Can we produce synthetic red blood cells lacking antigens?

Question

I had an idea come to me during Biology class and I immediately asked my teacher, but she couldn't really answer the question, so I'll ask it here.

What are the limiting factors in the production of synthetic red blood cells with no antigens? I mean, we do have the human genome mapped, but am I naive to think that we have genetic technology capable of doing this?

If red blood cells are too complex to manufacture, is it feasible to manufacture much smaller particles of just hemoglobin inside small spheres of cell membrane and use that as a temporary replacement for red blood cells?

(I was at a medical research talk a while ago and one professor was explaining that there are many other proteins bound onto a red blood cell that aren't of the ABO or RH system. Normally this isn't a problem for recipients who only occasionally received transfusions but for people who need a long-term supply of blood, their bodies do get sensitized to the foreign proteins and will eventually start attacking the foreign red blood cells).

Answer 1

Actually there are such particles. It is estimated that about 20% of the hemoglobin (HGB hereafter) is in HGB vesicles (HbV hereafter) formed by RBCs. So sure, it is possible to use small particles instead of RBCs, but these vesicles have major and minor antigens on their surface. According to some of the articles they cause other complications too by blood transfusions and they are destroyed by the immune system within 3 to 7 days. So they don't solve the problem.

• In Vivo Volume and Hemoglobin Dynamics of Human Red Blood Cells
• Artificial Oxygen Carriers (Hemoglobin-Vesicles) as a Transfusion Alternative and for Oxygen Therapeutics
• Red blood cell vesiculation in hereditary hemolytic anemia
• The red cell revisited--matters of life and death.
• Red blood cell microparticles and blood group antigens: an analysis by flow cytometry
• Hemoglobin-Vesicles as Oxygen Carriers
• Physiological Capacity of the Reticuloendothelial System for the Degradation of Hemoglobin Vesicles (Artificial Oxygen Carriers) after Massive Intravenous Doses by Daily Repeated Infusions for 14 Days

HGB vesicles without major and minor antigens are not a perfect solution either (I think), because the immune system tends to attack such things. For example by viral infections the MHC1 levels are low (in cells with nucleus) to avoid T cell response and the NK cells does not like that, so they destroy such cells. I am almost sure something similar would happen with this kind of vesicles as well. At least afaik. the immune system checks not just the presence of these antigens, but their composition as well. So if a RBC is under stress, then it changes the antigen composition on its surface and the leukocytes destroy it if necessary. According to some of the experiments PEG can cover HbV antigens and increase immune compatibility, so having less surface antigens seems to be a better choice than having more.

• Development of a Synthetic Blood Substitute Utilizing Hemoglobin Vesicles
• Biocompatibility of Hemoglobin Vesicles, a Cellular-Type Artificial Oxygen Carrier, on Blood Cells and Plasma Proteins In Vitro and In Vivo
• Artificial Oxygen Carriers, Hemoglobin Vesicles and Albumin−Hemes, Based on Bioconjugate Chemistry
• Hemoglobin Vesicles, Polyethylene Glycol (PEG)ylated Liposomes Developed as a Red Blood Cell Substitute, Do Not Induce the Accelerated Blood Clearance Phenomenon in Mice

HGB vesicles have another problem. The HGB inactivates in them without reduction (metHb formation). Only Fe2+ HGB can carry oxygen. This can be solved with methylene blue according to this study.

• Red Blood Cells Donate Electrons to Methylene Blue Mediated Chemical Reduction of Methemoglobin Compartmentalized in Liposomes in Blood
• Inhibition of methemoglobin formation in aqueous solutions under aerobic conditions by the addition of amino acids

We cannot use free HGB either, because it would decrease the NO levels and lead to endothelial dysfunction. I think to small particles would have the same effect because of increased surface.

• Mechanisms of Slower Nitric Oxide Uptake by Red Blood Cells and Other Hemoglobin-containing Vesicles

• Microparticles in stored red blood cells as potential mediators of transfusion complications

• Removal of Cellular-Type Hemoglobin-Based Oxygen Carrier (Hemoglobin-Vesicles) From Blood Using Centrifugation and Ultrafiltration

According to other studies RHSA-heme (serum albumin bound to synthetic heme) is another option. It seems to be safe if you replace only 20% of blood volume (of rats). I think a complete transfusion is not safe, because it would reduce the NO levels as we already discussed. I have not found an experiment which does complete transfusion.

• Safety evaluation of an artificial O2 carrier as a red blood cell substitute by blood biochemical tests and histopathology observations.
• Exchange transfusion with synthetic oxygen-carrying plasma protein “albumin-heme” into an acute anemia rat model after seventy-percent hemodilution

So there is ongoing research in the topic. There is progress, but none of the current solutions is perfect I think.

Answer 2

Artificial blood substitutes are being researched and developed as alternatives for replacing RBCs for oxygen carrying capacity. Regular human blood has a shelf life of only 42 days which limits their utilization over more extended periods. This necessitates the development of blood substitutes which can be stored for longer duration. In addition, blood substitutes have universal compatibility, and therefore their application is not restricted by typing and cross-matching. Blood substitutes are extremely necessary in case of acute and chronic blood loss from injuries and accidents where a shortage of oxygen to cells affects the survival of patient by inflicting permanent damage to tissues.

Blood substitutes market is categorized into two segments viz. Perfluorocarbon-based oxygen carriers (PFBOC), and Hemoglobin-based oxygen carriers (HBOC). PFBOCs are based on inert components which replace hydrogen with fluorine. HBOCs consists of hemoglobin derived products sourced from humans blood, bovine blood, microorganisms and transgenic animals.

Answer 3

Artificial blood Substitute is an artificially developed substitute for red blood cells which is use for transporting oxygen and nutrients to the body cells and transporting back carbon dioxide, ammonia and other waste products away from cells.

Six potential application markets have been identified based on the possibility of replacing donor blood in critical medical treatments-

Injuries, Cardiovascular diseases, Malignant neoplasms, Neonatal Conditions, Organ transplants, Maternal condition