Modern management of anal fistula

Abstract

Ideal surgical treatment for anal fistula should aim to eradicate sepsis and promote healing of the tract, whilst preserving the sphincters and the mechanism of continence. For the simple and most distal fistulae, conventional surgical options such as laying open of the fistula tract seem to be relatively safe and therefore, well accepted in clinical practise. However, for the more complex fistulae where a significant proportion of the anal sphincter is involved, great concern remains about damaging the sphincter and subsequent poor functional outcome, which is quite inevitable following conventional surgical treatment. For this reason, over the last two decades, many sphincter-preserving procedures for the treatment of anal fistula have been introduced with the common goal of minimising the injury to the anal sphincters and preserving optimal function. Among them, the ligation of intersphincteric fistula tract procedure appears to be safe and effective and may be routinely considered for complex anal fistula. Another technique, the anal fistula plug, derived from porcine small intestinal submucosa, is safe but modestly effective in long-term follow-up, with success rates varying from 24%-88%. The failure rate may be due to its extrusion from the fistula tract. To obviate that, a new designed plug (GORE BioA^®) was introduced, but long term data regarding its efficacy are scant. Fibrin glue showed poor and variable healing rate (14%-74%). FiLaC and video-assisted anal fistula treatment procedures, respectively using laser and electrode energy, are expensive and yet to be thoroughly assessed in clinical practise. Recently, a therapy using autologous adipose-derived stem cells has been described. Their properties of regenerating tissues and suppressing inflammatory response must be better investigated on anal fistulae, and studies remain in progress. The aim of this present article is to review the pertinent literature, describing the advantages and limitations of new sphincter-preserving techniques.

Key Words: Anal fistula management, Ligation of intersphincteric fistula tract, Plug, Fibrin glue, Fistula laser closure, Video-assisted anal fistula treatment, Adipose-derived stem cells

Core tip: We present a review with a critical appraisal on the modern procedures for anal fistula which aims to the common goal of minimising the injury to the anal sphincters whilst preserving optimal function. We found the following ones as the most representative: Ligation of intersphincteric fistula tract, anal fistula plug derived from porcine small intestinal submucosa and the new designed GORE BioA^® plug, fibrin glue, fistula laser closure, video-assisted anal fistula treatment and adipose-derived stem cells. We examined the advantages and drawbacks for each procedure through the outcomes reported in literature.

INTRODUCTION

The ideal surgical treatment for anal fistula should eradicate sepsis and promote healing of the tract, whilst preserving the sphincters and the mechanism of continence. For the simple and most distal fistulae, conventional surgical treatment such as lay-open of the fistula tract as a complete transection of the tissue between the fistula tract and anoderm is very effective with a success rate of up to 100%[1]. Although reported incontinence rates following fistula surgery is very variable and is influenced by many factors, incontinence rate after laying open of intersphincteric and distal fistulae seems to be under 10%[2].

However, the risk of potential damage to the anal sphincters and subsequent poor functional outcome remains in a large proportion of patients with high fistulae when the tract crosses more than 30%-50% of the external sphincter, and with recurrent or complex fistulae with multiple extensions or separate tracts. Women with anterior fistula or previous obstetric injury as well as patients with pre-existing incontinence or specific risks such as previous local irradiation or co-existing Crohn’s disease[3,4] are also at significant risk of incontinence and poor outcome. In these circumstances, an endorectal advancement flap (ERAF) which avoids the division of the sphincter complex is considered a safer alternative. However, the reported success rate is widely variable, ranging from 24% to 100%. Further, functional outcome assessments, in terms of post-operative incontinence rates, have been described as high as 35%[5-10] .

