李立　柴益民

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富血小板血漿在糖尿病潰瘍創(chuàng)面的應(yīng)用

李立柴益民

糖尿病潰瘍創(chuàng)面常較普通創(chuàng)面難愈，相關(guān)機(jī)制主要包括周圍神經(jīng)病變、微循環(huán)障礙、炎癥及感染、細(xì)胞過(guò)度凋亡等。富血小板血漿(PRP)含有多種生長(zhǎng)因子及大量白細(xì)胞，能夠促進(jìn)創(chuàng)面微血管再生及周圍神經(jīng)修復(fù)，且有助于炎癥感染控制，減少細(xì)胞凋亡。該文圍繞PRP在糖尿病潰瘍創(chuàng)面的應(yīng)用作一綜述。

富血小板血漿；糖尿病潰瘍創(chuàng)面；血管；神經(jīng)

糖尿病潰瘍創(chuàng)面的治療一直是臨床工作中的難題，也是近年的研究熱點(diǎn)。富血小板血漿(PRP)含有多種生長(zhǎng)因子及大量白細(xì)胞，能夠促進(jìn)創(chuàng)面微血管再生及周圍神經(jīng)修復(fù)，且有助于炎癥感染控制，減少細(xì)胞凋亡。本文圍繞PRP在糖尿病潰瘍創(chuàng)面的應(yīng)用作一綜述。

1　糖尿病潰瘍創(chuàng)面難愈機(jī)制

創(chuàng)面愈合是一個(gè)由多種細(xì)胞、細(xì)胞外基質(zhì)及各類生長(zhǎng)因子等共同參與的復(fù)雜過(guò)程，包括第一期(涉及初始損傷及快速止血)、炎癥期、增殖期、重塑期等階段[1]。但糖尿病潰瘍創(chuàng)面愈合并不完全遵循上述過(guò)程。受機(jī)體持續(xù)高血糖及代謝相關(guān)因素影響，糖尿病潰瘍創(chuàng)面較普通創(chuàng)面難愈。影響其正常愈合的機(jī)制主要包括局部微循環(huán)障礙、周圍神經(jīng)病變、創(chuàng)面炎癥及感染、細(xì)胞過(guò)度凋亡等[2]。

1.1微循環(huán)障礙

糖尿病患者機(jī)體高血糖環(huán)境可引起血液黏度增加，造成局部缺氧，進(jìn)而導(dǎo)致血管內(nèi)皮損傷[3]。血管內(nèi)皮損傷又可導(dǎo)致內(nèi)皮細(xì)胞增生、管腔狹窄，造成局部血運(yùn)不暢，加重局部缺氧并形成惡性循環(huán)[4-5]，影響創(chuàng)面愈合。同時(shí)，糖尿病潰瘍創(chuàng)面中重要的促血管生成因子血管內(nèi)皮生長(zhǎng)因子(VEGF)和堿性成纖維細(xì)胞生長(zhǎng)因子(bFGF)表達(dá)下降，導(dǎo)致血管自我修復(fù)能力下降[6]，也影響糖尿病潰瘍創(chuàng)面修復(fù)。

1.2周圍神經(jīng)病變

表皮干細(xì)胞具有多向分化能力，是促進(jìn)創(chuàng)面修復(fù)的重要細(xì)胞。正常神經(jīng)末梢能分泌神經(jīng)肽P物質(zhì)，P物質(zhì)是受神經(jīng)調(diào)控的修復(fù)信號(hào)因子，可誘導(dǎo)表皮干細(xì)胞向創(chuàng)緣聚集以修復(fù)創(chuàng)面。糖尿病可引起周圍神經(jīng)病變，末梢神經(jīng)受損后分泌的P物質(zhì)明顯減少[7]，誘導(dǎo)表皮干細(xì)胞遷移分化的能力減弱，影響潰瘍創(chuàng)面修復(fù)。

