Wikipedia

Liver support system

A liver support system or diachysis is a type of therapeutic device to assist in performing the functions of the liver. Such systems focus either on removing the accumulating toxins (liver dialysis), or providing additional replacement of the metabolic functions of the liver through the inclusion of hepatocytes to the device (bioartificial liver device). A diachysis machine is used for acute care i.e. emergency care, as opposed to a dialysis machine which are typically used over the longer term. These systems are being trialed to help people with acute liver failure (ALF) or acute-on-chronic liver failure.[1]

Liver support systems
SpecialtyHepatology

The primary functions of the liver include removing toxic substances from the blood, manufacturing blood proteins, storing energy in the form of glycogen, and secreting bile. The hepatocytes that perform these tasks can be killed or impaired by disease, resulting in acute liver failure (ALF) which can be seen in person with previously diseased liver or a healthy one.

Etymology

edit
  • The word diachysis derives from the Greek word, διάχυσησ, which means "Diffusion"
  • The word dialysis derives from the Greek word, διάλυσις, which means "Dissolution"

Liver failure

edit
Classification of acute liver failure
HyperacuteAcuteSubacute
Interval between jaundice and encephalopathy (days) 0-7 8-28 29-84
Survival (%) without liver transplant 36 7 14
Coagulation disorder +++ ++ +
Jaundice + ++ +++
Cerebral edema ++ ++ +/-
Most frequent etiology Paracetamol
Hepatitis A
Hepatitis E
Ischemia		 Hepatitis B drugs Non-paracetamol

In hyperacute and acute liver failure, the clinical picture develops rapidly with progressive encephalopathy and multiorgan dysfunction such as hyperdynamic circulation, coagulopathy, acute kidney injury and respiratory insufficiency, severe metabolic alterations, and cerebral edema that can lead to brain death.[2][3] In these cases the mortality without liver transplantation (LTx) ranges between 40-80%.[4][5] LTx is the only effective treatment for these patients although it requires a precise indication and timing to achieve good results. Nevertheless, due to the scarcity of organs to carry out liver transplantations, it is estimated that one third of patients with ALF die while waiting to be transplanted.[6]

On the other hand, a patient with a chronic hepatic disease can suffer acute decompensation of liver function following a precipitating event such as variceal bleeding, sepsis and excessive alcohol intake among others that can lead to a condition referred to as acute-on-chronic liver failure (ACLF).

Both types of hepatic insufficiency, ALF and ACLF, can potentially be reversible and liver functionality can return to a level similar to that prior to the insult or precipitating event.

LTx has shown an improvement in the prognosis and survival with severe cases of ALF. Nevertheless, cost and donor scarcity have prompted researchers to look for new supportive treatments that can act as "bridge" to the transplant procedure. By stabilizing the patient's clinical state, or by creating the right conditions that could allow the recovery of native liver functions, both detoxification and synthesis can improve, after an episode of ALF or ACLF.[7]

Three different types of supportive therapies have been developed: bio-artificial, artificial and hybrid liver support systems (Table 2).

Table 2: Liver Support Systems
Bio-artificialArtificialHybrids
ELAD[8]

Extracorporeal liver assist device

 MARS[9]

Molecular adsorbent recirculating system

Hepat-Assist[10]
BLSS[11]

Bioartificial Liver Support System

Prometheus FPSA[12]

Fractionated plasma separation and adsorption system

 TECLA-HALSS[13]

TECA-Hybrid Artificial Liver Support System

RFB[14]

Radial Flow Bioreactor

 SPAD[15]

Single-pass albumin dialysis

 MELS[16]

Modular Extracorporeal Liver Support

AMC-BAL[17]

Bioartificial Liver

 SEPET[18]

Selective plasma filtration therapy

 -

Bioartificial liver devices

edit
Bioartificial liver device
SpecialtyInternal medicine

Bioartificial liver devices are experimental extracorporeal devices that use living cell lines to provide detoxification and synthesis support to the failing liver. Bio-artificial liver (BAL) Hepatassist 2000 uses porcine hepatocytes whereas ELAD system employs hepatocytes derived from human hepatoblastoma C3A cell lines.[19][20] Both techniques can produce, in fulminant hepatic failure (FHF), an improvement of hepatic encephalopathy grade and biochemical parameters. Potential side effects that have been documented include immunological issues (porcine endogenous retrovirus transmission), infectious complications, and tumor transmigration.

