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1
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Tonini L, Ahn C. Latest Advanced Techniques for Improving Intestinal Organoids Limitations. Stem Cell Rev Rep 2025:10.1007/s12015-025-10894-9. [PMID: 40388043 DOI: 10.1007/s12015-025-10894-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/06/2025] [Indexed: 05/20/2025]
Abstract
Intestinal organoids are valuable tools across different disciplines, from a clinical aspect to the biomedical research, providing a unique perspective on the complexity of the gastrointestinal system. They are alternatives to common cell lines as they can offer insights into architectural functionality and reduce the use of animal models. A deeper understanding of their organoid characteristics is required to harness their full potential. Despite their beneficial uses and multiple advantages, organoids have limitations that remain unaddressed. This review aims to elucidate the principal limitations of intestinal organoids, investigate structural defects such as the deficiency in a vascularized and lymphatic system, and absence of the microbiome, restrictions in mimicking the physiological gut model, including the lack of an acid-neutralizing system or a shortage of digestive enzymes, and the difficulties in their long-term maintenance and polarity accessibility. Development of innovative techniques to address these limitations will lead to improve in vivo recapitulation and pioneering further advancements in this field.
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Affiliation(s)
- Lisa Tonini
- Laboratory of Veterinary Physiology, College of Veterinary Medicine, Jeju National University, Jeju, 63243, Republic of Korea
| | - Changhwan Ahn
- Laboratory of Veterinary Physiology, College of Veterinary Medicine, Jeju National University, Jeju, 63243, Republic of Korea.
- Veterinary Medical Research Institute, Jeju National University, Jeju, 63243, Republic of Korea.
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2
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Adelfio M, Callen GE, He X, Paster BJ, Hasturk H, Ghezzi CE. Engineered Tissue Models to Decode Host-Microbiota Interactions. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2417687. [PMID: 40364768 DOI: 10.1002/advs.202417687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 04/13/2025] [Indexed: 05/15/2025]
Abstract
A mutualistic co-evolution exists between the host and its associated microbiota in the human body. Bacteria establish ecological niches in various tissues of the body, locally influencing their physiology and functions, but also contributing to the well-being of the whole organism through systemic communication with other distant niches (axis). Emerging evidence indicates that when the composition of the microbiota inhabiting the niche changes toward a pathogenic state (dysbiosis) and interactions with the host become unbalanced, diseases may present. In addition, imbalances within a single niche can cause dysbiosis in distant organs. Current research efforts are focused on elucidating the mechanisms leading to dysbiosis, with the goal of restoring tissue homeostasis. In vitro models can provide critical experimental platforms to address this need, by reproducing the niche cyto-architecture and physiology with high fidelity. This review surveys current in in vitro host-microbiota research strategies and provides a roadmap that can guide the field in further developing physiologically relevant in vitro models of ecological niches, thus enabling investigation of the role of the microbiota in human health and diseases. Lastly, given the Food and Drug Administration Modernization Act 2.0, this review highlights emerging in vitro strategies to support the development and validation of new therapies on the market.
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Affiliation(s)
- Miryam Adelfio
- Department of Biomedical Engineering, University of Massachusetts-Lowell, Lowell, MA, 01854, USA
| | - Grace E Callen
- Department of Biomedical Engineering, University of Massachusetts-Lowell, Lowell, MA, 01854, USA
| | - Xuesong He
- ADA Forsyth Institute, 245 First St, Cambridge, MA, 02142, USA
| | - Bruce J Paster
- ADA Forsyth Institute, 245 First St, Cambridge, MA, 02142, USA
| | - Hatice Hasturk
- ADA Forsyth Institute, 245 First St, Cambridge, MA, 02142, USA
| | - Chiara E Ghezzi
- Department of Biomedical Engineering, University of Massachusetts-Lowell, Lowell, MA, 01854, USA
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3
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Ashok D, Singh J, Howard HR, Cottam S, Waterhouse A, Bilek MMM. Interfacial engineering for biomolecule immobilisation in microfluidic devices. Biomaterials 2025; 316:123014. [PMID: 39708778 DOI: 10.1016/j.biomaterials.2024.123014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 11/25/2024] [Accepted: 12/13/2024] [Indexed: 12/23/2024]
Abstract
Microfluidic devices are used for various applications in biology and medicine. From on-chip modelling of human organs for drug screening and fast and straightforward point-of-care (POC) detection of diseases to sensitive biochemical analysis, these devices can be custom-engineered using low-cost techniques. The microchannel interface is essential for these applications, as it is the interface of immobilised biomolecules that promote cell capture, attachment and proliferation, sense analytes and metabolites or provide enzymatic reaction readouts. However, common microfluidic materials do not facilitate the stable immobilisation of biomolecules required for relevant applications, making interfacial engineering necessary to attach biomolecules to the microfluidic surfaces. Interfacial engineering is performed through various immobilisation mechanisms and surface treatment techniques, which suitably modify the surface properties like chemistry and energy to obtain robust biomolecule immobilisation and long-term storage stability suitable for the final application. In this review, we provide an overview of the status of interfacial engineering in microfluidic devices, covering applications, the role of biomolecules, their immobilisation pathways and the influence of microfluidic materials. We then propose treatment techniques to optimise performance for various biological and medical applications and highlight future areas of development.
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Affiliation(s)
- Deepu Ashok
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, NSW, 2006, Australia; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia; Heart Research Institute, Newtown, NSW, 2042, Australia; The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW, 2006, Australia; The Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia; School of Physics, Faculty of Science, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Jasneil Singh
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia; Heart Research Institute, Newtown, NSW, 2042, Australia; The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW, 2006, Australia; The Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Henry Robert Howard
- The Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Sophie Cottam
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, NSW, 2006, Australia; School of Physics, Faculty of Science, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Anna Waterhouse
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia; The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW, 2006, Australia; The Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia.
| | - Marcela M M Bilek
- School of Biomedical Engineering, Faculty of Engineering, The University of Sydney, NSW, 2006, Australia; The University of Sydney Nano Institute, The University of Sydney, Sydney, NSW, 2006, Australia; The Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia; School of Physics, Faculty of Science, The University of Sydney, Sydney, NSW, 2006, Australia.
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Barros NR, Kang R, Kim J, Ermis M, Kim HJ, Dokmeci MR, Lee J. A human skin-on-a-chip platform for microneedling-driven skin cancer treatment. Mater Today Bio 2025; 30:101399. [PMID: 39802827 PMCID: PMC11721494 DOI: 10.1016/j.mtbio.2024.101399] [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: 09/19/2024] [Revised: 12/06/2024] [Accepted: 12/09/2024] [Indexed: 01/16/2025] Open
Abstract
Skin-on-a-chip models provide physiologically relevant platforms for studying diseases and drug evaluation, replicating the native skin structures and functions more accurately than traditional 2D or simple 3D cultures. However, challenges remain in creating models suitable for microneedling applications and monitoring, as well as developing skin cancer models for analysis and targeted therapy. Here, we developed a human skin/skin cancer-on-a-chip platform within a microfluidic device using bioprinting/bioengineering techniques. The fabricated skin models include vascular, dermal, and epidermal layers, demonstrating increased functionalities and maturation of dermal (Collagen I & Fibronectin for 7 days) as well as epidermal (Filaggrin & Keratin 10, 14, and 19 at the air-liquid interface (ALI) for 21 days) layers. Histological analysis confirmed the formation of a differentiated epidermis and ridges at the dermal-epidermal junction in our model, closely resembling native skin tissue. Melanoma cells were embedded approximately 400 μm beneath the epidermis to simulate tumor invasion into the dermis. The platform was further used to test doxorubicin (DOX)-loaded gelatin methacryloyl (GelMA) microneedles (MNs) for localized transdermal drug delivery targeting melanoma. The DOX-loaded MNs penetrated uniformly to a depth of approximately 600 μm, effectively reaching the melanoma cells. Drug delivery via MNs demonstrated significantly higher efficiency than diffusion through media flow, confirming the practicality and robustness of the proposed model for future therapeutic applications.
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Affiliation(s)
- Natan R. Barros
- Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA, 90024, USA
- National Laboratory of Bioscience (LNBio), National Center of Research in Energy and Materials (CNPEM), Campinas, 13083-100, Brazil
| | - Raehui Kang
- Division of Interdisciplinary Bioscience & Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang, 790-784, Republic of Korea
| | - Jinjoo Kim
- Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA, 90024, USA
| | - Menekse Ermis
- Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA, 90024, USA
| | - Han-Jun Kim
- Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA, 90024, USA
- College of Pharmacy, Korea University, Sejong, 30019, Republic of Korea
| | - Mehmet R. Dokmeci
- Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA, 90024, USA
| | - Junmin Lee
- Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA, 90024, USA
- Division of Interdisciplinary Bioscience & Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang, 790-784, Republic of Korea
- Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), Pohang, 790-784, Republic of Korea
- Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Incheon, 21983, Republic of Korea
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Muttiah B, Law JX. Milk-derived extracellular vesicles and gut health. NPJ Sci Food 2025; 9:12. [PMID: 39885215 PMCID: PMC11782608 DOI: 10.1038/s41538-025-00375-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 01/07/2025] [Indexed: 02/01/2025] Open
Abstract
Milk is a nutrient-rich liquid produced by mammals, offering various health benefits due to its composition of proteins, fats, carbohydrates, vitamins, and minerals. Beyond traditional nutritional aspects, recent research has focused on extracellular vesicles (EVs) found in milk and their potential health benefits, especially for gastrointestinal (GI) health. Milk-derived EVs have been shown to influence gut microbiota, promote gut barrier integrity, support tissue repair and regeneration, modulate immune responses, and potentially aid in managing conditions like inflammatory bowel disease (IBD) and colorectal cancer. This review discusses the current understanding of milk-EVs' effects on gut health, highlighting their potential therapeutic applications and future research directions. These findings underscore the promising role of milk-derived EVs in advancing GI health and therapeutics, paving the way for innovative approaches in oral drug delivery and targeted treatments for GI disorders.
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Affiliation(s)
- Barathan Muttiah
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia
| | - Jia Xian Law
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia.
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Zheng X, Xia C, Liu M, Wu H, Yan J, Zhang Z, Huang Y, Gu Q, Li P. Role of folic acid in regulating gut microbiota and short-chain fatty acids based on an in vitro fermentation model. Appl Microbiol Biotechnol 2024; 108:40. [PMID: 38175236 DOI: 10.1007/s00253-023-12825-5] [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] [Received: 02/24/2023] [Revised: 10/04/2023] [Accepted: 10/14/2023] [Indexed: 01/05/2024]
Abstract
Folic acid deficiency is common worldwide and is linked to an imbalance in gut microbiota. However, based on model animals used to study the utilization of folic acid by gut microbes, there are challenges of reproducibility and individual differences. In this study, an in vitro fecal slurry culture model of folic acid deficiency was established to investigate the effects of supplementation with 5-methyltetrahydrofolate (MTHF) and non-reduced folic acid (FA) on the modulation of gut microbiota. 16S rRNA sequencing results revealed that both FA (29.7%) and MTHF (27.9%) supplementation significantly reduced the relative abundance of Bacteroidetes compared with control case (34.3%). MTHF supplementation significantly improved the relative abundance of Firmicutes by 4.49%. Notably, compared with the control case, FA and MTHF supplementation promoted an increase in fecal levels of Lactobacillus, Bifidobacterium, and Pediococcus. Short-chain fatty acid (SCFA) analysis showed that folic acid supplementation decreased acetate levels and increased fermentative production of isobutyric acid. The in vitro fecal slurry culture model developed in this study can be utilized as a model of folic acid deficiency in humans to study the gut microbiota and demonstrate that exogenous folic acid affects the composition of the gut microbiota and the level of SCFAs. KEY POINTS: • Establishment of folic acid deficiency in an in vitro culture model. • Folic acid supplementation regulates intestinal microbes and SCFAs. • Connections between microbes and SCFAs after adding folic acid are built.
