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Paik JW, Kwon YH, Park JY, Jung RE, Jung UW, Thoma DS. Effect of Membrane Fixation and the Graft Combinations on Horizontal Bone Regeneration: Radiographic and Histologic Outcomes in a Canine Model. Biomater Res 2024; 28:0055. [PMID: 39076892 PMCID: PMC11284130 DOI: 10.34133/bmr.0055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/20/2024] [Indexed: 07/31/2024] Open
Abstract
The aim of this study was to determine the effect of membrane fixation and combinations of bone substitute materials and barrier membranes on horizontal bone regeneration in peri-implant defects. Eight mongrel dogs underwent chronic buccal peri-implant dehiscence defects creation and were randomized into 4 groups: (a) deproteinized bovine bone mineral 1 (DBBM1) with a native collagen membrane (CM) (BB group, positive control group), (b) DBBM1 with native CM and 2 fixation pins (BBP group), (c) DBBM2 with a cross-linked CM (XC group), and (d) DBBM2 with cross-linked CM and 2 fixation pins (XCP group). Following 16 weeks of healing, tissues were radiographically and histomorphometrically analyzed. The total augmented area was significantly larger in the BBP, XC, and XCP groups compared to the BB group (4.27 ± 3.21, 7.17 ± 7.23, and 6.91 ± 5.45 mm2 versus 1.35 ± 1.28 mm2, respectively; P = 0.022). No significant difference for the augmented tissue thickness was observed among the 4 groups. The augmented tissue thickness measured at 3 mm below the implant shoulder was higher in BBP, XC, and XCP than that in BB (2.43 ± 1.53, 2.62 ± 1.80, and 3.18 ± 1.96 mm versus 0.80 ± 0.90 mm, respectively), trending toward significance (P = 0.052). DBBM2 and a cross-linked CM were significantly more favorable for horizontal bone regeneration compared to DBBM1 and a native CM. However, when DBBM1 and a native CM were secured with fixation pins, outcomes were similar. The addition of pins did not lead to more favorable outcomes when a cross-linked CM was used.
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Affiliation(s)
- Jeong-Won Paik
- Department of Periodontology, Research Institute for Periodontal Regeneration,
Yonsei University College of Dentistry, Seoul, Korea
| | - Yoon-Hee Kwon
- Department of Periodontology, Research Institute for Periodontal Regeneration,
Yonsei University College of Dentistry, Seoul, Korea
| | - Jin-Young Park
- Department of Periodontology, Research Institute for Periodontal Regeneration,
Yonsei University College of Dentistry, Seoul, Korea
| | - Ronald E. Jung
- Clinic of Reconstructive Dentistry, Center of Dental Medicine,
University of Zürich, Zürich, Switzerland
| | - Ui-Won Jung
- Department of Periodontology, Research Institute for Periodontal Regeneration,
Yonsei University College of Dentistry, Seoul, Korea
| | - Daniel S. Thoma
- Department of Periodontology, Research Institute for Periodontal Regeneration,
Yonsei University College of Dentistry, Seoul, Korea
- Clinic of Reconstructive Dentistry, Center of Dental Medicine,
University of Zürich, Zürich, Switzerland
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Shan S, Li Q, Criswell T, Atala A, Zhang Y. Stem cell therapy combined with controlled release of growth factors for the treatment of sphincter dysfunction. Cell Biosci 2023; 13:56. [PMID: 36927578 PMCID: PMC10018873 DOI: 10.1186/s13578-023-01009-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Sphincter dysfunction often occurs at the end of tubule organs such as the urethra, anus, or gastroesophageal sphincters. It is the primary consequence of neuromuscular impairment caused by trauma, inflammation, and aging. Despite intensive efforts to recover sphincter function, pharmacological treatments have not achieved significant improvement. Cell- or growth factor-based therapy is a promising approach for neuromuscular regeneration and the recovery of sphincter function. However, a decrease in cell retention and viability, or the short half-life and rapid degradation of growth factors after implantation, remain obstacles to the translation of these therapies to the clinic. Natural biomaterials provide unique tools for controlled growth factor delivery, which leads to better outcomes for sphincter function recovery in vivo when stem cells and growth factors are co-administrated, in comparison to the delivery of single therapies. In this review, we discuss the role of stem cells combined with the controlled release of growth factors, the methods used for delivery, their potential therapeutic role in neuromuscular repair, and the outcomes of preclinical studies using combination therapy, with the hope of providing new therapeutic strategies to treat incontinence or sphincter dysfunction of the urethra, anus, or gastroesophageal tissues, respectively.
