Artificial Liver Support Systems: Design, Challenges, and Improvements

This report provides a comprehensive overview of artificial liver support systems, focusing on their design, challenges, and potential improvements. It begins by discussing the range of artificial organs and prostheses used in human medicine, highlighting the shortage of organs, ethical issues, and the need for improved efficiency in transplantation. The report then delves into bioreactor geometry and working principles, emphasizing the importance of maintaining optimal conditions for cell culture. Experimental results of bioreactor designs are examined, particularly concerning oxygen supply and the viability of hepatocytes. The classification of bioreactor designs, including hollow fiber systems, perfused beds, and encapsulation chambers, is discussed, along with the key challenges in bioartificial liver (BAL) design, such as insufficient cell sources and immune system-related problems. Finally, the report proposes improvements to bioreactor design to enhance its potential for clinical application, focusing on morphological and functional perfection of cells. This student contributed document is available on Desklib, a platform offering a wide array of study resources including past papers and solved assignments.

Artificial Liver Support System
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Table of Contents
Introduction......................................................................................................................................2
Knowledge and Understanding of a Range of Artificial Organs and Prostheses currently used in
Human Medicine.............................................................................................................................3
Issues associated with artificial organ implantation and treatment success:...................................3
A brief overview of bioreactor geometry and working principle :..................................................5
Most important experimental results of bioreactor design:.............................................................6
Classification of bioreactor design to which the novel bioreactor belong to:.................................6
BAL design challenges:...................................................................................................................7
Improvements in the bioreactor design to increase its potential of future use as a Bioartificial
Liver (BAL) in a clinical application:.............................................................................................9
Conclusion.....................................................................................................................................11
References......................................................................................................................................12
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Introduction
Liver is one of the most important organs in our body that helps to remove toxins from the blood,
produce proteins of blood, stores energy in the form of glycogen and secretes bile. The liver cells
called hepatocytes, when not working properly or are killed due to any disease, causes Acute
Liver Failure (ALF) (Feng et al., 2018). Bioartificial liver support systems can be considered as a
useful therapeutic device for the persons that have liver damage. In this assignment we are going
to discus about the range of artificial organs and prostheses currently used in human medicine,
issues associated with artificial organ implantation and treatment success, a brief overview of
bioreactor geometry and working principle, important experimental results of bioreactor design,
classification of bioreactor design to which the novel bioreactor belong to, BAL design
challenges, and improvements in the bioreactor design to increase its potential of future use as a
Bioartificial Liver (BAL) in a clinical application.
Figure: Bioartificial liver support systems
(Source: Mitzner, 2016)
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Knowledge and Understanding of a Range of Artificial Organs and Prostheses currently
used in Human Medicine
When the body organs are not working properly or are damaged, artificial organs (ma-made
devices) can be used to replace those faulty organs to restore the normal body functions
(Koblihová et al., 2015). These artificial organs include ears, heart, brain, ovaries, liver or
artificial machines for kidneys, heart, lung etc. These artificial organs are the ultimate devices
that can give a life support and much research is going on to make it more perfect. It improves
the premature mortality rates, increases the patients self assessment, makes the patient to feel
more easy to interact with people and also restores the beauty of patient after going through any
misfortune or fatal disease like cancer. Prosthesis is also a term for artificial substitution for a
body part that has been missed. These body parts include arms, legs, bones, arteries, heart
valves, knee, ankle, foot etc. Hearing aid is one of the most common in nowadays life among
both adults as well as children (Olson and Karvellas, 2017). The problems with these organs may
be genetically acquired by the patient or he/ she may get it through any accidents in its life time
or due to some bad habits like smoking, alcohol consumption (leading to kidney, heart, liver,
lung problems). The first prosthetic was done in 16th century by French surgeon Ambroise Pare.
Issues associated with artificial organ implantation and treatment success:
 Shortage of Organs: The main problem of the artificial organ transplantation is shortage
of organs. As opined by Kashte et al. (2018), there are a great number of patients waiting
for the transplantation than the number of donors available. Though the medical and
surgical aspects of organ transplant have been greatly evolved through time, the shortage
of organs is not mitigated so far. In 1999, there were about more than 39,000 people in
America were in waiting lists for their organ transplantation (Feng et al., 2018). The most
vital organs in the list of this shortage were mostly kidneys, heart, liver, brain etc. similar
shortages were also found in Israel, USA etc.
