Alternatives to Animal Testing Models in Clinical and Biomedical Research
Over the past several years, a growing number of alternative techniques have been developed and used to replace animal testing models in clinical and biomedical research.
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- Before the FDA Modernization Act 2.0 was passed in December 2022, the US government required that all investigational drugs be tested on animals before they could advance to human trials. Although this act does not ban animal testing, it allows researchers to use scientifically proven, non-animal testing methods, such as cell-based assays, microfluidic chips, tissue models, computer models, and human volunteers, when possible.
Animal Testing
Animal testing models have been used throughout history, dating back to 500 BC in ancient Greece. Researching animals is essential for translating discoveries and observations in the laboratory or clinic into new treatments.
Today, standard animal models usually include mice and rats due to their anatomical, genetic, and physiological similarity to humans and their ease of maintenance and size, short life cycle, and abundant genetic resources.
In several research fields, non-human primates (NHPs) — a group of hominins, apes, and monkeys that are biologically and evolutionally similar to humans — are used for scientific, educational, and exhibition purposes. Because NHPs have short life spans and are susceptible to many of the same health conditions that affect humans, they serve as ideal research subjects for studying entire life cycles or several generations.
NHPs are vital for researching a wide array of diseases:
- central nervous system diseases (Alzheimer’s, Parkinson’s, and Huntington’s)
- cancer (liver, renal, gastric)
- metabolic disorders (diabetes and obesity)
- cardiovascular diseases (atherosclerosis and cardiac arrhythmias)
- infectious diseases (HIV/AIDS, malaria, SARS, COVID-19)
- ocular diseases (dry eyes, cataract glaucoma, age-related macular degeneration)
- reproductive conditions (endometriosis, polycystic ovarian syndrome, pelvic inflammatory diseases)
However, as NHP suppliers struggle to meet an unprecedented surge in global demand to study these types of diseases, research institutions have found it increasingly challenging to obtain NHPs in the past several months.
Animal Welfare
Although federal organizations have developed clinical laws and regulations — such as the Animal Welfare Act (AWA) and its succeeding policies — to regulate the treatment of research animals, this practice has been under intense scrutiny by animal rights advocates and policymakers for decades.
According to AWA regulations, principal investigators (PIs) must seek alternatives to painful or distressing procedures. If no other options are viable, researchers must submit a written notice to their Institutional Animal Care and Use Committee (IACUC) that outlines how the team determined that there are no alternatives available. To take it a step further, PIs must also supply written assurance that their research activities do not duplicate prior experiments unnecessarily.
While animal testing has helped humans advance our scientific understanding and develop new medicines and treatments, some experts who study animal testing argue that it can be expensive and ineffective.
“We have many important drugs that have been developed using animal tests. But as we get into some of these more difficult diseases, especially neurological diseases, the animal models aren't serving us as well,” Paul Locke, MPH, JD, DrPH, a scientist and lawyer at Johns Hopkins University, told Wired. “Researchers need new ways to unlock the molecular mechanisms causing these diseases, and the alternatives hold great promise.”
Advocates like Locke highlight studies that demonstrate animal testing can be an unreliable predictor of toxicity in the human body. For example, fialuridine, a drug developed for treating hepatitis B, causes liver failure and is toxic to humans but not mice.
Because 90% of general drug candidates in clinical trials never reach the market, drugs that target the brain typically have an even higher failure rate. These proven inconsistencies and associated time, cost, and ethical concerns have encouraged scientists to develop alternative testing methods that better recapitulate human physiology.
What Are Alternatives to Animal Testing?
Using alternatives to animal testing in clinical research when suitable does not put patients at risk or delay medical progress. Instead, non-animal testing methods such as human cell- and tissue-based testing, human volunteer testing, and computational and mathematical models can be more accurate, cost-effective, and quicker than traditional animal models.
Human Cell- and Tissue-Based Testing
Miniature cellular and tissue models, such as organs-on-a-chip and 3D bioprinting, use human cells to mimic organ functions and structures to screen treatments and test drugs. This allows researchers to simplify a system, limiting the number of variables. Instead of animals, these human-based models can be used to study biological and disease processes and drug metabolism.
Organs-on-a-Chip
Microfluidic organs-on-a-chip are small, clear, flexible polymer devices that comprise human cells and push fluid through tiny channels to imitate blood flow. In 2010, a team at Harvard University’s Wyss Institute developed the first successful human-cell chip. The first of its kind, the lung-on-a-chip, carried out basic lung functions, like respiration. And now, researchers have expanded upon this concept by successfully creating chips that mimic the liver, stomach, intestine, brain, and skin, among others.
Because roughly 30% of medications fail in human clinical trials due to toxicity — despite pre-clinical data using animal and cell models — tissue chips function as new human cell-based approaches that help researchers accurately determine how effective a therapeutic candidate would be in clinical studies.
By eliminating toxic or ineffective drugs earlier in development, drug manufacturers can save valuable time and money. These chips also could teach scientists a great deal about disease progression, leading to better prevention, diagnosis, and treatment approaches.
Because many industry experts recognize the widespread benefits of human-specific chips, this method is becoming popular in drug discovery and development.
Organs-on-a-chip technology allows scientists to easily replicate human tissue and organ functions to assess the safety and efficacy of new drugs. For instance, the Liver-Chip, a liver-on-a-chip device, can detect drug-induced liver injury missed by animal testing models.
Tissue Bioprinting
Three-dimensional (3D) tissue bioprinting is a revolutionary scientific advancement in drug discovery and development that uses new assay models to predict drug impacts on humans better. These tissue models mimic characteristics of live human tissues and are developed on microplates to test the toxicity and efficacy of small molecules or other therapeutics.
By leveraging tissue engineering, stem cell research, disease biology, and in situ detection devices for tissue characterization and drug development, 3D tissue bioprinting produces disease-relevant tissue models that can reduce the predictability gap between the results from current 2D cell-based assays and the results from testing in humans.
Human Volunteer Testing
Thanks to numerous technological advances, new and sophisticated scanning devices and recording methods can now be used to study human volunteers safely.
For example, advancements in brain imaging techniques allow researchers to see inside the brain to monitor the progression and treatment of certain brain diseases. Researchers use these approaches to better understand diseases by comparing their results with the results of healthy volunteers.
In other research areas, such as nutrition, substance use, and pain management, consenting humans can help replace animal testing models. Compared to animal subjects, human volunteers provide a significant advantage by having the ability to speak with researchers and offer additional information during the study.
As opposed to animal testing, human volunteers that donate healthy and compromised tissues via surgery provide a more appropriate way of studying human biology and disease. For example, skin and eye models made from reconstituted human skin and other tissues have been developed to replace rabbit irritation tests.
By donating tissue, alive and deceased donors increase the number of human samples available for research and reduce the number of animal subjects needed. In the past, post-mortem brain tissue has provided important breakthroughs in understanding brain regeneration and the effects of multiple sclerosis and Parkinson’s disease.
Computational and Mathematical Models
With the growing capabilities of computers and computer programs, the ability to model certain aspects of the human body has become easier than ever.
Current computer models of the heart, lungs, kidneys, skin, and digestive and musculoskeletal systems have been developed to conduct virtual experiments based on existing mathematical data and information. Additionally, data mining tools assist researchers in making predictions about one substance based on existing data from similar substances.
Many alternatives to animal testing methods aim to overcome translational barriers toward developing urgently needed treatments for unmet medical needs. As a result, using non-animal models for research could save the lives of more humans and animals, time, and money. And without sacrificing quality and safety, alternatives to animal testing could improve the quality of society while improving health outcomes.
