{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T22:29:55Z","timestamp":1775687395960,"version":"3.50.1"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB\/TRR 79"],"award-info":[{"award-number":["SFB\/TRR 79"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The treatment of osteoporotic fractures is still challenging and may be improved using materials for bone regeneration, such as pre-structured gelatin with calcium and strontium phosphates (PPGC+S), combined with brain-derived neurotrophic factor (BDNF). Recently, it was shown that PPGC+S stimulates bone formation, and BDNF improves cell survival. This study aimed to analyze the combined effect of PPGC+S and BDNF on the survival of mesenchymal stem cells (MSCs) from osteoporotic and non-osteoporotic female donors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In our study, cells were seeded on PPGC+S plates with the following mineral composition of C+S of (a) 5:5, (b) 3:7, and (c) 0:10 (PPGS 0:10). Apoptosis and necrosis were measured after the addition of BDNF, followed by light microscopic analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The application of BDNF resulted in reduced necrosis and apoptosis in all biomaterials. The lowest level of necrosis was found in the PPGC+S 5:5 group. Apoptosis was most reduced in the PPGC+S 3:7 group, although the difference compared to PPGC+S 5:5 was not statistically significant. No differences were observed between MSCs from osteoporotic and non-osteoporotic donors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Thus, PPGC+S 5:5 appears to be the most suitable composition for bone healing, especially when supplemented with BDNF.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fbioe.2025.1596846","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T09:01:56Z","timestamp":1751878916000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["BDNF improves the survival of mesenchymal stem cells cultured on pre-structured gelatin material containing strontium and calcium phosphates for bone regeneration"],"prefix":"10.3389","volume":"13","author":[{"given":"Paul T.","family":"Itting","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Kruppke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Hanke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vinu","family":"Vijayan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Heiss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin Susanne","family":"Lips","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7566","DOI":"10.3390\/app14177566","article-title":"The effects of the addition of strontium on the biological response to calcium phosphate biomaterials: a systematic review","volume":"14","author":"Alves C\u00f4rtes","year":"2024","journal-title":"Appl. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"5883","DOI":"10.1016\/j.biomaterials.2013.04.031","article-title":"Accelerated bone ingrowth by local delivery of strontium from surface functionalized titanium implants","volume":"34","author":"Andersen","year":"2013","journal-title":"Biomaterials"},{"key":"B3","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1016\/j.ecl.2012.04.006","article-title":"Pathophysiology of osteoporosis: new mechanistic insights","volume":"41","author":"Armas","year":"2012","journal-title":"Endocrinol. Metab. Clin. North Am."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1150","DOI":"10.1089\/scd.2014.0484","article-title":"The role of reactive oxygen species in mesenchymal stem cell adipogenic and osteogenic differentiation: a review","volume":"24","author":"Atashi","year":"2015","journal-title":"Stem Cells Dev."},{"key":"B5","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/1749-799X-8-16","article-title":"Strontium enhances osseointegration of calcium phosphate cement: a histomorphometric pilot study in ovariectomized rats","volume":"8","author":"Baier","year":"2013","journal-title":"J. Orthop. Surg. Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"26","DOI":"10.3390\/cells11010026","article-title":"Assessment of collagen-based nanostructured biomimetic systems with a Co-Culture of human bone-derived cells","volume":"11","author":"Borciani","year":"2021","journal-title":"Cells"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e45052","DOI":"10.1371\/journal.pone.0045052","article-title":"Aging effect on neurotrophic activity of human mesenchymal stem cells","volume":"7","author":"Brohlin","year":"2012","journal-title":"PLoS One"},{"key":"B8","doi-asserted-by":"publisher","first-page":"164","DOI":"10.37349\/emd.2024.00046","article-title":"Mesenchymal stromal cells from people with osteoporosis are fewer, and defective in both osteogenic and adipogenic capacity","volume":"2","author":"Cassidy","year":"2024","journal-title":"Explor Musculoskelet. Dis."