Minimally Invasive Microneedle Array Electrodes Employing Direct Electron Transfer Type Glucose Dehydrogenase for the Development of Continuous Glucose Monitoring Sensors

Closed loop systems hinge on the accuracy and precision of the continuous glucose monitoring sensors. Most of the commercially available continuous glucose monitoring sensors is implanted subcutaneously for a period of 7-14 days. The subsequent biofouling effects have implications on the performance of the sensors over time especially at low glucose concentrations. In addition, the commercially available sensors are sensitive to the presence of interfering species such as acetaminophen in the skin compartment. We report here on the marriage of minimally invasive, continuous glucose sensors and a direct electron transfer type glucose dehydrogenase enzymatic system. Whilst the microneedles here are designed to sit in the dermal interstitial fluid over a 24-48 hour period to minimize the biofouling effect, the direct electron transfer enzyme allows operation of the electrochemical sensor at lower potentials to minimize the effect of interference. The microneedle structure design also enables the use of compensation electrodes for background subtraction to further nullify the effects of interference

Development and evaluation of a novel microprobe array continuous glucose monitor for type 1 diabetes

Despite the evidence demonstrating benefits of continuous glucose monitoring (CGM), the technology has not been widely implemented in routine management of type 1 diabetes due to several challenges. Our group has developed a novel sensor for CGM based on microprobe technology. The sensor consists of an array of solid microprobes, which are functionalised for in situ electrochemical measurement of dermal interstitial fluid glucose. The unique minimally-invasive non-extractive approach provides several avenues to enhance CGM accuracy. In this thesis, I describe the work carried out aiming to transfer this novel technology from bench side to bedside. To evaluate sensor’s ability to penetrate stratum corneum, human skin was utilised ex vivo to assess the force required for microprobes’ insertion compared to that required for their fracture. These studies guided a change in the fabrication technique and a modification in microprobes’ design. In vitro studies showed high sensitivity to glucose, providing the potential to enhance sensor accuracy. Further evaluation showed that neither skin insertion nor gamma ray sterilisation had impacted sensor performance. Clinical evaluation of sensor safety and proof of concept started with phase 1. The six-hour study demonstrated that sensor use was associated with barely noticeable skin reaction and minimal pain. The work also includes a mixed-method study aimed at capturing patients’ views in relation to CGM and describes the role of patient and public involvement in this project. These findings have important implications for the development of an accurate, cost-effective and user-friendly CGM system. This may help in widespread implementation of CGM technology and enhance compliance with CGM use with subsequent improvement in clinical effectiveness. Finally, a re-analysis of 448 glucose profiles from the Juvenile Diabetes Research Foundation CGM study is presented. This describes measures of glycaemic variability in type 1 diabetes and demonstrates the value of CGM in reducing these measures.Open Acces

A pilot study in humans of microneedle sensor arrays for continuous glucose monitoring

Although subcutaneously implanted continuous glucose monitoring (CGM) devices have been shown to support diabetes self-management, their uptake remains low due to a combination of high manufacturing cost and limited accuracy and precision arising from their invasiveness. To address these points, minimally invasive, a solid microneedle array-based sensor for continuous glucose monitoring is reported here. These intradermal solid microneedle CGM sensors are designed for low cost manufacturing. The tolerability and performance of these devices is demonstrated through clinical studies, both in healthy volunteers and participants with type 1 diabetes (T1D). The geometry of these solid microneedles allows them to penetrate dermal tissue without the need for an applicator. The outer surface of these solid microneedles are modified as glucose biosensors. The microneedles sit in the interstitial fluid of the skin compartment and monitor real-time changes in glucose concentration. Optical coherence tomography measurements revealed no major axial movement of the microneedles in the tissue. No significant adverse events were observed and low pain scores were reported when compared to catheter insertion, deeming it safe for clinical studies in T1D. These amperometric sensors also yielded currents that tracked venous blood glucose concentrations, showing a clinically acceptable correlation. Studies in people with T1D gave a mean absolute relative difference (MARD) of 9% (with respect to venous blood glucose) with over 94% of the data points in the A and B zones of the Clarke error grid. These findings provide baseline data for further device development and a larger clinical efficacy and acceptability study of this microneedle intradermal glucose sensor in T1D

