From a needle in a haystack to shooting fish in a barrel: streamlining drug evaluation in zebrafish
A fully automated in vivo screening system offers a promising new tool for efficient and reliable drug evaluation.
A team of researchers from Sun Yat-sen University (Guangzhou, China) have developed a fully automated in vivo screening system (AISS) for rapid, precise and non-invasive multi-organ imaging of zebrafish. This system has the potential to transform preclinical drug evaluation, rivaling traditional methods and previous automated systems due to its low drug consumption and minimal human intervention.
The preclinical evaluation of drug-induced cardiotoxicity is an important stage in the drug development process; however, traditional methods for screening drug candidates, such as cardiomyocyte-based in vitro assays or manual manipulation of animal models, are inefficient and unable to fully reflect the impact on in vivo organ systems.
Zebrafish, with their small size, transparent organ systems, rapid development process and high degree of conservation to mammals, make an ideal model for high-throughput in vivo screening of drug cardiotoxicity. Yet, existing techniques for profiling cardiac functions in zebrafish rely on labor-intensive manipulation and anesthetic treatments, which compromise physiological responses and limit their applications in drug discovery.
While advancements in microfluidics and automatic control technology have allowed for automated drug screening systems using zebrafish larvae to be developed, the challenges presented by their use of anesthetics, manual manipulation and high drug consumption remain.
New approach speeds up Brillouin microscopy
Engineers have improved the speed and throughput of Brillouin microscopy 1000-fold.
To address these issues, the researchers developed AISS, a fully automated system that integrates microfluidic manipulation techniques with automated computer-vision feedback control methods, allowing for rapid evaluation of drug responses in non-anesthetized zebrafish. By using microfluidic chips, the AISS enabled automatic loading, encapsulation, transportation and immobilization of single larvae in droplets for precise drug exposure – at just 5.56 microliters – with minimal human intervention.
Unlike previous systems, the AISS eliminates the need for anesthesia, allowing for high-resolution imaging of organs such as the heart, brain and liver. Additionally, the ability of the AISS to generate multiple drug concentration gradients on-chip allows for detailed assessment of drug effects.
The team then validated their system by examining the cardiotoxic effects of the antipsychotic compound sertindole with multiple concentration gradients, which revealed significant changes in heart rate and ventricular function.
“This automated screening system represents a major advancement in preclinical drug evaluation,” commented study lead Xudong Lin. “By eliminating the need for anesthesia and manual manipulation, we can now observe real-time physiological responses in zebrafish with unprecedented precision.”
While the AISS is currently limited to handling one larva at a time, the system shows great promise for more efficient, reliable and cost-effective drug evaluation and expands the arsenal of tools available for in vivo screening.
