Engineering Personalized Devices for Craniomaxillofacial Defects

适当地恢复发育中儿童缺失的骨骼组织的形态和功能是值得注意的 挑战。幼儿颅颌面骨的缺陷表现为显著的情感和 经济负担，因为它们的修复/再生通常需要多次植骨手术(通常 从头骨、臀部或肋骨获取)，以便在孩子成长过程中获得足够的治疗结果。最近的 定制3D打印可降解生物活性陶瓷支架的研制 并在缺损区边缘快速再生骨可以提供一种新的解决方案，并将这些涂层 使用旨在促进更快和更完全的骨愈合的药物的支架可能会增加 生长中儿童颅颌面骨缺损的治疗。这样的方法将消除这种必要性 用于二次手术部位的骨移植采购，具有最大限度地减少/消除的巨大潜力 由于孩子的成长需要多次手术，因为再生的骨会跟随邻近部位的生长。 结构。这种骨缺陷治疗方案的开发将是史无前例的 儿童和成人骨重建手术的研究进展。我们最近做了 进行了定制3D打印可降解生物活性陶瓷支架涂层的初步研究 使用刺激腺苷受体的试剂(即潘生丁)，可以显著促进骨再生。 这种效应的细胞和分子基础目前正在1R01AR068593-01项下进行研究。 通过这种方法，我们已经成功地在兔模型中再生了带血管的骨 长骨和下颌骨的临界大小节段性缺损到极薄扁平的临界大小的缺损 颅颌面复合体的骨骼。因此，我们建议测试3D打印可降解的假设 双嘧达莫涂层生物活性陶瓷支架可促进骨组织的快速再生 再生的骨骼通常会跟随邻近结构在骨骼中的生长发育 未成熟的受试者，直到骨骼完全发育完成。因此，我们提出以下目标： 最大限度地将潘生丁与个性化3D打印生物活性支架结合在一起 骨质疏松症患者颅颌面缺损的修复及再生骨监测 随着时间的推移。在成功完成目标I(R21)后，我们将把开发的技术转化为再生 并在很长一段时间内监测临床相关的(人体大小)颅颌面部缺陷 骨骼不成熟、高度平移的大型动物物种，呈现骨组织生长动力学 更接近人类。目的二、(R33)翻译开发的个性化3D打印生物活性 陶瓷支架修复骨质疏松症高转移性颅颌面骨缺损 动物种类，并监测随着时间的推移再生的骨骼生长。

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.