1.3炎癥及感染

糖尿病潰瘍創(chuàng)面始終處于輕度炎癥反應(yīng)狀態(tài)，促炎性因子刺激固有免疫應(yīng)答，激活下游信號(hào)轉(zhuǎn)導(dǎo)通路，產(chǎn)生炎性介質(zhì)，導(dǎo)致慢性炎癥。促炎性因子如白細(xì)胞介素(IL)-1可誘發(fā)抗原遞呈細(xì)胞表面免疫分子表達(dá)，介導(dǎo)免疫球蛋白分泌，強(qiáng)化免疫介導(dǎo)的組織損傷過(guò)程。持續(xù)高血糖環(huán)境可激活核苷酸結(jié)合寡聚化結(jié)構(gòu)域樣受體蛋白 (NLRP) 3炎癥小體，誘導(dǎo)巨噬細(xì)胞分泌炎癥反應(yīng)的中心介質(zhì)IL-1β[8]，發(fā)生內(nèi)源性炎癥反應(yīng)，同時(shí)IL-1β也可促進(jìn)部分巨噬細(xì)胞促炎表型的表達(dá)[9]。

糖尿病潰瘍創(chuàng)面等修復(fù)緩慢的創(chuàng)面由于長(zhǎng)期缺少皮膚對(duì)外部環(huán)境的屏障保護(hù)，加上機(jī)體高代謝狀態(tài)與細(xì)胞凋亡加速，存在較高感染風(fēng)險(xiǎn)。感染可導(dǎo)致原有或新生組織壞死，創(chuàng)面肉芽組織形成障礙，影響創(chuàng)面愈合，并因局部生長(zhǎng)因子大量消耗導(dǎo)致生長(zhǎng)因子匱乏，延緩創(chuàng)面愈合過(guò)程[10]。

1.4細(xì)胞過(guò)度凋亡

糖尿病潰瘍創(chuàng)面中凋亡細(xì)胞明顯多于普通創(chuàng)面，其中以成纖維細(xì)胞占多數(shù)，細(xì)胞凋亡增加可導(dǎo)致創(chuàng)面長(zhǎng)期不愈[11]。高血糖環(huán)境可引起轉(zhuǎn)化生長(zhǎng)因子(TGF)-β信號(hào)轉(zhuǎn)導(dǎo)通路異常，抑制成纖維細(xì)胞的遷移、趨化及增殖[12]；同時(shí)可誘導(dǎo)Ras信號(hào)轉(zhuǎn)導(dǎo)通路表達(dá)異常，致使細(xì)胞周期停滯于有絲分裂前期，減少細(xì)胞增殖[13]。

Bcl-2基因與Bax基因是一對(duì)正負(fù)細(xì)胞凋亡調(diào)節(jié)基因，前者主要抑制細(xì)胞凋亡，后者主要促進(jìn)細(xì)胞凋亡。與正常創(chuàng)面組織相比，糖尿病潰瘍創(chuàng)面組織Bcl-2基因表達(dá)水平明顯降低、Bax基因表達(dá)水平升高[14]，這些變化正是由于高血糖環(huán)境所引起。Bcl-2與Bax基因表達(dá)水平的改變可使細(xì)胞凋亡增多，造成相關(guān)修復(fù)細(xì)胞減少，潰瘍創(chuàng)面愈合延遲或停滯。此外，糖尿病潰瘍創(chuàng)面中抑癌基因p53表達(dá)水平升高、氧自由基含量增多也可導(dǎo)致Bcl-2基因表達(dá)水平降低和Bax基因表達(dá)水平升高，致使細(xì)胞凋亡增多[15]。

2　PRP促進(jìn)糖尿病潰瘍創(chuàng)面愈合機(jī)制

PRP是自體血經(jīng)離心方法提取出的血小板濃縮物，含高濃度血小板、白細(xì)胞和纖維蛋白等，在凝血酶作用下可激活并釋放TGF-β、胰島素樣生長(zhǎng)因子(IGF)、血小板衍生因子(PDGF)、表皮生長(zhǎng)因子(EGF)、VEGF、bFGF等多種生長(zhǎng)因子[16-17]，這些生長(zhǎng)因子可刺激細(xì)胞增殖與分化，且相互之間具有良好的協(xié)同作用。隨著研究的深入，PRP促進(jìn)糖尿病潰瘍創(chuàng)面愈合機(jī)制也逐步清晰。

2.1PRP與微循環(huán)

