Exploring Organ-on-a-Chip Models as an Animal Model Alternative

March 20, 2023 - In 2010, researchers at Harvard University developed the first human organ-on-a-chip model. Since then, researchers have built on existing data to improve these once-unimaginable tools. After its first utility as a model for respiration and lung functions, coined lung-on-a-chip, organ-on-a-chip technology has invaded many aspects of research. The recent passage of the FDA Modernization Act 2.0 may further drive the growth and development of these clinical tools as an alternative to animal models.

While animal models have become the standard for clinical and commercial research, a growing backlash against this use of animals and technological advancements have prompted healthcare professionals and government officials to look to other tools.

Despite the complexity of developing and extrapolating data from an organ-on-a-chip model, scientists have incorporated them into commercial uses, research, and single-tissue organ models.

Animal Models

Over many millennia, animal models have been a critical asset for experimentation, with models dating back to ancient Greece. Today, animal models are a vital tool for clinicians and researchers working in the medical industry, whether developing drugs or analyzing relationships.

Most interventional clinical trials in the United States require animal model testing as part of the preclinical data before progressing into human clinical trials. Estimates by the Human Society of the United States note that, domestically, 50 million animals are used for research or educational purposes each year.

FDA Modernization Act

Despite the utility of animal models, clinical researchers and pharmaceutical developers may be turning to alternatives to animal trials moving forward. Recently, President Biden signed the FDA Modernization Act 2.0, updating section 505 of the Federal Food, Drug, and Cosmetics Act.

The newest revisions allow clinical trial applicants to forgo preclinical testing on animal models by submitting an additional application to the FDA, which may approve select alternatives to animal models.

Considering the most recent shortage of non-human primates — prompted by the illegal export of nonhuman primates from Cambodia to the US for clinical trials and the subsequent halt of exports from Cambodia — researchers have detected flaws in animal models. Beyond the potential shortage and the inability to readily conjure up new non-human primates, animal models do not share the exact genetic makeup of humans, leaving room for error when building on animal trial results.

While the revisions are recent, researchers have been working with alternatives to animal models for years. These alternatives include computational and mathematical models, tissue bioprinting, and organ-on-a-chip models.

Organ-on-a-Chip

Recent developments in organ-on-a-chip models have made them a widely sought-after tool for clinical researchers. Unlike animal models, organ-on-a-chip models allow clinicians to test chemicals and medications on human tissues, negating any errors that may arise from the heterogeneous relationship between animal and human genomes.

A review published in Nature defines organ-on-a-chip technology as “systems containing engineered or natural miniature tissues grown inside microfluidic chips.” While incomparably complex, the organ-on-a-chip system can be simply divided into the chip and organ components.

According to researchers in Nature, the microfluidic chip has small pores that allow solutions only as large as milliliters through the channels. On the flip side, the organ aspect of this biotechnology refers to the tissues grown inside the chip that can simulate varying kinds of tissue and their function, allowing for relatively accurate in vitro experiments.

Based on previous models, including animal-on-a-chip and body-on-a-chip, organ-on-a-chip is a growing advancement in biotechnology, driven by the need for more accurate preclinical research.

When developing an organ-on-a-chip technology, clinicians must be mindful of the in vivo environment they are trying to simulate, accounting for context, application, and the data needed to produce actionable clinical data.

Designing an organ-on-a-chip model requires four steps:

1. conceptualization and design
2. material selection and fabrication
3. selection of biological elements
4. supporting life inside devices

There are multiple applications of organ-on-a-chip models, with the development requiring extensive consideration of its future applications. However, researchers in Nature note, “As an in vitro system, organ-on-a-chip also cannot comprehensively capture the entire physiology of an organ or body. Hence, the final commercialized form factor of an organ-on-a-chip system is often informed by the tissue functions and read-outs that are essential for the intended application.”

Commercial Uses

One of the most prominent uses of organ-on-a-chip models is commercial compound testing. According to Nature, this application predominantly focuses on drug development. Clinicians can use their organ-on-a-chip model to assess how human tissues may react to a specific drug. Rather than using animal models, researchers can evaluate the efficacy and toxicity of a particular drug using these systems.

As pre-clinical research advances, so does the chip model, transitioning from simple to multi-organ human models. While fewer advancements have been made in the multi-organ framework, they can provide valuable and sophisticated data.

In addition to drug development, commercial uses of organ-on-a-chip models may include biomaterial testing. Using the model, which effectively simulates the physiology of the intended human organ or tissue, investigators can assess the biocompatibility of biomaterials, including catheters, surgical plates, or screws.

Research Uses

Beyond commercial uses, healthcare scientists can use this biotechnology for biological research. The cornerstone of organ on a chip for biological research is disease modeling. Using stem cells from patients, the principal investigator on a study may guide their team to integrate genetic factors that contribute to diseases. Additionally, they may genetically modify stem cells incorporated into the chip.

The ability to model diseases in a simplified manner may provide extraordinary benefits in researching rare diseases where the sample size is relatively small or spread out. Although these tools hold significant promise for disease modeling, additional advancements may be necessary before they can accurately reflect systemic diseases.

Another research function mentioned in Nature is the ability to mimic a cell’s microenvironment. Researchers have historically used organ-on-a-chip technology to alter environmental factors surrounding a cell and assess the impact on the cell’s function.

Single-Organ Tissue Uses

Another primary class of functions that organ-on-a-chip models allow is the ability to model single-organ tissue functions. Historically, these models have been used to analyze liver-specific processes, the mechanical and electrical activity of the heart, the blood–brain barrier or nervous tissues, and the epithelium. Researchers have recently developed a vagina-on-a-chip model that models the vaginal microbiome.