Other biological hepatic systems are Bioartificial Liver Support (BLSS) and Radial Flow Bioreactor (RFB). Detoxification capacity of these systems is poor and therefore they must be used combined with other systems to mitigate this deficiency. Today, its use is limited to centers with high experience in their application.[21]

A bioartificial liver device (BAL) is an artificial extracorporeal liver support (ELS) system for an individual who is suffering from acute liver failure (ALF) or acute-on-chronic liver failure (ACLF). The fundamental difference between artificial and BAL systems lies in the inclusion of hepatocytes into the reactor, often operating alongside the purification circuits used in artificial ELS systems. The overall design varies between different BAL systems, but they largely follow the same basic structure, with patient blood or plasma flow through an artificial matrix housing hepatocytes. Plasma is often separated from the patient's blood to improve efficiency of the system, and the device can be connected to artificial liver dialysis devices in order to further increase the effectiveness of the device in filtration of toxins. The inclusion of functioning hepatocytes in the reactor allows the restoration of some of the synthetic functions that the patient's liver is lacking.[22]

History

edit

Early history

edit

The first bioartificial liver device was developed in 1993 by Dr. Achilles A. Demetriou at Cedars-Sinai Medical Center. The bioartificial liver helped an 18-year-old southern California woman survive without her own liver for 14 hours until she received a human liver using a 20-inch-long, 4-inch-wide plastic cylinder filled with cellulose fibers and pig liver cells. Blood was routed outside the patient's body and through the artificial liver before being returned to the body.[23][24]

Dr. Kenneth Matsumara's work on the BAL led it to be named an invention of the year by Time magazine in 2001.[25] Liver cells obtained from an animal were used instead of developing a piece of equipment for each function of the liver. The structure and function of the first device also resembles that of today's BALs. Animal liver cells are suspended in a solution and a patient's blood is processed by a semipermeable membrane that allow toxins and blood proteins to pass but restricts an immunological response.[25]

Development

edit

Advancements in bioengineering techniques in the decade after Matsumara's work have led to improved membranes and hepatocyte attachment systems.[26] Cell sources now include primary porcine hepatocytes, primary human hepatocytes, human hepatoblastoma (C3A), immortalized human cell lines and stem cells.[26]

Use

edit

The purpose of BAL-type devices is not to permanently replace liver functions, but to serve as a supportive device,[27] either allowing the liver to regenerate properly upon acute liver failure, or to bridge the individual's liver functions until a transplant is possible.

Function

edit

BALs are essentially bioreactors, with embedded hepatocytes (liver cells) that perform the functions of a normal liver. They process oxygenated blood plasma, which is separated from the other blood constituents.[28] Several types of BALs are being developed, including hollow fiber systems and flat membrane sheet systems.[29]

Various types of hepatocytes are used in these devices. Porcine hepatocytes are often used due to ease of acquisition and cost; however, they are relatively unstable and carry the risk of cross-species disease transmission.[30] Primary human hepatocytes sourced from donor organs present several problems in their cost and difficulty to obtain, especially with the current lack in transplantable tissue.[30] In addition, questions have been raised about tissue collected from patients transmitting malignancy or infection via the BAL device. Several lines of human hepatocytes are also used in BAL devices, including C3A and HepG2 tumour cell lines, but due to their origin from hepatomas, they possess the potential to pass on malignancy to the patient.[31] There is ongoing research into the cultivation of new types of human hepatocytes capable of improved longevity and efficacy in a bioreactor over currently used cell types, that do not pose the risk of transfer of malignancy or infection, such as the HepZ cell line created by Werner et al..[32]

