Wearable Electrochemical Glucose Sensors in Diabetes Management: A Comprehensive Review.

With the rising diabetic population, the demand for glucose sensing devices has also been on an increasing trend. Accordingly, the field of glucose biosensors for diabetes management has witnessed tremendous scientific and technological advancements since the introduction of the first enzymatic glucose biosensor in the 1960s. Among these, electrochemical biosensors hold considerable potential for tracking dynamic glucose profiles in real time. The recent evolution of wearable devices has opened opportunities to use alternative body fluids in a pain-free, noninvasive or minimally invasive manner. This review aims to present a comprehensive report about the status and promise of wearable electrochemical sensors for on-body glucose monitoring. We start by highlighting the importance of diabetes management and how sensors can contribute toward its effective monitoring. We then discuss the electrochemical glucose sensing mechanisms, evolution of such glucose sensors over time, different versions of wearable glucose biosensors targeting various biofluids, and multiplexed wearable sensors toward optimal diabetes management. Finally, we focus on the commercial aspects of wearable glucose biosensors, starting with existing continuous glucose monitors, followed by other emerging sensing technologies, and concluding with highlighting the key prospects toward personalized diabetes management in connection to an autonomous closed-loop artificial pancreas.

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.

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.

Sputtering enhanced peroxidase like activity of a dendritic nanochip for amperometric determination of hydrogen peroxide in blood samples.

A nonenzymatic electrochemical nanoprobe is described for the fast determination of hydrogen peroxide (H2O2). A sputtered indium tin oxide electrode with a nano-hierarchical 3D gold structure is used. The nanoprobe was characterized by SEM, EDX, TEM, SAED, and electrochemical techniques. Figures of merit include (a) a fast response time (≤ 1.0 s), (b) two linear dynamic ranges that extend from 10-12 M to 10-10 M and from 10-10 M to10-5 M; and (c) a low limit of detection of 9.8 × 10-13 M. The nanoprobe works in the clinical range and was applied for trace analysis of H2O2 in spiked blood samples, and recoveries ranged between 90 and 96%. It has negligible response (p < 0.001, for n = 3) toward glucose, citric acid, ascorbic acid, uric acid, glycine, and alanine. The shelf-lifetime is found to be 12 weeks. Graphical abstract Schematic representation of a dendritic nanochip with peroxidase-like activity. It is made from an indium tin oxide electrode with a nanohierarchical gold structure and was used for amperometric determination of hydrogen peroxide.

A paper based microfluidic device for easy detection of uric acid using positively charged gold nanoparticles.

A paper based microfluidic device is fabricated that can rapidly detect very low concentrations of uric acid (UA) using 3,5,3',5'-tetramethyl benzidine (TMB), H2O2 and positively charged gold nanoparticles ((+)AuNPs). In the presence of (+)AuNPs, H2O2 reacts with TMB to produce a bluish-green colour which becomes colourless on reaction with UA. This colorimetric method can detect as low as 8.1 ppm of UA within <20 minutes on white filter paper. This technique provides an alternative way for UA detection.

Continuous Ketone Monitoring via Wearable Microneedle Patch Platform.

Ketone bodies (KBs), especially ß-hydroxybutyrate (BHB), have gained tremendous attention as potential biomarkers as their presence in bodily fluids is closely associated with health and wellness. While a variety of blood fingerstick test strips are available for self-testing of BHB, there are major needs for wearable devices capable of continuously tracking changing BHB concentrations. To address these needs, we present here the first demonstration of a wearable microneedle-based continuous ketone monitoring (CKM) in human interstitial fluid (ISF) and illustrate its ability to closely follow the intake of ketone drinks. To ensure highly stable and selective continuous detection of ISF BHB, the new enzymatic microneedle BHB sensor relies on a gold-coated platinum working electrode modified with a reagent layer containing toluidine blue O (TBO) redox mediator, ß-hydroxybutyrate dehydrogenase (HBD) enzyme, a nicotinamide adenine dinucleotide (NAD+) cofactor, along with carbon nanotubes (CNTs), chitosan (Chit), and a poly(vinyl chloride) (PVC) outer protective layer. The skin-worn microneedle sensing device operates with a miniaturized electrochemical analyzer connected wirelessly to a mobile electronic device for capturing, processing, and displaying the data. Cytotoxicity and skin penetration studies indicate the absence of potential harmful effects. A pilot study involving multiple human subjects evaluated continuous BHB monitoring in human ISF, against gold standard BHB meter measurements, revealing the close correlation between the two methods. Such microneedle-based CKM offers considerable promise for dynamic BHB tracking toward the management of diabetic ketoacidosis and personal nutrition and wellness.

