Cranial Defect Reconstruction With Custom 3D‐Printed Hydroxyapatite Scaffolds Augmented With rhBMP‐2 or Dipyridamole in a Nonhuman Primate Model

Objective 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. Methods 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 2A R) 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. Results 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 mm 3 ) significantly exceeded that of DIPY (6466 ± 693 mm 3 , p = 0.03) and uncoated scaffold (6348 ± 663 mm 3 , 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). Conclusions 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.