促进下颌骨牵引成骨新骨形成的研究进展

牵引成骨技术（distraction osteogenesis，DO）因其能在原位快速成骨而被称为是一种内源性组织工程技术。然而，DO的某些并发症（如骨再生不良、延迟愈合、不愈合），特别是其较长的疗程及牵引装置长时间留置于面部或口腔内所引发的各种问题（如固定螺钉松脱、伤口感染、骨折等）成为临床应用和推广该项新技术的瓶颈和主要障碍。     

上颌骨内置式持续等张缝牵引成骨机制的实验研究

目的：通过对山羊颧上颌缝持续等张缝牵引成骨来延长上颌骨复合体,探讨缝牵引成骨的机制。方法：在山羊两侧颧上颌缝安置自主设计制作的内置式微型自动持续等张缝牵引器,缝两侧钛钉标记,术后定期拍摄X线片,并在4、6、8周切取牵引和未牵引的颧上颌缝及新生骨组织,进行组织学观察。采用免疫组化染色方法研究标本中bFGF、TGF-β1、VEGF的表达和变化。结果：在牵引力的作用下,所有山羊上颌骨复合体均成功前徙。在牵引6周时出现软骨细胞团,细胞团之间有新生骨小梁形成。间充质细胞、成骨细胞及骨细胞中bFGF、TGF-β1、VEGF均有不同程度的阳性表达或阳性表达增加,呈时间和空间上的变化。结论：经缝牵引成骨的成骨机制以膜内成骨为主,但也有软骨成骨;bFGF、TGF-β1、VEGF以及3种胶原均参与了缝牵引成骨的成骨过程,促进了间充质细胞向成骨细胞的增殖、分化及新骨的改建。     

单侧骨皮质缺损对长管状骨生物力学的影响

目的探讨长管状骨骨干不同大小的单侧骨皮质缺损对长管状骨生物力学性质的影响。方法取76根三黄鸡胫骨,随机分7组(1.5mm组n=11,2.0mm组n=9,2.5mm组n=13,3.0mm组n=12,3.5mm组n=8,4.5mm组n=11,皮质完整组即正常对照组n=12),于后侧骨皮质造成直径分别为1.5～4.5mm的环形骨缺损,进行三点弯曲单一实验,皮质完整组作为正常组对照。结果缺损直径为1.5mm及2.0mm组鸡胫骨达到结构破坏时的最大载荷与正常组差异无统计学意义(P=0.824,0.865),2.5mm、3.0mm、3.5mm组的最大载荷较正常组降低14%左右,差异有统计学意义(P=0.015,0.010,0.021);4.5mm组较正常组降低23%左右,差异有统计学意义(P=0.001)。结论单侧皮质缺损直径在长管状骨外径的(22.6±1.4)%以内时,不影响其抗弯曲性能;当其超过长管状骨外径的(29.4±2.1)%时,将降低长管状骨的抗弯曲性能,但降低的幅度跟缺损大小并不完全呈正比。     

持续弹力牵引成骨修复腭裂的实验研究

目的：应用持续弹力牵引成骨技术进行封闭腭裂、延长硬腭的实验研究，探讨以组织新生方式修复腭裂的可行性。方法：6个月龄杂种犬10只，随机分为空白对照组、实验对照组、实验组。实验组人工制备宽8mm、长25mm硬腭裂隙，腭骨水平板周围切骨，经5d的间歇期后安置记忆合金牵引器，向后、向中线牵引，达到预期结果后，牵引器继续保持8周。结果：实验对照组裂隙无明显变化。实验组裂隙逐渐缩窄，裂隙后部于2－3周封闭，裂隙前部缩窄为1－2mm的缝隙，同时硬腭向后延长；组织学证实骨牵引区域完全为新生骨组织所填充。结论：持续弹力牵引成骨能够诱导腭裂犬腭骨和附着的软组织新生，有效封闭腭部裂隙、延长硬腭。     

缝牵引成骨扩展颧骨的初步实验研究

目的 探讨三维牵引正常山羊颧骨在缝区形成新骨的可行性和方法。 方法 将自行研制外固定三维缝牵引成骨器，安装固定后三维牵引山羊颧骨，于牵引后2周观察颧骨移动及缝区新组织形成情况。 结果 7只山羊的颧平均被牵引0.6cm缝区新组织生成确切。 结论 该外固定三维缝牵引成骨器操作简便，牵引效果稳定可靠，实验方法切实可行。     

