{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T12:57:19Z","timestamp":1772542639771,"version":"3.50.1"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007619","name":"Osteology Foundation","doi-asserted-by":"publisher","award":["18049"],"award-info":[{"award-number":["18049"]}],"id":[{"id":"10.13039\/501100007619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The architecture of bone substitute scaffolds\u2014particularly pore size and organization\u2014plays a crucial role in orchestrating immune responses, osteogenesis and angiogenesis. Yet, the mechanisms linking scaffold design to the temporal dynamics of bone regeneration remain partially understood. To address this, we established a refined\n                      <jats:italic>in vivo<\/jats:italic>\n                      model that integrates histological, molecular, and immunological analyses from a single explant, enabling spatially resolved insight into the bone healing process and dynamics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using a dynamic rabbit calvarial model, we investigated 3D-printed calcium phosphate cement scaffolds designed with concomitant macroarchitectures of 250\u00a0\u03bcm and 500\u00a0\u00b5m pores within a single construct, allowing direct intra-animal comparison. The model recapitulated three vertically migrating zones of regeneration\u2014regenerative, osteogenic, and granulation\u2014captured at 2 and 4 weeks. Histomorphometric analyses quantified bone ingrowth, while laser microdissection enabled zone-specific transcriptomic profiling from paraffin-embedded sections previously used for (immuno-)histology. Gene expression was further validated by qPCR and complemented with immunohistochemical characterization of macrophage and neutrophil populations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Histological analysis revealed a consistent spatial organization of bone regeneration across conditions. After 4 weeks, scaffolds with 250\u00a0\u00b5m pores exhibited more homogeneous and advanced bone formation than those with 500\u00a0\u00b5m pores or particulate substitutes. Transcriptomic analysis identified 280\u2013381 differentially expressed genes between microporous architectures, with over half being non-coding RNAs, suggesting an important role for post-transcriptional regulation. Enrichment analyses indicated modulation of pathways involved in immune activity, ossification, calcium signaling and autophagy. Immunohistochemistry confirmed similar inflammatory mechanisms across both macroarchitectures but revealed earlier M1-to-M2 macrophage transition and faster inflammatory resolution with the finest porous network.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This integrative\n                      <jats:italic>in vivo<\/jats:italic>\n                      model provides a robust workflow for correlating structural, cellular, and molecular dimensions of bone regeneration within the same specimen. The findings show that scaffold macroarchitecture influences both the extent and timing of immune and osteogenic processes. While scaffolds with 250\u00a0\u03bcm and 500\u00a0\u00b5m pores supported regeneration, the finer design consistently promoted more advanced tissue formation and maturation. These results underscore the key role of scaffold design in modulating bone healing and highlight this model as a platform for studying structure\u2013function relationships in bone tissue engineering.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fbioe.2026.1725958","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T06:56:45Z","timestamp":1771397805000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Refined in vivo model for bone regeneration: insights into scaffold architecture and porosity"],"prefix":"10.3389","volume":"14","author":[{"given":"Laurine","family":"Marger","sequence":"first","affiliation":[{"name":"Laboratory of Biomaterials, Faculty of Medicine, University Clinics of Dental Medicine, University of Geneva","place":["Gen\u00e8ve, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00e9lanie","family":"Freudenreich","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials, Faculty of Medicine, University Clinics of Dental Medicine, University of Geneva","place":["Gen\u00e8ve, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mustapha","family":"Mekki","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials, Faculty of Medicine, University Clinics of Dental Medicine, University of Geneva","place":["Gen\u00e8ve, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Manoil","sequence":"additional","affiliation":[{"name":"Division of Cariology and Endodonty, Faculty of Medicine, University Clinics of Dental Medicine, University of Geneva","place":["Gen\u00e8ve, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabrice","family":"Marger","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials, Faculty of Medicine, University Clinics of Dental Medicine, University of Geneva","place":["Gen\u00e8ve, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanae","family":"El Harane","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, University of Geneva","place":["Gen\u00e8ve, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baptiste","family":"Charbonnier","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, Oniris, INSERM, Regenerative Medicine and Skeleton, RMeS, UMR 1229","place":["Nantes, France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00e9r\u00f4me","family":"Charmet","sequence":"additional","affiliation":[{"name":"School of Engineering HE-Arc Ing\u00e9nierie, HES-SO University of Applied Sciences Western Switzerland","place":["Neuch\u00e2tel, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolo","family":"Brembilla","sequence":"additional","affiliation":[{"name":"Division of Dermatology and Venereology, University Hospitals of Geneva, Geneva, Switzerland and HekeTiss","place":["Geneva, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivier","family":"Preynat-Seauve","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, University of Geneva","place":["Gen\u00e8ve, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"St\u00e9phane","family":"Durual","sequence":"additional","affiliation":[{"name":"Laboratory of Biomaterials, Faculty of Medicine, University Clinics of Dental Medicine, University of Geneva","place":["Gen\u00e8ve, Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6899","DOI":"10.3390\/app15126899","article-title":"How does ceramic-based scaffold microarchitecture impact maxillofacial bone regeneration? 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