Rodent surgical models: The 4 key decisions that influence experimental success

Progress in drug discovery relies on genetically or surgically modified animal models that closely mimic human disease conditions. Scientific experiments designed to better understand disease progression or evaluate drug response will require periodic dosing and/or sampling of biological fluids. Such preclinical studies, serving as the foundation for clinical approval during the later stages of drug development, therefore, require robust methods and meticulous care, especially when it relates to performing sophisticated surgical procedures.

With a special focus on rodent surgical models used in cardiovascular applications, we explore four critical factors that influence the overall experimental success in translational research. In this exclusive SelectScience interview, we speak with Brad Gien, Global Head of Surgery at Inotiv, as he takes us behind the scenes at Inotiv’s rodent surgical services, where animal welfare and rigorous surgeon training are non-negotiable prerequisites. Plus, Gien shares his future hopes for reducing animal models used in research, and explains why these models are necessary to save lives and advance the medical field.

1. Like-for-like: Choose a rodent model to best mimic the human condition

When it comes to choosing a surgical animal model, it’s important to mimic disease conditions as close to the human experience as possible. This ensures that drugs can be effectively tested to improve clinical outcomes and quality of life in humans. “We work with industry partners to validate and improve our surgical rodent models,” explains Gien. “Our myocardial infarction model can mimic a small, medium, or large heart attack. It involves the permanent ligation of the left anterior descending artery (LAD), and causes heart damage almost immediately after surgery.”

This complex model simulates the permanent damage produced after a heart attack and is used to study treatments that can maintain the most minimal damage for the patient, or improve recovery of the heart muscle after severe injury.

“Our transverse aortic constriction model, on the other hand, is a little bit different,” continues Gien. “It doesn’t cause immediate damage to the heart. Instead, it causes gradual pressure overload. Here, we’re basically constricting the blood vessels and causing the heart to work a lot harder. So, over time, it can cause heart disease.”

In this instance, researchers would use this ‘slower’ model of heart disease to test drugs that can improve the condition before heart disease occurs.

Thousands of these surgical models that mimic myocardial infarction have helped to significantly advance drug compounds from the preclinical stage to clinical trials – and it all starts with choosing the right surgical model during the research phase.

2. Collaborate with the best: Work with trained and certified animal surgeons

“During surgery, the animal’s heart is beating 350 to 400 times a minute,” notes Gien. “Our surgeons need to tie or put a suture directly into the beating heart. And remember, they're going into an area that's about one-tenth the size of a human hair.”

Performing intricate surgeries on these rodents is no easy feat. Animal surgeons at Inotiv undergo rigorous training and supervision to uphold safety and quality standards.

“We maintain a very high level of competency amongst our surgical staff across five different global locations,” says Gien. “Upon joining our expert team, each member receives 18-24 months of training, after which a practical certification test is conducted. The surgery is closely observed for adherence to protocol, and the animals are monitored for several weeks. If the surgical technician passes the test, they are certified for six months. For each of the 55 surgical procedures we provide, the animal surgeon will need to have certification reviews every six months.”

Although intense and thorough, such a robust training process ensures that animals are humanely handled, and the surgical model is reliable and reproducible across multiple cohorts.

3. Thinking ahead: Choose the right catheterization option for long-term sampling

As the surgical animal models get transferred to a range of researchers studying to answer many diverse research questions, one key consideration is dosing and body fluid sampling to obtain the required data. To obtain results from experimental interventions, catheterization is typically used for periodic and long-term sampling from these animals, without causing additional stress or requiring repetitive invasive procedures.

The type of catheterization that best complements the experimental outcome, however, needs to be determined beforehand. “In early discovery or toxicology, vascular catheterization is most used. That is, implanting a catheter in the jugular vein, carotid artery, femoral vein, or femoral artery. These are primarily used for intravenous dosing and sampling of blood over time,” explains Gien.

Additionally, when looking at drug response, catheterization that can measure the body’s first-pass metabolism may also be equally important. “As the drug goes through the liver, if all of it is eliminated, the drug is not going to be successful,” notes Gien. “The second most popular non-vascular catheterization is the bile duct recirculation into the duodenum, where bile can then be sampled to examine how much of the drug has been eliminated from the liver.”

When relying on catheters, a common hurdle that researchers can face is the lack of patency – this is where blood vessel blockages prevent dosing or sampling from the catheter. At Inotiv, the animal surgeons take patency into account when performing catheterization. “We digitally measure veins, arteries, and ducts to make sure our catheters are custom-made to match the exact size and don’t cause patency issues,” says Gien. “We now have researchers using our surgical animals for a year-long study where they’ve maintained full patency.”

4. Protect: Always prioritize animal welfare and safety

Much like humans, animals are more fragile and tired after surgery. Animal recovery post-surgery and care during transportation need to be carefully considered when using rodent surgical models.

“We ensure proper recovery of our animals before shipping. But it's also important that they get to their destinations quickly and safely,” notes Gien. “So, we’ve strategically placed our surgery sites all across the country – in the West Coast, the Midwest, and the East Coast – for the shortest amount of transportation time.”

Gien continues: “We also monitor them continually during their travels. If there are any concerns, the transport driver or delivery person will immediately notify our attending veterinarian, who is on call 24 hours a day.”

In addition to technical expertise and transportation care, the team also regularly reviews its protocols to implement small changes that can further benefit the animals and improve research outputs. “We're keen on achieving the three Rs: reducing, refining, and replacing animals in research. Having better outcomes with our surgeries, including increased patency, has significantly reduced the number of animals used,” shares Gien. “In the near future, I see us refining our procedures even more to maximize the data points obtained from each animal model so that the number of animals used in research can be further reduced.”