牙槽嵴裂隙间固定对腭裂上颌复合体内置式牵引成骨生物力学的影响

目的 探讨裂隙间固定对唇腭裂上颌复合体牵引成骨生物力学的影响.方法 采用三维有限元方法,建立唇腭裂上颌复合体LeFort Ⅰ型截骨骨块及相应软组织有限元模型,在保留牙槽嵴裂隙与裂隙两侧钛板固定两种情况下,模拟临床上内置式牵引方式,使截骨块上牵引器固位点沿牵引方向前移10 mm,比较分析其生物力学变化.结果 唇腭裂上颌复合体LeFort Ⅰ型截骨内置式牵引下,腭部出现压缩现象,而裂隙两侧钛板固定腭部压缩现象不明显.矢向位移与垂直向位移在两种工况下比较,位移方向及大小与保留裂隙的前牵引无明显差异.结论 裂隙间固定后唇腭裂上颌复合体内置式牵引成骨,可以避免腭部出现压缩现象,有生物力学指导意义.     

骨牵引成骨与颅面骨延长术研究进展

本文回顾及复习有关骨牵引成骨技术的基础理论研究类文献 ,旨在明确其发展主流及方向 ,为颌骨正畸应用此技术寻求理论支持。1　骨延长的概念形成最早有关此类范畴的文章见于 190 5年 Codivilla报道的病案〔1〕。医生通过手术将患者肢体骨分断后 ,在麻醉状态下对断骨两侧施加突然的强迫牵拉而增长肢体长度 ,随即在施力后的状态下外加固定而维持其状态。这可能是最早的骨延长技术形式 ,但其效果不能确定 ,尤其是远期疗效的问题无法肯定。随后 ,Freiberg、Magnusson也进行了类似手术。由于经常碰到诸如断端固定不可靠、诱发癫痫、猝死等严重…     

牙颌面畸形的牵引成骨

牵引成骨(Distraction Osteogenesis)是通过牵张器固定在切开后仍保留骨膜及软组织附着与血供的骨段施行缓慢牵引以延长或重建骨组织及软组织的一项技术。相对于传统正颌手术，无需植骨，减少供区创伤，骨周围的软组织可同期获得扩张，且治疗范围广泛，从新生儿到成人均有成功范例。因此，自90年代以来，该技术已广泛用于治疗各种严重的牙颌面畸形。     

内置式牵引器经腭横缝牵引成骨对上颌骨及腭骨形态的研究

目的：在实验动物腭部置入牵引器,通过形态学观察及X线影像测量,观察SDO技术对犬上颌骨及腭骨形态生长发育影响。方法：选取12周龄雄性杂种犬16只,体重3～4kg,随机分为NC组4只及实验组（SDO组）12只（2组×6只）。牵引器直径分别为0.9mm、1.0mm。牵引器压缩前长度为2.8cm。牵引器在压缩距离为0.5～1.8cm时张力值分别为250～480g、350～760g。2个实验组牵引28～35天,陆续将3组犬处死。观察记录3组犬的腭部形态变化及关系变化。定期拍摄定上颌咬合片。结果：SDOI和I I组与NC组相比,硬腭长度明显增大。其中SDOI I组硬腭长度增大更为明显。结论：SDO技术明显延长腭骨长度,前移上颌骨。     

应用牵引成骨技术治疗中面部骨发育不良畸形

目的 探讨牵引成骨技术对因多颅缝早闭所致的中面部发育不良综合征的治疗效果。方法 冠状切口径路,先用LeFort Ⅲ型截骨法在眶面部截骨,使颅底和中面部先行离断,安装外置REDⅡ式中面部牵引器。术后5d开始牵拉,每天1mm牵拉前移;待中面部到达良好位置和咬合关系时,停止牵拉,并固定该装置2～4个月。结果 完成的8例患者平均手术时间3．5h,术中平均失血300ml,中面部平均前移9．0mm,下移1．5mm;术后面部外形明显改观,咬合关系接近正常;除1例固定脚处的头皮感染和1例头皮血清肿外,术后无严重并发症发生;平均随访5个月,无面部后缩等复发症状。结论 牵引成骨技术可有效治疗学龄儿童和畸形严重的中面部骨发育不良畸形。     

Radiographic classification of osteogenesis during bone distraction.

