Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles

The master template (grey) is fabricated using advanced lithographic techniques. A unique liquid fluoropolymer (green) is poured on the surface of the master template and photochemically cross linked (top row, left), then peeled away to generate a precise mold having micro- or nanoscale cavities (upper middle). The unique properties of the PRINT mold enable a liquid substance (red) to fill the cavities (top row, right) through capillary filling. Once the liquid in the mold cavities is converted to a solid, the array of particles (red) can be removed (bottom row, middle) from the mold (green) by bringing the mold in contact with a harvesting film (yellow) that enables the particles to be easily handled, chemically modified, and analyzed. At this point free flowing particles or stable dispersions can be obtained by separating the harvesting film from the particles (bottom row, left).

PNAS – Using mechanobiological mimicry of red blood cells to extend circulation times of hydrogel microparticles

A team of scientists has created particles that closely mirror some of the key properties of red blood cells, potentially helping pave the way for the development of synthetic blood. It could lead to more effective treatments for life threatening medical conditions such as cancer.

Beyond moving closer to producing fully synthetic blood, the findings could affect approaches to treating cancer. Cancer cells are softer than healthy cells, enabling them to lodge in different places in the body, leading to the disease’s spread. Particles loaded with cancer-fighting medicines that can remain in circulation longer may open the door to more aggressive treatment approaches.

UNC researchers designed the hydrogel material for the study to make particles of varying stiffness. Then, using PRINT technology — a technique invented in DeSimone’s lab to produce nanoparticles with control over size, shape and chemistry — they created molds, which were filled with the hydrogel solution and processed to produce thousands of red blood cell-like discs, each a mere 6 micrometers in diameter.

The team then tested the particles to determine their ability to circulate in the body without being filtered out by various organs. When tested in mice, the more flexible particles lasted 30 times longer than stiffer ones: the least flexible particles disappeared from circulation with a half-life of 2.88 hours, compared to 93.29 hours for the most flexible ones. Stiffness also influenced where particles eventually ended up: more rigid particles tended to lodge in the lungs, but the more flexible particles did not; instead, they were removed by the spleen, the organ that typically removes old real red blood cells.

Over their 120-day lifespan, real cells gradually become stiffer and eventually are filtered out of circulation when they can no longer deform enough to pass through pores in the spleen. To date, attempts to create effective red blood cell mimics have been limited because the particles tend to be quickly filtered out of circulation due to their inflexibility.

It has long been hypothesized that elastic modulus governs the biodistribution and circulation times of particles and cells in blood; however, this notion has never been rigorously tested. We synthesized hydrogel microparticles with tunable elasticity in the physiological range, which resemble red blood cells in size and shape, and tested their behavior in vivo. Decreasing the modulus of these particles altered their biodistribution properties, allowing them to bypass several organs, such as the lung, that entrapped their more rigid counterparts, resulting in increasingly longer circulation times well past those of conventional microparticles. An 8-fold decrease in hydrogel modulus correlated to a greater than 30-fold increase in the elimination phase half-life for these particles. These results demonstrate a critical design parameter for hydrogel microparticles.

University of North Carolina at Chapel Hill researchers used technology known as PRINT (Particle Replication in Non-wetting Templates) to produce very soft hydrogel particles that mimic the size, shape and flexibility of red blood cells, allowing the particles to circulate in the body for extended periods of time.

Developed in the DeSimone Lab, PRINT® technology drives both our Life Science and Materials Science research. A powerful nano-molding technique, PRINT enables the fabrication of particles with precise control over the shape, size, composition, and surface functionality. Figures 1 and 2 below illustrate the breadth of shapes, sizes, and compositions possible for nanoparticle fabrication using the PRINT process.

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