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Henderson T, Christman KL, Alperin M. Regenerative Medicine in Urogynecology: Where We Are and Where We Want to Be. UROGYNECOLOGY (PHILADELPHIA, PA.) 2024; 30:519-527. [PMID: 38683203 PMCID: PMC11342648 DOI: 10.1097/spv.0000000000001461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/01/2024]
Abstract
ABSTRACT Pelvic floor disorders (PFDs) constitute a major public health issue given their negative effect on quality of life for millions of women worldwide and the associated economic burden. As the prevalence of PFDs continues to increase, novel therapeutic approaches for the effective treatment of these disorders are urgently needed. Regenerative medicine techniques, including cellular therapies, extracellular vesicles, secretomes, platelet-rich plasma, laser therapy, and bioinductive acellular biomaterial scaffolds, are emerging as viable clinical options to counteract urinary and fecal incontinence, as well as pelvic organ prolapse. This brief expert review explores the current state-of-science regarding application of these therapies for the treatment of PFDs. Although regenerative approaches have not been widely deployed in clinical care to date, these innovative techniques show a promising safety profile and potential to positively affect the quality of life of patients with PFDs. Furthermore, investigations focused on regeneration of the main constituents of the pelvic floor and lower urinary tract improve our understanding of the underlying pathophysiology of PFDs. Regenerative medicine techniques have a high potential not only to revolutionize treatment of PFDs but also to prevent these complex conditions.
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Affiliation(s)
- Tatyanna Henderson
- Division of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics, Gynecology, and Reproductive Sciences
| | - Karen L. Christman
- Shu Chien-Gene Lay Department of Bioengineering, University of California San Diego
- Sanford Consortium for Regenerative Medicine, La Jolla, CA
| | - Marianna Alperin
- Division of Urogynecology and Reconstructive Pelvic Surgery, Department of Obstetrics, Gynecology, and Reproductive Sciences
- Sanford Consortium for Regenerative Medicine, La Jolla, CA
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Bai L, Zhang X, Li X, Wang S, Zhang Y, Xu G. Impact of a Novel Hydrogel with Injectable Platelet-Rich Fibrin in Diabetic Wound Healing. J Diabetes Res 2023; 2023:7532637. [PMID: 37546354 PMCID: PMC10403326 DOI: 10.1155/2023/7532637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/14/2023] [Accepted: 06/18/2023] [Indexed: 08/08/2023] Open
Abstract
Diabetic wounds are serious complications caused by diabetes mellitus (DM), which are further exacerbated by angiogenesis disorders and prolonged inflammation. Injectable platelet-rich fibrin (i-PRF) is rich in growth factors (GFs) and has been used for the repair and regeneration of diabetic wounds; however, direct application of i-PRF has certain disadvantages, including the instability of the bioactive molecules. Sericin hydrogel, fabricated by silkworm-derived sericin, is a biocompatible material that has anti-inflammatory and healing-promoting properties. Therefore, in this study, we developed a novel hydrogel (named sericin/i-PRF hydrogel) using a simple one-step activation method. The in vitro studies showed that the rapid injectability of the sericin/i-PRF hydrogel allows it to adapt to the irregular shape of the wounds. Additionally, sericin hydrogel could prolong the release of i-PRF-derived bioactive GFs in the sericin/i-PRF hydrogel. Furthermore, sericin/i-PRF hydrogel effectively repaired diabetic wounds, promoted angiogenesis, and reduced inflammation levels in the diabetic wounds of nude mice. These results demonstrate that the sericin/i-PRF hydrogel is a promising agent for diabetic wound healing.
