Hollow-fiber Dialysis Membranes Research Articles

A comprehensive study of glucose transfer in the human small intestine using an in vitro intestinal digestion system (i-IDS) based on a dialysis membrane process

Human digestion is a complex process that involves several phenomena: chemical and enzymatic reactions, absorption, hydrodynamic processes, and mass transfer. The most accurate way to determine the bioavailability of different nutrients is through human studies. However, there are ethical, economic, and technical reasons that restrict their application. Aiming at contributing with a new experimental prototype and phenomenological model to study nutrient absorption in the human small intestine, an in vitro intestinal digestion system (i-IDS), based on a hollow fiber dialysis membrane process, was constructed and tested under different operational conditions of feed flow/dialysate flow ratio. This dialysis membrane process here presented, allowed to simulate and extrapolate results of the process of glucose transfer in the human small intestine, where the glucose mass transfer reached around 90% at times ranging between 25 and 40 min. The mathematical model was validated with respect to the experimental results, obtaining a good agreement (root mean square error, %RMS, between 3% and 19%) among them. Overall permeabilities for the experimental conditions ranged between 3.85 × 10−6 and 4.86 × 10−6 m3/s. The experimental results of glucose absorption were extrapolated to those found in the human small intestine using a phenomenological model, where a good agreement among results of glucose absorption was found in human studies. This first experimental and phenomenological approach allows to acquire a better knowledge of the complex mass transfer processes found in human small intestine for nutrient absorption.

Evaluation of blood adsorption onto dialysis membranes by time-of-flight secondary ion mass spectrometry and near-field infrared microscopy.

Blood adsorption onto the inside surface of hollow fiber dialysis membranes was investigated by means of time-of-flight secondary ion mass spectrometry (TOF-SIMS) and near-field infrared microscopy (NFIR) in order to evaluate the biocompatibility and permeability of dialysis membranes. TOF-SIMS is useful for the imaging of particular molecules with a high spatial resolution of approximately 100nm. In contrast, infrared spectra provide quantitative information and NFIR enables analysis with a high spatial resolution of less than 1μm, which is close to the resolution of TOF-SIMS. A comparison was made of one of the most widely used dialysis membranes made of polysulfone (PSf), that has an asymmetric and inhomogeneous pore structure, and a newly developed asymmetric cellulose triacetate (ATA) membrane that also has an asymmetric pore structure, even though the conventional cellulose triacetate membrane has a symmetric and homogeneous pore structure. As a result, it was demonstrated that blood adsorption on the inside surface of the ATA membrane is more reduced than that on the PSf membrane. Graphical abstract Analysis of blood adsorption on inside surface of hollow fiber membrane.

Internal and surface structure characterization of cellulose triacetate hollow-fiber dialysis membranes

A cellulose triacetate (CTA) dialysis membrane is generally regarded as a homogeneous membrane. The objective of the present study was to characterize the internal structure of CTA dialysis membranes. We used FB-150E, FB-150F, and FB-150UH CTA hollow-fiber membrane dialyzers. The pore-size distribution and porosity of the CTA membrane surfaces were calculated from surface image data obtained by using atomic force microscopy (AFM). The internal porosity of the CTA membranes was measured by weight analysis. Further, the pore diameter of the CTA membranes was calculated from data on pure-water permeability and diffusive permeability using a pore diffusion model. The pore diameters on the inner surface of the CTA membranes were much greater than those on the outer surface. The surface porosity determined using AFM was much lesser than the internal porosity determined using weight analysis. The pore diameters on the inner and outer surfaces of the CTA membranes determined using AFM were much lesser than pore diameter calculated on the basis of the permeability data. We conclude that the CTA dialysis membrane, which is generally regarded as a homogeneous membrane, is actually a multilayer membrane. The CTA dialysis membrane has tight layers at the inner and outer surfaces, and has a loose layer inside the membrane.

