Bioartificial Liver Devices

Although certain simple functions of the liver, such as the removal of some toxins, can be performed by using dialysis and adsorption with activated charcoal, it is clear that such a simple artificial approach cannot perform the complex functions of the liver, and that any practical liver support system must use living hepatocytes. It should be mentioned at this point that hepatocytes have an anchorage-dependent nature that is, they require a form of anchor (i.e., a solid surface or scaffold) on which to grow. Thus, the use of single-cell suspensions is not appropriate for liver cell culture, and fiver cells attached to solid surfaces are normally used. Encapsulated fiver cells and spheroids (i.e., spherical aggregates of fiver cells) may also be used for this purpose. 

In recent years, many investigations have been conducted, including clinical trials, with bioartificial fiver devices using either animal or human liver cells. Likewise, many reports have been made with various designs of bioartificial fiver device [19]. However, there are no established fiver support systems that can be used routinely in the same way as hemodialyzers or blood oxygenators. Today, bioartificial fiver devices can be used to assist the fiver functions of patients with fiver failure on only a partial and/or a temporary basis. Moreover, none of these devices can excrete bile, as does the human fiver. 

It should be noted here that the bioartificial fiver device is not only a bioreactor but also a mass transfer device. The mass transfer of various nutrients from the blood into the liver cells, and also the transfer of many products of biochemical reactions from the cells into the bloodstream, should be efficient processes. In human fiver, the oxygen-rich blood is delivered via the hepatic artery, and bioartificial devices should be so designed that the oxygen can be easily delivered to the cells. 

1) Hollow Fibers. The general configuration of the hollow-fiber apparatus is similar to that of hemodialyzers and blood oxygenators. Hepatocytes or microcarrier-attached hepatocytes are cultured either inside the hollow fibers or in the extra-fiber spaces, and the patient s blood is passed outside or inside the fibers. A bioartificial liver of this type, using 1.5 mm o.d. hollow fibers with 1.5 mm clearance between them, and with tissue-like aggregates of animal hepatocytes cultured in the extra-fiber spaces, can maintain liver functions for a few months [20]. 

2) Flat Plates. In this case, the hepatocytes are cultured on multilayered solid sheets, between which the blood is passed through narrow channels. This configuration, with direct blood-cell contact, somewhat resembles that ofthe human liver. However, scale-up is not easy because of the possible maldistribution of blood, and the existence of large dead spaces. 

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In order to sustain life, a bioartificial liver device should contain at least 10-30% of the normal liver mass (i.e., 150-450 g of cells in the case of an adult). In a bioartificial liver device, the animal or human liver cells can conceivably be cultured and used in several forms, including (i) independent single-cell suspensions (ii) spheroid (i.e., globular) aggregates of cells of 100-150 pm diameter (iii) cylindroid, rod-like aggregates of cells of 100-150 pm diameter (iv) encapsulated cells and (v) cells attached to solid surfaces, such as microcarriers, flat surfaces, and the inside or outside of hollow fibers. In order to facilitate mass transfer, a direct contact between the cells and the blood seems preferable. Among the various types of bioartificial liver device tested to date, four distinct groups can be identified [19] ... 

There are two basic types of liver support devices nonbiologic artificial devices and bioartificial devices. Artificial bver devices primarily attempt to mimic the liver s role in detoxification, typically by chemical and physical separation through sorption and filtration. On the other hand, bioartificial liver devices aim not only to detoxify, but also to replicate the liver s synthetic properties by using human or animal hepatocytes. Modern support devices typically use a combination of functional components, either in series or parallel, to augment the therapeutic effect. Currently available devices vary in the length of their treatment sessions, anywhere from 6 through 8 h a day to continuous use for several days. ... 

Other bioartificial liver devices under study include the bioartificial extracorporeal liver support (BELS) system, which uses porcine hepatocytes with separate capillary systems arranged to mimic hepatic architecture. 

