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Bobrova M, Safonova L, Efimov A, Lyundup A, Mozheiko N, Agapova O, Agapov I. Scaffolds Based on Silk Fibroin with Decellularized Rat Liver Microparticles: Investigation of the Structure, Biological Properties and Regenerative Potential for Skin Wound Healing. Pharmaceutics 2022; 14:2313. [PMID: 36365132 PMCID: PMC9693194 DOI: 10.3390/pharmaceutics14112313] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/19/2022] [Accepted: 10/25/2022] [Indexed: 10/18/2023] Open
Abstract
The development of advanced biomaterials and constructs for accelerated recovery of damaged tissues is a key direction in regenerative medicine. Biocompatible scaffolds based on natural biopolymers are widely used for these tasks. Organ decellularization enables obtaining a cell-free extracellular matrix (ECM) with preserved composition and biological activity. The objectives of the present work were combining these two approaches for the development of a composite scaffold based on silk fibroin and ECM microparticles and assessing its structure, biological properties, and regenerative potential. ECM microparticles were obtained by grinding the decellularized matrix of Wistar rat liver in liquid nitrogen. Scaffolds in the form of films were prepared by the casting method. The sinuous and rough topography of the scaffold surface was assessed by the scanning probe nanotomography (SPNT) technique. The inclusion of ECM microparticles in the composition did not affect the elasticity and tensile strength of the scaffolds. The obtained scaffold was non-toxic to cells, maintained high levels of adhesion and proliferation of mouse 3T3 fibroblast and Hep-G2 cells, and showed high regenerative potential, which was studied in the experimental model of full-thickness rat skin wound healing. The wound healing was accelerated by 1.74 times in comparison with the control.
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Affiliation(s)
- Maria Bobrova
- Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs, Ministry of Health of the Russian Federation, 1 Shchukinskaya Street, 123182 Moscow, Russia
| | - Liubov Safonova
- Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs, Ministry of Health of the Russian Federation, 1 Shchukinskaya Street, 123182 Moscow, Russia
| | - Anton Efimov
- Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs, Ministry of Health of the Russian Federation, 1 Shchukinskaya Street, 123182 Moscow, Russia
| | - Alexey Lyundup
- Educational Resource Center for Cellular Technologies, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia
| | - Natalya Mozheiko
- Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs, Ministry of Health of the Russian Federation, 1 Shchukinskaya Street, 123182 Moscow, Russia
| | - Olga Agapova
- Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs, Ministry of Health of the Russian Federation, 1 Shchukinskaya Street, 123182 Moscow, Russia
| | - Igor Agapov
- Academician V.I. Shumakov National Medical Research Center of Transplantology and Artificial Organs, Ministry of Health of the Russian Federation, 1 Shchukinskaya Street, 123182 Moscow, Russia
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2
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Aravalli RN. Generating liver using blastocyst complementation: Opportunities and challenges. Xenotransplantation 2020; 28:e12668. [PMID: 33372360 DOI: 10.1111/xen.12668] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/05/2020] [Accepted: 11/26/2020] [Indexed: 12/28/2022]
Abstract
Orthotopic liver transplantation (OLT) is the only definitive treatment option for many patients with end-stage liver disease. Current supply of donor livers for OLT is not keeping up with the growing demand. To overcome this problem, a number of experimental strategies have been developed either to provide a bridge to transplant for patients on the waiting list or to bioengineer whole livers for OLT by replenishing them with fresh supplies of hepatic cells. In recent years, blastocyst complementation has emerged as the most promising approach for generating whole organs and, in combination with gene editing technology, it has revolutionized regenerative medicine. This methodology was successful in producing xenogeneic organs in animal hosts. Blastocyst complementation has the potential to produce whole livers in large animals that could be xenotransplanted in humans, thereby reducing the shortage of livers for OLT. However, significant experimental and ethical barriers remain for the production of human livers in domestic animals, such as the pig. This review summarizes the current knowledge and provides future perspectives for liver xenotransplantation in humans.
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Affiliation(s)
- Rajagopal N Aravalli
- Department of Electrical and Computer Engineering, College of Science and Engineering, University of Minnesota, Minneapolis, MN, USA
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3
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Huang X, Lee F, Teng Y, Lingam CB, Chen Z, Sun M, Song Z, Balachander GM, Leo HL, Guo Q, Shah I, Yu H. Sequential drug delivery for liver diseases. Adv Drug Deliv Rev 2019; 149-150:72-84. [PMID: 31734169 DOI: 10.1016/j.addr.2019.11.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 11/03/2019] [Accepted: 11/04/2019] [Indexed: 12/12/2022]
Abstract
The liver performs critical physiological functions such as metabolism/detoxification and blood homeostasis/biliary excretion. A high degree of blood access means that a drug's resident time in any cell is relatively short. This short drug exposure to cells requires local sequential delivery of multiple drugs for optimal efficacy, potency, and safety. The high metabolism and excretion of drugs also impose both technical challenges and opportunities to sequential drug delivery. This review provides an overview of the sequential events in liver regeneration and the related liver diseases. Using selected examples of liver cancer, hepatitis B viral infection, fatty liver diseases, and drug-induced liver injury, we highlight efforts made for the sequential delivery of small and macromolecular drugs through different biomaterials, cells, and microdevice-based delivery platforms that allow fast delivery kinetics and rapid drug switching. As this is a nascent area of development, we extrapolate and compare the results with other sequential drug delivery studies to suggest possible application in liver diseases, wherever appropriate.