},{"key":"B9","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1080\/03008207.2017.1290085","article-title":"Osteoblast-osteoclast interactions","volume":"59","author":"Chen","year":"2018","journal-title":"Connect. Tissue Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/S8756-3282(96)00316-X","article-title":"Effects of strontium ions on growth and dissolution of hydroxyapatite and on bone mineral detection","volume":"20","author":"Christoffersen","year":"1997","journal-title":"Bone"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e210","DOI":"10.1002\/cpz1.210","article-title":"Measurement of cell death in mammalian cells","volume":"1","author":"Cummings","year":"2021","journal-title":"Curr. Protoc."},{"key":"B12","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1007\/s40520-021-01799-x","article-title":"Cardiovascular safety of calcium, magnesium and strontium: what does the evidence say?","volume":"33","author":"Curtis","year":"2021","journal-title":"Aging Clin. Exp. Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/0167-5699(86)90152-0","article-title":"Death and the cell","volume":"7","author":"Duvall","year":"1986","journal-title":"Immunol. Today"},{"key":"B14","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s11010-017-3251-2","article-title":"Long non-coding RNA BDNF-AS modulates osteogenic differentiation of bone marrow-derived mesenchymal stem cells","volume":"445","author":"Feng","year":"2018","journal-title":"Mol. Cell Biochem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.1016\/j.addr.2012.01.008","article-title":"Calcium phosphate cements as drug delivery materials","volume":"64","author":"Ginebra","year":"2012","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B16","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/j.micron.2005.07.005","article-title":"Bone matrix like assemblies of collagen: from liquid crystals to gels and biomimetic materials","volume":"36","author":"Giraud Guille","year":"2005","journal-title":"Micron"},{"key":"B17","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.bbrc.2014.08.055","article-title":"Mesenchymal stem cells from osteoporotic patients reveal reduced migration and invasion upon stimulation with BMP-2 or BMP-7","volume":"452","author":"Haasters","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B18","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/s0109-5641(96)80020-0","article-title":"In vitro models of biocompatibility: a review","volume":"12","author":"Hanks","year":"1996","journal-title":"Dent. Mater"},{"key":"B19","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1002\/jbm.820040306","article-title":"Bio-compatibility in selection of materials for implantation","volume":"4","author":"Homsy","year":"1970","journal-title":"J. Biomed. Mater Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1007\/s11427-019-1555-9","article-title":"Characterization and immunogenicity of bone marrow-derived mesenchymal stem cells under osteoporotic conditions","volume":"63","author":"Huang","year":"2020","journal-title":"Sci. China Life Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1074\/jbc.M801668200","article-title":"The calcium-sensing receptor is involved in strontium ranelate-induced osteoclast apoptosis","volume":"284","author":"Hurtel-Lemaire","year":"2009","journal-title":"J. Biol. Chem."},{"key":"B22","doi-asserted-by":"publisher","first-page":"16259","DOI":"10.1074\/jbc.M800668200","article-title":"Brain-derived neurotrophic factor stimulates bone\/cementum-related protein gene expression in cementoblasts","volume":"283","author":"Kajiya","year":"2008","journal-title":"J. Biol. Chem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1186\/s13287-020-02001-1","article-title":"Mesenchymal stem cells: amazing remedies for bone and cartilage defects","volume":"11","author":"Kangari","year":"2020","journal-title":"Stem Cell Res. Ther."},{"key":"B24","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s00198-018-4704-5","article-title":"European guidance for the diagnosis and management of osteoporosis in postmenopausal women","volume":"30","author":"Kanis","year":"2019","journal-title":"Osteoporos. Int."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e0193468","DOI":"10.1371\/journal.pone.0193468","article-title":"Effects of new beta-type Ti-40Nb implant materials, brain-derived neurotrophic factor, acetylcholine and nicotine on human mesenchymal stem cells of osteoporotic and non osteoporotic donors","volume":"13","author":"Kauschke","year":"","journal-title":"PLoS One"},{"key":"B26","doi-asserted-by":"publisher","first-page":"3531","DOI":"10.3390\/ijms19113531","article-title":"Effects of a pasty bone cement containing brain-derived neurotrophic factor-functionalized mesoporous bioactive glass particles on metaphyseal healing in a new murine osteoporotic fracture model","volume":"19","author":"Kauschke","year":"","journal-title":"Int. J. Mol. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.aanat.2014.06.001","article-title":"BDNF and its TrkB receptor in human fracture healing","volume":"196","author":"Kilian","year":"2014","journal-title":"Ann. Anat."},{"key":"B28","doi-asserted-by":"publisher","first-page":"6564","DOI":"10.3390\/ijms22126564","article-title":"The influence of strontium on bone tissue metabolism and its application in osteoporosis treatment","volume":"22","author":"Ko\u0142odziejska","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/j.actbio.2015.12.035","article-title":"Gelatine modified monetite as a bone substitute material: an in vitro assessment of bone biocompatibility","volume":"32","author":"Kruppke","year":"2016","journal-title":"Acta Biomater."},{"key":"B30","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1002\/jbm.a.37057","article-title":"Strontium substitution of gelatin modified calcium hydrogen phosphates as porous hard tissue substitutes","volume":"109","author":"Kruppke","year":"2021","journal-title":"J. Biomed. Mater Res. A"},{"key":"B31","doi-asserted-by":"publisher","first-page":"5103","DOI":"10.3390\/molecules25215103","article-title":"Gelatin-modified calcium\/strontium hydrogen phosphates stimulate bone regeneration in osteoblast\/osteoclast Co-Culture and in osteoporotic rat femur Defects-in vitro to in vivo translation","volume":"25","author":"Kruppke","year":"2020","journal-title":"Molecules"},{"key":"B32","doi-asserted-by":"publisher","first-page":"109933","DOI":"10.1016\/j.msec.2019.109933","article-title":"Biomaterial based treatment of osteoclastic\/osteoblastic cell imbalance - gelatin-modified calcium\/strontium phosphates","volume":"104","author":"Kruppke","year":"2019","journal-title":"Mater Sci. Eng. C Mater Biol. Appl."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1089\/ten.TEA.2017.0462","article-title":"Effect of brain-derived neurotrophic factor on the neurogenesis and osteogenesis in bone engineering","volume":"24","author":"Liu","year":"2018","journal-title":"Tissue Eng. Part A"},{"key":"B34","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.biomaterials.2018.09.028","article-title":"Bone physiology as inspiration for tissue regenerative therapies","volume":"185","author":"Lopes","year":"2018","journal-title":"Biomaterials"},{"key":"B35","doi-asserted-by":"publisher","first-page":"100273","DOI":"10.1016\/j.bonr.2020.100273","article-title":"A review of the latest insights into the mechanism of action of strontium in bone","volume":"12","author":"Marx","year":"2020","journal-title":"Bone Rep."},{"key":"B36","doi-asserted-by":"publisher","first-page":"522","DOI":"10.3389\/fncel.2018.00522","article-title":"The role of BDNF in peripheral nerve regeneration: activity-dependent treatments and Val66Met","volume":"12","author":"McGregor","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"B37","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1302\/2046-3758.66.BJR-2016-0311.R1","article-title":"In vivo and clinical application of strontium-enriched biomaterials for bone regeneration: a systematic review","volume":"6","author":"Neves","year":"2017","journal-title":"Bone Jt. Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"279","DOI":"10.4067\/S0716-97602012000300009","article-title":"In osteoporosis, differentiation of mesenchymal stem cells (MSCs) improves bone marrow adipogenesis","volume":"45","author":"Pino","year":"2012","journal-title":"Biol. Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"171","DOI":"10.5312\/wjo.v7.i3.171","article-title":"Major osteoporotic fragility fractures: risk factor updates and societal impact","volume":"7","author":"Pisani","year":"2016","journal-title":"World J. Orthop."},{"key":"B40","doi-asserted-by":"publisher","first-page":"56","DOI":"10.2174\/138161210789941793","article-title":"Mechanisms of tumor cell necrosis","volume":"16","author":"Proskuryakov","year":"2010","journal-title":"Curr. Pharm. Des."},{"key":"B41","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.msec.2017.11.038","article-title":"Strontium-modification of porous scaffolds from mineralized collagen for potential use in bone defect therapy","volume":"84","author":"Quade","year":"2018","journal-title":"Mater Sci. Eng. C Mater Biol. Appl."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1517\/14740338.2014.939169","article-title":"Cardiac concerns associated with strontium ranelate","volume":"13","author":"Reginster","year":"2014","journal-title":"Expert Opin. Drug Saf."