The oldest surgical approach, first detailed by Hippocrates, is the use of a seton, which enables preservation of the sphincter mechanism[11]. The seton placement has been advocated either loose, to control infection, or cutting through the sphincter muscle gradually or as a bridge between two separate partial fistulotomies[12,13]. The short-term healing rate of loose seton ranges between 44% and 83%[14-18]. Cutting setons have been used in the attempt to slowly divide the sphincters while allowing scarring to occur and limit disruption of the muscular ring, with recurrence rates from 22% to 39%[19,20]. Regarding the comparison between seton and other fistulectomy, Quah et al[21] in a large multicenter Indian study (n = 503), showed longer healing with chemical setons but lower recurrence rate (4% vs 11%). Recently, a modified seton technique has been applied to treatment of trans-sphincteric and supra-sphincteric anal fistulas[22]. Recurrence rate was 0 in trans-sphincteric fistula and 4.9% in supra-sphincteric fistula. The technique provided favourable results in the treatment of complex anal fistula while preserving the sphincter function and conservation of faecal continence (0 incontinence rate).

Recently, a number of new sphincter-preserving techniques have been developed and proposed, all with the common goal of minimising the injury to the anal sphincters and optimise the functional outcome. However, the number of different procedures suggested, associated with a lack of follow-up data and the often variable and conflicting clinical outcomes has generated confusion and scepticism, resulting in a limited translation of these procedure into clinical practise.

The aim of this article is to provide an overview of the new sphincter-preserving techniques proposed for the treatment of fistula-in-ano, in particular assessing the efficacy and safety of these new procedures.

LITERATURE SEARCH

A search of the English-language literature was performed using PubMed, Cochrane, EMBASE and Ovid database to identify manuscripts reporting on the management of peri-anal fistula. The key-words used for this search included anal fistula treatments, fibrin glue, anal fistula plug, Ligation of the intersphincteric fistula tract (LIFT), expanded adipose-derived stem-cells (ASCs), video-assisted anal fistula treatment (VAAFT) and Radial-emitting laser probe (FiLaC^TM). Following articles of the available literature, 69 were selected as the most informative and recent publications. A further, more thorough review of these manuscripts was undertaken.

Available options of treatment

LIFT: Since it was first described by Rojanasakul et al[23] in 2006, LIFT gained popularity due to its high success rate and preservation of continence. This technique involves disconnection of the internal opening from the fistula tract at the level of the intersphincteric plane and removal of the residual infected glands, without dividing any part of the anal sphincter complex. Following the identification of the internal opening by injecting hydrogen peroxide from the external opening or gently probing the fistula tract, a 3-4 cm curvilinear incision along the anal margin is performed at the site of the fistula and the intersphincteric plane is entered. The fistula tract is exposed and ligated with two absorbable sutures. The tract is then divided distal to the point of ligation, with removal of the remnant of the fistula tract and any infected gland. Currette of the fistula tract and drainage of the external opening by an additional incision or an insertion of a catheter can also be performed. Re-approximation of the intersphincteric incision wound is achieved with interrupted absorbable sutures.

A recent metanalysis[24] over 24 original articles, showed at a pooled mean 10-mo of follow-up, 76.5% mean success rate, 0 incontinence and and 5.5% post-operative complication rate. In Table 1, there are listed 14 articles[24,25] reporting on their experiences with LIFT procedure.

Table 1 Published articles on ligation of the intersphincteric fistula tract.

Ref.	No. Patients	Follow-up (wk)	Healing rate	Complications	Type of study
Rojanasakul et al[23]	18	4	94%	NR	Prospective observational
Shanwani et al[26]	45	7	82%	NR	Prospective observational
Ellis et al[27]	31	6	94%	NR	Retrospective
Bleier et al[28]	39	10	57%	1 Anal fissure;	Retrospective
				1 Persistent pain
Ooi et al[29]	25	6	96%	NR	Prospective observational
Tan et al[30]	93	4	92%	NR	Retrospective review
Steiner et al[31]	18	6	83%	1 hemorrhoidal thrombosis	Retrospective
Aboulian et al[32]	25	24	68%	2 Vaginal fungal infection	Retrospective review
Mushaya et al[33]	25	4	68%	1 Secondary bleeding;	Prospective randomized
				2 Superficial perineal wound dehiscence
Abcarian et al[34]	50	15	74%	NR	Retrospective
Lo et al[35]	25	2	98%	NR	Retrospective
van Onkelen et al[36]	42	12	51%	NR	Prospective
Chen et al[37]	10	6	100%	NR	Retrospective
Lehmann et al[38]	17	4	47%	1 perianal haematoma;	Prospective
				1 wound infection
Liu et al[39]	38	26	61%	NR	Retrospective