Evaluation of Dialyzer Jacket Structure and Hollow‐Fiber Dialysis Membranes to Achieve High Dialysis Performance

The objective of this study was to determine the optimum dialyzer jacket structure and hollow-fiber dialysis membrane, both of which are indispensable factors for achieving high dialysis performance, by clarifying the relationship between the dialysis performance and the flow of dialysate and blood in a hollow-fiber dialyzer. We evaluated the clearance, dialysate, and blood flow for four commercially available hollow-fiber dialyzers, namely, the APS-15S, APS-15SA, TS-1.6UL, and CX-1.6U. To evaluate dialysate and blood flow, we measured the residence-time distribution of dialysate and blood flow of these dialyzers by the pulse-response method. We also determined the clearances of urea, creatinine, vitamin B(12), and lysozyme to evaluate the dialysis performance of these dialyzers. While the baffle and taper structures allow effective supply of dialysate into the dialyzer jacket, the hollow-fiber shape, inner diameter, and packing density significantly influence the dialysate flow. In dialyzers with long taper-holding slits, the slit area is a key design parameter for achieving optimum dialysate flow. Similarly, the blood flow is significantly influenced by the structure of the inflowing and outflowing blood ports at the header of a dialyzer, and the shape and inner diameter of the hollow fibers. Hollow fibers with smaller inner diameters cause an increase in blood pressure, which causes blood to enter the hollow fibers more easily. The hollow-fiber shape hardly affects the blood flow. While improved dialysate and blood flow cause higher clearance of low molecular-weight substances, higher membrane area and pure-water permeability accelerate internal filtration, thereby causing an increase in the clearance of large molecular-weight substances.

Functional-group analysis of polyvinylpyrrolidone on the inner surface of hollow-fiber dialysis membranes, by near-field infrared microspectroscopy

Near-field infrared microspectroscopy (NFIR) is a newly developed surface analysis method that is based on functional-group analysis and has a high spatial resolution. The objective of the present study is to perform nanoscale functional-group analysis of dialysis membrane surfaces by using NFIR. We focused on polyvinylpyrrolidone (PVP), which is employed as an additive to hydrophilize and create pores in synthetic polymer dialysis membranes, and evaluated the PVP distribution on the inner surface of the dialysis membranes. Dialysis membranes made from polysulfone (PSf) and polyester–polymer alloy (PEPA) were first assessed by NFIR and then by attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). The nanoscale NFIR analysis showed heterogeneous distribution of PVP on the PSf membrane even though the amount of PVP on the membrane surface was high. PVP was homogeneously distributed on the PEPA membrane even though the amount of PVP on the membrane surface was low. In contrast, the microscale ATR-FTIR results showed that PVP was homogeneously distributed on both PSf and PEPA membranes. PVP-rich and PVP-poor regions were distinguishable by NFIR and not by ATR-FTIR, because the spatial resolution of NFIR is higher than that of ATR-FTIR. This study demonstrates for the first time that NFIR can provide nanoscale chemical information on the structures of porous membranes.

Membrane potential and charge density of hollow-fiber dialysis membranes

Abstract Membrane charge affects diffusive permeability for ions. Hence, evaluation of membrane charge density is necessary to clarify diffusive permeability for ions. The objective of the present study is to measure stable and reproducible membrane potentials with hollow-fiber membranes and to evaluate the electrostatic characteristics of dialysis membrane by applying membrane potential measurement method for flat membrane to hollow-fiber membranes. Membrane charge density was calculated from data on the membrane potential. Values for membrane charge density obtained as electrostatic characteristics of AM-UP150 (regenerated cellulose), KF-15C (ethylenevinylalcohol copolymer), PAN-150SF (polyacrylonitrile), AM-BC150X (polyethylene glycol-modified regenerated cellulose), FB-150U (cellulose triacetate), APS-150E (polysulfone), FLX-15GW (polyester–polymer alloy) and BLF-10GW (diethylaminoethyl-modified regenerated cellulose) were −0.9, −0.9, −0.7, −0.5, −0.1, +0.1, +0.35 and +3.1 mol/m 3 , respectively. This method allows determination of the membrane charge density of hollow-fiber dialysis membrane.

Hollow-fiber blood-dialysis membranes: superoxide generation, permeation, and dismutation measured by chemiluminescence

