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
Research background

Digestive tract anastomoses and sutures are prone to leakages even if all the classical surgical principles for a successful anastomosis are accomplished. Leakage rates have remained almost unchanged for the last decades and usually associate high morbidity and mortality. Leakages are usually due to failed healing. Stem cells (SCs) have emerged as a promising tool to enhance healing in a wide variety of experimental and clinical settings, including particularly unfavorable environments such as anal fistulas and Crohn´s disease. Since 2008, SCs have been proven as an alternative to improve anastomoses outcomes.

Research motivation

To know if SC therapy could improve postoperative healing mechanisms in digestive anastomosis and sutures in the published literature. If this hypothesis is correct, many patients would benefit from better surgical outcomes reducing morbidity and mortality.

Research objectives

To review the published literature related to SC use for digestive anastomoses and sutures and the registered clinical trials. When this manuscript was confected, there was only one published review including studies published prior to September 2014. This is important for possible future investigations on the field.

Research methods

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 period 2000-2021. The United States and European Union (EU) official registries of clinical trials, and EU Clinical Trials Register, were also searched. Studies employing SCs, performing digestive anastomoses or 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, animal and 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 in a descriptive way.

Research results

Eighteen preclinical studies and three review papers were identified; there are no published clinical studies or registered clinical trials. Colon and colorectal anastomoses are the most frequently examined (ten studies) and rats (12 studies) are the mostly employed animals followed by pigs (4). Three anastomotic models have been described: conventional (4 studies), high risk of AL (8) and insufficient (2); gastric perforation models either included (2 studies) or did not include (1) repair. Most analyzed SCs were Mesenchymal (16 studies); cell transplant was autologous in 8 studies, allogeneic in 7 and xenogeneic in 2 (human); SCs dosage ranged from 5 × 105 to 1 × 107 and delivery routes were mainly local injections (7) and cell sheets (4) followed by biosutures (sutures coated by SCs) or purely topical (2 studies each one). Random assignation of treatments was applied only in 3 publications and blinded evaluations were scarce.

Related to outcome measures, the most frequent evaluation periods were in the first week (9 studies) or during the first month (5). All studies evaluated morphologically the abdominal cavity and/or anastomosis or digestive sutures, and eleven out of 17 analyzed anastomotic or suture strength with bursting pressure evaluation.

All investigations confirmed the safety and absence of relevant adverse events attributable to SCs. It must be highlighted the relatively low rate of severe complications and the extremely low mortality rate reported.

In general, good and encouraging morphological (mainly histological, nearly all the studies), functional (8 studies positive and 3 without effect) and even clinical results have been observed as well as some data suggesting regeneration. Clinically, five studies reported significant lower AL incidence, five fewer adhesions, four fewer abscesses and one less mortality. Eight studies analyzed SC labelling and confirmed SC survival in this potentially septic area.

As potential weaknesses, animal models need to be improved to make them more comparable, and the SC isolation processes need to be standardised.

Research conclusions

There is notable heterogeneity in the studies, making them difficult to compare. Further investigations are needed. The future role of SC therapy in digestive anastomoses/sutures still needs to be determined and seems to be currently far from clinical use.

Research perspectives

In the experimental setting SCs applied to digestive anastomosis or perforation healing have been proven to be safe and may be potentially effective. Areas needing further studying would be: Defining the best model of anastomosis healing; Obtaining deeper knowledge about SCs mechanism of action; Improving SC delivery, survival and function (cytokine or molecule addition, etc.); Supplying SCs through minimally invasive methods; Determining the indications, adjuvants, real efficacy and to confirm safety and definitely discard oncological concerns.

This review suggests that more studies on animal models and with better statistical quality are needed prior to human use. Only in this case SC therapy could be tried on humans in highly controlled settings as clinical trials.