{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:39:50Z","timestamp":1753889990396,"version":"3.41.2"},"reference-count":40,"publisher":"IMR Press","issue":"6","license":[{"start":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T00:00:00Z","timestamp":1687824000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Facial reconstruction represents one of the main challenges for surgeons. Stem cells (SC) represent the most studied solution for tissue regeneration. This approach appears particularly promising in combination with bioengineered scaffolds and 3D bioprinting. The purpose of this systematic review is to define the main domains of current application of SC therapy within contemporary clinical workflows, evaluate indications and limitations, report current knowledge in this innovative field of research, and define the landscape of evidence for such approaches. Methods: A systematic review was performed on the pertinent literature regarding stem cell-based cell therapies currently available in the reconstruction of the face. The review used the main databases for scientific literature based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: A total of 15 papers were selected after an independent search was performed. The two major domains for current application of stem cells in clinical practice were bone and skin categories. Conclusions: Cell therapy in the field of facial reconstruction represents a promising approach. The evidence regarding the current clinical use, however, seems to show this option to be limited. Bioengineering advances and the parallel development of 3D bioprinting technology can potentially enhance the role of stem cells in the future.<\/jats:p>","DOI":"10.31083\/j.fbl2806123","type":"journal-article","created":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T01:24:58Z","timestamp":1687915498000},"source":"Crossref","is-referenced-by-count":2,"title":["Stem Cells in Facial Regenerative Surgery: Current Clinical Applications. A Multidisciplinary, Systematic Review"],"prefix":"10.31083","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8395-5272","authenticated-orcid":true,"given":"Alessandro","family":"Tel","sequence":"first","affiliation":[{"name":"Clinic of Maxillofacial Surgery, Head-Neck and NeuroScience Department University Hospital of Udine, 33100 Udine, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3185-7595","authenticated-orcid":true,"given":"Giovanni","family":"Miotti","sequence":"first","affiliation":[{"name":"Department of Plastic Surgery, University Hospital of Udine, 33100 Udine, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3741-0639","authenticated-orcid":true,"given":"Tamara","family":"Ius","sequence":"first","affiliation":[{"name":"Neurosurgery Unit, Head-Neck and NeuroScience Department University Hospital of Udine, 33100 Udine, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3408-0841","authenticated-orcid":true,"given":"Luca de","family":"Marco","sequence":"first","affiliation":[{"name":"Department of Plastic Surgery, University Hospital of Udine, 33100 Udine, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2178-5022","authenticated-orcid":true,"given":"Massimo","family":"Robiony","sequence":"first","affiliation":[{"name":"Clinic of Maxillofacial Surgery, Head-Neck and NeuroScience Department University Hospital of Udine, 33100 Udine, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4677-8198","authenticated-orcid":true,"given":"Pier Camillo","family":"Parodi","sequence":"first","affiliation":[{"name":"Department of Plastic Surgery, University Hospital of Udine, 33100 Udine, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9891-936X","authenticated-orcid":true,"given":"Pier Paolo","family":"Panciani","sequence":"first","affiliation":[{"name":"Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0999-5545","authenticated-orcid":true,"given":"Marco","family":"Zeppieri","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"16242","published-online":{"date-parts":[[2023,6,27]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Carroll SH, Ravid K. Differentiation of mesenchymal stem cells to osteoblasts and chondrocytes: a focus on adenosine receptors. Expert Reviews in Molecular Medicine. 