{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T23:37:39Z","timestamp":1785886659470,"version":"3.56.0"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T00:00:00Z","timestamp":1764115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinics and Practice"],"abstract":"<jats:p>Background\/Objectives: Periodontal diseases are highly prevalent worldwide, causing progressive destruction of the alveolar bone and eventual tooth loss when not treated. Despite advances in conventional periodontal therapies, complete tissue regeneration remains limited. This review aims to evaluate the efficacy, safety, and clinical relevance of stem cell-based tissue engineering approaches for regeneration of periodontal bone lesions. Methods: Following PRISMA guidelines, a systematic search was conducted across multiple databases, resulting in the inclusion of 17 studies in humans that met predefined PICO criteria. The study protocol was registered on PROSPERO (CRD420251229271). These studies assessed various stem cell sources, including dental and bone marrow-derived cells among others, both on their own and in combination with scaffolds or growth factors. Results: Most studies reported favorable outcomes in terms of clinical attachment gain, radiographic bone fill, probing depth reduction, and implant stability. No major adverse effects were noted, indicating good safety. However, results varied based on cell type, culture protocols, and defect characteristics. Conclusions: Stem cell therapy shows strong potential for periodontal regeneration, with outcomes that may potentially surpass those of conventional methods in selected cases. Further standardization, cost reduction, and long-term clinical trials are essential to confirm these findings and support their integration into daily dental practice.<\/jats:p>","DOI":"10.3390\/clinpract15120222","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T10:25:16Z","timestamp":1764239116000},"page":"222","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Effectiveness and Safety of Stem Cell-Based Tissue Engineering in the Regeneration of Periodontal Bone Lesions: A Systematic Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0912-7997","authenticated-orcid":false,"given":"Marouan","family":"Fanid","sequence":"first","affiliation":[{"name":"Faculty of Dental Medicine, University Institute of Health Sciences (IUCS), Cooperativa de Ensino Superior Polit\u00e9cnico e Universit\u00e1rio (CESPU), 4585-116 Gandra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1444-000X","authenticated-orcid":false,"given":"Ana Sofia","family":"Vinhas","sequence":"additional","affiliation":[{"name":"Department of Medicine and Oral Surgery, University Institute of Health Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal"},{"name":"Oral Pathology and Rehabilitation Research Unit (UNIPRO), University Institute of Health Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7342-067X","authenticated-orcid":false,"given":"C\u00e1tia","family":"Reis","sequence":"additional","affiliation":[{"name":"Department of Medicine and Oral Surgery, University Institute of Health Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal"},{"name":"Oral Pathology and Rehabilitation Research Unit (UNIPRO), University Institute of Health Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0713-2041","authenticated-orcid":false,"given":"Marta","family":"Relvas","sequence":"additional","affiliation":[{"name":"Department of Medicine and Oral Surgery, University Institute of Health Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal"},{"name":"Oral Pathology and Rehabilitation Research Unit (UNIPRO), University Institute of Health Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2462-4734","authenticated-orcid":false,"given":"Rosana","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Medicine and Oral Surgery, University Institute of Health Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal"},{"name":"Oral Pathology and Rehabilitation Research Unit (UNIPRO), University Institute of Health Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3108-9717","authenticated-orcid":false,"given":"Cristina","family":"Cabral","sequence":"additional","affiliation":[{"name":"Department of Medicine and Oral Surgery, University Institute of Health Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal"},{"name":"Oral Pathology and Rehabilitation Research Unit (UNIPRO), University Institute of Health Sciences (IUCS-CESPU), 4585-116 Gandra, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2146160","DOI":"10.1155\/2020\/2146160","article-title":"Global Prevalence of Periodontal Disease and Lack of Its Surveillance","volume":"2020","author":"Nazir","year":"2020","journal-title":"Sci. World J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1111\/idj.12630","article-title":"Current Concepts in the Management of Periodontitis","volume":"71","author":"Kwon","year":"2021","journal-title":"Int. Dent. J."