組織修復(fù)重建中最重要的是局部血管系統(tǒng)重建，新生血管形成、血供充足為促進(jìn)創(chuàng)面愈合的主要因素，而血管內(nèi)皮細(xì)胞增殖則為關(guān)鍵環(huán)節(jié)[18]。糖尿病潰瘍創(chuàng)面中血管內(nèi)皮細(xì)胞損傷且自我修復(fù)能力下降。張?jiān)扑傻萚19]在培養(yǎng)人臍靜脈血管內(nèi)皮細(xì)胞時(shí)加入PRP，觀察血管內(nèi)皮細(xì)胞增殖及血管形成情況，發(fā)現(xiàn)PRP能促進(jìn)人臍靜脈血管內(nèi)皮細(xì)胞增殖及毛細(xì)血管腔形成。動(dòng)物實(shí)驗(yàn)[20-22]表明，采用皮瓣覆蓋治療創(chuàng)面時(shí)應(yīng)用PRP可促進(jìn)皮瓣新生毛細(xì)血管形成，加快血運(yùn)重建。Kontopodis等[23]研究發(fā)現(xiàn)，使用PRP治療糖尿病潰瘍創(chuàng)面時(shí)，創(chuàng)面新生血管形成增加。糖尿病潰瘍創(chuàng)面中VEGF、bFGF表達(dá)下降，而PRP中含有高濃度生長(zhǎng)因子，包括大量VEGF、bFGF和TGF-β。當(dāng)組織缺血、缺氧或內(nèi)皮細(xì)胞受損時(shí)，VEGF和bFGF通過(guò)增加內(nèi)皮細(xì)胞通透性，促進(jìn)血管內(nèi)皮細(xì)胞增殖分化，加速血管新生[24]。VEGF和bFGF對(duì)維持血管內(nèi)皮的通透性、整體性及血管形成有重要作用[25]；TGF-β可通過(guò)Smad蛋白調(diào)控VEGF表達(dá)，進(jìn)一步調(diào)控血管化進(jìn)程[26]。

2.2PRP與周圍神經(jīng)修復(fù)

神經(jīng)損傷修復(fù)對(duì)于現(xiàn)代醫(yī)學(xué)而言仍是一個(gè)極具挑戰(zhàn)的難題，而周圍神經(jīng)修復(fù)對(duì)于糖尿病潰瘍創(chuàng)面修復(fù)意義重大。Sariguney等[27]采用PRP對(duì)大鼠坐骨神經(jīng)損傷模型的神經(jīng)吻合進(jìn)行術(shù)中干預(yù)研究，結(jié)果發(fā)現(xiàn)PRP能明顯改善大鼠周圍神經(jīng)修復(fù)效果，認(rèn)為PRP所含的生長(zhǎng)因子參與了神經(jīng)軸突髓鞘再生修復(fù)過(guò)程。Lichtenfels等[28]采用PRP聯(lián)合神經(jīng)導(dǎo)管對(duì)大鼠坐骨神經(jīng)部分缺損模型進(jìn)行修復(fù)治療，結(jié)果發(fā)現(xiàn)PRP能促進(jìn)周圍神經(jīng)功能恢復(fù)，其效果接近自體神經(jīng)移植。糖尿病潰瘍創(chuàng)面中神經(jīng)生長(zhǎng)因子(NGF)明顯缺失，而PRP中含有NGF，可能有助于創(chuàng)面神經(jīng)再生修復(fù)。NGF也可刺激VEGF表達(dá)分泌，促進(jìn)潰瘍創(chuàng)面血管床再生，抑制血管內(nèi)皮細(xì)胞凋亡[29]。PRP的應(yīng)用為周圍神經(jīng)修復(fù)提供了新的方法和思路，在神經(jīng)修復(fù)方面具有很大潛力。但PRP是否也促進(jìn)糖尿病潰瘍創(chuàng)面周圍神經(jīng)或神經(jīng)末梢的修復(fù)，尚需進(jìn)一步研究。

