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Chinese Journal of Burns and Wounds logoLink to Chinese Journal of Burns and Wounds
. 2022 Dec 20;38(12):1162–1169. [Article in Chinese] doi: 10.3760/cma.j.cn501120-20211213-00412

机械张力对兔耳增生性瘢痕的形成及转化生长因子β1/Smad信号通路的影响

Effects of mechanical tension on the formation of hypertrophic scars in rabbit ears and transforming growth factor-β1/Smad signaling pathway

Peng Cao 1, Yunwei Wang 2, Hao Guan 2, Yunshu Yang 2, Shaohui Li 2, Yang Chen 2, Chan Zhu 2, Yu Wan 1, Liying Ren 1, Ming Yao 1,*
PMCID: PMC11821336  PMID: 36594147

Abstract

Objective

To explore the effects of mechanical tension on the formation of hypertrophic scars in rabbit ears and transforming growth factor-β1 (TGF-β1)/Smad signaling pathway.

Methods

The experimental research method was adopted. Six New Zealand white rabbits, male or female, aged 3-5 months were used and 5 full-thickness skin defect wounds were made on the ventral surface of each rabbit ear. The appearance of all rabbit ear wounds was observed on post surgery day (PSD) 0 (immediately), 7, 14, 21, and 28. On PSD 28, the scar formation rate was calculated. Three mature scars in the left ear of each rabbit were included in tension group and the arch was continuously expanded with a spiral expander. Three mature scars in the right ear of each rabbit were included in sham tension group and only the spiral expander was sutured without expansion. There were 18 scars in each group. After mechanical tension treatment (hereinafter referred to as treatment) for 40 days, the color and texture of scar tissue in the two groups were observed. On treatment day 40, the scar elevation index (SEI) was observed and calculated; the histology was observed after hematoxylin eosin staining, and the collagen morphology was observed after Masson staining; mRNA expressions of TGF-β1, Smad3, collagen Ⅰ, collagen Ⅲ, and α-smooth muscle actin (α-SMA) in scar tissue were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction; and the protein expressions of TGF-β1, collagen Ⅰ, collagen Ⅲ, and α-SMA, and phosphorylation level of Smad3 in scar tissue were detected by Western blotting. The number of samples of each group in the experiments was 3. Data were statistically analyzed with independent sample t test.

Results

On PSD 0, 5 fresh wounds were formed on all the rabbit ears; on PSD 7, the wounds were scabbed; on PSD 14, most of the wounds were epithelialized; on PSD 21, all the wounds were epithelialized; on PSD 28, obvious hypertrophic scars were formed. The scar formation rate was 75% (45/60) on PSD 28. On treatment day 40, the scar tissue of rabbit ears in tension group was more prominent than that in sham tension group, the scar tissue was harder and the color was more ruddy; the SEI of the scar tissue of rabbit ears in tension group (2.02±0.08) was significantly higher than 1.70±0.08 in sham tension group (t=5.07, P < 0.01). On treatment day 40, compared with those in sham tension group, the stratum corneum of scar tissue became thicker, and a large number of new capillaries, inflammatory cells, and fibroblasts were observed in the dermis, and collagen was more disordered, with nodular or swirling distribution in the scar tissue of rabbit ears in tension group. On treatment day 40, the mRNA expressions of TGF-β1, Smad3, collagen Ⅰ, collagen Ⅲ, and α-SMA in the scar tissue of rabbit ears in tension group were respectively 1.81±0.25, 5.71±0.82, 7.86±0.56, 4.35±0.28, and 5.89±0.47, which were significantly higher than 1.00±0.08, 1.00±0.12, 1.00±0.13, 1.00±0.14, and 1.00±0.14 in sham tension group (with t values of 5.36, 9.82, 20.60, 18.26, and 17.13, respectively, all P < 0.01); the protein expressions of TGF-β1, collagen Ⅰ, collagen Ⅲ, and α-SMA, and phosphorylation level of Smad3 in the scar tissue of rabbit ears in tension group were respectively 0.865±0.050, 0.895±0.042, 0.972±0.027, 1.012±0.057, and 0.968±0.087, which were significantly higher than 0.657±0.050, 0.271±0.029, 0.631±0.027, 0.418±0.023, and 0.511±0.035 in sham tension group (with t values of 5.08, 21.27, 15.55, 16.70, and 8.40, respectively, all P < 0.01).