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Affiliation(s)
- Shengzhou Shan
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
| | - Qingfeng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
| | - Tracy Criswell
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Yuanyuan Zhang
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
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Sun L, Billups A, Rietsch A, Damaser MS, Zutshi M. Stromal cell derived factor 1 plasmid to regenerate the anal sphincters. J Tissue Eng Regen Med 2022; 16:355-366. [PMID: 35092171 DOI: 10.1002/term.3283] [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: 04/08/2021] [Revised: 12/21/2021] [Accepted: 01/07/2022] [Indexed: 11/09/2022]
Abstract
The aim of this study was to evaluate regeneration of a chronic large anal sphincter defect in a pig model after treatment with a plasmid encoding Stromal Cell Derived Factor-1(SDF-1). METHODS Under ethics approved protocol 19 age/weight matched Sinclair mini-pigs were subjected to excision of the posterior 50% of anal sphincter muscle and left to recover for 6 weeks. They were randomly allocated to receive either saline treatment (Saline 1 ml, n = 5), 1 injection of SDF-1 plasmid 2 mg/ml (1 SDF-1, n = 9) or 2 injections of SDF-1, 2 mg/ml each at 2 weeks intervals (2 SDF-1, n = 5). Euthanasia occurred 8 weeks after the last treatment. In vivo outcomes included anal resting pressures done under anesthesia pre-injury, pre-injection and before euthanasia (8 weeks after treatment). Anal ultrasound was done pre injury and pre-euthanasia. Tissues were saved for histology and analyzed quantitatively. Two way ANOVA followed by Holm-Sidak test and one way ANOVA followed by the Tukey test were used for data analysis, p < 0.05 was regarded as significant. RESULTS Posterior anal pressures at the 3 time points were not significantly different in the saline group. In contrast, post-treatment pressures in the 1 SDF-1 group pressures were significantly higher than both pre-injury (p = 0.001) and pre-treatment time points (p = 0.003). At the post-treatment time point, both 1 SDF-1 (p = 0.01) and 2 SDF-1 (p = 0.01) groups had significantly higher mean pressures compared to the saline group. Histology showed distortion of normal anatomy with patchy regeneration in the control group while muscle was more organized in both treatment groups. CONCLUSIONS Eight weeks after a single or two doses of SDF-1injected into a chronic anal sphincter injury improved resting anal pressures and regenerated muscle in the entire defect. SDF-1 plasmid is effective in treating chronic defects of the anal sphincter in a large animal and could be clinically translated.
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Affiliation(s)
- Li Sun
- Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, USA
| | - Alanna Billups
- Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, USA
| | - Anna Rietsch
- Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, USA
| | - Margot S Damaser
- Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, USA.,Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Advanced Platform Technology Center, Cleveland, Ohio, USA
| | - Massarat Zutshi
- Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio, USA
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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.
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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.)
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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.
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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
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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.
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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
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Hoogduijn MJ, Lombardo E. Mesenchymal Stromal Cells Anno 2019: Dawn of the Therapeutic Era? Concise Review. Stem Cells Transl Med 2019; 8:1126-1134. [PMID: 31282113 PMCID: PMC6811696 DOI: 10.1002/sctm.19-0073] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 06/17/2019] [Indexed: 12/11/2022] Open
Abstract
2018 was the year of the first marketing authorization of an allogeneic stem cell therapy by the European Medicines Agency. The authorization concerns the use of allogeneic adipose tissue-derived mesenchymal stromal cells (MSCs) for treatment of complex perianal fistulas in Crohn's disease. This is a breakthrough in the field of MSC therapy. The last few years have, furthermore, seen some breakthroughs in the investigations into the mechanisms of action of MSC therapy. Although the therapeutic effects of MSCs have largely been attributed to their secretion of immunomodulatory and regenerative factors, it has now become clear that some of the effects are mediated through host phagocytic cells that clear administered MSCs and in the process adapt an immunoregulatory and regeneration supporting function. The increased interest in therapeutic use of MSCs and the ongoing elucidation of the mechanisms of action of MSCs are promising indicators that 2019 may be the dawn of the therapeutic era of MSCs and that there will be revived interest in research to more efficient, practical, and sustainable MSC-based therapies. Stem Cells Translational Medicine 2019;8:1126-1134.
