Tiny, flexible particles designed to mimic red blood cells can circulate through the body much like real blood cells do, according to a new study. These particles may one day be the basis for a new type of blood substitute, or could be used to deliver drugs for disease such as cancer, the researchers say.

Real red blood cells are quite flexible and can squeeze though narrow blood vessels. Gradually, they age and become stiffer, and are filtered out of circulation after about 120 days. Earlier designs of synthetic red blood cells have not been very flexible, so they are removed from the bloodstream too rapidly to be used in treatments.

In the study, the researchers used a technology to create red blood cell-like particles — some of which had great flexibility. The most flexible particles circulated 30 times longer than the least flexible ones when they were tested in mice.

However, unlike real red blood cells that carry oxygen to the body's tissues, the synthetic particles are empty-handed. The next step will be to see if they can be made to carry substances such as oxygen, said study researcher Joseph DeSimone, a professor of chemistry at the University of North Carolina at Chapel Hill.

While still years away from developing artificial blood, the researchers could use these particles to improve upon the current blood substitutes that have been tested in clinical trials. Previous attempts at blood substitutes have revolved around modifying hemoglobin — the protein in red blood cells that carries oxygen. But hemoglobin by itself, freed from a red blood cell, is toxic. These particles could get around this by carrying hemoglobin within them.

"If we physically entrap the hemoglobin in these particles, so there was no free hemoglobin in blood, then, presumably, that would eliminate the toxicity issue and still be an effective [oxygen] carrier, just like a real red blood cell," DeSimone said.

An "ice cube tray" for making red blood cells

To make the particles, DeSimone and his colleagues used a technology known as Particle Replication in Non-wetting Templates, or PRINT, which is similar to the methods used to make transistors for computers. The technique, invented by the researchers, allowed them to precisely control the size, shape and properties of the particles, and can be used to crank out thousands of particles, each 6 micrometers in size (a micrometer is one millionth of a meter).

"We basically think of it as an ice cube tray on the micro scale," DeSimone said.

Inside mice, the least flexible particles circulated for about 2.9 hours, while the most flexible particles continued circulating for 93.3 hours, or almost four days.

The flexibility of the particles influenced where they ended up in the mice's body. The stiffer particles stuck in the lungs, while the squishier particles ended up in the spleen, the organ that normally removes real blood cells.

"I think this is an important achievement," to show that the flexibility of these particles relates to their circulation time, said Joerg Lahann, a professor of chemical engineering at the University of Michigan, who was not involved in the study.

However, Lahann noted that particles are still filtered out long before real red blood cells would be. Manipulating the properties of the particles' surface may improve their circulation time, he said.

Future therapies

In addition to oxygen, the particles could also carry drugs and slowly release medicine as they circulate, the researchers said. These types of slow-release drugs could treat  cancer and cardiovascular disease, among other illnesses.

The particles might also be designed to scavenge unwanted substances from the blood, such as cholesterol, DeSimone said. In this case, the particles would start out empty, but made to take up cholesterol. The new load would make the particles stiffer, triggering them for removal.

"Kind of like an empty truck driving around, till it was filled up," DeSimone said.

And because the flexibility of the particles influenced where they ended up in the body, the particles might be used to target specific organs, such as the spleen, Lahann said.

The results will be published this week in the journal Proceedings of the National Academy of Sciences.

Pass it on: Flexible particles made to mimic red blood cells may one day serve as an improved synthetic blood substitute.

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