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Affiliation(s)
- Limin Bai
- Department of Burn and Plastic Surgery, Northern Jiangsu People's Hospital, Yangzhou 225001, China
| | - Xiaowei Zhang
- Department of Burn and Plastic Surgery, Northern Jiangsu People's Hospital, Yangzhou 225001, China
| | - Xiaomei Li
- Department of Burn and Plastic Surgery, Northern Jiangsu People's Hospital, Yangzhou 225001, China
| | - Susu Wang
- College of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang Jiangsu 212100, China
| | - Yeshun Zhang
- College of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang Jiangsu 212100, China
- Key Laboratory of Silkworm and Mulberry Genetic Improvement, Ministry of Agriculture and Rural Affairs, Sericultural Research Institute, Chinese Academy of Agricultural Sciences, Zhenjiang Jiangsu 212100, China
| | - Gang Xu
- Department of Burn and Plastic Surgery, Northern Jiangsu People's Hospital, Yangzhou 225001, China
- Clinical Medical College, Yangzhou University, Yangzhou 225009, China
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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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Li Y, Liu D, Tan F, Yin W, Li Z. Umbilical cord derived mesenchymal stem cell-GelMA microspheres for accelerated wound healing. Biomed Mater 2022; 18. [PMID: 36541452 DOI: 10.1088/1748-605x/aca947] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 12/06/2022] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) are an ideal seed cell for tissue engineering and stem cell transplantation. MSCs combined with biological scaffolds play an important role in promoting the repair of cutaneous wound. However, direct administration of MSCs is challenging for MSCs survival and integration into tissues. Providing MSCs with a biocompatible scaffold can improve MSCs survival, but the effect of gelatin methacrylate (GelMA) loaded MSCs from umbilical cord MSCs (UC-MSCs) in wound healing remains unknown. Here, we investigated the ability of GelMA with UC-MSCs complexes to promote migration and proliferation and the effect on wound healing in mouse models. We discovered that UC-MSCs attached to GelMA and promoted the proliferation and migration of fibroblasts. Both UC-MSCs and UC-MSCs-derived extracellular vesicles accelerated wound healing. MSC + Gelatin methacrylate microspheres (GMs) application decreased expression of transforming growth factor-β(TGF-β) and Type III collagen (Col3)in vivo, leading to new collagen deposition and angiogenesis, and accelerate wound healing and skin tissue regeneration. Taken together, these findings indicate MSC + GMs can promote wound healing by regulating wound healing-related factors in the paracrine. Therefore, our research proves that GelMA is an ideal scaffold for the top management of UC-MSCs in wound healing medical practice.
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Affiliation(s)
- Yanqun Li
- Dongguan Enlife Stem Cell Biotechnology Institute, Zheshang Building, #430 Dongguan Ave., Dongguan, Guangdong 523000, People's Republic of China
| | - Dongyu Liu
- Dongguan Enlife Stem Cell Biotechnology Institute, Zheshang Building, #430 Dongguan Ave., Dongguan, Guangdong 523000, People's Republic of China
| | - Fengming Tan
- Dongguan Enlife Stem Cell Biotechnology Institute, Zheshang Building, #430 Dongguan Ave., Dongguan, Guangdong 523000, People's Republic of China
| | - Wenling Yin
- Dongguan Enlife Stem Cell Biotechnology Institute, Zheshang Building, #430 Dongguan Ave., Dongguan, Guangdong 523000, People's Republic of China
| | - Zhihuan Li
- Dongguan Enlife Stem Cell Biotechnology Institute, Zheshang Building, #430 Dongguan Ave., Dongguan, Guangdong 523000, People's Republic of China
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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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Speer AL, Ren X, McNeill EP, Aziz JM, Muir SM, Marino DI, Dadhich P, Sawant K, Ciccocioppo R, Asthana A, Bitar KN, Orlando G. Bioengineering of the digestive tract: approaching the clinic. Cytotherapy 2021; 23:381-389. [PMID: 33840629 DOI: 10.1016/j.jcyt.2021.02.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 01/29/2021] [Accepted: 02/08/2021] [Indexed: 12/18/2022]
Abstract
The field of regenerative medicine is developing technologies that, in the near future, will offer alternative approaches to either cure diseases affecting the gastrointestinal tract or slow their progression by leveraging the intrinsic ability of our tissues and organs to repair after damage. This article will succinctly illustrate the three technologies that are closer to clinical translation-namely, human intestinal organoids, sphincter bioengineering and decellularization, whereby the cellular compartment of a given segment of the digestive tract is removed to obtain a scaffold consisting of the extracellular matrix. The latter will be used as a template for the regeneration of a functional organ, whereby the newly generated cellular compartment will be obtained from the patient's own cells. Although clinical application of this technology is approaching, product development challenges are being tackled to warrant safety and efficacy.
