{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T13:20:25Z","timestamp":1776864025426,"version":"3.51.2"},"reference-count":52,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T00:00:00Z","timestamp":1638316800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Materials"],"abstract":"<jats:p>The physicochemical properties of synthetically produced bone substitute materials (BSM) have a major impact on biocompatibility. This affects bony tissue integration, osteoconduction, as well as the degradation pattern and the correlated inflammatory tissue responses including macrophages and multinucleated giant cells (MNGCs). Thus, influencing factors such as size, special surface morphologies, porosity, and interconnectivity have been the subject of extensive research. In the present publication, the influence of the granule size of three identically manufactured bone substitute granules based on the technology of hydroxyapatite (HA)-forming calcium phosphate cements were investigated, which includes the inflammatory response in the surrounding tissue and especially the induction of MNGCs (as a parameter of the material degradation). For the in vivo study, granules of three different size ranges (small = 0.355\u20130.5 mm; medium = 0.5\u20131 mm; big = 1\u20132 mm) were implanted in the subcutaneous connective tissue of 45 male BALB\/c mice. At 10, 30, and 60 days post implantationem, the materials were explanted and histologically processed. The defect areas were initially examined histopathologically. Furthermore, pro- and anti-inflammatory macrophages were quantified histomorphometrically after their immunohistochemical detection. The number of MNGCs was quantified as well using a histomorphometrical approach. The results showed a granule size-dependent integration behavior. The surrounding granulation tissue has passivated in the groups of the two bigger granules at 60 days post implantationem including a fibrotic encapsulation, while a granulation tissue was still present in the group of the small granules indicating an ongoing cell-based degradation process. The histomorphometrical analysis showed that the number of proinflammatory macrophages was significantly increased in the small granules at 60 days post implantationem. Similarly, a significant increase of MNGCs was detected in this group at 30 and 60 days post implantationem. Based on these data, it can be concluded that the integration and\/or degradation behavior of synthetic bone substitutes can be influenced by granule size.<\/jats:p>","DOI":"10.3390\/ma14237372","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T02:40:02Z","timestamp":1638412802000},"page":"7372","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["The Granule Size Mediates the In Vivo Foreign Body Response and the Integration Behavior of Bone Substitutes"],"prefix":"10.3390","volume":"14","author":[{"given":"Manuel","family":"Abels","sequence":"first","affiliation":[{"name":"BerlinAnalytix GmbH, 12109 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Said","family":"Alkildani","sequence":"additional","affiliation":[{"name":"BerlinAnalytix GmbH, 12109 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7251-7621","authenticated-orcid":false,"given":"Annica","family":"Pr\u00f6hl","sequence":"additional","affiliation":[{"name":"BerlinAnalytix GmbH, 12109 Berlin, Germany"},{"name":"Clinic and Policlinic for Dermatology and Venereology, University Medical Center Rostock, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0902-7886","authenticated-orcid":false,"given":"Xin","family":"Xiong","sequence":"additional","affiliation":[{"name":"NMI Natural and Medical Sciences Institute, University of T\u00fcbingen, 72770 Reutlingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1890-0707","authenticated-orcid":false,"given":"Rumen","family":"Krastev","sequence":"additional","affiliation":[{"name":"Faculty of Applied Chemistry, Reutlingen University, 72762 Reutlingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadas","family":"Korzinskas","sequence":"additional","affiliation":[{"name":"Bok\u0161t\u0173 Odontologijos Klinika, 92125 Klaip\u0117da, Lithuania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanja","family":"Stojanovic","sequence":"additional","affiliation":[{"name":"Department for Cell and Tissue Engineering, Faculty of Medicine, University of Ni\u0161, 18000 Ni\u0161, Serbia"},{"name":"Department of Biology and Human Genetics, Faculty of Medicine, University of Ni\u0161, 18000 Ni\u0161, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ole","family":"Jung","sequence":"additional","affiliation":[{"name":"Clinic and Policlinic for Dermatology and Venereology, University Medical Center Rostock, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2411-9802","authenticated-orcid":false,"given":"Stevo","family":"Najman","sequence":"additional","affiliation":[{"name":"Department for Cell and Tissue Engineering, Faculty of Medicine, University of Ni\u0161, 18000 Ni\u0161, Serbia"},{"name":"Department of Biology and Human Genetics, Faculty of Medicine, University of Ni\u0161, 18000 Ni\u0161, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3001-1347","authenticated-orcid":false,"given":"Mike","family":"Barbeck","sequence":"additional","affiliation":[{"name":"Department of Ceramic Materials, Chair of Advanced Ceramic Materials, Institute for Materials Science and Technologies, Technical University of Berlin, 10623 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Rolvien, T., Barbeck, M., Wenisch, S., Amling, M., and Krause, M. (2018). Cellular Mechanisms Responsible for Success and Failure of Bone Substitute Materials. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19102893"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jdsr.2018.09.003","article-title":"Bone grafting materials in dentoalveolar reconstruction: A comprehensive review","volume":"55","author":"Titsinides","year":"2018","journal-title":"Jpn. Dent. Sci. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.oooo.2016.04.010","article-title":"Biologic and clinical aspects of integration of different bone substitutes in oral surgery: A literature review","volume":"122","author":"Zizzari","year":"2016","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1111\/j.1600-0501.2010.01918.x","article-title":"Alveolar ridge preservation with guided bone regeneration and a synthetic bone substitute or a bovine-derived xenograft: A randomized, controlled clinical trial","volume":"21","author":"Mardas","year":"2010","journal-title":"Clin. Oral Implant. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1111\/j.1600-0501.2011.02384.x","article-title":"Histologic and histomorphometric evaluation of a synthetic bone substitute for maxillary sinus grafting in humans","volume":"24","author":"Tosta","year":"2011","journal-title":"Clin. Oral Implant. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1056943","DOI":"10.1080\/21592535.2015.1056943","article-title":"Small-sized granules of biphasic bone substitutes support fast implant bed vascularization","volume":"5","author":"Barbeck","year":"2015","journal-title":"Biomatter"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.tripleo.2011.04.013","article-title":"Osteoinductive activity of biphasic calcium phosphate with different rhBMP-2 doses in rats","volume":"113","author":"Jang","year":"2011","journal-title":"Oral Surg. Oral Med. Oral Pathol. Oral Radiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1002\/jbm.b.34495","article-title":"Size matters: Effect of granule size of the bone graft substitute (Herafill\u00ae) on bone healing using Masquelet\u2019s induced membrane in a critical size defect model in the rat\u2019s femur","volume":"108","author":"Leiblein","year":"2019","journal-title":"J. Biomed. Mater. Res. Part B: Appl. Biomater."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/(SICI)1097-4636(199907)46:1<103::AID-JBM12>3.0.CO;2-Z","article-title":"Influence of biphasic calcium phosphate granulometry on bone ingrowth, ceramic resorption, and inflammatory reactions: Preliminary in vitro and in vivo study","volume":"46","author":"Malard","year":"1999","journal-title":"J. Biomed. Mater. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Dondossola, E., Holzapfel, B.M., Alexander, S., Filippini, S., Hutmacher, D.W., and Friedl, P. (2016). Examination of the foreign body response to biomaterials by nonlinear intravital microscopy. Nat. Biomed. Eng., 1.","DOI":"10.1038\/s41551-016-0007"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1002\/jbm.a.36594","article-title":"Biomaterial-induced multinucleated giant cells express proinflammatory signaling molecules: A histological study in humans","volume":"107","author":"Zhang","year":"2018","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"557","DOI":"10.21873\/invivo.11808","article-title":"Implantation of an Injectable Bone Substitute Material Enables Integration Following the Principles of Guided Bone Regeneration","volume":"34","author":"Barbeck","year":"2020","journal-title":"In Vivo"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.21873\/invivo.12148","article-title":"Specialized Histological and Histomorphometrical Analytical Methods for Biocompatibility Testing of Biomaterials for Maxillofacial Surgery in (Pre-) Clinical Studies","volume":"34","author":"Lindner","year":"2020","journal-title":"In Vivo"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.actbio.2020.06.022","article-title":"\u03b2-tricalcium phosphate for bone substitution: Synthesis and properties","volume":"113","author":"Bohner","year":"2020","journal-title":"Acta Biomater."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hettich, G., Schierjott, R.A., Epple, M., Gbureck, U., Heinemann, S., Mozaffari-Jovein, H., and Grupp, T.M. (2019). Calcium Phosphate Bone Graft Substitutes with High Mechanical Load Capacity and High Degree of Interconnecting Porosity. Materials, 12.","DOI":"10.3390\/ma12213471"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6199","DOI":"10.1016\/j.actbio.2012.12.017","article-title":"Properties of injectable ready-to-use calcium phosphate cement based on water-immiscible liquid","volume":"9","author":"Heinemann","year":"2012","journal-title":"Acta Biomater."