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Affiliation(s)
- Xiaozhong Huang
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore
| | - Fan Lee
- Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore
| | - Yao Teng
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore
| | - Corey Bryen Lingam
- Department of Biomedical Engineering, National University of Singapore, Engineering Drive 3, Engineering Block 4, #04-08, Singapore 117583, Singapore
| | - Zijian Chen
- Department of Biomedical Engineering, National University of Singapore, Engineering Drive 3, Engineering Block 4, #04-08, Singapore 117583, Singapore; Department of Biomedical Engineering, Southern University of Science and Technology, 1088 Xueyuan Avenue, Shenzhen 518055, China
| | - Min Sun
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Ziwei Song
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore
| | - Gowri M Balachander
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore
| | - Hwa Liang Leo
- Department of Biomedical Engineering, National University of Singapore, Engineering Drive 3, Engineering Block 4, #04-08, Singapore 117583, Singapore
| | - Qiongyu Guo
- Department of Biomedical Engineering, Southern University of Science and Technology, 1088 Xueyuan Avenue, Shenzhen 518055, China
| | - Imran Shah
- National Center for Computational Toxicology, United States Environmental Protection Agency, 4930 Old Page Rd., Durham, NC 27703, USA
| | - Hanry Yu
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD9-04-11, 2 Medical Drive, Singapore 117593, Singapore; Institute of Bioengineering and Nanotechnology, A*STAR, The Nanos, #06-01, 31 Biopolis Way, Singapore 138669, Singapore; Mechanobiology Institute, National University of Singapore, T-Lab, #05-01, 5A Engineering Drive 1, Singapore 117411, Singapore; CAMP, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Level 4 Enterprise Wing, Singapore 138602, Singapore; Gastroenterology Department, Southern Medical University, Guangzhou 510515, China.
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4
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Crane AT, Aravalli RN, Asakura A, Grande AW, Krishna VD, Carlson DF, Cheeran MCJ, Danczyk G, Dutton JR, Hackett PB, Hu WS, Li L, Lu WC, Miller ZD, O'Brien TD, Panoskaltsis-Mortari A, Parr AM, Pearce C, Ruiz-Estevez M, Shiao M, Sipe CJ, Toman NG, Voth J, Xie H, Steer CJ, Low WC. Interspecies Organogenesis for Human Transplantation. Cell Transplant 2019; 28:1091-1105. [PMID: 31426664 PMCID: PMC6767879 DOI: 10.1177/0963689719845351] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Blastocyst complementation combined with gene editing is an emerging approach in the
field of regenerative medicine that could potentially solve the worldwide problem of organ
shortages for transplantation. In theory, blastocyst complementation can generate fully
functional human organs or tissues, grown within genetically engineered livestock animals.
Targeted deletion of a specific gene(s) using gene editing to cause deficiencies in organ
development can open a niche for human stem cells to occupy, thus generating human
tissues. Within this review, we will focus on the pancreas, liver, heart, kidney, lung,
and skeletal muscle, as well as cells of the immune and nervous systems. Within each of
these organ systems, we identify and discuss (i) the common causes of organ failure; (ii)
the current state of regenerative therapies; and (iii) the candidate genes to knockout and
enable specific exogenous organ development via the use of blastocyst complementation. We
also highlight some of the current barriers limiting the success of blastocyst
complementation.
