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Kumagai-Braesch M, Yao M, Ågren N, Karadagi A, Ericzon BG, Domogatskaya A. Monolayer whole adherent islets: A novel tool for studying drug-induced diabetic phenotypes in vitro. PLoS One 2025; 20:e0325421. [PMID: 40460156 PMCID: PMC12132926 DOI: 10.1371/journal.pone.0325421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 05/13/2025] [Indexed: 06/18/2025] Open
Abstract
To understand the mechanisms of diabetes and develop novel drugs, various animal diabetes models as well as in vitro experimental systems have been established. Using isolated islets in vitro is associated with several problems: (1) discontinued blood microcirculation causes ischemia and central necrosis in isolated islets, (2) dissociation of islets into single cells reduces the total number of cells and impairs endocrine function. Here, we aim to establish a novel experimental method using isolated islets to characterize cell physiology and drug effects. We have developed a method to flatten islets into monolayers by culturing small, whole, non-disrupted mouse islets on laminin-521. In this culture, islet cells remain intact, and cell-cell junctions are not broken mechanically. Small mouse islets were cultured in a 96-well plate coated with laminin-521 for six days and then exposed to various concentrations of streptozotocin (STZ) for 24 hours. Monolayer islets exposed to 0.6 mM STZ-induced a metabolic diabetes-like phenotype, i.e., islet cell death, predominantly of beta cells, causing a shift in alpha-to-beta cell ratio. The stimulation index in a glucose-stimulated insulin secretion assay was reduced in STZ-treated islets. However, insulin production per beta cell did not change significantly. The monolayer whole islet assay format allows the extraction of quantitative data regarding endocrine cell populations, "endocrine sensitivity" (stimulation index), and "endocrine power" (amount of hormone secreted per cell). It is a novel, versatile, user-friendly, semi-automated, and financially attractive experimental platform.
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Affiliation(s)
- Makiko Kumagai-Braesch
- Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Department of Transplantation Surgery, Karolinska University Hospital, Huddinge, Sweden
| | - Ming Yao
- Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Department of Transplantation Surgery, Karolinska University Hospital, Huddinge, Sweden
| | - Nils Ågren
- Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Department of Transplantation Surgery, Karolinska University Hospital, Huddinge, Sweden
| | - Ahmad Karadagi
- Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Department of Transplantation Surgery, Karolinska University Hospital, Huddinge, Sweden
| | - Bo-Göran Ericzon
- Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
- Department of Transplantation Surgery, Karolinska University Hospital, Huddinge, Sweden
| | - Anna Domogatskaya
- Division of Transplantation Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
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Chen W, Nie M, Gan J, Xia N, Wang D, Sun L. Tailoring cell sheets for biomedical applications. SMART MEDICINE 2024; 3:e20230038. [PMID: 39188516 PMCID: PMC11235941 DOI: 10.1002/smmd.20230038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 01/04/2024] [Indexed: 08/28/2024]
Abstract
Cell sheet technology has emerged as a novel scaffold-free approach for cell-based therapies in regenerative medicine. Techniques for harvesting cell sheets are essential to preserve the integrity of living cell sheets. This review provides an overview of fundamental technologies to fabricate cell sheets and recent advances in cell sheet-based tissue engineering. In addition to the commonly used temperature-responsive systems, we introduce alternative approaches, such as ROS-induced, magnetic-controlled, and light-induced cell sheet technologies. Moreover, we discuss the modification of the cell sheet to improve its function, including stacking, genetic modification, and vascularization. With the significant advances in cell sheet technology, cell sheets have been widely applied in various tissues and organs, including but not limited to the lung, cornea, cartilage, periodontium, heart, and liver. This review further describes both the preclinical and clinical applications of cell sheets. We believe that the progress in cell sheet technology would further propel its biomedical applications.
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Affiliation(s)
- Weiwei Chen
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Min Nie
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Jingjing Gan
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Nan Xia
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Dandan Wang
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Lingyun Sun
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
- Department of Rheumatology and ImmunologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
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Duman BÖ, Yazir Y, Halbutoğullari ZS, Mert S, Öztürk A, Gacar G, Duruksu G. Production of alginate macrocapsule device for long-term normoglycaemia in the treatment of type 1 diabetes mellitus with pancreatic cell sheet engineering. Biomed Mater 2024; 19:025008. [PMID: 38194706 DOI: 10.1088/1748-605x/ad1c9b] [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: 08/15/2023] [Accepted: 01/09/2024] [Indexed: 01/11/2024]
Abstract
Type 1 diabetes-mellitus (T1DM) is characterized by damage of beta cells in pancreatic islets. Cell-sheet engineering, one of the newest therapeutic approaches, has also been used to create functional islet systems by creating islet/beta cell-sheets and transferring these systems to areas that require minimally invasive intervention, such as extrahepatic areas. Since islets, beta cells, and pancreas transplants are allogeneic, immune problems such as tissue rejection occur after treatment, and patients become insulin dependent again. In this study, we aimed to design the most suitable cell-sheet treatment method and macrocapsule-device that could provide long-term normoglycemia in rats. Firstly, mesenchymal stem cells (MSCs) and beta cells were co-cultured in a temperature-responsive culture dish to obtain a cell-sheet and then the cell-sheets macroencapsulated using different concentrations of alginate. The mechanical properties and pore sizes of the macrocapsule-device were characterized. The viability and activity of cell-sheets in the macrocapsule were evaluatedin vitroandin vivo. Fasting blood glucose levels, body weight, and serum insulin & C-peptide levels were evaluated after transplantation in diabetic-rats. After the transplantation, the blood glucose level at 225 mg dl-1on the 10th day dropped to 168 mg dl-1on the 15th day, and remained at the normoglycemic level for 210 days. In this study, an alginate macrocapsule-device was successfully developed to protect cell-sheets from immune attacks after transplantation. The results of our study provide the basis for future animal and human studies in which this method can be used to provide long-term cellular therapy in T1DM patients.
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Affiliation(s)
- Büşra Öncel Duman
- European Vocational School, Medical Laboratory Techniques Program, Kocaeli Health and Technology University, 41030 Kocaeli, Turkey
| | - Yusufhan Yazir
- Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli University (KOGEM), TR41001 Izmit, Kocaeli, Turkey
- Department of Stem Cell, Institute of Health Sciences, Kocaeli University, Kocaeli, Turkey
- Department of Histology and Embryology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Zehra Seda Halbutoğullari
- Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli University (KOGEM), TR41001 Izmit, Kocaeli, Turkey
- Department of Stem Cell, Institute of Health Sciences, Kocaeli University, Kocaeli, Turkey
- Department of Medical Biology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Serap Mert
- Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli University (KOGEM), TR41001 Izmit, Kocaeli, Turkey
- Department of Stem Cell, Institute of Health Sciences, Kocaeli University, Kocaeli, Turkey
- Department of Chemistry and Chemical Processing Technology, Kocaeli University, Kocaeli, Turkey
- Department of Polymer Science and Technology, Kocaeli University, Kocaeli, Turkey
| | - Ahmet Öztürk
- Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli University (KOGEM), TR41001 Izmit, Kocaeli, Turkey
- Department of Stem Cell, Institute of Health Sciences, Kocaeli University, Kocaeli, Turkey
- Department of Histology and Embryology, Faculty of Medicine, Kocaeli University, Kocaeli, Turkey
| | - Gülçin Gacar
- Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli University (KOGEM), TR41001 Izmit, Kocaeli, Turkey
- Department of Stem Cell, Institute of Health Sciences, Kocaeli University, Kocaeli, Turkey
| | - Gökhan Duruksu
- Center for Stem Cell and Gene Therapies Research and Practice, Kocaeli University (KOGEM), TR41001 Izmit, Kocaeli, Turkey
- Department of Stem Cell, Institute of Health Sciences, Kocaeli University, Kocaeli, Turkey
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Duman BO, Sariboyaci AE, Karaoz E. Bio-engineering of 3-D cell sheets for diabetic rats: Interaction between mesenchymal stem cells and beta cells in functional islet regeneration system. Tissue Cell 2022; 79:101919. [DOI: 10.1016/j.tice.2022.101919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/22/2022] [Accepted: 09/03/2022] [Indexed: 11/15/2022]
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The Potential of Cell Sheet Technology for Beta Cell Replacement Therapy. CURRENT TRANSPLANTATION REPORTS 2022. [DOI: 10.1007/s40472-022-00371-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
Abstract
Purpose of Review
Here, we review the use of cell sheet technology using different cell types and its potential for restoring the extracellular matrix microenvironment, perfusion, and immunomodulatory action on islets and beta cells.
Recent Findings
Cell sheets can be produced with different fabrication techniques ranging from the widely used temperature responsive system to the magnetic system. A variety of cells have been used to produce cell sheets including skin fibroblasts, smooth muscle cells, human umbilical vein endothelial cells, and mesenchymal stem cells.
Summary
CST would allow to recreate the ECM of islets which would provide cues to support islet survival and improvement of islet function. Depending on the used cell type, different additional supporting properties like immunoprotection or cues for better revascularization could be provided. Furthermore, CST offers the possibility to use other implantation sites than inside the liver. Further research should focus on cell sheet thickness and size to generate a potential translational therapy.
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Adel IM, ElMeligy MF, Elkasabgy NA. Conventional and Recent Trends of Scaffolds Fabrication: A Superior Mode for Tissue Engineering. Pharmaceutics 2022; 14:306. [DOI: https:/doi.org/10.3390/pharmaceutics14020306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2023] Open
Abstract
Tissue regeneration is an auto-healing mechanism, initiating immediately following tissue damage to restore normal tissue structure and function. This falls in line with survival instinct being the most dominant instinct for any living organism. Nevertheless, the process is slow and not feasible in all tissues, which led to the emergence of tissue engineering (TE). TE aims at replacing damaged tissues with new ones. To do so, either new tissue is being cultured in vitro and then implanted, or stimulants are implanted into the target site to enhance endogenous tissue formation. Whichever approach is used, a matrix is used to support tissue growth, known as ‘scaffold’. In this review, an overall look at scaffolds fabrication is discussed, starting with design considerations and different biomaterials used. Following, highlights of conventional and advanced fabrication techniques are attentively presented. The future of scaffolds in TE is ever promising, with the likes of nanotechnology being investigated for scaffold integration. The constant evolvement of organoids and biofluidics with the eventual inclusion of organ-on-a-chip in TE has shown a promising prospect of what the technology might lead to. Perhaps the closest technology to market is 4D scaffolds following the successful implementation of 4D printing in other fields.
