Microneedle Aptamer-Based Sensors for Continuous, Real-Time Therapeutic Drug Monitoring.

The ability to continuously monitor the concentration of specific molecules in the body is a long-sought goal of biomedical research. For this purpose, interstitial fluid (ISF) was proposed as the ideal target biofluid because its composition can rapidly equilibrate with that of systemic blood, allowing the assessment of molecular concentrations that reflect full-body physiology. In the past, continuous monitoring in ISF was enabled by microneedle sensor arrays. Yet, benchmark microneedle sensors can only detect molecules that undergo redox reactions, which limits the ability to sense metabolites, biomarkers, and therapeutics that are not redox-active. To overcome this barrier, here, we expand the scope of these devices by demonstrating the first use of microneedle-supported electrochemical, aptamer-based (E-AB) sensors. This platform achieves molecular recognition based on affinity interactions, vastly expanding the scope of molecules that can be sensed. We report the fabrication of microneedle E-AB sensor arrays and a method to regenerate them for multiple uses. In addition, we demonstrate continuous molecular measurements using these sensors in flow systems in vitro using single and multiplexed microneedle array configurations. Translation of the platform to in vivo measurements is possible as we demonstrate with a first E-AB measurement in the ISF of a rodent. The encouraging results reported in this work should serve as the basis for future translation of microneedle E-AB sensor arrays to biomedical research in preclinical animal models.

Green MIP-202(Zr) Catalyst: Degradation and Thermally Robust Biomimetic Sensing of Nerve Agents.

Rapid and robust sensing of nerve agent (NA) threats is necessary for real-time field detection to facilitate timely countermeasures. Unlike conventional phosphotriesterases employed for biocatalytic NA detection, this work describes the use of a new, green, thermally stable, and biocompatible zirconium metal-organic framework (Zr-MOF) catalyst, MIP-202(Zr). The biomimetic Zr-MOF-based catalytic NA recognition layer was coupled with a solid-contact fluoride ion-selective electrode (F-ISE) transducer, for potentiometric detection of diisopropylfluorophosphate (DFP), a F-containing G-type NA simulant. Catalytic DFP degradation by MIP-202(Zr) was evaluated and compared to the established UiO-66-NH2 catalyst. The efficient catalytic DFP degradation with MIP-202(Zr) at near-neutral pH was validated by 31P NMR and FT-IR spectroscopy and potentiometric F-ISE and pH-ISE measurements. Activation of MIP-202(Zr) using Soxhlet extraction improved the DFP conversion rate and afforded a 2.64-fold improvement in total percent conversion over UiO-66-NH2. The exceptional thermal and storage stability of the MIP-202/F-ISE sensor paves the way toward remote/wearable field detection of G-type NAs in real-world environments. Overall, the green, sustainable, highly scalable, and biocompatible nature of MIP-202(Zr) suggests the unexploited scope of such MOF catalysts for on-body sensing applications toward rapid on-site detection and detoxification of NA threats.

Electrochemical glucose sensors in diabetes management: an updated review (2010-2020).

While over half a century has passed since the introduction of enzyme glucose biosensors by Clark and Lyons, this important field has continued to be the focus of immense research activity. Extensive efforts during the past decade have led to major scientific and technological innovations towards tight monitoring of diabetes. Such continued progress toward advanced continuous glucose monitoring platforms, either minimal- or non-invasive, holds considerable promise for addressing the limitations of finger-prick blood testing toward tracking glucose trends over time, optimal therapeutic interventions, and improving the life of diabetes patients. However, despite these major developments, the field of glucose biosensors is still facing major challenges. The scope of this review is to present the key scientific and technological advances in electrochemical glucose biosensing over the past decade (2010-present), along with current obstacles and prospects towards the ultimate goal of highly stable and reliable real-time minimally-invasive or non-invasive glucose monitoring. After an introduction to electrochemical glucose biosensors, we highlight recent progress based on using advanced nanomaterials at the electrode-enzyme interface of three generations of glucose sensors. Subsequently, we cover recent activity and challenges towards next-generation wearable non-invasive glucose monitoring devices based on innovative sensing principles, alternative body fluids, advanced flexible materials, and novel platforms. This is followed by highlighting the latest progress in the field of minimally-invasive continuous glucose monitoring (CGM) which offers real-time information about interstitial glucose levels, by focusing on the challenges toward developing biocompatible membrane coatings to protect electrochemical glucose sensors against surface biofouling. Subsequent sections cover new analytical concepts of self-powered glucose sensors, paper-based glucose sensing and multiplexed detection of diabetes-related biomarkers. Finally, we will cover the latest advances in commercially available devices along with the upcoming future technologies.

