Partners at the cutting edge of technology

Dr Xue-Feng Yuan and his team at Manchester’s new Interdisciplinary Biocentre are working in collaboration with UK’s instrumentation company, Linkam Scientific, to develop new tools to better understand flow characterisation on the micro scale.

Blood flow at flow rate of about 0.01 ml/hour in a microfluidic chip

THE Manchester Interdisciplinary Biocentre moved into its new facility in October 2006, a £38 million project as part of Manchester’s £360 million investment in bringing together the Victoria University of Manchester and UMIST. While the MIB had existed for a number of years, the move to the new centre has brought scientists from many different traditional disciplines (physics, engineering, chemistry, biology, etc.) into a single working environment designed to enhance communications between researchers from different disciplines as well as to maximise spatial use with hot desks for researchers to share enabling more laboratory space to be made available. The lack of telephones is readily apparent as one walks through the airy atrium built on five levels.

The MIB has been created to promote interdisciplinary, challenge-oriented bioscience and biotechnology at the highest international level, and to train future generations of interdisciplinary investigators in key skills that will enable them to work successfully across the disciplinary interfaces to biology.

Dr Xue-Feng Yuan, a Reader in Biochemical Physics has a research team of ten who range from theoretical and computational modelers to bench practitioners to deliver a better understanding to dynamics of biofluids and biomaterials in a flow situation. While biologists use analytical instruments familiar to chemists, e.g. NMR, X-ray and other spectroscopies, the results derived are usually under equilibrium or near-equilibrium conditions. Yuan’s goal is to combine a variety of physical measurements and computational approaches to quantitatively characterise the highly non-equilibrium behaviour of soft biological materials from molecular, cellular and tissue levels to full-scale biofluid flows in organs.

The University is linked to Europe’s largest hospital specialising in the treatment and study of premature babies. In the cases of many babies born ahead of their time, breathing will be a key difficulty with the lungs being too small or collapsed in such a way as to restrict efficient operation. Getting a good blood supply to the lungs is vital if the baby is to survive and then grow normally. With machines being used to aid both the mechanical function of the lungs and to drive the blood flow, it is critical to understand the issues of getting blood through tiny capillaries just about 10 micron in diameter, less than the size of a human hair. The goal of Dr Yuan’s research is to understand the effects of pressure, gas composition, flow rates, viscosity of blood and cellular adhesion within a capillary.

Red blood cells in a simple shear flow, captured by a Linkam Optical Shearing System

This will lead to a better knowledge understanding of the efficiency of gas exchange through a thin film membrane in a simulated microcirculation environment. His work sets about this by building a prototype instrument where he can artificially create different scenarios such as creation of a blockage and learn how this may be cleared through the addition of the appropriate chemistries, for example, a surfactant. Thus, the long term goal is the development of a universal instrument for quantitative characterisation of physiological fluid flows from which routine quantitative measurements may provide a predictive means to aid treatment and recovery in cases of premature birth.

There is an increasing amount of clinical and experimental data clearly indicating that the flow behaviour of blood is a major determinant of proper tissue perfusion and also the rheological abnormalities correlate strongly with various diseases, Figure 1. Increased whole blood viscosity and red blood cell (RBC) aggregation have been observed in patients with risk factors for cardiovascular disease such as hypercholesterolemia, hypertension, diabetes mellitus and cigarette smoking. Rheological alterations are also found in malignant disease and are most pronounced in advanced cancer. This includes a marked increase in plasma viscosity, aggregation and rigidity of RBCs. Although the blood rheological abnormalities are not specific to malignancy, increase of viscosity reduces blood flow, especially in small vessels, and hence can initiate deep vein thrombosis, which is the most frequent and life-threatening complications in cancer patients. Unfortunately a common clinical practice in haemorheological characterisation involves only a few measurements of blood viscosity at a quite arbitrarily fixed shear rate. Such an approach is economic but not sensitive enough and difficult to pinpoint the sources of the abnormalities. An ideal approach - quantitative haemorheology - should extract the physical parameters from relevant physical processes in haemodynamics across various characteristic length and time scales in a coherent way. In 2000, Dr Yuan bought his first system from Linkam. This was an optical shear system and he used this to examine aggregation of red blood cells and platelets under shear, hence to correlate rheological data with the structural information of cellular components and to develop a quantitative haemodynamic model.

Dr Yuan has entered a collaboration where Linkam, as an industrial partner, has committed about £100k contribution (including a partial funding of a studentship) toward a new EPSRC grant (£700k) to develop a universal instrument platform for the characterisation of blood and biofluids. This is part of the EPSRC’s program that encourages university research groups to work with successful SMEs to help them enhance their competitiveness in overseas markets.

Starting in April 2007, the three year project will develop a state-of-the-art characterisation platform coupled with a portable and high precision environment control unit for measurement of velocity field, pressure drop, anisotropic optical properties (stress field) and concentration fluctuations of complex fluids across microscopic flow geometries. The experimental data for various flow configurations will be used to validate the constitutive model and its parameters by comparison with calculated results. The effects of shrinking the flow geometry, from a characteristic length scale of 600m to one of 3m, on complex fluid flows will be carefully investigated. Such a quantitative approach promises to extract “total constitutive information” for any given complex fluid in microscopic flow. This systematic and integrated approach will be the first of its kind to be applied to microfluidic technology. A bottom-up nano/micro fabrication approach akin to the work of Feynman will be the methodology followed by Yuan and his team.

In the new system development, the goal is to apply very precise and accurate sensor technologies developed at Linkam to control and monitor properties such as temperature, humidity, pressure, stress and atmosphere within a flowcell. Linkam have demonstrated their ability to provide an integrated system using the latest embedded technology for both physical and chemical sensing combined with full environmental control (e.g. oxygen, carbon dioxide).

An example of this is seen with the Linkam tensile stage which has been used to characterise fibre performance. Atmosphere control is critical in trying to mimic the spider’s spinning process. It is another example of working in a microchannel where the monitoring of fluid flow and structure is vital due to the sensitivity of fibre production due to changes in pH and relative humidity. For example, temperature must be controlled to better than +/-0.02°C while oxygen levels must be kept to better 1%.

Vince Kamp, Director of Operations at Linkam, has several reasons for collaborating with leading university research groups like Dr Yuan’s. “We like to work with UK universities through sponsoring collaborations as it gives us the opportunity to get real scientific knowledge and insight into what potential user requirements will be. Then, we can customise our designs to ensure that the final product is exactly what is required. An important bonus to the collaboration is that we become integrated with novel instrument based-research projects that,
without our design expertise, could not take place. We help through building prototypes to advance research in a timely and cost-effective manner.”

There are many benefits in the production of a new characterisation system. Dr Yuan sees the potential of developing new diagnosis protocols to identify diabetes and cardiovascular disease. It may also have application in joint fluid study where study of mechanical behaviour and composition may lead to improved performance. Working closely with the Linkam organisation, he is excited and confident about delivering his research goals in the coming years in the knowledge that he has the support of Linkam.

By Jezz Lekenby. Jezz runs a marketing company, IMS Europe. He has worked in the field of science & technology for over thirty years specializing in materials characterization at the nano and micro scales.