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Affiliation(s)
- Andrew T Crane
- Department of Neurosurgery, University of Minnesota, Minneapolis, USA
| | - Rajagopal N Aravalli
- Department of Electrical and Computer Engineering, University of Minnesota, Minneapolis, USA
| | - Atsushi Asakura
- Stem Cell Institute, University of Minnesota, Minneapolis, USA.,Department of Neurology, University of Minnesota, Minneapolis, USA
| | - Andrew W Grande
- Department of Neurosurgery, University of Minnesota, Minneapolis, USA
| | | | | | - Maxim C-J Cheeran
- Department of Veterinary Population Medicine, University of Minnesota, St. Paul, USA
| | - Georgette Danczyk
- Department of Neurosurgery, University of Minnesota, Minneapolis, USA
| | - James R Dutton
- Stem Cell Institute, University of Minnesota, Minneapolis, USA.,Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, USA
| | - Perry B Hackett
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, USA
| | - Wei-Shou Hu
- Department of Chemical Engineering and Material Science, University of Minnesota, Minneapolis, USA
| | - Ling Li
- Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, USA
| | - Wei-Cheng Lu
- Department of Neurosurgery, University of Minnesota, Minneapolis, USA
| | - Zachary D Miller
- Department of Neurosurgery, University of Minnesota, Minneapolis, USA
| | - Timothy D O'Brien
- Stem Cell Institute, University of Minnesota, Minneapolis, USA.,Department of Veterinary Population Medicine, University of Minnesota, St. Paul, USA
| | | | - Ann M Parr
- Department of Neurosurgery, University of Minnesota, Minneapolis, USA.,Stem Cell Institute, University of Minnesota, Minneapolis, USA
| | - Clairice Pearce
- Department of Neurosurgery, University of Minnesota, Minneapolis, USA
| | | | - Maple Shiao
- Department of Neurosurgery, University of Minnesota, Minneapolis, USA
| | | | - Nikolas G Toman
- Department of Neurosurgery, University of Minnesota, Minneapolis, USA
| | - Joseph Voth
- Department of Neurosurgery, University of Minnesota, Minneapolis, USA
| | - Hui Xie
- Department of Neurosurgery, University of Minnesota, Minneapolis, USA
| | - Clifford J Steer
- Stem Cell Institute, University of Minnesota, Minneapolis, USA.,Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, USA.,Department of Medicine, University of Minnesota, Minneapolis, USA
| | - Walter C Low
- Department of Neurosurgery, University of Minnesota, Minneapolis, USA.,Stem Cell Institute, University of Minnesota, Minneapolis, USA
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5
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Ye S, Boeter JWB, Penning LC, Spee B, Schneeberger K. Hydrogels for Liver Tissue Engineering. Bioengineering (Basel) 2019; 6:E59. [PMID: 31284412 PMCID: PMC6784004 DOI: 10.3390/bioengineering6030059] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 06/28/2019] [Accepted: 07/03/2019] [Indexed: 12/14/2022] Open
Abstract
Bioengineered livers are promising in vitro models for drug testing, toxicological studies, and as disease models, and might in the future be an alternative for donor organs to treat end-stage liver diseases. Liver tissue engineering (LTE) aims to construct liver models that are physiologically relevant. To make bioengineered livers, the two most important ingredients are hepatic cells and supportive materials such as hydrogels. In the past decades, dozens of hydrogels have been developed to act as supportive materials, and some have been used for in vitro models and formed functional liver constructs. However, currently none of the used hydrogels are suitable for in vivo transplantation. Here, the histology of the human liver and its relationship with LTE is introduced. After that, significant characteristics of hydrogels are described focusing on LTE. Then, both natural and synthetic materials utilized in hydrogels for LTE are reviewed individually. Finally, a conclusion is drawn on a comparison of the different hydrogels and their characteristics and ideal hydrogels are proposed to promote LTE.
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Affiliation(s)
- Shicheng Ye
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Jochem W B Boeter
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Louis C Penning
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Bart Spee
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Kerstin Schneeberger
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands.
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6
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Intrasplenic Transplantation of Cytotoxic T-Lymphocyte Associated Protein 4-Fas Ligand--Modified Hepatic Oval Cells for Acute Liver Injury in Rats. Transplant Proc 2019; 51:942-950. [PMID: 30979487 DOI: 10.1016/j.transproceed.2019.01.060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 12/19/2018] [Accepted: 01/17/2019] [Indexed: 11/20/2022]
Abstract
BACKGROUND Intrasplenic transplantation of xenogeneic hepatic oval cells (HOCs) may provide metabolic support for acute liver injury. However, xenoreactive lymphocyte-mediated immune response hinders HOCs' survival in the xeno-spleen parenchyma. Cytotoxic T-lymphocyte associated protein 4-Fas ligand (CTLA4.FasL), a fusion product integrating 2 inhibitory elements against lymphocytes into 1 molecule, effectively inhibited the proliferation of allogeneic and autoimmune lymphocytes. The purpose of this study was to explore the effect of CTLA4.FasL on the proliferation of xenoreactive lymphocytes and evaluate the therapeutic efficacy of CTLA4.FasL-modified HOC transplantation on acute liver injury in rats. METHODS The effect of CTLA4.FasL-modified mouse liver epithelial progenitor cells (CTLA4.FasL-LEPCs) on the proliferation of rat lymphocytes in xeno-mixed lymphocyte reaction was investigated. Furthermore, CTLA4.FasL-LEPCs were intrasplenically transplanted in carbon tetrachloride- and partial hepatectomy-treated rats, and the therapeutic effect was evaluated using hematoxylin and eosin staining and alanine aminotransferase and aspartate aminotransferase assays. The hepatocytic differentiation of CTLA4.FasL-LEPCs in xenogeneic spleen was monitored by immunohistochemical staining for albumin. RESULTS In xeno-mixed lymphocyte reaction, CTLA4.FasL-LEPCs substantially inhibited the rat lymphocytes proliferation. CTLA4.FasL-LEPC transplantation significantly ameliorated liver injury compared with mCherry-modified LEPC and LEPC transplantation, as assessed by hematoxylin and eosin staining, alanine aminotransferase, and aspartate aminotransferase assays. Albumin positive cells appeared only in CTLA4.FasL-LEPCs group, but not in the mCherry-modified LEPCs group and LEPCs group. CONCLUSIONS Our results indicate CTLA4.FasL-LEPCs substantially improved liver function and structure in carbon tetrachloride- and partial hepatectomy-induced acute liver injury rats through long-term hepatocytic differentiation.
