研究目的 颅面短小畸形（CFM）是一种常见的先天性畸形，下颌骨骨性畸形的矫正是该疾 病治疗的核心。儿童期的患者可能会从下颌牵引成骨（MDO）治疗中受益；临床观察 表明在固定期下颌骨的畸形有一定的复发，然而，在固定期下颌骨的重塑尚未通过 计算机断层扫描进行定量分析。本研究临床研究部分探讨了在去除牵引器之前，接 受MDO治疗的IIA型CFM儿童下颌骨的重塑情况，以及影响下颌骨垂直延长效率的 因素。MDO 治疗后下颌骨畸形的复发是影响远期效果的重要因素，既有的MDO术后 的长期效果评估大多数基于二维头影测量，遗漏了三维的形态信息。本研究还利用 三维CT，基于骨单位分析，描述下颌骨各部分（髁突，体部，下颌角）在MDO后的 较远期的生长特点，并分析术后复发的原因。髁突是下颌骨垂直向生长的关键位点， 已有的大鼠牵引成骨模型均为水平向牵引，与临床CFM治疗采用的方向有差异，为 了更好地探索MDO对髁突的影响，需要建立与临床实际更符合的垂直向牵引成骨模 型。动物实验部分，本研究设计了新型的大鼠下颌骨延长器，评估基于该延长器的 MDO 模型对于发育期和发育完成的大鼠一般状况，咬合状态的影响，并评价不同时 间点的成骨质量及该模型的牵引效率。临床研究部分结果提示MDO对于髁突的影响 可能是复发的原因之一，本研究采用发育期大鼠MDO的模型，旨在分析MDO对髁突 宏微观形态以及与髁突内成骨偶联的H型血管的影响。 研究方法 一、颅面短小畸形早期牵引成骨治疗固定期下颌骨重塑的评估 本部分纳入23例单侧IIA型CFM患儿，通过术前（T0）、延长期末（T1）及固 定期末（T2）的 CT数据，重建三维下颌模型并基于稳定的颏部区域进行配准，分析 髁突垂直和前后向位移（COD和CCD）、下颌倾斜度（MMC）及牵引效率（EV）。采用 配对t检验比较各阶段差异，Pearson相关分析评估术前解剖学因素与EV的关系。 二、IIA型颅面短小畸形患儿牵引成骨术后下颌骨生长的CT研究 本部分对15例IIA型患儿术前（T0）、固定期末（T1）及术后4-6年（T2）的 CT 数据进行三维测量，分割髁突、体部及角骨单位，比较线性长度（CUL、BUL、AUL） 及角度（BUA、CoBA）变化，计算生长率（GR）。 三、大鼠下颌骨升支牵引成骨模型的建立 7 中国医学科学院 北京协和医学院 博⼠研究⽣学位论⽂ 本部分设计3D打印钛合金内置式牵引器，置入5周龄（发育组）和12周龄（成 年组）SD大鼠下颌骨，设置3日延迟期后以0.350/0.525/0.700 mm/d速率牵引4.2 mm（对应12，8，6日的延长期）。通过micro-CT、HE/Masson/番红固绿染色分析固 定期（14/28天）新生骨形态与成骨方式，计算牵引效率（髁突/乙状切迹高度变化 与理论延长量的比值）。 四、MDO对发育期大鼠髁突宏微观结构影响的实验研究 本部分将20只5周龄SD大鼠分为牵引组（I+D，0.7 mm/d牵引4.2 mm）和假 手术组（I，仅置入延长器）。术后14和28天取髁突标本，以非牵引侧（非手术侧） 作为对照，通过大体标本测量髁突的形态与空间位置，micro-CT 分析骨小梁参数， 组织学测量评估软骨层厚度，免疫荧光（CD31/Endomucin）定量H型血管密度。 研究结果 一、儿童颅面短小畸形早期牵引成骨治疗固定期下颌骨重塑的评估 牵引期患侧髁突垂直向延长28.84±4.08 mm、前后向延长2.85±4.33 mm，而 固定期垂直延长量丢失7.66±2.64 mm；髁突垂直延长复发率为27%，下颌骨倾斜 度复发率为35%；术前下颌支高度比（患侧/健侧）与垂直延长效率呈正相关（r=0.61, p<0.01）。 二、IIA型颅面短小畸形患儿牵引成骨术后下颌骨生长的CT研究 术前患侧髁突（CUL）与体部单位（BUL）较健侧显著缩短（分别减少13.6±3.7mm、 5.1±2.7mm）， 而 角单位（AUL）增大3.7±3.8mm（p<0.01）术后短期（T1）患侧BUL 与AUL显著增加（p=0.000），下颌体前旋角度（BUA、CoBA）改善，提示对称性得到 改善。长期随访4-6年（T2）显示，健侧各单位持续生长（CUL生长速率1.2±0.5mm/ 年），而患侧髁突生长速率显著低于健侧（0.2±0.3mm/年，p=0.000）， 且 角单位出 现吸收（GR=-1.6±1.4mm/年）。术后患侧下颌骨相对健侧发生后旋（BUA从4.2°降 至1.1°）。 三、大鼠下颌骨升支牵引成骨模型的建立 大鼠对延长器植入手术耐受良好，慢速牵引在相同的时间点成骨质量较快速牵 引更好，快速牵引在成年大鼠中可引起部分纤维性愈合。髁突牵引效率61-68%，乙 状切迹牵引效率69-79%； 四、MDO对发育期大鼠髁突宏微观结构影响的实验研究 8 中国医学科学院 北京协和医学院 博⼠研究⽣学位论⽂ I+D 组牵引侧相较于对侧髁突与喙突和下颌下缘的夹角增大，提示其可能发生 生长方向的改变，髁突软骨前后径缩短，且组织学分析显示各层厚度减少；micro CT 骨小梁分析提示软骨下骨质丢失。免疫荧光染色显示较对侧H型血管面积占比减 少至63.4%（2周）和72.1%（4周）； I 组手术侧髁突软骨增殖层和肥大层变薄和骨量的丢失在2周较对侧有统计学 意义，而在4周时双侧已无差异，H型血管在2周和4周相比对侧均无统计学意义 的差异。提示牵引是I+D组髁突变化的原因。 结论 本研究围绕颅面短小畸形CFM的牵引成骨治疗，通过临床研究系统探讨了MDO 的短期骨重塑、长期生长模式，并在建立的动物模型中初步探索了髁突MDO后生 长减慢的可能机制。在CFM儿童中，可能由于较低的骨质量，延长器与下颌骨之 间的骨移位在部分患者中是引起早期复发的重要原因。因此应关注固定期下颌骨 垂直延长的稳定性和咬合平面复发，严重减低的下颌骨升支高度比是固定期垂直 骨骼复发的术前风险因素。未来的研究应该探索有效的减小牵引对骨造成的应力 以提高牵引效率的方法。我们发现基于骨单位的三维分析有助于探究MDO的疗 效。从骨单位长度的动态变化分析，术后4-6年患侧髁突、体部及角单位呈现绝 对与相对生长不足，部分抵消MDO对IIA型CFM的矫正作用。除了新生骨在压力 下的吸收，早期MDO对CFM患儿下颌生长的潜在抑制效应应受重视。动物实验部 分我们构建了垂直向MDO模型，确定0.350-0.700 mm/d对于发育期大鼠均为合适 的牵引速率。在快速（0.7mm/d）的牵引速率下，髁突发生宏观和微观层面的骨质 减少，并伴有H型血管的减少，提示H型血管可能介导了MDO后髁突的成骨的降 低。这些研究提示了未来对于CFM下颌骨生长潜力关注的重要性，未来的研究需 要在大样本长时间的随访中动态关注MDO的生长趋势，同时需要验证H型血管是 否可以作为减轻MDO术后IIA型CFM患者髁突吸收，提高远期稳定性的靶点。

