Traumatic brain injury neuroelectrochemical monitoring: behind-the-ear micro-instrument and cloud application

BACKGROUND: Traumatic Brain Injury (TBI) is a leading cause of fatality and disability worldwide, partly due to the occurrence of secondary injury and late interventions. Correct diagnosis and timely monitoring ensure effective medical intervention aimed at improving clinical outcome. However, due to the limitations in size and cost of current ambulatory bioinstruments, they cannot be used to monitor patients who may still be at risk of secondary injury outside the ICU. METHODS: We propose a complete system consisting of a wearable wireless bioinstrument and a cloud-based application for real-time TBI monitoring. The bioinstrument can simultaneously record up to ten channels including both ECoG biopotential and neurochemicals (e.g. potassium, glucose and lactate), and supports various electrochemical methods including potentiometry, amperometry and cyclic voltammetry. All channels support variable gain programming to automatically tune the input dynamic range and address biosensors' falling sensitivity. The instrument is flexible and can be folded to occupy a small space behind the ear. A Bluetooth Low-Energy (BLE) receiver is used to wirelessly connect the instrument to a cloud application where the recorded data is stored, processed and visualised in real-time. Bench testing has been used to validate device performance. RESULTS: The instrument successfully monitored spreading depolarisations (SDs) - reproduced using a signal generator - with an SNR of 29.07 dB and NF of 0.26 dB. The potentiostat generates a wide voltage range from -1.65V to +1.65V with a resolution of 0.8mV and the sensitivity of the amperometric AFE was verified by recording 5 pA currents. Different potassium, glucose and lactate concentrations prepared in lab were accurately measured and their respective working curves were constructed. Finally,the instrument achieved a maximum sampling rate of 1.25 ksps/channel with a throughput of 105 kbps. All measurements were successfully received at the cloud. CONCLUSION: The proposed instrument uniquely positions itself by presenting an aggressive optimisation of size and cost while maintaining high measurement accuracy. The system can effectively extend neuroelectrochemical monitoring to all TBI patients including those who are mobile and those who are outside the ICU. Finally, data recorded in the cloud application could be used to help diagnosis and guide rehabilitation

3D Printed Microfluidic Device with Integrated Biosensors for Online Analysis of Subcutaneous Human Microdialysate

We thank the EPSRC (EP/H009744/1) and Wellcome Trust DOH (HICF-0510-080) for fundin

Development of a minimally invasive microneedle-based sensor for continuous monitoring of β-lactam antibiotic concentrations in vivo

Antimicrobial resistance poses a global threat to patient health. Improving the use and effectiveness of antimicrobials is critical in addressing this issue. This includes optimizing the dose of antibiotic delivered to each individual. New sensing approaches that track antimicrobial concentration for each patient in real time could allow individualized drug dosing. This work presents a potentiometric microneedle-based biosensor to detect levels of β-lactam antibiotics in vivo in a healthy human volunteer. The biosensor is coated with a pH-sensitive iridium oxide layer, which detects changes in local pH as a result of β-lactam hydrolysis by β-lactamase immobilized on the electrode surface. Development and optimization of the biosensor coatings are presented, giving a limit of detection of 6.8 μM in 10 mM PBS solution. Biosensors were found to be stable for up to 2 weeks at -20 °C and to withstand sterilization. Sensitivity was retained after application for 6 h in vivo. Proof-of-concept results are presented showing that penicillin concentrations measured using the microneedle-based biosensor track those measured using both discrete blood and microdialysis sampling in vivo. These preliminary results show the potential of this microneedle-based biosensor to provide a minimally invasive means to measure real-time β-lactam concentrations in vivo, representing an important first step toward a closed-loop therapeutic drug monitoring system

Real-time continuous measurement of lactate through a minimally invasive microneedle patch: a phase I clinical study

Introduction Determination of blood lactate levels supports decision-making in a range of medical conditions. Invasive blood-sampling and laboratory access are often required, and measurements provide a static profile at each instance. We conducted a phase I clinical study validating performance of a microneedle patch for minimally invasive, continuous lactate measurement in healthy volunteers. Methods Five healthy adult participants wore a solid microneedle biosensor patch on their forearms and undertook aerobic exercise for 30 min. The microneedle biosensor quantifies lactate concentrations in interstitial fluid within the dermis continuously and in real-time. Outputs were captured as sensor current and compared with lactate concentrations from venous blood and microdialysis. Results The biosensor was well-tolerated. Participants generated a median peak venous lactate of 9.25 mmol/L (IQR 6.73–10.71). Microdialysate concentrations of lactate closely correlated with blood. Microneedle biosensor current followed venous lactate concentrations and dynamics, with good agreement seen in all participants. There was an estimated lag-time of 5 min (IQR −4 to 11 min) between microneedle and blood lactate measurements. Conclusion This study provides first-in-human data on use of a minimally invasive microneedle patch for continuous lactate measurement, providing dynamic monitoring. This low-cost platform offers distinct advantages to frequent blood sampling in a wide range of clinical settings, especially where access to laboratory services is limited or blood sampling is infeasible. Implementation of this technology in healthcare settings could support personalised decision-making in a variety of hospital and community settings

Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers

Background: We report the first-in-human evaluation of realtime penicillin monitoring using a microneedle-based beta-lactam biosensor.Methods: Participants taking phenoxymethylpenicillin (penicillin-V) at steady state had venous blood (via cannula, T=- 30,0,10,20,30,45,60,90,120,150,180,210,240mins) and extracellular fluid (ECF; via microdialysis, every 15mins) pharmacokinetic (PK) samples taken during one dosing interval. During this period, a solid microneedle betalactam biosensor was worn to provide real-time monitoring of ECF penicillin-V concentration. Penicillin-V concentration data obtained from the microneedles was calibrated using locally-estimated-scatter-plot smoothing and compared to free blood and microdialysis (gold standard) data. Penicillin-V PK for each method was evaluated using noncompartmental analysis. Area-under-the-concentration-time-curve (AUC), Cmax, and tmax were compared. Bias and limits of agreement were investigated with Bland-Altman plots. Microneedle biosensor limits of detection were estimated. The study was approved by London-HarrowRegional ethics committee (Ref:18/LO/0054, NCT03847610).Findings: Ten healthy volunteers participated. Mean (SD) age was 42 (14) years. Seven (70%) were male. Penicillin-V ECF determined through microdialysis and microneedle methods demonstrated similar Cmax (0.74mg/L vs. 0.64mg/L, p=0.53; 95%CI: -0.24;0.44), tmax (1.18hrs vs. 1.10hrs, p=0.79; 95%CI:-0.52;0.67), and AUC (1.54mg*h/L vs. 1.67 mg*h/L p=0.79;95%CI:-1.10;0.85). In total, 440 time points were compared with mean (95%CI) difference between measurements -0.15 mg/L (95%CI:-0.11;0.20). Mean (SD) penicillin-V AUC values for free serum and microneedle PK were similar at 1.77 (0.59) mg*h/L and 1.67 (1.06) mg*h/L, respectively (p=0.81; 95%CI:-0.77;0.97). Percentage coefficient of variation betweensensors within individuals was median (IQR) 7 (4-17)%. Limit of detection for the microneedles was estimated at 0.17 mg/L.Interpretation: This demonstrates proof-of-concept of real-time, microneedle sensing of penicillin in vivo. Future work will explore microneedle use in patient populations, their role in data generation to inform dosing recommendations, and their incorporation into closed-loop control systems for automated drug delivery

The effectiveness, acceptability and cost-effectiveness of psychosocial interventions for maltreated children and adolescents: an evidence synthesis.

BACKGROUND: Child maltreatment is a substantial social problem that affects large numbers of children and young people in the UK, resulting in a range of significant short- and long-term psychosocial problems. OBJECTIVES: To synthesise evidence of the effectiveness, cost-effectiveness and acceptability of interventions addressing the adverse consequences of child maltreatment. STUDY DESIGN: For effectiveness, we included any controlled study. Other study designs were considered for economic decision modelling. For acceptability, we included any study that asked participants for their views. PARTICIPANTS: Children and young people up to 24 years 11 months, who had experienced maltreatment before the age of 17 years 11 months. INTERVENTIONS: Any psychosocial intervention provided in any setting aiming to address the consequences of maltreatment. MAIN OUTCOME MEASURES: Psychological distress [particularly post-traumatic stress disorder (PTSD), depression and anxiety, and self-harm], behaviour, social functioning, quality of life and acceptability. METHODS: Young Persons and Professional Advisory Groups guided the project, which was conducted in accordance with Cochrane Collaboration and NHS Centre for Reviews and Dissemination guidance. Departures from the published protocol were recorded and explained. Meta-analyses and cost-effectiveness analyses of available data were undertaken where possible. RESULTS: We identified 198 effectiveness studies (including 62 randomised trials); six economic evaluations (five using trial data and one decision-analytic model); and 73 studies investigating treatment acceptability. Pooled data on cognitive-behavioural therapy (CBT) for sexual abuse suggested post-treatment reductions in PTSD [standardised mean difference (SMD) -0.44 (95% CI -4.43 to -1.53)], depression [mean difference -2.83 (95% CI -4.53 to -1.13)] and anxiety [SMD -0.23 (95% CI -0.03 to -0.42)]. No differences were observed for post-treatment sexualised behaviour, externalising behaviour, behaviour management skills of parents, or parental support to the child. Findings from attachment-focused interventions suggested improvements in secure attachment [odds ratio 0.14 (95% CI 0.03 to 0.70)] and reductions in disorganised behaviour [SMD 0.23 (95% CI 0.13 to 0.42)], but no differences in avoidant attachment or externalising behaviour. Few studies addressed the role of caregivers, or the impact of the therapist-child relationship. Economic evaluations suffered methodological limitations and provided conflicting results. As a result, decision-analytic modelling was not possible, but cost-effectiveness analysis using effectiveness data from meta-analyses was undertaken for the most promising intervention: CBT for sexual abuse. Analyses of the cost-effectiveness of CBT were limited by the lack of cost data beyond the cost of CBT itself. CONCLUSIONS: It is not possible to draw firm conclusions about which interventions are effective for children with different maltreatment profiles, which are of no benefit or are harmful, and which factors encourage people to seek therapy, accept the offer of therapy and actively engage with therapy. Little is known about the cost-effectiveness of alternative interventions. LIMITATIONS: Studies were largely conducted outside the UK. The heterogeneity of outcomes and measures seriously impacted on the ability to conduct meta-analyses. FUTURE WORK: Studies are needed that assess the effectiveness of interventions within a UK context, which address the wider effects of maltreatment, as well as specific clinical outcomes. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013003889. FUNDING: The National Institute for Health Research Health Technology Assessment programme