},{"key":"B43","doi-asserted-by":"publisher","first-page":"e9690","DOI":"10.1371\/journal.pone.0009690","article-title":"Neurotrophins regulate bone marrow stromal cell IL-6 expression through the MAPK pathway","volume":"5","author":"Rezaee","year":"2010","journal-title":"PLoS One"},{"key":"B44","doi-asserted-by":"publisher","first-page":"e16866","DOI":"10.7759\/cureus.16866","article-title":"End-stage tibiotalar osteoarthritis and chronic strontium toxicity","volume":"13","author":"Ricci","year":"2021","journal-title":"Cureus"},{"key":"B45","doi-asserted-by":"publisher","first-page":"2010","DOI":"10.1016\/S0140-6736(06)68891-0","article-title":"Osteoporosis","volume":"367","author":"Sambrook","year":"2006","journal-title":"Lancet"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fmats.2021.734683","article-title":"Bioactive 3D scaffolds for the delivery of NGF and BDNF to improve nerve regeneration","volume":"8","author":"Sandoval-Castellanos","year":"2021","journal-title":"Front. Mater."},{"key":"B47","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.actbio.2016.04.016","article-title":"Strontium substitution in apatitic CaP cements effectively attenuates osteoclastic resorption but does not inhibit osteoclastogenesis","volume":"37","author":"Schumacher","year":"2016","journal-title":"Acta Biomater."},{"key":"B48","doi-asserted-by":"publisher","first-page":"8662","DOI":"10.1039\/c2jm16141a","article-title":"Bone regeneration: importance of local pH\u2014Strontium-doped borosilicate scaffold","volume":"22","author":"Shen","year":"2012","journal-title":"J. Mater Chem."},{"key":"B49","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1359\/jbmr.2001.16.6.1120","article-title":"Number and proliferative capacity of osteogenic stem cells are maintained during aging and in patients with osteoporosis","volume":"16","author":"Stenderup","year":"2001","journal-title":"J. Bone Min. Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1258","DOI":"10.1002\/jbmr.2786","article-title":"Neurotrophin-3 induces BMP-2 and VEGF activities and promotes the bony repair of injured growth plate cartilage and bone in rats","volume":"31","author":"Su","year":"2016","journal-title":"J. Bone Min. Res."},{"key":"B51","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1002\/jcp.25936","article-title":"Roles of neurotrophins in skeletal tissue formation and healing","volume":"233","author":"Su","year":"2018","journal-title":"J. Cell Physiol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1038\/s41413-022-00240-x","article-title":"Hallmarks of peripheral nerve function in bone regeneration","volume":"11","author":"Tao","year":"2023","journal-title":"Bone Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"8589","DOI":"10.1016\/j.biomaterials.2013.07.036","article-title":"Bone formation induced by strontium modified calcium phosphate cement in critical-size metaphyseal fracture defects in ovariectomized rats","volume":"34","author":"Thormann","year":"2013","journal-title":"Biomaterials"},{"key":"B54","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1046\/j.1523-1755.2003.00123.x","article-title":"Dose-dependent effects of strontium on osteoblast function and mineralization","volume":"64","author":"Verberckmoes","year":"2003","journal-title":"Kidney Int."},{"key":"B55","doi-asserted-by":"publisher","first-page":"226","DOI":"10.12659\/msm.897044","article-title":"Differentiation of bone marrow mesenchymal stem cells in osteoblasts and adipocytes and its role in treatment of osteoporosis","volume":"22","author":"Wang","year":"2016","journal-title":"Med. Sci. Monit."},{"key":"B56","doi-asserted-by":"publisher","first-page":"2409","DOI":"10.1080\/15548627.2023.2186112","article-title":"The role of autophagy in bone metabolism and clinical significance","volume":"19","author":"Wang","year":"2023","journal-title":"Autophagy"},{"key":"B57","doi-asserted-by":"publisher","first-page":"10792","DOI":"10.1111\/jcmm.15704","article-title":"BDNF promoted osteoblast migration and fracture healing by up-regulating integrin \u03b21 via TrkB-mediated ERK1\/2 and AKT signalling","volume":"24","author":"Zhang","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"B58","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.3892\/mmr.2017.6110","article-title":"BDNF regulates the expression and secretion of VEGF from osteoblasts via the TrkB\/ERK1\/2 signaling pathway during fracture healing","volume":"15","author":"Zhang","year":"2017","journal-title":"Mol. Med. Rep."}],"container-title":["Frontiers in Bioengineering and Biotechnology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2025.1596846\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T09:01:56Z","timestamp":1751878916000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fbioe.2025.1596846\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,7]]},"references-count":58,"alternative-id":["10.3389\/fbioe.2025.1596846"],"URL":"https:\/\/doi.org\/10.3389\/fbioe.2025.1596846","relation":{},"ISSN":["2296-4185"],"issn-type":[{"value":"2296-4185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,7]]},"article-number":"1596846"}}