正弦调制偏振光无创血糖检测的研究

常规的有创血糖检测方法有较多的局限性,光学无创血糖检测是糖尿病患者自我血糖评估的最佳方法,提出了一种偏振光无创血糖检测方法,将正弦调制偏振光通过血糖引起的微小偏振角的变化转化为电光调制器基频和倍频两个分量的变化,由相关原理高灵敏锁相放大器检测基频信号,控制法拉第线圈电流补偿血糖引起的偏转角变化,利用血糖浓度与法拉第线圈电流的线性关系,计算获得血糖浓度。以LX-20全自动生化分析仪测得的数据作为标准进行对比实验,葡萄糖溶液实验的相关系数为0.9952。研究表明偏振光无创血糖检测方法具有较高的检测灵敏度和准确度,为研制实用的新型无创血糖检测仪打下了基础。     

In silico evaluation of glucose control protocols for critically ill patients

This letter presents an in silico evaluation method of glucose control protocols for critically ill patients with hyperglycemia. Although various glucose control protocols were introduced and investigated in clinical trials, development and validation of a novel glucose control protocol for critically ill patients require too much time and resources in clinical evaluation. We employed a virtual patient model of the critically ill patient with hyperglycemia and evaluated the clinically investigated glucose control protocols in a computational environment. The three-day simulation results presented the time profiles of glucose and insulin concentrations, the amount of enteral feed and intravenous bolus of glucose, and the intravenous insulin infusion rate. The hyperglycemia and hypoglycemia index, blood glucose concentrations, insulin doses, intravenous glucose infusion rates, and glucose feed rates were compared between different protocols. It is shown that a similar hypoglycemia incidence exists in simulation and clinical results. We concluded that this in silico simulation method using a virtual patient model could be useful for predicting hypoglycemic incidence of novel glucose control protocols for critically ill patients, prior to clinical trials.     

An adaptive plasma glucose controller based on a nonlinearinsulin/glucose model

The design of plasma glucose controllers traditionally relies on linear approaches. The implementation of an appropriate nonlinear model of the insulin/glucose regulatory system into an adaptive controller should predict the insulin-dependent glucose removal more reliably and hence provide better control over a wide spectrum of insulin signals. A discretized form of the model leads to a two-step procedure. First, the measured plasma glucose levels associated with the erogeneous glucose infusion rates are used in the estimation of the past removal rates which, in turn, can be expressed as a weighted sum of past insulin inputs and previous values of the removal rate. Parameters of the sum are adjusted on-line by a recursive method of estimation which features a prefiltering of data to account for a corrupting coloured process noise. The same equation is in turn used to predict the time course of the insulin-dependent fractional rate of glucose removal. The performance of the controller. Tested in vivo in three pigs, is presented for various intravenous or subcutaneous rapid injections and staircase infusions of insulin. Plasma glucose is maintained at an average level of 99.9±8.7% of the target value (% set point±coefficient of variation). The controller reacts promptly to large and rapid variations in insulin action. Although control improves with the number of glucose measurements, the prediction of glucose removal allows for some flexibility in the monitoring of the plasma glucose. Sampling frequency varied from a 2 min interval during transient periods to 7 min as steady states were reached     

基于光学旋光法的血糖浓度测量

采用光学原理测量血糖是近年国际上热门的研究课题,目的是为糖尿病患者研制出无创、方便、连续实时监测血溏浓度的便携式监测仪。本文介绍了光学旋光法测量血糖的原理,对采用旋光法进行无创血溏测量技术的研究现状进行综述,讨论了影响测量的各种因素。     

A semiclosed-loop algorithm for the control of blood glucose levelsin diabetics

In this paper, a theoretical analysis of the control of plasma glucose levels in diabetic individuals is undertaken using a simple mathematical model of the dynamics of glucose and insulin interaction in the blood system. Mathematical optimization techniques are applied to the mathematical model to derive insulin infusion programs for the control of blood levels in diabetic individuals. Based on the results of the mathematical optimization, a semiclosed-loop algorithm is proposed for continuous insulin delivery to diabetic patients. The algorithm is based on three hourly plasma glucose samples. A theoretical evaluation of the effectiveness of this algorithm shows that it is superior to two existing algorithms in controlling hyperglycemia. A glucose infusion term representing the effect of glucose intake resulting from a meal is then introduced into the model equations. Various insulin infusion programs for the control of plasma glucose levels following a meal are then assessed. The theoretical results suggest that the most effective short-term control is achieved by an insulin infusion program which incorporates an injection to coincide with the meal.     

