Abstract
Large bone defects caused by trauma, tumor resection, or congenital abnormalities remain a major clinical challenge. Standard titanium implants are widely used due to their strength and biocompatibility, but their bioinert surfaces often lead to poor osseointegration. The emergence of 3D printing has enabled patient-specific titanium implants with tailored architecture and mechanical properties. However, these constructs still lack the bioactivity required for robust and spatially uniform bone integration, particularly within the implant core. To address this limitation, we developed a bioactive, cell-free strategy that integrates porous titanium implants with a nanofibrillar peptide-hyaluronic acid scaffold, delivered either as a hydrogel or in lyophilized form. The scaffold exhibited enhanced enzymatic stability and supported osteoblast-like cell adhesion in vitro. In a rabbit calvarial critical-size bone defect model, scaffold-integrated implants significantly outperformed inert controls, with hydrogel integration nearly doubling inner bone volume and improving trabecular architecture. Histological analysis confirmed enhanced bone-implant integration, active periosteum, healthy marrow, and reduced inflammation. This acellular, growth-factor-free approach combines the structural precision of titanium with the regenerative potential of ECM-mimicking scaffolds, offering a translatable pathway for personalized skeletal repair.