Evidence outside the box: Minimally invasive treatment for anal fistula

Abstract

Management of the complex anal fistula represents a perennial challenge to surgeons. Conventional approaches often upset the balance between recurrence prevention and continence preservation with their high failure rates and significant associated morbidity. The emergence of minimally invasive treatment in recent years, however, offers a promising paradigm shift. Regenerative solutions like autologous stem cell therapy or fistula plugs with extracellular and synthetic matrices represent new frontiers in anal fistula treatment, harnessing physiological regenerative capacities and avoiding the traditional postoperative burden of open wounds, drains, or setons in situ. Together with novel techniques like fistula laser closure, video-assisted fistula treatment, or over-the-scope clip burgeoning over the last decade, these state-of-the-art approaches have been touted for their total sphincter-sparing nature, preserving functional outcomes and quality of life. Despite gaining much scientific and clinical momentum, do these newer modalities live up to their promise? This review aims to critically appraise the latest evidence surrounding minimally invasive approaches, providing up-to-date insights into the constantly evolving landscape of anal fistula management. Further long-term and comparative studies will nevertheless be needed to supplement the significantly heterogenous, retrospective analyses consolidated.

Key Words: Anal fistula management; Minimally invasive; Regenerative methods; Stem cells; Fistula plug; Matrix; Ligation of intersphincteric fistula tract; Fistula laser closure; Video-assisted anal fistula treatment; Over-the-scope clip

Core Tip: We present a review summarising the most up-to-date insights into minimally invasive treatment for anal fistulae. Representing new frontiers in fistula treatment, these “sphincter-preserving” modalities seek to balance both recurrence prevention and continence preservation. The newest regenerative solutions, including autologous stem cell therapy and fistula plugs derived from extracellular and synthetic matrices, will be covered, as well as pertinent non-regenerative solutions like fistula laser closure, video-assisted anal fistula treatment, and over-the-scope clips. We consolidated and examined pertinent literature while weighing the pros and cons of each procedure.

INTRODUCTION

Minimally invasive treatment for anal fistulae represents a paradigm shift in the bid to balance both recurrence prevention and continence preservation. Modern techniques demonstrate high clinical efficacy while preserving function. This is pertinent especially in managing complex fistulae, which typically involve over 30% of the sphincter complex, possess side branches, or contain more than one internal and/or external openings[1].

Fistula laser closure (FiLaC), video-assisted fistula treatment (VAAFT), and over-the-scope clip (OTSC) are novel surgical approaches that emerged in the last decade at a time when the older, more invasive ligation of inter-sphincteric fistula tract (LIFT) was being increasingly adopted in surgical armamentarium. Grounded in core principles of conventional management, these distinguish themselves by employing modern tools to reduce invasiveness and enable intra-fistula surgery. For instance, VAAFT involves usage of a fistuloscope to directly visualize the fistula in ano (FIA) interior, allowing for endoscopic visualization and closure of the internal fistula opening, in addition to destruction of the pathway. FiLaC and OTSC reinterpret excisional elimination of the tract through usage of radial laser energy for ablation and mechanical sealing of the internal opening, respectively.

Regenerative methods are the newest breakthrough in minimally invasive methods, going beyond the surgical principles of traditional fistula management and targeting various pathogeneses of the fistula itself. Mesenchymal stem cells (MSCs), originating from bone marrow or adipose tissue, possess the ability to regenerate themselves and differentiate into multiple lineages. Fistula plugs with acellular extracellular matrices (AEMs) are regenerative biomaterials that include the myriad matrix (often derived from porcine small intestinal submucosa) and ovine forestomach matrix (OFM). Conversely, the GORE BioA^® plug is a recently developed synthetic bioabsorbable scaffold that mimics the function of AEMs. These regenerative solutions target the pathophysiology of fistula formation itself and crucially harness physiological regenerative capacities to enhance outcomes.

Yet, despite the burgeoning plethora of techniques all lauded for minimal invasiveness, clinical consensus regarding which modalities reliably provide the most efficacious and safe outcomes is still evolving. With many newer modalities like stem cell therapy now in later phases of clinical trials and soon entering broader clinical use, it is crucial to make sense of the latest evidence. This present article hence aims to consolidate and review pertinent literature, weigh the pros and cons, and succinctly summarise minimally invasive treatment for anal fistulae.