Point-of-Care Devices for Viral Detection: COVID-19 Pandemic and Beyond.

The pandemic of COVID-19 and its widespread transmission have made us realize the importance of early, quick diagnostic tests for facilitating effective cure and management. The primary obstacles encountered were accurately distinguishing COVID-19 from other illnesses including the flu, common cold, etc. While the polymerase chain reaction technique is a robust technique for the determination of SARS-CoV-2 in patients of COVID-19, there arises a high demand for affordable, quick, user-friendly, and precise point-of-care (POC) diagnostic in therapeutic settings. The necessity for available tests with rapid outcomes spurred the advancement of POC tests that are characterized by speed, automation, and high precision and accuracy. Paper-based POC devices have gained increasing interest in recent years because of rapid, low-cost detection without requiring external instruments. At present, microfluidic paper-based analysis devices have garnered public attention and accelerated the development of such POCT for efficient multistep assays. In the current review, our focus will be on the fabrication of detection modules for SARS-CoV-2. Here, we have included a discussion on various strategies for the detection of viral moieties. The compilation of these strategies would offer comprehensive insight into the detection of the causative agent preparedness for future pandemics. We also provide a descriptive outline for paper-based diagnostic platforms, involving the determination mechanisms, as well as a commercial kit for COVID-19 as well as their outlook.

Trends in Paper-Based Sensing Devices for Clinical and Environmental Monitoring.

Environmental toxic pollutants and pathogens that enter the ecosystem are major global issues. Detection of these toxic chemicals/pollutants and the diagnosis of a disease is a first step in efficiently controlling their contamination and spread, respectively. Various analytical techniques are available to detect and determine toxic chemicals/pathogens, including liquid chromatography, HPLC, mass spectroscopy, and enzyme-linked immunosorbent assays. However, these sensing strategies have some drawbacks such as tedious sample pretreatment and preparation, the requirement for skilled technicians, and dependence on large laboratory-based instruments. Alternatively, biosensors, especially paper-based sensors, could be used extensively and are a cost-effective alternative to conventional laboratory testing. They can improve accessibility to testing to identify chemicals and pollutants, especially in developing countries. Due to its low cost, abundance, easy disposal (by incineration, for example) and biocompatible nature, paper is considered a versatile material for the development of environmentally friendly electrochemical/optical (bio) sensor devices. This review presents an overview of sensing platforms constructed from paper, pointing out the main merits and demerits of paper-based sensing systems, their fabrication techniques, and the different optical/electrochemical detection techniques that they exploit.

In-ear integrated sensor array for the continuous monitoring of brain activity and of lactate in sweat.

Owing to the proximity of the ear canal to the central nervous system, in-ear electrophysiological systems can be used to unobtrusively monitor brain states. Here, by taking advantage of the ear's exocrine sweat glands, we describe an in-ear integrated array of electrochemical and electrophysiological sensors placed on a flexible substrate surrounding a user-generic earphone for the simultaneous monitoring of lactate concentration and brain states via electroencephalography, electrooculography and electrodermal activity. In volunteers performing an acute bout of exercise, the device detected elevated lactate levels in sweat concurrently with the modulation of brain activity across all electroencephalography frequency bands. Simultaneous and continuous unobtrusive in-ear monitoring of metabolic biomarkers and brain electrophysiology may allow for the discovery of dynamic and synergetic interactions between brain and body biomarkers in real-world settings for long-term health monitoring or for the detection or monitoring of neurodegenerative diseases.

Wearable chemical sensors for biomarker discovery in the omics era.