Suicidal attempt among patients with schizophrenia: A cross-sectional study from Morocco

Suicide constitutes the greatest risk factor for mortality in individuals with schizophrenia. Although numerous risk factors have been suggested as important predictors of suicidality in schizophrenia, most studies have focused on Caucasian and Chinese patients. This study aimed to examine the prevalence of suicide attempts in schizophrenia patients in Rabat-Sale-Kenitra, Morocco, and to identify associated clinical and sociodemographic characteristics. A cross-sectional study was conducted at the Ar-RAZI Psychiatric Center of Ibn Sina Hospital in Rabat. We examined 175 Moroccan schizophrenic patients. The sociodemographic and clinical variables were analyzed based on the presence or absence of suicide attempts. The prevalence of suicide attempts among patients was 32%. 43% of them had reported multiple suicide attempts. The majority of those who attempted suicide were single, younger, and with a lower economic status. Visual hallucinations were significantly prevalent among attempter patients compared to non-attempters (p =0.032). Consequently, visual hallucinations could be a risk factor for suicide attempts in the Moroccan population. Understanding sociodemographic and clinical characteristics associated with suicide attempts can help identify patients at higher risk and provide appropriate support and interventions to prevent suicide among the Moroccan population

Minimally-invasive Microneedle-based Biosensor Array for Simultaneous Lactate and Glucose Monitoring in Artificial Interstitial Fluid

Here we report the first mediated pain free microneedle‐based biosensor array for the continuous and simultaneous monitoring of lactate and glucose in artificial interstitial fluid (ISF). The gold surface of the microneedles has been modified by electrodeposition of Au‐multiwalled carbon nanotubes (MWCNTs) and successively by electropolymerization of the redox mediator, methylene blue (MB). Functionalization of the Au‐MWCNTs/polyMB platform with the lactate oxidase (LOX) enzyme (working electrode 1) and with the FAD‐Glucose dehydrogenase (FADGDH) enzyme (working electrode 2) enabled the continuous monitoring of lactate and glucose in the artificial ISF. The lactate biosensor exhibited a high sensitivity (797.4±38.1 μA cm−2 mM−1), a good linear range (10–100 μM) with a detection limit of 3 μM. The performance of the glucose biosensor were also good with a sensitivity of 405.2±24.1 μA cm−2 mM−1, a linear range between 0.05 and 5 mM and a detection limit of 7 μM. The biosensor array was tested to detect the amount of lactate generated after 100 minutes of cycling exercise (12 mM) and of glucose after a normal meal for a healthy patient (10 mM). The results reveal that the new microneedles‐based biosensor array seems to be a promising tool for the development of real‐time wearable devices with a variety of sport medicine and clinical care applications

Rapid, low cost prototyping of transdermal devices for personal healthcare monitoring

The next generation of devices for personal healthcare monitoring will comprise molecular sensors to monitor analytes of interest in the skin compartment. Transdermal devices based on microneedles offer an excellent opportunity to explore the dynamics of molecular markers in the interstitial fluid, however good acceptability of these next generation devices will require several technical problems associated with current commercially available wearable sensors to be overcome. These particularly include reliability, comfort and cost. An essential pre-requisite for transdermal molecular sensing devices is that they can be fabricated using scalable technologies which are cost effective.We present here a minimally invasive microneedle array as a continuous monitoring platform technology. Method for scalable fabrication of these structures is presented. The microneedle arrays were characterised mechanically and were shown to penetrate human skin under moderate thumb pressure. They were then functionalised and evaluated as glucose, lactate and theophylline biosensors. The results suggest that this technology can be employed in the measurement of metabolites, therapeutic drugs and biomarkers and could have an important role to play in the management of chronic diseases

