上颌扩弓动物模型及应用效果的研究进展

Progress on animal models of maxillary expansion and its application effect

摘要

上颌扩弓是临床上颌骨横向发育不足的主要治疗方法，为评估其机制、效果以及稳定性，在动物体内模拟上颌扩弓是主要研究方式，上颌扩弓动物模型在口腔正畸学研究中具有重要意义。上颌扩弓动物模型选择动物种属时，鼠和兔的饲养成本相对较低，但其口腔结构及咀嚼习惯与人类存在显著差异，且骨代谢速率远高于人类，因此在将研究成果转化为临床应用时需予以充分考虑；小型猪和犬的解剖结构及生理特征与人类较为相似，然而较高的饲养成本及伦理问题限制了其广泛应用。对于上颌扩弓动物模型造模方法，口内空间小的鼠类多采用弹性不锈钢丝弯制的扩弓装置，分为前腭缝扩弓和后腭缝扩弓两种方式；兔、小型猪及犬口腔操作空间充足，能够负载传统的牙支抗螺旋扩弓、微种植钉辅助扩弓及新兴磁力扩弓等多种扩弓装置。目前上颌扩弓动物模型的应用研究包括：探究机械力诱导骨重塑机制，为临床正畸治疗提供促进骨重建的潜在治疗靶点；对不同扩弓矫治器比较评估，以验证新型扩弓器的矫治效果，为其临床应用提供实验证据；筛选扩弓治疗的辅助措施，探究加速腭中缝成骨的药物和物理手段，以缩短临床扩弓的保持时间，为患者提供更高效、舒适的治疗方案。本文对上颌扩弓动物模型及应用效果进行综述，旨在为研究人员应用上颌扩弓动物模型提供参考。

Abstract

Maxillary expansion serves as the principal treatment for maxillary transverse deficiency in clinical practice. Simulating maxillary expansion in animals is the main research approach to assess its mechanism, effect, and stability. Thus, the animal model of maxillary expansion holds great significance in orthodontic research. Rats and rabbits are typically selected for common animal models because the maintenance cost is relatively low; however, their oral anatomy and masticatory behaviors differ significantly from those of humans, and their bone metabolism rates are substantially higher. Consequently, these factors should be carefully considered when extrapolating research findings and applying them to human clinical applications. Miniature pigs and dogs exhibit maxillofacial structures and chewing patterns that closely resemble those of humans; however, their broader application in research is constrained by high maintenance costs and ethical concerns. Rats with small oral space typically require the use of an elastic stainless steel wire expansion appliance, which can be divided into anterior maxillary expansion and posterior maxillary expansion. Rabbits, miniature pigs, and dogs have sufficient oral space and can be fitted with a variety of expansion appliances, including traditional tooth-borne expansion, microimplant-assisted expansion, and new magnetic expansion appliance. Animal models of maxillary expansion are currently used to study the mechanism of mechanically induced bone remodeling in order to provide potential therapeutic targets to promote bone remodeling in clinical orthodontic treatment; different orthodontic devices have been compared and evaluated to verify the correction effect of a new type of orthodontic device and provide experimental evidence for its clinical application; and supplementary methods of maxillary expansion have been screened to explore drug and physical therapy to accelerate the osteogenesis of the palatal suture, so as to shorten the retention time of clinical maxillary expansion and provide patients with more efficient and comfortable treatment. This paper summerized advances in animal models of maxillary expansion and the application effects in order to provide a reference for using an animal model of maxillary expansion.

Graphical abstract

关键词

口腔 / 正畸 / 错畸形 / 上颌横向发育不足 / 上颌扩弓 / 动物模型 / 正畸装置 / 应用前景

Key words

stomatology / orthodontic / malocclusion / maxillary transverse deficiency / maxillary expansion / animal model / orthodontic appliances / application prospect

上颌横向发育不足（maxillary transverse deficiency，MTD）是临床正畸常见的问题之一，表现为上牙弓狭窄和上下颌牙弓及基骨宽度不调，常伴有前牙拥挤、后牙反 和腭穹隆高拱等^［1］。相比垂直向和矢状向的发育，横向发育开始和结束的时间相对较早^［2］。MTD很难通过生长发育的进程自发缓解，未经治疗可造成咬合紊乱甚至是阻塞性睡眠呼吸暂停综合征（obstructive sleep apnea hypopnea syndrome，OSAHS）等问题^［3-4］，因此早期诊断和矫正十分重要^［5］。

上颌扩弓是MTD的经典治疗手段之一，利用矫形力扩张尚未完全骨化的腭中缝协调上下颌宽度，并提供间隙^［6］。此外上颌扩弓还可以改善舌位和鼻咽体积缓解上呼吸道阻塞^［7］，与腺样体扁桃体切除术联合治疗能够有效改善儿童OSAHS^［8-9］，但目前扩弓存在较高的复发率^［10］。

多种动物模型被应用于上颌扩弓实验当中，通过建立上颌扩弓动物模型，可研究机械力诱导骨重塑的机制、比较不同扩弓矫治器的效果和筛选扩弓治疗的辅助措施^［11］等。笔者将对上颌扩弓动物模型的建立方法及应用进行综述。

1 动物种属的选择

1.1 鼠

鼠类因成本低、繁殖快、易于饲养和管理、造模耐受性强，能提供大量样本，广泛用于科学研究中。

大鼠与小鼠均广泛用于上颌扩弓模型的建立，大鼠的操作难度更低，应用更广。常用品系包括SD大鼠、Wistar大鼠、C57BL/6小鼠。近年来，使用基因敲除小鼠研究相应基因在成骨方面作用的研究也逐渐增加^［12-13］。实验动物多选择5～8周龄，其中6周龄鼠因处于生长发育期^［14］，常用于模拟人类青春期扩弓。

