UNIVERSI - International Journal of Education, Science, Technology, Innovation, Health and Environment
(ISSN: 1857- 9450)
Volume 02– Issue 01, April 2016
UDC: 615.384
Artificial blood: An update on blood substitutes
Biu E1 , Kurti F1,4, Ohri I3, Nunci L3, Beraj S1, Shehu K1, Faskaj B2,6, Ҫina T1,5
1
Department of Para clinical Sciences, Faculty of Technical Medical Sciences, UMT, Tirana, Albania
2
Department of Clinical Sciences, Faculty of Technical Medical Sciences, UMT, Tirana, Albania
3
Central Anaesthesiology and Intensive Care Service of UHCT “Mother Theresa”, Tirana, Albania
4
Gastroenterology-Hepatology Service of UHCT “Mother Theresa”, Tirana, Albania
5
National Blood Transfusion Centre, Tirana, Albania
6
Plastic and Reconstructive Surgery Service of UHCT “Mother Theresa”, Tirana, Albania
E-mail: [email protected]
___________________________________________________________________________
Abstract:
The quest of nowdays is the difficulty to fulfill all the needs of blood requests. It is a limited resource because
it’s transfusion rate has been increasing much more the rate of donor collection. Also other problems linked to
transfusion of allogenic blood carries a lot of risks such as: viral agents transmission ,bacterial
contamination,cross-matching cause of blood group antigens and short-term storage.
For this reason, researchers have done many efforts through all these years in order to produce substitutes for
red blood cells to offer an alternative to blood transfusion and it can be used for short term replacement in cases
of surgery emergencies. This blood substitutes don’t aim to replace real blood functions but to play the role as
the oxygen carriers in the cases when the real blood of the patient can’t do it on it’s own. Currently two types of
artificial oxygen carriers are experimentally and clinically investigated for their capacity to ensure adequate
tissue oxygenation: hemoglobin-based oxygen carriers and perfluorocarbons.
The aim of this review is to emphasize the importance of artificial blood, it’s validity and future perspectives.
Key words: blood, hemoglobin – based oxygen carriers, perfluorocarbons
___________________________________________________________________________
Introduction
Blood is a limited resource and a number of causes have led to the development of artificial blood
substitutes. Number of units transfused each year has been increasing at twice the rate of donor
collection. So many reasons such as donor blood shortages, transfusion associated complications such
as increased risks of viral agents that can be transmitted through blood transfusion such hepatitis
viruses, HIV, cytomegalovirus (CMV) etc.; bacterial and protozoal infections, increased numbers of
elective surgeries, have raised the attempts through all these years to develop a synthetic substitute for
human blood.
Artificial oxygen carriers aim at improving oxygen transport and may thus be used as an alternative
to allogenic blood transfusions or to improve tissue oxygenation and function of organs with marginal
oxygen supply.[1]
Blood is a type of connective tissue that has two main components: formed elements and plasma.
Formed elements include white blood cells , which are responsible for the immune system and
platelets for blood clotting and wound healing, while red blood cells transport oxygen and carbon
dioxide to the tissues of our body.It doesn’t have plasma and figured elements, but it transports and
delivers oxygen to the body’s tissues until the recipients patient’s bone marrow can regenerate their
own blood cells.[13]
Artificial blood doesn’t pretend to fulfill all the functions of real blood. No substitutes have yet been
invented that can replace the other vital functions of blood: coagulation and immune defense.
So, artificial blood products are only designed to replace the function of red blood cells as oxygen
carriers instead of all functions of real blood.