Conclusions

Mechanical tension can inhibit the regression of hypertrophic scars in rabbit ears through stimulating the hyperplasia of scars, inhibiting the normal arrangement of dermal collagen fibers, and intensifying the deposition of collagen fibers, and the mechanism may be related to the activation of TGF-β1/Smad signaling pathway by mechanical tension.

Keywords: Cicatrix, Transforming growth factor beta1, Smad proteins, Mechanical tension

增生性瘢痕是由烧创伤、手术或炎症后的创面愈合反应异常引起的, 这些病变的特征是红斑、隆起, 并伴随瘙痒和疼痛等症状, 是一种皮肤纤维增生性疾病[1-7]。增生性瘢痕的预防和治疗是临床医师面临的世界性难题之一, 虽然现有的预防和治疗增生性瘢痕形成的方法策略已有很大的进步, 但仍然和期望中的治疗效果存在非常大的差距[8-9]。近年来的实验和临床研究表明, 机械张力会促进病理性瘢痕的形成, 切口减张可以减少增生性瘢痕的形成, 进一步强调了机械环境在皮肤病理性瘢痕形成中的关键作用[10-12]。TGF-β1/Smad信号通路调节胶原合成, 在瘢痕形成过程中起着重要作用[2, 9, 13-14]。目前, 机械张力影响增生性瘢痕TGF-β1/Smad信号通路的分子机制尚不清楚。因此, 本实验通过构建兔耳增生性瘢痕模型, 观察机械张力对增生性瘢痕的形成及其对TGF-β1/Smad信号通路的影响, 为增生性瘢痕的治疗和预防提供理论依据。

1. 材料与方法

本实验研究遵循空军军医大学动物实验伦理委员会和国家有关实验动物管理和使用的规定。

1.1. 动物及主要试剂与仪器来源

6只3~5个月龄体重2.0~2.5 kg的雌雄不拘清洁级新西兰大白兔, 双侧兔耳发育良好、未见畸形, 由空军军医大学实验动物中心提供, 许可证号：SCXK（陕）2019-001。HE染色试剂盒、Masson染色试剂盒均购自北京索莱宝生物科技有限公司, 反转录试剂盒、荧光染料试剂盒均购自日本Takara公司, 小鼠抗兔TGF-β1单克隆抗体、Evos FL Auto 2型激光扫描共聚焦显微镜均购自美国Invitrogen公司, 小鼠抗兔Smad3多克隆抗体、小鼠抗兔磷酸化Smad3（p-Smad3）多克隆抗体购自美国Affinity公司, 小鼠抗兔Ⅰ型胶原多克隆抗体购自美国Proteintech公司, 小鼠抗兔Ⅲ型胶原单克隆抗体、小鼠抗兔β肌动蛋白单克隆抗体购自美国GeneTex公司, 小鼠抗兔α平滑肌肌动蛋白（α-SMA）单克隆抗体购自美国Novus公司, 辣根过氧化物酶（HRP）标记的山羊抗小鼠IgG多克隆抗体购自北京康为世纪生物科技有限公司。直径1 cm的圆形打孔器购自江阴市精英实验仪器有限公司, 28 mm螺旋扩弓器购自杭州市亚宏医疗器械有限公司, 弹簧测力计购自东莞新马电子工具仪器有限公司。大体标本成像仪购自西安市瑞丰公司, DU800型分光光度计购自贝克曼库尔特商贸（中国）有限公司, Mini型蛋白电泳系统、电转印系统均购自美国Bio-Rad公司, M200型全波段酶标仪购自瑞士Tecan公司。

1.2. 兔耳增生性瘢痕模型的建立

将6只兔单笼饲养1周（人工混合饲料）, 兔舍恒温17~25 ℃, 相对湿度为50%~75%。术前禁食和禁饮, 8 h后称体重。将兔固定在动物实验操作台, 经耳缘静脉注射30 g/L戊巴比妥钠3.0 mg/kg麻醉（麻醉方法下同）, 剃除兔耳腹侧短毛。于每侧兔耳腹侧面设计5个直径为1 cm的圆形创面, 避开可见血管, 各创面间相距1.5 cm以上, 共60个创面；用直径1 cm圆形打孔器标记出轮廓, 沿标记线切开皮肤全层直至耳软骨膜, 分离软骨膜及全层皮肤, 刮除创面残留组织。无菌生理盐水纱布压迫止血后用红霉素软膏涂抹创面以预防感染。暴露创面, 直至创面形成成熟的兔耳增生性瘢痕[15-17]。

