余龍威 綜述 柯昌能 審校

（廣東醫(yī)科大學(xué)附屬觀瀾醫(yī)院 深圳市龍華新區(qū)中心醫(yī)院燒傷整形科，廣東 深圳 518100）

臨床創(chuàng)面治療新進(jìn)展

余龍威 綜述 柯昌能 審校

（廣東醫(yī)科大學(xué)附屬觀瀾醫(yī)院 深圳市龍華新區(qū)中心醫(yī)院燒傷整形科，廣東 深圳 518100）

隨著創(chuàng)面治療需求日益增加，涌現(xiàn)出越來越多新的治療方法。目前很難鑒別哪些產(chǎn)品或設(shè)備可切實(shí)有效的促進(jìn)創(chuàng)面愈合，因此，有必要探索和發(fā)現(xiàn)新的研究進(jìn)展。為盡可能促進(jìn)創(chuàng)面愈合，可在基本創(chuàng)面處理包括創(chuàng)面清創(chuàng)、負(fù)壓引流和控制感染等的基礎(chǔ)上，同時(shí)采取其他先進(jìn)的療法。本文旨在關(guān)注以下三種方法，即創(chuàng)面持續(xù)性負(fù)壓引流、生物工程敷料和羊膜制品。但由于缺乏有力的文獻(xiàn)及實(shí)驗(yàn)數(shù)據(jù)支持，目前創(chuàng)面治療研究的新進(jìn)展方面仍有很大的進(jìn)步空間。

創(chuàng)面負(fù)壓治療；羊膜；生物工程敷料；Integra

創(chuàng)面治療仍是目前最具挑戰(zhàn)的領(lǐng)域之一，隨著醫(yī)學(xué)技術(shù)的發(fā)展，新產(chǎn)品和新興的療法不斷涌入市場(chǎng)，但每個(gè)產(chǎn)品或技術(shù)都缺乏強(qiáng)有力的循證醫(yī)學(xué)證據(jù)支持。許多相關(guān)專家仍是根據(jù)自身臨床經(jīng)驗(yàn)來選擇治療方案，因?yàn)楹芏喈a(chǎn)品都缺乏足夠的數(shù)據(jù)支持證明其有效性和安全性。就此看來，這些新產(chǎn)品和技術(shù)仍有許多問題尚待解決。目前已出現(xiàn)了一些被證實(shí)切之有效的新技術(shù)，但仍需謹(jǐn)慎地評(píng)價(jià)它們的使用過程和療效。目前，負(fù)壓創(chuàng)面治療技術(shù)(negative pressure wound therapy，NPWT)有著長(zhǎng)足的進(jìn)步。最近NPWT滴注灌洗法被引入以解決創(chuàng)面床問題，同時(shí)也引進(jìn)了一些便攜式NPWT設(shè)備。細(xì)胞和組織相關(guān)的產(chǎn)品(cell and tissue products，CTPs)在暫時(shí)或永久性創(chuàng)面覆蓋以及促進(jìn)創(chuàng)面愈合方面也取得較大的發(fā)展。此外，以干細(xì)胞為基礎(chǔ)的創(chuàng)面治療產(chǎn)品吸引著許多專家學(xué)者，這類產(chǎn)品在加強(qiáng)創(chuàng)面愈合和促進(jìn)皮膚再生方面有著巨大的潛能。本文將分析這些產(chǎn)品和技術(shù)在當(dāng)前的使用狀況及在文獻(xiàn)搜索中的結(jié)果。

1 基礎(chǔ)治療

盡管創(chuàng)面治療的技術(shù)取得了很大的進(jìn)步，但是基本的治療原則目前仍然適用。促進(jìn)創(chuàng)面愈合是多因素的，涉及到藥物和治療創(chuàng)面的最優(yōu)化。處理患者的并發(fā)癥和分析創(chuàng)面致病因素對(duì)于創(chuàng)面愈合是必要的。不管治療技術(shù)多么先進(jìn)，控制感染、改善血運(yùn)、減壓治療和解決生物力學(xué)問題都是治療創(chuàng)面的首要考慮點(diǎn)。

