|
1
|
SULMIATI S, ISLAM AA, JOSH F, WARSINGGIH W, MAHMUDI A, HATTA M, NATZIR R, BUKHARI A, WAHYUNI S, PATELLONGI I. Effect of platelet-rich plasma plus stromal vascular fraction on epithelialization and collagenization of rectoanal wounds in Wistar rats. GAZZETTA MEDICA ITALIANA ARCHIVIO PER LE SCIENZE MEDICHE 2023; 182. [DOI: 10.23736/s0393-3660.23.05007-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
|
|
2
|
Kim M, Oh BY, Lee JS, Yoon D, Kim YR, Chun W, Kim JW, Son IT. Differentiation of Adipose-Derived Stem Cells into Smooth Muscle Cells in an Internal Anal Sphincter-Targeting Anal Incontinence Rat Model. J Clin Med 2023; 12:jcm12041632. [PMID: 36836167 PMCID: PMC9959483 DOI: 10.3390/jcm12041632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/05/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
OBJECTIVE Studies on development of an anal incontinence (AI) model targeting smooth muscle cells (SMCs) of the internal anal sphincter (IAS) have not been reported. The differentiation of implanted human adipose-derived stem cells (hADScs) into SMCs in an IAS-targeting AI model has also not been demonstrated. We aimed to develop an IAS-targeting AI animal model and to determine the differentiation of hADScs into SMCs in an established model. MATERIALS AND METHODS The IAS-targeting AI model was developed by inducing cryoinjury at the inner side of the muscular layer via posterior intersphincteric dissection in Sprague-Dawley rats. Dil-stained hADScs were implanted at the IAS injury site. Multiple markers for SMCs were used to confirm molecular changes before and after cell implantation. Analyses were performed using H&E, immunofluorescence, Masson's trichrome staining, and quantitative RT-PCR. RESULTS Impaired smooth muscle layers accompanying other intact layers were identified in the cryoinjury group. Specific SMC markers, including SM22α, calponin, caldesmon, SMMHC, smoothelin, and SDF-1 were significantly decreased in the cryoinjured group compared with levels in the control group. However, CoL1A1 was increased significantly in the cryoinjured group. In the hADSc-treated group, higher levels of SMMHC, smoothelin, SM22α, and α-SMA were observed at two weeks after implantation than at one week after implantation. Cell tracking revealed that Dil-stained cells were located at the site of augmented SMCs. CONCLUSIONS This study first demonstrated that implanted hADSc restored impaired SMCs at the injury site, showing stem cell fate corresponding to the established IAS-specific AI model.
Collapse
Affiliation(s)
- Minsung Kim
- Department of Surgery, Hallym Sacred Heart Hospital, College of Medicine, Hallym University, Anyang 14068, Republic of Korea
| | - Bo-Young Oh
- Department of Surgery, Hallym Sacred Heart Hospital, College of Medicine, Hallym University, Anyang 14068, Republic of Korea
| | - Ji-Seon Lee
- Burn Institute, Hangang Sacred Heart Hospital, College of Medicine, Hallym University, Seoul 07247, Republic of Korea
| | - Dogeon Yoon
- Burn Institute, Hangang Sacred Heart Hospital, College of Medicine, Hallym University, Seoul 07247, Republic of Korea
| | - You-Rin Kim
- Burn Institute, Hangang Sacred Heart Hospital, College of Medicine, Hallym University, Seoul 07247, Republic of Korea
| | - Wook Chun
- Burn Institute, Hangang Sacred Heart Hospital, College of Medicine, Hallym University, Seoul 07247, Republic of Korea
- Department of Surgery, Hangang Sacred Heart Hospital, College of Medicine, Hallym University, Seoul 07247, Republic of Korea
| | - Jong Wan Kim
- Department of Surgery, Dontan Sacred Heart Hospital, College of Medicine, Hallym University, Hwaseong-si 18450, Republic of Korea
| | - Il Tae Son
- Department of Surgery, Hallym Sacred Heart Hospital, College of Medicine, Hallym University, Anyang 14068, Republic of Korea
- Institute for Regenerative Medicine, Hallym Sacred Heart Hospital, College of Medicine, Hallym University, Anyang 14068, Republic of Korea
