Droplet based microfluidics
The advancement of in vitro models has reshaped the landscape of biomedical research, providing unprecedented opportunities for simulating human organ functions. Microphysiological systems (MPS), encompassing organoids and organ-on-a-chip (OoC) technologies, are redefining how we study human biology. These systems represent a significant step forward from traditional 2D cell cultures by extending the life span of cell cultures and adding physiological complexity. MPS models are particularly impactful in cancer research, enabling long-term pharmacokinetic and pharmacodynamic evaluations. Both of which are reshaping how we study diseases, test drugs, and explore the intricacies of human biology. However, these two systems differ significantly in how they replicate organ structures, their applications, limitations, and future prospects.
Organoids are miniature, three-dimensional cellular structures that closely mimic the architecture and functionality of human organs. The development of organoids dates back to 2009, when Hans Clevers’ research team demonstrated that a single LGR5+ intestinal stem cell could differentiate and form an entire crypt-villus structure in a 3D culture environment. This was achieved by embedding cells in Matrigel and culturing them with specific growth factors, such as R-spondin 1 (a WNT agonist), epidermal growth factor (EGF), and bone morphogenetic protein (BMP) inhibitors. Today, organoid models have been established from nearly every major human tissue, including the brain, lung, liver, pancreas, and kidneys.
Organoid development relies on the self-organizing capacity of stem cells, either adult stem cells or induced pluripotent stem cells (iPSCs). Notably, iPSCs offer higher cellular diversity, making them advantageous for creating complex tissue models. These stem cells are grown in a gel-like matrix, often Matrigel, which mimics the extracellular matrix and provides structural support. Non-adherent microwell plates and hanging drop cultures are also used to facilitate 3D growth. The organoid culture environment requires specific media formulations tailored to the organ type, often involving multiple growth factors and signaling inhibitors to help cells differentiate. This intricate setup allows the organoid to develop tissue-specific features, such as epithelial layers, glandular structures, and neuronal networks.
The versatility of organoids has opened new avenues for research in several areas:
Adapted image from Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver, Meritxell Hutch et al., 10.1016/j.cell.2014.11.050
Despite their advantages, organoids face several limitations:
Organ-on-a-chip (OoC) technology represents a more engineered approach to replicating organ functions by using microfluidic devices designed to simulate tissue-tissue interfaces, mechanical forces, and chemical gradients found in human organs. These devices house different cell types in synergy, mimicking the complex interplay present in living tissues.
Typically made from optically transparent materials like polydimethylsiloxane (PDMS), OoC systems feature microchannels lined with living cells, often separated by semipermeable membranes or embedded in extracellular matrix (ECM) gels, with a controlled microfluidic system. This setup enables the efficient transport of nutrients and waste, provides mechanical stimuli, and allows for precise management of the microenvironment and establishing chemical gradients. Originating from advances in microfluidics and tissue engineering, OoC technology offers more physiologically relevant in vitro models compared to traditional 2D cell cultures or static 3D organoids.
The fabrication of organ-on-a-chip devices often involves techniques like soft lithography, which requires clean room facilities and specialized equipment to mold intricate microfluidic channels. Researchers are also exploring alternative fabrication methods, such as 3D printing, laser cutting, and adhesive layer stacking. Once fabricated, the chips are connected to external reservoirs, pumps, and tubing, creating a dynamic flow system that supplies fresh media and removes waste. This setup replicates physiological processes like the rhythmic contractions of heart tissue, alveolar gas exchange in the lung, and kidney filtration.
Organ-on-a-Chip (OoC) systems are at the cutting edge of drug development and precision medicine:
While organ-on-a-chip technology provides dynamic and physiologically relevant models, it comes with several challenges:
The future of in vitro modeling lies in integrating organoids with organ-on-a-chip technology, paving the way for advancements in personalized medicine and pharmacogenomics. These hybrid models could enable more accurate disease modeling, drug screening, and the development of targeted therapies using patient-derived cells. However, the field still faces challenges and need to focus on common perspectives:
The concept of Organoids-on-a-chip represents a groundbreaking approach to overcoming the limitations of traditional organoids and organ-on-a-chip systems. By integrating organoids into microfluidic platforms, researchers can provide a more physiologically relevant microenvironment with controlled perfusion, mechanical stimuli, and biochemical gradients. This integration allows for better modeling of organ-specific functions, such as vascularized tissues, and facilitates the study of organ-organ interactions in a dynamic setting. Organoids-on-a-chip platforms are poised to transform drug testing and disease research by offering higher reproducibility, enhanced scalability, and the ability to capture complex physiological processes. The development of these hybrid systems could mark a significant step forward in creating in vitro models that closely mimic human organs, bringing us closer to personalized and precision medicine.
Organoids and organ-on-a-chip systems represent complementary approaches to advancing biomedical research. Organoids excel in capturing the genetic and histological features of human tissues, making them ideal for personalized medicine and cancer research. In contrast, organ-on-a-chip devices provide a dynamic, perfused environment that mimics organ functions, offering insights into drug efficacy and toxicity. By addressing the limitations of each technology and exploring their integration, researchers can unlock new possibilities for understanding human biology and developing more effective therapies. A concerted effort toward standardization is essential for maximizing the potential of these technologies, ultimately paving the way for a future where personalized and precision medicine becomes the norm.
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At the beginning of the third millennium, due to prolonged aging, neurodevelopmental disorders are growing and a much deeper understanding of the brain is necessary.
The liver is involved in more than 300 vital functions, but is mainly known for being part of the digestive tract, where it has the extremely important role of metabolizing both xenobiotics and nutrients (carbohydrates and lipids).
A heart-on-chip is a microfluidic chip reproducing the mechanisms of a heart, in order to test medicine quickly and observe the reaction of heart cells. Great care is given to mimic the mechanics of a heart in an artificial structure, lined with live heart cells.
While many animal models have been used to study lung diseases, they lack sufficient similarity with human systems, leaving gaps in what is possible in animal-based platforms.
It could be extremely interesting to build a human-on-chip that will model the interactions between different organs, but it is also essential to develop simulations of tissue-tissue interfaces and more generally of local organ behavior.
Since 2012, more and more people, companies or lab, have worked on the organ-on-a-chip. These cell cultures can, thanks to microfluidics, mimic the cells microenvironment of the human body. Thus, these chips could become wonderful search accelerators and we can hope that, in ten years, they could replace the animal testing. Finally, organs on chips could lead us to personalized medicine.
Cell culture consists in growing cells in an artificial environment in order to study their behavior in response to their environment[1]. Different kinds of cell cultures can be found nowadays, and some would be more suited than others depending on its properties and applications.
Organ-on-chip companies developping innovative technologies
Although we take part in various research projects such as artificial photosynthesis, pathogen detection and stem cell differentiation, the ultimate goal of our entrepreneurial adventure is to accelerate anti-aging research.
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