扩弓装置多用弹性不锈钢丝弯制，分为前腭缝扩弓和后腭缝扩弓，以前者居多。大鼠的扩弓力值多在50～150 g，在扩弓7 d后，100 g组在扩张腭中缝的同时扩弓力造成的牙效应更小，表明100 g是大鼠前腭缝扩弓的最优力值^［15］；Jin等^［16］建立的大鼠微种植钉辅助快速扩弓（microimplant-assisted rapid palatal expansion，MARPE）模型证明100 g为后腭缝扩弓的最优力值；小鼠扩弓多在30～100 g，以50 g左右居多^［17-18］。口内造模后，初戴的不适及加力的疼痛使动物短期内进食困难，体重降低，通常可在1～3 d适应并缓解。

操作方面，鼠类的颌骨尺寸较小，这要求扩弓装置的制作和安装更精细。口腔生理功能方面，鼠类口腔结构及咀嚼习惯与人类差异较大^［19］，其前牙不断生长且啃食食物，加载于前牙的装置易脱落。在代谢方面，鼠的代谢速度远高于人类^［20］，在扩弓后的骨改建过程中表现为不同于人类的骨愈合过程和骨密度变化趋势。综上所述，将鼠类扩弓动物模型的研究结果向人类临床应用转化时需要谨慎考虑各方面差异带来的影响。

1.2 兔

兔类动物成本较低、生长周期短，且性情温顺，对于饲养环境适应性较强。研究多采用雄性新西兰白兔，不同文献采用的兔龄在8周龄^［21］、3～4月龄^［22］、20～24周龄^［23］、24～30周龄^［24］不等。

相较鼠类，兔的口腔空间更大，视野良好，可操作性更强。这使得兔可以装载Hyrax螺旋扩弓器^［22］，定期加力，能够更好地模拟临床正畸扩弓过程。兔的牙齿较大，便于在磨牙上预备固位形，增强扩弓装置的固位力。相较于鼠类，兔的观察周期更长，可进行更长时间的保持期研究。此外尚有部分研究将Hyrax螺旋扩弓器置于兔颅骨正中矢状缝上，利用微种植钉固定，以模拟腭中缝扩张^［23-24］。

同鼠类似，兔的咀嚼习惯和力量与人类不同，骨重建速度较人类更快，可能会影响扩弓实验结果的外推，需要在实验设计及结果分析时加以考虑。

1.3 小型猪

小型猪的颌面部结构在许多方面与人类相似，已经广泛应用于口腔颌面部生物研究中^［25］。

在可操作性方面，小型猪体型适中，便于在口内安装上颌扩弓装置，可在上颌磨牙带环固位^［26］，对于扩弓后的调整和检查操作较为便利。

口腔生理功能方面，小型猪的口咽结构及咀嚼功能与人类相似^［27］，是扩弓对咀嚼功能影响的理想动物模型；肥胖小型猪作为OSAHS动物模型^［28-29］，可评估上颌扩弓对OSAHS治疗的潜在价值。小型猪的硬腭形态及其生长发育模式与人类相似，其骨骼成分、密度和质量方面也与人类相近^［30］，常被应用于微种植体相关的实验中^［31］，因此在研究种植支抗式扩弓方面更具优势。

小型猪饲养成本高，需要专门的饲养设施和管理条件，限制了其广泛应用。一部分研究采用了猪离体上颌骨进行研究^［32-34］，但在离体组织无法进行长时间的扩弓观察。

1.4 犬

近年来犬类广泛应用于口腔领域，尤其是种植方面的研究，在正畸领域应用尚少。

比格犬性格温顺，适合饲养和管理，适合进行长期的实验研究。研究用犬多采用6月龄^［35］，此时期的比格犬处于生长发育阶段。Liu等^［36］使用比格犬模型探究扩弓力对于植骨区的影响，为临床唇腭裂治疗提供参考。

目前犬类已被用于MARPE^［37］和新型磁力扩弓矫治器^［35］等研究中。但比格犬的购买和饲养成本较高，且涉及相关伦理问题，目前仍未被广泛应用于上颌扩弓实验中。

2 扩弓造模方法

2.1 前腭缝扩弓

2.1.1 单眼圈簧法

目前应用于上颌扩弓实验研究最多的建模方法是较为成熟的上颌扩弓动物模型。以大鼠为例，造模利用0.014英寸不锈钢丝弯制直径1.5～2 mm的小圈曲，双侧连接5～8 mm长延伸臂，延伸臂末端弯制成弧形提供固位^{［15， 38］}。末端伸入上切牙之间，使用光固化树脂粘接固定（图1a）。若需对扩弓保持及复发进行研究，则需在扩弓期结束之后使用光固化树脂粘固小圈曲，消除扩弓簧的张力，以起保持器的作用；保持期结束后拆除扩弓器，以研究复发。

此方法通过调整扩弓簧延伸臂的打开角度能够实现不同的扩张力值，且易于改造成保持器，是鼠类扩弓建模最常用的方法。然而此方法仍存在一些缺陷，如常规鼠的上颌切牙间邻接紧密，难以将上颌扩弓器置于上切牙间，强行塞入也难以粘接固位。随着前腭缝的扩展，扩弓力的方向无法保持垂直于腭中缝。将扩弓器转为保持器时，仅用树脂粘固无法完全固定扩弓簧，仍会对中切牙施加部分张力。