2013; 15: e1.","DOI":"10.1017\/erm.2013.2"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"Pittenger MF, Discher DE, P\u00e9ault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regenerative Medicine. 2019; 4: 22.","DOI":"10.1038\/s41536-019-0083-6"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Miotti G, Parodi PC, Zeppieri M. Stem cell therapy in ocular pathologies in the past 20 years. World Journal of Stem Cells. 2021; 13: 366\u2013385.","DOI":"10.4252\/wjsc.v13.i5.366"},{"key":"ref4","doi-asserted-by":"crossref","unstructured":"Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Engineering. 2001; 7: 211\u2013228.","DOI":"10.1089\/107632701300062859"},{"key":"ref5","doi-asserted-by":"crossref","unstructured":"Xu Y, Guo S, Wei C, Li H, Chen L, Yin C, et al. The Comparison of Adipose Stem Cell and Placental Stem Cell in Secretion Characteristics and in Facial Antiaging. Stem Cells International. 2016; 2016: 7315830.","DOI":"10.1155\/2016\/7315830"},{"key":"ref6","doi-asserted-by":"crossref","unstructured":"Charles-de-S\u00e1 L, Gontijo-de-Amorim NF, Rigotti G, Sbarbati A, Bernardi P, Benati D, et al. Photoaged Skin Therapy with Adipose-Derived Stem Cells. Plastic and Reconstructive Surgery. 2020; 145: 1037e\u20131049e.","DOI":"10.1097\/PRS.0000000000006867"},{"key":"ref7","doi-asserted-by":"crossref","unstructured":"Vats A, Bielby RC, Tolley NS, Nerem R, Polak JM. Stem cells. Lancet. 2005; 366: 592\u2013602.","DOI":"10.1016\/S0140-6736(05)66879-1"},{"key":"ref8","doi-asserted-by":"crossref","unstructured":"Zhang Y, Liu T. Adipose-derived stem cells exosome and its potential applications in autologous fat grafting. Journal of Plastic, Reconstructive & Aesthetic Surgery. 2023; 76: 219\u2013229.","DOI":"10.1016\/j.bjps.2022.10.050"},{"key":"ref9","doi-asserted-by":"crossref","unstructured":"Yi Y, Hu W, Zhao C, Wu M, Zeng H, Xiong M, et al. Deciphering the Emerging Roles of Adipocytes and Adipose-Derived Stem Cells in Fat Transplantation. Cell Transplantation. 2021; 30: 963689721997799.","DOI":"10.1177\/0963689721997799"},{"key":"ref10","doi-asserted-by":"crossref","unstructured":"Hoseini SJ, Ghazavi H, Forouzanfar F, Mashkani B, Ghorbani A, Mahdipour E, et al. Fibroblast Growth Factor 1-Transfected Adipose-Derived Mesenchymal Stem Cells Promote Angiogenic Proliferation. DNA and Cell Biology. 2017; 36: 401\u2013412.","DOI":"10.1089\/dna.2016.3546"},{"key":"ref11","doi-asserted-by":"crossref","unstructured":"Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008; 2: 141\u2013150.","DOI":"10.1016\/j.stem.2007.11.014"},{"key":"ref12","doi-asserted-by":"crossref","unstructured":"Svolacchia L, Prisco C, Giuzio F, Svolacchia F. Adipose Autologous Micrograft and Its Derived Mesenchymal Stem Cells in a Bio Cross-Linked Hyaluronic Acid Scaffold for Correction Deep Wrinkles, Facial Depressions, Scars, Face Dermis and Its Regenerations: A Pilot Study and Cases Report. Medicina. 2022; 58: 1692.","DOI":"10.3390\/medicina58111692"},{"key":"ref13","doi-asserted-by":"crossref","unstructured":"Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions. 2nd edn. Wiley-Blackwell: Hoboken, NJ, USA. 2019.","DOI":"10.1002\/9781119536604"},{"key":"ref14","unstructured":"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. British Medical Journal. 2021; 372: n71."},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Methley AM, Campbell S, Chew-Graham C, McNally R, Cheraghi-Sohi S. PICO, PICOS and SPIDER: a comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Services Research. 2014; 14: 579.","DOI":"10.1186\/s12913-014-0579-0"},{"key":"ref16","doi-asserted-by":"crossref","unstructured":"Bock C, Kiskinis E, Verstappen G, Gu H, Boulting G, Smith ZD, et al. Reference Maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell. 2011; 144: 439\u2013452.","DOI":"10.1016\/j.cell.2010.12.032"},{"key":"ref17","doi-asserted-by":"crossref","unstructured":"Ullah I, Subbarao RB, Rho GJ. Human mesenchymal stem cells - current trends and future prospective. Bioscience Reports. 