皮膚和組織若無豐富的血運(yùn)，創(chuàng)面就難以愈合。所以需設(shè)法增加創(chuàng)面的血流灌注，必要時(shí)還需顯微血管吻合技術(shù)的介入和干預(yù)。同時(shí)，若不減少致病菌落數(shù)和控制感染，創(chuàng)面將毫無進(jìn)展，最終步入慢性難愈合的狀態(tài)。定期徹底的創(chuàng)面清創(chuàng)有利于減少細(xì)菌負(fù)荷、減輕皮膚過度角化及促進(jìn)相關(guān)生長(zhǎng)因子的釋放，從而減少感染概率，提高治愈率[1-6]。嚴(yán)重的感染則需口服或靜脈應(yīng)用抗生素加以控制。因此，在應(yīng)用新興的治療措施之前，基本的創(chuàng)面處理是必需的。

適當(dāng)?shù)臏p壓和生物力學(xué)治療常被臨床學(xué)者忽視，許多傷口(譬如糖尿病足潰瘍)之所以出現(xiàn)在足底是因?yàn)樵摬课粔毫^大。許多研究證明適當(dāng)?shù)臏p壓能明顯的促進(jìn)創(chuàng)面愈合[7-9]。另有研究表明可移動(dòng)塑形助行器比傳統(tǒng)的治療鞋更有利于類似創(chuàng)面的愈合[7,9-10]。

在某些情況下，單純地通過可移動(dòng)塑形助行器或治療鞋只能達(dá)到暫時(shí)的減壓效果，若根本的生物力學(xué)問題沒有解決，則創(chuàng)面易復(fù)發(fā)。評(píng)估患者足部的結(jié)構(gòu)及功能和任何可能導(dǎo)致創(chuàng)傷的畸形，這些都是治療的必要前提，最常見的例子之一就是馬蹄足。馬蹄足減少了踝關(guān)節(jié)背屈而導(dǎo)致足底壓力增加，進(jìn)而增加足底潰瘍和潰瘍復(fù)發(fā)的概率[11-17]。目前可通過經(jīng)皮跟腱延長(zhǎng)術(shù)以減少足底壓力峰值來解決[11,13,15,17]。其他如足內(nèi)翻、扁平足、搖椅底狀腳、高弓內(nèi)翻足、足拇外翻和下垂足等畸形，都能通過手術(shù)或穿戴治療鞋及支撐裝置，以預(yù)防壓力性創(chuàng)面的生成。

2 創(chuàng)面負(fù)壓治療技術(shù)

創(chuàng)面負(fù)壓治療技術(shù)是目前應(yīng)用范圍較廣的創(chuàng)面治療方法之一。20世紀(jì)90年代被首次發(fā)明并用于處理開放性骨折所致的軟組織損傷[18]和創(chuàng)面床的準(zhǔn)備、皮片移植及皮瓣覆蓋的術(shù)前準(zhǔn)備。此外還常用于皮片移植或生物工程替代組織以增強(qiáng)移植存活率和封閉高風(fēng)險(xiǎn)創(chuàng)面。創(chuàng)面負(fù)壓治療技術(shù)有著眾多獨(dú)特的優(yōu)勢(shì)，包括促進(jìn)肉芽組織生長(zhǎng)、增加創(chuàng)面床的血管分布、控制細(xì)菌繁殖和創(chuàng)面感染、減少組織水腫，減少換藥次數(shù)和降低治療費(fèi)用[19-21]。2015年國際糖尿病足治療指南(IWGDF)指出：術(shù)后未愈合創(chuàng)面仍有應(yīng)用局部負(fù)壓治療而治愈的可能，但其有效性和成本效益仍待考察[22]。首個(gè)商業(yè)化的創(chuàng)面負(fù)壓治療系統(tǒng)是封閉負(fù)壓引流(VAC)治療系統(tǒng)。許多設(shè)備制造商開發(fā)出促進(jìn)創(chuàng)面治愈和改善設(shè)備便攜性、易用性和患者舒適度的新型設(shè)備。