Of all the studies, only the Mushaya et al[33] one has a prospective randomized design, in which a group of 25 patients underwent LIFT and 14 advancement flap. Although, at 19 mo of follow-up, the recurrence rate was 7% (n = 1) in the ERAF group and 8% (n =2) in the LIFT group, the only patient with post-operative minor incontinence belonged to the advancement flap group. Furthermore, the operating time was shorter for LIFT procedures, as patients’ return time to normal activities. As it emerges from the literature, 92.6% of all the patients treated, had a transphincteric fistula. The overall success rate ranges from 51% to 100% over a mean period of 2-24 wk. They report no postoperative impairment of continence or worsening of it, although it is not evaluated with a unique and different scoring system. Only 8 patients had minor postoperative complications (Table 1). Two studies[31,34] report a positive association between recurrence and the number of previous operations. This may be due to the presence of scar tissue that makes the identification of the intersphincteric tract more challenging. Indeed, in this procedure, an accurate dissection along the intersphicteric plane while maintaining the integrity of the internal sphincter is of vital importance for successful outcome. It is to be stressed the importance of an adequate drainage and elimination of any septic tissue via insertion of an indwelling seton for 6-12 wk prior to LIFT procedure. This allows a better outcome.

According to the literature, LIFT procedure has the advantages of preservation of the anal sphincters, minimal tissue injury, short healing time with no additional costs. In case of failure, the procedure can be readily repeated. However, to date, there is only one prospective-randomized trial and most of the evidence relies on small case-series with variable follow up and no objective assessment of incontinence.

In 2005, Ellis[27] introduced a variation of the LIFT technique in which a bioprosthetic graft was placed in the intersphincteric plane to reinforce the closure of the fistula tract (Bio-LIFT procedure). The bioprosthetic graft (Surgis Biodesign, Cook Surgical Inc, Bloomington, Indiana) was trimmed to the appropriate width and placed into the intersphincteric grove with at least 1 to 2 cm of overlap on all the sides of the transected fistula tract. The bioprosthesis was secured with 3/0 polyglicolic acid sutures to the levator ani muscle and the external sphincter to prevent migration. The fistula tract through the external sphincter was left open to facilitate drainage from the wound. Ellis treated 31 patients, all with transphincteric fistula. The overall healing rate was 94% after a minimum follow-up of 12 mo with no postoperative complications.

The only other description of the Bio-LIFT technique was for the management of rectovaginal fistulae[40] made by the same author. The bioprosthetic graft was deemed by the author to act as a physical barrier to separate the transected ends of the fistula.

However, we believe that a wider dissection into the intershincteric plane, the additional cost of the material and the higher learning-curve of this procedure, to date, is difficult to justify without any further supportive evidence.

Anal fistula plug

The anal fistula plug is a composed of lyophilized porcine-derived small intestinal submucosa [Surgis^® anal fistula plug (AFP), Cook Biotech Incorporated, West Lafayette, Indiana, United States]. It is a strong pliable tissue denuded of cells, that provides a scaffold for host fibroblasts to promote tissue healing and repair damaged tissue. This material was initially intended for bridging large tissue defects in the abdominal and chest walls. Interestingly, a group of surgeons[41] rolled it into a cone and inserted it into anal fistula in the attempt to achieve closure. Surgisis is a biocompatible material and has been documented to have an inherent resistance to infections in contaminated abdominal wounds in 2 series[42,43].

The technique of plug deployment is as follows: the tract is gently debrided with a curette and irrigated with hydrogen peroxide. The tapered end of the fistula plug is then tied to a probe and dragged through from the internal opening to the external. It is then pulled out to fit to the tract and anchored to the mucosa/submucosa and the internal sphincter at the primary opening with a “figure of 8” stitch to be eventually incorporated with the mucosa of anorectum and closure of the internal opening.

