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Volume 38 Issue 8
Aug.  2022
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Abstract
References
Article Navigation >  CHINESE JOURNAL OF BURNS AND WOUNDS  > 2022  >  38(8): 767-777
You AJ,Li WJ,Zhou JL,et al.Meta-analysis of the effects of xenogeneic acellular dermal matrix dressings in the treatment of wounds in burn patients[J].Chin J Burns Wounds,2023,39(2):175-183.DOI: 10.3760/cma.j.cn501120-20220106-00008.
Citation: Shan H,Zhang ZR,Wang XY,et al.Regulatory mechanism of deferoxamine on macrophage polarization and wound healing in mice with deep tissue injury[J].Chin J Burns Wounds,2022,38(8):767-777.DOI: 10.3760/cma.j.cn501225-20220114-00007.
shu

Regulatory mechanism of deferoxamine on macrophage polarization and wound healing in mice with deep tissue injury

doi: 10.3760/cma.j.cn501225-20220114-00007
  • 1.

    School of Nursing, Qingdao University, Qingdao 266071, China

  • 2.

    Department of Intensive Care Medicine, Affiliated Hospital of Qingdao University, Qingdao 266555, China

Funds:

Youth Science Foundation Project of National Natural Science Foundation of China 81701838

China Postdoctoral Science Foundation Project 2018M632628

More Information
  • Corresponding author: Zhang Ju, Email: zhangju111@qdu. edu. cn
  • Received Date: 2022-01-14
    Abstract
  •   Objective  To investigate the effects of deferoxamine on macrophage polarization and wound healing in mice with deep tissue injury (DTI) and its mechanism.  Methods  The experimental research methods were adopted. Fifty-four male C57BL/6J mice of 6-8 weeks old were divided into DTI control group, 2 mg/mL deferoxamine group, and 20 mg/mL deferoxamine group according to random number table, with 18 mice in each group. DTI was established on the back of mice by magnet compression method. From post injury day (PID) 1, mice were injected subcutaneously with 100 µL normal saline or the corresponding mass concentration of deferoxamine solution every other day at the wound edge until the samples were collected. Another 6 mice without any treatment were selected as normal control group. Six mice in each of the three DTI groups were collected on PID 3, 7, and 14 to observe the wound changes and calculate the wound healing rate. Normal skin tissue of mice in normal control group was collected on PID 3 in other groups (the same below) and wound tissue of mice in the other three groups on PID 7 and 14 was collected for hematoxylin-eosin (HE) staining to observe the tissue morphology. Normal skin tissue of mice in normal control group and wound tissue of mice in the other three groups on PID 7 were collected, and the percentages of CD206 and CD11c positive area were observed and measured by immunohistochemical staining, and the mRNA and protein expressions of CD206, CD11c, and inducible nitric oxide synthase (iNOS) were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction and Western blotting, respectively. Normal skin tissue of mice in normal control group and wound tissue of mice in DTI control group and 20 mg/mL deferoxamine group were collected on PID 3, 7, and 14, and the protein expressions of signal transducer and activator of transcription 3 (STAT3) and interleukin-10 (IL-10) were detected by Western blotting. The sample number in each group at each time point in the above experiments. The RAW264.7 cells were divided into 50 μmol/L deferoxamine group, 100 μmol/L deferoxamine group, 200 μmol/L deferoxamine group, and blank control group, which were treated correspondingly, with 3 wells in each group. The positive cell percentages of CD206 and CD86 after 48 h of culture were detected by flow cytometry. Data were statistically analyzed with analysis of variance for repeated measurement, one-way analysis of variance, and least significant difference test.  Results  On PID 7, the wound healing rates of mice in 2 mg/mL and 20 mg/mL deferoamine groups were (17.7±3.7)% and (21.5±5.0)%, respectively, which were significantly higher than (5.1±2.3)% in DTI control group (P<0.01). On PID 14, the wound healing rates of mice in 2 mg/mL and 20 mg/mL deferoamine groups were (51.1±3.8)% and (57.4±4.4)%, respectively, which were significantly higher than (25.2±3.8)% in DTI control group (P<0.01). HE staining showed that the normal skin tissue layer of mice in normal control group was clear, the epidermis thickness was uniform, and skin appendages such as hair follicles and sweat glands were visible in the dermis. On PID 7, inflammation in wound tissue was obvious, the epidermis was incomplete, and blood vessels and skin appendages were rare in mice in DTI control group; inflammatory cells in wound tissue were reduced in mice in 2 mg/mL and 20 mg/mL deferoxamine groups, and a