MINIMALLY INVASIVE TREATMENT FOR ANAL FISTULAE

Non-regenerative/surgical methods

FiLaC: The first instance of laser employment in the surgical management of anal fistulae was a carbon dioxide laser beam that reduced inadvertent damage to nearby tissues due to its precise focus[1]. This concept was emulated when Wilhelm[2] then described in 2011 a novel sphincter-sparing approach employing a radial beam emitting diode laser probe (FiLaC^TM, Biolitec, Germany). This allowed for circumferential obliteration of fistulous and granulation tissue and concomitant tract destruction through shrinkage effect. After tract closure, the internal opening is typically sealed using advancement flaps; however, a revised technique introduced by Giamundo et al[3] renders this redundant by capitalising on the laser’s shrinkage effect to completely destroy the opening.

The procedure generally has the following principles[4]: (1) Tract probed with localisation of internal opening; (2) Check for adequate drainage previously and no residual infection; (3) Catheter introduction into external then internal opening via guide-wire; (4) Introduction of fibre laser diode with radial emission wavelength of 1470 nm into catheter with end at internal opening; and (5) Ignition of laser with incremental recession (about 1 mm/s) causing obliteration of tract. Wavelength and power utilised can be varied depending on tract diameter.

The initial pilot study with 11 patients with cryptoglandular fistulae had an overall success of 81% at 7 months of follow-up[2]. More recently, several systematic reviews by Elfeki et al[5] and Frountzas et al[6] in 2020 showed comparable healing rates of 67.3% and 63% respectively. Complication rates of 4% and 8% respectively involved minor (grade I or II on Clavien–Dindo scale[5]) complications of pain, abscess, or bleeding, with 1% and 0.8% of patients experiencing minor soiling, respectively. Both these reviews involved predominantly transsphincteric (69.2% and 66%) and intersphincteric (20.9% and 22%) fistulae, originating mostly from cryptoglandular origin (92.2% in the latter). FiLaC’s efficacy in Crohn’s fistulae is also comparable, with preliminary studies demonstrating healing rates of 55% at 7.1 months[7], corroborating subsequent follow-up by Wilhelm et al[8] that showed 69.5% healing rates in the 13 patients with Crohn’s fistulae (vs 63.5% in those of cryptoglandular origin).

A retrospective comparative study in 2024 by Uzun et al[9] also showed superior success rates of 95.5% when combined with advancement flaps as opposed to 72% in FiLaC alone. In the study, sealing of the internal opening via a combination of FiLaC and advancement flap proved especially potent in complex fistulae, i.e., transsphincteric fistulae exceeding 30% sphincter involvement, suprasphincteric, extrasphincteric, or horseshoe fistulae[10].

In literature, FiLaC has only been compared to a limited number of alternative procedures, such as fistulotomy with primary sphincteroplasty (FIPS)[11] or LIFT[12] in the treatment of transsphincteric and complex fistulae, respectively. Recurrence rates of FiLaC were higher when compared to FIPS but similar to LIFT. Both studies, however, demonstrated superior functional outcomes in FiLaC, including mean operative time and postoperative hospital stay.

Mainly lauded for continence maintenance and modest detriment to sphincters, FiLaC’s main advantage lies in its remarkable approach toward both tract destruction and internal opening sealing featuring a measured hyperthermic effect on target tissues. Studies have shown its feasibility to be performed in even outpatient contexts[13]. Furthermore, FiLaC is technically more straightforward and enables shorter average inpatient treatment than endorectal advancement flap or LIFT[5]. Access to presumably inconvenient regions of the tract, frequently those in the complex course of supra-sphincteric fistulas, is made possible by the laser probe’s flexibility–this is a predominant edge over techniques like VAAFT.

Its most prominent shortcoming lies in the inability of direct tract visualisation. Although laser penetration can be tailored to varying degrees by modifying probe energy levels, any unvisualised branching tracts may hence be poorly reached by blind introduction. Arbitrarily enhancing probe energy to intensify tissue destruction could induce iatrogenic damage of the sphincter complex. On balance, FiLaC may hence prove most efficacious in the case of simple fistulae with less complex courses. Cost-effectiveness further hinders widespread usage, as the laser diode often necessitates pricey apparatus, especially in comparison to other minimally invasive techniques. In more complex fistulous anatomy, FiLaC may be best used as an adjunct, and indeed, a combination with VAAFT has recently been described[14]. Further randomized trials comparing FiLaC with conventional techniques are therefore required.

VAAFT: VAAFT is another sphincter-preserving procedure first described by Meinero and Mori[15] in 2011 that differentiates itself through full endoluminal tract visualisation. Usage of a fistuloscope enables precise localisation of the main tract, as well as the presence of any secondary branches and the internal opening itself. This is opposed to blind probing, which may predicate high recurrence rates.

Generally, VAAFT consists of two phases: Diagnostic and therapeutic[15]. The initial phase involves fistuloscopic tract visualisation and localisation of the internal opening, secondary tract, branches, and abscesses. The subsequent therapeutic phase features electrodesiccation of both main and any secondary tracts by means of a monopolar electrode introduced via the scope lumen. Thereafter, dead tissue is debrided and the internal opening is sealed.