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Affiliation(s)
- Allison L Speer
- McGovern Medical School, The University of Texas Health Science Center, Houston, Texas, USA
| | - Xi Ren
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA
| | - Eoin P McNeill
- McGovern Medical School, The University of Texas Health Science Center, Houston, Texas, USA
| | - Justine M Aziz
- Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Sean M Muir
- Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Domenica I Marino
- College of Arts and Sciences, Ohio State University, Columbus, Ohio, USA
| | | | - Ketki Sawant
- Cellf Bio LLC, Winston-Salem, North Carolina, USA
| | - Rachele Ciccocioppo
- Department of Medicine, Gastroenterology Unit, Giambattista Rossi University Hospital, University Hospital Integrated Trust of Verona, University of Verona, Verona, Italy
| | - Amish Asthana
- Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Khalil N Bitar
- Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA; Cellf Bio LLC, Winston-Salem, North Carolina, USA
| | - Giuseppe Orlando
- Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
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Plair A, Bennington J, Williams JK, Parker-Autry C, Matthews CA, Badlani G. Regenerative medicine for anal incontinence: a review of regenerative therapies beyond cells. Int Urogynecol J 2020; 32:2337-2347. [PMID: 33247762 DOI: 10.1007/s00192-020-04620-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 11/16/2020] [Indexed: 12/14/2022]
Abstract
INTRODUCTION AND HYPOTHESIS Current treatment modalities for anal sphincter injuries are ineffective for many patients, prompting research into restorative and regenerative therapies. Although cellular therapy with stem cells and progenitor cells show promise in animal models with short-term improvement, there are additional regenerative approaches that can augment or replace cellular therapies for anal sphincter injuries. The purpose of this article is to review the current knowledge of cellular therapies for anal sphincter injuries and discusses the use of other regenerative therapies including cytokine therapy with CXCL12. METHODS A literature search was performed to search for articles on cellular therapy and cytokine therapy for anal sphincter injuries and anal incontinence. RESULTS The article search identified 337 articles from which 33 articles were included. An additional 12 referenced articles were included as well as 23 articles providing background information. Cellular therapy has shown positive results for treating anal sphincter injuries and anal incontinence in vitro and in one clinical trial. However, cellular therapy has disadvantages such as the source and processing of stem cells and progenitor cells. CXCL12 does not have such issues while showing promising in vitro results for treating anal sphincter injuries. Additionally, electrical stimulation and extracorporeal shock wave therapy are potential regenerative medicine adjuncts for anal sphincter injuries. A vision for future research and clinical applications of regenerative medicine for anal sphincter deficiencies is provided. CONCLUSION There are viable regenerative medicine therapies for anal sphincter injuries beyond cellular therapy. CXCL12 shows promise as a focus of therapeutic research in this field.
