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Giri S, Anirvan P, Vaidya A, Praharaj DL. Dengue-related acute liver failure-A scoping review. Indian J Gastroenterol 2024; 43:407-424. [PMID: 38687431 DOI: 10.1007/s12664-024-01570-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 03/09/2024] [Indexed: 05/02/2024]
Abstract
Infection by dengue virus is common in tropical countries. Hepatic involvement in dengue can range from asymptomatic elevation of transaminases to life-threatening acute liver failure (ALF). Dengue-related ALF (DALF) is responsible for significant morbidity and mortality, especially in Southeast Asia. However, there is a scarcity of literature on DALF, necessitating a thorough examination of its clinical determinants and management strategies. All relevant studies related to DALF were reviewed until December 2023. Case reports, case series and studies reporting ALF in dengue infection were included. Demographics, clinical profiles, management and outcomes of DALF cases were analyzed, which revealed a predominance of DALF incidence in pediatric patients (1.1% to 15.8%) and an upward trend over the years, particularly in India. The proportion of ALF cases attributable to dengue was also higher among pediatric ALF patients (6.7% to 34.3%). Age ≤ 40 years, persistent nausea, vomiting and elevated serum bilirubin and alkaline phosphatase (ALP) with aspartate aminotransferase (AST) > 1000 IU/mL within the first five days of illness, more than 10% of atypical lymphocytes in peripheral blood, platelet count of < 50,000/cu·mm, severe hepatitis at presentation and baseline model for end-stage liver disease (MELD) > 15 were the risk factors for the development of DALF. Histopathological features of DALF included multi-lobular hepatic necrosis, steatosis and occasional cholestasis. Mortality in DALF ranged from 0% to 80%; admission pH and lactate strongly predicted mortality, while mortality was found to be significantly higher in patients with cirrhosis. N-Acetyl cysteine (NAC) has been used as a treatment modality with varying results. There is limited evidence regarding the use of extra-corporeal support systems, while candidate selection for liver transplantation (LT) in DALF remains poorly defined.
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Affiliation(s)
- Suprabhat Giri
- Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, 751 024, India
| | - Prajna Anirvan
- Kalinga Gastroenterology Foundation, Cuttack, 753 001, India
| | - Arun Vaidya
- Department of Gastroenterology, Seth G S Medical College and K E M Hospital, Mumbai, 400 012, India
| | - Dibya Lochan Praharaj
- Department of Gastroenterology and Hepatology, Kalinga Institute of Medical Sciences, Bhubaneswar, 751 024, India.
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2
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Silvariño R, San Román S, Peluffo L, Opertti A, Grecco G, Noboa O, Rosa-Diez G. Extended online hemodiafiltration associated with single-pass albumin dialysis, a feasible alternative for patients with hepatorenal insufficiency. Nefrologia 2023; 43:801-803. [PMID: 38212172 DOI: 10.1016/j.nefroe.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/09/2021] [Indexed: 01/13/2024] Open
Affiliation(s)
- Ricardo Silvariño
- Centro de Nefrología, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay; Servicio de Nefrología de Cooperativa de Servicios Médicos (COSEM), Montevideo, Uruguay.
| | - Sofía San Román
- Servicio de Nefrología de Cooperativa de Servicios Médicos (COSEM), Montevideo, Uruguay
| | - Leticia Peluffo
- Servicio de Nefrología de Cooperativa de Servicios Médicos (COSEM), Montevideo, Uruguay
| | | | - Gustavo Grecco
- Centro de Terapia Intensiva, Sanatorio Americano, Montevideo, Uruguay
| | - Oscar Noboa
- Centro de Nefrología, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay; Servicio de Nefrología de Cooperativa de Servicios Médicos (COSEM), Montevideo, Uruguay
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Nelson VL, Stumbras AR, Palumbo RN, Riesgraf SA, Balboa MS, Hannah ZA, Bergstrom IJ, Fecteau CJ, Lake JR, Barry JJ, Ross JJ. Manufacturing and Functional Characterization of Bioengineered Liver Grafts for Extracorporeal Liver Assistance in Acute Liver Failure. Bioengineering (Basel) 2023; 10:1201. [PMID: 37892931 PMCID: PMC10604724 DOI: 10.3390/bioengineering10101201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 09/29/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Acute Liver Failure (ALF) is a life-threatening illness characterized by the rapid onset of abnormal liver biochemistries, coagulopathy, and the development of hepatic encephalopathy. Extracorporeal bioengineered liver (BEL) grafts could offer a bridge therapy to transplant or recovery. The present study describes the manufacture of clinical scale BELs created from decellularized porcine-derived liver extracellular matrix seeded entirely with human cells: human umbilical vein endothelial cells (HUVECs) and primary human liver cells (PHLCs). Decellularized scaffolds seeded entirely with human cells were shown to adhere to stringent sterility and safety guidelines and demonstrated increased functionality when compared to grafts seeded with primary porcine liver cells (PPLCs). BELs with PHLCs were able to clear more ammonia than PPLCs and demonstrated lower perfusion pressures during patency testing. Additionally, to determine the full therapeutic potential of BELs seeded with PHLCs, longer culture periods were assessed to address the logistical constraints associated with manufacturing and transporting a product to a patient. The fully humanized BELs were able to retain their function after cold storage simulating a product transport period. Therefore, this study demonstrates the manufacture of bioengineered liver grafts and their potential in the clinical setting as a treatment for ALF.
