{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:11:07Z","timestamp":1789495867667,"version":"build-2803163510"},"reference-count":41,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T00:00:00Z","timestamp":1636502400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Although bone tissue engineering for dentistry has been studied for many years, the clinical outcome for severe cases has not been established. Furthermore, there are limited numbers of studies that include long-term follow-up. In this study, the safety and efficacy of bone tissue engineering for patients with a severely atrophic alveolar bone were examined using autogenous bone marrow stromal cells (BMSCs), and the long-term stability was also evaluated. Methods: BMSCs from iliac bone marrow aspirate were cultured and expanded. Then, induced osteogenic cells were transplanted with autogenous platelet-rich plasma (PRP) and \u03b2-tricalcium phosphate granules (\u03b2-TCP) for maxillary sinus floor and alveolar ridge augmentation. Eight patients (two males and six females) with an average age of 54.2 years underwent cell transplantation. Safety was assessed by monitoring adverse events. Radiographic evaluation and bone biopsies were performed to evaluate the regenerated bone. Results: The major population of transplanted BMSCs belonged to the fraction of CD34\u2212, CD45dim, and CD73+ cells, which was only 0.065% of the total bone marrow cells. Significant deviations were observed in cell growth and alkaline phosphatase activities among individuals. However, bone regeneration was observed in all patients and the average bone area in the biopsy samples was 41.9% 6 months following transplantation, although there were also significant deviations among each case. No adverse events related to the transplants were observed. In the regenerated bone, 27 out of 29 dental implants were integrated. Dental implants and regenerated bone were stable for an average follow-up period of 7 years and 10 months. Conclusions: Although individual variations were observed, the results showed that bone tissue engineering using BMSCs with PRP and \u03b2-TCP was feasible for patients with severe atrophic maxilla throughout a long-term follow-up period and was considered safe. However, further studies with a larger number of cases and controls to confirm the efficacy of BMSCs and the development of a protocol to establish a reproducible quality of stem cell-based graft material will be required.<\/jats:p>","DOI":"10.3390\/jcm10225231","type":"journal-article","created":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T09:19:21Z","timestamp":1636535961000},"page":"5231","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Clinical Outcome and 8-Year Follow-Up of Alveolar Bone Tissue Engineering for Severely Atrophic Alveolar Bone Using Autologous Bone Marrow Stromal Cells with Platelet-Rich Plasma and \u03b2-Tricalcium Phosphate Granules"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9448-2001","authenticated-orcid":false,"given":"Izumi","family":"Asahina","sequence":"first","affiliation":[{"name":"Division of Stem Cell Engineering, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"},{"name":"Department of Regenerative Oral Surgery, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2285-2602","authenticated-orcid":false,"given":"Hideaki","family":"Kagami","sequence":"additional","affiliation":[{"name":"Division of Stem Cell Engineering, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"},{"name":"Tissue Engineering Research Group, Division of Molecular Therapy, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"},{"name":"Department of Oral and Maxillofacial Surgery, Matsumoto Dental University, Shiojiri 399-0781, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Agata","sequence":"additional","affiliation":[{"name":"Division of Stem Cell Engineering, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"},{"name":"Department of Regenerative Oral Surgery, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki J.","family":"Honda","sequence":"additional","affiliation":[{"name":"Division of Stem Cell Engineering, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"},{"name":"Department of Oral Anatomy, Aichi-Gakuin University School of Dentistry, Nagoya 464-0821, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1247-9763","authenticated-orcid":false,"given":"Yoshinori","family":"Sumita","sequence":"additional","affiliation":[{"name":"Division of Stem Cell Engineering, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"},{"name":"Department of Regenerative Oral Surgery, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Inoue","sequence":"additional","affiliation":[{"name":"Tissue Engineering Research Group, Division of Molecular Therapy, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"},{"name":"Department of Oral and Maxillofacial Surgery, Matsumoto Dental University, Shiojiri 399-0781, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tokiko","family":"Nagamura-Inoue","sequence":"additional","affiliation":[{"name":"Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arinobu","family":"Tojo","sequence":"additional","affiliation":[{"name":"Tissue Engineering Research Group, Division of Molecular Therapy, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.jpor.2017.08.010","article-title":"Current bone substitutes for implant dentistry","volume":"62","author":"Yamada","year":"2018","journal-title":"J. Prosthodont. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.biomaterials.2018.07.017","article-title":"Bone regeneration strategies: Engineered scaffolds, bioactive molecules and stem cells current stage and future perspectives","volume":"180","author":"Bolander","year":"2018","journal-title":"Biomaterials"},{"key":"ref_3","first-page":"124","article-title":"A feasibility study evaluating rhBMP-2\/absorbable collagen sponge device for local alveolar ridge preservation or augmentation","volume":"17","author":"Howell","year":"1997","journal-title":"Int. J. Periodontics Restor. Dent."