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Affiliation(s)
- Islam M. Adel
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt
| | - Mohamed F. ElMeligy
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt
| | - Nermeen A. Elkasabgy
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt
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Adel IM, ElMeligy MF, Elkasabgy NA. Conventional and Recent Trends of Scaffolds Fabrication: A Superior Mode for Tissue Engineering. Pharmaceutics 2022; 14:306. [PMID: 35214038 PMCID: PMC8877304 DOI: 10.3390/pharmaceutics14020306] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/19/2022] [Accepted: 01/24/2022] [Indexed: 12/16/2022] Open
Abstract
Tissue regeneration is an auto-healing mechanism, initiating immediately following tissue damage to restore normal tissue structure and function. This falls in line with survival instinct being the most dominant instinct for any living organism. Nevertheless, the process is slow and not feasible in all tissues, which led to the emergence of tissue engineering (TE). TE aims at replacing damaged tissues with new ones. To do so, either new tissue is being cultured in vitro and then implanted, or stimulants are implanted into the target site to enhance endogenous tissue formation. Whichever approach is used, a matrix is used to support tissue growth, known as 'scaffold'. In this review, an overall look at scaffolds fabrication is discussed, starting with design considerations and different biomaterials used. Following, highlights of conventional and advanced fabrication techniques are attentively presented. The future of scaffolds in TE is ever promising, with the likes of nanotechnology being investigated for scaffold integration. The constant evolvement of organoids and biofluidics with the eventual inclusion of organ-on-a-chip in TE has shown a promising prospect of what the technology might lead to. Perhaps the closest technology to market is 4D scaffolds following the successful implementation of 4D printing in other fields.
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Affiliation(s)
- Islam M. Adel
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt; (M.F.E.); (N.A.E.)
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Nagaya M, Hasegawa K, Uchikura A, Nakano K, Watanabe M, Umeyama K, Matsunari H, Osafune K, Kobayashi E, Nakauchi H, Nagashima H. Feasibility of large experimental animal models in testing novel therapeutic strategies for diabetes. World J Diabetes 2021; 12:306-330. [PMID: 33889282 PMCID: PMC8040081 DOI: 10.4239/wjd.v12.i4.306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 01/30/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes is among the top 10 causes of death in adults and caused approximately four million deaths worldwide in 2017. The incidence and prevalence of diabetes is predicted to increase. To alleviate this potentially severe situation, safer and more effective therapeutics are urgently required. Mice have long been the mainstay as preclinical models for basic research on diabetes, although they are not ideally suited for translating basic knowledge into clinical applications. To validate and optimize novel therapeutics for safe application in humans, an appropriate large animal model is needed. Large animals, especially pigs, are well suited for biomedical research and share many similarities with humans, including body size, anatomical features, physiology, and pathophysiology. Moreover, pigs already play an important role in translational studies, including clinical trials for xenotransplantation. Progress in genetic engineering over the past few decades has facilitated the development of transgenic animals, including porcine models of diabetes. This article discusses features that attest to the attractiveness of genetically modified porcine models of diabetes for testing novel treatment strategies using recent technical advances.
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Affiliation(s)
- Masaki Nagaya
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Department of Immunology, St. Marianna University School of Medicine, Kawasaki 261-8511, Kanagawa, Japan
| | - Koki Hasegawa
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Ayuko Uchikura
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Kazuaki Nakano
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Masahito Watanabe
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Kazuhiro Umeyama
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Hitomi Matsunari
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Kenji Osafune
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Kyoto, Japan
| | - Eiji Kobayashi
- Department of Organ Fabrication, Keio University School of Medicine, Shinjuku 160-8582, Tokyo, Japan
| | - Hiromitsu Nakauchi
- Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, United States
- Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Minato 108-8639, Tokyo, Japan
| | - Hiroshi Nagashima
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
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Goto H, Komae H, Sekine H, Homma J, Lee S, Yokota T, Matsuura K, Someya T, Ono M, Shimizu T. Continuous measurement of surface electrical potentials from transplanted cardiomyocyte tissue derived from human-induced pluripotent stem cells under physiological conditions in vivo. Heart Vessels 2021; 36:899-909. [PMID: 33683408 DOI: 10.1007/s00380-021-01824-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/26/2021] [Indexed: 10/22/2022]
Abstract
Recording the electrical potentials of bioengineered cardiac tissue after transplantation would help to monitor the maturation of the tissue and detect adverse events such as arrhythmia. However, a few studies have reported the measurement of myocardial tissue potentials in vivo under physiological conditions. In this study, human-induced pluripotent stem cell-derived cardiomyocyte (hiPSCM) sheets were stacked and ectopically transplanted into the subcutaneous tissue of rats for culture in vivo. Three months after transplantation, a flexible nanomesh sensor was implanted onto the hiPSCM tissue to record its surface electrical potentials under physiological conditions, i.e., without the need for anesthetic agents that might adversely affect cardiomyocyte function. The nanomesh sensor was able to record electrical potentials in non-sedated, ambulating animals for up to 48 h. When compared with recordings made with conventional needle electrodes in anesthetized animals, the waveforms obtained with the nanomesh sensor showed less dispersion of waveform interval and waveform duration. However, waveform amplitude tended to show greater dispersion for the nanomesh sensor than for the needle electrodes, possibly due to motion artifacts produced by movements of the animal or local tissue changes in response to surgical implantation of the sensor. The implantable nanomesh sensor utilized in this study potentially could be used for long-term monitoring of bioengineered myocardial tissue in vivo under physiological conditions.
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Affiliation(s)
- Hiroshi Goto
- Department of Cardiac Surgery, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.,Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Hyoe Komae
- Department of Cardiac Surgery, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. .,Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
| | - Hidekazu Sekine
- Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan.
| | - Jun Homma
- Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Sunghoon Lee
- Department of Electrical Engineering and Information Systems, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Tomoyuki Yokota
- Department of Electrical Engineering and Information Systems, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Katsuhisa Matsuura
- Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Takao Someya
- Department of Electrical Engineering and Information Systems, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Minoru Ono
- Department of Cardiac Surgery, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tatsuya Shimizu
- Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
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Akolpoglu MB, Inceoglu Y, Bozuyuk U, Sousa AR, Oliveira MB, Mano JF, Kizilel S. Recent advances in the design of implantable insulin secreting heterocellular islet organoids. Biomaterials 2020; 269:120627. [PMID: 33401104 DOI: 10.1016/j.biomaterials.2020.120627] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 12/14/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022]
Abstract
Islet transplantation has proved one of the most remarkable transmissions from an experimental curiosity into a routine clinical application for the treatment of type I diabetes (T1D). Current efforts for taking this technology one-step further are now focusing on overcoming islet donor shortage, engraftment, prolonged islet availability, post-transplant vascularization, and coming up with new strategies to eliminate lifelong immunosuppression. To this end, insulin secreting 3D cell clusters composed of different types of cells, also referred as heterocellular islet organoids, spheroids, or pseudoislets, have been engineered to overcome the challenges encountered by the current islet transplantation protocols. β-cells or native islets are accompanied by helper cells, also referred to as accessory cells, to generate a cell cluster that is not only able to accurately secrete insulin in response to glucose, but also superior in terms of other key features (e.g. maintaining a vasculature, longer durability in vivo and not necessitating immunosuppression after transplantation). Over the past decade, numerous 3D cell culture techniques have been integrated to create an engineered heterocellular islet organoid that addresses current obstacles. Here, we first discuss the different cell types used to prepare heterocellular organoids for islet transplantation and their contribution to the organoids design. We then introduce various cell culture techniques that are incorporated to prepare a fully functional and insulin secreting organoids with select features. Finally, we discuss the challenges and present a future outlook for improving clinical outcomes of islet transplantation.
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Affiliation(s)
- M Birgul Akolpoglu
- Chemical and Biological Engineering, Koc University, Sariyer, 34450, Istanbul, Turkey
| | - Yasemin Inceoglu
- Chemical and Biological Engineering, Koc University, Sariyer, 34450, Istanbul, Turkey
| | - Ugur Bozuyuk
- Chemical and Biological Engineering, Koc University, Sariyer, 34450, Istanbul, Turkey
| | - Ana Rita Sousa
- Department of Chemistry, CICECO - Aveiro Institute of Materials. University of Aveiro. Campus Universitário de Santiago. 3810-193 Aveiro. Portugal
| | - Mariana B Oliveira
- Department of Chemistry, CICECO - Aveiro Institute of Materials. University of Aveiro. Campus Universitário de Santiago. 3810-193 Aveiro. Portugal.
| | - João F Mano
- Department of Chemistry, CICECO - Aveiro Institute of Materials. University of Aveiro. Campus Universitário de Santiago. 3810-193 Aveiro. Portugal
| | - Seda Kizilel
- Chemical and Biological Engineering, Koc University, Sariyer, 34450, Istanbul, Turkey.
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11
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Temperature-responsive and multi-responsive grafted polymer brushes with transitions based on critical solution temperature: synthesis, properties, and applications. Colloid Polym Sci 2020. [DOI: 10.1007/s00396-020-04750-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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12
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Shodeinde AB, Murphy AC, Oldenkamp HF, Potdar AS, Ludolph CM, Peppas NA. Recent Advances in Smart Biomaterials for the Detection and Treatment of Autoimmune Diseases. ADVANCED FUNCTIONAL MATERIALS 2020; 30:1909556. [PMID: 33071713 PMCID: PMC7566744 DOI: 10.1002/adfm.201909556] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 01/15/2020] [Indexed: 05/07/2023]
Abstract
Autoimmune diseases are a group of debilitating illnesses that are often idiopathic in nature. The steady rise in the prevalence of these conditions warrants new approaches for diagnosis and treatment. Stimuli-responsive biomaterials also known as "smart", "intelligent" or "recognitive" biomaterials are widely studied for their applications in drug delivery, biosensing and tissue engineering due to their ability to produce thermal, optical, chemical, or structural changes upon interacting with the biological environment. This critical analysis highlights studies within the last decade that harness the recognitive capabilities of these biomaterials towards the development of novel detection and treatment options for autoimmune diseases.
