Cargando…
Evaluation of Encapsulated Liver Cell Spheroids in a Fluidised-Bed Bioartificial Liver for Treatment of Ischaemic Acute Liver Failure in Pigs in a Translational Setting
Liver failure is an increasing problem. Donor-organ shortage results in patients dying before receiving a transplant. Since the liver can regenerate, alternative therapies providing temporary liver-support are sought. A bioartificial-liver would temporarily substitute function in liver failure buyin...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867376/ https://www.ncbi.nlm.nih.gov/pubmed/24367515 http://dx.doi.org/10.1371/journal.pone.0082312 |
_version_ | 1782296292138942464 |
---|---|
author | Selden, Clare Spearman, Catherine Wendy Kahn, Delawir Miller, Malcolm Figaji, Anthony Erro, Eloy Bundy, James Massie, Isobel Chalmers, Sherri-Ann Arendse, Hiram Gautier, Aude Sharratt, Peter Fuller, Barry Hodgson, Humphrey |
author_facet | Selden, Clare Spearman, Catherine Wendy Kahn, Delawir Miller, Malcolm Figaji, Anthony Erro, Eloy Bundy, James Massie, Isobel Chalmers, Sherri-Ann Arendse, Hiram Gautier, Aude Sharratt, Peter Fuller, Barry Hodgson, Humphrey |
author_sort | Selden, Clare |
collection | PubMed |
description | Liver failure is an increasing problem. Donor-organ shortage results in patients dying before receiving a transplant. Since the liver can regenerate, alternative therapies providing temporary liver-support are sought. A bioartificial-liver would temporarily substitute function in liver failure buying time for liver regeneration/organ-procurement. Our aim: to develop a prototype bioartificial-liver-machine (BAL) comprising a human liver-derived cell-line, cultured to phenotypic competence and deliverable in a clinical setting to sites distant from its preparation. The objective of this study was to determine whether its use would improve functional parameters of liver failure in pigs with acute liver failure, to provide proof-of-principle. HepG2cells encapsulated in alginate-beads, proliferated in a fluidised-bed-bioreactor providing a biomass of 4–6×10(10)cells, were transported from preparation-laboratory to point-of-use operating theatre (6000miles) under perfluorodecalin at ambient temperature. Irreversible ischaemic liver failure was induced in anaesthetised pigs, after portal-systemic-shunt, by hepatic-artery-ligation. Biochemical parameters, intracranial pressure, and functional-clotting were measured in animals connected in an extracorporeal bioartificial-liver circuit. Efficacy was demonstrated comparing outcomes between animals connected to a circuit containing alginate-encapsulated cells (Cell-bead BAL), and those connected to circuit containing alginate capsules without cells (Empty-bead BAL). Cells of the biomass met regulatory standards for sterility and provenance. All animals developed progressive liver-failure after ischaemia induction. Efficacy of BAL was demonstrated since animals connected to a functional biomass (+ cells) had significantly smaller rises in intracranial pressure, lower ammonia levels, more bilirubin conjugation, improved acidosis and clotting restoration compared to animals connected to the circuit without cells. In the +cell group, human proteins accumulated in pigs' plasma. Delivery of biomass using a short-term cold-chain enabled transport and use without loss of function over 3days. Thus, a fluidised-bed bioreactor containing alginate-encapsulated HepG2cell-spheroids improved important parameters of acute liver failure in pigs. The system can readily be up-scaled and transported to point-of-use justifying development at clinical scale. |
format | Online Article Text |
id | pubmed-3867376 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38673762013-12-23 Evaluation of Encapsulated Liver Cell Spheroids in a Fluidised-Bed Bioartificial Liver for Treatment of Ischaemic Acute Liver Failure in Pigs in a Translational Setting Selden, Clare Spearman, Catherine Wendy Kahn, Delawir Miller, Malcolm Figaji, Anthony Erro, Eloy Bundy, James Massie, Isobel Chalmers, Sherri-Ann Arendse, Hiram Gautier, Aude Sharratt, Peter Fuller, Barry Hodgson, Humphrey PLoS One Research Article Liver failure is an increasing problem. Donor-organ shortage results in patients dying before receiving a transplant. Since the liver can regenerate, alternative therapies providing temporary liver-support are sought. A bioartificial-liver would temporarily substitute function in liver failure buying time for liver regeneration/organ-procurement. Our aim: to develop a prototype bioartificial-liver-machine (BAL) comprising a human liver-derived cell-line, cultured to phenotypic competence and deliverable in a clinical setting to sites distant from its preparation. The objective of this study was to determine whether its use would improve