With the advent of an aging society, the disease incidence rate is increasing, and the cost of drug development and disease treatment is expanding exponentially. According to the World Health Organization (WHO), nearly one billion people in the world suffer from neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s diseases. Despite decades of research on neurodegenerative diseases by many biologists and pharmaceutical companies, the underlying mechanism of their onset and progression is still largely unknown.
The brain is the most complex organ in the human body, comprising the central nervous system (CNS) along with the spinal cord. As the upper backbone of CNS, the brain processes, integrates, and coordinates the received information, and then makes decisions, in order to organize the activities of individual body parts. The brain comprises numerous neurons that unidirectionally communicate with each other via synapses, where the axon terminal of one cell contacts the dendrites of another in a specific direction. These neurons also communicate with nonneuronal cells such as astrocytes, microglia, and oligodendrocytes. The functions of the brain are maintained by passing electrical or chemical signals between neurons through the synapses, and if this is not done correctly, it can become a neurodegenerative disease.
Alzheimer’s disease (AD), which is a neurodegenerative disorder, is known to be associated with neuronal cell death and neuroinflammation, as well as deposition of neurotoxic protein plaques, which have been observed in human postmortem and animal studies. The AD drugs developed so far have shown good efficacy in the treatment of AD mouse models but consecutively failed in phase III clinical trials, while raising concerns about using animal models, which are biologically different with human models, in mechanism studies and drug screening.
Huntington’s disease (HD), which is a heritable neurodegenerative disorder, results in the death of brain cells, according to animal studies, and has a substantial effect on synaptic alterations in the corticostriatal network. However, these results, obtained from animal studies, are an end point assay, and thus, while HD is progressing, it is not clear how it progresses and through which path. Traditionally, two-dimensional (2D) culture models and animal models have been used for mechanism research and drug development. However, 2D models, such as Petri dishes and culture flasks, cannot mimic the physiology of human tissue in terms of number of cell types, mechanical properties, chemokine-mediated cross talk, and fluidic conditions. Therefore, cellular behaviors and drug responses have been frequently over- or underestimated, and the results provide biased information.
The resolution of these diseases has a long way to go, and such steps are limited due to the lack of a suitable in vitro model system for mechanism study and drug development. In particular, the complex tissue structures and cell–cell interactions of the in vivo system make it challenging to unravel the underlying mechanism of the diseases and to predict the efficacy of clinical medicine. This is why FDA approval rates are low, and some of them are even withdrawn after commercialization.
Since the advent of organ-on-a-chip, many researchers have tried to mimic the physiology of human tissue on an engineered platform. In the case of brain tissue, structural connections and cell–cell interactions are important factors for brain function. The recent development of brain-on-a-chip is an effort to mimic those structural and functional aspects of brain tissue within a miniaturized engineered platform.
One of the challenge of BOC is the requirement of human cell sources for recapitulating the human brain physiology and developing personalized medicine. Animal-originated cells differ from human cells in terms of their genetics, and cell lines frequently lose key functions. Furthermore, human-originated primary cells are difficult to acquire. In this regard, the induced pluripotent stem cell (iPSC) technology, introduced in 2006, is a good candidate for supplying human cells.
Although many BoC models have been developed, the following additional factors need to be considered to precisely mimic the structure and physiology of the brain tissue: (1) cell sources, (2) cell–cell interactions, and (3) cell–extracellular matrix (ECM) interactions. Cell–cell interactions toned should be closely investigated to understand brain diseases better. The on-chip approach is useful for studying cell–cell interactions because it can simplify various complex interactions between cells and identify how the disease initiates and progresses through cell–cell communication. In addition, the on-chip research simplifies the cell population and allows one to monitor the response of each cell type to the developed drugs and, thus, will enable commercializing by selecting the active drugs and minimizing the undesired side-effects.
Recent developments in BoCs can be divided into three categories depending on their high-throughput or high-content screening abilities: (1) 3D high-content systems, which mimic the 3D brain tissue environment in terms of materials, cell types, and physiological stimulation; (2) interconnected multichip systems, which simulate cell-to-cell and organ-to-organ interactions; and (3) high-throughput systems, which can massively screen various experimental conditions by making them compatible with conventional well plate-based assay systems
Brain on Chip devices
Researchers at the Lawrence Livermore National Laboratory have devised a new use for “brain-on-a-chip” technology: testing the effects of biological and chemical agents on the brain over time. Their research was published in PLOS in November 2017. This work is part of an ever-growing body of research dedicated to developing “brain-on-a-chip” technology in hopes that one day, it may eliminate the need for animal testing.
The so-called brain-on-a-chip is essentially a wafer of semiconductors to which researchers affix a network of nanowires. When brain cells are introduced onto the chip, they can use the nanowire as scaffolding to build functional neuronal circuits that mimic the interconnectivity of neurons in the brain. Once the lattice is constructed, researchers can not only observe the connectivity as-is but study the impact of disease and trauma.
In January 2017, researchers at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS) first made headlines with such a “brain-on-a-chip” device. This chip allowed them to identify the differences between neurons depending on where in the brain they originate from, as well as how those different neurons connect with one another, specifically providing insight into the neurological basis of schizophrenia. Researchers at the Australian National University later refined the nanowire scaffolding technique, developing the first-ever working neuronal circuits.