few of blood vessels and skin appendages could be seen. On PID 14, inflammation was significantly alleviated and blood vessels and skin appendages were increased in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoxamine groups compared with those in DTI control group. On PID 7, the percentages of CD206 positive area in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoxamine groups were significantly higher than that in DTI control group (P<0.01), the percentage of CD206 positive area in wound tissue of mice in DTI control group was significantly lower than that in normal skin tissue of mice in normal control group (P<0.01), the percentage of CD206 positive area in wound tissue of mice in 20 mg/mL deferoxamine group was significantly higher than that in normal skin tissue of mice in normal control group (P<0.01). The percentages of CD11c positive area in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoxamine groups were significantly lower than those in DTI control group and normal skin tissue in normal control group (P<0.05 or P<0.01), and the percentage of CD11c positive area in normal skin tissue of mice in normal control group was significantly higher than that in DTI control group (P<0.05). On PID 7, the CD206 mRNA expressions in the wound tissue of mice in 2 mg/mL and 20 mg/mL deferoxamine groups were significantly higher than that in DTI control group (P<0.01), but significantly lower than that in normal skin tissue in normal control group (P<0.01); the CD206 mRNA expression in wound tissue of mice in DTI control group was significantly lower than that in normal skin tissue in normal control group (P<0.01). The mRNA expressions of CD11c and iNOS in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoamine groups were significantly lower than those in DTI control group (P<0.01). The mRNA expressions of CD11c in the wound tissue of mice in DTI control group, 2 mg/mL and 20 mg/mL deferoamine groups were significantly higher than that in normal skin tissue in normal control group (P<0.01). Compared with that in normal skin tissue in normal control group, the mRNA expressions of iNOS in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoamine groups were significantly decreased (P<0.01), and the mRNA expression of iNOS in wound tissue of mice in DTI control group was significantly increased (P<0.01). On PID 7, the protein expressions of CD206 in the wound tissue of mice in 2 mg/mL and 20 mg/mL deferoamine groups were significantly higher than those in DTI control group and normal skin tissue in normal control group (P<0.01), and the protein expression of CD206 in wound tissue of mice in DTI control group was significantly lower than that in normal skin tissue in normal control group (P<0.01). The protein expressions of CD11c and iNOS in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoamine groups were significantly lower than those in DTI control group (P<0.01). The protein expressions of CD11c and iNOS in wound tissue of mice in DTI control group were significantly higher than those in normal skin tissue in normal control group (P<0.01). The CD11c protein expressions in wound tissue of mice in 2 mg/mL and 20 mg/mL deferoamine groups were significantly higher than those in normal skin tissue in normal control group (P<0.05 or P<0.01). The protein expression of iNOS in wound tissue of mice in 2 mg/mL deferoamine group was significantly lower than that in 20 mg/mL deferoamine group and normal skin tissue in normal control group (P<0.05). On PID 3, 7, and 14, the protein expressions of STAT3 and IL-10 in wound tissue of mice in 20 mg/mL deferoxamine group were significantly higher than those in DTI control group (P<0.05 or P<0.01), and the protein expressions of STAT3 were significantly higher than those in normal skin tissue in normal control group (P<0.05 or P<0.01). On PID 7 and 14, the protein expressions of IL-10 in wound tissue of mice in 20 mg/mL deferoxamine group were significantly higher than those in normal skin tissue in normal control group (P<0.01). On PID 3, 7, and 14, the protein expressions of IL-10 in wound tissue of mice in DTI control group were significantly lower than those in normal skin tissue in normal control group (P<0.05 or P<0.01). After 48 h of culture, compared with those in blank control group, the CD206 positive cell percentages in 100 μmol/L and 200 μmol/L deferoamine groups were significantly increased (P<0.01), while the CD86 positive cell percentages in 100 μmol/L and 200 μmol/L deferoamine groups were significantly decreased (P<0.01).  Conclusions  Deferoxamine can promote the polarization of macrophages toward the anti-inflammatory M2 phenotype and improve wound healing by enhancing the STAT3/IL-10 signaling pathway in DTI mice.