为进一步解决以上建模方式存在的技术问题，多项研究对此扩弓簧进行了改造。部分研究将扩弓簧延伸臂末端弯制为圈型，放置于上颌中切牙远中，使用金属结扎丝固位^［39-41］（图1b）。另有部分研究结束后拆除扩弓器，使用不锈钢方丝粘固于上颌中切牙之间作为保持器^{［38， 42］}，或直接用树脂粘固中切牙进行保持^［43］。Zhao等^［15］在原装置基础上进行了改良，在上颌切牙之间进行邻面去釉，扩大牙缝便于延伸臂置入；在延伸臂近小圈曲2 mm处增加一处弯折，将小圈曲及延伸臂弯折上缘一同粘固保持，以进一步消除扩弓力。

2.1.2 不锈钢扩张环法

使用0.5 mm不锈钢丝弯制3圈，形成厚度为1.5 mm的不锈钢扩张环，缓慢推入中切牙之间^［44-45］（图1c）。为稳定扩张环，在中切牙的远中龈缘磨出凹槽，并使用结扎丝固定。

由于此方法将上颌中切牙间行1.5 mm宽的即刻扩张，无法模拟临床缓慢加力的扩弓方式。Reis等^［46］将该模型应用于上颌快速扩弓后c-Fos基因表达水平的研究，以评估上颌骨快速扩弓后的疼痛。

2.2 后腭缝扩弓

2.2.1 双眼圈簧法

双眼圈簧法首先需要制取鼠上颌模型，根据模型使用0.014、0.016英寸的澳丝或不锈钢丝弯制双眼圈簧，双侧连接延伸臂。牙支持式扩弓器主要分为两种安装方式，一种将延伸臂直接粘结到两侧上颌第一、二磨牙的咬合面上^［47-49］；另一种延伸臂向外弯折，从腭侧插入上颌第一、二磨牙邻接点之下，再将其与大鼠磨牙腭侧粘接固定^［50-52］，第二种方法同时包含机械固位与粘接固位，增强了装置的固位力（图2a）。同单眼圈簧法一样，在扩弓期结束后可粘固小圈曲消除扩弓加力，以进行保持期的研究。冯光耀等^［53］将双眼圈簧延伸臂沿唇颊侧弯制，从颊侧将末端插入上颌第一、二磨牙之间，制成扩弓后的缩弓器，进行上颌牙弓反复扩缩的实验研究。

另有研究使用双眼圈簧建立种植支抗辅助上颌扩弓模型（图2b）。Jin等^［16］将定制不锈钢螺钉植入双侧上颌第一、二磨牙之间的腭侧牙槽骨，将0.016英寸不锈钢丝弯制的双眼圈簧延伸臂末端弯折环绕螺钉，并粘接固定，成功建立了大鼠的MARPE模型。

目前此方法多用于鼠类动物，相较于单眼圈簧法能够更好模拟临床扩弓的模式，然而磨牙区操作有一定难度，在日常检查方面也无法清晰可视。

2.2.2 “Ω”型扩弓簧法

Koehne等^［54］将0.016英寸澳丝弯制成“Ω”型，将末端插入上颌第一、二磨牙之间并粘固，建立小鼠后牙扩弓模型（图2c）。Sun等^［12］分别将0.008和0.010英寸镍钛丝弯制成“Ω”型，插入小鼠上颌第一、二磨牙之间，以分别产生10 g和20 g的力。

2.2.3 “W”型扩弓簧法

“W”型扩弓簧使用0.014英寸澳丝弯制，末端回折插入上颌第一、二磨牙之间或于磨牙腭侧粘接固定（图2d）；Xu等^［55］在此基础上进行了改良，在上颌磨牙的腭侧粘接腭管，将扩弓簧末端插入腭管中，此方法可以将装置从口内取出重新激活加力而免于重新粘接。

2.2.4 螺旋扩弓法

相较于鼠类，口腔空间充足的兔、小型猪以及比格犬等动物可采用螺旋扩弓器。通过在尖牙及磨牙上制作个别带环^{［26， 37］}，或使用自凝塑料制作分离基托^［22］，再将矫治器粘接于上颌牙弓上，实现传统的牙支抗螺旋扩弓。通过在螺旋扩弓器上焊接或打孔等方式，可以个性化制作MARPE^［37］。使用螺旋扩弓器更接近临床上的正畸扩弓方式，能够定量加力，且更容易粘固保持，为人类上颌扩弓治疗提供更直接的参考。

2.2.5 磁力扩弓矫治器

磁力扩弓通过磁体间的斥力作用于支抗牙，由于扩弓过程具有个体差异，磁力扩弓矫治器对不同个体的组织适应性改建提供了个体化调节时间。目前磁力扩弓矫治器在正畸领域有一定的应用前景，但其与传统扩弓方法的效果和稳定性差异仍需要进一步研究。研究常使用比格犬，在尖牙和第一磨牙上制作个别带环，将带环与磁力扩弓矫治器相焊接，建立比格犬磁力扩弓模型^［56］。Tong等^［35］使用比格犬，基于钕-铁-硼磁铁的排斥力结合再激活系统设计了一种磁力扩弓器，与牙支抗扩弓和种植支抗扩弓进行对比研究。

