Biosensor Strip for Rapid On-site Assessment of Levodopa Pharmacokinetics along with Motor Performance in Parkinson's Disease.

While levodopa (L-Dopa) is the primary treatment for alleviating Parkinson's disease (PD), its efficacy is hindered by challenges such as a short half-life and inconsistent plasma levels. As PD progresses, the rising need for increased and more frequent L-Dopa doses coupled with symptom fluctuations and dyskinesias underscores the urgency for improved comprehension of the interplay between L-Dopa levels and PD motor symptoms. Addressing this critical need, we present a decentralized testing method using a disposable biosensor strip and a universal slope (U-slope) calibration-free approach. This enables reliable, rapid, simple, and cost-effective decentralized L-Dopa measurements from capillary blood. A pilot study with PD persons demonstrates the ability to monitor real-time L-Dopa pharmacokinetics from fingerstick blood after oral L-Dopa-Carbidopa (C-Dopa) tablet administration. Correlating capillary blood L-Dopa levels with PD motor scores revealed a well-defined inverse correlation with temporal motor fluctuations. We compared the resulting dynamic capillary blood L-Dopa levels with plasma L-Dopa levels using the traditional but clinically impractical high-performance liquid chromatography technique. By providing timely feedback on a proper L-Dopa dosing regimen in a decentralized and rapid fashion, this new biosensing platform will facilitate tailored optimal L-Dopa dosing, towards improving symptom management and enhancing health-related quality of life.

Self-Testing of Ketone Bodies, along with Glucose, Using Touch-Based Sweat Analysis.

ß-Hydroxybutyrate (HB) is one of the main physiological ketone bodies that play key roles in human health and wellness. Besides their important role in diabetes ketoacidosis, ketone bodies are currently receiving tremendous attention for personal nutrition in connection to the growing popularity of oral ketone supplements. Accordingly, there are urgent needs for developing a rapid, simple, and low-cost device for frequent onsite measurements of ß-hydroxybutyrate (HB), one of the main physiological ketone bodies. However, real-time profiling of dynamically changing HB concentrations is challenging and still limited to laboratory settings or to painful and invasive measurements (e.g., a commercial blood ketone meter). Herein, we address the critical need for pain-free frequent HB measurements in decentralized settings and report on a reliable noninvasive, simple, and rapid touch-based sweat HB testing and on its ability to track dynamic HB changes in secreted fingertip sweat, following the intake of commercial ketone supplements. The new touch-based HB detection method relies on an instantaneous collection of the fingertip sweat at rest on a porous poly(vinyl alcohol) (PVA) hydrogel that transports the sweat to a biocatalytic layer, composed of the ß-hydroxybutyrate dehydrogenase (HBD) enzyme and its nicotinamide adenine dinucleotide (NAD+) cofactor, covering the modified screen-printed carbon working electrode. As a result, the sweat HB can be measured rapidly by the mediated oxidation reaction of the nicotinamide adenine dinucleotide (NADH) product. A personalized HB dose-response relationship is demonstrated within a group of healthy human subjects taking commercial ketone supplements, along with a correlation between the sweat and capillary blood HB levels. Furthermore, a dual disposable biosensing device, consisting of neighboring ketone and glucose enzyme electrodes on a single-strip substrate, has been developed toward the simultaneous touch-based detection of dynamically changing sweat HB and glucose levels, following the intake of ketone and glucose drinks.

Closing the loop for patients with Parkinson disease: where are we?

Although levodopa remains the most efficacious symptomatic therapy for Parkinson disease (PD), management of levodopa treatment during the advanced stages of the disease is extremely challenging. This difficulty is a result of levodopa's short half-life, a progressive narrowing of the therapeutic window, and major inter-patient and intra-patient variations in the dose-response relationship. Therefore, a suitable alternative to repeated oral administration of levodopa is being sought. Recent research efforts have focused on the development of novel levodopa delivery strategies and wearable physical sensors that track symptoms and disease progression. However, the need for methods to monitor the levels of levodopa present in the body in real time has been overlooked. Advances in chemical sensor technology mean that the development of wearable and mobile biosensors for continuous or frequent levodopa measurements is now possible. Such levodopa monitoring could help to deliver personalized and timely medication dosing to alleviate treatment-related fluctuations in the symptoms of PD. Therefore, with the aim of optimizing therapeutic management of PD and improving the quality of life of patients, we share our vision of a future closed-loop autonomous wearable 'sense-and-act' system. This system consists of a network of physical and chemical sensors coupled with a levodopa delivery device and is guided by effective big data fusion algorithms and machine learning methods.