Successful limb lengthening requires serial radiological evaluation of the progression of healing of the regenerate bone. However, there is no radiographic classification system that shows how the regenerate should progress during treatment in adults. The study aimed to address this need.A series of radiographs were studied from 92 patients (125 segments) who had undergone bone lengthening. A radiographic classification of osteogenesis was developed based on callus shape and radiographic features that occur between osteotomy and fixator removal.This classification system used both shape and type of feature to condense and record the radiographic information, but type of feature alone was sufficient to predict outcome. The concurrence and reproducibility of the classification system was tested by inter- and intra-observer studies. The degree of consistent repetition and agreement between observers suggests that the classification system is reliable, reproducible, and therefore should be robust in use.This classification system provides an insight into osteogenesis; it allows the progress of the bone healing to be assessed against a successful pattern of healing. Hence, potential problems can be predicted and clinical changes made to improve outcome. The classification can be simplified to make it more appropriate for clinical use.     

Inhibin A enhances bone formation during distraction osteogenesis

Given the aging population and the increased incidence of fracture in the elderly population, the need exists for agents that can enhance bone healing, particularly in situations of delayed fracture healing and/or non‐union. Our previous studies demonstrated that overexpression of the gonadal peptide, human inhibin A (hInhA), in transgenic mice enhances bone formation and strength via increased osteoblast activity. We tested the hypothesis that hInhA can also exert anabolic effects in a murine model of distraction osteogenesis (DO), using both transgenic hInhA overexpression and administration of normal physiological levels of hInhA in adult male Swiss‐Webster mice. Tibial osteotomies and external ring fixation were performed, followed by a 3‐day latency period, 14‐day distraction, and sacrifice on day 18. Supraphysiological levels of hInhA in transgenic mice, but not normal physiological levels of hInhA, significantly increased endosteal bone formation and mineralized bone area in the distraction gap, as determined by radiographic and µCT analysis. Significantly, increased PCNA and osteocalcin expression in the primary matrix front suggested that hInhA increased osteoblast proliferation. This mechanism is consistent with the effects of other agents and pathologies that modulate bone formation during DO, and demonstrates the potential of hInhA to enhance bone repair and regeneration. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:288–295, 2012     

Staphylococcal enterotoxin C2 expedites bone consolidation in distraction osteogenesis

Distraction osteogenesis (DO) technique could be used to manage large‐size bone defect successfully, but DO process usually requires long duration of bone consolidation. Innovative approaches for augmenting bone consolidation are of great need. Staphylococcal enterotoxin C2 (SEC2) has been found to suppress osteoclastogenesis of mesenchymal stem cells in vitro. In this study, we investigated the effect of SEC2 on proliferation and osteogenic differentiation of rat bone marrow derived mesenchymal stem cells (rBMSCs). Further, we locally administrated SEC2 (10 ng/ml) or PBS into the distraction gap in Sprague–Dawley male rat DO model every 3 days till termination at 3 and 6 weeks. The regenerates were subjected to X‐rays, micro‐computed tomography, mechanical testing, histology, and immunohischemistry examinations to assess new bone quality. SEC2 had no effect on cell viability. The calcium deposition was remarkably increased and osteogenic marker genes were significantly up‐regulated in rBMSCs treated with SEC2. In rat DO model, SEC2 group had higher bone volume/total tissue volume in the regenerates. At 6 weeks, mechanical properties were significantly higher in SEC2‐treated tibiae comparing to the control group. Histological analysis confirmed that the new bone had improved quality in SEC2 treated group, where the osteocalcin and osterix expression in the regenerates was up‐regulated, indicating faster bone formation. The current study demonstrated that SEC2 local injection promotes osteogenesis and enhanced bone consolidation in DO. The findings support application of SEC2 as a potential novel strategy to expedite bone consolidation in patients undergoing DO treatment. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1215–1225, 2017.

     

Stimulation of EP4 receptor enhanced bone consolidation during distraction osteogenesis.