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Affiliation(s)
- Aaliyah B. Shodeinde
- McKetta Department of Chemical Engineering, 200 E. Dean Keeton St. Stop C0400, Austin, TX, USA, 78712
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX, USA, 78712
| | - Andrew C. Murphy
- McKetta Department of Chemical Engineering, 200 E. Dean Keeton St. Stop C0400, Austin, TX, USA, 78712
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX, USA, 78712
| | - Heidi F. Oldenkamp
- McKetta Department of Chemical Engineering, 200 E. Dean Keeton St. Stop C0400, Austin, TX, USA, 78712
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX, USA, 78712
| | - Abhishek S. Potdar
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX, USA, 78712
| | - Catherine M. Ludolph
- McKetta Department of Chemical Engineering, 200 E. Dean Keeton St. Stop C0400, Austin, TX, USA, 78712
| | - Nicholas A. Peppas
- McKetta Department of Chemical Engineering, 200 E. Dean Keeton St. Stop C0400, Austin, TX, USA, 78712
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX, USA, 78712
- Department of Biomedical Engineering, The University of Texas at Austin, 107 W Dean Keeton Street Stop C0800, Austin, TX, USA, 78712
- Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, 2409 University Ave. Stop A1900, Austin, TX, USA, 78712
- Department of Surgery and Perioperative Care, Dell Medical School, 1601 Trinity St., Bldg. B, Stop Z0800, Austin, TX, USA, 78712
- Department of Pediatrics, Dell Medical School, 1400 Barbara Jordan Blvd., Austin, TX, USA, 78723
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13
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Lee YN, Yi HJ, Kim YH, Lee S, Oh J, Okano T, Shim IK, Kim SC. Evaluation of Multi-Layered Pancreatic Islets and Adipose-Derived Stem Cell Sheets Transplanted on Various Sites for Diabetes Treatment. Cells 2020; 9:1999. [PMID: 32878048 PMCID: PMC7563383 DOI: 10.3390/cells9091999] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/22/2020] [Accepted: 08/26/2020] [Indexed: 12/31/2022] Open
Abstract
Islet cell transplantation is considered an ideal treatment for insulin-deficient diabetes, but implantation sites are limited and show low graft survival. Cell sheet technology and adipose-derived stem cells (ADSCs) can be useful tools for improving islet cell transplantation outcomes since both can increase implantation efficacy and graft survival. Herein, the optimal transplantation site in diabetic mice was investigated using islets and stem cell sheets. We constructed multi-layered cell sheets using rat/human islets and human ADSCs. Cell sheets were fabricated using temperature-responsive culture dishes. Islet/ADSC sheet (AI sheet) group showed higher viability and glucose-stimulated insulin secretion than islet-only group. Compared to islet transplantation alone, subcutaneous AI sheet transplantation showed better blood glucose control and CD31+ vascular traits. Because of the adhesive properties of cell sheets, AI sheets were easily applied on liver and peritoneal surfaces. Liver or peritoneal surface grafts showed better glucose control, weight gain, and intraperitoneal glucose tolerance test (IPGTT) profiles than subcutaneous site grafts using both rat and human islets. Stem cell sheets increased the therapeutic efficacy of islets in vivo because mesenchymal stem cells enhance islet function and induce neovascularization around transplanted islets. The liver and peritoneal surface can be used more effectively than the subcutaneous site in future clinical applications.
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Affiliation(s)
- Yu Na Lee
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (Y.N.L.); (H.-J.Y.); (Y.H.K.); (S.L.); (J.O.)
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Hye-Jin Yi
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (Y.N.L.); (H.-J.Y.); (Y.H.K.); (S.L.); (J.O.)
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Yang Hee Kim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (Y.N.L.); (H.-J.Y.); (Y.H.K.); (S.L.); (J.O.)
- Regenerative Medicine Research Center, Dalim Tissen Co., Ltd., 31, Yeonhui-ro, Mapo-gu, Seoul 03982, Korea
| | - Song Lee
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (Y.N.L.); (H.-J.Y.); (Y.H.K.); (S.L.); (J.O.)
| | - Jooyun Oh
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (Y.N.L.); (H.-J.Y.); (Y.H.K.); (S.L.); (J.O.)
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Teruo Okano
- Cell Sheet Tissue Engineering Center, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA;
| | - In Kyong Shim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea; (Y.N.L.); (H.-J.Y.); (Y.H.K.); (S.L.); (J.O.)
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Song Cheol Kim
- Department of Medical Science, Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
- Department of Surgery & Department of Biomedical Engineering, AMIST, University of Ulsan College of Medicine &Asan Medical Center, Seoul 05505, Korea
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14
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Murata D, Arai K, Nakayama K. Scaffold-Free Bio-3D Printing Using Spheroids as "Bio-Inks" for Tissue (Re-)Construction and Drug Response Tests. Adv Healthc Mater 2020; 9:e1901831. [PMID: 32378363 DOI: 10.1002/adhm.201901831] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 02/21/2020] [Accepted: 03/04/2020] [Indexed: 02/06/2023]
Abstract
In recent years, scaffold-free bio-3D printing using cell aggregates (spheroids) as "bio-inks" has attracted increasing attention as a method for 3D cell construction. Bio-3D printing uses a technique called the Kenzan method, wherein spheroids are placed one-by-one in a microneedle array (the "Kenzan") using a bio-3D printer. The bio-3D printer is a machine that was developed to perform bio-3D printing automatically. Recently, it has been reported that cell constructs can be produced by a bio-3D printer using spheroids composed of many types of cells and that this can contribute to tissue (re-)construction. This progress report summarizes the production and effectiveness of various cell constructs prepared using bio-3D printers. It also considers the future issues and prospects of various cell constructs obtained by using this method for further development of scaffold-free 3D cell constructions.
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Affiliation(s)
- Daiki Murata
- Center for Regenerative Medicine ResearchFaculty of MedicineSaga University Honjo‐machi Saga 840‐8502 Japan
| | - Kenichi Arai
- Center for Regenerative Medicine ResearchFaculty of MedicineSaga University Honjo‐machi Saga 840‐8502 Japan
| | - Koichi Nakayama
- Center for Regenerative Medicine ResearchFaculty of MedicineSaga University Honjo‐machi Saga 840‐8502 Japan
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15
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Nakamura K, Saotome T, Shimada N, Matsuno K, Tabata Y. A Gelatin Hydrogel Nonwoven Fabric Facilitates Metabolic Activity of Multilayered Cell Sheets. Tissue Eng Part C Methods 2020; 25:344-352. [PMID: 31062648 DOI: 10.1089/ten.tec.2019.0061] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
IMPACT STATEMENT This study introduces the utility of gelatin hydrogel nonwoven fabrics (GHNFs) for cell sheet engineering. The GHNF had the mechanical property strong enough to hold by forceps even in the swollen condition. The cell sheet harvest and transfer processes were performed simpler and faster than those without using the GHNF. The GHNF facilitates the metabolic activity of three-layered cell sheets, and the cell migration from cell sheets into the GHNF was observed. The GHNF is a promising material used to support cell sheets during the process of assemble formulation and contributes to the improved biological functions of tissue-like cell constructs.
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Affiliation(s)
- Koichiro Nakamura
- 1 Research and Development Center, The Japan Wool Textile Co., Ltd., Hyogo, Japan.,2 Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Toshiki Saotome
- 1 Research and Development Center, The Japan Wool Textile Co., Ltd., Hyogo, Japan.,2 Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Naoki Shimada
- 1 Research and Development Center, The Japan Wool Textile Co., Ltd., Hyogo, Japan
| | - Kumiko Matsuno
- 1 Research and Development Center, The Japan Wool Textile Co., Ltd., Hyogo, Japan.,2 Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Yasuhiko Tabata
- 2 Laboratory of Biomaterials, Department of Regeneration Science and Engineering, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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16
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Hori T, Kurosawa O, Ishihara K, Mizuta T, Iwata H. Three-Dimensional Cell Sheet Construction Method with a Polyester Micromesh Sheet. Tissue Eng Part C Methods 2020; 26:170-179. [PMID: 32186996 DOI: 10.1089/ten.tec.2019.0330] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Cell sheet engineering has become important in a variety of fields, including regenerative medicine and transplantation. Our research group previously developed micromesh cultures that enable cells to form a cell sheet on a microstructured mesh sheet. Here, we present a more usable micromesh culture and devices that make it possible, aiming for widespread use. The devices are mainly constituted of a polyester micromesh sheet and three-dimensional (3D)-printed simple frames that fix the mesh sheet on it. Cells such as fibroblast Tig-1-20 cells, hepatoma HepG2 cells, or mesenchymal stem cells (MSC) were easily seeded on the polyester mesh sheet in the device and cultured for 16 days, which was followed by the formation of a 100-400-μm-thick cell sheet. The cell sheet was very robust, easy to handle, and could be readily removed from the device for subsequent analysis. Optical coherence tomography revealed the structure of the cell sheet as having the mesh sheet layer in the center of the cell sheet. Confocal microscopy demonstrated that Tig-1-20 cells in the cell sheet were aligned according to the shape of the mesh apertures, indicating that cell orientation can be controlled with this micromesh culture. As for another application, the device was used to construct a multilayered cell sheet that consists of three different types of cells. Furthermore, for mass production, the device frames were made using polyoxymethylene (POM) instead of 3D printing materials. Using the POM devices, a large MSC sheet for 10 cm dishes was successfully produced 7 days after cell seeding. This micromesh culture may become one of the useful cell sheet construction methods in future for medical and research fields. Impact statement Currently, cell sheets are constructed, for example, on a temperature-responsive polymer-coated dish or a porous membrane. These cell sheets are widely used but are not completely suitable in terms of robustness, ease of handling, cost, ease of microscopic cell observation, or nutrient supply. We previously reported that the micromesh culture can provide a three-dimensional (3D) cell sheet that has advantages for cell observation and nutrient supply. In this study, the micromesh culture was enhanced with a polyester micromesh sheet and a series of devices of polyoxymethylene, helping us to produce a robust, cost-effective, easily layered, and easy-to-use 3D cell sheet.
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Affiliation(s)
- Takeshi Hori
- Compass to Healthy Life Research Complex Program, RIKEN, Kobe, Japan
| | - Osamu Kurosawa
- Compass to Healthy Life Research Complex Program, RIKEN, Kobe, Japan
| | | | | | - Hiroo Iwata
- Compass to Healthy Life Research Complex Program, RIKEN, Kobe, Japan
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17
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Alblawi A, Ranjani AS, Yasmin H, Gupta S, Bit A, Rahimi-Gorji M. Scaffold-free: A developing technique in field of tissue engineering. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2020; 185:105148. [PMID: 31678793 DOI: 10.1016/j.cmpb.2019.105148] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 10/17/2019] [Accepted: 10/20/2019] [Indexed: 06/10/2023]
Abstract
Scaffold-free tissue engineering can be considered as a rapidly developing technique in the field of tissue engineering. In the areas of regenerative medicine and wound healing, there is a demand of techniques where no scaffolds are used for the development of desired tissue. These techniques will overcome the problems of rejection and tissue failure which are common with scaffolds. Main breakthrough of scaffold free tissue engineering was after invention of 3-D printers which made it possible to print complex tissues which were not possible by conventional methods. Mathematical modeling is a prediction technique is used in tissue engineering for simulation of the model to be constructed. Coming to scaffold-free technique, mathematical modeling is necessary for the processing of the model that has to be bio-printed so as to avoid and changes in the final construct. Tissue construct is developed by use of non-destructive imaging techniques i.e. computed tomography (CT) and magnetic resonance imaging (MRI).In this review, we discussed about various mathematical models and the models which are widely used in bioprinting techniques such as Cellular Potts Model (CPM) and Cellular Particle Dynamic (CPD) model. Later, developed of 3-D tissue construct using micro CT scan images was explained. Finally, we discussed about scaffold free techniques such as 3-D bioprinting and cell sheet technology. In this manuscript, we proposed a cell sheet based bioprinting technique where mesenchymal stem cells (MSCs) on the surface of thermoresponsive polymer were subjected to mechanosensing either by introducing acoustic energies or stress created by polymeric strain energy function. Mechanosensing stimulus will trigger the intracellular signal transduction pathway leading to differentiation of the MSCs into desired cells.
