Background Exosome administration is a novel medical approach that promises excellent immunomodulatory properties without the conventional side effects of current antitumor necrosis factor drugs and stem cells. This study aimed to assess the safety and efficacy of using mesenchymal stem cell (MSC) exosomes to treat refractory fistulas in patients with inflammatory bowel disease. Methods MSCs were derived from the umbilical cords and their exosomes were isolated. Five patients with refractory perianal Crohn’s disease fistulas with a median age of 35 years (range 31–47 years) were enrolled in the study. Exosome injections were administered in the operating room to patients with refractory fistula (fistulas that are irresponsive to anti-tumor necrosis factor-α administration within 6 months). Six months later, a physical examination, face-to-face interviews, and magnetic resonance imaging were employed to evaluate the therapy responses of patients. Results The outcomes within 6 months after initiation of therapy showed that four patients had responded to therapy. Three patients who received exosome injections exhibited complete healing, while one reported no improvement and active discharge from the fistula site. In addition, five patients (100%) reported neither systemic nor local adverse effects. Conclusions Injection of exosomes extracted from MSCs demonstrates safety and a satisfactory therapeutic effect, as evidenced in this and other studies, and may play a significant role in the future treatment of gastrointestinal fistulas.

Background and Aim:A perianal fistula is an abnormal tract that connects anal canal to skin. Current medical and surgical interventions have a high failure rate particularly in complex and refractory cases. MSC-derived exosomes have demonstrated immunomodulatory effects without the conventional complications; hence, in this study, we evaluated the safety of their application for complex perianal fistula. Methods: Placenta-derived MSCs were cultured, and exosomes were isolated using ultracentrifugation. Exosome injections were administered in the operating room to 11 patients with complex perianal fistula (presence of fistulas for at least 1 year alongside medical and surgical treatment). The patients were followed for 6 months, and the patients were evaluated using physical examination, face-to-face interviews, and magnetic resonance imaging (MRI). Results: Among 11 patients only one did not show any improvement upon physical examination. Five patients showed complete tract resolve. While the discharge was stopped in eight patients, two patients showed only reduction. None of the patients showed any acute or latent allergic reaction or injection related complications. Conclusion: Administration of exosomes isolated from MSCs demonstrates safety and a satisfactory therapeutic effect in treatment complex perianal fistulae; therefore, it can be a candidate for future studies and might play a significant role in treatment.Ethical approval: This study was submitted to and ethically approved by the Iranian clinical registry system and committee under the reference number "IRCT20200413047063N3." This study was also approved by the Research Deputy and the Ethics Committee of the Tehran University of Medical Sciences (Reference number: IR.TUMS.IKHC. REC.1400.184). This study was also approved by the US Clinical Trial Registry (reference number: NCT05402748) and was carried out per the ethical standards outlined in the 1964 Declaration of Helsinki and all subsequent revisions. All participants signed a written informed consent form. Informed consent: All patients signed informed consent forms. Financial support: This study was self-funded by its authors and received no funding from any government/non-governmental organization. 1 Haleh Pak and Alireza Hadizadeh contributed equally to this study.

Regenerative medicine is an emerging therapeutic method that aims to reconstruct tissues and organs. This advanced therapeutic approach has demonstrated great potential in addressing the limitations of medical and surgical procedures for treating perineal fistula in patients with Crohn’s disease. Recent developments in stem cell technology have led to a massive good manufacturing practices (GMPs) production of various stem cells, including mesenchymal and embryonic cells, along with induction of pluripotent stem cells to repair damaged tissues in the fistula. The recent advances in separation and purification of exosomes, as biologic nanovesicles carrying anti-inflammatory and regenerative agents, have made them powerful tools to treat this inflammatory disease. Further, tremendous advances in nanotechnology, biomaterials, and scaffold fabrication methods enable tissue engineering methods to synthesize tissue-like structures to assist surgical techniques. This review focuses on advanced regenerative-based methods including stem cell therapy, exosome therapy, and tissue engineering used in the treatment of perianal fistula. Relevant in vitro and in vivo studies and the latest innovations in implementation of regenerative medicine for this disease are also separately reviewed. Additionally, current challenges regarding implementation of g stem cells, exosomes, and tissue engineering methods for bridging the gaps between laboratory findings and clinic application will be discussed.

Graphical abstractThe design and fabrication of poly vinyl alcohol sealant film and evaluating efficacy of this novel patch for prevention of anastomosis leakage.