The objective of this study was to confirm whether an agonist of prostaglandin E receptor subtype EP4 can enhance bone consolidation in distraction osteogenesis. A rat distraction osteogenesis model was generated. A unilateral external fixator was fixed to the left femur of the rats of this model after osteotomy. Seven days later, 0.25 mm/12 h or 0.5 mm/12 h elongation was performed for 2 weeks. A systemic administration of an EP4 receptor agonist (ONO 4819 . CD, 3, 10, 30 microg/kg) or normal saline by subcutaneous injection was also performed for 2 weeks. The animals were sacrificed 10, 14, 17, 21, and 42 days after the operation. Radiographic examination, histological examination, and measurements of bone mineral density (BMD) and distraction-callus hardness were performed to qualitatively and quantitatively evaluate new bone formation. Twenty-one days after the operation, the experimental group had a higher BMD and a higher distraction-callus hardness than that of the control group. Forty-two days after the operation, BMD was similar among all of the groups. But the hardness of the experimental groups increased more than that of the control group, so the statistical differences in distraction-callus hardness became more distinct between the two groups, indicating an improved remodeling of the distraction callus. These findings are also supported by histological examination. Subcutaneous injection of an EP4 receptor agonist can promote bone formation and remodeling during distraction osteogenesis. ONO 4819 * CD might be a potential candidate for shortening the treatment time of distraction osteogenesis.     

Cisplatin inhibits bone healing during distraction osteogenesis

Osteosarcoma (OS) is the most common malignant bone tumor affecting children and adolescents. Many patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. Surgical reconstructions after tumor resection include structural allografts, non‐cemented endoprostheses, and distraction osteogenesis (DO), which require direct bone formation. Although cisplatin (CDP) is extensively used for OS chemotherapy, the effects on bone regeneration are not well studied. The effects of CDP on direct bone formation in DO were compared using two dosing regimens and both C57BL/6 (B6) and tumor necrosis factor receptor 1 knockout (TNFR1KO) mice, as CDP toxicity is associated with elevated TNF levels. Detailed evaluation of the five‐dose CDP regimen (2 mg/kg/day), demonstrated significant decreases in new bone formation in the DO gaps of CDP treated versus vehicle treated mice (p < 0.001). Further, no significant inhibitory effects from the five‐dose CDP regimen were observed in TNFR1KO mice. The two‐dose regimen significantly inhibited new bone formation in B6 mice. These results demonstrate that CDP has profound short term negative effects on the process of bone repair in DO. These data provide the mechanistic basis for modeling peri‐operative chemotherapy doses and schedules and may provide new opportunities to identify molecules that spare normal cells from the inhibitory effects of CDP. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:464–470, 2014.     

Low intensity pulsed ultrasound accelerated bone remodeling during consolidation stage of distraction osteogenesis.

Bone regeneration in distraction osteogenesis occurs under tensile stress with axial rhythmic distraction after osteotomy. In this study, we evaluated if the low intensity pulsed ultrasound (LIPUS) was also effective on enhancement of bone remodeling during consolidation stage of distraction osteogenesis. Open osteotomy of seventeen 18-week-old female New Zealand rabbit tibiae were performed. The distraction was applied with the rate of 1 mm per day. LIPUS (30 mW/cm(2), 1.5 MHz) was delivered for 20 min per day during 4-week consolidation stage (n=10). The animals without treatment served as sham group (n=7). Plain X-ray, peripheral quantitative computational tomography (pQCT), and torsional test were performed. Results showed that smaller radiolucent interzone of LIPUS treatment group was gradually occupied by calcified tissue in plain X-ray at week 2. The bone mineral density (BMD) measured on radiographs increased by 9.18% in the LIPUS group. Bone mineral content (BMC), hard callus volume, and bone strength index (BSI) measured by pQCT were 83%, 116%, and 94%, respectively, in LIPUS group that were significantly greater than those of the controls. At the 4th week, LIPUS-treated callus showed the development of neocorticalization in the proximal and distal region. The BMC, hard callus volume, and BSI of LIPUS group decreased and was not significantly different from control. This was also confirmed by the maximum torque of LIPUS-treated callus (1424.2+/-457.3 N . mm) obtained at week 4, which did not differ from that of the sham group (1968.8+/-895.1 N . mm). In conclusion, the effective period of LIPUS treatment was at the initial stage of consolidation, with accelerated bone formation and remodeling.     

