儿童瘢痕的综合治疗

2017-01-11 22:22梁奕敏综述王丹茹审校
组织工程与重建外科杂志 2017年5期
关键词:瘢痕局部激光

梁奕敏 综述 王丹茹 审校

儿童瘢痕的综合治疗

梁奕敏 综述 王丹茹 审校

瘢痕会给患儿带来容貌和功能损伤,并可能产生一系列并发症,包括多毛症、汗腺分泌障碍、疼痛、瘙痒、感觉迟钝等,亦可能影响受累部位的发育。目前,治疗瘢痕的方法很多,但尚无针对儿童的特异性治疗方法。但是,一些新的治疗方法可能使瘢痕患儿得到更好地治疗,如瘢痕综合疗法、自体脂肪移植、剥脱性点阵激光等。我们对目前比较前沿的与儿童相关的瘢痕治疗策略进行综述。

瘢痕 儿童 综合治疗

任何深度到达真皮深层的创伤,如烧伤和其他外伤、炎症或手术,都可导致瘢痕形成[1]。瘢痕以及伴随的临床症状,可对患儿身心造成伤害,并影响患儿及其家庭的生活质量[2-4]。

由于儿童群体较高的瘢痕患病率及其相关的生理、心理和社会并发症,对于瘢痕的综合治疗有着更为迫切的需求。临床上,瘢痕的治疗目标都应与患者共同制定,应侧重于减轻症状、减少合并症、缩小瘢痕体积,并尽可能地恢复功能和外观。我们就目前最新的关于儿童瘢痕的治疗策略进行综述。

1 前沿性的瘢痕治疗策略

对于瘢痕的广泛研究,使得对这一领域的认识越来越深刻,已有多种临床综合治疗方案获得了较好的治疗效果,并被逐渐用于儿童患者[5-7]。

1.1 多学科联合治疗

瘢痕的预防已得到了临床足够的重视,但仍需要贯穿于创伤愈合的所有环节,如及时和正确的清创、减张缝合、预防感染和血肿形成、避免日晒以减少炎症后色素沉着,弹力绷带的使用等[8]。在创伤的治疗和愈合过程中,张力较高的部位,如肩、颈、胸骨柄、踝关节等,以及深色皮肤和具有瘢痕家族史的患者更应该重视。应将瘢痕预防的理念贯彻到所有的医学专业和医疗行为中去。

针对复杂的瘢痕,需要多种治疗方式多管齐下,可以同时治疗或是按序逐步治疗,以取得最好的疗效[9]。单一专业或单一学科可能无法实施所有的治疗措施,需要临床各科协同治疗,多学科组成的瘢痕治疗团队可以产生更高的效率,使复杂瘢痕的治疗获得更好的效果[10-13]。

1.2 瘢痕内皮质类固醇的应用

瘢痕的治疗仍是临床一大难题,尚无一种安全、可靠、疗效完好的治疗方法。瘢痕内激素注射是治疗增生性瘢痕和瘢痕疙瘩的重要方法。皮质类固醇激素可以抑制继发炎症反应,促进胶原降解,抑制胶原蛋白生成,并限制伤口的氧合与营养[14]。但激素的副作用和可能存在的对儿童生长发育的影响,在儿童中的应用历来都较为保守。但目前也有越来越多的文献显示了儿童应用激素的可靠性。据报道,约50%~100%的患者对激素注射有反应,复发率为9%~50%[15]。有报道称,对15例行耳垂瘢痕疙瘩切除的患儿进行了术前、术中及术后的病灶内曲安奈德注射,作为辅助治疗。对坚持治疗的患儿进行了6个月的随访,随访中未发现瘢痕疙瘩复发的迹象,在18个月的随访中,仅有1例复发[16]。激素在治疗和预防儿童瘢痕上作用显著,长期观察也未发现对儿童的生长发育存在着明显的不利因素[17]。皮质类固醇的最佳治疗剂量尚未确定,这是因为病灶内瘢痕治疗的剂量取决于病变的特征和解剖位置。局部皮肤萎缩和色素减退是激素治疗中最常见的副作用,而疼痛也极大妨碍了其在儿科的应用。有研究显示,有近1/3疗效显著的面部瘢痕疙瘩患儿因为疼痛而放弃了治疗[18]。目前,临床上有采用治疗前外敷利多卡因乳膏,可以适当地减少不适感[19-20]。曲安奈德混悬液含有苯酒精,会引起新生儿的毒性反应,尤其是早产儿。虽然局部使用剂量可能是微小的,但多少剂量会导致苯甲醇中毒目前尚不明确,所以这种药物不建议在新生儿中使用。