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Affiliation(s)
- Martin J Hoogduijn
- Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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El-Said MM, Emile SH. Cellular therapy: A promising tool in the future of colorectal surgery. World J Gastroenterol 2019; 25:1560-1565. [PMID: 30983816 PMCID: PMC6452228 DOI: 10.3748/wjg.v25.i13.1560] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 02/28/2019] [Accepted: 03/01/2019] [Indexed: 02/06/2023] Open
Abstract
Cellular therapy may be the solution of challenging problems in colorectal surgery such as impaired healing leading to anastomotic leakage and metastatic colorectal cancer (CRC). This review aimed to illustrate the role of cellular therapy in promotion of wound healing and management of metastatic CRC. An organized literature search for the role of cellular therapy in promotion of wound healing and management of metastatic CRC was conducted. Electronic databases including PubMed/Medline, Scopus, and Embase were queried for the search process. Two types of cellular therapy have been recognized, the mesenchymal stem cells (MSCs) and bone marrow-mononuclear cells (BM-MNCs) therapy. These cells have been shown to accelerate and promote healing of various tissue injuries in animal and human studies. In addition, experimental studies have reported that MSCs may help suppress the progression of colon cancer in rat models. This article reviews the possible mechanisms of action and clinical utility of MSCs and BM-MNCs in promotion of healing and suppression of tumor growth in light of the published literature. Cellular therapy has a potentially important role in colorectal surgery, particularly in the promotion of wound healing and management of metastatic CRC. Future directions of cellular therapy in colorectal surgery were explored which may help stimulate futures studies on the role of cellular therapy in colorectal surgery.
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Affiliation(s)
- Mohammed Mohammed El-Said
- Colorectal Surgery Unit, General Surgery Department, Mansoura University Hospitals, Mansoura University, Mansoura 35516, Egypt
| | - Sameh Hany Emile
- Colorectal Surgery Unit, General Surgery Department, Mansoura University Hospitals, Mansoura University, Mansoura 35516, Egypt
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Mardones R, Camacho D, Monsalvo F, Zulch N, Jofre C, Minguell JJ. Treatment of osteonecrosis of the femoral head by core decompression and implantation of fully functional ex vivo-expanded bone marrow-derived mesenchymal stem cells: a proof-of-concept study. STEM CELLS AND CLONING-ADVANCES AND APPLICATIONS 2019; 12:11-16. [PMID: 30881048 PMCID: PMC6402444 DOI: 10.2147/sccaa.s181883] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Based on several attributes involved in bone formation, bone marrow-resident mesenchymal stem cells (MSCs) have been employed in the treatment of patients suffering from femoral head osteonecrosis. Due to the low content of MSCs in the bone marrow, ex vivo expansion procedures are utilized to increase the cell number. Customarily, before administration of the resulting expanded cell product MSCs to the patient, its cellular identity is usually evaluated according to a set of “minimal phenotypic” markers, which are not modified by ex vivo processing. However, MSC functional (“reparative”) markers, which are severely impaired along the ex vivo expansion routine, are usually not assessed. Patients and methods In this proof-of-concept study, a cohort of five avascular osteonecrosis patients received an instillation of ex vivo-expanded autologous MSCs, manufactured under controlled conditions, with an aim to protect their functional (“reparative”) capacity. Results and conclusion Outcomes of this study confirmed the safety and effectiveness of the MSC-based therapy used. After a follow-up period (19–54 months), in all patients, the hip function was significantly improved and pain intensity markedly reduced. As a corollary, no patient required hip arthroplasty.
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Affiliation(s)
| | - Daniel Camacho
- Department of Orthopedics, Clínica Las Condes, Santiago, Chile.,Department of Orthopedics, Instituto Traumatológico, Santiago, Chile
| | | | - Nicolás Zulch
- Department of Orthopedics, Clínica Las Condes, Santiago, Chile
| | - Claudio Jofre
- Centro de Terapia Regenerativa Celular, Clínica Las Condes, Santiago, Chile,
| | - José J Minguell
- Centro de Terapia Regenerativa Celular, Clínica Las Condes, Santiago, Chile,
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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.
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11
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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.
