Effect of Collagen Adjunct After Fistulotomy and Endorectal Advancement Flap on Healing and Recurrence in Primary Cryptoglandular Anal Fistula: A Retrospective Comparative Study

Effect of Collagen Adjunct After Fistulotomy and Endorectal Advancement Flap on Healing and Recurrence in Primary Cryptoglandular Anal Fistula: A Retrospective Comparative Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Effect of Collagen Adjunct After Fistulotomy and Endorectal Advancement Flap on Healing and Recurrence in Primary Cryptoglandular Anal Fistula: A Retrospective Comparative Study Mehmet Furkan Avcı, Mehmet Fatih Özsaray, Turgay Şimşek, Ahmet Oktay Yirmibeşoğlu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7889453/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Collagen scaffolds are increasingly used as adjuncts in sphincter-preserving surgery for anal fistula, yet comparative data when combined with endorectal advancement flap are limited. Methods Single-center retrospective cohort of 100 consecutive adults with primary cryptoglandular fistula (January 2023–December 2024). Patients underwent fistulotomy plus endorectal advancement flap with (Collagen, n = 50) or without collagen (Control, n = 50). The prespecified primary endpoint was fistula/surgical site discharge at 2 months. Secondary endpoints were fistula/surgical site discharge at 6 and 12 months, reoperation by 12 months, pain, pruritus, erythema, incontinence, stenosis, and wound dehiscence. Analyses used chi-square/Fisher’s exact tests and multivariable logistic regression adjusting for age, sex, smoking, fistula class, and diabetes. Effect sizes are reported as risk ratio (RR) and absolute risk difference (ARD) with 95% CIs. Results Baseline characteristics did not differ between the groups. Discharge at 2-monts was significantly less likely in the group treated with collagen (32% vs 56%; RR 0.57, 95% CI 0.36–0.90; ARD − 24%, 95% CI − 42% to − 6%; p = 0.027). In adjusted analysis, collagen adjunct treatment remained associated with reduced discharge (aOR 0.40, 95% CI 0.17–0.95). At 12 months, discharge (14% vs 30%; RR 0.47, 95% CI 0.21–1.05) and reoperation (0% vs 0%) favored the collagen group descriptively, but did not reach conventional significance. No incontinence events occurred in the collagen group. Conclusions Collagen adjunct in patients undergoing fistulotomy plus advancement flap improved 2-month wound outcomes and showed favorable later trends (at 6 and 12 months) without compromising fecal continence. Prospective randomized trials are warranted. Anal fistula Collagen Endorectal advancement flap Fistulotomy Wound healing Figures Figure 1 1. Introduction Cryptoglandular anal fistula is a chronic inflammatory condition characterized by an abnormal tract between the anal canal and perianal skin. The Parks classification remains foundational for operative planning and anticipates the trade-off between definitive tract eradication and sphincter preservation [ 1 ]. Over the last two decades, the therapeutic paradigm has shifted from aggressive division of sphincter components toward techniques that minimize sphincter injury while maintaining acceptable healing rates. This evolution has paralleled refinements in imaging, particularly magnetic resonance imaging (MRI)-based mapping, which improves delineation of secondary tracts and abscesses and thereby facilitates individualized strategies [ 1 ]. Among sphincter-preserving options, endorectal advancement flap is widely used across fistula phenotypes when a definable internal opening can be addressed. However, recurrence and delayed wound healing remain significant challenges in real-world practice, especially where local inflammation persists. Collagen-based devices delivered as plugs, pastes, or gels provide a biocompatible scaffold that supports granulation and epithelialization without additional sphincter division. Early experiences with collagen plugs demonstrated safety with variable efficacy across heterogeneous cohorts [ 2 , 3 ]. More recently, non-cross-linked equine collagen gels/pastes have shown feasibility and encouraging healing signals in prospective multicenter settings, particularly when sepsis control and careful tract preparation are ensured [ 4 , 5 ]. At the same time, minimally invasive modalities such as ligation of intersphincteric fistula tract (LIFT) , video-assisted anal fistula treatment (VAAFT) , and fistula laser closure (FiLaC) have provided additional surgical options.[ 6 ]. While attractive for reduced tissue trauma, the long-term durability of these techniques varies, and late morbidity can be substantial in some series, emphasizing that simple, anatomy-driven surgical techniques remain essential benchmarks. Given this evidence, adjunctive collagen placed at the time of a conventional fistulotomy combined with an endorectal advancement flap may optimize short-term wound healing, reduce exudate and persistent drainage, and ultimately lower the need for reintervention, while not increasing the incontinence risk [ 7 ]. The present study compared outcomes after fistulotomy + endorectal advancement flap with or without collagen application in adults with primary cryptoglandular fistula. It was hypothesized that collagen would reduce early postoperative discharge and favorably influence late clinical events, such as persistent discharge and reoperation, without compromising continence. 2. Materials and Methods Study design and setting This was a retrospective, comparative study at the general surgery department of a tertiary university teaching hospital. The sample included consecutive adults meeting the inclusion criteria who were operated for primary cryptoglandular anal fistula between January 2023 and December 2024. Inclusion and exclusion criteria Inclusion: aged ≥ 18 years; primary cryptoglandular anal fistula; and no prior fistula surgery. Exclusion: recurrent or non-cryptoglandular fistula (e.g., Crohn’s disease, trauma, malignancy); inflammatory bowel disease; prior pelvic radiotherapy/chemotherapy; chronic kidney disease stage ≥ 3; or systemic immunosuppression. Of note, Type 2 diabetes mellitus (DM) was not an exclusion criterion and was recorded as a baseline covariate. Surgical technique and collagen adjunct All procedures followed a standardized unit protocol. After tract identification and internal opening control, fistulotomy was performed for the extrasphincteric portion