1.3. 动物分组及处理

术后28 d, 将每只兔左耳的3个成熟瘢痕纳入张力组, 右耳的3个成熟瘢痕纳入假张力组, 每组共18个瘢痕。张力组：使用4-0尼龙丝线沿着瘢痕缘周1 cm×1 cm正方形的4个角将28 mm螺旋扩弓器缝合至兔耳瘢痕上, 每个瘢痕上缝合1个扩弓器, 当日扩弓2 mm, 之后隔日扩弓2 mm, 达到最大值后再沿着新的瘢痕缘周的4个角重新缝合, 继续扩弓, 以使其保持持续的张力[18-19]；假张力组：仅将扩弓器缝合至兔耳瘢痕上, 不扩弓。见图 1。

图 1.

图 1

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螺旋扩弓器及其缝合至兔耳增生性瘢痕。1A.28 mm螺旋扩弓器；1B.兔耳瘢痕组织上用于缝合扩弓器的4个角；1C.将扩弓器缝合至瘢痕

1.4. 观测指标

1.4.1. 大体外观

术后0（即刻）、7、14、21、28 d, 观察所有兔耳创面颜色、瘢痕质地和凸起, 并用大体标本成像仪拍照。术后28 d, 计算瘢痕形成率。机械张力处理40 d（以下简称处理40 d）[20], 观察2组兔耳瘢痕颜色和质地并拍照。

1.4.2. 瘢痕增生指数（SEI）

处理40 d, 将所有兔麻醉后, 采用空气栓塞法处死, 完整切取2组所有瘢痕标本, 将每个标本从凸起最明显处切开, 部分置于-80 ℃冰箱中冻存, 部分采用石蜡包埋用于后续实验。取全部石蜡包埋组织制作切片, 部分切片行HE染色后将其分别置于20倍和100倍激光扫描共聚焦显微镜下观察, 采用Image J 1.8.0图像分析软件（美国国立卫生研究院）测量瘢痕凸起最高点至耳软骨表面的垂直距离和耳腹面皮肤表面至耳软骨表面的垂直距离, 并计算SEI, SEI=瘢痕凸起最高点至耳软骨表面的垂直距离÷耳腹面皮肤表面至耳软骨表面的垂直距离[21]。

1.4.3. 瘢痕组织形态

另取部分1.4.2中组织切片, 分别行常规HE、Masson染色, 均于激光扫描共聚焦显微镜20、100倍视野下观察瘢痕组织形态学变化和胶原（阳性染色为蓝色）形态情况。

1.4.4. 瘢痕组织中的TGF-β1、Smad3、Ⅰ型胶原、Ⅲ型胶原、α-SMA的mRNA表达

采用实时荧光定量RT-PCR法检测。取1.4.2部分冻存的组织提取总RNA, 取1 μg总RNA, 检测瘢痕组织中相关因子的mRNA表达。引物均由北京擎科生物科技有限公司合成, 见表 1。以GAPDH为内参照, 采用基于Δ循环阈值（Ct）的2-ΔΔCt法计算TGF-β1、Smad3、Ⅰ型胶原、Ⅲ型胶原、α-SMA的mRNA表达量。

表 1.

采用实时荧光定量反转录PCR法检测兔耳增生性瘢痕组织中TGF-β1、Smad3、Ⅰ型胶原、Ⅲ型胶原、α-SMA的mRNA表达的引物序列及产物大小

基因名称 引物序列（5'→3'） 产物大小（bp）
注：GAPDH为3-磷酸甘油醛脱氢酶, TGF-β1为转化生长因子β1, α-SMA为α平滑肌肌动蛋白
GAPDH 上游：GCTTCTTCTCGTGCAGTGCTA下游：ATGACCAGCTTCCCGTTCTC 239
TGF-β1 上游：CCAAGTGGACATCAACGGGA下游：CTCTGTGGAGCTGAAGCAGT 175
Smad3 上游：AGACCTGACATCCGAGACGA下游：CATCAGGACAGCCGAACAGT 105
Ⅰ型胶原 上游：GCAAGAACGGAGATGACGGA下游：TTGGCACCATCCAAACCACT 151
Ⅲ型胶原 上游：CCGAACCGTGCCAAATATGC下游：AACAGTGCGGGGAGTAGTTG 158
α-SMA 上游：AACAATGTGCTCTCAGGGGG下游：TCTGGAGGGGCAATTATCTTGA 116
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1.4.5. 瘢痕组织中TGF-β1、Ⅰ型胶原、Ⅲ型胶原、α-SMA的蛋白表达和Smad3磷酸化水平