目前，創(chuàng)面負(fù)壓治療技術(shù)的最新進(jìn)展之一就是聯(lián)合持續(xù)滴注灌洗，且被用于準(zhǔn)備創(chuàng)面床的整個(gè)環(huán)節(jié)。持續(xù)滴注灌洗的同時(shí)可以結(jié)合負(fù)壓封閉引流以間斷排出灌洗液，溶液的類型和數(shù)量及其留滯時(shí)間等參數(shù)均可靈活調(diào)整。一些研究發(fā)現(xiàn)該系統(tǒng)有可去除感染灶和失活組織等潛在優(yōu)勢(shì)[23-26]，創(chuàng)面負(fù)壓治療技術(shù)聯(lián)合持續(xù)或間歇的滴注灌洗在促進(jìn)創(chuàng)面愈合和創(chuàng)面床的準(zhǔn)備方面將大有前途[23,25,27-30]。

大量的調(diào)查研究正在評(píng)估創(chuàng)面負(fù)壓治療聯(lián)合滴注灌洗法的療效，觀察它對(duì)創(chuàng)面的影響和使用效果[23,27,31-37]。Phillips等[28]在豬試驗(yàn)中觀察在創(chuàng)面負(fù)壓治療聯(lián)合滴注灌洗法中分別加入6種不同的溶液，記錄其對(duì)綠膿桿菌菌落數(shù)的影響，研究表明用聚亞已基雙胍、聚二甲基二烯丙基氯化銨和聚維酮碘作為灌洗液比生理鹽水更能降低創(chuàng)面的細(xì)菌負(fù)荷。另一研究分別對(duì)比標(biāo)準(zhǔn)NPWT、NPWT加生理鹽水滴注、NPWT聯(lián)合聚六亞甲基雙胍液滴注和對(duì)照組用于銅綠假單胞菌感染創(chuàng)面的療效，結(jié)論為NPWT聯(lián)合持續(xù)滴注灌洗法比對(duì)照組和標(biāo)準(zhǔn)NPWT組更能顯著降低細(xì)菌負(fù)荷[29]。這兩個(gè)研究表明持續(xù)滴注法能顯著減少創(chuàng)面菌落數(shù)，對(duì)感染傷口可能有用處。

2011年，Lehner等[27]進(jìn)行了一項(xiàng)多中心前瞻性非隨機(jī)對(duì)照試驗(yàn)，將NPWT聯(lián)合持續(xù)滴注法用于處理植入手術(shù)的術(shù)后感染。受試對(duì)象大部分為膝蓋和臀部感染患者，除接受NPWY加聚鹽酸已雙胍滴注治療組外，其余患者都接受了清創(chuàng)灌洗和系統(tǒng)性的抗生素治療。研究表明在4～6個(gè)月內(nèi)，有86%急性感染和80%慢性感染患者保全了他們的關(guān)節(jié)組織。Brinkert等[30]觀察131例患者(其中13%為糖尿病足潰瘍)使用NPWT加生理鹽水滴注治療感染或復(fù)雜的整形外科傷口，結(jié)果發(fā)現(xiàn)98%的創(chuàng)面閉合周期平均為12 d，同時(shí)發(fā)現(xiàn)當(dāng)創(chuàng)面出現(xiàn)生物膜時(shí)則必須加用抗菌素。

另一項(xiàng)研究對(duì)比標(biāo)準(zhǔn)NPWT法和NPWT加滴注灌洗治療慢性創(chuàng)面。142例患者(神經(jīng)性潰瘍占18%～22%)在接受創(chuàng)面清創(chuàng)治療后分為三組，74例患者接受標(biāo)準(zhǔn)NPWT治療，34例接受6 min滴注灌洗，另外34例接受20 min滴注灌洗。研究表明，相比標(biāo)準(zhǔn)NPWT治療組，另外兩種滴注灌洗法能明顯縮短手術(shù)時(shí)間和住院周期。另發(fā)現(xiàn)接受6 min滴注灌洗組創(chuàng)面閉合率為94%，而標(biāo)準(zhǔn)NPWT組僅為62%。這些發(fā)現(xiàn)表明NPWT滴注灌洗法在處理急性感染傷口時(shí)優(yōu)于標(biāo)準(zhǔn)NPWT法[25]。但最佳的灌注解決方案還有待發(fā)現(xiàn)，包括灌洗液作用時(shí)間和負(fù)壓的持續(xù)時(shí)間。