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Affiliation(s)
- Victoria L. Nelson
- Miromatrix Medical Inc., Eden Prairie, MN 55344, USA; (A.R.S.); (R.N.P.); (S.A.R.); (M.S.B.); (Z.A.H.); (C.J.F.); (J.R.L.); (J.J.R.)
| | - Aron R. Stumbras
- Miromatrix Medical Inc., Eden Prairie, MN 55344, USA; (A.R.S.); (R.N.P.); (S.A.R.); (M.S.B.); (Z.A.H.); (C.J.F.); (J.R.L.); (J.J.R.)
| | - R. Noelle Palumbo
- Miromatrix Medical Inc., Eden Prairie, MN 55344, USA; (A.R.S.); (R.N.P.); (S.A.R.); (M.S.B.); (Z.A.H.); (C.J.F.); (J.R.L.); (J.J.R.)
| | - Shawn A. Riesgraf
- Miromatrix Medical Inc., Eden Prairie, MN 55344, USA; (A.R.S.); (R.N.P.); (S.A.R.); (M.S.B.); (Z.A.H.); (C.J.F.); (J.R.L.); (J.J.R.)
| | - Marie S. Balboa
- Miromatrix Medical Inc., Eden Prairie, MN 55344, USA; (A.R.S.); (R.N.P.); (S.A.R.); (M.S.B.); (Z.A.H.); (C.J.F.); (J.R.L.); (J.J.R.)
| | - Zachary A. Hannah
- Miromatrix Medical Inc., Eden Prairie, MN 55344, USA; (A.R.S.); (R.N.P.); (S.A.R.); (M.S.B.); (Z.A.H.); (C.J.F.); (J.R.L.); (J.J.R.)
| | - Isaac J. Bergstrom
- Miromatrix Medical Inc., Eden Prairie, MN 55344, USA; (A.R.S.); (R.N.P.); (S.A.R.); (M.S.B.); (Z.A.H.); (C.J.F.); (J.R.L.); (J.J.R.)
| | - Christopher J. Fecteau
- Miromatrix Medical Inc., Eden Prairie, MN 55344, USA; (A.R.S.); (R.N.P.); (S.A.R.); (M.S.B.); (Z.A.H.); (C.J.F.); (J.R.L.); (J.J.R.)
| | - John R. Lake
- Miromatrix Medical Inc., Eden Prairie, MN 55344, USA; (A.R.S.); (R.N.P.); (S.A.R.); (M.S.B.); (Z.A.H.); (C.J.F.); (J.R.L.); (J.J.R.)
- Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN 55455, USA
| | - John J. Barry
- Miromatrix Medical Inc., Eden Prairie, MN 55344, USA; (A.R.S.); (R.N.P.); (S.A.R.); (M.S.B.); (Z.A.H.); (C.J.F.); (J.R.L.); (J.J.R.)
| | - Jeff J. Ross
- Miromatrix Medical Inc., Eden Prairie, MN 55344, USA; (A.R.S.); (R.N.P.); (S.A.R.); (M.S.B.); (Z.A.H.); (C.J.F.); (J.R.L.); (J.J.R.)
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Agumava LU, Gulyaev VA, Lutsyk KN, Olisov OD, Akhmetshin RB, Magomedov KM, Kazymov BI, Akhmedov AR, Alekberov KF, Yaremin BI, Novruzbekov MS. Issues of intensive care and liver transplantation tactics in fulminant liver failure. BULLETIN OF THE MEDICAL INSTITUTE "REAVIZ" (REHABILITATION, DOCTOR AND HEALTH) 2023. [DOI: 10.20340/vmi-rvz.2023.1.tx.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
Abstract
Fulminant liver failure is usually characterized as severe acute liver injury with encephalopathy and synthetic dysfunction (international normalized ratio [INR] ≥1.5) in a patient without cirrhosis or previous liver disease. Management of patients with acute liver failure includes ensuring that the patient is cared for appropriately, monitoring for worsening liver failure, managing complications, and providing nutritional support. Patients with acute liver failure should be treated at a liver transplant center whenever possible. Serial laboratory tests are used to monitor the course of a patient's liver failure and to monitor for complications. It is necessary to monitor the level of aminotransferases and bilirubin in serum daily. More frequent monitoring (three to four times a day) of blood coagulation parameters, complete blood count, metabolic panels, and arterial blood gases should be performed. For some causes of acute liver failure, such as acetaminophen intoxication, treatment directed at the underlying cause may prevent the need for liver transplantation and reduce mortality. Lactulose has not been shown to improve overall outcomes, and it can lead to intestinal distention, which can lead to technical difficulties during liver transplantation. Early in acute liver failure, signs and symptoms of cerebral edema may be absent or difficult to detect. Complications of cerebral edema include increased intracranial pressure and herniation of the brain stem. General measures to prevent increased intracranial pressure include minimizing stimulation, maintaining an appropriate fluid balance, and elevating the head of the patient's bed. For patients at high risk of developing cerebral edema, we also offer hypertonic saline prophylaxis (3%) with a target serum sodium level of 145 to 155 mEq/L (level 2C). High-risk patients include patients with grade IV encephalopathy, high ammonia levels (>150 µmol/L), or acute renal failure, and patients requiring vasopressor support. Approximately 40 % of patients with acute liver failure recover spontaneously with supportive care. Predictive models have been developed to help identify patients who are unlikely to recover spontaneously, as the decision to undergo liver transplant depends in part on the likelihood of spontaneous recovery of the liver. However, among those who receive a transplant, the one-year survival rate exceeds 80 %, making this treatment the treatment of choice in this difficult patient population.