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.

Continuous Opioid Monitoring along with Nerve Agents on a Wearable Microneedle Sensor Array.

There are urgent needs for sensing devices capable of distinguishing between episodes of opioid overdose and nerve agent poisoning. This work presents a wearable microneedle sensor array for minimally invasive continuous electrochemical detection of opioid (OPi) and organophosphate (OP) nerve agents on a single patch platform. The new multimodal microneedle sensor array relies on unmodified and organophosphorus hydrolase (OPH) enzyme-modified carbon paste (CP) microneedle electrodes for square wave voltammetric (SWV) detection of the fentanyl and nerve agent targets, respectively. Such real-time simultaneous sensing provides distinct unique information, along with attractive analytical performance, including high sensitivity, selectivity, and stability, for real-time on-body OPi-OP analysis. The patch represents the first sensing device capable of continuously monitoring fentanyl down to the nanomolar level through a nanomaterial-based multilayered surface architecture. Applicability of the sensor array toward opioids screening is demonstrated for morphine and norfentanyl. Successful OPi-OP detection conducted in a skin-mimicking phantom gel demonstrates the suitability of the device for rapid on-body sensing. Such progress toward continuous minimally invasive transdermal analysis of drugs of abuse and nerve agents holds promise for rapid countermeasures for protecting soldiers, civilians, and healthcare personnel.

Microneedle-Based Detection of Ketone Bodies along with Glucose and Lactate: Toward Real-Time Continuous Interstitial Fluid Monitoring of Diabetic Ketosis and Ketoacidosis.

Diabetic ketoacidosis (DKA), a severe complication of diabetes mellitus with potentially fatal consequences, is characterized by hyperglycemia and metabolic acidosis due to the accumulation of ketone bodies, which requires people with diabetes to monitor both glucose and ketone bodies. However, despite major advances in diabetes management mainly since the emergence of new-generation continuous glucose monitoring (CGM) devices capable of in vivo monitoring of glucose directly in the interstitial fluid (ISF), the continuous monitoring of ketone bodies is yet to be addressed. Here, we present the first use of a real-time continuous ketone bodies monitoring (CKM) microneedle platform. The system is based on the electrochemical monitoring of ß-hydroxybutyrate (HB) as the dominant biomarker of ketone formation. Such real-time HB detection has been realized using the ß-hydroxybutyrate dehydrogenase (HBD) enzymatic reaction and by addressing the major challenges associated with the stable confinement of the enzyme/cofactor couple (HBD/NAD+) and with a stable and selective low-potential fouling-free anodic detection of NADH. The resulting CKM microneedle device displays an attractive analytical performance, with high sensitivity (with low detection limit, 50 µM), high selectivity in the presence of potential interferences, along with good stability during prolonged operation in artificial ISF. The potential applicability of this microneedle sensor toward minimally invasive monitoring of ketone bodies has been demonstrated in a phantom gel skin-mimicking model. The ability to detect HB along with glucose and lactate on a single microneedle array has been demonstrated. These findings pave the way for CKM and for the simultaneous microneedle-based monitoring of multiple diabetes-related biomarkers toward a tight glycemic control.

Enzymatic/Immunoassay Dual-Biomarker Sensing Chip: Towards Decentralized Insulin/Glucose Detection.

Performing bioassay formats based on enzyme and antibody recognition reactions with a single detection chip remains an unmet challenge owing to the different requirements of such bioassays. Herein, we describe a dual-marker biosensor chip, integrating enzyme and antibody-based assays for simultaneous electrochemical measurements of insulin (I) and glucose (G). Simultaneous G/I sensing has been realized by addressing key fabrication and operational challenges associated with the different assay requirements and surface chemistry. The I immunosensor relies on a peroxidase-labeled sandwich immunoassay, while G is monitored through reaction with glucose oxidase. The dual diabetes biomarker chip offers selective and reproducible detection of picomolar I and millimolar G concentrations in a single microliter sample droplet within less than 30 min, including direct measurements in whole blood and saliva samples. The resulting integrated enzymatic-immunoassay biosensor chip opens a new realm in point-of-care multiplexed biomarker detection.

Chemical/Light-Powered Hybrid Micromotors with "On-the-Fly" Optical Brakes.