functional parameters of liver failure in pigs with acute liver failure, to provide proof-of-principle. HepG2cells encapsulated in alginate-beads, proliferated in a fluidised-bed-bioreactor providing a biomass of 4–6×10(10)cells, were transported from preparation-laboratory to point-of-use operating theatre (6000miles) under perfluorodecalin at ambient temperature. Irreversible ischaemic liver failure was induced in anaesthetised pigs, after portal-systemic-shunt, by hepatic-artery-ligation. Biochemical parameters, intracranial pressure, and functional-clotting were measured in animals connected in an extracorporeal bioartificial-liver circuit. Efficacy was demonstrated comparing outcomes between animals connected to a circuit containing alginate-encapsulated cells (Cell-bead BAL), and those connected to circuit containing alginate capsules without cells (Empty-bead BAL). Cells of the biomass met regulatory standards for sterility and provenance. All animals developed progressive liver-failure after ischaemia induction. Efficacy of BAL was demonstrated since animals connected to a functional biomass (+ cells) had significantly smaller rises in intracranial pressure, lower ammonia levels, more bilirubin conjugation, improved acidosis and clotting restoration compared to animals connected to the circuit without cells. In the +cell group, human proteins accumulated in pigs' plasma. Delivery of biomass using a short-term cold-chain enabled transport and use without loss of function over 3days. Thus, a fluidised-bed bioreactor containing alginate-encapsulated HepG2cell-spheroids improved important parameters of acute liver failure in pigs. The system can readily be up-scaled and transported to point-of-use justifying development at clinical scale. Public Library of Science 2013-12-18 /pmc/articles/PMC3867376/ /pubmed/24367515 http://dx.doi.org/10.1371/journal.pone.0082312 Text en © 2013 Selden et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Selden, Clare Spearman, Catherine Wendy Kahn, Delawir Miller, Malcolm Figaji, Anthony Erro, Eloy Bundy, James Massie, Isobel Chalmers, Sherri-Ann Arendse, Hiram Gautier, Aude Sharratt, Peter Fuller, Barry Hodgson, Humphrey Evaluation of Encapsulated Liver Cell Spheroids in a Fluidised-Bed Bioartificial Liver for Treatment of Ischaemic Acute Liver Failure in Pigs in a Translational Setting |
title | Evaluation of Encapsulated Liver Cell Spheroids in a Fluidised-Bed Bioartificial Liver for Treatment of Ischaemic Acute Liver Failure in Pigs in a Translational Setting |
title_full | Evaluation of Encapsulated Liver Cell Spheroids in a Fluidised-Bed Bioartificial Liver for Treatment of Ischaemic Acute Liver Failure in Pigs in a Translational Setting |
title_fullStr | Evaluation of Encapsulated Liver Cell Spheroids in a Fluidised-Bed Bioartificial Liver for Treatment of Ischaemic Acute Liver Failure in Pigs in a Translational Setting |
title_full_unstemmed | Evaluation of Encapsulated Liver Cell Spheroids in a Fluidised-Bed Bioartificial Liver for Treatment of Ischaemic Acute Liver Failure in Pigs in a Translational Setting |
title_short | Evaluation of Encapsulated Liver Cell Spheroids in a Fluidised-Bed Bioartificial Liver for Treatment of Ischaemic Acute Liver Failure in Pigs in a Translational Setting |
title_sort | evaluation of encapsulated liver cell spheroids in a fluidised-bed bioartificial liver for treatment of ischaemic acute liver failure in pigs in a translational setting |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3867376/ https://www.ncbi.nlm.nih.gov/pubmed/24367515 http://dx.doi.org/10.1371/journal.pone.0082312 |
work_keys_str_mv | AT seldenclare evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting AT spearmancatherinewendy evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting AT kahndelawir evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting AT millermalcolm evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting AT figajianthony evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting AT erroeloy evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting AT bundyjames evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting AT massieisobel evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting AT chalmerssherriann evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting AT arendsehiram evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting AT gautieraude evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting AT sharrattpeter evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting AT fullerbarry evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting AT hodgsonhumphrey evaluationofencapsulatedlivercellspheroidsinafluidisedbedbioartificialliverfortreatmentofischaemicacuteliverfailureinpigsinatranslationalsetting |