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      Alginate Microencapsulated Hepatocytes Optimised for Transplantation in Acute Liver Failure

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          Background and Aim

          Intraperitoneal transplantation of alginate-microencapsulated human hepatocytes is an attractive option for the management of acute liver failure (ALF) providing short-term support to allow native liver regeneration. The main aim of this study was to establish an optimised protocol for production of alginate-encapsulated human hepatocytes and evaluate their suitability for clinical use.


          Human hepatocyte microbeads (HMBs) were prepared using sterile GMP grade materials. We determined physical stability, cell viability, and hepatocyte metabolic function of HMBs using different polymerisation times and cell densities. The immune activation of peripheral blood mononuclear cells (PBMCs) after co-culture with HMBs was studied. Rats with ALF induced by galactosamine were transplanted intraperitoneally with rat hepatocyte microbeads (RMBs) produced using a similar optimised protocol. Survival rate and biochemical profiles were determined. Retrieved microbeads were evaluated for morphology and functionality.


          The optimised HMBs were of uniform size (583.5±3.3 µm) and mechanically stable using 15 min polymerisation time compared to 10 min and 20 min (p<0.001). 3D confocal microscopy images demonstrated that hepatocytes with similar cell viability were evenly distributed within HMBs. Cell density of 3.5×10 6 cells/ml provided the highest viability. HMBs incubated in human ascitic fluid showed better cell viability and function than controls. There was no significant activation of PBMCs co-cultured with empty or hepatocyte microbeads, compared to PBMCs alone. Intraperitoneal transplantation of RMBs was safe and significantly improved the severity of liver damage compared to control groups (empty microbeads and medium alone; p<0.01). Retrieved RMBs were intact and free of immune cell adherence and contained viable hepatocytes with preserved function.


          An optimised protocol to produce GMP grade alginate-encapsulated human hepatocytes has been established. Transplantation of microbeads provided effective metabolic function in ALF. These high quality HMBs should be suitable for use in clinical transplantation.

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          Most cited references 28

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          Microcapsules and microcarriers for in situ cell delivery.

          In recent years, the use of transplanted living cells pumping out active factors directly at the site has proven to be an emergent technology. However a recurring impediment to rapid development in the field is the immune rejection of transplanted allo- or xenogeneic cells. Immunosuppression is used clinically to prevent rejection of organ and cell transplants in humans, but prolonged usage can make the recipient vulnerable to infections, and increase the likelihood of tumorigenesis of the transplanted cells. Cell microencapsulation is a promising tool to overcome these drawbacks. It consists of surrounding cells with a semipermeable polymeric membrane. The latter permits the entry of nutrients and the exit of therapeutic protein products, obtaining in this way a sustained delivery of the desirable molecule. The membrane isolates the enclosed cells from the host immune system, preventing the recognition of the immobilization cells as foreign. This review paper intends to overview the current situation in the cell encapsulation field and discusses the main events that have occurred along the way. The technical advances together with the ever increasing knowledge and experience in the field will undoubtedly lead to the realization of the full potential of cell encapsulation in the future. 2010 Elsevier B.V. All rights reserved.
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            Therapeutic applications of polymeric artificial cells.

             Thomas Chang (2005)
            Polymeric artificial cells have the potential to be used for a wide variety of therapeutic applications, such as the encapsulation of transplanted islet cells to treat diabetic patients. Recent advances in biotechnology, molecular biology, nanotechnology and polymer chemistry are now opening up further exciting possibilities in this field. However, it is also recognized that there are several key obstacles to overcome in bringing such approaches into routine clinical use. This review describes the historical development and principles behind polymeric artificial cells, the present state of the art in their therapeutic application, and the promises and challenges for the future.
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              Biocompatibility of microcapsules for cell immobilization elaborated with different type of alginates.

              The biocompatibility of alginate-PLL-alginate (APA) microcapsules has been evaluated with respect to impurity levels. The impurity content of three different alginates (a raw high M-alginate, a raw high G-alginate and a purified high G-alginate) has been determined and the in vivo antigenic response of APA beads made with each alginate assessed. Results show that purification of the alginate not only reduces the total amount of impurities (63% less in polyphenols, 91.45% less in endotoxins and 68.5% less in protein in relation to raw high M-alginate), but also avoids an antibody response when microcapsules of this material are implanted in mice. In contrast, raw alginates produced a detectable antibody response though the differences in their impurity content. Consequently, this work revealed that purity of the alginate rather than their chemical composition, is probably of greater importance in determining microcapsule biocompatibility.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1 December 2014
                : 9
                : 12
                [1 ]Institute of Liver Studies, King's College London School of Medicine, London, United Kingdom
                [2 ]British Heart Foundation Centre of Excellence Cardiovascular Division, King's College London School of Medicine, London, United Kingdom
                UNIFESP Federal University of São Paulo, Brazil
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SJ RRM RDH AD CF. Performed the experiments: SJ RRM CF DS MSL CP SCL. Analyzed the data: SJ RDH CF DS. Contributed reagents/materials/analysis tools: NDH DS. Wrote the paper: SJ RRM RDH AD.


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Pages: 23
                This work was supported by the National Institute for Health Research (AD and RDH), funds for consumables; and WellChild (RRM and AD), funds were given to purchase the encapsulator used in the work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cell Physiology
                Cell Metabolism
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Acute Liver Failure
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                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper.



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