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7
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Gong W, Cheng T, Liu Q, Xiao Q, Li J. Surgical repair of abdominal wall defect with biomimetic nano/microfibrous hybrid scaffold. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2018; 93:828-837. [DOI: 10.1016/j.msec.2018.08.053] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 07/10/2018] [Accepted: 08/27/2018] [Indexed: 01/10/2023]
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8
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Patel P, Okoronkwo N, Pyrsopoulos NT. Future Approaches and Therapeutic Modalities for Acute Liver Failure. Clin Liver Dis 2018; 22:419-427. [PMID: 29605076 DOI: 10.1016/j.cld.2018.01.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The current gold standard for the management of acute liver failure is liver transplantation. However, because of organ shortages, other modalities of therapy are necessary as a possible bridge. This article discusses the current modalities as well as the future management of acute liver failure. Liver assist devices, hepatocyte transplantation, stem cell transplant, organogenesis, and repopulation of decellularized organs are discussed.
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Affiliation(s)
- Pavan Patel
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB H-538, Newark, NJ 07103, USA
| | - Nneoma Okoronkwo
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB H-538, Newark, NJ 07103, USA
| | - Nikolaos T Pyrsopoulos
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB H-538, Newark, NJ 07103, USA.
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9
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Ogoke O, Oluwole J, Parashurama N. Bioengineering considerations in liver regenerative medicine. J Biol Eng 2017; 11:46. [PMID: 29204185 PMCID: PMC5702480 DOI: 10.1186/s13036-017-0081-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 09/25/2017] [Indexed: 12/19/2022] Open
Abstract
Background Liver disease contributes significantly to global disease burden and is associated with rising incidence and escalating costs. It is likely that innovative approaches, arising from the emerging field of liver regenerative medicine, will counter these trends. Main body Liver regenerative medicine is a rapidly expanding field based on a rich history of basic investigations into the nature of liver structure, physiology, development, regeneration, and function. With a bioengineering perspective, we discuss all major subfields within liver regenerative medicine, focusing on the history, seminal publications, recent progress within these fields, and commercialization efforts. The areas reviewed include fundamental aspects of liver transplantation, liver regeneration, primary hepatocyte cell culture, bioartificial liver, hepatocyte transplantation and liver cell therapies, mouse liver repopulation, adult liver stem cell/progenitor cells, pluripotent stem cells, hepatic microdevices, and decellularized liver grafts. Conclusion These studies highlight the creative directions of liver regenerative medicine, the collective efforts of scientists, engineers, and doctors, and the bright outlook for a wide range of approaches and applications which will impact patients with liver disease.
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Affiliation(s)
- Ogechi Ogoke
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Furnas Hall, Buffalo, NY 14260 USA.,Clinical and Translation Research Center (CTRC), University at Buffalo (State University of New York), 875 Ellicott St., Buffalo, NY 14203 USA
| | - Janet Oluwole
- Clinical and Translation Research Center (CTRC), University at Buffalo (State University of New York), 875 Ellicott St., Buffalo, NY 14203 USA.,Department of Biomedical Engineering, University at Buffalo (State University of New York), Furnas Hall, 907 Furnas Hall, Buffalo, NY 14260 USA
| | - Natesh Parashurama
- Department of Chemical and Biological Engineering, University at Buffalo (State University of New York), Furnas Hall, Buffalo, NY 14260 USA.,Clinical and Translation Research Center (CTRC), University at Buffalo (State University of New York), 875 Ellicott St., Buffalo, NY 14203 USA.,Department of Biomedical Engineering, University at Buffalo (State University of New York), Furnas Hall, 907 Furnas Hall, Buffalo, NY 14260 USA
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10
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Mi P, Wang F, Nishiyama N, Cabral H. Molecular Cancer Imaging with Polymeric Nanoassemblies: From Tumor Detection to Theranostics. Macromol Biosci 2016; 17. [PMID: 27739631 DOI: 10.1002/mabi.201600305] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 09/06/2016] [Indexed: 02/05/2023]
Affiliation(s)
- Peng Mi
- State Key Laboratory of Biotherapy and Cancer Center and Department of Cardiovascular Surgery; West China Hospital; Sichuan University and Collaborative Innovation Center for Biotherapy; Chengdu 610041 P. R. China
| | - Fang Wang
- State Key Laboratory of Biotherapy and Cancer Center and Department of Cardiovascular Surgery; West China Hospital; Sichuan University and Collaborative Innovation Center for Biotherapy; Chengdu 610041 P. R. China
| | - Nobuhiro Nishiyama
- Laboratory for Chemistry and Life Science; Institute of Innovative Research; Tokyo Institute of Technology; R1-11, 4259 Nagatsuta Midori-ku, Yokohama 226-8503 Japan
| | - Horacio Cabral
- Department of Bioengineering; Graduate School of Engineering; The University of Tokyo; 7-3-1 Hongo Bunkyo-ku Tokyo 113-8656 Japan
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11
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Nguyen DK, Son YM, Lee NE. Hydrogel Encapsulation of Cells in Core-Shell Microcapsules for Cell Delivery. Adv Healthc Mater 2015; 4:1537-44. [PMID: 25963828 DOI: 10.1002/adhm.201500133] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 04/20/2015] [Indexed: 01/20/2023]
Abstract
A newly designed 3D core-shell microcapsule structure composed of a cell-containing liquid core and an alginate hydrogel shell is fabricated using a coaxial dual-nozzle electrospinning system. Spherical alginate microcapsules are successfully generated with a core-shell structure and less than 300 μm in average diameter using this system. The thickness of the core and shell can be easily controlled by manipulating the core and shell flow rates. Cells encapsulated in core-shell microcapsules demonstrate better cell encapsulation and immune protection than those encapsulated in microbeads. The observation of a high percentage of live cells (≈80%) after encapsulation demonstrates that the voltage applied for generation of microcapsules does not significantly affect the viability of encapsulated cells. The viability of encapsulated cells does not change even after 3 d in culture, which suggests that the core-shell structure with culture medium in the core can maintain high cell survival by providing nutrients and oxygen to all cells. This newly designed core-shell structure can be extended to use in multifunctional platforms not only for delivery of cells but also for factor delivery, imaging, or diagnosis by loading other components in the core or shell.