2.3 扩弓模型的建立效果

腭中缝和牙槽骨宽度的增加标志着上颌扩弓模型的成功建立。前腭缝扩张模型在扩弓7 d后，前腭缝呈“V”形显著加宽^［15］；而后腭缝扩张模型的腭中缝呈平行扩增。MARPE模型的前后腭缝均有明显扩张，且扩张效率更高^［16］。这些动物模型的扩张特征提供了多个扩张位点^［57］，有助于全面了解上颌扩弓的生物反应。

除腭中缝的扩张，牙支持式扩弓模型还通过牙的颊倾扩大牙弓宽度^［49］。明确扩弓的牙效应和骨效应在扩张和复发时的比例有助于理解其潜在机制并促进扩弓疗效的稳定性，对临床上选择合适的扩弓策略具有重要意义^［58］。

3 研究应用

3.1 探究机械力诱导骨重塑机制

利用上颌扩弓动物模型可以对上颌骨骨缝在力学作用下发生的生物学变化进行观察，并探究其中介导骨重建的机制（表1）。Guerrero等^［18］利用小鼠扩弓模型，探究上颌快速扩弓中涉及的细胞变化和潜在分子通路，证明了该模型作为机械诱导骨重塑模型的可行性。

3.2 不同扩弓器效果的比较评估

目前临床上有多种类型的上颌扩弓矫治器，如四眼圈簧扩弓器、传统螺旋扩弓器、MARPE以及新型的磁力扩弓器等。将不同矫治器应用于动物实验，通过对比扩弓量、扩弓速度、对牙以及牙周组织的影响等指标，可以评估不同矫治器的优缺点。Fox等^［32］和Oliveira等^［26］使用离体猪上颌骨建立MARPE模型，探究快速腭中缝扩张时牙槽骨和上颌周围骨缝的机械应变，证明MARPE在骨缝扩张过程中张力更恒定。Tong等^［35］使用比格犬建立磁力扩弓器模型，将其与传统螺旋扩弓器比较，研究证实磁力扩弓器对支抗牙的力更加温和，为后续磁力扩弓的临床研究提供动物实验基础。根据动物模型中上颌扩弓矫治器的应用结果，可以对矫治器进行优化，以提高矫治器的临床应用效果。

3.3 筛选扩弓治疗的辅助措施

尽管上颌扩弓可以在短时间内显著扩张腭中缝，但其具有较高的复发率^［66］。充分的成骨是降低复发率的关键，目前临床防止复发主要通过延长机械保持的时间来实现。然而保持期过长也会大幅阻碍正畸序列治疗的进程^［67］。因此亟需可靠且可推广的辅助加快扩弓的方法。

通过建立上颌扩弓动物模型，可以评估与扩弓联合使用的辅助措施对腭中缝处新骨形成的有效性（表2）。近年来已有激素类、化学制剂类、药物类、生物制剂类、蛋白质类和非手术物理措施等多种辅助方法纳入研究^［11］。在动物实验中研究扩弓合并辅助措施的效果，可以为临床治疗提供更准确的预测模型。

4 小结与展望

在口腔正畸学研究发展中，上颌扩弓动物模型仍有着诸多研究场景亟待发掘。如在基因研究方面，通过特定基因编辑动物建立上颌扩弓动物模型，可以探究某些基因在机械力诱导骨重塑中的作用；在生物材料研究领域，可以利用上颌扩弓动物模型测试新型生物材料在正畸领域的应用潜力。在口腔生理方面，可以更深入了解腭中缝成熟和骨化过程，以确定上颌扩弓的最佳时间和力值^［78］。然而将上颌扩弓动物模型的相关研究转化为临床应用需要考虑多种因素，如种属间生理结构差异、经济成本和伦理问题等，研究者需要进行严谨的分析确保动物实验结果能够可靠地外推到临床实践中，未来还有望对其在正畸学乃至其他领域的应用有更多的探索。

参考文献

[1] Chamberland S. Maxillary expansion in nongrowing patients. Conventional, surgical, or miniscrew-assisted, an update[J]. J World Fed Orthod, 2023, 12(4): 173-183. doi: 10.1016/j.ejwf.2023.04.005 .

[2] Mehta S, Arqub SA, Vishwanath M, et al. Biomechanics of conventional and miniscrew-assisted rapid palatal expansion[J]. J World Fed Orthod, 2024, 13(3): 105-112. doi: 10.1016/j.ejwf.2024.03.002 .

[3] Alsawaf DH, Almaasarani SG, Hajeer MY, et al. The effectiveness of the early orthodontic correction of functional unilateral posterior crossbite in the mixed dentition period: a systematic review and meta-analysis[J]. Prog Orthod, 2022, 23(1): 5. doi: 10.1186/s40510-022-00398-4 .

[4] Bucci R, Rongo R, Zunino B, et al. Effect of orthopedic and functional orthodontic treatment in children with obstructive sleep apnea: a systematic review and meta-analysis[J]. Sleep Med Rev, 2023, 67: 101730. doi: 10.1016/j.smrv.2022.101730 .

[5] Bin Dakhil N, Bin Salamah F. The diagnosis methods and management modalities of maxillary transverse discrepancy[J]. Cureus, 2021, 13(12): e20482. doi: 10.7759/cureus.20482 .

[6] 刘从华, 毛琴, 王春林. 上颌横向扩弓技术的应用及研究进展[J]. 口腔疾病防治, 2020, 28(11): 689-697. doi: 10.12016/j.issn.2096-1456.2020.11.002 .

