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. 2019 Aug 18;51(4):778–782. [Article in Chinese] doi: 10.19723/j.issn.1671-167X.2019.04.033

脱细胞异体真皮在泌尿生殖疾病手术治疗中的应用

Appllication of human acellular dermal matrix in surgical treatment of genitourinary disease

Zhong-cheng XIN 1,△, Bi-cheng YANG 1, Meng LI 1, Yi-ming YUAN 1, Wan-shou CUI 1, Yuan TANG 1, Dong FANG 1, Wei-dong SONG 1
PMCID: PMC7433487  PMID: 31420640

Abstract

Humanacellular dermal matrix (HADM) is widely used in the field of burn wound repair and tissue engineering plastic surgery. HADM is manufactored by physical and chemical decellular process to remove the antigenic components that might cause immune rejection in dermis.The extracellular matrix of three-dimensional cell scaffold structure with collagen fibers had been used for wound repair and tissue regeneration, while HADM characterized with low absorption rate after implantation and strong ability to induce angiogenesis in host tissue. Studies reported that after the HADM was implanted into the patient, the host cells, such as fibroblasts and myofibroblasts, as well as lymphocytes, macrophages, granulocytes and mast cells, rapidly infiltrated the graft. The connective tissue and neovascularization were then formed within the HADM three-dimensional cell scaffold, the lymphatic system also appears after vascular reconstruction. Traditional urethral reconstruction using autologous skin flaps has some defects, such as complexity of the technology, risk of necrosis of the skin flaps after transplantation, and failure to achieve functional repair of the urethral epithelium. It has been reported that using HADM to reconstruct the urethra in patients with urethral stricture, hypospadias and bladder-vaginal fistula, showed promising results. Others have reported the experience of using HADM to repair and reconstruct congenital classic bladder exstrophy. HADM has also been used for tissue repair in patients with penile skin defect caused by Fonier’s gangrene and hidradenitis suppurativa, and implanted under Bucks’ fascia to enlarge the penis. The report of HADM implantation for treating premature ejaculation also deserves attention. Researchers found that HADM implantation can form a tissue barrier between the skin and corpus cavernosum, which can effectively reduce penile sensitivity and treat premature ejaculation. The safety and effectiveness of HADM implantation in the treatment of premature ejaculation need to be further standardized by data from multi-center, large-sample clinical studies. In summary, HADM is the extracellular matrix and three-dimensional cell scaffold of human dermis. As a new type of tissue repair material, new blood vessels are formed actively after implantation, which shows good histocompatibility. HADM has shown increasingly broad application prospects in treatment of genitourinary diseases including penis, urethra and bladder diseases. HADM has also been used in the treatment of premature ejaculation in recent clinical studies, and its long-term safety and efficacy need to be further investigated.

Keywords: Human acellular dermal matrix (HADM), Plastic surgery, Urethra, Bladder, Penis, Premature ejaculation

脱细胞异体真皮(human acellular dermal man-trix, HADM)是人体真皮的细胞外基质和三维框架结构,在泌尿外科领域被应用于多种疾病的治疗,近年还开展了旨在治疗小阴茎和早泄的HADM植入术。本文对HADM在泌尿生殖疾病手术治疗中的应用现状和前景做一综述。

1. HADM概述

HADM作为真皮缺损修复材料被广泛应用于烧伤科、整形科、口腔科、乳腺外科等诸多临床领域[1,2]。HADM取材于人体皮肤组织,通过脱细胞加工去除引起免疫排斥反应的抗原成分,保留了人体真皮的细胞外基质和三维框架结构。目前通常使用物理处理和化学处理结合的方法对组织进行脱细胞加工[3]。脱细胞加工的目标是有效去除所有细胞成分,同时尽量减少对细胞外基质的组成、生物活性和机械完整性的影响。物理处理法包括搅拌、超声波、机械按摩或冷冻和解冻,这些方法可破坏细胞膜并释放细胞内容物,但物理处理法通常不能达到完全脱细胞的目的,因此必须与胰蛋白酶消化和离子及非离子生物洗涤剂等化学处理法相结合,以进一步破坏细胞膜和细胞间连接[4]。