Non-Invasive Sweat-Based Tracking of L-Dopa Pharmacokinetic Profiles Following an Oral Tablet Administration.

Levodopa (L-Dopa) is the "gold-standard" medication for symptomatic therapy of Parkinson disease (PD). However, L-Dopa long-term use is associated with the development of motor and non-motor complications, primarily due to its fluctuating plasma levels in combination with the disease progression. Herein, we present the first example of individualized therapeutic drug monitoring for subjects upon intake of standard L-Dopa oral pill, centered on dynamic tracking of the drug concentration in naturally secreted fingertip sweat. The touch-based non-invasive detection method relies on instantaneous collection of fingertip sweat on a highly permeable hydrogel that transports the sweat to a biocatalytic tyrosinase-modified electrode, where sweat L-Dopa is measured by reduction of the dopaquinone enzymatic product. Personalized dose-response relationship is demonstrated within a group of human subjects, along with close pharmacokinetic correlation between the finger touch-based fingertip sweat and capillary blood samples.

Touch-Based Fingertip Blood-Free Reliable Glucose Monitoring: Personalized Data Processing for Predicting Blood Glucose Concentrations.

Diabetes prevalence has been rising exponentially, increasing the need for reliable noninvasive approaches for glucose monitoring. Different biofluids have been explored recently for replacing current blood finger-stick glucose strips with noninvasive painless sensing devices. While sweat has received considerable attention, there are mixed reports on correlating the sweat results with blood glucose levels. Here, we demonstrate a new rapid and reliable approach that combines a simple touch-based fingertip sweat electrochemical sensor with a new algorithm that addresses for personal variations toward the accurate estimate of blood glucose concentrations. The new painless and simple glucose self-testing protocol leverages the fast sweat rate on the fingertip for rapid assays of natural perspiration, without any sweat stimulation, along with the personalized sweat-response-to-blood concentration translation. A reliable estimate of the blood glucose sensing concentrations can thus be realized through a simple one-time personal precalibration. Such system training leads to a substantially improved accuracy with a Pearson correlation coefficient higher than 0.95, along with an overall mean absolute relative difference of 7.79%, with 100% paired points residing in the A + B region of the Clarke error grid. The speed and simplicity of the touch-based blood-free fingertip sweat assay, and the elimination of periodic blood calibrations, should lead to frequent self-testing of glucose and enhanced patient compliance toward the improved management of diabetes.

A self-sustainable wearable multi-modular E-textile bioenergy microgrid system.

Despite the fast development of various energy harvesting and storage devices, their judicious integration into efficient, autonomous, and sustainable wearable systems has not been widely explored. Here, we introduce the concept and design principles of e-textile microgrids by demonstrating a multi-module bioenergy microgrid system. Unlike earlier hybrid wearable systems, the presented e-textile microgrid relies solely on human activity to work synergistically, harvesting biochemical and biomechanical energy using sweat-based biofuel cells and triboelectric generators, and regulating the harvested energy via supercapacitors for high-power output. Through energy budgeting, the e-textile system can efficiently power liquid crystal displays continuously or a sweat sensor-electrochromic display system in pulsed sessions, with half the booting time and triple the runtime in a 10-min exercise session. Implementing "compatible form factors, commensurate performance, and complementary functionality" design principles, the flexible, textile-based bioenergy microgrid offers attractive prospects for the design and operation of efficient, sustainable, and autonomous wearable systems.

Touch-Based Stressless Cortisol Sensing.

Tracking fluctuations of the cortisol level is important in understanding the body's endocrine response to stress stimuli. Traditional cortisol sensing relies on centralized laboratory settings, while wearable cortisol sensors are limited to slow and complex assays. Here, a touch-based non-invasive molecularly imprinted polymer (MIP) electrochemical sensor for rapid, simple, and reliable stress-free detection of sweat cortisol is described. The sensor readily measures fingertip sweat cortisol via highly selective binding to the cortisol-imprinted electropolymerized polypyrrole coating. The MIP network is embedded with Prussian blue redox probes that offer direct electrical signaling of the binding event to realize sensitive label-free amperometric detection. Using a highly permeable sweat-wicking porous hydrogel, instantaneously secreted fingertip sweat can be conveniently and rapidly collected without any assistance. By eliminating time lags, such rapid (3.5 min) fingertip assay enables the capture of sharp variations in cortisol levels, compared to previous methods. Such advantages are demonstrated by tracking cortisol response in short cold-pressor tests and throughout day-long circadian rhythm, along with gold-standard immunoassay validation. A stretchable epidermal MIP sensor is also described for directly tracking cortisol in exercise-induced sweat. The rapid touch-based cortisol sensor offers an attractive, accessible, stressless avenue for quantitative stress management.

