{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:52:16Z","timestamp":1790470336247,"version":"4.1.0"},"reference-count":58,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,21]],"date-time":"2022-01-21T00:00:00Z","timestamp":1642723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Injectable bone substitutes (IBS) are increasingly being used in the fields of orthopedics and maxillofacial\/oral surgery. The rheological properties of IBS allow for proper and less invasive filling of bony defects. Vaterite is the most unstable crystalline polymorph of calcium carbonate and is known to be able to transform into hydroxyapatite upon contact with an organic fluid (e.g., interstitial body fluid). Two different concentrations of hydrogels based on poly(ethylene glycol)-acetal-dimethacrylat (PEG-a-DMA), i.e., 8% (w\/v) (VH-A) or 10% (w\/v) (VH-B), were combined with vaterite nanoparticles and implanted in subcutaneous pockets of BALB\/c mice for 15 and 30 days. Explants were prepared for histochemical staining and immunohistochemical detection methods to determine macrophage polarization, and energy-dispersive X-ray analysis (EDX) to analyze elemental composition was used for the analysis. The histopathological analysis revealed a comparable moderate tissue reaction to the hydrogels mainly involving macrophages. Moreover, the hydrogels underwent a slow cellular infiltration, revealing a different degradation behavior compared to other IBS. The immunohistochemical detection showed that M1 macrophages were mainly found at the material surfaces being involved in the cell-mediated degradation and tissue integration, while M2 macrophages were predominantly found within the reactive connective tissue. Furthermore, the histomorphometrical analysis revealed balanced numbers of pro- and anti-inflammatory macrophages, demonstrating that both hydrogels are favorable materials for bone tissue regeneration. Finally, the EDX analysis showed a stepwise transformation of the vaterite particle into hydroxyapatite. Overall, the results of the present study demonstrate that hydrogels including nano-vaterite particles are biocompatible and suitable for bone tissue regeneration applications.<\/jats:p>","DOI":"10.3390\/ijms23031196","type":"journal-article","created":{"date-parts":[[2022,1,23]],"date-time":"2022-01-23T20:32:52Z","timestamp":1642969972000},"page":"1196","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["In Vivo Biocompatibility Investigation of an Injectable Calcium Carbonate (Vaterite) as a Bone Substitute including Compositional Analysis via SEM-EDX Technology"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2482-9705","authenticated-orcid":false,"given":"Ronald E.","family":"Unger","sequence":"first","affiliation":[{"name":"Repair-Lab, Institute of Pathology, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanja","family":"Stojanovic","sequence":"additional","affiliation":[{"name":"Department of Biology and Human Genetics, Faculty of Medicine, University of Ni\u0161, 18108 Ni\u0161, Serbia"},{"name":"Scientific Research Center for Biomedicine, Department for Cell and Tissue Engineering, Faculty of Medicine, University of Ni\u0161, 18108 Ni\u0161, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Besch","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry and Analytical Chemistry, Johannes Gutenberg-University of Mainz, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Said","family":"Alkildani","sequence":"additional","affiliation":[{"name":"BerlinAnalytix GmbH, Ullsteinstrasse 108, 12109 Berlin, Germany"},{"name":"Clinic and Policlinic for Dermatology and Venereology, University Medical Center Rostock, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Schr\u00f6der","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry and Analytical Chemistry, Johannes Gutenberg-University of Mainz, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8005-2916","authenticated-orcid":false,"given":"Ole","family":"Jung","sequence":"additional","affiliation":[{"name":"Clinic and Policlinic for Dermatology and Venereology, University Medical Center Rostock, 18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Bogram","sequence":"additional","affiliation":[{"name":"BerlinAnalytix GmbH, Ullsteinstrasse 108, 12109 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7978-2484","authenticated-orcid":false,"given":"Oliver","family":"G\u00f6rke","sequence":"additional","affiliation":[{"name":"Institute of Materials Science and Technology, Chair of Advanced Ceramic Materials, Technical University Berlin, Hardenbergstr. 40, 10623 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2411-9802","authenticated-orcid":false,"given":"Stevo","family":"Najman","sequence":"additional","affiliation":[{"name":"Department of Biology and Human Genetics, Faculty of Medicine, University of Ni\u0161, 18108 Ni\u0161, Serbia"},{"name":"Scientific Research Center for Biomedicine, Department for Cell and Tissue Engineering, Faculty of Medicine, University of Ni\u0161, 18108 Ni\u0161, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4536-994X","authenticated-orcid":false,"given":"Wolfgang","family":"Tremel","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry and Analytical Chemistry, Johannes Gutenberg-University of Mainz, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3001-1347","authenticated-orcid":false,"given":"Mike","family":"Barbeck","sequence":"additional","affiliation":[{"name":"Institute of Materials Science and Technology, Chair of Advanced Ceramic Materials, Technical University Berlin, Hardenbergstr. 