| |
Collapse
|
|
3
|
The Effect of Mesenchymal Stem Cells, Adipose Tissue Derived Stem Cells, and Cellular Stromal Vascular Fraction on the Repair of Acute Anal Sphincter Injury in Rats. Bioengineering (Basel) 2022; 9:bioengineering9070318. [PMID: 35877369 PMCID: PMC9311655 DOI: 10.3390/bioengineering9070318] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/20/2022] [Accepted: 06/21/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Anal sphincter incontinence (ASI) can cause a serious decline in the quality of life and can cause a socioeconomic burden. Studies have shown that bone marrow mesenchymal stem cells (MSC) have significant therapeutic effects on ASI, but the cost and risk of MSC harvest limit their further application. In contrast, adipose tissue derived stem cells (ADSC) and cellular stromal vascular fraction (CSVF) as stem cell sources have multipotency and the advantage of easy harvest. Objective: Here we aim to investigate the effects of ADSC and CSVF on treating ASI and compare them to that of bone marrow MSC. Methods: Bone marrow MSC, ADSC, and CSVF were obtained and labeled with green fluorescent protein (GFP), and CSVF was labeled with DIL. Sprague Dawley (SD) rats were divided into 5 groups. Four groups were injected with 0.2 mL phosphate buffer saline (PBS), 1 × 107/0.2 mL of MSC, ADSC, or CSVF, respectively, after model establishment. The control group received no treatment. The repair was assessed by anal functional tests and immunostaining on day 5 and day 10 after injection. Results: MSC, ADSC, and CSVF significantly promoted tissue repair and the recovery of muscle contraction and electromyographic activity in ASI. The generation of myosatellite cells by injected MSC, ADSC, and CSVF was found in the wounded area. On day 5, CSVF showed highest therapeutic effect, while on day 10, MSC and ADSC showed higher therapeutic effects than CSVF. When comparing the effects of MSC and ADSC, ADSC was slightly better than MSC in the indexes of anal pressure, etc. Conclusion: ADSC and CVSF are alternative stem cell sources for ASI repair.
Collapse
|
|
4
|
Kim M, Oh BY, Lee JS, Yoon D, Chun W, Son IT. A systematic review of translation and experimental studies on internal anal sphincter for fecal incontinence. Ann Coloproctol 2022; 38:183-196. [PMID: 35678021 PMCID: PMC9263305 DOI: 10.3393/ac.2022.00276.0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Accepted: 05/10/2022] [Indexed: 12/05/2022] Open
Abstract
The complexity in the molecular mechanism of the internal anal sphincter (IAS) limits preclinical or clinical outcomes of fecal incontinence (FI) treatment. So far, there are no systematic reviews of IAS translation and experimental studies that have been reported. This systematic review aims to provide a comprehensive understanding of IAS critical role in FI. Previous studies revealed the key pathway for basal tone and relaxation of IAS in different properties as follows; calcium, Rho-associated, coiled-coil containing serine/threonine kinase, aging-associated IAS dysfunction, oxidative stress, renin-angiotensin-aldosterone, cyclooxygenase, and inhibitory neurotransmitters. Previous studies have reported improved functional outcomes of cellular treatment for regeneration of dysfunctional IAS, using various stem cells, but did not demonstrate the interrelationship between those results and basal tone or relaxation-related molecular pathway of IAS. Furthermore, these results have lower specificity for IAS-incontinence due to the included external anal sphincter or nerve injury regardless of the cell type. An acellular approach using bioengineered IAS showed a physiologic response of basal tone and relaxation response similar to human IAS. However, in both cellular and acellular approaches, the lack of human IAS data still hampers clinical application. Therefore, the IAS regeneration presents more challenges and warrants more advances.