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Affiliation(s)
- Xiaogu Zheng
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, People's Republic of China
| | - Chenlan Xia
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, People's Republic of China
| | - Manman Liu
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, People's Republic of China
| | - Hongchen Wu
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, People's Republic of China
| | - Jiaqian Yan
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, People's Republic of China
| | - Zihao Zhang
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, People's Republic of China
| | - Yingjie Huang
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, People's Republic of China
| | - Qing Gu
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, People's Republic of China
| | - Ping Li
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, Zhejiang, 310018, People's Republic of China.
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7
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Gao D, Zhang H, Sun W, Wang H, Wang H. Radiation-Induced Intestinal Injury: Molecular Mechanisms and Therapeutic Status. DNA Cell Biol 2024; 43:537-548. [PMID: 39235407 DOI: 10.1089/dna.2024.0105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/06/2024] Open
Abstract
Radiation-induced intestinal injury is one of the most common intestinal complications caused by pelvic and abdominal tumor radiotherapy, severely impacting patients' quality of life. Ionizing radiation, while killing tumor cells, inevitably damages healthy tissue. Radiation-induced enteropathy results from radiation therapy-induced intestinal tissue damage and inflammatory responses. This damage involves various complex molecular mechanisms, including cell apoptosis, oxidative stress, release of inflammatory mediators, disruption of immune responses, and imbalance of intestinal microbiota. A thorough understanding of these molecular mechanisms is crucial for developing effective prevention and treatment strategies.
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Affiliation(s)
- Dandan Gao
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Oncology, Tianjin Union Medical Center, Nankai University, Tianjin, China
- Tianjin Cancer Institute of Integrative Traditional Chinese and Western Medicine, Tianjin 300121, China
| | - Heng Zhang
- Department of Oncology, Tianjin Union Medical Center, Nankai University, Tianjin, China
- Tianjin Cancer Institute of Integrative Traditional Chinese and Western Medicine, Tianjin 300121, China
| | - Wanjun Sun
- Department of Oncology, Tianjin Union Medical Center, Nankai University, Tianjin, China
- Tianjin Cancer Institute of Integrative Traditional Chinese and Western Medicine, Tianjin 300121, China
| | - Huaqing Wang
- Department of Oncology, Tianjin Union Medical Center, Nankai University, Tianjin, China
- Tianjin Cancer Institute of Integrative Traditional Chinese and Western Medicine, Tianjin 300121, China
| | - Hui Wang
- Department of Oncology, Tianjin Union Medical Center, Nankai University, Tianjin, China
- Tianjin Cancer Institute of Integrative Traditional Chinese and Western Medicine, Tianjin 300121, China
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Beneke V, Grieger KM, Hartwig C, Müller J, Sohn K, Blaudszun AR, Hilger N, Schaudien D, Fricke S, Braun A, Sewald K, Hesse C. Homeostatic T helper 17 cell responses triggered by complex microbiota are maintained in ex vivo intestinal tissue slices. Eur J Immunol 2024; 54:e2350946. [PMID: 38763899 DOI: 10.1002/eji.202350946] [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] [Received: 12/08/2023] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/21/2024]
Abstract
Segmented filamentous bacteria (SFB) are members of the commensal intestinal microbiome. They are known to contribute to the postnatal maturation of the gut immune system, but also to augment inflammatory conditions in chronic diseases such as Crohn's disease. Living primary tissue slices are ultrathin multicellular sections of the intestine and provide a unique opportunity to analyze tissue-specific immune responses ex vivo. This study aimed to investigate whether supplementation of the gut flora with SFB promotes T helper 17 (Th17) cell responses in primary intestinal tissue slices ex vivo. Primary tissue slices were prepared from the small intestine of healthy Taconic mice with SFB-positive and SFB-negative microbiomes and stimulated with anti-CD3/CD28 or Concanavalin A. SFB-positive and -negative mice exhibited distinct microbiome compositions and Th17 cell frequencies in the intestine and complex microbiota including SFB induced up to 15-fold increase in Th17 cell-associated mediators, serum amyloid A (SAA), and immunoglobulin A (IgA) responses ex vivo. This phenotype could be transmitted by co-housing of mice. Our findings highlight that changes in the gut microbiome can be observed in primary intestinal tissue slices ex vivo. This makes the system very attractive for disease modeling and assessment of new therapies.
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Affiliation(s)
- Valerie Beneke
- Division of Preclinical Pharmacology and Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) Research Network, Hannover, Germany
- Member of the Fraunhofer Excellence Cluster of Immune Mediated Diseases (CIMD), Germany
| | - Klaudia M Grieger
- Division of Preclinical Pharmacology and Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) Research Network, Hannover, Germany
- Member of the Fraunhofer Excellence Cluster of Immune Mediated Diseases (CIMD), Germany
| | - Christina Hartwig
- Member of the Fraunhofer Excellence Cluster of Immune Mediated Diseases (CIMD), Germany
- Department of In-vitro Diagnostics, Fraunhofer Institute for Interfacial Engineering and Biotechnology, Stuttgart, Germany
| | - Jan Müller
- Member of the Fraunhofer Excellence Cluster of Immune Mediated Diseases (CIMD), Germany
- Department of In-vitro Diagnostics, Fraunhofer Institute for Interfacial Engineering and Biotechnology, Stuttgart, Germany
- Center of Integrative Bioinformatics Vienna (CIBIV), Max Perutz Labs, University of Vienna and Medical University of Vienna, Vienna BioCenter, Vienna, Austria
- Member of the Vienna Biocenter PhD Program, University of Vienna and the Medical University of Vienna, Vienna, Austria
| | - Kai Sohn
- Member of the Fraunhofer Excellence Cluster of Immune Mediated Diseases (CIMD), Germany
- Department of In-vitro Diagnostics, Fraunhofer Institute for Interfacial Engineering and Biotechnology, Stuttgart, Germany
| | - André-René Blaudszun
- Member of the Fraunhofer Excellence Cluster of Immune Mediated Diseases (CIMD), Germany
- Department of Cell and Gene Therapy Development, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Nadja Hilger
- Member of the Fraunhofer Excellence Cluster of Immune Mediated Diseases (CIMD), Germany
- Department of Cell and Gene Therapy Development, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Dirk Schaudien
- Division of Preclinical Pharmacology and Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
| | - Stephan Fricke
- Member of the Fraunhofer Excellence Cluster of Immune Mediated Diseases (CIMD), Germany
- Department of Cell and Gene Therapy Development, Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany
| | - Armin Braun
- Division of Preclinical Pharmacology and Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) Research Network, Hannover, Germany
- Member of the Fraunhofer Excellence Cluster of Immune Mediated Diseases (CIMD), Germany
- Institute for Immunology, Hannover Medical School, Hannover, Germany
| | - Katherina Sewald
- Division of Preclinical Pharmacology and Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) Research Network, Hannover, Germany
- Member of the Fraunhofer Excellence Cluster of Immune Mediated Diseases (CIMD), Germany
| | - Christina Hesse
- Division of Preclinical Pharmacology and Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany
- Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH) Research Network, Hannover, Germany
- Member of the Fraunhofer Excellence Cluster of Immune Mediated Diseases (CIMD), Germany
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Smolen P, Ruiz L, Barai A, Minc N, Delacour D. [A role of astral microtubules in the orientation of cell division: when length counts… too!]. Med Sci (Paris) 2024; 40:608-612. [PMID: 39303109 DOI: 10.1051/medsci/2024087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/22/2024] Open
Affiliation(s)
- Prune Smolen
- Université d'Aix-Marseille, CNRS UMR 7288, Institut de biologie du développement de Marseille, Centre Turing des systèmes vivants, Marseille, France - Équipe labellisée Fondation ARC
| | - Laura Ruiz
- Université d'Aix-Marseille, CNRS UMR 7288, Institut de biologie du développement de Marseille, Centre Turing des systèmes vivants, Marseille, France - Équipe labellisée Fondation ARC
| | - Amlan Barai
- Université d'Aix-Marseille, CNRS UMR 7288, Institut de biologie du développement de Marseille, Centre Turing des systèmes vivants, Marseille, France - Équipe labellisée Fondation ARC
| | - Nicolas Minc
- Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France - Équipe labellisée La ligue contre le cancer
| | - Delphine Delacour
- Université d'Aix-Marseille, CNRS UMR 7288, Institut de biologie du développement de Marseille, Centre Turing des systèmes vivants, Marseille, France - Équipe labellisée Fondation ARC
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Wang H, Li X, Shi P, You X, Zhao G. Establishment and evaluation of on-chip intestinal barrier biosystems based on microfluidic techniques. Mater Today Bio 2024; 26:101079. [PMID: 38774450 PMCID: PMC11107260 DOI: 10.1016/j.mtbio.2024.101079] [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: 02/03/2024] [Revised: 04/17/2024] [Accepted: 05/01/2024] [Indexed: 05/24/2024] Open
Abstract
As a booming engineering technology, the microfluidic chip has been widely applied for replicating the complexity of human intestinal micro-physiological ecosystems in vitro. Biosensors, 3D imaging, and multi-omics have been applied to engineer more sophisticated intestinal barrier-on-chip platforms, allowing the improved monitoring of physiological processes and enhancing chip performance. In this review, we report cutting-edge advances in the microfluidic techniques applied for the establishment and evaluation of intestinal barrier platforms. We discuss different design principles and microfabrication strategies for the establishment of microfluidic gut barrier models in vitro. Further, we comprehensively cover the complex cell types (e.g., epithelium, intestinal organoids, endothelium, microbes, and immune cells) and controllable extracellular microenvironment parameters (e.g., oxygen gradient, peristalsis, bioflow, and gut-organ axis) used to recapitulate the main structural and functional complexity of gut barriers. We also present the current multidisciplinary technologies and indicators used for evaluating the morphological structure and barrier integrity of established gut barrier models in vitro. Finally, we highlight the challenges and future perspectives for accelerating the broader applications of these platforms in disease simulation, drug development, and personalized medicine. Hence, this review provides a comprehensive guide for the development and evaluation of microfluidic-based gut barrier platforms.
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Affiliation(s)
- Hui Wang
- Master Lab for Innovative Application of Nature Products, National Center of Technology Innovation for Synthetic Biology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences (CAS), Tianjin, 300308, China
| | - Xiangyang Li
- Henan Engineering Research Center of Food Microbiology, College of Food and Bioengineering, Henan University of Science and Technology, Luoyang, 471023, China
- Haihe Laboratory of Synthetic Biology, Tianjin, 300308, China
| | - Pengcheng Shi
- Henan Engineering Research Center of Food Microbiology, College of Food and Bioengineering, Henan University of Science and Technology, Luoyang, 471023, China
| | - Xiaoyan You
- Master Lab for Innovative Application of Nature Products, National Center of Technology Innovation for Synthetic Biology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences (CAS), Tianjin, 300308, China
- Henan Engineering Research Center of Food Microbiology, College of Food and Bioengineering, Henan University of Science and Technology, Luoyang, 471023, China
| | - Guoping Zhao
- Master Lab for Innovative Application of Nature Products, National Center of Technology Innovation for Synthetic Biology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences (CAS), Tianjin, 300308, China
- CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, 200032, China
- CAS-Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
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11
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Xu X, Ye A, Zhang T, Pan Y, Jiang H, Deng L, Qin Y, Li J, Han J, Liu W. The novel lactoferrin and DHA-codelivered liposomes with different membrane structures: Fabrication, in vitro infant digestion, and suckling pig intestinal organoid absorption. Food Chem 2024; 441:138346. [PMID: 38241927 DOI: 10.1016/j.foodchem.2023.138346] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/27/2023] [Accepted: 12/30/2023] [Indexed: 01/21/2024]
Abstract
Inspired by membrane structure of breast milk and infant formula fat globules, four liposomes with different particle size (large and small) and compositions (Single phospholipids contained phosphatidylcholine, complex phospholipids contained phosphatidylcholine, phosphatidylethanolamine and sphingomyelin) were fabricated to deliver lactoferrin and DHA. In vitro infant semi-dynamic digestive behavior and absorption in intestinal organoids of liposomes were investigated. Liposomal structures were negligible changed during semi-dynamic gastric digestion while damaged in intestine. Liposomal degradation rate was primarily influenced by particle size, and complex phospholipids accelerated DHA hydrolysis. The release rate of DHA (91.7 ± 1.3 %) in small-sized liposomes (0.181 ± 0.001 μm) was higher than free DHA (unencapsulated, 64.6 ± 3.4 %). Complex phospholipids liposomal digesta exhibited higher transport efficiency (3.4-fold for fatty acids and 2.0-fold for amino acids) and better organoid growth than digesta of bare nutrients. This study provided new insights into membrane structure-functionality relationship of liposomes and may aid in the development of novel infant nutrient carriers.
