Portable glucose sensors with an accurate and longterm stable in vivo function have been in demand for several decades because such devices are of strategic importance in the diagnosis and treatment of diabetes mellitus [1±3]. Despite remarkable progress, the development of new and improvement of existing prototypes is desirable.Efforts have focused on transdermal glucose sensors because the glucose concentrations of capillary blood and interstitial liquid of the subcutaneous tissue are closely related [4±8]. These sensors measure the glucose concentration either after electroosmotic transfer of the interstitial liquid to the skin surface [9] or by a microsensor implanted into the subcutaneous tissue. Most work has been carried out using needle-like transdermal amperometric sensors with immobilised glucose oxidase (GOD) [10±18]. To render the highly sensitive and oxygen-dependent enzyme reaction glucose-limited, the immobilised enzyme is usually covered by a membrane that is less Diabetologia (2001) Abstract Aims/hypothesis. To provide a nonenzymatic sensor for glucose monitoring in subcutaneous tissue. Methods. A continuously working affinity sensor based on the glucose-dependent viscosity of a sensitive liquid containing dextran and concanavalin A has been designed by arranging a microdialysis probe, two flow-resisting capillaries and two pressure transducers in a linear flow system. It allows synchronous processing of the viscosity of the sensitive liquid at the standard glucose concentration and the glucose concentration to be measured. In preliminary human trials the sensor was implanted into the subcutaneous tissue of the forearm and its read-out was compared with capillary blood concentrations.Results. In vitro, the viscometric sensor shows a linear and long-term stable dependence on the glucose concentration without detectable drift. At the applied flow rate of the sensitive liquid (about 5 ml/h) the technical delay is 5 to 10 min. The read-out of the implanted sensor followed the dynamics of the capillary blood glucose concentrations with a time-shift of 10 to 15 min but showed a systematic error when based on precalibration with polymer-free glucose solutions. After appropriate in vivo calibration, the readout was in good or acceptable coincidence with capillary blood concentrations according to the error grid method and did not show any detectable reduction of sensitivity during the periods of measurement (up to 44 h). Conclusion/interpretion. The viscometric-affinity sensor is an efficient tool for current research on glucose monitoring in the subcutaneous tissue and can potentially be further developed for routine clinical use.[ Diabetologia (2001) 44: 416±423]

The performance of the viscometric affinity sensor shows the potential of the measuring principle under in vivo conditions. Forearm and abdomen seem to be similarly well suited for the application of subcutaneous sensors. The signal stability over time and the absence of enzymatic, chemical, or electrode reactions are advantages of the viscometric affinity principle.

A viscometer suitable for rapid measurements in small volumes of highly viscous liquids is described. Using this device the viscometric affinity assay for glucose was studied under variable conditions in order to obtain basic information for the design of a viscometric glucose sensor. The viscosity of the dextran/Concanavalin A (ConA) solution is sensitive to glucose in a broad range of the shear stress. However, for measuring the glucose concentration with this sensitive liquid the strong dependence of the absolute viscosity on temperature and ConA concentration has to be taken into account. For the purpose of calibration a parameter more suitable than the absolute viscosity is the relative fluidity (F(r)) that is defined by the actual measured viscosity at a given glucose concentration, the reference viscosity at a standard glucose concentration, and a constant linearization coefficient. F(r) shows a linear dependence on the glucose concentration in the therapeutically interesting range up to 30 mM and is not significantly changed by moderate variations of the ConA concentration or temperature.

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Glucose-dependent low-stress and high-stress rheology of a sensitive fluid (SF) containing high-molecular-weight dextran (30 g/L) and Concanavalin A (ConA, 10 g/L) was studied to define conditions for reproducible glucose determination by a viscosimetric sensor. The viscosity of the investigated SF was reproducibly glucose-dependent only at sufficient shear stresses (>0.5 Pa). Rheometric parameters measured at low stresses (<0.1 Pa) were strongly dependent on the shear history. Low-stress viscosity measured after laminar flow with a high rate (90 s, 100 s -1 , 4.5 Pa) increased by more than 2 orders of magnitude with slow kinetics. Solutions thickened after laminar flow acquired gel-like properties (storage modulus nearly equal to loss modulus in a broad range of frequencies). The highly viscous and gel-like state developed after flow was stable up to a yield stress of ca. 0.05 Pa. The ConA-mediated contribution to high-stress viscosity was almost completely suppressed by the presence of glucose (100 mM), whereas thickening after flow was rather insensitive to the competing sugar. Interaction of diffusion-controlled ligand exchange at the ConA binding sites with convective displacement of dextran molecules has been considered a main reason for the observed thickening effect. It is proposed that the shear field has an orientating effect on lectin distribution in the dextran matrix, whereby far-reaching lamellar affinity clusters are developed. In the subsequently unloaded fluid, residues of these structures can reorientate and be cross-linked to a weak metastable gel by redistributing ConA.