Collapse
Affiliation(s)
- Minsung Kim
- Department of Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
| | - Bo-Young Oh
- Department of Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
| | - Ji-Seon Lee
- Burn Institute, Hangang Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Dogeon Yoon
- Burn Institute, Hangang Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Wook Chun
- Burn Institute, Hangang Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea.,Department of Surgery, Hangang Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Il Tae Son
- Department of Surgery, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea.,Institute for Regenerative Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
| |
Collapse
|
|
5
|
El Haraki AS, Lankford S, Li W, Williams KJ, Matthews CA, Badlani GH. Chemokine therapy for anal sphincter injury in a rat model: a pilot study. Int Urogynecol J 2022; 33:3283-3289. [PMID: 35445812 DOI: 10.1007/s00192-022-05195-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/20/2022] [Indexed: 11/29/2022]
Abstract
INTRODUCTION AND HYPOTHESIS To determine whether delayed administration of CXCL12 alters anorectal manometric pressures and histology in rats following anal sphincterotomy compared to primary surgical repair alone. METHODS Adult female rats were divided into three groups: A, a control group that did not undergo surgery; B, anal sphincterotomy with primary surgical repair; C, anal sphincterotomy with primary surgical repair and intra-sphincteric injection of CXCL12 at 6 weeks post-injury. All rats underwent anal manometry measurements at baseline and at 6 and 12 weeks post-injury. Histologic analysis of the anal sphincters was also performed. RESULTS At baseline and 6 weeks, there were no statistically significant differences among D, Tmax and P∆ of Groups A, B and C. At 12-week manometry, the total duration of contractions on anal manometry was significantly less in Group C compared to Groups A and B (3.65, 5.5, 5.3 p < 0.01) as was time to peak of contraction at 12 weeks (1.6, 2.1, 3.1, p < 0.01); however, group C had a significantly higher P∆ at 12 weeks compared to Groups A and B (2.25, 1.4, 0.34, p < 0.01). There were no statistically significant differences in the ratio of muscle to collagen at the site of injury; however, muscle fibers were significantly smaller in group C and less per bundle than the other groups. CONCLUSIONS Administration of chemokine therapy at 6 weeks post-repair using CXCL12 enhanced the magnitude of anal sphincter contractions in a rat model of anal sphincter injury but decreased overall duration of contraction. Increased anal sphincter contraction magnitude was not explained by histologic differences in explanted specimens.
Collapse
Affiliation(s)
- Amr S El Haraki
- Department of Urology, Wake Forest Baptist Medical Center, 1 Medical Center Blvd, Winston-Salem, NC, 27157, USA.
| | - S Lankford
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA
| | - Wencheng Li
- Department of Pathology, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA
| | - Koudy J Williams
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA
| | - Catherine A Matthews
- Department of Urology, Wake Forest Baptist Medical Center, 1 Medical Center Blvd, Winston-Salem, NC, 27157, USA
| | - Gopal H Badlani
- Department of Urology, Wake Forest Baptist Medical Center, 1 Medical Center Blvd, Winston-Salem, NC, 27157, USA
| |
Collapse
|
|
6
|
Sujana RS, Sulmiati, Mariana N, Josh F, Laidding SR, Zainuddin AA, Faruk M. The effect of stromal vascular fraction and Platelet-Rich Plasma combination on basic Fibroblast Growth Factor serum level during anal trauma healing in a Wistar rat model. Ann Med Surg (Lond) 2022; 76:103375. [PMID: 35295741 PMCID: PMC8918729 DOI: 10.1016/j.amsu.2022.103375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 02/06/2022] [Accepted: 02/10/2022] [Indexed: 11/21/2022] Open
Abstract
Introduction Stromal Vascular Fraction (SVF) and Platelet-Rich Plasma (PRP) application play important roles in the healing process by increasing basic Fibroblast Growth Factor (bFGF) secretion. This research assesses the effect of combined SVF and PRP local injection on bFGF levels, using an anal trauma model in Wistar rats. Method Twenty-eight adult Wistar rats were divided into three groups. Groups A and B underwent modified surgical anal trauma and repair; Group A was treated with the SVF and PRP combination local injection, while Group B was treated with only normal saline. Subsequently, we examined bFGF levels in Groups A and B on days 1, 7, and 14. Group C consisted of healthy controls sacrificed on day 0 to obtain baseline data on bFGF levels. Results The bFGF levels were higher in Group A than in Group B on every experimental day. The Repeated Measures test shows a significant increase in bFGF levels on day 1 (p = 0.000), day 7 (p = 0.000), and day 14 (p = 0.000). This test also indicates that the local injection combination of SVF and PRP increased bFGF levels by 96.2% compared to the placebo group. Conclusion The combination of SVF and PRP can increase bFGF levels during anal trauma healing in the Wistar rat model. Basic FGF is an important factor throughout the anal trauma healing process.