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Affiliation(s)
- Xiankang Xu
- Food Nutrition Science Center, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China.
| | - Aiqian Ye
- Riddet Institute, Massey University, Private Bag 11 222, Palmerston North 4442, New Zealand.
| | - Tingting Zhang
- Food Nutrition Science Center, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China.
| | - Yujie Pan
- Food Nutrition Science Center, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China.
| | - Hanyun Jiang
- Food Nutrition Science Center, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China.
| | - Leiyu Deng
- Food Nutrition Science Center, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China.
| | - Yumei Qin
- Food Nutrition Science Center, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China.
| | - Jessie Li
- Alliance Nutrition Group, Shanghai-Mira Commercial Centre, Suite C206, No.2633, West Yanan Road, 200336 Shanghai, China.
| | - Jianzhong Han
- Food Nutrition Science Center, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China.
| | - Weilin Liu
- Food Nutrition Science Center, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China.
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12
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Park S, Laskow TC, Chen J, Guha P, Dawn B, Kim D. Microphysiological systems for human aging research. Aging Cell 2024; 23:e14070. [PMID: 38180277 PMCID: PMC10928588 DOI: 10.1111/acel.14070] [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] [Received: 06/30/2023] [Revised: 11/28/2023] [Accepted: 11/30/2023] [Indexed: 01/06/2024] Open
Abstract
Recent advances in microphysiological systems (MPS), also known as organs-on-a-chip (OoC), enable the recapitulation of more complex organ and tissue functions on a smaller scale in vitro. MPS therefore provide the potential to better understand human diseases and physiology. To date, numerous MPS platforms have been developed for various tissues and organs, including the heart, liver, kidney, blood vessels, muscle, and adipose tissue. However, only a few studies have explored using MPS platforms to unravel the effects of aging on human physiology and the pathogenesis of age-related diseases. Age is one of the risk factors for many diseases, and enormous interest has been devoted to aging research. As such, a human MPS aging model could provide a more predictive tool to understand the molecular and cellular mechanisms underlying human aging and age-related diseases. These models can also be used to evaluate preclinical drugs for age-related diseases and translate them into clinical settings. Here, we provide a review on the application of MPS in aging research. First, we offer an overview of the molecular, cellular, and physiological changes with age in several tissues or organs. Next, we discuss previous aging models and the current state of MPS for studying human aging and age-related conditions. Lastly, we address the limitations of current MPS and present future directions on the potential of MPS platforms for human aging research.
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Affiliation(s)
- Seungman Park
- Department of Mechanical EngineeringUniversity of Nevada, Las VegasLas VegasNevadaUSA
| | - Thomas C. Laskow
- Department of MedicineJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Jingchun Chen
- Nevada Institute of Personalized MedicineUniversity of Nevada, Las VegasLas VegasNevadaUSA
| | - Prasun Guha
- Nevada Institute of Personalized MedicineUniversity of Nevada, Las VegasLas VegasNevadaUSA
- School of Life SciencesUniversity of Nevada, Las VegasLas VegasNevadaUSA
| | - Buddhadeb Dawn
- Department of Internal Medicine, Kirk Kerkorian School of MedicineUniversity of Nevada, Las VegasLas VegasNevadaUSA
| | - Deok‐Ho Kim
- Department of MedicineJohns Hopkins University School of MedicineBaltimoreMarylandUSA
- Department of Biomedical EngineeringJohns Hopkins UniversityBaltimoreMarylandUSA
- Center for Microphysiological SystemsJohns Hopkins UniversityBaltimoreMarylandUSA
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13
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Baker TK, Van Vleet TR, Mahalingaiah PK, Grandhi TSP, Evers R, Ekert J, Gosset JR, Chacko SA, Kopec AK. The Current Status and Use of Microphysiological Systems by the Pharmaceutical Industry: The International Consortium for Innovation and Quality Microphysiological Systems Affiliate Survey and Commentary. Drug Metab Dispos 2024; 52:198-209. [PMID: 38123948 DOI: 10.1124/dmd.123.001510] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 11/21/2023] [Accepted: 11/27/2023] [Indexed: 12/23/2023] Open
Abstract
Microphysiological systems (MPS) are comprised of one or multiple cell types of human or animal origins that mimic the biochemical/electrical/mechanical responses and blood-tissue barrier properties of the cells observed within a complex organ. The goal of incorporating these in vitro systems is to expedite and advance the drug discovery and development paradigm with improved predictive and translational capabilities. Considering the industry need for improved efficiency and the broad challenges of model qualification and acceptance, the International Consortium for Innovation and Quality (IQ) founded an IQ MPS working group in 2014 and Affiliate in 2018. This group connects thought leaders and end users, provides a forum for crosspharma collaboration, and engages with regulators to qualify translationally relevant MPS models. To understand how pharmaceutical companies are using MPS, the IQ MPS Affiliate conducted two surveys in 2019, survey 1, and 2021, survey 2, which differed slightly in the scope of definition of the complex in vitro models under question. The surveys captured demographics, resourcing, rank order for organs of interest, compound modalities tested, and MPS organ-specific questions, including nonclinical species needs and cell types. The major focus of this manuscript is on results from survey 2, where we specifically highlight the context of use for MPS within safety, pharmacology, or absorption, disposition, metabolism, and excretion and discuss considerations for including MPS data in regulatory submissions. In summary, these data provide valuable insights for developers, regulators, and pharma, offering a view into current industry practices and future considerations while highlighting key challenges impacting MPS adoption. SIGNIFICANCE STATEMENT: The application of microphysiological systems (MPS) represents a growing area of interest in the drug discovery and development framework. This study surveyed 20+ pharma companies to understand resourcing, current areas of application, and the key challenges and barriers to internal MPS adoption. These results will provide regulators, tech providers, and pharma industry leaders a starting point to assess the current state of MPS applications along with key learnings to effectively realize the potential of MPS as an emerging technology.
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Affiliation(s)
- Thomas K Baker
- Investigative Toxicology, Eli Lilly, Indianapolis, Indiana (T.K.B.); Investigative Toxicology and Pathology, AbbVie, Inc., Chicago, Illinois (T.R.V.F., P.K.M.); Complex In Vitro Models Group, GSK, Collegeville, Pennsylvania (T.S.P.G.); Preclinical Sciences and Translational Safety, Johnson & Johnson, Janssen Pharmaceuticals, Spring House, Pennsylvania (R.E.); UCB Pharma, Cambridge, Massachusetts (J.E.); Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer, Inc., Cambridge, Massachusetts (J.R.G.); Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey (S.A.C.); and Drug Safety Research & Development, Pfizer, Inc., Groton, Connecticut (A.K.K.) baker_thomas_k@lilly
| | - Terry R Van Vleet
- Investigative Toxicology, Eli Lilly, Indianapolis, Indiana (T.K.B.); Investigative Toxicology and Pathology, AbbVie, Inc., Chicago, Illinois (T.R.V.F., P.K.M.); Complex In Vitro Models Group, GSK, Collegeville, Pennsylvania (T.S.P.G.); Preclinical Sciences and Translational Safety, Johnson & Johnson, Janssen Pharmaceuticals, Spring House, Pennsylvania (R.E.); UCB Pharma, Cambridge, Massachusetts (J.E.); Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer, Inc., Cambridge, Massachusetts (J.R.G.); Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey (S.A.C.); and Drug Safety Research & Development, Pfizer, Inc., Groton, Connecticut (A.K.K.)
| | - Prathap Kumar Mahalingaiah
- Investigative Toxicology, Eli Lilly, Indianapolis, Indiana (T.K.B.); Investigative Toxicology and Pathology, AbbVie, Inc., Chicago, Illinois (T.R.V.F., P.K.M.); Complex In Vitro Models Group, GSK, Collegeville, Pennsylvania (T.S.P.G.); Preclinical Sciences and Translational Safety, Johnson & Johnson, Janssen Pharmaceuticals, Spring House, Pennsylvania (R.E.); UCB Pharma, Cambridge, Massachusetts (J.E.); Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer, Inc., Cambridge, Massachusetts (J.R.G.); Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey (S.A.C.); and Drug Safety Research & Development, Pfizer, Inc., Groton, Connecticut (A.K.K.)
| | - Taraka Sai Pavan Grandhi
- Investigative Toxicology, Eli Lilly, Indianapolis, Indiana (T.K.B.); Investigative Toxicology and Pathology, AbbVie, Inc., Chicago, Illinois (T.R.V.F., P.K.M.); Complex In Vitro Models Group, GSK, Collegeville, Pennsylvania (T.S.P.G.); Preclinical Sciences and Translational Safety, Johnson & Johnson, Janssen Pharmaceuticals, Spring House, Pennsylvania (R.E.); UCB Pharma, Cambridge, Massachusetts (J.E.); Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer, Inc., Cambridge, Massachusetts (J.R.G.); Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey (S.A.C.); and Drug Safety Research & Development, Pfizer, Inc., Groton, Connecticut (A.K.K.)
| | - Raymond Evers
- Investigative Toxicology, Eli Lilly, Indianapolis, Indiana (T.K.B.); Investigative Toxicology and Pathology, AbbVie, Inc., Chicago, Illinois (T.R.V.F., P.K.M.); Complex In Vitro Models Group, GSK, Collegeville, Pennsylvania (T.S.P.G.); Preclinical Sciences and Translational Safety, Johnson & Johnson, Janssen Pharmaceuticals, Spring House, Pennsylvania (R.E.); UCB Pharma, Cambridge, Massachusetts (J.E.); Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer, Inc., Cambridge, Massachusetts (J.R.G.); Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey (S.A.C.); and Drug Safety Research & Development, Pfizer, Inc., Groton, Connecticut (A.K.K.)
| | - Jason Ekert
- Investigative Toxicology, Eli Lilly, Indianapolis, Indiana (T.K.B.); Investigative Toxicology and Pathology, AbbVie, Inc., Chicago, Illinois (T.R.V.F., P.K.M.); Complex In Vitro Models Group, GSK, Collegeville, Pennsylvania (T.S.P.G.); Preclinical Sciences and Translational Safety, Johnson & Johnson, Janssen Pharmaceuticals, Spring House, Pennsylvania (R.E.); UCB Pharma, Cambridge, Massachusetts (J.E.); Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer, Inc., Cambridge, Massachusetts (J.R.G.); Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey (S.A.C.); and Drug Safety Research & Development, Pfizer, Inc., Groton, Connecticut (A.K.K.)
| | - James R Gosset
- Investigative Toxicology, Eli Lilly, Indianapolis, Indiana (T.K.B.); Investigative Toxicology and Pathology, AbbVie, Inc., Chicago, Illinois (T.R.V.F., P.K.M.); Complex In Vitro Models Group, GSK, Collegeville, Pennsylvania (T.S.P.G.); Preclinical Sciences and Translational Safety, Johnson & Johnson, Janssen Pharmaceuticals, Spring House, Pennsylvania (R.E.); UCB Pharma, Cambridge, Massachusetts (J.E.); Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer, Inc., Cambridge, Massachusetts (J.R.G.); Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey (S.A.C.); and Drug Safety Research & Development, Pfizer, Inc., Groton, Connecticut (A.K.K.)
| | - Silvi A Chacko
- Investigative Toxicology, Eli Lilly, Indianapolis, Indiana (T.K.B.); Investigative Toxicology and Pathology, AbbVie, Inc., Chicago, Illinois (T.R.V.F., P.K.M.); Complex In Vitro Models Group, GSK, Collegeville, Pennsylvania (T.S.P.G.); Preclinical Sciences and Translational Safety, Johnson & Johnson, Janssen Pharmaceuticals, Spring House, Pennsylvania (R.E.); UCB Pharma, Cambridge, Massachusetts (J.E.); Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer, Inc., Cambridge, Massachusetts (J.R.G.); Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey (S.A.C.); and Drug Safety Research & Development, Pfizer, Inc., Groton, Connecticut (A.K.K.)
| | - Anna K Kopec
- Investigative Toxicology, Eli Lilly, Indianapolis, Indiana (T.K.B.); Investigative Toxicology and Pathology, AbbVie, Inc., Chicago, Illinois (T.R.V.F., P.K.M.); Complex In Vitro Models Group, GSK, Collegeville, Pennsylvania (T.S.P.G.); Preclinical Sciences and Translational Safety, Johnson & Johnson, Janssen Pharmaceuticals, Spring House, Pennsylvania (R.E.); UCB Pharma, Cambridge, Massachusetts (J.E.); Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer, Inc., Cambridge, Massachusetts (J.R.G.); Research and Development, Bristol Myers Squibb Company, Princeton, New Jersey (S.A.C.); and Drug Safety Research & Development, Pfizer, Inc., Groton, Connecticut (A.K.K.)