 Comparatively high death rate after organ transplantation: As stated by Arroyo et al.
(2016), it was often found that there was a critical increase in the death rate after the
organ transplantation operation. There may be several causes behind this death like the
immune system of the patients may not accept the new replaced organ thus resulting in an
anti- feedback in the body resulting in death or there may be other side effects of organ
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transplant that was faced by the patient like organ failure or heart problems or digestive
problems of respiratory problems etc.
 Ethical issues: There is a great increase in the number of live donors that is people are
getting influenced to donate their organs after death. As opined by Dorado-Moreno et al.
(2017), but this may make a problem with their family, who are emotionally connected
with the patients and may convince them not to take such decisions. There are also
several religious problems associated with the organ donation and artificial organ
implantation. There are some religions those believe in the state that people should leave
the world with all the things with which they came, thus protesting against the removal of
any organ from the body even after his / her death (Ide et al., 2015). This ultimately leads
to low number of donor in the market of organ implantation.
 Low efficiency: The efficiency of organ transplantation is sufficiently low which means
there is no assurance that the operation of organ transplantation will be successful and the
patient will come back to home. This highly expensive surgery provides no such
guarantee of providing perfect functioning of the organ that has been transplanted newly.
The WHO has set an effective mechanism that will efficiently track the efficiency of the
steps involved in organ transplantation.
 Programs implemented: There must be some special programs organized that will
increase the efficiency of organ donation and also the organs available for implantation.
There must be some procedures before the implantation process, like blood group
matching of donor and patient to measure their compatibility (Kobashi-Margáin et al.,
2016). There must be some awareness programs implemented by the social organizations
that will help to get people more knowledge about this organ donation system and can
raise their concerns about the need of organs which are being wasted by burying or
burning. As opined by Lexmond et al. (2015), there are programs like non- heart-beating-
donors (NHBD) for ten countries in Europe to increase the awareness.
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A brief overview of bioreactor geometry and working principle :
Due to several factors like lifestyle, disease, environmental factor etc, nowadays there are
millions of cases of people with damaged liver which is one of the most important organs of
body and resulting ultimately in death. Thus, there is a pinpoint focus on this issue to get some
life support devices that will restore the normal body function when implanted inside the body at
the site of damage via surgeries. As stated by Ren and Irudayam (2015), Bioreactors are such an
innovation done in between 1990’s and 2011 that can be used as an essential tool in this aspect.
It is actually a container carrying out some biological reactions inside it that can be utilized to
culture cells that will conduct the normal body functions. It is normally aerobic process. It is a
cylindrical vessel, and is found in many types like batch, fed batch or continuous or airlift, rotary
cell culture systems etc. It works mainly on the principle which states for the production of
therapeutic recombinant protein by growing a large amount of animal cells artificially. This
system is designed especially for immobilized cells to serve the cells for optimum conditions.
During the development of the system several important factors need to be concerned i.e.
temperature, DO (dissolved oxygen), CO2 concentration, very low amount of toxicants, etc. to
maximize its function (Singanayagam and Bernal, 2015).
Figure 2: Bioreactor
(Source: Wang et al., 2016)
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Most important experimental results of bioreactor design:
According to Sarin and Choudhury (2016), Bioreactors are one of the basic things that are
required for tissue engineering which produces actually functioning normal cells artificially.
Thus it needs critical investigation about the internal and external conditions which are fluid
velocity, shearing stress, current and potential etc. these parameters need to be checked
thoroughly through experiments to increase the potential, efficacy of bioreactor. Several
experiments have been performed by the time that shows the effects of the applied conditions on
bioreactors. During aerobic fermentation, oxygen is supplied by air in dissolved condition within
the bioreactor vessel, where the O2 is diffused within in medium to produce Dissolved oxygen
(DO), which in turn is diffused in microbial cells, where it is used for their respiration (Sarin and
Choudhury, 2016).