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Affiliation(s)
- L. U. Agumava
- Research Institute of Ambulance them. N.V. Sklifosovsky, liver transplant center
| | - V. A. Gulyaev
- Research Institute of Ambulance them. N.V. Sklifosovsky, liver transplant center
| | - K. N. Lutsyk
- Research Institute of Ambulance them. N.V. Sklifosovsky, liver transplant center
| | - O. D. Olisov
- Research Institute of Ambulance them. N.V. Sklifosovsky, liver transplant center; Pirogov Russian National Research Medical University, Department of Transplantology and Artificial Organs
| | - R. B. Akhmetshin
- Research Institute of Ambulance them. N.V. Sklifosovsky, liver transplant center
| | - K. M. Magomedov
- Research Institute of Ambulance them. N.V. Sklifosovsky, liver transplant center
| | - B. I. Kazymov
- Research Institute of Ambulance them. N.V. Sklifosovsky, liver transplant center
| | - A. R. Akhmedov
- Research Institute of Ambulance them. N.V. Sklifosovsky, liver transplant center
| | - K. F. Alekberov
- Research Institute of Ambulance them. N.V. Sklifosovsky, liver transplant center
| | - B. I. Yaremin
- Research Institute of Ambulance them. N.V. Sklifosovsky, liver transplant center; Pirogov Russian National Research Medical University, Department of Transplantology and Artificial Organs
| | - M. S. Novruzbekov
- Research Institute of Ambulance them. N.V. Sklifosovsky, liver transplant center; Pirogov Russian National Research Medical University, Department of Transplantology and Artificial Organs
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Hemodiafiltración en línea extendida asociada a diálisis con albúmina de paso simple, una alternativa factible para pacientes con insuficiencia hepatorrenal. Nefrologia 2021. [DOI: 10.1016/j.nefro.2021.09.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Duy Nguyen BT, Nguyen Thi HY, Nguyen Thi BP, Kang DK, Kim JF. The Roles of Membrane Technology in Artificial Organs: Current Challenges and Perspectives. MEMBRANES 2021; 11:239. [PMID: 33800659 PMCID: PMC8065507 DOI: 10.3390/membranes11040239] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/20/2021] [Accepted: 03/20/2021] [Indexed: 02/07/2023]
Abstract
The recent outbreak of the COVID-19 pandemic in 2020 reasserted the necessity of artificial lung membrane technology to treat patients with acute lung failure. In addition, the aging world population inevitably leads to higher demand for better artificial organ (AO) devices. Membrane technology is the central component in many of the AO devices including lung, kidney, liver and pancreas. Although AO technology has improved significantly in the past few decades, the quality of life of organ failure patients is still poor and the technology must be improved further. Most of the current AO literature focuses on the treatment and the clinical use of AO, while the research on the membrane development aspect of AO is relatively scarce. One of the speculated reasons is the wide interdisciplinary spectrum of AO technology, ranging from biotechnology to polymer chemistry and process engineering. In this review, in order to facilitate the membrane aspects of the AO research, the roles of membrane technology in the AO devices, along with the current challenges, are summarized. This review shows that there is a clear need for better membranes in terms of biocompatibility, permselectivity, module design, and process configuration.
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Affiliation(s)
- Bao Tran Duy Nguyen
- Department of Energy and Chemical Engineering, Incheon National University, Incheon 22012, Korea; (B.T.D.N.); (H.Y.N.T.); (B.P.N.T.)
| | - Hai Yen Nguyen Thi
- Department of Energy and Chemical Engineering, Incheon National University, Incheon 22012, Korea; (B.T.D.N.); (H.Y.N.T.); (B.P.N.T.)
| | - Bich Phuong Nguyen Thi
- Department of Energy and Chemical Engineering, Incheon National University, Incheon 22012, Korea; (B.T.D.N.); (H.Y.N.T.); (B.P.N.T.)
| | - Dong-Ku Kang
- Department of Chemistry, Incheon National University, Incheon 22012, Korea
| | - Jeong F. Kim
- Department of Energy and Chemical Engineering, Incheon National University, Incheon 22012, Korea; (B.T.D.N.); (H.Y.N.T.); (B.P.N.T.)
- Innovation Center for Chemical Engineering, Incheon National University, Incheon 22012, Korea
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Yang J, Nikanjam M, Best BM, Pinto J, Chadwick EG, Daar ES, Havens PL, Rakhmanina N, Capparelli EV. Population Pharmacokinetics of Lopinavir/Ritonavir: Changes Across Formulations and Human Development From Infancy Through Adulthood. J Clin Pharmacol 2018; 58:1604-1617. [PMID: 30252146 PMCID: PMC6604805 DOI: 10.1002/jcph.1293] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 07/06/2018] [Indexed: 11/05/2022]
Abstract
Lopinavir/ritonavir (LPV/r) is recommended by the World Health Organization as first-line treatment for HIV-infected infants and young children. We performed a composite population pharmacokinetic (PK) analysis on LPV plasma concentration data from 6 pediatric and adult studies to determine maturation and formulation effects from infancy to adulthood. Intensive PK data were available for infants, children, adolescents, and adults (297 intensive profiles/1662 LPV concentrations). LPV PK data included 1 adult, 1 combined pediatric-adult, and 4 pediatric studies (age 6 weeks to 63 years) with 3 formulations (gel-capsule, liquid, melt-extrusion tablets). LPV concentrations were modeled using nonlinear mixed effects modeling (NONMEM v. 7.3; GloboMax, Hanover, Maryland) with a one compartment semiphysiologic model. LPV clearance was described by hepatic plasma flow (QHP ) times hepatic extraction (EH ), with EH estimated from the PK data. Volume was scaled by linear weight (WT/70)1.0 . Bioavailability was assessed separately as a function of hepatic extraction and the fraction absorbed from the gastrointestinal tract. The absorption component of bioavailability increased with age and tablet formulation. Monte Carlo simulations of the final model using current World Health Organization weight-band dosing recommendations demonstrated that participants younger than 6 months of age had a lower area under the drug concentration-time curve (94.8 vs >107.4 μg hr/mL) and minimum observed concentration of drug in blood plasma (5.0 vs > 7.1 μg/mL) values compared to older children and adults. Although World Health Organization dosing recommendations include a larger dosage (mg/m2 ) in infants to account for higher apparent clearance, they still result in low LPV concentrations in many infants younger than 6 months of age receiving the liquid formulation.