     

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    (1)总结并论证了异种脱细胞真皮基质敷料治疗烧伤患者创面的临床效果，为临床敷料选择提供循证医学依据。

    (2)荟萃分析结果显示使用异种脱细胞真皮基质敷料可从缩短创面愈合时间，改善瘢痕情况，减少烧伤后并发症发生、瘢痕增生、植皮和细菌检出比例，明显提高烧伤创面的愈合质量。

    烧伤是一种由火焰、蒸汽、热液等因素引起的皮肤黏膜损伤，容易出现组织缺氧坏死、皮肤屏障功能受损和机体免疫系统紊乱等严重问题，给患者的预后带来很大的困难。而且烧伤作为举世关注的公共卫生问题之一，其发生率和病死率居高不下［1, 2］。创面处理是救治的关键环节。目前对于烧伤创面的处理仍然以凡士林纱布覆盖和绷带包扎为主，但是这些传统敷料的疗效不甚理想，其吸收渗液后不能及时引流，久而久之会与新生肉芽组织粘连在一起，影响皮肤损伤的愈合效果。近年来随着社会医疗水平的提高，涌现出了许多新型敷料。异种ADM敷料被认为是一种理想的临床敷料，能够及时覆盖创面并维持湿润的创面微环境，促进创面再上皮化并使创面顺利过渡到皮肤屏障重建［3］。异种ADM敷料除了适用于修复组织缺损外，还作为临时性创面覆盖物被广泛应用于烧伤领域，为创面提供生物膜屏障保护。异种ADM敷料具有以下优点：免疫原性低，无排斥反应；可隔离创面和空气，有效降低创面感染率；多孔的网状结构为皮肤细胞生长提供天然的生物支架，加速其增殖分化；还保留了皮肤的ECM成分，可为皮肤再生供给充足的营养，因此被认为是烧伤救治的有效方法之一［4］。尽管异种ADM敷料在烧伤领域使用广泛，但目前尚缺乏系统的荟萃分析。因此本研究收集和整理了异种ADM敷料治疗烧伤患者创面的随机对照试验并进行荟萃分析，客观评价异种ADM敷料在烧伤创面中的临床治疗效果及其应用价值，旨在为临床选择合适的创面覆盖物提供循证医学依据。

    1.   资料与方法

    1.1   文献入选标准

    纳入标准：（1）研究类型为国内外公开发表的异种ADM敷料对比其他方式治疗烧伤创面的随机对照试验。（2）研究对象为烧伤患者。（3）干预措施中试验组使用异种ADM敷料治疗或联合其他烧伤治疗方案，对照组使用非异种ADM敷料的其他烧伤治疗方案。（4）结局指标包括创面愈合时间、瘢痕增生比例、温哥华瘢痕量表（VSS）评分、并发症（创面液化、创面感染、发热和脓毒血症）发生比例、植皮比例、细菌检出比例。

    排除标准：（1）重复发表的研究。（2）综述性文献或会议论文。（3）文献数据缺失。（4）无法下载全文或无法联系到作者获取全文的文献。

    1.2   文献检索

    以“异种脱细胞真皮基质、敷料、烧伤创面、烧伤”为中文检索词检索《中国期刊全文数据库》《万方数据库》《维普数据库》《中国生物医学文献数据库》，以“xenogeneic acellular dermal matrix、dressing、burn wound、burn”为英文检索词检索《PubMed》《Embase》《Web of Science》《Cochrane Library》数据库，检索时限均为建库时至2021年12月。检索策略遵循《Cochrane系统评价员手册》。由本文第1作者和通信作者分别对检索到的文献剔重之后，根据入选标准依次阅读文献的标题、摘要、全文并筛选，当意见不统一时，与第2作者协商解决。

    1.3   资料提取

    由本文的第2、3作者按照文献入选标准独立提取纳入文献的数据，出现分歧时与通信作者协商解决。提取资料：纳入研究的基本信息，包含第1作者与组别及患者例数、性别、年龄、烧伤总面积、干预措施、随访时间；结局指标，包括创面愈合时间、瘢痕增生比例、VSS评分、并发症发生比例、植皮比例、细菌检出比例。

