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Abstract
總結(jié)電刺激促進(jìn)周圍神經(jīng)再生的研究進(jìn)展，歸納臨床前實(shí)驗(yàn)的電刺激參數(shù)并探討其對神經(jīng)再生的影響，介紹條件化電刺激模式和神經(jīng)導(dǎo)管支架技術(shù)等最新研究。
Keywords: 電刺激, 周圍神經(jīng)再生, 神經(jīng)損傷
耳鼻咽喉頭頸區(qū)域涉及多組重要腦神經(jīng)，腦神經(jīng)的周圍性損傷會(huì)導(dǎo)致面癱、聲嘶、吞咽困難等一系列相應(yīng)癥狀[1]。不僅嚴(yán)重影響患者的生活質(zhì)量，也會(huì)帶來巨大的經(jīng)濟(jì)負(fù)擔(dān)[2]。目前對于腦神經(jīng)損傷尚缺乏令人滿意的治療手段，針對周圍性神經(jīng)損傷的治療有諸多嘗試，其中電刺激促進(jìn)周圍神經(jīng)再生的研究歷經(jīng)數(shù)十年發(fā)展，取得了顯著進(jìn)展。新近的研究更多關(guān)注電刺激模式的優(yōu)化及將其與生物工程技術(shù)結(jié)合，為周圍神經(jīng)功能修復(fù)提供了新的思路。本文就電刺激促進(jìn)周圍神經(jīng)再生的研究進(jìn)展進(jìn)行綜述。
1943年Hyden開創(chuàng)性地評估了電刺激對軸突再生的影響：利用1~2 mA的正弦交流電刺激脊髓背根神經(jīng)節(jié)1~10 min后觀察到神經(jīng)節(jié)細(xì)胞中尼氏體增加。1952年Hoffman[3]提出了促進(jìn)軸突再生的電刺激參數(shù)：部分橫斷脊髓腰5神經(jīng)根后對坐骨神經(jīng)施加50~100 Hz、10~60 min的電刺激能夠增加軸突出芽的速率。Pockett等[4]在大鼠坐骨神經(jīng)擠壓傷后15~60 min內(nèi)給予1 Hz的電刺激，觀察到電刺激組的跖反射恢復(fù)時(shí)間縮短(4.14 d/10.40 d)。
Mendez等[5]觀察到短暫電刺激能加速擠壓或橫斷的面神經(jīng)恢復(fù)，并誘導(dǎo)損傷后的面神經(jīng)運(yùn)動(dòng)神經(jīng)元的通路特異性再生。但在Raslan等[6]研究大鼠面神經(jīng)切斷吻合模型中，60 min 20 Hz的電刺激無法明顯加速面神經(jīng)恢復(fù)，其效果顯著弱于股神經(jīng)模型。這提示腦神經(jīng)和脊神經(jīng)對電刺激的機(jī)制可能不同，電刺激促進(jìn)腦神經(jīng)損傷修復(fù)效果還需更多的實(shí)驗(yàn)驗(yàn)證。
近年來臨床試驗(yàn)也在逐步開展。Gordon等[7]隨機(jī)對照試驗(yàn)納入21例正中神經(jīng)損傷的受試者：正中神經(jīng)減壓后15 min內(nèi)應(yīng)用20 Hz、4~6 V的電刺激持續(xù)刺激正中神經(jīng)1 h，隨訪6~8個(gè)月后發(fā)現(xiàn)接受正中神經(jīng)電刺激的11例受試者比對照組在更短時(shí)間內(nèi)實(shí)現(xiàn)了感覺神經(jīng)動(dòng)作電位(sensory nerve action potential，SNAP)波幅的提高、SNAP傳導(dǎo)速度的增加和肌肉的再支配。此外，在指神經(jīng)橫斷、肘管綜合征、副神經(jīng)損傷的患者中進(jìn)行的隨機(jī)對照試驗(yàn)均發(fā)現(xiàn)接受電刺激的患者神經(jīng)電生理、感覺和運(yùn)動(dòng)功能均能更快恢復(fù)[8-11]。