compatible with sphincter preservation, followed by an endorectal advancement flap fashioned with a broad, well-vascularized base. The flap was advanced and secured with Caproyn sutures in continuous fashion. In the Collagen group, a non-cross-linked equine collagen gel (Salvecoll® E, Bioteck, Vicenza, Italy) was applied after thorough curettage and saline irrigation of the tract. The material was gently injected to fill the tract and dead space without tension before flap advancement. Perioperative antibiotics were standardized (first-generation cephalosporin, prophylactic intraoperative dose continued orally for 7 days). Preoperative MRI was obtained in approximately 40% of patients. Seton placement prior to definitive surgery was not used in this cohort. Outcomes and definitions The prespecified primary outcome was patient-reported or clinician-observed discharge at 2 months, confirmed by perianal inspection. Secondary outcomes included discharge at 6 and 12 months; reoperation for persistent/non-healing fistula or complication within 12 months; pain, pruritus, erythema; anal stenosis; wound dehiscence; and incontinence. Recurrence/persistence was defined as ongoing external drainage with a persistent tract on examination, abscess formation, or the need for reintervention after initial wound healing. Incontinence was assessed using the Wexner score (Cleveland Clinic Florida Fecal Incontinence Score) [ 8 ]; scores > 0 were recorded as events and reported descriptively. Anal stenosis was defined as symptomatic narrowing requiring dilation or surgical revision. All outcomes were assessed at day 14 and months 2, 6, and 12 in the outpatient clinic. Fistula classification was based on the Parks classification [ 9 ], and MRI-based staging was applied per routine where applicable [ 10 ]. Statistical analysis Normality of continuous variables was assessed using the Shapiro–Wilk test. Data are presented as mean ± standard deviation (SD) or median and interquartile range (IQR), and categorical variables as n (%). Between-group comparisons used independent t-test or Mann–Whitney U test, and chi-square or Fisher’s exact test as appropriate. Two-sided α = 0.05. Analyses were performed in IBM SPSS v29 (IBM Inc., Armonk, NY, USA). The prespecified primary outcome was fistula discharge at 2 months. Effect sizes are reported as risk ratio (RR), absolute risk difference (ARD), and number-needed-to-treat (NNT) with 95% CIs. A multivariable logistic regression model estimated adjusted odds ratios (aORs) for 2-month discharge, including age, sex, smoking status, fistula class (intersphincteric vs other), and diabetes as covariates. Secondary outcomes were considered exploratory; p-values are provided without multiplicity adjustment. There were no missing data because follow-up completion was 100% in both groups. This study was approved by the Kocaeli University Non-Interventional Clinical Research Ethics Committee (Decision no. 2025/183; 08 May 2025). In accordance with institutional policy for retrospective chart reviews, the committee granted a waiver for informed consent. All data abstraction and analyses were initiated after ethics approval, and records were de-identified prior to analysis. The study adhered to the Declaration of Helsinki. 3. Results Cohort and baseline characteristics One hundred consecutive adults met inclusion criteria (Control n = 50; Collagen n = 50). Groups were comparable at baseline (Table 1 ). Intersphincteric fistulas predominated (~ 57% overall), followed by transsphincteric, suprasphincteric, and rare extrasphincteric types, and this distribution of type did nor differ between groups Table 1 Baseline characteristics of patients Variable Control (n = 50) Collagen (n = 50) p -value Age, years (mean ± SD) 38.0 ± 8.1 38.8 ± 8.7 0.65 Male sex, n (%) 34 (68%) 33 (66%) 0.82 Smoker, n (%) 12 (24%) 11 (22%) 0.81 Diabetes mellitus, n (%) 3 (6%) 2 (4%) 0.65 Fistula class, n (%) • Intersphincteric 28 (56%) 29 (58%) 0.84 • Transsphincteric 15 (30%) 14 (28%) 0.82 • Suprasphincteric 5 (10%) 5 (10%) 1.00 • Extrasphincteric 2 (4%) 2 (4%) 1.00 Preoperative MRI, n (%) 20 (40%) 20 (40%) 1.00 Patient flow All 100 eligible patients were included (Control n = 50; Collagen n = 50), and complete follow-up was achieved at day 14 and at months 2, 6, and 12. No patient was lost to follow-up or crossed over between groups. A STROBE flow diagram is provided (Fig. 1 ). Early postoperative course (day 14) At postoperative day 14, symptom profiles were broadly similar: pain, pruritus, erythema, and discharge showed no statistically significant between-group differences (all p > 0.30). This early time-point likely reflects incision-related inflammation and wound remodeling common to both strategies. Primary outcome Discharge at 2 months occurred in 16/50 (32%) patients in the Collagen group versus 28/50 (56%) in Controls (RR 0.57, 95% CI 0.36–0.90; ARD − 24%, 95% CI − 42% to − 6%; NNT 4.2, 95% CI 2.4–16.7). In a multivariable logistic regression adjusting for age, sex, smoking, fistula class, and diabetes, collagen remained significantly associated with reduced discharge (aOR 0.40, 95% CI 0.17–0.95). Month 6 outcomes At month 6, discharge and pruritus remained numerically lower with collagen (32%→16% vs 24%→10% in raw proportions across groups), though differences were not statistically significant ( p = 0.10–0.11). Pain and erythema were uncommon and similar between groups. The wound dehiscence signal also favored collagen (8% vs 22%; p = 0.093), suggestive of improved tissue integration, albeit underpowered for definitive inference. Month 12 reoperation No patient in either group required reoperation during 12 months of follow-up. No incontinence occurred in the Collagen group at any time point; incontinence was rare overall and comparable in frequency across the cohort. Anal stenosis was infrequent and occurred at a similar rate in both groups. No device-related adverse reactions were recorded. The Wexner score was 0 (0–0) in both groups at all visits. Postoperative outcomes by visit are presented in Table 2 . Table 2 Postoperative outcomes at each follow-up Outcome Day 14 (n = 50/50) Month 2 (n = 50/50) Month 6 (n = 50/50) Month 12 (n = 50/50) Discharge Ctrl 20 (40%) vs Col 18 (36%) Ctrl 28 (56%) vs Col 16 (32%) *p = 0.027* Ctrl 12 (24%) vs Col 5 (10%) Ctrl 15 (30%) vs Col 7 (14%) *p = 0.091* Pain Ctrl 25 (50%) vs Col 24 (48%) Ctrl 10 (20%) vs Col 8 (16%) Ctrl 