By Cristina Riquelme Vano
Drug screening and discovery has a financial problem, the vast expenses increasing due to the limited predictability of 2D culture and animal models and the time that clinical studies take to be completed. The results of such experiments often do not correlate with clinical findings or in actual human reactions. Yet, this problem could be solved with an alternative to the conventional preclinical model, potentially, there are other ways to mimic human pathophysiology in vitro to enhance drug development, disease modelling, and personalised medicine. The answer is in microfluidic devices lined with living human cells, known as human organs-on-chips. A human organ-on-chip (OOC) is a multi-channel 3D microfluidic cell culture that mimics the activities, mechanics and physiological response of human organs and organs systems. Organs that have already been simulated include the lung, intestine, kidney, skin, heart, arteries and bones, among others.
There have already been other alternatives to traditional drug screening. For instance, 3D cell culture models exceeding the traditional 2D cell culture system. The flexibility the 3D cell culture extracellular matrix gels provide to living cells to change shape and cell-to-cell adhesions brings a great advantage as compared to traditional cell culture. Nevertheless, even this 3D cell cultures often fail to simulate the properties of human organs (the micro-environments, the spatiotemporal gradients of chemical etc.). Thus, the current transition from 3D culture models to OOCs.
Each OOC is made of a clear flexible polymer of about the size of a memory stick that contains hollow microfluidic channels lined by living human organ-specific cells interfaced with a human endothelial cell-lined artificial vasculature and mechanical forces can be applied to mimic the physical microenvironment of the living organs (i.e. arteries vasoconstriction and vasodilator responses to temperature differences). Having the ability to combine different types of cells and tissues OOCs present an ideal opportunity to study the molecular and cellular mechanisms of human organs and mimic organ diseases to identify therapeutic targets in vitro. For example, they can target new therapeutic treatments for strokes by recreating a biologically relevant blood-brain barrier interface. Another application of OOCs could be to enable insights into how intestinal microbes influence health and diseases by culturing a living microbiome for extended times in direct contact with living human intestinal cells. On the following subsections, see different examples of how OOCs mimic different human organs.
Brain-on-a-chip devices create an interface between neuroscience and microfluidics. Organotypic brain slices are an in vitro model that replicates in vivo physiology having advantages over primary cell culture in that tissue architecture is preserved and multicellular interactions can still occur. There is flexibility in their use, as slices can be used acutely (less than six hours after slice harvesting) or cultured for later experimental use. As organotypic brain slices can maintain viability for weeks, they allow for long-term effects to be studied. Slice-based systems also provide experimental access with precise control of extracellular environments, making it a suitable platform for correlating disease with neuropathological outcomes (Humpel, 2015). Brain-on-a-chip systems can model organ-level physiology in neurological diseases, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis more accurately than with traditional 2D and 3D cell culture techniques.
Lung-on-a-chips improve the physiological relevance of existing in vitro alveolar-capillary interface models. The device comprises three microfluidic channels, and only the middle one holds the porous membrane. Human alveolar epithelial cells are grown on one side of the membrane and human pulmonary microvascular endothelial cells on the other side. The compartmentalisation of the channels facilitates not only the flow of air as a fluid which delivers cells and nutrients to the apical surface of the epithelium, but also allows for pressure differences to exist between the middle and side channels. During normal inspiration in a human’s respiratory cycle, intrapleural pressure decreases, triggering an expansion of the alveoli. As air is pulled into the lungs, alveolar epithelium and the coupled endothelium in the capillaries are stretched. Since a vacuum is connected to the side channels, a decrease in pressure will cause the middle channel to expand, thus stretching the porous membrane and subsequently, the entire alveolar-capillary interface (Nalayanda et al., 2009). Lung-on-a-chip systems can model organ-level physiology in respiratory diseases, such as pulmonary inflammation and infection as well as to study the pulmonary response to nanoparticles.
In addition to simulation of normal organ structures, Wyss Institute researchers have gone further and have mimicked the interconnectedness of human organs. To do so they have linked multiple OOCs together by transferring fluid between their common vascular channels. This “human body-on-chips” approach controls fluid flow and cell viability while permitting real-time observation of the cultured tissues and the ability to analyse complex interconnected biochemical and physiological responses across ten different organs, promising accurate and precise predictions on human pharmacokinetic and pharmacodynamics (PK/PD) responses of drugs in vitro. (Human Organs-on-Chips, n.d.).
In conclusion, organ-on-chip technology will revolutionise the healthcare domain by offering new and groundbreaking solutions to different industries and especially for regenerative medicine and drug screening.
Wyss Institute. n.d. Human Organs-On-Chips. [online] Available at: <https://wyss.harvard.edu/technology/human-organs-on-chips/> [Accessed 26 August 2020].
Humpel, C., 2015. Organotypic brain slice cultures: A review. Neuroscience, 305, pp.86-98.
Nalayanda, D.D., Puleo, C., Fulton, W.B. et al. An open-access microfluidic model for lung-specific functional studies at an air-liquid interface. Biomed Microdevices 11, 1081 (2009). https://doi.org/10.1007/s10544-009-9325-5