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14
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Taraz T, Mahmoudi-Ghehsareh M, Asri N, Nazemalhosseini-Mojarad E, Rezaei-Tavirani M, Jahani-Sherafat S, Naseh A, Rostami-Nejad M. Overview of the compromised mucosal integrity in celiac disease. J Mol Histol 2024; 55:15-24. [PMID: 38165564 DOI: 10.1007/s10735-023-10175-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 11/02/2023] [Indexed: 01/04/2024]
Abstract
Intestinal epithelium is a dynamic cellular layer that lines the small-bowel and makes a relatively impenetrable barrier to macromolecules. Intestinal epithelial cell polarity is crucial in coordinating signalling pathways within cells and mainly regulated by three conserved polarity protein complexes, the Crumbs (Crb) complex, partitioning defective (PAR) complex, and Scribble (Scrib) complex. Polarity proteins regulate the proper establishment of the intercellular junctional complexes including tight junctions (TJs), adherence junctions (AJs), and desmosomes which hold epithelial cells together and play a major role in maintaining intestinal barrier integrity. Impaired intestinal epithelial cell polarity and barrier integrity result in irreversible immune responses, the host- microbial imbalance and intestinal inflammatory disorders. Disassembling the epithelial tight junction and augmented paracellular permeability is a conspicuous hallmark of celiac disease (CD) pathogenesis. There are several dietary components that can improve intestinal integrity and function. The aim of this review article is to summarize current information about the association of polarity proteins and AJC damages with pathogenesis of CD.
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Affiliation(s)
- Tannaz Taraz
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohadeseh Mahmoudi-Ghehsareh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nastaran Asri
- Celiac Disease and Gluten Related Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Somayeh Jahani-Sherafat
- Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Naseh
- Department of Pediatrics and Neonatology, Clinical Research Development Center, Mahdiyeh Educational Hospital, Shahid-Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Rostami-Nejad
- Celiac Disease and Gluten Related Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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15
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Wang H, Xu C, Tan M, Su W. Advanced gut-on-chips for assessing carotenoid absorption, metabolism, and transport. Crit Rev Food Sci Nutr 2023; 65:1344-1362. [PMID: 38095598 DOI: 10.1080/10408398.2023.2293250] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
Bioengineered strategies enable gut chips to faithfully replicate essential features of intestinal microsystems, encompassing geometric properties, peristalsis, intraluminal fluid flow, oxygen gradients, and the microbiome. This emerging technique serves as a powerful tool for nutrition studies by emulating the absorption and distribution processes in a manner highly relevant to human physiology. It offers unprecedented accessibility for investigating the mechanisms governing nutrition metabolism. While the application of gut-on-chip models in disease modeling and drug screening has been extensively explored, their potential in dietary nutrition research remains relatively unexplored. This comprehensive review provides an overview of the different approaches employed in constructing gut-on-chip platforms using diverse cell sources and niche mimics. Furthermore, it explores the applications and prospects of gut-on-chips in nutrition-related investigations, with a specific focus on carotenoid transport, absorption, and metabolism. Lastly, this review discusses the future development trajectory of this groundbreaking technology paradigm, highlighting its broad applicability in the field of food technology. By harnessing the capabilities of these state-of-the-art techniques within gut chip platforms, researchers can establish a robust scientific foundation for unraveling the intricate mechanisms that govern the behavior and functional properties of carotenoids.
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Affiliation(s)
- Hui Wang
- Dalian Institute of Chemical Physics, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Dalian, China
| | - Cong Xu
- Department of Biomedical Engineering, Columbia University Medical Center, New York, USA
| | - Mingqian Tan
- SKL of Marine Food Processing & Safety Control, Dalian Polytechnic University, Dalian, China
- Academy of Food Interdisciplinary Science, School of Food Science and Technology, Dalian Polytechnic University, Dalian, China
- National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian, China
| | - Wentao Su
- SKL of Marine Food Processing & Safety Control, Dalian Polytechnic University, Dalian, China
- Academy of Food Interdisciplinary Science, School of Food Science and Technology, Dalian Polytechnic University, Dalian, China
- National Engineering Research Center of Seafood, Dalian Polytechnic University, Dalian, China
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16
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Lawal SA, Voisin A, Olof H, Bording-Jorgensen M, Armstrong H. Diversity of the microbiota communities found in the various regions of the intestinal tract in healthy individuals and inflammatory bowel diseases. Front Immunol 2023; 14:1242242. [PMID: 38022505 PMCID: PMC10654633 DOI: 10.3389/fimmu.2023.1242242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
The severe and chronic inflammatory bowel diseases (IBD), Crohn disease and ulcerative colitis, are characterized by persistent inflammation and gut damage. There is an increasing recognition that the gut microbiota plays a pivotal role in IBD development and progression. However, studies of the complete microbiota composition (bacteria, fungi, viruses) from precise locations within the gut remain limited. In particular, studies have focused primarily on the bacteriome, with available methods limiting evaluation of the mycobiome (fungi) and virome (virus). Furthermore, while the different segments of the small and large intestine display different functions (e.g., digestion, absorption, fermentation) and varying microenvironment features (e.g., pH, metabolites), little is known about the biogeography of the microbiota in different segments of the intestinal tract or how this differs in IBD. Here, we highlight evidence of the differing microbiota communities of the intestinal sub-organs in healthy and IBD, along with method summaries to improve future studies.
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Affiliation(s)
- Samuel Adefisoye Lawal
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
- Manitoba Centre for Proteomics and Systems Biology, University of Manitoba, Winnipeg, MB, Canada
- IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada
| | - Athalia Voisin
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
- Manitoba Centre for Proteomics and Systems Biology, University of Manitoba, Winnipeg, MB, Canada
- IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada
| | - Hana Olof
- Manitoba Centre for Proteomics and Systems Biology, University of Manitoba, Winnipeg, MB, Canada
- IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada
| | | | - Heather Armstrong
- Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada
- Manitoba Centre for Proteomics and Systems Biology, University of Manitoba, Winnipeg, MB, Canada
- IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
- Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada
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17
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Arenas-Gómez CM, Garcia-Gutierrez E, Escobar JS, Cotter PD. Human gut homeostasis and regeneration: the role of the gut microbiota and its metabolites. Crit Rev Microbiol 2023; 49:764-785. [PMID: 36369718 DOI: 10.1080/1040841x.2022.2142088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 08/18/2022] [Accepted: 10/26/2022] [Indexed: 11/13/2022]
Abstract
The healthy human gut is a balanced ecosystem where host cells and representatives of the gut microbiota interact and communicate in a bidirectional manner at the gut epithelium. As a result of these interactions, many local and systemic processes necessary for host functionality, and ultimately health, take place. Impairment of the integrity of the gut epithelium diminishes its ability to act as an effective gut barrier, can contribute to conditions associated to inflammation processes and can have other negative consequences. Pathogens and pathobionts have been linked with damage of the integrity of the gut epithelium, but other components of the gut microbiota and some of their metabolites can contribute to its repair and regeneration. Here, we review what is known about the effect of bacterial metabolites on the gut epithelium and, more specifically, on the regulation of repair by intestinal stem cells and the regulation of the immune system in the gut. Additionally, we explore the potential therapeutic use of targeted modulation of the gut microbiota to maintain and improve gut homeostasis as a mean to improve health outcomes.
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Affiliation(s)
- Claudia Marcela Arenas-Gómez
- Vidarium-Nutrition, Health and Wellness Research Center, Grupo Empresarial Nutresa, Medellin, Colombia
- Dirección Académica, Universidad Nacional de Colombia, Sede de La Paz, La Paz 202017, Colombia
| | - Enriqueta Garcia-Gutierrez
- Teagasc Food Research Centre Moorepark, Fermoy, Ireland
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- VistaMilk SFI Research Centre, Moorepark, Fermoy, Ireland
| | - Juan S Escobar
- Vidarium-Nutrition, Health and Wellness Research Center, Grupo Empresarial Nutresa, Medellin, Colombia
| | - Paul D Cotter
- Teagasc Food Research Centre Moorepark, Fermoy, Ireland
- APC Microbiome Ireland, University College Cork, Cork, Ireland
- VistaMilk SFI Research Centre, Moorepark, Fermoy, Ireland
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18
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Michael D, Kerry-Smith J, Webberley T, Murphy K, Plummer S, Parry L, Marchesi J. Does flow culture impact upon gut-probiotic interactions: A comparison with static culture. J Funct Foods 2023. [DOI: 10.1016/j.jff.2023.105519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023] Open
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19
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Xiang X, Wang X, Shang Y, Ding Y. Microfluidic intestine-on-a-chip: Current progress and further perspectives of probiotic-foodborne pathogen interactions. Trends Food Sci Technol 2023. [DOI: 10.1016/j.tifs.2023.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
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20
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Morelli M, Kurek D, Ng CP, Queiroz K. Gut-on-a-Chip Models: Current and Future Perspectives for Host-Microbial Interactions Research. Biomedicines 2023; 11:biomedicines11020619. [PMID: 36831155 PMCID: PMC9953162 DOI: 10.3390/biomedicines11020619] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 02/10/2023] [Accepted: 02/15/2023] [Indexed: 02/22/2023] Open
Abstract
The intestine contains the largest microbial community in the human body, the gut microbiome. Increasing evidence suggests that it plays a crucial role in maintaining overall health. However, while many studies have found a correlation between certain diseases and changes in the microbiome, the impact of different microbial compositions on the gut and the mechanisms by which they contribute to disease are not well understood. Traditional pre-clinical models, such as cell culture or animal models, are limited in their ability to mimic the complexity of human physiology. New mechanistic models, such as organ-on-a-chip, are being developed to address this issue. These models provide a more accurate representation of human physiology and could help bridge the gap between clinical and pre-clinical studies. Gut-on-chip models allow researchers to better understand the underlying mechanisms of disease and the effect of different microbial compositions on the gut. They can help to move the field from correlation to causation and accelerate the development of new treatments for diseases associated with changes in the gut microbiome. This review will discuss current and future perspectives of gut-on-chip models to study host-microbial interactions.
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21
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Shapiro RL, DeLong K, Zulfiqar F, Carter D, Better M, Ensign LM. In vitro and ex vivo models for evaluating vaginal drug delivery systems. Adv Drug Deliv Rev 2022; 191:114543. [PMID: 36208729 PMCID: PMC9940824 DOI: 10.1016/j.addr.2022.114543] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 08/26/2022] [Accepted: 09/13/2022] [Indexed: 01/24/2023]
Abstract
Vaginal drug delivery systems are often preferred for treating a variety of diseases and conditions of the female reproductive tract (FRT), as delivery can be more targeted with less systemic side effects. However, there are many anatomical and biological barriers to effective treatment via the vaginal route. Further, biocompatibility with the local tissue and microbial microenvironment is desired. A variety of in vitro and ex vivo models are described herein for evaluating the physicochemical properties and toxicity profile of vaginal drug delivery systems. Deciding whether to utilize organoids in vitro or fresh human cervicovaginal mucus ex vivo requires careful consideration of the intended use and the formulation characteristics. Optimally, in vitro and ex vivo experimentation will inform or predict in vivo performance, and examples are given that describe utilization of a range of methods from in vitro to in vivo. Lastly, we highlight more advanced model systems for other mucosa as inspiration for the future in model development for the FRT.