[7] Liu CH, Mao Q, Wang CL. Advances and applications of the maxillary expansion technique[J]. J Prev Treat Stomatol Dis, 2020, 28(11): 689-697. doi: 10.12016/j.issn.2096-1456.2020.11.002 .

[8] Zhao Z, Cao R, Yao M, et al. Effects of hyrax maxillary expander on nasal cavity and upper airway in adolescents: a systematic review and meta-analysis[J]. Healthcare(Basel), 2024, 12(21): 2148. doi: 10.3390/healthcare12212148 .

[9] 王超杰, 温和, 金欣哲, 等. 儿童错(牙合)畸形合并阻塞性睡眠呼吸暂停综合征的诊疗研究进展[J]. 口腔疾病防治, 2024, 32(5): 388-394. doi: 10.12016/j.issn.2096-1456.2024.05.009 .

[10] Wang CJ, Wen H, Jin XZ, et al. Research progress on the diagnosis and treatment of pediatric malocclusion combined with obstructive sleep apnea-hypopnea syndrome[J]. J Prev Treat Stomatol Dis, 2024, 32(5): 388-394. doi: 10.12016/j.issn.2096-1456.2024.05.009 .

[11] Guo F, Li Q, Ngan P, et al. Impact of tonsillectomy on the efficacy of Alt-RAMEC/PFM treatment protocols in children with class III malocclusion and tonsillar hypertrophy: protocol for a cluster randomised controlled trial[J]. BMJ Open, 2024, 14(6): e084703. doi: 10.1136/bmjopen-2024-084703 .

[12] Beltrami F, Kiliaridis S, Antonarakis GS. Long-term stability of posterior crossbite correction, treated in the mixed or permanent dentition of growing children: a systematic review and meta-analysis[J]. Orthod Craniofac Res, 2024, 27(1): 1-14. doi: 10.1111/ocr.12690 .

[13] Vali S, Khosravani S, Nobar BR, et al. Rapid maxillary expansion supplementary methods: a scoping review of animal studies[J]. Int Orthod, 2022, 20(1): 100614. doi: 10.1016/j.ortho.2022.100614 .

[14] Sun J, Eleniste PP, Utreja A, et al. Pyk2 deficiency enhances bone mass during midpalatal suture expansion[J]. Orthod Craniofac Res, 2020, 23(4): 501-508. doi: 10.1111/ocr.12402 .

[15] Santos MS, Lima VTM, Barrioni BR, et al. Targeting phosphatidylinositol-3-kinase for inhibiting maxillary bone resorption[J]. J Cell Physiol, 2023, 238(11): 2651-2667. doi: 10.1002/jcp.31121 .

[16] Andreollo NA, Santos EF, Araújo MR, et al. Rat’s age versus human’s age: what is the relationship?[J]. Arq Bras Cir Dig, 2012, 25(1): 49-51. doi: 10.1590/s0102-67202012000100011 .

[17] Zhao H, Wang X, Jin A, et al. Reducing relapse and accelerating osteogenesis in rapid maxillary expansion using an injectable mesoporous bioactive glass/fibrin glue composite hydrogel[J]. Bioact Mater, 2022, 18: 507-525. doi: 10.1016/j.bioactmat.2022.03.001 .

[18] Jin Y, Yuan X, Zhang H, et al. A rat model for microimplant-assisted rapid palatal expansion[J]. Biochem Biophys Res Commun, 2024, 741: 150964. doi: 10.1016/j.bbrc.2024.150964 .

[19] Li J, Yu TT, Yan HC, et al. T cells participate in bone remodeling during the rapid palatal expansion[J]. FASEB J, 2020, 34(11): 15327-15337. doi: 10.1096/fj.202001078R .

[20] Guerrero JA, Silva RS, de Abreu Lima IL, et al. Maxillary suture expansion: a mouse model to explore the molecular effects of mechanically-induced bone remodeling[J]. J Biomech, 2020, 108: 109880. doi: 10.1016/j.jbiomech.2020.109880 .

[21] Gorucu-Coskuner H, Al-Yassary M, Billiaert K, et al. Effect of masticatory muscle function on the craniofacial sutures of the anterior viscerocranium in growing rats[J]. Eur J Oral Sci, 2024, 132(6): e13027. doi: 10.1111/eos.13027 .

[22] Stein M, Elefteriou F, Busse B, et al. Why animal experiments are still indispensable in bone research: a statement by the European calcified tissue society[J]. J Bone Miner Res, 2023, 38(8): 1045-1061. doi: 10.1002/jbmr.4868 .

[23] Abdel-Haffiez SH, Khalil NM. Effect of platelet rich plasma injection on bone formation in the expanded mid-palatal suture in rabbits: a randomized controlled animal study[J]. BMC Oral Health, 2024, 24(1): 167. doi: 10.1186/s12903-024-03922-6 .

[24] Li Q, Wang W, Zhang Q, et al. Changes in CT cerebral blood flow and volume associated with rapid maxillary expansion in a rabbit model[J]. Angle Orthod, 2012, 82(3): 418-423. doi: 10.2319/051211-328.1 .

[25] Alyessary AS, Yap AUJ, Othman SA, et al. Effect of piezoelectric sutural ostectomies on accelerated bone-borne sutural expansion[J]. J Oral Maxillofac Surg, 2018, 76(3): 616-630. doi: 10.1016/j.joms.2017.08.018 .