采用蛋白质印迹法检测。取1.4.2剩余的冻存组织来提取组织总蛋白, 然后进行检验。其中一抗为小鼠抗兔TGF-β1、Ⅲ型胶原、α-SMA单克隆抗体（稀释比均为1∶1 000）和小鼠抗兔β肌动蛋白单克隆抗体（稀释比为1∶3 000）, 小鼠抗兔Smad3、p-Smad3、Ⅰ型胶原多克隆抗体（稀释比均为1∶1 000）；二抗为HRP标记的山羊抗小鼠IgG多克隆抗体（稀释比为1∶3 000）。应用Image J图像分析软件进行灰度分析, 以β肌动蛋白为内参照, 计算TGF-β1、Ⅰ型胶原、Ⅲ型胶原、α-SMA的相对蛋白表达, 同时计算p-Smad3与Smad3比值, 以此表示TGF-β1、Ⅰ型胶原、Ⅲ型胶原、α-SMA的蛋白表达水平及Smad3的磷酸化水平。

以上实验各组样本数均为3。

1.5. 统计学处理

采用SPSS 19.0统计软件进行数据分析。计量资料数据均符合正态分布, 以x±s表示, 组间两两比较行独立样本t检验。P < 0.05为差异有统计学意义。

2. 结果

2.1. 大体外观

术后0 d, 所有兔耳腹面均形成5个直径1 cm的圆形新鲜创面；术后7 d, 可见创面结痂；术后14 d, 大部分创面已上皮化；术后21 d, 可见全部创面上皮化, 能明显触摸到硬结；术后28 d, 形成明显的增生性瘢痕, 外观明显凸起、质地坚硬及颜色红润, 其增生范围不超过原创缘, 厚度约为耳厚度的2倍。术后28 d, 瘢痕形成率为75%（45/60）。处理40 d, 张力组的兔耳瘢痕组织凸起较假张力组明显, 瘢痕组织较硬, 颜色较红润。见图 2。

图 2.

图 2

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兔耳增生性瘢痕模型的构建及经机械张力处理40 d的2组兔耳瘢痕的大体外观。2A.术后0 d（即刻）, 可见5个直径为1 cm的圆形新鲜创面；2B.术后7 d, 可见各创面已结痂；2C.术后14 d, 可见部分创面上皮化；2D.术后21 d, 可见全部创面上皮化；2E.术后28 d, 形成明显的增生性瘢痕, 外观明显凸起、颜色红润, 其增生范围不超过原创缘；2F、2G.分别为处理前假张力组、张力组瘢痕, 均明显凸起；2H、2I.分别为处理40 d假张力组、张力组瘢痕, 图 2I瘢痕凸起更加明显且颜色红润

2.2. SEI

处理40 d, 张力组兔耳瘢痕的SEI为2.02±0.08, 明显高于假张力组的1.70±0.08（t=5.07, P=0.007）。

2.3. 瘢痕组织形态

处理40 d, 与假张力组相比, 张力组兔耳瘢痕组织角质层变厚, 真皮层可见大量新生的毛细血管、炎症细胞和Fb；胶原排列更加紊乱, 呈结节状或旋涡状分布。见图 3。

图 3.

