Blood substitute

Blood substitutes are used for oxygen supply of any or all organs, is about when suitable donor blood acutely not available ( eg after accidents or surgery) or target specific organs are to be supplied with oxygen. In heavy blood loss can occur to collapse the oxygen supply to the brain and throughout the body, which can have severe brain damage or even death.

A distinction volume expander (liquids, thin the remaining residual blood and to the extent added that the bloodstream can function again), can not physiological function of the blood itself, and blood substitutes in the strict sense. The latter should be able to actively take on the primary oxygen transport. There are two basic directions of development: Blood substitutes based on the red blood pigment hemoglobin and blood substitutes perfluorocarbon base.

Advantages over donor blood are missing risk of disease transmission (for example, AIDS, hepatitis B and others), the lack of blood group specificity, and the longer shelf life.

Hemoglobin -based blood substitutes

On the red blood pigment hemoglobin -based blood substitutes ( hemoglobin- based blood substitutes, HBBS, English: hemoglobin based oxygen carrier, HBOC ) use as starting materials in both human hemoglobin from expired blood units or biotechnological production, as outlandish hemoglobin ( for example, beef or pork).

Native hemoglobin is a protein compound which is composed of 4 subunits ( α2β2 - tetramer), each one of which α - subunit is connected to a stable β - subunit ( αβ dimer). Outside the erythrocyte hemoglobin has a very short half -life. It is unstable and rapidly breaks down into its two dimers that act is highly nephrotoxic ( kidney damaging). Hemoglobin has an S-shaped oxygen binding curve, the oxygen binding property sensitive depends on the oxygen partial pressure in the physiological range. Among other things, the concentration of 2,3- bisphosphoglycerate (2,3- BPG ) plays a major role, which is too low, outside the red blood cells to ensure an adequate oxygen supply to the surrounding tissue. Furthermore, hemoglobin penetrates the walls of blood vessels, and it binds nitric oxide, a vasodilator substance. This results in an increase in blood pressure and tissue hypoperfusion, which may take undesirable proportions.

For these reasons, hemoglobin must be modified accordingly before operating as a donor blood substitute. There are various approaches:

• Intramolecular cross-linking to stabilize the tetrameric structure of hemoglobin, and to prevent the disintegration of the toxic dimers. Be networked two dimers each either between their α - subunits or between the β - subunits ( eg O, O- Succinyldi ( salicylic acid ) or 2 -nor- 2- Formylpyridoxal -5- phosphate).
• Recombinant production of human hemoglobin, its two dimers are stably connected to each other via appropriate modification in the amino acid sequence of its α - subunits.
• Improving attachment of pyridoxal-5- phosphate on human hemoglobin to its oxygen binding properties ( pyridoxylation ).
• Intermolecular cross-linking to obtain larger molecules. As the crosslinking agent polyaldehydische compounds are used such as glutaraldehyde or o- raffinose. Hemoglobin glutamer example, has an average molecular weight corresponding to about three to four times that of the hemoglobin.
• Attachment of macromolecules to the hemoglobin, such as dextrans, polysaccharides, hydroxyethyl starch, or synthetic water-soluble macromolecules such as polyethylene glycols (conjugation). Larger molecules have a longer half-life and are less vasoconstrictor.
• Packaging of hemoglobin in liposomes or artificial membrane envelopes ("artificial red blood cell ").

Of the hemoglobin- based developments have been two hemoglobin glutamer preparations made ​​from bovine hemoglobin has been approved ( in South Africa Hemopure ® for use in human medicine, in the U.S. and Europe oxyglobin ® for use in veterinary medicine).

Perfluorocarbons

Perfluorocarbons synthetically produced (PFC ) such as Perflunafen or Perflubron solve very good oxygen and carbon dioxide and are chemically inert. Since they are not miscible with water, they must be dispersed as fine droplets with a suitable physiologically acceptable emulsifier in water. The average droplet diameter is about 100 to 200 nm, the emulsion which may be added to adjust the osmotic and oncotic pressure, other substances such as salts, can be mixed with blood, and this can be substituted in part in the bloodstream, whereby it takes over the transport of oxygen. The oxygen content of the perfluorocarbons is directly proportional to the partial pressure of oxygen ( oxygen binding linear graph). Perfluorocarbons are not metabolized but is exhaled through the lungs.

A disadvantage of perfluorocarbon emulsions is that they are the reticuloendothelial system (RES ), whose cells phagocytose and store, are harmful to the emulsion droplets. As a result, it may cause a malfunction of the immune system.

In the U.S. and a few European countries than was previously only parenteral perfluorocarbon Fluosol ® means that, for the first time in 1989, admitted to the oxygen supply to the heart muscle during percutaneous transluminal coronary angioplasty. In the treatment of anemia Fluosol had, however, shown no benefit and is therefore not indicated for replacement in case of loss of blood. 1994 took the manufacturers from the market. In Russia and Mexico is a similar product in the market with a range of indications for clinical use ( Perftoran ®, PerfTec ®). These emulsions of the first generation contained 20 % (w / v ) of a mixture of Perflunafen and another perfluorocarbon are stabilized by a synthetic emulsifier Poloxamerbasis and only frozen for longer. Because of their oxygen-binding properties, they are most effective under artificial respiration oxygen.

In the development of the second generation, which can absorb more oxygen, better tolerated contain emulsifiers perfluorocarbon emulsions, and thereby have a more favorable chemical and physical stability (eg Oxygent ®, Oxycyte ®). They contain as compared to the earlier developments substantially higher concentrations of perfluorocarbons, with the cyclic Perflunafen also differs and compounds having a higher gas- dissolving power such as bromine-containing linear perflubron. As emulsifier act substances of biological origin such as phospholipids from egg or soy lecithin. The emulsions are stable at refrigerated storage. Possible applications are targeted oxygenation of certain organs, such as the brain after a traumatic brain injury.

Sources and Literature

• Blood Substitutes: Principles, Methods, Products and Clinical Trials, Volume 1 TMS Chang, Karger Landes, CH- Basel, 1997 ( PDF)