Locally applied nerve growth factor enhances bone consolidation in a rabbit model of mandibular distraction osteogenesis.

Distraction osteogenesis is widely used in treating deformities, defects, and fractures of both long bones and craniofacial bones. Demands for acceleration of bone consolidation are increased in distraction osteogenesis. Nerve growth factor (NGF) can enhance innervation and bone regeneration in a fracture model and stimulate differentiation of osteoblastic cells. In this study, we tested the ability of locally applied NGF to enhance bone regeneration in a rabbit model of mandibular distraction osteogenesis. Twenty rabbits underwent bilateral distraction osteogenesis with a rate of 0.5 mm per 12 h. Two times 0.04 mg human NGFbeta (hNGFbeta) in buffer was injected into the callus after distraction. The contralateral side received placebo injections. Rabbits were euthanized at consolidation times of 14 and 28 days. Specimens were subjected to radiography, callus dimensions measurement, mechanical testing, and bone histological and histomorphometric analysis. The maximum load, bone volume/total volume, mineral apposition rate of the 1st to 11th day, and mineralized bone percentage were significantly higher in the hNGFbeta side at 14 and 28 days (p<0.05). The data indicate that locally applied hNGFbeta can accelerate callus maturation and may be an option to shorten the consolidation period in distraction osteogenesis.     

体外冲击波对兔长骨牵伸骨痂形成的早期作用

目的观察体外冲击波对兔长骨牵伸骨痂形成的早期作用,探讨其作用机制。方法30只成年新西兰大白兔胫骨中段截断,5d后开始延长,每天延长1mm,10d后停止延长,待骨痂形成10d;随机分成实验组和对照组,实验组于牵伸骨痂中心区进行体外冲击波(ESW)处理,冲击波能量密度0.54mJ/mm2,脉冲1000次;对照组不予任何处理。两组于截骨后45、60、75d取材,采用X线片、骨密度检测对牵伸骨痂形成进行观察,并行统计学分析,组织学观察比较。结果术后45d和60d,X线片及骨密度检测显示实验组牵伸骨痂形成量及骨密度值明显高于对照组(P<0.05),75d两组比较差异无显著意义;组织学观察发现45d实验组成熟软骨和类骨组织形成量均较对照组多,实验组新生骨痂内毛细血管数量较多,60d实验组可见大量新生骨组织,有丰富的骨髓腔和原始骨髓,对照组以类骨组织为主,原始骨髓少,75d两组间组织学形态趋于一致。结论在兔胫骨牵伸骨形成过程中,ESW可加速骨痂的早期形成、矿化和改建。     

Novel application of HA‐TCP biomaterials in distraction osteogenesis shortened the lengthening time and promoted bone consolidation

This study tested the hypothesis that use of biomaterials in distraction osteogenesis (DO) would reduce the treatment time and enhance bone formation quality. A 1.0‐cm tibial shaft was removed in the left tibia of 36 rabbits. Rabbits were randomly divided into three groups: group A, the defect gap was reduced with the tibia shortened for 1.0‐cm; group B, the defect gap was filled with 1.0‐cm restorable porous hydroxyapatite and Tri‐calcium phosphates cylindrical block (HA/TCP block, diameter is 0.5‐cm); group C, The 1.0‐cm defect gap was reduced 0.5 cm and the remaining 0.5‐cm defect gap was filled with the 0.5‐cm HA/TCP block. The tibia was then fixed with unilateral lengthener; for groups A and C; lengthening started 7 days after surgery at a rate of 1.0 mm/day, in two steps. Group A received lengthening for 10 days and group C for 5 days, there was no lengthening for group B. All animals were terminated at day 37 following surgery. The excised bone specimens were subject to microcomputed tomography (micro‐CT), mechanical testing, and histological examinations. Bone mineral density and content and tissue mineral density and content, as well as the mechanical properties of the regenerates were significantly higher in group C compared to groups A and B. Micro‐CT and histological examinations also confirmed that the regenerates in Group C had most advanced bone formation, consolidation, and remodeling compared to other groups. In conclusion, the combined use of biomaterials and DO technique can reduce the treatment time and enhance bone consolidation in bone defect management. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 477–482, 2009