Systematic Reviews
Copyright ©©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Jan 26, 2022; 14(1): 117-141
Published online Jan 26, 2022. doi: 10.4252/wjsc.v14.i1.117
Stem cell therapy applied for digestive anastomosis: Current state and future perspectives
Jacobo Trébol, Tihomir Georgiev-Hristov, Isabel Pascual-Miguelañez, Hector Guadalajara, Mariano García-Arranz, Damian García-Olmo
Jacobo Trébol, Servicio de Cirugía General y del Aparato Digestivo, Complejo Asistencial Universitario de Salamanca, Salamanca 37007, Spain
Jacobo Trébol, Departamento de Anatomía e Histología Humanas, Universidad de Salamanca, Salamanca 37007, Spain
Tihomir Georgiev-Hristov, Servicio de Cirugía General y del Aparato Digestivo, Hospital General Universitario de Villalba, Madrid 28400, Spain
Isabel Pascual-Miguelañez, Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario La Paz, Madrid 28046, Spain
Hector Guadalajara, Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Fundación Jiménez Díaz, Madrid 28040, Spain
Mariano García-Arranz, Grupo de Investigación en Nuevas Terapias, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid 28040, Spain
Mariano García-Arranz, Damian García-Olmo, Departamento de Cirugía, Universidad Autónoma de Madrid, Madrid 28029, Spain
Damian García-Olmo, Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Fundación Jiménez Díaz y Grupo Quiron-Salud Madrid, Madrid 28040, Spain
Author contributions: All authors equally contributed to this paper with drafting and critical revision. Trebol J and Georgiev-Hristov T performed literature review and analysis; Georgiev-Hristov T, Pascual I and Guadalajara H revised language editing; Trebol J wrote the paper; all authors reviewed the paper and gave their final approval of manuscript.
Conflict-of-interest statement: García-Olmo D is a member of the Advisory Board of Tigenix S.A.U. García-Olmo D and García-Arranz M co-hold patent rights for patents related to this study entitled Biomaterial for suture/suturing (WO2006035083A1), Identification and isolation of multipotent cells from non-osteochondral mesenchymal tissue (WO2006037649A1) and about Use of adipose tissue-derived stromal stem cells in treating fistula (WO2006136244A2). García-Olmo D and García-Arranz M are shareholders of Biosurgery, an educational company providing services to Takeda. Other authors disclosed no potential conflicts of interest.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist statement, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist statement.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Jacobo Trébol, MD, PhD, Adjunct Professor, Surgeon, Surgical Oncologist, Servicio de Cirugía General y del Aparato Digestivo, Complejo Asistencial Universitario de Salamanca, Paseo de San Vicente, No. 58-182, Salamanca 37007, Spain.
Received: March 24, 2021
Peer-review started: March 24, 2021
First decision: June 5, 2021
Revised: June 21, 2021
Accepted: December 31, 2021
Article in press: December 31, 2021
Published online: January 26, 2022

Digestive tract resections are usually followed by an anastomosis. Anastomotic leakage, normally due to failed healing, is the most feared complication in digestive surgery because it is associated with high morbidity and mortality. Despite technical and technological advances and focused research, its rates have remained almost unchanged the last decades. In the last two decades, stem cells (SCs) have been shown to enhance healing in animal and human studies; hence, SCs have emerged since 2008 as an alternative to improve anastomoses outcomes.


To summarise the published knowledge of SC utilisation as a preventative tool for hollow digestive viscera anastomotic or suture leaks.


PubMed, Science Direct, Scopus and Cochrane searches were performed using the key words “anastomosis”, “colorectal/colonic anastomoses”, “anastomotic leak”, “stem cells”, “progenitor cells”, “cellular therapy” and “cell therapy” in order to identify relevant articles published in English and Spanish during the years of 2000 to 2021. Studies employing SCs, performing digestive anastomoses in hollow viscera or digestive perforation sutures and monitoring healing were finally included. Reference lists from the selected articles were reviewed to identify additional pertinent articles.

Given the great variability in the study designs, anastomotic models, interventions (SCs, doses and vehicles) and outcome measures, performing a reliable meta-analysis was considered impossible, so we present the studies, their results and limitations.


Eighteen preclinical studies and three review papers were identified; no clinical studies have been published and there are no registered clinical trials. Experimental studies, mainly in rat and porcine models and occasionally in very adverse conditions such as ischaemia or colitis, have been demonstrated SCs as safe and have shown some encouraging morphological, functional and even clinical results. Mesenchymal SCs are mostly employed, and delivery routes are mainly local injections and cell sheets followed by biosutures (sutures coated by SCs) or purely topical. As potential weaknesses, animal models need to be improved to make them more comparable and equivalent to clinical practice, and the SC isolation processes need to be standardised. There is notable heterogeneity in the studies, making them difficult to compare. Further investigations are needed to establish the indications, the administration system, potential adjuvants, the final efficacy and to confirm safety and exclude definitively oncological concerns.


The future role of SC therapy to induce healing processes in digestive anastomoses/sutures still needs to be determined and seems to be currently far from clinical use.

Keywords: Surgical anastomosis, Anastomotic leak, Digestive system surgical procedure, Cell transplantation, Cell therapy, Stem cells, Tissue engineering

Core Tip: Digestive anastomoses leakages reflect impaired healing, are frequent and are associated with severe consequences. Despite technical and technological advancements, leakage rates have remained stable in the last decades. Stem cells (SCs) could improve anastomotic healing, as they have in other altered healing conditions. We present a descriptive review of the published literature about digestive anastomoses and sutures and SCs, analyzing the results and discussing their limitations and concerns. Eighteen preclinical studies have confirmed the feasibility and safety and have shown interesting results, however, with some limitations and high heterogenicity. Additional studies and better models are needed prior to human testing.