PTH and Calcium Synergy for Craniofacial Regeneration

PTH 和钙协同促进颅面再生

基本信息

批准号：
9038175
负责人：
PETER X MA
金额：
$ 38.88万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9038175
关键词：
Adverse effects Anabolic Agents Animal Model Biological Assay Biomimetics Bone Growth Bone Regeneration Calcium Calcium-Sensing Receptors Cell Cycle Cells Clinical Coupling Defect Dental Dependence Device Designs Devices Dose Drug Exposure Drug Targeting Engineering FDA approved Gene Targeting Healed Healthcare Hormones Human In Vitro Injection of therapeutic agent Kinetics Local Therapy Mediator of activation protein Medical Methods Modeling Natural regeneration Oral Osteoblasts Osteoclasts Osteogenesis Osteoporosis PTH gene Patients Polymers Rattus Regenerative Medicine Research Research Personnel Resources Site System TNFSF11 gene Technology Therapeutic Tissue Engineering Tooth Extraction Translating Trauma Widespread Disease Work Wound Healing base bone bone healing calcium metabolism calcium phosphate clinical application clinically relevant craniofacial design dosage experience healing improved in vitro activity in vivo innovation nanofiber novel osteoclastogenesis prototype scaffold targeted delivery

项目摘要

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.

描述（由申请人提供）：颅面骨创伤和疾病是广泛的医疗保健问题。尽管骨骼具有显着的愈合能力，但新骨需要恢复各种医疗疾病患者的大骨缺陷和缺陷的要求是主要的临床挑战。目前，甲状旁腺激素（PTH）是FDA批准治疗美国骨质疏松症的唯一批准的合成代谢剂，并且对颅面骨再生保持着强烈的希望。我们的初步研究表明，在工程的再生医学模型中，系统性间歇性施用PTH（每日注射）显着刺激了骨骼再生。但是，没有可用于局部输送应用的间歇性PTH递送系统，此外，在骨伤口愈合模型中刺激骨骼再生的作用机制尚不清楚。我们开发了聚合物，该聚合物可以启用一种可植入的原型装置，用于脉冲PTH递送以及纳米纤维聚合物/磷酸钙复合材料支架，从而增强骨骼的再生。因为PTH的主要功能之一是调节钙水平，而钙则是成骨细胞的促成性，因此我们假设PTH的合成代谢活性取决于钙的可用性。这项拟议的研究将团结两个经验丰富的PI和一个Co-I的专业知识和资源，以调查PTH递送与钙可用性之间的协同作用，并在仿生支架中具有转化潜力，以改善颅面骨骼再生。我们将首先开发脉动和连续的PTH递送系统，纳米纤维聚合物/磷酸钙复合支架具有不同的钙可用性，以及PTH递送和含钙的支架的最佳组合。然后，我们将研究与钙可用性相关的PTH作用的机制。最后，基于这些理解，我们将在临床上相关的牙齿拔牙伤口愈合模型中使用开发的PTH递送和脚手架技术再生颅面骨。