How do organs-on-a-chip allow more predictive drug discovery?

Drug discovery and development mostly rely on animal and cellular models. However, these models often fail to predict new drugs´ safety and efficacy in clinical trials.

Organ-on-a-chip platforms could provide a more accurate model for predicting drug response and potentially reduce the costs and time associated with pre-clinical drug development.

This article will discuss how this technology is changing drug screening and evaluation. We´ll also show you the minimum experimental setup to start working with organs-on-a-chip.

Current Challenges in Drug Discovery

Most preclinical studies use in vitro and animal models to assess the compound´s pharmacodynamics and pharmacokinetics. Cell cultures are widely used as in vitro models to study human disease and therapy. While 2D cell culture methods have evolved with time, they don´t represent the complex microenvironment of living tissues effectively, [1].

This is because cells live inside our body´s 3D environment, interacting with other cells and their extracellular matrix. These interactions are essential for cell differentiation and function. Keeping them would allow a more precise mimicking of physiological and pathological conditions, [1].

Despite their valuable contributions to biomedical sciences, animal models are also being replaced due to ethical concerns. Additionally, many drug candidates fail to demonstrate an acceptable efficacy and safety profile in clinical trials, [1].

These limitations of preclinical models make drug discovery a costly and time-consuming process, [2].

So, the pharmaceutical industry urgently needs more representative human organ models for drug development, [1].

Organs-on-a chip as More Accurate Models

An organ-on-a-chip (OoC) is a miniaturized system that mimics human organ´s physiology and function, [1, 2].

This technology is promising due to its modularity and diversity of complex organ systems that it can simulate. Furthermore, OoCs could provide a better model for drug screening since they use a dynamic 3D environment similar to the human body. They can also help researchers understand diseases better, [1].

How do organs-on-chip work?

An OoC is a microfluidic device which can be made from a number of different materials and methods including, but not limited to:

Silicon-based organic polymer polydimethylsiloxane (PDMS) using the soft lithography technique, [2]. This method is popular in academic labs as it is an easy method to rapidly prototype different chip designs.
Injection moulding of plastic microfluidic chips and,
Glass chips

Each chip, despite it’s material or method of fabrication, is compact and has microchannels to pattern cells and manipulate several fluidic and chemical parameters such as flow rate, pressure, oxygen, and pH, [2].

These parameters should reflect the in vivo characteristics of human organs and tissues, [2].

Organ-on-a-Chip Platforms in Drug Development

The OoC technology can be helpful in many stages of drug development, from early drug discovery to preclinical screening and testing, [2]:

Early drug discovery and disease modeling

OoCs allow spotting drug targets in a more controlled and traceable manner than animal models. For instance, they can be used to study cancer progression mechanisms such as cell migration and invasion, extracellular signaling, and tumor heterogeneity and microenvironment, [2].

Notably, scientists have developed 3D cancer-on-a-chip models to mimic solid and liquid tumor microenvironments with different components, immune suppressor cells, and chemokines. This model could help explain chemotherapy and immunotherapy resistance mechanisms, [2].

Pharmacodynamics and pharmacokinetics studies

Systems representing metabolically related organs can be ideal for pharmacokinetics and pharmacodynamics studies under various drug conditions and across diverse organ sites, [2].

For example, the liver and kidney play an essential role in drug metabolism. The heart, in turn, is strongly affected by drug toxicity. These OoC systems can help researchers answer critical questions about drug candidates’ behavior in the human body, [2].

Efficacy and safety evaluation

OoCs can be valuable tools for efficiently assessing toxicity in the pre-clinical stages of drug development. For example, researchers use human liver chips to analyze adverse events associated with drug interactions during liver metabolism, [2].

Additionally, multi-organ chips allow integrating multiple biomarkers analysis to monitor drug toxicity in the heart and liver. This method was used to show that certain anti-cancer drugs were toxic for the heart and liver, [2].

Moreover, incorporating patient-derived cells would allow more accurate drug response and therapy outcome prediction, [2].

How to Get Started?

The opportunities that OoCs bring to R&D in Life Sciences are fascinating. Next, you´ll see the minimum requirements your lab must have to start experimenting with OoCs:

Microfluidic chips – to emulate in-vivo physiological conditions and mechanical forces.
Microfluidic pumps – to deliver cell culture media. Cellix´s 4U 4-channel Microfluidic Pump is a precision pressure pump with a stable and accurate flow rate that enables independent control of 4 different channels. It allows efficient management of both pressure and flow.
Flow sensors – to give you feedback on the flow control, keeping experiments on track.
Sample reservoir and other accessories –hold the culture media, deliver drugs, or flow a cell suspension through the organ-on-a-chip.

We can provide you with a complete set-up (organ-on-chip kit) or just the components you need. To learn more about our products or request a quote, please get in touch.

References

Mittal, R, Woo, FW, Castro, CS, et al. Organ-on-chip models: Implications in drug discovery and clinical applications. J Cell Physiol. 2019; 234: 8352– 8380. https://doi.org/10.1002/jcp.27729
Ma, Chao et al. “Organ-on-a-Chip: A New Paradigm for Drug Development.” Trends in pharmacological sciences vol. 42,2 (2021): 119-133. doi:10.1016/j.tips.2020.11.009