{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:17:53Z","timestamp":1787822273815,"version":"build-2784847793"},"reference-count":44,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biomed Mater Res"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Calcium hydroxyapatite (CaHA) is a well\u2010established biocompatible material widely used to stimulate collagen formation in soft tissues; however, its clinical use is largely restricted to invasive deep dermal injection due to safety concerns associated with microstructured formulations, such as superficial nodule formation and vascular occlusion. Here, we report the development of a nanostructured, lactose\u2010functionalized CaHA produced by nanospray drying, enabling safer and more versatile delivery strategies. Physicochemical properties were systematically characterized, and biological performance was evaluated in human dermal fibroblasts and co\u2010culture with peripheral blood mononuclear cells (PBMCs). The resulting nanostructured CaHA (nanoCaHA) exhibited a submicron particle size (181.06\u2009\u00b1\u200923.83\u2009nm), narrow polydispersity (PDI 0.23\u2009\u00b1\u20090.17), and a positive surface charge (+11.75\u2009\u00b1\u20093.63\u2009mV), attributed to surface protonation during processing. NanoCaHA showed no cytotoxic, genotoxic, or irritant effects in\u00a0vitro and induced a shift in fibroblast cell\u2010cycle distribution consistent with enhanced proliferative activity. While both nano\u2010 and microCaHA increased total collagen production, nanoCaHA significantly upregulated COL1A1 and COL3A1 mRNA expression, particularly under PBMC co\u2010culture conditions, outperforming a commercially available CaHA formulation. Moreover, nanoCaHA sustained collagen production for up to 5\u2009days after treatment withdrawal. Scanning electron microscopy revealed persistent particulate structures closely associated with fibroblasts after washout, while energy\u2010dispersive X\u2010ray spectroscopy confirmed that these deposits were enriched in calcium and phosphorus, consistent with CaHA composition. Furthermore, skin permeation assays using porcine skin in Saarbr\u00fccken diffusion cells showed that the nanoCaHA formulation significantly increased calcium delivery into the skin (34.53\u2009\u00b1\u20096.64\u2009\u03bcg\/cm\n                    <jats:sup>2<\/jats:sup>\n                    ) compared to endogenous control levels (23.43\u2009\u00b1\u20093.96\u2009\u03bcg\/cm\n                    <jats:sup>2<\/jats:sup>\n                    ). Collectively, these findings demonstrate that nanoscale engineering of CaHA modulates cell\u2013material interactions, supporting the development of safer superficial dermal and novel topical\/transdermal delivery systems for regenerative aesthetics.\n                  <\/jats:p>","DOI":"10.1002\/jbm.b.70144","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T09:25:18Z","timestamp":1787390718000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nanostructured and Functionalized Calcium Hydroxyapatite Enhances Collagen Production by Human Dermal Fibroblasts Compared With Microstructured Counterparts In\u00a0Vitro"],"prefix":"10.1002","volume":"114","author":[{"given":"Elizabeth Cristina Iseke","family":"Bispo","sequence":"first","affiliation":[{"name":"Laboratory of Hematology and Stem Cells (LHCT), School of Health Sciences University of Brasilia  Bras\u00edlia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefhani Martins","family":"de Barcelos","sequence":"additional","affiliation":[{"name":"Interdisciplinary Biosciences Laboratory, Faculty of Medicine University of Bras\u00edlia  Bras\u00edlia Brazil"},{"name":"AMA\u2014Atomized Modern Actives  Bras\u00edlia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonad Logan A.","family":"Contarato","sequence":"additional","affiliation":[{"name":"Laboratory of Food, Drugs, and Cosmetics (LTMAC), School of Health Sciences University of Brasilia  Bras\u00edlia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atailson Oliveira","family":"da Silva","sequence":"additional","affiliation":[{"name":"Green Nanotechnology Group University of Brasilia  Brasilia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael Vieira","family":"Rocho","sequence":"additional","affiliation":[{"name":"Laboratory of Food, Drugs, and Cosmetics (LTMAC), School of Health Sciences University of Brasilia  Bras\u00edlia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Clara Nogueira","family":"Brathwaite","sequence":"additional","affiliation":[{"name":"Laboratory of Food, Drugs, and Cosmetics (LTMAC), School of Health Sciences University of Brasilia  Bras\u00edlia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ven\u00e2ncio Alves","family":"Amaral","sequence":"additional","affiliation":[{"name":"Laboratory of Food, Drugs, and Cosmetics (LTMAC), School of Health Sciences University of Brasilia  Bras\u00edlia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula Martins","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"AMA\u2014Atomized Modern Actives  Bras\u00edlia Brazil"},{"name":"Laboratory of Food, Drugs, and Cosmetics (LTMAC), School of Health Sciences University of Brasilia  Bras\u00edlia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Vict\u00f3ria","family":"Souto\u2010Silva","sequence":"additional","affiliation":[{"name":"Interdisciplinary Biosciences Laboratory, Faculty of Medicine University of Bras\u00edlia  Bras\u00edlia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graziella Anselmo","family":"Joanitti","sequence":"additional","affiliation":[{"name":"Laboratory of Bioactive Compounds and Nanobiotechnology (LCBNano), Campus Darcy Ribeiro University of Brasilia  Brasilia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9167-6852","authenticated-orcid":false,"given":"Marcilio","family":"Cunha\u2010Filho","sequence":"additional","affiliation":[{"name":"Laboratory of Food, Drugs, and Cosmetics (LTMAC), School of Health Sciences University of Brasilia  Bras\u00edlia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilherme Martins","family":"Gelfuso","sequence":"additional","affiliation":[{"name":"Laboratory of Food, Drugs, and Cosmetics (LTMAC), School of Health Sciences University of Brasilia  