Objective: To retrospectively report the long-term results of the use of a small intestinal submucosa (SIS) graft in bulbar urethral repair.
Methods: From 2003 to 2007, 25 men (mean age 40.5 years) with bulbar strictures underwent patch graft urethroplasty using SIS placed on the dorsal or ventral or dorsal plus ventral surface of the urethra. The mean follow-up period was 71 months (range 52-100). The clinical outcome was considered a failure when any postoperative instrumentation, including dilation, was needed.
Results: Of the 25 cases, 19 (76%) were successful and 6 (24%) were failures. No postoperative complications were related to the use of heterologous graft material, such as infection or rejection. The failure rate was 14% for strictures 4 cm.
Conclusions: At long-term follow-up, in bulbar stricture repair, SIS grafts showed similar results to penile skin grafts but were less effective than buccal mucosa grafts. The use of SIS as graft material should not be the first choice but represents an alternative option for patients with bulbar strictures that are not long and who refuse the harvesting or are not ideal candidates for buccal mucosa or penile skin grafts. Larger series of patients with longer follow-up are needed before widespread use can be advocated.
Despite developments in the surgical techniques, the type of substitutive material for use in the repair of urethral strictures remains one of the most challenging problems in urethral reconstructive surgery. Various autologous grafts or flaps from skin or mucosa have been proposed for urethral stricture repairs, but today the buccal mucosa (BM) is considered the best tissue for urethral substitution [ 1 ].Urethral tissue engineering is an emerging field in which the main aim is the development of an ideal material for urethral substitution, avoiding the problems related to the use of autologous tissue such as donor site morbidity and time-consuming harvesting. Various heterologous materials have been used but with poor results in the long term. Biodegradable organic matrices have been proposed as scaffolds promoting urethral regeneration, but with potential risks of infection or antigenic complications. Several collagen matrices have already been applied for urethroplasty [ 2 ].
Promising results have been reported with the use of small intestinal submucosa (SIS) as urethral substitute material in animals [ 3 ]. Lately, SIS has also been tested in the urethra of human patients for the repair of urethral strictures [ 4 ].However, the literature reported only a few studies and with short follow-up of urethral reconstruction with SIS [ 4 – 8 ]. Moreover, these series were non-homogeneus regarding the site of urethral reconstruction, because they included both penile or bulbar or penile-bulbar urethral repairs [ 5, 6 ]. The aim of this study was to extend our previously published short-term follow-up [ 6 ], by reporting a long-term follow-up in a homogeneus series of 25 patients with urethral stricture localized only in the bulbar tract who underwent patch graft urethroplasty using SIS. To our knowledge, this is the study on SIS graft bulbar urethroplasty with longest follow-up.
2.Materials and methods
2.1 Patient population
We retrospectively evaluated 25 men, 40,5 mean years old (range 23 to 66 yr) with bulbar urethral strictures who, between 2003 and 2007, underwent graft urethroplasty using SIS. Patients with penile and peno-bulbar stricture were excluded. All patients were informed of the good results using the BM in the repair of urethral strictures, but they chose the SIS in order to reduce the eventual donor site discomfort. Patients were also informed about the lack of long-term results using the SIS. All patients were interviewed to exclude sensitivity to porcine material. Preoperative evaluation included clinical history, uroflowmetry, urethrography and urethroscopy. Stricture etiology was unknown in 16 patients, iatrogenic in 8, and traumatic in 1. Of the patients 21 (84%) had undergone prior stricture treatment including urethral dilation in 3, internal urethrotomy in 11, dilation plus internal urethrotomy in 5, dilations plus urethroplasty in 2. Stricture length ranged from 1,5 to 6 cm (mean 3,3 cm). Grafts ranged from 4 to 7 cm (mean 4,7 cm).
