How Artificial Blood Works

It can seem improbable, or even impossible, that an artificial substance could replace something that does all this work and is so central to human life. To understand the process, it helps to know a little about how real blood works. Blood has two main components -- plasma and formed elements. Nearly everything that blood carries, including nutrients, hormones and waste, is dissolved in the plasma, which is mostly water. Formed elements, which are cells and parts of cells, also float in the plasma. Formed elements include white blood cells (WBCs), which are part of the immune system, and platelets, which help form clots. Red blood cells (RBCs) are responsible for one of blood's most important tasks -- carrying oxygen and carbon dioxide.

RBCs are numerous; they make up more than 90 percent of the formed elements in the blood. Virtually everything about them helps them carry oxygen more efficiently. An RBC is shaped like a disc that's concave on both sides, so it has lots of surface area for oxygen absorption and release. Its membrane is very flexible and has no nucleus, so it can fit through tiny capillaries without rupturing.

A red blood cell's lack of nucleus also gives it more room for hemoglobin (Hb), a complex molecule that carries oxygen. It's made of a protein component called a globin and four pigments called hemes. The hemes use iron to bond to oxygen. Inside each RBC are about 280 million hemoglobin molecules.

If you lose a lot of blood, you lose a lot of your oxygen delivery system. The immune cells, nutrients and proteins that blood carries are important, too, but doctors are generally most concerned with whether your cells are getting enough oxygen.

In an emergency situation, doctors will often give patients volume expanders, like saline, to make up for lost blood volume. This helps restore normal blood pressure and lets the remaining red blood cells continue to carry oxygen. Sometimes, this is enough to keep the body going until it can produce new blood cells and other blood elements. If not, doctors can give patents blood transfusions to replace some of the lost blood. Blood transfusions are also fairly common during some surgical procedures.

This process works pretty well, but there are several challenges that can make it difficult or impossible to get patients the blood they need:

This is where artificial blood comes in. Artificial blood doesn't do all the work of real blood -- sometimes, it can't even replace lost blood volume. Instead, it carries oxygen in situations where a person's red blood cells can't do it on their own. For this reason, artificial blood is often called an oxygen therapeutic. Unlike real blood, artificial blood can be sterilized to kill bacteria and viruses. Doctors can also give it to patients regardless of blood type. Many current types have a shelf life of more than a year and don't need to be refrigerated, making them ideal for use in emergency and battlefield situations. So even though it doesn't actually replace human blood, artificial blood is still pretty amazing.

We'll look at where artificial blood comes from and how it works in a person's bloodstream next.

Until recently, most attempts to create artificial blood failed. In the 19th century, doctors unsuccessfully gave patients animal blood, milk, oils and other liquids intravenously. Even after the discovery of human blood types in 1901, doctors kept looking for blood substitutes. World Wars I and II and the discoveries of hepatitis and the human immunodeficiency virus (HIV) also raised interest in its development.

Pharmaceutical companies developed a few varieties of artificial blood in the 1980s and 1990s, but many abandoned their research after heart attacks, strokes and deaths in human trials. Some early formulas also caused capillaries to collapse and blood pressure to skyrocket. However, additional research has led to several specific blood substitutes in two classes -- hemoglobin-based oxygen carriers (HBOCs) and perflourocarbons (PFCs). Some of these substitutes are nearing the end of their testing phase and may be available to hospitals soon. Others are already in use. For example, an HBOC called Hemopure is currently used in hospitals in South Africa, where the spread of HIV has threatened the blood supply. A PFC-based oxygen carrier called Oxygent is in the late stages of human trials in Europe and North America.

The two types have dramatically different chemical structures, but they both work primarily through passive diffusion. Passive diffusion takes advantage of gasses' tendency to move from areas of greater concentration to areas lesser concentration until it reaches a state of equilibrium. In the human body, oxygen moves from the lungs (high concentration) to the blood (low concentration). Then, once the blood reaches the capillaries, the oxygen moves from the blood (high concentration) to the tissues (low concentration).

See the next page to learn more about HBOC blood.

HBOC vaguely resemble blood. They are very dark red or burgundy and are made from real, sterilized hemoglobin, which can come from a variety of sources:

However, doctors can't just simply inject hemoglobin into the human bloodstream. When it's inside blood cells, hemoglobin does a great job of carrying and releasing oxygen. But without the cell's membrane to protect it, hemoglobin breaks down very quickly. Disintegrating hemoglobin can cause serious kidney damage. For this reason, most HBOCs use modified forms of hemoglobin that are sturdier than the naturally-occurring molecule. Some of the most common techniques are:

Scientists have also researched HBOCs wrap hemoglobin in a synthetic membrane made from lipids, cholesterol or fatty acids. One HBOC, called MP4, is made from hemoglobin coated in polyethylene glycol.