经机械张力处理40 d的2组兔耳增生性瘢痕组织形态观察。3A.假张力组可见少量新生毛细血管HE×20；3B.图 3A中方框处放大图, 可见少量炎症细胞和Fb HE×100；3C.张力组可见角质层较图 3A变厚, 真皮层可见大量新生的毛细血管HE×20；3D.图 3C中方框处放大图, 可见大量炎症细胞和Fb HE×100；3E.假张力组可见少量胶原, 排列较紊乱Masson×20；3F.图 3E中方框处放大图, 可见少量排列较紊乱的胶原Masson×100；3G.张力组可见胶原排列图较图 3E更加紊乱, 呈结节状或旋涡状分布Masson×20；3H.图 3G中方框处放大图, 可见大量纤维化和胶原, 胶原排列更加紊乱Masson×100

注：HE为苏木精-伊红, Fb为成纤维细胞, 胶原Masson阳性染色为蓝色

图 3

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2.4. 瘢痕组织中TGF-β1、Smad3、Ⅰ型胶原、Ⅲ型胶原、α-SMA的mRNA表达

处理40 d, 张力组兔耳瘢痕组织中TGF-β1、Smad3、Ⅰ型胶原、Ⅲ型胶原、α-SMA的mRNA表达量分别为1.81±0.25、5.71±0.82、7.86±0.56、4.35±0.28、5.89±0.47, 分别明显高于假张力组的1.00±0.08、1.00±0.12、1.00±0.13、1.00±0.14、1.00±0.14（t值分别为5.36、9.82、20.60、18.26、17.13, P值分别为0.006、0.001、 < 0.001、 < 0.001、 < 0.001）。

2.5. 瘢痕组织中TGF-β1、Ⅰ型胶原、Ⅲ型胶原、α-SMA的蛋白表达和Smad3磷酸化水平

处理40 d, 张力组兔耳瘢痕组织中TGF-β1、Ⅰ型胶原、Ⅲ型胶原、α-SMA的蛋白表达以及Smad3磷酸化水平分别为0.865±0.050、0.895±0.042、0.972±0.027、1.012±0.057、0.968±0.087, 分别明显高于假张力组的0.657±0.050、0.271±0.029、0.631±0.027、0.418±0.023、0.511±0.035（t值分别为5.08、21.27、15.55、16.70、8.40, P值分别为0.007、 < 0.001、 < 0.001、 < 0.001、0.001）。见图 4。

图 4.

蛋白质印迹法检测经机械张力处理40 d的2组兔耳增生性瘢痕组织中TGF-β1、Ⅰ型胶原、Ⅲ型胶原、α-SMA的蛋白表达和Smad3磷酸化水平

注：TGF-β1为转化生长因子β1, α-SMA为α平滑肌肌动蛋白, 条带上方1、2分别指假张力组、张力组

图 4

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3. 讨论

超过70%的患者在烧创伤后会发生增生性瘢痕, 并且伴有广泛的瘙痒、疼痛等症状, 出现在关节活动部位的瘢痕甚至会影响关节的活动, 给患者及其家人带来巨大的身心和经济负担[1, 22]。针对烧创伤相关损伤后的增生性瘢痕的治疗方法可分为手术治疗和非手术治疗两大类[23]。在手术治疗之前, 通常人们更愿意采用非手术治疗方法来抑制和减轻瘢痕的形成。非手术治疗方法包括压力治疗、激光治疗、放射治疗、注射治疗、冷冻疗法、药物治疗及减张等多种方式[24-27]；长期以来, 减张一直是临床上预防和治疗增生性瘢痕形成的关键因素。近些年来, 关于机械张力与增生性瘢痕的研究日益增多, 但仍然缺乏有关机械张力对增生性瘢痕形成及TGF-β1/Smad信号通路影响的相关研究。

有效的瘢痕治疗方法的发展依赖于有效模拟人类增生性瘢痕的动物模型[28]。以往研究机械张力对增生性瘢痕影响的动物模型大都选用小鼠, 本课题组选用兔来制作增生性瘢痕模型是本实验的创新点之一, 原因是兔耳瘢痕模型对创伤的修复反应过程与人类病理性瘢痕产生的过程比较相似[29], 可以对创伤后病理性瘢痕的发生、发展及预后进行连续性的动态观察。

既往研究表明, 局部机械张力的作用可以促进胶原的过度沉积和Fb增殖, 最终导致增生性瘢痕的形成[30]。在临床上有大量研究证明机械张力与增生性瘢痕的关系, 张力越大的切口越容易形成增生性瘢痕, 因此降低创面的张力对预防瘢痕的形成起至关重要的作用[10-11, 31-33]。本实验利用构建好的兔耳增生性瘢痕模型, 处理40 d（有实验证明兔耳瘢痕增生持续约80 d左右, 其中35~42 d瘢痕增生最为明显[20]）, 结果表明张力组兔耳瘢痕的SEI明显高于假张力组；HE染色结果表明, 与假张力组相比, 张力组兔耳瘢痕可见角质层变厚, 真皮层可见大量新生的毛细血管、炎症细胞和Fb。Masson染色结果表明张力组兔耳瘢痕可见胶原排列更加紊乱, 呈结节状或旋涡状分布。以上结果证实机械张力促进了增生性瘢痕的形成。