Johnson et al[41] prospectively compared 2 cohort group of patients undergoing plug procedure or fibrin glue closure. They reported an 87% of healing rate on the plug group, against 40% on the fibrin glue group. These initial results attracted significant interest in this technique, but such success rates have not been reproduced since (Table 2). Early implant extrusion has been reported as one of the most consistent reasons for failure[59]. It is also of crucial importance for such a procedure using biomaterials, that adequate removal of any chronic granulation or septic tissue lining the fistula tract is carried out, to initiate the healing process and allow migration of fibroblasts and endothelial cells. Another prospective randomized comparative trial was directed by Ortiz et al[55]. In this trial, 15 patients underwent plug insertion while 16 underwent an endorectal advancement flap (EAF) procedure. After 12 mo of follow-up, a large number of recurrences in the plug group (12 of 15 against 2 of 16 in EAF group) led to the premature closure of the trial. The literature reports a success rate ranging from 24% to 88% with a mean follow-up of 8 mo. A possible explanation for this discrepancy could be differences in patient selection and variation of the technique with respect to placement of the plug, bowel preparation, suture material, or coverage of the primary opening. For this reason, in an attempt to standardize the indications for use of bioprosthetic AFP and techniques for its placement, a consensus conference was held in 2007. According to that, the use of AFP should be recommended in transphincteric anal fistulae without any acute inflammation or infection. It was also suggested that a frequent issue affecting the AFP procedure, is a failure in technique of the plug placement[60].

Table 2 Published studies on anal fistula plug.

Ref.	Type of study	No. Patients	Success rate	Follow-up (mo)
Johnson et al[41]	Prospective	15	87%	7
	Non-randomized
	Controlled trial
Champagne et al[44]	Prospective	46	83%	12
O’Connor et al[45]	Prospective	20 (Crohn’s)	80%	10
Van Koperen et al[46]	Prospective	17	42%	7
Ellis[47]	Retrospective	18 (5 rectovaginal)	88%	6
Lawes et al[48]	Retrospective	17 plug	66%	7.4
		3 pug+flap
Ky et al[49]	Prospective	44 plug+flap	54.6%	6.5
Schwandner et al[50]	Prospective	19 (7 Crohn’s)	61% overall	9
			45.5% cryptoglandular
			85.7% Crohn’s
Garg[51]	Prospective	21	71%	10
Christoforidis et al[52]	Retrospective	47	43%	6.5
Thekkinkattil et al[53]	Prospective	43	44%	11
Safar et al[54]	Retrospective	35	14%	4
Ortiz et al[55]	Prospective Randomized trial	31 cryptoglandular: -15 plug -16 endorectal-advancement flap (EAF)	20% (plug group) 87.5% (EAF)	12
El-Gazzaz et al[56]	Retrospective	33	25%	7.4
Chan et al[57]	Prospective	44	50%	10.5
Cintron et al[58]	Prospective	73	42.5%	15

Because of the fixation problem with the use of AFP, a new absorbable plug that could be better fixated, thanks to its design, has been introduced. The GORE BioA^® fistula plug (W.L. GORE and Associated Flagstaff, Arizona, United States) is composed of a bio-absorbable monofilamentos compound with polyglycolic acid: trimethylene carbonate. Histological assessment confirms that the material is completely absorbed by 7 mo with no chronic inflammatory response evidence[61]. It is a 6 arms plug, of a length of 9 cm attached to a circular disc. The disc is meant to be sutured at the internal opening and, if necessary, some of the arms can be cut to fit to the fistula tract. After its disc is fixed to the internal opening by 2-3 absorbable stitches, a mucosa/submucosa flap, proximal to the internal opening, is raised to cover the suture.