1.3 局部注射5-氟尿嘧啶

五氟尿嘧啶(5-FU)是一种干扰代谢过程的嘧啶类似物,已被证实能够在体内和体外有效抑制胶原的合成[21-22]。用于成人的研究显示,5-FU治疗瘢痕疙瘩和增生性瘢痕效果显著[24-26]。一项为期44周的双盲、随机试验比较了病灶内注射曲安奈德(40 mg/mL)和5-FU(50 mg/mL)治疗瘢痕疙瘩的效果,每4周注射一次,总计12周,两组都获得了非常好的疗效,且5-FU组改善更明显[27]。但5-FU治疗瘢痕这一方法在儿童中使用的安全性和有效性尚未明确。文献报道,在儿童瘢痕高发的手术部位,如腹股沟部位,术后联合应用糖皮质激素和5-FU,不仅获得了比单纯使用激素更好的疗效,也大大减少了激素用量[23]。5-FU的不良反应包括疼痛和色素沉着。对于孕妇而言,该药物是妊娠期D类药物,且可能对胎儿造成伤害[28]。

1.4 自体脂肪移植

对于容积有缺失的瘢痕,自体脂肪移植技术(AFT)和复合移植具有强大的治疗潜力[29]。在儿科治疗领域中,AFT被用于Goldenhar综合征、面部畸形、Treacher Collins综合征和半侧面部肢体发育不良的治疗[30]。AFT技术远远超出了容量替代的效应,可以通过加速血管化反应和减少热损伤后的纤维化来介导动态重建的过程[31-32]。对于儿童瘢痕患者而言,脂肪的存活更好,手术损伤小,术后护理也较为简单。联合AFT和点阵激光或PRP技术被证明能加强瘢痕治疗的效果[33]。

1.5 手术治疗

在保守治疗无效的情况下,需要手术治疗,尤其是某些功能部位,或是某些特殊部位的瘢痕挛缩,如四肢关节、颈部、胸部等,更需要尽早地进行手术松解,以避免进一步的挛缩而影响肢体功能和患儿的生长发育。单纯切除瘢痕疙瘩,其复发率接近100%[34-36]。因此,瘢痕切除通常与辅助治疗联合应用,以减少复发的风险[37-38]。一项研究针对11~79岁患者的病理性瘢痕进行综合治疗,在切除瘢痕以后,每两周进行皮质类固醇注射(共注射5次),每日涂抹类固醇软膏,共涂抹6个月。随访发现,瘢痕疙瘩的复发率为14.3%,增生性瘢痕的复发率为16.7%[39]。

患儿非功能部位的瘢痕修复手术,一般在瘢痕成熟之后实施更为稳妥,建议在瘢痕形成之后至少1年。这已经成为瘢痕治疗的规范。因为,手术本身可能产生新的瘢痕,并且存在较高的复发率[34,36]。手术方法包括松解并延长挛缩皮肤的各类皮瓣法和游离皮片移植。对于瘢痕患儿来说,较大面积的创伤往往优先采用皮片移植覆盖创面。但由于移植皮片较难随着患儿的生长发育而呈相应比例生长,并且存在皮片挛缩的现象,植皮后期会重新出现受区挛缩,需要进一步手术修复。皮瓣法则避免了这一缺点,可以应用于后期的手术修复。传统皮瓣法包括了Z成形和W成形,前者是延长瘢痕的轴径,以缓解张力,减少挛缩,提高活动范围,后者则通过使线性瘢痕以淡化瘢痕外观[40]。对于面积较大的瘢痕,局部皮瓣的应用受到限制,而皮肤扩张术则可发挥重要作用。扩张的皮肤能够提供相同的皮肤厚度、颜色和质地,并且极大地降低了供区损伤,避免了植皮带来的并发症,已在儿童大面积瘢痕治疗中获得了广泛应用。但同一皮肤组织的反复扩张以及下肢的扩张容易出现并发症。头面部的扩张治疗一般在出生6~9个月以后实施更好,可避免对颅面骨塑形的影响[41]。

