{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T13:23:47Z","timestamp":1781616227909,"version":"3.54.5"},"reference-count":35,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,8,31]],"date-time":"2024-08-31T00:00:00Z","timestamp":1725062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Researchers Supporting Project","award":["RSP2024R478"],"award-info":[{"award-number":["RSP2024R478"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JFB"],"abstract":"<jats:p>The study aimed to develop a biodegradable scaffold incorporating valproic acid (VPA) for improved human bone marrow-derived mesenchymal stem cell (hBMSC) proliferation, differentiation, and bone mineral synthesis. A chitosan\u2013gelatin (CH-G) scaffold was fabricated and loaded with varying concentrations of VPA (1, 3, 5 mM\/L). In vitro studies assessed drug release, cell proliferation, morphology, mineralization, and gene expression. VPA was rapidly released from the scaffold, with over 90% cumulative release within seven days. Cells cultured on VPA-loaded scaffolds exhibited significantly enhanced proliferation and mineralization compared to the control. VPA treatment upregulated osteocalcin and runt-related transcription factor 2 (Runx-2) expression, key markers of osteogenic differentiation. The CH-G scaffold, particularly with 1 mM\/L VPA, demonstrates excellent biocompatibility and promotes hBMSC-mediated bone regeneration. This novel approach holds promise for future applications in bone tissue engineering.<\/jats:p>","DOI":"10.3390\/jfb15090252","type":"journal-article","created":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T06:51:17Z","timestamp":1725259877000},"page":"252","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel Chitosan-Gelatin Scaffold with Valproic Acid Augments In Vitro Osteoblast Differentiation of Mesenchymal Stem Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1244-1845","authenticated-orcid":false,"given":"Maha","family":"Alghofaily","sequence":"first","affiliation":[{"name":"Restorative Dental Sciences, College of Dentistry, King Saud University, Riyadh 11541, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1168-0729","authenticated-orcid":false,"given":"Fahd","family":"Alsalleeh","sequence":"additional","affiliation":[{"name":"Restorative Dental Sciences, College of Dentistry, King Saud University, Riyadh 11541, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7462-070X","authenticated-orcid":false,"given":"Lamees","family":"Alssum","sequence":"additional","affiliation":[{"name":"Department of Periodontics and Community Dentistry, College of Dentistry, King Saud University, Riyadh 11545, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3057-1851","authenticated-orcid":false,"given":"Manikandan","family":"Muthurangan","sequence":"additional","affiliation":[{"name":"Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Musaad","family":"Alfayez","sequence":"additional","affiliation":[{"name":"Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Weir","sequence":"additional","affiliation":[{"name":"Department of Biomaterials and Regenerative Dental Medicine, University of Maryland School of Dentistry, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hockin H. K.","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Biomaterials and Regenerative Dental Medicine, University of Maryland School of Dentistry, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"201371","DOI":"10.4061\/2011\/201371","article-title":"Epigenetic regulation of mesenchymal stem cells: A focus on osteogenic and adipogenic differentiation","volume":"2011","author":"Teven","year":"2011","journal-title":"Stem Cells Int."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Man, K., Lawlor, L., Jiang, L.H., and Yang, X.B. (2021). The Selective Histone Deacetylase Inhibitor MI192 Enhances the Osteogenic Differentiation Efficacy of Human Dental Pulp Stromal Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22105224"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5304860","DOI":"10.1155\/2022\/5304860","article-title":"The Role of Epigenetic in Dental and Oral Regenerative Medicine by Different Types of Dental Stem Cells: A Comprehensive Overview","volume":"2022","author":"Hussain","year":"2022","journal-title":"Stem Cells Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9840","DOI":"10.1073\/pnas.1321330111","article-title":"Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells","volume":"111","author":"Jamaladdin","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Chen, G., Yin, S., Zeng, H., Li, H., and Wan, X. (2022). Regulation