2015; 35: e00191.","DOI":"10.1042\/BSR20150025"},{"key":"ref18","doi-asserted-by":"crossref","unstructured":"Trounson A, McDonald C. Stem Cell Therapies in Clinical Trials: Progress and Challenges. Cell Stem Cell. 2015; 17: 11\u201322.","DOI":"10.1016\/j.stem.2015.06.007"},{"key":"ref19","doi-asserted-by":"crossref","unstructured":"Shih PY, Chen HH, Chen CH, Hong HS, Yang CH. Rapid recurrence of keloid after pulse dye laser treatment. Dermatologic Surgery. 2008; 34: 1124\u20131127.","DOI":"10.1111\/j.1524-4725.2008.34225.x"},{"key":"ref20","doi-asserted-by":"crossref","unstructured":"Cao Y, Sun Z, Liao L, Meng Y, Han Q, Zhao RC. Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochemical and Biophysical Research Communications. 2005; 332: 370\u2013379.","DOI":"10.1016\/j.bbrc.2005.04.135"},{"key":"ref21","doi-asserted-by":"crossref","unstructured":"Ya\u00f1ez R, Lamana ML, Garc\u00eda-Castro J, Colmenero I, Ram\u00edrez M, Bueren JA. Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells. 2006; 24: 2582\u20132591.","DOI":"10.1634\/stemcells.2006-0228"},{"key":"ref22","doi-asserted-by":"crossref","unstructured":"Pak J, Lee JH, Lee SH. Regenerative repair of damaged meniscus with autologous adipose tissue-derived stem cells. BioMed Research International. 2014; 2014: 436029.","DOI":"10.1155\/2014\/436029"},{"key":"ref23","doi-asserted-by":"crossref","unstructured":"Egawa G, Natsuaki Y, Miyachi Y, Kabashima K. Three-dimensional imaging of epidermal keratinocytes and dermal vasculatures using two-photon microscopy. Journal of Dermatological Science. 2013; 70: 143\u2013145.","DOI":"10.1016\/j.jdermsci.2013.01.005"},{"key":"ref24","doi-asserted-by":"crossref","unstructured":"Israeli R, Funk S, Reaven NL. Comparative analysis of 18-month outcomes and costs of breast reconstruction flap procedures. Plastic and Reconstructive Surgery. 2014; 133: 471\u2013479.","DOI":"10.1097\/PRS.0000000000000064"},{"key":"ref25","doi-asserted-by":"crossref","unstructured":"Ude CC, Shah S, Ogueri KS, Nair LS, Laurencin CT. Stromal Vascular Fraction for Osteoarthritis of the Knee Regenerative Engineering. Regenerative Engineering and Translational Medicine. 2022; 8: 210\u2013224.","DOI":"10.1007\/s40883-021-00226-x"},{"key":"ref26","doi-asserted-by":"crossref","unstructured":"Cohen SR, Hewett S, Ross L, Delaunay F, Goodacre A, Ramos C, et al. Regenerative Cells For Facial Surgery: Biofilling and Biocontouring. Aesthetic Surgery Journal. 2017; 37: S16\u2013S32.","DOI":"10.1093\/asj\/sjx078"},{"key":"ref27","doi-asserted-by":"crossref","unstructured":"Castillo-Cardiel G, L\u00f3pez-Echaury AC, Saucedo-Ortiz JA, Fuentes-Orozco C, Michel-Espinoza LR, Irusteta-Jim\u00e9nez L, et al. Bone regeneration in mandibular fractures after the application of autologous mesenchymal stem cells, a randomized clinical trial. Dental Traumatology. 2017; 33: 38\u201344.","DOI":"10.1111\/edt.12303"},{"key":"ref28","doi-asserted-by":"crossref","unstructured":"Zalewska A, Kna\u015b M, Maciejczyk M, Waszkiewicz N, Klimiuk A, Choroma\u0144ska M, et al. Antioxidant profile, carbonyl and lipid oxidation markers in the parotid and submandibular glands of rats in different periods of streptozotocin induced diabetes. Archives of Oral Biology. 2015; 60: 1375\u20131386.","DOI":"10.1016\/j.archoralbio.2015.06.012"},{"key":"ref29","doi-asserted-by":"crossref","unstructured":"Bi H, Li H, Zhang C, Mao Y, Nie F, Xing Y, et al. Stromal vascular fraction promotes migration of fibroblasts and angiogenesis through regulation of extracellular matrix in the skin wound healing process. Stem Cell Research & Therapy. 2019; 10: 302.","DOI":"10.1186\/s13287-019-1415-6"},{"key":"ref30","doi-asserted-by":"crossref","unstructured":"Moraes DA, Sibov TT, Pavon LF, Alvim PQ, Bonadio RS, Da Silva JR, et al. A reduction in CD90 (THY-1) expression results in increased differentiation of mesenchymal stromal cells. Stem Cell Research & Therapy. 2016; 7: 97.","DOI":"10.1186\/s13287-016-0359-3"},{"key":"ref31","doi-asserted-by":"crossref","unstructured":"Sch\u00e4ffler A, B\u00fcchler C. Concise review: adipose tissue-derived stromal cells\u2013basic and clinical implications for novel cell-based therapies. Stem Cells. 