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Affiliation(s)
- Andre Plair
- Department of Urology, Wake Forest Baptist Health, Winston Salem, NC, USA.
| | - Julie Bennington
- Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA
| | | | | | | | - Gopal Badlani
- Department of Urology, Wake Forest Baptist Health, Winston Salem, NC, USA
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Dadhich P, Bohl JL, Tamburrini R, Zakhem E, Scott C, Kock N, Mitchell E, Gilliam J, Bitar KN. BioSphincters to treat Fecal Incontinence in Nonhuman Primates. Sci Rep 2019; 9:18096. [PMID: 31792260 PMCID: PMC6888838 DOI: 10.1038/s41598-019-54440-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 11/12/2019] [Indexed: 02/07/2023] Open
Abstract
Loss of anorectal resting pressure due to internal anal sphincter (IAS) dysfunctionality causes uncontrolled fecal soiling and leads to passive fecal incontinence (FI). The study is focused on immediate and long-term safety and potential efficacy of bioengineered IAS BioSphincters to treat passive FI in a clinically relevant large animal model of passive FI. Passive FI was successfully developed in Non-Human Primates (NHPs) model. The implantation of autologous intrinsically innervated functional constructs resolved the fecal soiling, restored the resting pressure and Recto Anal Inhibitory Reflex (RAIR) within 1-month. These results were sustained with time, and efficacy was preserved up to 12-months. The histological studies validated manometric results with the regeneration of a well-organized neuro-muscular population in IAS. The control groups (non-treated and sham) remained affected by poor anal hygiene, lower resting pressure, and reduced RAIR throughout the study. The pathological assessment of implants, blood, and the vital organs confirmed biocompatibility without any adverse effect after implantation. This regenerative approach of implanting intrinsically innervated IAS BioSphincters has the potential to offer a better quality of life to the patients suffering from FI.
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Affiliation(s)
- Prabhash Dadhich
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston Salem, NC, USA
- Program in Neuro-Gastroenterology and Motility, Wake Forest School of Medicine, Winston Salem, NC, USA
| | - Jaime L Bohl
- Department of Surgery, Wake Forest School of Medicine, Winston Salem, NC, USA
| | - Riccardo Tamburrini
- Department of Surgery, Wake Forest School of Medicine, Winston Salem, NC, USA
| | - Elie Zakhem
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston Salem, NC, USA
- Program in Neuro-Gastroenterology and Motility, Wake Forest School of Medicine, Winston Salem, NC, USA
| | - Christie Scott
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston Salem, NC, USA
| | - Nancy Kock
- Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston Salem, NC, USA
| | - Erin Mitchell
- Animal Resources Program, Wake Forest Baptist Health, Winston Salem, NC, USA
| | - John Gilliam
- Section on Gastroenterology, Wake Forest School of Medicine, Winston Salem, NC, USA
| | - Khalil N Bitar
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston Salem, NC, USA.
- Program in Neuro-Gastroenterology and Motility, Wake Forest School of Medicine, Winston Salem, NC, USA.
- Section on Gastroenterology, Wake Forest School of Medicine, Winston Salem, NC, USA.
- Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Wake Forest School of Medicine, Winston Salem, NC, USA.
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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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Bohl JL, Zakhem E, Bitar KN. Successful Treatment of Passive Fecal Incontinence in an Animal Model Using Engineered Biosphincters: A 3-Month Follow-Up Study. Stem Cells Transl Med 2017; 6:1795-1802. [PMID: 28678378 PMCID: PMC5689776 DOI: 10.1002/sctm.16-0458] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 04/17/2017] [Indexed: 12/20/2022] Open
Abstract
