Enterocutaneous fistula: Successful treatment of two cases with urinary bladder matrix xenograft

Introduction: Enterocutaneous fistula (ECF) represents a challenging clinical condition in surgery. Two cases of ECF are presented that were successfully treated with MatriStem, a porcine urinary bladder matrix xenograft application. Case Series: The cases were treated with a procedure involving curettage of the tract, followed by injection of a MatriStem slurry, and insertion of a rolled MatriStem graft. In both cases, the ECF ceased to drain bilious fluid. After a week, both patients began a liquid diet, and no recurrent fistula occurred after six months of follow-up. Conclusion: In this study, treatment of ECF using MatriStem resulted in successful clinical healing of the ECF. The use of biologically derived materials for ECF is a relatively new concept. There is precedent for using biological plugs with some reported examples of success, but use of porcine urinary bladder matrix is novel for this purpose. (This page in not part of the published article.) International Journal of Case Reports and Images, Vol. 6 No. 12, December 2015. ISSN – [0976-3198] Int J Case Rep Images 2015;6(12):730–733. www.ijcasereportsandimages.com Sasse et al. 730 CASE REPORT OPEN ACCESS Enterocutaneous fistula: Successful treatment of two cases with urinary bladder matrix xenograft Kent C. Sasse, David L. Warner


INtrODUctION
Enterocutaneous fistula (ECF) remains among the most challenging clinical conditions in general and colorectal surgery. ECF is a source of significant morbidity for patients and frequently results in the need for costly and morbid interventions in an attempt to resolve the condition, particularly when associated with additional risk factors such as cancer, immunosuppression, irradiated tissue, tobacco abuse, Crohn's disease, diabetes, and obesity [1][2][3][4]. Treatment of routinely includes invasive surgery, total parenteral nutrition (TPN), expensive medical therapies, personnel time, and imaging procedures, often without predictable closure of the ECF [5].
MatriStem (ACell Inc., Columbia, MD, USA) is a regenerative extracellular matrix (ECM) material derived from porcine urinary bladder that has been demonstrated to facilitate regeneration of host tissues in many anatomical regions and organ systems in mammals [6]; it has since been proven effective in the treatment of complex wounds, esophageal repair, and muscle injury applications [7][8][9][10][11][12]. However, the use of ECM materials for ECF is a relatively new practice. A recent report of seven cases of ECF managed conservatively with an acellular ECF product derived from porcine intestinal submucosa suggests that ECM scaffolds are a promising new approach managing ECF in complex patients [13]. The aim of this report is to contribute to the growing evidence of biological

cAsE sErIEs
In Case 1, a 69-year-old female presented with a history of chronic obstructive pulmonary disease, diverticulitis and a prior surgical colectomy complicated by anastomotic leak and multiple reoperations at an outside facility. In late 2013, she underwent ileostomy takedown, extensive adhesiolysis and ileorectal anastomosis, complicated by a late postoperative enterocutaneous fistula measuring 6 cm in length. Despite bowel rest and TPN, the fistula drained 200 cc per day of bilious succus entericus. The patient did report passage of flatus and stool per rectum. Clean radiographs showed no bowel dilatation, and passage of flatus and bowel movements indicated that no downstream obstruction was present. Clinical assessment of lack of distention and vomiting also supported that conclusion. Contrast studies downstream would serve as further confirmation, but were not felt to be mandatory at that point in time, and an effort was made to minimize the tests and procedures that the patients was undergoing. Major surgery was inadvisable due to extensive multiple previous operations and high risk of further bowel injury, and additional complications if laparotomy were undertaken; thus, a less invasive solution was sought.
In Case 2, a 67-year-old female with stage IV colorectal cancer and intra-abdominal recurrence presented with a chronic enterocutaneous fistula. She had undergone a bowel resection procedure in 2012 to alleviate obstructive symptoms and was found to have extensive tumor in the abdomen. She recovered from surgery but continued to experience persistent drainage from two separate, unconnected sinus tracts in the abdominal midline. The more superior sinus drained 15 cc per day of serous fluid, but the lower tract drained 150 cc per day of bilious succus entericus despite bowel rest and administration of TPN. The length of the ECF tract measured 4 cm in length. The patient did pass stool per rectum intermittently. For the same reasons as mentioned in Case 1, major surgery was considered inadvisable, and a less invasive solution was sought.
Each patient was taken to the operating room for management of the fistula using a standardized technique. First, the fistula tract was debrided and curetted ( Figure 1A). The fistula tract was then filled with a thick suspension of 200 mg of MicroMatrix powder in 4 cc of saline delivered via an 18 g syringe ( Figure  1B). Next, a MatriStem Surgical Matrix RS device was hydrated in saline per the instructions for use and rolled ( Figure 1C) for insertion into the fistula tract ( Figure 1D and Figure 2). The rolled MatriStem device was finally sutured to the skin ( Figure 1E).
In both cases, the enterocutaneous fistula ceased to drain bilious fluid immediately. After a week, both patients were started on a liquid diet, which was then advanced as tolerated. No recurrent fistula has occurred after more than six months of follow-up. In Case 2, the untreated superior tract resumed drainage of 10-15 cc per day of non-bilious serous fluid.