40, 10623 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s41536-018-0044-5","article-title":"Comparative regenerative mechanisms across different mammalian tissues","volume":"3","author":"Iismaa","year":"2018","journal-title":"NPJ Regen. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Rider, P., Ka\u010darevi\u0107, \u017d.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_3","doi-asserted-by":"crossref","unstructured":"Stewart, S., Bryant, S.J., Ahn, J., and Hankenson, K.D. (2015). Bone Regeneration. Translational Regenerative Medicine, Elsevier.","DOI":"10.1016\/B978-0-12-410396-2.00024-4"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1563\/1548-1336(2002)028<0220:CAAIMI>2.3.CO;2","article-title":"Collagen as an Implantable Material in Medicine and Dentistry","volume":"28","author":"Neiders","year":"2002","journal-title":"J. Oral Implantol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/jcpe.13068","article-title":"Barrier membranes: More than the barrier effect?","volume":"46","author":"Omar","year":"2019","journal-title":"J. Clin. Periodontol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1111\/eos.12364","article-title":"Guided bone regeneration: Materials and biological mechanisms revisited","volume":"125","author":"Elgali","year":"2017","journal-title":"Eur. J. Oral Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1097\/01.scs.0000179662.38172.dd","article-title":"Allograft and alloplastic bone substitutes: A review of science and technology for the craniomaxillofacial surgeon","volume":"16","author":"Eppley","year":"2005","journal-title":"J. Craniofac. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bae, E.-B., Kim, H.-J., Ahn, J.-J., Bae, H.-Y., Kim, H.-J., and Huh, J.-B. (2019). Comparison of Bone Regeneration between Porcine-Derived and Bovine-Derived Xenografts in Rat Calvarial Defects: A Non-Inferiority Study. Materials, 12.","DOI":"10.3390\/ma12203412"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1177\/0391398819876286","article-title":"An introduction to bone tissue engineering","volume":"43","author":"Rider","year":"2020","journal-title":"Int. J. Artif. Organs"},{"key":"ref_10","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":"2019","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_11","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 Implantol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Abels, M., Alkildani, S., Pr\u00f6hl, A., Xiong, X., Krastev, R., Korzinskas, T., Stojanovic, S., Jung, O., Najman, S., and Barbeck, M. (2021). The Granule Size Mediates the In Vivo Foreign Body Response and the Integration Behavior of Bone Substitutes. Materials, 14.","DOI":"10.3390\/ma14237372"},{"key":"ref_13","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_14","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1002\/path.4133","article-title":"Macrophage plasticity and polarization in tissue repair and remodelling","volume":"229","author":"Mantovani","year":"2013","journal-title":"J. Pathol."},{"key":"ref_15","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_16","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\u2014New insights into the material-mediated healing process","volume":"105","author":"Barbeck","year":"2017","journal-title":"Biomed. Mater. Res. A"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1097\/00062752-200001000-00008","article-title":"Multinucleated giant cells","volume":"7","author":"Anderson","year":"2000","journal-title":"Curr. Opin. Hematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4476","DOI":"10.1016\/j.actbio.2010.07.006","article-title":"Influence of beta-tricalcium phosphate granule size and morphology on tissue reaction in vivo","volume":"6","author":"Ghanaati","year":"2010","journal-title":"Acta Biomater."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"398","DOI":"10.18502\/ijaai.v17i5.298","article-title":"Modulation of macrophage polarization for bone tissue engineering applications","volume":"17","author":"Jamalpoor","year":"2018","journal-title":"Iran. J. Allergy Asthma Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.coms.2007.06.002","article-title":"A review of bone substitutes","volume":"19","author":"Kao","year":"2007","journal-title":"Oral Maxillofac. Surg. Clin. N. Am."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7079","DOI":"10.1039\/C5TB01032B","article-title":"Transformation of vaterite nanoparticles to hydroxycarbonate apatite in a hydrogel scaffold: Relevance to bone formation","volume":"3","author":"Pohlit","year":"2015","journal-title":"J. Mater. Chem. B"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.actbio.2019.04.039","article-title":"Calcium carbonate: Adored and ignored in bioactivity assessment","volume":"91","author":"Mozafari","year":"2019","journal-title":"Acta Biomater."