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Affiliation(s)
- Adel Alblawi
- Mechanical Engineering Department, College of Engineering, Shaqra University, Dawadmi, P.O. 11911, Ar Riyadh, Saudi Arabia.
| | - Achalla Sri Ranjani
- Department of Biomedical Engineering, National Institute of Technology, Raipur, India
| | - Humaira Yasmin
- Department of Mathematics, College of Science, Majmaah University, 11952, Saudi Arabia.
| | - Sharda Gupta
- Department of Biomedical Engineering, National Institute of Technology, Raipur, India
| | - Arindam Bit
- Department of Biomedical Engineering, National Institute of Technology, Raipur, India.
| | - Mohammad Rahimi-Gorji
- Faculty of Medicine and Health Science, Ghent University, 9000 Gent, Belgium; Biofluid, Tissue and Solid Mechanics for Medical Applications Lab (IBiTech, bioMMeda), Ghent University, Gent 9000, Belgium.
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18
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Raju R, Oshima M, Inoue M, Morita T, Huijiao Y, Waskitho A, Baba O, Inoue M, Matsuka Y. Three-dimensional periodontal tissue regeneration using a bone-ligament complex cell sheet. Sci Rep 2020; 10:1656. [PMID: 32015383 PMCID: PMC6997427 DOI: 10.1038/s41598-020-58222-0] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 01/13/2020] [Indexed: 02/06/2023] Open
Abstract
Periodontal tissue is a distinctive tissue structure composed three-dimensionally of cementum, periodontal ligament (PDL) and alveolar bone. Severe periodontal diseases cause fundamental problems for oral function and general health, and conventional dental treatments are insufficient for healing to healthy periodontal tissue. Cell sheet technology has been used in many tissue regenerations, including periodontal tissue, to transplant appropriate stem/progenitor cells for tissue regeneration of a target site as a uniform tissue. However, it is still difficult to construct a three-dimensional structure of complex tissue composed of multiple types of cells, and the transplantation of a single cell sheet cannot sufficiently regenerate a large-scale tissue injury. Here, we fabricated a three-dimensional complex cell sheet composed of a bone-ligament structure by layering PDL cells and osteoblast-like cells on a temperature responsive culture dish. Following ectopic and orthotopic transplantation, only the complex cell sheet group was demonstrated to anatomically regenerate the bone-ligament structure along with the functional connection of PDL-like fibers to the tooth root and alveolar bone. This study represents successful three-dimensional tissue regeneration of a large-scale tissue injury using a bioengineered tissue designed to simulate the anatomical structure.
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Affiliation(s)
- Resmi Raju
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Masamitsu Oshima
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Miho Inoue
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Tsuyoshi Morita
- Department of Oral and Maxillofacial Anatomy, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Yan Huijiao
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Arief Waskitho
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Otto Baba
- Department of Oral and Maxillofacial Anatomy, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan
| | - Masahisa Inoue
- Laboratories for Structure and Function Research, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, 770-8055, Japan
| | - Yoshizo Matsuka
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, 770-8503, Japan.
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19
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Doberenz F, Zeng K, Willems C, Zhang K, Groth T. Thermoresponsive polymers and their biomedical application in tissue engineering - a review. J Mater Chem B 2020; 8:607-628. [PMID: 31939978 DOI: 10.1039/c9tb02052g] [Citation(s) in RCA: 195] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Thermoresponsive polymers hold great potential in the biomedical field, since they enable the fabrication of cell sheets, in situ drug delivery and 3D-printing under physiological conditions. In this review we provide an overview of several thermoresponsive polymers and their application, with focus on poly(N-isopropylacrylamide)-surfaces for cell sheet engineering. Basic knowledge of important processes like protein adsorption on surfaces and cell adhesion is provided. For different thermoresponsive polymers, namely PNIPAm, Pluronics, elastin-like polypeptides (ELP) and poly(N-vinylcaprolactam) (PNVCL), synthesis and basic chemical and physical properties have been described and the mechanism of their thermoresponsive behavior highlighted. Fabrication methods of thermoresponsive surfaces have been discussed, focusing on PNIPAm, and describing several methods in detail. The latter part of this review is dedicated to the application of the thermoresponsive polymers and with regard to cell sheet engineering, the process of temperature-dependent cell sheet detachment is explained. We provide insight into several applications of PNIPAm surfaces in cell sheet engineering. For Pluronics, ELP and PNVCL we show their application in the field of drug delivery and tissue engineering. We conclude, that research of thermoresponsive polymers has made big progress in recent years, especially for PNIPAm since the 1990s. However, manifold research possibilities, e.g. in surface fabrication and 3D-printing and further translational applications are conceivable in near future.
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Affiliation(s)
- Falko Doberenz
- Department Biomedical Materials, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 4, 06120 Halle (Saale), Germany.
| | - Kui Zeng
- Wood Technology and Wood Chemistry, University of Goettingen, Büsgenweg 4, D-37077 Göttingen, Germany
| | - Christian Willems
- Department Biomedical Materials, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 4, 06120 Halle (Saale), Germany.
| | - Kai Zhang
- Wood Technology and Wood Chemistry, University of Goettingen, Büsgenweg 4, D-37077 Göttingen, Germany
| | - Thomas Groth
- Department Biomedical Materials, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Heinrich-Damerow-Strasse 4, 06120 Halle (Saale), Germany. and Interdisciplinary Center of Material Science, Martin Luther University, Halle-Wittenberg, 06099 Halle (Saale), Germany and Institute for Bionic Technologies and Engineering, I.M. Sechenov First Moscow State Medical University, 1, 19991, Trubetskaya st. 8, Moscow, Russian Federation
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20
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Reyes‐Martínez JE, Ruiz‐Pacheco JA, Flores‐Valdéz MA, Elsawy MA, Vallejo‐Cardona AA, Castillo‐Díaz LA. Advanced hydrogels for treatment of diabetes. J Tissue Eng Regen Med 2019; 13:1375-1393. [DOI: 10.1002/term.2880] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 03/31/2019] [Accepted: 04/29/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Juana E. Reyes‐Martínez
- Departamento de Biología. División de Ciencias Naturales y ExactasUniversidad de Guanajuato Guanajuato México
| | | | - Mario A. Flores‐Valdéz
- Biotecnología Médica y FarmacéuticaCentro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ) Guadalajara México
| | - Mohamed A. Elsawy
- School of Pharmacy and Biomedical SciencesUniversity of Central Lancashire Preston UK
| | - Alba A. Vallejo‐Cardona
- Biotecnología Médica y FarmacéuticaCentro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco (CIATEJ) Guadalajara México
| | - Luis A. Castillo‐Díaz
- Departamento de Medicina y Ciencias de la Salud, División de Ciencias Biológicas y de la SaludUniversidad de Sonora Hermosillo México
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21
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22
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Perez-Basterrechea M, Esteban MM, Vega JA, Obaya AJ. Tissue-engineering approaches in pancreatic islet transplantation. Biotechnol Bioeng 2018; 115:3009-3029. [PMID: 30144310 DOI: 10.1002/bit.26821] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/08/2018] [Accepted: 08/14/2018] [Indexed: 12/15/2022]
Abstract
Pancreatic islet transplantation is a promising alternative to whole-pancreas transplantation as a treatment of type 1 diabetes mellitus. This technique has been extensively developed during the past few years, with the main purpose of minimizing the complications arising from the standard protocols used in organ transplantation. By using a variety of strategies used in tissue engineering and regenerative medicine, pancreatic islets have been successfully introduced in host patients with different outcomes in terms of islet survival and functionality, as well as the desired normoglycemic control. Here, we describe and discuss those strategies to transplant islets together with different scaffolds, in combination with various cell types and diffusible factors, and always with the aim of reducing host immune response and achieving islet survival, regardless of the site of transplantation.
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Affiliation(s)
- Marcos Perez-Basterrechea
- Unidad de Terapia Celular y Medicina Regenerativa, Servicio de Hematología y Hemoterapia, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.,Plataforma de Terapias Avanzadas, Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Manuel M Esteban
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
| | - Jose A Vega
- Departamento de Morfología y Biología Celular, Universidad de Oviedo, Oviedo, Spain.,Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Alvaro J Obaya
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
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23
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Sigmundsson K, Ojala JR, Öhman MK, Österholm AM, Moreno-Moral A, Domogatskaya A, Chong LY, Sun Y, Chai X, Steele JA, George B, Patarroyo M, Nilsson AS, Rodin S, Ghosh S, Stevens MM, Petretto E, Tryggvason K. Culturing functional pancreatic islets on α5-laminins and curative transplantation to diabetic mice. Matrix Biol 2018; 70:5-19. [DOI: 10.1016/j.matbio.2018.03.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 03/22/2018] [Accepted: 03/22/2018] [Indexed: 12/15/2022]
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24
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Peloso A, Citro A, Zoro T, Cobianchi L, Kahler-Quesada A, Bianchi CM, Andres A, Berishvili E, Piemonti L, Berney T, Toso C, Oldani G. Regenerative Medicine and Diabetes: Targeting the Extracellular Matrix Beyond the Stem Cell Approach and Encapsulation Technology. Front Endocrinol (Lausanne) 2018; 9:445. [PMID: 30233489 PMCID: PMC6127205 DOI: 10.3389/fendo.2018.00445] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 07/18/2018] [Indexed: 12/20/2022] Open
Abstract
According to the Juvenile Diabetes Research Foundation (JDRF), almost 1. 25 million people in the United States (US) have type 1 diabetes, which makes them dependent on insulin injections. Nationwide, type 2 diabetes rates have nearly doubled in the past 20 years resulting in more than 29 million American adults with diabetes and another 86 million in a pre-diabetic state. The International Diabetes Ferderation (IDF) has estimated that there will be almost 650 million adult diabetic patients worldwide at the end of the next 20 years (excluding patients over the age of 80). At this time, pancreas transplantation is the only available cure for selected patients, but it is offered only to a small percentage of them due to organ shortage and the risks linked to immunosuppressive regimes. Currently, exogenous insulin therapy is still considered to be the gold standard when managing diabetes, though stem cell biology is recognized as one of the most promising strategies for restoring endocrine pancreatic function. However, many issues remain to be solved, and there are currently no recognized treatments for diabetes based on stem cells. In addition to stem cell resesarch, several β-cell substitutive therapies have been explored in the recent era, including the use of acellular extracellular matrix scaffolding as a template for cellular seeding, thus providing an empty template to be repopulated with β-cells. Although this bioengineering approach still has to overcome important hurdles in regards to clinical application (including the origin of insulin producing cells as well as immune-related limitations), it could theoretically provide an inexhaustible source of bio-engineered pancreases.
