Long-term Continuous Glucose Monitoring Research Articles

Explainable Machine-Learning Models to Predict Weekly Risk of Hyperglycemia, Hypoglycemia, and Glycemic Variability in Patients With Type 1 Diabetes Based on Continuous Glucose Monitoring.

The aim of this study was to develop and validate explainable prediction models based on continuous glucose monitoring (CGM) and baseline data to identify a week-to-week risk of CGM key metrics (hyperglycemia, hypoglycemia, glycemic variability). By having a weekly prediction of CGM key metrics, it is possible for the patient or health care personnel to take immediate preemptive action. We analyzed, trained, and internally tested three prediction models (Logistic regression, XGBoost, and TabNet) using CGM data from 187 type 1 diabetes patients with long-term CGM monitoring. A binary classification approach combined with feature engineering deployed on the CGM signals was used to predict hyperglycemia, hypoglycemia, and glycemic variability based on consensus targets (time above range ≥5%, time below range ≥4%, coefficient of variation ≥36%). The models were validated in two independent cohorts with a total of 223 additional patients of varying ages. A total of 46 593 weeks of CGM data were included in the analysis. For the best model (XGBoost), the area under the receiver operating characteristic curve (ROC-AUC) was 0.9 [95% confidence interval (CI) = 0.89-0.91], 0.89 [95% CI = 0.88-0.9], and 0.8 [95% CI = 0.79-0.81] for predicting hyperglycemia, hypoglycemia, and glycemic variability in the interval validation, respectively. The validation test showed good generalizability of the models with ROC-AUC of 0.88 to 0.95, 0.84 to 0.89, and 0.80 to 0.82 for predicting the glycemic outcomes. Prediction models based on real-world CGM data can be used to predict the risk of unstable glycemic control in the forthcoming week. The models showed good performance in both internal and external validation cohorts.

Efficacy and Safety of Continuous Glucose Monitoring and Intermittently Scanned Continuous Glucose Monitoring in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis of Interventional Evidence.

Traditional diabetes self-monitoring of blood glucose (SMBG) involves inconvenient finger pricks. Continuous glucose monitoring (CGM) and intermittently scanned CGM (isCGM) systems offer CGM, enhancing type 2 diabetes (T2D) management with convenient, comprehensive data. To assess the benefits and potential harms of CGM and isCGM compared with usual care or SMBG in individuals with T2D. We conducted a comprehensive search of MEDLINE, Embase, the Cochrane Library, Web of Science, and bibliographies up to August 2023. We analyzed studies meeting these criteria: randomized controlled trials (RCT) with comparison of at least two interventions for ≥8 weeks in T2D patients, including CGM in real-time/retrospective mode, short-/long-term CGM, isCGM, and SMBG, reporting glycemic and relevant data. We used a standardized data collection form, extracting details including author, year, study design, baseline characteristics, intervention, and outcomes. We included 26 RCTs (17 CGM and 9 isCGM) involving 2,783 patients with T2D (CGM 632 vs. usual care/SMBG 514 and isCGM 871 vs. usual care/SMBG 766). CGM reduced HbA1c (mean difference -0.19% [95% CI -0.34, -0.04]) and glycemic medication effect score (-0.67 [-1.20 to -0.13]), reduced user satisfaction (-0.54 [-0.98, -0.11]), and increased the risk of adverse events (relative risk [RR] 1.22 [95% CI 1.01, 1.47]). isCGM reduced HbA1c by -0.31% (-0.46, -0.17), increased user satisfaction (0.44 [0.29, 0.59]), improved CGM metrics, and increased the risk of adverse events (RR 1.30 [0.05, 1.62]). Neither CGM nor isCGM had a significant impact on body composition, blood pressure, or lipid levels. Limitations include small samples, single-study outcomes, population variations, and uncertainty for younger adults. Additionally, inclusion of <10 studies for most end points restricted comprehensive analysis, and technological advancements over time need to be considered. Both CGM and isCGM demonstrated a reduction in HbA1c levels in individuals with T2D, and unlike CGM, isCGM use was associated with improved user satisfaction. The impact of these devices on body composition, blood pressure, and lipid levels remains unclear, while both CGM and isCGM use were associated with increased risk of adverse events.