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Affiliation(s)
- Duy Khiem Nguyen
- School of Advanced Materials Science & Engineering; Sungkyunkwan University (SKKU); Suwon Gyeonggi-do 440 - 746 Republic of Korea
| | - Young Min Son
- Samsung Advanced Institute for Health Sciences & Technology (SAIHST); Sungkyunkwan University (SKKU); Suwon Gyeonggi-do 440 - 746 Republic of Korea
| | - Nae-Eung Lee
- School of Advanced Materials Science & Engineering; SKKU Advanced Institute of Nanotechnology (SAINT) and Samsung Advanced Institute for Health Sciences & Technology (SAIHST); Sungkyunkwan University (SKKU); Suwon Gyeonggi-do 440 - 746 Republic of Korea
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12
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High efficient differentiation of functional hepatocytes from porcine induced pluripotent stem cells. PLoS One 2014; 9:e100417. [PMID: 24949734 PMCID: PMC4065042 DOI: 10.1371/journal.pone.0100417] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 05/23/2014] [Indexed: 01/15/2023] Open
Abstract
Hepatocyte transplantation is considered to be a promising therapy for patients with liver diseases. Induced pluripotent stem cells (iPSCs) provide an unlimited source for the generation of functional hepatocytes. In this study, we generated iPSCs from porcine ear fibroblasts (PEFs) by overexpressing Sox2, Klf4, Oct4, and c-Myc (SKOM), and developed a novel strategy for the efficient differentiation of hepatocyte-like cells from porcine iPSCs by following the processes of early liver development. The differentiated cells displayed the phenotypes of hepatocytes, exhibited classic hepatocyte-associated bio-functions, such as LDL uptake, glycogen storage and urea secretion, as well as possessed the metabolic activities of cytochrome P-450 (CYP) 3A and 2C. Furthermore, we compared the hepatocyte differentiation efficacy of our protocol with another published method, and the results demonstrated that our differentiation strategy could significantly improve the generation of morphological and functional hepatocyte-like cells from porcine iPSCs. In conclusion, this study establishes an efficient method for in vitro generation of functional hepatocytes from porcine iPSCs, which could represent a promising cell source for preclinical testing of cell-based therapeutics for liver failure and for pharmacological applications.
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13
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Lee JS, Shin J, Park HM, Kim YG, Kim BG, Oh JW, Cho SW. Liver extracellular matrix providing dual functions of two-dimensional substrate coating and three-dimensional injectable hydrogel platform for liver tissue engineering. Biomacromolecules 2013; 15:206-18. [PMID: 24350561 DOI: 10.1021/bm4015039] [Citation(s) in RCA: 165] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Decellularization of tissues or organs can provide an efficient strategy for preparing functional scaffolds for tissue engineering. Microstructures of native extracellular matrices and their biochemical compositions can be retained in the decellularized matrices, providing tissue-specific microenvironments for efficient tissue regeneration. Here, we report the versatility of liver extracellular matrix (LEM) that can be used for two-dimensional (2D) coating and three-dimensional (3D) hydrogel platforms for culture and transplantation of primary hepatocytes. Collagen type I (Col I) has typically been used for hepatocyte culture and transplantation. In this study, LEM was compared with Col I in terms of biophysical and mechanical characteristics and biological performance for enhancing cell viability, differentiation, and hepatic functions. Surface properties of LEM coating and mechanical properties and gelation kinetics of LEM hydrogel could be manipulated by adjusting the LEM concentration. In addition, LEM hydrogel exhibited improved elastic properties, rapid gelation, and volume maintenance compared to Col I hydrogel. LEM coating significantly improved hepatocyte functions such as albumin secretion and urea synthesis. More interestingly, LEM coating upregulated hepatic gene expression of human adipose-derived stem cells, indicating enhanced hepatic differentiation of these stem cells. The viability and hepatic functions of primary hepatocytes were also significantly improved in LEM hydrogel compared to Col I hydrogel both in vitro and in vivo. Albumin and hepatocyte transcription factor expression was upregulated in hepatocytes transplanted in LEM hydrogels. In conclusion, LEM can provide functional biomaterial platforms for diverse applications in liver tissue engineering by promoting survival and maturation of hepatocytes and hepatic commitment of stem cells. This study demonstrates the feasibility of decellularized matrix for both 2D coating and 3D hydrogel in liver tissue engineering.