The interaction of blood with a material surface results in activation of the body's humoral immune system and the generation of reactive oxygen species (ROS). It has recently become clear that ROS are central to the pathology of many diseases. In this study, we evaluated the superoxide generation, permeation, and dismutation in hollow-fiber dialysis membranes by using 2-methyl-6-p-methoxyphenylethynyl-imidazopyrazinone (MPEC) as a superoxide-reactive chemiluminescence producer and an optical fiber probe to detect the resulting chemiluminescence in the hollow fiber lumen. We measured the superoxide generated when bovine blood leukocytes were brought into contact with dialysis membranes. Superoxide permeation was determined by measuring MPEC chemiluminescence in the hollow fiber lumen using an optical fiber probe. Additionally, superoxide dismutation was evaluated by examining the difference in superoxide permeability for membranes with and without vitamin E coating. Superoxide generation varies for different membrane materials, depending on the membrane's biocompatibility. Superoxide permeability depends on the diffusive permeability of membranes. No marked decrease in superoxide permeability was observed among membrane materials. The superoxide permeability of vitamin E-coated membrane was smaller than that of uncoated membrane. The antioxidant property of vitamin E-coated membranes is hence effective in causing superoxide dismutation.

Evaluation of asymmetrical structure dialysis membrane by tortuous capillary pore diffusion model

The tortuous capillary pore diffusion model (TCPDM) has been used for estimating diffusive and pure water permeability from simple structure parameters such as pore diameter, surface porosity, wall thickness and tortuosity. The validity of this model for evaluation of homogeneous membrane has been already confirmed. Recently, there is a trend toward the use of asymmetrical dialysis membranes made of synthetic polymer such as poly(acrylonitrile) (PAN), polysulfone (PS) and a polyethersulfone polyarylate (PEPA) blend polymer. The purpose of the present study is to apply the TCPDM to evaluation of commercially available hollow-fiber dialysis membranes with asymmetrical structures by simplifying them to a double-layer membrane. The TCPDM is capable of estimating pore tortuosity of asymmetrical dialysis membranes having skin and supporting layers from data on membrane thickness, pore diameter, pure water permeability and water content. Values for diffusive permeability obtained by the TCPDM are in a good agreement with experimental data. This TCPDM model is useful for evaluation of not only homogeneous membrane but also asymmetrical membrane.

Mutual information theory for biomedical applications: Estimation of three protein-adsorbed dialysis membranes

Protein-adsorbed dialysis membranes are evaluated with time-of-flight secondary ion mass spectrometry (TOF-SIMS) chemical imaging technique. Protein adsorption causing permeability change is one of big issues in the development of dialysis membranes. Bovine serum albumin adsorption onto three kinds of dialysis membranes has been evaluated with TOF-SIMS. In the present study three kinds of proteins, bovine serum albumin, α-chymotripsinogen A, and cytochrome C adsorbed onto hollow-fiber dialysis membranes, were measured by means of TOF-SIMS and then TOF-SIMS spectra were analyzed using mutual information. Then specific peaks of fragment ions related to α-chymotripsinogen A and bovine serum albumin were found, respectively. In this condition, however, specific peaks to cytochrome C were not able to find compared with other samples. Finally, chemical images of α-chymotripsinogen A and bovine serum albumin, respectively, adsorbed onto the membranes with co-existing proteins were obtained. The results of TOF-SIMS images of the proteins on the membranes show different tendency of adsorption depending on co-existing proteins. Further study is needed to study more detailed protein adsorption onto the membranes with co-existing proteins.

Hollow-fiber blood-dialysis membranes: superoxide generation, permeation, and dismutation measured by chemiluminescence

The interaction of blood with a material surface results in activation of the body's humoral immune system and the generation of reactive oxygen species (ROS). It has recently become clear that ROS are central to the pathology of many diseases. In this study, we evaluated the superoxide generation, permeation, and dismutation in hollow-fiber dialysis membranes by using 2-methyl-6-p-methoxyphenylethynyl-imidazopyrazinone (MPEC) as a superoxide-reactive chemiluminescence producer and an optical fiber probe to detect the resulting chemiluminescence in the hollow fiber lumen. We measured the superoxide generated when bovine blood leukocytes were brought into contact with dialysis membranes. Superoxide permeation was determined by measuring MPEC chemiluminescence in the hollow fiber lumen using an optical fiber probe. Additionally, superoxide dismutation was evaluated by examining the difference in superoxide permeability for membranes with and without vitamin E coating. Superoxide generation varies for different membrane materials, depending on the membrane's biocompatibility. Superoxide permeability depends on the diffusive permeability of membranes. No marked decrease in superoxide permeability was observed among membrane materials. The superoxide permeability of vitamin E-coated membrane was smaller than that of uncoated membrane. The antioxidant property of vitamin E-coated membranes is hence effective in causing superoxide dismutation.