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Affiliation(s)
- Andrea Peloso
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- HepatoPancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Antonio Citro
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Tamara Zoro
- Department of General Surgery, IRCCS Policlinico San Matteo, Pavia, Italy
- Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, Pavia, Italy
| | - Lorenzo Cobianchi
- Department of General Surgery, IRCCS Policlinico San Matteo, Pavia, Italy
- Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, Pavia, Italy
| | - Arianna Kahler-Quesada
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Carlo M. Bianchi
- Department of General Surgery, IRCCS Policlinico San Matteo, Pavia, Italy
- Department of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, Pavia, Italy
| | - Axel Andres
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- HepatoPancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Ekaterine Berishvili
- Cell Isolation and Transplantation Center, University of Geneva, Geneva, Switzerland
- Institute of Medical Research, Ilia State University, Tbilisi, Georgia
| | - Lorenzo Piemonti
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Thierry Berney
- Cell Isolation and Transplantation Center, University of Geneva, Geneva, Switzerland
| | - Christian Toso
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- HepatoPancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
| | - Graziano Oldani
- Division of Abdominal Surgery, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- HepatoPancreato-Biliary Centre, Geneva University Hospitals, Geneva, Switzerland
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25
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Nagaya M, Katsumata Y, Arai Y, Umeki I, Nakano K, Kasai Y, Hasegawa K, Okamoto K, Itazaki S, Matsunari H, Watanabe M, Umeyama K, Nagashima H. Effectiveness of bioengineered islet cell sheets for the treatment of diabetes mellitus. J Surg Res 2018; 227:119-129. [PMID: 29804843 DOI: 10.1016/j.jss.2018.02.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 01/29/2018] [Accepted: 02/13/2018] [Indexed: 01/17/2023]
Abstract
BACKGROUND The present study aimed to evaluate whether bioengineered mouse islet cell sheets can be used for the treatment of diabetes mellitus. METHODS Isolated mouse pancreatic islets were dispersed, and cells were plated on temperature-responsive culture plates coated with iMatrix-551. On day 3 of culture, the sheets were detached from the plates and used for further analysis or transplantation. The following parameters were assessed: (1) morphology, (2) expression of β-cell-specific transcription factors and other islet-related proteins, (3) methylation level of the pancreatic duodenal homeobox-1 (Pdx-1) promoter, as determined by bisulfite sequencing, and (4) levels of serum glucose after transplantation of one or two islet cell sheets into the abdominal cavity of streptozotocin-induced diabetic severe combined immunodeficiency mice. RESULTS From each mouse, we recovered approximately 233.3 ± 12.5 islets and 1.4 ± 0.1 × 105 cells after dispersion. We estimate that approximately 68.2% of the cells were lost during dispersion. The viability of recovered single cells was 91.3 ± 0.9%. The engineered islet cell sheets were stable, but the messenger RNA levels of various β-cell-specific transcription factors were significantly lower than those of primary islets, whereas Pdx-1 promoter methylation and the expression of NeuroD, Pdx-1, and glucagon proteins were similar between sheets and islets. Moreover, transplantation of islet cell sheets did not revert serum hyperglycemia in any of the recipient mice. CONCLUSIONS Engineering effective islet cell sheets require further research efforts, as the currently produced sheets remain functionally inferior compared with primary islets.
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Affiliation(s)
- Masaki Nagaya
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan; Department of Immunology, St. Marianna University School of Medicine, Kawasaki, Japan.
| | - Yuki Katsumata
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Yoshikazu Arai
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Ikuma Umeki
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Kazuaki Nakano
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan; Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Yuri Kasai
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Koki Hasegawa
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Kazutoshi Okamoto
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Shiori Itazaki
- Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Hitomi Matsunari
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan; Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Masahito Watanabe
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan; Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Kazuhiro Umeyama
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan; Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Hiroshi Nagashima
- Meiji University International Institute for Bio-Resource Research, Kawasaki, Japan; Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan.
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26
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Fujita I, Utoh R, Yamamoto M, Okano T, Yamato M. The liver surface as a favorable site for islet cell sheet transplantation in type 1 diabetes model mice. Regen Ther 2018; 8:65-72. [PMID: 30271868 PMCID: PMC6147207 DOI: 10.1016/j.reth.2018.04.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/19/2018] [Accepted: 04/12/2018] [Indexed: 01/21/2023] Open
Abstract
INTRODUCTION Islet transplantation is one of the most promising therapeutic approaches for patients with severe type 1 diabetes mellitus (T1DM). Transplantation of engineered islet cell sheets holds great potential for treating T1DM as it enables the creation of stable neo-islet tissues. However, a large mass of islet cell sheets is required for the subcutaneous transplantation to reverse hyperglycemia in diabetic mice. Here, we investigated whether the liver surface could serve as an alternative site for islet cell sheet transplantation. METHODS Dispersed rat islet cells (0.8 × 106 cells) were cultured on laminin-332-coated thermoresponsive culture dishes. After 2 days of cultivation, we harvested the islet cell sheets by lowering the culture temperature using a support membrane with a gelatin gel. We transplanted two recovered islet cell sheets into the subcutaneous space or onto the liver surface of severe combined immunodeficiency (SCID) mice with streptozocin-induced diabetes. RESULTS In the liver surface group, the non-fasting blood glucose level decreased rapidly within several days after transplantation. In marked contrast, the hyperglycemia state was maintained in the subcutaneous space transplantation group. The levels of rat C-peptide and insulin in the liver surface group were significantly higher than those in the subcutaneous space group. An immunohistological analysis confirmed that most of the islet cells engrafted on the liver surface were insulin-positive. The CD31-positive endothelial cells formed vascular networks within the neo-islets and in the surrounding tissues. In contrast, viable islet cells were not found in the subcutaneous space group. CONCLUSIONS Compared with the subcutaneous space, a relatively small mass of islet cell sheets was enough to achieve normoglycemia in diabetic mice when the liver surface was selected as the transplantation site. Our results demonstrate that the optimization of the transplantation site for islet cell sheets leads to significant improvements in the therapeutic efficiency for T1DM.
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Affiliation(s)
- Izumi Fujita
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Rie Utoh
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
| | - Masakazu Yamamoto
- Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Teruo Okano
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Masayuki Yamato
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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Mu S, Tee BC, Emam H, Zhou Y, Sun Z. Culture-expanded mesenchymal stem cell sheets enhance extraction-site alveolar bone growth: An animal study. J Periodontal Res 2018; 53:514-524. [DOI: 10.1111/jre.12541] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2018] [Indexed: 12/25/2022]
Affiliation(s)
- S. Mu
- Department of Periodontology and Oral Mucosa; The Second Affiliated Hospital of Harbin Medical University; Harbin China
| | - B. C. Tee
- Division of Biosciences; College of Dentistry; The Ohio State University; Columbus OH USA
| | - H. Emam
- Division of Oral and Maxillofacial Surgery; College of Dentistry; The Ohio State University; Columbus OH USA
| | - Y. Zhou
- Department of Chemistry and Biochemistry; The Ohio State University; Columbus OH USA
| | - Z. Sun
- Division of Orthodontics; College of Dentistry; The Ohio State University; Columbus OH USA
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28
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Kirby GT, Michelmore A, Smith LE, Whittle JD, Short RD. Cell sheets in cell therapies. Cytotherapy 2018; 20:169-180. [DOI: 10.1016/j.jcyt.2017.11.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 09/28/2017] [Accepted: 11/03/2017] [Indexed: 12/21/2022]
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29
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TERAMURA Y. Design and Application of Cell Glue. KOBUNSHI RONBUNSHU 2018. [DOI: 10.1295/koron.2017-0052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Yuji TERAMURA
- Department of Bioengineering, Graduate School of Engineering, The University of Tokyo
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30
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Nagase K, Yamato M, Kanazawa H, Okano T. Poly(N-isopropylacrylamide)-based thermoresponsive surfaces provide new types of biomedical applications. Biomaterials 2017; 153:27-48. [PMID: 29096399 DOI: 10.1016/j.biomaterials.2017.10.026] [Citation(s) in RCA: 257] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 10/12/2017] [Accepted: 10/15/2017] [Indexed: 02/06/2023]
Abstract
Thermoresponsive surfaces, prepared by grafting of poly(N-isopropylacrylamide) (PIPAAm) or its copolymers, have been investigated for biomedical applications. Thermoresponsive cell culture dishes that show controlled cell adhesion and detachment following external temperature changes, represent a promising application of thermoresponsive surfaces. These dishes can be used to fabricate cell sheets, which are currently used as effective therapies for patients. Thermoresponsive microcarriers for large-scale cell cultivation have also been developed by taking advantage of the thermally modulated cell adhesion and detachment properties of thermoresponsive surfaces. Furthermore, thermoresponsive bioseparation systems using thermoresponsive surfaces for separating and purifying pharmaceutical proteins and therapeutic cells have been developed, with the separation systems able to maintain their activity and biological potency throughout the procedure. These applications of thermoresponsive surfaces have been improved with progress in preparation techniques of thermoresponsive surfaces, such as polymerization methods, and surface modification techniques. In the present review, the various types of PIPAAm-based thermoresponsive surfaces are summarized by describing their preparation methods, properties, and successful biomedical applications.
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Affiliation(s)
- Kenichi Nagase
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato, Tokyo 105-8512, Japan; Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan.
| | - Masayuki Yamato
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan
| | - Hideko Kanazawa
- Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato, Tokyo 105-8512, Japan
| | - Teruo Okano
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, TWIns, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan; Cell Sheet Tissue Engineering Center (CSTEC) and Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 30 South 2000 East, Salt Lake City, Utah 84112, USA.