    1.4   纳入研究偏倚风险评估

    由本文第1、2作者采用Cochrane偏倚风险评估工具5.1.0［5］独立评估纳入研究的风险偏倚情况。包括随机序列产生的方法是否正确，是否做到了分配隐藏，是否对参与者及实施者实施了盲法，结局指标测量是否实施盲法，资料是否完整，是否完整报告所有结局指标、有无选择性报道，是否有其他偏倚风险这7个偏倚风险条目，并以“低风险”“高风险”和“风险未知”来进行判断。

    1.5   统计学处理

    采用Rev Man 5.3统计软件进行荟萃分析。针对计数资料和计量资料数据分别采用相对危险度（RR）和标准化均数差（SMD）作为效应统计分析的指标，并计算95%置信区间，P<0.05为差异有统计学意义。采用χ2检验评估各研究间的异质性，并结合I2检验对异质性进行定量分析。若I²<50%、P>0.1，判定为无明显异质性，采用固定效应模型分析。若I²≥50%、P≤0.1，判定为存在明显异质性，采用随机效应模型分析。采用敏感性分析评估剔除任意一项研究对效应量的影响，如果剔除该单项研究后合并效应量有明显变化，说明该项研究可能是异质性来源；如果剔除该单项研究后合并效应量无明显变化，则说明纳入研究总体合并效应量稳定性良好。进一步对可能导致异质性的因素进行亚组分析评估时，若分组后异质性较分组前总体异质性有明显变化，提示该分组因素可能是异质性来源，若无明显变化则提示该分组因素可能不是异质性来源。使用Stata 14.0统计软件评估纳入研究结果的发表偏倚性，P<0.05为存在发表偏倚，P≥0.05为不存在发表偏倚。

    2.   结果

    2.1   文献检索结果

    初步检索获得相关文献266篇，经逐层筛选，最终纳入16篇文献［6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21］。见图1。

    1  异种脱细胞真皮基质敷料治疗烧伤患者创面效果的文献筛选流程图
    下载: 全尺寸图片 幻灯片

    2.2   纳入文献的基本资料和结局指标

    本研究纳入的16篇文献共有1 596例烧伤患者，包含接受异种ADM敷料治疗的试验组患者835例和接受其他方式治疗的对照组患者761例。纳入文献的基本资料见表1，纳入文献的部分结局指标见表2、3。另仅3项研究描述了试验组和对照组患者的VSS评分：包括文献［15］中的（4.02±0.72）、（8.20±1.09）分，文献［17］中的（2.94±0.47）、（5.18±0.82）分和文献［18］中的（3.64±0.88）、（5.23±1.14）分；仅2项研究描述了试验组和对照组患者的植皮比例：包括文献［12］中的8/165、21/155与文献［13］中的0、4/45；仅2项研究描述了试验组和对照组患者的细菌检出比例：包括文献［8］中的3/33、10/32与文献［9］中的2/27、8/27。

