Cranial Defect Reconstruction With Custom 3D-Printed Hydroxyapatite Scaffolds Augmented With rhBMP-2 or Dipyridamole...

Reconstruction of critical-sized bone defects, particularly in the cranio-maxillofacial region, presents unique challenges due to the need for integration with adjacent well-vascularized tissue and the absence of significant load-bearing requirements. This study evaluated the clinical readiness of bone tissue engineering (BTE) for critically sized cranial defects using custom 3D-printed hydroxyapatite scaffolds augmented with either recombinant human bone morphogenetic protein-2 (rhBMP-2) or dipyridamole (DIPY) in a highly translational nonhuman primate model.

Identical 5 × 5-cm vertex guided craniotomies were created in 12 macaques: Three cynomolgus macaques served as negative controls to validate the critical size nature of the defect, while nine rhesus macaques underwent scaffold reconstruction. Subjects were divided into three groups: uncoated scaffolds (n = 3), scaffolds augmented with rhBMP-2 (Infuse® Medtronic, n = 3), and scaffolds coated with DIPY, an adenosine A_2A receptor (A_2AR) indirect agonist (n = 3). Bone growth and integration were assessed over 12 months through serial CT scans, followed by ex vivo micro-CT scanning, histology, and nanoindentation testing.

Negative control subjects did not demonstrate new bone formation, confirming the critical defect model. Subjects treated with scaffolds through all treatment groups remained intact throughout the 12-month follow-up. The rhBMP-2-treated group exhibited bridging, ∼90% circumferentially, significantly greater than DIPY (∼9%) or the uncoated scaffold (10%) (p < 0.001). Bone volume within rhBMP-2-treated scaffolds (7621 ± 145 mm³) significantly exceeded that of DIPY (6466 ± 693 mm³, p = 0.03) and uncoated scaffold (6348 ± 663 mm³, p = 0.02) groups at 12 months. Quantitative histological micrograph analysis demonstrated that rhBMP-2 scaffolds were associated with the highest bone ingrowth (∼64%) relative to DIPY (∼39%) and uncoated scaffolds (∼27%). Nanoindentation yielded superior mechanical properties (Young's modulus and hardness) of newly generated bone with defects treated with rhBMP-2 scaffolds (p < 0.05).

Reconstructing critically sized cranial defects with custom 3D-printed hydroxyapatite scaffolds was successful and yielded favorable results in this model. Scaffolds augmented with rhBMP-2 demonstrated superior bone ingrowth, integration, and mechanical properties, highlighting their potential as a viable alternative to autografts and allograft materials for cranioplasty.