Long-term stable wireless smart contact lens for robust digital diabetes diagnosis

Wearable devices for digital continuous glucose monitoring (CGM) have attracted great attention as a new paradigm medical device for diabetes management. However, the relatively inaccurate performance and instability of CGM devices have limited their wide applications in the clinic. Here, we developed hyaluronate (HA) modified Au@Pt bimetallic electrodes for long-term accurate and robust CGM of smart contact lens. After glucose oxidation reaction, the bimetallic electrodes facilitated the rapid decomposition of hydrogen peroxide and charge transfer for robust CGM. The passivation of Au@Pt bimetallic electrode with branch-type thiolated HA prevented the dissolution of Au electrode by chloride ions in tears. In diabetic and normal rabbits, the smart contact lens with HA-Au@Pt bimetallic electrodes enabled the high correlation (ρ = 0.88) CGM with 98.6% clinically acceptable data for 3 weeks. Taken together, we could confirm the feasibility of our smart contact lens for long-term CGM for further clinical development.

Abstract #1392967: Effects of Long-Term Use of Continuous Glucose Monitoring on Hemoglobin A1c Levels in Patients with Type 2 Diabetes

Over the past decade, continuous glucose monitoring (CGM) systems have allowed for better insight into short-term glycemic control and the ability to assess for blood glucose variability throughout the day. Multiple studies have shown the benefits of CGM on Hemoglobin A1c (HbA1c) reduction in patients with type 1 diabetes mellitus (T1DM). However, few studies have shown the benefits of long-term CGM use on patients with type 2 diabetes mellitus (T2DM) who are on oral medications, insulin, or both. Our study aimed to determine the change in laboratory HbA1c levels in patients with T2DM after using a continuous CGM long-term. In this retrospective study we determined if HbA1c levels in patients with T2DM are reduced after using a CGM device for at least 90 days. The pre-HbA1c was a value within 12 months prior to using a CGM device, and the post-HbA1c was a value at least 3 months after using CGM. Patients served as their own control. HbA1c changes over time were assessed via a non-parametric paired t-test using SAS v9.4. There is a significant change in HbA1c from Pre CGM-initiation and 6- and 12-month post-CGM initiation, with a median HbA1c reduction of 0.6 for both. There is a significant change in HbA1c from Pre CGM-initiation and 24-month post-CGM initiation, with a median HbA1c reduction of 0.4. The median HbA1c pre-CGM was 8.4, and the median HbA1c 6-, 12-, and 24-months post-CGM initiation was 7.6. Long-term CGM use of at least 90 days in patients with T2DM was associated with a decrease in HbA1c over time which was statistically significant. Further studies will hopefully lead the way for CGM devices to be used as the standard of care for all patients with diabetes, as these devices have been shown to have significant effects on glycemic control.

Highly Miniaturized, Low-Power CMOS ASIC Chip for Long-Term Continuous Glucose Monitoring.

The objective of this work is to develop a highly miniaturized, low-power, biosensing platform for continuous glucose monitoring (CGM). This platform is based on an application-specific integrated circuit (ASIC) chip that interfaces with an amperometric glucose-sensing element. To reduce both size and power requirements, this custom ASIC chip was implemented using 65-nm complementary metal oxide semiconductor (CMOS) technology node. Interfacing this chip to a frequency-counting microprocessor with storage capabilities, a miniaturized transcutaneous CGM system can be constructed for small laboratory animals, with long battery life. A 0.45 mm × 1.12 mm custom ASIC chip was first designed and implemented using the Taiwan Semiconductor Manufacturing Company (TSMC) 65-nm CMOS technology node. This ASIC chip was then interfaced with a multi-layer amperometric glucose-sensing element and a frequency-counting microprocessor with storage capabilities. Variation in glucose levels generates a linear increase in frequency response of this ASIC chip. In vivo experiments were conducted in healthy Sprague Dawley rats. This highly miniaturized, 65-nm custom ASIC chip has an overall power consumption of circa 36 µW. In vitro testing shows that this ASIC chip produces a linear (R2 = 99.5) frequency response to varying glucose levels (from 2 to 25 mM), with a sensitivity of 1278 Hz/mM. In vivo testing in unrestrained healthy rats demonstrated long-term CGM (six days/per charge) with rapid glucose response to glycemic variations induced by isoflurane anesthesia and tail vein injection. The miniature footprint of the biosensor platform, together with its low-power consumption, renders this CMOS ASIC chip a versatile platform for a variety of highly miniaturized devices, intended to improve the quality of life of patients with type 1 and type 2 diabetes.

