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Žukauskaitė K, Li M, Horvath A, Jarmalaitė S, Stadlbauer V. Cellular and Microbial In Vitro Modelling of Gastrointestinal Cancer. Cancers (Basel) 2024; 16:3113. [PMID: 39272971 PMCID: PMC11394127 DOI: 10.3390/cancers16173113] [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: 07/12/2024] [Revised: 08/27/2024] [Accepted: 09/04/2024] [Indexed: 09/15/2024] Open
Abstract
Human diseases are multifaceted, starting with alterations at the cellular level, damaging organs and their functions, and disturbing interactions and immune responses. In vitro systems offer clarity and standardisation, which are crucial for effectively modelling disease. These models aim not to replicate every disease aspect but to dissect specific ones with precision. Controlled environments allow researchers to isolate key variables, eliminate confounding factors and elucidate disease mechanisms more clearly. Technological progress has rapidly advanced model systems. Initially, 2D cell culture models explored fundamental cell interactions. The transition to 3D cell cultures and organoids enabled more life-like tissue architecture and enhanced intercellular interactions. Advanced bioreactor-based devices now recreate the physicochemical environments of specific organs, simulating features like perfusion and the gastrointestinal tract's mucus layer, enhancing physiological relevance. These systems have been simplified and adapted for high-throughput research, marking significant progress. This review focuses on in vitro systems for modelling gastrointestinal tract cancer and the side effects of cancer treatment. While cell cultures and in vivo models are invaluable, our main emphasis is on bioreactor-based in vitro modelling systems that include the gut microbiome.
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Affiliation(s)
- Kristina Žukauskaitė
- Department of Gastroenterology and Hepatology, Medical University of Graz, 8036 Graz, Austria
- Institute of Biosciences, Life Sciences Center, Vilnius University, 10257 Vilnius, Lithuania
| | - Melissa Li
- Department of Gastroenterology and Hepatology, Medical University of Graz, 8036 Graz, Austria
- Biotech Campus Tulln, Fachhochschule Wiener Neustadt, 3430 Tulln, Austria
| | - Angela Horvath
- Department of Gastroenterology and Hepatology, Medical University of Graz, 8036 Graz, Austria
- Center for Biomarker Research in Medicine (CBmed GmbH), 8010 Graz, Austria
| | - Sonata Jarmalaitė
- Institute of Biosciences, Life Sciences Center, Vilnius University, 10257 Vilnius, Lithuania
- National Cancer Institute, 08406 Vilnius, Lithuania
| | - Vanessa Stadlbauer
- Department of Gastroenterology and Hepatology, Medical University of Graz, 8036 Graz, Austria
- Center for Biomarker Research in Medicine (CBmed GmbH), 8010 Graz, Austria
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2
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Herath M, Speer AL. Bioengineering of Intestinal Grafts. Gastroenterol Clin North Am 2024; 53:461-472. [PMID: 39068007 PMCID: PMC11284275 DOI: 10.1016/j.gtc.2023.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Intestinal failure manifests as an impaired capacity of the intestine to sufficiently absorb vital nutrients and electrolytes essential for growth and well-being in pediatric and adult populations. Although parenteral nutrition remains the mainstay therapeutic approach, the pursuit of a definitive and curative strategy, such as regenerative medicine, is imperative. Substantial advancements in the field of engineered intestinal tissues present a promising avenue for addressing intestinal failure; nevertheless, extensive research is still necessary for effective translation from experimental benchwork to clinical bedside applications.
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Affiliation(s)
- Madushani Herath
- Program in Children's Regenerative Medicine, Department of Pediatric Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth Houston), 6431 Fannin Street, Suite 5.254, Houston, TX 77030, USA
| | - Allison L Speer
- Program in Children's Regenerative Medicine, Department of Pediatric Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth Houston), 6431 Fannin Street, Suite 5.254, Houston, TX 77030, USA.
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3
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Meran L, Tullie L, Eaton S, De Coppi P, Li VSW. Bioengineering human intestinal mucosal grafts using patient-derived organoids, fibroblasts and scaffolds. Nat Protoc 2023; 18:108-135. [PMID: 36261633 DOI: 10.1038/s41596-022-00751-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 06/30/2022] [Indexed: 01/14/2023]
Abstract
Tissue engineering is an interdisciplinary field that combines stem cells and matrices to form functional constructs that can be used to repair damaged tissues or regenerate whole organs. Tissue stem cells can be expanded and functionally differentiated to form 'mini-organs' resembling native tissue architecture and function. The choice of the scaffold is also pivotal to successful tissue reconstruction. Scaffolds may be broadly classified into synthetic or biological depending upon the purpose of the engineered organ. Bioengineered intestinal grafts represent a potential source of transplantable tissue for patients with intestinal failure, a condition resulting from extensive anatomical and functional loss of small intestine and therefore digestive and absorptive capacity. Prior strategies in intestinal bioengineering have predominantly used either murine or pluripotent cells and synthetic or decellularized rodent scaffolds, thus limiting their translation. Microscale models of human intestinal epithelium on shaped hydrogels and synthetic scaffolds are more physiological, but their regenerative potential is limited by scale. Here we present a protocol for bioengineering human intestinal grafts using patient-derived materials in a bioreactor culture system. This includes the isolation, expansion and biobanking of patient-derived intestinal organoids and fibroblasts, the generation of decellularized human intestinal scaffolds from native human tissue and providing a system for recellularization to form transplantable grafts. The duration of this protocol is 12 weeks, and it can be completed by scientists with prior experience of organoid culture. The resulting engineered mucosal grafts comprise physiological intestinal epithelium, matrix and surrounding niche, offering a valuable tool for both regenerative medicine and the study of human gastrointestinal diseases.
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Affiliation(s)
- Laween Meran
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK
- Stem Cell and Regenerative Medicine Section, DBC, Great Ormond Street Institute of Child Health, University College London, London, UK
- Medical Research Council Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Lucinda Tullie
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK
- Stem Cell and Regenerative Medicine Section, DBC, Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Simon Eaton
- Stem Cell and Regenerative Medicine Section, DBC, Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Paolo De Coppi
- Stem Cell and Regenerative Medicine Section, DBC, Great Ormond Street Institute of Child Health, University College London, London, UK.
- Specialist Neonatal and Paediatric Surgery Unit, Great Ormond Street Hospital, London, UK.
| | - Vivian S W Li
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK.
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Elia E, Brownell D, Chabaud S, Bolduc S. Tissue Engineering for Gastrointestinal and Genitourinary Tracts. Int J Mol Sci 2022; 24:ijms24010009. [PMID: 36613452 PMCID: PMC9820091 DOI: 10.3390/ijms24010009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/10/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
The gastrointestinal and genitourinary tracts share several similarities. Primarily, these tissues are composed of hollow structures lined by an epithelium through which materials need to flow with the help of peristalsis brought by muscle contraction. In the case of the gastrointestinal tract, solid or liquid food must circulate to be digested and absorbed and the waste products eliminated. In the case of the urinary tract, the urine produced by the kidneys must flow to the bladder, where it is stored until its elimination from the body. Finally, in the case of the vagina, it must allow the evacuation of blood during menstruation, accommodate the male sexual organ during coitus, and is the natural way to birth a child. The present review describes the anatomy, pathologies, and treatments of such organs, emphasizing tissue engineering strategies.
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Affiliation(s)
- Elissa Elia
- Centre de Recherche en Organogénèse Expérimentale/LOEX, Regenerative Medicine Division, CHU de Québec-Université Laval Research Center, Québec, QC G1J 1Z4, Canada
| | - David Brownell
- Centre de Recherche en Organogénèse Expérimentale/LOEX, Regenerative Medicine Division, CHU de Québec-Université Laval Research Center, Québec, QC G1J 1Z4, Canada
| | - Stéphane Chabaud
- Centre de Recherche en Organogénèse Expérimentale/LOEX, Regenerative Medicine Division, CHU de Québec-Université Laval Research Center, Québec, QC G1J 1Z4, Canada
| | - Stéphane Bolduc
- Centre de Recherche en Organogénèse Expérimentale/LOEX, Regenerative Medicine Division, CHU de Québec-Université Laval Research Center, Québec, QC G1J 1Z4, Canada
- Department of Surgery, Faculty of Medicine, Université Laval, Québec, QC G1V 0A6, Canada
- Correspondence: ; Tel.: +1-418-525-4444 (ext. 42282)
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Tullie L, Jones BC, De Coppi P, Li VSW. Building gut from scratch - progress and update of intestinal tissue engineering. Nat Rev Gastroenterol Hepatol 2022; 19:417-431. [PMID: 35241800 DOI: 10.1038/s41575-022-00586-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/31/2022] [Indexed: 12/18/2022]
Abstract
Short bowel syndrome (SBS), a condition defined by insufficient absorptive intestinal epithelium, is a rare disease, with an estimated prevalence up to 0.4 in 10,000 people. However, it has substantial morbidity and mortality for affected patients. The mainstay of treatment in SBS is supportive, in the form of intravenous parenteral nutrition, with the aim of achieving intestinal autonomy. The lack of a definitive curative therapy has led to attempts to harness innate developmental and regenerative mechanisms to engineer neo-intestine as an alternative approach to addressing this unmet clinical need. Exciting advances have been made in the field of intestinal tissue engineering (ITE) over the past decade, making a review in this field timely. In this Review, we discuss the latest advances in the components required to engineer intestinal grafts and summarize the progress of ITE. We also explore some key factors to consider and challenges to overcome when transitioning tissue-engineered intestine towards clinical translation, and provide the future outlook of ITE in therapeutic applications and beyond.
