Microfluidics Separation and Analysis of Biological Particles

In the last decade, powerful communication and information technology in the form of the mobile phone has been put into the hands of more than 50% of the global population. In stark contrast, a lack of access to medical diagnostic technology with which to diagnose both communicable and non-communicable diseases will mean that many of these people will die of easily treatable conditions. Small, portable, effective and affordable devices able to give relevant information about the health of an individual, even in resource poor environments, could potentially help to change this. And the developing world is not the only resource poor environment; areas struck by natural disaster or by outbreaks of infectious disease or on the battlefield or even at the frontiers of exploration we find environments in which a mobile phone-sized laboratory would have a profound impact, not only on medical, but environmental diagnostics. There are also less dramatic examples. Compared to a well-equipped hospital most environments are resource poor, including the home. Blood sugar measuring devices for example put important information immediately into the hands of the diabetes sufferer in their own home, allowing them to make informed, life-saving decisions about food intake and medication without recourse to medical doctors. These diagnostic devices will be based on technologies that go under the collective names of micro-total-analysis systems, µTAS, or Lab-on-a-Chip. One of the uniting, integral features of all these technologies is the need to manipulate small volumes of fluids, often containing cells or other particles, from which the diagnostic information is to be wrung. The manipulation of such small volumes of fluids is known as microfluidics. This doctoral thesis is concerned with particle separation science. More specifically it is concerned with the development of tools for the separation of biologically relevant particles, an important step in almost any analysis, using techniques that have been made possible through the advent of microfluidics. A technique based on the flow of fluid through arrays of micrometre-sized obstacles, Deterministic Lateral Displacement (DLD), is promising because of its exceptional resolution, its suitability for biological separations, the wide range of sizes across which it works and not least because of the promise it holds as a candidate for integration within a lab-on-a-chip. The first devices utilizing the principle were limited to use in the separation of particles by size only. However, there are many physical properties other than size holding a wealth of information about particles, for example cancer and infection with malaria or HIV have been shown to change the deformability of cells and so measuring deformability could provide a means of diagnosing these conditions. The central tenet of this work is that DLD can be used to separate particles by highly relevant physical properties other than size, for example shape, deformability or electrical properties and that devices that can do this in a cheap and simple way will constitute powerful particle separation tools, useful for diagnostic applications and well suited for integration in a Lab-on-a-Chip. The aim of this thesis is to present four research papers, documenting the development of new methods that improve the existing DLD technique. Paper I describes how the elastomeric properties of polydimethylsiloxane can be utilized to achieve tuneable separation in DLD devices, making it easier to take advantage of the high resolution inherent in the method. Paper II presents the use of dielectrophoresis to achieve tuneability, improve dynamic range and open up for the separation of particles with regard to factors other than size. Paper III describes how control of particle orientation can be used to separate particles based on their shape and how this can be used to separate blood-borne parasites from blood. Finally Paper IV deals with the size, shape and deformability of cells and how DLD devices can be used, both to measure these properties, and to perform separations based on them. The hope is that these methods might ultimately play a small part in helping diagnostics technology to become as ubiquitous as information technology has become in the last ten years and that this will have a profound impact on global health