HBOCs work much like ordinary RBCs. The molecules of the HBOC float in the blood plasma, picking up oxygen from the lungs and dropping it off in the capillaries. The molecules are much smaller than RBCs, so they can fit into spaces that RBCs cannot, such as into extremely swollen tissue or abnormal blood vessels around cancerous tumors. Most HBOCs stay in a person's blood for about a day -- far less than the 100 days or so that ordinary RBCs circulate.

However, HBOCs also have a few side effects. The modified hemoglobin molecules can fit into very small spaces between cells and bond to nitric oxide, which is important to maintaining blood pressure. This can cause a patient's blood pressure to rise to dangerous levels. HBOCs can also cause abdominal discomfort and cramping that is most likely due to the release of free radicals, harmful molecules that can damage cells. Some HBOCs can cause a temporary, reddish discoloration of the eyes or flushed skin.

Next, learn about PFC blood and how it is different from HBOCs.

Unlike HBOCs, PFCs are usually white and are entirely synthetic. They're a lot like hydrocarbons -- chemicals made entirely of hydrogen and carbon -- but they contain fluorine instead of carbon.

PFCs are chemically inert, but they are extremely good at carrying dissolved gasses. They can carry between 20 and 30 percent more gas than water or blood plasma, and if more gas is present, they can carry more of it. For this reason, doctors primarily use PFCs in conjunction with supplemental oxygen. However, extra oxygen can cause the release of free radicals in a person's body. Researchers are studying whether PFCs can work without the additional oxygen.

PFCs are oily and slippery, so they have to be emulsified, or suspended in a liquid, to be used in the blood. Usually, PFCs are mixed with other substances frequently used in intravenous drugs, such as lecithin or albumin. These emulsifiers eventually break down as they circulate from the blood. The liver and kidneys remove them from the blood, and the lungs exhale the PFCs the way they would carbon dioxide. Sometimes people experience flu-like symptoms as their bodies digest and exhale the PFCs.

PFCs, like HBOCs, are extremely small and can fit into spaces that are inaccessible to RBCs. For this reason, some hospitals have studied whether PFCs can treat traumatic brain injury (TBI) by delivering oxygen through swollen brain tissue.

Pharmaceutical companies are testing PFCs and HBOCs for use in specific medical situations, but they have similar potential uses, including:

Artificial blood is not without controversy. Next, we'll look at some of the issues surrounding its use as well as its future in medicine.

At first glance, artificial blood seems like a good thing. It has a longer shelf life than human blood. Since the manufacturing process can include sterilization, it doesn't carry the risk for disease transmission. Doctors can administer it to patients of any blood type. In addition, many people who cannot accept blood transfusions for religious reasons can accept artificial blood, particularly PFCs, which are not derived from blood.

However, artificial blood has been at the center of several controversies. Doctors abandoned the use of HemAssist, the first HBOC tested on humans in the United States, after patients who received the HBOC died more often than those who received donated blood. Sometimes, pharmaceutical companies have had trouble proving that their oxygen carriers are effective. Part of this is because artificial blood is different from real blood, so it can be difficult to develop accurate methods for comparison. In other cases, such as when artificial blood is used to deliver oxygen through swollen brain tissue, the results can be hard to quantify.

Another source of controversy has involved artificial blood studies. From 2004 to 2006, Northfield Laboratories began testing an HBOC called PolyHeme on trauma patients. The study took place at more than 20 hospitals around the United States. Since many trauma patients are unconscious and can't give consent for medical procedures, the Food and Drug Administration (FDA) approved the test as a no-consent study. In other words, doctors could give patients PolyHeme instead of real blood without asking first.

Northfield Laboratories held meetings to educate people in the communities where the study took place. The company also gave people the opportunity to wear a bracelet informing emergency personnel that they preferred not to participate. However, critics claimed that Northfield Laboratories had not done enough to educate the public and accused the company of violating medical ethics.

Blood substitutes may be used as performance-enhancing drugs, much like human blood can when used in blood doping. An October 2002 article in "Wired" reported that some bicyclists were using Oxyglobin, a veterinary HBOC, to increase the amount of oxygen in their blood.

In spite of the controversy, artificial blood may be in widespread use within the next several years. The next generations of blood substitutes will also probably become more sophisticated. In the future, HBOCs and PFCs may look a lot more like red blood cells, and they may carry some of the enzymes and antioxidants that real blood carries.

See the links on the next page for more information on blood, artificial blood and related topics.