4 (8%) vs Col 2 (4%) Ctrl 1 (2%) vs Col 1 (2%) Pruritus Ctrl 10 (20%) vs Col 9 (18%) Ctrl 8 (16%) vs Col 5 (10%) Ctrl 5 (10%) vs Col 3 (6%) Ctrl 3 (6%) vs Col 2 (4%) Erythema Ctrl 12 (24%) vs Col 11 (22%) Ctrl 6 (12%) vs Col 4 (8%) Ctrl 2 (4%) vs Col 1 (2%) 0 vs 0 Wound dehiscence Ctrl 4 (8%) vs Col 3 (6%) Ctrl 3 (6%) vs Col 1 (2%) Ctrl 11 (22%) vs Col 4 (8%) *p = 0.093* Ctrl 2 (4%) vs Col 1 (2%) Anal stenosis 0 vs 0 0 vs 0 1 (2%) vs 0 1 (2%) vs 0 Abbreviations: Ctrl, control group; Col, collagen group. Summary of effect signals Collagen adjunct produced a significant improvement in early wound milieu (discharge at month 2) and consistent, favorable late signals for fewer persistent discharges and reoperations by month 12, without continence trade-offs. 4. Discussion In this single-center cohort of primary cryptoglandular anal fistulas treated with fistulotomy plus endorectal advancement flap, the use of a collagen adjunct was associated with a significant and clinically meaningful reduction in 2-month discharge. Late outcomes, including discharge and reoperation at 12 months, also showed favorable trends but were exploratory given the modest sample size and absence of reoperation events [ 11 ]. These results align with the biological rationale of collagen scaffolding, which is to support granulation and tract collapse after meticulous sepsis control and tract preparation and appear to improve short term outcomes in this anatomy-anchored procedure. The secondary endpoints were exploratory and multiple time-points were assessed, so inferences beyond the prespecified primary outcome (at 2 months post surgery) should be made cautiously and confirmed in adequately powered randomized trials [ 12 , 13 ]. Relationship to prior literature Early collagen plug series reported safe but variable healing in heterogeneous cohorts [ 14 ]. More recent experiences with non-cross-linked equine collagen gels/pastes have documented improved feasibility andoutcomes in prospective multicenter studies. Our results complement these observations by embedding collagen within a conventional, anatomy-driven operation rather than as a stand-alone closure device, thereby combining the advantages of mechanical tract control (fistulotomy + flap) and biologic support (collagen). The continence profile of no events in the Collagen group is in keeping with long-standing evidence that avoiding additional sphincter division preserves function [ 15 ]. Position among sphincter-preserving strategies Minimally invasive options, such as VAAFT and FiLaC, are associated with the benefit of tissue sparing but exhibit heterogeneous long-term durability [ 16 ]. LIFT has demonstrated reliable mid-term healing but recurrence may be relatively frequent in complex anatomy [ 17 ]. Our data indicate that additional biological augmentation during a standard, well-understood operation yielded early symptomatic gains and suggested potentially fewer late interventions. This is also an approach that would be cheaper than using advanced energy platforms and is feasible for use in general surgical settings. Clinical implications For primary cryptoglandular fistulas in which fistulotomy + endorectal advancement flap is planned, adding collagen appears to: Reduce discharge in the short term, an outcome linked to quality of life; Possibly reduce the incidence of later term discharge and reoperations by month 12; Have no effect on post-operative fecal continence. These advantages may be particularly attractive in patients with local inflammatory burden, where exudate control is problematic. However, the present study was not powered for definitive subgroup analysis. Thus further, large prospective studies will be required to validate these potential sub-group differences. Strengths and limitations Strengths include a clearly defined, homogeneous indication (primary cryptoglandular disease), standardized perioperative care within one service, and prespecified, clinically relevant timepoints. The significant month-2 effect with coherent late signals across endpoints supports biological plausibility. Limitations are inherent in the design: retrospective, single-center, modest sample size, and a 12-month follow-up that may under-ascertain very late recurrence after this time point. We did not perform time-to-event modeling or adjust for potential residual confounders, for example subtle differences in tract complexity,. Imaging confirmation at each timepoint was performed in less than half of patients, which reflects real-world practice at our center. Future directions A prospective, randomized trial comparing advancement flap ± collagen with standardized tract preparation and MRI-based phenotyping is warranted. Such a study should incorporate patient-reported outcomes (soiling, lifestyle impact), use blinded outcome adjudication for recurrence, and extend follow-up to ≥ 24 months. Cost-effectiveness analyses versus energy-based modalities (VAAFT/FiLaC) would further inform resource-constrained settings. Within a conventional surgical framework, collagen is a low-risk, biologically rational adjunct that appears to improve early wound healing and may reduce the need for further, later clinical intervention. In our small cohort this addition did not compromise post-operative continence thereby meriting consideration in routine care [ 18 ]. 5. Conclusion Collagen application as an adjunct to combined fistulotomy and endorectal advancement flap was associated with improved healing in the short term. There was also a trend towards a lower incidence of discharge after this time point and may also reduce the need for reoperations by 12 months. Adding collagen treatment had no effect on patient fecal continence. Collagen appears to be a safe, sphincter-preserving additive but larger, prospective, randomized studies are needed to confirm these potential long-term benefits. Declarations Conflicts of Interest: The authors declare no conflicts of interest. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author Contribution Mehmet Furkan Avcı Conceptualization, Data Curation, Writing – Original Draft, Writing – Review & EditingMehmet Fatih Özsaray Formal Analysis, Funding Acquisition, Writing – Original Draft, Writing – Review & EditingTurgay Şimşek Methodology, Project Administration, Writing – Original Draft, Writing – Review & EditingAhmet Oktay Yirmibeşoğlu Visualization, Investigation, Writing – Original Draft, Writing – Review & EditingNuh Zafer Cantürk Supervision, Validation, Resources, Investigation, Writing – Review & Editing Data Availability The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. References Gaertner WB, Burgess PL, Davids JS, Clinical Practice Guidelines Committee of the ASCRS et al (2022) The American Society of Colon and Rectal Surgeons clinical practice guidelines for the management of anorectal abscess, fistula-in-ano, and rectovaginal fistula. 