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UNIVERSI - International Journal of Education, Science, Technology, Innovation, Health and Environment
(ISSN: 1857- 9450)
Volume 02– Issue 01, April 2016
Red blood cells substitutes are being developed for use in blood replacement therapies, either for
perioperative haemodiluation o for resuscitation from hemorrhagic blood loss.[11]
Increasing concerns about viral transmission and immunosuppressive side effects of allogenic blood
transfusion and shortfall of blood products have reinforced the studies with alternative oxygen carriers
in the last years. Modern perfluorochemicals and cell-free hemoglobin solutions can be applied
without prior cross-matching because they do not harbor blood group antigens and are now available
as stable formulations with long shelf life.[2]
An Ideal blood substitute…
So, There are two significantly different products that are under development as blood substitutes:
hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbon-based oxygen carriers
(PFBOCs).[3,4]
Those carriers based on hemoglobin are derived from animals, outdated banked human blood, or
recombinant systems. Other solutions based on perfluorocarbons, in contrast to hemoglobin, which
chemically binds oxygen, carry oxygen as a dissolved gas [5]
Artificial blood products offer many important benefits. Blood transfusion is associated with adverse
side effects, so an ideal blood substitutes should lack antigenicity. So, they do not require blood
typing, so they can be infused immediately and for all patient blood types. They do not appear to
cause immunosuppression in the recipient. The ability to transmit infections is also eleminated or
reduced because they can undergo filtration and pasteurization processes to virtually eliminate
microbial contamination. In addition, it should have a long half-life, and should be capable of being
stored at room temperature. The biologic properties of an ideal blood substitute should include a
reasonable amount of oxygen delivery, when compared to normal human red blood cells.[6]
While some disadvantages include: free radical induction, haemodynamic and gastrointestinal
perturbations and alterations of biochemical and haematological parameters increase in liver enzyme
levels, platelet aggregation.[11] Also, other problems that must be overcome before HBOCs can
become broadly useful transfusion products is the fact that some hemoglobin solutions also have
vasopressor effects, so, they increase blood pressure and decrease cardiac output. Several studies
have indicated that this vasopressor effect is partly attributable to the ability of cell-free hemoglobin
to scavenge nitric oxide, a cellular chemical messenger that stimulates blood vessel relaxation.
Although this vasopressor effect is undesirable for most applications, it may turn out to be clinically
advantageous for treating a small subpopulation of patients with septic shock who suffer from an
uncontrollable decrease in blood pressure[7]
Hemoglobin based oxygen carriers
Hemoglobin, is the oxygen carrying protein which even extracted from red blood cells as raw
hemoglobin cannot be used as a blood substitute because when infused into the body, it breaks down
into smaller, toxic compounds within the body. There are also problems with the stability of
hemoglobin in a solution. Intracellular hemoglobin has the same life-span as the erythrocyte, about
120 days, but in solution the hemoglobin tetramer readily dissociates into monomers and dimers that
are quickly eliminated by the kidneys. The challenge is to modify chemically the hemoglobin
molecule in order to create a hemoglobin-based artificial blood, a stabilized hemoglobin which
involves chemically cross-linking molecules or using recombinant DNA technology to produce
modified proteins so that it can be used as a blood substitute.[4,7]
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UNIVERSI - International Journal of Education, Science, Technology, Innovation, Health and Environment
(ISSN: 1857- 9450)
Volume 02– Issue 01, April 2016
So, all these attempts are done to prevent the rapid breakdown and elimination by the kidney in order
to overcome their short intravascular dwell times and their reduced ability to oxygenate tissues
relative to normal hemoglobin.
The therapeutic goal of these compounds is to avoid or reduce blood transfusions in different surgical
situations or severe acute anemia due to Hb deficiency.[13]
The hemoglobin-based substitutes use hemoglobin from several different sources: human, animal, and
recombinant.
Human hemoglobin is obtained from donated blood that has reached its expiration date and from the
small amount of red cells collected as a by-product during plasma donation. One unit of hemoglobin
solution can be produced from 2 units of discarded blood. There is a concern that the worsening
shortage of blood donors will eventually limit the availability of human hemoglobin for processing.[6]
There are three types of modified hemoglobin currently in advanced clinical trials:
1.
2.
3.
Polyheme- a polymerized human hemoglobin product
Hemopure- a polymerized bovine hemoglobin product from Biopure which has received
approval for use as a blood substitute in the Republic of South Africa and is now waiting
FDA review of a phase III clinical trial in the United States
Hemolink – a partially polymerized ( an oligomeric) human hemoglobin product from
Hemosol which is also under review from FDA.[7]
But, limited supply of human blood has lead to difficulties in developing a human derived HBOC.
While, bovine blood is developed through a more readily available and cheaper source such as
cows.Bovine Hb is not recognized by human immune system as foreign but, however This source
handle the possibility of transmission of animal pathogens, specifically bovine spongiform
encephalopathy.[6,7]
Recombinant hemoglobin is obtained by inserting the gene for human hemoglobin into bacteria and
then isolating the hemoglobin from the culture. Then the hemoglobin is grown in a seed tank and
fermented. [6,7]
On one hand, Polyheme had shown to be effective in reducing mortality of patients with severe acute
anemia, Hemopure and Hemolink have been shown to reduce allogenic RBC transfusion in patients
undergoing cardiac surgery [3].While in the other hand, a study from Natanson et al showed that use
of HBOC is associated with a significantly increased risk of death and myocardial infarction.[12]
Once obtained from any of these sources, the hemoglobin must be purified and modified to decrease
its toxicity and increase its effectiveness[6]
Modified HBOCs, is treated with 3,5- dibromosalicyl fumarate which results in a strong covalent
bond that maintains the integrity of the hemoglobin tetramer.This results in a specific chemical crosslinks that are established between hemoglobin polypeptide chains to prevent the dissociation of the
hemoglobin tetramer, thus retarding renal elimination because it prolongs intravascular dwell time of
up to 12 hours; while untreated cell-free hemoglobin is eliminated by the kidney in less than 6 hours.