Integration of matching smart phone data with long-term continuous glucose monitoring data pictures of food intake

Integration of matching smart phone data with long-term continuous glucose monitoring data pictures of food intake

Near-Infrared Optical Transducer for Dynamic Imaging of Cerebrospinal Fluid Glucose in Brain Tumor.

Aberrant cerebral glucose metabolism is related to many brain diseases, especially brain tumor. However, it remains challenging to measure the dynamic changes in cerebral glucose. Here, we developed a near-infrared (NIR) optical transducer to sensitively monitor the glucose variations in cerebrospinal fluid in vivo. The transducer consists of an oxygen-sensitive nanoparticle combined with glucose oxidase (GOx), yielding highly sensitive NIR phosphorescence in response to blood glucose change. We demonstrated long-term continuous glucose monitoring by using the NIR transducer. After subcutaneous implantation, the glucose transducer provides a strong luminescence signal that can continuously monitor blood glucose fluctuations for weeks. By using the NIR emission of the transducer, we further observed abnormal dynamic changes in cerebrospinal fluid glucose and quantitatively assessed cerebral glucose uptake rates in transgenic mice bearing brain tumors. This study provides a promising method for the diagnosis of various metabolic diseases with altered glucose metabolism.

Covalent incorporation of metalloporphyrin in luminescent polymer dot transducer for continuous glucose monitoring

Luminescent dye-doped polymer dots (Pdots) have been demonstrated for various biosensing applications. However, the dye doping strategy may suffer from dye aggregation and dye leaching issues which limit the long-term sensor performance. Here, we show that covalent incorporation of metalloporphyrin in polyfluorene backbone for continuous glucose monitoring. The resulting polymer was used to develop luminescent Pdots transducer that overcome the dye-aggregation problem. We characterized the spectroscopic properties of the metalloporphyrin covalently-linked Pdots, which showed reduced batch-to-batch variation, enhanced intra-particle energy transfer, and improved luminescence stability as compared to the metalloporphyrin-doped Pdots. After bioconjugation with glucose oxidase (GOx), the oxygen-sensitive phosphorescence is highly sensitive to glucose variations. The metalloporphyrin-linked Pdots transducer showed good performance in long-term continuous glucose monitoring in mouse models. This work demonstrates that covalent incorporation of porphyrin dyes in Pdots transducer is a reliable strategy to improve their stability and reproducibility for long-term continuous glucose monitoring in vivo.

Long-Term In Vivo Glucose Monitoring by Polymer-Dot Transducer in an Injectable Hydrogel Implant.

Optical sensors have attracted a great deal of interest for glucose detection. However, their practical applications for continuous glucose monitoring are still constrained by operational reliability in subcutaneous tissues. Here, we show an implantable hydrogel platform embedded with luminescent polymer dots (Pdots) for sensitive and long-term glucose monitoring. We use Pdot transducer in a polyacrylamide hydrogel matrix to construct an implantable platform. The hydrogel-Pdot transducer showed bright luminescence with ratiometric response to glucose changes. The in vitro and in vivo sensitivities of the hydrogel implant were enhanced by varying the enzyme concentration and injection volume. After implantation, the hydrogel with Pdot transducer remained at the implanted site without migration for 1 month and can be removed from the subcutaneous tissue for further analysis. Our results indicate that the hydrogel-Pdot platform maintains the intrinsic sensing property with excellent stability during 1 month implantation, while fibrous capsule formation on the implant in some cases needs to be solved for long-term continuous glucose monitoring.

