寇玉輝，姜保國

(北京大學人民醫(yī)院創(chuàng)傷骨科，北京大學交通醫(yī)學中心， 北京 100044)

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·工作綜述·

周圍神經(jīng)缺損修復新方法
——神經(jīng)延長術

寇玉輝，姜保國△

(北京大學人民醫(yī)院創(chuàng)傷骨科，北京大學交通醫(yī)學中心， 北京 100044)

周圍神經(jīng)； 神經(jīng)延長； 神經(jīng)缺損； 修復

周圍神經(jīng)缺損在臨床上常見，也是臨床治療的難點[1]。創(chuàng)傷性神經(jīng)缺失、神經(jīng)腫瘤醫(yī)源性切除、神經(jīng)延期修復時的神經(jīng)短縮等均可導致不同程度的神經(jīng)缺損[2-5]，我國每年周圍神經(jīng)缺損患者高達30～50萬例。對于小的周圍神經(jīng)缺損，可通過神經(jīng)游離、轉(zhuǎn)位、改變患肢體位和姿勢等方法，將神經(jīng)兩斷端接近后進行直接縫合[6]。對于較大的周圍神經(jīng)缺損，應用上述方法無法達到神經(jīng)的無張力修復時，則需采用其他方法進行神經(jīng)修復。目前臨床上最常采用的是神經(jīng)移植術[7-8]，即采用自體神經(jīng)段橋接缺損的神經(jīng)，進而達到神經(jīng)缺損修復的效果，但由于神經(jīng)移植術的移植神經(jīng)來源有一定的限制, 且通常還要以犧牲供區(qū)神經(jīng)功能為代價[9-10]，因此尋找其他修復方法和技術一直是周圍神經(jīng)缺損研究領域的熱點。

我們從肢體延長手術中獲得啟示：周圍神經(jīng)的特殊組織結(jié)構及力學性質(zhì)使得神經(jīng)干具有一定限度的抗張性，一定范圍內(nèi)延長神經(jīng)不會對神經(jīng)造成損傷。經(jīng)過延長神經(jīng)可以使神經(jīng)斷端長度得到增加，從而達到縮短神經(jīng)缺損距離的目的，使得缺損的神經(jīng)能夠直接縫合修復，因此我們開展了用周圍神經(jīng)延長技術修復周圍神經(jīng)缺損的系統(tǒng)研究：完成了周圍神經(jīng)延長器研發(fā)、周圍神經(jīng)延長極限、延長神經(jīng)修復神經(jīng)缺損效果等多個研究，現(xiàn)將此系統(tǒng)性研究成果報道如下。

1 適合周圍神經(jīng)緩慢均勻延長的周圍神經(jīng)延長器

最初的神經(jīng)延長是通過對延長神經(jīng)斷端進行簡單機械拉伸，這種方法易造成神經(jīng)損傷，而且延長后的神經(jīng)也易產(chǎn)生回縮[6]。隨后，有學者采用皮膚或軟組織擴張器對神經(jīng)進行延長，雖然能夠達到延長神經(jīng)的效果，但其在延長神經(jīng)的有效固定、神經(jīng)延長的精確量化方面存在不足[11-12]。針對上述缺陷，我們設計研發(fā)了周圍神經(jīng)延長器，延長器采用球囊結(jié)構對神經(jīng)干進行均勻延長，通過向球囊注水使球囊擴張，進而利用球囊擴張的張力使固定于球囊表面的待延長神經(jīng)獲得均勻延長。這種延長一方面避免了簡單的機械牽拉造成的神經(jīng)損傷，更重要的一方面是可以完成多次、緩慢、均勻的延長，從而有效達到用神經(jīng)自體延長的長度修復斷端缺損的目的。我們研發(fā)的周圍神經(jīng)延長器獲得多項國家專利，有望近期獲得醫(yī)療器械準入批件，成為臨床產(chǎn)品。