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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
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Kuismanen K, Juntunen M, Narra Girish N, Tuominen H, Huhtala H, Nieminen K, Hyttinen J, Miettinen S. Functional Outcome of Human Adipose Stem Cell Injections in Rat Anal Sphincter Acute Injury Model. Stem Cells Transl Med 2018; 7:295-304. [PMID: 29383878 PMCID: PMC5827744 DOI: 10.1002/sctm.17-0208] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 12/24/2017] [Indexed: 02/06/2023] Open
Abstract
Anal incontinence is a devastating condition that significantly reduces the quality of life. Our aim was to evaluate the effect of human adipose stem cell (hASC) injections in a rat model for anal sphincter injury, which is the main cause of anal incontinence in humans. Furthermore, we tested if the efficacy of hASCs could be improved by combining them with polyacrylamide hydrogel carrier, Bulkamid. Human ASCs derived from a female donor were culture expanded in DMEM/F12 supplemented with human platelet lysate. Female virgin Sprague‐Dawley rats were randomized into four groups (n = 14–15/group): hASCs in saline or Bulkamid (3 × 105/60 μl) and saline or Bulkamid without cells. Anorectal manometry (ARM) was performed before anal sphincter injury, at two (n = 58) and at four weeks after (n = 33). Additionally, the anal sphincter tissue was examined by micro‐computed tomography (μCT) and the histological parameters were compared between the groups. The median resting and peak pressure during spontaneous contraction measured by ARM were significantly higher in hASC treatment groups compared with the control groups without hASCs. There was no statistical difference in functional results between the hASC‐carrier groups (saline vs. Bulkamid). No difference was detected in the sphincter muscle continuation between the groups in the histology and μCT analysis. More inflammation was discovered in the group receiving saline with hASC. The hASC injection therapy with both saline and Bulkamid is a promising nonsurgical treatment for acute anal sphincter injury. Traditional histology combined with the 3D μCT image data lends greater confidence in assessing muscle healing and continuity. Stem Cells Translational Medicine2018;7:295–304
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Affiliation(s)
- Kirsi Kuismanen
- Tampere University Hospital, department of Obstetrics and Gynecology, Tampere, Finland.,University of Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland
| | - Miia Juntunen
- University of Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland
| | | | - Heikki Tuominen
- Tampere University Hospital, department of Clinical Physiology and Nuclear Medicine, Tampere, Finland
| | - Heini Huhtala
- University of Tampere, Faculty of Social Sciences, Tampere, Finland
| | - Kari Nieminen
- Tampere University Hospital, department of Obstetrics and Gynecology, Tampere, Finland
| | | | - Susanna Miettinen
- University of Tampere, Faculty of Medicine and Life Sciences, Tampere, Finland
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Trébol J, Georgiev-Hristov T, Vega-Clemente L, García-Gómez I, Carabias-Orgaz A, García-Arranz M, García-Olmo D. Rat model of anal sphincter injury and two approaches for stem cell administration. World J Stem Cells 2018; 10:1-14. [PMID: 29391927 PMCID: PMC5785699 DOI: 10.4252/wjsc.v10.i1.1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Revised: 10/26/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To establish a rat model of anal sphincter injury and test different systems to provide stem cells to injured area. METHODS Adipose-derived stem cells (ASCs) were isolated from BDIX rats and were transfected with green fluorescent protein (GFP) for cell tracking. Biosutures (sutures covered with ASCs) were prepared with 1.5 x 106 GFP-ASCs, and solutions of 106 GFP-ASCs in normal saline were prepared for injection. Anorectal normal anatomy was studied on Wistar and BDIX female rats. Then, we designed an anal sphincter injury model consisting of a 1-cm extra-mucosal miotomy beginning at the anal verge in the anterior middle line. The sphincter lesion was confirmed with conventional histology (hematoxylin and eosin) and immunofluorescence with 4', 6-diamidino-2-phenylindole (commonly known as DAPI), GFP and α-actin. Functional effect was assessed with basal anal manometry, prior to and after injury. After sphincter damage, 36 BDIX rats were randomized to three groups for: (1) Cell injection without repair; (2) biosuture repair; and (3) conventional suture repair and cell injection. Functional and safety studies were conducted on all the animals. Rats were sacrificed after 1, 4 or 7 d. Then, histological and immunofluorescence studies were performed on the surgical area. RESULTS With the described protocol, biosutures had been covered with at least 820000-860000 ASCs, with 100% viability. Our studies demonstrated that some ASCs remained adhered after suture passage through the muscle. Morphological assessment showed that the rat anal anatomy is comparable with human anatomy; two sphincters are present, but the external sphincter is poorly developed. Anal sphincter pressure data showed spontaneous, consistent, rhythmic anal contractions, taking the form of "plateaus" with multiple twitches (peaks) in each pressure wave. These basal contractions were very heterogeneous; their frequency was 0.91-4.17 per min (mean 1.6980, SD 0.57698), their mean duration was 26.67 s and mean number of peaks was 12.53. Our morphological assessment revealed that with the aforementioned surgical procedure, both sphincters were completely sectioned. In manometry, the described activity disappeared and was replaced by a gentle oscillation of basal line, without a recognizable pattern. Surprisingly, these findings appeared irrespective of injury repair or not. ASCs survived in this potentially septic area for 7 d, at least. We were able to identify them in 84% of animals, mainly in the muscular section area or in the tissue between the muscular endings. ASCs formed a kind of "conglomerate" in rats treated with injections, while in the biosuture group, they wrapped the suture. ASCs were also able to migrate to the damaged zone. No relevant adverse events or mortality could be related to the stem cells in our study. We also did not find unexpected tissue growths. CONCLUSION The proposed procedure produces a consistent sphincter lesion. Biosutures and injections are suitable for cell delivery. ASCs survive and are completely safe in this clinical setting.
