Multi-scale assessment of scaffold-guided regeneration in human extraction sockets using an ultra-porous TiO₂...

Ultra-porous TiO₂ scaffolds are architected non-degradable ceramic graft substitutes, but human evidence relating their structural integration to local tissue maturation remains limited. This exploratory study assessed scaffold-associated healing in a prospective clinical cohort registered at ClinicalTrials.gov (NCT06269497; 10 patients, 11 treated sites). Cone-beam computed tomography (CBCT)-based segmentation at baseline and follow-up was used to quantify changes in bone volume, radiographic low-density/non-mineralized volume, and radiographically detectable scaffold volume. Eleven scaffold-associated specimens were examined using non-decalcified histology, histomorphometry, and immunohistochemistry; nine were retrieved at approximately 6 months, one at 4 months, and one at 9 months. CBCT showed within-site increases in bone and total tissue volume and a reduction in radiographically detectable scaffold volume. Histology showed extensive pore colonization by osteoid-rich tissue, localized mineralization, and limited residual cartilage, consistent with ongoing but incomplete matrix maturation. Normalized RunX2 showed a positive exploratory association with absolute bone volume change, whereas associations with osteocalcin were uncertain and endpoint-dependent. CD206/CD68 and the vessel-to-osteoid ratio were more closely associated with low-density/non-mineralized volume outcomes than with bone-volume change. Osteoclast-associated variables were evaluable in only four sites and were interpreted descriptively. These findings are exploratory and do not establish causality or comparative efficacy, but they characterize tissue-scaffold interactions during human extraction-socket healing. STATEMENT OF SIGNIFICANCE: Permanent, highly porous scaffolds are intended to guide tissue growth without being replaced, but human evidence linking scaffold architecture to tissue maturation remains limited. This study combines serial cone-beam computed tomography (CBCT), non-decalcified histology, histomorphometry, and immunohistochemistry to characterize tissue development within an ultra-porous TiO₂ scaffold placed in human extraction sockets. The findings show extensive pore colonization by osteoid-rich tissue containing vascular structures, with localized mineralization and spatially heterogeneous remodeling, immune, and Wnt-regulatory features. The analyses are exploratory and do not establish causality or comparative efficacy; however, they provide human tissue-level data on how a permanent architected ceramic scaffold coexists with regenerating bone. This work supports biomaterials-focused evaluation of scaffold-guided regeneration and informs the design of larger controlled studies.