PTH and Calcium Synergy for Craniofacial Regeneration

描述（由申请人提供）：颅面骨创伤和疾病是普遍的医疗保健问题。尽管骨具有显著的愈合能力，但需要新骨来修复具有各种医疗状况的患者的大的骨缺损和缺损是一个主要的临床挑战。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，对颅面骨再生有很大的希望。我们的初步研究表明，在工程再生医学模型中，全身间歇性给予PTH（每日注射）可显著刺激骨再生。然而，没有可用于局部递送应用的间歇性PTH递送系统，此外，PTH在骨创伤愈合模型中刺激骨再生的作用机制尚不清楚。我们已经开发了聚合物，使植入式原型装置的脉动PTH输送以及纳米纤维聚合物/磷酸钙复合支架，增强骨再生。因为PTH的主要功能之一是调节钙水平，并且钙对于成骨细胞是促增殖的，所以我们假设PTH的合成代谢活性取决于钙的可用性。这项拟议的研究将联合两名经验丰富的PI和一名Co-I的专业知识和资源，以研究具有改善颅面骨再生的转化潜力的仿生支架中PTH递送和钙可用性之间的协同作用。我们将首先开发脉冲式和连续式PTH输送系统，具有不同钙可用性的纳米纤维聚合物/磷酸钙复合支架，以及PTH输送和含钙支架的最佳组合。然后，我们将研究PTH作用与钙利用率的关系。最后，基于这些理解，我们将在临床相关的拔牙伤口愈合模型中使用开发的PTH递送和支架技术再生颅面骨。

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.