Fecal incontinence (FI) is the involuntary passage of fecal material. Current treatments have limited successful outcomes. The objective of this study was to develop a large animal model of passive FI and to demonstrate sustained restoration of fecal continence using anorectal manometry in this model after implantation of engineered autologous internal anal sphincter (IAS) biosphincters. Twenty female rabbits were used in this study. The animals were divided into three groups: (a) Non‐treated group: Rabbits underwent IAS injury by hemi‐sphincterectomy without treatment. (b) Treated group: Rabbits underwent IAS injury by hemi‐sphincterectomy followed by implantation of autologous biosphincters. (c) Sham group: Rabbits underwent IAS injury by hemi‐sphincterectomy followed by re‐accessing the surgical site followed by immediate closure without implantation of biosphincters. Anorectal manometry was used to measure resting anal pressure and recto‐anal inhibitory reflex (RAIR) at baseline, 1 month post‐sphincterectomy, up to 3 months after implantation and post‐sham. Following sphincterectomy, all rabbits had decreased basal tone and loss of RAIR, indicative of FI. Anal hygiene was also lost in the rabbits. Decreases in basal tone and RAIR were sustained more than 3 months in the non‐treated group. Autologous biosphincters were successfully implanted into eight donor rabbits in the treated group. Basal tone and RAIR were restored at 3 months following biosphincter implantation and were significantly higher compared with rabbits in the non‐treated and sham groups. Histologically, smooth muscle reconstruction and continuity was restored in the treated group compared with the non‐treated group. Results in this study provided promising outcomes for treatment of FI. Results demonstrated the feasibility of developing and validating a large animal model of passive FI. This study also showed the efficacy of the engineered biosphincters to restore fecal continence as demonstrated by manometry. Stem Cells Translational Medicine2017;6:1795–1802
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Affiliation(s)
- Jaime L Bohl
- Department of Surgery, Wake Forest School of Medicine, Medical Center Boulevard, Winston Salem, North Carolina, USA
| | - Elie Zakhem
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina, USA.,Department of Molecular Medicine and Translational Sciences, Wake Forest School of Medicine, Winston Salem, North Carolina, USA
| | - Khalil N Bitar
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina, USA.,Department of Molecular Medicine and Translational Sciences, Wake Forest School of Medicine, Winston Salem, North Carolina, USA.,Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Winston Salem, North Carolina, USA.,Section on Gastroenterology, Wake Forest School of Medicine, Winston Salem, North Carolina, USA
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Hydrogel and Platelet-Rich Plasma Combined Treatment to Accelerate Wound Healing in a Nude Mouse Model. Arch Plast Surg 2017; 44:194-201. [PMID: 28573093 PMCID: PMC5447528 DOI: 10.5999/aps.2017.44.3.194] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Revised: 04/26/2017] [Accepted: 04/28/2017] [Indexed: 12/24/2022] Open
Abstract
Background Platelet-rich plasma (PRP) contains high concentrations of growth factors involved in wound healing. Hydrogel is a 3-dimensional, hydrophilic, high-molecular, reticular substance generally used as a dressing formulation to accelerate wound healing, and also used as a bio-applicable scaffold or vehicle. This study aimed to investigate the effects of PRP and hydrogel on wound healing, in combination and separately, in an animal wound model. Methods A total of 64 wounds, with 2 wounds on the back of each nude mouse, were classified into 4 groups: a control group, a hydrogel-only group, a PRP-only group, and a combined-treatment group. All mice were assessed for changes in wound size and photographed on scheduled dates. The number of blood vessels was measured in all specimens. Immunohistochemical staining was used for the analysis of vascular endothelial growth factor (VEGF) expression. Results Differences in the decrease and change in wound size in the combined-treatment group were more significant than those in the single-treatment groups on days 3, 5, 7, and 10. Analysis of the number of blood vessels through histological examination showed a pattern of increase over time that occurred in all groups, but the combined-treatment group exhibited the greatest increase on days 7 and 14. Immunohistochemical staining showed that VEGF expression in the combined-treatment group exhibited its highest value on day 7. Conclusions This experiment demonstrated improved wound healing using a PRP–hydrogel combined treatment compared to either treatment individually, resulting in a decrease in wound size and a shortening of the healing period.