The advantages of VAAFT first propounded were its feasibility in outpatient day surgery settings with few surgical wounds and, most importantly, full confidence in internal opening localisation[15]. In the initial analysis, 136 patients with non-Crohn’s disease-related anal fistulae achieved an overall success rate of 73.5%, with no postoperative incontinence or worsening reported. Early studies show a mean recurrence rate anywhere from 17.7%, as demonstrated by Emile et al[16], to as low as 5.26% at 6 months of follow-up[17]. Specifically in the context of fistulae of cryptoglandular origin, pooled success rates of up to 76% with a complication rate of 16.2% (mostly discharge, itch, and bleeding but no worsening of continence in all 786 patients) were reported in a large meta analyses[18]. VAAFT may also have a role in Crohn’s fistulae, with recent studies showing statistically significant improvements of 87% at 30 days for perianal disease activity, which includes scores of discharge, pain, and sexual activity scores[19]. A combination with advancement flap repair also demonstrated 82% success rates with no continence deterioration at 9 months[20]. Nevertheless, further larger centre studies are required for VAAFT in Crohn’s fistulae.

Table 1 summarises 4 recent comparative studies with large sample sizes and follow-up duration that show the utility of VAAFT as opposed to other traditional and novel techniques[21-24]. These are up-to-date, comprehensive evidence that give insights into the role of VAAFT today.

Table 1 Comparative studies with video-assisted fistula treatment.

Ref.	Studies	Sample size	Follow-up duration	Surgical outcomes	P value	Functional outcomes	P value
Zheng et al[21], 2018	VAAFT vs fistula resection plus seton	87 (high fistulae 73.8% vs 82.2%)	> 6 months	Recurrence: 7.1% vs 15.6%	0.317	Visual analogue scale for pain: 2.9 vs 7.3; Hospital stays: 4.1 days vs 7.5 days; Faecal incontinence: 2.4% vs 20.0%	0.000; 0.000; 0.015
Liu et al[22], 2020	VAAFT vs fistulotomy plus seton	148 (high fistulae 75% vs 70%; trans-sphincteric 57.4% vs 52.5%)	1 year	Healing: 84.4% vs 82.8%; Recurrence: 15.6% vs 17.2%	1.000; 1.000	Postoperative pain: 2.9 vs 4.4; Postoperative stay: 6.8 vs 5.0; Wexner incontinence score: 0.9 vs 1.9	< 0.001; < 0.001; 0.003
Sørensen et al[23], 2021	VAAFT vs fistulectomy and sphincter repair	47 (anterior fistulae 52% vs 64%, Crohn’s 0%)	6 months	Recurrence: 65% vs 27%	0.016	Faecal incontinence: (1) Wexner score: Improvement in both groups; and (2) Manometry: Decrease in both groups	0.011 vs 0.022; NS vs 0.018
La Torre et al[24], 2020	VAAFT vs LIFT	54; (all high trans-sphincteric fistulae)	1.5 years	Failure: 14.2% vs 19.2%; 9.1% vs 50% (abscess group); recurrence: 39.2% vs 42%; 11% vs 70% (abscess group)	NS; < 0.05; NS; < 0.05	Visual analogue scale for pain: 2.75 vs 2.65; Faecal incontinence: (1) CCFIS: 2.8 vs 3; (2) Visual analogue scale: 2.7 vs 2.6; and (3) Manometry: 28.7 vs 27.5 (resting); 95.6 vs 95.8 (squeeze)	NS; NS; NS; NS; NS

VAAFT: Video-assisted fistula treatment; NS: Not significant; CCFIS: Cleveland Clinc Fecal Incontinence Score.

When comparing VAAFT against LIFT, La Torre et al[24] found no significant difference in terms of both healing and recurrence rates. There was also no significant difference in postoperative incontinence regardless of scores used (Cleveland Clinic Fecal Incontinence Score, visual analogue scale, or manometry pressures). However, fistulae associated with perianal abscess with subsequent VAAFT had better outcomes as compared to LIFT. It was postulated that the posterior location of abscesses could complexify LIFT; VAAFT is preferred in such patients by localising the intersphincteric tract and enhancing technical success.