Evaluation of a minimally invasive glucose biosensor for continuous tissue monitoring

We describe here a minimally invasive glucose biosensor based on a microneedle array electrode fabricated from an epoxy-based negative photoresist (SU8 50) and designed for continuous measurement in the dermal compartment with minimal pain. These minimally invasive, continuous monitoring sensor devices (MICoMS) were produced by casting the structures in SU8 50, crosslinking and then metallising them with platinum or silver to obtain the working and reference electrodes, respectively. The metallised microneedle array electrodes were subsequently functionalised by entrapping glucose oxidase in electropolymerised polyphenol (PP) film. Sensor performance in vitro showed that glucose concentrations down to 0.5 mM could be measured with a response times (T90) of 15 s. The effect of sterilisation by Co60 irradiation was evaluated. In preparation for further clinical studies, these sensors were tested in vivo in a healthy volunteer for a period of 3–6 h. The sensor currents were compared against point measurements obtained with a commercial capillary blood glucometer. The epoxy MICoMS devices showed currents values that could be correlated with these

A randomized controlled pilot study of continuous glucose monitoring and flash glucose monitoring in people with Type 1 diabetes and impaired awareness of hypoglycaemia

AIM: Hypoglycaemia in Type 1 diabetes is associated with mortality and morbidity, especially where awareness of hypoglycaemia is impaired. Clinical pathways for access to continuous glucose monitoring (CGM) and flash glucose monitoring technologies are unclear. We assessed the impact of CGM and flash glucose monitoring in a high-risk group of people with Type 1 diabetes. METHODS: A randomized, non-masked parallel group study was undertaken. Adults with Type 1 diabetes using a multiple-dose insulin-injection regimen with a Gold score of ≥ 4 or recent severe hypoglycaemia were recruited. Following 2 weeks of blinded CGM, they were randomly assigned to CGM (Dexcom G5) or flash glucose monitoring (Abbott Freestyle Libre) for 8 weeks. The primary outcome was the difference in time spent in hypoglycaemia (below 3.3 mmol/l) from baseline to endpoint with CGM versus flash glucose monitoring. RESULTS: Some 40 participants were randomized to CGM (n = 20) or flash glucose monitoring (n = 20). The participants (24 men, 16 women) had a median (IQR) age of 49.6 (37.5-63.5) years, duration of diabetes of 30.0 (21.0-36.5) years and HbA1c of 56 (48-63) mmol/mol [7.3 (6.5-7.8)%]. The baseline median percentage time < 3.3 mmol/l was 4.5% in the CGM group and 6.7% in the flash glucose monitoring. At the end-point the percentage time < 3.3 mmol/l was 2.4%, and 6.8% respectively (median between group difference -4.3%, P = 0.006). Time spent in hypoglycaemia at all thresholds, and hypoglycaemia fear, were different between groups, favouring CGM. CONCLUSION: CGM more effectively reduces time spent in hypoglycaemia in people with Type 1 diabetes and impaired awareness of hypoglycaemia compared with flash glucose monitoring. (Clinical Trial Registry No: NCT03028220)

Towards a Physiological Prandial Insulin Profile: Enhancement of Subcutaneously Injected Prandial Insulin Using Local Warming Devices

The need to develop an insulin delivery system that can closely mimic physiologically induced changes in prandial insulin release has been a major research target since the discovery of insulin. The challenges facing existing insulin delivery systems, related to relatively slow pharmacokinetics and pharmacodynamics, have been further highlighted by rapid advances in diabetes technology and progress in artificial pancreas research. Despite the growing interest in alternative routes of insulin administration, the subcutaneous route remains—at least for now—the preferred route for insulin administration. In this article, we review efforts aimed at developing subcutaneously injected ultrafast-acting insulin and measures aimed at enhancing insulin absorption, focusing on local warming devices