Background:
An anti-inflammatory drug-loaded composite coating (dexamethasone-loaded poly (lactic-co-glycolic acid) PLGA microspheres/polyvinyl alcohol PVA hydrogel) was previously developed to ...counter the foreign body reaction to a fully implantable continuous glucose monitoring biosensor. The long-term sensor functionality was ensured in the presence of the drug-loaded composite coating thus facilitating better diabetes control and management. In order to advance such a drug-device combination product toward clinical testing, addressing sterilization remains a key step due to the heterogeneity of the product components. The main objective of this research was to investigate the effect of two terminal sterilization techniques: gamma radiation and ethylene oxide (EO) on the stability of the anti-inflammatory coatings as well as retention of the glucose sensing ability of the implantable sensor.
Method:
The composite coatings, their individual components, and the glucose-sensing elements of the biosensor were subjected to low-temperature gamma radiation and EO cycles. Detailed characterization was conducted on all components before and after sterilization.
Results:
Exposure to gamma radiation affected dexamethasone crystallinity and glucose response linearity of the sensing element, whereas physical aging of microspheres in composite coatings was observed poststerilization with EO. Despite these effects, dexamethasone drug release from coatings was not significantly affected by either technique.
Conclusion:
The research findings indicate that both sterilization techniques are feasible for the sterilization of the dexamethasone-loaded PLGA microspheres/PVA hydrogel composite coatings, while EO was preferred for the sterilization of the glucose-sensing element of the biosensor.
Background:
The objective of this work is to develop a highly miniaturized, low-power, biosensing platform for continuous glucose monitoring (CGM). This platform is based on an application-specific ...integrated circuit (ASIC) chip that interfaces with an amperometric glucose-sensing element. To reduce both size and power requirements, this custom ASIC chip was implemented using 65-nm complementary metal oxide semiconductor (CMOS) technology node. Interfacing this chip to a frequency-counting microprocessor with storage capabilities, a miniaturized transcutaneous CGM system can be constructed for small laboratory animals, with long battery life.
Method:
A 0.45 mm × 1.12 mm custom ASIC chip was first designed and implemented using the Taiwan Semiconductor Manufacturing Company (TSMC) 65-nm CMOS technology node. This ASIC chip was then interfaced with a multi-layer amperometric glucose-sensing element and a frequency-counting microprocessor with storage capabilities. Variation in glucose levels generates a linear increase in frequency response of this ASIC chip. In vivo experiments were conducted in healthy Sprague Dawley rats.
Results:
This highly miniaturized, 65-nm custom ASIC chip has an overall power consumption of circa 36 µW. In vitro testing shows that this ASIC chip produces a linear (R2 = 99.5) frequency response to varying glucose levels (from 2 to 25 mM), with a sensitivity of 1278 Hz/mM. In vivo testing in unrestrained healthy rats demonstrated long-term CGM (six days/per charge) with rapid glucose response to glycemic variations induced by isoflurane anesthesia and tail vein injection.
Conclusions:
The miniature footprint of the biosensor platform, together with its low-power consumption, renders this CMOS ASIC chip a versatile platform for a variety of highly miniaturized devices, intended to improve the quality of life of patients with type 1 and type 2 diabetes.
This paper presents the design and fabrication of a wireless, highly miniaturized, low-power electrochemical pH sensing system employing complementary metal-oxide- semiconductor (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.
Development of electrochemical sensors for continuous glucose monitoring is currently hindered by a variety of problems associated with low selectivity, low sensitivity, narrow linearities, delayed ...response times, hysteresis, biofouling, and tissue inflammation. We present an optimized sensor architecture based on layer stratification, which provides solutions that help address the aforementioned issues.