DIscUssION
In this study, treatment of two enterocutaneous fistulae using MatriStem application resulted in successful clinical healing of the enterocutaneous fistula without complications, re-infection, or reoperation. In both cases, the clinical assessment was that there was no downstream intestinal obstruction and that reoperation was clinically inadvisable. The application of MatriStem was performed with a minimally invasive technique of curettage, injection of a suspension of MatriStem MicroMatrix powder, and insertion of a rolled MatriStem Surgical Matrix RS graft. In both of the cases presented here, the fistula closed with a single application of the standard treatment method. However, it stands to reason that repeated treatments with MatriStem might be required to achieve successful closure of some fistulae with little additional risk to the patient. Lyon et al. report treatment of six patients with ECF utilizing a porcine small intestinal submucosa xenograft; two patients achieved closure with no recurrence beyond two years, but also reported two deaths [11]. Piduru et al. also describe treatment of ECF using small intestine submucosa, and report a clinical benefit of 42%, and a complete closure rate of 21% [13].
MatriStem (ACell Inc.) has proven effective in achieving constructive tissue remodeling and wound healing across an array of complex clinical situations [12][13][14]. The mechanism by which MatriStem facilitates the body's ability to heal wounds is not completely understood, but it is thought that the presence of an intact epithelial basement membrane plays an important role [15]. Epithelial basement membrane is known to support the regenerative capacity of numerous anatomical regions and organs, such as the thoracic wall, the esophagus, the liver and bone [8,16]. It has also been shown that the immune response to MatriStem includes a more prominent role for the M2 macrophage phenotype [17]. Further studies are required to further elucidate the body's response to this material [15,18].
Management of ECF can be an arduous and expensive process; many conservative treatments have high recurrence rates, while more efficacious procedures tend to be quite invasive [1-3]. Additionally, ECF frequently presents in patients with comorbid conditions such as cancer, diabetes, irradiated tissue, immunosuppression, and Crohn's disease, which impair the healing process [1,4]. MatriStem has been effective in facilitating healing of surgically repaired soft tissues and wounds across a diverse spectrum of anatomical settings [8-11, 13, 18].

cONcLUsION
This report establishes a novel application of MatriStem in the minimally invasive management of enterocutaneous fistula (ECF) in patients with complex medical problems. The evidence provided in these cases suggests that the application of MatriStem may meet the need for a conservative, practical, and cost-effective technique for managing some cases of ECF. *********

Author contributions
Kent C. Sasse -Substantial contributions to conception and design, Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published David L. Warner -Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published

Guarantor
The corresponding author is the guarantor of submission.

conflict of Interest
Dr. Sasse receives speaking honoraria from ACell organization outside the submitted work, and also serves as a consultant to ACell. Warner has no conflicts of interest to disclose.

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