October 2016 | Issue 26
Seizing up opportunities

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By Nicole Lim, Assistant Director, Communications & External Relations

It’s all about size for LKCMedicine Senior Research Fellow Dr Hou Han Wei. Working on tiny devices, he uses forces and the fluid flow unique to microscale environments to accurately separate cells by size – isolating anything from cancer cells to bacteria and now white blood cells from blood in minutes.

White blood cells, a cornerstone of the immune system, consist mainly of lymphocytes, monocytes and neutrophils. Handily, these differ in cell size, a fact which Dr Hou, who received the inaugural LKCMedicine Postdoctoral Fellowship in 2014, is using to transform how full blood count tests are performed.

He said, “Isolating immune cells from blood is difficult. A full blood count test currently requires a teaspoon of blood and hours of processing to extract these fragile cells.”

Employing his lab-on-a-chip microfluidic technology, Dr Hou has reduced the processing time to mere minutes. The added benefits – it needs just a drop of blood and the microchip costs less than one dollar.

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Prof Boehm and Dr Hou show off the lab-on-a-chip that sorts immune cells by size using just a fingerprick of blood

After destroying (or lysing) the red blood cells, the remaining cells are pumped into spirals on the microchip. Using the naturally occurring centrifugal forces within the spirals, cells of different size migrate to distinct positions within the channel. The sorted cells are then extracted via different outlets – two for any waste and remnants of lysed red blood cells and platelets, another for lymphocytes and one for neutrophils. Harnessing natural forces means that Dr Hou can do away with adding expensive antibodies, making his lab-on-a-chip cheap as chips.

Dr Hou, who collaborated with NTU engineering colleagues on this device, added, “With just a very small volume of blood, we can isolate the cells in a single step within minutes. The label-free approach and short processing time ensures that the cells are in their native condition, which we can then study, something that is hard to achieve with existing technologies.”

Making use of this breakthrough, Dr Hou plunged into the unknown – to understand how neutrophil function is affected in people with diabetes. While it is known that neutrophil counts are increased in people with diabetes, how they function is a black box.

In healthy individuals, neutrophils are the first responders to an infection. From floating free in the blood stream, they attach to and roll along the vessel walls. When they reach the site of infection, they squeeze through the cell wall and migrate to the infection site. Dr Hou’s research found that in people with diabetes, the neutrophils roll faster along the blood vessels than in healthy individuals, which means that fewer manage to stick to the wall and migrate to the infection site. This makes the infection more likely to bloom and spread.

“These increased rolling speeds correlate closely with cholesterol and C-reactive protein (a marker of inflammation) levels, giving us a much clearer picture of an individual’s risk of infection,” said Dr Hou.

There is good news. Existing drugs used in the management of diabetes such as the first-line drug metformin, which also offers some cardio-protective benefits, and drugs such as pravastatin that are used to reduce the risk of cardiovascular events in people with diabetes, seem to affect the rolling speed of neutrophils. Scientific Director of LKCMedicine’s Metabolic Disease Research Programme and Professor of Metabolic Medicine Bernhard Boehm said, “Some drugs like metformin and pravastatin mitigate cardiovascular risks such as atherosclerosis in people with diabetes. In doing so, these drugs may modify neutrophil function as neutrophils are a key driver in atherosclerosis. But the precise interaction and extent of any beneficial effect on neutrophils has yet to be fully studied.”

The homerun vision for this research? To offer personalised precision treatments to all diabetic patients. “We want to enable clinicians to accurately tailor the right combination of drugs for each patient based on their immune status,” said Dr Hou.

With the initial data in hand, Dr Hou plans to team up with clinician-scientists at LKCMedicine and Tan Tock Seng Hospital (TTSH) to conduct a bigger clinical study of the device,  using it in diabetic patients, and exploring the influence of other neutrophil functions, such as migration and their ability to kill bacteria.

At the same time, he’s also using his lab-on-a-chip technology to drive functional biomarker discovery that enables clinicians to stratify patients’ immune risks precisely and from the outset.

Summing up the significance of this breakthrough, Prof Boehm, who is also a senior consultant endocrinologist at TTSH, said, “A test that shows that a drug is doing good things much more rapidly would be of enormous value to doctors, patients and drug companies and would support the more accurate risk stratification and disease characterisation in individual patients.”