[26] Alatabi HSH, Tobji S, Haouas Z. Effects of calcitonin administration on the amount of bone formation after sutural expansion using micro-CT[J]. J Craniofac Surg, 2023, 34(8): 2556-2559. doi: 10.1097/SCS.0000000000009575 .

[27] 周建, 杨子, 王松灵. 小型猪模式动物在口腔颌面生物医学研究中的应用[J]. 生物医学转化, 2021, 2(3): 1-5, 36. doi: 10.12287/j.issn.2096-8965.20210301 .

[28] Zhou J, Yang Z, Wang SL. The miniature pig: as an experimental model for dental and orofacial research[J]. Biomed Transform, 2021, 2(3): 1-5, 36. doi: 10.12287/j.issn.2096-8965.20210301 .

[29] Oliveira PLE, Campos V, de Andrade RM, et al. Deformation of the circummaxillary sutures during acute micro-implant assisted rapid palatal expansion and tooth-supported expansion: an ex vivo study[J]. Orthod Craniofac Res, 2021, 24(3): 396-404. doi: 10.1111/ocr.12450 .

[30] Rosero Salazar DH, Honnlee S, Liu ZJ. Tongue, palatal, hyoid and pharyngeal muscle activity during chewing, swallowing, and respiration[J]. Arch Oral Biol, 2024, 157: 105845. doi: 10.1016/j.archoralbio.2023.105845 .

[31] Leotta DF, Ly D, Galil B, et al. Tissue properties and respiratory kinematics of the tongue base and soft palate in the obese OSA minipig[J]. PLoS One, 2023, 18(12): e0293907. doi: 10.1371/journal.pone.0293907 .

[32] Zong S, Du P, Li H, et al. Advances in animal models of obstructive sleep apnea[J]. Front Med(Lausanne), 2023, 10: 988752. doi: 10.3389/fmed.2023.988752 .

[33] Cañas-Gutiérrez A, Arboleda-Toro D, Monsalve-Vargas T, et al. Techniques for bone assessment and characterization: porcine hard palate case study[J]. Heliyon, 2022, 8(6): e09626. doi: 10.1016/j.heliyon.2022.e09626 .

[34] Valeri C, Aloisio A, Quinzi V, et al. Characterizing orthodontic mini-screws in the hard palate of pigs: an experimental and finite-element study[J]. Heliyon, 2024, 10(3): e24952. doi: 10.1016/j.heliyon.2024.e24952 .

[35] Fox GC, Jones TA, Wilson JM, et al. Sutural loading in bone- versus dental-borne rapid palatal expansion: an ex vivo study[J]. Orthod Craniofac Res, 2020, 23(4): 419-426. doi: 10.1111/ocr.12384 .

[36] Al Dayeh A, Williams RA, Trojan TM, et al. Deformation of the zygomaticomaxillary and nasofrontal sutures during bone-anchored maxillary protraction and reverse-pull headgear treatments: an ex-vivo study[J]. Am J Orthod Dentofacial Orthop, 2019, 156(6): 745-757. doi: 10.1016/j.ajodo.2018.12.019 .

[37] Hoang TH, Nguyen KT, Kaipatur NR, et al. Ultrasonic mapping of midpalatal suture–an ex-vivo study[J]. J Dent, 2024, 145: 105024. doi: 10.1016/j.jdent.2024.105024 .

[38] Tong F, Miao Z, Zhou X, et al. Treatment and posttreatment effects of a novel magnetic palatal expansion appliance with reactivation system in dogs[J]. Am J Orthod Dentofacial Orthop, 2020, 157(2): 194-204. doi: 10.1016/j.ajodo.2019.03.020 .

[39] Liu A, Huang J. Mechanical tension-stress in alveolar cleft repaired with autogenous bone in canine models[J]. Cleft Palate Craniofac J, 2022, 59(4): 442-452. doi: 10.1177/10556656211018950 .

[40] Awni KM, Dewachi Z, Al-Hyani OH. Effect of Injectable platelet-rich fibrin (i-PRF) on new bone formation in surgical expansion with mini-screw assisted rapid palatal expander: a dog model study[J]. J Orthod Sci, 2023, 12: 12. doi: 10.4103/jos.jos_56_22 .

[41] Dursun S, Sezen Erhamza T, Önder ME, et al. Effect of methylphenidate at different doses on new bone formation with rapid maxillary expansion: a micro-CT and histomorphometric study in rats[J]. Orthod Craniofac Res, 2022, 25(3): 384-392. doi: 10.1111/ocr.12547 .

[42] Simsek D, Gok GD, Delipinar SD. Does krill oil enhancing the new bone formation in orthopedically expanded median palatal suture in rat model?A micro-CT and immunohistochemical analysis[J]. BMC Oral Health, 2024, 24(1): 862. doi: 10.1186/s12903-024-04644-5 .

[43] Koca CG, Sadry S, Asker H, et al. Effects of the different administration frequencies of teriparatide (PTH [1-34]) on new bone formation of expanded midpalatal sutures in rats: a histomorphometric and micro-computed tomography analysis[J]. Orthod Craniofacial Res, 2021, 24(3): 449-457. doi: 10.1111/ocr.12512 .

[44] Ebadifar A, Eslamian L, Motamedian SR, et al. Effect of mesenchymal stem cells with platelet-rich plasma carriers on bone formation after rapid maxillary expansion: an animal study[J]. Orthod Craniofac Res, 2022, 25(2): 151-158. doi: 10.1111/ocr.12518 .