CMOS potentiometric FET array platform using sensor learning for multi-ion imaging.

This work describes an array of 1024 Ion-Sensitive Field-Effect Transistors (ISFETs) using sensor learning techniques to perform multi-ion imaging for concurrent detection of potassium, sodium, calcium and hydrogen. Analyte specific ionophore membranes are deposited on the surface of the ISFET array chip, yielding pixels with quasi-Nernstian sensitivity to K+, Na+ or Ca2+. Uncoated pixels display pH sensitivity from the standard Si3N4 passivation layer. The platform is then trained by inducing a change in single ion concentration and measuring the responses of all pixels. Sensor learning relies on k-means clustering and DBSCAN to yield membrane mapping and sensitivity of each pixel to target electrolytes. We demonstrate multi-ion imaging with an average error of 3.7 % (K+), 4.6 % (Na+), and 1.8 % (pH) for each ion respectively, while Ca2+ incurs a larger error 24.2 % and hence is included to demonstrate versatility. We validate the platform with a brain dialysate fluid sample and demonstrate reading by comparing with a gold-standard spectrometry technique

Fiber-based electrochemical biosensors for monitoring pH and transient neurometabolic lactate.

Developing tools that are able to monitor transient neurochemical dynamics is important to decipher brain chemistry and function. Multifunctional polymer-based fibers have been recently applied to monitor and modulate neural activity. Here, we explore the potential of polymer fibers comprising six graphite-doped electrodes and two microfluidic channels within a flexible polycarbonate body as a platform for sensing pH and neurometabolic lactate. Electrodes were made into potentiometric sensors (responsive to pH) or amperometric sensors (lactate biosensors). The growth of an iridium oxide layer made the fiber electrodes responsive to pH in a physiologically relevant range. Lactate biosensors were fabricated via platinum black growth on the fiber electrode, followed by an enzyme layer, making them responsive to lactate concentration. Lactate fiber biosensors detected transient neurometabolic lactate changes in an in vivo mouse model. Lactate concentration changes were associated with spreading depolarizations, known to be detrimental to the injured brain. Induced waves were identified by a signature lactate concentration change profile and measured as having a speed of ∼2.7 mm/min (n = 4 waves). Our work highlights the potential applications of fiber-based biosensors for direct monitoring of brain metabolites in the context of injury

Simultaneous monitoring of potassium, glucose and lactate during spreading depolarisation in the injured human brain - proof of principle of a novel real-time neurochemical analysis system, continuous online microdialysis (coMD)

Spreading Depolarisations (SDs) occur spontaneously and frequently in injured human brain. They propagate slowly through injured tissue often cycling around a local area of damage. Tissue recovery after an SD requires greatly augmented energy utilisation to normalise ionic gradients from a virtually complete loss of membrane potential. In the injured brain this is difficult because local blood flow is often low and unreactive. In this study we use a new variant of microdialysis, continuous on-line microdialysis (coMD), to observe the effects of SDs on brain metabolism. The neurochemical changes are dynamic and take place on the timescale of the passage of an SD past the microdialysis probe. Dialysate potassium levels provide an ionic correlate of cellular depolarisation and show a clear transient increase. Dialysate glucose levels reflect a balance between local tissue glucose supply and utilization. These show a clear transient decrease of variable magnitude and duration. Dialysate lactate levels indicate non-oxidative metabolism of glucose and show a transient increase. Preliminary data suggest that the transient changes recover more slowly after the passage of a sequence of multiple SD’s giving rise to a decrease in basal dialysate glucose and an increase in basal dialysate potassium and lactate levels