By Yu Kiu Victor Chan
For years, blood donation has been vital for treating medical conditions such as anaemia, cancer and various blood disorders. It is also crucial for surgeries, alongside treating blood loss after childbirth (How blood is used, 2020). To serve these purposes, an adequate supply of safe blood and a stable base of regular, voluntary, unpaid blood donors, whose prevalence of bloodborne infections are low is required (World Health Organization, 2020). Whilst the blood donation rate of the United Kingdom is amongst the highest in the world, the donation rate is considerably lower in developing countries and this threatens the stability and safety of blood supply for medical treatments (World Health Organization, 2017). In the field of tissue engineering, scientists are focusing on creating replacement biological tissues, with the aim that these artificial substitutes will mimic and replicate the original biological structure and function of the tissue. Artificial blood can alleviate the shortage of blood donation, but also avoid the risk of disease transmission, and address the concerns of those who have religious objections towards receiving blood transfusions. This review introduces the latest development in artificial blood and the challenges this technology is facing now.
Research has been devoted to replicating the core functions of blood, and so far, two classes of potential blood substitutes have been developed: perfluorocarbons (PFC) and haemoglobin-based oxygen carriers (HBOC).
PFC is a compound containing only carbon and fluorine. Due to the strength of carbon-fluorine bonds, PFC is a very stable compound, and is suitable for introduction into patients due to it being a biologically inert material (O’Hagan, 2008). It can dissolve 50 times more oxygen than blood plasma and is relatively inexpensive to produce (Sarkar, 2008). A product of this class, Fluosol, was approved by the U.S. Food and Drug Administration (FDA) in 1989. However, it was removed from the market in 1994 due to multiple adverse effects and inefficient oxygen delivery at microvasculature (Lu, Ma and Su, 2011). Other disadvantages include insolubility in water, and it carries less oxygen compared with the alternative blood substitute HBOC (Sarkar, 2008).
As its name suggests, HBOC mimics red blood cells and delivers the main function of blood through the use of haemoglobin as an oxygen carrier. Whilst haemoglobin is effective as an oxygen carrier, it is well known that free haemoglobin can trigger certain pathophysiologies such as acute and chronic vascular disease, inflammation, thrombosis and renal impairment and can therefore be toxic to the human body (Schaer et al., 2013). Hence, a well-designed packaging system is crucial for HBOC. One of the successful examples of HBOC is called Erythromer, which was developed in 2016. While previous HBOCs had failed to efficiently deliver oxygen with minimal toxicity, Erythromer was able to emulate natural red blood cells by encapsulating purified haemoglobin within nanoparticles. By using a novel 2,3-Bisphosphoglyceric acid (2,3-DPG) shuttle, it was able to control oxygen capture and release effectively (Pan et al., 2016). It is responsive to pH change and its affinity for oxygen shifts at different locations in the body, ensuring optimal oxygen transfer. Previous HBOC had been shown to trap the vasodilator NO and cause vasoconstriction, but Erythromer used a novel polymer shell that does not interfere with vascular tone (ErythroMer – KaloCyte, 2020). Moreover, it offers two more advantages over blood transfusion. First, it can be freeze dried and converted into a solid powder. Thus, it is capable of long-term storage and it has a prolonged shelf-life. After 3 months of dry storage, less than 10% of change was observed in its properties such as size, zeta potential and polydispersity (Pan et al., 2016). It is a significant advantage over normal blood, which has limited shelf life. For example, red blood cells can be stored for at most 35 days. (Demand for different blood types, 2020) Secondly, it does not require blood typing, which means that one formulation is universal for all humans regardless of blood type. This offers benefits over usual blood transfusion in situations such as in emergencies and a lack of necessary equipment, where the blood type of the patient is unknown (Erythromer – KaloCyte, 2020). Initial ex-vivo and in-vivo studies have shown that Erythromer has overcome challenges in mimicking red blood cells and can perform normal red blood cell activities (Pan et al., 2016).
If artificial blood is so beneficial, how has it not fully replaced blood transfusion yet? Currently there are several limitations that hinder the popular use of blood substitutes. First, artificial blood has not fully replicated all human blood functions. Human blood is a complex mixture of cells, sugar and proteins that deliver a range of functions, including carrying oxygen and carbon dioxide, coagulation and immune defence involvement. Whilst the current blood substitutes function well as oxygen carriers, and there have been promising attempts to mimic the blood clotting of platelets, (Hickman et al., 2018) no substitute products are able to fully replicate the pathogenic defence properties of human blood. Thus, it can only be used as a temporary remedy when blood transfusion is not immediately available. Second, there is insufficient evidence to prove the safety and efficacy of the technology. Erythomer has shown positive results in rat studies but to ensure its safety, larger scale in vivo studies such as rabbits or human clinical trials are required. Therefore, more time and data is necessary for the establishment of safety standards and regulations for artificial blood, before mass adoption of the technology can take place.
With the rapid development and mass funding invested into this technology, (KaloCyte, 2020) it is foreseeable that application of artificial blood will become more popular in the near future. In which case, should it replace blood donation as the main source of blood supply? Since it provides many benefits, such as addressing the shortage of blood donation and avoiding the risks of disease transmission, it can be an excellent alternative to traditional blood transfusion. However, full replacement should only take place given that the following conditions are fulfilled. First, it must be well-proven that no major health adversities result from using blood substitute products, and the safety and health of patients must be closely monitored after the usage of such products. Second, the general public and patients must be educated on the safety and risks of this novel technology to avoid any misunderstanding or stigma against this “lab-made blood”. Patients should also reserve the right to choose whether they use traditional blood transfusion or blood substitutes for their own health benefits.
In conclusion, the perfect substitution for human blood does not exist, yet. However, in the last 200 years, we have progressed from injecting milk into patients, to blood transfusion – an incredible accomplishment; with time, we can expect the advancement from blood transfusions to the application of artificial blood to become a reality.
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