2007; 25: 818\u2013827.","DOI":"10.1634\/stemcells.2006-0589"},{"key":"ref32","doi-asserted-by":"crossref","unstructured":"Akhlaghi F, Hesami N, Rad MR, Nazeman P, Fahimipour F, Khojasteh A. Improved bone regeneration through amniotic membrane loaded with buccal fat pad-derived MSCs as an adjuvant in maxillomandibular reconstruction. Journal of Cranio-Maxillo-Facial Surgery. 2019; 47: 1266\u20131273.","DOI":"10.1016\/j.jcms.2019.03.030"},{"key":"ref33","doi-asserted-by":"crossref","unstructured":"Redondo LM, Garc\u00eda V, Peral B, Verrier A, Becerra J, S\u00e1nchez A, et al. Repair of maxillary cystic bone defects with mesenchymal stem cells seeded on a cross-linked serum scaffold. Journal of Cranio-Maxillo-Facial Surgery. 2018; 46: 222\u2013229.","DOI":"10.1016\/j.jcms.2017.11.004"},{"key":"ref34","doi-asserted-by":"crossref","unstructured":"Khojasteh A, Kheiri L, Behnia H, Tehranchi A, Nazeman P, Nadjmi N, et al. Lateral Ramus Cortical Bone Plate in Alveolar Cleft Osteoplasty with Concomitant Use of Buccal Fat Pad Derived Cells and Autogenous Bone: Phase I Clinical Trial. BioMed Research International. 2017; 2017: 6560234.","DOI":"10.1155\/2017\/6560234"},{"key":"ref35","doi-asserted-by":"crossref","unstructured":"Al-Ahmady HH, Abd Elazeem AF, Bellah Ahmed NEM, Shawkat WM, Elmasry M, Abdelrahman MA, et al. Combining autologous bone marrow mononuclear cells seeded on collagen sponge with Nano Hydroxyapatite, and platelet-rich fibrin: Reporting a novel strategy for alveolar cleft bone regeneration. Journal of Cranio-Maxillo-Facial Surgery. 2018; 46: 1593\u20131600.","DOI":"10.1016\/j.jcms.2018.05.049"},{"key":"ref36","doi-asserted-by":"crossref","unstructured":"De Riu G, Vaira LA, Carta E, Meloni SM, Sembronio S, Robiony M. Bone marrow nucleated cell concentrate autograft in temporomandibular joint degenerative disorders: 1-year results of a randomized clinical trial. Journal of Cranio-Maxillo-Facial Surgery. 2019; 47: 1728\u20131738.","DOI":"10.1016\/j.jcms.2018.11.025"},{"key":"ref37","doi-asserted-by":"crossref","unstructured":"Sembronio S, Tel A, Tremolada C, Lazzarotto A, Isola M, Robiony M. Temporomandibular Joint Arthrocentesis and Microfragmented Adipose Tissue Injection for the Treatment of Internal Derangement and Osteoarthritis: A Randomized Clinical Trial. Journal of Oral and Maxillofacial Surgery. 2021; 79: 1447\u20131456.","DOI":"10.1016\/j.joms.2021.01.038"},{"key":"ref38","doi-asserted-by":"crossref","unstructured":"La Padula S, Hersant B, Meningaud JP, D\u2019Andrea F. Use of autologous fat graft and fractiononal co_\u20622 laser to optimize the aesthetic and functional results in patients with severe burn outcomes of the face. Journal of Stomatology, Oral and Maxillofacial Surgery. 2018; 119: 279\u2013283.","DOI":"10.1016\/j.jormas.2018.04.005"},{"key":"ref39","doi-asserted-by":"crossref","unstructured":"Lameirinhas NS, Teixeira MC, Carvalho JPF, Valente BFA, Pinto RJB, Oliveira H, et al. Nanofibrillated cellulose\/gellan gum hydrogel-based bioinks for 3D bioprinting of skin cells. International Journal of Biological Macromolecules. 2023; 229: 849\u2013860.","DOI":"10.1016\/j.ijbiomac.2022.12.227"},{"key":"ref40","doi-asserted-by":"crossref","unstructured":"Ullah F, Javed F, Mushtaq I, Rahman LU, Ahmed N, Din IU, et al. Development of highly-reproducible hydrogel based bioink for regeneration of skin-tissues via 3-D bioprinting technology. International Journal of Biological Macromolecules. 2023; 230: 123131.","DOI":"10.1016\/j.ijbiomac.2022.123131"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/28\/6\/10.31083\/j.fbl2806123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T12:54:33Z","timestamp":1732712073000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/28\/6\/10.31083\/j.fbl2806123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,27]]},"references-count":40,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023]]}},"alternative-id":["S2768-6701(23)00909-7"],"URL":"https:\/\/doi.org\/10.31083\/j.fbl2806123","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"type":"print","value":"2768-6701"},{"type":"electronic","value":"2768-6698"}],"subject":[],"published":{"date-parts":[[2023,6,27]]},"article-number":"123"}}