The combination of SVFs and PRP is effective to increase the concentration of bFGF. Administration of SVFS + PRP by injection was better at increasing the expression of bFGF than by placebo. The combination of SVFs and PRP increases the level of bFGF in the healing process of anal trauma.
Collapse
|
|
7
|
Trébol J, Georgiev-Hristov T, Pascual-Miguelañez I, Guadalajara H, García-Arranz M, García-Olmo D. Stem cell therapy applied for digestive anastomosis: Current state and future perspectives. World J Stem Cells 2022; 14:117-141. [PMID: 35126832 PMCID: PMC8788180 DOI: 10.4252/wjsc.v14.i1.117] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/21/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND 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. AIM To summarise the published knowledge of SC utilisation as a preventative tool for hollow digestive viscera anastomotic or suture leaks. 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 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. RESULTS 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. CONCLUSION 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.
Collapse
Affiliation(s)
- Jacobo Trébol
- Servicio de Cirugía General y del Aparato Digestivo, Complejo Asistencial Universitario de Salamanca, Salamanca 37007, Spain
- 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
- Departamento de Cirugía, Universidad Autónoma de Madrid, Madrid 28029, Spain
| | - Damian García-Olmo
- Departamento de Cirugía, Universidad Autónoma de Madrid, Madrid 28029, Spain
- Servicio de Cirugía General y del Aparato Digestivo, Hospital Universitario Fundación Jiménez Díaz y Grupo Quiron-Salud Madrid, Madrid 28040, Spain
| |
Collapse
|
|
8
|
The effect of Platelet-Rich Plasma and Stromal Vascular Fraction combination on Epidermal Growth Factor serum level for anal trauma healing in the Wistar rat model. Ann Med Surg (Lond) 2021; 70:102773. [PMID: 34584679 PMCID: PMC8450198 DOI: 10.1016/j.amsu.2021.102773] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 08/23/2021] [Accepted: 09/02/2021] [Indexed: 11/26/2022] Open
Abstract
Introduction Stromal Vascular Fraction cells (SVFs) and Platelet Rich Plasma (PRP) are clinically proven to aid in cell regeneration and wound healing. The healing effects can be measured by the level of Epidermal Growth Factor (EGF). This study aims to investigate the effect of an SVFs and PRP combination on EGF levels in the anal trauma model. Method Twenty-eight adult Wistar rats were divided into 3 groups: Group A consisted of healthy rats as a normal control group; Group B and C underwent modified anal surgical trauma and repair. Group B was treated with saline only and Group C was treated with local injection of a combination of SVFs and PRP after anal surgical repair. The EGF level was subsequently assessed on days 1, 7, and 14. Results EGF levels were generally increased in Group C compared to Group B. A one-way ANOVA test result showed significantly increased EGF levels on days 7 (p = 0.038) and 14 (p = 0.018). Based on the linear regression test results, we found that local injection of PRP and SVFs after anal repair on an anal surgical trauma model can increase the EGF level in group C by 36.9% more than that of group B. Conclusion The combination of PRP and SVFs can increase the EGF level in the wound healing process of anal trauma. EGF is critical in the anal trauma healing process.
Application of PRP and SVFs can increase EGF level in the anal trauma healing process PRP and SVFs combination therapy is a promising treatment to increase growth factor levels.
Collapse
|
|
9
|
Balaphas A, Meyer J, Meier RPH, Liot E, Buchs NC, Roche B, Toso C, Bühler LH, Gonelle-Gispert C, Ris F. Cell Therapy for Anal Sphincter Incontinence: Where Do We Stand? Cells 2021; 10:2086. [PMID: 34440855 PMCID: PMC8394955 DOI: 10.3390/cells10082086] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 12/12/2022] Open
Abstract
Anal sphincter incontinence is a chronic disease, which dramatically impairs quality of life and induces high costs for the society. Surgery, considered as the best curative option, shows a disappointing success rate. Stem/progenitor cell therapy is pledging, for anal sphincter incontinence, a substitute to surgery with higher efficacy. However, the published literature is disparate. Our aim was to perform a review on the development of cell therapy for anal sphincter incontinence with critical analyses of its pitfalls. Animal models for anal sphincter incontinence were varied and tried to reproduce distinct clinical situations (acute injury or healed injury with or without surgical reconstruction) but were limited by anatomical considerations. Cell preparations used for treatment, originated, in order of frequency, from skeletal muscle, bone marrow or fat tissue. The characterization of these preparations was often incomplete and stemness not always addressed. Despite a lack of understanding of sphincter healing processes and the exact mechanism of action of cell preparations, this treatment was evaluated in 83 incontinent patients, reporting encouraging results. However, further development is necessary to establish the correct indications, to determine the most-suited cell type, to standardize the cell preparation method and to validate the route and number of cell delivery.
