Implantable sensors for continuous glucose monitoring hold great potential for optimal diabetes management. This is often undermined by a variety of issues associated with: (1) negative tissue response; (2) poor sensor performance; and (3) lack of device miniaturization needed to reduce implantation trauma. Herein, we report our initial results towards constructing an implantable device that simultaneously address all three aforementioned issues. In terms of device miniaturization, a highly miniaturized CMOS (complementary metal-oxide-semiconductor) potentiostat and signal processing unit was employed (with a combined area of 0.665 mm2). The signal processing unit converts the current generated by a transcutaneous, Clark-type amperometric sensor to output frequency in a linear fashion. The Clark-type amperometric sensor employs stratification of five functional layers to attain a well-balanced mass transfer which in turn yields a linear sensor response from 0 to 25 mM of glucose concentration, well beyond the physiologically observed (2 to 22 mM) range. In addition, it is coated with a thick polyvinyl alcohol (PVA) hydrogel with embedded poly(lactic-co-glycolic acid) (PLGA) microspheres intended to provide continuous, localized delivery of dexamethasone to suppress inflammation and fibrosis. In vivo evaluation in rat model has shown that the transcutaneous sensor system reproducibly tracks repeated glycemic events. Clarke’s error grid analysis on the as –obtained glycemic data has indicated that all of the measured glucose readings fell in the desired Zones A & B and none fell in the erroneous Zones C, D and E. Such reproducible operation of the transcutaneous sensor system, together with low power (140 μW) consumption and capability for current-to-frequency conversion renders this a versatile platform for continuous glucose monitoring and other biomedical sensing devices.

The performance of implantable electrochemical glucose sensors is highly dependent on the flux-limiting (glucose, H2O2, O2) properties of their outer membranes. A careful understanding of the diffusion profiles of the participating species throughout the sensor architecture (enzyme and membrane layer) plays a crucial role in designing a robust sensor for both in vitro and in vivo operation. This paper reports the results from the mathematical modeling of Clark's first generation amperometric glucose sensor coated with layer-by-layer assembled outer membranes in order to obtain and compare the diffusion profiles of various participating species and their effect on sensor performance. Devices coated with highly glucose permeable (HAs/Fe3+) membranes were compared with devices coated with PSS/PDDA membranes, which have an order of magnitude lower permeability. The simulation showed that the low glucose permeable membrane (PSS/PDDA) sensors exhibited a 27% higher amperometric response than the high glucose permeable (HAs/Fe3+) sensors. Upon closer inspection of H2O2 diffusion profiles, this non-typical higher response from PSS/PDDA is not due to either a larger glucose flux or comparatively larger O2 concentrations within the sensor geometry, but rather is attributed to a 48% higher H2O2 concentration in the glucose oxidase enzyme layer of PSS/PDDA coated sensors as compared to HAs/Fe3+ coated ones. These simulated results corroborate our experimental findings reported previously. The high concentration of H2O2 in the PSS/PDDA coated sensors is due to the low permeability of H2O2 through the PSS/PDDA membrane, which also led to an undesired increase in sensor response time. Additionally, it was found that this phenomenon occurs for all enzyme thicknesses investigated (15, 20 and 25 nm), signifying the need for a holistic approach in designing outer membranes for amperometric biosensors.

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This paper presents the design and fabrication of a wireless, highly miniaturized, low-power electrochemical pH sensing system employing complementary metal-oxidesemiconductor (CMOS) electronics. Since plasma pH readings directly correlate to carbon dioxide levels present in the human body, this paper holds great promise for continuous monitoring of carbon dioxide in totally implantable device applications. In this paper, we have integrated a CMOS voltage controlled oscillator, which consumes only 120 µW of power and occupies an area of 0.045 mm 2 , together with a miniature electrochemical pH sensor which detects real-time changes in pH levels. The fabricated sensor employs an electropolymerized poly(o-phenylenediamine) layer atop a platinum working electrode which yields linear operation well above and below the physiological pH range of 7.38-7.42, with sensitivities as high as 56 mV/pH. In turn, the fabricated CMOS electronics convert the voltage generated by the sensor to output frequency pulses in a linear fashion. Furthermore, a wireless transmission link was designed which broadcasts the resulting sensor data to a computer which displays real-time continuous pH readings. The miniature footprint of both the sensor and electronics, together with its low power consumption, renders this a versatile platform for facile carbon dioxide monitoring and other metabolic sensing systems.

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The design and fabrication of multi-layer amperometric electrochemical glucose sensors is dependent upon the diffusional kinetics of the chemical/biochemical species which contribute to the sensor’s response. Considerable effort has been carried out to coat the working electrode with appropriate glucose flux-limiting membranes which is pertinent for superior in vivo performance, and hence requires a careful understanding of the participating species within the sensor cross-sectional architecture. This contribution reports the computational modeling of Clark’s first generation amperometric glucose sensor coated with an electro-polymerized glucose oxidase (GOx) layer along with a layer of polyurethane (PU) employed to reduce the glucose-influx in order to generate linear operation over the normal physiological glucose range in vivo. The model was programmed using MATLAB and utilizes the finite-difference method for the solution to the enzymatic reaction-based diffusion equations. Additionally, experimental devices were fabricated, tested and compared with the simulated results. The simulation of these devices have been shown to align well with experimentally fabricated devices in terms of amperometric current density. The increase in device linearity with the addition of the outer glucose-flux limiting PU membrane corroborate our experimental findings reported in this study which can be used as a powerful analytical tool in designing high–performance next generation implantable glucose sensors.

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