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Affiliation(s)
- Rachel L Shapiro
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, 3400 N Charles St., Baltimore, MD 21218, USA.
| | - Kevin DeLong
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 1800 Orleans St., Baltimore, MD 21287, USA.
| | - Fareeha Zulfiqar
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 1800 Orleans St., Baltimore, MD 21287, USA.
| | - Davell Carter
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N Wolfe St., Baltimore, MD 21287, USA.
| | - Marina Better
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N Wolfe St., Baltimore, MD 21287, USA.
| | - Laura M Ensign
- Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD 21231, USA; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, 1800 Orleans St., Baltimore, MD 21287, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N Wolfe St., Baltimore, MD 21287, USA; Department of Chemical & Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA; Departments of Gynecology and Obstetrics, Infectious Diseases, and Oncology, Johns Hopkins University School of Medicine, 1800 Orleans St., Baltimore, MD 21287, USA; Department of Biomedical Engineering, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218, USA.
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22
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Chunduri V, Maddi S. Role of in vitro two-dimensional (2D) and three-dimensional (3D) cell culture systems for ADME-Tox screening in drug discovery and development: a comprehensive review. ADMET & DMPK 2022; 11:1-32. [PMID: 36778905 PMCID: PMC9909725 DOI: 10.5599/admet.1513] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/07/2022] [Indexed: 11/18/2022]
Abstract
Drug discovery and development have become a very time-consuming and expensive process. Preclinical animal models have become the gold standard for studying drug pharmacokinetic and toxicity parameters. However, the involvement of a huge number of animal subjects and inter-species pathophysiological variations between animals and humans has provoked a lot of debate, particularly because of ethical concerns. Although many efforts are being established by biotech and pharmaceutical companies for screening new chemical entities in vitro before preclinical trials, failures during clinical trials are still involved. Currently, a large number of two- dimensional (2D) in vitro assays have been developed and are being developed by researchers for the screening of compounds. Although these assays are helpful in screening a huge library of compounds and have shown perception, there is a significant lack in predicting human Absorption, Distribution, Metabolism, Excretion and Toxicology (ADME-Tox). As a result, these assays cannot completely replace animal models. The recent inventions in three-dimensional (3D) cell culture-based assays like organoids and micro-physiological systems have shown great potential alternative tools for predicting the compound pharmacokinetic and pharmacodynamic fate in humans. In this comprehensive review, we have summarized some of the most commonly used 2D in vitro assays and emphasized the achievements in next-generation 3D cell culture-based systems for predicting the compound ADME-Tox.
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23
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Matthewman C, Narin A, Huston H, Hopkins CE. Systems to model the personalized aspects of microbiome health and gut dysbiosis. Mol Aspects Med 2022; 91:101115. [PMID: 36104261 DOI: 10.1016/j.mam.2022.101115] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 08/03/2022] [Indexed: 01/17/2023]
Abstract
The human gut microbiome is a complex and dynamic microbial entity that interacts with the environment and other parts of the body including the brain, heart, liver, and immune system. These multisystem interactions are highly conserved from invertebrates to humans, however the complexity and diversity of human microbiota compositions often yield a context that is unique to each individual. Yet commonalities remain across species, where a healthy gut microbiome will be rich in symbiotic commensal biota while an unhealthy gut microbiota will be experiencing abnormal blooms of pathobiont bacteria. In this review we discuss how omics technologies can be applied in a personalized approach to understand the microbial crosstalk and microbial-host interactions that affect the delicate balance between eubiosis and dysbiosis in an individual gut microbiome. We further highlight the strengths of model organisms in identifying and characterizing these conserved synergistic and/or pathogenic host-microbe interactions. And finally, we touch upon the growing area of personalized therapeutic interventions targeting gut microbiome.
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24
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Luo H, Li M, Wang F, Yang Y, Wang Q, Zhao Y, Du F, Chen Y, Shen J, Zhao Q, Zeng J, Wang S, Chen M, Li X, Li W, Sun Y, Gu L, Wen Q, Xiao Z, Wu X. The role of intestinal stem cell within gut homeostasis: Focusing on its interplay with gut microbiota and the regulating pathways. Int J Biol Sci 2022; 18:5185-5206. [PMID: 35982910 PMCID: PMC9379405 DOI: 10.7150/ijbs.72600] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 07/29/2022] [Indexed: 12/05/2022] Open
Abstract
Intestinal stem cells (ISCs) play an important role in maintaining intestinal homeostasis via promoting a healthy gut barrier. Within the stem cell niche, gut microbiota linking the crosstalk of dietary influence and host response has been identified as a key regulator of ISCs. Emerging insights from recent research reveal that ISC and gut microbiota interplay regulates epithelial self-renewal. This article reviews the recent knowledge on the key role of ISC in their local environment (stem cell niche) associating with gut microbiota and their metabolites as well as the signaling pathways. The current progress of intestinal organoid culture is further summarized. Subsequently, the key challenges and future directions are discussed.
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Affiliation(s)
- Haoming Luo
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Fang Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Yifei Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Qin Wang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China.,South Sichuan Institute of Translational Medicine, Luzhou 646000, Sichuan, China
| | - Qianyun Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Jiuping Zeng
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Luzhou 646000, Sichuan, China
| | - Shengpeng Wang
- State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
| | - Meijuan Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Xiaobing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Wanping Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Yuhong Sun
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Li Gu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Qinglian Wen
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Zhangang Xiao
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, China.,Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China.,State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, China
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25
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Yu Y, Wen H, Li S, Cao H, Li X, Ma Z, She X, Zhou L, Huang S. Emerging microfluidic technologies for microbiome research. Front Microbiol 2022; 13:906979. [PMID: 36051769 PMCID: PMC9424851 DOI: 10.3389/fmicb.2022.906979] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
The importance of the microbiome is increasingly prominent. For example, the human microbiome has been proven to be strongly associated with health conditions, while the environmental microbiome is recognized to have a profound influence on agriculture and even the global climate. Furthermore, the microbiome can serve as a fascinating reservoir of genes that encode tremendously valuable compounds for industrial and medical applications. In the past decades, various technologies have been developed to better understand and exploit the microbiome. In particular, microfluidics has demonstrated its strength and prominence in the microbiome research. By taking advantage of microfluidic technologies, inherited shortcomings of traditional methods such as low throughput, labor-consuming, and high-cost are being compensated or bypassed. In this review, we will summarize a broad spectrum of microfluidic technologies that have addressed various needs in the field of microbiome research, as well as the achievements that were enabled by the microfluidics (or technological advances). Finally, how microfluidics overcomes the limitations of conventional methods by technology integration will also be discussed.
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Affiliation(s)
- Yue Yu
- CAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Hui Wen
- CAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Sihong Li
- CAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Haojie Cao
- CAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Xuefei Li
- CAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhixin Ma
- CAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Xiaoyi She
- CAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Lei Zhou
- CAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Shuqiang Huang
- CAS Key Laboratory of Quantitative Engineering Biology, Guangdong Provincial Key Laboratory of Synthetic Genomics, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
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26
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Nahak BK, Mishra A, Preetam S, Tiwari A. Advances in Organ-on-a-Chip Materials and Devices. ACS APPLIED BIO MATERIALS 2022; 5:3576-3607. [PMID: 35839513 DOI: 10.1021/acsabm.2c00041] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The organ-on-a-chip (OoC) paves a way for biomedical applications ranging from preclinical to clinical translational precision. The current trends in the in vitro modeling is to reduce the complexity of human organ anatomy to the fundamental cellular microanatomy as an alternative of recreating the entire cell milieu that allows systematic analysis of medicinal absorption of compounds, metabolism, and mechanistic investigation. The OoC devices accurately represent human physiology in vitro; however, it is vital to choose the correct chip materials. The potential chip materials include inorganic, elastomeric, thermoplastic, natural, and hybrid materials. Despite the fact that polydimethylsiloxane is the most commonly utilized polymer for OoC and microphysiological systems, substitute materials have been continuously developed for its advanced applications. The evaluation of human physiological status can help to demonstrate using noninvasive OoC materials in real-time procedures. Therefore, this Review examines the materials used for fabricating OoC devices, the application-oriented pros and cons, possessions for device fabrication and biocompatibility, as well as their potential for downstream biochemical surface alteration and commercialization. The convergence of emerging approaches, such as advanced materials, artificial intelligence, machine learning, three-dimensional (3D) bioprinting, and genomics, have the potential to perform OoC technology at next generation. Thus, OoC technologies provide easy and precise methodologies in cost-effective clinical monitoring and treatment using standardized protocols, at even personalized levels. Because of the inherent utilization of the integrated materials, employing the OoC with biomedical approaches will be a promising methodology in the healthcare industry.
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Affiliation(s)
- Bishal Kumar Nahak
- Institute of Advanced Materials, IAAM, Gammalkilsvägen 18, Ulrika 59053, Sweden
| | - Anshuman Mishra
- Institute of Advanced Materials, IAAM, Gammalkilsvägen 18, Ulrika 59053, Sweden
| | - Subham Preetam
- Institute of Advanced Materials, IAAM, Gammalkilsvägen 18, Ulrika 59053, Sweden
| | - Ashutosh Tiwari
- Institute of Advanced Materials, IAAM, Gammalkilsvägen 18, Ulrika 59053, Sweden
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27
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Lucafò M, Muzzo A, Marcuzzi M, Giorio L, Decorti G, Stocco G. Patient-derived organoids for therapy personalization in inflammatory bowel diseases. World J Gastroenterol 2022; 28:2636-2653. [PMID: 35979165 PMCID: PMC9260862 DOI: 10.3748/wjg.v28.i24.2636] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/21/2022] [Accepted: 05/17/2022] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the intestinal tract that have emerged as a growing problem in industrialized countries. Knowledge of IBD pathogenesis is still incomplete, and the most widely-accepted interpretation considers genetic factors, environmental stimuli, uncontrolled immune responses and altered intestinal microbiota composition as determinants of IBD, leading to dysfunction of the intestinal epithelial functions. In vitro models commonly used to study the intestinal barrier do not fully reflect the proper intestinal architecture. An important innovation is represented by organoids, 3D in vitro cell structures derived from stem cells that can self-organize into functional organ-specific structures. Organoids may be generated from induced pluripotent stem cells or adult intestinal stem cells of IBD patients and therefore retain their genetic and transcriptomic profile. These models are powerful pharmacological tools to better understand IBD pathogenesis, to study the mechanisms of action on the epithelial barrier of drugs already used in the treatment of IBD, and to evaluate novel target-directed molecules which could improve therapeutic strategies. The aim of this review is to illustrate the potential use of organoids for therapy personalization by focusing on the most significant advances in IBD research achieved through the use of adult stem cells-derived intestinal organoids.
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Affiliation(s)
- Marianna Lucafò
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste 34137, Italy
| | - Antonella Muzzo
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste 34127, Italy
| | - Martina Marcuzzi
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
| | - Lorenzo Giorio
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
| | - Giuliana Decorti
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste 34137, Italy
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste 34127, Italy
| | - Gabriele Stocco
- Advanced Translational Diagnostics Laboratory, Institute for Maternal and Child Health-IRCCS “Burlo Garofolo”, Trieste 34137, Italy
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
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28
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Lai Y, Chu X, Di L, Gao W, Guo Y, Liu X, Lu C, Mao J, Shen H, Tang H, Xia CQ, Zhang L, Ding X. Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development. Acta Pharm Sin B 2022; 12:2751-2777. [PMID: 35755285 PMCID: PMC9214059 DOI: 10.1016/j.apsb.2022.03.009] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 11/07/2021] [Accepted: 11/10/2021] [Indexed: 02/08/2023] Open
Abstract
Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.