2.3PRP與炎癥感染

糖尿病潰瘍創(chuàng)面感染是常見(jiàn)的并發(fā)癥，嚴(yán)重影響創(chuàng)面愈合。袁霆等[30]報(bào)道1例采用PRP治療慢性骨髓炎病例，創(chuàng)面膿性滲出物迅速減少。PRP所含的高濃度白細(xì)胞被局部炎性因子激活后，具有較好的抗感染能力，可抑制炎癥反應(yīng)[31-33]。PRP能聚集并趨化大量巨噬細(xì)胞浸潤(rùn)于糖尿病潰瘍創(chuàng)面，同時(shí)誘導(dǎo)細(xì)胞向非炎癥表型分化，抑制炎性因子表達(dá)，促進(jìn)抗炎性因子表達(dá)。PRP能上調(diào)IL-4的表達(dá)，IL-4早期可促進(jìn)炎癥反應(yīng)，后期可抑制IL-1等促炎性因子的表達(dá)，有利于纖維蛋白生成[34-35]。Bendinelli等[36]、Kim等[37]研究發(fā)現(xiàn)，PRP能降低核因子-κB(NF-κB)的轉(zhuǎn)移活性，減弱NF-κB對(duì)NLRP3炎癥小體的上調(diào)功能，減少IL-1β分泌，終止炎癥反應(yīng)。

2.4PRP與細(xì)胞凋亡

正常創(chuàng)面愈合過(guò)程中所需的細(xì)胞和信號(hào)分子在糖尿病潰瘍創(chuàng)面嚴(yán)重受損，成纖維細(xì)胞的功能、反應(yīng)性、增殖能力和趨化能力明顯下降，凋亡增加，導(dǎo)致潰瘍創(chuàng)面膠原合成及代謝異常。劉宸等[38]研究發(fā)現(xiàn)，PRP促進(jìn)糖尿病大鼠潰瘍創(chuàng)面愈合的作用與強(qiáng)化成纖維細(xì)胞功能、促進(jìn)潰瘍創(chuàng)面修復(fù)相關(guān)膠原蛋白合成有關(guān)。bFGF是維持正常細(xì)胞有絲分裂及增強(qiáng)細(xì)胞趨化的重要因素，PRP中含大量bFGF，可高速增加成纖維細(xì)胞數(shù)量以滿足潰瘍創(chuàng)面修復(fù)需求。

PRP中含有的TGF-β和IGF可修復(fù)和增強(qiáng)TGF-β信號(hào)轉(zhuǎn)導(dǎo)通路，其中TGF-β可刺激巨噬細(xì)胞分泌細(xì)胞因子，促進(jìn)成纖維細(xì)胞和平滑肌細(xì)胞增殖趨化，刺激Ⅰ型膠原蛋白合成，增強(qiáng)細(xì)胞收縮能力，促進(jìn)血管和細(xì)胞外基質(zhì)生成[39-41]。PRP還可修復(fù)Ras信號(hào)轉(zhuǎn)導(dǎo)通路，使成纖維細(xì)胞恢復(fù)正常細(xì)胞分裂周期，增加成纖維細(xì)胞比例并改善其細(xì)胞功能，還可促進(jìn)基質(zhì)金屬蛋白酶分泌，從而改善膠原結(jié)構(gòu)，對(duì)膠原重塑和代謝有重要影響[42]。PRP還可促進(jìn)細(xì)胞外基質(zhì)蛋白合成[43]，從而加速潰瘍創(chuàng)面愈合。實(shí)驗(yàn)[44]發(fā)現(xiàn)，PRP可引起B(yǎng)ax基因表達(dá)水平降低，減弱其促細(xì)胞凋亡能力，從而減少成纖維細(xì)胞凋亡。

3　PRP在糖尿病潰瘍創(chuàng)面應(yīng)用的臨床效果

大量臨床研究證實(shí)，局部應(yīng)用PRP能促進(jìn)骨與軟組織創(chuàng)面的修復(fù)。近年來(lái)，眾多學(xué)者嘗試將PRP應(yīng)用于糖尿病潰瘍創(chuàng)面，并取得了良好效果。