此外，還出現(xiàn)一類便攜性NPWT系統(tǒng)包括智能負(fù)壓系統(tǒng)(SNaP)、創(chuàng)面護(hù)理系統(tǒng)(Spiracur，Sunnyvale，CA)和PICO負(fù)壓創(chuàng)面治療系統(tǒng)(Smith&Nephew, Memphis，TN)。該系統(tǒng)的特點(diǎn)為一次性使用、噪音低和便攜性佳，其中可移動(dòng)性更為突出[38-40]。生物力學(xué)和動(dòng)物研究已經(jīng)初步表明SNaP有類似的相關(guān)特性[41-42]。2010年有一項(xiàng)關(guān)于SNaP治療21例難治性創(chuàng)面患者的研究，其中47.6%是糖尿病性潰瘍。與試驗(yàn)組相比，對(duì)照組采用標(biāo)準(zhǔn)傷口護(hù)理方案。結(jié)果發(fā)現(xiàn)SNaP與標(biāo)準(zhǔn)NPWT組有相似的治愈周期[43]。另一項(xiàng)多中心隨機(jī)對(duì)照試驗(yàn)通過比較SNaP機(jī)械動(dòng)力系統(tǒng)和VAC治療系統(tǒng)，受試對(duì)象為非感染、缺血性、非糖尿病足和靜脈曲張潰瘍患者，在16周內(nèi)，SNaP系統(tǒng)與VAC系統(tǒng)有著相似的創(chuàng)面收縮率和愈合率。此外還發(fā)現(xiàn)SNaP系統(tǒng)的便攜性更佳[44]。筆者還把這些設(shè)施聯(lián)合生物敷料應(yīng)用于中厚皮片移植(STSGs)，術(shù)后5～7 d，發(fā)現(xiàn)能增強(qiáng)移植成活率。該系統(tǒng)還廣泛用于閉合高風(fēng)險(xiǎn)類手術(shù)切口[39-4]。由于其實(shí)用性和便攜性較強(qiáng)，患者滿意度較高。

創(chuàng)面負(fù)壓治療技術(shù)已經(jīng)被證實(shí)為一種有價(jià)值的創(chuàng)面療法，能夠滿足患者需求及提高創(chuàng)面治愈率。相信隨著VSD技術(shù)的不斷改進(jìn)，其應(yīng)用范圍將更加廣泛。

3 組織工程人工皮膚產(chǎn)品(CTPs)

在創(chuàng)面治療領(lǐng)域最具挑戰(zhàn)性的話題之一是組織工程人工皮膚產(chǎn)品的研發(fā)，它曾被應(yīng)用于傷口閉合過程的始終環(huán)節(jié)。這類產(chǎn)品不僅價(jià)格昂貴且應(yīng)用局限，只可用于準(zhǔn)備完善的創(chuàng)面。包括STSG在內(nèi)的自體組織移植，仍是閉合創(chuàng)面的首選方法，但并不合適缺乏可利用皮膚軟組織的病患[45]。2007年Kim等[46]首次將CTPs分為皮膚誘導(dǎo)類產(chǎn)品和皮膚支架類產(chǎn)品。盡管這類產(chǎn)品種類豐富且甚為流行，但I(xiàn)WGDF2015版指出：對(duì)于慢性創(chuàng)面，任何譬如生長(zhǎng)因子類產(chǎn)品、組織工程人工皮膚和氣壓治療類產(chǎn)品，在接受標(biāo)準(zhǔn)的基礎(chǔ)治療之前使用是毫無意義的[22]。