隨著電刺激研究的深入，研究者注意到電刺激可能導(dǎo)致一些不良反應(yīng)：表面電極需要高電流來克服皮膚阻抗到達(dá)深層組織，可能會(huì)導(dǎo)致疼痛、皮膚刺激和局部燒傷[12]；袖帶電極易于植入、創(chuàng)傷性小，可以提供準(zhǔn)確定位的局部電刺激，但也會(huì)使神經(jīng)出現(xiàn)病理反應(yīng)、機(jī)械損傷[13]。
1. 電刺激促進(jìn)周圍神經(jīng)再生的機(jī)制
周圍神經(jīng)損傷后遠(yuǎn)端神經(jīng)發(fā)生華勒氏(Wallerian)變性、髓鞘崩解、軸突骨架變性[14]，這通常發(fā)生于損傷后24~48 h。損傷后期遠(yuǎn)端神經(jīng)骨架發(fā)生萎縮、軸突末端脫離靶肌肉/器官[15]。近端神經(jīng)在再生過程開始前發(fā)生退行性改變?nèi)缟窠?jīng)元胞體腫脹、尼氏體變性，同時(shí)細(xì)胞內(nèi)基因表達(dá)改變[16]。軸突整體再生的速度緩慢，約1~3 mm/d[17]；在此過程中遠(yuǎn)端肌肉因失神經(jīng)支配逐漸萎縮變性，時(shí)間越長、預(yù)后越差[18]。
周圍神經(jīng)損傷后的修復(fù)過程中損傷部位局部微環(huán)境會(huì)發(fā)生一系列結(jié)構(gòu)變化：首先是髓鞘解體, 施萬細(xì)胞去分化為修復(fù)細(xì)胞[19]，巨噬細(xì)胞活化吞噬髓鞘沉積物[20]；除清除髓鞘碎片外，巨噬細(xì)胞和施萬細(xì)胞可產(chǎn)生細(xì)胞因子如白細(xì)胞介素-6(IL-6)以促進(jìn)軸突生長；隨著碎片的清除，再生將從損傷部位的近端開始向遠(yuǎn)端延伸；施萬細(xì)胞能夠引導(dǎo)兩側(cè)神經(jīng)末端基底膜之間的軸突萌發(fā)的胞漿延伸[21]，Büngner帶由縱行排列的施萬細(xì)胞和新生的內(nèi)膜管形成，內(nèi)膜管將引導(dǎo)萌發(fā)的軸突向目標(biāo)組織移動(dòng)以重新獲得神經(jīng)支配[22-23]；同時(shí)Büngner帶會(huì)釋放生長因子包括成纖維細(xì)胞生長因子(fibroblast growth factor，F(xiàn)GF)、神經(jīng)生長因子(nerve growth factor，NGF)、白細(xì)胞介素樣生長因子(Interleukin-like growth factor，IGF)、腦源性神經(jīng)營養(yǎng)因子(brain-derived growth factor，BDNF)和血管內(nèi)皮生長因子(vascular endothelial growth factor，VEGF)加速軸突再生[15, 24-25]；損傷后1~2 d促炎癥的M1巨噬細(xì)胞明顯增加，損傷后3~4 d向促再生和抗炎癥的M2巨噬細(xì)胞分化從而減少局部炎癥反應(yīng)、促進(jìn)神經(jīng)再生[26]。
體外實(shí)驗(yàn)發(fā)現(xiàn)電刺激能促進(jìn)脊髓背根神經(jīng)節(jié)中神經(jīng)元內(nèi)的環(huán)腺苷酸(cyclic Adenosine Monophosphate，cAMP)和施萬細(xì)胞中的NGF分泌，cAMP持續(xù)升高可促進(jìn)NGF和細(xì)胞骨架蛋白的表達(dá)[27]。在損傷部位植入預(yù)先電刺激后的施萬細(xì)胞，神經(jīng)元的生長明顯加速[28]。大鼠脛神經(jīng)脫髓鞘模型中電刺激對巨噬細(xì)胞表型產(chǎn)生了顯著的影響，使巨噬細(xì)胞表型從主要的M1型轉(zhuǎn)變?yōu)镸2型[29]。磷脂酰肌醇3-激酶/蛋白激酶B(phosphatidylinositol 3-kinase/protein kinase B，PI3-K/Akt)細(xì)胞通路在神經(jīng)營養(yǎng)分子的下游信號傳遞中至關(guān)重要[30]，而電刺激能減少此通路抑制基因磷酸酶和張力蛋白同源基因(phosphatase and tensin homolog，PTEN)的表達(dá)[31-32]，對PI3-K/Akt的藥理性阻斷降低了電刺激對神經(jīng)再生的促進(jìn)作用。