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Mihara Y, Matsuura K, Sakamoto Y, Okano T, Kokudo N, Shimizu T. Production of pancreatic progenitor cells from human induced pluripotent stem cells using a three-dimensional suspension bioreactor system. J Tissue Eng Regen Med 2017; 11:3193-3201. [DOI: 10.1002/term.2228] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 04/11/2016] [Accepted: 04/25/2016] [Indexed: 01/06/2023]
Affiliation(s)
- Yuichiro Mihara
- Institute of Advanced Biomedical Engineering and Science; Tokyo Women's Medical University; Tokyo Japan
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine; The University of Tokyo; Tokyo Japan
| | - Katsuhisa Matsuura
- Institute of Advanced Biomedical Engineering and Science; Tokyo Women's Medical University; Tokyo Japan
| | - Yoshihiro Sakamoto
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine; The University of Tokyo; Tokyo Japan
| | - Teruo Okano
- Institute of Advanced Biomedical Engineering and Science; Tokyo Women's Medical University; Tokyo Japan
| | - Norihiro Kokudo
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine; The University of Tokyo; Tokyo Japan
| | - Tatsuya Shimizu
- Institute of Advanced Biomedical Engineering and Science; Tokyo Women's Medical University; Tokyo Japan
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32
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Ichihara Y, Utoh R, Yamada M, Shimizu T, Uchigata Y. Size effect of engineered islets prepared using microfabricated wells on islet cell function and arrangement. Heliyon 2016; 2:e00129. [PMID: 27441299 PMCID: PMC4946309 DOI: 10.1016/j.heliyon.2016.e00129] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Revised: 05/29/2016] [Accepted: 06/23/2016] [Indexed: 01/02/2023] Open
Abstract
Pancreatic islets are heterogeneous clusters mainly composed of α and β cells, and these clusters range in diameter from 50 to several hundred micrometers. Native small islets are known to have a higher insulin secretion ability in vitro and to provide better transplantation outcomes when compared with large islets. In this study, we prepared microengineered pseudo-islets from dispersed rat islet cells using precisely-fabricated agarose gel-based microwells with different diameters (100, 300, or 500 μm) to investigate the function and survival of islet cell aggregates with well-controlled sizes. We observed that dead cells were rarely present in the small pseudo-islets with an average diameter of ∼60 μm prepared using 100 μm microwells. In contrast, we observed more dead cells in the larger pseudo-islets prepared using 300 and 500 μm microwells. The relative amount of hypoxic cells was significantly low in the small pseudo-islets whereas a hypoxic condition was present in the core region of the larger pseudo-islets. In addition, we found that the small-sized pseudo-islets reconstituted the in vivo-tissue like arrangement of the α and β cells, and restored the high insulin secretory capacity in response to high glucose. These results clearly suggest that precise size control of pseudo-islets is essential for maintaining islet cell function and survival in vitro. The small-sized pseudo-islets may be advantageous for providing a better therapeutic approach for treating type 1 diabetes mellitus via islet reorganization and transplantation.
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Affiliation(s)
- Yumie Ichihara
- Diabetes Center, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Rie Utoh
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
- Corresponding author at: Research Fellow of the Japan Society for the Promotion of Science (JSPS). Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1–33 Yayoi-cho, Inage-ku, Chiba 263–8522, Japan.Department of Applied Chemistry and BiotechnologyGraduate School of EngineeringChiba University1-33 Yayoi-choInage-kuChiba263-8522Japan
| | - Masumi Yamada
- Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
| | - Tatsuya Shimizu
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Yasuko Uchigata
- Diabetes Center, Tokyo Women's Medical University School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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Shalaly ND, Ria M, Johansson U, Åvall K, Berggren PO, Hedhammar M. Silk matrices promote formation of insulin-secreting islet-like clusters. Biomaterials 2016; 90:50-61. [PMID: 26986856 DOI: 10.1016/j.biomaterials.2016.03.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 02/26/2016] [Accepted: 03/01/2016] [Indexed: 11/29/2022]
Abstract
Ex vivo expansion of endocrine cells constitutes an interesting alternative to be able to match the unmet need of transplantable pancreatic islets. However, endocrine cells become fragile once removed from their extracellular matrix (ECM) and typically become senescent and loose insulin expression during conventional 2D culture. Herein we develop a protocol where 3D silk matrices functionalized with ECM-derived motifs are used for generation of insulin-secreting islet-like clusters from mouse and human primary cells. The obtained clusters were shown to attain an islet-like spheroid shape and to maintain functional insulin release upon glucose stimulation in vitro. Furthermore, in vivo imaging of transplanted murine clusters showed engraftment with increasing vessel formation during time. There was no sign of cell death and the clusters maintained or increased in size throughout the period, thus suggesting a suitable cluster size for transplantation.
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Affiliation(s)
- Nancy Dekki Shalaly
- Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden
| | - Massimiliano Ria
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, S-17176 Stockholm, Sweden
| | - Ulrika Johansson
- Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden
| | - Karin Åvall
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, S-17176 Stockholm, Sweden
| | - Per-Olof Berggren
- The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, S-17176 Stockholm, Sweden
| | - My Hedhammar
- Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, S-106 91 Stockholm, Sweden; Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, S-750 07 Uppsala, Sweden.
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Arnal-Pastor M, Martínez-Ramos C, Vallés-Lluch A, Pradas MM. Influence of scaffold morphology on co-cultures of human endothelial and adipose tissue-derived stem cells. J Biomed Mater Res A 2016; 104:1523-33. [DOI: 10.1002/jbm.a.35682] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 02/03/2016] [Accepted: 02/05/2016] [Indexed: 11/08/2022]
Affiliation(s)
- M. Arnal-Pastor
- Center for Biomaterials and Tissue Engineering; Universitat Politècnica de València; C. de Vera s/n Valencia 46022 Spain
| | - C. Martínez-Ramos
- Center for Biomaterials and Tissue Engineering; Universitat Politècnica de València; C. de Vera s/n Valencia 46022 Spain
| | - A. Vallés-Lluch
- Center for Biomaterials and Tissue Engineering; Universitat Politècnica de València; C. de Vera s/n Valencia 46022 Spain
| | - M. Monleón Pradas
- Center for Biomaterials and Tissue Engineering; Universitat Politècnica de València; C. de Vera s/n Valencia 46022 Spain
- Networking Research Center on Bioengineering; Biomaterials and Nanomedicine; Valencia Spain
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35
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Takahashi Y, Takebe T, Taniguchi H. Engineering pancreatic tissues from stem cells towards therapy. Regen Ther 2016; 3:15-23. [PMID: 31245468 PMCID: PMC6581807 DOI: 10.1016/j.reth.2016.01.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 12/17/2015] [Accepted: 01/20/2016] [Indexed: 12/20/2022] Open
Abstract
Pancreatic islet transplantation is performed as a potential treatment for type 1 diabetes mellitus. However, this approach is significantly limited due to the critical shortage of islet sources. Recently, a number of publications have developed protocols for directed β-cell differentiation of pluripotent cells, such as embryonic stem (ES) or induced pluripotent stem (iPS) cells. Decades of studies have led to the development of modified protocols that recapitulate molecular developmental cues by combining various growth factors and small molecules with improved efficiency. However, the later step of pancreatic differentiation into functional β-cells has yet to be satisfactory in vitro, highlighting alternative approach by recapitulating spatiotemporal multicellular interaction in three-dimensional (3D) culture. Here, we summarize recent progress in the directed differentiation into pancreatic β-cells with a focus on both two-dimensional (2D) and 3D differentiation settings. We also discuss the potential transplantation strategies in combination with current bioengineering approaches towards diabetes therapy.
Transplantation of stem cell derived pancreatic progenitors is a possible approach for generating mature β-cell in vivo. Promise of 3-D (or 4-D) culture has started to be explored by reconstituting pancreatic tissue structures. Self-condensation culture is a basic technique of integrating multiple heterotypic lineages including vasculatures. Bioengineering approach has been combined for developing effective transplant strategies.
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Key Words
- 2D, two-dimensional
- 3D, three-dimensional
- BMP, bone morphogenic protein
- Diabetes
- ES, embryonic stem
- FGF, fibroblast growth factors
- Heterotypic cellular interaction
- IBMIR, instant blood-mediated reaction
- ILV, indolactam V
- Ngn3, neurogenin 3
- PEG, polyethylene glycol
- PI3K, phosphatidylinositol-3 kinase
- PIPAAm, poly-N-isopropylacrylamide
- PVA, polyvinyl alcohol
- Pancreas
- Pdx1, pancreatic and duodenal homeobox 1
- Ptf1a, pancreatic transcription factor 1a
- Regenerative medicine
- VEGF, vascular endothelial growth factor
- Vascularization
- iPS, induced pluripotent stem
- iPS/ES cell
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Affiliation(s)
- Yoshinobu Takahashi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan
| | - Takanori Takebe
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan.,Advanced Medical Research Center, Yokohama City University, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan.,PRESTO, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi, Saitama, 332-0012, Japan.,Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH, 45229- 3039, USA
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan.,Advanced Medical Research Center, Yokohama City University, Kanazawa-ku 3-9, Yokohama, Kanagawa, 236-0004, Japan
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Matsushima H, Kuroki T, Adachi T, Kitasato A, Ono S, Tanaka T, Hirabaru M, Kuroshima N, Hirayama T, Sakai Y, Soyama A, Hidaka M, Takatsuki M, Kin T, Shapiro J, Eguchi S. Human Fibroblast Sheet Promotes Human Pancreatic Islet Survival and Function In Vitro. Cell Transplant 2016; 25:1525-1537. [PMID: 26877090 DOI: 10.3727/096368916x690854] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
In previous work, we engineered functional cell sheets using bone marrow-derived mesenchymal stem cells (BM-MSCs) to promote islet graft survival. In the present study, we hypothesized that a cell sheet using dermal fibroblasts could be an alternative to MSCs, and then we aimed to evaluate the effects of this cell sheet on the functional viability of human islets. Fibroblast sheets were fabricated using temperature-responsive culture dishes. Human islets were seeded onto fibroblast sheets. The efficacy of the fibroblast sheets was evaluated by dividing islets into three groups: the islets-alone group, the coculture with fibroblasts group, and the islet culture on fibroblast sheet group. The ultrastructure of the islets cultured on each fibroblast sheet was examined by electron microscopy. The fibroblast sheet expression of fibronectin (as a component of the extracellular matrix) was quantified by Western blotting. After 3 days of culture, islet viabilities were 70.2 ± 9.8%, 87.4 ± 5.8%, and 88.6 ± 4.5%, and survival rates were 60.3 ± 6.8%, 65.3 ± 3.0%, and 75.8 ± 5.6%, respectively. Insulin secretions in response to high-glucose stimulation were 5.1 ± 1.6, 9.4 ± 3.8, and 23.5 ± 12.4 µIU/islet, and interleukin-6 (IL-6) secretions were 3.0 ± 0.7, 5.1 ± 1.2, and 7.3 ± 1.0 ng/day, respectively. Islets were found to incorporate into the fibroblast sheets while maintaining a three-dimensional structure and well-preserved extracellular matrix. The fibroblast sheets exhibited a higher expression of fibronectin compared to fibroblasts alone. In conclusion, human dermal fibroblast sheets fabricated by tissue-engineering techniques could provide an optimal substrate for human islets, as a source of cytokines and extracellular matrix.