2 周圍神經(jīng)的可延長性及神經(jīng)缺損修復范圍

2.1 周圍神經(jīng)對快速/緩慢延長的耐受性

首先，我們研究了周圍神經(jīng)對單次快速延長的耐受性。通過動物實驗證實，在單次快速延長時，神經(jīng)在10%延長率內(nèi)耐受性較好，當延長率超過20%時將會對延長神經(jīng)造成不可逆的損傷。隨后，我們在周圍神經(jīng)慢性延長耐受性的研究中發(fā)現(xiàn)，當進行緩慢神經(jīng)延長(延長速度1 mm/d)時，神經(jīng)在27.0%延長率內(nèi)耐受性較好，延長率超過37.5%時可導致對延長神經(jīng)不可逆的損傷[11-12]。上述研究結(jié)果表明周圍神經(jīng)對慢性延長的耐受性遠優(yōu)于一次性的急性延長，對于較小的神經(jīng)缺損可以采用單次快速延長，而對于較大的神經(jīng)缺損，則可采用慢性延長[11-12]。

2.2 近端神經(jīng)和遠端神經(jīng)的延長極限及神經(jīng)缺損修復范圍

上述周圍神經(jīng)延長耐受性的研究結(jié)果提示修復過程中近端和遠端神經(jīng)均可進行延長,但在神經(jīng)修復后的再生過程中，近、遠端神經(jīng)的病理生理過程卻是完全不同的[10]，由此推斷近端和遠端神經(jīng)在對神經(jīng)延長的耐受性上可能存在差異,而近、遠端神經(jīng)可延長的極限，決定了神經(jīng)延長修復神經(jīng)缺損的可修復范圍,為此我們對近端神經(jīng)和遠端神經(jīng)的延長極限及神經(jīng)缺損修復范圍進行了系統(tǒng)的研究。在近、遠端神經(jīng)的單次快速延長耐受極限的研究中，我們發(fā)現(xiàn)近端神經(jīng)單次快速延長率極限為10.0%，而遠端神經(jīng)單次快速延長率極限為20.0%，由此明確了周圍神經(jīng)損傷后采用單次快速神經(jīng)延長技術可以修復神經(jīng)缺損的最大長度=近端神經(jīng)長度的10.0%+遠端神經(jīng)長度的20.0%[11-12]。在近、遠端神經(jīng)的多次緩慢延長耐受極限的研究中，我們發(fā)現(xiàn)近端神經(jīng)多次緩慢延長率極限為18.4%，遠端神經(jīng)神經(jīng)多次緩慢延長率極限可達52.0%，因此我們認為周圍神經(jīng)損傷后采用多次緩慢神經(jīng)延長技術可以修復神經(jīng)缺損的最大長度=近端神經(jīng)長度的18.4%+遠端神經(jīng)長度的52.0%[11-13]。

3 周圍神經(jīng)延長的組織學基礎及病理生理學變化規(guī)律

在系統(tǒng)完成周圍神經(jīng)單次及多次延長極限的基礎上，我們采用組織學染色、免疫組織化學染色以及單根神經(jīng)纖維剝離技術對周圍神經(jīng)延長過程中神經(jīng)干組織的病理生理學變化特點進行研究，發(fā)現(xiàn)方塔納帶(Fontana)是決定周圍神經(jīng)單次延長極限的重要結(jié)構基礎[13]；當神經(jīng)延長幅度達到10%時，神經(jīng)干內(nèi)方塔納帶結(jié)構消失，郎飛結(jié)(nodes of Ranvier)、施-蘭切跡(Schmidt-Lantermann incisure)等增寬，但無軸索及髓鞘的斷裂；當神經(jīng)單次延長幅度達到20%時，出現(xiàn)神經(jīng)軸索及郎飛結(jié)的斷裂，同時神經(jīng)延長過程中的神經(jīng)電生理檢測結(jié)果與這一病理生理學過程相符[13-17]。

4 周圍神經(jīng)延長和神經(jīng)移植

自體神經(jīng)移植一直被認為是臨床周圍神經(jīng)缺損修復治療的金標準，我們在動物實驗中，對比研究了周圍神經(jīng)延長與自體神經(jīng)移植修復周圍神經(jīng)缺損的效果，證實一定范圍的延長神經(jīng)修復神經(jīng)缺損能夠取得與自體神經(jīng)移植等效的修復效果[11-13]。

在此研究基礎上，我們開展了神經(jīng)延長修復神經(jīng)缺損的臨床研究，采用術中延長器對13例神經(jīng)缺損患者進行遠端神經(jīng)延長的治療，臨床應用結(jié)果表明，在4 cm的缺損范圍內(nèi)，延長的神經(jīng)能夠填補缺損范圍，所有的患者神經(jīng)均可進行無張力縫合。通過對患者進行系統(tǒng)的隨訪證實，患者神經(jīng)修復后，受損神經(jīng)再生良好，可達到同類型無缺損神經(jīng)損傷患者的修復效果[18]。對比性研究證實神經(jīng)延長技術可用于臨床周圍神經(jīng)缺損的修復，并在一定程度上可以替代神經(jīng)移植技術，成為臨床應用的新方法。