And albeit sparse, the most studied area of comparison is that between VAAFT and fistulectomy. Existing studies do not show significantly superior rates of healing or recurrence in VAAFT, with one Danish study by Sørensen et al[23] even showing inferior recurrence rates compared to fistulectomy and sphincter repair. Nevertheless, VAAFT shows far superior functional outcomes, including those of postoperative pain, incontinence, and hospital stay duration. Indeed, large systematic analyses have concluded that the technique reduced tissue damage, which improved functional outcomes like postoperative pain, recovery duration, and continence[25]. This seems to be the technique’s main advantage. While VAAFT tends to have poorer outcomes compared to fistula tract resection, outcomes appear comparable at one-year follow-up-the Danish study in this case demonstrated inferior results at 6 months and required early cessation due to significantly higher than predicted recurrence rates in VAAFT; however, it also reported no impairment of faecal continence following VAAFT and a non-significant decrease in pressure measurements by anal manometry[23]. VAAFT is not considered the gold standard for high transphincteric fistulas but is still a considerable option in specific cases for continence preservation. It can also be repeated effectively without severe detrimental effects or continence degradation, as demonstrated in other long-term series[26,27].

Indeed, VAAFT remains the only technique with intraoperative visualization of the entire fistulous anatomy, including the internal opening, secondary tracts, and abscesses. This remains its greatest strength in minimising recurrence rates. This may prove vital in instances of complex fistulae with concomitant secondary tracts or abscess formation. Notably, endoscopic fistula treatment has yet to be associated with any significant adverse complications. Lastly, the technique allows for subsequent re-attempts as aforementioned[27].

VAAFT has several intrinsic disadvantages, mostly owing to its inflexible design. This often hinders the fistuloscope from traversing more complex tract anatomy, seen particularly in suprasphincteric fistulae. Furthermore, fistulae of larger width or containing significant fibrosis may be unsatisfactorily sealed by intraluminal electrocauterization alone. Conversely, collateral tissue destruction and unintentional false tract development are then the pitfalls of injudicious cauterization[28]. More long-term data is needed to ascertain specific indications for VAAFT and how its application can be optimised for routine clinical usage.

OTSC: The OTSC system was originally manufactured as an endoscopic device utilised for gastrointestinal conditions, allowing for the sealing of perforations, non-variceal bleeding, and fistulae. In 2008, Ovesco Endoscopy AG introduced a Nitinol clip with administration by means of an applicator cap at the end of a flexible scope[4]. This served as a novel substitute for suturing in the precise surgical closure of perianal tissue. Utilizing a transanal route, its greatest advantage lies in reliable sealing of the internal opening, circumventing the need for tissue or muscle resection. Continuous, rigid circumferential constriction of the internal opening is enabled by the clip’s unique shape memory and deformable qualities, enhancing healing while avoiding vascular compromise. Although the clip does not obviate the need to manage the underlying tract, the OTSC is a promising adjunct for internal orifice closure.

2012 saw the OTSC^® concept first tailored to the proctologic context when Prosst and Ehni[29] used the OTSC^® proctology variant in successful fistula closure following seton drainage. A later prospective pilot study in 10 patients by the same authors showed a 10% recurrence rate and 72% in situ placement of the clip at 6 months post-seton drainage and clip placement[30]. There was also no fecal incontinence observed at follow-up.

Generally, OTSC involves the following principles as outlined by Ovesco Endoscopy AG[30] with accompanying figures: (1) Fistula localisation and examination under anaesthesia; (2) Circumferential excision (approximately 2 cm diameter) of tissue surrounding the internal opening and insertion of U-shaped sutures (Figure 1A); (3) Debridement of granulation tissue; (4) Accurate alignment of applicator cap to internal opening via U-shaped sutures (Figure 1B); (5) Suture knotting: Precise situating of OTSC proctology flexible endoscope; and (6) OTSC proctology clip application (Figure 1C).

Figure 1 Schematic application of the over the scope clip. A: Circumferential excision (approximately 2 cm diameter) of tissue surrounding internal opening and insertion of U-shaped sutures, positioned to allow for subsequent tensioning and guidance; B: Correct positioning of over the scope clip (OTSC) proctology applicator and subsequent advancement toward internal opening with sutures as guidance. Applicator cap should be accurately aligned to internal opening and overall orientation of applicator is parallel to axis of the anal canal; C: OTSC proctology clip application in situ.

Its use remains promising, particularly in complex or recurrent cases, especially if other conventional techniques were unfeasible or had failed. Subsequent retrospective studies have propounded its safety and efficacy in fistulae of both cryptoglandular and Crohn’s origin, with one involving 40% cryptoglandular and 60% Crohn’s fistulae demonstrating closure rates of 70% with no postoperative incontinence[31]. For Crohn’s fistulae in particular, OTSC has demonstrated 63% and 42% healing in suprasphincteric and high transsphincteric fistulae, respectively, in another study involving 29% Crohn’s associated fistulae[32]. Another systematic review in 2022 found a clinical success rate of 74.3% for repair of anastomotic leak of fistulae following colorectal surgery with a complication rate of just 1.8%[33].