To date, there are only 4 published studies assessing the GORE plug (Table 3). One of them retrospectively compared a series of patients treated with the Surgis AFP with those treated with GORE BioA^® plug[61]. It reports that the patients treated with BioA^® plug have higher initial clinical success rate and this seems to be due to less frequent implant extrusion rather than any biological advantage. The overall success rate, according to these studies, ranges from 16% to 73%, decreasing with the length of follow-up, which ranges from 2 to 12 mo. The highest number of patients among these studies, belongs to Ommer et al[64], where a group of 40 patients underwent GORE plug insertion, with a success rate of 57.5%. They reported higher healing rates in patients with transphicteric rather than suprasphincteric fistulae. No negative impact on anal continence was observed. The other studies are small case-series and all of them reporting heterogeneity of fistula aetiology and variability in terms of management of the primary tract and postoperative protocols. The cost, at €500, for the GORE plug is relatively high. Bigger cases series and comparative studies with other procedure are desirable, to further elucidate the cost-effectiveness of this technique.

Table 3 Published studies on GORE BioA fistula plug.

Ref.	Study design	No. patients	Aetiology and classification	Healing-rate	Follow-up (mo)	Complications
Buchberg et al[61]	Retrospective	10	6 cryptoglandular	54%	2	NR
	Case-series		3 iatrogenic
			1 HIV
de la Portilla et al[62]	Prospective	19	10 high- transphincteric	16%	12	1 Acute sepsis
	Case-series		9 low transphicteric			1 Urge incontinence
						1 Plug extrusion
Ratto et al[63]	Prospective	11	11 High-	73%	5	NR
	Case-series		transphincteric
Ommer et al[64]	Retrospective	40	28 High-transphincteric	57.5%	12	1 Plug extrusion
	Case-series		12 Suprasphincteric			1 abscess
			4 Crohn’s			1 Dehiscence

Fibrin glue

Initial studies on fibrin glue injection for the management of complex anal fistulae were promising. The first of these was published in 1991 by Hjortrup et al[65] and was the result of a pioneering series of treatments for perianal fistulae with fibrin glue. The mode of action is thought to be by stimulating the growth of fibroblasts and pluripotent endothelial cells into the fistula tract to seal it off. These cells then lay collagen and an extracellular matrix during the process of wound healing. Early results were encouraging, but further data showed a very wide range of success from as low as 14%[66] to as high as 74%[67]. As many subsequent studies confirmed, long-term follow-up evaluation is very important when using fibrin glue because later follow-ups revealed the healing rates decrease markedly[68-70]. In their review, Swinscoe et al[68] noticed that, when fibrin glue was applied to complex fistulae in particular, it achieves a lower success rate (mean 70%) than simple fistulae (mean 32%). Furthermore, shorter fistulae (< 4 cm) tend to recur more frequently than longer ones (> 4 cm), with rates of 54% as compared with 11% respectively. A possible explanation is that shorter fistulae do not hold the glue as well as longer-tract fistulae do[71]. Despite the absence of impairment of normal continence as a complication of this procedure, formation of abscesses and new secondary tracts have been reported with a incidence of up to 3%[69,72]. As Lindsey et al[72] showed in a randomized comparative trial, patients treated with fibrin glue didn’t suffer any form of incontinence whilst the group treated with conventional surgical techniques did, but at post-operative MRI scan review, showed non-eradicated septic collections that potentially leads to secondary tracts.

Poor outcomes with fibrin glue may be explained with the failure of the formed glue clot to seal the tract properly, due to its liquid consistency[48]. Also, as Buchanan et al[66] reported, there may be formation of abscesses that lead to longer-term recurrences. Particularly, this event occurs when synthetic glue (cyanoacrylate glue, Glubran^® 2, GEM S.R.L., Viareggio, Italy) is used. This glue occludes the fistula and degenerates into multiple abscesses around the glue remnants. It still has a role in reinforcing suture closure of the internal opening in other procedures such as VAAFT.

Fistula laser closure

The use of laser in the treatment of anal fistula was initially described in 2011 in a pilot study by Wilhelm[73]. This novel sphincter-saving technique uses an emitting laser probe [Fistula laser closure (FiLaC™), Biolitec, Germany], which destroys the fistula epithelium and simultaneously obliterates the remaining fistula tract. Since the main reason for surgical failure is a persistent fistula tract or remnants of fistula epithelium which were not excised, it was postulated that the benefit of this newly designed radial-emitting laser probe was to eliminate fistula epithelium or any granulation tissue in a circular manner and then, to obliterate the fistula tract by a shrinkage effect. Simple diathermy cannot elicit the shrinkage effect on tissues and it’s more difficult to regulate its potential thermal damage on the sphincter muscles.

