{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:02:59Z","timestamp":1760144579142,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T00:00:00Z","timestamp":1714608000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Missouri"},{"name":"start-up funds as well as a College of Engineering Incentive Fund Grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Though crucial for natural bone healing, local calcium ion (Ca2+) and phosphate ion (Pi) concentrations can exceed the cytotoxic limit leading to mitochondrial overload, oxidative stress, and cell death. For bone tissue engineering applications, H2S can be employed as a cytoprotective molecule to enhance mesenchymal stem cell (MSC) tolerance to cytotoxic Ca2+\/Pi concentrations. Varied concentrations of sodium hydrogen sulfide (NaSH), a fast-releasing H2S donor, were applied to assess the influence of H2S on MSC proliferation. The results suggested a toxicity limit of 4 mM for NaSH and that 1 mM of NaSH could improve cell proliferation and differentiation in the presence of cytotoxic levels of Ca2+ (32 mM) and\/or Pi (16 mM). To controllably deliver H2S over time, a novel donor molecule (thioglutamic acid\u2014GluSH) was synthesized and evaluated for its H2S release profile. Excitingly, GluSH successfully maintained cytoprotective level of H2S over 7 days. Furthermore, MSCs exposed to cytotoxic Ca2+\/Pi concentrations in the presence of GluSH were able to thrive and differentiate into osteoblasts. These findings suggest that the incorporation of a sustained H2S donor such as GluSH into CaP-based bone graft substitutes can facilitate considerable cytoprotection, making it an attractive option for complex bone regenerative engineering applications.<\/jats:p>","DOI":"10.3390\/ph17050585","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T08:42:57Z","timestamp":1714639377000},"page":"585","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hydrogen Sulfide Delivery to Enhance Bone Tissue Engineering Cell Survival"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1850-6950","authenticated-orcid":false,"given":"Soheila","family":"Ali Akbari Ghavimi","sequence":"first","affiliation":[{"name":"Department of Chemical and Biomedical Engineering, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trent J.","family":"Faulkner","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomedical Engineering, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4906-0712","authenticated-orcid":false,"given":"Rama Rao","family":"Tata","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomedical Engineering, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"August J.","family":"Hemmerla","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomedical Engineering, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3362-5149","authenticated-orcid":false,"given":"Samantha E.","family":"Huddleston","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomedical Engineering, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farnoushsadat","family":"Rezaei","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomedical Engineering, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ethan S.","family":"Lungren","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomedical Engineering, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8698-7808","authenticated-orcid":false,"given":"Erin E.","family":"Bumann","sequence":"additional","affiliation":[{"name":"Department of Oral and Craniofacial Sciences, University of Missouri, Kansas City, MO 64110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bret D.","family":"Ulery","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomedical Engineering, University of Missouri, Columbia, MO 65211, USA"},{"name":"NextGen Precision Health Institute, University of Missouri, Columbia, MO 65211, USA"},{"name":"Materials Science & Engineering Institute, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/S0140-6736(16)31012-1","article-title":"Global, Regional, and National Life Expectancy, All-Cause Mortality, and Cause-Specific Mortality for 249 Causes of Death, 1980\u20132015: A Systematic Analysis for the Global Burden of Disease Study 2015","volume":"388","author":"Wang","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"519","DOI":"10.2174\/138920007780866852","article-title":"Calcium Metabolism and Oxidative Stress in Bone Fractures: Role of Antioxidants","volume":"8","author":"Sheweita","year":"2007","journal-title":"Curr. Drug Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"203","DOI":"10.4248\/BR201303001","article-title":"The Key Role of the Blood Supply to Bone","volume":"1","author":"Marenzana","year":"2013","journal-title":"Bone Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.ceca.2004.02.006","article-title":"The Role of Calcium in Hypoxia-Induced Signal Transduction and Gene