Hollow fibre systems

edit

Similar to kidney dialysis, hollow fiber systems employ a hollow fiber cartridge. Hepatocytes are suspended in a gel solution such as collagen, which is injected into a series of hollow fibers. In the case of collagen, the suspension is then gelled within the fibers, usually by a temperature change. The hepatocytes then contract the gel by their attachment to the collagen matrix, reducing the volume of the suspension and creating a flow space within the fibers. Nutrient media is circulated through the fibers to sustain the cells. During use, plasma is removed from the patients blood. The patient's plasma is fed into the space surrounding the fibers. The fibers, which are composed of a semi-permeable membrane, facilitate transfer of toxins, nutrients and other chemicals between the blood and the suspended cells. The membrane also keeps immune bodies, such as immunoglobulins, from passing to the cells to prevent an immune system rejection.[33]

Cryogel-Based Systems

edit

Currently, hollow-fibre bioreactors are the most commonly accepted design for clinical use due to their capillary-network allowing for easy perfusion of plasma across cell populations.[34] However, these structures have their limitations, with convectional transport issues, nutritional gradients, non-uniform seeding, inefficient immobilisation of cells, and reduced hepatocyte growth restricting their effectiveness in BAL designs.[35] Researchers are now investigating the use of cryogels to replace hollow-fibres as the cell carrier components in BAL systems.

Cryogels are super-macroporous three-dimensional polymers prepared at sub-zero temperatures, by the freezing of a solution of cryogel precursors and solvent. The pores develop during this freezing process – as the cryogel solution cools, the solvent begins to form crystals. This causes the concentration of the cryogel precursors in the solution to increase, initiating the cryogelation process and forming the polymer walls. As the cryogel warms, the solvent crystals thaw, leaving cavities that form the pores.[36] Cryogel pores range in size from 10-100 μm in size, forming an interconnected network that mimics a capillary system with a very large surface area to volume ratio, supporting large numbers of immobilised cells. Convection mediated transport is also supported by cryogels, enabling even distribution of nutrients and metabolite elimination, overcoming some of the shortcomings of hollow-fibre systems.[35] Cryogel scaffolds demonstrate good mechanical strength and biocompatibility without triggering an immune response, improving their potential for long-term inclusion in BAL devices or in-vitro use.[37] Another advantage of cryogels is their flexibility for use in a variety of tasks, including separation and purification of substances, along with acting as extracellular matrix for cell growth and proliferation. Immobilisation of specific ligands onto cryogels enables adsorption of specific substances, supporting their use as treatment options for toxins,[38] for separation of haemoglobin from blood,[39] and as a localised and sustained method for drug delivery.[40]

Liver dialysis

edit

Artificial liver support systems are aimed to temporarily replace native liver detoxification functions and they use albumin as scavenger molecule to clear the toxins involved in the physiopathology of the failing liver. Most of the toxins that accumulate in the plasma of patients with liver insufficiency are protein bound, and therefore conventional renal dialysis techniques, such as hemofiltration, hemodialysis or hemodiafiltration are not able to adequately eliminate them.

Liver dialysis has shown promise for patients with hepatorenal syndrome. It is similar to hemodialysis and based on the same principles, but hemodialysis does not remove toxins bound to albumin that accumulate in liver failure. Like a bioartificial liver device, it is a form of artificial extracorporeal liver support.[41][42]

A critical issue of the clinical syndrome in liver failure is the accumulation of toxins not cleared by the failing liver. Based on this hypothesis, the removal of lipophilic, albumin-bound substances such as bilirubin, bile acids, metabolites of aromatic amino acids, medium-chain fatty acids and cytokines should be beneficial to the clinical course of a patient in liver failure. This led to the development of artificial filtration and absorption devices.

Liver dialysis is performed by physicians and surgeons and specialized nurses with training in gastroenterological medicine and surgery, namely, in hepatology, alongside their colleagues in the intensive or critical care unit and the transplantation department, which is responsible for procuring and implanting a new liver, or a part (lobe) of one, if and when it becomes available in time and the patient is eligible. Because of the need for these experts, as well as the relative newness of the procedure in certain areas, it is usually available only in larger hospitals, such as level I trauma center teaching hospitals connected with medical schools.

