 

  55. Bracht L, Caparroz-Assef SM, Magon TF, Ritter AM, Cuman RK, Bersani-Amado CA (2011) Topical anti-inflammatory effect of hypocholesterolaemic drugs. J Pharm Pharmacol 63:971–975. https://doi.org/10.1111/j.2042-7158.2011.01302.x

    Article  PubMed  Google Scholar 

  56. Barbalho JC, Vasconcellos RJH, de Morais HH, Santos LAM, Almeida RAC, Rêbelo HL, Lucena EE, de Araújo SQ (2017) Effects of co-administered dexamethasone and nimesulide on pain, swelling, and trismus following third molar surgery: a randomized, triple-blind, controlled clinical trial. Int J Oral Maxillofac Surg 46:236–242. https://doi.org/10.1016/j.ijom.2016.10.011

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the University of Pernambuco and the research team for their support, the study participants and the Brazilian funding agencies. We would like to thank Editage (www.editage.com) for English language editing.

Funding

The study was funded by the following Brazilian funding agencies: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior [CAPES (Coordination for the Improvement of Higher Education Personnel) – Finance Code 001], Conselho Nacional de Desenvolvimento Científico e Tecnológico [CNPq (National Council for Scientific and Technological Development)] and Fundação de Amparo à Ciência e Tecnologia do Estado de Pernambuco [FACEPE (Science and Technology Support Foundation of the State of Pernambuco)].

Author information

Authors and Affiliations

  1. University of Pernambuco, Recife, PE, Brazil

    Jiordanne Araújo Diniz, Davi da Silva Barbirato & José Rodrigues Laureano Filho

  2. Department of Clinical and Preventive Dentistry, Federal University of Pernambuco, Recife, PE, Brazil

    Eduarda Helena Leandro do Nascimento & Andrea dos Anjos Pontual

  3. Division of Oral and Maxillofacial Surgery, Dental School, University of Pernambuco, Arnóbio Marques St., 310, Recife, PE, 50100-130, Brazil

    Ana Cláudia Amorim Gomes Dourado

Authors
  1. Jiordanne Araújo Diniz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Davi da Silva Barbirato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eduarda Helena Leandro do Nascimento
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea dos Anjos Pontual
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ana Cláudia Amorim Gomes Dourado
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. José Rodrigues Laureano Filho
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed and have equal responsibility for the design and execution of the research, analysis and interpretation of the results and writing of the article.

Corresponding author

Correspondence to Ana Cláudia Amorim Gomes Dourado.

Ethics declarations

Informed consent

Informed consent was obtained from all individual participants included in the study.

Consent to publish

Patients signed informed consent regarding publishing their data and photographs.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Diniz, J.A., Barbirato, D.d., do Nascimento, E.H.L. et al. Tomographic evaluation of the effect of simvastatin topical use on alveolar bone microarchitecture, pain and swelling after mandibular third molar extraction: a randomized controlled trial. Clin Oral Invest 26, 3533–3545 (2022). https://doi.org/10.1007/s00784-021-04322-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00784-021-04322-8

Keywords

Search

Navigation