Biomarkers are crucial biological indicators in medical diagnostics and therapy. However, the process of biomarker discovery and validation is hindered by a lack of standardized protocols for analytical studies, storage and sample collection. Wearable chemical sensors provide a real-time, non-invasive alternative to typical laboratory blood analysis, and are an effective tool for exploring novel biomarkers in alternative body fluids, such as sweat, saliva, tears and interstitial fluid. These devices may enable remote at-home personalized health monitoring and substantially reduce the healthcare costs. This Review introduces criteria, strategies and technologies involved in biomarker discovery using wearable chemical sensors. Electrochemical and optical detection techniques are discussed, along with the materials and system-level considerations for wearable chemical sensors. Lastly, this Review describes how the large sets of temporal data collected by wearable sensors, coupled with modern data analysis approaches, would open the door for discovering new biomarkers towards precision medicine.

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.

A self-powered ingestible wireless biosensing system for real-time in situ monitoring of gastrointestinal tract metabolites.

Information related to the diverse and dynamic metabolite composition of the small intestine is crucial for the diagnosis and treatment of various diseases. However, our current understanding of the physiochemical dynamics of metabolic processes within the small intestine is limited due to the lack of in situ access to the intestinal environment. Here, we report a demonstration of a battery-free ingestible biosensing system for monitoring metabolites in the small intestine. As a proof of concept, we monitor the intestinal glucose dynamics on a porcine model. Battery-free operation is achieved through a self-powered glucose biofuel cell/biosensor integrated into a circuit that performs energy harvesting, biosensing, and wireless telemetry via a power-to-frequency conversion scheme using magnetic human body communication. Such long-term biochemical analysis could potentially provide critical information regarding the complex and dynamic small intestine metabolic profiles.

An integrated wearable microneedle array for the continuous monitoring of multiple biomarkers in interstitial fluid.

Implementations of wearable microneedle-based arrays of sensors for the monitoring of multiple biomarkers in interstitial fluid have lacked system integration and evidence of robust analytical performance. Here we report the development and testing of a fully integrated wearable array of microneedles for the wireless and continuous real-time sensing of two metabolites (lactate and glucose, or alcohol and glucose) in the interstitial fluid of volunteers performing common daily activities. The device works with a custom smartphone app for data capture and visualization, comprises reusable electronics and a disposable microneedle array, and is optimized for system integration, cost-effective fabrication via advanced micromachining, easier assembly, biocompatibility, pain-free skin penetration and enhanced sensitivity. Single-analyte and dual-analyte measurements correlated well with the corresponding gold-standard measurements in blood or breath. Further validation of the technology in large populations with concurrent validation of sensor readouts through centralized laboratory tests should determine the robustness and utility of real-time simultaneous monitoring of several biomarkers in interstitial fluid.

Lab under the Skin: Microneedle Based Wearable Devices.

While the current smartwatches and cellphones can readily track mobility and vital signs, a new generation of wearable devices is rapidly developing to enable users to monitor their health parameters at the molecular level. Within this emerging class of wearables, microneedle-based transdermal sensors are in a prime position to play a key role in synergizing the significant advantages of dermal interstitial fluid (ISF) as a rich source of clinical indicators and painless skin pricking to allow the collection of real-time diagnostic information. While initial efforts of microneedle sensing focused on ISF extraction coupled with either on-chip analysis or off-chip instrumentation, the latest trend has been oriented toward assembling electrochemical biosensors on the tip of microneedles to allow direct continuous chemical measurements. In this context, significant advances have recently been made in exploiting microneedle-based devices for real-time monitoring of various metabolites, electrolytes, and therapeutics and toward the simultaneous multiplexed detection of key chemical markers; yet, there are several grand challenges that still exist. In this review, we outline current progress, recent trends, and new capabilities of microneedle-empowered sensors, along with the current unmet challenges and a future roadmap toward transforming the latest innovations in the field to commercial products.

Clinically comparable impedimetric immunosensor for serum alkaline phosphatase detection based on electrochemically engineered Au-nano-Dendroids and graphene oxide nanocomposite.

