PTH and Calcium Synergy for Craniofacial Regeneration

描述(申请人提供)：颅面骨创伤和疾病是普遍存在的医疗保健问题。尽管骨具有显著的愈合能力，但对新骨的需求是临床上的一大挑战。甲状旁腺激素(PTH)是目前美国FDA批准的唯一一种治疗骨质疏松症的合成代谢药物，对颅面骨再生具有很强的前景。我们的初步研究表明，在工程化再生医学模型中，全身间歇注射甲状旁腺素(每日注射)显著刺激骨再生。然而，目前还没有可用于局部给药的间歇性甲状旁腺素给药系统，此外，甲状旁腺素在骨创伤愈合模型中刺激骨再生的作用机制尚不清楚。我们已经开发出能够实现脉动甲状旁腺素输送的植入性原型装置的聚合物，以及增强骨再生的纳米纤维聚合物/磷酸钙复合支架。由于甲状旁腺素的主要功能之一是调节钙水平，而钙对成骨细胞具有促增殖作用，因此我们推测甲状旁腺素的合成代谢活性依赖于钙的供应。这项拟议的研究将联合两个经验丰富的PI和一个Co-I的专业知识和资源来研究PTH释放和钙利用率之间的协同作用，这种仿生支架具有促进颅面骨再生的翻译潜力。我们将首先开发脉冲式和连续式PTH给药系统，具有不同钙利用率的纳米纤维聚合物/磷酸钙复合支架，以及PTH给药和含钙支架的最佳组合。然后，我们将研究甲状旁腺素与钙利用率的作用机制。最后，在这些理解的基础上，我们将在临床相关的拔牙伤口愈合模型中使用开发的PTH输送和支架技术再生颅面骨。 公共卫生相关性：甲状旁腺激素(PTH)目前用于人类刺激骨质疏松症患者的骨生长，并已被发现有益于颅面骨的再生。遗憾的是，甲状旁腺激素的局部传递能力还没有被认识到，其作用机制也不清楚，这阻碍了临床应用。该项目将通过一种新的局部给药策略来研究甲状旁腺激素刺激骨生长的作用机制和适用性。这一创新和信息对于阐明甲状旁腺素作为一种辅助口腔骨愈合的治疗方法的临床潜力至关重要。

DESCRIPTION (provided by applicant): Craniofacial bone trauma and disease are widespread healthcare problems. Despite the significant healing capability of bone, the requirement for new bone to restore large osseous defects and defects in patients with various medical conditions is a major clinical challenge. Parathyroid hormone (PTH) is currently the only FDA approved anabolic agent to treat osteoporosis in the US, and holds strong promise for craniofacial bone regeneration. Our preliminary studies indicate that a systemic intermittent administration of PTH (daily injection) significantly stimulates bone regeneration in an engineered regenerative medicine model. However, there is no intermittent PTH delivery system available for local delivery applications and furthermore, the mechanisms of action of PTH to stimulate bone regeneration in an osseous wound healing model are unknown. We have developed polymers that enable an implantable prototype device for pulsatile PTH delivery as well as nanofibrous polymer/calcium phosphate composite scaffolds that enhance bone regeneration. Because one of the main functions of PTH is to regulate calcium levels and calcium is pro-proliferative for osteoblastic cells, we hypothesize that the anabolic activity of PTH depends on calcium availability. This proposed research will unite the expertise and resources of two experienced PIs and a Co-I to investigate the synergy between the PTH delivery and calcium availability in a biomimetic scaffold with translational potential for improve craniofacial bone regeneration. We will first develop both pulsatile and continuous PTH delivery systems, nanofibrous polymer/calcium phosphate composite scaffolds with varying calcium availability, and the optimal combination of the PTH delivery and calcium-containing scaffold. We will then investigate the mechanisms of the PTH action in relation to the calcium availability. Finally, based on these understandings we will regenerate craniofacial bone using the developed PTH delivery and scaffold technologies in a clinically relevant tooth extraction wound healing model. PUBLIC HEALTH RELEVANCE: Parathyroid hormone (PTH) is currently used in humans to stimulate bone growth in patients with osteoporosis, and has been found to be beneficial in regenerating craniofacial bone. Unfortunately, the ability to deliver PTH locally has not been realized and its mechanisms of action are unclear which hinder clinical application. This project will investigate the mechanisms of action and applicability of using PTH to stimulate bone growth using a novel local delivery strategy. This innovation and information is critical in order o elucidate the clinical potential of PTH as a therapy to assist in oral bone healing.