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cassiano, L.S., Peres, M.A., Motta, J.V.S., Demarco, F.F., Horta, B.L., Ribeiro, C.C., and Nascimento, G.G. (2022). Periodontitis Is Associated with Consumption of Processed and Ultra-Processed Foods: Findings from a Population-Based Study. Nutrients, 14.","DOI":"10.3390\/nu14183735"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s12010-022-04127-9","article-title":"Periodontitis: An Oral Disease with Severe Consequences","volume":"195","author":"Ray","year":"2023","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/jre.12805","article-title":"Periodontal Disease and Quality of Life: Umbrella Review of Systematic Reviews","volume":"56","author":"Wong","year":"2021","journal-title":"J. Periodontal Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Borsa, L., Dubois, M., Sacco, G., and Lupi, L. (2021). Analysis the Link between Periodontal Diseases and Alzheimer\u2019s Disease: A Systematic Review. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph18179312"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.identj.2024.03.010","article-title":"Relationship Between Diabetes Mellitus and Periodontal\/Peri-Implant Disease: A Contemporaneous Review","volume":"74","author":"Enteghad","year":"2024","journal-title":"Int. Dent. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/prd.12430","article-title":"Interconnection of Periodontal Disease and Comorbidities: Evidence, Mechanisms, and Implications","volume":"89","author":"Hajishengallis","year":"2022","journal-title":"Periodontol. 2000"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"101498","DOI":"10.1016\/j.jebdp.2020.101498","article-title":"Periodontitis May Be Associated With Respiratory Diseases Such as Asthma, COPD, and Pneumonia","volume":"20","author":"Kelly","year":"2020","journal-title":"J. Evid. Based Dent. Pract."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1111\/jcpe.13189","article-title":"Periodontitis and Cardiovascular Diseases: Consensus Report","volume":"47","author":"Sanz","year":"2020","journal-title":"J. Clin. Periodontol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/odi.14062","article-title":"Association between Chronic Kidney Disease and Periodontitis. A Systematic Review and Metanalysis","volume":"29","author":"Serni","year":"2023","journal-title":"Oral. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/prd.12447","article-title":"Risk Factors for Periodontitis & Peri-Implantitis","volume":"90","author":"Darby","year":"2022","journal-title":"Periodontol. 2000"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1002\/cre2.360","article-title":"The Impact of Vaping on Periodontitis: A Systematic Review","volume":"7","author":"Figueredo","year":"2021","journal-title":"Clin. Exp. Dent. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Zhao, P., Xu, A., and Leung, W.K. (2022). Obesity, Bone Loss, and Periodontitis: The Interlink. Biomolecules, 12.","DOI":"10.3390\/biom12070865"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e7","DOI":"10.1017\/erm.2013.8","article-title":"Inflammatory Mediators in the Pathogenesis of Periodontitis","volume":"15","year":"2013","journal-title":"Expert. Rev. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S173","DOI":"10.1002\/JPER.17-0721","article-title":"Periodontitis: Consensus Report of Workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions","volume":"89","author":"Papapanou","year":"2018","journal-title":"J. Periodontol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Marian, D., Toro, G., D\u2019Amico, G., Trotta, M.C., D\u2019Amico, M., Petre, A., Lile, I., Hermenean, A., and Fratila, A. (2025). Challenges and Innovations in Alveolar Bone Regeneration: A Narrative Review on Materials, Techniques, Clinical Outcomes, and Future Directions. Medicina, 61.","DOI":"10.3390\/medicina61010020"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.jpor.2012.06.001","article-title":"Stem Cells in Dentistry\u2013Part I: Stem Cell Sources","volume":"56","author":"Egusa","year":"2012","journal-title":"J. Prosthodont. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1097\/01.NAJ.0000450430.97383.64","article-title":"JBI\u2019s Systematic Reviews: Study Selection and Critical Appraisal","volume":"114","author":"Porritt","year":"2014","journal-title":"Am. J. Nurs."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e20230442","DOI":"10.1590\/1678-7757-2023-0442","article-title":"Platelet Rich Fibrin Matrix (PRFM) and Peripheral Blood Mesenchymal Stem Cells (PBMSCs) in the Management of Intraosseous Defects\u2014A Randomized Clinical Trial","volume":"32","author":"Sreeparvathy","year":"2024","journal-title":"J. Appl. Oral Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s00784-024-05754-8","article-title":"Inflammatory and Bone Remodelling Related Biomarkers Following Periodontal Transplantation of the Tissue Engineered Biocomplex","volume":"28","author":"Apatzidou","year":"2024","journal-title":"Clin. Oral Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s10006-022-01045-2","article-title":"The Effect of Dental Pulp Stem Cells and L-PRF When Placed into the Extraction Sockets of Impacted Mandibular Third Molars on the Periodontal Status of Adjacent Second Molars: A Split-Mouth, Randomized, Controlled Clinical Trial","volume":"27","author":"Cubuk","year":"2023","journal-title":"Oral Maxillofac. Surg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"135","DOI":"10.4103\/ccd.ccd_183_22","article-title":"Clinical and Radiographic Evaluation of Locally Delivered Plant Stem Cells for Treatment of Periodontitis: Randomized Clinical Trial","volume":"14","author":"Elboraey","year":"2023","journal-title":"Contemp. Clin. Dent."