Affinity-based turbidity sensor for glucose monitoring by optical coherence tomography: toward the development of an implantable sensor.
ABSTRACT We investigated the feasibility of constructing an implantable optical-based sensor for seminoninvasive continuous monitoring of analytes. In this novel sensor, analyte concentration-dependent changes induced in the degree of optical turbidity of the sensing element can be accurately monitored by optical coherence tomography (OCT), an interferometric technique. To demonstrate proof-of-concept, we engineered a sensor for monitoring glucose concentration that enabled us to quantitatively monitor the glucose-specific changes induced in bulk scattering (turbidity) of the sensor. The sensor consists of a glucose-permeable membrane housing that contains a suspension of macroporous hydrogel particles and concanavalin A (ConA), a glucose-specific lectin, that are designed to alter the optical scattering of the sensor as a function of glucose concentration. The mechanism of modulation of bulk turbidity in the sensor is based on glucose-specific affinity binding of ConA to pendant glucose residues of macroporous hydrogel particles. The affinity-based modulation of the scattering coefficient was significantly enhanced by optimizing particle size, particle size distribution, and ConA concentration. Successful operation of the sensor was demonstrated under in vitro condition where excellent reversibility and stability (160 days) of prototype sensors with good overall response over the physiological glucose concentration range (2.5-20 mM) and good accuracy (standard deviation 5%) were observed. Furthermore, to assess the feasibility of using the novel sensor as one that can be implanted under skin, the sensor was covered by a 0.4 mm thick tissue phantom where it was demonstrable that the response of the sensor to 10 mM glucose change could still be measured in the presence of a layer of tissue shielding the sensor aiming to simulate in vivo condition. In summary, we have demonstrated that it is feasible to develop an affinity-based turbidity sensor that can exhibit a highly specific optical response as a function of changes in local glucose concentration and such response can be accurately monitored by OCT suggesting that the novel sensor can potentially be engineered to be used as an implantable sensor for in vivo monitoring of analytes.
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ABSTRACT: In this paper, we describe the concept of a novel implantable fiber-optic Turbidity Affinity Sensor (TAS) and report on the findings of its in-vitro performance for continuous glucose monitoring. The sensing mechanism of the TAS is based on glucose-specific changes in light scattering (turbidity) of a hydrogel suspension consisting of small particles made of crosslinked dextran (Sephadex G100), and a glucose- and mannose-specific binding protein - Concanavalin A (ConA). The binding of ConA to Sephadex particles results in a significant turbidity increase that is much greater than the turbidity contribution by the individual components. The turbidity of the TAS was measured by determining the intensity of light passing through the suspension enclosed within a small semi-permeable hollow fiber (OD: 220μm, membrane thickness: 20μm, molecular weight cut-off: 10kDa) using fiber optics. The intensity of measured light of the TAS was proportional to the glucose concentration over the concentration range from 50mg/dL to 400mg/dL in PBS and whole blood at 37°C (R>0.96). The response time was approximately 4min. The stability of the glucose response of the TAS decreased only slightly (by 20%) over an 8-day study period at 37°C. In conclusion, this study demonstrated proof-of-concept of the TAS for interstitial glucose monitoring. Due to the large signal amplitude of the turbidity change, and the lack of need for wavelength-specific emission and excitation filters, a very small, robust and compact TAS device with an extremely short optical pathlength could be feasibly designed and implemented for in-vivo glucose monitoring in people with diabetes.Biosensors & bioelectronics. 05/2014; 61C:280-284.
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ABSTRACT: The progressive scaling in semiconductor technology allows for advanced miniaturization of intelligent systems like implantable biosensors for low-molecular weight analytes. A most relevant application would be the monitoring of glucose in diabetic patients, since no commercial solution is available yet for the continuous and drift-free monitoring of blood sugar levels. We report on a biosensor chip that operates via the binding competition of glucose and dextran to concanavalin A. The sensor is prepared as a fully embedded micro-electromechanical system and operates at GHz frequencies. Glucose concentrations derive from the assay viscosity as determined by the deflection of a 50 nm TiN actuator beam excited by quasi-electrostatic attraction. The GHz detection scheme does not rely on the resonant oscillation of the actuator and safely operates in fluidic environments. This property favorably combines with additional characteristics—(i) measurement times of less than a second, (ii) usage of biocompatible TiN for bio-milieu exposed parts, and (iii) small volume of less than 1 mm3—to qualify the sensor chip as key component in a continuous glucose monitor for the interstitial tissue.Journal of Applied Physics 06/2013; 113(24). · 2.19 Impact Factor
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ABSTRACT: The reliability of optical techniques for non-invasive monitoring of glucose can be significantly improved by the deployment of a subcutaneous implantable sensor that can closely track the changes in the local concentration of glucose in skin. We have developed a novel implantable sensor that can track glucose-induced changes in the optical turbidity of the implant. In this sensor, optical turbidity decreases significantly with increased glucose concentrations. We performed comparative measurements by optical coherence tomography (OCT) used to monitor backscattering or specular reflection originated from specific structures within the sensor and by collimated light transmission measurement technique to measure the changes in light attenuation as function of glucose concentration within the sensor as well as when the sensor was implanted in phantom media or in tissue samples. These measurements showed that glucose-induced changes in the transmission values derived from OCT monitoring of the sensor turbidity differed up two times from those obtained by collimated transparency measurement (CTM) technique. These results were used to determine the values for scattering coefficients of tissue and the sensor and to estimate the relative loss in sensor sensitivity as a function of implantation depth in tissue. The results suggest that the implantable sensor can be placed in turbid medium such as skin up to an optical depth of 12 mean free paths (mfp), one could expect. For a turbid medium such as skin with a scattering coefficient (ÃÂµs ) of 10mm-1, this would result in geometrical depth of implantation at 1.2 mm beneath the tissue where sensor sensitivity of 50% or higher is expected. The study demonstrates that it could be feasible to engineer a novel optical sensor for glucose monitoring that can be implanted under the skin while providing a high degree of sensitivity and specificity for non-invasive glucose monitoring.Society of Photo-Optical Instrumentation Engineers (SPIE) - Photonics West; 01/2008