[45] Bulut M, Korkmaz YN, Erimsah S. Effects of isotretinoin on new bone formation after maxillary sutural expansion[J]. J Orofac Orthop, 2020, 81(6): 440-446. doi: 10.1007/s00056-019-00209-2 .

[46] Kamimoto H, Kobayashi Y, Moriyama K. Relaxin 2 carried by magnetically directed liposomes accelerates rat midpalatal suture expansion and subsequent new bone formation[J]. Bone Rep, 2019, 10: 100202. doi: 10.1016/j.bonr.2019.100202 .

[47] Stuani AS, Silvano PRÁ, Arnez MFM, et al. VEGF and FGF-2 released in palatal suture after rapid maxillary expansion (RME)[J]. Braz Dent J, 2021, 32(1): 98-103. doi: 10.1590/0103-6440202103527 .

[48] Pirmoradian M, Safiaghdam H, Nokhbatolfoghahaei H, et al. Effect of photobiomodulation on relapse in an experimental rapid maxillary expansion model in rat[J]. Photochem Photobiol, 2021, 97(3): 634-640. doi: 10.1111/php.13365 .

[49] Reis CLB, Pingueiro-Okada EM, Luiz KG, et al. Orthodontic pain: c-Fos expression in rat brain nuclei after rapid maxillary expansion[J]. J World Fed Orthod, 2023, 12(1): 3-8. doi: 10.1016/j.ejwf.2022.09.003 .

[50] Zhao T, Tao Z, Zhang G, et al. Fat mass and obesity-associated protein (FTO) affects midpalatal suture bone remodeling during rapid maxillary expansion[J]. Eur J Orthod, 2024, 46(2): cjae009. doi: 10.1093/ejo/cjae009 .

[51] Xiao X, Chen J, Zhai Q, et al. Suppressing STAT3 activation impairs bone formation during maxillary expansion and relapse[J]. J Appl Oral Sci, 2023, 31: e20230009. doi: 10.1590/1678-7757-2023-0009 .

[52] Cheng Y, Lv C, Li T, et al. Palatal expansion and relapse in rats: a histologic and immunohistochemical study[J]. Am J Orthod Dentofacial Orthop, 2020, 157(6): 783-791. doi: 10.1016/j.ajodo.2019.06.017 .

[53] Yang Y, Chen D, Li Y, et al. Effect of puerarin on osteogenic differentiation in vitro and on new bone formation in vivo [J]. Drug Des Devel Ther, 2022, 16: 2885-2900. doi: 10.2147/DDDT.S379794 .

[54] Yi J, Mei L, Li X, et al. Effects of continuous and intermittent parathyroid hormone administration on midpalatal suture expansion in rats[J]. Arch Oral Biol, 2019, 99: 161-168. doi: 10.1016/j.archoralbio.2019.01.014 .

[55] Li J, Wang X, Yang F, et al. Matrine enhances osteogenic differentiation of bone marrow-derived mesenchymal stem cells and promotes bone regeneration in rapid maxillary expansion[J]. Arch Oral Biol, 2020, 118: 104862. doi: 10.1016/j.archoralbio.2020.104862 .

[56] 冯光耀, 邹冰爽, 高雪梅, 等. 上颌牙弓反复快速扩缩对大鼠环上颌周围骨缝的组织学影响[J]. 北京大学学报(医学版), 2016, 48(1): 30-36. doi: 10.3969/j.issn.1671-167X.2016.01.006 .

[57] Feng GY, Zou BS, Gao XM, et al. Histological changes in the circum-maxillary sutures during alternate maxillary expansions and constrictions in a rat model[J]. J Peking Univ Health Sci, 2016, 48(1): 30-36. doi: 10.3969/j.issn.1671-167X.2016.01.006 .

[58] Koehne T, Kahl-Nieke B, Amling M, et al. Inhibition of bone resorption by bisphosphonates interferes with orthodontically induced midpalatal suture expansion in mice[J]. Clin Oral Investig, 2018, 22(6): 2345-2351. doi: 10.1007/s00784-018-2335-z .

[59] Xu M, Li Y, Feng X, et al. Parathyroid hormone promotes maxillary expansion and reduces relapse in the repeated activation maxillary expansion rat model by regulating Wnt/β-catenin pathway[J]. Prog Orthod, 2022, 23(1): 1. doi: 10.1186/s40510-021-00394-0 .

[60] Tong F, Liu F, Liu J, et al. Effects of a magnetic palatal expansion appliance with reactivation system: an animal experiment[J]. Am J Orthod Dentofacial Orthop, 2017, 151(1): 132-142. doi: 10.1016/j.ajodo.2016.06.030 .

[61] Ouldyerou A, Ngan P, Alsharif K, et al. Biomechanical performance of ATOZ expander: finite-element analysis[J]. Am J Orthod Dentofac Orthop, 2025, 167(3): 331-344. doi: 10.1016/j.ajodo.2024.10.015 .

[62] Ouldyerou A, Mamboleo E, Gilchrist L, et al. In-silico evaluation of orthodontic miniscrew-assisted rapid palatal expanders for patients with various stages of skeletal maturation[J]. Am J Orthod Dentofacial Orthop, 2024, 166(6): 561-571. doi: 10.1016/j.ajodo.2024.07.018 .

[63] Huang X, Li Z, Liu P, et al. Gli1⁺ cells residing in bone sutures respond to mechanical force via IP₃R to mediate osteogenesis[J]. Stem Cells Int, 2021, 2021: 8138374. doi: 10.1155/2021/8138374 .