In terms of clinical trials, prospective studies analysing the efficacy of the OTSC in comparison to traditional surgical techniques have been performed in recent years. A 2019 trial by Mascagni et al[34] comparing OTSC to fistulectomy with primary sphincter reconstruction demonstrated a 93.3% healing rate in fistulae repaired by OTSC and better functional outcomes, including postoperative pain, recovery and inpatient duration, and incontinence.

Notably, the FISCLOSE trial is an ongoing multicentre trial by Dubois et al[35] that aims to evaluate the efficacy and safety profile of the nitinol clip compared with the rectal mucosa advancement flap for complex anal fistulae. Another active trial (NCT06243302) is evaluating a combination of VAAFT with internal opening closure via OTSC.

The OTSC system exemplifies the paradigm shift toward minimally invasive techniques for anal fistula surgery with its intuitive design for internal opening closure. Premature clip displacement or relocation, together with the need for reapplication owing to clip ineffectiveness, are potential complications that warrant further analysis for future studies. Another main limitation is the lack of large-scale, randomized trials with long-term recurrence data that may inform clinical usage over other techniques. Nevertheless, initial results remain encouraging.

Regenerative methods

Fistula plug with AEMs: The concept of an anal fistula plug (AFP) for anal fistula treatment is not new. Largely similar in its concept to occluding fistula openings in a minimally invasive manner, AFP deployment generally has the following principles[36]: (1) Tract delineated using hydrogen peroxide test; (2) Tract probed; (3) Localisation of the internal opening; (4) Prolene 2-0 suture passed through tract; (5) Attachment of suture to the tail end of the plug (Figure 2A); (6) Plug is pulled into the tract via the suture, tail first (Figure 2B), until internal opening is fully occluded and plug is tightly fit within tract; (7) Secure suturing of plug to internal opening with a “figure of 8” stitch (Figure 2C); and (8) External opening is intentionally not sealed to allow for tract drainage.

Figure 2 Schematic deployment of anal fistula plug. A: Suture attached to the tail of the fistula plug; B: Plug is pulled into the tract via the suture, tail first, until internal opening is fully occluded and plug is tightly fit within tract; C: Secure suturing of plug inner tail with a “figure of 8” stitch which should seal the internal opening.

An AFP comprises robust, flexible, cell-free tissue. Its primary mode of action is tract occlusion and serving as a scaffold for cellular proliferation and tissue reorganisation, achieved particularly via fibroblasts that enhance healing and restore compromised tissue. The most prevalent cause of failure, however, is placement technique and premature dislodgement of the plug as early as within the first week[4]. This is a generic problem that pervades all types of plug material.

Much contention continues to surround which biomaterial type should form the plug, which should ideally withstand surrounding inflammation and possible infection. The material should also allow for a secure fit within the tract to circumvent the risk of dislodgement. In the market, there exist the following predominant materials, introduced in chronological order: Surgisis AFP, GORE BioA^® Fistula Plug, and the Myriad Matrix. The advent of each new material has mostly been to improve on the aforementioned plug properties.

Surgisis AFP: The earliest documented use of a bioabsorbable AFP was the Surgisis AFP, composed of lyophilized porcine-derived small intestinal submucosa (Surgis^® AFP, Cook Biotech Incorporated, West Lafayette, Indiana, United States)[4]. Following United States Food and Drug Administration clearance in 2005 as the first surgical device approved for anal fistula repair, subsequent studies reported success rates of up to 71.4% and no postoperative incontinence in patients with high cryptoglandular fistulae, of which 38% had multiple tracts[37]. A study involving AFP usage in Crohn’s fistulae, of which 35% had multiple tracts, showed 80% overall successful closure and no continence deterioration at 10 months median follow-up, although failed closure was significantly associated with multiple tracts[38]. Significantly greater success rates of 87% were also demonstrated when compared to existing techniques like fibrin glue in treating those with high transsphincteric fistulae[39].

However, the recent FIAT trial in 2021 comparing the efficacy of Surgisis AFP to the surgeon's own preference in treating cryptoglandular transsphincteric fistula-in-ano produced largely similar success rates at 12 months. Despite potentially higher costs in some cases, healing rates with the fistula plug were at best comparable to that of existing prevalent techniques[40]. Various long-term systematic reviews comparing healing rates of AFP against flap in complex cryptoglandular anal fistulae[41] or amongst different types of fistulae (Crohn’s vs cryptoglandular) at 110 months[42] also demonstrate no significant difference.