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Affiliation(s)
- Jincheng Yang
- Skaggs School of Pharmacy and Pharmaceutical Science, University of California, San Diego, California
| | - Mina Nikanjam
- Division of Hematology-Oncology, University of California San Diego, California
| | - Brookie M. Best
- Skaggs School of Pharmacy and Pharmaceutical Science, University of California, San Diego, California
- Division of Host-Microbe Systems and Therapeutics, University of California San Diego School of Medicine, San Diego, California
| | - Jorge Pinto
- Division of Immunology, School of Medicine, Federal University of Minas Gerais, Minas Gerais, Brazil
| | - Ellen G. Chadwick
- Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Eric S. Daar
- Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, California
| | - Peter L. Havens
- Division of Pediatric Infectious Diseases, Medical College of Wisconsin and Children’s Hospital of Wisconsin, Milwauke, CA
| | - Natella Rakhmanina
- Division of Pediatric Infectious Diseases, Children’s National Medical Center; The George Washington University, Washington DC
- Elizabeth Glaser Pediatric AIDS Foundation, Washington DC
| | - Edmund V. Capparelli
- Skaggs School of Pharmacy and Pharmaceutical Science, University of California, San Diego, California
- Division of Host-Microbe Systems and Therapeutics, University of California San Diego School of Medicine, San Diego, California
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Sarin SK, Choudhury A. Management of acute-on-chronic liver failure: an algorithmic approach. Hepatol Int 2018; 12:402-416. [PMID: 30116993 DOI: 10.1007/s12072-018-9887-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 07/13/2018] [Indexed: 02/07/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a distinct syndrome of liver failure in a patient with chronic liver disease presenting with jaundice, coagulopathy and ascites and/or hepatic encephalopathy, developing following an acute hepatic insult and associated with high 28-day mortality. The definition though lacks global consensus, excludes patients with known distinct entities such as acute liver failure and those with end-stage liver disease. The initial Systemic Inflammatory Response Syndrome (SIRS) because of cytokine storm in relation to acute insult and/or subsequent development of sepsis due to immunoparalysis leads to extrahepatic organ failure. These cascades of events progress through a 'Golden Window' period of about 7 days, subsequent to which majority of the patients develop complications, such as sepsis and extrahepatic organ failure. Prevention of sepsis, support of organs and management of organ failure (commonly hepatic, renal, cerebral, coagulation) and early referral for transplant is crucial. The APASL ACLF research consortium (AARC) liver failure score is a dynamic prognostic model for management decisions and is superior to existing models. Aggressive multidisciplinary approach can lead to a transplant-free survival in nearly half of the cases. The present review provides an algorithmic approach to management of organ failure, sepsis prevention, use of dynamic prognostic models for management decision and is aimed to improve the skills for managing and improving the outcomes of such critically ill patients.
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Affiliation(s)
- Shiv Kumar Sarin
- Department of Hepatology and Liver Transplant, Institute of Liver and Biliary Sciences, D-1, VasantKunj, New Delhi, 110070, India.
| | - Ashok Choudhury
- Department of Hepatology and Liver Transplant, Institute of Liver and Biliary Sciences, D-1, VasantKunj, New Delhi, 110070, India
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Schmuck RB, Nawrot GH, Fikatas P, Reutzel-Selke A, Pratschke J, Sauer IM. Single Pass Albumin Dialysis-A Dose-Finding Study to Define Optimal Albumin Concentration and Dialysate Flow. Artif Organs 2016; 41:153-161. [DOI: 10.1111/aor.12736] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 12/29/2015] [Accepted: 02/04/2016] [Indexed: 12/21/2022]
Affiliation(s)
- Rosa Bianca Schmuck
- General, Visceral and Transplantation Surgery, & Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum; Germany
| | - Gesa-Henrike Nawrot
- General, Visceral and Transplantation Surgery, & Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum; Germany
| | - Panagiotis Fikatas
- General, Visceral and Transplantation Surgery, & Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum; Germany
| | - Anja Reutzel-Selke
- General, Visceral and Transplantation Surgery, & Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum; Germany
| | - Johann Pratschke
- General, Visceral and Transplantation Surgery, & Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum; Germany
| | - Igor Maximilian Sauer
- General, Visceral and Transplantation Surgery, & Experimental Surgery and Regenerative Medicine, Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum; Germany
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Lu J, Zhang X, Li J, Yu L, Chen E, Zhu D, Zhang Y, Li L. A New Fluidized Bed Bioreactor Based on Diversion-Type Microcapsule Suspension for Bioartificial Liver Systems. PLoS One 2016; 11:e0147376. [PMID: 26840840 PMCID: PMC4739599 DOI: 10.1371/journal.pone.0147376] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 01/04/2016] [Indexed: 12/25/2022] Open
Abstract
A fluidized bed bioreactor containing encapsulated hepatocytes may be a valuable alternative to a hollow fiber bioreactor for achieving the improved mass transfer and scale-up potential necessary for clinical use. However, a conventional fluidized bed bioreactor (FBB) operating under high perfusion velocity is incapable of providing the desired performance due to the resulting damage to cell-containing microcapsules and large void volume. In this study, we developed a novel diversion-type microcapsule-suspension fluidized bed bioreactor (DMFBB). The void volume in the bioreactor and stability of alginate/chitosan microcapsules were investigated under different flow rates. Cell viability, synthesis and metabolism functions, and expression of metabolizing enzymes at transcriptional levels in an encapsulated hepatocyte line (C3A cells) were determined. The void volume was significantly less in the novel bioreactor than in the conventional FBB. In addition, the microcapsules were less damaged in the DMFBB during the fluidization process as reflected by the results for microcapsule retention rates, swelling, and breakage. Encapsulated C3A cells exhibited greater viability and CYP1A2 and CYP3A4 activity in the DMFBB than in the FBB, although the increases in albumin and urea synthesis were less prominent. The transcription levels of several CYP450-related genes and an albumin-related gene were dramatically greater in cells in the DMFBB than in those in the FBB. Taken together, our results suggest that the DMFBB is a promising alternative for the design of a bioartificial liver system based on a fluidized bed bioreactor with encapsulated hepatocytes for treating patients with acute hepatic failure or other severe liver diseases.