2.2 Surgical techniques
In all patients we performed urethroplasty using SIS as patch grafts for the urethral augmentation. To augment the urethra the graft was placed dorsally in 11 patients (respectively, by Asopa’s procedure in 8 patients and by Barbagli’s procedure in 3), ventrally as McAninch group suggested in 6 (fig. 1), and ventrally plus dorsally by Palminteri’s technique in 8 (fig. 2) [ 9 – 12 ]. In all patients after ventral or dorsal opening of the stricture, fibrotic urethral tissues were partially excised while preserving the remaining urethral plate. Neourethras were created by anastomoting the matrices in inlay/onlay patch fashion to the mucosal urethral plate. In all patients we used SIS (COOK ®) grafts, size 2 x 10 cm, four-layers. After being discarded, the material was rehydrated with saline solution. The sheet was trimmed to fit the urethral defect size, providing small allowance for overlap. SIS is non elastic, so it is advisable to work with larger patches than the urethral defect. A 18 Fr Silicon Foley catheter was left in place. All surgical procedures were performed by the same surgeon (E.P.).
2.3 Postoperative course and follow-up criteria
Patients were discharged home 3 days after surgery. Voiding cystourethrography was done at the catheter removal 3 weeks after surgery. All patients received perioperative broad-spectrum antibiotics followed by nitrofurantoin for 3 weeks until catheter removal. We used the same follow-up and successful criteria already used by other leading Authors [ 1, 10 ]. Uroflowmetry and urine cultures were repeated every 4 months in year 1 and annually thereafter. When obstructive symptoms developed or peak flow rate deteriorated < 14 ml/s, urethrography and urethroscopy were repeated. Successful reconstruction was defined as normal voiding without need for any postoperative procedure including dilatation and no evidence of stricture on urethrography. The mean follow up in the entire serie was 71 months (range 52 to 100).
Of 25 cases 19 (76%) were successful and 6 (24%) failures. There were no postoperative complications related to the use of heterologous material such as infection, allergic reaction or rejection. No fistulae were evident at the voiding urethrography after catheter removal. Of the 19 successful cases, mean stricture length was 3 cm and mean graft length was 4,6 cm. Of the 6 failed cases, mean stricture length was 4,1 cm (range 1,5 to 6) and mean graft length was 5,2 cm. Particularly, the failure rate was 14% for strictures < 4 cm and 100% for strictures > 4 cm.
Postoperative mean peak urinary flow of successful patients was 26,9 ml/s versus the preoperative mean peak urinary flow of 10,5 ml/s. Eight (42%) of the successful patients agreed to undergo urethrography and urethroscopy, 1 year after the surgery. In all patients these exams revealed adequate calibre lumens and the SIS grafted area were completely replaced by urothelium. Failures developed within 18 months after surgery.
In 3 cases the recurrence was only a slight fibrotic ring which was managed by a single successful endoscopical urethrotomy in 2 patients, whereas 1 patient required 3 urethrotomies. In 3 cases the fibrosis involved the entire grafted area. In these patients the fibrotic urethra was laid open leaving a urethrostomy proximal to the stricture: currently they are awaiting staged solutions.
At present, BM is considered the gold standard substitute material in the treatment of bulbar strictures. Previously, penile skin (PS) was the preferred tissue used for urethroplasty. Other types of autologous and eterologous material were tested but with uncertain results. Graft urethroplasty steadily deteriorates with time, so the question that the reconstructive surgeons are asking is: which is truly the best urethral replacement tissue at long-term follow-up? A recent review of the outcomes of bulbar graft urethroplasties using different types of grafts and differently placed, sinthetized that BM has a overall 90% success rate at a medium follow-up of 3 years and with different techniques. SIS would seem to have a similar success rate but the follow-up was shorter and the patients were fewer (table 2) [ 1 ]. If we shift the focus on long-term results, we observe that, at a longer follow-up (60,8 months), the success rate of PS goes down to 79.9%. In his series with long-term results, Barbagli showed that success rate of PS grafts decreases to 73% with mean follow-up of 71 mo [ 13 ] and to 65,8% with a follow-up of 111 mo [ 14 ].