Collapse
Affiliation(s)
- Alexandre Balaphas
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (J.M.); (E.L.); (N.C.B.); (B.R.); (C.T.); (F.R.)
- Department of Surgery, Geneva Medical School, University of Geneva, 1205 Geneva, Switzerland
| | - Jeremy Meyer
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (J.M.); (E.L.); (N.C.B.); (B.R.); (C.T.); (F.R.)
| | - Raphael P. H. Meier
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Emilie Liot
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (J.M.); (E.L.); (N.C.B.); (B.R.); (C.T.); (F.R.)
| | - Nicolas C. Buchs
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (J.M.); (E.L.); (N.C.B.); (B.R.); (C.T.); (F.R.)
| | - Bruno Roche
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (J.M.); (E.L.); (N.C.B.); (B.R.); (C.T.); (F.R.)
| | - Christian Toso
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (J.M.); (E.L.); (N.C.B.); (B.R.); (C.T.); (F.R.)
| | - Leo H. Bühler
- Faculty of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland; (L.H.B.); (C.G.-G.)
| | - Carmen Gonelle-Gispert
- Faculty of Science and Medicine, University of Fribourg, 1700 Fribourg, Switzerland; (L.H.B.); (C.G.-G.)
| | - Frédéric Ris
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (J.M.); (E.L.); (N.C.B.); (B.R.); (C.T.); (F.R.)
| |
Collapse
|
|
10
|
de la Portilla F, Guerrero JL, Maestre MV, Leyva L, Mera S, García-Olmo D, Rodríguez A, Mata R, Lora F. Treatment of faecal incontinence with autologous expanded mesenchymal stem cells: results of a pilot study. Colorectal Dis 2021; 23:698-709. [PMID: 32986295 DOI: 10.1111/codi.15382] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 09/09/2020] [Accepted: 09/15/2020] [Indexed: 02/08/2023]
Abstract
AIM Management of faecal incontinence (FI) remains challenging because no definitive optimal treatment for this condition has yet been determined. Regenerative medicine could be an attractive therapeutic alternative for treating FI. Here, we aimed to determine the safety and feasibility of autologous expanded mesenchymal stem cells derived from adipose tissue (AdMSCs) in the treatment of patients diagnosed with structural FI. METHOD This was a randomized, multicentre, triple-blinded, placebo-controlled pilot study conducted at four sites in Spain with 16 adults with FI and a sphincter defect. Autologous AdMSCs were obtained from patients from surgically excised adipose tissue. These patients were intralesionally infused with a single dose of 4 × 107 AdMSCs or a placebo while under anaesthesia. We assessed the safety and feasibility of the treatment as the cumulative incidence of adverse events and the treatment efficacy using the Cleveland Clinic Faecal Incontinence Score, Faecal Incontinence Quality of Life score and Starck criteria to classify sphincter defects and anorectal physiology outcomes. RESULTS Adipose tissue extraction, cell isolation and intralesional infusion procedures were successful in all the patients. There was only one adverse event connected to adipose tissue extraction (a haematoma), and none was associated with the injection procedure. There were no significant differences in any of the assessed clinical, manometric or ultrasonographic parameters. CONCLUSION This study indicates that this infusion procedure in the anal sphincter is feasible and safe. However, it failed to demonstrate efficacy to treat patients with structural FI.