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Affiliation(s)
- Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xiaoqian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jianzhou Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Liang Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Ermei Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Danhua Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yimin Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - LanJuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- * E-mail:
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11
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Deng F, Chen L, Zhang Y, Zhao S, Wang Y, Li N, Li S, Guo X, Ma X. Development of a bioreactor based on magnetically stabilized fluidized bed for bioartificial liver. Bioprocess Biosyst Eng 2015; 38:2369-77. [PMID: 26391509 DOI: 10.1007/s00449-015-1472-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Accepted: 09/07/2015] [Indexed: 12/12/2022]
Abstract
Bioartificial liver (BAL) based on microcapsules has been proposed as a potential treatment for acute liver failure. The bioreactors used in such BAL are usually expected to achieve sufficient flow rate and minimized void volume for effective application. Due to the superiorities in bed pressure drop and operation velocity, magnetically stabilized fluidized beds (MSFBs) show the potential to serve as ideal microcapsule-based bioreactors. In the present study, we attempted to develop a microcapsule-based MSFB bioreactor for bioartificial liver device. Compared to conventional-fluidized bed bioreactors, the bioreactor presented here increased perfusion velocity and decreased void volume significantly. Meanwhile, the mechanical stability as well as the immunoisolation property of magnetite microcapsules were well maintained during the fluidization. Besides, the magnetite microcapsules were found no toxicity to cell survival. Therefore, our study might provide a novel approach for the design of microcapsule-based bioartificial liver bioreactors.
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Affiliation(s)
- Fei Deng
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.,University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
| | - Li Chen
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.,University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
| | - Ying Zhang
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.
| | - Shan Zhao
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.,University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
| | - Yu Wang
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.,University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
| | - Na Li
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.,University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
| | - Shen Li
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.,University of Chinese Academy of Sciences, 19 Yuquan Road, Beijing, 100049, China
| | - Xin Guo
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China
| | - Xiaojun Ma
- Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China.
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12
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Lin CC, Wang CC, Hung KC, Chen CL, Yong CC, Young TH, Kobayash E. Study of porcine hepatocyte-entrapped bioartificial liver in surgery-induced fulminant hepatic failure rabbits. Biochem Eng J 2013. [DOI: 10.1016/j.bej.2013.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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13
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Effect of fulminant hepatic failure porcine plasma supplemented with essential components on encapsulated rat hepatocyte spheroids. Transplant Proc 2012; 44:1009-11. [PMID: 22564611 DOI: 10.1016/j.transproceed.2012.01.106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The development of bioartificial liver (BAL) systems has required detailed information about the functional capabilities of cultured hepatocytes during blood or plasma passage. In this study we investigated the effects of porcine plasma and various supplements on the viability and function of adult rat hepatocytes in vitro. Primary rat hepatocytes cultured in porcine plasma supplemented with various substances showed albumin synthesis rates and viability equal to or higher than those of controls. Supplementation with calcium chloride, magnesium sulfate, trace elements, amino acids, insulin, and epidermal growth factor were essential to maintain viability and high albumin synthesis. Especially, trace elements showed significantly higher and longer albumin secretion. Isolated rat hepatocytes were cultured in Spinner flasks for 24 hours to form spheroids that were harvested and encapsulated with chitosan-alginate solution before transfer to the bioreactor in the BAL system. Encapsulated rat hepatocyte spheroids cultured with porcine plasma including trace elements showed higher viability (57%) than controls (40%) after 24 hours, with ammonia removal values of 30.92 μg/10(6) cells versus the control 9.04 μg/10(6) cells. After 24 hours of operation the urea secretion value of encapsulated rat hepatocyte spheroids cultured in porcine plasma in the presence versus absence of trace elements was 76.73 μg/10(6) cells and 18.80 μg/10(6) cells, respectively. We concluded that encapsulated hepatocyte spheroids in a packed-bed bioreactor operated with human plasma including trace elements enhanced cell viability and liver function as a bases for an in vivo clinical trial of the BAL system.
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14
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Davidson AJ, Ellis MJ, Chaudhuri JB. A theoretical approach to zonation in a bioartificial liver. Biotechnol Bioeng 2012; 109:234-43. [PMID: 21809328 PMCID: PMC3579238 DOI: 10.1002/bit.23279] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Revised: 07/11/2011] [Accepted: 07/12/2011] [Indexed: 01/19/2023]
Abstract
Bioartificial livers have yet to gain clinical acceptance. In a previous study, a theoretical model was utilized to create operating region charts that graphically illustrated viable bioartificial liver configurations. On this basis a rationale for the choice of operating and design parameters for the device was created. The concept is extended here to include aspects of liver zonation for further design optimization. In vivo, liver cells display heterogeneity with respect to metabolic activity according to their position in the liver lobule. It is thought that oxygen tension is a primary modulator of this heterogeneity and on this assumption a theoretical model to describe the metabolic zonation within an in vitro bioartificial liver device has been adopted. The distribution of the metabolic zones under varying design and operating parameters is examined. In addition, plasma flow rates are calculated that give rise to an equal distribution of the metabolic zones. The results show that when a clinically relevant number of cells are contained in the BAL (10 billion), it is possible to constrain each of the three metabolic zones to approximately one-third of the cell volume. This is the case for a number of different bioreactor designs. These considerations allow bioartificial liver design to be optimized.
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Affiliation(s)
- Adam J Davidson
- Centre for Regenerative Medicine, Department of Chemical Engineering, University of BathBath BA2 7AY, UK
| | - Marianne J Ellis
- Centre for Regenerative Medicine, Department of Chemical Engineering, University of BathBath BA2 7AY, UK
| | - Julian B Chaudhuri
- Centre for Regenerative Medicine, Department of Chemical Engineering, University of BathBath BA2 7AY, UK
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15
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Pless G, Sauer IM, Rauen U. Improvement of the cold storage of isolated human hepatocytes. Cell Transplant 2011; 21:23-37. [PMID: 21669032 DOI: 10.3727/096368911x580509] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Increasing amounts of human hepatocytes are needed for clinical applications and different fields of research, such as cell transplantation, bioartificial liver support, and pharmacological testing. This demand calls for adequate storage options for isolated human liver cells. As cryopreservation results in severe cryoinjury, short-term storage is currently performed at 2-8°C in preservation solutions developed for the storage of solid organs. However, besides slowing down cell metabolism, cold also induces cell injury, which is, in many cell types, iron dependent and not counteracted by current storage solutions. In this study, we aimed to characterize storage injury to human hepatocytes and develop a customized solution for cold storage of these cells. Human hepatocytes were isolated from material obtained from partial liver resections, seeded in monolayer cultures, and, after a preculture period, stored in the cold in classical and new solutions followed by rewarming in cell culture medium. Human hepatocytes displayed cold-induced injury, resulting in >80% cell death (LDH release) after 1 week of cold storage in University of Wisconsin solution or cell culture medium and 3 h of rewarming. Cold-induced injury could be significantly reduced by the addition of the iron chelators deferoxamine and LK 614. Experiments with modified solutions based on the new organ preservation solution Custodiol-N showed that ion-rich variants were better than ion-poor variants, chloride-rich solutions better than chloride-poor solutions, potassium as main cation superior to sodium, and pH 7.0 superior to pH 7.4. LDH release after 2 weeks of cold storage in the thus optimized solution was below 20%, greatly improving cold storage of human hepatocytes. The results were confirmed by the assessment of hepatocellular mitochondrial membrane potential and functional parameters (resazurin reduction, glucagon-stimulated glucose liberation) and thus suggest the use of a customized hepatocyte storage solution for the cold storage of these cells.