Objective Craniofacial microsomia (CFM) is a common congenital deformity, and the correction of mandibular skeletal malformation is central to its treatment. Pediatric patients may benefit from mandibular distraction osteogenesis (MDO); however, clinical observations indicate a certain degree of relapse during the consolidation period, which has not been quantitatively analyzed using computed tomography (CT). This study explores the remodeling of the mandible in children with type IIA CFM treated with MDO before device removal, as well as factors influencing the efficiency of vertical mandibular elongation. Relapse after MDO is a significant factor affecting long-term outcomes, and most existing long-term evaluations of MDO are based on two dimensional cephalometric analysis, omitting three-dimensional morphological information. This study also utilizes three-dimensional CT and bone unit analysis to describe the growth characteristics of various mandibular regions (condyle, body, and angle) in the longer term after MDO and to analyze the causes of postoperative relapse. The condyle is a key site for vertical mandibular growth, and existing rat distraction osteogenesis models are all horizontal, differing from the vertical direction used in clinical CFM treatment. To better explore the effects of MDO on the condyle, a vertical distraction osteogenesis model more consistent with clinical practice is needed. In the animal experiment section, this study designed a novel rat mandibular distractor to evaluate the impact of the MDO model based on this device on the general condition and occlusal status of developing and mature rats, and to assess the quality of osteogenesis and distraction efficiency at different time points. The clinical study results suggest that the impact of MDO on the condyle may be one of the causes of relapse. This study employs a developing rat MDO model to analyze the effects of MDO on the macro- and micro-morphology of the condyle and its coupling with type H vessels. Methods 1. Evaluation of Mandibular Remodeling During the Consolidation Period of Early MDO in Children with CFM This section included 23 children with unilateral type IIA CFM. 10 中国医学科学院 北京协和医学院 博⼠研究⽣学位论⽂ Preoperative (T0), post-distraction (T1), and post-consolidation (T2) CT data were used to reconstruct three-dimensional mandibular models and register them based on stable chin regions. Condylar vertical and anteroposterior displacement (COD and CCD), mandibular inclination (MMC), and distraction efficiency (EV) were analyzed. Paired t-tests compared differences between stages, and Pearson correlation analysis assessed the relationship between preoperative anatomical factors and EV. 2. CT Study of Mandibular Growth in Type IIA CFM Children After MDO This section analyzed preoperative (T0), post-consolidation (T1), and 4 6 years postoperative (T2) CT data from 15 type IIA CFM children. The condyle, body, and angle bone units were segmented, and linear lengths (CUL, BUL, AUL) and angles (BUA, CoBA) were compared, with growth rates (GR) calculated. 