Biomedical Diagnostics Enabled by Integrated Organic and Printed Electronics

© 2017 American Chemical Society. Organic and printed electronics integration has the potential to revolutionize many technologies, including biomedical diagnostics. This work demonstrates the successful integration of multiple printed electronic functionalities into a single device capable of the measurement of hydrogen peroxide and total cholesterol. The single-use device employed printed electrochemical sensors for hydrogen peroxide electroreduction integrated with printed electrochromic display and battery. The system was driven by a conventional electronic circuit designed to illustrate the complete integration of silicon integrated circuits via pick and place or using organic electronic circuits. The device was capable of measuring 8 μL samples of both hydrogen peroxide (0-5 mM, 2.72 × 10 -6 A·mM -1 ) and total cholesterol in serum from 0 to 9 mM (1.34 × 10 -8 A·mM -1 , r 2 = 0.99, RSD < 10%, n = 3), and the result was output on a semiquantitative linear bar display. The device could operate for 10 min via a printed battery, and display the result for many hours or days. A mobile phone "app" was also capable of reading the test result and transmitting this to a remote health care provider. Such a technology could allow improved management of conditions such as hypercholesterolemia

Measurement of the viscoelastic properties of blood plasma clot formation in response to tissue factor concentration-dependent activation

© 2016, The Author(s). The coagulation of blood plasma in response to activation with a range of tissue factor (TF) concentrations was studied with a quartz crystal microbalance (QCM), where frequency and half width at half maximum (bandwidth) values measured from the conductance spectrum near resonant frequency were used. Continuous measurement of bandwidth along with the frequency allows for an understanding of the dissipative nature of the forming viscoelastic clot, thus providing information on the complex kinetics of the viscoelastic changes occurring during the clot formation process. Using a mathematical model, these changes in frequency and bandwidth have been used to derive novel QCM parameters of effective elasticity, effective mass density and rigidity factor of the viscoelastic layer. The responses of QCM were compared with those from thromboelastography (TEG) under identical conditions. It was demonstrated that the nature of the clot formed, as determined from the QCM parameters, was highly dependent on the rate of clot formation resulting from the TF concentration used for activation. These parameters could also be related to physical clot characteristics such as fibrin fibre diameter and fibre density, as determined by scanning electron microscopic image analysis. The maximum amplitude (MA) as measured by TEG, which purports to relate to clot strength, was unable to detect these differences

Novel Smartphone-Based Optical Point-of-Care Method for Blood Coagulation Monitoring

Blood coagulation self-monitoring is vital in modern day healthcare, in particular supporting patients on anticoagulant or antiplatelet therapy. Commercially available coagulation self-monitoring devices are typically based on conventional end-point based haemostatic tests and, measuring clotting time within a narrow range of values being connected to specific aspects of clot formation. In the present study, a novel optical coagulation monitoring method was developed and implemented in a form of compact system where a commercially available smartphone is used as the optical detector and the signal processor. The customized Android App was developed to calibrate and drive the smartphone camera, record the optical signal during the test and process the data in order to return clotting time value being the main output parameter of the monitoring. The data processing algorithm provides low risk of false clot detection and precise clotting time measurement. The method was utilised for analysis of normal whole blood sample coagulation, activated by various tissue factor concentrations. The results demonstrated the ability of such a system to measure a wide range of clotting time values with appropriate level of accuracy and precision similar to standard thromboelastography method. Additionally, the ability of the method to measure some aspects of erythrocyte aggregation was demonstrated. Significantly, the use of a smartphone as an optical detector and signal processor potentiates system miniaturisation, pertinent to high levels of functionality, cost-efficiency and user-friendliness

Simple and convenient measurement of RBC deformability using QCM integrated with a novel model of cell viscoelasticity