As seen above, the artificial systems are only able to supply detoxication functions of the liver. In some cases, this might not be enough to save patients. An alternative is the design of bioartificial liver. A simplistic approach consists in considering such a device as a bioreactor based on synthetic elements able to offer an adequate environment to the liver cells. This environment would in turn lead to the maintenance of efficient functions of the cells aiming at liver supply, when placed in a bioreactor located in an extracorporeal circuit. The mandatory requirements for acceptable cell viability and functions in a bioartificial liver (BAL) are tentatively listed below, according to a biotechnological point of view ... 

Stably immobilized 3D flat aggregates and exhibited superior cell bioactivity with higher levels of liver-specific function maintenance in terms of albumin secretion, urea synthesis and cytochrome P-450 enzyme than 3D spheroid aggregates formed on GC films. These results suggested that the GC-based nanofibrous scaffolds could be useful for various applications such as bioartificial liver-assist devices and tissue engineering for liver regeneration as primary hepatocytes culture substrates. 

Bioartificial hollow-fiber liver devices have cultured liver cells (hepatocytes) growing in between hollow fibers. The patient s blood is passed through the fibers, where it diffuses into the extra-fiber spaces, interacts with the hepatocytes, and returns to the patient. In laboratory tests, such devices maintained liver function for a few months. 

The BAL performs some of the functions usually performed by the liver It processes blood, removes impurities, produces proteins, and aids in the synthesis of digestive enzymes. The BAL is not intended to permanently replace the liver but rather to supplement liver function or to allow a patient to survive until a liver transplant can be arranged. The bioartificial liver enables patients to forgo dialysis treatments, and some researchers hope to develop BAL devices that may function as a permanent replacement for patients in need of dialysis. 

Over 50 types of cells, tissue constructs, and even tissue explants have been cultured in these bioreactors, which appear to be ideally suited to promote the expression of tissue-specific functions in the cultured cells and preserve the three-dimensional morphological characteristics of the native tissue. Thus, this system should be useful to create and maintain bioartificial tissues to be subsequently implanted in vivo. On the other hand, these devices would not be appropriate for tissue engineering applications requiring a combination of very high cell densities and very low liquid hold-up volumes, such as in the case of extracorporeal bioartificial livers. 

Introduction The Normal Liver Liver Failure The Ideal Liver Support Device Components of a Liver Support Device Nonbiologic Artificial Liver Support Devices Bioartificial Liver Support Devices Where We Are Now Conclusions Defining Terms References Further Information... 

TABLE 80.1 Comparison of Nonbiologic versus Bioartificial Liver Support Devices... 

The bioartificial liver support devices that are under investigation include the extracorporeal liver assist device (ELAD, Vital Therapies, San Diego, Cahfornia, USA) and the HepatAssist Liver Support System (HepaLife Technologies, Boston, Massachusetts, USA). 

There are artificial liver support devices available commercially with some evidence of efficacy with regard to secondary outcomes, such as improvements in encephalopathy and nephropathy, but no single device has clearly demonstrated convincing improvements in survival. Bioartificial liver systems continue to offer promise but are still in clinical trials. Systematic reviews combining the outcomes from several support devices have suggested reductions in mortality in AOCLF when compared to standard medical therapy, but a recent review evaluating more modern support devices found a benefit only in ALF. A number of large, multicenter randomized studies are currently underway. 

Examples of medical textiles used in extracorporeal medical devices include the use of hollow fibres and membranes (made om polyester, polypropylene, silicone, viscose) for production of bioartificial organs, such as the kidneys, liver and lungs. 

Below, we will refer to two typical cases of MBR application in artificial organ engineering the bioartificial kidney and bioartifidal liver. It should be noted that the clinical impact of the artifidal kidney and liver is quite different. The artificial kidney, in its hollow-fiber modules form, is the most employed hemopurification device. The therapy for chronic renal failure concerns hundreds of thousands of patients all over the dvilized world, making the artificial kidney one of the most diffused biomedical devices on... 

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