Diana Spencer catches up with Lorna Ewart, PhD, Chief Scientific Officer of Emulate, about the rise of organ-on-a-chip technology.
Organ-chips combine cell culture with microfluidics to emulate the biological forces of different organ tissues and/or disease states, allowing pharmaceutical researchers to determine a drug candidates’ efficacy and toxicity ahead of clinical trials.
Could organ-chips replace other research methods?
Organ-on-a-chip technology provides an alternative to other preclinical research models, and can overcome some of the issues of inaccuracy. Animal models, Ewart explains, are limited by their genetic and physiological differences from humans. “This inaccuracy leads to toxic drugs inappropriately advancing into clinical trials, where ~30% of drugs currently fail due to unexpected toxicity and as much as 50% fail due to a lack of efficacy1,” she adds.
Alternatively, conventional cell culture enables the use of human cells and is amenable to high-throughput screening, but this comes at a significant loss of physiological accuracy.
“Organ-chips overcome these hurdles by culturing human cells in a 3D setting that is modeled after the tissue of interest,” Ewart expands. “With cues from a diverse population of tissue-specific cell types, extracellular matrix proteins, and biomechanical forces, cells grown in organ-chips closely emulate their in vivo counterparts and replicate tissue-level functions. This accurate modeling of human tissue means researchers can better predict how drug candidates are likely to affect the corresponding organ in patients.”
But can organ-chips entirely replace other models? Not yet, according to Ewart. While the FDA’s Modernisation Act 2.0 has opened the way for alternative research methods and encouraged a move away from animal research, there is still currently a reliance on this approach. As organ-chips are further qualified by future data-sets, Ewart foresees a period of reduction and refinement, which would include a reassessment of the number of animal models used in a particular context. Though this, she cautions, would require investment from government and regulatory agencies to catalyse the large-scale studies needed to qualify new organ-chips.
What role do organ-chips play in cancer research?
Accurate modeling of the human tumour microenvironment is essential to the development of new cancer therapies, but has always been a challenge for drug developers. Ewart explains why: “Tumour cells often reside in dense, three-dimensional clusters that are replete with overlapping gradients. How a tumour cell behaves, and specifically how it responds to a therapeutic, partially depends on its position within these gradients. Cells that are exposed to low levels of oxygen, for example, may not proliferate as fast as cells in more oxygenated parts of the tissue. A therapeutic targeting proliferating cells would thus be more effective against the latter.”
Another factor is the dynamic nature of the tumour microenvironment. Blood flow brings fluids into and out of the tumour; the extracellular matrix is broken down and built up, and non-malignant (such as endothelial and immune) cells percolate throughout. All of this will influence a tumour cell’s transcriptome and proteome and affect how vulnerable tumour cells are to therapeutics, and this is particularly pronounced for biologics and other human-specific treatment, Ewart continues.
“Organ-on-a-chip technology allows researchers to recreate the human tumour microenvironment in vitro, using human cells and capturing much of the complexity that characterises in vivo environments,” she says. “This enables mechanistic studies of cancer cell behaviour, drug efficacy and safety. Endothelial co-culture provides important cell-cell interactions, while media flow and tissue-relevant stretch help model the mechanical forces cancer cells experience in the body. With these highly tunable models, it is possible to modulate various cellular, molecular, chemical and biophysical properties in a controlled manner to investigate their impact on cancer progression and behaviour.”
To provide an example, Ewart points to a recent study2, in which human immunocompetent models of the lung and intestine were created using Emulate’s organ-on-chip technology.
How do organ-chips support gene therapy delivery?
Organ-chips are also playing a role in helping scientists overcome the challenge of developing safe and efficient delivery vehicles for gene therapies, like lipid nanoparticles (LNP). The liver is the major site of LNP accumulation, leading to localised toxicity and reduced overall treatment efficacy.
It is possible to reduce hepatic accumulation of LNPs through alteration of size, composition and physicochemical characteristics, surface charge, and the inclusion of neutral lipids, and organ-chips are offering a potential solution. Emulate’s liver-chip contains three non-parenchymal cells, the liver sinusoidal endothelial, Kupffer, and stellate cells, on one channel of the chip, with the hepatocytes located in the opposite channel. They can therefore lend themselves to studying how systemic delivery of LNPs is restricted from the liver by the sinusoidal endothelial cell fenestrations, its high endocytic capacity, and the presence of scavenger receptors.
Ewart explains: “The Kupffer cells interact first with LNPs, and because they represent the largest phagocytic centre of the body, they are involved in LNP elimination which will impact both efficacy as well as localised hepatotoxicity. Stellate cells are the site of vitamin A storage, but in cases of liver injury, they become activated and transition to myofibroblast-like cells resulting in connective tissue formation that can impede the entry of LNPs, especially important when the liver is the therapeutic target of the LNP. With the hepatocytes located on the opposite channel of the chip, researchers can also study direct access to hepatocytes which contain cell surface receptors that are important for LNP recognition, such as the low-density lipoprotein receptor (LDLR) and the asialoglycoprotein receptor (ASGPR).”
What are the limitations of the technology?
Organ-chips sound like the future of preclinical research, but there are challenges preventing their wider use, such as a lack of industry standardisation and the high cost of production.
Ewart explains how the company is overcoming the issue of qualification and regulatory scrutiny: “Establishing the quality of these models in a standardised way that allows them to be compared with one another has been difficult. Fortunately, the IQ Consortium recently released guidance on how some organ-chips (such as liver-chips) can be qualified against discrete contexts of use. We recently used these guidelines as a starting point when demonstrating the validity of our liver-chip for predicting hepatotoxic potential of a compound.
“Another challenge is that the drug development field needs guidance on how organ-chip data can be integrated into the decision-making process, for example, the progression of a candidate drug into first-in-human trials. We hope to help with this in an upcoming paper which is currently in review.”
When considering the cost, Ewart says it is important to look at the bigger picture to weigh the benefits of using organ-chips for drug development programs. In a recent paper3, Ewart and colleagues demonstrated that the use of a liver-chip model greatly increased the sensitivity and specificity of toxic drug detection. “Economic modeling based on these results suggests that industry-wide use of the liver-chip has the potential to increase productivity in the pharmaceutical industry by nearly $3 billion dollars per year,” she adds.
DDW Volume 24 – Issue 4, Fall 2023
References
- Sun D, Gao W, Hu H, Zhoub S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B. 2022;12(7):3049–3062.
- Kerns SJ, Belgur C, Petropolis D, et al. Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies. eLife 10:e67106.
- Ewart L, Apostolou A, Briggs SA, et al. Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology. Commun Med 2022;2:154.
Biography:
Lorna Ewart is the Chief Scientific Officer at Emulate, where she provides oversight for the company’s scientific vision and advancement with academic, industry, and regulatory partners. Earlier in her career, she successfully established the Microphysiological Systems Centre of Excellence within AstraZeneca’s R&D Biopharmaceuticals Unit in Cambridge, UK, and was the therapy area lead toxicologist for Respiratory and Inflammation in AstraZeneca’s Gothenburg R&D site in Sweden.