[64] Li M, Zhang Z, Gu X, et al. MicroRNA-21 affects mechanical force-induced midpalatal suture remodelling[J]. Cell Prolif, 2020, 53(1): e12697. doi: 10.1111/cpr.12697 .

[65] Li L, Zhai M, Cheng C, et al. Mechanically induced M2 macrophages are involved in bone remodeling of the midpalatal suture during palatal expansion[J]. Prog Orthod, 2024, 25(1): 30. doi: 10.1186/s40510-024-00529-z .

[66] He Z, Du Y, Peng C, et al. Piezo1 promotes osteogenesis through CaMKII signalling in a rat maxillary expansion model[J]. Orthod Craniofac Res, 2025, 28(1): 196-206. doi: 10.1111/ocr.12862 .

[67] Li Y, Qiao Y, Wang H, et al. Intraperitoneal injection of PDTC on the NF-kB signaling pathway and osteogenesis indexes of young adult rats with anterior palatal suture expansion model[J]. PLoS One, 2021, 16(7): e0243108. doi: 10.1371/journal.pone.0243108 .

[68] Pang H, Ding L, Che X. Early effects of α7nAChR regulation on maxillary expansion in mice: a study on osteogenesis and inflammatory factors[J]. J Orofac Orthop, 2024. doi: 10.1007/s00056-024-00565-8 .

[69] Jiang T, Tang XY, Su H, et al. Neutrophils are involved in early bone formation during midpalatal expansion[J]. Oral Dis, 2024, 30(7): 4483-4494. doi: 10.1111/odi.14849 .

[70] Chen H, Kapetanović A, Piao Z, et al. Stability of expansion effects following miniscrew-assisted rapid palatal expansion: a prospective longitudinal cohort study[J]. Oral Maxillofac Surg, 2025, 29(1): 23. doi: 10.1007/s10006-024-01319-x .

[71] Marañón-Vásquez GA, de Andrade ACDV, Maia LC, et al. Effect of treatment of transverse maxillary deficiency using rapid palatal expansion on oral health-related quality of life in children: complementary results for a controlled clinical trial[J]. Clin Oral Investig, 2024, 28(10): 525. doi: 10.1007/s00784-024-05902-0 .

[72] Hong C, Song D, Lee DK, et al. Reducing posttreatment relapse in cleft lip palatal expansion using an injectable estrogen-nanodiamond hydrogel[J]. Proc Natl Acad Sci USA, 2017, 114(35): E7218-E7225. doi: 10.1073/pnas.1704027114 .

[73] Kayalar E, Deynek GT, Tok OE, et al. Effect of salvianolic acid B on new bone formation in the orthopedically expanded suture[J]. Angle Orthod, 2021, 91(2): 248-254. doi: 10.2319/042620-360.1 .

[74] Liang W, Ding P, Li G, et al. Hydroxyapatite nanoparticles facilitate osteoblast differentiation and bone formation within sagittal suture during expansion in rats[J]. Drug Des Devel Ther, 2021, 15: 905-917. doi: 10.2147/DDDT.S299641 .

[75] Farzan A, Moshiri A, Andalib S, et al. Effect of simvastatin and low-level laser therapy on sutural bone formation after expansion in rats: biomechanical, computed tomography and immunohistochemical assessment[J]. J Lasers Med Sci, 2022, 13: e21. doi: 10.34172/jlms.2022.21 .

[76] Liu Y, Zhong Y, Zheng B, et al. Extracellular vesicles derived from M1 macrophages enhance rat midpalatal suture expansion by promoting initial bone turnover and inflammation[J]. Prog Orthod, 2023, 24(1): 34. doi: 10.1186/s40510-023-00477-0 .

[77] Liu B, Wang B, Wang Z, et al. Near-infrared light-controlled microRNA-21-loaded upconversion nanoparticles to promote bone formation in the midpalatal suture[J]. ACS Appl Mater Interfaces, 2023, 15(37): 43503-43514. doi: 10.1021/acsami.3c08616 .

[78] Cheng Y, Chen J, Zou S, et al. The mechanism underlying the remodeling effect of lactoferrin on midpalatal sutures during maxillary expansion and relapse in rats[J]. Am J Orthod Dentofacial Orthop, 2023, 163(6): e137-e151. doi: 10.1016/j.ajodo.2023.03.006 .

[79] Xiao X, Cheng Y, Huang L, et al. Gavage-administered lactoferrin promotes palatal expansion stability in a dose-dependent manner[J]. Oral Dis, 2023, 29(1): 254-264. doi: 10.1111/odi.13989 .

[80] Lai PS, Fierro C, Bravo L, et al. Benefits of using low-level laser therapy in the rapid maxillary expansion: a systematic review[J]. Int J Clin Pediatr Dent, 2021, 14(): S101-S106. doi: 10.5005/jp-journals-10005-1966 .

[81] Eslamian L, Ebadifar A, Mohebbi Rad M, et al. Comparison of single and multiple low-level laser applications after rapid palatal expansion on bone regeneration in rats[J]. J Lasers Med Sci, 2020, 11(): S37-S42. doi: 10.34172/jlms.2020.S6 .

[82] Gao L, Xu T, Zhang L, et al. Midpalatal suture: single-cell RNA-seq reveals intramembrane ossification and Piezo2 chondrogenic mesenchymal cell involvement[J]. Cells, 2022, 11(22): 3585. doi: 10.3390/cells11223585 .

基金资助

湖南省自然科学基金(2022JJ30855)

中南大学中央高校基本科研业务费专项资金(2024ZZTS0940)