1.6 激光

随着激光技术的不断发展,激光在瘢痕的治疗中也获得了广泛的应用,如血管靶向的脉冲染料激光和全层剥脱的CO2激光等。但是,由于激光的作用相对温和,并且会产生过度的热损伤,因此在较大面积的创伤性瘢痕中的应用受到限制[42-44]。脉冲染料激光是一种基于选择性光热作用、以血红蛋白作为靶目标的激光类型,对局部血管的热损伤较小,可在刺激组织重塑的过程中减少红斑、疼痛和瘙痒的症状[45-50]。激光的治疗过程相对较短,风险和副作用较小,对于儿童瘢痕的治疗是一个有效的手段。点阵激光通过特殊的方式使激光的无数个点阵光束作用于皮肤组织,每个细小光斑之间有正常组织作为热扩散区,减少了对皮肤的热损伤(组织汽化或凝固)。点阵激光治疗用于瘢痕治疗,其旺盛的组织重塑反应可使瘢痕组织衍变为皮肤的结构,使胶原类型的比例也接近于正常皮肤[51-55];另外,由于每个光斑间有正常组织进行热扩散,使得点阵激光高效、安全,成为治疗痤疮、手术瘢痕和创伤瘢痕的首选[56-59]。研究发现,剥脱性点阵激光能有效地改善瘢痕,可能对于儿童创伤性瘢痕的治疗有着重要意义[48,59-61]。

大量证据表明,点阵激光治疗时,患者耐受性好,且并发症少,但是目前尚缺乏其在儿童中应用安全性的报道[48,61-66]。激光治疗过程中可能产生明显的不适感,针对性地方法包括局部外敷麻药、局部皮内注射麻药、局部神经阻滞、口服和静脉注射镇静、麻醉等,这些方法都已成功地用于儿童患者的激光治疗[67-68]。

1.7 激光辅助药物应用

糖皮质激素的局部应用目前已不被推荐,因为该方法缺乏有效性,且存在表皮萎缩的风险[44,69]。大量研究都在试图通过纤维化的瘢痕组织局部给药,而激光辅助给药技术(LAD)利用剥脱性和非剥脱点阵激光引起的临时屏障受损,来加强局部给药的渗透和药物吸收。

虽然目前的文献中该技术的使用较为有限,但有几篇报告显示了这种方法潜在效用。有报道显示,在对15个增生性瘢痕患者使用了剥脱性激光治疗后,立即局部应用曲安奈德(10~20 mg/mL,取决于瘢痕位置和厚度),受试者在 2~3个月间隔内接受3至5个疗程。结果发现,瘢痕的质地得到了显著改善,而皮肤颜色的改善程度最小[70]。另一项研究针对对4例增生性疤痕患者,以剥脱性点阵激光治疗后外用曲安奈德20 mg/mL,应用声压超声帮助“推动”去炎舒松分子通过剥脱性的微通道。随访显示,1例病灶在鼻和下颌骨的患者得到了完全治愈,而4次治疗后所有的病灶区域都有明显的改善。LAD对于儿童瘢痕的治疗具有重要意义,在获得治疗有效性的同时,可避免激素注射产生的副作用。

LAD的一个潜在缺点是,许多外用药物都没有应用于这一治疗方法的评估标准,因而可能在局部给药或激光手术之后产生副作用。同样地,在促进局部渗透的同时,也会促进赋形剂的渗透。在治疗的同时还必须注意无菌操作,并考虑到意外的副作用[71]。

2 基础研究和展望

对于瘢痕形成和胎儿伤口愈合的病理生理学的认识已获得了极大地进步。研究显示,瘢痕形成的机制与表达CD26分子的En阳性成纤维细胞密切相关。西格列汀和维格列汀等口服降糖药,有可能抑制这一类型成纤维细胞的活性,为临床转化应用提供了理论基础[72]。另外,更多的瘢痕治疗方案正在逐渐显现出强大的应用价值,有望实现无瘢痕愈合的理想。

2.1 生长因子

儿童皮肤组织发育未完善,且含水量较高,烫伤后易发生急性炎症性水肿,导致损伤程度比成人严重。同时,儿童好动且不耐疼痛,治疗的依从性差,采用完全性的暴露制痂治疗易发生创面感染,从而进一步加深创面,延长愈合时间,导致后期瘢痕形成,对患儿身心发育均存在影响。生长因子具有诸多功能,可通过促进细胞的有丝分裂及糖、蛋白质、RNA及DNA的合成,促进上皮细胞增殖,以缩短创面愈合时间。在受伤后早期应用生长因子可明显加快创面的愈合,并对后期的瘢痕形成具有明显抑制作用。

转化生长因子β(TGF-β)被认为是瘢痕生成的重要因子。TGF-β1、TGF-β2在伤口正常愈合的增生期促进成纤维细胞增殖和胶原蛋白合成,而在瘢痕疙瘩中则过度生成而失去调控[73]。相反,TGF-β3被认为是瘢痕抑制剂[74]。