of embryonic stem cell self-renewal. Life, 12.","DOI":"10.3390\/life12081151"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"24","DOI":"10.2174\/1574888X14666190905155516","article-title":"Effect of the Histone Deacetylases Inhibitors on the Differentiation of Stem Cells in Bone Damage Repairing and Regeneration","volume":"15","author":"Zhao","year":"2020","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1089\/ten.tea.2012.0163","article-title":"HDAC inhibitor trichostatin A promotes proliferation and odontoblast differentiation of human dental pulp stem cells","volume":"19","author":"Jin","year":"2013","journal-title":"Tissue Eng. Part A"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.joen.2011.12.014","article-title":"Histone deacetylase inhibitors induced differentiation and accelerated mineralization of pulp-derived cells","volume":"38","author":"Duncan","year":"2012","journal-title":"J. Endod."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Shnayder, N.A., Grechkina, V.V., Khasanova, A.K., Bochanova, E.N., Dontceva, E.A., Petrova, M.M., Asadullin, A.R., Shipulin, G.A., Altynbekov, K.S., and Al-Zamil, M. (2023). Therapeutic and Toxic Effects of Valproic Acid Metabolites. Metabolites, 13.","DOI":"10.3390\/metabo13010134"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5671","DOI":"10.1007\/s00415-024-12436-8","article-title":"New valproate regulations, informed choice and seizure risk","volume":"271","author":"Arkell","year":"2024","journal-title":"J. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1158\/0008-5472.CAN-04-3011","article-title":"Valproic acid stimulates proliferation and self-renewal of hematopoietic stem cells","volume":"65","author":"Bug","year":"2005","journal-title":"Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"95","DOI":"10.2174\/1874467210902010095","article-title":"Biochemical, molecular and epigenetic mechanisms of valproic acid neuroprotection","volume":"2","author":"Monti","year":"2009","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"27","DOI":"10.2174\/1874467213666200713102410","article-title":"Valproic acid, A Potential Inducer of Osteogenesis in Mouse Mesenchymal Stem Cells","volume":"14","author":"Akshaya","year":"2021","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1002\/jcb.20544","article-title":"Induction of osteogenic differentiation of human mesenchymal stem cells by histone deacetylase inhibitors","volume":"96","author":"Cho","year":"2005","journal-title":"J. Cell. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5313","DOI":"10.1021\/acsabm.9b00570","article-title":"Antibacterial PEG-Chitosan Hydrogels for Controlled Antibiotic\/Protein Delivery","volume":"2","author":"Sharma","year":"2019","journal-title":"ACS Appl. Bio Mater."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1016\/j.joen.2016.06.017","article-title":"Effects of a Bioactive Scaffold Containing a Sustained Transforming Growth Factor-\u03b21-releasing Nanoparticle System on the Migration and Differentiation of Stem Cells from the Apical Papilla","volume":"42","author":"Bellamy","year":"2016","journal-title":"J. Endod."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Alghofaily, M., Almana, A., Alrayes, J., Lambarte, R., Weir, M.D., and Alsalleeh, F. (2024). Chitosan\u2013Gelatin Scaffolds Loaded with Different Antibiotic Formulations for Regenerative Endodontic Procedures Promote Biocompatibility and Antibacterial Activity. J. Funct. Biomater., 15.","DOI":"10.3390\/jfb15070186"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3453","DOI":"10.1016\/j.actbio.2009.05.012","article-title":"Chitosan-gelatin scaffolds for tissue engineering: Physico-chemical properties and biological response of buffalo embryonic stem cells and transfectant of GFP-buffalo embryonic stem cells","volume":"5","author":"Saikhun","year":"2009","journal-title":"Acta Biomater."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1016\/j.yexcr.2013.02.022","article-title":"Histone deacetylase inhibitors epigenetically promote reparative events in primary dental pulp cells","volume":"319","author":"Duncan","year":"2013","journal-title":"Exp. Cell Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.bbrc.2004.11.059","article-title":"Maintenance of differentiation potential of human bone marrow mesenchymal stem cells immortalized by human telomerase reverse transcriptase gene despite [corrected] extensive proliferation","volume":"326","author":"Abdallah","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/nbt0602-592","article-title":"Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells","volume":"20","author":"Simonsen","year":"2002","journal-title":"Nat. Biotechnol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.diff.2018.10.003","article-title":"NR2F1 