PTH and Calcium Synergy for Craniofacial Regeneration

PTH 和钙协同促进颅面再生

• 批准号: 8435366
• 负责人: PETER X MA
• 金额: $ 37.32万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435366
• 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; Parathyroid gland; 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

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（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，但在各种疾病的患者中，需要新骨来修复较大的骨缺损和缺陷是一项重大的临床挑战。甲状旁腺激素（PTH）是目前美国FDA批准的唯一用于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，系统间歇给药PTH（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激素给药系统，此外，甲状旁腺激素在骨伤口愈合模型中刺激骨再生的作用机制尚不清楚。我们已经开发了一种聚合物，可以用于脉动性PTH输送的可植入原型装置，以及纳米纤维聚合物/磷酸钙复合支架，可以增强骨再生。由于甲状旁腺激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，因此我们假设甲状旁腺激素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位经验丰富的pi和一位Co-I的专业知识和资源，研究具有改善颅面骨再生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。我们将首先开发脉动式和连续式甲状腺激素输送系统，具有不同钙可用性的纳米纤维聚合物/磷酸钙复合支架，以及甲状腺激素输送和含钙支架的最佳组合。然后我们将研究甲状旁腺激素作用与钙可用性的关系。最后，基于这些认识，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。