Hybrid micromotors capable of both chemically powered propulsion and fuel-free light-driven actuation and offering built-in optical brakes for chemical propulsion are described. The new hybrid micromotors are designed by combining photocatalytic TiO2 and catalytic Pt surfaces into a Janus microparticle. The chemical reactions on the different surfaces of the Janus particle hybrid micromotor can be tailored by using chemical or light stimuli that generate counteracting propulsion forces on the catalytic Pt and photocatalytic TiO2 sides. Such modulation of the surface chemistry on a single micromotor leads to switchable propulsion modes and reversal of the direction of motion that reflect the tuning of the local ion concentration and hence the dominant propulsion force. An intermediate Au layer (under the Pt surface) plays an important role in determining the propulsion mechanism and operation of the hybrid motor. The built-in optical braking system allows "on-the-fly" control of the chemical propulsion through a photocatalytic reaction on the TiO2 side to counterbalance the chemical propulsion force generated on the Pt side. The adaptive dual operation of these chemical/light hybrid micromotors, associated with such control of the surface chemistry, holds considerable promise for designing smart nanomachines that autonomously reconfigure their propulsion mode for various on-demand operations.

Bioinspired Chemical Communication between Synthetic Nanomotors.

While chemical communication plays a key role in diverse natural processes, the intelligent chemical communication between synthetic nanomotors remains unexplored. The design and operation of bioinspired synthetic nanomotors is presented. Chemical communication between nanomotors is possible and has an influence on propulsion behavior. A chemical "message" is sent from a moving activator motor to a nearby activated (receiver) motor by release of Ag+ ions from a Janus polystyrene/Ni/Au/Ag activator motor to the activated Janus SiO2 /Pt nanomotor. The transmitted silver signal is translated rapidly into a dramatic speed change associated with the enhanced catalytic activity of activated motors. Selective and successive activation of multiple nanomotors is achieved by sequential localized chemical communications. The concept of establishing chemical communication between different synthetic nanomotors paves the way to intelligent nanoscale robotic systems that are capable of cooperating with each other.

Development of a Novel Insulin Sensor for Clinical Decision-Making.

BACKGROUND: Clinical decision support systems that incorporate information from frequent insulin measurements to enhance individualized diabetes management remain an unmet goal. The development of a disposable insulin strip for fast decentralized point-of-care detection replacing the current centralized lab-based methods used in clinical practice would be highly desirable to improve the establishment of individual insulin absorption patterns and algorithm modeling processes. METHODS: We carried out the development and optimization of a novel decentralized disposable insulin electrochemical sensor focusing on obtaining high analytical and operational performance toward achieving a true point-of-care insulin testing device for clinical on-site application. RESULTS: Our novel insulin immunosensor demonstrated an attractive performance and efficient user-friendly operation by providing high sensitivity capability to detect endogenous and analog insulin with a limit of detection of 30.2 pM (4.3 µiU/mL), rapid time-to-result, stability toward remote site application, and scalable low-cost fabrication with an estimated cost-of-goods for disposable consumables of below $5, capable of near real-time insulin detection in a microliter (≤10 µL) sample droplet of undiluted serum within 30 minutes. CONCLUSIONS: The results obtained in the optimization and characterization of our novel insulin sensor illustrate its suitability for its potential application in remote clinical environments for frequent insulin monitoring. Future work will test the insulin sensor in a clinical research setting to assess its efficacy in individuals with type 1 diabetes.

Clinical Evaluation of a Novel Insulin Immunosensor.

BACKGROUND: The estimation of available active insulin remains a limitation of automated insulin delivery systems. Currently, insulin pumps calculate active insulin using mathematical decay curves, while quantitative measurements of insulin would explicitly provide person-specific PK insulin dynamics to assess remaining active insulin more accurately, permitting more effective glucose control. METHODS: We performed the first clinical evaluation of an insulin immunosensor chip, providing near real-time measurements of insulin levels. In this study, we sought to determine the accuracy of the novel insulin sensor and assess its therapeutic risk and benefit by presenting a new tool developed to indicate the potential therapeutic consequences arising from inaccurate insulin measurements. RESULTS: Nine adult participants with type-1 diabetes completed the study. The change from baseline in immunosensor-measured insulin levels was compared with values obtained by standard enzyme-linked immunosorbant assay (ELISA) after preprandial injection of insulin. The point-of-care quantification of insulin levels revealed similar temporal trends as those from the laboratory insulin ELISA. The results showed that 70% of the paired immunosensor-reference values were concordant, which suggests that the patient could take action safely based on insulin concentration obtained by the novel sensor. CONCLUSIONS: This proposed technology and preliminary feasibility evaluation show encouraging results for near real-time evaluation of insulin levels, with the potential to improve diabetes management. Real-time measurements of insulin provide person-specific insulin dynamics that could be used to make more informed decisions regarding insulin dosing, thus helping to prevent hypoglycemia and improve diabetes outcomes.

