A Review of Progress Towards Artificial Blood
In the long run it should be possible to produce safe forms of artificial or augmented blood with superior characteristics to the real thing, whether built on a largely biological or largely non-biological foundation. A fair amount of theorizing and some practical work has gone into ways to enormously increase oxygenation, to the point of not needing to breathe for ten to twenty times longer, for example. There are also lines of research that might improve clotting or reduce side-effects of blood oxygenation, as well as other lines of augmentation. However, meaningful progress past the trial stage has yet to occur. Meanwhile, the ever greater ability to generate large amounts of patient-matched cells of any desired type makes it likely that production of real blood in cell factories will dominate this niche in the near future. True artificial blood still lies some way beyond that.
Understanding the blood behavior at the microcirculation level where blood and tissues come into contact is a key step in the development and application of blood substitutes. Development of an agent properly mimicking the oxygen-carrying capability of blood among its various functions has been of great interest, and many products have been established based on this property. Red blood cells (RBCs) isolated from donated blood are an important component widely used to save patients' lives via oxygen-carrying capacity owing to hemoglobin (Hb). However, there are complications associated with transfusion of RBCs to patients, such as risk of infection. These complications are the most important concerns for the application of RBCs. Furthermore, crossmatch and blood group typing are needed before transfusion, which is challenging in case of emergencies and when rare blood group types are needed. Hence, it is essential to develop efficient RBC substitutes capable of active oxygen and carbon dioxide transfer. RBC substitutes or synthetic oxygen transporters studied so far are of mainly two types: perfluorocarbon and Hb-based substitutes.
Perfluorochemicals (PFCs) are colorless, inert, and apparently nontoxic liquids with low boiling point temperatures and are insoluble in water and alcohol. The level of oxygen dissolved in PFCs has a direct linear relationship with oxygen pressure, and therefore, high oxygen pressure is necessary for maximum oxygen-carrying capacity. Since hydrogen atoms are replaced by fluorine atoms in PFCs, these compounds are not metabolized due to the strong bond between carbon and fluorine atoms. PFCs are insoluble in aqueous phase, and in case of their clinical application, they are solubilized using an emulsifying agent. Oxygen is dissolved in PFCs at a concentration of about 40%-50%, which is 20 times higher than the capacity of water and 2 times higher than plasma. PFCs are heat resistant and can withstand 300°C and higher temperatures without any change, which makes them easily amenable to heat sterilization. Their small sizes enable them to easily pass through the vessels occluded in some diseases, where RBCs cannot pass; hence, their application helps improving the oxygenation rate. An in vitro study showed that use of PFCs as artificial blood is considerably advantageous in occluded coronary artery to maintain myocardial function.
Human hemoglobin (Hb) derived from expired RBC bags is the main source of Hb for the production of Hb-based RBC substitutes. The half-life of Hb is equal inside and outside the RBCs; however, outside the RBCs, the natural tetramer molecule of Hb rapidly converts to dimer and monomer Hb species, which cause severe complications such as kidney damage. On the other hand, it has been shown that Hb scavenges the existing nitrous oxide (NO) molecules by its heme groups. NO is also involved in relaxation of smooth muscles of blood vessels, and this property is responsible for the vasoactivity of Hb-based products. Overall, this type of Hb must be modified before its application as an oxygen carrier. The Hb-based oxygen carriers (HBOCs) are divided into the following two groups: acellular and cellular HBOCs. Acellular HBOCs have been developed to increase Hb performance and decrease its side effects. These are now in various phases of clinical trials and belong to three categories including cross-linked HBOC, polymerized HBOC, and conjugated HBOC. However, among different modifications of Hb, only nanotechnology-based polyhemoglobin (PolyHb) and conjugated Hb are effective. However, due to their short blood half-lives and side effects, a majority of these products did not achieve required criteria in clinical trials.
Cellular HBOCs are those in which Hb is encapsulated in a cell-like structure. In this way, some products with highest similarity to RBCs were produced, which do not cause vasoactivation due to scavenging of NO. Encapsulation of Hb by a phospholipid layer prolonged its half-life and shelf-life comparing to acellular products. These particles are much smaller than RBCs. This small size enables their entry into areas of body that are not accessible for RBCs. Hence, they can pass through clots and blockages causing more oxygenation during stroke. However, this product has a short circulation half-life, which can be solved by a number of approaches for example by PEGylation of the particles' surface. Another series of products used as RBC imitators are biodegradable Hb-loaded polymeric nanoparticle (HbPNP). However, the most important problem with their application is rapid clearance by phagocytes. Other cellular-based biocompatible Hb products with repetitively branched molecular structures are dendrimers. The shape and size of these products are similar to Hb, and they are able to bind and release oxygen. However, their production is time consuming and costly. Therefore, a kind of dendrimer known as hyperbranched polymer has been developed, with reduced problems, which can be used as oxygen carrier by some adaptations. Dendrimers are also used for encapsulation in drug delivery. Therefore, it has been suggested that dendrimers could be used as artificial oxygen carriers by encapsulating Hb.
Due to the increased demand for blood transfusion and concerns about blood-borne pathogens, development of artificial blood substitutes, especially HBOCs, is under intensive focus. However, although many important steps have been taken to date, no oxygen-carrying blood substitutes are approved for use by the US FDA. Side effects and short half-life are the two main reasons that they did not met criteria for being approved. The fact of having no approved product in this field shows that there is an important challenge against formulation and application of promising and effective blood substitutes. In addition, it indicates the immense potential that exists in this field. However, being optimistic, it seems that science and technology would facilitate developing real blood substitutes, at least oxygen-carrying blood substitutes, whose production will substantially alleviate the worldwide shortage of blood needed for transfusion. It seems that future studies on artificial blood substitutes would focus on real blood substitutes, ie, RBCs obtained through differentiation of stem cells, however.
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