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Affiliation(s)
- Lucinda Tullie
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK.,Stem Cell and Regenerative Medicine Section, DBC, Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Brendan C Jones
- Stem Cell and Regenerative Medicine Section, DBC, Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Paolo De Coppi
- Stem Cell and Regenerative Medicine Section, DBC, Great Ormond Street Institute of Child Health, University College London, London, UK. .,Specialist Neonatal and Paediatric Surgery Unit, Great Ormond Street Hospital, London, UK.
| | - Vivian S W Li
- Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK.
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6
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Collier CA, Mendiondo C, Raghavan S. Tissue engineering of the gastrointestinal tract: the historic path to translation. J Biol Eng 2022; 16:9. [PMID: 35379299 PMCID: PMC8981633 DOI: 10.1186/s13036-022-00289-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 03/08/2022] [Indexed: 11/15/2022] Open
Abstract
The gastrointestinal (GI) tract is imperative for multiple functions including digestion, nutrient absorption, and timely waste disposal. The central feature of the gut is peristalsis, intestinal motility, which facilitates all of its functions. Disruptions in GI motility lead to sub-optimal GI function, resulting in a lower quality of life in many functional GI disorders. Over the last two decades, tissue engineering research directed towards the intestine has progressed rapidly due to advances in cell and stem-cell biology, integrative physiology, bioengineering and biomaterials. Newer biomedical tools (including optical tools, machine learning, and nuanced regenerative engineering approaches) have expanded our understanding of the complex cellular communication within the GI tract that lead to its orchestrated physiological function. Bioengineering therefore can be utilized towards several translational aspects: (i) regenerative medicine to remedy/restore GI physiological function; (ii) in vitro model building to mimic the complex physiology for drug and pharmacology testing; (iii) tool development to continue to unravel multi-cell communication networks to integrate cell and organ-level physiology. Despite the significant strides made historically in GI tissue engineering, fundamental challenges remain including the quest for identifying autologous human cell sources, enhanced scaffolding biomaterials to increase biocompatibility while matching viscoelastic properties of the underlying tissue, and overall biomanufacturing. This review provides historic perspectives for how bioengineering has advanced over time, highlights newer advances in bioengineering strategies, and provides a realistic perspective on the path to translation.
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Affiliation(s)
- Claudia A Collier
- Department of Biomedical Engineering, Texas A&M University, Emerging Technologies Building, 3120 TAMU, College Station, TX, 77843, USA
| | - Christian Mendiondo
- Department of Biomedical Engineering, Texas A&M University, Emerging Technologies Building, 3120 TAMU, College Station, TX, 77843, USA
| | - Shreya Raghavan
- Department of Biomedical Engineering, Texas A&M University, Emerging Technologies Building, 3120 TAMU, College Station, TX, 77843, USA.
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA.
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7
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Jones BC, Shibuya S, Durkin N, De Coppi P. Regenerative medicine for childhood gastrointestinal diseases. Best Pract Res Clin Gastroenterol 2021; 56-57:101769. [PMID: 35331401 DOI: 10.1016/j.bpg.2021.101769] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/30/2021] [Accepted: 10/08/2021] [Indexed: 01/31/2023]
Abstract
Several paediatric gastrointestinal diseases result in life-shortening organ failure. For many of these conditions, current therapeutic options are suboptimal and may not offer a cure. Regenerative medicine is an inter-disciplinary field involving biologists, engineers, and clinicians that aims to produce cell and tissue-based therapies to overcome organ failure. Exciting advances in stem cell biology, materials science, and bioengineering bring engineered gastrointestinal cell and tissue therapies to the verge of clinical trial. In this review, we summarise the requirements for bioengineered therapies, the possible sources of the various cellular and non-cellular components, and the progress towards clinical translation of oesophageal and intestinal tissue engineering to date.
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Affiliation(s)
- Brendan C Jones
- Stem Cell and Regenerative Medicine Section, Developmental Biology and Cancer Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; Specialist Neonatal and Paediatric Surgery Unit, Great Ormond Street Hospital, London, United Kingdom
| | - Soichi Shibuya
- Stem Cell and Regenerative Medicine Section, Developmental Biology and Cancer Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Natalie Durkin
- Stem Cell and Regenerative Medicine Section, Developmental Biology and Cancer Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; Specialist Neonatal and Paediatric Surgery Unit, Great Ormond Street Hospital, London, United Kingdom
| | - Paolo De Coppi
- Stem Cell and Regenerative Medicine Section, Developmental Biology and Cancer Research and Teaching Department, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; Specialist Neonatal and Paediatric Surgery Unit, Great Ormond Street Hospital, London, United Kingdom.
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8
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Kanetaka K, Eguchi S. Regenerative medicine for the upper gastrointestinal tract. Regen Ther 2020; 15:129-137. [PMID: 33426211 PMCID: PMC7770370 DOI: 10.1016/j.reth.2020.07.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 06/21/2020] [Accepted: 07/01/2020] [Indexed: 12/12/2022] Open
Abstract
The main surgical strategy for gastrointestinal tract malignancy is en bloc resection, which consists of not only resection of the involved organs but also simultaneous resection of the surrounding or adjacent mesenteries that contain lymph vessels and nodes. After resection of the diseased organs, the defect of the gastrointestinal conduit is replaced with organs located downstream, such as the stomach and jejunum. However, esophageal and gastric reconstruction using these natural substitutes is associated with a diminished quality of life due to the loss of the reserve function, damage to the antireflux barrier, and dumping syndrome. Thus, replacement of the deficit after resection with the patient's own regenerated tissue to compensate for the lost function and tissue using regenerative medicine will be an ideal treatment. Many researchers have been trying to construct artificial organs through tissue engineering techniques; however, none have yet succeeded in growing a whole organ because of the complicated functions these organs perform, such as the processing and absorption of nutrients. While exciting results have been reported with regard to tissue engineering techniques concerning the upper gastrointestinal tract, such as the esophagus and stomach, most of these achievements have been observed in animal models, and few successful approaches in the clinical setting have been reported for the replacement of mucosal defects. We review the recent progress in regenerative medicine in relation to the upper gastrointestinal tract, such as the esophagus and stomach. We also focus on the functional capacity of regenerated tissue and its role as a culture system to recapitulate the mechanisms underlying infectious disease. With the emergence of technology such as the fabrication of decellularized constructs, organoids and cell sheet medicine, collaboration between gastrointestinal surgery and regenerative medicine is expected to help establish novel therapeutic modalities in the future.
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Affiliation(s)
- Kengo Kanetaka
- Tissue Engineering and Regenerative Therapeutics in Gastrointestinal Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Japan
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Mezoff EA, Minneci PC, Dienhart MC. Intestinal Failure: A Description of the Problem and Recent Therapeutic Advances. Clin Perinatol 2020; 47:323-340. [PMID: 32439114 DOI: 10.1016/j.clp.2020.02.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Pediatric intestinal failure occurs when gut function is insufficient to meet the nutrient and hydration needs of the growing child. The commonest cause is short bowel syndrome with maldigestion and malabsorption following massive bowel loss. The remnant bowel adapts during the process of intestinal rehabilitation. Management promotes the achievement of enteral autonomy while mitigating the risk of comorbid disease. The future of care is likely to see expansion of pharmacologic methods for augmenting bowel adaptation, tissue engineering techniques enabling immune suppression-free autologous bowel transplant, and the development of electronic health record tools for efficient, collaborative study and care improvement.