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Affiliation(s)
- Yurong Lai
- Drug Metabolism, Gilead Sciences Inc., Foster City, CA 94404, USA
| | - Xiaoyan Chu
- Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, NJ 07033, USA
| | - Li Di
- Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, CT 06340, USA
| | - Wei Gao
- Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, NJ 07033, USA
| | - Yingying Guo
- Eli Lilly and Company, Indianapolis, IN 46221, USA
| | - Xingrong Liu
- Drug Metabolism and Pharmacokinetics, Biogen, Cambridge, MA 02142, USA
| | - Chuang Lu
- Drug Metabolism and Pharmacokinetics, Accent Therapeutics, Inc. Lexington, MA 02421, USA
| | - Jialin Mao
- Department of Drug Metabolism and Pharmacokinetics, Genentech, A Member of the Roche Group, South San Francisco, CA 94080, USA
| | - Hong Shen
- Drug Metabolism and Pharmacokinetics Department, Bristol-Myers Squibb Company, Princeton, NJ 08540, USA
| | - Huaping Tang
- Bioanalysis and Biomarkers, Glaxo Smith Kline, King of the Prussia, PA 19406, USA
| | - Cindy Q. Xia
- Department of Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co., Cambridge, MA 02139, USA
| | - Lei Zhang
- Office of Research and Standards, Office of Generic Drugs, CDER, FDA, Silver Spring, MD 20993, USA
| | - Xinxin Ding
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
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29
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Hartwig O, Loretz B, Nougarede A, Jary D, Sulpice E, Gidrol X, Navarro F, Lehr CM. Leaky gut model of the human intestinal mucosa for testing siRNA-based nanomedicine targeting JAK1. J Control Release 2022; 345:646-660. [PMID: 35339579 PMCID: PMC9168449 DOI: 10.1016/j.jconrel.2022.03.037] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/11/2022] [Accepted: 03/20/2022] [Indexed: 02/07/2023]
Abstract
Complex in vitro models of human immune cells and intestinal mucosa may have a translation-assisting role in the assessment of anti-inflammatory compounds. Chronic inflammation of the gastrointestinal tract is a hallmark of inflammatory bowel diseases (IBD). In both IBD entities, Crohn's disease and ulcerative colitis, impaired immune cell activation and dysfunctional epithelial barrier are the common pathophysiology. Current therapeutic approaches are targeting single immune modulator molecules to stop disease progression and reduce adverse effects. Such molecular targets can be difficult to assess in experimental animal models of colitis, due to the disease complexity and species differences. Previously, a co-culture model based on human epithelial cells and monocytes arranged in a physiological microenvironment was used to mimic inflamed mucosa for toxicological and permeability studies. The leaky gut model described here, a co-culture of Caco-2, THP-1 and MUTZ-3 cells, was used to mimic IBD-related pathophysiology and for combined investigations of permeability and target engagement of two Janus kinase (JAK) inhibitors, tofacitinib (TOFA) and a JAK1-targeting siRNA nanomedicine. The co-culture just before reaching confluency of the epithelium was used to mimic the compromised intestinal barrier. Delivery efficacy and target engagement against JAK1 was quantified via downstream analysis of STAT1 protein phosphorylation after IFN-γ stimulation. Compared to a tight barrier, the leaky gut model showed 92 ± 5% confluence, a barrier function below 200 Ω*cm2, and enhanced immune response to bacteria-derived lipopolysaccharides. By confocal microscopy we observed an increased accumulation of siJAK1-nanoparticles within the sub-confluent regions leading to uptake into immune cells near the epithelium. A concentration-dependent downregulation of JAK/STAT pathway was observed for siJAK1-nanoparticles (10 ± 12% to 16 ± 12%), whereas TOFA inhibition was 86 ± 2%, compared to untreated cells. By mimicking the status of severely damaged epithelium, like in IBD, the leaky gut model holds promise as a human in vitro system to evaluate the efficacy of anti-inflammatory drugs and nanomedicines.
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Affiliation(s)
- Olga Hartwig
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, D-66123 Saarbrücken, Germany
| | - Brigitta Loretz
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany.
| | - Adrien Nougarede
- University Grenoble Alpes, F-38000 Grenoble, France; CEA LETI, Minatec Campus, F-38054 Grenoble, France
| | - Dorothée Jary
- University Grenoble Alpes, F-38000 Grenoble, France; CEA LETI, Minatec Campus, F-38054 Grenoble, France
| | - Eric Sulpice
- University Grenoble Alpes, CEA, INSERM, IRIG, Biomics, F-38000 Grenoble, France
| | - Xavier Gidrol
- University Grenoble Alpes, CEA, INSERM, IRIG, Biomics, F-38000 Grenoble, France
| | - Fabrice Navarro
- University Grenoble Alpes, F-38000 Grenoble, France; CEA LETI, Minatec Campus, F-38054 Grenoble, France
| | - Claus-Michael Lehr
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, D-66123 Saarbrücken, Germany
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30
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Zhang J, Zhang M, Wang Y, Donarski E, Gahlmann A. Optically Accessible Microfluidic Flow Channels for Noninvasive High-Resolution Biofilm Imaging Using Lattice Light Sheet Microscopy. J Phys Chem B 2021; 125:12187-12196. [PMID: 34714647 DOI: 10.1021/acs.jpcb.1c07759] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Imaging platforms that enable long-term, high-resolution imaging of biofilms are required to study cellular level dynamics within bacterial biofilms. By combining high spatial and temporal resolution and low phototoxicity, lattice light sheet microscopy (LLSM) has made critical contributions to the study of cellular dynamics. However, the power of LLSM has not yet been leveraged for biofilm research because the open-on-top imaging geometry using water-immersion objective lenses is not compatible with living bacterial specimens; bacterial growth on the microscope's objective lenses makes long-term time-lapse imaging impossible and raises considerable safety concerns for microscope users. To make LLSM compatible with pathogenic bacterial specimens, we developed hermetically sealed, but optically accessible, microfluidic flow channels that can sustain bacterial biofilm growth for multiple days under precisely controllable physical and chemical conditions. To generate a liquid- and gas-tight seal, we glued a thin polymer film across a 3D-printed channel, where the top wall had been omitted. We achieved negligible optical aberrations by using polymer films that precisely match the refractive index of water. Bacteria do not adhere to the polymer film itself, so that the polymer window provides unobstructed optical access to the channel interior. Inside the flow channels, biofilms can be grown on arbitrary, even nontransparent, surfaces. By integrating this flow channel with LLSM, we were able to record the growth of S. oneidensis MR-1 biofilms over several days at cellular resolution without any observable phototoxicity or photodamage.
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Affiliation(s)
- Ji Zhang
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States
| | - Mingxing Zhang
- School of Materials Science and Engineering, Northeastern University, Shenyang, Liaoning 110819, China
| | - Yibo Wang
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States
| | - Eric Donarski
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States
| | - Andreas Gahlmann
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States.,Department of Molecular Physiology & Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia 22903, United States
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Liu Z, Ulrich vonBargen R, McCall LI. Central role of metabolism in Trypanosoma cruzi tropism and Chagas disease pathogenesis. Curr Opin Microbiol 2021; 63:204-209. [PMID: 34455304 PMCID: PMC8463485 DOI: 10.1016/j.mib.2021.07.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 07/19/2021] [Accepted: 07/21/2021] [Indexed: 01/17/2023]
Abstract
Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi parasites. During mammalian infection, T. cruzi alternates between an intracellular stage and extracellular stage. T. cruzi adapts its metabolism to this lifestyle, while also reshaping host metabolic pathways. Such host metabolic adaptations compensate for parasite-induced stress, but may promote parasite survival and proliferation. Recent work has demonstrated that metabolism controls parasite tropism and location of Chagas disease symptoms, and regulates whether infection is mild or severe. Such findings have important translational applications with regards to treatment and diagnostic test development, though further research is needed with regards to in vivo parasite metabolic gene expression, relationship between magnitude of local metabolic perturbation, parasite strain and disease location, and host-parasite-microbiota co-metabolism.
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Affiliation(s)
- Zongyuan Liu
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, 73019, United States; Laboratories of Molecular Anthropology and Microbiome Research, University of Oklahoma, Norman, Oklahoma, 73019, United States
| | - Rebecca Ulrich vonBargen
- Department of Biomedical Engineering, University of Oklahoma, Norman, Oklahoma, 73019, United States
| | - Laura-Isobel McCall
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, 73019, United States; Laboratories of Molecular Anthropology and Microbiome Research, University of Oklahoma, Norman, Oklahoma, 73019, United States; Department of Microbiology and Plant Biology, University of Oklahoma, Norman, Oklahoma, 73019, United States.
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Puschhof J, Pleguezuelos-Manzano C, Martinez-Silgado A, Akkerman N, Saftien A, Boot C, de Waal A, Beumer J, Dutta D, Heo I, Clevers H. Intestinal organoid cocultures with microbes. Nat Protoc 2021; 16:4633-4649. [PMID: 34381208 DOI: 10.1038/s41596-021-00589-z] [Citation(s) in RCA: 126] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 06/14/2021] [Indexed: 12/12/2022]
Abstract
Adult-stem-cell-derived organoids model human epithelial tissues ex vivo, which enables the study of host-microbe interactions with great experimental control. This protocol comprises methods to coculture organoids with microbes, particularly focusing on human small intestinal and colon organoids exposed to individual bacterial species. Microinjection into the lumen and periphery of 3D organoids is discussed, as well as exposure of organoids to microbes in a 2D layer. We provide detailed protocols for characterizing the coculture with regard to bacterial and organoid cell viability and growth kinetics. Spatial relationships can be studied by fluorescence live microscopy, as well as scanning electron microscopy. Finally, we discuss considerations for assessing the impact of bacteria on gene expression and mutations through RNA and DNA sequencing. This protocol requires equipment for standard mammalian tissue culture, or bacterial or viral culture, as well as a microinjection device.
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Affiliation(s)
- Jens Puschhof
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
| | - Cayetano Pleguezuelos-Manzano
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
| | - Adriana Martinez-Silgado
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
| | - Ninouk Akkerman
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
| | - Aurelia Saftien
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
| | - Charelle Boot
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
| | - Amy de Waal
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
| | - Joep Beumer
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
| | - Devanjali Dutta
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
- Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, School of Life Sciences (SV), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Inha Heo
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, the Netherlands
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands
- Janssen Pharmaceutica N.V., Beerse, Belgium
| | - Hans Clevers
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, Utrecht, the Netherlands.
- Oncode Institute, Hubrecht Institute, Utrecht, the Netherlands.
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Harriman R, Lewis JS. Bioderived materials that disarm the gut mucosal immune system: Potential lessons from commensal microbiota. Acta Biomater 2021; 133:187-207. [PMID: 34098091 DOI: 10.1016/j.actbio.2021.05.045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/25/2021] [Accepted: 05/20/2021] [Indexed: 12/12/2022]
Abstract
Over the course of evolution, mammals and gut commensal microbes have adapted to coexist with each other. This homeostatic coexistence is dependent on an intricate balance between tolerogenic and inflammatory responses directed towards beneficial, commensal microbes and pathogenic intruders, respectively. Immune tolerance towards the gut microflora is largely sustained by immunomodulatory molecules produced by the commensals, which protect the bacteria from immune advances and maintain the gut's unique tolerogenic microenvironment, as well as systemic homeostasis. The identification and characterization of commensal-derived, tolerogenic molecules could lead to their utilization in biomaterials-inspired delivery schemes involving nano/microparticles or hydrogels, and potentially lead to the next generation of commensal-derived therapeutics. Moreover, gut-on-chip technologies could augment the discovery and characterization of influential commensals by providing realistic in vitro models conducive to finicky microbes. In this review, we provide an overview of the gut immune system, describe its intricate relationships with the microflora and identify major genera involved in maintaining tolerogenic responses and peripheral homeostasis. More relevant to biomaterials, we discuss commensal-derived molecules that are known to interface with immune cells and discuss potential strategies for their incorporation into biomaterial-based strategies aimed at culling inflammatory diseases. We hope this review will bridge the current findings in gut immunology, microbiology and biomaterials and spark further investigation into this emerging field. STATEMENT OF SIGNIFICANCE: Despite its tremendous potential to culminate into revolutionary therapeutics, the synergy between immunology, microbiology, and biomaterials has only been explored at a superficial level. Strategic incorporation of biomaterial-based technologies may be necessary to fully characterize and capitalize on the rapidly growing repertoire of immunomodulatory molecules derived from commensal microbes. Bioengineers may be able to combine state-of-the-art delivery platforms with immunomodulatory cues from commensals to provide a more holistic approach to combating inflammatory disease. This interdisciplinary approach could potentiate a neoteric field of research - "commensal-inspired" therapeutics with the promise of revolutionizing the treatment of inflammatory disease.
