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Is the search for safe transfusions turning into a bloodless coup?

Less than a generation ago the idea of using chemistry to make artificial cells as substitutes for biological cells in living animals was regarded too far-fetched for serious consideration. But today, the man who kept faith in the concept of man-made cells wears a smile of satisfaction: it is an idea whose time has come.

Thomas Chang always believed artifical cells would prove as valuable a tool in medicine as artificial limbs and organs, but when he started work in the 1950s he was ploughing virtually a lone furrow. In the last six years, designer cells have become fashionable, attracting higher levels of funding for research which has been rewarded with unexpected results. Ironically it was probably the AIDS epidemic which did most to arouse this new interest.

For Chang, based at McGill University (Montreal), has been working specifically on modifying haemoglobin in his own cell structures for use as a blood substitute.

The quest for a successful artificial red-blood cell system has occupied Chang's life since he was an undergraduate more than 30 years ago. His early work concentrated on the design and synthesis of artificial cell membranes from various polymers, protein-lipid and polymer-lipid combinations. Now companies are realising the full commercial potential of his revolutionary ideas.

Chang is credited with inventing microencapsulation, the technique for making artificial cells. It enables functional bio-chemicals to be held inside artificial membranes so they can emulate both in vitro and in vivo the behavior of some natural cells.

'Artificial cells' already have many medical applications. A hemoperfusion column is in effect a large cell filtering waste materials from the blood before it is returned to the patient's body. It is used in cases of chronic renal failure, drug poisoning, liver failure, enzyme therapy and metabolic function replacement.

Microencapsulation, enabled cells of less than a micron in diameter with the potential to carry out the function of natural cells to be synthesized for infusion into the blood stream. The best example is the microencapsulation of the natural oxygen carrier haemoglobin.

Reverse phase evaporation is used to create these synthetic cells 'trapping' the haemoglobin molecules in membranes made of cross-linked proteins, bi-layers or phospholipid-cholesterol complexed on cross-linked protein membrane. These ultra-thin protein 'package' the haemoglobin molecules and protect them from exposure to the hostile extracellular environment, while allowing them to transport oxygen and carbon dioxide. Chang discovered these man-made membranes do not react with blood antibodies so there was no risk of infection.

There were two main problems with Chang's membranes. The artificial cells were rapidly removed from circulation and they give unfavourable oncotic pressure levels crucial for efficient [O.sub.2]-[CO.sub.2] exchange. Work has centred on solving these snags by varying the cell membrane diameters, surface charges and other properties and creating in artificial cells, as far as possible, the conditions which occur in natural cells.

Change recognized that inside natural red blood cells (RBCs) 2,3, diphosphoglycerate is available for binding to haemoglobin. In this regime the haemoglobin readily releases oxygen to the tissue. When it is outside natural red cells 2,3 DPG is not available and haemoglobin has a detrimentally high oxygen affinity. Sure enough, he found using 2,3 DPG in his cells improved their efficiency.

Also inside natural red cells haemoglobin is tetrameric, while outside the cell membrane it is dimeric. The dimer is readily excreted by the kidneys resulting in a low half-life in the biosystem. A lipid-cholesterol membrane microencapsulating haemoglobin and pyridoxal-5-phosphate gave oxygen affinity values similar to haemoglobin in natural red cells. Unfortunately, the tetramer tended to degenerate to the dimer, resulting in a short half-life.

So they looked at polyhaemoglobin, saw that it maintained its tetrameric form and hence had a good half-life, but suffered because of its high oxygen affinity. Chang and others combined the two approaches pyridoxylating the polyhaemoglobin and this gave a considerably improved half-life and oxygen carrying efficiency.

Studies have shown pyridoxylated polyhaemoglobin in an artificial lipid membrane to be as effective as a whole blood substitute in the resuscitation of experimental rats suffering fatal haemorrhagic shock. Rats with chronic haemorrhraging were kept alive with up to 100% exchange between natural blood and cellular pyridoxylated polyhaemoglobin. Long-term survival rates were 80%, 63% and 50% following isovolemic exchanges of 70%, 85% and 100% respectively.

These artificial RBCs had an in-body half-life of 30 hours after 97-100% replacement; 20 hours after 70% and seven hours after only 15% replacement. The survival rate of the rats was measured as a balance of the rate of removal of the pyridoxylated polyhaemoglobin against the rate of production of natural RBCs by the animal.

New areas of research are opening up using haemoglobin cross-linked to soluable macromolecules like dextran or polyethylene glycol. Here too, the half-life is improved. Other groups are investigating the use of adenosine tri-phosphate (ATP) instead of pyridoxal phosphate.

In a separate diversion Robert Geyer at a Havard School of Health has even eliminated the need for haemoglobin and cell structures. He is using perfluorochemicals as artificial oxygen transport vehicles. Geyer found that rats breathing an oxygen-rich atmosphere can survive having their blood completely replaced with a mixture of emulsified PFCs, electrolytes, and an agent to maintain the oncotic pressure. The rats' oxygen requirements were met despite the lack of red-blood cells and they soon produced new plasma proteins and red cells. Geyer even found that these bloodless rats could be exposed to lethal doses of carbon monoxide because carbon monoxide would not bind to PFCs as it does to natural haemoglobin.

Chang recognizes the potential of Geyer's PFCs as a blood substitute because they can be manufactured easily and in large amounts. However, he keeps his faith in artificial cells rather than replacement chemicals believing modified haemoglobin structures offer a better prospect for clinical applications.
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Title Annotation:Thomas Chang's search for artificial red blood cells continues
Author:Martin, Dermot
Publication:Canadian Chemical News
Date:Aug 1, 1991
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