The procedure also includes the closure of the internal opening by means of an anorectal flap. When some scar tissue prevents that, either mucosa or anodermal flap is used for closure of the internal opening. In this pilot study, 11 patients with cryptoglandular fistulae, underwent FiLaC™ procedure with an overall success of 81% at 7, 4 mo of follow-up.

A modified laser procedure was adopted by Giamundo el al[74]. It consists of sealing the fistula tract by laser with no need for endorectal flap. The closure of the internal opening is allowed by a laser shrinkage effect.

The procedure in carried out similarly in both techniques, except from the performance of an advancement flap prior to the laser application. It is as follows: Identification and localization of the internal opening by the injection of hydrogen peroxide or methylene blue from the external opening. Debriding of the fistula tract with a curette. Insertion of a plastic hollow 14F catheter using a guide-wire. Insertion of 400 micron radial-emitting disposable laser fibre into the catheter with its tip emerging at the internal orifice. The fibre delivers laser energy homogenously at 360° and by applying continuous energy, the tract is closed while withdrawing it at a speed of 1 mm/s. Depending on the width of the tract, a 980 nm or 1470 nm diode laser, delivering different wavelengths, could be deployed. The first delivers 13 watts power, whereas the second 10 W.

Giamundo et al[74] performed FiLaC™ procedure on 35 patients with cryptoglandular and Crohn’s disease-related fistulae. The overall success rate was 71% at 20 mo of follow-up. They didn’t report any impairment of continence, but postoperative pain and anismus in 8 patients treated with the 980 nm diode laser. This may be due to the application of higher energy volumes. For this reason, the authors consider that the use of a 1479 nm diode laser for FiLaC™ is preferable to the 980 nm. They also suggest the use of a draining seton prior to the procedure, to help to create a more homogenous calibre of the tract and contribute to the closure on secondary tracts. Oztürk et al[75] reported a success rate of 82% at 12 mo of follow-up, on 50 patients treated for inter-sphincteric and ranssphinteric fistulas.

From these studies, it emerges that this procedure has some advantages. It doesn’t affect continence, administers controlled hyperthermic effect to the tissues, has a short learning-curve and reduces postoperative hospital stay as compared to endorectal advancement flap or LIFT. However, it has also some drawbacks. It is a ‘‘blind’’ procedure, as it’s not possible a direct visualization of the fistula tract or any secondary tracts and this may lead to recurrence. It requires expensive equipment, particularly if compared to other sphincter-saving techniques. Randomized trials comparing FiLaC™ with the most common sphincter-preserving procedure are therefore required.

Video-assisted anal fistula treatment

Video-assisted anal fistula treatment is performed with a kit which includes a fistuloscope manufactured by karl Storz GmbH ( Tuttlingen, Germany), an obturator, an unipolar electrode, an endobrush and 0.5 mL of synthetic cyanoacrylate glue (Glubran^® 2, GEM S.R.L., Viareggio, Italy). The fistuloscope has an 80 angled eyepiece and is equipped with an optical channel and also a working and irrigating channel. Its diameter is 3.3 mm × 4.7 mm and its operative length is 18 cm. The fistuloscope has 2 taps, one of which is connected to a 5000 mL bag of glycine-mannitol 1% solution, depending on the position of the fistula. This technique was developed by Meinero and Mori[76] in 2006 and his study is the only available to date. VAAFT consists of a diagnostic phase, followed by an operative phase. In the diagnostic phase, the fistuloscope is inserted through the external opening and advanced by the irrigation of the glycine-mannitol which expands the fistula tract. The fistuloscope, usually, exits through the internal opening. Once the internal opening is located, 2/3 stitches are placed to isolate without closing it. During the next operative phase, the aim is to destroy the fistula tract from the inside, curette it and close the internal opening. For this purpose, the electrode replaces the obturator from the external opening, under direct vision. The fistula wall is cauterized and all wasted material is eliminated into the rectum through the internal opening. Ultimately, the internal opening is sutured by a semicircular or linear stapler (roticulator). When the tissue around the internal opening is too thick to be stapled, a cutaneous or mucosal flap is fashioned. In order to reinforce the suture or staple line, 0.5 mL of synthetic cyanoacrylate glue can be applied.

