Modelling and control of dynamic platelet aggregation under disturbed blood flow

Diagnosis of platelet function is fundamental for identifying blood disorders of patients, assessing the impact of antiplatelet agents, and enabling the appropriate titration of individual antithrombotic treatments. Following the advancement of new technologies such as microfluidic devices and the use of control engineering methods, new devices have the potential to offer new opportunities in point-of-care diagnosis of platelet function. Such new devices may have significant utility in the development of more tailored antiplatelet therapies. The aim of this thesis is to investigate modelling and control systems which support the study of the dynamic relationship between newly discovered mechanisms of platelet aggregation and disturbed blood flow, using state-of-the-art micro-engineered technologies. In order to observe the dynamics of platelet aggregation under disturbed blood flow, blood perfusion experiments carried out on a device mimicking a scenario of severe vessel narrowing are presented. The resulting biological response, that is the aggregation of platelets, is monitored in real-time and synthesised through novel measures developed using image processing techniques. A mechanistic model identifying four distinct stages observed in the formation of the aggregate is formulated, describing the nonlinear relationship between blood flow dynamics and platelet aggregation. The observed effect of disturbed blood flow on the aggregation of platelets is then modelled mathematically employing System Identification methods. A detailed account of a novel approach for the generation of experimental data is presented, as well as the formulation of tailored mathematical model structures and the calculation of their parameters using collected data. The proposed models replicate experimental results with low variation, and the reduced number of model parameters is suggested as a novel systematic measure of platelet aggregation dynamics in the presence of blood flow disturbances. In order to stabilise, optimise, and automate the measurement of platelet function in response to disturbed blood flow, custom-made control algorithms based on principles of Sliding Mode Control and Pulse-Width Modulation are developed. Moreover, the control algorithms are developed to handle the large variability of the aggregation responses from blood types with platelet hyper- and hypo-function. Simulation results illustrate the robustness of the control algorithms in the presence of time-varying nonlinearities and model uncertainty, and indicate the possibility to regulate the extent of aggregation in the device through modulation of the blood flow rate in the microchannel. The main contribution of this thesis is the development of dynamic models and control systems that allow a systematic measurement of platelet function in response to rapid changes in the blood flow (shear rate micro-gradients), in a microfluidics device containing a scenario of disturbed blood flow. Analysis of the platelet aggregation dynamics revealed that although the aggregate growth appears to be constant at times, measuring its mean fluorescence intensity indicates an increase in the dynamics of platelet density. This densification process appears fundamental for the development of an amplification phase in the aggregation response. The proposed mathematical models and control algorithms facilitate the systematic measurement of platelet function in vitro, pioneering the development of a novel framework for automated blood disorder diagnosis

Microengineered structures for rapid automatic loading of optical fibre segments

We present a technique to rapidly and automatically produce sections of optical fibre and load them into arrays such that they can be nano-imprinted in parallel. The technique makes use of automated fibre feeding, cutting and alignment with microfabricated groove arrays. The system is analyzed and optimized and it is found that the geometry of the arrays themselves is a critical factor. Three types of array are investigated-simple grooves, grooves with lateral funnels at the input, and bulk silicon machined V-groove arrays with funnels in both lateral and vertical dimensions. It is found that the incorporation of funnels significantly increases the accuracy of loading, overcoming the need for precise alignment, such that a throughput nearing 1000 fibre segments an hour can be achieved. This system forms part of a sequence of novel processes for the production of nano-photonic sensors

Modeling of dynamic platelet aggregation in response to shear rate micro-gradients in a microfluidics device

Cardiovascular diseases remain the main cause of death worldwide despite decades of intensive research. Understanding the role that hemodynamics play in dynamic platelet aggregation is fundamental to the development of new antithrombotic treatments able to minimise associated morbidity rates. In this paper we explore the dynamics of platelet aggregation in response to shear rate micro-gradients in vitro in a microfluidics device, and formulate dynamical linear models using system identification techniques. The proposed models provide insight into the mechanistic variables regulating platelet aggregation and warrant further work in the dynamic exploration of platelet mechanotransduction