Appropriate restoration of form and function of the missing skeletal tissue of growing children is a remarkable challenge. Defects in the craniomaxillofacial bones of young children represent a significant emotional and economic burden as their restoration/regeneration often requires multiple bone grafting procedures (usually procured from the skull, hip, or ribs) for adequate treatment outcomes as the child grows. The recent development of custom 3D printed degradable bioactive ceramic scaffolds that can fit and fill large bone defects and quickly regenerate bone within defect margins may provide a novel solution and coating these scaffolds with agents designed to promote more rapid and complete bone healing may increase the efficacy of craniomaxillofacial bone defect treatment in growing children. Such an approach would eliminate the necessity for secondary surgical sites for bone graft procurement and has tremendous potential to minimize/eliminate multiple surgical procedures due to child growth, as the regenerated bone will follow the growth of adjacent structures. The development of such a treatment option for skeletal defects would be an unprecedented advance in bone reconstructive surgery of both growing children and that of adults. We have recently conducted preliminary studies where customized 3D printed degradable bioactive ceramic scaffolds coated with agents, which stimulate adenosine receptors (i.e. dipyridamole), remarkably enhanced bone regeneration. The cellular and molecular basis for this effect is currently under investigation under 1R01AR068593-01. Through this approach, we have successfully regenerated vascularized bone in rabbit models ranging from critical size segmental defects of long bones and mandible to critical size defects of extremely thin and flat bones of the craniomaxillofacial complex. Thus, we propose to test the hypothesis that 3D printed degradable bioactive ceramic scaffolds coated with dipyridamole can promote rapid bone regeneration into a defect and that the regenerated bone will normally follow adjacent structures? growth and development in skeletally immature subjects until full skeletal growth is complete. We therefore propose the following aims: To maximize the combination of dipyridamole with personalized 3D printed bioactive scaffolds for the repair of craniomaxillofacial defects in skeletally immature subjects and monitor the regenerated bone over time. After successfully completing Aim I (R21), we will translate the developed technology to regenerate and monitor over an extended period of time clinically relevant (human size) craniomaxillofacial defects in skeletally immature highly translational large animal species, which presents bone tissue growth dynamics more similar to human.
Aim II. (R33) To translate the developed personalized 3D printed bioactive ceramic scaffolds to treat craniomaxillofacial bone defects in a skeletally immature highly translational animal species and monitor the regenerated bone growth over time.
This proposal seeks funding to develop and test three-dimensionally (3D) printed degradable bioactive ceramic scaffolds coated with a bone forming agent for the reconstruction of craniomaxillofacial defects for skeletally immature subjects. Cleft palate, the most common birth defect of the face and the second most common human birth defect, along with craniosynostosis, a malfunction of cranial suture growth, respectively affect 1:600 and 1:2000-2500 live births in the United States. We propose here to develop and test 3D printed degradable scaffolds devices to promote personalized defect rapid bone regeneration so the regenerated bone will normally follow adjacent structures growth until full skeletal growth is complete.