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.
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.
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.
Graphical abstractThe design and fabrication of poly vinyl alcohol sealant film and evaluating efficacy of this novel patch for prevention of anastomosis leakage.
Purpose Anastomosis is a standard technique following different conditions, such as obstruction, tumor, and trauma. Obstruction, adhesion, or anastomosis leakage can be some of its complications. To improve healing and prevent postoperative complications, we design a hybrid scaffold containing acellular human Amniotic membranes and Polycaprolactone-Molybdenum disulfide nanosheets for colon anastomosis. Methods The animal model of colocolonic anastomosis was performed on two groups of rats; control and scaffold. The hybrid scaffold was warped around the anastomosis site in the scaffold group. Samples from the anastomosis site were resected on the third and seventh postoperative days for histopathological and molecular assessment. Results Histopathologic score and burst pressure had shown significant improvement in the scaffold group. No mortality and anastomosis leakage was reported in the scaffold group. In addition, inflammatory markers were significantly decreased, while anti-inflammatory cytokines were increased in the scaffold group. Conclusion The result indicates that our hybrid scaffold is a proper choice for colorectal anastomosis repair by declining postoperative complications and accelerating healing.
Purpose The formation of chronic wounds accounts for considerable costs in health care systems. Despite the several benefits of decellularized small intestinal submucosa (SIS) as an appropriate scaffold for different tissue regeneration, it has shortcomings such as lack of antibacterial features and inappropriate mechanical properties for skin tissue regeneration. We aimed to examine the efficacy and safety of decellularized SIS scaffold enhanced with cellulose acetate (CA) and silver (Ag) nanoparticles (NPs) for healing full-thickness wounds.Methods The scaffolds were prepared by decellularizing bovine SIS and electrospinning CA/Ag nanoparticles and characterized using a transmission electron microscope (TEM), scanning electron microscope (SEM), tensile testing, and X-ray diffraction. In vivo evaluations were performed using full-thickness excisions covered with sterile gauze as the control group, SIS, SIS/CA, and SIS/CA/Ag scaffolds on the dorsum of twenty male Wistar rats divided into four groups randomly with 21-days follow-up. All in vivo specimens underwent Masson's trichrome (MT) staining for evaluation of collagen deposition, transforming growth factor-β (TGF-β) immunohistochemistry (IHC), and Haematoxylin Eosin(H&E) staining. The IHC and MT data were analyzed with the ImageJ tool by measuring the stained area.Results The TEM results revealed that Ag nanoparticles are successfully incorporated into CA nanofibers. Assessment of scaffolds hydrophilicity demonstrated that the contact angle of SIS/CA/Ag scaffold was the lowest. The in vivo results indicated that the SIS/CA/Ag scaffold had the most significant wound closure. H&E staining of the in vivo specimens showed the formation of epidermal layers in the SIS/CA/Ag group on day 21. The percentage of the stained area of MT and TGF-β IHC staining’s was highest in the SIS/CA/Ag group.Conclusion The decellularized SIS/CA/Ag scaffolds provided the most significant wound closure compared to other groups and caused the formation of epidermal layers and can be considered a novel method for enhancement of healing full-thickness wounds. Additionally, the collagen deposition and expression of TGF-β increased significantly in SIS/CA/Ag group.
Background and objectives: Exosomes therapy is a promising technique that can decrease the concern related to the fate of transplanted stem cells to the fistula location. The unique properties of mesenchymal stem cells (MSCs)-derived exosomes can improve fistula healing because of their high ability to regulate and modify immune responses. This project aims to examine the safety and efficacy of implementing MSCs-exosomes in treating refractory fistulas in inflammatory bowel disease (IBD) patients. Methods: The exosomes were isolated from umbilical cord-derived MSCs and characterized using flow cytometry, western blotting, and transmittance electron microscope (TEM). Five patients (three men and two women) with refractory perianal Crohn’s disease with an average age of 35.4 years old were included. The patients did not match the exclusion criteria, and the presence of refractory fistulas was the main inclusion criteria. These patients have their exosomes injections in the operation room. The therapy responses of patients were assessed using physical examination, face-to-face interviews, computerized tomography (CT) scan, and magnetic resonance imaging (MRI) six months later. Result: The Following injection, patients reported a 70% improvement on average. Two patients claimed complete healing after exosome injections, while one patient reported no improvement and active discharge from the fistula site. In addition, five patients reported no adverse effects, both systemic or on the injection site. Conclusion: Injection of exosomes extracted from MSCs shows total safety and a satisfactory therapeutic impact, as shown in this and other research, and could play a significant role in the treatment of gastrointestinal fistulas in the future.
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