Erik Johannessen

Toward an Injectable Continuous Osmotic Glucose Sensor

Background: The growing pandemic of diabetes mellitus places a stringent social and economic burden on the society. A tight glycemic control circumvents the detrimental effects, but the prerogative is the development of new more effective tools capable of longterm tracking of blood glucose (BG) in vivo. Such discontinuous sensor technologies will benefit from an unprecedented marked potential as well as reducing the current life expectancy gap of eight years as part of a therapeutic regime. Method: A sensor technology based on osmotic pressure incorporates a reversible competitive affinity assay performing glucose-specific recognition. An absolute change in particles generates a pressure that is proportional to the glucose concentration. An integrated pressure transducer and components developed from the silicon micro- and nanofabrication industry translate this pressure into BG data. Results: An in vitro model based on a 3.6 × 8.7 mm large pill-shaped implant is equipped with a nanoporous membrane holding 4–6 nm large pores. The affinity assay offers a dynamic range of 36–720 mg/dl with a resolution of ±16 mg/dl. An integrated 1 × 1 mm2 large control chip samples the sensor signals for data processing and transmission back to the reader at a total power consumption of 76 μW. Conclusions: Current studies have demonstrated the design, layout, and performance of a prototype osmotic sensor in vitro using an affinity assay solution for up to four weeks. The small physical size conforms to an injectable device, forming the basis of a conceptual monitor that offers a tight glycemic control of BG.

Analog to interval encoder with active use of gate leakage for an implanted blood-sugar sensor

We have developed an ultra low power integrated circuit control module that will be incorporated into a micro machined pill-sized medical implant that continuously monitors blood-sugar levels for patients with Diabetes mellitus. The circuit converts a piezoresistive sensor signal to an inter-pulse interval suited for digital transmission through a wire-less inductive link. Instead of a full analog-to-digital conversion, this analog-to-analog conversion is much simpler and more power conservative. The circuit is entirely asynchronous, requiring no energy consuming clock and operates on sub-threshold currents. A first prototype, produced with the STM 90 nm CMOS process, consumes 1.7muW. A compact on-chip resistive element is employed in a feedback loop to cancel 1/f-noise and offsets in both the sensor and the initial amplification stage. The resistive element is implemented using the quantum effect of gate-leakage, achieving an equivalent resistance of several GOmega with minimal consumption of layout space. The effectiveness of this noise reduction has been asserted in a 62 hour recording with fixed input. The measured noise spectrum appears completely white down to the minimal frequency of the recording, i.e. 4.5muHz. The standard deviation of single pulse intervals (dynamic range from 4.3ms to 15.4 ms) restricts the reconstruction of the sensor value to an accuracy equivalent to 4.41 bits. Averaging over the samples during 1 second increases this accuracy to 7.84 bits. Longer averaging will further improve that figure at the cost of longer periods of active power consumption of the implant, which will be woken up only once every 5 minutes.

Inflammatory response induced by candidate biomaterials of an implantable microfabricated sensor

The implantation of synthetic medical devices is known to generate an immediate and complex material-related inflammatory response. Consequently, 15 candidate materials for a new microfabricated sensor were investigated. A human whole blood model that permits the interaction of all the putative inflammatory systems was used. The experiments were performed by administering 500 μL of lepirudin-anticoagulated blood in each well of a 24-well polystyrene microtiter plate preloaded with the respective materials. The degree of inflammation was evaluated by assessing four complement activation markers, six proinflammatory cytokines, and chemokines, the expression of monocyte tissue factor (TF), as well as platelet activation. The complement system was inhibited with the C5-inhibitor eculizumab. Three of the materials distinctly activated complement through the alternative pathway, whereas the rest of the materials were virtually inert. Notably, the same three materials induced a marked and selective expression of TF as well as the release of five of the six cytokines. All these increases were statistically significant (p < 0.05). Inhibition of complement by the C5-inhibitor virtually abolished TF expression and markedly reduced several of the cytokines, suggesting that complement is a particularly useful tool to reveal the immediate inflammatory-inducing properties of these biomaterials.