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Dis Colon Rectum 49(12):1817–1821. 10.1007/s10350-006-0755-3 Aho Fält U, Zawadzki A, Starck M, Bohe M, Johnson LB (2021) Long-term outcome of the Surgisis® (Biodesign®) anal fistula plug for complex cryptoglandular and Crohn’s fistulas. Colorectal Dis 23(1):178–185. 10.1111/codi.15429 Maternini M, Guttadauro A, Mascagni D et al (2020) Non cross-linked equine collagen (Salvecoll-E gel) for treatment of complex ano-rectal fistula. Asian J Surg 43(2):401–404. 10.1016/j.asjsur.2019.06.009 Jorge JM, Wexner SD (1993) Etiology and management of fecal incontinence. Dis Colon Rectum 36(1):77–97. 10.1007/BF02050307 Parks AG, Gordon PH, Hardcastle JD (1976) A classification of fistula-in-ano. Br J Surg 63(1):1–12. 10.1002/bjs.1800630102 Buchanan G, Halligan S, Williams AB, Bartram CI, Phillips RKS (2002) Effect of MRI on clinical outcome of recurrent fistula-in-ano. Lancet 360(9346):1661–1662. 10.1016/S0140-6736(02)11605-0 Meinero P, Mori L (2011) Video-assisted anal fistula treatment (VAAFT): technique and outcomes. Colorectal Dis 13(10):e264–e267 Cao D, Wang X, Qian K et al (2024) Long-term outcomes of fistula-tract laser closure for complex perianal fistulizing Crohn’s disease. Tech Coloproctol 28(1):89. 10.1007/s10151-024-02949-9 Ambe PC, Martin-Martin GP, Alam AA et al (2025) Laser fistula treatment: beyond the controversial aspects—best clinical practice recommendations from an international group of surgeons (the FiLaC recommendations). Tech Coloproctol 29(1):131. 10.1007/s10151-025-03164-w Fuschillo G, Pata F, D’Ambrosio M et al (2025) Failure rates and complications of four sphincter-sparing techniques for the treatment of fistula-in-ano: a systematic review and network meta-analysis. Tech Coloproctol 29(1):116. 10.1007/s10151-025-03152-0 Emile SH, Dourado J, Rogers P et al (2025) Systematic review and meta-analysis of the efficacy and safety of stem cell treatment of anal fistulas. Tech Coloproctol 29(1):100. 10.1007/s10151-025-03138-y Tang X-L, Xu Z-Y, Yang J et al (2024) Assessing the suitability of video-assisted anal fistula treatment for obese patients compared to conventional surgery: a question worth investigating. Int J Colorectal Dis 39(1):108. 10.1007/s00384-024-04683-y Buchanan GN, Halligan S, Bartram CI, Williams AB, Tarroni D, Cohen CRG (2004) Clinical examination, endosonography, and MR imaging in preoperative assessment of fistula in ano: comparison with outcome-based reference standard. Radiology 233(3):674–681. 10.1148/radiol.2333031724 Halligan S, Stoker J (2006) Imaging of fistula-in-ano. Radiology 239(1):18–33. 10.1148/radiol.2391041043 Additional Declarations No competing interests reported. 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13:13:24","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":81565,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7889453/v1/4a1c890f7795590923236552.html"},{"id":95205835,"identity":"1b4a054f-fbc9-47f5-a602-070bad0bd315","added_by":"auto","created_at":"2025-11-05 13:13:24","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":59680,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePatient flow diagram\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7889453/v1/9aa668b2b3b1949df8d501da.jpg"},{"id":96252669,"identity":"cd067a2a-1e0f-4cb2-9e5b-f759fa303c2b","added_by":"auto","created_at":"2025-11-19 07:41:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1051724,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7889453/v1/e1f50826-4a88-46eb-b047-0ee65e7fd063.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of Collagen Adjunct After Fistulotomy and Endorectal Advancement Flap on Healing and Recurrence in Primary Cryptoglandular Anal Fistula: A Retrospective Comparative Study","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCryptoglandular anal fistula is a chronic inflammatory condition characterized by an abnormal tract between the anal canal and perianal skin. The Parks classification remains foundational for operative planning and anticipates the trade-off between definitive tract eradication and sphincter preservation [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Over the last two decades, the therapeutic paradigm has shifted from aggressive division of sphincter components toward techniques that minimize sphincter injury while maintaining acceptable healing rates. This evolution has paralleled refinements in imaging, particularly magnetic resonance imaging (MRI)-based mapping, which improves delineation of secondary tracts and abscesses and thereby facilitates individualized strategies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAmong sphincter-preserving options, endorectal advancement flap is widely used across fistula phenotypes when a definable internal opening can be addressed. However, recurrence and delayed wound healing remain significant challenges in real-world practice, especially where local inflammation persists. Collagen-based devices delivered as plugs, pastes, or gels provide a biocompatible scaffold that supports granulation and epithelialization without additional sphincter division. Early experiences with collagen plugs demonstrated safety with variable efficacy across heterogeneous cohorts [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. More recently, non-cross-linked equine collagen gels/pastes have shown feasibility and encouraging healing signals in prospective multicenter settings, particularly when sepsis control and careful tract preparation are ensured [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAt the same time, minimally invasive modalities such as \u003cb\u003eligation of intersphincteric fistula tract (LIFT)\u003c/b\u003e, \u003cb\u003evideo-assisted anal fistula treatment (VAAFT)\u003c/b\u003e, and \u003cb\u003efistula laser closure (FiLaC)\u003c/b\u003e have provided additional surgical options.