增生性瘢痕表现为大量胶原纤维和ECM沉积[34], Ⅰ型胶原和Ⅲ型胶原是ECM的主要成分, 在增生性瘢痕的形成过程中Ⅰ型胶原和Ⅲ型胶原均有增加, 胶原的过度沉积与增生性瘢痕的形成有着紧密联系[27, 35-36]。Ⅰ型胶原、Ⅲ型胶原、α-SMA是最常见的瘢痕组织检测指标之一。机械作用可以促进Fb向肌Fb转化, 肌Fb是一种表达α-SMA并参与创面收缩和纤维化的特化Fb, 可更好地促进胶原合成, 而α-SMA在肌Fb收缩、瘢痕挛缩和创面过度愈合的过程中起关键作用[36-37]。本实验观察了机械张力对兔耳增生性瘢痕的影响, 结果表明张力组兔耳瘢痕Ⅰ型胶原、Ⅲ型胶原、α-SMA的mRNA及蛋白表达均明显高于假张力组, 这一结果与之前结论[31-33]是相一致的。这些结果进一步证实了机械张力对增生性瘢痕形成的促进作用。

TGF-β1参与炎症、血管生成、Fb增殖、胶原合成和ECM的重塑。研究表明, 创面愈合和瘢痕形成与TGF-β1有密切关系[38], 增生性瘢痕组织中TGF-β1增加, 而无瘢痕组织中TGF-β1缺乏[39-40], 研究表明TGF-β1/Smad信号通路参与病理性瘢痕的形成过程[12, 41]。Smad3是TGF-β1/Smad信号通路中的重要中间信号分子, 它的主要作用是介导TGF-β1信号进入细胞核内, 并进一步影响下游相关基因的表达, 它的高表达与瘢痕增生的形成有着紧密的关系[42-43]。本实验进一步观察了机械张力对兔耳瘢痕组织中TGF-β1及其下游信号分子Smad3表达的影响, 结果表明, 张力组兔耳瘢痕TGF-β1、Smad3的mRNA表达及TGF-β1的蛋白表达、Smad3磷酸化水平均明显高于假张力组。

综上所述, 本研究证实了机械张力能够促进TGF-β1、Smad3、Ⅰ型胶原、Ⅲ型胶原和α-SMA的表达, 刺激瘢痕的增生, 抑制真皮层胶原纤维的正常排列, 加剧胶原纤维的沉积, 促进瘢痕的形成, 从而对兔耳增生性瘢痕的消退起抑制作用, 其作用机制可能与机械张力激活TGF-β1/Smad信号通路有关。因此机械张力在创面愈合和瘢痕形成中是非常重要的, 在临床手术中要注重术中切口减张缝合, 同时要注意预防术后张力的产生。本研究为临床上预防和治疗增生性瘢痕的形成提供了新的思路和方向。

Funding Statement

国家自然科学基金面上项目（82172209）

General Program of National Natural Science Foundation of China (82172209)

本文亮点

(1) 证实机械张力会刺激瘢痕增生, 抑制真皮层胶原纤维的正常排列, 加剧胶原纤维的沉积, 促进瘢痕形成, 对兔耳增生性瘢痕的消退起到了抑制作用。

(2) 机械张力促进兔耳增生性瘢痕形成的作用机制可能为机械张力可激活转化生长因子β1/Smad信号通路。

(3) 选用新西兰大白兔制作增生性瘢痕模型来研究机械张力对增生性瘢痕的影响及其机制是创新点之一。

利益冲突  所有作者均声明不存在利益冲突

作者贡献声明  曹鹏：酝酿和设计实验, 起草文章, 实施研究, 采集数据；王运帷：实施研究, 分析、解释数据；官浩、姚明：酝酿和设计实验, 对文章的知识性内容作批评性审阅, 获取研究经费, 行政、技术或材料支持, 指导性贡献；杨云舒、李少珲、陈阳、朱婵、万瑀、任丽颖：对文章的知识性内容作批评性审阅, 指导性贡献

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