Between the different albumin dialysis modalities, single pass albumin dialysis (SPAD) has shown some positive results at a very high cost;[43] it has been proposed that lowering the concentration of albumin in the dialysate does not seem to affect the detoxification capability of the procedure.[44] Nevertheless, the most widely used systems today are based on hemodialysis and adsorption. These systems use conventional dialysis methods with an albumin containing dialysate that is later regenerated by means of adsorption columns, filled with activated charcoal and ion exchange resins. At present, there are two artificial extracorporeal liver support systems: the Molecular Adsorbents Recirculating System (MARS) from Gambro and Fractionated Plasma Separation and Adsorption (FPSA), commercialised as Prometheus (PROM) from Fresenius Medical Care. Of the two therapies, MARS is the most frequently studied, and clinically used system to date.

Prognosis/survival

edit

Liver dialysis is currently only considered to be a bridge to transplantation or liver regeneration (in the case of acute liver failure)[45][46][47] and, unlike kidney dialysis (for kidney failure), cannot support a patient for an extended period of time (months to years).[48]

See also

edit

References

edit
  1. ↑ Pless, G. (2007). "Artificial and bioartificial liver support". Organogenesis. 3 (1): 20–24. doi:10.4161/org.3.1.3635. PMC 2649611. PMID 19279696.
  2. ↑ Shakil, OA; Kramer D; Mazariegos GV; Fung JJ; Rakela J (2000). "Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria". Liver Transpl. 6 (2): 163–169. doi:10.1002/lt.500060218. PMID 10719014. S2CID 33789452.
  3. ↑ Jalan, R; Williams R (2002). "Acute on chronic liver failure. Pathophysiological basis of therapeutic options". Blood Purif. 20 (3): 252–261. doi:10.1159/000047017. PMID 11867872. S2CID 36924439.
  4. ↑ Stravitz, RT (2008). "Critical management decisions in patients with acute liver failure". Chest. 134 (5): 1092–1102. doi:10.1378/chest.08-1071. PMID 18988787.
  5. ↑ Auzinger, G; Wendon, J (April 2008). "Intensive care management of acute liver failure". Current Opinion in Critical Care. 14 (2): 179–88. doi:10.1097/MCC.0b013e3282f6a450. PMID 18388681. S2CID 1289311.
  6. ↑ Sen, S; Williams R; Jalan R (2005). "Emerging indications for albumin dialysis". Am. J. Gastroenterol. 100 (2): 468–475. doi:10.1111/j.1572-0241.2005.40864.x. PMID 15667509. S2CID 20937240.
  7. ↑ Allen, JW; Hassanein, T; Bhatia, SN (September 2001). "Advances in bioartificial liver devices". Hepatology. 34 (3): 447–55. doi:10.1053/jhep.2001.26753. PMID 11526528. S2CID 6852149.
  8. ↑ Sussman, NL; Chong, MG; Koussayer, T; He, DE; Shang, TA; Whisennand, HH; Kelly, JH (July 1992). "Reversal of fulminant hepatic failure using an extracorporeal liver assist device". Hepatology. 16 (1): 60–5. doi:10.1002/hep.1840160112. PMID 1618484. S2CID 45920140.
  9. ↑ Stange, J; Ramlow, W; Mitzner, S; Schmidt, R; Klinkmann, H (September 1993). "Dialysis against a recycled albumin solution enables the removal of albumin-bound toxins". Artificial Organs. 17 (9): 809–13. doi:10.1111/j.1525-1594.1993.tb00635.x. PMID 8240075.
