A portable blood plasma clot micro-elastometry device based on resonant acoustic spectroscopy

Abstract

Abnormal blood clot stiffness is an important indicator of coagulation disorders arising from a variety of cardiovascular diseases and drug treatments. Here, we present a portable instrument for elastometry of microliter volume blood samples based upon the principle of resonant acoustic spectroscopy, where a sample of well-defined dimensions exhibits a fundamental longitudinal resonance mode proportional to the square root of the Young's modulus. In contrast to commercial thromboelastography, the resonant acoustic method offers improved repeatability and accuracy due to the high signal-to-noise ratio of the resonant vibration. We review the measurement principles and the design of a magnetically actuated microbead force transducer applying between 23 pN and 6.7 nN, providing a wide dynamic range of elastic moduli (3 Pa-27 kPa) appropriate for measurement of clot elastic modulus (CEM). An automated and portable device, the CEMport, is introduced and implemented using a 2 nm resolution displacement sensor with demonstrated accuracy and precision of 3% and 2%, respectively, of CEM in biogels. Importantly, the small strains (<0.13%) and low strain rates (<1/s) employed by the CEMport maintain a linear stress-to-strain relationship which provides a perturbative measurement of the Young's modulus. Measurements of blood plasma CEM versus heparin concentration show that CEMport is sensitive to heparin levels below 0.050 U/ml, which suggests future applications in sensing heparin levels of post-surgical cardiopulmonary bypass patients. The portability, high accuracy, and high precision of this device enable new clinical and animal studies for associating CEM with blood coagulation disorders, potentially leading to improved diagnostics and therapeutic monitoring.

Elastometry of clot phantoms via magnetomotive ultrasound-based resonant acoustic spectroscopy

“…Following the procedure suggested by Lathi and Green (2018), and previously employed by Oldenburg (Oldenburg and Boppart 2010) and Krebs (Krebs et al 2015), the resonance frequency f 0 of a simulated or experimental cylinder is determined by fitting a Lorentzian to its complex, frequency-domain transfer function, or 'mechanical spectral response.' Briefly, the MRAS system applies a chirped, sinusoidal magnetic driving force F(t), and measures the resulting volume-averaged displacement Δz(t).…”

“…Resonant acoustic spectroscopy provides an exciting alternative for characterizing the mechanical properties of soft tissues, since increased vibration amplitude at resonance promises a higher signal-to-noise ratio without relying on quantitative force measurements (Oldenburg and Boppart 2010). Because this method depends on the geometry and boundary conditions of resonating structures being well known, it is ideal for measuring the Young's moduli of blood clots formed in microwells, which can be actuated via magnetic bead force transducers (Wu et al 2013, Krebs et al 2015. When using MNPs as transducers instead, the Young's moduli of gelatin phantoms have been demonstrated to affect their resonance frequencies (Oldenburg andBoppart 2010, Ersepke et al 2017), and with associated modelling based on phantom geometry, quantitative elastometry was shown to be possible with OCT (Oldenburg and Boppart 2010).…”

Stabilized sensing of heparin in whole blood using the ‘gate effect’ of heparin-imprinted polymer grafted onto an electrode

“…Therefore, there has been significant effort devoted to developing a simple method for sensing heparin in blood. For example, Krebs et al attempted to quantify heparin by elastometric measurements of blood clots, but the dynamic range of the measurements did not include physiologically-relevant levels of heparin in blood (Krebs et al 2015). Li et al (2013) proposed a new heparin sensor based on potentiometry using a carbon electrode covered with heparin-specific molecularly imprinted polymer (MIP).…”