© 2018 Elsevier B.V. It is well-established that alterations in cell morphology are regulated by cell signalling pathways, with the qualitative and quantitative monitoring of these intrinsic processes being of potential diagnostic value. Moreover, the deformability of red blood cells (RBCs) plays a key role in microcirculation, with alterations in rigidity correlated with disease models such as diabetes mellitus, sickle cell anaemia and sepsis. Here a novel assay for monitoring changes in deformability of RBCs is described that integrates quartz-crystal microbalance and a mathematical model, and extrapolates qualitative and quantitative information pertinent to changes in cell elasticity. The ability of this assay to differentiate reliably between normal RBCs and ones artificially rigidized in a manner consistent with the disease-state RBCs is demonstrated. This simple, benchtop assay has significant potential for application in disease cohorts where aberrant deformability of RBCs is indicative of disease progression

Modelling of blood component flexibility using quartz crystal microbalance

Quartz crystal microbalance (QCM) is a sensitive technique for real-time monitoring of cell adsorption, aggregation and cell-to-surface interaction processes. However, cell adhesion time courses are usually considered as merely qualitative, being presented in terms of QCM resonant frequency shift and/or changes in the dissipation parameter, the precise physical meanings of which are not derived. In the present study, a model of cell adhesion to the QCM sensor surface was proposed. The main output parameter of the model is the rigid mass density, Mr, being related to QCM resonant frequency and dissipation with a simple expression. From this, it can be determined that Mr is the mass density of the layer formed by all directly adhered parts of the cell, being rigidly coupled to the sensor surface. We postulate that the Mr(t) value is proportional to the number of cells adhered by the time t, and that the coefficient of this proportionality is strongly dependent on cell-to-surface interaction forces

Measurement of the evolution of rigid and viscoelastic mass contributions from fibrin network formation during plasma coagulation using quartz crystal microbalance

The coagulation of blood plasma and the effect of fibrinogen concentration were studied with a quartz crystal microbalance (QCM), where frequency and half-width at half-maximum (bandwidth) values measured from the conductance spectrum near resonant frequency were used. Bandwidth change is an indicator of energy dissipation, allowing for an understanding of qualitative changes occurring during fibrin clot formation. Both frequency shift (Δf) and bandwidth shift (ΔΓ) were dependent on the concentration of fibrinogen in plasma. We defined a sum of squares function α (= Δf2/1000 + ΔΓ2/1000) that measures absolute changes in QCM resonant characteristics to semi-quantitatively include an overall contribution of adsorbed mass and elastic modulus components and a function β (= 1 - ΔΓ/Δf) that indicates qualitatively the nature of response based on its deviation from ideal Newtonian behaviour. Increasing concentration of fibrinogen resulted in an increase in the value of α, showing that a larger amount of fibrinogen results in larger amount of coupled viscoelastic mass. Changes in β indicated that the nature of changes occurring was very similar to Newtonian and that coupling of rigid-mass dominates the overall response in the early stage of coagulation and in the later stage growing elastic mass compensates some of the response. © 2013 Published by Elsevier B.V

The modelling of blood coagulation using the quartz crystal microbalance

Blood is a clinically-important analytical matrix that is routinely selected for disease monitoring. Having a clear understanding of the mechanisms involved in blood coagulation is a key consideration in haemostasis, with modern clinical practices requiring rapid, miniaturised and informative diagnostic platforms to reliably study changes in viscoelasticity (VE). Oscillatory transducers such as the Quartz Crystal Microbalance (QCM) have considerable potential in this area, provided that they present simple, linear rheometric readings which can be adequately analysed and interpreted. Hence, integrating QCM data obtained in the laboratory with mathematical modelling of acoustic interactions between quartz crystal surfaces and coagulating blood is an important consideration for modelling thrombus formation. Here, we provide a comprehensive overview of experimental and theoretical applications currently being employed to monitor and model the VE properties of coagulating blood when applied to a QCM resonator, with key emphasis on data modelling and interpretation. © 2012 Elsevier Ltd