Cobos等[45]在PRP治療糖尿病潰瘍創(chuàng)面效果與效率評(píng)估研究中發(fā)現(xiàn)，與傳統(tǒng)治療方法相比，PRP組愈合率為73%～80%，而傳統(tǒng)方法組愈合率僅為20%，PRP組創(chuàng)面愈合時(shí)間約為15周，而傳統(tǒng)方法組為35.5周。另一項(xiàng)關(guān)于PRP治療糖尿病潰瘍創(chuàng)面效率及費(fèi)用方面的研究[46]顯示，PRP治療糖尿病潰瘍創(chuàng)面治愈率為81.3%，平均花費(fèi)約15 159美元/人，而傳統(tǒng)方法治療糖尿病潰瘍創(chuàng)面治愈率僅為42.1%，平均花費(fèi)約33 214美元/人。與傳統(tǒng)方法相比，PRP治療糖尿病潰瘍創(chuàng)面治愈率更高，并發(fā)癥更少，截肢率、感染率更低，手術(shù)清創(chuàng)次數(shù)更少，表明PRP能有效改善糖尿病潰瘍創(chuàng)面治療效果。Yotsu等[47]對(duì)糖尿病引起的下肢潰瘍創(chuàng)面局部應(yīng)用PRP，以1周為1個(gè)療程，前3天使用PRP覆蓋創(chuàng)面，后4天去除PRP，并使用凡士林紗布覆蓋，如此反復(fù)直至創(chuàng)面愈合，多數(shù)患者經(jīng)2周治療后，創(chuàng)面面積明顯縮小，且基本在1～2個(gè)月的平均治療時(shí)間內(nèi)完全愈合。Mehrannia等[48]采用PPR治療1例持續(xù)6個(gè)月不愈的57歲2型糖尿病患者足潰瘍創(chuàng)面，發(fā)現(xiàn)PRP能促進(jìn)潰瘍創(chuàng)面修復(fù)，表明PRP對(duì)遷延不愈的糖尿病潰瘍創(chuàng)面也有較好療效。Kontopodis等[23]研究發(fā)現(xiàn)，對(duì)于肢體嚴(yán)重缺血或下肢動(dòng)脈栓塞的糖尿病患者，PRP仍可有效促進(jìn)其潰瘍創(chuàng)面愈合，表明PRP對(duì)于局部組織血液循環(huán)較差的潰瘍創(chuàng)面也有治療效果。Scimeca等[49]對(duì)1例糖尿病足潰瘍導(dǎo)致跖趾關(guān)節(jié)損壞患者行關(guān)節(jié)置換術(shù)并以PRP覆蓋創(chuàng)面，4周后成功治愈潰瘍創(chuàng)面，且未出現(xiàn)關(guān)節(jié)感染等并發(fā)癥，表明PRP不僅促進(jìn)創(chuàng)面愈合，在炎癥控制方面也有效果。Saad-Setta等[50]將PRP與去血小板血漿(PPP)作對(duì)比，發(fā)現(xiàn)PRP對(duì)糖尿病潰瘍創(chuàng)面的治療效果明顯優(yōu)于PPP，認(rèn)為是PRP中的高濃度血小板及相關(guān)生長(zhǎng)因子促進(jìn)潰瘍創(chuàng)面愈合。Villela等[51]的薈萃分析表明，影響糖尿病潰瘍創(chuàng)面愈合因素眾多，PRP可作為綜合治療手段之一，且與其他治療方法聯(lián)合應(yīng)用時(shí)促進(jìn)糖尿病潰瘍創(chuàng)面愈合效果明顯。

4　結(jié)語(yǔ)

PRP對(duì)于糖尿病潰瘍創(chuàng)面愈合有獨(dú)特的優(yōu)勢(shì)和效果,且PRP來(lái)源于自體，不存在免疫排斥和疾病傳播風(fēng)險(xiǎn)，使用安全，制備簡(jiǎn)便快捷，對(duì)機(jī)體損傷較小，在促進(jìn)組織修復(fù)和再生方面有廣闊的應(yīng)用前景。隨著對(duì)PRP臨床應(yīng)用的增多和對(duì)其作用機(jī)制研究的深入，PRP用于糖尿病潰瘍創(chuàng)面修復(fù)將得到更全面的闡述。

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(收稿：2016-01-29；修回：2016-04-03)

(本文編輯：李圓圓)

200233，上海交通大學(xué)附屬第六人民醫(yī)院骨科

柴益民E-mail: chaiyimin@vip.163.com

10.3969/j.issn.1673-7083.2016.03.010