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

面中部发育不全是一种生长缺陷，可导致严重畸形，并伴有进食和营养障碍 呼吸。目前的治疗方法包括剧烈的手术，重新定位骨骼，但不能促进生长。这 该项目评估了一种侵入性较小的机械治疗策略预防早期融合的潜力 发育不良的面中部缝合线。循环负荷对缝合线来说是合成代谢的。作为一个工作假说，我们提出 循环负荷通过促进缝合细胞和中央区的增殖而保持通畅性 这些细胞被抑制成为骨祖细胞。建议的发生机制是 当循环负荷扰乱血液流动时，缝合的中心区会变得缺氧。然后低氧导致 到间充质增殖、血管生成和基质重塑；这些事件抑制细胞 骨分化，直到它们移出中央区进入成骨区。以这种方式 机械疗法既能保持缝合通畅，又能促进骨生长。该项目的目标将是 检验循环负荷概念、工作假说和所提出的血管的临床有效性 机制。它将作为未来分子机制和分子机制研究的原则性证明 开发新的治疗方式。小型猪在头面部生理上与人类相似，它们的 缝合力学有很好的记录。我们将使用一种独特的小型猪品种，面部中部严重 发育不全与发育不良、早期融合的面部缝合有关。循环载荷或假载荷将应用于 使用应变片测量缝合线和所产生的应变。《特定目标1》将测试 发育不良的缝合线对治疗的反应是增加它们的生长。《特定目标2》将测试工作情况 通过测定骨缝的增殖/凋亡率和确定骨祖细胞是否 在中心区下调了监管。特定目标3将测试对血管机制的预测 负重会增加血管，使缝合韧带紊乱。这项研究将推动我们的 认识缝合通畅的生物学规律，阐明面中部骨折的发病机制 发育不全。如果该发现支持概念、工作假说和/或血管机制， 我们的长期目标将是为这种严重的疾病开发机械和药物疗法。

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.