Evaluation of the activity of endotoxin trapped by a hollow-fiber dialysis membrane

All available dialysis membranes prevent endotoxin (Et) from mixing with the blood under clinical conditions. However, maintenance dialysis patients are at risk of amyloidosis attributed to Et. This suggests that Et may affect the blood even if it does not mix with the blood. The objective of the present study is to evaluate the activity of Et trapped by membranes. We made mini modules out of hollow fibers using three different types of membranes and filtered Et solution. The lumen of the hollow fibers was then filled with limulus amebocyte lysate (LAL) for 15 min at 310 K. Et activity was then determined by measuring absorbance of the LAL reagent. The surfaces of test membranes were studied using an atomic force microscope. With polyester polymer alloy (PEPA), no Et leakage or Et activity was detected in the hollow fibers under any conditions. With polysulfone (PS) and polyether sulfone (PES), no Et leakage was detected under clinical conditions, but Et activity was detected in the hollow fibers. These results show that Et trapped by the inner skin may affect the blood, even if Et does not mix with the blood. Therefore, Et should be trapped by an outer skin or the part somewhat far from the blood which does not contact with the blood directly.

Estimation of protein adsorption on dialysis membrane by means of TOF-SIMS imaging

Protein adsorption on dialysis membrane was studied by time-of-flight secondary ion mass spectrometry (TOF-SIMS), which is expected to be capable of chemical imaging of insulated samples, such as hollow-fiber dialysis membranes. Three commercially available hollow-fiber dialysis membranes having different pore sizes and structures, were tested in the present study. Bovine serum albumin (BSA) solutions were used to adsorb the protein on the samples. TOF-SIMS images and spectra of native membranes and membranes treated with BSA were compared in order to identify secondary ions related to BSA and membranes. Mutual information, one of applications of information theory, was employed to select fragment ions related to BSA. TOF-SIMS images show distribution of adsorbed BSA on the dialysis membranes and indicate that BSA permeability and interaction between the membranes and BSA definitely depend on pore size, structure and material.

TOF-SIMS imaging of protein adsorption on dialysis membrane

Time-of-flight secondary ion mass spectrometry (TOF-SIMS) is capable of chemical imaging of proteins on insulated samples such as hollow-fiber dialysis membranes. Albumin loss and a lowering of diffusive permeability caused by protein adsorption on dialysis membranes should be reduced in order to enhance dialysis adequacy of the patients. Bovine serum albumin (BSA)-adsorbed hollow-fiber dialysis membranes were tested in the present study. TOF-SIMS images and spectra of both native membranes and BSA-adsorbed membranes were compared in order to identify secondary ions related to BSA and membranes. Peaks of secondary ions related to BSA and each membrane were selected by means of information theory, and they are characterized by principal component analysis (PCA). Chemical images of BSA adsorption on both native and treated membranes were obtained to find that BSA permeability and interaction between the membranes and BSA definitely depend on the properties of a membrane. TOF-SIMS imaging obtained with information theory is a powerful tool to estimate protein adsorption on the dialysis membranes.

How polysulfone dialysis membranes containing polyvinylpyrrolidone achieve excellent biocompatibility?

Polysulfone (PS) dialysis membranes hydrophilized by blending polyvinylpyrrolidone (PVP) are well known to have excellent biocompatibility in clinical use. The objective of the present study is thus to clarify how PVP improves biocompatibility of PS membranes and furthermore to develop a patient-friendly PS dialysis membrane with higher biocompatibility. Biocompatibility based on both lactate dehydrogenase (LDH) activity and amount of protein adsorption was greatly different among four commercially available PS hollow-fiber dialysis membranes. PVP present on the inner surface of the hollow fiber was quantitatively determined by X-ray photoelectron spectroscopy (XPS), demonstrating the amount of PVP to be varying for each membrane. Structure parameters such as surface roughness, three-dimensional surface area and polymer particle diameter, indications of the physicochemical properties of the membranes, were measured on the observed inner surface images in both wet and dry conditions by atomic force microscopy (AFM) to account for dependence of biocompatibility on these structure parameters. The higher regularity polymer particle structure has in the wet condition, the lower wet/dry ratio surface roughness has and the larger wet/dry ratio polymer particle diameter has, that is, the more greatly the polymer particles swell by wetting, the higher biocompatibility is achieved by “cushion effect”.