Collapse
Affiliation(s)
- Fernando de la Portilla
- Coloproctology Clinical Management Unit, General and Gastrointestinal Surgery Division, Biomedical Research Institute (IBIS), Hospital Universitario Virgen del Rocio/CSIC University of Seville, Seville, Spain
| | - José Luis Guerrero
- Coloproctology Clinical Management Unit, General and Gastrointestinal Surgery Division, Biomedical Research Institute (IBIS), Hospital Universitario Virgen del Rocio/CSIC University of Seville, Seville, Spain
| | - Maria Victoria Maestre
- Coloproctology Clinical Management Unit, General and Gastrointestinal Surgery Division, Biomedical Research Institute (IBIS), Hospital Universitario Virgen del Rocio/CSIC University of Seville, Seville, Spain
| | - Laura Leyva
- GMP Cell Manufacturing Unit, Biomedical Research Institute of Malaga (IBIMA), Hospital Regional Universitario de Malaga, Málaga, Spain
| | - Santiago Mera
- Coloproctology Unit Clinical Management, Unit of General Surgery Division, Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Damián García-Olmo
- Department of Surgery, University Hospital Fundación Jiménez Díaz, Madrid, Spain
| | - Antonio Rodríguez
- GMP Cell Manufacturing Unit, Biomedical Research Institute of Malaga (IBIMA), Hospital Regional Universitario de Malaga, Málaga, Spain
| | - Rosario Mata
- Andalusian Network for Design and Translation of Advanced Therapies, Seville, Spain
| | - Fabiola Lora
- Andalusian Network for Design and Translation of Advanced Therapies, Seville, Spain
| |
Collapse
|
|
11
|
Li P, Ma X, Jin W, Li X, Hu J, Jiang X, Guo X. Effects of local injection and intravenous injection of allogeneic bone marrow mesenchymal stem cells on the structure and function of damaged anal sphincter in rats. J Tissue Eng Regen Med 2020; 14:989-1000. [PMID: 32537834 DOI: 10.1002/term.3079] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 04/09/2020] [Accepted: 05/11/2020] [Indexed: 12/21/2022]
Abstract
Anal sphincter injury leads to damage to the anal structure and functions and has been identified as a major risk factor for fecal incontinence. Bone marrow mesenchymal stem cells (BMSCs) with capacities of multidifferentiation, paracrine, and low immunogenicity have been widely used in tissue repair and regeneration. The primary objective of this research was to compare the effects of different injection therapies of BMSCs on the injured anal sphincters. Ninety-six Sprague-Dawley female rats were randomly divided into four groups (n = 24 each): intravenous injection, local injection, sham operation, and normal control. For the first three groups, 25% removal of the anal sphincter complex was performed and 0.3-ml phosphate-buffered saline (PBS) (containing 107 green fluorescent protein-labeled allogeneic BMSCs) was given accordingly to the treatment group 24 h after operation for 7 consecutive days. The sham operation group was injected with 0.3-ml PBS only. All cases had undergone evaluation in the 1st, 7th, 14th, and 28th postoperative days. The rats were sacrificed on the 28th postoperative day, and the anal sphincters were dissected to be analyzed by morphological examination. At 14 days postoperatively, local injection of BMSC significantly improved the peak contraction pressure, electromyography amplitude, and frequency of the injured anal sphincter compared with tail vein, but there was no significant difference in resting pressure until 28 days after sphincterectomy. Masson staining results confirmed that the local injection group had significantly more new muscles on the wound. BMSC could remarkably improve peak contraction pressure, electromyography amplitude, and muscle fibers on the wound, and local injection is superior to intravenous injection.