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Affiliation(s)
- Jung Seung Lee
- Department of Biotechnology, Yonsei University , Seoul 120-749, Republic of Korea
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Esrefoglu M. Role of stem cells in repair of liver injury: Experimental and clinical benefit of transferred stem cells on liver failure. World J Gastroenterol 2013; 19:6757-6773. [PMID: 24187451 PMCID: PMC3812475 DOI: 10.3748/wjg.v19.i40.6757] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Revised: 07/23/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
Although the liver has a high regenerative capacity, as a result of massive hepatocyte death, liver failure occurs. In addition to liver failure, for acute, chronic and hereditary diseases of the liver, cell transplantation therapies can stimulate regeneration or at least ensure sufficient function until liver transplantation can be performed. The lack of donor organs and the risks of rejection have prompted extensive experimental and clinical research in the field of cellular transplantation. Transplantation of cell lineages involved in liver regeneration, including mature hepatocytes, fetal hepatocytes, fetal liver progenitor cells, fetal stem cells, hepatic progenitor cells, hepatic stem cells, mesenchymal stem cells, hematopoietic stem cells, and peripheral blood and umbilical cord blood stem cells, have been found to be beneficial in the treatment of liver failure. In this article, the results of experimental and clinical cell transplantation trials for liver failure are reviewed, with an emphasis on regeneration.
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Lee JY, Choi B, Wu B, Lee M. Customized biomimetic scaffolds created by indirect three-dimensional printing for tissue engineering. Biofabrication 2013; 5:045003. [PMID: 24060622 DOI: 10.1088/1758-5082/5/4/045003] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Three-dimensional printing (3DP) is a rapid prototyping technique that can create complex 3D structures by inkjet printing of a liquid binder onto powder biomaterials for tissue engineering scaffolds. Direct fabrication of scaffolds from 3DP, however, imposes a limitation on material choices by manufacturing processes. In this study, we report an indirect 3DP approach wherein a positive replica of desired shapes was printed using gelatin particles, and the final scaffold was directly produced from the printed mold. To create patient-specific scaffolds that match precisely to a patient's external contours, we integrated our indirect 3DP technique with imaging technologies and successfully created custom scaffolds mimicking human mandibular condyle using polycaprolactone and chitosan for potential osteochondral tissue engineering. To test the ability of the technique to precisely control the internal morphology of the scaffolds, we created orthogonal interconnected channels within the scaffolds using computer-aided-design models. Because very few biomaterials are truly osteoinductive, we modified inert 3D printed materials with bioactive apatite coating. The feasibility of these scaffolds to support cell growth was investigated using bone marrow stromal cells (BMSC). The BMSCs showed good viability in the scaffolds, and the apatite coating further enhanced cellular spreading and proliferation. This technique may be valuable for complex scaffold fabrication.
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Affiliation(s)
- Ju-Yeon Lee
- Division of Advanced Prosthodontics, University of California, Los Angeles, CA 90095, USA
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16
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Aravalli RN, Cressman EN, Steer CJ. Hepatic differentiation of porcine induced pluripotent stem cells in vitro. Vet J 2012; 194:369-74. [DOI: 10.1016/j.tvjl.2012.05.013] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Revised: 04/06/2012] [Accepted: 05/19/2012] [Indexed: 12/14/2022]
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17
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Hou YT, Ijima H, Shirakigawa N, Takei T, Kawakami K. Development of growth factor-immobilizable material for hepatocyte transplantation. Biochem Eng J 2012. [DOI: 10.1016/j.bej.2012.09.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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18
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Venkatraman L, Chia SM, Narmada B, White J, Bhowmick S, Forbes Dewey C, So P, Tucker-Kellogg L, Yu H. Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1. Biophys J 2012; 103:1060-8. [PMID: 23009856 PMCID: PMC3433618 DOI: 10.1016/j.bpj.2012.06.050] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Revised: 06/24/2012] [Accepted: 06/28/2012] [Indexed: 01/13/2023] Open
Abstract
Transforming growth factor-β1 (TGF-β1) is a potent regulator of extracellular matrix production, wound healing, differentiation, and immune response, and is implicated in the progression of fibrotic diseases and cancer. Extracellular activation of TGF-β1 from its latent form provides spatiotemporal control over TGF-β1 signaling, but the current understanding of TGF-β1 activation does not emphasize cross talk between activators. Plasmin (PLS) and thrombospondin-1 (TSP1) have been studied individually as activators of TGF-β1, and in this work we used a systems-level approach with mathematical modeling and in vitro experiments to study the interplay between PLS and TSP1 in TGF-β1 activation. Simulations and steady-state analysis predicted a switch-like bistable transition between two levels of active TGF-β1, with an inverse correlation between PLS and TSP1. In particular, the model predicted that increasing PLS breaks a TSP1-TGF-β1 positive feedback loop and causes an unexpected net decrease in TGF-β1 activation. To test these predictions in vitro, we treated rat hepatocytes and hepatic stellate cells with PLS, which caused proteolytic cleavage of TSP1 and decreased activation of TGF-β1. The TGF-β1 activation levels showed a cooperative dose response, and a test of hysteresis in the cocultured cells validated that TGF-β1 activation is bistable. We conclude that switch-like behavior arises from natural competition between two distinct modes of TGF-β1 activation: a TSP1-mediated mode of high activation and a PLS-mediated mode of low activation. This switch suggests an explanation for the unexpected effects of the plasminogen activation system on TGF-β1 in fibrotic diseases in vivo, as well as novel prognostic and therapeutic approaches for diseases with TGF-β dysregulation.