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Affiliation(s)
- Jacobo Trébol
- Department of General and Digestive Tract Surgery, University Hospital "La Paz", Madrid 28046, Spain
| | - Tihomir Georgiev-Hristov
- Department of General and Digestive Tract Surgery, Villalba General Hospital, Madrid 28400, Spain
| | - Luz Vega-Clemente
- New Therapies Laboratory, Instituto de Investigación Sanitaria- Fundación Jiménez Díaz, Madrid 28040, Spain
| | - Ignacio García-Gómez
- Senior Research Associate, Hektoen Institute of Medicine, Chicago, Illinois 60612, United States
| | - Ana Carabias-Orgaz
- Department of Anaesthesiology, Complejo Asistencial de Ávila, Ávila 05004, Spain
| | - Mariano García-Arranz
- Scientific Head, New Therapies Laboratory, Instituto de Investigación Sanitaria- Fundación Jiménez Díaz, Madrid 28040, Spain
| | - Damián García-Olmo
- Head of Department, Department of General and Digestive Tract Surgery, Quiron-Salud Hospitals, Madrid 28040, Spain
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Stromal Cell-Derived Factor 1 Plasmid Regenerates Both Smooth and Skeletal Muscle After Anal Sphincter Injury in the Long Term. Dis Colon Rectum 2017; 60:1320-1328. [PMID: 29112569 DOI: 10.1097/dcr.0000000000000940] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Regenerating muscle at a time remote from injury requires re-expression of cytokines to attract stem cells to start and sustain the process of repair. OBJECTIVE We aimed to evaluate the sustainability of muscle regeneration after treatment with a nonviral plasmid expressing stromal cell-derived factor 1. DESIGN This was a randomized study. SETTINGS The study was conducted with animals in a single research facility. INTERVENTIONS Fifty-six female age-/weight-matched Sprague-Dawley rats underwent excision of the ventral half of the anal sphincter complex. Three weeks later, rats were randomly allocated (n = 8) to one of the following groups: no treatment, 100 μg of plasmid encoding stromal cell-derived factor 1 injected locally, local injection of plasmid and 8 × 10 bone marrow-derived mesenchymal stem cells, and plasmid encoding stromal cell-derived factor 1 injected locally with injection of a gelatin scaffold mixed with bone marrow-derived mesenchymal stem cells. MAIN OUTCOME MEASURES Anal manometry, histology, immunohistochemistrym and morphometry were performed 8 weeks after treatment. Protein expression of cytokines CXCR4 and Myf5 was investigated 1 week after treatment (n = 6 per group). ANOVA was used, with p < 0.0083 indicating significant differences for anal manometry and p < 0.05 for all other statistical analysis. RESULTS Eight weeks after treatment, all of the groups receiving the plasmid had significantly higher anal pressures than controls and more organized muscle architecture in the region of the defect. Animals receiving plasmid alone had significantly greater muscle in the defect (p = 0.03) than either animals with injury alone (p = 0.02) or those receiving the plasmid, cells, and scaffold (p = 0.03). Both smooth and skeletal muscles were regenerated significantly more after plasmid treatment. There were no significant differences in the protein levels of CXCR4 or Myf5. LIMITATIONS The study was limited by its small sample size and because stromal cell-derived factor 1 was not blocked. CONCLUSIONS A plasmid expressing stromal cell-derived factor 1 may be sufficient to repair an injured anal sphincter even long after the injury and in the absence of mesenchymal stem cell or scaffold treatments. See Video Abstract at http://links.lww.com/DCR/A451.