基于以上證據(jù)，電刺激促進(jìn)周圍神經(jīng)再生機(jī)制可概括為以下幾個(gè)方面：①促進(jìn)巨噬細(xì)胞浸潤，加速髓鞘和軸突的瓦解及碎片的清除；②上調(diào)BDNF和NGF表達(dá)，加速神經(jīng)元生長和分化[33]；③促進(jìn)施萬細(xì)胞遷移：近端和遠(yuǎn)端神經(jīng)殘端上的施萬細(xì)胞長入神經(jīng)橋形成施萬細(xì)胞束，引導(dǎo)軸突再生[34]；④直接或間接地促進(jìn)內(nèi)皮細(xì)胞的遷移和血管生成相關(guān)的功能基因的表達(dá)，施萬細(xì)胞和內(nèi)皮細(xì)胞的遷移、血管的生成都有利于神經(jīng)橋的形成——這些作用可能由PI3K-Akt信號通路介導(dǎo)；⑤通過加速早期軸突和血管再生來延緩周圍神經(jīng)損傷后的靶器官/肌肉萎縮。
2. 電刺激的方式和參數(shù)
90年代以來，更多的嚙齒類動(dòng)物損傷模型表明：電刺激能促進(jìn)多種類型周圍神經(jīng)損傷的再生包括神經(jīng)擠壓傷、橫斷傷和慢性損傷[35-36]，但不同研究的電刺激方式、刺激參數(shù)(如頻率、脈沖寬度、刺激時(shí)間和周期)以及電極類型差異較大。本研究對近5年各項(xiàng)臨床前實(shí)驗(yàn)的電刺激方式、刺激參數(shù)和電極類型進(jìn)行了回顧總結(jié)。
2.1. 電刺激方式
目前3種主要電刺激方式包括植入式電刺激、一次性直接電刺激和經(jīng)皮電刺激，前2種為有創(chuàng)操作。Ju等[37]在大鼠坐骨神經(jīng)擠壓傷模型中比較了植入式和經(jīng)皮電刺激的效果：均使用25 Hz、0.1 ms、2~3 V的模式每天刺激30 min，每周5次，持續(xù)6周，實(shí)驗(yàn)結(jié)果提示雖然經(jīng)皮電刺激組大鼠在軸突直徑和肌纖維面積上優(yōu)于空白對照組，但效果不及植入電極組。但Pion等[38]在小鼠坐骨神經(jīng)切斷-縫合模型中證實(shí)經(jīng)皮電刺激與直接電刺激在促進(jìn)成年小鼠坐骨神經(jīng)功能恢復(fù)方面同樣有效。相比于一次性直接電刺激，Ju等[37]使用長時(shí)間、高密度的電刺激模式，可能更能發(fā)揮植入電極的優(yōu)勢，因而獲得更好的效果。
除電刺激方式外，對刺激電極的更新和探索也是研究重點(diǎn)之一，近5年動(dòng)物實(shí)驗(yàn)的電極應(yīng)用總結(jié)見表 1。Yu等[39]比較了植入不同接觸面積的電極對大鼠坐骨神經(jīng)切斷-縫合模型再生效果的影響：點(diǎn)接觸電極和1/4圈接觸組在植入后4周和10周的坐骨神經(jīng)功能指數(shù)(sciatic functional index，SFI)、復(fù)合肌肉動(dòng)作電位(compound muscle action potential，CMAP)和運(yùn)動(dòng)神經(jīng)傳導(dǎo)速度(motor nerve conduction velocity，MNCV)方面的表現(xiàn)都顯著優(yōu)于無電極組。與全接觸組比較，點(diǎn)和1/4圈接觸能夠促進(jìn)坐骨神經(jīng)的再生，且在植入后4周和10周觀察到的神經(jīng)干的機(jī)械損傷較少。在電極設(shè)計(jì)上，MacEwan等[40]研發(fā)的植入式薄膜無線神經(jīng)刺激器可顯著改善大鼠的功能恢復(fù)，并且具有可完全植入、無連接線、無電源的優(yōu)勢，方便重復(fù)、長時(shí)間給予治療性電刺激。