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.21873\/invivo.12040","article-title":"In Vitro and In Vivo Biocompatibility Analysis of a New Transparent Collagen-based Wound Membrane for Tissue Regeneration in Different Clinical Indications","volume":"34","author":"Jung","year":"2020","journal-title":"In Vivo"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Steigmann, L., Jung, O., Kieferle, W., Stojanovic, S., Proehl, A., G\u00f6rke, O., Emmert, S., Najman, S., Barbeck, M., and Rothamel, D. (2020). Biocompatibility and Immune Response of a Newly Developed Volume-Stable Magnesium-Based Barrier Membrane in Combination with a PVD Coating for Guided Bone Regeneration (GBR). Biomedicines, 8.","DOI":"10.3390\/biomedicines8120636"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Oberdiek, F., Vargas, C., Rider, P., Batinic, M., G\u00f6rke, O., Radenkovi\u0107, M., Najman, S., Baena, J., Jung, O., and Barbeck, M. (2021). Ex Vivo and In Vivo Analyses of Novel 3D-Printed Bone Substitute Scaffolds Incorporating Biphasic Calcium Phosphate Granules for Bone Regeneration. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073588"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1089\/ten.teb.2017.0242","article-title":"Multinucleated Giant Cells: Good Guys or Bad Guys?","volume":"24","author":"Miron","year":"2018","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"342304","DOI":"10.1155\/2015\/342304","article-title":"Innate Immunity and Biomaterials at the Nexus: Friends or Foes","volume":"2015","author":"Christo","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1002\/jbm.a.36006","article-title":"Multinucleated giant cells in the implant bed of bone substitutes are foreign body giant cells-New insights into the material-mediated healing process","volume":"105","author":"Barbeck","year":"2017","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1001\/jama.1937.02780450005002","article-title":"Simplified Technic of Onlay Grafts","volume":"109","author":"Harkins","year":"1937","journal-title":"J. Am. Med. Assoc."},{"key":"ref_24","first-page":"303","article-title":"The fate of transplanted bone and regenerative power of its various constituents","volume":"19","author":"Phemister","year":"1914","journal-title":"Surg. Gynecol. Obstet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"15005","DOI":"10.1088\/1748-6041\/7\/1\/015005","article-title":"The chemical composition of synthetic bone substitutes influences tissue reactions in vivo: Histological and histomorphometrical analysis of the cellular inflammatory response to hydroxyapatite, beta-tricalcium phosphate and biphasic calcium phosphate ceramics","volume":"7","author":"Ghanaati","year":"2012","journal-title":"Biomed. Mater."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Rider, P., Ka\u010darevi\u0107, P., Alkildani, S., Retnasingh, S., Schnettler, R., and Barbeck, M. (2018). Additive Manufacturing for Guided Bone Regeneration: A Perspective for Alveolar Ridge Augmentation. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113308"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1016\/j.biomaterials.2008.03.028","article-title":"The slow resorption with replacement by bone of a hydrothermally synthesized pure calcium-deficient hydroxyapatite","volume":"29","author":"Okuda","year":"2008","journal-title":"Biomaterials"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e212","DOI":"10.1563\/aaid-joi-D-14-00168","article-title":"High-Temperature Sintering of Xenogeneic Bone Substitutes Leads to Increased Multinucleated Giant Cell Formation: In Vivo and Preliminary Clinical Results","volume":"41","author":"Barbeck","year":"2015","journal-title":"J. Oral Implant."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.smim.2007.11.004","article-title":"Foreign body reaction to biomaterials","volume":"20","author":"Anderson","year":"2008","journal-title":"Semin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1016\/j.biomaterials.2012.02.034","article-title":"Macrophage polarization: An opportunity for improved outcomes in biomaterials and regenerative medicine","volume":"33","author":"Brown","year":"2012","journal-title":"Biomaterials"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.jconrel.2016.01.026","article-title":"Delivery strategies to control inflammatory response: Modulating M1\u2013M2 polarization in tissue engineering applications","volume":"240","author":"Alvarez","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.actbio.2016.07.003","article-title":"Macrophage reaction against biomaterials in the mouse model\u2013Phenotypes, functions and markers","volume":"43","author":"Klopfleisch","year":"2016","journal-title":"Acta Biomater."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.mattod.2015.01.019","article-title":"Biomaterial based modulation of macrophage polarization: A review and suggested design principles","volume":"18","author":"Sridharan","year":"2015","journal-title":"Mater. Today"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Barbeck, M., Schr\u00f6der, M.-L., Alkildani, S., Jung, O., and Unger, R. (2021). Exploring the Biomaterial-Induced Secretome: Physical Bone Substitute Characteristics Influence the Cytokine Expression of Macrophages. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094442"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4476","DOI":"10.1016\/j.actbio.2010.07.006","article-title":"Influence of \u03b2-tricalcium phosphate granule size and morphology on tissue reaction in vivo","volume":"6","author":"Ghanaati","year":"2010","journal-title":"Acta Biomater."