In their study, 136 patients with non-Crohn’disease- related anal fistulae, within 2-3 mo of follow-up, achieved an overall success rate of 73.5%. No postoperative incontinence or its worsening was reported. We believe that the rational of this technique regarding the precise identification of the fistula tract is robust, and there are minimal postoperative wounds. However, it shouldn’t be denied that in some cases, an excessive dilatation of the fistula to insert the fistuloscope, the risk of missing other secondary tracts or the internal opening itself and also, the risk of thermal damage by the electrode (which is higher than that of the laser) cannot justify the high cost of the kit, plus the stapler, a healing rate comparable to other procedure and, least of all, a long operative time. Therefore, improvements of the technique and further studies are required.

Adipose-derived stem cells

The potential role of mesenchymal adult stem cells in differentiating into various types of cells may have a role in the treatment of anal fistula. In a pilot trial, Garcia-Olmo et al[77,78] chose adipose ASCs. Application of autologus ASCs (Cx401) represents a novel approach for enhancing regeneration of damaged tissues in an environment particularly unfavourable for wound healing. ASCs can be obtained from subcutaneous fat[79,80] by liposuction and this process yields 100 times more stem cells than bone marrow-aspirates[81]. Following curettage of the fistula tract and suture closure of the internal opening, ASCs solution was injected into the tract and into the walls of the fistula. The tract was subsequently sealed with fibrin glue.

It was deemed that ASCs biological properties of suppressing inflammation and promoting differentiation can accelerate wound healing. Two previous trials were conducted by the same authors: a concept phase I clinical trial in Crohn’s disease[77] fistulae and a phase II clinical trial[78,82] in fistulae of cryptoglandular origin and associated with Crohn’s disease. In those trial, they found that the ASCs use is safe and effective. With the phase III trial[83], they aimed to further investigate the effectiveness and safety of ASCs in the treatment of cryptoglandular complex anal fistulae. In this latter multicentre, randomized, single-blinded clinical trial, 200 adult patients from 19 centres were randomly assigned to receive either 20 million adipose-derived stem cells (group A, 64 patients), another 20 million stem cells plus a glue containing human fibrinogen and thrombin and bovine aprotin (group B, 60 patients) or fibrin glue (group C, 59 patients), all after closure of the internal opening. After 1 year of follow-up, they achieved a healing rate of 57%, 52% and 37% in group A, B and C respectively. No statistically significant differences were found when the 3 groups were compared. The use of ASCs was proved to be safe without any incontinence risk or procedure-related adverse events; however, its healing rate was not superior to fibrin glue alone and lower than other sphincter-preserving procedures.

To date, it is difficult to make a firm judgment of this technique because available data is limited. Many questions still remain unanswered, including whether the stem-cell suspension can be placed over the fistula tract and how much financially viable this technique is.

CONCLUSION

Currently, we confirm that the variety of procedures that can be used to treat fistulae, which testifies to the variable complexity of anal fistula and its unpredictable and non-reproducible results.

To improve the healing rates, patient selection is imperative, and control of sepsis, identification of secondary extensions and tracts of the fistula from the anal canal before any attempt of repair, is strongly suggested. The advancement flap still remains the gold standard, but LIFT may potentially play a fundamental role in the future. Furthermore, the use of biological material could be an alternative. Unfortunately, to date, it’s technically difficult from the available literature, to determine any comparison between strategies, as patient demographics and disease vary considerably. Results are often not reported relatively to the specific aetiology or classification, and there is not any universally accepted method of evaluation of fistula healing during the follow-up period.

For all these reasons, the optimal procedure is the one tailored to the individual fistula.