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Affiliation(s)
- Lakshmi Venkatraman
- Singapore-MIT Alliance, Computational Systems Biology Programme, Singapore
- School of Computer Engineering, Nanyang Technological University, Singapore
| | - Ser-Mien Chia
- Singapore-MIT Alliance, Computational Systems Biology Programme, Singapore
| | | | - Jacob K. White
- Singapore-MIT Alliance, Computational Systems Biology Programme, Singapore
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Sourav S. Bhowmick
- Singapore-MIT Alliance, Computational Systems Biology Programme, Singapore
- School of Computer Engineering, Nanyang Technological University, Singapore
| | - C. Forbes Dewey
- Singapore-MIT Alliance, Computational Systems Biology Programme, Singapore
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Peter T. So
- Singapore-MIT Alliance, Computational Systems Biology Programme, Singapore
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Lisa Tucker-Kellogg
- Singapore-MIT Alliance, Computational Systems Biology Programme, Singapore
- Mechanobiology Institute, Temasek Laboratories, National University of Singapore, Singapore
| | - Hanry Yu
- Singapore-MIT Alliance, Computational Systems Biology Programme, Singapore
- NUS Graduate School for Integrative Sciences, Singapore
- Department of Physiology, Temasek Laboratories, National University of Singapore, Singapore
- Mechanobiology Institute, Temasek Laboratories, National University of Singapore, Singapore
- Institute of Bioengineering and Nanotechnology, ASTAR, Singapore
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19
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Liver tissue engineering: Recent advances in the development of a bio-artificial liver. BIOTECHNOL BIOPROC E 2012. [DOI: 10.1007/s12257-012-0047-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Renette T, Librizzi D, Endres T, Merkel O, Beck-Broichsitter M, Bege N, Petersen H, Curdy C, Kissel T. Poly(ethylene carbonate) Nanoparticles as Carrier System for Chemotherapy Showing Prolonged in vivo Circulation and Anti-Tumor Efficacy. Macromol Biosci 2012; 12:970-8. [DOI: 10.1002/mabi.201100499] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Revised: 02/25/2012] [Indexed: 11/08/2022]
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Lee BH, Li B, Guelcher SA. Gel microstructure regulates proliferation and differentiation of MC3T3-E1 cells encapsulated in alginate beads. Acta Biomater 2012; 8:1693-702. [PMID: 22306825 DOI: 10.1016/j.actbio.2012.01.012] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Revised: 12/27/2011] [Accepted: 01/10/2012] [Indexed: 12/17/2022]
Abstract
For cell transplantation into damaged tissues, viable cells must be delivered to the defect site in a suitable carrier. However, the hypoxic and nutrient-limited environment in the carrier can induce massive cell death. The aims of this study were to increase the viability and regulate the behavior of osteoprogenitor cells encapsulated in alginate hydrogels through control of the gel microstructure. Cell survivability in alginate beads was improved through the use of α-MEM as the solvent for alginic acid sodium salt, and by CaCl(2) solutions, which supplied additional nutrients for the cells compared to water or buffer. The mesh size and shear modulus of the hydrogel were hypothesized to regulate proliferation and differentiation of osteoprogenitor cells. MC3T3-E1 cells demonstrated enhanced osteoblast differentiation when encapsulated in high-density alginate with smaller mesh size and more rigid mechanical properties, as confirmed by increased alkaline phosphatase activity and osteocalcin secretion. However, MC3T3-E1 cells encapsulated in low-density alginate beads with a larger mesh size and more compliant mechanical properties exhibited increased proliferation. These results demonstrate that the microstructure of alginate hydrogels can regulate the behavior of osteoprogenitor cells, thus suggesting that the tuning the properties of the gel may be a useful approach for enhancing new bone formation.