The working electrode of the electrochemical glucose sensors is sequentially coated with five layers containing: (1) electropolymerized polyphenol (PPh), (2) glutaraldehyde-immobilized glucose oxidase (GOx) enzyme, (3) dip-coated polyurethane (PU), (4) glutaraldehyde-immobilized catalase enzyme, and (5) a physically cross linked polyvinyl alcohol (PVA) hydrogel membrane. The response of these sensors to glucose and electroactive interference agents (i.e., acetaminophen) was investigated following application of the various layers. Sensor hysteresis (i.e., the difference in current for a particular glucose concentration during ascending and descending cycles after 200 s) was also investigated.
The inner PPh membrane improved sensor selectivity via elimination of electrochemical interferences, while the third PU layer afforded high linearity by decreasing the glucose-to-O2 ratio. The fourth catalase layer improved sensor response time and eliminated hysteresis through active withdrawal of GOx-generated H2O2 from the inner sensory compartments. The outer PVA hydrogel provided mechanical support and a continuous pathway for diffusion of various participating species while acting as a host matrix for drug-eluting microspheres.
Optimal sensor performance has been achieved through a five-layer stratification, where each coating layer works complementarily with the others. The versatility of the sensor design together with the ease of fabrication renders it a powerful tool for continuous glucose monitoring.
Needle-implantable sensors have shown to provide reliable continuous glucose monitoring for diabetes management. In order to reduce tissue injury during sensor implantation, there is a constant need ...for device size reduction, which imposes challenges in terms of sensitivity and reliability, as part of decreasing signal-to-noise and increasing layer complexity. Herein, we report sensitivity enhancement via electrochemical surface rebuilding of the working electrode (WE), which creates a three-dimensional nanoporous configuration with increased surface area.
The gold WE was electrochemically rebuilt to render its surface nanoporous followed by decoration with platinum nanoparticles. The efficacy of such process was studied using sensor sensitivity against hydrogen peroxide (H2O2). For glucose detection, the WE was further coated with five layers, namely, (1) polyphenol, (2) glucose oxidase, (3) polyurethane, (4) catalase, and (5) dexamethasone-releasing poly(vinyl alcohol)/poly(lactic-co-glycolic acid) composite. The amperometric response of the glucose sensor was noted in vitro and in vivo.
Scanning electron microscopy revealed that electrochemical rebuilding of the WE produced a nanoporous morphology that resulted in a 20-fold enhancement in H2O2 sensitivity, while retaining >98% selectivity. This afforded a 4-5-fold increase in overall glucose response of the glucose sensor when compared with a control sensor with no surface rebuilding and fittable only within an 18 G needle. The sensor was able to reproducibly track in vivo glycemic events, despite the large background currents typically encountered during animal testing.
Enhanced sensor performance in terms of sensitivity and large signal-to-noise ratio has been attained via electrochemical rebuilding of the WE. This approach also bypasses the need for conventional and nanostructured mediators currently employed to enhance sensor performance.
Nanopatterning as a surface area enhancement method has the potential to increase signal and sensitivity of biosensors. Platinum-based bulk metallic glass (Pt-BMG) is a biocompatible material with ...electrical properties conducive for biosensor electrode applications, which can be processed in air at comparably low temperatures to produce nonrandom topography at the nanoscale. Work presented here employs nanopatterned Pt-BMG electrodes functionalized with glucose oxidase enzyme to explore the impact of nonrandom and highly reproducible nanoscale surface area enhancement on glucose biosensor performance. Electrochemical measurements including cyclic voltammetry (CV) and amperometric voltammetry (AV) were completed to compare the performance of 200 nm Pt-BMG electrodes vs Flat Pt-BMG control electrodes. Glucose dosing response was studied in a range of 2 mM to 10 mM. Effective current density dynamic range for the 200 nm Pt-BMG was 10–12 times greater than that of the Flat BMG control. Nanopatterned electrode sensitivity was measured to be 3.28 μA/cm2/mM, which was also an order of magnitude greater than the flat electrode. These results suggest that nonrandom nanotopography is a scalable and customizable engineering tool which can be integrated with Pt-BMGs to produce biocompatible biosensors with enhanced signal and sensitivity.