Complement activation by candidate biomaterials of an implantable microfabricated medical device

Implantable devices realized by microfabrication have introduced a new class of potential biomaterials whose properties would need to be assessed. Such devices include sensors for measuring biological substances like glucose. Thus, 14 different candidate materials intended for design of such a device were investigated with respect to their complement activation potential in human serum. The fluid-phase activation was measured by the products C4d, Bb, C3bc, and the terminal complement complex (TCC), whereas solid-phase activation was measured by deposition of TCC on the material surfaces. No fluid-phase activation was found for materials related to the capsule, carrier, or sealing. Fluid-phase activation was, however, triggered to a various extent in three of the four nanoporous membranes (cellulose, polyamide, and aluminium oxide), whereas polycarbonate was rendered inactive. Solid-phase activation discriminated more sensitively between all the materials, revealing that the capsule candidate polydimethylsiloxane and sealing candidate silicone 3140 were highly compatible, showing significantly lower TCC deposition than the negative control (p < 0.01). Three of the candidate materials were indifferent, whereas the remaining nine showed significantly higher deposition of TCC than the negative control (p < 0.01). In conclusion, complement activation, in particular when examined on the solid phase, discriminated well between the different candidate materials tested and could be used as a guide for the selection of the best-suited materials for further investigation and development of the device.

Activation of Polymorphonuclear Leukocytes by Candidate Biomaterials for an Implantable Glucose Sensor

Background: Continuous monitoring of glucose by implantable microfabricated devices offers key advantages over current transcutaneous glucose sensors that limit usability due to their obtrusive nature and risk of infection. A successful sensory implant should be biocompatible and retain long-lasting function. Polymorphonuclear leukocytes (PMN) play a key role in the inflammatory system by releasing enzymes, cytokines, and reactive oxygen species, typically as a response to complement activation. The aim of this study was to perform an in vitro analysis of PMN activation as a marker for biocompatibility of materials and to evaluate the role of complement in the activation of PMN. Methods: Fifteen candidate materials of an implantable glucose sensor were incubated in lepirudin-anticoagulated whole blood. The cluster of differentiation molecule 11b (CD11b) expression on PMN was analyzed with flow cytometry and the myeloperoxidase (MPO) concentration in plasma was analyzed with enzyme-linked immunosorbent assay. Complement activation was prevented by the C3 inhibitor compstatin or the C5 inhibitor eculizumab. Results: Three of the biomaterials (cellulose ester, polyamide reverse osmosis membrane, and polyamide thin film membrane), all belonging to the membrane group, induced a substantial and significant increase in CD11b expression and MPO release. The changes were virtually identical for these two markers. Inhibition of complement with compstatin or eculizumab reduced the CD11b expression and MPO release dose dependently and in most cases back to baseline. The other 12 materials did not induce significant PMN activation. Conclusion: Three of the 15 candidate materials triggered PMN activation in a complement-dependent manner and should therefore be avoided for implementation in implantable microsensors.

Activation of coagulation and platelets by candidate membranes of implantable devices in a whole blood model without soluble anticoagulant.

Implantable devices are challenged with thrombus formation at their biomaterial interface. Thus the importance of identifying compatible biomaterials that will help to improve the performance of these devices are becoming increasingly paramount. The aim of this study was to evaluate the activation of coagulation and platelets by candidate membranes considered for use in implantable devices on the basis of an adapted whole blood model without soluble anticoagulants. Evaluated materials were incubated with whole blood without soluble anticoagulant in wells coated with heparin. Prothrombin fragment 1+2 (PTF 1+2), thrombin-antithrombin complex (TAT), and β-thromboglobulin (BTG) were analyzed in plasma samples using enzyme immunoassays. The C5 inhibitor eculizumab was used to evaluate the role of complement. Incubation of two of the polyamide membranes PAR and PATF led to an increase in concentration of PTF 1+2 and TAT (p < 0.01 for PAR, ns for PATF). The BTG concentration was significantly increased for five materials [PAR, PATF, polycarbonate (PC), and two polyarylethersulphone membranes PAES-1 and PAES-2]. Complement inhibition had no effect on coagulation or platelet activation induced by PAR and PATF. In conclusion, PAR and PATF were not compatible with blood and should be avoided for use in implantable devices.

The assessment of potentially interfering metabolites and dietary components in blood using an osmotic glucose sensor based on the concanavalin A-dextran affinity assay.