    表1  纳入荟萃分析的16篇异种ADM敷料治疗烧伤患者创面效果的文献的基本资料
    第1作者与组别例数性别（例）年龄（岁，x¯±s）烧伤总面积（%TBSA）干预措施随访时间
    男女
    冯祥生［6］
    试验组674819—67.5±6.3基础治疗+异种ADM敷料覆盖+红外线灯照射3个月~2年
    对照组1064—63.6±11.3基础治疗+皮维碘软膏处理+红外线灯照射3个月~2年
    陈善伟［7］
    试验组32248—36±5.62基础治疗+异种ADM敷料覆盖3个月~4年
    对照组28208—34±6.2基础治疗+磺胺嘧啶银处理3个月~4年
    覃秋海［8］
    试验组33191432.5±10.327.0±9.3基础治疗+异种ADM敷料覆盖6个月
    对照组32181430.5±10.725.0±9.7基础治疗+聚维酮碘膏处理6个月
    曹峰［9］
    试验组27161130.01±1.4—基础治疗+异种ADM敷料覆盖+红外线灯照射—
    对照组27151229.57±1.32—基础治疗+纳米银抗菌敷料覆盖—
    邱玉友［10］
    试验组50262436.8±7.24~10基础治疗+异种ADM敷料覆盖—
    对照组50282237.2±9.84~10基础治疗+磺胺嘧啶银处理—
    胡检［11］
    试验组60332745.4±6.763.2±3.6基础治疗+异种ADM敷料覆盖+红外线灯照射1年
    对照组60342643.4±6.466.2±3.6基础治疗+凡士林纱布覆盖1年
    黄亚川［12］
    试验组165——3.21±2.6113.89±3.21基础治疗+异种ADM敷料覆盖—
    对照组155——3.02±1.5413.25±3.12基础治疗+银离子敷料覆盖—
    李津［13］
    试验组45————基础治疗+异种ADM敷料覆盖3个月~1年
    对照组45————基础治疗+磺胺嘧啶银处理+护架烤灯照射3个月~1年
    吴日强［14］
    试验组30————基础治疗+异种ADM敷料覆盖—
    对照组30————基础治疗+聚维酮碘膏处理+护架烤灯照射—
    郭慧芳［15］
    试验组4626203.61±1.33—基础治疗+消毒后的异种ADM敷料覆盖—
    对照组4425193.81±1.45—基础治疗+皮维碘软膏处理+红外线灯照射—
    赵飞龙［16］
    试验组48272144.45±2.1411.35±3.51基础治疗+异种ADM敷料覆盖—
    对照组48282043.24±2.2610.24±3.45基础治疗+重组人碱性成纤维细胞生长因子喷涂—
    陆金云［17］
    试验组45291640.3±6.421.3±3.5基础治疗+异种ADM敷料覆盖+红外线灯照射—
    对照组45281741.4±6.322.1±3.8基础治疗+凡士林纱布覆盖—
    成鑫［18］
    试验组62372537.14±10.2314.73±2.45基础治疗+异种ADM敷料覆盖+VSD—
    对照组62382436.23±10.7513.64±2.65基础治疗+凡士林纱布覆盖+VSD—
    谢晓勇［19］
    试验组50272343.50±6.41—基础治疗+异种ADM敷料覆盖+红外线灯照射—
    对照组50262444.00±6.87—基础治疗+凡士林纱布覆盖—
    万能［20］
    试验组35221324.85±17.4344.98±14.35基础治疗+异种ADM敷料覆盖+红外线灯照射6个月
    对照组35211424.76±16.9745.01±14.29基础治疗+创面薄化术+红外线灯照射6个月
    林桂清［21］
    试验组40241644.21±2.8028.24±2.12基础治疗+异种ADM敷料覆盖+红外线灯照射—
    对照组40231744.16±2.7828.16±2.15基础治疗—
    注：ADM为脱细胞真皮基质，TBSA为体表总面积，VSD为负压封闭引流；“—”表示无此项；文献[13]、[14]的2组患者整体年龄范围分别为1个月~12岁、（2±1.2）岁；文献[10]烧伤总面积数据以范围表示，其余有该项目文献烧伤总面积数据以x¯±s表示；文献[6]、[15]、[20]明确了试验组患者应用异种ADM敷料的具体参数，打孔尺寸分别为1.5 cm×0.4 cm、0.25 cm×0.25 cm、1 cm，间隔分别为1.0~1.5 cm、1.0~1.5 cm、10 cm；基础治疗指清创、营养支持、抗感染、抗休克等治疗
    下载: 导出CSV 
    | 显示表格
    表2  纳入荟萃分析的8篇异种脱细胞真皮基质敷料治疗烧伤患者创面效果的文献的部分结局指标
    第1作者与组别例数创面愈合时间（d，x¯±s）瘢痕增生比例并发症发生比例
    冯祥生［6］
    试验组6712.2±2.6——
    对照组1027.4±3.5——
    陈善伟［7］
    试验组3212.6±3.8——
    对照组2826.6±5.9——
    覃秋海［8］
    试验组3314.3±2.7——
    对照组3219.4±3.4——
    曹峰［9］
    试验组278.12±1.04——
    对照组2712.14±1.17——
    邱玉友［10］
    试验组509.8±1.3——
    对照组5015.2±1.2——
    胡检［11］
    试验组6014.1±4.339/605/60
    对照组6023.5±3.757/6013/60
    黄亚川［12］
    试验组16518.3±3.1012/165—
    对照组15525.10±5.5340/155—
    李津［13］
    试验组457.2±1.48/45—
    对照组4510.6±3.219/45—
    注：“—”表示无此项；并发症包括创面液化、创面感染、发热和脓毒血症
    下载: 导出CSV 
    | 显示表格
    表3  纳入荟萃分析的另8篇异种脱细胞真皮基质敷料治疗烧伤患者创面效果的文献的部分结局指标
    第1作者与组别例数创面愈合时间（d，x¯±s）瘢痕增生比例并发症发生比例
    吴日强［14］
    试验组305.0±1.32/30—
    对照组3010.0±2.88/30—
    郭慧芳［15］
    试验组4612.58±1.70——
    对照组4415.90±1.40——
    赵飞龙［16］
    试验组48——2/48
    对照组48——12/48
    陆金云［17］
    试验组4514.0±2.2—3/45
    对照组4523.4±3.6—10/45
    成鑫［18］
    试验组6221.06±4.34—4/62
    对照组6223.52±4.26—12/62
    谢晓勇［19］
    试验组5014.28±2.5438/501/50
    对照组5023.67±3.7646/507/50
    万能［20］
    试验组3515.12±4.3223/352/35
    对照组3524.76±3.6833/3517/35
    林桂清［21］
    试验组4016.55±2.54—1/40
    对照组4023.15±3.62—8/40
    注：“—”表示无此项；并发症包括创面液化、创面感染、发热和脓毒血症
    下载: 导出CSV 
    | 显示表格

