PTH and Calcium Synergy for Craniofacial Regeneration

PTH 和钙协同促进颅面再生

• 批准号: 8299750
• 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
• 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/8299750
• 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 Delivery Systems; Drug Exposure; 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. 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.

描述（由申请人提供）：颅面骨创伤和疾病是普遍存在的医疗保健问题。尽管骨具有显着的愈合能力，但需要新骨来修复患有各种疾病的患者的大骨缺损和缺损，这是一个重大的临床挑战。甲状旁腺激素 (PTH) 是目前美国 FDA 唯一批准用于治疗骨质疏松症的合成代谢药物，对颅面骨再生具有广阔的前景。我们的初步研究表明，在工程再生医学模型中，全身间歇性施用 PTH（每日注射）可显着刺激骨再生。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 在骨伤口愈合模型中刺激骨再生的作用机制尚不清楚。我们开发了聚合物，可实现用于脉冲 PTH 输送的可植入原型装置，以及可增强骨再生的纳米纤维聚合物/磷酸钙复合支架。由于 PTH 的主要功能之一是调节钙水平，而钙可以促进成骨细胞增殖，因此我们假设 PTH 的合成代谢活性取决于钙的可用性。这项拟议的研究将结合两位经验丰富的 PI 和一位 Co-I 的专业知识和资源，研究仿生支架中 PTH 输送和钙可用性之间的协同作用，并具有改善颅面骨再生的转化潜力。我们将首先开发脉冲式和连续式 PTH 输送系统、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 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的机制。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 输送和支架技术来再生颅面骨。 公共健康相关性：甲状旁腺激素（PTH）目前用于人类刺激骨质疏松症患者的骨骼生长，并且已被发现有益于颅面骨的再生。不幸的是，局部递送PTH的能力尚未实现，其作用机制尚不清楚，这阻碍了临床应用。该项目将研究使用 PTH 通过新颖的局部递送策略刺激骨骼生长的作用机制和适用性。这一创新和信息对于阐明 PTH 作为辅助口腔骨愈合疗法的临床潜力至关重要。