  10. ↑ Demetriou AA, Brown RS Jr, Busuttil RW, Fair J, McGuire BM, Rosenthal P, Am Esch JS 2nd, Lerut J, Nyberg SL, Salizzoni M, Fagan EA, de Hemptinne B, Broelsch CE, Muraca M, Salmeron JM, Rabkin JM, Metselaar HJ, Pratt D, De La Mata M, McChesney LP, Everson GT, Lavin PT, Stevens AC, Pitkin Z, Solomon BA (May 2004). "Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure". Annals of Surgery. 239 (5): 660–7, discussion 667–70. doi:10.1097/01.sla.0000124298.74199.e5. PMC 1356274. PMID 15082970.
  11. ↑ Mazariegos GV, Patzer JF 2nd, Lopez RC, Giraldo M, Devera ME, Grogan TA, Zhu Y, Fulmer ML, Amiot BP, Kramer DJ (March 2002). "First clinical use of a novel bioartificial liver support system (BLSS)". American Journal of Transplantation. 2 (3): 260–6. doi:10.1034/j.1600-6143.2002.20311.x. PMID 12096789.
  12. ↑ Falkenhagen, D; Strobl, W; Vogt, G; Schrefl, A; Linsberger, I; Gerner, FJ; Schoenhofen, M (January 1999). "Fractionated plasma separation and adsorption system: a novel system for blood purification to remove albumin bound substances". Artificial Organs. 23 (1): 81–6. doi:10.1046/j.1525-1594.1999.06292.x. PMID 9950184.
  13. ↑ Xue, YL; Zhao, SF; Luo, Y; Li, XJ; Duan, ZP; Chen, XP; Li, WG; Huang, XQ; Li, YL; Cui, X; Zhong, DG; Zhang, ZY; Huang, ZQ (December 2001). "TECA hybrid artificial liver support system in treatment of acute liver failure". World Journal of Gastroenterology. 7 (6): 826–9. doi:10.3748/wjg.v7.i6.826. PMC 4695603. PMID 11854910.
  14. ↑ Morsiani E, Pazzi P, Puviani AC, Brogli M, Valieri L, Gorini P, Scoletta P, Marangoni E, Ragazzi R, Azzena G, Frazzoli E, Di Luca D, Cassai E, Lombardi G, Cavallari A, Faenza S, Pasetto A, Girardis M, Jovine E, Pinna AD (March 2002). "Early experiences with a porcine hepatocyte-based bioartificial liver in acute hepatic failure patients". The International Journal of Artificial Organs. 25 (3): 192–202. doi:10.1177/039139880202500305. hdl:11380/703833. PMID 11999191. S2CID 196422022.
  15. ↑ Sauer, IM; Goetz, M; Steffen, I; Walter, G; Kehr, DC; Schwartlander, R; Hwang, YJ; Pascher, A; Gerlach, JC; Neuhaus, P (May 2004). "In vitro comparison of the molecular adsorbent recirculation system (MARS) and single-pass albumin dialysis (SPAD)". Hepatology. 39 (5): 1408–14. doi:10.1002/hep.20195. PMID 15122770.
  16. ↑ Mundt, A; Puhl, G; Müller, A; Sauer, I; Müller, C; Richard, R; Fotopoulou, C; Doll, R; Gäbelein, G; Höhn, W; Hofbauer, R; Neuhaus, P; Gerlach, J (June 2002). "A method to assess biochemical activity of liver cells during clinical application of extracorporeal hybrid liver support". The International Journal of Artificial Organs. 25 (6): 542–8. doi:10.1177/039139880202500609. PMID 12117294. S2CID 38686470.
  17. ↑ van de Kerkhove MP, Di Florio E, Scuderi V, Mancini A, Belli A, Bracco A, Dauri M, Tisone G, Di Nicuolo G, Amoroso P, Spadari A, Lombardi G, Hoekstra R, Calise F, Chamuleau RA (October 2002). "Phase I clinical trial with the AMC-bioartificial liver". The International Journal of Artificial Organs. 25 (10): 950–9. doi:10.1177/039139880202501009. PMID 12456036. S2CID 196427668.
  18. ↑ Rozga, J (September 2006). "Liver support technology--an update". Xenotransplantation. 13 (5): 380–9. doi:10.1111/j.1399-3089.2006.00323.x. PMID 16925661. S2CID 7562668.