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Affiliation(s)
- Ethan A Mezoff
- Division of Gastroenterology, Hepatology & Nutrition, The Ohio State University College of Medicine, Center for Intestinal Rehabilitation and Nutrition Support, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
| | - Peter C Minneci
- Department of Surgery, The Ohio State University College of Medicine, Center for Surgical Outcomes Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA
| | - Molly C Dienhart
- Division of Gastroenterology, Hepatology & Nutrition, The Ohio State University College of Medicine, Center for Intestinal Rehabilitation and Nutrition Support, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA
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10
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Dosh RH, Jordan-Mahy N, Sammon C, Le Maitre CL. Use of l-pNIPAM hydrogel as a 3D-scaffold for intestinal crypts and stem cell tissue engineering. Biomater Sci 2020; 7:4310-4324. [PMID: 31410428 DOI: 10.1039/c9bm00541b] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Intestinal stem cells hold great potential in tissue regeneration of the intestine, however, there are key limitations in their culture in vitro. We previously reported a novel synthetic non-biodegradable hydrogel as a 3D culture model for intestinal epithelium using Caco2 and HT29-MTX cells. Here, we investigated the potential of this system as a 3D scaffold for crypts and single intestinal stem cells to support long-term culture and differentiation. Intestinal crypts were extracted from murine small intestines and Lgr5+ stem cells isolated by magnetic activated cell sorting. Crypts and stem cells were suspended within Matrigel or l-pNIPAM for 14 days or suspended within Matrigel for 7 days then released, dissociated, and suspended within, or on l-pNIPAM hydrogel for 28 days. Cellular behaviour and phenotype were determined by histology and immunohistochemistry for stem cell and differentiation markers: Lgr5, E-cadherin MUC2 chromograninA and lysozymes. Isolated crypts and Lgr5+ intestinal stem cells formed enteroids with a central lumen surrounded by multiple crypt-like buds when cultured in Matrigel. In contrast, when crypts and stem cells were directly suspended within, or layered on l-pNIPAM hydrogel under dynamic culture conditions they formed spherical balls of cells, with no central lumen. When enteroids were initially formed in Matrigel from crypts or single Lgr5+ intestinal stem cells and dissociated into small fragments or single cells and transferred to l-pNIPAM hydrogel they formed new larger enteroids with numerous crypt-like buds. These crypt-like buds showed the presence of mucin-producing cells, which resembled goblet cells, scattered throughout their structures. Immunohistochemistry staining also showed the expression of Lgr5 and differentiation markers of all the main intestinal cell types including: enterocytes, goblet cells, enteroendocrine and Paneth cells. This demonstrated that l-pNIPAM hydrogel supported long-term culture of crypts and Lgr5+ stem cells and promoted intestinal cell differentiation.
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Affiliation(s)
- Rasha H Dosh
- Biomolecular Sciences Research Centre, Sheffield Hallam University, S1 1WB, UK.
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12
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Abstract
The generation of tissue engineered organs from autologous cells will allow replacement of diseased or absent organs without the need for immunosuppression. Common steps of tissue engineering include isolation of pluripotent or multipotent stem cells, preparation of synthetic or biologic scaffold, and implantation into a host to support the proliferation of engineered tissue. Some organs have been successfully transplanted in human patients; gastrointestinal tract tissues are nearing clinical introduction. The state of the science has progressed rapidly and providers and researchers alike must take appropriate steps to ensure strict adherence to ethical standards before introduction to human therapy.
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Affiliation(s)
- Daniel Levin
- Division of Pediatric Surgery, Department of Surgery, University of Virginia, 1300 Jefferson Park Avenue, PO BOX 800709, Charlottesville, VA 22908-0709, USA.
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Generating an Artificial Intestine for the Treatment of Short Bowel Syndrome. Gastroenterol Clin North Am 2019; 48:585-605. [PMID: 31668185 DOI: 10.1016/j.gtc.2019.08.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Intestinal failure is defined as the inability to maintain fluid, nutrition, energy, and micronutrient balance that leads to the inability to gain or maintain weight, resulting in malnutrition and dehydration. Causes of intestinal failure include short bowel syndrome (ie, the physical loss of intestinal surface area and severe intestinal dysmotility). For patients with intestinal failure who fail to achieve enteral autonomy through intestinal rehabilitation programs, the current treatment options are expensive and associated with severe complications. Therefore, the need persists for next-generation therapies, including cell-based therapy, to increase intestinal regeneration, and development of the tissue-engineered small intestine.
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14
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Almeqdadi M, Mana MD, Roper J, Yilmaz ÖH. Gut organoids: mini-tissues in culture to study intestinal physiology and disease. Am J Physiol Cell Physiol 2019; 317:C405-C419. [PMID: 31216420 PMCID: PMC6766612 DOI: 10.1152/ajpcell.00300.2017] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 06/14/2019] [Accepted: 06/16/2019] [Indexed: 02/06/2023]
Abstract
In vitro, cell cultures are essential tools in the study of intestinal function and disease. For the past few decades, monolayer cellular cultures, such as cancer cell lines or immortalized cell lines, have been widely applied in gastrointestinal research. Recently, the development of three-dimensional cultures known as organoids has permitted the growth of normal crypt-villus units that recapitulate many aspects of intestinal physiology. Organoid culturing has also been applied to study gastrointestinal diseases, intestinal-microbe interactions, and colorectal cancer. These models are amenable to CRISPR gene editing and drug treatments, including high-throughput small-molecule testing. Three-dimensional intestinal cultures have been transplanted into mice to develop versatile in vivo models of intestinal disease, particularly cancer. Limitations of currently available organoid models include cost and challenges in modeling nonepithelial intestinal cells, such as immune cells and the microbiota. Here, we describe the development of organoid models of intestinal biology and the applications of organoids for study of the pathophysiology of intestinal diseases and cancer.
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Affiliation(s)
- Mohammad Almeqdadi
- The David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, Cambridge, Massachusetts
- Department of Internal Medicine, St. Elizabeth's Medical Center, Boston, Massachusetts
- Division of Gastroenterology and Hepatology, SUNY Downstate Medical Center, Brooklyn, New York
| | - Miyeko D Mana
- The David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Jatin Roper
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina
| | - Ömer H Yilmaz
- The David H. Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, Cambridge, Massachusetts
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
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15
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Zakhem E, Raghavan S, Suhar RA, Bitar KN. Bioengineering and regeneration of gastrointestinal tissue: where are we now and what comes next? Expert Opin Biol Ther 2019; 19:527-537. [PMID: 30880502 DOI: 10.1080/14712598.2019.1595579] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
INTRODUCTION The field of tissue engineering and regenerative medicine has been applied to the gastrointestinal (GI) tract for a couple decades. Several achievements have been accomplished that provide promising tools for treating diseases of the GI tract. AREAS COVERED The work described in this review covers the traditional aspect of using cells and scaffolds to replace parts of the tract. Several studies investigated different types of biomaterials and different types of cells. A more recent approach involved the use of gut-derived organoid units that can differentiate into all gut cell layers. The most recent approach introduced the use of organ-on-a-chip concept to understand the physiology and pathophysiology of the GI system. EXPERT OPINION The different approaches tackle the diseases of the GI tract from different perspectives. While all these different approaches provide a promising and encouraging future for this field, the translational aspect is yet to be studied.
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Affiliation(s)
- Elie Zakhem
- a Wake Forest Institute for Regenerative Medicine , Wake Forest School of Medicine , Winston Salem , NC , USA.,b Section on Gastroenterology , Wake Forest School of Medicine , Winston Salem , NC , USA
| | - Shreya Raghavan
- c Department of Materials Science and Engineering , University of Michigan , Ann Arbor , MI , USA
| | - Riley A Suhar
- d Department of Materials Science and Engineering , Stanford University , Stanford , CA , USA
| | - Khalil N Bitar
- a Wake Forest Institute for Regenerative Medicine , Wake Forest School of Medicine , Winston Salem , NC , USA.,b Section on Gastroenterology , Wake Forest School of Medicine , Winston Salem , NC , USA.,e Virginia Tech-Wake Forest School of Biomedical Engineering Sciences , Winston-Salem , NC , USA
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Tasnim N, Chattopadhyay M, Joddar B. Scaffolds for tissue engineering of stomach. HANDBOOK OF TISSUE ENGINEERING SCAFFOLDS: VOLUME TWO 2019:633-646. [DOI: 10.1016/b978-0-08-102561-1.00025-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Composite Scaffolds Based on Intestinal Extracellular Matrices and Oxidized Polyvinyl Alcohol: A Preliminary Study for a New Regenerative Approach in Short Bowel Syndrome. BIOMED RESEARCH INTERNATIONAL 2018; 2018:7824757. [PMID: 29992163 PMCID: PMC5994320 DOI: 10.1155/2018/7824757] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 04/17/2018] [Indexed: 12/11/2022]
Abstract
Pediatric Short Bowel Syndrome is a rare malabsorption disease occurring because of massive surgical resections of the small intestine. To date, the issues related to current strategies including intestinal transplantation prompted the attention towards tissue engineering (TE). This work aimed to develop and compare two composite scaffolds for intestinal TE consisting of a novel hydrogel, that is, oxidized polyvinyl alcohol (OxPVA), cross-linked with decellularized intestinal wall as a whole (wW/OxPVA) or homogenized (hW/OxPVA). A characterization of the supports was performed by histology and Scanning Electron Microscopy and their interaction with adipose mesenchymal stem cells occurred by MTT assay. Finally, the scaffolds were implanted in the omentum of Sprague Dawley rats for 4 weeks prior to being processed by histology and immunohistochemistry (CD3; F4/80; Ki-67; desmin; α-SMA; MNF116). In vitro studies proved the effectiveness of the decellularization, highlighting the features of the matrices; moreover, both supports promoted cell adhesion/proliferation even if the wW/OxPVA ones were more effective (p < 0.01). Analysis of explants showed a continuous and relatively organized tissue wall around the supports with a connective appearance, such as myofibroblastic features, smooth muscle, and epithelial cells. Both scaffolds, albeit with some difference, were promising; nevertheless, further analysis will be necessary.
