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We recently reported a real-time method to measure heparin in blood based on photoacoustic (PA) signal from methylene blue (MB). The PA enhancement was surprisingly accompanied by a decrease in absorbance. Here, we describe a mechanistic study of the MB-heparin binding in water and phosphate buffered saline. The addition of 0.79 mg/mL heparin decreased the nuclear magnetic resonance (NMR) magnitude of 0.90 mg/mL MB by 63% with a 0.25 ppm downshift—this indicated formation of MB aggregates due to π-π staking of MB. We also observed nanoscale MB/heparin aggregates under transmission electron microscopy (TEM). Spectroscopic analysis of the isolated aggregates found that the percentage of MB inside the MB-heparin aggregate increased from 3.6% to 82.5% when heparin concentration was increased from 0.16 mg/mL to 0.79 mg/mL. Meanwhile, the photoacoustic intensity increased 25-fold. The signal increase was largely due to the aggregates rather than free MB in the solution. These trends suggested that the MB-heparin aggregation was responsible for the PA enhancement likely due to the decreased degrees of freedom for MB. Molecular dynamics simulations revealed MB dimer formation on heparin and indicated that electrostatic binding occurred between the central thiazine ring of MB and the sulfates and glucosamines in heparin via electrostatic interaction. These findings elucidate the binding process of MB and heparin and provide strategies for immobilizing MB-like molecules on implantable devices for intravascular heparin sensing.
Junxin Wang,Ananthakrishnan S. Jeevarathinam,Kathryn Humphries,Bill R. Miller III, andJesse V. Jokerst
"The interaction mechanism of methylene blue and heparin in phosphate buffered saline (Conference Presentation)", Proc. SPIE 10878, Photons Plus Ultrasound: Imaging and Sensing 2019, 108782A (4 March 2019); https://doi.org/10.1117/12.2508130
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Junxin Wang, Ananthakrishnan S. Jeevarathinam, Kathryn Humphries, Bill R. Miller III, Jesse V. Jokerst, "The interaction mechanism of methylene blue and heparin in phosphate buffered saline (Conference Presentation)," Proc. SPIE 10878, Photons Plus Ultrasound: Imaging and Sensing 2019, 108782A (4 March 2019); https://doi.org/10.1117/12.2508130