  19. ↑ Sussman, NL; Gislason, GT; Conlin, CA; Kelly, JH (May 1994). "The Hepatix extracorporeal liver assist device: initial clinical experience". Artificial Organs. 18 (5): 390–6. doi:10.1111/j.1525-1594.1994.tb02221.x. PMID 8037614.
  20. ↑ Ellis, AJ; Hughes, RD; Wendon, JA; Dunne, J; Langley, PG; Kelly, JH; Gislason, GT; Sussman, NL; Williams, R (December 1996). "Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure". Hepatology. 24 (6): 1446–51. doi:10.1002/hep.510240625. PMID 8938179. S2CID 22557163.
  21. ↑ Phua, J; Lee, KH (April 2008). "Liver support devices". Current Opinion in Critical Care. 14 (2): 208–15. doi:10.1097/MCC.0b013e3282f70057. PMID 18388685. S2CID 30297978.
  22. ↑ Aron, Jonathan; Agarwal, Banwari; Davenport, Andrew (2016-04-02). "Extracorporeal support for patients with acute and acute on chronic liver failure". Expert Review of Medical Devices. 13 (4): 367–380. doi:10.1586/17434440.2016.1154455. ISSN 1743-4440. PMID 26894968. S2CID 13059506.
  23. ↑ "Artificial Liver Used After Removal of Organ". The New York Times. Associated Press. 1993-05-19. ISSN 0362-4331. Retrieved 2020-02-06.
  24. ↑ "Medical Miracles". PEOPLE.com. Retrieved 2020-02-06.
  25. 1 2 "Best Inventions of 2001". Time. 2001-11-19.
  26. 1 2 Tilles A, Berthiaume F, Yarmush M, Tompkins R, Toner M (2002). "Bioengineering of liver assist devices". Hepatobiliary Pancreat Surg. 9 (6): 686–696. doi:10.1007/s005340200095. PMID 12658402.
  27. ↑ Allen J, Hassanein T, Bhatia S (2001). "Advances in bioartificial liver devices". Hepatology. 34 (3): 447–55. doi:10.1053/jhep.2001.26753. PMID 11526528. S2CID 6852149. Free Full Text.
  28. ↑ Strain A, Neuberger J (2002). "A bioartificial liver--state of the art". Science. 295 (5557): 1005–9. Bibcode:2002Sci...295.1005S. doi:10.1126/science.1068660. PMID 11834813. S2CID 30433745.
  29. ↑ "Current Work on the Bioartificial Liver". Archived from the original on 2007-04-07. Retrieved 2020-12-24.
  30. 1 2 He, Yu-Ting; Qi, Ya-Na; Zhang, Bing-Qi; Li, Jian-Bo; Bao, Ji (2019-07-21). "Bioartificial liver support systems for acute liver failure: A systematic review and meta-analysis of the clinical and preclinical literature". World Journal of Gastroenterology. 25 (27): 3634–3648. doi:10.3748/wjg.v25.i27.3634. ISSN 1007-9327. PMC 6658398. PMID 31367162.
  31. ↑ Tsiaoussis, J (January 2001). "Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems". Liver Transplantation. 7 (1): 2–10. doi:10.1053/jlts.2001.20845. PMID 11150414.
  32. ↑ Werner, Andreas; Duvar, Sevim; Müthing, Johannes; Büntemeyer, Heino; Lünsdorf, Heinrich; Strauss, Michael; Lehmann, Jürgen (2000). "Cultivation of immortalized human hepatocytes HepZ on macroporous CultiSpher G microcarriers". Biotechnology and Bioengineering. 68 (1): 59–70. doi:10.1002/(SICI)1097-0290(20000405)68:1<59::AID-BIT7>3.0.CO;2-N. ISSN 1097-0290. PMID 10699872.
  33. ↑ "University of Minnesota Bioartificial Liver: How it Works". Archived from the original on 2006-09-02. Retrieved 2020-12-24.
  34. ↑ Wung, Nelly; Acott, Samuel M.; Tosh, David; Ellis, Marianne J. (December 2014). "Hollow fibre membrane bioreactors for tissue engineering applications". Biotechnology Letters. 36 (12): 2357–2366. doi:10.1007/s10529-014-1619-x. ISSN 0141-5492. PMID 25064452. S2CID 10046204.