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Dosh RH, Jordan-Mahy N, Sammon C, Le Maitre CL. Tissue Engineering Laboratory Models of the Small Intestine. TISSUE ENGINEERING PART B-REVIEWS 2018; 24:98-111. [DOI: 10.1089/ten.teb.2017.0276] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Rasha Hatem Dosh
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, United Kingdom
- Department of Anatomy and Histology, Faculty of Medicine, University of Kufa, Kufa, Iraq
| | - Nicola Jordan-Mahy
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, United Kingdom
| | - Christopher Sammon
- Materials and Engineering Research Institute, Sheffield Hallam University, Sheffield, United Kingdom
| | - Christine Lyn Le Maitre
- Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield, United Kingdom
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19
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Development and Application of Cryoprotectants. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1081:339-354. [DOI: 10.1007/978-981-13-1244-1_18] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Martin LY, Ladd MR, Werts A, Sodhi CP, March JC, Hackam DJ. Tissue engineering for the treatment of short bowel syndrome in children. Pediatr Res 2018; 83:249-257. [PMID: 28937976 PMCID: PMC6002962 DOI: 10.1038/pr.2017.234] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 09/07/2017] [Indexed: 12/11/2022]
Abstract
Short bowel syndrome is a major cause of morbidity and mortality in children. Despite decades of experience in the management of short bowel syndrome, current therapy is primarily supportive. Definitive treatment often requires intestinal transplantation, which is associated with significant morbidity and mortality. In order to develop novel approaches to the treatment of short bowel syndrome, we and others have focused on the development of an artificial intestine, by placing intestinal stem cells on a bioscaffold that has an absorptive surface resembling native intestine, and taking advantage of neovascularization to develop a blood supply. This review will explore recent advances in biomaterials, vascularization, and progress toward development of a functional epithelium and mesenchymal niche, highlighting both success and ongoing challenges in the field.
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Affiliation(s)
- Laura Y. Martin
- Division of General Pediatric Surgery, Johns Hopkins Children's Center, Baltimore MD 21287
- Department of Surgery, Johns Hopkins University and Johns Hopkins children's Center, Baltimore MD 21287
| | - Mitchell R. Ladd
- Division of General Pediatric Surgery, Johns Hopkins Children's Center, Baltimore MD 21287
- Department of Surgery, Johns Hopkins University and Johns Hopkins children's Center, Baltimore MD 21287
| | - Adam Werts
- Division of General Pediatric Surgery, Johns Hopkins Children's Center, Baltimore MD 21287
- Department of Surgery, Johns Hopkins University and Johns Hopkins children's Center, Baltimore MD 21287
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University and Johns Hopkins children's Center, Baltimore MD 21287
| | - Chhinder P. Sodhi
- Division of General Pediatric Surgery, Johns Hopkins Children's Center, Baltimore MD 21287
- Department of Surgery, Johns Hopkins University and Johns Hopkins children's Center, Baltimore MD 21287
| | - John C. March
- Department of Biomedical Engineering, Cornell University, Ithica, NY
| | - David J. Hackam
- Division of General Pediatric Surgery, Johns Hopkins Children's Center, Baltimore MD 21287
- Department of Surgery, Johns Hopkins University and Johns Hopkins children's Center, Baltimore MD 21287
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21
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Trecartin A, Grikscheit T. Tissue Engineering Functional Gastrointestinal Regions: The Importance of Stem and Progenitor Cells. Cold Spring Harb Perspect Med 2017; 7:cshperspect.a025700. [PMID: 28320829 DOI: 10.1101/cshperspect.a025700] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The intestine shows extraordinary regenerative potential that might be harnessed to alleviate numerous morbid and lethal human diseases. The intestinal stem cells regenerate the epithelium every 5 days throughout an individual's lifetime. Understanding stem-cell signaling affords power to influence the niche environment for growing intestine. The manifold approaches to tissue engineering may be organized by variations of three basic components required for the transplantation and growth of stem/progenitor cells: (1) cell delivery materials or scaffolds; (2) donor cells including adult stem cells, induced pluripotent stem cells, and in vitro expansion of isolated or cocultured epithelial, smooth muscle, myofibroblasts, or nerve cells; and (3) environmental modulators or biopharmaceuticals. Tissue engineering has been applied to the regeneration of every major region of the gastrointestinal tract from esophagus to colon, with scientists around the world aiming to carry these techniques into human therapy.
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Affiliation(s)
- Andrew Trecartin
- Department of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California 90027
| | - Tracy Grikscheit
- Department of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, California 90027
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22
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Zhou J, O'Connor MD, Ho V. The Potential for Gut Organoid Derived Interstitial Cells of Cajal in Replacement Therapy. Int J Mol Sci 2017; 18:ijms18102059. [PMID: 28954442 PMCID: PMC5666741 DOI: 10.3390/ijms18102059] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 09/15/2017] [Accepted: 09/24/2017] [Indexed: 12/24/2022] Open
Abstract
Effective digestion requires propagation of food along the entire length of the gastrointestinal tract. This process involves coordinated waves of peristalsis produced by enteric neural cell types, including different categories of interstitial cells of Cajal (ICC). Impaired food transport along the gastrointestinal tract, either too fast or too slow, causes a range of gut motility disorders that affect millions of people worldwide. Notably, loss of ICC has been shown to affect gut motility. Patients that suffer from gut motility disorders regularly experience diarrhoea and/or constipation, insomnia, anxiety, attention lapses, irritability, dizziness, and headaches that greatly affect both physical and mental health. Limited treatment options are available for these patients, due to the scarcity of human gut tissue for research and transplantation. Recent advances in stem cell technology suggest that large amounts of rudimentary, yet functional, human gut tissue can be generated in vitro for research applications. Intriguingly, these stem cell-derived gut organoids appear to contain functional ICC, although their frequency and functional properties are yet to be fully characterised. By reviewing methods of gut organoid generation, together with what is known of the molecular and functional characteristics of ICC, this article highlights short- and long-term goals that need to be overcome in order to develop ICC-based therapies for gut motility disorders.
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Affiliation(s)
- Jerry Zhou
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia.
- Medical Sciences Research Group, Western Sydney University, Campbelltown, NSW 2560, Australia.
| | - Michael D O'Connor
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia.
- Medical Sciences Research Group, Western Sydney University, Campbelltown, NSW 2560, Australia.
| | - Vincent Ho
- School of Medicine, Western Sydney University, Campbelltown, NSW 2560, Australia.
- Medical Sciences Research Group, Western Sydney University, Campbelltown, NSW 2560, Australia.
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Moisenovich MM, Kulikov DA, Goncharenko AV, Arkhipova AY, Vasiljeva TV, Filyushkin YN, Arkhipova LV, Kotlyarova MS, Kulikov AV, Mashkov AE, Agapov II, Kirpichnikov MP. Regeneration of jejunal wall defect using an implant based on silk fibroin fibers. DOKL BIOCHEM BIOPHYS 2017; 472:12-14. [PMID: 28421432 DOI: 10.1134/s1607672917010045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Indexed: 02/04/2023]
Abstract
Regenerative properties of fibroin implant vitalized with allogeneic bone marrow cells were assessed. The study was performed using the experimental model of rat jejunum wall damage. Three weeks after surgery, we observed recovery of all layers of the jejunum wall at the site of injury and complete degradation of the implant material.
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Affiliation(s)
- M M Moisenovich
- Biological Faculty, Moscow State University, Moscow, 119234, Russia.
| | - D A Kulikov
- Vladimirskii Moscow Regional Research Clinical Institute, Moscow, 129110, Russia
| | - A V Goncharenko
- Biological Faculty, Moscow State University, Moscow, 119234, Russia
| | - A Y Arkhipova
- Biological Faculty, Moscow State University, Moscow, 119234, Russia
| | - T V Vasiljeva
- Biological Faculty, Moscow State University, Moscow, 119234, Russia
| | - Yu N Filyushkin
- Vladimirskii Moscow Regional Research Clinical Institute, Moscow, 129110, Russia
| | - L V Arkhipova
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow oblast, 142290, Russia
| | - M S Kotlyarova
- Biological Faculty, Moscow State University, Moscow, 119234, Russia
| | - A V Kulikov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow oblast, 142290, Russia
| | - A E Mashkov
- Vladimirskii Moscow Regional Research Clinical Institute, Moscow, 129110, Russia
| | - I I Agapov
- Shumakov Federal Research Center of Transplantation and Artificial Organs, Ministry of Healthcare of the Russian Federation, Moscow, 113182, Russia
| | - M P Kirpichnikov
- Biological Faculty, Moscow State University, Moscow, 119234, Russia
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24
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Using 3D Organoid Cultures to Model Intestinal Physiology and Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2017; 13:183-191. [PMID: 29276469 DOI: 10.1007/s11888-017-0363-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The three-dimensional (3D) structure of the intestine is a key determinant of differentiation and function; thus, preserving this architecture is an important consideration for studies of intestinal homeostasis and disease. Over the past decade, a number of systems for 3D intestinal organoid cultures have been developed and adapted to model a wide variety of biological phenomenon. Purpose of this review We discuss the current state of intestinal and colorectal cancer (CRC) 3D modeling, the most common methods for generating organoid cultures, and how these have yielded insights into intestinal physiology and tumor biology. Recent findings Organoids have been used to model numerous aspects of intestinal physiology and disease. Recent adaptations have further improved disease modeling and high-throughput therapeutic screening. Summary These studies show intestinal organoid models are a robust, highly tractable system which maintains many vital features of intestinal tissue, making them a pivotal step forward in the field of gastroenterology.