HADM具有植入体内后吸收率低和诱导宿主组织血管再生能力强的特点。HADM在植入患者体内后,成纤维细胞和肌成纤维细胞,以及淋巴细胞、巨噬细胞、粒细胞和肥大细胞均会迅速浸润移植物[5],随之在HADM内形成结缔组织和新生血管,淋巴系统也会在血管重建后出现。应注意的是,尽管在大鼠实验中移植后2周即可观察到HADM内新生血管形成,但在人和大型哺乳动物体内,这一过程需要相对较长的时间。在一项猪移植实验中,新生血管形成出现在移植后8周[6]。

在生物组织材料领域,也出现了动物源的真皮材料的探索,如猪源、牛源等,但动物源真皮材料与人源真皮材料相比,存在许多弊端,科学界目前仍无法解决,如猪真皮材料从显微到超微层次的研究结果表明,猪真皮具有较为致密的三维空间结构,明显不同于人的真皮,猪真皮将会影响血浆营养成分的渗透,延缓血管化进程,从而降低移植成活率。猪真皮中Ⅰ型胶原含量高,Ⅲ型胶原和弹性纤维含量少,这些成分在含量和功能上的差异会导致真皮生物力学性能的差异。因而,猪真皮反映弹性性能的最大应变低于人真皮,弹性模量高于人真皮,而反映强度性能的最大应力高于人真皮,表现为质地僵硬、弹性差和伸展性差。临床上选择脱细胞真皮时应考虑移植物组织结构和相容性,优先选择同种(即人类)来源的脱细胞真皮[7,8]。

此外,由于种属差异,猪真皮容易引起超急性排异反应。猪真皮生产过程中的交联过程包埋了引起超急性排异反应的α-(1,3)-半乳糖基抗原,只能推迟引起排异反应,不能从根本解决排异液化的问题。随着植入时间的延长,细胞浸润程度的加深,最终产生迟发性异种排异反应[9]。

2. HADM在泌尿外科疾病手术治疗中的应用

2.1. 尿道重建

传统尿道重建采用自体皮瓣修复,存在技术复杂,移植后皮瓣有坏死风险,无法达到尿道上皮的功能性修复等缺陷[10]。HADM为克服尿道重建中的上述困难提供了新的治疗方案。国内研究者通过术中将HADM缝合成管状修复切除的尿道狭窄段完成尿道重建[11],术后尿道造影和膀胱尿道镜显示HADM与周围组织融合良好,15例尿道狭窄患者中3例出现术后尿道再狭窄,并接受尿道扩张或切开,在平均45.6个月的随访中,患者术后排尿功能正常。于旸等[12]报道了对16名28岁阴茎体型尿道下裂、术后尿道瘘或尿道狭窄儿童的HADM尿道重建经验,在36个月的随访中,术后患儿排尿正常,无尿道瘘发生。杨勇等[13]报道了利用HADM修补膀胱阴道瘘和重建尿道狭窄患者尿道的手术方法,术者采用腹膜外经膀胱入路,切除瘘管周围组织后使用HADM作为组织补片修补4例复杂性膀胱阴道瘘,达到良好的术后效果,在412个月的随访中,未见患者报告复发漏尿,此外,术者对4名炎性狭窄和1名外伤后狭窄的前尿道狭窄患者进行尿道狭窄段切除术后HADM修补术,在3个月的随访中,患者未见尿道狭窄复发。