“CUSHION EFFECT” OF POLYVINYLPIRROLIDONE POLYMER PARTICLES IMPROVES BIOCOMPATIBILITY OF POLYSULFONE DIALYSIS MEMBRANES

Some polysulfone (PS) dialysis membranes hydrophilized with poly-vinylpyrrolidone (PVP) have excellent biocompatibility in clinical use. The objective of the present study is to clarify the mechanism how such membranes achieve excellent biocompatibility and furthermore to develop a patient-friendly PS dialysis membrane. Inner surfaces of nine kinds of wet and dry PS hollow-fiber dialysis membranes prepared by varying spinning and sterilization methods were observed by atomic force microscopy (SPM 9500-J3; Shimadzu, Japan). The same observation mode (contact mode) and probe (NP-S; Nihon Veeco KK, Japan) were used to quantitatively evaluate surface structures of wet and dry samples. C5a activity at 60 min was used for evaluating biocompatibility. The more γ-ray irradiated membranes, the more PVP bridged and the more rigid PVP polymer particles (PPP) were formed on the surface, resulting in a lowering of biocompatibility. Softness of PPP works like a cushion and improves biocompatibility, indicating that biocompatibility is determinable by swelling and shrinking behavior of PPP caused by wetting and drying. Gamma-ray sterilization in aqueous glycerin (AG) prevented PPP from becoming rigid and was superior to that in water on biocompatibility. There was no significant difference in biocompatibility between continuous and batch spinning methods.Table

TOF-SIMS Imaging of Protein Adsorption on Dialysis Membrane by means of Information Entropy

Time-of-flight secondary ion mass spectrometry (TOF-SIMS) is expected to contribute to the evaluation of biomaterial surfaces interacting with proteins, cells and microbes because it requires no sample pre-treatments, such as labeling with probes and coating with metallic thin films for insulated samples. TOF-SIMS measurement provides chemical distribution of biomaterials with high spatial resolution. Since it is difficult for TOF-SIMS to generate enough characteristic secondary ions for imaging from large molecules such as proteins, multivariate analysis techniques such as principal component analysis (PCA) have been employed to characterize the spectra with fragment ions considered to be related to proteins. However, some of those fragment ions are also related to substrate especially polymers. Information theory was employed for the first time to analyze TOF-SIMS spectra of hollow-fiber dialysis membranes treated with a protein solution. TOF-SIMS spectra and images of protein adsorbed membranes and native membranes were compared based on mutual entropy in order to discriminate secondary ions related to protein from membranes. TOF-SIMS images with the fragment ion groups related to proteins and membrane were obtained respectively, and they show clearly the distribution of adsorbed protein on the dialysis membranes. [DOI: 10.1380/ejssnt.2003.67]

AFM observation of small surface pores of hollow-fiber dialysis membrane using highly sharpened probe

Determining pore size distribution is important for characterization of a dialysis membrane. However, conventional microscopic techniques cannot present a sufficient image for determining pore size distribution. In the present study, tapping mode atomic force microscopy (TMAFM) has been shown to be a powerful tool for observing and evaluating the small surface pores of a hollow-fiber dialysis membrane. Sample fixing technique described below and a highly sharpened probe have made it possible to observe small pores on a soft and undulant surface of a dialysis membrane. This is the first time that clear TMAFM images of surface pores of a hollow-fiber dialysis membrane at such high resolution have been presented. Pore diameter was determined by image analysis. Average pore diameter of APS-150 (Asahi-kasei, Japan) determined by TMAFM was compared with those by field emission scanning electron microscopy (FESEM) and by the Hagen–Poiseuille equation. The average pore diameter of APS-150 determined by TMAFM was slightly higher than that by FESEM. The average pore diameter determined by the Hagen–Poiseuille equation was intermediate between values for that of inside and outside surfaces determined by TMAFM.