Optimal Data Collection Period for Continuous Glucose Monitoring to Assess Long-Term Glycemic Control: Revisited.

It is not clear how the short-term continuous glucose monitoring (CGM) sampling time could influence the bias in estimating long-term glycemic control. A large bias could, in the worst case, lead to incorrect classification of patients achieving glycemic targets, nonoptimal treatment, and false conclusions about the effect of new treatments. This study sought to investigate the relation between sampling time and bias in the estimates. We included a total of 329 type 1 patients (age 14-86 years) with long-term CGM (90 days) data from three studies. The analysis calculated the bias from estimating long-term glycemic control based on short-term sampling. Time in range (TIR), time above range (TAR), time below range (TBR), correlation, and glycemic target classification accuracy were assessed. A sampling time of ten days is associated with a high bias of 10% to 47%, which can be reduced to 4.9% to 26.4% if a sampling time of 30 days is used (P < .001). Correct classification of patients archiving glycemic targets can also be improved from 81.5% to 91.9 to 90% to 95.2%. Our results suggest that the proposed 10-14 day CGM sampling time may be associated with a high correlation with three-month CGM. However, these estimates are subject to large intersubject bias, which is clinically relevant. Clinicians and researchers should consider using assessments of longer durations of CGM data if possible, especially when assessing time in hypoglycemia or while testing a new treatment.

Hemoglobin A1c and Fructosamine Evaluated in Patients with Type 2 Diabetes Receiving Peritoneal Dialysis Using Long-Term Continuous Glucose Monitoring

Introduction: Shortened erythrocyte life span and erythropoietin-stimulating agents may affect hemoglobin A_1c (HbA_1c) levels in patients receiving peritoneal dialysis (PD). We compared HbA_1c with interstitial glucose measured by continuous glucose monitoring (CGM) in patients with type 2 diabetes receiving PD. Methods: Fourteen days of CGM (Ipro2, Medtronic) were performed in 23 patients with type 2 diabetes receiving PD and in 23 controls with type 2 diabetes and an estimated glomerular filtration rate over 60 mL/min/1.73 m². Patients were matched on gender and age (±5 years). HbA_1c (mmol/mol), its derived estimate of mean plasma glucose (eMPG_A1c) (mmol/L), and fructosamine (µmol/L) were measured at the end of the CGM period and compared with the mean sensor glucose (mmol/L) from CGM. Results: In the PD group, mean sensor glucose was 0.98 (95% con­fidence interval (CI): 0.43–1.54) mmol/L higher than the eMPG_A1c compared with the control group (p = 0.002) where glucose levels were nearly identical (−0.05 (95% CI: −0.35–0.25) mmol/L). A significant association was found between fructosamine and mean sensor glucose using linear regression with no difference between slopes (p = 0.89) or y-intercepts (p = 0.28). Discussion/Conclusion: HbA_1c underestimates mean plasma glucose levels in patients with type 2 diabetes receiving PD. However, the clinical significance of this finding is undetermined. Fructosamine seems to more accurately reflect glycemic status. CGM or fructosamine could complement HbA_1c to increase the accuracy of glycemic monitoring in the PD population.

The Accuracy of Hemoglobin A1c and Fructosamine Evaluated by Long-Term Continuous Glucose Monitoring in Patients with Type 2 Diabetes Undergoing Hemodialysis

