The goal in every lab is to ‘work smarter, not harder.’ This is especially true in pharmacological labs, where there is an ever-greater focus to develop drugs that include in-depth research into their safety and toxicology. Despite promising preclinical studies in animals, these drugs are still failing toxicity investigations; a 2022 study found that around 90% of candidate drugs fail clinical trials because they are found to be unsafe or ineffective. A similar story plays out with monolayer monocultures of immortal or primary cell lines – they’re just not enough to account for human safety.
Years of workshops and conferences led the research community to start looking at ways to eventually replace the animal models that are currently used for hazard identification, risk assessment and drug evaluation.
Enter micro-physical systems (MPS). These systems are made of 2D or 3D cellular constructs from human tissues or organs, that then recreate their structures and functions. These systems allow researchers to test possible effects of different substances across the entire body before involving human participants. These have a great potential to speed up drug testing and approval process, meaning health professionals can get safer treatments to patients faster and more efficiently.
How they work
Researchers often call MPS the ‘human body on a chip’ since they can mimic complex biological functions of specific organs on such a small surface.
First, plastic cavities the size of a USB are lined with stem cells and a circuit to mimic the mechanisms of an organ. The cavities that now contain living tissue derived from human primary and induced stem cells can be used to create 3D tissue ‘organoids’ resembling miniature human organs. These 2D or 3D cellular constructs are adapted to mimic the microenvironment and heterogeneity of their native environment as much as possible.
The conditions in each call can also be altered to grow different cell types, or recreate environments in the body. For example, fluid flows through the channels and tissues to replicate cellular functions and interactions. The chip also has electrodes and electrical connectors to stimulate muscle cell contraction. This intricate yet amazing system has the potential to mimic several organs on one chip.
Together, these systems provide a human-cell based platform to support studies investigating tissue function, for example the effects of toxicants/pathogens. Drug safety and toxicity can also be evaluated on more than one organ.
This uncovers a huge scientific milestone that was not previously possible without live animals. In recognition of this, MPS was named as one of 2016’s top 10 emerging technologies by the World Economic Forum.
So why do pharma labs not have cabinets full of MPS chips? Unfortunately the cell’s size, efficiency, and cell quantity still pose big challenges.
The device’s small size and complexity of biology mean that it needs small, controlled fluids to ensure reliable results. The relatively small amount of cells in each MPS also makes analysis challenging, since small volumes are produced. Strong quantitative information needs to be extracted for findings to be applicable in drug testing. The heterogenous 3D tissue constructs also need to be maintained with the correct functional scaling and control over the integrated organs. Right now, it’s just not easy to do in a cost- efficient and time- efficient way.
MPS models also need to meet a minimum criterion, be robust and reproducible. Again, this presents its own challenges as experimental design must be considered. Complex models may be more physiologically relevant, but difficult to reproduce. This could potentially affect the workflow and accuracy in pharma labs.
Finally, enough quality primary human cells need to be obtained. This can be particularly challenging if the system was to contain multiple cell types and represent an immune component. If this was the case, specific donor-matched cells would be needed, and it would take a long time to attain enough. Adapting and optimising micro-physiological systems is a time-consuming process.
For now MPS development is an upfront investment in R&D. Most approaches are still exploratory, and require attention before they are suitable for market use. It is predicted that in the next five years fully developed micro-physiological systems have the potential to reduce R&D cost significantly. The medical science community needs to work together to find appropriate ways to standardise models in an efficient manner; to reduce overall R&D cost and address clinical challenges efficiently.
To sum up, relevant strong micro-physiological models will improve R&D efficiency and reduce drug attrition. Micro-physiological systems show great promise once fully developed. Like most medical devices, the models are challenged and present many obstacles. As the system is small and intricate, it takes longer for the models to be optimised. Initially the availability of MPS models for drug assessment will improve human safety whilst keeping controversies at bay. By establishing sustainable MPS banks, relevant quantitative data can be reproduced and applied to various studies. The life sciences community need to collaborate and communicate with each other to generate quality systems efficiently.