    2.3   偏倚风险评估结果

    在随机序列产生的方法方面，15项研究［7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21］进行了描述且随机化方法正确，1项研究［6］不清楚；16项研究［6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21］未表明是否分配隐藏；1项研究［18］采取双盲法，15项研究［6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17，19, 20, 21］不清楚是否对参与者与实施者实施盲法评估；1项研究［7］报告了对照组因感染而转手术治疗，15项研究［6，8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21］资料完整；16项研究［6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21］在是否完整报告所有结局指标、有无选择性报道、是否存在其他偏倚风险方面均不清楚。本研究中纳入的16项研究存在的偏倚风险不确定。

    2.4   荟萃分析结果

    2.4.1   创面愈合时间

    15项研究［6, 7, 8, 9, 10, 11, 12, 13, 14, 15，17, 18, 19, 20, 21］间存在明显异质性（I²=93%，P<0.001），随机效应模型合并分析结果显示，试验组患者创面愈合时间明显短于对照组（SMD=-2.50，95%置信区间为-3.02~-1.98，P<0.001）。敏感性分析结果显示，逐一剔除文献［6］、［7］、［8］、［9］、［10］、［11］、［12］、［13］、［14］、［15］、［17］、［18］、［19］、［20］、［21］后，余下14项研究中试验组患者创面愈合时间均明显短于对照组（SMD分别为-2.32、-2.48、-2.57、-2.43、-2.37、-2.52、-2.59、-2.59、-2.52、-2.53、-2.45、-2.63、-2.47、-2.51、-2.53，95%置信区间分别为-2.80~-1.84、-3.02~-1.94、-3.12~-2.02、-2.95~-1.90、-2.85~-1.88、-3.08~-1.96、-3.17~-2.00、-3.14~-2.04、-3.07~-1.97、-3.09~-1.98、-2.99~-1.92、-3.11~-2.16、-3.01~-1.93、-3.06~-1.96、-3.09~-1.98，P<0.001），显示创面愈合时间合并效应量结果稳定性良好，剩余14项研究均存在明显异质性（I2值分别为92%、93%、94%、93%、92%、94%、93%、93%、94%、94%、93%、91%、93%、94%、94%，P<0.001）。异质性可能来源于患者年龄和对照组干预措施差异。亚组分析显示，按患者年龄分组后，未成年组存在明显异质性（I²=66%），成年组存在较大异质性（I²=94%），可见患者年龄差异可能不是异质性来源。按对照组干预措施分为聚维酮碘膏组与其他治疗组，聚维酮碘膏组存在轻度异质性（I²=48%），其他治疗组存在较大异质性（I²=94%），可见对照组的干预措施差异可能是异质性来源。见表4。

    表4  纳入荟萃分析的15篇异种ADM敷料治疗烧伤患者创面效果的文献的创面愈合时间的异质性来源亚组分析
    分组因素与亚组研究数（项）统计模型类型异质性检验P值标准化均数差95%置信区间Z值P值
    患者年龄
    未成年组4随机0.030-1.75-2.13~-1.379.01<0.001
    成年组9随机<0.001-2.52-3.29~-1.756.38<0.001
    对照组干预措施
    聚维酮碘膏组2随机0.160-1.93-2.53~-1.336.28<0.001
    其他治疗组13随机<0.001-2.59-3.18~-2.018.67<0.001
    注：未成年组患者年龄≤18岁，成年组患者年龄>18岁；ADM为异种脱细胞真皮基质
    下载: 导出CSV 
    | 显示表格
    2.4.2   瘢痕增生比例