As opined by Park et al. (2016), in an experiment, the BAL support system was combined with
human hepatocytes, hollow fiber bioreactor and circulatory system and were transplanted in
dizhepatic dogs and the results showed that there were more than 95% liver cells viable and
there correct features were also retained until the whole process was completed the life times of
the treated dogs were also increased with a change in blood pressure, pulse rate etc. The serum
ammonia level as well as the lactate level both decreased (Khan, 2016). Thus it was concluded
from the experiment that BAL is sufficiently good tool to combat the liver damage issues in the
patients. Moreover, to mimic the liver environment of within body in vivo system, bioreactors
have been proved as a great device in an experiment where cells called liver bud cells,
resembling the liver hepatocytes were generated, though it was unable to meet the high rate of
production of mammalian matured hepatocytes (Gonzalez et al., 2017).
Classification of bioreactor design to which the novel bioreactor belong to:
There is no insufficiency in the designs of reactors for BAL support systems the designs are
continuously getting better to give better results. Bioreactors can be classified into 4 types i.e. (1)
hollow fiber, (2) flat plate or monolayer cultures, (3) perfused beds or scaffolds and (4)
suspension or encapsulation chambers, in which all have something good in them as well as
some bad sides also. As stated by Kashte et al. (2018), The BAL system is most commonly
produced around hollow fiber ones as it is most efficient among all 4 types. Hollow fiber system
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provides different chambers for perfusion and cell attachment, but there is no such aspect of
serving as selectively permeable barrier for transportation, though it is better than the rest ones.
Perfused bed reactors which are designed with very small carriers made of glasses, vessels of
polyester fabrics provides enhanced nutrient exchange in Bioartificial liver support systems. The
system should also be able to give an efficient mass transport of hepatocytes. For this, several
membrane-based bioreactors can be produced to meet increased diffusion distances and also
some bead like structures can be implemented in this to increase the rate of stabilizations of the
cell resisting it from diffusion (Kobashi-Margáin et al., 2016). The main area to be concerned
about in a bioreactor design is always that the cell must be morphologically and functionally
perfect which is always need to be checked.
BAL design challenges:
The key challenges in the bioartificial designs are:
1. Insufficient classic cell source: the cell sources which are used in bioartificial liver
support system in the mean time are mainly hepatocytes from pig, human and human
hepatic tumor-derived cells. As stated by Dorado-Moreno et al. (2017), the
hepatocytes collected from pig are the cell components of all the bioartificial liver
support system till now. But disease transmission between vertebrates and
invertebrates and the immune system related problems have been interfering with
their use. The pig and a human being resemble each other in a great amount in all
biological aspects but pig is different from human in respect of production of
coagulation factors that is pigs cannot produce these factors in them. According to
Feng et al. (2018), the human hepatic cells are not that much used in these systems as
there are only 2-3 clinical trials of them in this system and only C3A cell lines,
HepG2 heptoma sub clone have been used among all. There are several other cell
lines that can further be utilized in the bioartificial liver support system like
immortalized fetal human hepatocytes, immortalized adult human hepatocytes and
human stem cell-derived hepatocytes and will be best cell sources for bioartificial
liver support system (Dhal et al., 2015).
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2. Difference in oxygen supply: The liver of has high level of oxygen supply as oxygen
is supplied through both hepatic arteries and the portal vein, both of which enters into
the liver sinusoids and supply them adequate oxygen. As opined by Kashte et al.
(2018), the average level of blood flow in liver in optimum condition is more than
1400 mL/ min. thus the high level of oxygen supply is must to maintain the proper
feature of liver hepatocytes. But in near about all bioartificial liver support systems,
the fluids used are ultimate filtered fluid of either plasma or blood as use of whole
blood will result in lyses of blood cells or blood coagulation issues (Lexmond et al.,
2015). On the other hand, the oxygen carrying capacity of filtered blood fluids is
relatively low than the whole blood containing red blood cells, leading to create an
hypoxic condition. The measures which have been taken to meet these problems are
use of combined oxygenator in which oxygen- vessels are distributed throughout the
bioreactor chamber. As stated by Ren and Irudayam (2015), but it doesn’t have the
ability to self regulate. The other measure is to combine the filtered fluid with red
blood cells and then take for use in bioartificial liver support system.