表 1. 電刺激促進(jìn)周圍神經(jīng)再生臨床前實(shí)驗(yàn)中對電刺激方式、電極材料、參數(shù)的研究
參考文獻(xiàn) 臨床疾病模型 電刺激參數(shù) 電極 動(dòng)物模型 實(shí)驗(yàn)結(jié)論 [38] 周圍神經(jīng)損傷 20 Hz，0.1 ms，5 V，1 h 雙極鉤狀電極 小鼠，坐骨神經(jīng)切斷-縫合模型 經(jīng)皮電刺激與直接電刺激對成年小鼠坐骨神經(jīng)功能恢復(fù)有相同的促進(jìn)作用，顯著優(yōu)于單純軸突切斷后縫合 [54] 周圍神經(jīng)損傷后異體移植修復(fù) 20 Hz，0.2 ms，1 h/d，0/3/6/9/12 d 植入式薄膜無線神經(jīng)刺激器 大鼠，坐骨神經(jīng)橫斷后移植40 mm的同種異體神經(jīng) 持續(xù)6 d治療性電刺激對功能恢復(fù)最為有效 [43] 周圍神經(jīng)損傷 16 Hz，0.1 ms，0.5 mA，10/60 min 不銹鋼304鉤狀電極 大鼠，坐骨神經(jīng)切斷-縫合模型 10 min電刺激與60 min方案促進(jìn)效果相似 [42] 周圍神經(jīng)損傷 16 Hz，0.5 mA，10/60 min 不銹鋼鉤狀電極 小鼠，坐骨神經(jīng)切斷-縫合模型 10 min電刺激能夠加速軸突再生并促進(jìn)功能恢復(fù) [55] 周圍神經(jīng)損傷后自體移植修復(fù) 20 Hz，0.1 ms，3~5 V，1 h Cooner銅導(dǎo)線末端 大鼠，腓總神經(jīng)切斷后移植對側(cè)腓總神經(jīng) 單次電刺激能夠促進(jìn)自體神經(jīng)移植后的軸突再生；延遲電刺激的效果有限 [37] 周圍神經(jīng)損傷 25 Hz，0.1 ms，2~3 V，30 min，每周5次，持續(xù)6周 植入電極/經(jīng)皮電刺激 大鼠，單側(cè)坐骨神經(jīng)擠壓傷 植入電極組的大鼠較經(jīng)皮電刺激組神經(jīng)功能恢復(fù)更快 [39] 周圍神經(jīng)損傷 20 Hz，0.1 ms，9 V，30 min/d，持續(xù)20 d 點(diǎn)接觸電極、1/4環(huán)接觸電極、整圓接觸電極 小鼠，坐骨神經(jīng)切斷-縫合模型 點(diǎn)接觸組與1/4環(huán)接觸組均能夠促進(jìn)坐骨神經(jīng)再生，且較全接觸組機(jī)械損傷小 [56] 周圍神經(jīng)損傷 20 Hz，0.3 ms，1 h/3 d，持續(xù)2周 植入式袖狀電極 小鼠，坐骨神經(jīng)切斷-縫合模型 重復(fù)電刺激無法提高肌肉神經(jīng)再支配恢復(fù)率，并導(dǎo)致反射亢進(jìn) [44] 周圍神經(jīng)損傷 5/100 Hz，0.2 ms，30 min/d，持續(xù)7 d 經(jīng)皮電刺激 大鼠，單側(cè)坐骨神經(jīng)擠壓傷 經(jīng)皮高頻電刺激具有促進(jìn)運(yùn)動(dòng)神經(jīng)再生的潛力 [40] 周圍神經(jīng)損傷 20 Hz，0.2 ms，2.5 V，1 h 植入式神經(jīng)刺激器 大鼠，坐骨神經(jīng)擠壓傷/坐骨神經(jīng)切斷-縫合模型 植入式無線刺激器對損傷的周圍神經(jīng)組織有治療作用，適宜臨床轉(zhuǎn)化 2.2. 電刺激參數(shù)
有效的電刺激治療需要確定安全的、最佳的刺激參數(shù)，電刺激的效果取決于各種變量如電流、頻率、持續(xù)時(shí)間、波形等，不同頻率和電流的電刺激對神經(jīng)元影響差異較大，但機(jī)制尚不明晰[41]。