GORE BioA^® fistula plug: In an attempt to ameliorate frequent challenges of plug migration, the GORE BioA^® fistula plug was proposed by Ratto et al[43] in 2012. The GORE BioA^® fistula plug (W.L. GORE and Associated Flagstaff, Arizona, United States) comprises a monofilamentous compound of polyglycolic acid and trimethylene carbonate shown to be entirely bioabsorbable at 7 months without long-term inflammation[44]. Its striking design allows for more bespoke placement–arms can be trimmed to specifically fit tract anatomy. Initial studies demonstrated success rates from 16% in transsphincteric fistulae at 12 months[45] to 72.7% in high transsphincteric fistulae at 5 months with no postoperative incontinence[43], and comparative analyses with the Surgisis AFP demonstrated superior success rates in complex anal fistulae with the GORE BioA^® Fistula Plug of 54.5% compared to 12.5% at 28 months for the former[44]. Nevertheless, long-term studies on both plug types by Hansen et al[46] from 2008 to 2015 showed only modest healing rates of 52.8% and high failure and recurrence rates of 44.4% and 26.3%, respectively, suggesting that despite their viability, bioprosthetic plugs should not be considered first-line.

Myriad matrix: In 2023, OFM, or Myriad Matrix (Myriad Matrix Soft Tissue Bioscaffold^TM, Aroa Biosurgery Limited, Auckland, New Zealand) was introduced by Hsu et al[47] as a novel biomaterial that saw precedent utilisation within wounds with high levels of inflammation and contamination[48]. OFM is a decellularized extracellular matrix originally manufactured to serve a variety of soft tissue functions, including regeneration, remodeling, and wound healing. Entirely bio-absorbable into surrounding soft tissue once placed, it is able to conserve original host tissue structures following remodeling and reperfusion. Interestingly, it has been shown to also recruit host mesenchymal stromal cells[49], enhancing cellular expansion and angiogenesis[50] which has advantages in contaminated soft tissue lesions such as anal fistulae.

The initial case series showed promising healing rates of 64% at 8 weeks in predominantly high transsphincteric fistulae (88%), which is superior to that of Surgisis AFP, with no reported postoperative infections, adverse reactions, or incontinence, highlighting its utility in this group of patients[47]. A technical approach for myriad matrix application in anal fistulae has also been described and was found to preserve physiological extracellular matrix structure during healing with minimal scarring on endoanal ultrasound[51]. However, apart from isolated non-peer-reviewed retrospective studies, literature on efficacy in other types of anal fistulae, especially those of Crohn’s origin, remains scarce. Further prospective randomized studies of substantial sample size and standardized measurements are needed to further evaluate its efficacy and how it may compare to those of Surgisis or GORE BioA^®. Given the typically high expenditures associated with AFPs in general, the cost-effectiveness of these techniques also remains to be elucidated. Our findings indicate that for both superficial transsphincteric and intersphincteric FIAs, surgical management with the insertion of ovine ECM into the fistulas preserves the structure and complexity of the natural ECM during healing. This approach also provides biological cues that facilitate tissue regeneration and promote angioconduction. Postoperative healing was confirmed by endoanal ultrasound, which showed minimal scarring associated with the intersphincteric fistulas.

Highly inconsistent success rates across different plug materials and studies, together with the prevalent risks of plug extrusion, have made routine adoption of the fistula plug difficult. Despite the abundance of single-centre studies such as those aforementioned, their healing and recurrence rates should be interpreted in the context of more extensive, comparative analyses, which we still lack. With the advent of novel materials like the Myriad Matrix that seem to promisingly address the drawbacks of its older counterparts, we remain expectant that more conclusive evidence on the efficacy of the plug will soon emerge.

Stem cell therapy: The utility of stem cell-based therapy in anal fistulae was a serendipitous discovery first described in the context of a rectovaginal fistula secondary to Crohn’s disease. In 1993, autologous bone marrow transplantation for a 41-year-old female, initially for non-Hodgkin’s lymphoma, coincidentally induced remission of concomitant longstanding Crohn’s disease and subsequent resolution of the fistula[52]. Phase I trials in 2005 by García-Olmo et al[53] then facilitated widespread acknowledgement of stem cell therapy as a possible efficacious and safe alternative for otherwise medically resistant Crohn’s disease[54,55].

In today’s context, the localised administration of MSCs represents the mainstay for stem cell therapy. Autologous or allogenic MSCs may refer to those derived from bone marrow (BM-MSCs) or adipose-derived stem cells (ASCs) derived from subcutaneous fat by liposuction[56].

Their mechanism of action in anal fistulae is mainly twofold: Firstly, as multipotent adult stem cells, these possess anti-angiogenic, immunomodulatory, and regenerative abilities[57,58] which are particularly efficacious in chronic inflammatory fistulizing diseases[59]. Secondly, stem cells exert anti-inflammatory mechanisms that may regulate the proinflammatory environment often implicated in the chronicity of the fistula[60]. Consequently, cellular expansion augments wound healing and accurate tissue reorganisation as demonstrated in Figure 3.