5 總結(jié)與展望

上述系列實驗研究解釋了周圍神經(jīng)自身可延長性的生物現(xiàn)象，并清楚的記錄了其延長過程中的特定變化及極限，證實神經(jīng)延長技術可以取得傳統(tǒng)的神經(jīng)移植修復周圍神經(jīng)缺損的修復效果，并具有如下優(yōu)點：采用神經(jīng)自體延長，無需神經(jīng)移植和人工神經(jīng)，因此不受自體神經(jīng)取材限制，無需犧牲供區(qū)神經(jīng)功能；無人工神經(jīng)機體免疫排斥反應，神經(jīng)再生效果優(yōu)于人工神經(jīng)移植；外科操作方便，延長后神經(jīng)可進行直接外膜縫合，容易被外科醫(yī)師接受，將會成為神經(jīng)缺損修復的創(chuàng)新性治療技術[19-20]。

周圍神經(jīng)延長技術修復周圍神經(jīng)缺損的效果已經(jīng)得到初步驗證，但真正的臨床廣泛應用仍有諸多工作需要開展。后續(xù)研究中，一方面我們將通過專利轉(zhuǎn)化促進神經(jīng)延長器的產(chǎn)業(yè)化，獲得國家醫(yī)療器械的正式批件；另一方面，我們開展更加廣泛的應用周圍神經(jīng)延長修復周圍神經(jīng)損傷的臨床研究，進一步對其在周圍神經(jīng)損傷修復中的效果進行驗證。

[1]H?ke A. Mechanisms of disease:what factors limit the success of peripheral nerve regeneration in humans? [J].Nat Clin Pract Neuro, 2006, 2(8): 448-454.

[2]Saadat S, Eslami V, Rahimi-Movaghar V,et al.The incidence of peripheral nerve injury in trauma patients in Iran[J].Ulus Travma Acil Cerrahi Derg, 2011, 17(6): 539-544.

[3]K?mürcü F, Zwolak P, Benditte-Klepetko H, et al.Management strategies for peripheral iatrogenic nerve lesions[J]. Ann Plas Surg, 2005, 54(2): 132-140.

[4]Deumens R, Bozkurt A, Meek M, et al. Repairing injured peripheral nerves: Bridging the gap[J]. Prog Neurobiol, 2010, 92(3): 245-276.

[5]Antoine J, Camdessanché J. Peripheral nervous system involvement in patients with cancer[J]. Lancet Neurol, 2007, 6(1): 75-86.

[6]Boyd K, Nimigan A, Mackinnon S,et al. Nerve reconstruction in the hand and upper extremity [J].Clin Plast Surg, 2011, 38(4): 643-660.

[7]Millesi H. The nerve gap.Theory and clinical practice[J]. Hand Clin, 1986, 2(4): 651-663.

[8]Brown JM, Mackinnon SE. Nerve transfers in the forearm and hand[J]. Hand Clin, 2008, 24(4): 319-340.

[9]Dahlin L, Johansson F, Lindwall C, et al. Chapter 28:Future perspective in peripheral nerve reconstruction[J]. Int Rev Neurobiol, 2009, 87: 507-530.

[10]Evans GR. Challenges to nerve regeneration[J]. Semin Surg Oncol, 2000, 19(3): 312-318.

[11]Jiang BG, Shibata M, Matsuzaki H, et al. Proximal nerve elongationvs. nerve grafting in repairing segmental nerve defects in rabbits [J].Microsurgery, 2004, 24(3): 213-217.

[12]Shibata M, Matsuzaki H, Jiang BG, et al. Distal nerve elongationvs. nerve grafting in repairing segmental nerve defects in rabbits[J]. Microsurgery, 2004, 24(3): 207-212.

[13]閆家智,姜保國,徐海林,等. 周圍神經(jīng)損傷遠端延長修復自身缺損的實驗研究[J]. 中華實驗外科雜志, 2001,18(3): 253-254.

