Suture Mechanobiology and the Vasculature: A New Approach to Midfacial Hypoplasia

缝合机械生物学和脉管系统：面中部发育不全的新方法

• 批准号: 9181214
• 负责人: SUSAN W HERRING
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181214
• 关键词: Address; Affect; Animal Model; Animals; Apoptosis; Apoptotic; Biological; Biology; Blood Vessels; Blood flow; Bone Growth; Breathing; Breeding; Cell Proliferation; Cells; Cellularity; Clinical; Collagen; Congenital abnormal Synostosis; Deformity; Development; Disease; Dysplasia; Employee Strikes; Endothelial Cells; Environment; Event; Exhibits; Face; Future; Genes; Goals; Growth; Growth Disorders; Human; Hypoxia; Immunohistochemistry; Impairment; Investigation; Jaw; Label; Lead; Legal patent; Ligaments; Literature; Malocclusion; Mastication; Measures; Mechanical Stress; Mechanics; Mesenchymal; Minerals; Miniature Swine; Modality; Molecular; Molecular Probes; Operative Surgical Procedures; Osteogenesis; Pathogenesis; Pharmaceutical Preparations; Phenotype; Physiology; Positioning Attribute; Regulation; Research; Role; Staining method; Stains; Stimulus; Surgical sutures; Testing; Therapeutic; Undifferentiated; Width; Work; angiogenesis; bone; craniofacial; feeding; in vivo; midfacial hypoplasia; mineralization; new therapeutic target; novel strategies; osteogenic; osteoprogenitor cell; premature; prevent; response; success; treatment response; treatment strategy

Midfacial hypoplasia is a growth deficiency that can lead to severe deformity with impairment of feeding and breathing. Current treatments include drastic surgeries that reposition bones but do not promote growth. This project assesses the potential of a less invasive mechanotherapeutic strategy for preventing the early fusion of hypoplastic midfacial sutures. Cyclic loading is anabolic for sutures. As a working hypothesis, we propose that cyclic loading preserves patency by promoting the proliferation of sutural cells, and that in the central zone these cells are inhibited from becoming osteoprogenitors. The proposed mechanism by which this occurs is that the central zone of the suture becomes hypoxic as cyclic loading disrupts blood flow. Hypoxia then leads to mesenchymal proliferation, angiogenesis, and matrix remodeling; these events inhibit cells from osteodifferentiation until they move out of the central zone into the bone-forming zones. In this way mechanotherapy would both preserve sutural patency and promote bone growth. The Aims of the project will test the clinical validity of the cyclic loading concept, the working hypothesis, and the proposed vascular mechanism. It will serve as proof of principle for future investigations of molecular mechanisms and the development of new treatment modalities. Minipigs are similar to humans in craniofacial physiology, and their sutural mechanics are well documented. We will employ a unique minipig breed with severe midfacial hypoplasia related to hypoplastic, early fusing facial sutures. Cyclic or sham loads will be applied to sutures and the resulting strains measured using strain gages. Specific Aim 1 will test whether the hypoplastic sutures increase their growth in response to the treatment. Specific Aim 2 will test the working hypothesis by determining sutural proliferation/apoptotic rates and establishing whether osteoprogenitors are downregulated in the central zone. Specific Aim 3 will test the predictions of the vascular mechanism that loading will increase vascularity and disorganize the sutural ligament. This research will advance our understanding of the biological regulation of suture patency and elucidate the pathogenesis of midfacial hypoplasia. If the concept, working hypothesis and/or the vascular mechanism are supported by the findings, our long-term goal will be to develop mechanical and pharmacological therapies for this serious disorder.

中间性发育不全是一种生长缺乏症，可以随着喂养和 呼吸。当前的治疗方法包括重新定位骨骼但不会促进生长的严重手术。这 项目评估了一种侵入性较小的治疗策略的潜力，以防止早期融合 肿瘤中间缝合线。循环载荷是缝合线的合成代谢。作为一个工作假设，我们提出了 循环载荷通过促进缝合细胞的扩散来保留通畅，并在中央区域 这些细胞被抑制成为破骨者。发生这种情况的提议的机制是 缝合线的中心区域变成低氧，因为环状负荷破坏了血液的流动。然后缺氧导致 进行间充质增殖，血管生成和基质重塑；这些事件抑制了细胞 整个分化直到它们移出中心区域进入骨形区域。这样 机械疗法既可以保留缝合通畅，又可以促进骨骼生长。该项目的目的将 测试环状加载概念，工作假设和提议的血管的临床有效性 机制。它将作为未来对分子机制进行研究的原则证明和 开发新的治疗方式。 Minipigs与颅面生理学中的人类相似，它们的 缝合力学有充分的记录。我们将采用一个独特的Minipig品种，具有严重的中等种族 与肿瘤性，早期融合的面部缝合线有关的下降症。循环或假载载荷将用于 缝合线和所得菌株使用应变级测量。具体目标1将测试是否 缝合缝合物会因治疗而增加其生长。特定目标2将测试工作 假设通过确定缝合增殖/凋亡率并确定破骨者是否为 在中央区域下调。具体目标3将测试血管机制的预测 负荷会增加血管性并混乱缝合韧带。这项研究将推动我们的 了解缝合通畅的生物学调节并阐明中期的发病机理 发育不全。如果发现的概念，工作假设和/或血管机制得到了发现， 我们的长期目标是为这种严重疾病开发机械和药理疗法。