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Abstract
The gastrointestinal (GI) tract is responsible for conducting multiple functions including motility, digestion and absorption. In gastrointestinal disorders, some of those functions are weakened or lost. Excision of the diseased segment of the GI tract is a common treatment; however, patients suffer from complications and low quality of life. Functional replacements are therefore needed to restore, repair or replace damaged parts of the tract. Tissue engineering and regenerative medicine provide an alternative approach to reconstruct different segments of the GI tract. The GI tract is a complex system with multiple cell types and layers. In previous years, bioengineering approaches focused on identifying an optimal cell source and scaffolding material to engineer GI tissues. In this editorial, we address some of our thoughts with regard to the recent discoveries in bioengineering the GI tract.
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Affiliation(s)
- Khalil N Bitar
- a Wake Forest Institute for Regenerative Medicine , Wake Forest School of Medicine , Winston Salem , NC , USA.,b Department of Molecular Medicine and Translational Sciences , Wake Forest School of Medicine , Winston Salem , NC , USA.,c Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences , Winston Salem , NC , USA
| | - Elie Zakhem
- a Wake Forest Institute for Regenerative Medicine , Wake Forest School of Medicine , Winston Salem , NC , USA.,b Department of Molecular Medicine and Translational Sciences , Wake Forest School of Medicine , Winston Salem , NC , USA
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26
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Generation of an artificial intestine for the management of short bowel syndrome. Curr Opin Organ Transplant 2016; 21:178-85. [PMID: 26867049 DOI: 10.1097/mot.0000000000000284] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
PURPOSE OF REVIEW This article discusses the current state of the art in artificial intestine generation in the treatment of short bowel syndrome. RECENT FINDINGS Short bowel syndrome defines the condition in which patients lack sufficient intestinal length to allow for adequate absorption of nutrition and fluids, and thus need parenteral support. Advances toward the development of an artificial intestine have improved dramatically since the first attempts in the 1980s, and the last decade has seen significant advances in understanding the intestinal stem cell niche, the growth of complex primary intestinal stem cells in culture, and fabrication of the biomaterials that can support the growth and differentiation of these stem cells. There has also been recent progress in understanding the role of the microbiota and the immune cells on the growth of intestinal cultures on scaffolds in animal models. Despite recent progress, there is much work to be done before the development of a functional artificial intestine for short bowel syndrome is successfully achieved. SUMMARY Continued concerted efforts by cell biologists, bioengineers, and clinician-scientists will be required for the development of an artificial intestine as a clinical treatment modality for short bowel syndrome.
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27
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Abstract
Functions of the gastrointestinal tract include motility, digestion and absorption of nutrients. These functions are mediated by several specialized cell types including smooth muscle cells, neurons, interstitial cells and epithelial cells. In gastrointestinal diseases, some of the cells become degenerated or fail to accomplish their normal functions. Surgical resection of the diseased segments of the gastrointestinal tract is considered the gold-standard treatment in many cases, but patients might have surgical complications and quality of life can remain low. Tissue engineering and regenerative medicine aim to restore, repair, or regenerate the function of the tissues. Gastrointestinal tissue engineering is a challenging process given the specific phenotype and alignment of each cell type that colonizes the tract - these properties are critical for proper functionality. In this Review, we summarize advances in the field of gastrointestinal tissue engineering and regenerative medicine. Although the findings are promising, additional studies and optimizations are needed for translational purposes.
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Affiliation(s)
- Khalil N Bitar
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way NE, Winston Salem, North Carolina 27101, USA.,Department of Molecular Medicine and Translational Sciences, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston Salem, North Carolina 27157, USA.,Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, 391 Technology Way NE, Winston Salem, North Carolina 27101, USA
| | - Elie Zakhem
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way NE, Winston Salem, North Carolina 27101, USA.,Department of Molecular Medicine and Translational Sciences, Wake Forest School of Medicine, 1 Medical Center Blvd, Winston Salem, North Carolina 27157, USA
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28
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Sears NA, Seshadri DR, Dhavalikar PS, Cosgriff-Hernandez E. A Review of Three-Dimensional Printing in Tissue Engineering. TISSUE ENGINEERING PART B-REVIEWS 2016; 22:298-310. [DOI: 10.1089/ten.teb.2015.0464] [Citation(s) in RCA: 203] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Nick A. Sears
- Department of Biomedical Engineering, Texas A&M University, College Station, Texas
| | - Dhruv R. Seshadri
- Department of Biomedical Engineering, Texas A&M University, College Station, Texas
| | - Prachi S. Dhavalikar
- Department of Biomedical Engineering, Texas A&M University, College Station, Texas
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29
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Gupta A, Seifalian AM, Ahmad Z, Edirisinghe MJ, Winslet MC. Novel Electrohydrodynamic Printing of Nanocomposite Biopolymer Scaffolds. J BIOACT COMPAT POL 2016. [DOI: 10.1177/0883911507078268] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In this paper, we uncover a new method for the preparation of biopolymer scaffolds and demonstrate its potential for the development of organs with the aid of tissue engineering. Two novel nanocomposite polymers, a nonbiodegradable polyhedral oligomeric silsesquioxane-poly (carbonate-urea)urethane and a biodegradable polyhedral oligomeric silsesquioxane-polycaprolactone-poly(carbonate-urea)urethane, have been subjected to flow in an electric field. Electrically forced microthreading of the polymers occurs and a three-dimensional print-patterning device was used to deposit fine (<50 µm) threads of polymer according to a predesigned architecture to prepare scaffolds. The technique can offer tremendous potential in the development of organs.
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Affiliation(s)
- Ashish Gupta
- Biomaterials and Tissue Engineering Centre, Academic Division of Surgery and Interventional Sciences, University College London, Hampstead Campus, London NW3 2PF, UK
| | - Alexander M. Seifalian
- Biomaterials and Tissue Engineering Centre, Academic Division of Surgery and Interventional Sciences, University College London, Hampstead Campus, London NW3 2PF, UK
| | - Zeeshan Ahmad
- Department of Mechanical Engineering, University College London, Torrington Place, London WC1E 7JE, UK
| | - Mohan J. Edirisinghe
- Department of Mechanical Engineering, University College London, Torrington Place, London WC1E 7JE, UK,
| | - Marc C. Winslet
- Royal Free Hampstead NHS Trust Hospital, Pond Street, London NW3 2QG, UK
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Aurora M, Spence JR. hPSC-derived lung and intestinal organoids as models of human fetal tissue. Dev Biol 2016; 420:230-238. [PMID: 27287882 DOI: 10.1016/j.ydbio.2016.06.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2016] [Revised: 05/23/2016] [Accepted: 06/04/2016] [Indexed: 02/07/2023]
Abstract
In vitro human pluripotent stem cell (hPSC) derived tissues are excellent models to study certain aspects of normal human development. Current research in the field of hPSC derived tissues reveals these models to be inherently fetal-like on both a morphological and gene expression level. In this review we briefly discuss current methods for differentiating lung and intestinal tissue from hPSCs into individual 3-dimensional units called organoids. We discuss how these methods mirror what is known about in vivo signaling pathways of the developing embryo. Additionally, we will review how the inherent immaturity of these models lends them to be particularly valuable in the study of immature human tissues in the clinical setting of premature birth. Human lung organoids (HLOs) and human intestinal organoids (HIOs) not only model normal development, but can also be utilized to study several important diseases of prematurity such as respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), and necrotizing enterocolitis (NEC).
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Affiliation(s)
- Megan Aurora
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Jason R Spence
- Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, United States; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, United States; Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI, United States
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31
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Dedhia PH, Bertaux-Skeirik N, Zavros Y, Spence JR. Organoid Models of Human Gastrointestinal Development and Disease. Gastroenterology 2016; 150:1098-1112. [PMID: 26774180 PMCID: PMC4842135 DOI: 10.1053/j.gastro.2015.12.042] [Citation(s) in RCA: 171] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Revised: 12/23/2015] [Accepted: 12/23/2015] [Indexed: 12/21/2022]
Abstract
We have greatly advanced our ability to grow a diverse range of tissue-derived and pluripotent stem cell-derived gastrointestinal (GI) tissues in vitro. These systems, broadly referred to as organoids, have allowed the field to move away from the often nonphysiological, transformed cell lines that have been used for decades in GI research. Organoids are derived from primary tissues and have the capacity for long-term growth. They contain varying levels of cellular complexity and physiological similarity to native organ systems. We review the latest discoveries from studies of tissue-derived and pluripotent stem cell-derived intestinal, gastric, esophageal, liver, and pancreatic organoids. These studies have provided important insights into GI development, tissue homeostasis, and disease and might be used to develop personalized medicines.