Figure 3 Mechanism of action of stem cells in anal fistulae treatment. (1) Regeneration and proliferation; and (2) Anti-inflammatory, immunomodulatory effects.

Pertinently, administration of MSCs via localised injection is minimally invasive and has not been implicated in sphincter damage or faecal incontinence like in other more conventional treatments for complex fistulae[60]. In fact, stem cell injection may even ameliorate the continence of certain patients[61].

García-Olmo et al[62] first successfully utilised autologous ASCs for the treatment of a refractory rectovaginal fistula in the context of Crohn’s disease in 2003. Subsequent phase I[53], multi-centre phase II[63], and phase III trials[64] by the same authors all demonstrated ASC safety and efficacy for complex fistulae of both cryptoglandular and Crohn’s origin.

There is at present still no clear surgical protocol for the administration of MSCs in anal fistula therapy, although several proposed practical considerations and stepwise techniques like that described by Georgiev-Hristov et al[65] have been described in the past decade. Much variation remains with regard to the choice between BM-MSCs or ASCs, the type of antibiotic or anaesthesia used, the ideal cell dosage, the administration procedure (direct injection vs fibrin glue), etc. Generally, administration involves the following key steps detailed briefly below: (1) Antibiotic prophylaxis and treatment; (2) Anaesthesia administration; (3) Surgical decontamination; (4) Localisation of internal opening; (5) Tract debridement; (6) Sealing of internal opening; (7) Stem cell handling and resuspension; and (8) Stem cell injection (Figure 4).

Figure 4  Mesenchymal stem cell suspension injection process (1/3 into submucosa surrounding internal opening, 2/3 through external opening intramurally along course of fistula).

Ideal administration involves a cautious injection process utilising a fine and long needle to circumvent cellular friction and death. Studies have shown that up to 26G bore needles are suitable for administration with no alteration to cellular viability, even following three passes through the needle[66]. An optimal cell dosage remains disputed, although recent systematic reviews showed no significant impact of dosage on treatment success[67] and no evidence of dose-dependent efficacy in studies that trialed dose augmentation[68,69]. Current best practice seems to be a steady injection dependent on fistula dimensions, instead of a definite dose[70].

MSCs can also be delivered combined with fibrin glue or fixed on a fistula plug. Studies have shown a benefit in utilising scaffolds that can ensure definitive surgical placement and localisation. To this end, Dozois et al[71] have recently described an approach to introduce autologous MSCs intraluminally via attachment to a bioabsorbable matrix. STOMP (stem cells on matrix plugs), their phase 1 clinical trial in refractory Crohn’s-related perianal fistulae, has shown favourable clinical healing rates of 76% and a significant decrease in Van Assche perianal severity scores on magnetic resonance imaging assessment (median 13 to 9) at 12 months.

Following the success of autologous ASCs in clinical trials, De La Portilla et al[68] achieved proof of concept using expanded allogeneic adipose-derived stem cells (e-ASCs) in an open-label phase I-IIa trial. Darvadstrocel, a preparation of human allogeneic, expanded, adipose-derived stem cells known as Cx601, was then used in a phase III trial (known as ADMIRE-CD) published in the Lancet in 2016, demonstrating a 50% remission rate of complex Crohn’s perianal fistulae at week 24 compared with 34% of those who received placebo[72]. The 17% of patients in the Cx601 group, as compared to 29% in the placebo group, suffered adverse events, most commonly abscess or proctalgia, with none experiencing incontinence.

A subsequent follow-up study showed that Darvadstrocel was well tolerated and clinical remission may be maintained for up to 104 weeks post-administration[73]. Finally, a long-term follow-up in 2018 by Panés et al[74] showed fistula healing maintained up to 3 years in about 60% of refractory Crohn’s disease patients (with mean disease duration of 11.6 years) treated with Cx601, with a similar rate of adverse events in both the Cx601 and control groups. These were most commonly abscesses or proctalgia, and none suffered incontinence. To date, the European Medicines Agency has approved Cx601-Darvadstrocel (Alofisel^®) for the treatment of refractory perianal Crohn’s disease in adult patients[75,76].

In Europe, a post-approval study named INSPIRE[77] assessed the real-life efficacy and safety profile of Darvadstrocel for up to 36 months post-treatment, with provisional results corroborating the ADMIRE-CD study. In the United States, however, the ADMIRE-CD-II trial aimed at eventual FDA approval of Darvadstrocel in America proved futile after 2024 results showed no statistical difference in efficacy vs placebo.

