Sugar scissors and nanoblood

Due to the demographic development and the existing age limit for blood donors, the number of blood donations in Germany is decreasing; in parallel, an increase in the number of blood reserves required is expected. One solution to this problem could be artificial blood as a transfusion substitute. This is still only a dream of the future, but various research groups are working on finally realizing this long-held idea.

Over three and a half million whole blood donations were collected last year. In total, about half of all people in Germany have donated blood at some time, but the number of donors is decreasing - about 14,000 blood donations are needed every day. (1) (2) (3) Artificial blood, in which the essential blood components are industrially produced, is increasingly being mentioned as an alternative. Until now, however, such approaches have failed due to the complexity of this "very special juice" - as Goethe called it.

Blood consists of two main components: blood plasma and blood cells. Blood plasma makes up about 55% of the blood and contains water in which proteins, salts and other nutrients are dissolved. Blood cells are divided into red blood cells (erythrocytes), white blood cells (leukocytes) and blood platelets (thrombocytes). The latter play an important role in blood clotting, while leukocytes are components of the immune system. The erythrocytes make up most of the blood cells; their task is to transport oxygen from the lungs to the cells and to remove carbon dioxide. (4)

For the patient care, blood is separated into red blood cells, platelets and plasma after a donation. In this way, each recipient receives only the components he or she needs. However, not all blood donations are available to all recipients, because prior to a blood transfusion it is important to ensure that the blood group is compatible with that of the donor. The AB0 rhesus blood group system is used for this.

This system is based on special surface sugars of the erythrocytes called A and B. If a person has only one of the two molecules on his erythrocytes, he or she has either blood group A or B, and if the person has both molecules, he or she has blood group AB. However, the erythrocytes of people with blood group 0 have neither A nor B. They are therefore suitable as universal red blood cell donors and make up about 40% of potential donors. If a recipient is given blood of an unsuitable group, this can lead to serious complications such as cardiovascular problems, allergic shock, kidney failure and even blood clotting. This is due to blood group antibodies that are directed against the other blood group antigens. Thus, blood group B carriers react with antibodies against blood group antigen A and vice versa. Only people with blood group AB do not produce blood group antibodies - and are therefore universal recipients.

A Canadian research group has now developed a technique to convert erythrocytes from group A donor blood to universal donor group 0. (5) In Germany, A is the most common blood group with over 40 percent. As the group describes in the journal Nature Microbiology, this new technology is designed to circumvent the additional problem of blood group compatibility when there is a shortage of blood. The core of the new method is an enzyme pair that the scientists have extracted from human intestinal bacteria. This can cut off the specific sugar molecules on erythrocytes of blood group A. Since the resulting erythrocytes no longer carry blood group antigens, they are identical to those from group 0 donor blood.

Although enzymes with similar properties are already known, the team has now succeeded for the first time in using their "sugar scissors" to make them directly active in the blood conserve. Previously, the red blood cells always had to be transferred to special buffers for the enzymatic reaction. According to transfusion physicians, the new method therefore represents an important step in the development of novel blood substitutes. However, they also point out that the enzyme treatment requires the transport bags to be opened, which might increase the risk of contamination. In addition, the enzymes must be removed from the blood bag as they are bacterial proteins, otherwise there would be a risk of a body's immune response during transfusion. (6)

In an article in ACS Nano, a team from China and the USA describes a technique that can be used to generate artificial red blood cells using donor erythrocytes. (7) For the production of the "Reconstructed Red Blood Cells" (RRBCs), as the authors call their development, a silica gel-based supporting scaffold is first created. For this purpose, donor erythrocytes are incubated in various silica-containing buffers, whereby a solid silica gel shell is formed around the cells. This and subsequent strong heating causes the typical concave structure of the red blood cells to be transferred to the scaffold.

The silica gel skeleton is covered with natural sugars in several layers, after which the silica gel is dissolved again. What remains are elastic sugar polymers in the form of natural erythrocytes. In the last step, donor erythrocytes are used again, whose empty membrane shells are put over the artificial blood cells. Laboratory tests have shown that the RRBCs are both stable over a long period of time and flexible enough to dynamically adapt their shape to narrow blood vessels.

The aim of this development was to use RRBCs as a starting point for several medical applications. If they are filled with the blood pigment hemoglobin, for example, they can transport oxygen and CO2 like their natural counterparts. Other modifications during the gradual assembly process of the RRBCs are also suitable for functions other than gas transport, for example RRBCs as biosensors for the cellular energy carrier ATP or as so-called nanocarriers. These are transport vehicles that transport active substances to their specific destinations - for example chemotherapeutic substances in tumour tissue. In addition, the research groups succeeded in designing the surfaces of the RRBCs in such a way that they can intercept certain bacterial toxins and prevent the death of natural cells.

However, until the novel blood substitutes are developed to maturity and all the necessary safety tests are completed, people will continue to rely on blood donations - and therefore all eligible individuals are encouraged to donate blood. Detailed information in German is provided by the Federal Centre for Health Education at www.blutspenden.de.