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Abstract
BACKGROUND Healing of an anal sphincter defect at a time distant from injury is a challenge. OBJECTIVE We aimed to investigate whether re-establishing stem cell homing at the site of an anal sphincter defect when cytokine expression has declined using a plasmid engineered to express stromal derived factor 1 with or without mesenchymal stem cells can improve anatomic and functional outcome. DESIGN This was a randomized animal study. SETTINGS Thirty-two female age- and weight-matched Sprague Dawley rats underwent 50% excision of the anal sphincter complex. Three weeks after injury, 4 interventions were randomly allocated (n = 8), including no intervention, 100-μg plasmid, plasmid and 800,000 cells, and plasmid with a gelatin scaffold mixed with cells. MAIN OUTCOME MEASURES The differences in anal sphincter resting pressures just before and 4 weeks after intervention were used for functional analysis. Histology was analyzed using Masson staining. One-way ANOVA followed by the Tukey post hoc test was used for pressure and histological analysis. RESULTS All 3 of the intervention groups had a significantly greater change in resting pressure (plasmid p = 0.009; plasmid + cells p = 0.047; plasmid + cells in scaffold p = 0.009) compared with the control group. The plasmid-with-cells group showed increased organization of muscle architecture and increased muscle percentage, whereas the control group showed disorganized architecture at the site of the defect. Histological quantification revealed significantly more muscle at the site of defect in the plasmid-plus-cells group compared with the control group, which had the least muscle. Quantification of connective tissue revealed significantly less fibrosis at the site of defect in the plasmid and plasmid-plus-cells groups compared with the control group. LIMITATIONS Midterm evaluation and muscle morphology were not defined. CONCLUSIONS At this midterm follow-up, local delivery of a stromal derived factor 1 plasmid with or without local mesenchymal stem cells enhanced anal sphincter muscle regeneration long after an anal sphincter injury, thereby improving functional outcome. See Video Abstract at http://links.lww.com/DCR/A324.
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Abstract
Fecal incontinence is a highly prevalent and distressing condition that has a negative impact on quality of life. The etiology is often multifactorial, and the evaluation and treatment of this condition can be hindered by a lack of understanding of the mechanisms and currently available treatment options. This article reviews the evidence-based update for the management of fecal incontinence.
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Affiliation(s)
- Isuzu Meyer
- Division of Urogynecology and Pelvic Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 1700 6th Avenue South, Suite 10382, Birmingham, AL 35233, USA.
| | - Holly E Richter
- Division of Urogynecology and Pelvic Reconstructive Surgery, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 1700 6th Avenue South, Suite 10382, Birmingham, AL 35233, USA
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Turrioni AP, Basso FG, Montoro LA, Almeida LFD, de Souza Costa CA, Hebling J. Transdentinal photobiostimulation of stem cells from human exfoliated primary teeth. Int Endod J 2016; 50:549-559. [PMID: 27238557 DOI: 10.1111/iej.12665] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 05/27/2016] [Indexed: 01/09/2023]
Abstract
AIM To evaluate the effects of infrared light-emitting diode (LED) irradiation on stem cells from human exfoliated deciduous teeth (SHEDs). METHODOLOGY Exfoliated primary teeth were obtained (n = 3), and SHEDs obtained from the teeth were seeded on the pulpal surface of 0.2-mm-thick dentine discs produced from permanent molars. The cells were incubated for 24 h by placing the discs in plain Dulbecco's modified Eagle's medium (DMEM). The DMEM was then replaced with new culture medium formulated for odontoblast differentiation. After 12 h in the second medium, SHEDs were irradiated through the dentine discs using an infrared LED (850 nm) with a power density of 80 mW cm-2 . Energy doses (EDs) delivered to the occlusal surface of the dentine discs were 0 (control), 2 and 4 J cm-2 (n = 6). Subsequent tests were performed 72 h after irradiation. These tests included cell viability (MTT), alkaline phosphatase activity (ALP), total protein production (TP), scanning electron microscopy (SEM), as well as gene expression for ALP, Col I, DSPP and DMP-1. Data were analysed using Kruskal-Wallis and Mann-Whitney t-tests (α = 0.05). RESULTS Both EDs (2 and 4 J cm-2 ) significantly increased cell viability and ALP activity. For TP, ALP and Col I gene expression, only the 4 J cm-2 group had significantly higher values compared to the control group. Cell morphology was not affected by irradiation. CONCLUSION Infrared LED irradiation was capable of biostimulating SHEDs through a 0.2 mm thickness of dentine, especially at the 4 J cm-2 level.