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Affiliation(s)
- Hajime Matsushima
- Department of Surgery, Nagasaki University, Graduate School of Biomedical Sciences, Sakamoto, Nagasaki, Japan
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Amagai Y, Karasawa K, Kyungsook J, Matsuda A, Kojima M, Watanabe J, Hibi T, Matsuda H, Tanaka A. Development of a novel carrier optimized for cell sheet transplantation. BIOMATTER 2015; 5:e1027846. [PMID: 25869322 PMCID: PMC4581122 DOI: 10.1080/21592535.2015.1027846] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Tissue engineering is a rapidly advancing technology in the field of regenerative medicine. For the transplantation of cell sheets, a carrier must maintain the shape of a cell sheet from a culture dish to affected sites as well as release the sheet easily onto the lesion. In this study, we examined the utility of a novel, poly(lactic acid)-based carrier for cell sheets transplantation to the cornea of dogs and the skin of rats. The poly(lactic acid)-based carrier easily picked a cell sheet up from the dish, fit to the shape of the transplantation sites, and saved time for cell sheets detachment comparing to a conventional carrier. Thus, the poly(lactic acid)-based carrier would be useful for easy cell sheet transplantations.
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Affiliation(s)
- Yosuke Amagai
- a Cooperative Major in Advanced Health Science; Graduate School of Bio-Applications and System Engineering; Laboratories of
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Hanayama H, Ohashi K, Utoh R, Shimizu H, Ise K, Sakurai F, Mizuguchi H, Tsuchiya H, Okano T, Gotoh M. Efficient Gene Transduction of Dispersed Islet Cells in Culture Using Fiber-Modified Adenoviral Vectors. CELL MEDICINE 2015; 8:31-8. [PMID: 26858906 DOI: 10.3727/215517915x689083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
To establish novel islet-based therapies, our group has recently developed technologies for creating functional neo-islet tissues in the subcutaneous space by transplanting monolithic sheets of dispersed islet cells (islet cell sheets). Improving cellular function and viability are the next important challenges for enhancing the therapeutic effects. This article describes the adenoviral vector-mediated gene transduction of dispersed islet cells under culture conditions. Purified pancreatic islets were obtained from Lewis rats and dissociated into single islet cells. Cells were plated onto laminin-5-coated temperature-responsive polymer poly(N-isopropylacrylamide)-immobilized plastic dishes. At 0 h, islet cells were infected for 1 h with either conventional type 5 adenoviral vector (Ad-CA-GFP) or fiber-modified adenoviral vector (AdK7-CA-GFP) harboring a polylysine (K7) peptide in the C terminus of the fiber knob. We investigated gene transduction efficiency at 48 h after infection and found that AdK7-CA-GFP yielded higher transduction efficiencies than Ad-CA-GFP at a multiplicity of infection (MOI) of 5 and 10. For AdK7-CA-GFP at MOI = 10, 84.4 ± 1.5% of islet cells were found to be genetically transduced without marked vector infection-related cellular damage as determined by viable cell number and lactate dehydrogenase (LDH) release assay. After AdK7-CA-GFP infection at MOI = 10, cells remained attached and expanded to nearly full confluency, showing that this adenoviral infection protocol is a feasible approach for creating islet cell sheets. We have shown that dispersed and cultured islet cells can be genetically modified efficiently using fiber-modified adenoviral vectors. Therefore, this gene therapy technique could be used for cellular modification or biological assessment of dispersed islet cells.
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Affiliation(s)
- Hiroyuki Hanayama
- Department of Regenerative Surgery, Fukushima Medical University , Hikarigaoka, Fukushima , Japan
| | - Kazuo Ohashi
- † iPS Cell-based Projects on Cell Transplantation and Cell Dynamics, Graduate School of Pharmaceutical Sciences, Osaka University , Suita, Osaka , Japan
| | - Rie Utoh
- ‡ Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University , Shinjuku, Tokyo , Japan
| | - Hirofumi Shimizu
- Department of Regenerative Surgery, Fukushima Medical University , Hikarigaoka, Fukushima , Japan
| | - Kazuya Ise
- Department of Regenerative Surgery, Fukushima Medical University , Hikarigaoka, Fukushima , Japan
| | - Fuminori Sakurai
- § Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University , Suita, Osaka , Japan
| | - Hiroyuki Mizuguchi
- § Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University , Suita, Osaka , Japan
| | - Hiroyuki Tsuchiya
- † iPS Cell-based Projects on Cell Transplantation and Cell Dynamics, Graduate School of Pharmaceutical Sciences, Osaka University , Suita, Osaka , Japan
| | - Teruo Okano
- ‡ Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University , Shinjuku, Tokyo , Japan
| | - Mitsukazu Gotoh
- Department of Regenerative Surgery, Fukushima Medical University , Hikarigaoka, Fukushima , Japan
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Abstract
Tissue engineering aims at developing the necessary technological strategies for replacement or regeneration tissues. However, the number of cells required is much greater than the number obtained from a cell source. Expanding the cells' number in cell culture for a long period is required until the necessary amount of cells is obtained. While in culture, cells often go unwanted differentiation. Little attention has been given to the use of proteolytic enzymes in cell passage. Review the importance of extracellular matrix and surface proteins for cell behavior and the possible mechanisms of cellular changes that may occur due to the use of proteolytic enzymes is an essential issue. Possible alternative to replace these enzymes in cell passage has also been developed.
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Chuah YJ, Zhang Y, Wu Y, Menon NV, Goh GH, Lee AC, Chan V, Zhang Y, Kang Y. Combinatorial effect of substratum properties on mesenchymal stem cell sheet engineering and subsequent multi-lineage differentiation. Acta Biomater 2015; 23:52-62. [PMID: 26026305 DOI: 10.1016/j.actbio.2015.05.023] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 05/12/2015] [Accepted: 05/21/2015] [Indexed: 10/23/2022]
Abstract
Cell sheet engineering has been exploited as an alternative approach in tissue regeneration and the use of stem cells to generate cell sheets has further showed its potential in stem cell-mediated tissue regeneration. There exist vast interests in developing strategies to enhance the formation of stem cell sheets for downstream applications. It has been proved that stem cells are sensitive to the biophysical cues of the microenvironment. Therefore we hypothesized that the combinatorial substratum properties could be tailored to modulate the development of cell sheet formation and further influence its multipotency. For validation, polydimethylsiloxane (PDMS) of different combinatorial substratum properties (including stiffness, roughness and wettability) were created, on which the human bone marrow derived mesenchymal stem cells (BMSCs) were cultured to form cell sheets with their multipotency evaluated after induced differentiation. The results showed that different combinatorial effects of these substratum properties were able to influence BMSC behavior such as adhesion, spreading and proliferation during cell sheet development. Collagen formation within the cell sheet was enhanced on substrates with lower stiffness, higher hydrophobicity and roughness, which further assisted the induced chondrogenesis and osteogenesis, respectively. These findings suggested that combinatorial substratum properties had profound effects on BMSC cell sheet integrity and multipotency, which had significant implications for future biomaterials and scaffold designs in the field of BMSC-mediated tissue regeneration.
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Yamashita S, Ohashi K, Utoh R, Okano T, Yamamoto M. Human Laminin Isotype Coating for Creating Islet Cell Sheets. CELL MEDICINE 2015; 8:39-46. [PMID: 26858907 DOI: 10.3727/215517915x689029] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Our experimental approach toward the development of new islet-based treatment for diabetes mellitus has been the creation of a monolayered islet cell construct (islet cell sheet), followed by its transplantation into a subcutaneous pocket. Previous studies describe rat laminin-5 (chain composition: α3, β3, γ2) as a suitable extracellular matrix (ECM) for surfaces comprised of a coated temperature-responsive polymer, poly(N-isopropylacrylamide) (PIPAAm). To progress toward the clinical application of this approach, the present study attempted to identify an optimal human ECM as a coating material on PIPAAm surfaces, which allowed islet cells to attach on the surfaces and subsequently to be harvested as a monolithic cell sheet. Dispersed rat islet cells were seeded onto PIPAAm dishes coated with various human laminin isotypes: human laminin (HL)-211, HL-332, HL-411, HL-511, and HL-placenta. Plating efficiency at day 1, the confluency at day 3, and glucose-stimulated insulin secretion test at day 3 were performed. The highest value of plating efficiency was found in the HL-332-PIPAAm group (83.1 ± 0.7%). The HL-332-PIPAAm group also showed the highest cellular confluency (98.6 ± 0.5%). Islet cells cultured on the HL-332-PIPAAm surfaces showed a positive response in the glucose-stimulated insulin secretion test. By reducing culture temperature from 37°C to 20°C in the HL-332-PIPAAm group, cells were able to be harvested as a monolithic islet sheet. The present study showed that HL-332 was an optimal human-derived ECM on a PIPAAm coating for preparing islet cell sheets.
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Affiliation(s)
- Shingo Yamashita
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan; †Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan
| | - Kazuo Ohashi
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan; †Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan; ‡iPS Cell-based Projects on Cell Transplantation and Cell Dynamics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
| | - Rie Utoh
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University , Shinjuku-ku, Tokyo , Japan
| | - Teruo Okano
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University , Shinjuku-ku, Tokyo , Japan
| | - Masakazu Yamamoto
- † Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University , Shinjuku-ku, Tokyo , Japan
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Age-related decline in the matrix contents and functional properties of human periodontal ligament stem cell sheets. Acta Biomater 2015; 22:70-82. [PMID: 25922305 DOI: 10.1016/j.actbio.2015.04.024] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 04/16/2015] [Accepted: 04/19/2015] [Indexed: 02/08/2023]
Abstract
In this study, periodontal ligament (PDL) stem cells (PDLSCs) derived from different-aged donors were used to evaluate the effect of aging on cell sheet formation. The activity of PDLSCs was first determined based on their colony-forming ability, surface markers, proliferative/differentiative potentials, senescence-associated β-galactosidase (SA-βG) staining, and expression of pluripotency-associated transcription factors. The ability of these cells to form sheets, based on their extracellular matrix (ECM) contents and their functional properties necessary for osteogenic differentiation, was evaluated to predict the age-related changes in the regenerative capacity of the cell sheets in their further application. It was found that human PDLSCs could be isolated from the PDL tissue of different-aged subjects. However, the ability of the PDLSCs to proliferate and to undergo osteogenic differentiation and their expression of pluripotency-associated transcription factors displayed age-related decreases. In addition, these cells exhibited an age-related increase in SA-βG expression. Aged cells showed an impaired ability to form functional cell sheets, as determined by morphological observations and Ki-67 immunohistochemistry staining. Based on the production of ECM proteins, such as fibronectin, integrin β1, and collagen type I; alkaline phosphatase (ALP) activity; and the expression of osteogenic genes, such as ALP, Runt-related transcription factor 2, and osteocalcin, cell sheets formed by PDLSCs derived from older donors demonstrated a less potent osteogenic capacity compared to those formed by PDLSCs from younger donors. Our data suggest that the age-associated decline in the matrix contents and osteogenic properties of PDLSC sheets should be taken into account in cell sheet engineering research and clinical periodontal regenerative therapy.
