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Seeing the Invisible with Microfluidic Devices

The laboratory is the traditional home of the scientific experiment. A biology lab is often like a cell nursery, where the cells are lovingly nurtured in conditions optimal for their growth. A chemistry lab might be filled with glassware, where humans or machines mix together various liquids to synthesise new compounds or drugs. But what happens when you take a lab and shrink it down to the microscale, making it so small you could carry it around in your pocket?

It’s a little difficult to squeeze a graduate student into a laboratory that can fit onto a microchip. However, it turns out that scaling down the size of the lab is not just a great space saver; it can actually result in faster reaction times for creating chemicals or quicker assays for identifying and analysing chemicals and cells. This isn’t due to human inefficiency either but comes from some of the weird and wonderful effects involved in microfluidics.

Microfluidics is all about controlling the flow of liquids on the micro-scale. Much like an engineer might build a series of dams and dykes to steer the course of a river, in microfluidics tiny channels are etched onto circuit boards, smaller than a human fingernail, through which miniscule volumes of chemicals and other liquids can flow. One use of this technology is for everyday inkjet printers, where the channels help carefully control where the ink is sprayed in the printing process. These channels can also be merged, allowing two separate chemicals to mix and react, which is why some of these microfluidic devices are sometimes known as the ‘lab-on-a-chip’.

Dr Stefan H. Bossmann and Dr Christopher Culbertson at Kansas State University are very excited by some of the possibilities that microfluidics and the lab-on-a-chip offers. In their highly interdisciplinary and collaborative project, their teams are working together to develop this technology into a miniature analysis lab. Their technology will, for the first time, offer profiling sufficiently rapid that it could be used to monitor a patient’s response to disease treatments. Such a device would also have the unprecedented ability to perform other kinds of cell analysis, in combination with the team’s work to design and synthesise new markers to help report cell activities, such as proteolytic profiles for early cancer detection.

Figure Laser light from the microscope objective under the chip is focused into both the microfluidic channel and the fibre optic.

Microfluidic devices are inherently well-suited to looking at biological processes, as the micrometre channel size conveniently corresponds to the size of cells. Most cells are between 1 – 100 micrometres, with a human hair being approximately 60 micrometres thick. This means that the channels can not only be used to provide a highly controlled environment for cell growth, that is often more effective than a human-scale lab, but also to separate out different cells of different sizes.

Many diseases are diagnosed by visually looking for deformations or abnormalities in the cell structure. For example, one of the diagnostic tests for leukaemia involves inspection under a microscope of the white blood cells taken from the patient’s bone marrow. The size and shape of the cells can indicate whether the cells are immature and not fully developed, otherwise known as lymphoblasts. Very high proportions of lymphoblasts in the bone marrow cells is one indicator of certain types of leukaemia.

However, with the multitude of sizes and types of cell, it can be hard to differentiate them with a microscope alone. This is why it is common to use stains, which colour only specific kinds of cell, or other kinds of chemical markers that bind selectively to a cell target, and if they are illuminated and excited with a laser, the cell then glows brightly in a particular colour that acts as a flag for a certain cell type.

Drs Bossmann and Culbertson have already succeeded at using optical fibres to integrate this light detection technology onto their lab-on-a-chip. What is unique about their design and project is off-chip placement of the optical fibre bridge: this means the chip design is not further complicated by the inclusion of the fibre. One of the big challenges with microfluidic devices is in their manufacture; making components on such small scales is difficult to do reliably and inexpensively so this is a key advantage of their design.

Another unique feature of their project is creating a microfluidic device with multiple detection and excitation spots to detect the sample of interest, while still using only one laser and detector. The motivation behind this is to increase the versatility and capabilities of the device. Now with the integration of the optical fibres they can detect the intact cell before breakdown of the cell membrane as well as the components from the cell after it is lysed. Each of the excitation spots on the microchip is like a viewing window for the cell’s activities, so the greater the number of spots you have, the greater the amount of information you can obtain. And with more information, it becomes possible to better understand exactly how diseases lead to deformation and destruction of the cell.

Drs Bossmann and Culbertson want to go beyond just being able to image and identify cells. As part of this joint project, Dr Bossmann is working on the development of new biomarkers for single-cell detection. His work involves designing very bright markers, so when the cells bind a chemical marker that glows after it absorbs light from a laser, this emitted light from the cell is sufficiently intense that a single molecule in a single cell can be detected. These markers also have to be rapidly uptaken by the cell so that the detection can be done in ‘real-time’. This is important if this device will be used to reduce patient diagnosis times.

By making it easier to see the cells, and developing highly selective markers, Drs Bossmann and Culbertson have made it possible to investigate enzymatic activity and how cytokines, small proteins that are commonly produced by cells in association with disease, behave. The more sophisticated protease detection (detection of the enzymes that break down proteins) offered by their lab-on-a-chip will make it possible to understand how the misregulation of enzyme activity leads to the development of various diseases. The large number of enzyme markers that can be monitored will allow for the detection of many possible diseases.

The work combining optical fibres with microfluidic devices by Drs Bossmann and Culbertson will open up many new possibilities in understanding diseases at the cellular level and more tools for cell imaging and diagnosis. All of this is an important part in the development of lab-on-a-chip technology for making rapid, handheld diagnostic devices a routine part of healthcare.

Source: Research Features

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