Organ-on-a-chip

An organ-on-a-chip (OOC) is a multi-channel 3-D microfluidic cell culture chip that simulates the activities, mechanics and physiological response of entire organs and organ systems, a type of artificial organ. It constitutes the subject matter of significant biomedical engineering research, more precisely in bio-MEMS. The convergence of labs-on-chips (LOCs) and cell biology has permitted the study of human physiology in an organ-specific context, introducing a novel model of in vitro multicellular human organisms. One day, they will perhaps abolish the need for animals in drug development and toxin testing. An organ-on-a-chip (OOC) is a multi-channel 3-D microfluidic cell culture chip that simulates the activities, mechanics and physiological response of entire organs and organ systems, a type of artificial organ. It constitutes the subject matter of significant biomedical engineering research, more precisely in bio-MEMS. The convergence of labs-on-chips (LOCs) and cell biology has permitted the study of human physiology in an organ-specific context, introducing a novel model of in vitro multicellular human organisms. One day, they will perhaps abolish the need for animals in drug development and toxin testing. Although multiple publications claim to have translated organ functions onto this interface, the movement towards this microfluidic application is still in its infancy. Organs-on-chips will vary in design and approach between different researchers. As such, validation and optimization of these systems will likely be a long process. Organs that have been simulated by microfluidic devices include the heart, the lung, kidney, artery, bone, cartilage, skin and more. Nevertheless, building valid artificial organs requires not only a precise cellular manipulation, but a detailed understanding of the human body’s fundamental intricate response to any event. A common concern with organs-on-chips lies in the isolation of organs during testing. 'If you don’t use as close to the total physiological system that you can, you’re likely to run into troubles' says William Haseltine, founder of Human Genome Sciences in Rockville, Maryland. Microfabrication, microelectronics and microfluidics offer the prospect of modeling sophisticated in vitro physiological responses under accurately simulated conditions. A lab-on-a-chip is a device that integrates one or several laboratory functions on a single chip that deals with handling particles in hollow microfluidic channels. It has been developed for over a decade. Advantages in handling particles at such a small scale include lowering fluid volume consumption (lower reagents costs, less waste), increasing portability of the devices, increasing process control (due to quicker thermo-chemical reactions) and decreasing fabrication costs. Additionally, microfluidic flow is entirely laminar (i.e., no turbulence). Consequently, there is virtually no mixing between neighboring streams in one hollow channel. In cellular biology convergence, this rare property in fluids has been leveraged to better study complex cell behaviors, such as cell motility in response to chemotactic stimuli, stem cell differentiation, axon guidance, subcellular propagation of biochemical signaling and embryonic development. 3D cell-culture models exceed 2D culture systems by promoting higher levels of cell differentiation and tissue organization. 3D culture systems are more successful because the flexibility of the ECM gels accommodates shape changes and cell-cell connections – formerly prohibited by rigid 2D culture substrates. Nevertheless, even the best 3D culture models fail to mimic an organ’s cellular properties in many aspects, including tissue-to-tissue interfaces (e.g., epithelium and vascular endothelium), spatiotemporal gradients of chemicals, and the mechanically active microenvironments (e.g. arteries’ vasoconstriction and vasodilator responses to temperature differentials). The application of microfluidics in organs-on-chips enables the efficient transport and distribution of nutrients and other soluble cues throughout the viable 3D tissue constructs. Organs-on-chips are referred to as the next wave of 3D cell-culture models that mimic whole living organs’ biological activities, dynamic mechanical properties and biochemical functionalities. Brain-on-a-chip devices create an interface between neuroscience and microfluidics by: 1) improving culture viability; 2) supporting high-throughput screening; 3) modeling organ-level physiology and disease in vitro/ex vivo, and 4) adding high precision and tunability of microfluidic devices. Brain-on-a-chip devices span multiple levels of complexity in terms of cell culture methodology. Devices have been made using platforms that range from traditional 2D cell culture to 3D tissues in the form of organotypic brain slices. Organotypic brain slices are an in vitro model that replicates in vivo physiology with additional throughput and optical benefits, thus pairing well with microfluidic devices. Brain slices have 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 6 hours after slice harvesting) or cultured for later experimental use. Because 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. Because approximately 10 to 20 slices can be extracted from a single brain, animal usage is significantly reduced relative to in vivo studies. Organotypic brain slices can be extracted and cultured from multiple animal species (eg. rats), but also from humans. Microfluidic devices have been paired with organotypic slices to improve culture viability. The standard procedure for culturing organotypic brain slices (around 300 microns in thickness) uses semi-porous membranes to create an air-medium interface, but this technique results in diffusion limitations of nutrients and dissolved gases. Because microfluidic systems introduce laminar flow of these necessary nutrients and gases, transport is improved and higher tissue viability can be achieved. In addition to keeping standard slices viable, brain-on-a-chip platforms have allowed the successful culturing of thicker brain slices (approximately 700 microns), despite a significant transport barrier due to thickness. As thicker slices retain more native tissue architecture, this allows brain-on-a-chip devices to achieve more “in vivo-like” characteristics without sacrificing cell viability. Microfluidic devices support high-throughput screening and toxicological assessments in both 2D and slice cultures, leading to the development of novel therapeutics targeted for the brain. One device was able to screen the drugs Pitavastatin and Irinotecan combinatorically in glioblastoma multiform (the most common form of human brain cancer). These screening approaches have been combined with the modeling of the blood-brain barrier (BBB), a significant hurdle for drugs to overcome when treating the brain, allowing for drug efficacy across this barrier to be studied in vitro. Microfluidic probes have been used to deliver dyes with high regional precision, making way for localized microperfusion in drug applications. Because microfluidic devices can be designed with optical accessibility, this also allows for the visualization of morphology and processes in specific regions or individual cells. 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. The ability to model these diseases in a way that is indicative of in vivo conditions is essential for the translation of therapies and treatments. Additionally, brain-on-a-chip devices have been used for medical diagnostics, such as in biomarker detection for cancer in brain tissue slices. Brain-on-a-chip devices can cause shear stress on cells/tissue due to flow through small channels, which can result in cellular damage. These small channels also introduce susceptibility to the trapping of air bubbles that can disrupt flow and potentially cause damage to the cells. The widespread use of PDMS (Polydimethylsiloxane) in brain-on-a-chip devices has some drawbacks. Although PDMS is cheap, malleable, and transparent, proteins and small molecules can absorb to it and later leech at uncontrolled rates.