The Low-Potential Approach of Glucose Sensing

Study of glucose sensing using a smooth Pt electrode and cyclic voltammetry (CV) at low potentials revealed two well-defined, redox current peaks of adsorbed species. At 370 C a reduction peak occurs at ?0.80 V versus Ag/AgCl and an oxidation peak at ?0.72 V. Furthermore, the redox couple has been shown to be reversible, involving a simple, direct, electron-transfer process under diffusion control. The reaction is not complicated by secondary chemical (nonelectro-chemical) reactions. Based on this approach, a square wave voltammetry (SWV) technique has been adopted to obtain pure faradaic currents (noncapacitance current), fast response times, and enhanced sensitivity-for the designated reversible redox peaks. The SWV technique also permits the employment of much smaller-sized Pt wire electrodes (0.5 mm diameter) for glucose sensing. Plots of current versus glucose concentration in Krebs-Ringer solutions, for both redox peaks, are linear for glucose levels in the 70-350 mg/dl range. Studies of glucose concentration variations in the ultrafiltrate of human serum have also demonstrated a linear relationship between current and glucose level. Thus far, the linearity is limited to a narrow glucose range (80?180 mg/dl), but this is within the critical domain for diabetic control. The advantages of the low-potential approach using SWV is an improvement over CV and could be a promising method for implantable microelectrode glucose sensing.     

Neural network incorporating meal information improves accuracy of short-time prediction of glucose concentration

Diabetes mellitus is one of the most common chronic diseases, and a clinically important task in its management is the prevention of hypo/hyperglycemic events. This can be achieved by exploiting continuous glucose monitoring (CGM) devices and suitable short-term prediction algorithms able to infer future glycemia in real time. In the literature, several methods for short-time glucose prediction have been proposed, most of which do not exploit information on meals, and use past CGM readings only. In this paper, we propose an algorithm for short-time glucose prediction using past CGM sensor readings and information on carbohydrate intake. The predictor combines a neural network (NN) model and a first-order polynomial extrapolation algorithm, used in parallel to describe, respectively, the nonlinear and the linear components of glucose dynamics. Information on the glucose rate of appearance after a meal is described by a previously published physiological model. The method is assessed on 20 simulated datasets and on 9 real Abbott FreeStyle Navigator datasets, and its performance is successfully compared with that of a recently proposed NN glucose predictor. Results suggest that exploiting meal information improves the accuracy of short-time glucose prediction.     

Glucose‐Responsive Bioinorganic Nanohybrid Membrane for Self‐Regulated Insulin Release

A bioinorganic nanohybrid glucose‐responsive membrane is developed for self‐regulated insulin delivery analogous to a healthy human pancreas. The application of MnO₂ nanoparticles as a multifunctional component in a glucose‐responsive, protein‐based membrane with embedded pH‐responsive hydrogel nanoparticles is proposed. The bio‐nanohybrid membrane is prepared by crosslinking bovine serum albumin (BSA)–MnO₂ nanoparticle conjugates with glucose oxidase and catalase in the presence of poly(N‐isopropyl acrylamide‐co‐methacrylic acid) nanoparticles. The preparation and performance of this new nanocomposite material for a glucose‐responsive insulin release system is presented. The activity and stability of immobilized glucose oxidase and the morphology and mechanical properties of the membrane are investigated. The enzymatic activity is well preserved in the membranes. The use of MnO₂ nanoparticles not only reinforces the mechanical strength and the porous structure of the BSA‐based membrane, but enhances the long‐term stability of the enzymes. The in vitro release of insulin across the membrane is modulated by changes in glucose concentration mimicking possible fluctuations of blood‐glucose level in diabetic patients. A four‐fold increase in insulin permeation is observed when the glucose concentration is increased from normal to hyperglycemic levels, which returns to the baseline level when the glucose concentration is reduced to a normal level.     

Evaluation of Portal/Peripheral Route and of Algorithms for Insulin Delivery in the Closed-Loop Control of Glucose in Diabetes?A Modeling Study

In this paper we present an evaluation of portal versus peripheral routes for insulin delivery in diabetes with three representative closed-loop glucose control algorithms. A novel noninvasive approach is used which is based on a model of the blood glucose regulation system which simulates a Type I diabetic subject. The two routes and three algorithms are compared in controlling the simulated patient for 24 h, challenged with two dynamic glucose perturbations. The evaluation is performed by comparing both plasma accessible variables (e.g., glucose and insulin) and metabolic fluxes (e.g., glucose production and uptake, peripheral glucose utilization). Similar performances are achieved by the three algorithms both with peripheral and with portal infusions, especially in the postabsorptive steady state. An almost complete metabolic normalization is obtained with the portal route. With the peripheral route, normality is not restored; in particular, hyperinsulinemia and enhanced insulin-dependent glucose utilization are produced. From these simulation results, it is the site of insulin infusion, which appears to play an essential role in terms of the ability to normalize the metabolic state of a diabetic subject.     