The latest in brain-on-a-chip applications from LLNL found that the technology can be used to study the impact of long-term exposure to biological and chemical agents on the brain. The team was primarily interested in the kinds of chemical exposures that might be experienced by those in the military — a demographic of patients that are already of interest to neurological study, on account of the prevalence of post-traumatic stress disorder. The hope is that through a deeper understanding of the mechanisms at play, antidotes, treatments, or preventative efforts could be developed and deployed to troops to help protect them.
The “brain-on-a-chip” device used by the team at LLNL was designed to have custom-built inserts that give them the ability to model different regions of the brain, swapping them in and out to study their interconnectivity as needed. It also lets the researchers shift easily from the “macro world to the micro world,” since they can place multiple cell types in much smaller areas than has ever been possible before.
From there, the team was able to monitor the bursts that occur between brain cells when they communicate — called “action potential patterns” — as well as give them an idea of how that communication changed over time, particularly if the brain were exposed to something that could change those patterns, like a chemical agent. “Obviously at a high dose, we know exposure is going to be detrimental, but think about the warfighter who is exposed to a low level of chemical for a long time,” iCHIP principal investigator Elizabeth Wheeler explained in an LLNL press release. “Using this device in the future, we might be able to predict how that brain is going to be affected. If we understand how it’s affected, then we can develop a countermeasure to protect the warfighter.”
Breakthrough unlocks progress in brain-on-a-chip technology
Cambridge Consultants and Neuro Engineering Technologies Research Institute (NETRI) announce a breakthrough in precision imaging of brain activity. Working with NETRI’s brain-on-a-chip technology and lensless imaging approach that detects the activity of neurons in brain tissue, Cambridge Consultants was able to accelerate the processing of individual images by over three orders of magnitude, moving from about 20 minutes to process an image to just hundreds of milliseconds. This step-change in speed opens up radical new possibilities, including real-time processing of neural activity and mimicking of neural activity on engineered platforms, supporting the development of novel treatments for conditions such as Parkinson’s and Alzheimer’s diseases.
Organ-on-a-chip is an emerging and highly promising area of biomedical research. The technology involves the ex-vivo (outside of the body) simulation of organ function on a chip. The ultimate promise of such technologies is to greatly reduce the time and cost of testing new therapies for safety and efficacy. Brain-on-a-chip technologies seek to apply this approach to the neural circuitry of the brain, the most complex organ in the human body.
French startup NETRI creates disruptive technologies for brain-on-a-chip applications in neuroscience. Its focus is on ex-vivo replication of human neural circuits in order to understand how neurological disorders, treatments and chemicals affect the brain. NETRI uses a combination of brain-on-a-chip technology and lensless microscopy to record the activity of millions of connected neurons, mimicking the neural circuits implicated in neurological disorders.
However, by detecting something as complex as neural activity, the approach generates an enormous amount of data, requiring many hours of computation effort in order to fully reconstruct the spatio-temporal map of neuron communication. The imaging system runs at approximately 1,000 frames per second, and the baseline algorithm took an average of 1,090 seconds – 18 minutes – to process a single image on a powerful desktop PC. Without improvement, a single second of recording can take 12 days to process.
Recognizing its world-class expertise in medical imaging and high-performance computation, NETRI approached Cambridge Consultants to address this bottleneck, challenging the company to develop a radical algorithm acceleration. A scientific imaging team was set to work within the company’s Data Lab, an on-site facility with state-of-the-art compute infrastructure, allowing rapid exploration of data and compute-heavy approaches, such as high-definition imaging and deep learning.
Cambridge Consultants selected the NVIDIA DGX POD architecture for their AI infrastructure, deploying the NetApp ONTAP AI solution that combines NVIDIA DGX-1™ with NetApp ONTAP storage and network fabric. Through a series of optimizations, the team was able to show that the NVIDIA DGX-1 system delivers the AI supercomputing power required to process a frame in an average of 0.3 seconds, around 3,000 times quicker than the original approach. This acceleration was achieved through a series of optimizations including the design and application of mathematical and algorithmic improvements, leveraging NumPY GPU-accelerated with RAPIDS (CuPy), and exploiting the sheer power of the DGX-1 system. The combined result enables NETRI to completely reimagine their approach and to set their sights on the most radical possibilities, including developing a fully scalable and real-time medical service for hospitals and pharmaceutical industries to perform both in-vitro diagnostics and personalized treatment for every patient suffering from a neurological condition.
Sally Epstein, Head of Strategic Technology at Cambridge Consultants, commented: “Lensless imaging replaces traditional optics with computation, creating a new set of optimization challenges that our team was excited to address. We’re proud to be at the leading-edge of developments in brain-on-a-chip technology and neural imaging, at the point where radical improvements can be unlocked by those with the right combination of vision, experience and compute power.”
Thibault Honegger, Chief Scientific Officer, President & Co-founder of NETRI, commented: “By combining the expertise of Cambridge Consultants with NVIDIA-based computational power, the real-time processing of neural communications becomes possible. This can mark a paradigm shift in assessing the functional aspects of in-vitro neural networks. With this level of resolution, we will be able to accurately measure the “wellness” of the network, in relation to neurological conditions and potential recovery.”