The research process for drug toxicology in horses has always been long, slow, and expensive. Too often, when veterinarians want to more about the way a drug behaves in horses, they find themselves relying on limited data collected from a small number of horses. That's because there is a lot of expense and regulation associated with using live animals for research of any kind, even a simple drug administration study aimed at determining how quickly horses' bodies metabolize a therapeutic substance. It's also expensive for universities to maintain horse research herds of significant size year after year, awaiting their use in a short study.
A research group at the Gluck Equine Research Center is hopeful they have a solution that will make it quicker and easier for scientists to understand how drugs behave in horses, and it sounds like something out of a sci-fi drama: microscopic equine organ systems.
It's no longer science fiction. Dr. Carrie Shaffer said researchers aren't reconstructing full-size organs, but rather are using defined layers of cells that mirror what you'd find in an equine kidney, liver, lung, or intestine. The cells come from tissue-specific stem cells collected from a Thoroughbred foal that had to be euthanized due to an unrelated structural deformity. Stem cells have the ability to become any kind of differentiated cell upon command, so the researchers are able to direct the cells to form a particular organ tissue.
“We can prove, using a variety of different methods, that our equine microscopic organ systems are stem-cell derived and have the same characteristics and architecture as the corresponding tissue in the horse.”
These microscopic organ systems are grown in clear, plastic microfluidic chips that are about the size of a AA battery. In human medicine, similar microfluidic chips have been developed to mimic the human liver, lung, intestine, kidney, and blood/brain barrier and are used to study various aspects of cell biology and tissue responses to therapeutics.
The metabolism of a drug isn't dependent on the full-size physical structure of an equine liver or kidney, according to Shaffer – it's how the cells of those organs interact with drugs they encounter as the substance passes through an animal's bloodstream and into the organ tissue. Shaffer is able to grow specific liver cells in one channel of the microfluidic chip while creating artificial blood vessels and blood-like fluid flow on the opposite channel of the chip. This simulates a continuous blood supply interfaced with the mucous membranes that are normally found in the body. The blood flow can go in only one direction, which also mimics the horse's body, where veins and arteries carry blood through an organ in only one direction at a time.
“In the case of the lung chip and the intestine chip, we can also introduce relevant biomechanical forces that simulate complex biological processes,” she said. “We can introduce physical stresses into the chip that mimic breathing and lung inflation, or recreate defined patterns of stretch across the intestine chip that simulate the wave-like pattern of nutrients and waste products moving along the equine intestinal system.”
These forces have been shown to direct gene expression in the cells, which create small, but critical, changes that make the microfluidic chips behave more like the cells found in a live animal.
Previous iterations of this technology didn't include biomechanical forces like stretch, so the tissue wasn't as true to that in a horse's body. Additionally, previous tissue culture systems did not allow for directional fluid flow, but rather exposed a single type of liver or kidney cell to static fluid containing a drug at a fixed concentration. That's not how real kidneys and livers actually work, said Shaffer – the organs contain multiple cell types that are exposed to blood flowing at a relatively high rate. Therapeutics within the bloodstream pass through various organ systems within seconds, and carry metabolized drug away from one organ system for delivery to another.
“Under normal drug testing conditions, we are able to analyze a blood sample from a horse after a drug is administered, but we cannot tell in that blood sample where the drug metabolism occurred,” she said. “We don't know whether the drug was liver-metabolized, intestinal-metabolized, or metabolized in the lung. Our horse-on-a-chip microfluidic technology allows us to isolate exactly where drug metabolism occurs within the horse.”
Some drugs metabolize at different rates in different organs, and organs probably take turns at metabolizing a drug but there's currently no way to know in what order metabolism occurs for a given therapeutic. That information could be useful because some drugs linger longer in the body than expected, and scientists often don't know where the hold-up is.
Shaffer said her lab has performed only a handful of studies with the technology because it's so new. So far, the team has pulsed a drug through an equine lung-chip and a liver-chip for sample collection from the apparatus at defined times post-administration to see how much of the drug had been metabolized by specific tissues in a set timeframe.
The team is still validating these emerging methods and drafting papers for peer-reviewed journals describing the process they've used to create this technology. Shaffer said they're still a few months away from using the organ chips en masse for huge studies – and they need to expand to include tissues from other breeds – but she thinks the microfluidic chips could be useful for pre-clinical analysis of new therapeutic drugs.
“The big sell with our horse-on-a-chip technology is that it's going to significantly reduce animal use for studies – reduce euthanasia, reduce the need for research herds,” she said. “We can now perform the majority of upstream pre-clinical analyses in the lab using our technology that recreates the dynamic environment within the horse. Before, we'd study the effects of a new drug using expensive and limited research herds. Now, we can perform critical toxicity and safety studies before the candidate drug is ever injected into a horse.
“The key to our technology is that we don't need to euthanize additional horses. We can go back to our cryobank of Thoroughbred tissue and enrich for tissue-specific stem cells to essentially grow equine microfluidic organ-chips indefinitely. My research team has developed several innovative methods that allow us to keep using and expanding these diverse equine tissues indefinitely.”
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