Integrated multi-biosensors based on an ion-sensitive field-effecttransistor using photolithographic techniques

Two kinds of multifunctional biosensors, one sensitive to glucose and triolein and the other to glucose and urea, have been constructed using semiconductor fabrication techniques. An integrated ISFET (ion-sensitive field-effect transistor) with three hydrogen-ion-sensitive FET elements on one chip was used as a transducer for the biosensor. A photolithographic technique with a water-soluble photocrosslinkable polymer made possible the deposition of patterned enzyme membranes (glucose oxidase, lipase, and urease membranes) and bovine serum albumin membrane around each gate surface of ISFET elements. The multibiosensor for measuring glucose and triolein concentrations determined both glucose concentrations up to 5 mM and triolein concentrations up to 3 mM simultaneously. The biosensor for glucose and urea has a detection range of 0.03 to 3 mM for glucose and 0.1 to 20 mM for urea. Some multibiosensors showed a cross-sensitivity problem due to enzyme contamination. An improved membrane fabrication method to prevent the enzyme contamination is described     

Computer-aided continuous drug infusion: setup and test of a mobile closed-loop system for the continuous automated infusion of insulin.

For a diabetes mellitus patient, tight control of glucose level is essential. Results are reported of an investigation of the suitability of existing wearable continuous insulin infusors controlled and adjusted by a control algorithm using continuous glucose measurements as input to perform the functionality of an artificial pancreas. Special attention was given to the development of a continuous glucose monitor and to evaluate which quality of input data is necessary for the control algorithm. In clinical trials, it was found that for patients in a controlled environment an autonomously regulating control algorithm leads to an improved adjustment of patient glucose values and less overall insulin infusion as compared with the best fixed preprogrammed insulin infusion profiles of standard pump therapy. For the limited number of cases studied here, functionality of the control algorithm could tolerate some delay between the actual glucose values in the patient interstitial fluid and the algorithm input of up to 30 min. A quasicontinuous glucose measurement delivering actual glucose values every 5-10 min seems to be suited to control an artificial pancreas.     

Blood glucose measurement by multiple attenuated total reflectionand infrared absorption spectroscopy

The difficulty of measuring physiological concentrations of glucose in blood by conventional infrared absorption spectroscopy is due to the intrinsic high background absorption of water. This limitation can be largely overcome by the use of a CO2 laser as an infrared source in combination with a multiple attenuated total reflection (ATR) technique. To demonstrate the applicability of this technique, we compared in vitro measurements of glucose in blood obtained from an experimental infrared laser spectrometer with independent measurements made by a standard YSI 23A laboratory glucose analyzer. The capability of continuous measurement of blood glucose concentration is of primary importance in the future development of a glucose sensor for diabetic patients.     

Prediction of interstitial glucose level

Glucose is an important source of energy for cells. In clinical practice, we measure glucose level in blood and interstitial fluid. Each method has its pros and cons, and both levels correlate with each other. As the body tries to maintain the glucose level within a particular range to avoid adverse effects, it is desirable to predict future glucose levels in order to aid provided health care. We can see this desire in research, e.g., research on glucose transporters of cells. As yet another example, we can see it with diabetic patients, patients in a metabolic intensive care unit, particularly. In this paper, a glucose level prediction method is proposed.     

New noninvasive transcutaneous approach to blood glucosemonitoring: successful glucose monitoring on human 75 g OGTT with novelsampling chamber

A novel noninvasive and quasi-continuous method of transcutaneous blood glucose monitoring for use with the human 75 g oral glucose tolerance test (OGTT) has been developed. The effused fluid was obtained by applying suction on the skin surface and labeled suction effusion fluid (SEF). The system consists of two main parts: a suction apparatus and the glucose sensor system. The suction apparatus applies vacuum to the patient's skin at 400 mmHg absolute pressure to collect the SEF. The miniature ion sensitive field effect transistor (ISFET) based glucose sensor can measure glucose in small SEF quantities. The monitoring system is based on the association between the glucose concentration in the SEF and in the serum. During the 75 g OGTT, the glucose change in the SEF was measured every 10 min. Although a response delay of up to 20 min was observed in the SEF glucose change, it was possible to perform the 75 g OGTT by this noninvasive monitoring method.     