There are also two other ways of treating hemoglobin: one is with bifunctional cross-linking agents,
such as o-raffinose or glutaraldehyde, that polymerize the hemoglobin molecule, producing a
polyhemoglobin, composed of four or five hemoglobin molecules and second hemoglobin can be
conjugated to a variety of larger molecules such as dextran, polyethylene glycol retarding the rate at
which it is cleared from the circulation, so the intravascular dwell time can be extended to 48 hours.
[4,7]
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UNIVERSI - International Journal of Education, Science, Technology, Innovation, Health and Environment
(ISSN: 1857- 9450)
Volume 02– Issue 01, April 2016
Perfluorocarbons
Perfluorochemicals are biologically inert materials made into fine emulsions in which oxygen can
dissolve about 50 times more oxygen than blood plasma. They are relatively inexpensive to produce
and can be made devoid of any biological materials.[4,8] PFC are chemically inert compounds
consisting fluorine- substituted hydrocarbons.[11]
Intravenously administered perfluorocarbon (PFC) emulsions increase oxygen solubility in plasma.
PFC might temporarily replace red cells (RBCs) lost during intraoperative hemorrhage and treat
diseases with compromised tissue oxygenation such as cerebral and myocardial ischaemia and
emergency or trauma surgery.[1]
In contrast to HBOC’s, they also dissolve oxygen which is not subject to the effects of temperature,
pH, 2,3 –DPG. [11]
For religious reasons certain groups of people are unable to accept transfusions of either donor blood
or human animal proteins such as hemoglobin. So, PFC are their only option if transfusion is
required.The possibility to transmit infectious disease via blood transfusion due to their composition
doesn’t exist.But these compounds have also disadvantages that should be passed, such as PFC should
be prepared as emulsions because they are not miscible with aqueous solutions.[7]
Green Cross Corperation in Osaka Japan developed Fluosol-DA , the first PFBOC. The problem with
Fluosol-DA is that they dissolve less oxygen than pure liquids, only 0,4 ml oxygen per 100 ml. In
order to fulfill the metabolic oxygen demands, the patients should breathe in 100% oxygen gas, which
would lead to oxygen toxicity.While , Alliance Corperation developed Oxygent that can deliver more
oxygen , up to 1,3 ml per 100 ml, butthis is still much lower than normal blood which can deliver
blood up to 5 ml oxygen per 100 ml. Oxygent compared to Fluosol-DA has longer circulation time
andit can be excreted from the body in four days, while Fluosol-DA requires much more time,
months. [13]
There are many studies that evaluate effectiveness of PFC. Habler OP et al showed that
perfluorocarbon emulsion were as effective as autologous RBC transfusion in maintaining tissue
oxygenation during volume-compensated blood loss designed to mimic surgical bleeding.[9]
While another study from Keipert PE showed that Oxygent , is being evaluated as an alternative to
allogeneic blood transfusion in patients undergoing medium- to high-blood-loss surgical
procedures.[10]
While clinical studies with human cross-linked hemoglobin (DCLHb) have been stopped last year
because of the results of two clinical trials showing an increased mortality in patients with stroke and
multiple injury shock being treated with DCLHb in comparison with saline, a phase III study with
polymerized bovine hemoglobin HBOC-201 is actually being performed in noncardiac patients with
perioperative bleeding. The objective of this multicenter study is to show that treatment with HBOC201 can reduce or avoid allogenic RBC transfusion [2]
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UNIVERSI - International Journal of Education, Science, Technology, Innovation, Health and Environment
(ISSN: 1857- 9450)
Volume 02– Issue 01, April 2016
Conclusion
Artificial blood plays an important role in carrying and transporting oxygen to tissues for the survival
of patients for short-term cases of emergencies when blood transfusions is required in trauma and
surgery.
Future perspectives show that researchers are working to use nanothechnology to encapsulate human
hemoglobin in artificial red blood cells with biodegradable membranes.
According to all studies that have shown that these substitutes carry benefits and risks, we can
conclude that there is still a long way and challenges to overcome before artificial blood can replace
red blood cells in main transfusions and become broadly useful.
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