Determination of effective charge density of hollow-fiber dialysis membranes and its effects on phosphate ion permeability

Phosphate ion, which is a cause of metabolic bone disease, is excessively accumulated in the blood of chronic dialysis patients, because many of dialysis membranes have negative charge, which inhibit removal of phosphate ion from their blood. The ability to remove phosphate ion can be evaluated by membrane charge. The electrical charge of the membrane affects the rate of ion permeability, and the phosphate ion is no exception. The membrane charge of sheet dialysis membranes can be readily evaluated by measuring the membrane potential and calculating the effective charge density. Accordingly a study was made of the influence on the phosphate ion permeability exerted by the membrane charge of sheet membranes composed of the same material as the hollow-fiber membranes used in hemodialysis. The diffusive permeability of phosphate ion was greater due to the result that the higher the ionic strength in the solution, the higher the absolute ion mobility. On the other hand, because of their shape, it is impossible to measure the membrane potential of hollow-fiber membranes using conventional techniques, making it difficult to determine the effective charge density. The authors therefore, have proposed a novel technique to enable the measurement of membrane potential in hollow-fiber membranes, and have studied the influence exerted on the phosphate ion permeability by the effective charge density calculated by this technique. The phosphate ion permeability increases when the following situations occur: (1) the smaller the absolute value of effective charge density, (2) the greater the ionic strength of the solution, and (3) the greater the concentration of plasma proteins. This agrees with the theoretical results. By calculating the effective charge density from the membrane potential of the hollow-fiber membranes, as measured by the technique proposed here, it is possible to evaluate the rate of phosphate ion permeability in such membranes.

On-line coupling of hollow fiber membranes with electrospray ionization mass spectrometry for continuous affinity selection, concentration and identification of small-molecule libraries.

Combinatorial chemistry has been widely employed in the pharmaceutical industry in the effort towards drug discovery. Rapid and sensitive screening of lead candidates among library compounds has thus imposed significant analytical challenges in recent years. This work involved the development of a continuous affinity capture and concentration system, providing cost-effective and structural analysis of drug candidates in a flow-through format. The system combines the strengths of a hollow fiber dialysis membrane of ease and speed of purification and concentration with the specificity of affinity interactions in solution. The complexes between the lead compounds and the affinity binding proteins are separated from other chemical components inside a dialysis hollow fiber as the result of their differences in size. The affinity complexes are further concentrated inside a second dialysis fiber. The concentrated drug candidates are liberated from the binding proteins in a microdialysis junction and can be directly identified using electrospray ionization mass spectrometry. Two model systems, including human serum albumin-warfarin-related compounds and anti-phenobarbital antibody-barbiturates, were employed for mechanistic studies of dialysis versus dissociation kinetics and competitive selection of drug candidates according to their binding strengths.

A fluorescence affinity hollow fiber sensor for continuous transdermal glucose monitoring.

A novel concept of a fluorescence affinity hollow fiber sensor for transdermal glucose monitoring is demonstrated. The glucose-sensing principle is based on the competitive reversible binding of a mobile fluorophore-labeled Concanavalin A (Con A) to immobile pendant glucose moites inside of intensely colored Sephadex beads. The highly porous beads (molecular weight cutoff of 200 kDa) were colored with two red dyes, Safranin O and Pararosanilin, selected to block the excitation and spectrum of the fluorophore Alexa488. The sensor consists of the dyed beads and Alexa488-Con A confined inside a sealed, small segment of a hollow fiber dialysis membrane (diameter 0.5 mm, length 0.5 cm, molecular weight cutoff 10 kDa). In the absence of glucose, the majority of Alexa488-Con A resides inside the colored beads bound to fixed glucose. Thus, excitation light at 490 nm impinging on the sensor is strongly absorbed by the dyes, resulting in a drastically reduced fluorescence emission at 520 nm from the Alexa488-Con A residing within the beads. However, when the hollow fiber sensor is exposed to glucose, glucose diffuses through the membrane into the sensor chamber and competitively displaces Alexa 488-Con A molecules from the glucose residues of the Sephadex beads. Thus, Alexa 488-Con A appears in the void space outside of the beads and is fully exposed to the excitation light, and a strong increase in fluorescence emission at 520 nm is measured. At a medium to high loading degree of Sephadex with Alexa488-Con A (10 mg mL(-1) bead suspension), the absolute fluorescence increase due to 20 mM glucose was very large. It exceeded the response of other sensor devices based on FRET by a factor of 50 (Meadows and Schultz Anal. Chim. Acta 1993, 280, 21-30; Russell et al. Anal. Chem. 1999, 71, 3126-3132). The new sensor featured a glucose detection range extending from 0.15 to 100 mM, exhibiting the strongest dynamic signal change from 0.2 to 30 mM. It showed a reasonably fast response time (4-5 min). The combination of all the beneficial sensor features makes this sensor extremely attractive for future in vivo implantation studies for glucose monitoring in subdermal tissue.