摘要
传统膀胱粘膜剥脱术是治疗膀胱原位癌及膀胱粘膜白斑、腺性膀胱炎等癌前病变的有效手段，但因剥脱工具及剥脱方法的缺陷而濒于被废止的边缘；CO_2激光是汽化、切割生物组织能力强、止血效果好且副损伤小的“最理想的激光手术刀”，但因受缺乏适宜柔性传能工具的困扰而长期徘徊于腔内外科手术的之外。空芯金属红外波导的问世为实现CO_2激光在腔内泌尿外科的应用创造了条件，但相关基础研究及临床应用均属空白。本课题以经国产空芯金属红外波导传输的CO_2激光为工具，首先进行开放性犬膀胱粘膜剥脱术的实验研究，在对手术的有效性及安全性做出全面评估的基础上，进一步对腔内CO_2激光膀胱粘膜剥脱术的可行性进行了初步的探讨。
1．目的
探讨以经多晶锗空芯金属红外波导传输的CO_2激光为工具的膀胱粘膜剥脱术的可行性、有效性与安全性，以及CO_2激光对膀胱组织的相关作用机制。
2．方法
2．1 CO_2激光犬膀胱粘膜剥脱术研究
以Beagle犬为研究对象，以经国产多晶锗空芯金属红外波导传输的CO_2激光为手术工具，在观察波导的机械性能、传能功耗及光斑特性并筛选出针对膀胱组织的适宜激光工作参数的基础上，行开放性CO_2激光膀胱粘膜剥脱术。采用膀胱组织测温及常规组织病理学检查等手段观察CO_2激光对膀胱组织的汽化效果及膀胱粘膜上皮的再生过程；通过围手术期观察及膀胱测压、静脉肾盂造影等功能检查方法观察手术的远期疗效，进而综合评价CO_2激光膀胱粘膜剥脱术的可行性、有效性及安全性。
2．2 CO_2激光对犬膀胱组织作用范围的显微FT-IR分析
以术后即刻的膀胱组织冰冻切片为研究对象，应用显微FT-IR原位检测技术获取来源于不同层次的膀胱肌肉组织的原始FT-IR光谱，通过光谱重建、差谱分析及曲线拟合等方法，定量分析膀胱肌肉组织蛋白质二级结构组成及其相对含量的变化，观察CO_2激光对膀胱组织在分子水平上的实际作用范围。
2．3 CO_2激光对成纤维细胞光生物调节效应的观察
以体外培养的人皮肤成纤维细胞为观察对象，建立CO_2激光的光生物调节效应研究模型，通过对CO_2激光照射后成纤维细胞增殖规律的观察，探讨CO_2激光与膀胱纤维化间的潜在关系。
2．4腔内CO_2激光膀胱粘膜剥脱术的体外模拟试验
以空芯金属红外波导为主要材料，设计制作膀胱粘膜剥脱器，建立以生理盐水为充盈介质的膀胱腔内手术模型，以离体新鲜犬膀胱组织为实验对象，进行水下CO_2激光膀胱粘膜剥脱试验，探讨腔内CO_2激光膀胱粘膜剥脱术的可行性。
3．结果
3．1 CO_2激光膀胱粘膜剥脱术研究
国产多晶锗空芯金属红外波导的可曲半径≤10.0cm，传输功耗约20％，照射距离≤5.0cm时的输出光斑服从高斯分布，波导使用灵活，操作方便，能够满足膀胱粘膜剥脱术的需要。照射距离≤5cm、光斑移动速度2～8mm/s是膀胱粘膜剥脱的适宜工作参数。CO_2激光的汽化深度仅限于粘膜及粘膜下层，对膀胱肌层无明显损伤。术后2周膀胱组织以非特异性炎症反应为主要病理变化，术后4周粘膜上皮再生活跃，术后12周膀胱粘膜完全再生。围手术期动物康复顺利，未见有大量血尿及膀胱穿孔等严重并发症发生。观察期末(12周)动物膀胱顺应性良好，上尿路形态及功能未见异常。实验结果表明，CO_2激光膀胱粘膜剥脱术安全、有效、可行。
3．2 CO_2激光对犬膀胱组织作用范围的显微FT-IR分析
CO_2激光照射后，蛋白质分子二级结构组成及其相对含量的变化区域位于膀胱肌层的组织学损伤界面(光镜水平)外约60μm的范围内，而蛋白质分子能量状态变化区域则延伸至约90μm的范围内。实验结果提示，动态扫描式剥脱过程中的CO_2激光对膀胱肌层的实际作用范围可超出其组织学损伤边界，但仍小于其静态作用时的范围。
3．3 CO_2激光对成纤维细胞光生物调节效应的观察
CO_2激光对人皮肤成纤维细胞的增殖有明显抑制作用，二者间存在一定的剂量—效应与时间—效应依赖关系，照射后24小时的抑制作用最显著。实验结果表明，CO_2激光与术后膀胱膀胱纤维化间无直接的因果关系。
3．4腔内CO_2激光膀胱粘膜剥脱术的体外模拟试验
CO_2激光可以在水下有效剥脱膀胱粘膜，组织碳化轻微，创面基底洁净。实验结果表明，CO_2激光可以在水下有效剥脱膀胱粘膜，具备与腔内泌尿外科技术结合可行性。
4．结论
经国产多晶锗空芯金属红外波导传输的CO_2激光在开放手术条件下能够有效地剥脱膀胱粘膜，对膀胱肌肉组织损伤轻微且无促进膀胱纤维化的直接作用。术后并发症少，膀胱粘膜上皮再生完全，膀胱及上尿路的形态与功能无明显改变。开放性CO_2激光犬膀胱粘膜剥脱术安全、有效、可行，并有望实现与腔内泌尿外科技术的结合，进而成为治疗膀胱粘膜病变的一种新的实用手段。
Objective: Denudations of canine bladder mucosa by carbon dioxide laser transmitted through indigenous metal hollow wave guide were performed in order to evaluate the feasibility, validity and safety of the operation.