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Affiliation(s)
- Priya H. Dedhia
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA,Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Nina Bertaux-Skeirik
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, OH 45229, USA
| | - Yana Zavros
- Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio.
| | - Jason R. Spence
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA,Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA,Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA,Authors for Correspondence: Jason R. Spence – , Twitter: @TheSpenceLab, Yana Zavros –
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32
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Shirafkan A, Montalbano M, McGuire J, Rastellini C, Cicalese L. New approaches to increase intestinal length: Methods used for intestinal regeneration and bioengineering. World J Transplant 2016; 6:1-9. [PMID: 27011901 PMCID: PMC4801784 DOI: 10.5500/wjt.v6.i1.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 12/01/2015] [Accepted: 01/11/2016] [Indexed: 02/05/2023] Open
Abstract
Inadequate absorptive surface area poses a great challenge to the patients suffering a variety of intestinal diseases causing short bowel syndrome. To date, these patients are managed with total parenteral nutrition or intestinal transplantation. However, these carry significant morbidity and mortality. Currently, by emergence of tissue engineering, anticipations to utilize an alternative method to increase the intestinal absorptive surface area are increasing. In this paper, we will review the improvements made over time in attempting elongating the intestine with surgical techniques as well as using intestinal bioengineering. Performing sequential intestinal lengthening was the preliminary method applied in humans. However, these methods did not reach widespread use and has limited outcome. Subsequent experimental methods were developed utilizing scaffolds to regenerate intestinal tissue and organoids unit from the intestinal epithelium. Stem cells also have been studied and applied in all types of tissue engineering. Biomaterials were utilized as a structural support for naive cells to produce bio-engineered tissue that can achieve a near-normal anatomical structure. A promising novel approach is the elongation of the intestine with an acellular biologic scaffold to generate a neo-formed intestinal tissue that showed, for the first time, evidence of absorption in vivo. In the large intestine, studies are more focused on regeneration and engineering of sphincters and will be briefly reviewed. From the review of the existing literature, it can be concluded that significant progress has been achieved in these experimental methods but that these now need to be fully translated into a pre-clinical and clinical experimentation to become a future viable therapeutic option.
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Cromeens BP, Liu Y, Stathopoulos J, Wang Y, Johnson J, Besner GE. Production of tissue-engineered intestine from expanded enteroids. J Surg Res 2016; 204:164-75. [PMID: 27451883 DOI: 10.1016/j.jss.2016.02.030] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 02/08/2016] [Accepted: 02/24/2016] [Indexed: 01/08/2023]
Abstract
BACKGROUND Short bowel syndrome is a life-threatening condition with few solutions. Tissue-engineered intestine (TEI) is a potential treatment, but donor intestine is a limiting factor. Expanded epithelial surrogates termed enteroids may serve as a potential donor source. MATERIALS AND METHODS To produce TEI from enteroids, crypts were harvested from mice and enteroid cultures established. Enteroids were seeded onto polymer scaffolds using Matrigel or culture medium and implanted in immunosuppressed mice for 4 wk. Histology was analyzed using Periodic acid-Schiff staining and immunofluorescence. Neomucosa was quantified using ImageJ software. To determine whether TEI could be produced from enteroids established from small intestinal biopsies, 2 × 2-mm pieces of jejunum were processed for enteroid culture, enteroids were expanded and seeded onto scaffolds, and scaffolds implanted for 4 wk. RESULTS Enteroids in Matrigel produced TEI in 15 of 15 scaffolds, whereas enteroids in medium produced TEI in 9 of 15 scaffolds. Use of Matrigel led to more neomucosal surface area compared to media (10,520 ± 2905 μm versus 450 ± 127 μm, P < 0.05). Histologic examination confirmed the presence of crypts and blunted villi, normal intestinal epithelial lineages, intestinal subepithelial myofibroblasts, and smooth muscle cells. Crypts obtained from biopsies produced an average of 192 ± 71 enteroids. A single passage produced 685 ± 58 enteroids, which was adequate for scaffold seeding. TEI was produced in 8 of 9 scaffolds seeded with expanded enteroids. CONCLUSIONS Enteroids can be obtained from minimal starting material, expanded ex vivo, and implanted to produce TEI. This method shows promise as a solution to the limited donor intestine available for TEI production in patients with short bowel syndrome.
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Affiliation(s)
- Barrett P Cromeens
- Department of General Pediatric Surgery, Nationwide Children's Hospital, Columbus, Ohio
| | - Yanchun Liu
- Department of General Pediatric Surgery, Nationwide Children's Hospital, Columbus, Ohio
| | | | - Yijie Wang
- Department of General Pediatric Surgery, Nationwide Children's Hospital, Columbus, Ohio
| | | | - Gail E Besner
- Department of General Pediatric Surgery, Nationwide Children's Hospital, Columbus, Ohio.
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Evidence of Absorptive Function in vivo in a Neo-Formed Bio-Artificial Intestinal Segment Using a Rodent Model. J Gastrointest Surg 2016; 20:34-42; discussion 42. [PMID: 26464017 DOI: 10.1007/s11605-015-2974-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2015] [Accepted: 09/28/2015] [Indexed: 02/06/2023]
Abstract
A promising therapeutic approach for intestinal failure consists in elongating the intestine with a bio-engineered segment of neo-formed autologous intestine. Using an acellular biologic scaffold (ABS), we, and others, have previously developed an autologous bio-artificial intestinal segment (BIS) that is morphologically similar to normal bowel in rodents. This neo-formed BIS is constructed with the intervention of naïve stem cells that repopulate the scaffold in vivo, and over a period of time, are transformed in different cell populations typical of normal intestinal mucosa. However, no studies are available to demonstrate that such BIS possesses functional absorptive characteristics necessary to render this strategy a possible therapeutic application. The aim of this study was to demonstrate that the BIS generated has functional absorptive capacity. Twenty male August × Copenhagen-Irish (ACI) rats were used for the study. Two-centimeter sections of ABS were transplanted in the anti-mesenteric border of the small bowel. Animals were studied at 4, 8, and 12 weeks post-engraftment. Segments of intestine with preserved vascular supply and containing the BIS were isolated and compared to intestinal segments of same length in sham control animals (n = 10). D-Xylose solution was introduced in the lumen of the intestinal segments and after 2 h, urine and blood were collected to evaluate D-Xylose levels. Quantitative analysis was performed using ELISA. Morphologic, ultrastructural, and indirect functional absorption analyses were also performed. We observed neo-formed intestinal tissue with near-normal mucosa post-implantation as expected from our previously developed model. Functional characteristics such as morphologically normal enterocytes (and other cell types) with presence of brush borders and preserved microvilli by electron microscopy, preserved water, and ion transporters/channels (by aquaporin and cystic fibrosis transmembrane conductance regulator (CFTR)) were also observed. The capacity of BIS containing neo-formed mucosa to increase absorption of d-Xylose in the blood compared to normal intestine was also confirmed. With this study, we demonstrated for the first time that BIS obtained from ABS has functional characteristics of absorption confirming its potential for therapeutic interventions.
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Jerman UD, Kreft ME, Veranič P. Epithelial-Mesenchymal Interactions in Urinary Bladder and Small Intestine and How to Apply Them in Tissue Engineering. TISSUE ENGINEERING PART B-REVIEWS 2015; 21:521-30. [PMID: 26066408 DOI: 10.1089/ten.teb.2014.0678] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Reciprocal interactions between the epithelium and mesenchyme are essential for the establishment of proper tissue morphology during organogenesis and tissue regeneration as well as for the maintenance of cell differentiation. With this review, we highlight the importance of epithelial-mesenchymal cross talk in healthy tissue and further discuss its significance in engineering functional tissues in vitro. We focus on the urinary bladder and small intestine, organs that are often compromised by disease and are as such in need of research that would advance effective treatment or tissue replacement. To date, the understanding of epithelial-mesenchymal reciprocal interactions has enabled the development of in vitro biomimetic tissue equivalents that have provided many possibilities in treating defective, damaged, or even cancerous tissues. Although research of the past several years has advanced the field of bladder and small intestine tissue engineering, one must be aware of its current limitations in successfully and above all safely introducing tissue-engineered constructs into clinical practice. Special attention is in particular needed when treating cancerous tissues, as initially successful tumor excision and tissue reconstruction may later on result in cancer recurrence due to oncogenic signals originating from an altered stroma. Recent rather poor outcomes in pioneering clinical trials of bladder reconstructions should serve as a reminder that recreating a functional organ to replace a dysfunctional one is an objective far more difficult to reach than initially foreseen. When considering effective tissue engineering approaches for diseased tissues in humans, it is imperative to introduce animal models with dysfunctional or, even more importantly, cancerous organs, which would greatly contribute to predicting possible complications and, hence, reducing risks when translating to the clinic.