},{"key":"ref_4","first-page":"109","article-title":"Three-dimensional ridge augmentation with xenograft and recombinant human platelet-derived growth factor-BB in humans: Report of two cases","volume":"27","author":"Simion","year":"2007","journal-title":"Int. J. Periodontics Restor. Dent."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1097\/SCS.0b013e3181843312","article-title":"Bone morphogenetic protein 2 therapy for craniofacial surgery","volume":"19","author":"Smith","year":"2008","journal-title":"J. Craniofac. Surg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1016\/j.joms.2009.07.085","article-title":"Reconstruction of mandibular continuity defects using recombinant human bone morphogenetic protein 2: A note of caution in an atmosphere of exuberance","volume":"67","author":"Bell","year":"2009","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/ten.teb.2015.0357","article-title":"A Review of the Clinical Side Effects of Bone Morphogenetic Protein-2","volume":"22","author":"James","year":"2016","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"343","DOI":"10.3727\/000000004783983909","article-title":"Translational research for injectable tissue-engineered bone regeneration using mesenchymal stem cells and platelet-rich plasma: From basic research to clinical case study","volume":"13","author":"Yamada","year":"2004","journal-title":"Cell Transplant."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.1016\/j.biomaterials.2008.03.012","article-title":"Cell based bone tissue engineering in jaw defects","volume":"29","author":"Meijer","year":"2008","journal-title":"Biomaterials"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.joms.2004.01.009","article-title":"Tissue-engineered bone for maxillary sinus augmentation","volume":"67","author":"Schimming","year":"2004","journal-title":"J. Oral Maxillofac. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2649","DOI":"10.1089\/ten.2006.12.2649","article-title":"Two techniques for the preparation of cell-scaffold constructs suitable for sinus augmentation: Steps into clinical application","volume":"12","author":"Springer","year":"2006","journal-title":"Tissue Eng."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.ijom.2009.01.001","article-title":"Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells","volume":"38","author":"Lindroos","year":"2009","journal-title":"Int. J. Oral Maxillofac. Surg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"530","DOI":"10.5966\/sctm.2013-0173","article-title":"Adipose stem cells used to reconstruct 13 cases with cranio-maxillofacial hard-tissue defects","volume":"3","author":"Numminen","year":"2014","journal-title":"Stem. Cells Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Amable, P.R., Teixeira, M.V., Carias, R.B., Granjeiro, J.M., and Borojevic, R. (2014). Mesenchymal stromal cell proliferation, gene expression and protein production in human platelet-rich plasma-supplemented media. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104662"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/j.bone.2004.07.014","article-title":"Periosteum: Biology, regulation, and response to osteoporosis therapies","volume":"35","author":"Allen","year":"2004","journal-title":"Bone"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.biocel.2010.12.006","article-title":"Bone marrow stromal cells (bone marrow-derived multipotent mesenchymal stromal cells) for alveolar bone tissue engineering: Basic science to clinical translation","volume":"43","author":"Kagami","year":"2011","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Arthur, A., and Gronthos, S. (2020). Clinical Application of Bone Marrow Mesenchymal Stem\/Stromal Cells to Repair Skeletal Tissue. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249759"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"100009","DOI":"10.1016\/j.mtbio.2019.100009","article-title":"Biomaterial-based endochondral bone regeneration: A shift from traditional tissue engineering paradigms to developmentally inspired strategies","volume":"3","author":"Sheehy","year":"2019","journal-title":"Mater. Today Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.2174\/138920112800624472","article-title":"Current knowledge and perspectives for the use of platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) in oral and maxillofacial surgery part 2: Bone graft, implant and reconstructive surgery","volume":"13","author":"Simonpieri","year":"2012","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.jobcr.2020.06.007","article-title":"Efficacy of autologous stem cells for bone regeneration during endosseous dental implants insertion-A systematic review of human studies","volume":"10","author":"Varshney","year":"2020","journal-title":"J. Oral Biol. Craniofac. Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Egido-Moreno, S., Valls-Roca-Umbert, J., C\u00e9spedes-S\u00e1nchez, J.M., L\u00f3pez-L\u00f3pez, J., and Velasco-Ortega, E. (2021). Clinical Efficacy of Mesenchymal Stem Cells in Bone Regeneration in Oral Implantology. Systematic Review and Meta-Analysis. Int. J. Env. Res. Public Health, 18.","DOI":"10.3390\/ijerph18030894"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1089\/ten.teb.2013.0578","article-title":"The use of bone marrow stromal cells (bone marrow-derived multipotent mesenchymal stromal cells) for alveolar bone tissue engineering: Basic science to clinical translation","volume":"20","author":"Kagami","year":"2014","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1177\/154405910708600113","article-title":"Effective bone engineering using periosteum-derived cells","volume":"86","author":"Agata","year":"2007","journal-title":"J. Dent. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/0923-2508(93)90057-9","article-title":"Detection and tentative identification of dominant mycoplasma species in cell cultured by restriction analysis of the 16S\u201323S, rNFA intergenic spacer regions","volume":"144","author":"Harasawa","year":"1993","journal-title":"Res. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1708-8208.2003.tb00198.x","article-title":"Donor site morbidity in two different approaches to anterior iliac crest bone harvesting","volume":"5","author":"Cricchio","year":"2003","journal-title":"Clin. Implant. Dent. Relat. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1056\/NEJM200102013440516","article-title":"Repair of large bone defects with the use of autologous bone marrow stromal cells","volume":"344","author":"Quatro","year":"2001","journal-title":"N. Eng. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1089\/ten.2006.0271","article-title":"Stem cells associated with macroporous bioceramics for long bone repair: 6- to 7-year outcome of a pilot clinical study","volume":"13","author":"Marcacci","year":"2007","journal-title":"Tissue Eng."},{"key":"ref_28","first-page":"635","article-title":"Clinical and histologic evaluation of implant integration in the posterior maxilla after sinus floor augmentation with autogenous bone, bovine hydroxyapatite, or a 20:80 mixture","volume":"17","author":"Hallman","year":"2002","journal-title":"Int. J. Oral Maxillofac. Implant."},{"key":"ref_29","first-page":"351","article-title":"The use of intraorally harvested autogenous block grafts for vertical alveolar ridge augmentation: A human study","volume":"25","author":"Proussaefs","year":"2005","journal-title":"Int. J. Periodontics Restor. Dent."},{"key":"ref_30","first-page":"371","article-title":"Prospective multicenter randomized clinical trial of autogenous bone versus beta-tricalcium phosphate graft alone for bilateral sinus elevation: Histologic and histomorphometric evaluation","volume":"20","author":"Huys","year":"2005","journal-title":"Int. J. Oral Maxillofac. Implant."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1111\/j.1600-0501.2009.01765.x","article-title":"Vertical ridge augmentation of the atrophic posterior mandible with interpositional bloc grafts: Bone from the iliac crest vs. bovine anorganic bone. Clinical and histological results up to one year after loading from a randomized-controlled clinical trial","volume":"20","author":"Felice","year":"2009","journal-title":"Clin. Oral Implant. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1111\/j.1708-8208.2005.tb00063.x","article-title":"Histomorphometric evaluation of human sinus floor augmentation healing responses to placement of calcium phosphate or Ricinus communis polymer associated with autogenous bone","volume":"7","author":"Gabrielli","year":"2005","journal-title":"Clin. Implant. Dent. Relat. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1111\/j.1600-0501.2009.01697.x","article-title":"Long-term changes in graft height after maxillary sinus floor elevation with different grafting materials: Radiographic evaluation with a minimum follow-up of 4.5 years","volume":"20","author":"Zijderveld","year":"2009","journal-title":"Clin. Oral Implant. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1111\/j.1600-0501.2006.01295.x","article-title":"Bone formation after sinus augmentation with engineered bone","volume":"18","author":"Zizelmann","year":"2007","journal-title":"Clin. Oral Implant. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1089\/ten.tea.2009.0500","article-title":"Characteristic change and loss of in vivo osteogenic abilities of human bone marrow stromal cells during passage","volume":"16","author":"Agata","year":"2010","journal-title":"Tissue Eng. Part A"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1080\/14653240500319234","article-title":"International Society for Cellular Therapy. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement","volume":"7","author":"Horwitz","year":"2005","journal-title":"Cytotherapy"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1002\/jbmr.2464","article-title":"Bone Engineering of Maxillary Sinus Bone Deficiencies Using Enriched CD90+ Stem Cell Therapy: A Randomized Clinical Trial","volume":"30","author":"Kaigler","year":"2015","journal-title":"J. Bone Miner. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/j.1600-0501.2010.01981.x","article-title":"Maxillary sinus floor elevation with bovine bone mineral combined with either autogenous bone or autogenous stem cells: A prospective randomized clinical trial","volume":"22","author":"Rickert","year":"2011","journal-title":"Clin. Oral Implant. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/s13287-018-0951-9","article-title":"Cell therapy induced regeneration of severely atrophied mandibular bone in a clinical trial","volume":"9","author":"Gjerde","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"767","DOI":"10.3727\/096368912X652968","article-title":"Stem cell therapy for craniofacial bone regeneration: A randomized, controlled feasibility trial","volume":"22","author":"Kaigler","year":"2013","journal-title":"Cell Transplant."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1111\/cid.12506","article-title":"Stem cell therapy for reconstruction of alveolar cleft and trauma defects in adults: A randomized controlled, clinical trial","volume":"19","author":"Bajestan","year":"2017","journal-title":"Clin. Implant. Dent. Relat. Res."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/22\/5231\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:27:59Z","timestamp":1760167679000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/22\/5231"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,10]]},"references-count":41,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["jcm10225231"],"URL":"https:\/\/doi.org\/10.3390\/jcm10225231","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,10]]}}}