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Affiliation(s)
- Gesine Pless
- Institut für Physiologische Chemie, Universitätsklinikum Essen, Essen, Germany
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16
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Continuous veno-venous single-pass albumin hemodiafiltration in children with acute liver failure. Pediatr Crit Care Med 2011; 12:257-64. [PMID: 20921923 DOI: 10.1097/pcc.0b013e3181f35fa2] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVE To investigate the applicability, efficacy, and safety of single-pass albumin dialysis in children. DESIGN Retrospective data review of uncontrolled clinical data. SETTING University-based pediatric intensive care unit collaborating with a local center for liver transplantation. PATIENTS Nine children, aged 2 to 15 yrs, who were treated with single-pass albumin dialysis for acute liver failure of various origins under a compassionate-use protocol between 2000 and 2006. All patients met high-urgency liver transplantation criteria. INTERVENTIONS Single-pass albumin dialysis was performed as rescue therapy for children with acute liver failure. MEASUREMENTS AND MAIN RESULTS The decrease in hepatic encephalopathy (grades 1-4) and the serum levels of bilirubin, bile acids, and ammonium were measured to assess the efficacy of detoxification. As a measure of liver synthesis function, thromboplastin time and fibrinogen were analyzed. The safety of the procedure was assessed by documenting adverse effects on mean arterial blood pressure, platelet count, and clinical course. Seven out of nine patients were bridged successfully to either native organ recovery (n = 1) or liver transplantation (n = 6), one of them twice. Six out of nine patients undergoing single-pass albumin dialysis (ten treatments) survived. In six patients, hepatic encephalopathy could be reduced at least by one degree. Ammonium, bilirubin, and bile acid levels decreased in all patients. One patient had an allergic reaction to albumin. CONCLUSIONS In childhood acute liver failure, treatment with single-pass albumin dialysis was generally well tolerated and seems to be effective in detoxification and in improving blood pressure, thus stabilizing the critical condition of children before liver transplantation and facilitating bridging to liver transplantation. It may be beneficial in avoiding severe neurologic sequelae after acute liver failure and thereby improve survival. Single-pass albumin dialysis is an inexpensive albumin-based detoxification system that is easy to set up and requires little training. Whether and to what extent single-pass albumin dialysis can support children with acute liver failure until native liver recovery remains unclear.
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17
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Kahan BD. Forty years of publication of Transplantation Proceedings--the fourth decade: Globalization of the enterprise. Transplant Proc 2011; 43:3-29. [PMID: 21335147 DOI: 10.1016/j.transproceed.2010.12.052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Barry D Kahan
- Division of Immunology and Organ Transplantation, The University of Texas-Health Science Center at Houston Medical School, Houston, Texas 77030, USA.
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18
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Davidson AJ, Ellis MJ, Chaudhuri JB. A theoretical method to improve and optimize the design of bioartificial livers. Biotechnol Bioeng 2010; 106:980-8. [PMID: 20506230 DOI: 10.1002/bit.22765] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Bioartificial livers (BALs) are a potentially effective countermeasure against liver failure, particularly in cases of acute or fulminant liver failure. It is hoped these devices can sustain a patient's liver function until recovery or transplant. However, no large-scale clinical trial has yet proven that BALs are particularly effective and evidently design issues remain to be addressed. One aspect of BAL design that must be considered is the mass transfer of adequate oxygen to the hepatocytes within the device. We present here a mathematical modeling approach to oxygen mass transport in a BAL. A mathematical model based upon Krogh cylinders is outlined to describe a diffusion-limited hollow fiber bioreactor. In addition, operating constraints are defined on the system--cells should not experience hypoxia and the cell population should be of adequate size. By combining modeling results with these operating constraints and presenting the results graphically, "operating region" charts can be constructed for the hollow fiber BAL (HF-BAL). The effects of varying various operating parameters on the BAL are then established. It is found that smaller radii and short, thin walled fibers are generally advantageous while cell populations in excess of 10 billion could be supported in the BAL with a plasma flow rate of 200 mL/min. For fibers of intermediate length and lumen radius, the minimum number of fibers required to produce a viable design ranges approximately from 7,000-10,000. In theory, this may be enough to support patients with failing livers.
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Affiliation(s)
- Adam J Davidson
- Department of Chemical Engineering, Centre for Regenerative Medicine, University of Bath, Bath BA2 7AY, UK
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19
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Abstract
In the last 15 years many different liver cell culture devices, consisting of functional liver cells and artificial materials, have been developed. They have been devised for numerous different applications, such as temporary organ replacement (a bridge to liver transplantation or native liver regeneration) and as in vitro screening systems in the early stages of the drug development process, like assessing hepatotoxicity, hepatic drug metabolism, and induction/inhibition studies. Relevant literature is summarized about artificial human liver cell culture systems by scrutinizing PubMed from 2003 to 2009. Existing devices are divided in 2D configurations (e.g., static monolayer, sandwich, perfused cells, and flat plate) and 3D configurations (e.g., liver slices, spheroids, and different types of bioreactors). The essential features of an ideal liver cell culture system are discussed: different types of scaffolds, oxygenation systems, extracellular matrixes (natural and artificial), cocultures with nonparenchymal cells, and the role of shear stress problems. Finally, miniaturization and high-throughput systems are discussed. All these factors contribute in their own way to the viability and functionality of liver cells in culture. Depending on the aim for which they are designed, several good systems are available for predicting hepatotoxicity and hepatic metabolism within the general population. To predict hepatotoxicity in individual cases genomic analysis might be essential as well.