2.2. 膀胱外翻

Bonitz等[14]报道了对623岁的男性先天性典型膀胱外翻患者使用HADM进行修复重建的经验,该研究对这6名患者使用HADM修补腹壁缺损,术后13年随访的结果表明,6名患者均未出现腹壁疝,且达到正常腹壁强度,其中两名患者接受了二期膀胱颈重建和双侧输尿管吻合术,并获得尿流控制能力,提示HADM可以作为耻骨截骨的替代手段修复加固大龄患者腹壁,并填充组织间隙,术者认为其操作简单,安全有效,并可获得良好的美观效果。

2.3. 阴茎皮肤缺损

Ludolph等[15]利用HADM对两名阴茎福尼尔坏疽(Fournier’s gangrene)和1名化脓性汗腺炎导致阴茎皮肤组织缺损的患者进行了组织修复,术者首先在清创后利用HADM覆盖创面,并进行负压封闭包扎,等待5 d后可见HADM初步与组织融合和血管生成,此时进行大腿皮瓣移植修复,并再次给予负压封闭包扎,34 d后去除包扎,术后移植组织血运良好,无排尿困难,该研究为分期手术修复阴茎皮肤缺损提供了新方法。

3. HADM植入术治疗小阴茎

3.1. HADM植入术治疗小阴茎的适应证和禁忌证

小阴茎是指男性生殖器形态正常,阴茎伸展长度低于相同年龄或相同性发育状态人群平均值减2.5个标准差者[16,17]。临床上青春期后内分泌治疗无效的小阴茎、隐匿性阴茎以及阴茎短小综合征常需要阴茎整形手术治疗,既往阴茎延长术包括阴茎根部耻骨前皮肤V-W成型术、阴茎悬韧带松解术、会阴区脂肪切除术等[18]。阴茎增粗术包括自体脂肪、透明质酸或硅胶注射,皮下脂肪或皮瓣移植,自体静脉移植,可吸收性生物材料植入等[19,20]。

有报道应用HADM植入Bucks筋膜下加粗阴茎,术后自然状态下阴茎周径加大 1.33.1 cm,平均 2.6 cm [21],术后3个月可正常性生活,且该方法用于阴茎增大,具有创伤少、操作简便、效果确实、无不良反应的特点。吴小蔚等[22]报道了35例利用HADM补片双平面植入阴茎增粗术,其中25例获得624个月的随访,未见并发症发生,取得良好增粗效果和性生活满意度。在临床工作中应当遵循该手术的适应证和禁忌证。HADM治疗小阴茎的手术适应证包括:(1)青春期后内分泌治疗无效的小阴茎;(2)隐匿阴茎;(3)阴茎短小综合征。该手术的禁忌证有:(1)泌尿生殖道感染者;(2)糖尿病血糖控制不佳者;(3)阴茎包皮过短者;(4)精神心理障碍者;(5)对阴茎增大过度期待者。

3.2. HADM植入术治疗小阴茎手术方法

北京大学第一医院男科中心常规开展HADM(北京桀亚莱福生物技术有限责任公司)植入加阴茎延长术,治疗内分泌治疗无效的成人小阴茎、隐匿性阴茎及阴茎短小综合征,取得较为满意的效果。具体手术步骤如下:(1)麻醉下术野常规消毒;(2)以包皮环切口依次切开皮肤及筋膜,暴露阴茎白膜,阴茎白膜脱套,清除纤维条索(图1A、1B);(3)切断悬韧带拉伸阴茎(图1C);(4)2-0尼龙编织线在距离阴茎根部外24 cm 钟表位置2点和10点处分别与两侧阴茎白膜缝合固定(图1D);(5)取HADM(面积约5 cm×6 cm)覆盖阴茎白膜背侧,拉伸阴茎后利用3-0可吸收线将HADM两侧边缘与白膜分别缝合固定3针(图1E、1F);(6)复位筋膜层以覆盖HADM,依次缝合筋膜与皮肤切口(图1G、1H);(7)包扎并留置导尿管(图1I)。

1.