Introduction: The accuracy of hemoglobin A1c (HbA1c) as a glycemic marker in patients with type 2 diabetes (T2D) receiving hemodialysis (HD) remains unknown. To assess accuracy, we compared HbA1c and fructosamine levels with interstitial glucose measured by continuous glucose monitoring (CGM) in patients with T2D receiving HD. Methods: Thirty patients in the HD group and 36 patients in the control group (T2D and an estimated glomerular filtration rate >60 mL/min/1.73 m²) completed the study period of 17 weeks. CGM (Ipro2^®, Medtronic) was performed 5 times for periods of up to 7 days (with 4-week intervals) during a 16-week period. HbA1c (mmol/mol), the estimated mean plasma glucose from HbA1c (eMPGA1c [mmol/L]) and fructosamine (μmol/L) was measured at week 17 and compared with mean sensor glucose levels from CGM. Findings: In the HD group, mean sensor glucose was 1.4 mmol/L (95% confidence interval [CI]: 1.0–1.8) higher than the eMPGA1c, whereas the difference for controls was 0.1 mmol/L (95% CI: −0.1–[0.4]; p < 0.001). Adjusted for mean sensor glucose, HbA1c was lower in the HD group (−7.3 mmol/mol, 95% CI: −10.0–[−4.7]) than in the control group (p < 0.001), with no difference detected for fructosamine (p = 0.64). Discussion: HbA1c evaluated by CGM underestimates plasma glucose levels in patients receiving HD. The underestimation represents a clinical challenge in optimizing glycemic control in the HD population. Fructosamine is unaffected by the factors affecting HbA1c and appears to be more accurate for glycemic monitoring. CGM or fructosamine could thus complement HbA1c in obtaining more accurate glycemic control in this patient group.

Baseline Glucose Variability and Interweek Variability Affects the Time to Stability of Continuous Glucose Monitoring-Derived Glycemic Indices.

Objectives: To study the effect of baseline glucose variability (GV) on the time to stability and interweek variability (IWV) of continuous glucose monitoring (CGM)-derived glycemic indices. Materials and Methods: Anonymized CGM data (median duration 32 weeks, ≥70% data coverage) of 85 adults with type 1 diabetes; age (41 ± 12 years), 66.3% women, HbA1c (7.5% ± 1.2%, 58 mmol/mol) were analyzed. We evaluated the time to stability, that is, the minimum duration of data that provided a close (r2 ≥ 0.9) correlation with data taken across the whole sampling period and IWV. We also evaluated the impact of baseline variability on the time to stability. Results: For the whole data set, all indices achieved stability (r2 ≥ 0.9) by 9 weeks (range 5-9). Time to stability progressively increased from the lowest quartile to the highest quartile of baseline coefficient of variation (CV). Time above range (TAR) and time below range (TBR) had higher IWV than time in range (TIR) (%CVIWV: TIR-16%, TAR-31%, TBR-62%). Conclusion: Baseline GV and IWV of indices affect the time to stability of glycemic indices. We recommend a minimum of 9 weeks of data to represent long-term CGM data.

An Optical Biosensor for Continuous Glucose Monitoring in Animal Cell Cultures.

Biosensors for continuous glucose monitoring in bioreactors could provide a valuable tool for optimizing culture conditions in biotechnological applications. We have developed an optical biosensor for long-term continuous glucose monitoring and demonstrated a tight glucose level control during cell culture in disposable bioreactors. The in-line sensor is based on a commercially available oxygen sensor that is coated with cross-linked glucose oxidase (GOD). The dynamic range of the sensor was tuned by a hydrophilic perforated diffusion membrane with an optimized permeability for glucose and oxygen. The biosensor was thoroughly characterized by experimental data and numerical simulations, which enabled insights into the internal concentration profile of the deactivating by-product hydrogen peroxide. The simulations were carried out with a one-dimensional biosensor model and revealed that, in addition to the internal hydrogen peroxide concentration, the turnover rate of the enzyme GOD plays a crucial role for culture monitoring is an integral part of animal cell cultivation. For several culture parameters, in situ sensors exist; others are predominantly monitored off-line. One important cell culture parameter is glucose concentration. Despite many efforts, there is still a lack of in situ sensors for continuous glucose monitoring. Such biosensors could provide a valuable tool for optimizing culture conditions in biotechnological applications. In this contribution, the manufacture of a long-term stable optical glucose sensor is described which is used to demonstrate glucose level monitoring during cell culture in disposable bioreactors. The in situ sensor is based on a commercially available oxygen sensor that is coated with cross-linked glucose oxidase and a hydrophilic perforated diffusion membrane. Glucose was measured in shake flasks and wave bags with only minor drifts of the sensor sensitivity during batch and fed-batch fermentations.