Separation detection of hemoglobin and glycated hemoglobin fractions in blood using the electrochemical microfluidic channel with a conductive polymer composite sensor.

Separation and detection of hemoglobin (Hb) and glycated hemoglobin fractions (HbA1c, HbAld1+2, HbAle, HbAld3a, HbAla+b, HbA2, and HbAld3b) was performed using an electrochemical AC field modulated separation channel (EMSC) coupled with a sensor probe. The sensor was fabricated based on immobilization of a redox mediator on the poly(2,2':5',5″-terthiophene-3'-p-benzoic acid, pTTBA) and N,S-doped porous carbon (NSPC) nanocomposite. The different types of catalytic redox mediators such as Nile Blue (NB), toluidine blue O (TBO), and Neutral Red (NR) were evaluated to achieve the efficient detection. Of these, the NB-based sensor showed the best analytical signal for Hb and HbA1c, thus it was characterized using various electrochemical and surface analysis methods. After that, the sensor was coupled with the EMSC to achieve the separation detection of the Hb family. The frequency and amplitude of the AC electrical field applied onto the EMSC walls were the main driving forces for the separation and sensitive detection of the analytes. Under optimized conditions, linear dynamic ranges for Hb and HbA1c among their fractions were obtained between 1.0 × 10-6 to 3.5 mM and 3.0 × 10-6 to 0.6 mM with the detection limit of 8.1 × 10-7 ± 3.0 × 10-8 and 9.2 × 10-7 ± 5 × 10-8 mM, respectively. Interference effects of other biomolecules were also investigated and the clinical applicability of the device was evaluated by the determination of total Hb and % HbA1c in real human blood samples.

Simultaneous detection of ATP metabolites in human plasma and urine based on palladium nanoparticle and poly(bromocresol green) composite sensor.

A sensitive voltammetric sensor based on palladium nanoparticles (PdNPs) and poly-bromocresol green (pBG) composite layer immobilized on amide functionalized single-walled carbon nanotubes (AmSWCNTs) modified pyrolytic graphite (PdNPs:pBG/AmSWCNTs/PG) has been prepared for the simultaneous determination of adenosine triphosphate (ATP) catabolites, inosine (INO), hypoxanthine (HX), xanthine (XT), and uric acid (UA). The modified PdNPs:pBG/AmSWCNTs/PG was characterized by electrochemical experiments and surface analysis, which exhibited exceptional electrocatalytic effects towards the oxidation of INO, HX, XT, and UA with a significant enhanced peak current and well resolved peaks separation for all the analytes. The linear calibration curves were obtained in the concentration range of 0.001-175 µM, 0.001-200 µM, 0.001-150 µM, and 0.001-200 µM and limits of detection were found as 0.95 nM, 1.04 nM, 1.07 nM, and 0.43 nM corresponding to INO, HX, XT, and UA, respectively. The common metabolites present in the biological fluids did not interfere in the determination. The applicability of the proposed sensor was successfully demonstrated by determining INO, HX, XT, and UA in the human plasma and urine and the obtained results were validated by using HPLC.

Magnetic force assisted electrochemical sensor for the detection of thrombin with aptamer-antibody sandwich formation.

A magnetic force assisted electrochemical aptamer-antibody sandwich assay (MESA) was developed for the detection of thrombin as a model protein in serum samples. The MESA using the formation of sandwich complexes on the electrochemical sensor probe for reaction and the removal of unbound bioconjugates from the sensor surface without washing are controlled by a magnetic field. Thrombin was determined by the cathodic currents of a toluidine blue O (TBO) attached with thrombin antibody modified magnetic nanoparticle (MNP) at the sensor surface. To detect thrombin in a serum sample, we applied a thrombin-specific aptamer as the capture molecule bound to the functionalized conducting polymer layer (poly-(2,2´:5´,5″-terthiophene-3´-p-benzoic acid) (pTBA)), and streptavidin and starch coated-MNP was conjugated with biotinylated thrombin antibodies (Ab) and TBO as the bioconjugate (MNP@Ab-TBO). The characterization of MNP@Ab-TBO and sensor probe was performed using voltammetry, impedance spectroscopy, XPS, and UV-VIS spectroscopy. The experimental conditions were optimized in terms of pH, binding time, removal time of unbound bioconjugates, and applied potential. The dynamic ranges of thrombin were from 1.0 to 500 nM with detection limit of 0.49 ( ±â€¯0.06) nM. The recovery test demonstrates the reliability of the proposed sensing system for a handheld device.