In this work, we demonstrate label-free electrochemical impedance spectroscopy (EIS) based alkaline phosphatase (ALP) detection using gold nanoparticles (AuNPs), electrochemically engineered Au-nano-Dendroids, and graphene oxide (GO) nanocomposite. These nanomaterials were sequentially deposited on to the screen-printed carbon electrode (SPCE) and antibodies against ALP (anti-ALP) were immobilized using carbodiimide bioconjugation process. The sensor probe has been characterized extensively using TEM, EDX, SAED, XRD, FE-SEM, FTIR, DIC, and electrochemical techniques. The analytical performance of fabricated biosensor has been evaluated using EIS, where linear dynamic range and limit of detection were obtained to be 100-1000 U/L and 9.10 (±0.12) U/L, respectively. The developed biosensor showed high selectivity towards ALP with negligible interference (ksel « 1; n = 3) due to coexisting molecules. The sensor probe has successfully recovered ALP between 108.84% and 172.50% (n = 3) in human serum samples. The sensor has been used to estimate ALP in clinical serum samples, where the level was found to be 83.15 U/L and was comparable with standard technique used in the hospitals. The shelf life, stability, and reproducibility have also been evaluated.

Paper-based miniaturized immunosensor for naked eye ALP detection based on digital image colorimetry integrated with smartphone.

Alkaline phosphatase (ALP) is a metalloprotein found naturally in raw milk samples and is considered as an important biomarker in quality control of milk. Its easy, personalized, as well as instrument-less detection is important to ensure the pasteurization and its differentiation form raw milk. In view of such importance of APL, we have developed an office punching machine crafted paper biosensor for naked eye detection of ALP in milk samples. The quantitative estimation is done by digital image colorimetry (DIC) based technique integrated with smartphone. The sensor-probe was developed by the covalent immobilization of ALP antibody (anti-ALP) onto the functionalized paper surface. The fabrication of the biosensing probe was characterized using DIC, Fourier transform infrared spectroscopy (FTIR), and atomic force microscopy (AFM). The detection was based on immunocomplexation between the sensor-probe and ALP, which generates blue-green precipitate as an analytical signal by exploiting the catalytic activity of ALP towards 5-bromo-4-chloro 3-indolyl phosphate (BCIP). The dose dependent appearance of the blue-green complex was captured using smartphone camera and DIC was employed using Red, Green, and Blue (RGB) profiling system, where the maximum sensitivity was obtained for the red color channel. Based on the DIC analysis, a wide dynamic range for the ALP detection is obtained from 10 to 1000 U/mL with the detection limit of 0.87 (±â€¯0.07) U/mL. The designed paper-based biosensor is successfully applied to detect ALP in commercial and raw milk samples. Interferences due to components present in the milk samples was evaluated and the long-term stability of the designed biosensor was examined. Based on the detection principle, a miniaturized kit [20.0 mm (L) × 20.0 mm (W) × 2.15 mm (H)] was developed and applied for the ALP detection to demonstrate the instrument-free direct in-kitchen applicability.

Novel electrochemical biosensor for serotonin detection based on gold nanorattles decorated reduced graphene oxide in biological fluids and in vitro model.

Abnormal level of serotonin (ST) in body fluids is related to various clinical conditions including behavioral and psychotic disorders; hence its fast detection in clinically relevant ranges have tremendous importance in medical science. In view of this, we have developed a novel biosensor for ST detection using Au-nanorattles (AuNRTs)- reduced graphene oxide (rGO) nanocomposite coated on to the gold nanoparticles (AuNPs) deposited glassy carbon electrode (GCE). The nanocomposite/sensor probe was characterized using UV-Vis, TEM, SAED, EDX, AFM, and electrochemical techniques including LSV and EIS. Thereafter, the suitability of fabricated GCE/AuNPs/AuNRTs-rGO-Naf sensor probe was applied for ST determination which showed a linear dynamic range (LDR) of 3 × 10-6 - 1 × 10-3 M and the detection limit (DL) of 3.87 (±0.02) ×10-7 (RSD < 4.2%) M, which falls in the ranges of normal as well as various abnormal pathophysiological conditions. The designed sensor is successfully applied to detect ST in various real matrices viz. urine, blood serum, and in vitro model to show its direct clinical/practical applicability. Interferences due to the coexisting molecules were assessed and the long-term stability of the designed sensor was also examined which was found to be 8 weeks.