3. Establishment of a Rat Mandibular Ramus Distraction Osteogenesis Model A 3D-printed titanium alloy internal distractor was designed and implanted into the mandibles of 5-week-old (developing group) and 12-week old (adult group) SD rats. After a 3-day latency period, distraction was performed at rates of 0.350/0.525/0.700 mm/day for 4.2 mm (corresponding to 12, 8, and 6 days of distraction). Micro-CT and HE/Masson/Safranin O staining were used to analyze new bone morphology and osteogenesis at consolidation periods (14/28 days), and distraction efficiency (ratio of condylar/sigmoid notch height change to theoretical elongation) was calculated. 4. Experimental Study on the Effects of MDO on the Macro- and Micro Morphology of the Condyle in Developing Rats Twenty 5-week-old SD rats were divided into a distraction group (I+D, 0.7 mm/day for 4.2 mm) and a sham surgery group (I, distractor implantation only). Condylar specimens were harvested at 14 and 28 days postoperatively, with the non-distraction side (non-surgical side) as a control. Gross measurements assessed condylar morphology and spatial position, micro-CT analyzed trabecular parameters, histological measurements evaluated 11 中国医学科学院 北京协和医学院 博⼠研究⽣学位论⽂ cartilage layer thickness, and immunofluorescence (CD31/Endomucin) quantified type H vessel density. Results 1. Evaluation of Mandibular Remodeling During the Consolidation Period of Early MDO in Children with CFM During the distraction period, the condyle on the affected side elongated vertically by 28.84±4.08 mm and anteroposteriorly by 2.85±4.33 mm, while vertical elongation loss during consolidation was 7.66±2.64 mm. The condylar vertical relapse rate was 27%, and mandibular inclination relapse rate was 35%. Preoperative mandibular ramus height ratio (affected/normal side) was positively correlated with vertical elongation efficiency (r=0.61, p<0.01). 2. CT Study of Mandibular Growth in Type IIA CFM Children After MDO Preoperatively, the condyle (CUL) and body unit (BUL) on the affected side were significantly shorter than the normal side (reduced by 13.6±3.7 mm and 5.1±2.7 mm, respectively), while the angle unit (AUL) increased by 3.7±3.8 mm (p<0.01). Postoperatively, short-term (T1) BUL and AUL on the affected side increased significantly (p=0.000), and mandibular body anterior rotation angles (BUA, CoBA) improved, indicating enhanced symmetry. Long-term follow-up (4-6 years, T2) showed continuous growth on the normal side (CUL growth rate 1.2±0.5 mm/year), while the condylar growth rate on the affected side was significantly lower than the normal side (0.2±0.3 mm/year, p=0.000), and the angle unit showed resorption (GR=-1.6±1.4 mm/year). Postoperatively, the affected mandible rotated posteriorly relative to the normal side (BUA decreased from 4.2° to 1.1°). 3. Establishment of a Rat Mandibular Ramus Distraction Osteogenesis Model Rats tolerated the distractor implantation well. Slow distraction resulted in better osteogenesis quality at the same time points compared to rapid distraction, while rapid distraction in adult rats led to partial fibrous healing. Condylar distraction efficiency was 61-68%, and sigmoid notch distraction efficiency was 69-79%. 