{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T11:07:06Z","timestamp":1789384026805,"version":"build-2803163510"},"reference-count":34,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Pers. Med.","JPM"],"abstract":"<jats:p>Background\/Objectives: Periodontitis is a chronic inflammatory disease characterized by progressive destruction of the periodontal supporting tissues. Regenerative responses may vary according to patient-related biological characteristics, periodontal defect morphology, the local inflammatory microenvironment, cellular source, biomaterial selection, and delivery strategy. Cell-based regenerative therapies may therefore provide a biological foundation for the future development of personalized periodontal regenerative approaches. This systematic review and meta-analysis evaluated the effectiveness of cell-based therapies for periodontal regeneration and considered how the current evidence may inform future personalized regenerative strategies. Methods: A comprehensive electronic search was conducted in MEDLINE via PubMed, Web of Science, Embase, and the Cochrane Library, with additional searches performed in SciELO and Latindex, in accordance with PRISMA guidelines. Randomized and quasi-randomized controlled clinical trials evaluating cell-based regenerative therapies for periodontal defects were included. The primary outcomes were clinical attachment level (CAL) gain and probing depth (PD) reduction, while radiographic bone regeneration was considered a secondary outcome. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using random-effects models. Leave-one-out sensitivity analyses were performed to assess the stability of the pooled estimates. Results: Six clinical trials were included in the qualitative synthesis, and five contributed to the quantitative analysis. Cell-based regenerative therapies showed a small, non-significant effect for CAL gain (SMD = 0.17; 95% CI: \u22120.12 to 0.45; I2 = 0%) and PD reduction (SMD = 0.13; 95% CI: \u22120.22 to 0.48; I2 = 33.0%). Radiographic bone regeneration showed a larger favorable effect, although statistical significance was not reached and substantial heterogeneity was present (SMD = 1.25; 95% CI: \u22120.08 to 2.58; I2 = 88.2%). Leave-one-out analyses did not materially alter the non-significant interpretation for CAL or PD, although some variation in effect magnitude and direction was observed. Radiographic bone regeneration was more sensitive to the exclusion of individual studies. Overall, superiority of cell-based regenerative therapies over control interventions was not demonstrated. Risk-of-bias assessment indicated a low overall risk for most randomized trials, with some concerns in one trial and moderate risk in the quasi-randomized study. Conclusions: Cell-based regenerative therapies showed preliminary but inconclusive signals of benefit for periodontal regeneration. However, no statistically significant superiority over control interventions was demonstrated for CAL gain, PD reduction, or radiographic bone regeneration. Further well-designed clinical trials are required before these approaches can be considered for routine or personalized periodontal regenerative strategies.<\/jats:p>","DOI":"10.3390\/jpm16090469","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:19:41Z","timestamp":1789381181000},"page":"469","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell-Based Therapies for Periodontal Regeneration: A Systematic Review and Meta-Analysis with Future Implications for Personalized Medicine"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3648-0827","authenticated-orcid":false,"given":"Rafael X.","family":"Erazo Vaca","sequence":"first","affiliation":[{"name":"College of Dentistry, University of Guayaquil, Guayaquil 090101, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6724-3216","authenticated-orcid":false,"given":"Gabriela G.","family":"Zambrano Manzaba","sequence":"additional","affiliation":[{"name":"School of Dentistry, Universidad Cat\u00f3lica de Santiago de Guayaquil (UCSG), Guayaquil 090101, Ecuador"},{"name":"Facultad de Ciencias de la Salud, Universidad Cat\u00f3lica de Santiago de Guayaquil (UCSG)\u2013SOADCO, Guayaquil 090615, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8713-951X","authenticated-orcid":false,"given":"Luis-Chauca","family":"Baja\u00f1a","sequence":"additional","affiliation":[{"name":"College of Dentistry, University of Guayaquil, Guayaquil 090101, Ecuador"},{"name":"School of Dentistry, Universidad Cat\u00f3lica de Santiago de Guayaquil (UCSG), Guayaquil 090101, Ecuador"},{"name":"College of Dentistry, Universidad Bolivariana del Ecuador, Dur\u00e1n 092406, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6559-4597","authenticated-orcid":false,"given":"Andrea-Ordo\u00f1ez","family":"Balladares","sequence":"additional","affiliation":[{"name":"College of Dentistry, University of Guayaquil, Guayaquil 090101, Ecuador"},{"name":"College