    6项研究［11, 12, 13, 14，19, 20］间存在明显异质性（I²=80%，P<0.001），随机效应模型合并分析结果显示，试验组患者瘢痕增生比例明显低于对照组（RR=0.58，95%置信区间为0.43~0.80，P<0.001）。敏感性分析显示，逐一剔除文献［11］、［12］、［13］、［14］、［19］、［20］后，余下5项研究中试验组患者瘢痕增生比例均明显少于对照组（RR分别为0.53、0.61、0.61、0.51、0.51、0.70，95%置信区间分别为0.34~0.81、0.45~0.82、0.45~0.84、0.31~0.84、0.34~0.76、0.57~0.85，P值分别为0.004、0.001、0.002、0.008、<0.001、<0.001），显示瘢痕增生比例合并效应量结果稳定性良好，剩余5项研究均存在明显异质性（I2值分别为85%、81%、81%、86%、76%、53%，P值分别为<0.001、<0.001、<0.001、<0.001、0.002、0.070）。

    2.4.3   VSS评分

    3项研究［15，17, 18］间存在明显异质性（I²=96%，P<0.001），随机效应模型合并分析结果显示，试验组患者VSS评分明显低于对照组（SMD=-3.10，95%置信区间为-4.87~-1.34，P<0.001）。敏感性分析结果显示，逐一剔除文献［15］、［17］、［18］后，余下2项研究中试验组患者VSS评分均明显低于对照组（SMD分别为-2.42、-3.01、-3.89，95%置信区间分别为-4.15~-0.68、-5.90~-0.11、-5.05~-2.73，P值分别为0.006、0.040、<0.001），显示VSS评分合并效应量结果稳定性良好，剩余2项研究均存在明显异质性（I2值分别为95%、98%、81%，P值分别为<0.001、<0.001、0.020）。

    2.4.4   并发症发生比例

    7项研究［11，16, 17, 18, 19, 20, 21］间无明显异质性（I²=0，P=0.760），固定效应模型合并分析结果显示，试验组患者并发症发生比例明显低于对照组（RR=0.23，95%置信区间为0.14~0.37，P<0.001）。

    2.4.5   植皮比例

    2项研究［12, 13］间无明显异质性（I²=0，P=0.440），固定效应模型合并分析结果显示，试验组患者植皮比例明显低于对照组（RR=0.32，95%置信区间为0.15~0.67，P=0.003）。

    2.4.6   细菌检出比例

    2项研究［8, 9］间无明显异质性（I²=0，P=0.870），固定效应模型合并分析结果显示，试验组患者细菌检出比例明显低于对照组患者（RR=0.27，95%置信区间为0.11~0.69，P=0.006）。

    2.4.7   发表偏倚

    瘢痕增生比例不存在发表偏倚（P=0.054），创面愈合时间、VSS评分、并发症发生比例存在发表偏倚（P值分别为<0.001、0.017、0.010），植皮比例和细菌检出比例由于仅有2项研究未行此检验。

    3.   讨论

    异种ADM敷料大部分取自猪皮［22］，经过病毒灭活和脱细胞工序处理后与人体皮肤结构和胶原成分相似，具备黏附性、透气性以及止血性等生物学特性。异种ADM敷料具有来源丰富、制备工艺成熟、抗原性弱、组织相容性好等特点，被广泛应用于Ⅱ度烧伤创面、磨痂植皮手术等［23, 24］。近年来，异种ADM敷料在取材来源和制备方法等方面有了不少新的发展。人源异种ADM、牛源异种ADM在临床医学领域都得到了充分的开发利用［25, 26］。而且目前已研发出多种制备方法，如分散酶Ⅱ-曲拉通法、机械刮除法、高渗盐水-十二烷基硫酸钠法、高渗盐水-氢氧化钠法和反复冻融后置于超声振荡仪洗脱法等，主要是为了去除α-半乳糖抗原、层粘连蛋白、Ⅳ型胶原蛋白等异质成分，保留真皮结构［27］。