皮膚誘導(dǎo)類產(chǎn)品包括Apligraf(Organogenesis Canton，MA)、Dermagraft(Organogenesis Canton，MA)、TheraSkin(Soluble Systems，LLC，Newport News，VA)、Biobrane(Smith&Nephew，Memphis，TN)和Epicel (Genzyme，Cambridge，MA)。這類產(chǎn)品能激活細(xì)胞潛能，促進(jìn)組織新生和肉芽組織的生長(zhǎng)[47-48]。由于Apligraf和Dermagraft這兩類產(chǎn)品運(yùn)用最為廣泛，因此收集了大量寶貴數(shù)據(jù)。其中Apligraf產(chǎn)品是將新生兒包皮細(xì)胞種植于牛膠原蛋白基質(zhì)上形成的一種雙層復(fù)合敷料[49-50]。2001年Veves等[51]發(fā)現(xiàn)在治療糖尿病足潰瘍的研究中，Apligraf組在65 d內(nèi)的治愈率為56%，而生理鹽水紗布敷料組在90 d內(nèi)的治愈率僅為38%。2009年另一項(xiàng)研究顯示，Apligraf組治愈率為56%，而對(duì)照組僅為37%[52]。2003年Marston等[53]進(jìn)行了一項(xiàng)隨機(jī)前瞻性人造皮膚研究，受試對(duì)象為314例難愈合糖尿病足患者，發(fā)現(xiàn)在12周內(nèi)Dermagraft組治愈率為30%，而生理鹽水紗布敷料組僅為18.3%。

皮膚支架產(chǎn)品包括Integra(LifeSciences，Plainsboro，NJ)、GraftJacket(Wright Medical Technology，Arlington TN)、Oasis(Smith&Nephew，Memphis，TN)、Alloderm(Life Cell，Branchburg，NJ)和EZ Derm(Molnlycke，Gothenburg，Sweden)，能為創(chuàng)面提供支架，協(xié)助細(xì)胞從周圍組織爬行至創(chuàng)面而形成新生皮膚[46-47,50]。Integra作為目前最常用的CTPs產(chǎn)品，由Ⅰ型膠原蛋白、硫酸軟骨素和一層薄膜硅膠組成[54-55]。Integra常應(yīng)用于皮膚移植或運(yùn)用皮膚誘導(dǎo)產(chǎn)品的前提準(zhǔn)備[54-56]。研究者根據(jù)傷口的深度和暴露的組織多少，制定了一組使用Integra治療復(fù)雜的下肢軟組織重建的標(biāo)準(zhǔn)[57]。Integra適用于大多數(shù)較為清潔或較深的傷口。雖治療深部傷口的難度較大，但仍有使用Integra治療跟腱和骨裸露創(chuàng)面取得成功的案例。若出現(xiàn)跟腱外露，則待肉芽組織爬滿創(chuàng)面后再覆蓋Integra。同樣，Integra用于治療小于0.5 cm的骨暴露創(chuàng)面也取得了成功[57]。

另一項(xiàng)關(guān)于Integra對(duì)保肢手術(shù)的療效評(píng)估的回顧性研究表明，Integra對(duì)105例受試對(duì)象(糖尿病相關(guān)占71.9%)的整體救治率為77%。根據(jù)創(chuàng)面感染和血供情況分為低風(fēng)險(xiǎn)組(清潔有血供)和高風(fēng)險(xiǎn)組(有細(xì)菌殘留且無血供)。結(jié)果發(fā)現(xiàn)低風(fēng)險(xiǎn)組保肢率為83%，而高風(fēng)險(xiǎn)組只有46%[58]。

雖研究數(shù)據(jù)有限，但越來越多的證據(jù)表明，組織工程人工皮膚產(chǎn)品可作為創(chuàng)面標(biāo)準(zhǔn)化治療方案的一種輔助手段。

4 羊膜制品

在創(chuàng)面治療等領(lǐng)域，干細(xì)胞治療已經(jīng)成為一種頗具前途的手段，在縮短愈合時(shí)間、提高治愈率、減少疤痕攣縮、促進(jìn)皮膚再生等方面扮演理想角色[59-60]。由于缺乏豐富的臨床試驗(yàn)數(shù)據(jù)支持，干細(xì)胞治療的研究目前尚處于初級(jí)階段。干細(xì)胞能產(chǎn)生大量的生長(zhǎng)因子和趨化因子，且有分化成不同類型細(xì)胞的潛能。根據(jù)來源不同，干細(xì)胞制品可分為同種異體和自體兩類[61-63]。