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Affiliation(s)
- B Andria
- Center of Biotechnologies, Cardarelli Hospital, Naples, Italy; †Faculty of Pharmacy, 'Federico II" University, Naples, Italy
| | - A Bracco
- Center of Biotechnologies, Cardarelli Hospital , Naples , Italy
| | - G Cirino
- † Faculty of Pharmacy, 'Federico II" University , Naples , Italy
| | - R A F M Chamuleau
- ‡ Academic Medical Center, Tytgat Institute for Liver and Intestinal Research, University of Amsterdam , Amsterdam , The Netherlands
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20
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Fonsato V, Herrera MB, Buttiglieri S, Gatti S, Camussi G, Tetta C. Use of a rotary bioartificial liver in the differentiation of human liver stem cells. Tissue Eng Part C Methods 2010; 16:123-32. [PMID: 19397473 DOI: 10.1089/ten.tec.2008.0634] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
The use of bioartificial livers (BALs) for the expansion of human adult liver stem cells and the production of growth factors could be a potential strategy for cell-based extracorporeal liver support. The present study aimed to assessing the differentiation of human adult liver stem cells in a rotary BAL. Liver stem cells were seeded into a polysulphone membrane filter at a density of 3 x 10(8) cells, and the filter was connected to a rotary bioreactor perfusion system (37 degrees C, 50 mL/min, 48 h). Viability, cell differentiation, and metabolic performances were evaluated at 24 and 48 h. Hepatocyte growth factor production from human adult liver stem cells, mature hepatocytes, and mesenchymal stem cells in adhesion and in the rotary BAL conditions was compared. Liver stem cells cultured in the rotary BAL produced the highest amounts of albumin (p = 0.002) and ammonia-induced urea (p = 0.0001), and had an increased cytochrome P450 expression in respect to liver stem cells in adhesion. Remarkably, liver stem cells in the rotary BAL produced very high amounts of hepatocyte growth factor (p = 0.005) in respect to hepatocytes and mesenchymal stem cells. Moreover, the cells lost their stem cell markers and acquired several markers of mature hepatocytes. In conclusion, the rotary BAL favored liver stem cell differentiation into mature hepatocyte-like cells.
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Affiliation(s)
- Valentina Fonsato
- Department of Internal Medicine, University of Turin , San Giovanni Battista Molinette Hospital,Turin, Italy.
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21
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22
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Abstract
Transplant professionals are often faced with ethical situations in practice. In the field of pediatric transplantation, these ethical dilemmas can be even more profound than in adults. Transplant professionals must have a firm foundation of professional and personal ethical principles in order to handle ethical situations they encounter. This paper provides an ethical review of issues that arise during live liver donation from a parent to a child.
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Affiliation(s)
- Kara Ann Ventura
- Morgan Stanley Children's Hospital of New York Presbyterian, New York
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23
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Wurm M, Lubei V, Caronna M, Hermann M, Buttiglieri S, Bodamer O, Muehl A, Tetta C, Margreiter R, Hengster P. Introduction of a Novel Prototype Bioartificial Liver Support System Utilizing Small Human Hepatocytes in Rotary Culture. Tissue Eng Part A 2009; 15:1063-73. [DOI: 10.1089/ten.tea.2008.0217] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Affiliation(s)
- Martin Wurm
- Department of General and Transplant Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Verena Lubei
- Department of General and Transplant Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Martin Hermann
- KMT Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Olaf Bodamer
- University Clinic for Paediatrics and Adolescent Medicine, Vienna Medical University, Vienna, Austria
| | - Adolf Muehl
- University Clinic for Paediatrics and Adolescent Medicine, Vienna Medical University, Vienna, Austria
| | - Ciro Tetta
- Research and Development, Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany
| | - Raimund Margreiter
- Department of General and Transplant Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Paul Hengster
- Department of General and Transplant Surgery, Medical University of Innsbruck, Innsbruck, Austria
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24
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Abstract
Liver transplantation is the only established treatment for acute liver failure (ALF), one of the most challenging clinical syndromes; however, donor shortages remain problematic. Artificial livers as a bridge to liver transplantation are being considered worldwide. Non-bioarticifical liver (NBAL) have limitations in improving the survival rates. Therefore, a biological artificial liver (BAL) that has metabolic, detoxic,and synthetic function of hepatocytes is anticipated. Biological artificial livers are classified by cell source, types of culture system for hepatocytes, and types of bioreactor. This paper reviews the bioartificial liver devices that have been clinically tested to support ALF patients. Finally, we identify several improvements critical to bioartificial liver replacement therapy in the future.
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25
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Abstract
Extracorporeal therapy has expanded significantly over the past few decades from solely artificial renal replacement therapy. In patients with multiple organ dysfunction syndrome, it becomes necessary to provide multiple organ support therapy. Technological advances have opened the door to a multifaceted intervention directed at supporting the function of multiple organs through the treatment of blood. Indications for "old" therapies such as hemofiltration and adsorption have been expanded, and using these therapies in combination further enhances blood detoxification capabilities. Furthermore, new devices are constantly in development. Nanotechnology allows us to refine membrane characteristics and design innovative monitoring/biofeedback devices. Miniaturization is leading down the path of wearable/implantable devices. With the incorporation of viable cells within medical devices, these instruments become capable not only of detoxification but synthetic functions as well, bringing us closer to the holy grail of complete replacement of organ function. This article provides a brief overview of current and future direction in extracorporeal support in the critical care setting.