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Affiliation(s)
- Rian Harriman
- University of California Davis, Department of Biomedical Engineering, Davis, CA 95616, USA
| | - Jamal S Lewis
- University of California Davis, Department of Biomedical Engineering, Davis, CA 95616, USA.
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Garcia-Gutierrez E, Cotter PD. Relevance of organ(s)-on-a-chip systems to the investigation of food-gut microbiota-host interactions. Crit Rev Microbiol 2021; 48:463-488. [PMID: 34591726 DOI: 10.1080/1040841x.2021.1979933] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The ever greater understanding of the composition and function of the gut microbiome has provided new opportunities with respect to understanding and treating human disease. However, the models employed for in vitro and in vivo animal studies do not always provide the required insights. As a result, one such alternative in vitro cell culture based system, organ-on-a-chip technology, has recently attracted attention as a means of obtaining data that is representative of responses in humans. Organ-on-a-chip systems are designed to mimic the interactions of different tissue elements that were missing from traditional two-dimensional tissue culture. While they do not traditionally include a microbiota component, organ-on-a-chip systems provide a potentially valuable means of characterising the interactions between the microbiome and human tissues with a view to providing even greater accuracy. From a dietary perspective, these microbiota-organ-on-a-chip combinations can help researchers to predict how the consumption of specific foods and ingredients can impact on human health and disease. We provide an overview of the relevance and interactions of the gut microbiota and the diet in human health, we summarise the components involved in the organ-on-a-chip systems, how these systems have been employed for microbiota based studies and their potential relevance to study the interplay between food-gut microbiota-host interactions.
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Affiliation(s)
| | - Paul D Cotter
- Teagasc Food Research Centre, Moorepark, Ireland.,APC Microbiome Ireland, University College Cork, Cork, Ireland.,VistaMilk SFI Research Centre, Moorepark, Ireland
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EFSA Scientific Committee, More S, Bampidis V, Benford D, Bragard C, Halldorsson T, Hernández‐Jerez A, Hougaard Bennekou S, Koutsoumanis K, Lambré C, Machera K, Naegeli H, Nielsen S, Schlatter J, Schrenk D, Silano (deceased) V, Turck D, Younes M, Castenmiller J, Chaudhry Q, Cubadda F, Franz R, Gott D, Mast J, Mortensen A, Oomen AG, Weigel S, Barthelemy E, Rincon A, Tarazona J, Schoonjans R. Guidance on risk assessment of nanomaterials to be applied in the food and feed chain: human and animal health. EFSA J 2021; 19:e06768. [PMID: 34377190 PMCID: PMC8331059 DOI: 10.2903/j.efsa.2021.6768] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/30/2021] [Indexed: 02/08/2023] Open
Abstract
The EFSA has updated the Guidance on risk assessment of the application of nanoscience and nanotechnologies in the food and feed chain, human and animal health. It covers the application areas within EFSA's remit, including novel foods, food contact materials, food/feed additives and pesticides. The updated guidance, now Scientific Committee Guidance on nano risk assessment (SC Guidance on Nano-RA), has taken account of relevant scientific studies that provide insights to physico-chemical properties, exposure assessment and hazard characterisation of nanomaterials and areas of applicability. Together with the accompanying Guidance on Technical requirements for regulated food and feed product applications to establish the presence of small particles including nanoparticles (Guidance on Particle-TR), the SC Guidance on Nano-RA specifically elaborates on physico-chemical characterisation, key parameters that should be measured, methods and techniques that can be used for characterisation of nanomaterials and their determination in complex matrices. The SC Guidance on Nano-RA also details aspects relating to exposure assessment and hazard identification and characterisation. In particular, nanospecific considerations relating to in vitro/in vivo toxicological studies are discussed and a tiered framework for toxicological testing is outlined. Furthermore, in vitro degradation, toxicokinetics, genotoxicity, local and systemic toxicity as well as general issues relating to testing of nanomaterials are described. Depending on the initial tier results, additional studies may be needed to investigate reproductive and developmental toxicity, chronic toxicity and carcinogenicity, immunotoxicity and allergenicity, neurotoxicity, effects on gut microbiome and endocrine activity. The possible use of read-across to fill data gaps as well as the potential use of integrated testing strategies and the knowledge of modes or mechanisms of action are also discussed. The Guidance proposes approaches to risk characterisation and uncertainty analysis.
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Hartwig O, Shetab Boushehri MA, Shalaby KS, Loretz B, Lamprecht A, Lehr CM. Drug delivery to the inflamed intestinal mucosa - targeting technologies and human cell culture models for better therapies of IBD. Adv Drug Deliv Rev 2021; 175:113828. [PMID: 34157320 DOI: 10.1016/j.addr.2021.113828] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/09/2021] [Accepted: 06/10/2021] [Indexed: 12/19/2022]
Abstract
Current treatment strategies for inflammatory bowel disease (IBD) seek to alleviate the undesirable symptoms of the disorder. Despite the higher specificity of newer generation therapeutics, e.g. monoclonal antibodies, adverse effects still arise from their interference with non-specific systemic immune cascades. To circumvent such undesirable effects, both conventional and newer therapeutic options can benefit from various targeting strategies. Of course, both the development and the assessment of the efficiency of such targeted delivery systems necessitate the use of suitable in vivo and in vitro models representing relevant pathophysiological manifestations of the disorder. Accordingly, the current review seeks to provide a comprehensive discussion of the available preclinical models with emphasis on human in vitro models of IBD, along with their potentials and limitations. This is followed by an elaboration on the advancements in the field of biology- and nanotechnology-based targeted drug delivery systems and the potential rooms for improvement to facilitate their clinical translation.
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Affiliation(s)
- Olga Hartwig
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, D-66123 Saarbrücken, Germany
| | | | - Karim S Shalaby
- Department of Pharmaceutics, University of Bonn, D-53121 Bonn, Germany; Department of Pharmaceutics and Industrial Pharmacy, Ain Shams University, Cairo, Egypt
| | - Brigitta Loretz
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany
| | - Alf Lamprecht
- Department of Pharmaceutics, University of Bonn, D-53121 Bonn, Germany.
| | - Claus-Michael Lehr
- Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), D-66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, D-66123 Saarbrücken, Germany.
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37
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Zhao H, Wu H, Duan M, Liu R, Zhu Q, Zhang K, Wang L. Cinnamaldehyde Improves Metabolic Functions in Streptozotocin-Induced Diabetic Mice by Regulating Gut Microbiota. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:2339-2355. [PMID: 34103897 PMCID: PMC8179756 DOI: 10.2147/dddt.s288011] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022]
Abstract
Purpose The aim of the present study was to examine the protective effects of cinnamaldehyde (CA) on type 1 diabetes mellitus (T1DM) and explore the underlying molecular mechanisms by using multiple omics technology. Methods T1DM was induced by streptozotocin in the mice. Immunostaining was performed to evaluate glycogen synthesis in the liver and morphological changes in the heart. Gut microbiota was analyzed using 16S rRNA gene amplification sequencing. The serum metabolomics were determined by liquid chromatography-mass spectrometry. The relevant gene expression levels were determined by quantitative real-time PCR. Results CA treatment significantly improved the glucose metabolism and insulin sensitivity in T1DM mice. CA increased glycogen synthesis in the liver and protected myocardial injury in T1DM mice. CA affected the gut microbiota particularly by increasing the relative abundance of Lactobacillus johnsonii and decreasing the relative abundance of Lactobacillus murinus in T1DM mice. The glucose level was positively correlated with 88 functional pathways of gut microbiota and negatively correlated with 2 functional pathways of gut microbiota. Insulin resistance was positively correlated with 11 functional pathways. The analysis of serum metabolomics showed that CA treatment significantly increased the levels of taurochenodeoxycholic acid, tauroursodeoxycholic acid, tauro-α-muricholic acid and tauro-β-muricholic acid, taurodeoxycholic acid, taurocholic acid and taurohyodeoxycholic acid in T1DM mice. Taurohyodeoxycholic acid level was highly correlated with the blood glucose levels. Furthermore, the abundance of Faecalibacterium prausnitzii was positively correlated with AKT2, insulin like growth factor 1 receptor, E2F1 and insulin receptor substrate 1 mRNA expression levels, while taurohyodeoxycholic acid level was negatively correlated with IRS1 mRNA expression level. Conclusion Our results indicated that CA may interfere with gut microbiota to affect host metabolomics, especially the bile acids, so as to directly or indirectly modulate the expression levels of glucose metabolism-related genes, thus subsequently reducing the blood glucose level in the T1DM mice.
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Affiliation(s)
- Honglei Zhao
- Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, People's Republic of China
| | - Hongyan Wu
- Research Center for Biomedical Information Technology, Shenzhen Institutes of Advanced Technologies, Chinese Academy of Sciences, Shenzhen, People's Republic of China
| | - Meitao Duan
- Research Center for Biomedical Information Technology, Shenzhen Institutes of Advanced Technologies, Chinese Academy of Sciences, Shenzhen, People's Republic of China
| | - Ruixuan Liu
- Research Center for Biomedical Information Technology, Shenzhen Institutes of Advanced Technologies, Chinese Academy of Sciences, Shenzhen, People's Republic of China
| | - Quanhong Zhu
- Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, People's Republic of China
| | - Kai Zhang
- Research Center for Biomedical Information Technology, Shenzhen Institutes of Advanced Technologies, Chinese Academy of Sciences, Shenzhen, People's Republic of China
| | - Lili Wang
- Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, People's Republic of China
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Fedi A, Vitale C, Ponschin G, Ayehunie S, Fato M, Scaglione S. In vitro models replicating the human intestinal epithelium for absorption and metabolism studies: A systematic review. J Control Release 2021; 335:247-268. [PMID: 34033859 DOI: 10.1016/j.jconrel.2021.05.028] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/18/2021] [Accepted: 05/20/2021] [Indexed: 12/17/2022]
Abstract
Absorption, distribution, metabolism and excretion (ADME) studies represent a fundamental step in the early stages of drug discovery. In particular, the absorption of orally administered drugs, which occurs at the intestinal level, has gained attention since poor oral bioavailability often led to failures for new drug approval. In this context, several in vitro preclinical models have been recently developed and optimized to better resemble human physiology in the lab and serve as an animal alternative to accomplish the 3Rs principles. However, numerous models are ineffective in recapitulating the key features of the human small intestine epithelium and lack of prediction potential for drug absorption and metabolism during the preclinical stage. In this review, we provide an overview of in vitro models aimed at mimicking the intestinal barrier for pharmaceutical screening. After briefly describing how the human small intestine works, we present i) conventional 2D synthetic and cell-based systems, ii) 3D models replicating the main features of the intestinal architecture, iii) micro-physiological systems (MPSs) reproducing the dynamic stimuli to which cells are exposed in the native microenvironment. In this review, we will highlight the benefits and drawbacks of the leading intestinal models used for drug absorption and metabolism studies.
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Affiliation(s)
- Arianna Fedi
- Department of Computer Science, Bioengineering, Robotics and Systems Engineering, University of Genoa, 16126 Genoa, Italy; National Research Council of Italy, Institute of Electronics, Computer and Telecommunications (IEIIT) Institute, 16149 Genoa, Italy
| | - Chiara Vitale
- National Research Council of Italy, Institute of Electronics, Computer and Telecommunications (IEIIT) Institute, 16149 Genoa, Italy
| | - Giulia Ponschin
- Department of Computer Science, Bioengineering, Robotics and Systems Engineering, University of Genoa, 16126 Genoa, Italy
| | | | - Marco Fato
- Department of Computer Science, Bioengineering, Robotics and Systems Engineering, University of Genoa, 16126 Genoa, Italy; National Research Council of Italy, Institute of Electronics, Computer and Telecommunications (IEIIT) Institute, 16149 Genoa, Italy
| | - Silvia Scaglione
- National Research Council of Italy, Institute of Electronics, Computer and Telecommunications (IEIIT) Institute, 16149 Genoa, Italy.