3. No secretion of biles: According to Rosenthal (2015), there is no biliary system in the
bioartificial liver support system that will be sufficient to collect the biles made by
liver hepatocytes and make it to move out of extracorporeal circulation. To combat
this problem, the bioartificial liver support system has been combined with an
artificial liver device such as albumin dialysis, plasma exchange or carbon absorption
though it is doubtful whether the biles are carried out by the artificial liver device or
not and also interferes with the efficiency of the bioartificial liver support system.
4. Inconvenience: the bioartificial liver support system is not so easily available device
that can be used by the normal people and also it is not so easy to be operated without
any expertise (Sarin and Choudhury, 2016). The operator has to do a number of
processes before connecting the bioartificial liver support system to a human body
like in case of pig hepatocyte based bioartificial support system, the pig must be
sacrificed and the cell collection should be done carefully, in case of human
hepatocyte based bioartificial liver support system, the hepatocytes must be collected
from the tissues carefully without damaging the cells and a culture of hepatocytes
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must be maintained , the cells need to adhere within the bioreactor, all of which is
very difficult to handle and also need a lot of time.
5. The evaluation of efficacy is difficult: As not all of the biological aspects of pig liver
cells resemble the human hepatocytes, there is a great extend of difficulty in the
evaluation process of bioartificial liver support system loaded with human
hepatocytes. According to Singanayagam and Bernal (2015), the human species is
also very much different from others greatly. Thus bioartificial liver support system
often ends with ultimate liver transplantation.
Improvements in the bioreactor design to increase its potential of future use as a
Bioartificial Liver (BAL) in a clinical application:
To get a successful bioprocessing it is very important to take effective scale-up. There are many
improvements that need to be carried to make the bioartificial live support system more
successful. These are as follows:
1. The cell lines used for bioartificial live support system needs to be customized. The cell
lines must be shear-sensitive that are intolerant to bubble aeration (Olson and Karvellas,
2017).
2. An increase in aeration or low pressure above the bioreactor culture media can result in a
low level of dissolved CO2 concentration. So bicarbonate can be used to make
equilibrium. The vessel must have a critically maintained pH buffer in it, otherwise the
pH of the medium will increase.
3. As stated by Nicolas et al. (2017), there is an increased advantage of high density cell
culture for the production of pharmaceuticals in compact bioreactors with also an
increased level of volume-wise production rate, though they are not so easy to design and
to be operated. Cells need to be adhered in the bioreactor throughout the perfusion. The
cell attachment design is the key factor working in high performance bioreactor.
4. The oxygenation within the bioreactor and media are another important factors need to be
maintained for increased efficiency of bioreactor (Lexmond et al., 2015). The cell
specific perfusion rate is used to maintain a perfect environment for heightening the cell
production.
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5. Densities of cell and other activities can be estimated online. There is also a problem
created by the dissolved carbon dioxide accumulation within the tubing aeration.
6. According to Kobashi-Margáin et al. (2016), base addition needs to be maintained in
order to inhibit the lyses of cells and staying away from getting a poor culture medium.
7. The reactors must be perfectly mixed in order to get a perfectly non-heterogenized cell
culture. Cells should not be aggregated so that there are no such different zones of
aggregated cells.
8. The membrane systems of the many bioreactors are not large enough to meet the high
production rate. As stated by Gonzalez et al. (2017), immobilization of cells or
encapsulations of cells must also be enhanced to achieve a greater quality of bioreactor
function. But this is highly expensive and time consuming matter.
9. Nutritional medium matters greatly in order to get high cell number in bioreactor.
Medium must be exchanged to maintain the sustainable growth of cells (Dhal et al.,
2015). To maintain a cell density more than 107 cells/ ml, the media must be exchanged
every day. The media perfusion can also be minimized to lower the expense and to
increase the ell production.
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