mediated down-regulation of osteoblast differentiation was rescued by bone morphogenetic protein-2 (BMP-2) in human MSC","volume":"104","author":"Manikandan","year":"2018","journal-title":"Differentiation"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Yarahmadi, A., Dousti, B., Karami-Khorramabadi, M., and Afkhami, H. (2024). Materials based on biodegradable polymers chitosan\/gelatin: A review of potential applications. Front. Bioeng. Biotechnol., 12.","DOI":"10.3389\/fbioe.2024.1397668"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1016\/S0142-9612(03)00117-0","article-title":"Study on physical properties and nerve cell affinity of composite films from chitosan and gelatin solutions","volume":"24","author":"Cheng","year":"2003","journal-title":"Biomaterials"},{"key":"ref_25","first-page":"624","article-title":"The addition of biphasic calcium phosphate to porous chitosan scaffolds enhances bone tissue development in vitro","volume":"81","author":"Jamison","year":"2007","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.ijpharm.2007.01.026","article-title":"Modulation of drug release kinetics from hydroxypropyl methyl cellulose matrix tablets using polyvinyl pyrrolidone","volume":"337","author":"Hardy","year":"2007","journal-title":"Int. J. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.actbio.2021.09.021","article-title":"Stem cells immortalized by hTERT perform differently from those immortalized by SV40LT in proliferation, differentiation, and reconstruction of matrix microenvironment","volume":"136","author":"Wang","year":"2021","journal-title":"Acta Biomater."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e05398","DOI":"10.1016\/j.heliyon.2020.e05398","article-title":"Establishment of human immortalized mesenchymal stem cells lines for the monitoring and analysis of osteogenic differentiation in living cells","volume":"6","author":"Narai","year":"2020","journal-title":"Heliyon"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1210\/me.2006-0061","article-title":"Histone deacetylase 1-mediated histone modification regulates osteoblast differentiation","volume":"20","author":"Lee","year":"2006","journal-title":"Mol. Endocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1007\/s11010-020-03955-9","article-title":"Effect of valproic acid on the hepatic differentiation of mesenchymal stem cells in 2D and 3D microenvironments","volume":"476","author":"Rashid","year":"2021","journal-title":"Mol. Cell. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2927","DOI":"10.1089\/ten.2006.12.2927","article-title":"Inhibition of histone acetylation as a tool in bone tissue engineering","volume":"12","author":"Licht","year":"2006","journal-title":"Tissue Eng."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1359\/JBMR.050813","article-title":"Histone deacetylase inhibitors promote osteoblast maturation","volume":"20","author":"Schroeder","year":"2005","journal-title":"J. Bone Miner. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1177\/0022034512443367","article-title":"Suberoylanilide hydroxamic acid enhances odontoblast differentiation","volume":"91","author":"Kwon","year":"2012","journal-title":"J. Dental. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/s10266-020-00588-8","article-title":"The histone deacetylase inhibitor, entinostat (MS-275), induces the odontogenic differentiation of an odontoblast-like cell line in the absence of an osteoblast mineralization medium","volume":"109","author":"Sultana","year":"2021","journal-title":"Odontology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1111\/j.1365-2184.2009.00633.x","article-title":"Histone deacetylase inhibitors decrease proliferation potential and multilineage differentiation capability of human mesenchymal stem cells","volume":"42","author":"Lee","year":"2009","journal-title":"Cell Prolif."}],"container-title":["Journal of Functional Biomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4983\/15\/9\/252\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:46:15Z","timestamp":1760111175000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4983\/15\/9\/252"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,31]]},"references-count":35,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["jfb15090252"],"URL":"https:\/\/doi.org\/10.3390\/jfb15090252","relation":{},"ISSN":["2079-4983"],"issn-type":[{"value":"2079-4983","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,31]]}}}