Continuous surveillance of blood glucose is a prerogative of maintaining a tight glycaemic control in people suffering from diabetes mellitus. Implantable sensor technology offers the potential of conducting direct long term continuous glucose measurements, but current size restrictions and operational challenges have limited their applications. The osmotic sensor utilises diffusion to create a hydrostatic pressure that is independent of sensor operation and power consumption. This permits ultra-low power architectures to be realized with a minimal start-up time in a package suitable for miniaturization. In contrast, osmotic sensors suffer from the inability of their membranes to discriminate between different constituents in blood or the interstitial fluid that are of comparable size to glucose. By implementing an affinity assay based on the competitive bonding between concanavalin A and dextran, the selectivity of the membrane can be transferred to the glucose specific recognition of the affinity assay. The osmotic effect from the physiological levels of several key metabolites and nutritional components has been addressed identifying in particular ethanol, lactate and amino acids as potential interfering constituents. Both ascorbic acid and mannose would have a normal physiological concentration that is too low to be detected. The studies shows that an osmotic glucose sensor equipped with the con A-dextran affinity assay, is able to filter out potential interfering constituents present in blood, plasma and the interstitial fluid yet retaining a pressure that is proportional to glucose only.

Low power integrated electronics system for the operation of a miniaturized hydration sensor

The application of MEMS devices with integrated electronics are paving the way for a new generation of miniaturized biomedical sensors with the potential of monitoring physiological parameters in the body. This article presents an application-specific integrated circuit (ASIC) that has been designed for integration in a biomedical sensor capable of detecting events associated with the dehydration and overhydration in the body and presents measurement results from a sensor prototype. The sensor converts the hydration level into an osmotic pressure which in turn is translated into a frequency modulated asynchronous digital signal with a 5.71 bit resolution (ENOB). The ASIC was designed and fabricated using the TSMC90nm CMOS processing technology and is based on a low power architecture with a simulated power consumption of 39.4 μW. The circuit layout has a footprint of 565×265 μm2 and the linear temperature dependent node of the voltage bandgap reference is used to monitor the temperature.

Design and Characterization of an Osmotic Sensor for the Detection of Events Associated With Dehydration and Overhydration

The level of hydration in the human body is carefully adjusted to control the electrolyte balance that governs the biochemical processes that sustain life. An electrolyte deficiency caused by de- or overhydration will not only limit human performance, but can also lead to serious health problems and death if left untreated. Because humans can withstand a change in hydration of only ±20%, frequent monitoring should be performed in risk groups. This paper presents an osmotic hydration sensor that can record the level of hydration as a function of osmotic pressure in phosphate buffered saline or sodium-chloride solutions that simulate the interstitial fluid in the body. The osmotic pressure is recorded with the aid of an ion-exchange membrane that facilitates the migration of water and cations, in favor of reverse osmosis or gas separation membranes. The hydration sensor is designed to be coupled to an inductively powered readout circuit designed for integration in a micro-implant that has previously been shown to consume only 76 μW of power. The dynamic range spans a state of serious overhydration (220 mOsm L-1) to a serious state of dehydration (340 mOsm L-1) with a response time of ~ 7 h (for a variation of hydration of 20%).

An Osmotic Pressure Sensor for Monitoring the Level of Hydration in Biological Fluids

A miniaturized hydration sensor that records the electrolyte balance in biological fluids and that translates this quantity into an osmotic pressure signal has been developed. The sensor measures 16 mm x 8 mm and integrates a semipermeable membrane, a piezoresistive pressure transducer, and an electronic readout platform. The dynamic measurement range of 220-340 mOsm L-1 (280 ± 60 mOsm L-1) covers a serious state of dehydration to a serious state of overhydration (represented by a Ahydration = ±20%). Ion exchange membranes were found to be the best candidates for integration with the hydration sensor. Reverse osmosis membranes with physical pores (zero Da molecular cutoff) had high ionic leakage rates, in contrast to gas permeable membranes, which proved to be almost impermeable to water vapor. Consequently, the use of a Nafion NR211 membrane facilitated a sensor response with a time constant of 2.5 h, which conforms to the slow change in osmotic pressure associated with hydration. The low-power front-end circuit architecture is based on an analog pressure-to-frequency converter, consuming only 39.4 μW, and capable of recording changes in hydration with a resolution of 5.71 bits (ENOBSNR). The small size of the sensor components, combined with the interface low-power architecture, renders it suitable for further miniaturization required for implantation into the human body.