基于隧道技术食管粘膜下吞咽感知程序起搏治疗贲门失弛缓症的实验研究

Patients with achalasia suffered a lot from recurrent dysphasia for the defeated lower esophageal sphincter (LES) relaxation and damaged esophageal body paralysis. Recengly, the number of Aclasia patients has been increasing gradually, with the origion of it still to be studied. The present treatments such as Heller myotomy and per-oral endoscopic myotom(POEM) aim at reducing LES pressure but can not improve esophageal body paralysis. It has been proven that electrical stimulation can promote gastrointestinal movement. Our preliminary study founded that submucosal electrical stimulation could increase esophageal body pressure and promote contraction of esophageal body， not only in healty control but also in achlasia patients. On the bases of POEM, we have filed a patent application on a method to treat achlasia with a swallow-sensory feedback controlled sequential esophageal pacemaking system. The proposed method offers a solution to treat achalasia by targeting to revive the esophageal body paralysis. This study will utilize electrophysiology, high resolution manometry(HRM), esophageal imaging, molecular biology, electron microscope and patch clamp technology, in vitro and in vivo, to explore the best method and threshold of swallow-sensation, the best parameter of the electrical pacemaking system to re-establish the esophageal body paralysis safely and effectively, and furthermore, to study the mechanism of swallow-sensory feedback controlled sequential esophageal pacemaking system on the treatment of achalasia. In a word, the aim of this study is to put a solid basis for the therapy of the submucosal swallow-sensory feedback controlled sequential esophageal pacemaking system on the treatment of achalasia.

贲门失弛缓症病因未明，患病人口逐年增加。因食管下括约肌（LES）松弛功能障碍及食管体部蠕动缺失导致吞咽困难，严重影响患者生活质量，甚至导致肿瘤和猝死。以减低LES压力为目的经口内镜肌切开术（POEM）及食管下段贲门部肌层切开术（Heller）不能恢复食管体部蠕动。既往研究证明电刺激消化道平滑肌可促进其运动，我们前期实验也发现正常人食管内和贲门失弛缓症患者食管粘膜下隧道内电刺激均可增加食管压力和运动，并申请了基于隧道技术吞咽感知、食管粘膜下程序电起搏治疗贲门失弛缓症的专利。本研究将应用食管电生理、高分辨食管测压、食管排空、分子生物学、电镜和膜片钳等技术，通过动物及人体实验研究，探讨吞咽动作的感知方法和阈值；确定有效且安全的程序电起搏治疗贲门失弛缓症的最佳参数；并探讨食管程序电起搏治疗贲门失弛缓症的电生理、细胞及分子机制。旨在为基于隧道技术食管粘膜下吞咽感知程序电起搏治疗贲门失弛缓症奠定基础。

背景：贲门失弛缓症病因不明，以食管下括约肌（LES）松弛障碍和食管体部蠕动缺失为主要病理生理机制。目前，该病的治疗主要包括药物，手术，扩张以及近期出现的POEM微创治疗，但以上方法均只能松弛LES,不能恢复食管体部蠕动。因此，恢复贲门失弛缓症患者食管体部蠕动是该病治疗中迫切需要解决的问题。既往研究表明电起搏治疗可以恢复心电节律；恢复胃电节律，改善胃排空；促进结肠蠕动，改善便秘。能否联合POEM技术和电起搏技术治疗贲门失弛缓症是本研究力图解决的问题。主要内容及关键数据：本研究成功建立了多种贲门失弛缓症动物模型。1，电起搏治疗贲门失弛缓症的有效性及安全性研究：我们分别通过在体以及离体实验、单点以及顺序多点电起搏，结果发现：单点电刺激可产生食管平滑肌收缩且贲门失弛缓症模型动物的食管平滑肌亦可经电刺激产生收缩；单点电刺激产生的刺激部位食管收缩的峰值与刺激电压、脉宽、频率呈正相关关系；多点顺序电起搏可促进食管排空。食管排空率与电压、脉宽、电刺激时间正相关，与电极间距负相关。电刺激导致食管收缩机制复杂。健康动物与神经肌肉接头的M受体相关；贲门失弛缓症动物则与电流直接刺激食管平滑肌有关。有效参数范围的电刺激未引起呼吸、循环系统的显著变化。通过猪及人体实验，我们进一步证通过POEM技术可于食管粘膜下置入起搏电极，并经粘膜下电刺激产生食管收缩。2，吞咽动作的监测方法以及电起搏设备的研发：通过低功耗单片机MSP430，利用吞咽传感器和前端模拟电路可检测吞咽动作；通过集成电路及无线信号传输技术可制作可植入食管起搏主机及电极。3，通过食管肌层标本的免疫组化研究，以及离体、在体食管的电生理研究，我们发现硫化氢合成酶缺乏可能是贲门失弛缓症新的病理生理机制。科学意义：本研究证明通过POEM技术置入食管起搏电极，连接皮下起搏主机进行食管顺序电起搏治疗贲门失弛缓症是可行的。硫化氢合成酶缺乏可能是该病新的病理生理机制。