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Affiliation(s)
- Urška Dragin Jerman
- Faculty of Medicine, Institute of Cell Biology, University of Ljubljana , Ljubljana, Slovenia
| | - Mateja Erdani Kreft
- Faculty of Medicine, Institute of Cell Biology, University of Ljubljana , Ljubljana, Slovenia
| | - Peter Veranič
- Faculty of Medicine, Institute of Cell Biology, University of Ljubljana , Ljubljana, Slovenia
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Bhatnagar D, Bherwani AK, Simon M, Rafailovich MH. Biomineralization on enzymatically cross-linked gelatin hydrogels in the absence of dexamethasone. J Mater Chem B 2015; 3:5210-5219. [PMID: 32262596 DOI: 10.1039/c5tb00482a] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
A mechanical stimulus and chemical induction by dexamethasone have been important factors in dental pulp stem cell (DPSC) differentiation and biomineralization. We have demonstrated that the enzymatically crosslinked gelatin hydrogels are extremely effective substrates for DPSC differentiation towards odontoblasts. DPSCs were seeded on the crosslinked hard (∼8 kPa) and soft (∼0.15 kPa) gelatin hydrogels for 35 days with and without dexamethasone. Odontogenic differentiation markers such as OCN, ALP and DSPP were upregulated after 35 days of culture on crosslinked hydrogels with and without dexamethasone. SEM and Alizarin red staining of the crosslinked hydrogels showed a biomineralized sheet of hydroxyapatite deposits laid by the DPSCs on the top surface and inside the hydrogel. We found that the DPSC differentiation and biomineralization were independent of the hydrogel stiffness and dexamethasone. We hypothesize that this biomineralization was indeed triggered by the surface chemistry of the crosslinked gelatin hydrogels since we did not observe any biomineralization on the uncrosslinked gelatin or mTG. We also showed that the DPSCs, when removed from hard hydrogel surfaces and re-seeded on a TCPS, retained their odontogenic lineage and showed a permanent mineralization effect. Our results show the potential of enzymatically crosslinked gelatin hydrogels as scaffolds for dentin regeneration.
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Affiliation(s)
- Divya Bhatnagar
- Department of Materials Science and Engineering, Stony Brook University, Stony Brook, NY 11790, USA.
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Abstract
Regenerative medicine has recently been established as an emerging interdisciplinary field focused on the repair; replacement or regeneration of cells, tissues and organs. It involves various disciplines, which are focused on different aspects of the regeneration process such as cell biology, gene therapy, bioengineering, material science and pharmacology. In this article, we will outline progress on tissue engineering of specific tissues and organs relevant to paediatric surgery.
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Affiliation(s)
- Panagiotis Maghsoudlou
- Surgery Unit, Institute of Child Health and Great Ormond Street Hospital, University College London, 30 Guilford St, London WC1N 1EH, UK
| | - Luca Urbani
- Surgery Unit, Institute of Child Health and Great Ormond Street Hospital, University College London, 30 Guilford St, London WC1N 1EH, UK
| | - Paolo De Coppi
- Surgery Unit, Institute of Child Health and Great Ormond Street Hospital, University College London, 30 Guilford St, London WC1N 1EH, UK.
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38
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Coletta R, Khalil BA, Morabito A. Short bowel syndrome in children: surgical and medical perspectives. Semin Pediatr Surg 2014; 23:291-7. [PMID: 25459014 DOI: 10.1053/j.sempedsurg.2014.09.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The main cause of intestinal failure in children is due to short bowel syndrome (SBS) resulting from congenital or acquired intestinal lesions. From the first lengthening procedure introduced by Bianchi, the last three decades have seen lengthening procedures established as fundamental components of multidisciplinary intestinal rehabilitation programs. Debate on indications and timing of the procedures is still open leaving SBS surgical treatment a great challenge. However, enteral autonomy is possible only with an individualized approach remembering that each SBS patient is unique. Current literature on autologous gastrointestinal reconstruction technique was reviewed aiming to assess a comprehensive pathway in SBS non-transplant management.
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Affiliation(s)
- Riccardo Coletta
- Paediatric Autologous Bowel Reconstruction and Rehabilitation Unit, Royal Manchester Children׳s Hospital, Oxford Rd, Manchester M13 9WL, UK; School of Medicine, University of Manchester, Manchester, UK
| | - Basem A Khalil
- Paediatric Autologous Bowel Reconstruction and Rehabilitation Unit, Royal Manchester Children׳s Hospital, Oxford Rd, Manchester M13 9WL, UK; School of Medicine, University of Manchester, Manchester, UK
| | - Antonino Morabito
- Paediatric Autologous Bowel Reconstruction and Rehabilitation Unit, Royal Manchester Children׳s Hospital, Oxford Rd, Manchester M13 9WL, UK; School of Medicine, University of Manchester, Manchester, UK.
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39
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Intestinal stem cells and stem cell-based therapy for intestinal diseases. Cytotechnology 2014; 67:177-89. [PMID: 24981313 DOI: 10.1007/s10616-014-9753-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Accepted: 06/07/2014] [Indexed: 01/17/2023] Open
Abstract
Currently, many gastrointestinal diseases are a major reason for the increased mortality rate of children and adults every year. Additionally, these patients may cope with the high cost of the parenteral nutrition (PN), which aids in the long-term survival of the patients. Other treatment options include surgical lengthening, which is not sufficient in many cases, and intestinal transplantation. However, intestinal transplantation is still accompanied by many challenges, including immune rejection and donor availability, which may limit the transplant's success. The development of more safe and promising alternative treatments for intestinal diseases is still ongoing. Stem cell-based therapy (SCT) and tissue engineering (TE) appear to be the next promising choices for the regeneration of the damaged intestine. However, suitable stem cell source is required for the SCT and TE process. Thus, in this review we discuss how intestinal stem cells (ISCs) are a promising cell source for small intestine diseases. We will also discuss the different markers were used to identify ISCs. Moreover, we discuss the dominant Wnt signaling pathway in the ISC niche and its involvement in some intestinal diseases. Additionally, we discuss ISC culture and expansion, which are critical to providing enough cells for SCT and TE. Finally, we conclude and recommend that ISC isolation, culture and expansion should be considered when SCT is a treatment option for intestinal disorders. Therefore, we believe that ISCs should be considered a cell source for SCT for many gastrointestinal diseases and should be highlighted in future clinical applications.
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40
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Costello CM, Hongpeng J, Shaffiey S, Yu J, Jain NK, Hackam D, March JC. Synthetic small intestinal scaffolds for improved studies of intestinal differentiation. Biotechnol Bioeng 2014; 111:1222-32. [PMID: 24390638 DOI: 10.1002/bit.25180] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2013] [Revised: 11/11/2013] [Accepted: 12/23/2013] [Indexed: 12/11/2022]
Abstract
In vitro intestinal models can provide new insights into small intestinal function, including cellular growth and proliferation mechanisms, drug absorption capabilities, and host-microbial interactions. These models are typically formed with cells cultured on 2D scaffolds or transwell inserts, but it is widely understood that epithelial cells cultured in 3D environments exhibit different phenotypes that are more reflective of native tissue. Our focus was to develop a porous, synthetic 3D tissue scaffold with villous features that could support the culture of epithelial cell types to mimic the natural microenvironment of the small intestine. We demonstrated that our scaffold could support the co-culture of Caco-2 cells with a mucus-producing cell line, HT29-MTX, as well as small intestinal crypts from mice for extended periods. By recreating the surface topography with accurately sized intestinal villi, we enable cellular differentiation along the villous axis in a similar manner to native intestines. In addition, we show that the biochemical microenvironments of the intestine can be further simulated via a combination of apical and basolateral feeding of intestinal cell types cultured on the 3D models.
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Affiliation(s)
- Cait M Costello
- Biological and Environmental Engineering, Cornell University, Ithaca, New York
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41
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Weigel T, Schinkel G, Lendlein A. Design and preparation of polymeric scaffolds for tissue engineering. Expert Rev Med Devices 2014; 3:835-51. [PMID: 17280547 DOI: 10.1586/17434440.3.6.835] [Citation(s) in RCA: 128] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Polymeric scaffolds for tissue engineering can be prepared with a multitude of different techniques. Many diverse approaches have recently been under development. The adaptation of conventional preparation methods, such as electrospinning, induced phase separation of polymer solutions or porogen leaching, which were developed originally for other research areas, are described. In addition, the utilization of novel fabrication techniques, such as rapid prototyping or solid free-form procedures, with their many different methods to generate or to embody scaffold structures or the usage of self-assembly systems that mimic the properties of the extracellular matrix are also described. These methods are reviewed and evaluated with specific regard to their utility in the area of tissue engineering.
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Affiliation(s)
- Thomas Weigel
- Department of Polymer Technology, Institute of Polymer Research, GKSS Research Center Geesthacht, Kantstr 55, D-14513 Teltow, Germany.