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Affiliation(s)
- A P Turrioni
- Department of Pediatric Dentistry and Orthodontics, Uberlândia School of Dentistry, Universidade Federal de Uberlândia (UFU), Uberlândia, Minas Gerais, Brazil
| | - F G Basso
- Department of Physiology and Pathology, Araraquara School of Dentistry, Universidade Estadual Paulista (UNESP), Araraquara, São Paulo, Brazil
| | - L A Montoro
- Department of Pediatric Dentistry and Orthodontics, Araraquara School of Dentistry, Universidade Estadual Paulista (UNESP), Araraquara, São Paulo, Brazil
| | - L F D Almeida
- Department of Operative Dentistry, Araraquara School of Dentistry, Universidade Estadual Paulista (UNESP), Araraquara, São Paulo, Brazil
| | - C A de Souza Costa
- Department of Physiology and Pathology, Araraquara School of Dentistry, Universidade Estadual Paulista (UNESP), Araraquara, São Paulo, Brazil
| | - J Hebling
- Department of Pediatric Dentistry and Orthodontics, Araraquara School of Dentistry, Universidade Estadual Paulista (UNESP), Araraquara, São Paulo, Brazil
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Gräs S, Tolstrup CK, Lose G. Regenerative medicine provides alternative strategies for the treatment of anal incontinence. Int Urogynecol J 2016; 28:341-350. [PMID: 27311602 DOI: 10.1007/s00192-016-3064-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 06/06/2016] [Indexed: 12/17/2022]
Abstract
INTRODUCTION AND HYPOTHESIS Anal incontinence is a common disorder but current treatment modalities are not ideal and the development of new treatments is needed. The aim of this review was to identify the existing knowledge of regenerative medicine strategies in the form of cellular therapies or bioengineering as a treatment for anal incontinence caused by anal sphincter defects. METHODS PubMed was searched for preclinical and clinical studies in English published from January 2005 to January 2016. RESULTS Animal studies have demonstrated that cellular therapy in the form of local injections of culture-expanded skeletal myogenic cells stimulates repair of both acute and 2 - 4-week-old anal sphincter injuries. The results from a small clinical trial with ten patients and a case report support the preclinical findings. Animal studies have also demonstrated that local injections of mesenchymal stem cells stimulate repair of sphincter injuries, and a complex bioengineering strategy for creation and implantation of an intrinsically innervated internal anal sphincter construct has been successfully developed in a series of animal studies. CONCLUSION Cellular therapies with myogenic cells and mesenchymal stem cells and the use of bioengineering technology to create an anal sphincter are new potential strategies to treat anal incontinence caused by anal sphincter defects, but the clinical evidence is extremely limited. The use of culture-expanded autologous skeletal myogenic cells has been most intensively investigated and several clinical trials were ongoing at the time of this report. The cost-effectiveness of such a therapy is an issue and muscle fragmentation is suggested as a simple alternative.
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Affiliation(s)
- Søren Gräs
- Department of Obstetrics and Gynecology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730, Herlev, Denmark.
| | - Cæcilie Krogsgaard Tolstrup
- Department of Obstetrics and Gynecology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730, Herlev, Denmark
| | - Gunnar Lose
- Department of Obstetrics and Gynecology, Copenhagen University Hospital Herlev, Herlev Ringvej 75, DK-2730, Herlev, Denmark
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Meyer I, Richter HE. Evolving Surgical Treatment Approaches for Fecal Incontinence in Women. CURRENT OBSTETRICS AND GYNECOLOGY REPORTS 2015. [DOI: 10.1007/s13669-015-0116-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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