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.

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.

Diabetes Technology Meeting 2021.

Diabetes Technology Society hosted its annual Diabetes Technology Meeting on November 4 to November 6, 2021. This meeting brought together speakers to discuss various developments within the field of diabetes technology. Meeting topics included blood glucose monitoring, continuous glucose monitoring, novel sensors, direct-to-consumer telehealth, metrics for glycemia, software for diabetes, regulation of diabetes technology, diabetes data science, artificial pancreas, novel insulins, insulin delivery, skin trauma, metabesity, precision diabetes, diversity in diabetes technology, use of diabetes technology in pregnancy, and green diabetes. A live demonstration on a mobile app to monitor diabetic foot wounds was presented.

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.

Wearable electrochemical biosensors in North America.

Tremendous research and commercialization efforts around the world are focused on developing novel wearable electrochemical biosensors that can noninvasively and continuously screen for biochemical markers in body fluids for the prognosis, diagnosis and management of diseases, as well as the monitoring of fitness. Researchers in North America are leading the development of innovative wearable platforms that can comfortably comply to the human body and efficiently sample fluids such as sweat, interstitial fluids, tear and saliva for the electrochemical detection of biomarkers through various sensing approaches such as potentiometric ion selective electrodes and amperometric enzymatic sensors. We start this review with a historical timeline overviewing the major milestones in the development of wearable electrochemical sensors by North American institutions. We then describe how such research efforts have led to pioneering developments and are driving the advancement and commercialization of wearable electrochemical sensors: from minimally invasive continuous glucose monitors for chronic disease management to non-invasive sweat electrolyte sensors for dehydration monitoring in fitness applications. While many countries across the globe have contributed significantly to this rapidly emerging field, their contributions are beyond the scope of this review. Furthermore, we share our perspective on the promising future of wearable electrochemical sensors in applications spanning from remote and personalized healthcare to wellness.

Wearable and Mobile Sensors for Personalized Nutrition.

While wearable and mobile chemical sensors have experienced tremendous growth over the past decade, their potential for tracking and guiding nutrition has emerged only over the past three years. Currently, guidelines from doctors and dietitians represent the most common approach for maintaining optimal nutrition status. However, such recommendations rely on population averages and do not take into account individual variability in responding to nutrients. Precision nutrition has recently emerged to address the large heterogeneity in individuals' responses to diet, by tailoring nutrition based on the specific requirements of each person. It aims at preventing and managing diseases by formulating personalized dietary interventions to individuals on the basis of their metabolic profile, background, and environmental exposure. Recent advances in digital nutrition technology, including calories-counting mobile apps and wearable motion tracking devices, lack the ability of monitoring nutrition at the molecular level. The realization of effective precision nutrition requires synergy from different sensor modalities in order to make timely reliable predictions and efficient feedback. This work reviews key opportunities and challenges toward the successful realization of effective wearable and mobile nutrition monitoring platforms. Non-invasive wearable and mobile electrochemical sensors, capable of monitoring temporal chemical variations upon the intake of food and supplements, are excellent candidates to bridge the gap between digital and biochemical analyses for a successful personalized nutrition approach. By providing timely (previously unavailable) dietary information, such wearable and mobile sensors offer the guidance necessary for supporting dietary behavior change toward a managed nutritional balance. Coupling of the rapidly emerging wearable chemical sensing devices-generating enormous dynamic analytical data-with efficient data-fusion and data-mining methods that identify patterns and make predictions is expected to revolutionize dietary decision-making toward effective precision nutrition.

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.

A review of biomarkers in the context of type 1 diabetes: Biological sensing for enhanced glucose control.

As wearable healthcare monitoring systems advance, there is immense potential for biological sensing to enhance the management of type 1 diabetes (T1D). The aim of this work is to describe the ongoing development of biomarker analytes in the context of T1D. Technological advances in transdermal biosensing offer remarkable opportunities to move from research laboratories to clinical point-of-care applications. In this review, a range of analytes, including glucose, insulin, glucagon, cortisol, lactate, epinephrine, and alcohol, as well as ketones such as beta-hydroxybutyrate, will be evaluated to determine the current status and research direction of those analytes specifically relevant to T1D management, using both in-vitro and on-body detection. Understanding state-of-the-art developments in biosensing technologies will aid in bridging the gap from bench-to-clinic T1D analyte measurement advancement.