动物研究显示,局部应用TGF-β1、TGF-β2β拮抗剂可以加速上皮化反应,抑制瘢痕形成和创面收缩[75-76]。此外,重组TGF-β3已被证明能够有效减少瘢痕面积,重组TGF-β3对于预防和治疗手术瘢痕也具有积极的效果[77-78]。

碱性成纤维细胞生长因子(bFGF)是一种重要的细胞因子,能够激活巨噬细胞,在早期伤口愈合中起着至关重要的作用[79-80]。一项外用bFGF的成人对照研究显示,bFGF能够改善瘢痕质地,并且加速伤口愈合[81]。目前,bFGF的治疗研究已在儿童群体中展开。一项研究表明,接受bFGF注射治疗的Ⅱ°烧伤患儿与只接受过纱布安慰剂的对照组在1年后进行随访,治疗组的瘢痕颜色与正常皮肤颜色的匹配度显著增高。此外,bFGF治疗组的10例伤口中未出现增生性瘢痕,而对照组10例伤口中出现了3例增生性瘢痕[82]。

2.2 干细胞

干细胞在瘢痕治疗和组织修复方面具有广阔的应用前景。诱导多能干细胞的条件培养基可以减少Ⅰ型胶原水平,并减弱局部炎症细胞反应[83]。另外,间充质干细胞可以被重编程为汗腺样细胞,为深度烧伤患儿修复皮肤附件结构提供了可能性[84]。儿童的干细胞相对于成人,其活力更好,诱导分化的能力也更强,应加强这方面的研究,以尽早地将其应用于临床儿童瘢痕的防治。

2.3 自体成纤维细胞的应用

在一项随机、多中心、双盲、安慰剂对照试验中,受试者皆有双侧中-重度的面颊部痤疮疤痕,受试者接受单边自体成纤维细胞注射治疗,对照组接受安慰剂治疗,治疗后4个月显示,两侧的效果具有明显差异[85]。试验目前还在进行中,以进一步了解自体成纤维细胞注射治疗是否能促进瘢痕的软化,改善瘢痕活动度,以及恢复瘢痕挛缩部位的功能。

2.4 白介素-10的应用

白细胞介素10(IL-10)在妊娠中期胎儿皮肤内高表达,但在胎儿出生后的皮肤内无表达[86]。研究证实,IL-10能抑制巨噬细胞和中性粒细胞活性,并减少促炎细胞因子IL-6和IL-8的产生[87-89]。此外,在出生后的组织修复中,IL-10水平与纤维化过程呈负相关[90]。两项小鼠研究和一项Ⅱ期随机对照试验已经证实,在皮肤切口内应用外源性重组的IL-10可以显著减少炎症反应、加速伤口愈合、抑制瘢痕形成,表明IL-10可能成为瘢痕治疗的新的方向[91]。

3 总结

目前,临床上对于瘢痕治疗有着众多的方案,而对于儿童这一特定年龄群体来说,由于缺少对照性实验研究,治疗方案还不成熟,效果和安全性都有待于积极的探索。相关研究取得了许多重要的成果,相信随着分子靶向治疗和细胞通路治疗的出现,儿童瘢痕治疗将变得更为有效且安全,瘢痕的预防和无瘢痕愈合有望得以实现。

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Composite Treatments of Scar in Children

LIANG Yimin,WANG Danru.Department of Plastic and Reconstructive Surgery,Shanghai Ninth People's Hospital,Shanghai Jiaotong University School of Medicine,Shanghai 200011,China.Corresponding author:WANG Danru(E-mail:wangdanru@126.com).

【Summary】Symptomatic scars can cause appearance disfigurements and functional damages.Beyond that,scars may be associated with a lot of physical comorbidities including hypertrichosis,dyshidrosis,pain,pruritus,dysesthesias,and functional impairments.Although a plethora of scar treatment exists,specific management guidelines for the pediatric populations do not.New modalities such as composite scar treatment,autologous fat transfer,and ablative fractional laser suggest a promising future for children who developed symptomatic scars.In this paper,state-of-the-art scar treatment strategies relate to the pediatric populations were reviewed.

Scar;Children; Composite treatment

R619+.6

B

1673-0364(2017)05-0263-06

10.3969/j.issn.1673-0364.2017.05.007

200011 上海市 上海交通大学医学院附属第九人民医院整复外科。

王丹茹(E-mail:wangdanru@126.com)。

2017年9月18日;

2017年10月9日)

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