The aim of this work is to realize a needle implantable biosensor for continuous monitoring of interstitial glucose levels. A highly miniaturized application specific integrated circuit (ASIC) is ...designed using 130 nm standard CMOS technology and combined with a glucose biosensor to produce a frequency signal proportional to the glucose concentration level. A prototype system incorporating an on-chip amperometric potentiostat and a signal processing unit (SPU) is designed and implemented to amperiometrically assess the performance of the biosensor in term of measurement of glucose values. This prototype system demonstrated measurement of a wide current range from 1 nA to 10 µA with the output read-out exhibiting linearity higher than 99%. The realized system is optimized with small physical footprint occupying a 1.5 mm × 0.439 mm die and maximum power consumption of about 80 µW.
Unlike non-invasive and minimally invasive continuous monitoring of glucose (CGM) devices, invasive devices require less rigorous calibration and exhibit smaller subject-to-subject variability. ...Biorasis, Inc. and the University of Connecticut are developing a totally implantable CGM device. Glucowizzard™ is engineered at the smallest possible footprint (0.5 × 0.5 × 5 mm). This miniaturization is made possible by utilizing light both for powering and wireless communication. In addition, Glucowizzard™ utilizes "smart" hydrogel coatings intended for localized release of various tissue response modifiers for effective control of negative tissue responses. The use of light-based powering and communication together with advanced microelectronic design rules has allowed the fabrication of truly miniaturized CGM device. The drug delivery coating has enabled substantial reduction of negative tissue responses for up to 1 month in small as well as large animals (rats and minipigs). The functionality of Glucowizzard™ has been demonstrated in vivo in both rats and minipigs.
This paper presents the design and fabrication of a highly-miniaturized system for continuous glucose monitoring which holds great promise for patients inflicted with diabetes mellitus. To achieve ...the realization of a truly implantable system, a variety of issues such as robust electrochemical sensor design, miniaturization of the electronic components and counteracting biofouling and negative tissue response need to be addressed. In this report, we present a highly-miniaturized transcutaneous continuous glucose monitoring system which holistically addresses the aforementioned tribulations associated with implantable devices. Specifically, a high performance amperometric electrochemical glucose sensor is integrated with custom designed complementary metal-oxide-semiconductor electronics. The fabricated electrochemical sensor is Clark-based, and employs stratification of five functional layers to achieve a linear response within the physiological range of glucose concentration (2-22 mM). Furthermore, the sensor is encased with a thick polyvinyl alcohol (PVA) hydrogel containing poly(lactic-co-glycolic acid) (PLGA) microspheres which provides continuous, localized delivery of dexamethasone utilized to combat inflammation and fibrosis. Such miniature size (0.665 mm 2 ) and low power operation (140 μW) of the electronic system render it ideal for continuous glucose monitoring devices and other metabolic sensing systems.
This paper presents the design and implementation of highly-miniaturized, low-power CMOS signal conditioning schemes intended for use in a totally implantable biomedical sensor platform. Due to the ...thrust for the development implantable biomedical sensing systems for health management and disease prevention, there exists a need for signal processing schemes which occupy very little on-chip real estate and consume negligible amounts of power. In light of this, this paper presents both a CMOS current-to-frequency converter and voltage-to-frequency converter which have been designed primarily for use in implantable biosensing platforms and applications. Such designs can be implemented in stand-alone single sensor designs, or in tandem to create multi-analyte architectures. The versatility of employing current-to-frequency as well as voltage-to-frequency signal transduction schemes presents an avenue for the integration with any electrochemical sensing element which has been fabricated in an amperometric or voltammetric fashion. Furthermore, we demonstrate the efficacy of both these circuit designs by integrating them together with high performance electrochemical implantable glucose and pH sensors. The low power consumption and miniature size of the amperometric and voltammetric signal processing units (0.25 mm 2 and 18 μW / 0.045 mm 2 and 122 μW, respectively) presents an ideal design for signal processing in implantable continuous metabolic monitoring devices.
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