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Wu F, Cristofoletti R, Zhao L, Rostami‐Hodjegan A. Scientific considerations to move towards biowaiver for biopharmaceutical classification system class III drugs: How modeling and simulation can help. Biopharm Drug Dispos 2021; 42:118-127. [DOI: 10.1002/bdd.2274] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/16/2021] [Accepted: 02/21/2021] [Indexed: 12/11/2022]
Affiliation(s)
- Fang Wu
- Division of Quantitative Methods and Modeling Office of Research and Standards Office of Generic Drugs Center for Drug Evaluation and Research U.S. Food and Drug Administration Silver Spring Maryland USA
| | - Rodrigo Cristofoletti
- Department of Pharmaceutics Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida Orlando Florida USA
| | - Liang Zhao
- Division of Quantitative Methods and Modeling Office of Research and Standards Office of Generic Drugs Center for Drug Evaluation and Research U.S. Food and Drug Administration Silver Spring Maryland USA
| | - Amin Rostami‐Hodjegan
- Centre for Applied Pharmacokinetic Research University of Manchester Manchester UK
- Certara UK Limited Sheffield UK
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40
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Thakral NK, Meister E, Jankovsky C, Li L, Schwabe R, Luo L, Chen S. Prediction of in vivo supersaturation and precipitation of poorly water-soluble drugs: Achievements and aspirations. Int J Pharm 2021; 600:120505. [PMID: 33753162 DOI: 10.1016/j.ijpharm.2021.120505] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/10/2021] [Accepted: 03/13/2021] [Indexed: 12/14/2022]
Abstract
This review focuses on options available to a pharmaceutical scientist to predict in vivo supersaturation and precipitation of poorly water-soluble drugs. As no single device or system can simulate the complex gastrointestinal environment, a combination of appropriate in vitro tools may be utilized to get optimal predictive information. To address the empirical issues encountered during small-scale and full-scale in vitro predictive testing, theoretical background and relevant case studies are discussed. The practical considerations for selection of appropriate tools at various stages of drug development are recommended. Upcoming technologies that have potential to further reduce in vivo studies and expedite the drug development process are also discussed.
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Affiliation(s)
- Naveen K Thakral
- Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, United States.
| | - Eva Meister
- Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, United States
| | - Corinne Jankovsky
- Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, United States
| | - Li Li
- Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, United States; Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4849 Calhoun Road, Houston, TX 77204, United States
| | - Robert Schwabe
- Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, United States
| | - Laibin Luo
- Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, United States
| | - Shirlynn Chen
- Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, United States
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41
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Xavier M, Parente IA, Rodrigues PM, Cerqueira MA, Pastrana L, Gonçalves C. Safety and fate of nanomaterials in food: The role of in vitro tests. Trends Food Sci Technol 2021. [DOI: 10.1016/j.tifs.2021.01.050] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Kulthong K, Hooiveld GJEJ, Duivenvoorde L, Miro Estruch I, Marin V, van der Zande M, Bouwmeester H. Transcriptome comparisons of in vitro intestinal epithelia grown under static and microfluidic gut-on-chip conditions with in vivo human epithelia. Sci Rep 2021; 11:3234. [PMID: 33547413 PMCID: PMC7864925 DOI: 10.1038/s41598-021-82853-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 01/22/2021] [Indexed: 02/06/2023] Open
Abstract
Gut-on-chip devices enable exposure of cells to a continuous flow of culture medium, inducing shear stresses and could thus better recapitulate the in vivo human intestinal environment in an in vitro epithelial model compared to static culture methods. We aimed to study if dynamic culture conditions affect the gene expression of Caco-2 cells cultured statically or dynamically in a gut-on-chip device and how these gene expression patterns compared to that of intestinal segments in vivo. For this we applied whole genome transcriptomics. Dynamic culture conditions led to a total of 5927 differentially expressed genes (3280 upregulated and 2647 downregulated genes) compared to static culture conditions. Gene set enrichment analysis revealed upregulated pathways associated with the immune system, signal transduction and cell growth and death, and downregulated pathways associated with drug metabolism, compound digestion and absorption under dynamic culture conditions. Comparison of the in vitro gene expression data with transcriptome profiles of human in vivo duodenum, jejunum, ileum and colon tissue samples showed similarities in gene expression profiles with intestinal segments. It is concluded that both the static and the dynamic gut-on-chip model are suitable to study human intestinal epithelial responses as an alternative for animal models.
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Affiliation(s)
- Kornphimol Kulthong
- Division of Toxicology, Wageningen University, P.O. box 8000, 6700 EA, Wageningen, The Netherlands.
- Wageningen Food Safety Research, P.O. Box 230, 6700 AE, Wageningen, The Netherlands.
- National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency, Pathum Thani, 12120, Thailand.
| | - Guido J E J Hooiveld
- Nutrition, Metabolism and Genomics group, Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Loes Duivenvoorde
- Wageningen Food Safety Research, P.O. Box 230, 6700 AE, Wageningen, The Netherlands
| | - Ignacio Miro Estruch
- Division of Toxicology, Wageningen University, P.O. box 8000, 6700 EA, Wageningen, The Netherlands
| | - Victor Marin
- Wageningen Food Safety Research, P.O. Box 230, 6700 AE, Wageningen, The Netherlands
| | - Meike van der Zande
- Wageningen Food Safety Research, P.O. Box 230, 6700 AE, Wageningen, The Netherlands
| | - Hans Bouwmeester
- Division of Toxicology, Wageningen University, P.O. box 8000, 6700 EA, Wageningen, The Netherlands.
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Xu M, Wang Y, Duan W, Xia S, Wei S, Liu W, Wang Q. Proteomic Reveals Reasons for Acquired Drug Resistance in Lung Cancer Derived Brain Metastasis Based on a Newly Established Multi-Organ Microfluidic Chip Model. Front Bioeng Biotechnol 2020; 8:612091. [PMID: 33415100 PMCID: PMC7783320 DOI: 10.3389/fbioe.2020.612091] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 11/25/2020] [Indexed: 12/30/2022] Open
Abstract
Anti-tumor drugs can effectively shrink the lesions of primary lung cancer; however, it has limited therapeutic effect on patients with brain metastasis (BM). A BM preclinical model based on a multi-organ microfluidic chip has been established proficiently in our previous work. In this study, the BM subpopulation (PC9-Br) derived from the parental PC9 cell line was isolated from the chip model and found to develop obvious resistance to antineoplastic drugs including chemotherapeutic agents (cisplatin, carboplatin, pemetrexed) and tyrosine kinase inhibitors (TKIs) which target epidermal growth factor receptor (EGFR); this suggested that the acquisition of drug-resistance by brain metastatic cells was attributable to the intrinsic changes in PC9-Br. Hence, we performed proteomic and revealed a greatly altered spectrum of BM protein expression compared with primary lung cancer cells. We identified the hyperactive glutathione (GSH) metabolism pathway with the overexpression of various GSH metabolism-related enzymes (GPX4, RRM2, GCLC, GPX1, GSTM4, GSTM1). Aldehyde dehydrogenases (ALDH1A1, ALDH3A1) were also found to be upregulated in BM. What's more, loss of EGFR and phosphorylated EGFR in PC9-Br gave reasons for the TKIs resistance. Collectively, our findings indicated potential mechanisms for the acquirement of drug resistance occurred in BM, providing new strategies to overcome therapeutic resistance in lung cancer BM.
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Affiliation(s)
- Mingxin Xu
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Yingyan Wang
- Laboratory Center for Diagnostics, Dalian Medical University, Dalian, China
| | - Wenzhe Duan
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Shengkai Xia
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Song Wei
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Wenwen Liu
- Cancer Translational Medicine Research Center, The Second Hospital, Dalian Medical University, Dalian, China
| | - Qi Wang
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China.,Cancer Translational Medicine Research Center, The Second Hospital, Dalian Medical University, Dalian, China
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García-Rodríguez I, Sridhar A, Pajkrt D, Wolthers KC. Put Some Guts into It: Intestinal Organoid Models to Study Viral Infection. Viruses 2020; 12:v12111288. [PMID: 33187072 PMCID: PMC7697248 DOI: 10.3390/v12111288] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/30/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023] Open
Abstract
The knowledge about enteric viral infection has vastly increased over the last eight years due to the development of intestinal organoids and enteroids that suppose a step forward from conventional studies using cell lines. Intestinal organoids and enteroids are three-dimensional (3D) models that closely mimic intestinal cellular heterogeneity and organization. The barrier function within these models has been adapted to facilitate viral studies. In this review, several adaptations (such as organoid-derived two-dimensional (2D) monolayers) and original intestinal 3D models are discussed. The specific advantages and applications, as well as improvements of each model are analyzed and an insight into the possible path for the field is given.
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Affiliation(s)
- Inés García-Rodríguez
- OrganoVIR Lab, Department of Medical Microbiology, Amsterdam UMC, Academic Medical Center, University of Amsterdam, 1100 AZ Amsterdam, The Netherlands; (I.G.-R.); (A.S.)
- Department of Pediatrics Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC, Academic Medical Center, University of Amsterdam, 1100 AZ Amsterdam, The Netherlands;
| | - Adithya Sridhar
- OrganoVIR Lab, Department of Medical Microbiology, Amsterdam UMC, Academic Medical Center, University of Amsterdam, 1100 AZ Amsterdam, The Netherlands; (I.G.-R.); (A.S.)
- Department of Pediatrics Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC, Academic Medical Center, University of Amsterdam, 1100 AZ Amsterdam, The Netherlands;
| | - Dasja Pajkrt
- Department of Pediatrics Infectious Diseases, Emma Children’s Hospital, Amsterdam UMC, Academic Medical Center, University of Amsterdam, 1100 AZ Amsterdam, The Netherlands;
| | - Katja C. Wolthers
- OrganoVIR Lab, Department of Medical Microbiology, Amsterdam UMC, Academic Medical Center, University of Amsterdam, 1100 AZ Amsterdam, The Netherlands; (I.G.-R.); (A.S.)
- Correspondence:
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Bédard P, Gauvin S, Ferland K, Caneparo C, Pellerin È, Chabaud S, Bolduc S. Innovative Human Three-Dimensional Tissue-Engineered Models as an Alternative to Animal Testing. Bioengineering (Basel) 2020; 7:E115. [PMID: 32957528 PMCID: PMC7552665 DOI: 10.3390/bioengineering7030115] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/11/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022] Open
Abstract
Animal testing has long been used in science to study complex biological phenomena that cannot be investigated using two-dimensional cell cultures in plastic dishes. With time, it appeared that more differences could exist between animal models and even more when translated to human patients. Innovative models became essential to develop more accurate knowledge. Tissue engineering provides some of those models, but it mostly relies on the use of prefabricated scaffolds on which cells are seeded. The self-assembly protocol has recently produced organ-specific human-derived three-dimensional models without the need for exogenous material. This strategy will help to achieve the 3R principles.
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Affiliation(s)
- Patrick Bédard
- Faculté de Médecine, Sciences Biomédicales, Université Laval, Québec, QC G1V 0A6, Canada; (P.B.); (S.G.); (K.F.)
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Québec, QC G1J 1Z4, Canada; (C.C.); (È.P.); (S.C.)
| | - Sara Gauvin
- Faculté de Médecine, Sciences Biomédicales, Université Laval, Québec, QC G1V 0A6, Canada; (P.B.); (S.G.); (K.F.)
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Québec, QC G1J 1Z4, Canada; (C.C.); (È.P.); (S.C.)
| | - Karel Ferland
- Faculté de Médecine, Sciences Biomédicales, Université Laval, Québec, QC G1V 0A6, Canada; (P.B.); (S.G.); (K.F.)
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Québec, QC G1J 1Z4, Canada; (C.C.); (È.P.); (S.C.)
| | - Christophe Caneparo
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Québec, QC G1J 1Z4, Canada; (C.C.); (È.P.); (S.C.)
| | - Ève Pellerin
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Québec, QC G1J 1Z4, Canada; (C.C.); (È.P.); (S.C.)
| | - Stéphane Chabaud
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Québec, QC G1J 1Z4, Canada; (C.C.); (È.P.); (S.C.)
| | - Stéphane Bolduc
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Centre de Recherche du CHU de Québec-Université Laval, Axe Médecine Régénératrice, Québec, QC G1J 1Z4, Canada; (C.C.); (È.P.); (S.C.)
- Département de Chirurgie, Faculté de Médecine, Université Laval, Québec, QC G1V 0A6, Canada
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