An emerging new electrophysiology technology, known as high-density microelectrode arrays, enables researchers to study in vitro models of human brain disease in detail. This creates new possibilities to understand the underlying mechanisms of neurological disorders, like Parkinson’s disease and amyotrophic lateral sclerosis, and advance therapy development.
The development of new treatments for neurological diseases has suffered from the lack of in vitro models that adequately represent the human in vivo condition. Other organs or animal models cannot translate the complexity of the human brain and nervous system.
The emergence of improved human brain disease models that exploit induced pluripotent stem cell (iPSC) technology is opening new routes for researchers to understand the mechanisms behind common neurological disorders and develop new treatments.
“iPSC technology makes it possible to create human neurons using blood or skin cells from any individual,” explained Michele Fiscella, Vice President of Scientific Affairs at MaxWell Biosystems, a Swiss company developing and providing advanced instruments, software, and solutions in the fields of neuroscience and drug discovery. “This is a game-changer because creating neurons from a patient with a neurological disease creates an entirely new means to study that disease.”
The need for complementary analysis techniques
Traditional methods for measuring the physiology of neurons have some drawbacks, including limited sensitivity and resolution.
The patch-clamp analysis is the gold standard in electrophysiology measurements, but it is time-consuming, labor intensive, and not amenable to high-throughput, in vitro analyses in connected neuronal networks. Traditional microelectrode arrays include just a few electrodes per well, which translates into just a few readout points, making it possible to miss the detection of a significant result completely.
Calcium imaging exposes samples to fluorescent dyes and laser light, which may influence the cells’ response and the results. Analysis time is limited from minutes to a few hours, and the sensitivity is not sufficient to reliably detect subtle differences in response to drug treatments.
Hence, to circumvent these limitations, new and complementary technologies will be critical for harnessing the full potential of iPSC models in neuroscience research and therapy development.
High-density recording systems for multi-level sample analysis
MaxWell Biosystems has developed high-content electrophysiology platforms that enable multi-level data collection. Its high-density microelectrode array platforms perform complex recordings of the electrical activities in cells and cell populations. The technology is entirely label-free, so there is no dye or light to interfere with the cells or the readout.
“Electrical activity is very fast – in the millisecond range – and our platforms can capture this because they directly detect the electrical signals,” explained Fiscella. “Standard physiological imaging techniques, such as calcium imaging, cannot achieve this temporal resolution because of limitations in the indicator dye.”
High-density microelectrode arrays are unique because they allow the extraction of data from multiple levels within a cell sample: at the population level, one can analyze the connections between individual cells; at the cellular level, one can examine the particular activity of each different cell; and at the deeper subcellular level, one can observe the initiation of an action potential and follow its propagation through a cell and to the next. It is also possible to see whether the propagation of an action potential speeds up or slows down upon the addition of a drug candidate.
Multi-level analyses are useful for studying brain cells because researchers can answer many questions in one experiment: Do the cells form connections? Do they produce oscillations? Which population and types of cells are affected when a compound is added?
“Most other technologies offer an endpoint analysis: you do an experiment and analyze a specific cell, and in the end, the result is just a summary of the cell population,” explained Marie Obien, Vice President of Marketing and Sales at MaxWell Biosystems. “Our high-density microelectrode array platforms allow you to follow the development of many cells in real-time over multiple days in great detail.”
Meet the MaxOne and MaxTwo
MaxWell Biosystems offers two high-density microelectrode array platforms, MaxOne and MaxTwo, which cover almost all research needs. MaxOne is a single-use chip with one culture well containing 26,000 electrodes that capture high-quality signals at a sub-cellular resolution.
For long-term experiments, cells are cultured and characterized directly in the well. For acute experiments, slices from tissues such as organoids, the brain, or the retina, are transferred to the well for analysis.
The MaxOne chip sits inside a small recording unit, which is placed inside the culture incubator and reads out the cell firings. MaxOne is well-suited for low-throughput analysis of all in vitro preparations.
MaxTwo is a multiwell platform with all the capabilities of MaxOne but with six or 24 wells. MaxTwo includes its own incubator that ensures a proper culture environment during data recording. MaxTwo is suitable for drug discovery, safety pharmacology, and iPSC phenotyping applications and is designed for integration with automation systems.
Application of high-content electrophysiology platforms
MaxWell’s high-density microelectrode arrays have been used in a variety of applications, including the general functional phenotyping of iPSCs and assessing the effects of gene modifications or chemical treatments. They have also been used to demonstrate the potential of iPSC-derived brain organoids in studies of disease, drug mechanisms, and responses to external stimuli.
In neurology drug discovery, the ability of high-density microelectrode arrays to collect information from many individual cells will make it possible to determine an experiment’s statistical significance from fewer wells. This will enable faster conclusions, saving effort and costs, and potentially reducing the time required for drug development.
“Our platforms are unique because of the subcellular details they detect,” explained Obien. “Not only can you see the initiation of an activity and watch it fire through the cell and move on to the next, but you can easily see this level of detail for thousands of neurons. This just isn’t possible with other technologies.”
Visit MaxWell Biosystems’ website to learn more about its high-density microelectrode array technology and high-content electrophysiology solutions.
Images via MaxWell Biosystems
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