It is worth noting that many of these trials were conducted in the context of complex fistula associated with Crohn’s disease. In comparison, scarce literature regarding the safety and efficacy of MSC treatment specifically in fistulae of cryptoglandular origin exists. Certain studies excluding fistulae of Crohn’s origin show relative success in achieving fistula healing at rates of approximately 40% at 6 months and of more than 50% at 1-year follow-up, which were equivalent to using fibrin glue alone[64]. Recently published meta-analyses demonstrated efficacy for both Crohn’s and cryptoglandular fistulae in the short-term, long-term, and over-long-term and superiority to conventional therapy like fibrin glue and surgery (42.4% vs 18.8%; 56.0% vs 42.9%; 49.4% vs 26.0%), and propounded efficacy in achieving radiographic improvement in cryptoglandular fistulae[67]. Others demonstrated universally positive results despite differences in both etiology (Crohn’s and/or cryptoglandular) and fistulous anatomy (e.g., anal, rectovaginal, and/or entercutaneous)[78]. On balance, it seems that MSCs continue to be a valid alternative for the treatment of both Crohn’s and non-Crohn’s fistulas.

In summary, stem cell therapy is undoubtedly one of the most promising therapeutic options for minimally invasive treatment of anal fistulae. Several pivotal developments have been made over the last decade: Pertinently, the ADMIRE-CD trial in 2016 was the turning point that paved the way for its broader clinical usage. While its safety and efficacy have been undoubtedly established, the ADMIRE-CD-II trial demonstrates persistent limitations to wider therapeutic use. Further studies are also required to standardize trials and optimise the technique of stem cell administration in terms of inclusion criteria, route of administration, type (autologous, allogeneic, etc.), and dosage, etc. for the best therapeutic effect. To this end, ongoing trials involve alterations of the MSC solution itself, for instance, using MSC-derived exosomes (NCT06568653), allogenic human umbilical cord MSCs, or autologous adipose-derived stromal vascular fraction[79]. Others evaluate the benefit of repeated injections and specific dosages. Nevertheless, key aspects of therapy, such as indications for MSCs in terms of patient and fistula suitability, also warrant further investigation.

CONCLUSION

Minimally invasive treatment for anal fistulae–do newer modalities live up to their promises? It depends. Most of the studies consolidated here are retrospective in nature, involve small sample sizes, and exhibit significant heterogeneity. Moreover, there is likely a publication bias, as predominantly positive findings tend to be published. Therefore, from an evidence-based perspective, these techniques may not yet fully live up to their initial promise. Minimally invasive surgical (MIS) techniques should be reserved for appropriately selected cases. Fistulectomy remains a time-tested and effective approach[80], continuing to demonstrate far superior healing rates exceeding 90% and low incontinence risk, especially amongst simple low anal fistulae in recent large comparative analyses, although the tradeoff with incontinence becomes increasingly skewed with increasing sphincter involvement[10,81,82]. It remains the treatment of choice for simple low-tract fistulas and should not be compromised by favouring MIS solely for the convenience of reduced postoperative pain or simpler wound care, particularly when long-term outcomes may be superior with fistulectomy. Nevertheless, the traction surrounding current literature should not be ignored. We possess today the most extensive armamentarium of techniques at our disposal than ever before. As newer evidence is put forward and more methods become clinically established, we must remain adaptable and be willing to adapt to best practices. LIFT and VAAFT, for instance, have already gained somewhat more extensive acceptance and demonstrated consistent safety and efficacy. Novel techniques and modern regenerative technology, such as AFP and MSCs, have proven promising despite their current omission in most clinical guidelines and warrant our close attention in the upcoming years. Pertinently, these regenerative methods have an increasingly established role in fistulae of Crohn’s origin–this may prove advantageous over purely surgical methods whose efficacy in cryptoglandular and Crohn’s fistulae have been largely comparable as per current literature. We must be ready to take these studies up on their promises, especially if they have been shown to consistently live up to expectations. Regardless, more randomized studies and long-term results are needed, while comparative studies will also be key in informing surgical decision-making in complex cases. Over time, as surgeons’ learning curve becomes less of a confounding factor, we can also expect to extrapolate better conclusions about superior techniques. Minimally invasive treatment of anal fistula remains an evolving field, with growing evidence suggesting promising outcomes. This review has attempted to summarize the key developments of the aforementioned techniques, along with their pros and cons. We emphasize, however, that the choice of technique should still depend on individual patient and disease factors, the surgeon’s preference, and practical considerations. With the growing body of evidence, this surgical decision-making should hopefully be much clearer in the years to come.

ACKNOWLEDGEMENTS

The authors would like to express their sincere gratitude to Mayanee Chai for her invaluable input with regard to surgical diagrams and figure drawing. Her creativity and artistic talent greatly enhance the clarity of our article.