Gold nanoparticle surface engineering strategies and their applications in biomedicine and diagnostics.

Gold nanoparticles (AuNPs) have found a wide range of biomedical and environmental monitoring applications (viz. drug delivery, diagnostics, biosensing, bio-imaging, theranostics, and hazardous chemical sensing) due to their excellent optoelectronic and enhanced physico-chemical properties. The modulation of these properties is done by functionalizing them with the synthesized AuNPs with polymers, surfactants, ligands, drugs, proteins, peptides, or oligonucleotides for attaining the target specificity, selectivity and sensitivity for their various applications in diagnostics, prognostics, and therapeutics. This review intends to highlight the contribution of such AuNPs in state-of-the-art ventures of diverse biomedical applications. Therefore, a brief discussion on the synthesis of AuNPs has been summarized prior to comprehensive detailing of their surface modification strategies and the applications. Here in, we have discussed various ways of AuNPs functionalization including thiol, phosphene, amine, polymer and silica mediated passivation strategies. Thereafter, the implications of these passivated AuNPs in sensing, surface-enhanced Raman spectroscopy (SERS), bioimaging, drug delivery, and theranostics have been extensively discussed with the a number of illustrations.

Fundamentals and commercial aspects of nanobiosensors in point-of-care clinical diagnostics.

Among various problems faced by mankind, health-related concerns are prevailing since long which are commonly found in the form of infectious diseases and different metabolic disorders. The clinical cure and management of such abnormalities are greatly dependent on the availability of their diagnoses. The conventional diagnostics used for such purposes are extremely powerful; however, most of these are limited by time-consuming protocols and require higher volume of test sample, etc. A new evolving technology called "biosensor" in this context shows an enormous potential for an alternative diagnostic device, which constantly compliments the conventional diagnoses. In this review, we have summarized different kinds of biosensors and their fundamental understanding with various state-of-the-art examples. A critical examination of different types of biosensing mechanisms is also reported highlighting the advantages of electrochemical biosensors for its great potentials in next-generation commercially viable modules. In recent years, a number of nanomaterials are extensively used to enhance not only the performance of biosensing mechanism, but also obtain robust, cheap, and fabrication-friendly durable mechanism. Herein, we have summarized the importance of nanomaterials in biosensing mechanism, their syntheses as well as characterization techniques. Subsequently, we have discussed the probe fabrication processes along with various techniques for assessing its analytical performances and potentials for commercial viability.

Shifting paradigm of cancer diagnoses in clinically relevant samples based on miniaturized electrochemical nanobiosensors and microfluidic devices.

Cancer is one of leading causes of death in the world and occurs in more than two hundred types according to the National Cancer Institute. Its early diagnosis has been remained a prime focus amongst scientists and clinicians since long, not only to understand the complications but also to mitigate its chance of further proliferation. Nowadays, tremendous advances in nanotechnology-empowered diagnostics are serving a substantial input to identify biomarkers associated with various cancers. These biomarkers are found in different forms including overexpressed proteins/surface antigens, metabolites, miRNA, and the entire cell as well. Several approaches have been adopted to detect such cancer biomarkers, where electrochemical sensors have widely been appreciated due to its high sensitivity, selectivity, robustness, and miniaturized point-of-care cancer diagnostics. Due to its immense importance, the present review has been formulated describing classical concepts of cancer biomarker discovery followed by the recent status of electrochemical biosensors for cancer diagnoses. Particularly, we have summarized the state-of-the-art technologies based on potentiometric, impedimetric, amperometric, voltammetric biosensors for the detection of different biomarkers viz. protein, miRNA, whole cell and biomarkers generated by metabolic shift in response to carcinoma population. Apart from these, we have also highlighted different deliverable microfluidics-based approaches and recent prototypes for cancer detection. To put various perceptive insights on the recent advancements in cancer diagnostics, an extended table is incorporated, which includes sensor fabrication strategies, type of biomarkers, detection strategies, and analytical performance of the cancer biosensor since last five years (2013-2017).