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. While attractive for reduced tissue trauma, the long-term durability of these techniques varies, and late morbidity can be substantial in some series, emphasizing that simple, anatomy-driven surgical techniques remain essential benchmarks. Given this evidence, \u003cb\u003eadjunctive collagen\u003c/b\u003e placed at the time of a conventional fistulotomy combined with an endorectal advancement flap may optimize short-term wound healing, reduce exudate and persistent drainage, and ultimately lower the need for reintervention, while not increasing the incontinence risk [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe present study compared outcomes after fistulotomy\u0026thinsp;+\u0026thinsp;endorectal advancement flap with or without collagen application in adults with primary cryptoglandular fistula. It was hypothesized that collagen would reduce early postoperative discharge and favorably influence late clinical events, such as persistent discharge and reoperation, without compromising continence.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003e\u003cb\u003eStudy design and setting\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThis was a retrospective, comparative study at the general surgery department of a tertiary university teaching hospital. The sample included consecutive adults meeting the inclusion criteria who were operated for primary cryptoglandular anal fistula between January 2023 and December 2024.\u003c/p\u003e\u003cp\u003e\u003cb\u003eInclusion and exclusion criteria\u003c/b\u003e\u003c/p\u003e\u003cp\u003eInclusion: aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years; primary cryptoglandular anal fistula; and no prior fistula surgery. Exclusion: recurrent or non-cryptoglandular fistula (e.g., Crohn\u0026rsquo;s disease, trauma, malignancy); inflammatory bowel disease; prior pelvic radiotherapy/chemotherapy; chronic kidney disease stage\u0026thinsp;\u0026ge;\u0026thinsp;3; or systemic immunosuppression.\u003c/p\u003e\u003cp\u003eOf note, Type 2 diabetes mellitus (DM) was not an exclusion criterion and was recorded as a baseline covariate.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSurgical technique and collagen adjunct\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAll procedures followed a standardized unit protocol. After tract identification and internal opening control, fistulotomy was performed for the extrasphincteric portion compatible with sphincter preservation, followed by an endorectal advancement flap fashioned with a broad, well-vascularized base. The flap was advanced and secured with Caproyn sutures in continuous fashion.\u003c/p\u003e\u003cp\u003eIn the Collagen group, a non-cross-linked equine collagen gel (Salvecoll\u0026reg; E, Bioteck, Vicenza, Italy) was applied after thorough curettage and saline irrigation of the tract. The material was gently injected to fill the tract and dead space without tension before flap advancement. Perioperative antibiotics were standardized (first-generation cephalosporin, prophylactic intraoperative dose continued orally for 7 days). Preoperative MRI was obtained in approximately 40% of patients. Seton placement prior to definitive surgery was not used in this cohort.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcomes and definitions\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe prespecified primary outcome was patient-reported or clinician-observed discharge at 2 months, confirmed by perianal inspection. Secondary outcomes included discharge at 6 and 12 months; reoperation for persistent/non-healing fistula or complication within 12 months; pain, pruritus, erythema; anal stenosis; wound dehiscence; and incontinence.\u003c/p\u003e\u003cp\u003eRecurrence/persistence was defined as ongoing external drainage with a persistent tract on examination, abscess formation, or the need for reintervention after initial wound healing. Incontinence was assessed using the Wexner score (Cleveland Clinic Florida Fecal Incontinence Score) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]; scores\u0026thinsp;\u0026gt;\u0026thinsp;0 were recorded as events and reported descriptively. Anal stenosis was defined as symptomatic narrowing requiring dilation or surgical revision. All outcomes were assessed at day 14 and months 2, 6, and 12 in the outpatient clinic.\u003c/p\u003e\u003cp\u003eFistula classification was based on the Parks classification [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and MRI-based staging was applied per routine where applicable [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eStatistical analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eNormality of continuous variables was assessed using the Shapiro\u0026ndash;Wilk test. Data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or median and interquartile range (IQR), and categorical variables as n (%). Between-group comparisons used independent t-test or Mann\u0026ndash;Whitney U test, and chi-square or Fisher\u0026rsquo;s exact test as appropriate. Two-sided α\u0026thinsp;=\u0026thinsp;0.05. Analyses were performed in IBM SPSS v29 (IBM Inc., Armonk, NY, USA).\u003c/p\u003e\u003cp\u003eThe prespecified primary outcome was fistula discharge at 2 months. Effect sizes are reported as risk ratio (RR), absolute risk difference (ARD), and number-needed-to-treat (NNT) with 95% CIs. A multivariable logistic regression model estimated adjusted odds ratios (aORs) for 2-month discharge, including age, sex, smoking status, fistula class (intersphincteric vs other), and diabetes as covariates. Secondary outcomes were considered exploratory; p-values are provided without multiplicity adjustment. There were no missing data because follow-up completion was 100% in both groups.\u003c/p\u003e\u003cp\u003eThis study was approved by the Kocaeli University Non-Interventional Clinical Research Ethics Committee (Decision no. 2025/183; 08 May 2025). In accordance with institutional policy for retrospective chart reviews, the committee granted a waiver for informed consent. All data abstraction and analyses were initiated after ethics approval, and records were de-identified prior to analysis. The study adhered to the Declaration of Helsinki.