976-P: Post Market Clinical Follow-Up (PMCF) Registry to Demonstrate the Long Term Safety of the Eversense CGM System

Background: Eversense CGM is the first implantable long-term continuous glucose monitoring system. Prior studies evaluated the safety of the system using a study design of one insertion and removal cycle. The purpose of this prospective PMCF registry was to assess the long-term safety of the Eversense CGM System after repeated insertions. Methods: Eversense users from 15 European countries were followed prospectively until the first 100 participants completed their 4th insertion cycle. Visits were made every 90 to 180 days (dependent on sensor configuration) to replace sensors once sensor end life was reached. At each visit, Adverse Events (AEs) that occurred during the visit or during use since the previous visit were recorded. The primary endpoint was the rate of serious adverse events (SAEs) that were device-related, procedure-related, or drug (dexamethasone acetate) related through the sensor insertion/removal cycles. Results: 3066 participants were enrolled in the study with 43% on 2 or more sensor cycles. There were no device- or procedure-related SAEs reported. A total of 130 potentially-related AEs were reported, of which 106 were adjudicated as related or possibly/probably related to the device or insertion/removal procedure. Conclusion: Repeat insertions of the Eversense CGM confirmed the promising safety profile of prior studies and show it to be safe for long-term continuous use. Disclosure G. Carlson: Consultant; Self; Abbott Laboratories, Edwards Lifesciences Corporation, Senseonics, St. Jude Medical. K.S. Tweden: Employee; Self; Senseonics. C. Mdingi: Employee; Self; Senseonics. H. Haridas: Employee; Self; Senseonics.

Toward Long-Term Implantable Glucose Biosensors for Clinical Use

Continuous glucose monitoring (CGM) sensors have led a paradigm shift to painless, continuous, zero-finger pricking measurement in blood glucose monitoring. Recent electrochemical CGM sensors have reached two-week lifespans and no calibration with clinically acceptable accuracy. The system with the recent CGM sensors is identified as an “integrated glucose monitoring system,” which can replace finger-pricking glucose-testing for diabetes treatment decisions. Although such innovation has brought CGM technology closer to realizing the artificial pancreas, discomfort and infection problems have arisen from short lifespans and open wounds. A fully implantable sensor with a longer-term lifespan (90 days) is considered as an alternative CGM sensor with high comfort and low running cost. However, it still has barriers, including surgery for applying and replacing and frequent calibration. If technical refinement is conducted (e.g., stability and reproducibility of sensor fabrication), fully implantable, long-term CGM sensors can open the new era of continuous glucose monitoring.

Resistance to Data Loss of Glycemic Variability Measurements in Long-Term Continuous Glucose Monitoring.

Background: Continuous glucose monitoring (CGM) is a method of estimating blood glucose values from those recorded in the interstitial fluid. Because increasingly longer CGM measurements are possible, errors and data loss become more and more likely and potentially more damaging to accurate calculations of glycemic variability (GV) indices. Our research investigates the resistance of the CGM recording to data loss. Methods: We collected 71 CGM recordings (duration of min: 2, max: 265, median: 42 days) from patients with type 1 diabetes and used three algorithms to introduce missing data. We calculated mean and standard deviation (SD) of absolute percentage error of 12 variability indices and correlated those with the percentage of missing data and duration of the measurements. Results: Mean absolute percentage error of variability indices increased linearly with the percentage of missing data along with SD of absolute percentage error. Except for mean amplitude of glycemic excursions and time spent in hypoglycemia, all absolute errors never exceeded 25%, while mean absolute errors stayed below 5%. The gradient removal algorithm introduced errors larger than the single datapoint and block removal algorithms. The absolute percentage error of variability indices correlated negatively with the duration of the CGM measurements. Conclusions: Standard GV measurements in long-term glucose monitoring are robustly resistant to data loss.