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Venkatraman L, Li H, Dewey CF, White JK, Bhowmick SS, Yu H, Tucker-Kellogg L. Steady states and dynamics of urokinase-mediated plasmin activation in silico and in vitro. Biophys J 2012; 101:1825-34. [PMID: 22004735 DOI: 10.1016/j.bpj.2011.08.054] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Revised: 08/05/2011] [Accepted: 08/15/2011] [Indexed: 11/28/2022] Open
Abstract
Plasmin (PLS) and urokinase-type plasminogen activator (UPA) are ubiquitous proteases that regulate the extracellular environment. Although they are secreted in inactive forms, they can activate each other through proteolytic cleavage. This mutual interplay creates the potential for complex dynamics, which we investigated using mathematical modeling and in vitro experiments. We constructed ordinary differential equations to model the conversion of precursor plasminogen into active PLS, and precursor urokinase (scUPA) into active urokinase (tcUPA). Although neither PLS nor UPA exhibits allosteric cooperativity, modeling showed that cooperativity occurred at the system level because of substrate competition. Computational simulations and bifurcation analysis predicted that the system would be bistable over a range of parameters for cooperativity and positive feedback. Cell-free experiments with recombinant proteins tested key predictions of the model. PLS activation in response to scUPA stimulus was found to be cooperative in vitro. Finally, bistability was demonstrated in vitro by the presence of two significantly different steady-state levels of PLS activation for the same levels of stimulus. We conclude that ultrasensitive, bistable activation of UPA-PLS is possible in the presence of substrate competition. An ultrasensitive threshold for activation of PLS and UPA would have ramifications for normal and disease processes, including angiogenesis, metastasis, wound healing, and fibrosis.
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Hou YT, Ijima H, Takei T, Kawakami K. Growth factor/heparin-immobilized collagen gel system enhances viability of transplanted hepatocytes and induces angiogenesis. J Biosci Bioeng 2011; 112:265-72. [DOI: 10.1016/j.jbiosc.2011.05.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2011] [Revised: 04/02/2011] [Accepted: 05/06/2011] [Indexed: 01/05/2023]
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McCullen SD, Chow AGY, Stevens MM. In vivo tissue engineering of musculoskeletal tissues. Curr Opin Biotechnol 2011; 22:715-20. [PMID: 21646011 DOI: 10.1016/j.copbio.2011.05.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Revised: 04/14/2011] [Accepted: 05/01/2011] [Indexed: 01/09/2023]
Abstract
Tissue engineering of musculoskeletal tissues often involves the in vitro manipulation and culture of progenitor cells, growth factors and biomaterial scaffolds. Though in vitro tissue engineering has greatly increased our understanding of cellular behavior and cell-material interactions, this methodology is often unable to recreate tissue with the hierarchical organization and vascularization found within native tissues. Accordingly, investigators have focused on alternative in vivo tissue engineering strategies, whereby the traditional triad (cells, growth factors, scaffolds) or a combination thereof are directly implanted at the damaged tissue site or within ectopic sites capable of supporting neo-tissue formation. In vivo tissue engineering may offer a preferential route for regeneration of musculoskeletal and other tissues with distinct advantages over in vitro methods based on the specific location of endogenous cultivation, recruitment of autologous cells, and patient-specific regenerated tissues.
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Affiliation(s)
- Seth D McCullen
- Department of Materials, Imperial College London, London SW7 2AZ, UK
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25
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Purpose-driven biomaterials research in liver-tissue engineering. Trends Biotechnol 2011; 29:110-8. [DOI: 10.1016/j.tibtech.2010.10.006] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2010] [Revised: 10/18/2010] [Accepted: 10/26/2010] [Indexed: 01/21/2023]
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Abstract
INTRODUCTION Due to a lack of adequate liver donors and post-surgical complications, researchers propose that cell therapy should be an alternative treatment for patients with end-stage liver diseases. DATA SOURCES We performed a literature review on cell-based therapy for liver disorders. AREAS OF AGREEMENT Due to growing numbers of patients on waiting lists for liver transplantation, a substitute treatment strategy is needed for our patients. Cell therapy can save patients who are in life-threatening situations, enabling them to have more time and increase their chances of survival. Pluripotent stem cells can be a good resource for cell-based therapy after the establishment of efficient differentiation protocols in addition to the settlement of ethical and immunological issues. Cell-based therapy will be applicable after the approval of its efficiency via animal model studies. AREAS OF CONTROVERSY Transplanted cells cannot integrate into the recipient liver and lose their functionality after a limited time. The rate of homing and transdifferentiation of transplanted cells into hepatocytes is scant. GROWING POINTS Application of autologous bone marrow mononuclear cells (MNCs), hematopoietic and mesenchymal stem cells (HSCs and MSCs) has improved the general conditions of certain patients. Although this improvement is temporary, new studies have focused on increasing their performance. TIMELY AREAS FOR DEVELOPING RESEARCH: The safety, feasibility and efficacy of applying MNCs, HSCs and MSCs in liver disorders have been proven in clinical trials. Patient-specific cell therapy after the production of induced pluripotent stem cells and new discoveries in somatic cell conversion during transdifferentiation are promising insights.
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Affiliation(s)
- Massoud Vosough
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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