Methods: Under open surgical procedures, 18 Beagle canines' bladder mucosa were denuded by carbon dioxide laser which was transmitted through indigenous metal hollow wave guide. Post operative complications, regeneration of bladder mucosa and functions of the urological system were evaluated by ordinary optical microscope, intravenous pyelography and urodynamic tests. The molecular boundary between the lased and the normal bladder tissue was investigated by Fourier Transformed Infrared micro-spectroscopy. Meanwhile, the underlying possibility of carbon dioxide laser to in induce the post operative bladder fibrosis was also investigated through a parallel test in the cultured fibroblasts. Finally, simulated denudations of bladder mucosa under water were performed to test the feasibility of carbon dioxide laser to be used with the combination of intravesical urologic procedures.
Results: Indigenous metal hollow wave guide has certain flexibility and maneuverability adapting to the surgical procedures. Leaving with the untouched bladder muscle (identified by the naked eyes and optical microscope), the bladder mucosa could be thoroughly denuded in less than 15 minutes and costs no more than 20000 Joules in each procedures. After surgery, regenerative bladder mucosa could be found since the 30th day, and last to the 120th day with a complete coverage of the bladder inner cavity surface. Post operative functional indexes, such as maximum bladder capacity and bladder compliance, and serum creatinine level, were found to have no obvious differences with that of before. FT-IR study revealed that optical energy could reach the bladder muscular layer and induced alteration of the secondary structure of proteins within no more than 90 millimeters. In vitra, carbon dioxide laser could down-regulate the growth of cultured human skin derived fibroblasts in a manner of amount-to-efficacy dependence, which indicates that carbon dioxide laser might has no potential stimulating effects on the formation of post operative bladder fibrosis. Carbon dioxide laser could effectively denuded bladder mucosa under water with more less injuries to the bladder muscle.
Conclusion: Carbon dioxide laser could effectively denude the canine bladder mucosa without any severe surgical complications and functional deteriorations in the canine urological systems. Carbon dioxide laser, which act more likely a kind of kinetic energy carrying optical particles, could induce modifications of secondary structure of proteins in the bladder muscles instead of significant histological changes. Carbon dioxide laser has no definite relationship with the post operative canine bladder fibrosis. There is obviously the possibility that transurethral denudation of bladder mucosa could be performed with the organically integration of carbon dioxide laser and the metal hollow wave guide.
引文
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