    本研究通过整理有关内容，对纳入的16项临床随机对照试验进行荟萃分析，结果显示，与对照组疗法相比，异种ADM敷料可显著缩短烧伤患者的创面愈合时间。这可能与异种ADM敷料作为创面覆盖物时，可以在相对无菌条件下创造一个湿润的微酸环境有关。微酸环境中，创面渗出液释放增多，激活多种酶及酶活化因子，如蛋白酶、尿激酶等，有利于清除和溶解创面坏死细胞［28］，加快愈合。从分子生物学看，异种ADM敷料维持了完整的真皮支架，可构建快速血管化通道，利于基底面血管的长入并吸引宿主Fb的附着增殖和新生胶原沉积，促进皮肤创面愈合［29］。另外，异种ADM敷料还可以在烧伤创面部位分泌FGF和TGF，介导创面血管的再生［30, 31］，通过改善血供来缩短创面愈合时间。

    深度烧伤的愈合过程中多伴随着大范围软组织损伤，形成以胶原纤维等结缔组织的基质过度沉积为特征的瘢痕组织，其过程并不可逆，影响了皮肤美观性。试验组在减轻烧伤患者瘢痕增生和降低VSS评分方面优于对照组，这可能与异种ADM敷料可显著缩短创面愈合时间，从根源上降低瘢痕增生程度有关［32］。Mansilla等［33］研究显示将异种ADM敷料与负载生长因子的纳米纤维相结合作用于烧伤猪模型后，其瘢痕厚度、柔软度、血管分布、色泽等情况得到改善，与本次研究的结果一致。

    烧伤后病情复杂多变，如果不及时覆盖创面容易引起创面液化、感染和发热、脓毒血症等并发症，创面愈合效果并不理想，往往需要植皮手术来封闭创面，然而植皮术后也存在着皮瓣坏死、瘢痕痉挛等问题。本研究显示，试验组患者的并发症发生比例和植皮比例均明显少于对照组。这可能与异种ADM加工后去除真皮层细胞仅保留胶原，无抗原干扰作用或排斥反应，能够直接参与愈合过程，对新生创面刺激小有关。

    另外烧伤导致皮肤这一层天然屏障的结构性和完整性被破坏，细菌微生物容易侵袭暴露在空气中的创面，从而引发全身性炎症反应或脓毒血症，直接影响了救治成功率及预后［34, 35, 36］。选择一种具有抗菌性的创面覆盖物以保护创面，对烧伤创面的修复具有重要意义。研究显示异种ADM敷料含有丰富的锌［37］。有学者指出，锌离子具有广谱抗菌性，在调节创面愈合过程中的氧化应激、凝血、炎症和免疫防御等阶段起着重要作用，锌离子的加入赋予了异种ADM敷料抗感染的新功能［38］。而且异种ADM敷料营造的微酸环境也可进一步减少创面定植菌的数量。本研究结果显示，试验组患者的细菌检出比例明显低于对照组，进一步证明异种ADM敷料抗菌性良好。综上所述，本次荟萃分析显示异种ADM敷料作用于烧伤创面具有良好的临床效果，可提升烧伤创面的愈合质量。

    本研究纳入文献均为中文文献，缺少其他语言种类的研究，可能造成发表偏倚。另外由于医患需共同参与敷料使用，纳入研究未能严格使用盲法。虽然总共有1 596例患者参与试验，但单项研究中样本量较小影响了论证强度。各研究中的随访时间不尽相同，可能造成偏倚。纳入文献中有的报告了具体的异种ADM敷料批号，而有的文献并未报告，这可能影响荟萃分析结果。市售异种ADM规格单一，多为8 cm×4 cm、8 cm×8 cm及10 cm×8 cm等，不同烧伤部位对敷料的规格要求各异，可能存在一定的偏倚。

    综上所述，异种ADM敷料作为烧伤创面覆盖物的临床效果较其他治疗更好。然而使用异种ADM敷料需要承担的医疗费用较高，因此应用于烧伤患者时需要综合考虑其经济支出能力，未来有必要加大异种ADM敷料的研发投入力度，优化生产率以降低成本从而减轻患者经济负担。且由于纳入研究的差异性和统计数据有限，期待未来开展更多高质量的随机对照试验，以全面评价异种ADM敷料对烧伤创面的治疗作用。

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