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Abstract
BACKGROUND Fecal incontinence is a common disorder, but its pathophysiology is not completely understood. OBJECTIVE The aim of this review is to present animal models that have a place in the study of fecal incontinence. DATA SOURCES A literature review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines performed in August 2016 revealed 50 articles of interest. Search terms included fecal/faecal incontinence and animal model or specific species. STUDY SELECTION Articles not describing an animal model, in vitro studies, veterinary literature, reviews, and non-English articles were excluded. MAIN OUTCOME MEASURES The articles described models in rats (n = 31), dogs (n = 8), rabbits (n = 7), and pigs (n = 4). RESULTS Different fecal incontinence etiologies were modeled, including anal sphincter lesions (33 articles) ranging from a single anal sphincter cut to destruction of 50% of the anal sphincter by sharp dissection, electrocautery, or diathermy. Neuropathic fecal incontinence (12 articles) was achieved by complete or incomplete pudendal, pelvic, or inferior rectal nerve damage. Mixed fecal incontinence (5 articles) was modeled either by the inflation of pelvic balloons or an array of several lesions including nervous and muscular damage. Anal fistulas (2 articles), anal sphincter resection (3 articles), and diabetic neuropathy (2 articles) were studied to a lesser extent. LIMITATIONS Bias may have arisen from the authors' own work on fecal incontinence and the absence of blinding to the origins of articles. CONCLUSIONS Validated animal models representing the main etiologies of fecal incontinence exist, but no animal model to date represents the whole pathophysiology of fecal incontinence. Therefore, the individual research questions still dictate the choice of model and species.
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Khafagy WW, El-Said MM, Thabet WM, Aref SES, Omar W, Emile SH, Elfeki H, El-Ghonemy MS, El-Shobaky MT. Evaluation of anatomical and functional results of overlapping anal sphincter repair with or without the injection of bone marrow aspirate concentrate: a case-control study. Colorectal Dis 2017; 19:O66-O74. [PMID: 27943520 DOI: 10.1111/codi.13579] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Accepted: 10/20/2016] [Indexed: 12/11/2022]
Abstract
AIM Overlapping anal sphincter repair (OASR) is used for treatment of faecal incontinence due to an external anal sphincter (EAS) defect; however, it is not the optimal treatment as its functional results tend to deteriorate significantly with time. The present study aimed to evaluate the effect of local injection of bone marrow aspirate concentrate (BMAC) on the outcome of OASR. METHOD We compared a prospective group of 20 patients with EAS defect who were managed with OASR and BMAC injection (group I) with a historical control group of an equal number of patients managed with OASR alone (group II). Patients were assessed preoperatively and during follow-up by the Wexner continence score and endoanal ultrasound. The primary end-points were the improvement of the continence level measured by the Wexner score and the residual EAS defect size measured by endoanal ultrasound. RESULTS At the end of follow-up, group I had significantly lower mean postoperative Wexner score (5.4 ± 7.6 vs 10.6 ± 7.4; P = 0.03) and smaller EAS defect percentage (12.2 ± 17.5 vs 18.3 ± 18.9). These findings were statistically significant in patients with a small preoperative EAS defect equal to or less than one-third of the anal circumference. Patients with larger preoperative EAS did not show a significant improvement of the continence level after repair in either group. CONCLUSION Augmenting OASR with local injection of BMAC in patients with faecal incontinence caused by an EAS defect, particularly a smaller defect, can improve both functional and anatomical outcomes of OASR.
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Affiliation(s)
- W W Khafagy
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura City, Dakahlia Providence, Egypt
| | - M M El-Said
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura City, Dakahlia Providence, Egypt
| | - W M Thabet
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura City, Dakahlia Providence, Egypt
| | - S E-S Aref
- Clinical Pathology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura City, Dakahlia Providence, Egypt
| | - W Omar
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura City, Dakahlia Providence, Egypt
| | - S H Emile
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura City, Dakahlia Providence, Egypt
| | - H Elfeki
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura City, Dakahlia Providence, Egypt
| | - M S El-Ghonemy
- Clinical Pathology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura City, Dakahlia Providence, Egypt
| | - M T El-Shobaky
- General Surgery Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura City, Dakahlia Providence, Egypt
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