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26
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Zhang SC, Wang YJ, Chen Z, Liu T, Liu J. Preliminary study of the viability of neonatal mini-porcine hepatocytes in extracorporeal circulation. Shijie Huaren Xiaohua Zazhi 2007; 15:3787-3792. [DOI: 10.11569/wcjd.v15.i36.3787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the viability of neonatal mini-porcine hepatocytes in extracorporeal circulation.
METHODS: A hepatocyte circulation system was constructed with Cello artificial capillary culture equipment and freshly isolated hepatocyte suspensions were circulated at 50 mL/min in vitro. The viability, function and morphological characteristics of hepatocytes were examined within 8 hours.
RESULTS: After 4 hours circulation, the viability and adherence ratio of hepatocytes were 76.1% ± 1.4% and 62.8% ± 1.8%, respectively, and the ratio of amino clearance was about 62.7% ± 14.6% of that in the control group. However, with time, many fragments of hepatocytes were observed in the circulating suspensions, as well as a significant increase in lactate dehydrogenase and aspartate aminotransferase (P < 0.01). The cell viability and adherence ratio, synthesis of urea and albumin, and the clearance rate of ammonia also decreased significantly (P < 0.05).
CONCLUSION: Porcine hepatocyte suspensions can be applied to BAL system in a circulation condition in order to strengthen the mass exchange. However, these cells need to be changed regularly to maintain cellular viability and the supporting effects of BAL.
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27
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Shinohara H, Shimada M, Ikemoto T, Morine Y, Imura S, Fujii M, Imaizumi T, Murayama M, Aiba Y. New type of artificial liver support system (ALSS) using the photocatalytic effect of titanium oxide. Dig Dis Sci 2007; 52:2271-5. [PMID: 17431780 DOI: 10.1007/s10620-006-9701-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2006] [Accepted: 11/26/2006] [Indexed: 01/04/2023]
Abstract
Although various types of artificial liver support systems (ALSSs) including a hybrid type have been made, few are practical ALSSs for treatment of acute and/or chronic hepatic failure. Titanium oxide (TiO(2)), a stable material, dismantles various materials using a photocatalytic action under ultraviolet irradiation. The aim of this study was to assess the effect of a new ALSS using TiO(2). Hepatic failure plasma obtained from patients undergoing plasma exchange therapy due to acute liver failure was used in these experiments. The plasma was perfused using a closed circuit model with a column filled with TiO(2). The plasma concentrations of total bilirubin, albumin, fibrinogen, interleukin (IL)-6, IL-8, and IL-10 were serially measured. We evaluated the photocatalytic effect of TiO(2) irradiated with ultraviolet light. The effect of initial perfusion with fresh-frozen plasma (FFP) was also investigated, focusing on the decrease in fibrinogen during perfusion. Levels of total bilirubin decreased after perfusion using the column filled with TiO(2), compared with no UV irradiation. The levels of IL-6, IL-8, and IL-10 decreased after perfusion using the TiO(2) device. The albumin level was maintained at the initial level, however, the fibrinogen level decreased within 4 hr. Initial perfusion of the circuit with FFP improved the decrease in fibrinogen for up to 8 hr. Our new perfusion device using the photocatalytic action of TiO(2) may be a promising ALSS.
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Affiliation(s)
- Hisamitsu Shinohara
- Department of Digestive and Pediatric Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima City, Tokushima 770-8503, Japan
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28
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Penafiel A, Devanand A, Tan HK, Eng P. Use of molecular adsorbent recirculating system in acute liver failure attributable to dengue hemorrhagic fever. J Intensive Care Med 2006; 21:369-71. [PMID: 17095501 DOI: 10.1177/0885066606293384] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Fulminant liver failure is an uncommon but life-threatening complication of severe dengue infection. Molecular adsorbent recirculating system (MARS), which reverses hepatic encephalopathy, is an emerging important element in the armamentarium of organ support in the intensive care unit in patients suffering from acute liver failure. We report an intensive care unit case of fulminant liver failure secondary to dengue hemorrhagic fever, which was supported with MARS. MARS led to rapid reversal of biochemical profile and encephalopathy, resulting in early extubation and intensive care unit discharge.
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Affiliation(s)
- Alvin Penafiel
- Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore.
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29
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Abstract
The incidence of hyperbilirubinemia is high clinically, which is difficult to cure by medication, surgery or interventional therapies. Non-bioartificial liver is the main alternative in the blood purification for hyperbilirubinemia, which includes plasma exchange, hemoperfusion, hemodialysis, molecular adsorbent recycling system and so on. The research results and clinical experiences in China show that these methods are effective in lowering high levels of bilirubin with fewer side effects. The hyperbilirubinemias of different causes, with different complications or accompanying different diseases can be treated by different methods. Bioartificial liver, hybrid artificial liver support system and adsorbent membrane material have also been studied and their development in reducing hyperbilirubinemias has been achieved. This article gives a brief overview on the actuality and research improvement in blood purification for hyperbilirubinemia in China.
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Affiliation(s)
- Zhi-Jun Duan
- Department of Gastroenterology, First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China.
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30
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Hentze H, Graichen R, Colman A. Cell therapy and the safety of embryonic stem cell-derived grafts. Trends Biotechnol 2006; 25:24-32. [PMID: 17084475 DOI: 10.1016/j.tibtech.2006.10.010] [Citation(s) in RCA: 137] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2006] [Revised: 10/06/2006] [Accepted: 10/26/2006] [Indexed: 10/23/2022]
Abstract
Recent developments in the identification, in vitro culture and differentiation of stem cells point to the unprecedented potential of these cells, or their derivatives, to cure degenerative disorders. Human embryonic stem cells (hESC) offer the particular advantage of prolonged proliferative capacity and great versatility in the lineages that can be formed in culture. Translating these advantages into clinical benefits faces many challenges, including efficient differentiation into the desired cell type(s), maintaining genetic stability during long-term culture and, finally, ensuring the absence of potentially tumorigenic hESC from the final product. It is this final safety issue that will form the focus of this review.
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Affiliation(s)
- Hannes Hentze
- ES Cell International, 11 Biopolis Way, #05-06 Helios Building, 138667 Singapore, Republic of Singapore
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