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Hirabaru M, Kuroki T, Adachi T, Kitasato A, Ono S, Tanaka T, Matsushima H, Sakai Y, Soyama A, Hidaka M, Yamanouchi K, Takatsuki M, Okano T, Eguchi S. A Method for Performing Islet Transplantation Using Tissue-Engineered Sheets of Islets and Mesenchymal Stem Cells. Tissue Eng Part C Methods 2015; 21:1205-15. [PMID: 26066973 DOI: 10.1089/ten.tec.2015.0035] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are known to have a protective effect on islet cells. Cell sheets developed using tissue engineering help maintain the function of the cells themselves. This study describes a tissue engineering approach using islets with MSC sheets to improve the therapeutic effect of islet transplantation. MSCs were obtained from Fischer 344 rats and engineered into cell sheets using temperature-responsive culture dishes. The islets obtained from Fischer 344 rats were seeded onto MSC sheets, and the islets with MSC sheets were harvested by low-temperature treatment after coculture. The functional activity of the islets with MSC sheets was confirmed by a histological examination, insulin secretion assay, and quantification of the levels of cytokines. The therapeutic effects of the islets with MSC sheets were investigated by transplanting the sheets at subcutaneous sites in severe combined immunodeficiency (SCID) mice with streptozotocin-induced diabetes. Improvement of islet function and viability was shown in situ on the MSC sheet, and the histological examination showed that the MSC sheet maintained adhesion factor on the surface. In the recipient mice, normoglycemia was maintained for at least 84 days after transplantation, and neovascularization was observed. These results demonstrated that islet transplantation in a subcutaneous site would be possible by using the MSC sheet as a scaffold for islets.
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Affiliation(s)
- Masataka Hirabaru
- 1 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan
| | - Tamotsu Kuroki
- 1 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan
| | - Tomohiko Adachi
- 1 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan
| | - Amane Kitasato
- 1 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan
| | - Shinichiro Ono
- 1 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan
| | - Takayuki Tanaka
- 1 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan
| | - Hajime Matsushima
- 1 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan
| | - Yusuke Sakai
- 1 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan
| | - Akihiko Soyama
- 1 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan
| | - Masaaki Hidaka
- 1 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan
| | - Kosho Yamanouchi
- 1 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan
| | - Mitsuhisa Takatsuki
- 1 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan
| | - Teruo Okano
- 2 Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University , Shinjuku, Tokyo, Japan
| | - Susumu Eguchi
- 1 Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences , Nagasaki, Japan
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Yasotharan S, Pinto S, Sled JG, Bolz SS, Günther A. Artery-on-a-chip platform for automated, multimodal assessment of cerebral blood vessel structure and function. LAB ON A CHIP 2015; 15:2660-9. [PMID: 25990299 DOI: 10.1039/c5lc00021a] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Abstract
We present a compact microfluidic platform for the automated, multimodal assessment of intact small blood vessels. Mouse olfactory artery segments were reversibly loaded onto a microfluidic device and kept under physiological (i.e., close to in vivo) environmental conditions. For immunohistochemical endpoint protein analysis, automated on chip fixation and staining of the artery eliminated the need for any subsequent tissue sectioning or processing outside the chip. In a first case study, we demonstrate the blood vessel abluminal structure based on the positions of smooth muscle cell nuclei, actin filaments and voltage gated calcium channels. In a second case study we incubated smooth muscle cells (SMCs) with a calcium-sensitive dye to simultaneously assess time-dependent, agonist-induced calcium and diameter changes of pressurized resistance arteries. We expect the presented microfluidic platform to promote routine on-chip staining and quantitative fluorescence imaging of intact blood vessels from different vascular beds, tissue engineered vascular constructs and vascularized microtissues. The at least tenfold reduction in required aliquot volumes for functional assessment and staining was achieved by on-board fluid manipulation of the syringe-pump free platform and may promote its applications for screening of newly synthesized compounds.
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Affiliation(s)
- Sanjesh Yasotharan
- Department of Mechanical and Industrial Engineering, University of Toronto, 5 King's College Road, Toronto, Ontario M5S3G8, Canada.
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45
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Re-engineering islet cell transplantation. Pharmacol Res 2015; 98:76-85. [PMID: 25814189 DOI: 10.1016/j.phrs.2015.02.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 02/23/2015] [Accepted: 02/23/2015] [Indexed: 12/12/2022]
Abstract
We are living exciting times in the field of beta cell replacement therapies for the treatment of diabetes. While steady progress has been recorded thus far in clinical islet transplantation, novel approaches are needed to make cell-based therapies more reproducible and leading to long-lasting success. The multiple facets of diabetes impose the need for a transdisciplinary approach to attain this goal, by targeting immunity, promoting engraftment and sustained functional potency. We discuss herein the emerging technologies applied to this rapidly evolving field.
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46
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Guo P, Zeng JJ, Zhou N. A novel experimental study on the fabrication and biological characteristics of canine bone marrow mesenchymal stem cells sheet using vitamin C. SCANNING 2015; 37:42-48. [PMID: 25588682 DOI: 10.1002/sca.21177] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2014] [Revised: 10/07/2014] [Accepted: 10/31/2014] [Indexed: 06/04/2023]
Abstract
The aim of this study was to fabricate canine bone marrow mesenchymal stem cell sheet through the use of vitamin C, to identify the biological characteristics of the resulting cell sheets, and to reveal the potential mechanism of cell-sheet promotion by vitamin C. This study used vitamin C to induce bone marrow mesenchymal stem cells to proliferate. The resulting cells secreted large amounts of collagen, thereby shortening the construction time of the cell-sheet layer. In addition to these aims, we identified biological microcharacteristics of the cell sheet through histological observation, transmission electron microscopy, real-time PCR detection, immunohistochemical detection, and osteogenesis-induction experiments on the cell sheet. We were able to stably and rapidly construct bone marrow mesenchymal stem cell sheet, effectively harvest it, and transfer the seed cells for tissue engineering. This study indicates that the use of vitamin C for harvesting mesenchymal stem cell sheets from bone marrow may provide an easy and practical approach for bone tissue regeneration.
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Affiliation(s)
- Peng Guo
- College of Stomatology, GuangXi Mediceal University, Nanning Guangxi, China
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47
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Muntimadugu E, Jain A, Khan W. Stimuli Responsive Carriers: Magnetically, Thermally and pH Assisted Drug Delivery. ADVANCES IN DELIVERY SCIENCE AND TECHNOLOGY 2015. [DOI: 10.1007/978-3-319-11355-5_10] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
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Abstract
Ultimately much work remains to be done in the companion fields of biomaterials and stem cells. Nonetheless, the monumental progress in TE that has been reported in the studies summarized here demonstrates that regenerative approaches to problems in general surgery need to be explored in more depth. Furthermore, the surgical disciplines of reconstruction and transplantation need to recognize their research counterparts in TE, given its potential to actualize freedom from immunosuppression, one of the most elusive goals in modern surgery. The engineering and proliferation of autologous cells, tissues, and organs ex vivo before surgical operation can significantly reduce the obstacles current practitioners are intimately familiar with: donor site morbidity and immunologic rejection. Therefore, in addition to the truly exciting research and development prospects and implications for the commercial sector, patients with end-stage diseases and debilitating injury stand to gain the most from clinically adapted TE therapies.
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Tang Z, Okano T. Recent development of temperature-responsive surfaces and their application for cell sheet engineering. Regen Biomater 2014; 1:91-102. [PMID: 26816628 PMCID: PMC4669004 DOI: 10.1093/rb/rbu011] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 08/29/2014] [Accepted: 08/30/2014] [Indexed: 12/16/2022] Open
Abstract
Cell sheet engineering, which fabricates sheet-like tissues without biodegradable scaffolds, has been proposed as a novel approach for tissue engineering. Cells have been cultured and proliferate to confluence on a temperature-responsive cell culture surface at 37°C. By decreasing temperature to 20°C, an intact cell sheet can be harvested from the culture surface without enzymatic treatment. This new approach enables cells to keep their cell–cell junction, cell surface proteins and extracellular matrix. Therefore, recovered cell sheet can be easily not only transplanted to host tissue, but also constructed a three-dimensional (3D) tissue by layering cell sheets. Moreover, cell sheet manipulation technology and bioreactor have been combined with the cell sheet technology to fabricate a complex and functional 3D tissue in vitro. So far, cell sheet technology has been applied in regenerative medicine for several tissues, and a number of clinical studies have been performed. In this review, recent advances in the preparation of temperature-responsive cell culture surface, the fabrication of organ-like tissue and the clinical application of cell sheet engineering are summarized and discussed.
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Affiliation(s)
- Zhonglan Tang
- Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Teruo Okano
- Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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Abstract
In addition to stem cell biology, tissue engineering is an essential research field for regenerative medicine. In contrast to cell injection, bioengineered tissue transplantation minimizes cell loss and has the potential to repair tissue defects. A popular approach is scaffold-based tissue engineering, which utilizes a biodegradable polymer scaffold for seeding cells; however, new techniques of cell sheet-based tissue engineering have been developed. Cell sheets are harvested from temperature-responsive culture dishes by simply lowering the temperature. Monolayer or stacked cell sheets are transplantable directly onto damaged tissues and cell sheet transplantation has already been clinically applied. Cardiac cell sheet stacking produces pulsatile heart tissue; however, lack of vasculature limits the viable tissue thickness to 3 layers. Multistep transplantation of triple-layer cardiac cell sheets cocultured with endothelial cells has been used to form thick vascularized cardiac tissue in vivo. Furthermore, in vitro functional blood vessel formation within 3-dimensional (3D) tissues has been realized by successfully imitating in vivo conditions. Triple-layer cardiac cell sheets containing endothelial cells were layered on vascular beds and the constructs were media-perfused using novel bioreactor systems. Interestingly, cocultured endothelial cells migrate into the vascular beds and form perfusable blood vessels. An in vitro multistep procedure has also enabled the fabrication of thick, vascularized heart tissues. Cell sheet-based tissue engineering has revealed great potential to fabricate 3D cardiac tissues and should contribute to future treatment of severe heart diseases and human tissue model production.
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Affiliation(s)
- Tatsuya Shimizu
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University
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