PTH Effects of Craniofacial Allografts

颅面同种异体移植物的 PTH 效应

• 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
• 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

 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（由适用提供）：虽然骨骼时机具有使骨折自我修复的再生能力，但在极端情况下，将不会发生完全的关键缺陷愈合。这种颅面复合体中这种骨缺损通常是出生缺陷，创伤或癌症手术的结果。不幸的是，由于手术后发生的压倒性组织纤维化和疤痕，颅颌面重建的长期结果非常差。这种对移植生物材料的炎症外交反应仍然是治疗这些患者的重大挑战之一。为了解决这个问题，我们的多机构调查团队维持了一项长期合作，在该领域取得了多个进步，包括在与重组甲状旁腺甲酮（RPTH，Teriparatide）中非统治的几个事实非工会的患者方面取得了非凡的成功。为了阐明负责这些RPTH对骨骼愈合作用的机制，并将其转化为临界骨缺陷的肌肉骨骼组织工程（MTE）溶液，我们发表了一些临床前发现。与此更新应用最相关的是：1）调节大容器血管发生的Angiopietins（Ang）1＆Ang-2受RPTH疗法的相互调节，以抑制近端移植物的大血管； 2）RPTH还抑制了与大血管相邻的促纤维肥大细胞的积累。基于此，我们假设RPTH疗法的收藏夹通过：1）：1）其对成骨细胞（Col1（2.3）+）的众所周知的合成代谢作用（Col1（2.3）+）增加了骨骼愈合，超出了关键缺陷的限制，2）骨细胞诱导的骨骼愈合 在愈合方面的小血管血管生成和3）对大血管血管生成，肥大细胞积累和纤维化的抑制作用。从技术上讲，我们：1）在Minipig下颌骨中开发了一种长期相关的临界缺陷愈合模型：3）开发了定制的3D打印的骨支架以取代大型合金； 4）开发了具有增强骨形成特性并降低转化潜力的自体成骨细胞（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骼临界缺陷性质的假设，2）正式阐明RPTH治疗抑制感染和纤维化以允许关键的颅骨骨缺陷骨缺损的机制，并为这项较大的挑战临床造型提供了关键的颅骨骨缺陷疗法。鉴于这些概念证明的临床相关性很高，对于这个重大问题，成功的潜在影响可能是巨大的。