Sayanagi等[42]和Roh等[43]分別在小鼠和大鼠的坐骨神經(jīng)損傷模型中應(yīng)用16 Hz、0.5 mA的電流進(jìn)行10 min或60 min的電刺激，評估神經(jīng)節(jié)基因表達(dá)、神經(jīng)元數(shù)量和形態(tài)、肌肉重量和行為學(xué)，發(fā)現(xiàn)持續(xù)10 min與60 min對神經(jīng)再生促進(jìn)作用相同。Su等[44]對坐骨神經(jīng)損傷的大鼠進(jìn)行了不同時(shí)間點(diǎn)、刺激頻率和強(qiáng)度的電刺激效果評價(jià)，發(fā)現(xiàn)即刻和遲期(損傷1周后)的高頻電刺激(100 Hz)都較低頻電刺激(5 Hz)的運(yùn)動(dòng)功能改善明顯，體內(nèi)、體外實(shí)驗(yàn)均提示高頻電刺激比低頻更能誘導(dǎo)背根神經(jīng)節(jié)細(xì)胞炎癥反應(yīng)的發(fā)生。對近5年周圍神經(jīng)再生動(dòng)物模型的電刺激參數(shù)研究的總結(jié)見表 1。目前周圍神經(jīng)損傷動(dòng)物模型中最常用的電刺激參數(shù)是20 Hz、0.1 ms、3~5 V或0.5 mA，每次刺激1 h，并傾向于短時(shí)間、單次應(yīng)用，這與目前臨床應(yīng)用于患者的電刺激標(biāo)準(zhǔn)模式一致：以20 Hz和0.1 ms脈沖刺激1 h。對于臨床前實(shí)驗(yàn)的參數(shù)研究有利于制定更有效的臨床方案。
3. 條件化電刺激
以上電刺激模式均應(yīng)用于神經(jīng)損傷后，但Senger團(tuán)隊(duì)研究發(fā)現(xiàn)：與擠壓傷類似，在神經(jīng)損傷前應(yīng)用電刺激也能夠促進(jìn)周圍神經(jīng)橫斷后再生。與對照組比較，損傷前1周進(jìn)行電刺激和神經(jīng)擠壓傷都使大鼠坐骨神經(jīng)切斷-縫合后1周的軸突再生長度增加3.8倍，軸突數(shù)量增加2.2倍[45]，通過比較機(jī)械感覺、復(fù)合肌肉動(dòng)作電位和行為學(xué)特性發(fā)現(xiàn)條件化電刺激在提高再生神經(jīng)功能方面更有優(yōu)勢[46]。但條件化電刺激對交感神經(jīng)軸突再生效果有限[47]，可能與交感神經(jīng)軸突對電刺激的反應(yīng)方式與運(yùn)動(dòng)神精軸突和感覺神精軸突不一致有關(guān)[47]。該團(tuán)隊(duì)同時(shí)提出，相比于損傷后電刺激，術(shù)前條件化電刺激在周圍神經(jīng)的軸突再生和功能恢復(fù)方面效果更佳，坐骨神經(jīng)損傷模型中條件化電刺激、損傷后電刺激、條件化+損傷后電刺激、對照組的7 d軸突再生長度分別是8.5 mm、5.5 mm、3.6 mm、2.7 mm。值得注意的是，在術(shù)前、術(shù)后同時(shí)進(jìn)行電刺激，神經(jīng)再生的效果并未出現(xiàn)疊加效應(yīng)[48]。
在此基礎(chǔ)上Senger團(tuán)隊(duì)利用脛神經(jīng)分支吻合腓總神經(jīng)遠(yuǎn)端殘端，并在術(shù)前1周對脛神經(jīng)進(jìn)行電刺激。與對照組比較，采用條件化電刺激治療的大鼠在行為學(xué)、電生理學(xué)以及神經(jīng)和肌肉組織學(xué)方面都存在明顯的改善[17]。