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Del Gaudio C, Baiguera S, Ajalloueian F, Bianco A, Macchiarini P. Are synthetic scaffolds suitable for the development of clinical tissue-engineered tubular organs? J Biomed Mater Res A 2013; 102:2427-47. [PMID: 23894109 DOI: 10.1002/jbm.a.34883] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 07/11/2013] [Accepted: 07/17/2013] [Indexed: 02/06/2023]
Abstract
Transplantation of tissues and organs is currently the only available treatment for patients with end-stage diseases. However, its feasibility is limited by the chronic shortage of suitable donors, the need for life-long immunosuppression, and by socioeconomical and religious concerns. Recently, tissue engineering has garnered interest as a means to generate cell-seeded three-dimensional scaffolds that could replace diseased organs without requiring immunosuppression. Using a regenerative approach, scaffolds made by synthetic, nonimmunogenic, and biocompatible materials have been developed and successfully clinically implanted. This strategy, based on a viable and ready-to-use bioengineered scaffold, able to promote novel tissue formation, favoring cell adhesion and proliferation, could become a reliable alternative to allotransplatation in the next future. In this article, tissue-engineered synthetic substitutes for tubular organs (such as trachea, esophagus, bile ducts, and bowel) are reviewed, including a discussion on their morphological and functional properties.
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Affiliation(s)
- Costantino Del Gaudio
- University of Rome "Tor Vergata", Department of Industrial Engineering, Intrauniversitary Consortium for Material Science and Technology (INSTM), Research Unit Tor Vergata, Rome, Italy
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43
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Son SR, Franco RA, Bae SH, Min YK, Lee BT. Electrospun PLGA/gelatin fibrous tubes for the application of biodegradable intestinal stent in rat model. J Biomed Mater Res B Appl Biomater 2013; 101:1095-105. [DOI: 10.1002/jbm.b.32923] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2012] [Revised: 01/10/2013] [Accepted: 02/11/2013] [Indexed: 01/03/2023]
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Bae SH. Recent achievements in stem cell therapy for pediatric gastrointestinal tract disease. Pediatr Gastroenterol Hepatol Nutr 2013; 16:10-6. [PMID: 24010100 PMCID: PMC3746046 DOI: 10.5223/pghn.2013.16.1.10] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 03/12/2013] [Accepted: 03/14/2013] [Indexed: 12/24/2022] Open
Abstract
The field of stem cell research has been rapidly expanding. Although the clinical usefulness of research remains to be ascertained through human trials, the use of stem cells as a therapeutic option for currently disabling diseases holds fascinating potential. Many pediatric gastrointestinal tract diseases have defect in enterocytes, enteric nervous system cells, smooth muscles, and interstitial cells of Cajal. Various kinds of therapeutic trials using stem cells could be applied to these diseases. This review article focuses on the recent achievements in stem cell applications for pediatric gastrointestinal tract diseases.
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Affiliation(s)
- Sun Hwan Bae
- Department of Pediatrics, School of Medicine, Konkuk University, Seoul, Korea
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45
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De Coppi P. Regenerative medicine for congenital malformations. J Pediatr Surg 2013; 48:273-80. [PMID: 23414851 DOI: 10.1016/j.jpedsurg.2012.11.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Accepted: 11/12/2012] [Indexed: 01/17/2023]
Abstract
This is a review of the progress in regenerative medicine and concepts behind the field of tissue engineering and cell transplantation as it applies to congenital malformations. It is based on the Journal of Pediatric Surgery invited lecture to the BAPS/EUPSA Congress in Rome, Italy, June 2012.
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Affiliation(s)
- Paolo De Coppi
- Department of Paediatric Surgery, Institute of Child Health & Great Ormond St Hospital, London, United Kingdom.
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46
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Carbone M, Lerut J, Neuberger J. How regenerative medicine and tissue engineering may complement the available armamentarium in gastroenterology? World J Gastroenterol 2012; 18:6908-6917. [PMID: 23322988 PMCID: PMC3531674 DOI: 10.3748/wjg.v18.i47.6908] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Revised: 09/10/2012] [Accepted: 10/30/2012] [Indexed: 02/06/2023] Open
Abstract
The increasing shortage of donors and the adverse effects of immunosuppression have restricted the impact of solid organ transplantation. Despite the initial promising developments in xenotransplantation, roadblocks still need to be overcome and this form of organ support remains a long way from clinical practice. While hepatocyte transplantation may be effectively correct metabolic defects, it is far less effective in restoring liver function than liver transplantation. Tissue engineering, using extracellular matrix scaffolds with an intact but decellularized vascular network that is repopulated with autologous or allogeneic stem cells and/or adult cells, holds great promise for the treatment of failure of organs within gastrointestinal tract, such as end-stage liver disease, pancreatic insufficiency, bowel failure and type 1 diabetes. Particularly in the liver field, where there is a significant mortality of patients awaiting transplant, human bioengineering may offer a source of readily available organs for transplantation. The use of autologous cells will mitigate the need for long term immunosuppression thus removing a major hurdle in transplantation.
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47
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Kurtz A, Oh SJ, Wu J, Chen H, Zhang Y, Zhao X, Chen X, Du W, Wang D, Lin X. Age related changes of the extracellular matrix and stem cell maintenance. Prev Med 2012; 54 Suppl:S50-6. [PMID: 22285947 DOI: 10.1016/j.ypmed.2012.01.003] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Revised: 01/04/2012] [Accepted: 01/04/2012] [Indexed: 02/07/2023]
Abstract
Aging is characterized by reduced tissue and organ function, regenerative capacity, and accompanied by a decrease in tissue resident stem cell numbers and a loss of potency. The impact of aging on stem cell populations differs between tissues and depends on a number of non cell-intrinsic factors, including systemic changes associated with immune system alterations, as well as senescence related changes of the local cytoarchitecture. The latter has been studied in the context of environmental niche properties required for stem cell maintenance. Here, we will discuss the impact of the extracellular matrix (ECM) on stem cell maintenance, its changes during aging and its significance for stem cell therapy. We provide an overview on ECM components and examples of age associated remodeling of the cytoarchitecture. The interaction of stem cells with the ECM will be described and the importance of an intact and hospitable ECM for stem cell maintenance, differentiation and stem cell initiated tissue repair outlined. It is concluded that a remodeled ECM due to age related inflammation, fibrosis or oxidative stress provides an inadequate environment for endogenous regeneration or stem cell therapies. Means to provide adequate ECM for stem cell therapies and endogenous regeneration and the potential of antioxidants to prevent ECM damage and promote its repair and subsequently support regeneration are discussed.
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Affiliation(s)
- Andreas Kurtz
- College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea.
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48
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Howell JC, Wells JM. Generating intestinal tissue from stem cells: potential for research and therapy. Regen Med 2012; 6:743-55. [PMID: 22050526 DOI: 10.2217/rme.11.90] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Intestinal resection and malformations in adult and pediatric patients result in devastating consequences. Unfortunately, allogeneic transplantation of intestinal tissue into patients has not been met with the same measure of success as the transplantation of other organs. Attempts to engineer intestinal tissue in vitro include disaggregation of adult rat intestine into subunits called organoids, harvesting native adult stem cells from mouse intestine and spontaneous generation of intestinal tissue from embryoid bodies. Recently, by utilizing principles gained from the study of developmental biology, human pluripotent stem cells have been demonstrated to be capable of directed differentiation into intestinal tissue in vitro. Pluripotent stem cells offer a unique and promising means to generate intestinal tissue for the purposes of modeling intestinal disease, understanding embryonic development and providing a source of material for therapeutic transplantation.
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Affiliation(s)
- Jonathan C Howell
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA
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49
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Saxena A, Ackbar R, Höllwarth M. Tissue Engineering for the Neonatal and Pediatric Patients. JOURNAL OF HEALTHCARE ENGINEERING 2012. [DOI: 10.1260/2040-2295.3.1.21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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50
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Totonelli G, Maghsoudlou P, Garriboli M, Riegler J, Orlando G, Burns AJ, Sebire NJ, Smith VV, Fishman JM, Ghionzoli M, Turmaine M, Birchall MA, Atala A, Soker S, Lythgoe MF, Seifalian A, Pierro A, Eaton S, De Coppi P. A rat decellularized small bowel scaffold that preserves villus-crypt architecture for intestinal regeneration. Biomaterials 2012; 33:3401-10. [PMID: 22305104 PMCID: PMC4022101 DOI: 10.1016/j.biomaterials.2012.01.012] [Citation(s) in RCA: 153] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2011] [Accepted: 01/05/2012] [Indexed: 12/20/2022]
Abstract
Management of intestinal failure remains a clinical challenge and total parenteral nutrition, intestinal elongation and/or transplantation are partial solutions. In this study, using a detergent-enzymatic treatment (DET), we optimize in rats a new protocol that creates a natural intestinal scaffold, as a base for developing functional intestinal tissue. After 1 cycle of DET, histological examination and SEM and TEM analyses showed removal of cellular elements with preservation of the native architecture and connective tissue components. Maintenance of biomechanical, adhesion and angiogenic properties were also demonstrated strengthen the idea that matrices obtained using DET may represent a valid support for intestinal regeneration.
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Affiliation(s)
- Giorgia Totonelli
- Surgery Unit, Institute of Child Health and Great Ormond Street Hospital, University College London, London WC1N 1EH, UK
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