Collapse
Affiliation(s)
- Peng Li
- Department of Anorectal, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoying Ma
- School of Pharmacy, East China University of Science and Technology, Shanghai, China
| | - Wenqi Jin
- Department of Anorectal, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaojia Li
- Department of Anorectal, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jie Hu
- Department of Anorectal, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaoxue Jiang
- Department of Anorectal Surgery, Shanghai Eighth People's Hospital, Shanghai, China
| | - Xiutian Guo
- Department of Anorectal, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| |
Collapse
|
|
12
|
De Ligny WR, Kerkhof MH, Ruiz-Zapata AM. Regenerative medicine as a therapeutic option for fecal incontinence: a systematic review of preclinical and clinical studies. Am J Obstet Gynecol 2019; 220:142-154.e2. [PMID: 30267651 DOI: 10.1016/j.ajog.2018.09.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/28/2018] [Accepted: 09/10/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Fecal incontinence is the uncontrollable loss of stool and has a prevalence of around 7-15%. This condition has serious implications for patients' quality of life. Current treatment options show unsatisfactory results. A novel treatment option is therefore needed. OBJECTIVE This systematic review aims to perform a quality assessment and to give a critical overview of the current research available on regenerative medicine as a treatment for fecal incontinence. STUDY DESIGN A systematic search strategy was applied in PubMed, Cochrane Library, EMBASE, MEDLINE, Web of Science, and Cinahl from inception until March of 2018. Studies were found relevant when the animals or patients in the studied group had objectively determined or induced fecal incontinence, and the intervention must have used any kind of cells, stem cells, or biocompatible material, with or without the use of trophic factors. Studies were screened on title and consecutively on abstract for relevance by 2 independent investigators. The risk of bias of preclinical studies was assessed using the SYstematic Review Centre for Laboratory animal Experimentation risk of bias tool for animal studies, and for clinical studies the Cochrane risk of bias tool for randomized trials was used. RESULTS In all, 34 preclinical studies and 5 clinical studies were included. Animal species, type of anal sphincter injury, intervention, and outcome parameters were heterogenous. Therefore, a meta-analysis could not be performed. The overall risk of bias of the included studies was high. CONCLUSION The efficacy of regenerative medicine to treat fecal incontinence could not be determined due to the high risk of bias and heterogenicity of the available preclinical and clinical studies. The findings of this systematic review may result in improved study design of future studies, which could help the translation of regenerative medicine to the clinic as an alternative to current treatments for fecal incontinence.
Collapse
|
|
13
|
Chitosan/LiCl composite scaffolds promote skin regeneration in full-thickness loss. SCIENCE CHINA-LIFE SCIENCES 2019; 63:552-562. [DOI: 10.1007/s11427-018-9389-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 11/24/2018] [Indexed: 12/21/2022]
|
|
14
|
Trébol J, Carabias-Orgaz A, García-Arranz M, García-Olmo D. Stem cell therapy for faecal incontinence: Current state and future perspectives. World J Stem Cells 2018; 10:82-105. [PMID: 30079130 PMCID: PMC6068732 DOI: 10.4252/wjsc.v10.i7.82] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/26/2018] [Accepted: 06/30/2018] [Indexed: 02/06/2023] Open
Abstract
Faecal continence is a complex function involving different organs and systems. Faecal incontinence is a common disorder with different pathogeneses, disabling consequences and high repercussions for quality of life. Current management modalities are not ideal, and the development of new treatments is needed. Since 2008, stem cell therapies have been validated, 36 publications have appeared (29 in preclinical models and seven in clinical settings), and six registered clinical trials are currently ongoing. Some publications have combined stem cells with bioengineering technologies. The aim of this review is to identify and summarise the existing published knowledge of stem cell utilization as a treatment for faecal incontinence. A narrative or descriptive review is presented. Preclinical studies have demonstrated that cellular therapy, mainly in the form of local injections of muscle-derived (muscle derived stem cells or myoblasts derived from them) or mesenchymal (bone-marrow- or adipose-derived) stem cells, is safe. Cellular therapy has also been shown to stimulate the repair of both acute and subacute anal sphincter injuries, and some encouraging functional results have been obtained. Stem cells combined with normal cells on bioengineered scaffolds have achieved the successful creation and implantation of intrinsically-innervated anal sphincter constructs. The clinical evidence, based on adipose-derived stem cells and myoblasts, is extremely limited yet has yielded some promising results, and appears to be safe. Further investigation in both animal models and clinical settings is necessary to drawing conclusions. Nevertheless, if the preliminary results are confirmed, stem cell therapy for faecal incontinence may well become a clinical reality in the near future.
Collapse
Affiliation(s)
- Jacobo Trébol
- General and Digestive Tract Surgery Department, Salamanca University Healthcare Centre, Salamanca 37007, Spain.
| | - Ana Carabias-Orgaz
- Anaesthesiology Department, Complejo Asistencial de Ávila, Ávila 05004, Spain
| | - Mariano García-Arranz
- New Therapies Laboratory, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid 28040, Spain
| | - Damián García-Olmo
- General and Digestive Tract Surgery Department, Quiron-Salud Hospitals, Madrid 28040, Spain
| |
Collapse
|