PTH Effects of Craniofacial Allografts

颅面同种异体移植物的 PTH 效应

基本信息

批准号：
8910905
负责人：
DAN GAZIT
金额：
$ 54.87万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8910905
关键词：
3D Print Address Adjuvant Therapy Adopted Affect Allografting Angiogenesis Inhibition Angiopoietin-1 Angiopoietin-2 Animal Model Appearance Autologous Autologous Transplantation Biocompatible Materials Biomechanics Blood Vessels Bone Tissue Bone Transplantation Calvaria Cells Cephalic Chronic Cicatrix Clinical Collaborations Collagen Collagen Type I Congenital Abnormality Coupled Cromoglicic Acid Custom Data Defect Disease Fibrosis Foreign Bodies Foreign-Body Reaction Fracture Funding Head Healed Histology Hormones Inflammation Inflammatory Information Technology Injury Laser Scanning Microscopy Life Maintenance Malignant Neoplasms Mandible Methods Miniature Swine Modeling Mus Musculoskeletal Natural regeneration Nature Operative Surgical Procedures Oral cavity Osteoblasts Osteogenesis Osteoporosis Outcome Measure Parathyroid gland Patients Pharmaceutical Preparations Property Publishing Radiology Specialty Recombinants Reconstructive Surgical Procedures Regulation Research Role Signal Transduction Smooth Muscle Myocytes Solutions Teriparatide Testing Tissue Engineering Tissues Translating Trauma allogenic bone transplantation angiogenesis base bone bone healing calcium phosphate cancer surgery clinically relevant craniofacial craniofacial complex craniomaxillofacial healing human MYH11 protein in vivo Model induced pluripotent stem cell innovative technologies loss of function mast cell novel osteogenic pre-clinical prevent primary outcome public health relevance reconstruction regenerative repaired response scaffold secondary outcome spatial relationship success technological innovation theories vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): While bone tissues have regenerative capabilities that enable self-repair of fractures, in extreme cases complete critical defect healing will not occur. Such bone defects in the craniofacial complex are often a result of birth defects, trauma or cancer surgery. Unfortunately, the long- term results of craniomaxillofacial reconstructions are very poor due to the overwhelming tissue fibrosis and scarring that occurs following surgery. This inflammatory-foreign body response to the grafted biomaterial remains one of the great challenges in treating these patients. To address this, our multi-institutional investigative team has sustained a long-term collaboration that produced several advances in this field including extraordinary success in treating several patients with facture non-unions non-surgically with recombinant parathyroid hormone (rPTH, teriparatide). To elucidate the mechanisms responsible for these rPTH effects on bone healing, and translate it to a Musculoskeletal Tissue Engineering (MTE) solution for critical bone defects, we published several preclinical discoveries. The most relevant to this renewal application are: 1) angiopoietins (Ang) 1 & Ang-2, which regulate large vessel vasculogenesis, are reciprocally regulated by rPTH therapy to inhibit large blood vessels proximal to the allograft; and 2) rPTH also inhibits the accumulation of pro-fibrotic mast cells adjacent to the large vessels. Based on this we hypothesize that rPTH therapy facilitates critical defect healing by: 1) its well-known anabolic effects on osteoblasts (Col1(2.3)+) to increase bone healing beyond the limits of a critical defect, 2) osteoblast-induced small vessel angiogenesis at the healing front, and 3) inhibitory effects on large vessel vasculogenesis, mast cell accumulation and fibrosis. Technologically, we: 1) developed a chronic cranial defect window chamber model for in vivo multiphoton laser scanning microscopy (MPLSM); 2) established a clinically relevant model of critical defect healing in the minipig mandible: 3) developed custom 3D-printed bone scaffolds to replace massive allografts; and 4) developed autologous osteogenic-iPS cells (iMSC) with enhanced bone forming properties and reduced transformation potential. Here we propose to use these innovative technologies to: 1) test our hypotheses on the nature of critical defects in craniofacial bones, 2) formally elucidate the mechanism by which rPTH therapy inhibits inflammation and fibrosis to allow for critical craniomaxillofacial bone defect healing, and 3) provide a translational MTE solution for this challenging clinical problem in a large animal model. Given the high clinical relevance of these proofs of concept, the potential impact of success could be huge for this significant problem.

描述（由申请人提供）：虽然骨组织具有能够自我修复骨折的再生能力，但在极端情况下，颅面复合体中的这种骨缺陷通常是由出生缺陷、创伤或癌症造成的。不幸的是，由于手术后发生的大量组织纤维化和疤痕，颅颌面重建的长期效果仍然很差。为了解决这些患者面临的巨大挑战，我们的多机构研究团队进行了长期合作，在该领域取得了多项进展，包括通过非手术重组治疗几名骨折不愈合患者。甲状旁腺激素（rPTH、特立帕肽）旨在阐明 rPTH 对骨骼愈合的影响机制，并将其转化为针对关键骨骼的肌肉骨骼组织工程 (MTE) 解决方案。缺陷，我们发表了几项与此更新应用最相关的临床前发现：1）调节大血管血管生成的血管生成素（Ang）1和Ang-2受到rPTH疗法的相互调节，以抑制同种异体移植物附近的大血管。 ; 2) rPTH 还可以抑制大血管附近促纤维化肥大细胞的积累，基于此，我们发现 rPTH 治疗有助于关键缺损的愈合。通过：1) 众所周知的对成骨细胞的合成代谢作用 (Col1(2.3)+)，可增加骨愈合，使其超出严重缺损的限度，2) 成骨细胞诱导愈合前沿的小血管血管生成，以及 3) 对大血管血管生成、肥大细胞积累和纤维化的抑制作用在技术上，我们：1) 开发了用于体内多光子激光扫描显微镜 (MPLSM) 的慢性颅骨缺损窗室模型 2； ) 建立了小型猪下颌骨关键缺损愈合的临床相关模型：3) 开发定制 3D 打印骨支架来替代大量同种异体移植物； 4）开发了具有增强的骨形成特性和降低的转化潜力的自体成骨-iPS细胞（iMSC），在这里我们建议使用这些创新技术来：1）测试我们关于颅面骨关键缺陷性质的假设，2）正式阐明。 rPTH 疗法抑制炎症和纤维化以实现关键颅颌面骨缺损愈合的机制，3) 为大型动物模型中这一具有挑战性的临床问题提供转化 MTE 解决方案。这些概念验证具有高度的临床相关性，成功的潜在影响对于这个重大问题可能是巨大的。