红外无创检测血糖仪研究

糖尿病为一种慢性病难以根治,对人民群众的生活与工作有着一定的影响。因此,为了控制机体内的血糖浓度,需对血糖进行检测。以往利用生化手段进行血糖检测,容易对患者造成损伤,影响患者血糖的测量结果。为了降低有创生化检测手段带来的影响,可选择光学无创检测技术弥补生化检测技术存在的弊端。该种检测技术可以让糖尿病患者的日常血糖检测变得越来越简单,更是满足了糖尿病患者的无痛需求,且具有便捷、无痛苦、实时检测的优势。本文基于红外光谱检测原理,设计了红外无创血糖仪。     

Epigallocatechin gallate decorated carbon nanotube chemiresistors for ultrasensitive glucose detection

The concentration of glucose in biological fluids is in the micromolar range, the detection of which requires devices with high sensitivity and low limit of detection (LOD). Here, we report the real-time electronic detection of glucose using an antioxidant found in green tea, namely, epigallocatechin gallate (EGCG), decorated on carbon nanotubes (CNTs) and tested in a chemiresistor configuration. The detection principle relies on the spontaneous reaction of EGCG with hydrogen peroxide, a reactive oxygen species released during glucose oxidation, which is translated electrically as a change in CNT conductance. Our results suggest that the response of EGCG decorated CNTs was far superior to that of the bare CNT based device. The sensor detected glucose ranging from 10 nM to 1 μM with LOD of ∼8.7 nM, which is much lower than the commercially available finger-pricking based glucose sensors. This could pave the way for developing simple resistivity-based sensors capable of glucose detection in biological fluids other than blood, such as sweat and saliva.     

Optical Absorption Glucose Measurements Using 2.3-$mu$m Vertical-Cavity Semiconductor Lasers

Continuous glucose monitoring has been shown to help diabetes mellitus patients stabilize their glucose levels, leading to improved patient health. One promising technique for monitoring blood glucose concentration is to use optical absorption spectroscopy. This letter proposes the use of thermally tunable 2.3-mum vertical-cavity surface-emitting lasers to obtain blood absorption spectra. The partial least squares technique is used to determine the glucose concentration from the spectra obtained in aqueous glucose solutions.     

Error grid analysis of noninvasive glucose monitoring via gingival cerevicular fluid

In order to realize a noninvasive blood glucose monitor, we monitored the gingival cerevicular fluid (GCF). In this paper, the clinical evaluations were performed on not only normal subjects but also diabetic subjects using a GCF-glucose monitor to determine blood glucose levels. Meal load tests were carried out and the time-course changes in blood glucose level and GCF glucose level were measured continuously. A positive correlation of more than 0.9 was found between blood glucose level and GCF glucose level, necessitating the calibration of individual correlations for every subject. Finally, the performance of the GCF-glucose monitor was evaluated using Error Grid Analysis. As the results, significant information for the glucose level decision was obtained not only for normal subjects, but also for diabetic subjects.     

Error grid analysis of noninvasive glucose monitoring via gingival crevicular fluid.

In order to realize a noninvasive blood glucose monitor, we monitored the gingival crevicular fluid (GCF). In this paper, the clinical evaluations were performed on not only normal subjects but also diabetic subjects using a GCF-glucose monitor to determine blood glucose levels. Meal load tests were carried out and the time-course changes in blood glucose level and GCF glucose level were measured continuously. A positive correlation of more than 0.9 was found between blood glucose level and GCF glucose level, necessitating the calibration of individual correlations for every subject. Finally, the performance of the GCF-glucose monitor was evaluated using Error Grid Analysis. As the results, significant information for the glucose level decision was obtained not only for normal subjects, but also for diabetic subjects.     

Porous Enzymatic Membrane for Nanotextured Glucose Sweat Sensors with High Stability toward Reliable Noninvasive Health Monitoring

Development of reliable glucose sensors for noninvasive monitoring without interruption or limiting users' mobility is highly desirable, especially for diabetes diagnostics, which requires routine/long‐term monitoring. However, their applications are largely limited by the relatively poor stability. Herein, a porous membrane is synthesized for effective enzyme immobilization and it is robustly anchored to the modified nanotextured electrode solid contacts, so as to realize glucose sensors with significantly enhanced sensing stability and mechanical robustness. To the best of our knowledge, this is the first report of utilizing such nanoporous membranes for electrochemical sensor applications, which eliminates enzyme escape and provides a sufficient surface area for molecular/ion diffusion and interactions, thus ensuring the sustainable catalytic activities of the sensors and generating reliable measureable signals during noninvasive monitoring. The as‐assembled nanostructured glucose sensors demonstrate reliable long‐term stable monitoring with a minimal response drift for up to 20 h, which delivers a remarkable enhancement. Moreover, they can be integrated into a microfluidic sensing patch for noninvasive sweat glucose monitoring. The as‐synthesized nanostructured glucose sensors with remarkable stability can inspire developments of various enzymatic biosensors for reliable noninvasive composition analysis and their ultimate applications in predictive clinical diagnostics, personalized health‐care monitoring, and chronic diseases management.