Bras\u00edlia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana Lott","family":"de Carvalho","sequence":"additional","affiliation":[{"name":"Interdisciplinary Biosciences Laboratory, Faculty of Medicine University of Bras\u00edlia  Bras\u00edlia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Saldanha\u2010Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology and Stem Cells (LHCT), School of Health Sciences University of Brasilia  Bras\u00edlia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6481-2364","authenticated-orcid":false,"given":"Ta\u00eds","family":"Gratieri","sequence":"additional","affiliation":[{"name":"Laboratory of Food, Drugs, and Cosmetics (LTMAC), School of Health Sciences University of Brasilia  Bras\u00edlia Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"e_1_2_10_2_1","first-page":"1047","article-title":"A Randomized, Split\u2010Face, Histomorphologic Study Comparing a Volumetric Calcium Hydroxylapatite and a Hyaluronic Acid\u2010Based Dermal Filler","volume":"13","author":"Yutskovskaya Y.","year":"2014","journal-title":"Journal of Drugs in Dermatology"},{"key":"e_1_2_10_3_1","first-page":"68","article-title":"Improved Neocollagenesis and Skin Mechanical Properties After Injection of Diluted Calcium Hydroxylapatite in the Neck and D\u00e9colletage:A Pilot Study","volume":"16","author":"Yutskovskaya Y. A.","year":"2017","journal-title":"Journal of Drugs in Dermatology"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2024.05.005"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/DSS.0000000000002375"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/ijd.16229"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2023.1195934"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1524\u20104725.2008.34245.x"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.2147\/CCID.S50546"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00266\u2010012\u20100052\u20106"},{"key":"e_1_2_10_11_1","first-page":"38","article-title":"Calcium Hydroxylapatite: Over a Decade of Clinical Experience","volume":"8","author":"Van Loghem J.","year":"2015","journal-title":"Journal of Clinical and Aesthetic Dermatology"},{"key":"e_1_2_10_12_1","first-page":"37","article-title":"Vascular Compromise From Soft Tissue Augmentation: Experience With 12 Cases and Recommendations for Optimal Outcomes","volume":"7","author":"Beleznay K.","year":"2014","journal-title":"Journal of Clinical and Aesthetic Dermatology"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/jocd.13353"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/DSS.0000000000000754"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/DSS.0000000000000670"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1524\u20104725.2008.34237.x"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/jocd.12326"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1001\/archderm.138.11.1462"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/jidsymp.2009.8"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.maturitas.2011.04.011"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20092126"},{"key":"e_1_2_10_22_1","unstructured":"ICCVAM ICCVAM\u2010Recommended Test Method Protocol: Hen's Egg Test\u2010Chorioallantoic Membrane (HET\u2010CAM) Test Method in: NIH Publication N. 10\u20107553 2010 https:\/\/ntp.niehs.nih.gov\/sites\/default\/files\/iccvam\/docs\/protocols\/ivocular\u2010hetcam.pdf."},{"key":"e_1_2_10_23_1","unstructured":"A. C. N.Brathwaite Development of a Topical Collagen\u2010Activating Formulation: Evaluation of Iontophoresis and Microneedling in Promoting Calcium Hydroxyapatite Permeation PhD Thesis University of Bras\u00edlia 2024."},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24010723"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10856\u2010007\u20103261\u20109"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26167766"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1177\/18479804211032851"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm.10280"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S256333"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204\u2010012\u20100827\u20101"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/jocd.12215"},{"key":"e_1_2_10_32_1","volume-title":"Guidance on the Safety Assessment of Nanomaterials in Cosmetics","author":"Directorate\u2010General for Health and Food Safety","year":"2019"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.113348"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.2147\/CCID.S212599"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201047491\u2010z"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0027106"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1590\/S0100\u201046702005000300005"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.5681\/apb.2013.011"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010025\u201018396\u2010x"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12249\u2010023\u201002611\u2010x"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1177\/2168479019875338"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2009.12.017"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.22087"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1089\/wound.2013.0485"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/jocd.15521"}],"container-title":["Journal of Biomedical Materials Research Part B: Applied Biomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbm.b.70144","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jbm.b.70144","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbm.b.70144","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T08:22:02Z","timestamp":1787818922000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jbm.b.70144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8]]},"references-count":44,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/jbm.b.70144"],"URL":"https:\/\/doi.org\/10.1002\/jbm.b.70144","archive":["Portico"],"relation":{},"ISSN":["1552-4973","1552-4981"],"issn-type":[{"value":"1552-4973","type":"print"},{"value":"1552-4981","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8]]},"assertion":[{"value":"2026-03-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70144"}}