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.reth.2022.09.008","article-title":"Study Protocol for Periodontal Tissue Regeneration with a Mixture of Autologous Adipose-Derived Stem Cells and Platelet Rich Plasma: A Multicenter, Randomized, Open-Label Clinical Trial","volume":"21","author":"Tobita","year":"2022","journal-title":"Regen. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1002\/term.3290","article-title":"A Comparative Evaluation of the Effect of Platelet Rich Fibrin Matrix with and without Peripheral Blood Mesenchymal Stem Cells on Dental Implant Stability: A Randomized Controlled Clinical Trial","volume":"16","author":"Singhal","year":"2022","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1111\/jcpe.13474","article-title":"A Tissue-Engineered Biocomplex for Periodontal Reconstruction. A Proof-of-Principle Randomized Clinical Study","volume":"48","author":"Apatzidou","year":"2021","journal-title":"J. Clin. Periodontol."},{"key":"ref_28","first-page":"8890873","article-title":"Dental Pulp Mesenchymal Stem Cells as a Treatment for Periodontal Disease in Older Adults","volume":"2020","year":"2020","journal-title":"Stem Cells Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1111\/jre.12728","article-title":"Regenerative Potential of Cultured Gingival Fibroblasts in Treatment of Periodontal Intrabony Defects (Randomized Clinical and Biochemical Trial)","volume":"55","author":"Ezzatt","year":"2020","journal-title":"J. Periodontal Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1111\/jcpe.13368","article-title":"Periodontal Regeneration Using a Xenogeneic Bone Substitute Seeded with Autologous Periodontal Ligament-Derived Mesenchymal Stem Cells: A 12-Month Quasi-Randomized Controlled Pilot Clinical Trial","volume":"47","author":"Fierravanti","year":"2020","journal-title":"J. Clin. Periodontol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.joen.2024.02.012","article-title":"Revolutionizing Endodontics: Innovative Approaches for Treating Mature Teeth With Closed Apices and Apical Lesions: A Report of Two Cases","volume":"50","author":"Brizuela","year":"2024","journal-title":"J. Endod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.joen.2023.10.015","article-title":"Pulp Regenerative Therapy Using Autologous Dental Pulp Stem Cells in a Mature Tooth with Apical Periodontitis: A Case Report","volume":"50","author":"Nakashima","year":"2024","journal-title":"J. Endod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.joen.2024.01.002","article-title":"Allogeneic Bone Marrow Mesenchymal Stromal Cell Transplantation Induces Dentin Pulp Complex-like Formation in Immature Teeth with Pulp Necrosis and Apical Periodontitis","volume":"50","author":"Cardier","year":"2024","journal-title":"J. Endod."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.joen.2022.03.002","article-title":"Dental Pulp Regeneration Induced by Allogenic Mesenchymal Stromal Cell Transplantation in a Mature Tooth: A Case Report","volume":"48","author":"Wittig","year":"2022","journal-title":"J. Endod."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1186\/s13287-021-02461-z","article-title":"Small Blood Stem Cells for Enhancing Early Osseointegration Formation on Dental Implants: A Human Phase I Safety Study","volume":"12","author":"Feng","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E236","DOI":"10.1097\/SCS.0000000000006147","article-title":"Reconstruction of Mandibular Defects With Bone Marrow-Derived Stem Cells in Odontogenic Myxoma","volume":"31","author":"Shin","year":"2020","journal-title":"J. Craniofacial Surg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1016\/j.joen.2020.04.007","article-title":"Allogeneic Cellular Therapy in a Mature Tooth with Apical Periodontitis and Accidental Root Perforation: A Case Report","volume":"46","author":"Cordero","year":"2020","journal-title":"J. Endod."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.22203\/eCM.v027a01","article-title":"VEGF and BMP-2 Promote Bone Regeneration by Facilitating Bone Marrow Stem Cell Homing and Differentiation","volume":"27","author":"Zhang","year":"2014","journal-title":"Eur. Cell Mater."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/j.job.2022.08.004","article-title":"The Hypoxia-Dependent Angiogenic Process in Dental Pulp","volume":"64","author":"Cardier","year":"2022","journal-title":"J. Oral Biosci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zhuo, H., Chen, Y., and Zhao, G. (2024). Advances in Application of Hypoxia-Preconditioned Mesenchymal Stem Cell-Derived Exosomes. Front. Cell Dev. Biol., 12.","DOI":"10.3389\/fcell.2024.1446050"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.pharma.2025.01.013","article-title":"Impact of Advanced Therapy Medicinal Products Status in European Regulations on Their Production Cost: The Case of Hematopoietic Stem Cells","volume":"83","author":"Cousin","year":"2025","journal-title":"Ann. Pharm. Fr."}],"container-title":["Clinics and Practice"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2039-7283\/15\/12\/222\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T09:11:20Z","timestamp":1778145080000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2039-7283\/15\/12\/222"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,26]]},"references-count":41,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["clinpract15120222"],"URL":"https:\/\/doi.org\/10.3390\/clinpract15120222","relation":{},"ISSN":["2039-7283"],"issn-type":[{"value":"2039-7283","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,26]]}}}