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cb\u003eCohort and baseline characteristics\u003c/b\u003e\u003c/p\u003e\u003cp\u003eOne hundred consecutive adults met inclusion criteria (Control n\u0026thinsp;=\u0026thinsp;50; Collagen n\u0026thinsp;=\u0026thinsp;50). Groups were comparable at baseline (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Intersphincteric fistulas predominated (~\u0026thinsp;57% overall), followed by transsphincteric, suprasphincteric, and rare extrasphincteric types, and this distribution of type did nor differ between groups\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline characteristics of patients\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eControl (n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCollagen (n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003ep\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38.0\u0026thinsp;\u0026plusmn;\u0026thinsp;8.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.65\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale sex, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34 (68%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33 (66%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.82\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSmoker, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 (24%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11 (22%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.81\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes mellitus, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.65\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFistula class, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026bull; Intersphincteric\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (56%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29 (58%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.84\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026bull; Transsphincteric\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 (30%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (28%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.82\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026bull; Suprasphincteric\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (10%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (10%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026bull; Extrasphincteric\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePreoperative MRI, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20 (40%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003ePatient flow\u003c/p\u003e\u003cp\u003eAll 100 eligible patients were included (Control n\u0026thinsp;=\u0026thinsp;50; Collagen n\u0026thinsp;=\u0026thinsp;50), and complete follow-up was achieved at day 14 and at months 2, 6, and 12. No patient was lost to follow-up or crossed over between groups. A STROBE flow diagram is provided (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eEarly postoperative course (day 14)\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAt postoperative day 14, symptom profiles were broadly similar: pain, pruritus, erythema, and discharge showed no statistically significant between-group differences (all \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.30). This early time-point likely reflects incision-related inflammation and wound remodeling common to both strategies.\u003c/p\u003e\u003cp\u003e\u003cb\u003ePrimary outcome\u003c/b\u003e\u003c/p\u003e\u003cp\u003eDischarge at 2 months occurred in 16/50 (32%) patients in the Collagen group versus 28/50 (56%) in Controls (RR 0.57, 95% CI 0.36\u0026ndash;0.90; ARD \u0026minus;\u0026thinsp;24%, 95% CI \u0026minus;\u0026thinsp;42% to \u0026minus;\u0026thinsp;6%; NNT 4.2, 95% CI 2.4\u0026ndash;16.7). In a multivariable logistic regression adjusting for age, sex, smoking, fistula class, and diabetes, collagen remained significantly associated with reduced discharge (aOR 0.40, 95% CI 0.17\u0026ndash;0.95).\u003c/p\u003e\u003cp\u003e\u003cb\u003eMonth 6 outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAt month 6, discharge and pruritus remained numerically lower with collagen (32%\u0026rarr;16% vs 24%\u0026rarr;10% in raw proportions across groups), though differences were not statistically significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.10\u0026ndash;0.11). Pain and erythema were uncommon and similar between groups. The \u003cb\u003ewound dehiscence\u003c/b\u003e signal also favored collagen (8% vs 22%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.093), suggestive of improved tissue integration, albeit underpowered for definitive inference.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMonth 12 reoperation\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eNo patient in either group required reoperation during 12 months of follow-up. No incontinence occurred in the Collagen group at any time point; incontinence was rare overall and comparable in frequency across the cohort.\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eAnal stenosis was infrequent and occurred at a similar rate in both groups. No device-related adverse reactions were recorded. The Wexner score was 0 (0\u0026ndash;0) in both groups at all visits. Postoperative outcomes by visit are presented in\u003c/b\u003e Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePostoperative outcomes at each follow-up\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOutcome\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDay 14 (n\u0026thinsp;=\u0026thinsp;50/50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMonth 2 (n\u0026thinsp;=\u0026thinsp;50/50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMonth 6 (n\u0026thinsp;=\u0026thinsp;50/50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMonth 12 (n\u0026thinsp;=\u0026thinsp;50/50)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDischarge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCtrl 20 (40%) vs Col 18 (36%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCtrl 28 (56%) vs Col 16 (32%) *p\u0026thinsp;=\u0026thinsp;0.027*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCtrl 12 (24%) vs Col 5 (10%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCtrl 15 (30%) vs Col 7 (14%) *p\u0026thinsp;=\u0026thinsp;0.091*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCtrl 25 (50%) vs Col 24 (48%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCtrl 10 (20%) vs Col 8 (16%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCtrl 4 (8%) vs Col 2 (4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCtrl 1 (2%) vs Col 1 (2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePruritus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCtrl 10 (20%) vs Col 9 (18%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCtrl 8 (16%) vs Col 5 (10%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCtrl 5 (10%) vs Col 3 (6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCtrl 3 (6%) vs Col 2 (4%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eErythema\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCtrl 12 (24%) vs Col 11 (22%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCtrl 6 (12%) vs Col 4 (8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCtrl 2 (4%) vs Col 1 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 vs 0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWound dehiscence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCtrl 4 (8%) vs Col 3 (6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCtrl 3 (6%) vs Col 1 (2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCtrl 11 (22%) vs Col 4 (8%) *p\u0026thinsp;=\u0026thinsp;0.093*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCtrl 2 (4%) vs Col 1 (2%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnal stenosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 vs 0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 vs 0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (2%) vs 0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (2%) vs 0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cem\u003eAbbreviations: Ctrl, control group; Col, collagen group.\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eSummary of effect signals\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eCollagen adjunct produced a significant improvement in early wound milieu (discharge at month 2) and consistent, favorable late signals for fewer persistent discharges and reoperations by month 12, without continence trade-offs.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this single-center cohort of primary cryptoglandular anal fistulas treated with fistulotomy plus endorectal advancement flap, the use of a collagen adjunct was associated with a significant and clinically meaningful reduction in 2-month discharge. Late outcomes, including discharge and reoperation at 12 months, also showed favorable trends but were exploratory given the modest sample size and absence of reoperation events [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThese results align with the biological rationale of collagen scaffolding, which is to support granulation and tract collapse after meticulous sepsis control and tract preparation and appear to improve short term outcomes in this anatomy-anchored procedure. The secondary endpoints were exploratory and multiple time-points were assessed, so inferences beyond the prespecified primary outcome (at 2 months post surgery) should be made cautiously and confirmed in adequately powered randomized trials [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eRelationship to prior literature\u003c/b\u003e\u003c/p\u003e\u003cp\u003eEarly collagen plug series reported safe but variable healing in heterogeneous cohorts [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. More recent experiences with \u003cb\u003enon-cross-linked equine collagen gels/pastes have\u003c/b\u003e documented improved feasibility andoutcomes in prospective multicenter studies. Our results complement these observations by embedding collagen within a \u003cb\u003econventional, anatomy-driven operation\u003c/b\u003e rather than as a stand-alone closure device, thereby combining the advantages of mechanical tract control (fistulotomy\u0026thinsp;+\u0026thinsp;flap) and biologic support (collagen). The continence profile of \u003cb\u003eno events\u003c/b\u003e in the Collagen group is in keeping with long-standing evidence that avoiding additional sphincter division preserves function [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003ePosition among sphincter-preserving strategies\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMinimally invasive options, such as VAAFT and FiLaC, are associated with the benefit of tissue sparing but exhibit heterogeneous long-term durability [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. LIFT has demonstrated reliable mid-term healing but recurrence may be relatively frequent in complex anatomy [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Our data indicate that \u003cb\u003eadditional biological augmentation\u003c/b\u003e during a standard, well-understood operation yielded early symptomatic gains and suggested potentially fewer late interventions. This is also an approach that would be cheaper than using advanced energy platforms and is feasible for use in general surgical settings.\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical implications\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFor \u003cb\u003eprimary cryptoglandular\u003c/b\u003e fistulas in which fistulotomy\u0026thinsp;+\u0026thinsp;endorectal advancement flap is planned, adding collagen appears to:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eReduce discharge in the short term, an outcome linked to quality of life;\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003ePossibly reduce the incidence of later term discharge and reoperations by month 12;\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eHave no effect on post-operative fecal continence.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eThese advantages may be particularly attractive in patients with local inflammatory burden, where exudate control is problematic. However, the present study was not powered for definitive subgroup analysis. Thus further, large prospective studies will be required to validate these potential sub-group differences.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStrengths and limitations\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eStrengths\u003c/b\u003e include a clearly defined, homogeneous indication (primary cryptoglandular disease), standardized perioperative care within one service, and prespecified, clinically relevant timepoints. The significant month-2 effect with coherent late signals across endpoints supports biological plausibility.