Conducting polymer-based electrochemical biosensors for neurotransmitters: A review.

Neurotransmitters are important biochemical molecules that control behavioral and physiological functions in central and peripheral nervous system. Therefore, the analysis of neurotransmitters in biological samples has a great clinical and pharmaceutical importance. To date, various methods have been developed for their assay. Of the various methods, the electrochemical sensors demonstrated the potential of being robust, selective, sensitive, and real time measurements. Recently, conducting polymers (CPs) and their composites have been widely employed in the fabrication of various electrochemical sensors for the determination of neurotransmitters. Hence, this review presents a brief introduction to the electrochemical biosensors, with the detailed discussion on recent trends in the development and applications of electrochemical neurotransmitter sensors based on CPs and their composites. The review covers the sensing principle of prime neurotransmitters, including glutamate, aspartate, tyrosine, epinephrine, norepinephrine, dopamine, serotonin, histamine, choline, acetylcholine, nitrogen monoxide, and hydrogen sulfide. In addition, the combination with other analytical techniques was also highlighted. Detection challenges and future prospective of the neurotransmitter sensors were discussed for the development of biomedical and healthcare applications.

A disposable amperometric dual-sensor for the detection of hemoglobin and glycated hemoglobin in a finger prick blood sample.

A disposable microfluidic amperometric dual-sensor was developed for the detection of glycated hemoglobin (HbA1C) and total hemoglobin (Hb), separately, in a finger prick blood sample. The accurate level of total Hb was determined through the measurements of the cathodic currents of total Hb catalyzed by a toluidine blue O (TBO)-modified working electrode. Subsequently, after washing unbound Hb in the fluidic channel of dual sensor with PBS, the cathodic current by only HbA1C captured on aptamer was monitored using another aptamer/TBO-modified working electrode in the channel. To modify the sensor probe, poly(2,2´:5´,5″-terthiophene-3´-p-benzoic acid) and a multi-wall carbon nanotube (MWCNT) composite layer (pTBA@MWCNT) was electropolymerized on a screen printed carbon electrode (SPCE), followed by immobilization of TBO for the total Hb probe and aptamer/TBO for the HbA1C probe, respectively. The characterization of each sensor surface was performed using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), X-ray photoelectron spectroscopy (XPS), quartz crystal microbalance (QCM), field-emission scanning electron microscopy (FE-SEM), and transmission electron microscopy (TEM). The experimental conditions affecting the analytical signal were optimized in terms of the amount of TBO, pH, temperature, binding time, applied potential, and the content ratio of monomer and MWCNT. The dynamic ranges of Hb and HbA1C were from 0.1 to 10µM and from 0.006 to 0.74µM, with detection limits of 82(±4.2)nM and 3.7(±0.8)nM, respectively. The reliability of the proposed microfluidic dual-sensor for a finger prick blood sample (1µL) was evaluated in parallel with a conventional method (HPLC) for point-of-care analysis.

A potentiometric non-enzymatic glucose sensor using a molecularly imprinted layer bonded on a conducting polymer.

A non-enzymatic potentiometric glucose sensor for the determination of glucose in the micomolar level in saliva was developed based on a molecularly imprinted polymer (MIP) binding on a conducting polymer layer. A MIP containing acrylamide, and aminophenyl boronic acid, as a host molecule to glucose, was immobilized on benzoic acid-functionalized poly(terthiophene) (pTBA) by the amide bond formation onto a gold nanoparticles deposited-screen printed carbon electrode (pTBA/AuNPs/SPCE). Aromatic boronic acid was incorporated into the MIP layer to stably capture glucose and create a potentiometric signal through the changed pKa value of polymer film by the formation of boronate anion-glucose complex with generation of H+ ions by the cis-diol reaction. Reversible binding and extraction of glucose on the sensor surface was observed using a quartz crystal microbalance. Each layer of the sensor probe was characterized by cyclic voltammetry, electrochemical impedance spectroscopy, X-ray photoelectron spectroscopy, and atomic force microscopy. The potentiometric response at the optimized conditions exhibited a wide linear dynamic range of 3.2×10-7 to 1.0×10-3M, with a detection limit of 1.9 (±0.15)×10-7M. The sensor probe revealed an excellent selectivity and sensitivity for glucose compared to other saccharides. In addition, the reliability of the proposed glucose sensor was evaluated in physiological fluid samples of saliva and finger prick blood.