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3369","DOI":"10.1021\/es000210b","article-title":"Interaction between calcium and phosphate adsorption on goethite","volume":"35","author":"Rietra","year":"2001","journal-title":"Environ. Sci. Technol."},{"key":"ref_24","unstructured":"Janeway, C., Travers, P., Walport, M., and Schlomchik, M.J. (2001). Immunobiology: The Immune Sytem in Health and Disease, Garland Science. [5th ed.]."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1563\/aaid-joi-D-14-00203","article-title":"Injectable Bone Substitute Based on beta-TCP Combined With a Hyaluronan-Containing Hydrogel Contributes to Regeneration of a Critical Bone Size Defect Towards Restitutio ad Integrum","volume":"42","author":"Barbeck","year":"2016","journal-title":"J. Oral Implantol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"636","DOI":"10.11607\/jomi.6026","article-title":"Injectable Bone Substitute Material on the Basis of beta-TCP and Hyaluronan Achieves Complete Bone Regeneration While Undergoing Nearly Complete Degradation","volume":"33","author":"Lorenz","year":"2018","journal-title":"Int. J. Oral Maxillofac. Implants"},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"17014","DOI":"10.1038\/boneres.2017.14","article-title":"Injectable hydrogels for cartilage and bone tissue engineering","volume":"5","author":"Liu","year":"2017","journal-title":"Bone Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.msec.2017.02.170","article-title":"The relationship between particle morphology and rheological properties in injectable nano-hydroxyapatite bone graft substitutes","volume":"75","author":"Ryabenkova","year":"2017","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Lindner, C., Pr\u00f6hl, A., Abels, M., L\u00f6ffler, T., Batinic, M., Jung, O., and Barbeck, M. (2020). Specialized Histological and Histomorphometrical Analytical Methods for Biocompatibility Testing of Biomaterials for Maxillofacial Surgery in (Pre-) Clinical Studies, International Institute of Anticancer Research.","DOI":"10.21873\/invivo.12148"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.1016\/j.biomaterials.2007.04.006","article-title":"The safety and efficacy of an injectable bone substitute in dental sockets demonstrated in a human clinical trial","volume":"28","author":"Weiss","year":"2007","journal-title":"Biomaterials"},{"key":"ref_32","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. Obs."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4018","DOI":"10.1016\/j.actbio.2011.07.003","article-title":"An injectable bone substitute composed of beta-tricalcium phosphate granules, methylcellulose and hyaluronic acid inhibits connective tissue influx into its implantation bed in vivo","volume":"7","author":"Ghanaati","year":"2011","journal-title":"Acta Biomater."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1097\/MOH.0b013e32831ac52e","article-title":"Giant cell formation and function","volume":"16","author":"Brodbeck","year":"2009","journal-title":"Curr. Opin. Hematol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Barbeck, M., Dard, M., Kokkinopoulou, M., Markl, J., Booms, P., Sader, R.A.R., Kirkpatrick, C.J., and Ghanaati, S. (2015). Small-sized granules of biphasic bone substitutes support fast implant bed vascularization. Biomatter, 5.","DOI":"10.1080\/21592535.2015.1056943"},{"key":"ref_36","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_37","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1091\/mbc.E19-01-0009","article-title":"An actin-based protrusion originating from a podosome-enriched region initiates macrophage fusion","volume":"30","author":"Faust","year":"2019","journal-title":"Mol. Biol. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4776","DOI":"10.4238\/2014.July.2.7","article-title":"New roles of filopodia and podosomes in the differentiation and fusion process of osteoclasts","volume":"13","author":"Song","year":"2014","journal-title":"Genet. Mol. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.yexmp.2005.06.008","article-title":"Multinucleated giant cell formation exhibits features of phagocytosis with participation of the endoplasmic reticulum","volume":"79","author":"McNally","year":"2005","journal-title":"Exp. Mol. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Barbeck, M., Schr\u00f6der, M.L., Alkildani, S., Jung, O., and Unger, R.E. (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_41","doi-asserted-by":"crossref","unstructured":"Pr\u00f6hl, A., Batinic, M., Alkildani, S., Hahn, M., Radenkovic, M., Najman, S., Jung, O., and Barbeck, M. (2021). In vivo analysis of the biocompatibility and bone healing capacity of a novel bone grafting material combined with hyaluronic acid. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094818"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Radenkovi\u0107, M., Alkildani, S., Stoewe, I., Bielenstein, J., Sundag, B., Bellmann, O., Jung, O., Najman, S., Stojanovi\u0107, S., and Barbeck, M. (2021). Comparative in vivo analysis of the integration behavior and immune response of collagen-based dental barrier membranes for guided bone regeneration (GBR). Membranes, 11.","DOI":"10.3390\/membranes11090712"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Jung, O., Smeets, R., Hartjen, P., Schnettler, R., Feyerabend, F., Klein, M., Wegner, N., Walther, F., Stangier, D., and Henningsen, A. (2019). Improved in vitro test procedure for full assessment of the cytocompatibility of degradable magnesium based on ISO 10993-5\/-12. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20020255"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"93","DOI":"10.6111\/JKCGCT.2010.20.2.093","article-title":"Determination of stoichiometric Ca\/P ratio in biphasic calcium phosphates using X-ray diffraction analysis","volume":"20","author":"Song","year":"2010","journal-title":"J. Korean Cryst. Growth Cryst. Technol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/S0022-0248(98)00385-6","article-title":"The transformation of vaterite to calcite: Effect of the conditions of the solutions in contact with the mineral phase","volume":"191","author":"Spanos","year":"1998","journal-title":"J. Cryst. Growth"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18232","DOI":"10.1039\/C9RA01473J","article-title":"Phase-specific bioactivity and altered Ostwald ripening pathways of calcium carbonate polymorphs in simulated body fluid","volume":"9","author":"Myszka","year":"2019","journal-title":"RSC Adv."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2007830","DOI":"10.1002\/adfm.202007830","article-title":"Insights into the In Vitro Formation of Apatite from Mg-Stabilized Amorphous Calcium Carbonate","volume":"31","author":"Opitz","year":"2021","journal-title":"Adv. Funct. Mater."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1002\/term.2703","article-title":"Particles of vaterite, a metastable CaCO3 polymorph, exhibit high biocompatibility for human osteoblasts and endothelial cells and may serve as a biomaterial for rapid bone regeneration","volume":"12","author":"Besch","year":"2018","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"8150","DOI":"10.1016\/j.biomaterials.2011.07.041","article-title":"Scaffold vascularization in vivo driven by primary human osteoblasts in concert with host inflammatory cells","volume":"32","author":"Ghanaati","year":"2011","journal-title":"Biomaterials"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6959","DOI":"10.1016\/j.biomaterials.2010.05.057","article-title":"The rapid anastomosis between prevascularized networks on silk fibroin scaffolds generated in vitro with cocultures of human microvascular endothelial and osteoblast cells and the host vasculature","volume":"31","author":"Unger","year":"2010","journal-title":"Biomaterials"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ghanaati, S.M., Thimm, B.W., Unger, R.E., Orth, C., Kohler, T., Barbeck, M., M\u00fcller, R., and Kirkpatrick, C.J. (2010). Collagen-embedded hydroxylapatite-beta-tricalcium phosphate-silicon dioxide bone substitute granules assist rapid vascularization and promote cell growth. Biomed. Mater., 5.","DOI":"10.1088\/1748-6041\/5\/2\/025004"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Ghanaati, S., Barbeck, M., Detsch, R., Deisinger, U., Hilbig, U., Rausch, V., Sader, R., Unger, R.E., Ziegler, G., and Kirkpatrick, C.J. (2012). 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 cer. Biomed. Mater., 7.","DOI":"10.1088\/1748-6041\/7\/1\/015005"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1002\/jbm.a.35579","article-title":"Heterogeneity of biomaterial-induced multinucleated giant cells: Possible importance for the regeneration process?","volume":"104","author":"Barbeck","year":"2016","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"150","DOI":"10.4103\/2231-0746.147106","article-title":"Induction of multinucleated giant cells in response to small sized bovine bone substitute (Bio-Oss TM) results in an enhanced early implantation bed vascularization","volume":"4","author":"Ghanaati","year":"2014","journal-title":"Ann. Maxillofac. Surg."},{"key":"ref_55","first-page":"208","article-title":"Analysis of the in vitro degradation and the in vivo tissue response to bi-layered 3D-printed scaffolds combining PLA and biphasic PLA\/bioglass components\u2014Guidance of the inflammatory response as basis for osteochondral regeneration","volume":"2","author":"Barbeck","year":"2017","journal-title":"Bioact. Mater."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.11607\/jomi.6226","article-title":"Sinus Floor Elevation Using the Lateral Approach and Window Repositioning and a Xenogeneic Bone Substitute as a Grafting Material: A Histologic, Histomorphometric, and Radiographic Analysis","volume":"33","author":"Tawil","year":"2018","journal-title":"Int. J. Oral Maxillofac. Implants"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2928","DOI":"10.1002\/jbm.a.35834","article-title":"Monocyte preseeding leads to an increased implant bed vascularization of biphasic calcium phosphate bone substitutes via vessel maturation","volume":"104","author":"Barbeck","year":"2016","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Barbeck, M., Najman, S., Stojanovic, S., Mitic, Z., Zivkovic, J.M., Choukroun, J., Kovacevic, P., Sader, R., Kirkpatrick, C.J., and Ghanaati, S. (2015). Addition of blood to a phycogenic bone substitute leads to increased in vivo vascularization. Biomed. 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