Glucose Sensing Using Surface-Enhanced Raman-Mode Constraining.

Diabetes mellitus is a chronic disease, and its management focuses on monitoring and lowering a patient's glucose level to prevent further complications. By tracking the glucose-induced shift in the surface-enhanced Raman-scattering (SERS) emission of mercaptophenylboronic acid (MPBA), we have demonstrated fast and continuous glucose sensing in the physiologically relevant range from 0.1 to 30 mM and verified the underlying mechanism using numerical simulations. Bonding of glucose to MPBA suppresses the "breathing" mode of MPBA at 1071 cm-1 and energizes the constrained-bending mode at 1084 cm-1, causing the dominant peak to shift from 1071 to 1084 cm-1. MPBA-glucose bonding is also reversible, allowing continuous tracking of ambient glucose concentrations, and the MPBA-coated substrates showed very stable performance over a 30 day period, making the approach promising for long-term continuous glucose monitoring. Using Raman-mode-constrained, miniaturized SERS implants, we also successfully demonstrated intraocular glucose measurements in six ex vivo rabbit eyes within ±0.5 mM of readings obtained using a commercial glucose sensor.

Optical biosensor optimized for continuous in-line glucose monitoring in animal cell culture.

Biosensors for continuous glucose monitoring in bioreactors could provide a valuable tool for optimizing culture conditions in biotechnological applications. We have developed an optical biosensor for long-term continuous glucose monitoring and demonstrated a tight glucose level control during cell culture in disposable bioreactors. The in-line sensor is based on a commercially available oxygen sensor that is coated with cross-linked glucose oxidase (GOD). The dynamic range of the sensor was tuned by a hydrophilic perforated diffusion membrane with an optimized permeability for glucose and oxygen. The biosensor was thoroughly characterized by experimental data and numerical simulations, which enabled insights into the internal concentration profile of the deactivating by-product hydrogen peroxide. The simulations were carried out with a one-dimensional biosensor model and revealed that, in addition to the internal hydrogen peroxide concentration, the turnover rate of the enzyme GOD plays a crucial role for biosensor stability. In the light of this finding, the glucose sensor was optimized to reach a long functional stability (>52days) under continuous glucose monitoring conditions with a dynamic range of 0-20mM and a response time of t 90≤10min. In addition, we demonstrated that the sensor was sterilizable with beta and UV irradiation and only subjected to minor cross sensitivity to oxygen, when an oxygen reference sensor was applied. Graphical abstract Measuring setup of a glucose biosensor in a shake flask for continuous glucose monitoring in mammalian cell culture.

First step toward near-infrared continuous glucose monitoring: invivo evaluation of antibody coupled biomaterials.

Continuous glucose monitoring (CGM) is crucial in diabetic care. Long-term CGM systems however require an accurate sensor as well as a suitable measuring environment. Since large intravenous sensors are not feasible, measuring inside the interstitial fluid is considered the best alternative. This option, unfortunately, has the drawback of a lag time with blood glucose values. A good strategy to circumvent this is to enhance tissue integration and enrich the peri-implant vasculature. Implants of different optically transparent biomaterials (poly(methyl-methacrylate) [PMMA] and poly(dimethylsiloxane) [PDMS]) - enabling glucose monitoring in the near-infrared (NIR) spectrum - were surface-treated and subsequently implanted in goats at various implantation sites for up to 3 months. The overall invivo biocompatibility, tissue integration, and vascularization at close proximity of the surfaces of these materials were assessed. Histological screening showed similar tissue reactions independent of the implantation site. No significant inflammation reaction was observed. Tissue integration and vascularization correlated, to some extent, with the biomaterial composition. A modification strategy, in which a vascular endothelial-cadherin antibody was coupled to the biomaterials surface through a dopamine layer, showed significantly enhanced vascularization 3 months after subcutaneous implantation. Our results suggest that the developed strategy enables the creation of tissue interactive NIR transparent packaging materials, opening the possibility of continuous glucose monitoring.