Expression","volume":"36","author":"Seta","year":"2004","journal-title":"Cell Calcium"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"100200","DOI":"10.1016\/j.bonr.2019.100200","article-title":"Calcium Isotope Ratios in Blood and Urine: A New Biomarker for the Diagnosis of Osteoporosis","volume":"10","author":"Eisenhauer","year":"2019","journal-title":"Bone Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1016\/j.injury.2011.03.031","article-title":"The Biology of Fracture Healing","volume":"42","author":"Marsell","year":"2011","journal-title":"Injury"},{"key":"ref_7","first-page":"1","article-title":"The Calcium Ion and Cell Death","volume":"43","author":"Orrenius","year":"1994","journal-title":"J. Neural Transm. Suppl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s13018-018-0724-2","article-title":"Scaffolds for the Repair of Bone Defects in Clinical Studies: A Systematic Review","volume":"13","author":"Zeng","year":"2018","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1097\/00003086-200202000-00009","article-title":"Properties of Osteoconductive Biomaterials: Calcium Phosphates","volume":"395","author":"LeGeros","year":"2002","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15226\/jdodt.2021.001124","article-title":"Calcium Sulfate as a Scaffold for Bone Tissue Engineering: A Descriptive Review","volume":"9","author":"Fernandes","year":"2021","journal-title":"J. Dent. Oral Disord. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4628","DOI":"10.1021\/cr0782574","article-title":"Calcium Orthophosphates: Crystallization and Dissolution","volume":"108","author":"Wang","year":"2008","journal-title":"Chem. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.ceca.2017.07.006","article-title":"Calcium Signaling and Cell Cycle: Progression or Death","volume":"70","author":"Humeau","year":"2018","journal-title":"Cell Calcium"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3876","DOI":"10.1016\/j.actbio.2012.07.002","article-title":"Current Views on Calcium Phosphate Osteogenicity and the Translation into Effective Bone Regeneration Strategies","volume":"8","author":"Chai","year":"2012","journal-title":"Acta Biomater."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ali Akbari Ghavimi, S., Allen, B.N., Stromsdorfer, J.L., Kramer, J.S., Li, X., and Ulery, B.D. (2018). Calcium and Phosphate Ions as Simple Signaling Molecules with Versatile Osteoinductivity. Biomed. Mater., 13.","DOI":"10.1088\/1748-605X\/aac7a5"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.ijbiomac.2019.02.086","article-title":"Inductive Co-Crosslinking of Cellulose Nanocrystal\/Chitosan Hydrogels for the Treatment of Vertebral Compression Fractures","volume":"130","author":"Ghavimi","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1208\/s12248-019-0311-4","article-title":"Effect of Dibasic Calcium Phosphate Incorporation on Cellulose Nanocrystal\/Chitosan Hydrogel Properties for the Treatment of Vertebral Compression Fractures","volume":"21","author":"Ghavimi","year":"2019","journal-title":"AAPS J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/j.1471-4159.2010.06580.x","article-title":"Hydrogen Sulfide as a Gasotransmitter","volume":"113","author":"Gadalla","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/ars.2008.2282","article-title":"Hydrogen Sulfide Increases Glutathione Production and Suppresses Oxidative Stress in Mitochondria","volume":"12","author":"Kimura","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6043038","DOI":"10.1155\/2016\/6043038","article-title":"Hydrogen Sulfide and Cellular Redox Homeostasis. Oxidative Medicine and Cellular Longevity","volume":"2016","author":"Xie","year":"2016","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Yi, J., Yuan, Y., Zheng, J., and Zhao, T. (2018). Hydrogen Sulfide Alleviates Uranium-Induced Rat Hepatocyte Cytotoxicity via Inhibiting Nox4\/ROS\/P38 MAPK Pathway. J. Biochem. Mol. Toxicol., 33.","DOI":"10.1002\/jbt.22255"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"758678","DOI":"10.1155\/2015\/758678","article-title":"Interaction of Hydrogen Sulfide with Oxygen Sensing under Hypoxia","volume":"2015","author":"Wu","year":"2015","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gambari, L., Grigolo, B., and Grassi, F. (2019). Hydrogen Sulfide in Bone Tissue Regeneration and Repair: State of the Art and New Perspectives. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205231"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6275","DOI":"10.1021\/jm901638j","article-title":"Synthesis and Biological Effects of Hydrogen Sulfide (H2S): Development of H2S-Releasing Drugs as Pharmaceuticals","volume":"53","author":"Caliendo","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1161\/CIRCULATIONAHA.107.753467","article-title":"Characterization of a Novel, Water-Soluble Hydrogen Sulfide\u2013Releasing Molecule (GYY4137)","volume":"117","author":"Li","year":"2008","journal-title":"Circulation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s11010-013-1946-6","article-title":"GYY4137, a Novel Hydrogen Sulfide-Releasing Molecule, Likely Protects against High Glucose-Induced Cytotoxicity by Activation of the AMPK\/MTOR Signal Pathway in H9c2 Cells","volume":"389","author":"Wei","year":"2013","journal-title":"Mol. Cell. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1161\/ATVBAHA.110.209783","article-title":"Hydrogen Sulfide Is an Endogenous Inhibitor of Phosphodiesterase Activity","volume":"30","author":"Bucci","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1182\/blood.V49.4.585.585","article-title":"CGMP Stimulation of Stem Cell Proliferation","volume":"49","author":"Oshita","year":"1977","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s10565-011-9198-2","article-title":"Increased Oxidative Stress and Cytotoxicity by Hydrogen Sulfide in HepG2 Cells Overexpressing Cytochrome P450 2E1","volume":"27","author":"Caro","year":"2011","journal-title":"Cell Biol. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1158\/1541-7786.MCR-06-0439","article-title":"Hydrogen Sulfide Induces Direct Radical-Associated DNA Damage","volume":"5","author":"Wagner","year":"2007","journal-title":"Mol. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.tibtech.2012.12.004","article-title":"Extracellular Matrix Scaffolds for Cartilage and Bone Regeneration","volume":"31","author":"Benders","year":"2013","journal-title":"Trends Biotechnol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.bbrc.2012.07.131","article-title":"Hydrogen Sulfide Prevents Hypoxia-Induced Apoptosis via Inhibition of an H2O2-Activated Calcium Signaling Pathway in Mouse Hippocampal Neurons","volume":"425","author":"Luo","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.mito.2011.04.006","article-title":"The Roles of Phosphate and the Phosphate Carrier in the Mitochondrial Permeability Transition Pore","volume":"12","author":"Varanyuwatana","year":"2012","journal-title":"Mitochondrion"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7159","DOI":"10.1016\/S0021-9258(19)42087-5","article-title":"The Regulation of Pyruvate Dehydrogenase in Isolated Beef Heart Mitochondria: The role of calcium, magnesium, and permeant anions","volume":"249","author":"Schuster","year":"1974","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1089\/ars.2009.2882","article-title":"Novel Insights into Hydrogen Sulfide\u2013Mediated Cytoprotection","volume":"12","author":"Calvert","year":"2010","journal-title":"Antioxid. Redox Signal."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"427","DOI":"10.3390\/cells4030427","article-title":"Mitochondrial Impairment May Increase Cellular NAD(P)H: Resazurin Oxidoreductase Activity, Perturbing the NAD(P)H-Based Viability Assays","volume":"4","author":"Aleshin","year":"2015","journal-title":"Cells"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.cca.2016.06.008","article-title":"Evaluation of Serum Bone Alkaline Phosphatase Activity in Patients with Liver Disease: Comparison between Electrophoresis and Chemiluminescent Enzyme Immunoassay","volume":"460","author":"Zhan","year":"2016","journal-title":"Clin. Chim. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"144855","DOI":"10.1016\/j.gene.2020.144855","article-title":"Alkaline Phosphatase: Structure, Expression and Its Function in Bone Mineralization","volume":"754","author":"Vimalraj","year":"2020","journal-title":"Gene"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.msec.2019.04.039","article-title":"Hydrogen Sulfide-Releasing Silk Fibroin Scaffold for Bone Tissue Engineering","volume":"102","author":"Gambari","year":"2019","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1053\/j.ajkd.2014.07.007","article-title":"Serum Bicarbonate and Bone Mineral Density in US Adults","volume":"65","author":"Chen","year":"2015","journal-title":"Am. J. Kidney Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1208\/s12248-017-0072-x","article-title":"Controlled Ion Release from Novel Polyester\/Ceramic Composites Enhances Osteoinductivity","volume":"19","author":"Tata","year":"2017","journal-title":"AAPS J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1016\/j.bmc.2012.02.028","article-title":"Thioglycine and L-Thiovaline: Biologically Active H2S-Donors","volume":"20","author":"Zhou","year":"2012","journal-title":"Bioorg. Med. Chem."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/5\/585\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:38:56Z","timestamp":1760107136000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/5\/585"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,2]]},"references-count":41,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ph17050585"],"URL":"https:\/\/doi.org\/10.3390\/ph17050585","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2024,5,2]]}}}