[14]閆家智,姜保國,徐海林,等. 周圍神經(jīng)延長后單根神經(jīng)纖維的組織學觀察[J]. 中華手外科雜志, 2004, 20(1): 58-60.

[15]Wang WB, Zhang PX, Yan JZ, et al.Histological analysis of single peripheral nerve fiber in acute nerve elongation process[J]. Artif Cells Blood Substit Immobil Biotechnol, 2010, 38(4): 165-168.

[16]Jiang BG, Zhang PX, Yan JZ, et al. Dynamic observation of biomechanic properties of sciatic nerve at the suture site in rats following repairing[J]. Artif Cells Blood Substit Immobil Biotechnol, 2008, 36(1): 45-50.

[17]閆家智,姜保國,趙富強,等. 大鼠坐骨神經(jīng)損傷修復后吻合處力學性能的動態(tài)觀察[J].中華外科雜志, 2005, 43(12): 792-794.

[18]Bai L, Wang TB, Wang X, et al. Use of nerve elongator to repair short-distance peripheral nerve defects:a prospective randomized study [J].Neural Regen Res, 2015, 10(1): 79-83.

[19]姜保國. 外周神經(jīng)延長的研究進展[J].當代醫(yī)學, 2001, 7(5): 72-76.

[20]Hara Y, Nishiura Y, Ochiai N, et al. New treatment for peri-pheral nerve defects: reconstructiond of a 2 cm, monkey median nerve gap by direct lengthening of both nerve stumps [J].J Orthop Res, 2012, 30(1): 153-161.

(2016-08-08收稿)

(本文編輯：劉淑萍)

(Department of Trauma and Orthopaedics, Peking University People’s Hospital; Peking University Traffic Medicine Center, Beijing 100044, China)

SUMMARY Peripheral nerve defects are still a major challenge in clinical practice, and the most commonly used method of treatment for peripheral nerve defects is nerve transplantation, which has certain limitations and shortcomings, so new repair methods and techniques are needed. The peripheral nerve is elongated in limb lengthening surgery without injury, from which we got inspirations and proposed a new method to repair peripheral nerve defects: peripheral nerve elongation. The peripheral nerve could beelongated by a certain percent, but the physiological change and the maximum elongation range were still unknown. This study discussed the endurance, the physiological and pathological change of peripheral nerve elongation in detail, and got a lot of useful data. First, we developed peripheral nerve extender which could match the slow and even extension of peripheral nerve. Then, our animal experiment result confirmed that the peripheral nerve had better endurance for chronic elongation than that of acute elongation and cleared the extensibility of peripheral nerve and the range of repair for peripheral nerve defects. Our result also revealed the histological basis and changed the rule for pathological physiology of peri-pheral nerve elongation: the most important structure foundation of peripheral nerve elongation was Fontana band, which was the coiling of nerve fibers under the epineurium, so peripheral nerve could be stretched for 8.5%-10.0% without injury because of the Fontana band. We confirmed that peripheral nerve extending technology could have the same repair effect as traditional nerve transplantation through animal experiments. Finally, we compared the clinical outcomes between nerve elongation and perfor-mance of the conventional method in the repair of short-distance transection injuries in human elbows, and the post-operative follow-up results demonstrated that early neurological function recovery was better in the nerve elongation group than in the conventional group. On the whole, all of these experimental results revealed the physiological phenomenon of peripheral nerve elongation, and described the physiological change and stretch range in detail. The systematic research results have filled the blank in this field, which is very helpful for clinical limb lengthening surgery, the design of elongation surgery and the evaluation of the peripheral nerve stretch injury. Peripheral nerve elongation will become an innovative treatment technology in repairing peripheral nerve defects.

New treatment for peripheral nerve defects: nerve elongationKOU Yu-hui, JIANG Bao-guo△

Peripheral nerves; Nerve elongation; Nerve Defect; Repair

國家自然科學基金(31571236, 81372044)和北京大學人民醫(yī)院研究與發(fā)展基金(RDB2015-11)資助Supported by the National Natural Science Fundation of China (31571236, 81372044) and Peking University People’s Hospital Research and Development Funds (RDB2015-11)

時間：2016-9-5 9：33：54

http://www.cnki.net/kcms/detail/11.4691.R.20160905.0933.010.html

R651.3

A

1671-167X(2016)05-0753-03

10.3969/j.issn.1671-167X.2016.05.001

△ Corresponding author’s e-mail, jiangbaoguo@vip.sina.com