條件化電刺激促進(jìn)神經(jīng)再生的機(jī)制可能是使神經(jīng)元胞體基因表達(dá)模式改變?yōu)椤皳p傷/修復(fù)”狀態(tài)，再生相關(guān)基因、軸突結(jié)構(gòu)蛋白基因的表達(dá)上調(diào)，但不引起軸突變性或巨噬細(xì)胞浸潤[49]。因此，條件化電刺激的一個(gè)臨床應(yīng)用場景是：當(dāng)腫瘤組織侵犯或嚴(yán)重的軟組織創(chuàng)傷難以避免犧牲神經(jīng)時(shí)，可考慮使用神經(jīng)跨接的方式吻合神經(jīng)或者暫時(shí)寄養(yǎng)神經(jīng)，防止支配的肌肉萎縮，并在神經(jīng)吻合前利用電刺激使供體神經(jīng)進(jìn)入儲備或應(yīng)激狀態(tài)，加速后期軸突再生。
4. 電刺激結(jié)合神經(jīng)導(dǎo)管技術(shù)
神經(jīng)引導(dǎo)支架可通過生物工程提供神經(jīng)外膜或神經(jīng)束膜的支架結(jié)構(gòu)，建立類似于細(xì)胞外基質(zhì)的微環(huán)境，利用電紡和3D打印等技術(shù)設(shè)計(jì)支架模仿自體移植的形態(tài)結(jié)構(gòu)，引導(dǎo)神經(jīng)再生、增強(qiáng)電刺激對軸突沿電場的引導(dǎo)作用。
Li等[50]將一種具有導(dǎo)電性和機(jī)械性能的碳納米管/絲氨酸神經(jīng)導(dǎo)管應(yīng)用于大鼠損傷模型中，結(jié)合電刺激修補(bǔ)橫斷坐骨神經(jīng)的10 mm缺口，12周后觀察到該導(dǎo)管結(jié)合電刺激可以有效地促進(jìn)結(jié)構(gòu)修復(fù)和功能恢復(fù)，與自體神經(jīng)移植效果相當(dāng)。張喜等[51]研發(fā)的神經(jīng)導(dǎo)管也獲得相似結(jié)果。Lu等[52]設(shè)計(jì)了一種可生物降解的導(dǎo)電聚/石墨烯復(fù)合導(dǎo)管，表面的微圖案是通過微壓印技術(shù)和自組裝的聚多巴胺制作的20 μm的凹槽，應(yīng)用于大鼠坐骨神經(jīng)擠壓傷模型中發(fā)現(xiàn)：帶有電刺激的傳導(dǎo)性微圖案導(dǎo)管能促進(jìn)髓鞘的生長和加快神經(jīng)再生，并在體內(nèi)實(shí)現(xiàn)20倍于對照組的功能恢復(fù)。更多體外試驗(yàn)證明帶有電刺激的導(dǎo)管能有效地刺激施萬細(xì)胞的定向遷移、黏附和伸長，促進(jìn)施萬細(xì)胞表達(dá)神經(jīng)生長因子[52-53]。
5. 展望
作為周圍神經(jīng)康復(fù)的重要手段，電刺激促進(jìn)周圍神經(jīng)再生的作用已經(jīng)被廣泛接受。臨床前實(shí)驗(yàn)和分子機(jī)制方面已取得顯著進(jìn)展，從機(jī)制的可行性及實(shí)際運(yùn)用的有效性而言，電刺激與手術(shù)結(jié)合可作為周圍神經(jīng)損傷的新型治療手段，尤其在聯(lián)合神經(jīng)營養(yǎng)藥物、理療等治療方式時(shí)可改善治療效果。臨床探索仍處于起步階段，在廣泛應(yīng)用于臨床前需對電刺激的最佳參數(shù)和安全范圍進(jìn)行更大范圍的研究；評估電刺激應(yīng)用于神經(jīng)移植前預(yù)處理的安全性和有效性。此外，在電刺激應(yīng)用于腦神經(jīng)方面需要更多的基礎(chǔ)研究和臨床數(shù)據(jù)。
Funding Statement
北京市自然科學(xué)基金資助(No：7242107)；中央高?；究蒲袠I(yè)務(wù)費(fèi)項(xiàng)目(No：3332021010)；中央高水平醫(yī)院臨床科研專項(xiàng)(No：2022-PUMCH-A-094)
Footnotes
References
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