目前，研究人胎盤來源的羊膜制品，處于創(chuàng)面治療發(fā)展的最前沿。包括Grafix(Osiris Therapeutics，Inc，Columbia，MD)、EpiFix(MiMedx Group Inc，Marietta，GA)、AmnioClear(Liventa Bioscience，Conshohocken，PA)和NEOX(Amniox Medical Inc，Atlanta，GA)[64-65]。人羊膜制品是無血管結(jié)構(gòu)的，其中包含一些生長(zhǎng)因子如血管內(nèi)皮細(xì)胞生長(zhǎng)因子、血小板源性生長(zhǎng)因子、堿性成纖維細(xì)胞生長(zhǎng)因子、表皮生長(zhǎng)因子、轉(zhuǎn)化生長(zhǎng)因子和神經(jīng)生長(zhǎng)因子[61,64-65]。大部分此類產(chǎn)品均需低溫貯藏以保持其活性，通常需每周換新。

一些個(gè)案正在研究羊膜產(chǎn)品的作用，2014年Lavery的一項(xiàng)多中心隨機(jī)對(duì)照試驗(yàn)評(píng)估了Grafix治療慢性糖尿病足潰瘍的臨床療效[64]。他們將患者隨機(jī)分組，其中50例患者接受Grafix治療，47例患者接受標(biāo)準(zhǔn)治療。受試對(duì)象每周接受創(chuàng)面清創(chuàng)和療效評(píng)估。結(jié)果為Grafix組治愈率為62%，而對(duì)照組只有21%，說明Grafix治療對(duì)比標(biāo)準(zhǔn)治療，治愈率差異有顯著統(tǒng)計(jì)學(xué)意義。另外還發(fā)現(xiàn)Grafix治療組能在42 d封閉創(chuàng)面，比之前報(bào)道的69.5 d更少。因此得以結(jié)論，羊膜制品能有效治療慢性糖尿病足潰瘍[64]。Grafix治療的治愈率甚至比Dermagraft(30%)和Apligraf (56%)還高[51,53,64]。

盡管數(shù)據(jù)有限，但隨著產(chǎn)能的提升，在未來幾年內(nèi)，相信這類產(chǎn)品在創(chuàng)面治療方面將會(huì)發(fā)揮越來越重要的作用。

5 結(jié)論

臨床醫(yī)生們正不斷地通過實(shí)踐來改善患者的預(yù)后，創(chuàng)面治療仍然是一個(gè)值得不斷探討的問題，只有通過不斷探索研究，我們才能加深對(duì)傷口愈合機(jī)制的理解，并找到促進(jìn)創(chuàng)面愈合的理想方法。盡管目前已經(jīng)取得了一些重大進(jìn)步，但是還缺乏高質(zhì)量的隨機(jī)對(duì)照試驗(yàn)來展示新興產(chǎn)品或設(shè)備的優(yōu)勢(shì)。目前臨床醫(yī)生必須結(jié)合有限的數(shù)據(jù)和臨床經(jīng)驗(yàn)來處理各類創(chuàng)面。最重要的一點(diǎn)是，不論新興產(chǎn)品和設(shè)備有多么大的優(yōu)勢(shì)，在使用之前，都必須遵從創(chuàng)面處理的基本原則，即清創(chuàng)、減壓、控制感染和提高組織血流灌注。

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New progress in clinical wound therapy.

YU Long-wei,KE Chang-neng.Department of Burn and Plastic,Shenzhen Longhua New District Central Hospital(Guanlan Affiliated Hospital of Guangdong Medical Uniwersity),Shenzhen 518100, Guangdong,CHINA

With the increasing demand for wound specialist treatment,there are more and more feasible methods of wound treatment.It is difficult to identify what products or devices can effectively promote wound healing.Therefore,it is necessary to discover new advances.Any wound treatment goals should be as far as possible to promote wound healing,by combining the basic treatment methods including debridement of wound,negative pressure drainage and infection control,at the same time when necessary should be combined with other advanced treatment methods.This review is to focus on the current use of continuous negative pressure drainage of wound surface,biological engineering dressing and amniotic membrane products.However,due to the lack of strong literature and experimental data,there is still much room for improvement in the research of wound healing.

Negative pressure wound therapy(NPWT);Amniotic membrane;Biological engineering dressing; Integra

R454

A

1003—6350（2017）03—0462—05

10.3969/j.issn.1003-6350.2017.03.038

2016-10-24)

廣東省深圳市衛(wèi)計(jì)委醫(yī)學(xué)科研基金（編號(hào)：20131020）

柯昌能。E-mail：kekey88@163.com