12 中国医学科学院 北京协和医学院 博⼠研究⽣学位论⽂ 4. Experimental Study on the Effects of MDO on the Macro- and Micro Morphology of the Condyle in Developing Rats In the I+D group, the condyle on the distracted side showed increased angles with the coronoid process and mandibular lower border, suggesting altered growth direction. The condylar cartilage anteroposterior diameter shortened, and histological analysis revealed reduced layer thickness. Micro CT trabecular analysis indicated subchondral bone loss. Immunofluorescence showed a 63.4% (2 weeks) and 72.1% (4 weeks) reduction in type H vessel area compared to the contralateral side. In the I group, the condylar cartilage proliferative and hypertrophic layers thinned, and bone loss was significant at 2 weeks but not at 4 weeks compared to the contralateral side. Type H vessel density showed no significant differences at 2 or 4 weeks, suggesting that distraction was the cause of condylar changes in the I+D group. Conclusion This study focuses on MDO treatment for CFM, systematically exploring short-term bone remodeling and long-term growth patterns through clinical research, and preliminarily investigating the potential mechanisms of condylar growth retardation after MDO in an animal model. In CFM children, bone displacement between the distractor and mandible may be an important cause of early relapse due to low bone quality. Therefore, attention should be paid to the stability of vertical mandibular elongation and occlusal plane relapse during the consolidation period. A severely reduced mandibular ramus height ratio is a preoperative risk factor for vertical skeletal relapse. Future research should explore effective methods to reduce stress on bone during distraction to improve efficiency. Three-dimensional analysis based on bone units is helpful in evaluating MDO efficacy. From the dynamic changes in bone unit length, the condyle, body, and angle units on the affected side showed absolute and relative growth insufficiency 4-6 years postoperatively, partially offsetting the corrective effects of MDO in type IIA CFM. In addition to resorption of new bone under pressure, the potential inhibitory effects of early MDO on mandibular growth in CFM children should be considered. In the animal experiment, a vertical MDO model was established, confirming that 0.350-0.7 mm/day are suitable distraction rates for developing rats. Under 13 中国医学科学院 北京协和医学院 博⼠研究⽣学位论⽂ rapid distraction (0.7 mm/day), the condyle exhibited macro- and micro-level bone loss, accompanied by reduced type H vessels, suggesting that type H vessels may mediate decreased osteogenesis in the condyle after MDO. These findings highlight the importance of future attention to the growth potential of the mandible in CFM, with long-term follow-up in large samples to dynamically monitor MDO growth trends. Additionally, type H vessels should be validated as a potential target to reduce condylar resorption and improve long-term stability in type IIA CFM patients after MDO.