SAVE: Selective Assessment of Valproate Efficacy with a Fiber-based Sensor

Introduction:: Bipolar disorder (BD) is a chronic disorder characterized by recurrent fluctuations in mood, affecting approximately 1% of the world's population. Bipolar disorder is a significant cause of disability among young people. Often diagnosed within 5-10 years after illness onset, bipolar disorder notably affects patients' quality of life. In 2020, 2.8% of US adults were diagnosed with bipolar disorder, impairing their ability to perform daily tasks. Valproic acid (VA) is one of the primary compounds in the antimanic drug prescribed for mood disorders. Lithium has a narrow effective therapeutic range in serum, 0.4−0.8 mM, and the risk of acute toxicity associated with coma, and metabolic acidosis, leading to severe adverse effects. Current monitoring methods require sophisticated equipment and expert personnel. However, in socioeconomically challenged or low-resource settings, lack of access to laboratories prevents rapid and frequent monitoring of drug uptake. Thus, there is an emergent need for low-cost, rapid monitoring tools for checking VA levels in biological fluids, including saliva and serum. Therefore, we developed a miniaturized fiber-based sensing platform for the real-time screening of VA in saliva.

Materials and Methods:: We prepared fiber-based electrodes by applying carbon ink on cotton fibers. The carbon ink was prepared by dispersing carbon black powder into a polymeric matrix of poly(vinyl chloride) and o-nitrophenyl-octyl-ether. Next, we dip-coated the fabricated conductive fibers into the VA selective membrane solutions precursor (Figure 1.A). Next, we fabricated chloride and reference electrodes while substituting the VA-selective membrane with chloride and reference membrane. The purpose of adding a chloride electrode was to monitor chloride levels in biofluid to improve the selectivity of the SAVE platform (Figure 1.B). We performed all potential measurements using a 16-channel potentiometer relative to a commercial reference electrode. All measurements were performed at room temperature with freshly prepared solutions from 0.1 M stock solutions using the standard addition of deionized water (18.2 MΩ/cm). We prepared the artificial biofluids based on their physiologically relevant composition.

Results, Conclusions, and Discussions:: We validated the SAVE platforms' practicability by comparing the obtained sensitivity -51.26±0.19 mV/decade for VA, to the theoretical Nerstian value of -59.2 mV/decade, with a detection limit of 27 µM, respectively (Figure 1.C). We assessed the reproducibility of the SAVE platform by finding the repeatability of the standard potential (SD=±2.10 mV), indicating excellent electrode-to-electrode reproducibility. Selectivity against interfering molecules is a critical parcel of any sensing electrode. Therefore we quantified the selectivity of the SAVE against physiologically relevant interfering electrolytes by utilizing a well-established fixed-interference method (FIM). Results indicated that the SAVE platform is 1.4 and 2.4 orders of magnitude more selective toward VA than bicarbonate and phosphate ions, respectively (Figure 1.D). However, the SAVE platform did not illustrate an excellent selectivity toward chloride (0.7 order of magnitude more selective toward VA). Therefore, we implemented a chloride electrode to correct the chloride levels in our platform. Finally, we assessed the feasibility of the SAVE platform by measuring VA concentrations in a panel of biofluids where the errors were within the FDA's acceptable range (Less than 20%).
The fabricated miniaturized SAVE platform illustrated a promising potential to be incorporated into point-of-care potentiometric sensors for wearable applications or as a point-of-care companion diagnostic tool. The value of such a technology for BD patients can be compared to the value of glucometers for managing diabetes.

Acknowledgements (Optional): : FA, AS, SK, VO would like to acknowledge the Viterbi Graduate School Fellowship.

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