In situ bone regeneration of large cranial defects using synthetic ceramic implants with a tailored composition and design

Significance Large cranial reconstructions are increasingly performed worldwide and still represent a substantial clinical challenge. The gold standard, autologous bone, has limited availability and high donor-site morbidity. Current alloplastic materials are associated with high complication and failure rates. This study shows the capacity of a customized, purely synthetic, 3D-manufactured bioceramic implant to regenerate and restore large cranial defects with mature, well-vascularized bone, with a morphology, ultrastructure, and composition similar to those of native skull bone. This approach triggers the regenerative potential of host tissue by tailoring the implant composition and design. The regeneration of large defects using purely synthetic material without adjunct cell therapy or growth factors represents a major advancement for rehabilitating patients in need of large cranial reconstructions.
The repair of large cranial defects with bone is a major clinical challenge that necessitates novel materials and engineering solutions. Three-dimensionally (3D) printed bioceramic (BioCer) implants consisting of additively manufactured titanium frames enveloped with CaP BioCer or titanium control implants with similar designs were implanted in the ovine skull and at s.c. sites and retrieved after 12 and 3 mo, respectively. Samples were collected for morphological, ultrastructural, and compositional analyses using histology, electron microscopy, and Raman spectroscopy. Here, we show that BioCer implants provide osteoinductive and microarchitectural cues that promote in situ bone regeneration at locations distant from existing host bone, whereas bone regeneration with inert titanium implants was confined to ingrowth from the defect boundaries. The BioCer implant promoted bone regeneration at nonosseous sites, and bone bonding to the implant was demonstrated at the ultrastructural level. BioCer transformed to carbonated apatite in vivo, and the regenerated bone displayed a molecular composition indistinguishable from that of native bone. Proof-of-principle that this approach may represent a shift from mere reconstruction to in situ regeneration was provided by a retrieved human specimen, showing that the BioCer was transformed into well-vascularized osteonal bone, with a morphology, ultrastructure, and composition similar to those of native human skull bone.