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1902\/jop.2006.050268","article-title":"The Effect of Varying the Particle Size of Beta Tricalcium Phosphate Carrier of Recombinant Human Bone Morphogenetic Protein-4 on Bone Formation in Rat Calvarial Defects","volume":"77","author":"Jung","year":"2006","journal-title":"J. Periodontol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Shrivastava, P., and Bagchi, T. (2013). IL-10 Modulates In Vitro Multinucleate Giant Cell Formation in Human Tuberculosis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0077680"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.actbio.2008.07.023","article-title":"Size effect of hydroxyapatite nanoparticles on proliferation and apoptosis of osteoblast-like cells","volume":"5","author":"Shi","year":"2009","journal-title":"Acta Biomater."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1002\/(SICI)1097-4636(19980305)39:3<390::AID-JBM7>3.0.CO;2-E","article-title":"Influence of hydroxyapatite particle size on bone cell activities: Anin vitro study","volume":"39","author":"Sun","year":"1998","journal-title":"J. Biomed. Mater. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1002\/jbm.b.32895","article-title":"The effect of particle size on the osteointegration of injectable silicate-substituted calcium phosphate bone substitute materials","volume":"101B","author":"Coathup","year":"2013","journal-title":"J. Biomed. Mater. Res. Part B Appl. Biomater."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1563\/1548-1336(2007)33[267:EOGSOT]2.0.CO;2","article-title":"Effects of Granule Size on the Osteoconductivity of Bovine and Synthetic Hydroxyapatite: A Histologic and Histometric Study in Dogs","volume":"33","author":"Carvalho","year":"2007","journal-title":"J. Oral Implant."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/j.biopha.2017.01.136","article-title":"Fundamentals of protein and cell interactions in biomaterials","volume":"88","author":"Aiyelabegan","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1084\/jem.20051123","article-title":"Macrophage fusion","volume":"202","author":"Vignery","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5671","DOI":"10.3390\/ma8095269","article-title":"Macrophages, Foreign Body Giant Cells and Their Response to Implantable Biomaterials","volume":"8","author":"Sheikh","year":"2015","journal-title":"Materials"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/s40145-017-0228-2","article-title":"Controlling calcium and phosphate ion release of 3D printed bioactive ceramic scaffolds: An in vitro study","volume":"6","author":"Witek","year":"2017","journal-title":"J. Adv. Ceram."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S1389-0344(02)00023-0","article-title":"In vitro studies of human and rat osteoclast activity on hydroxyapatite, \u03b2-tricalcium phosphate, calcium carbonate","volume":"19","author":"Monchau","year":"2002","journal-title":"Biomol. Eng."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"12880","DOI":"10.1021\/acsnano.0c08614","article-title":"Calcium ions promote membrane fusion by forming negative-curvature inducing clusters on specific anionic lipids","volume":"15","author":"Allolio","year":"2020","journal-title":"ACS Nano"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/BF02207227","article-title":"Bone remodelling in osteoporosis","volume":"8","year":"1989","journal-title":"Clin. Rheumatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s00590-012-0939-6","article-title":"Total hip arthroplasty for vascular necrosis of the femoral head in patients with systemic lupus erythematosus: A midterm follow-up study of 28 hips in 24 patients","volume":"23","author":"Kang","year":"2012","journal-title":"Eur. J. Orthop. Surg. Traumatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/j.1532-849X.2006.00129.x","article-title":"Calcium Phosphate Cement: Review of Mechanical and Biological Properties","volume":"15","author":"Ambard","year":"2006","journal-title":"J. Prosthodont."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.1016\/j.biomaterials.2009.12.039","article-title":"Resorption of monetite granules in alveolar bone defects in human patients","volume":"31","author":"Tamimi","year":"2010","journal-title":"Biomaterials"},{"key":"ref_52","first-page":"841","article-title":"Dimensional changes in the sinus membrane following maxillary sinus augmentation","volume":"49","author":"Mayer","year":"2018","journal-title":"Quintessence Int."}],"container-title":["Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1996-1944\/14\/23\/7372\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:38:28Z","timestamp":1760168308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1996-1944\/14\/23\/7372"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,1]]},"references-count":52,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ma14237372"],"URL":"https:\/\/doi.org\/10.3390\/ma14237372","relation":{},"ISSN":["1996-1944"],"issn-type":[{"value":"1996-1944","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,1]]}}}