With regard to the long-term results using the BM, Kulkarni showed excellent success rate (91%) at a long follow-up (56 mo) [ 15 ]. In contrast, other studies show that the success rate decreases to 83% (follow-up 58 mo) [ 16 ] and even Barbagli reported a lower success rate of 77% (follow-up 41 mo). Only 1 article reported a follow-up > 70 months (95% success rate) [ 17 ]. So, even if today BM is considered the gold-standard, we have to wait for more studies showing its real result at follow-up > 70 mo. Similarly to the above reported, in our study with follow-up (mean 71 mo) longer than the previous (mean 21 mo) [ 6 ], we observed a reduction in the success rate of the SIS from 100% to 76%.
At present, this study represents the largest series of bulbar SIS graft urethroplasty with the longest follow-up [Table 1 ]. The literature on SIS urethral repair is scarce. In particular, only a few articles focused on bulbar urethral repair but with small series of patients and short-term follow-up (Table 1) [ 4 – 8, 18 ]. We selected a homogeneus series of patients with only bulbar strictures, but we are conscious that the limitation of our study is the fact that the series is heterogeneous with respect to the different techniques used.
SIS appears to have the properties of a valid heterologous substitutive tissue: it is thin but strong, easy to handle and immediately ready for grafting. Prefabricated in different sizes, there is no limit to the length of graft that can be used. It is an acellular, nonimmunogenic, biocompatible, collagen matrix manufactured from porcine intestinal submucosa. Animal tests showed SIS to induce native tissue regeneration in various organs. Regarding its application in the urethra of animals, SIS was demonstrated to promote successful urethral regeneration [ 3, 19 ]. Conversely, in men with urethral strictures, SIS has been used in graft urethroplasties with contrasting results [ 4, 7, 18 ].
As all collagen matrices, SIS provides a scaffold for the regeneration of host tissues. It has tissue specific regeneration properties associated with low risk of infection and no risk of rejection because it is acellular [ 20 ]. It has never been shown to cause host immunogenic responses in cross-species transplantation. Matrix graft relies on angiogenesis of host tissue and the grafted area is vascularized and epithelialized. When SIS is grafted in healthy tissues, healing seems to occur by tissue regeneration and not by scar tissue formation. Otherwise, the regenerative process could be adversely affected by scarring associated with strictures, explaining the poor results of SIS in urethras considerably compromised by spongiofibrosis [ 4 ]. As a matter of fact, similarly to other authors [ 18 ], in our previous experience with SIS [ 6 ] we had failure in repairing long penile or penile-bulbar strictures characterized by extensive spongiofibrosis. By contrast, SIS appeared to work well in short/medium bulbar strictures. In the present study we had 100% failure rate in bulbar strictures longer than 4 cm, confirming the opinion that SIS patch grafts are successful only in short-medium bulbar strictures with mild spongiofibrosis when a strip of healthy urethra can be preserved and the remaining healthy spongiosum promotes urethral regeneration over the collagen scaffold. Conversely, SIS does not seem appropriate in penile or penile-bulbar strictures with extensive spongiofibrosis (e.g. Lichen Sclerosus and failed hypospadias strictures), and bulbar or posterior traumatic strictures with wide scarring [ 4 ].
Finally, it is necessary to emphasize that, to make a valid comparative evaluation between different materials, we need wide homogeneus series of patients who underwent the same surgical technique with long follow-ups.
Our long-term follow-up seems to show that SIS has similar results to PS graft but less effective than BM graft in repair of bulbar strictures. Furthermore, SIS seems unsuitable in long strictures, thus representing not the first choice but only an alternative option in patients with short/medium (< 4 cm) bulbar strictures who refuse harvesting or are not ideal candidates for BM or PS graft.
We found that at long-term follow-up, SIS grafts seem to show similar results to PS grafts but were less effective than BM grafts in the repair of bulbar strictures.
The use of SIS graft may represent no the first choice but only an alternative option in patients with short-medium bulbar strictures who refuse harvesting or are not ideal candidates for BM or PS grafts. It is mandatory to perform further long-term follow-ups with larger series of patients to better evaluate these results and our conclusions.
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