  35. 1 2 Bonalumi, Flavia; Crua, Cyril; Savina, Irina; Davies, Nathan; Habstesion, Abeba; Sandeman, Susan (April 2021). "Bioengineering a cryogel-derived bioartificial liver using particle image velocimetry defined fluid dynamics". Mater Sci Eng C. 123 (111983) 111983. doi:10.1016/j.msec.2021.111983. hdl:10446/162225. PMID 33812611.
  36. ↑ Lozinsky, V. I. (May 2008). "Polymeric cryogels as a new family of macroporous and supermacroporous materials for biotechnological purposes". Russian Chemical Bulletin. 57 (5): 1015–1032. doi:10.1007/s11172-008-0131-7. ISSN 1066-5285. S2CID 95352668.
  37. ↑ Erdem, Ahmet; Ngwabebhoh, Fahanwi Asabuwa; Yildiz, Ufuk (2016). "Fabrication and characterization of soft macroporous Jeffamine cryogels as potential materials for tissue applications". RSC Advances. 6 (113): 111872–111881. Bibcode:2016RSCAd...6k1872E. doi:10.1039/C6RA22523C. ISSN 2046-2069.
  38. ↑ Ingavle, Ganesh C.; Baillie, Les W.J.; Zheng, Yishan; Lis, Elzbieta K.; Savina, Irina N.; Howell, Carol A.; Mikhalovsky, Sergey V.; Sandeman, Susan R. (May 2015). "Affinity binding of antibodies to supermacroporous cryogel adsorbents with immobilized protein A for removal of anthrax toxin protective antigen". Biomaterials. 50: 140–153. doi:10.1016/j.biomaterials.2015.01.039. PMID 25736504.
  39. ↑ Derazshamshir, Ali; Baydemir, Gözde; Andac, Müge; Say, Rıdvan; Galaev, Igor Yu; Denizli, Adil (2010-03-15). "Molecularly Imprinted PHEMA-Based Cryogel for Depletion of Hemoglobin from Human Blood". Macromolecular Chemistry and Physics. 211 (6): 657–668. doi:10.1002/macp.200900425.
  40. ↑ Koshy, Sandeep T.; Zhang, David K.Y.; Grolman, Joshua M.; Stafford, Alexander G.; Mooney, David J. (January 2018). "Injectable nanocomposite cryogels for versatile protein drug delivery". Acta Biomaterialia. 65: 36–43. doi:10.1016/j.actbio.2017.11.024. PMC 5716876. PMID 29128539.
  41. ↑ "Google Scholar". scholar.google.com.
  42. ↑ "Advanced Search | Cochrane Library".
  43. ↑ Peszynski, P; Klammt, S; Peters, E; Mitzner, S; Stange, J; Schmidt, R (2002). "Albumin dialysis: single pass vs. recirculation (MARS)". Liver. 22 (Suppl 2): 40–2. doi:10.1034/j.1600-0676.2002.00007.x. PMID 12220302.
  44. ↑ Chawla, LS; Georgescu, F; Abell, B; Seneff, MG; Kimmel, PL (March 2005). "Modification of continuous venovenous hemodiafiltration with single-pass albumin dialysate allows for removal of serum bilirubin". American Journal of Kidney Diseases. 45 (3): e51–6. doi:10.1053/j.ajkd.2004.11.023. PMID 15754264.
  45. ↑ O'Grady J (June 2006). "Personal view: current role of artificial liver support devices". Aliment. Pharmacol. Ther. 23 (11): 1549–57. doi:10.1111/j.1365-2036.2006.02931.x. PMID 16696802. S2CID 31513268.
  46. ↑ van de Kerkhove MP, Hoekstra R, Chamuleau RA, van Gulik TM (August 2004). "Clinical application of bioartificial liver support systems". Ann. Surg. 240 (2): 216–30. doi:10.1097/01.sla.0000132986.75257.19. PMC 1356396. PMID 15273544.
  47. ↑ Neuberger J (January 2005). "Prediction of survival for patients with fulminant hepatic failure". Hepatology. 41 (1): 19–22. doi:10.1002/hep.20562. PMID 15690476.
  48. ↑ "Yaqrit". yaqrit.com. Retrieved 2019-11-04.

Further reading

edit
Retrieved from "https://en.wikipedia.org/w/index.php?title=Liver_support_system&oldid=1357959410"