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLimitations\u003c/b\u003e are inherent in the design: retrospective, single-center, modest sample size, and a 12-month follow-up that may under-ascertain very late recurrence after this time point. We did not perform time-to-event modeling or adjust for potential residual confounders, for example subtle differences in tract complexity,. Imaging confirmation at each timepoint was performed in less than half of patients, which reflects real-world practice at our center.\u003c/p\u003e\u003cp\u003eFuture directions\u003c/p\u003e\u003cp\u003eA \u003cb\u003eprospective, randomized trial\u003c/b\u003e comparing advancement flap\u0026thinsp;\u0026plusmn;\u0026thinsp;collagen with standardized tract preparation and MRI-based phenotyping is warranted. Such a study should incorporate patient-reported outcomes (soiling, lifestyle impact), use blinded outcome adjudication for recurrence, and extend follow-up to \u0026ge;\u0026thinsp;24 months. Cost-effectiveness analyses versus energy-based modalities (VAAFT/FiLaC) would further inform resource-constrained settings.\u003c/p\u003e\u003cp\u003eWithin a conventional surgical framework, collagen is a low-risk, biologically rational adjunct that appears to improve early wound healing and may reduce the need for further, later clinical intervention. In our small cohort this addition did not compromise post-operative continence thereby meriting consideration in routine care [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eCollagen application as an adjunct to combined fistulotomy and endorectal advancement flap was associated with improved healing in the short term. There was also a trend towards a lower incidence of discharge after this time point and may also reduce the need for reoperations by 12 months. Adding collagen treatment had no effect on patient fecal continence. Collagen appears to be a safe, sphincter-preserving additive but larger, prospective, randomized studies are needed to confirm these potential long-term benefits.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eConflicts of Interest:\u003c/h2\u003e\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMehmet Furkan Avcı Conceptualization, Data Curation, Writing \u0026ndash; Original Draft, Writing \u0026ndash; Review \u0026amp; EditingMehmet Fatih \u0026Ouml;zsaray Formal Analysis, Funding Acquisition, Writing \u0026ndash; Original Draft, Writing \u0026ndash; Review \u0026amp; EditingTurgay Şimşek Methodology, Project Administration, Writing \u0026ndash; Original Draft, Writing \u0026ndash; Review \u0026amp; EditingAhmet Oktay Yirmibeşoğlu Visualization, Investigation, Writing \u0026ndash; Original Draft, Writing \u0026ndash; Review \u0026amp; EditingNuh Zafer Cant\u0026uuml;rk Supervision, Validation, Resources, Investigation, Writing \u0026ndash; Review \u0026amp; Editing\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGaertner WB, Burgess PL, Davids JS, Clinical Practice Guidelines Committee of the ASCRS et al (2022) The American Society of Colon and Rectal Surgeons clinical practice guidelines for the management of anorectal abscess, fistula-in-ano, and rectovaginal fistula. 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Radiology 239(1):18\u0026ndash;33. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1148/radiol.2391041043\u003c/span\u003e\u003cspan address=\"10.1148/radiol.2391041043\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Anal fistula, Collagen, Endorectal advancement flap, Fistulotomy, Wound healing","lastPublishedDoi":"10.21203/rs.3.rs-7889453/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7889453/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eCollagen scaffolds are increasingly used as adjuncts in sphincter-preserving surgery for anal fistula, yet comparative data when combined with endorectal advancement flap are limited.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eSingle-center retrospective cohort of 100 consecutive adults with primary cryptoglandular fistula (January 2023\u0026ndash;December 2024). Patients underwent fistulotomy plus endorectal advancement flap with (Collagen, n\u0026thinsp;=\u0026thinsp;50) or without collagen (Control, n\u0026thinsp;=\u0026thinsp;50). The prespecified primary endpoint was fistula/surgical site discharge at 2 months. Secondary endpoints were fistula/surgical site discharge at 6 and 12 months, reoperation by 12 months, pain, pruritus, erythema, incontinence, stenosis, and wound dehiscence. Analyses used chi-square/Fisher\u0026rsquo;s exact tests and multivariable logistic regression adjusting for age, sex, smoking, fistula class, and diabetes. Effect sizes are reported as risk ratio (RR) and absolute risk difference (ARD) with 95% CIs.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eBaseline characteristics did not differ between the groups. Discharge at 2-monts was significantly less likely in the group treated with collagen (32% vs 56%; RR 0.57, 95% CI 0.36\u0026ndash;0.90; ARD \u0026minus;\u0026thinsp;24%, 95% CI \u0026minus;\u0026thinsp;42% to \u0026minus;\u0026thinsp;6%; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.027). In adjusted analysis, collagen adjunct treatment remained associated with reduced discharge (aOR 0.40, 95% CI 0.17\u0026ndash;0.95). At 12 months, discharge (14% vs 30%; RR 0.47, 95% CI 0.21\u0026ndash;1.05) and reoperation (0% vs 0%) favored the collagen group descriptively, but did not reach conventional significance. No incontinence events occurred in the collagen group.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eCollagen adjunct in patients undergoing fistulotomy plus advancement flap improved 2-month wound outcomes and showed favorable later trends (at 6 and 12 months) without compromising fecal continence. Prospective randomized trials are warranted.\u003c/p\u003e","manuscriptTitle":"Effect of Collagen Adjunct After Fistulotomy and Endorectal Advancement Flap on Healing and Recurrence in Primary Cryptoglandular Anal Fistula: A Retrospective Comparative Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-05 13:13:20","doi":"10.21203/rs.3.rs-7889453/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7d55e6fc-0ea7-4482-a3b0-edf1e3bb15bc","owner":[],"postedDate":"November 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-18T16:39:07+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-05 13:13:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7889453","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7889453","identity":"rs-7889453","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}