HADM植入术治疗小阴茎手术步骤

Procedure of HADM impantation for small penis

A, circumcision; B,degloving of the tunica albuginea; C, cut off the suspension ligament of the penis; D, 2-0 nylon thread was used to fix the tunica albuginea and subdermis. E. subfascial implantation of HADM; F, suture and fix HADM; G, suture fascia; H, suture the skin; I, bandage and indwelling catheter.

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HADM植入术治疗小阴茎的手术要点是严格掌握手术适应证和禁忌证,阴茎延长手术除了适当切断悬韧带及纤维条索,关键在于利用2-0尼龙编织线在距离阴茎根部外24 cm 钟表位置2点和10点处分别与两侧阴茎白膜侧弯处缝合固定,以防止阴茎回缩达到阴茎有效延长。HADM面积大小选择要依据拉伸阴茎后从阴茎白膜根部到冠状沟的长度,以及确保足够覆盖尿道外阴茎白膜。缝合时严密缝合筋膜层,包皮环状切口无张力缝合以免发生包皮淋巴肿。术后2个月内禁欲,定期随访。

3.3. HADM植入术治疗小阴茎手术效果

HADM植入加阴茎延长术治疗小阴茎,术前阴茎长度测量,阴茎长度6.5 cm,周径6.5 cm(图2A)。术后3个月随访,患者对阴茎增大效果很满意(阴茎长度8.5 cm,周径8.0 cm)(图2B),自诉性功能有改善,对排尿功能没有影响。

2.

HADM植入术前后阴茎外观对比

Comparison of penis appearance before and after HADM impantation

A,pre-operative; B,post-operative.

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4. HADM植入术治疗早泄(premature ejaculation, PE)

PE是一种常见的射精功能障碍,它不仅受躯体因素的影响,也受心理和精神因素的影响,发病率约为20%30%。PE还没有合理的动物模型用于研究其发病机制,目前对PE的病理生理学变化尚知之甚少。普遍认为精神心理因素是PE的重要病因,研究者发现利用五羟色胺再摄取抑制剂(selective serotonin reaptake inhibitor,SSIR)治疗抑郁症患者过程中,有患者出现射精困难的不良反应[23]。近年来,快速起效且快速代谢的新型SSIR制剂达泊西汀已被用于治疗PE,但是这种手段的临床治疗效果仍有待研究。笔者的研究表明[24],PE患者较健康人阴茎感觉敏感性高,利用能够降低阴茎感觉敏感性的药物涂抹阴茎龟头治疗,可显著延长PE患者射精时间和性生活满意度。

近年来有采用阴茎背神经切断手术[25,26]和透明质酸龟头增大术[27]治疗PE的报道。但由于可能发生术后器质性性功能障碍并发症和缺乏可靠的临床依据,这些治疗方法仍有待进一步研究[28]。HADM植入术治疗早泄的研究报道值得关注,研究者认为HADM植入术可在阴茎体的皮肤和海绵体之间形成一层组织屏障,能够有效降低阴茎敏感度从而治疗早泄[29]。数据显示,HADM植入术术前平均射精潜伏期 0.67 min(0.181.1 min),术后阴道内射精潜伏期为 2.37 min(0.828.4 min),HADM植入术成为小阴茎合并早泄患者的治疗选择[30,31]。目前国际性功能障碍学会(Internal Society of Sexual Medicine, ISSR)仍推荐新型选择性5-羟色胺再吸收抑制剂达泊西汀作为PE治疗的第一线治疗药物。HADM植入术治疗早泄的安全性和有效性有待于在符合循证医学的多中心大样本临床研究的数据指导下,进一步规范手术适应证、禁忌证和手术方法。

5. 小结

HADM保留了人体真皮的细胞外基质和三维框架结构,作为一种新型的组织修补材料,植入体内后新生血管形成活跃,体现出良好的组织相容性。HADM在泌尿生殖疾病包括阴茎、尿道、膀胱疾病手术治疗领域展现出日渐广阔的应用前景。在近期临床工作中HADM还被应用于早泄治疗, 其远期疗效有待进一步深入研究。

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