of Dentistry, Universidad Bolivariana del Ecuador, Dur\u00e1n 092406, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres-Villao","family":"Leon","sequence":"additional","affiliation":[{"name":"College of Dentistry, University of Guayaquil, Guayaquil 090101, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3724-7339","authenticated-orcid":false,"given":"Nayely J.","family":"Teran Sanchez","sequence":"additional","affiliation":[{"name":"College of Dentistry, University of Guayaquil, Guayaquil 090101, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gema N.","family":"Mendoza Manzaba","sequence":"additional","affiliation":[{"name":"School of Medicine, Faculty of Medical Sciences, Catholic University of Santiago de Guayaquil, Guayaquil 090615, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rito A.","family":"Salazar Rom\u00e1n","sequence":"additional","affiliation":[{"name":"School of Medicine, Faculty of Medical Sciences, Catholic University of Santiago de Guayaquil, Guayaquil 090615, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5644-3775","authenticated-orcid":false,"given":"Jorge L.","family":"Teran Sanchez","sequence":"additional","affiliation":[{"name":"Unidad de Ciencias B\u00e1sicas, Escuela Superior Polit\u00e9cnica Agropecuaria de Manab\u00ed Manuel F\u00e9lix L\u00f3pez, Calceta 130601, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1603-122X","authenticated-orcid":false,"given":"David A.","family":"Flor Ronquillo","sequence":"additional","affiliation":[{"name":"College of Dentistry, University of Guayaquil, Guayaquil 090101, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byron-Velasquez","family":"Ron","sequence":"additional","affiliation":[{"name":"Carrera de Odontolog\u00eda, Department Prosthesis Research, Universidad de Las Am\u00e9ricas (UDLA), Quito 170102, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/S0140-6736(05)67728-8","article-title":"Periodontal diseases","volume":"366","author":"Pihlstrom","year":"2005","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17038","DOI":"10.1038\/nrdp.2017.38","article-title":"Periodontal diseases","volume":"3","author":"Kinane","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1111\/prd.12048","article-title":"Clinical concepts for regenerative therapy in intrabony defects","volume":"68","author":"Cortellini","year":"2015","journal-title":"Periodontol. 2000"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1016\/j.stem.2021.09.006","article-title":"Mesenchymal stromal cells: Putative microenvironmental modulators become cell therapy","volume":"28","author":"Krampera","year":"2021","journal-title":"Cell Stem Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s10266-022-00725-5","article-title":"Regeneration of periodontal bone defects with mesenchymal stem cells in animal models. Systematic review and meta-analysis","volume":"111","year":"2023","journal-title":"Odontology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.reth.2018.07.002","article-title":"Periodontal regeneration with autologous periodontal ligament-derived cell sheets\u2014A safety and efficacy study in ten patients","volume":"9","author":"Iwata","year":"2018","journal-title":"Regen. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Onizuka, S., and Iwata, T. (2019). Application of Periodontal Ligament-Derived Multipotent Mesenchymal Stromal Cell Sheets for Periodontal Regeneration. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112796"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1126\/science.284.5411.143","article-title":"Multilineage potential of adult human mesenchymal stem cells","volume":"284","author":"Pittenger","year":"1999","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0140-6736(04)16627-0","article-title":"Investigation of multipotent postnatal stem cells from human periodontal ligament","volume":"364","author":"Seo","year":"2004","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13625","DOI":"10.1073\/pnas.240309797","article-title":"Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo","volume":"97","author":"Gronthos","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7154327","DOI":"10.1155\/2016\/7154327","article-title":"Gingival Mesenchymal Stem\/Progenitor Cells: A Unique Tissue Engineering Gem","volume":"2016","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1177\/154405910508401007","article-title":"Recovery of stem cells from cryopreserved periodontal ligament","volume":"84","author":"Seo","year":"2005","journal-title":"J. Dent. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41368-019-0060-3","article-title":"Stem cell-based bone and dental regeneration: A view of microenvironmental modulation","volume":"11","author":"Zheng","year":"2019","journal-title":"Int. J. Oral Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1089\/ten.tea.2007.0189","article-title":"Injectable tissue-engineered bone using autogenous bone marrow-derived stromal cells for maxillary sinus augmentation: Clinical application report from a 2-6-year follow-up","volume":"14","author":"Yamada","year":"2008","journal-title":"Tissue Eng. Part A"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1038\/sj.cdd.4402121","article-title":"Human postnatal dental pulp cells co-differentiate into osteoblasts and endotheliocytes: A pivotal synergy leading to adult bone tissue formation","volume":"14","author":"Graziano","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nri3785","article-title":"Periodontitis: From microbial immune subversion to systemic inflammation","volume":"15","author":"Hajishengallis","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41581-018-0023-5","article-title":"Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases","volume":"14","author":"Shi","year":"2018","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3323","DOI":"10.1007\/s00018-019-03125-1","article-title":"Biological functions of mesenchymal stem cells and clinical implications","volume":"76","author":"Naji","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1186\/s13287-017-0716-x","article-title":"Tissue source determines the differentiation potentials of mesenchymal stem cells: A comparative study of human mesenchymal stem cells from bone marrow and adipose tissue","volume":"8","author":"Xu","year":"2017","journal-title":"Stem Cell Res. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/j.1600-051X.2008.01263.x","article-title":"Regeneration of periodontal tissues: Combinations of barrier membranes and grafting materials\u2014Biological foundation and preclinical evidence: A systematic review","volume":"35","author":"Sculean","year":"2008","journal-title":"J. Clin. Periodontol."},{"key":"ref_21","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_22","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/s41392-025-02320-w","article-title":"Impact of allogeneic dental pulp stem cell injection on tissue regeneration in periodontitis: A multicenter randomized clinical trial","volume":"10","author":"Liu","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1111\/jcpe.12931","article-title":"Human intrabony defect regeneration with micrografts containing dental pulp stem cells: A randomized controlled clinical trial","volume":"45","author":"Ferrarotti","year":"2018","journal-title":"J. Clin. Periodontol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s13287-016-0288-1","article-title":"Treatment of periodontal intrabony defects using autologous periodontal ligament stem cells: A randomized clinical trial","volume":"7","author":"Chen","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_26","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_27","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_28","doi-asserted-by":"crossref","unstructured":"Higgins, J.P.T., Savovi\u0107, J., Page, M., Elbers, R., and Sterne, J.A.C. (2019). Assessing risk of bias in a randomized trial. Cochrane Handbook for Systematic Reviews of Interventions [Internet], Wiley-Blackwell. Available online: https:\/\/research.monash.edu\/en\/publications\/assessing-risk-of-bias-in-a-randomized-trial\/.","DOI":"10.1002\/9781119536604.ch8"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Sun, L., Du, X., Kuang, H., Sun, H., Luo, W., and Yang, C. (2023). Stem cell-based therapy in periodontal regeneration: A systematic review and meta-analysis of clinical studies. BMC Oral Health, 23.","DOI":"10.1186\/s12903-023-03186-6"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jdsr.2024.01.001","article-title":"Application of mesenchymal stem\/stromal cells in periodontal regeneration: Opportunities and challenges","volume":"60","author":"Gao","year":"2024","journal-title":"Jpn. Dent. Sci. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wetterslev, J., Jakobsen, J.C., and Gluud, C. (2017). Trial Sequential Analysis in systematic reviews with meta-analysis. BMC Med. Res. Methodol., 17.","DOI":"10.1186\/s12874-017-0315-7"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/prd.12086","article-title":"Biomaterials for promoting periodontal regeneration in human intrabony defects: A systematic review","volume":"68","author":"Sculean","year":"2015","journal-title":"Periodontol. 2000"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.stem.2018.05.004","article-title":"Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities","volume":"22","author":"Galipeau","year":"2018","journal-title":"Cell Stem Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/16\/9\/469\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:42:29Z","timestamp":1789382549000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/16\/9\/469"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,13]]},"references-count":34,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["jpm16090469"],"URL":"https:\/\/doi.org\/10.3390\/jpm16090469","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,13]]}}}