Continuous glucose monitoring facilitates the stringent control of blood glucose concentration in diabetic and intensive care patients. Low-cost, robust, and reusable continuous glucose monitoring systems that can provide quantitative measurements at point-of-care settings is an unmet medical need. Phenylboronic acids (PBAs) have emerged as synthetic receptors that can reversibly bind to cis-diols such as glucose molecules. The incorporation of phenylboronic acids in hydrogels offer exclusive attributes as the binding process with glucose induces Donnan potential that leads to osmotic pressure, resulting in volumetric changes in the hydrogel matrix. Optical glucose sensors based on PBA-functionalized hydrogels have emerged as strong candidates for commercialization; however, their complex and time-consuming fabrication process, and their bulky and expensive readouts methods made them undesirable for quantitative analyses. In this dissertation, optical hydrogel sensors have been developed and attached to contact lenses for continuous glucose detection in physiological conditions. A simple fabrication method was utilized, and smartphone technology was employed for recording the output signals. A 1D photonic structure was replicated on a PBA-functionalized hydrogel to function as a transducer and to improve the sensor performance. Upon binding glucose with boronate anions immobilized in the hydrogel matrix, a positive volumetric shift occurred modifying the periodic constant of the photonic structure, consequently its diffraction properties altered. A correlation has been established between the sensor’s periodic constant and glucose concentration in the range of 0-50 mM. The hydrogel sensor was attached to a soft commercial contact lens (ACUVUE) and was interrogated for glucose detection in artificial tears. The ambient light sensor of a smartphone captured the intensity of the laser diffracted signals and was correlated with glucose concentrations. The smart contact lens showed very short response time (3 s), and a saturation time of near 4 minutes in continuous monitoring conditions. However, a laser beam was necessary to interrogate the contact lens which is uncomfortable, and the frequent exposure might be harmful to the eye cornea. Alternatively, a novel transducer has been introduced to enable interrogating the smart contact lens by using a white light beam. Light diffusing microstructures (LDMs) have been introduced for the first time for the sensing applications. The LDMs can be considered as densely-packed microparticles of different shapes and dimensions which have the capacity to diffuse the polychromatic and monochromatic light in the forward and backward directions. The LDMs were imprinted on the glucose -responsive hydrogel to monitor the volumetric shift due to glucose complexation. The volumetric modification of the hydrogel upon glucose complexation induced a change in the dimensions and refractive index of the LDMs, resulting in a variation in the diffusion efficiency. The glucose sensor was attached to a commercial contact lens and a smartphone measured the optical output signals. The alternative transducer enabled interrogating the smart contact lens by a white light beam and retained on the simplicity of the fabrication and the readout methodology; however, the response time of the senor increased significantly. The proposed smart contact lenses can be considered as a non-invasive way for continuous glucose monitoring, and can detect many other biomarkers that are beneficial for medical diagnostic applications.
For implantable and remote monitoring of glucose concentration, fiber optic probes have been developed. Fiber optics have inherent advantages such as immunity to electromagnetic interference, miniaturization, and small volumes of samples. These merits candidate them for biosensing applications; however, complexity of the manufacturing process, poor mechanical properties, unpracticality of the readout methodology have hindered their practical applications. We have developed fiber optic probes for glucose detection that overcome the limitations mentioned above. Capability of the LDMs to scatter/diffuse the incident light beam in the forward and backward directions was exploited. The glucose responsive hydrogel imprinted with the LDMs was attached to the tip of a multimode silica fiber. Swelling of the attached hydrogel led to a decrease in the refractive index of the LDMs, inducing a decrease in the light scattering angles. Whereas the numerical aperture of the optical fiber indicates the range of the angles of the incident rays those satisfy the total internal reflection condition. Accordingly, swelling the hydrogel attached to the fiber result in more incident rays fall within the accepted range of angles to be guided in the optical fiber. Hence, the optical power guided in the fiber increased with glucose concentration. The fabricated fiber probe was interrogated for glucose detection in transmission configuration and the smartphone was utilized to pick up the fiber’s signals. Also, the probe was tested in reflection configuration which is a more practical mode for implantable biosensing applications. The probe overcame some limitations of the existing probes such as interferometric, SPR, and fluorescent probes in terms of ease of the fabrication and the interrogation processes. Additionally, the probe showed high sensitivity, rapid response, and selectivity for glucose over lactate. The lactate interference was found to be ~ 0.1% in the physiological condition. Furthermore, biocompatible hydrogel fibers were introduced to prevent or reduce the immune reaction in the implantation sites. The probes were tested for glucose detection and showed similar response to that of silica fiber probes; however, they presented lower sensitivity which might be the result of a higher light loss in the hydrogel fiber. In order to emphasize the variety of applications of these novel fiber optic probes that we developed, two more probes were fabricated for alcohol detection and pH measurements. The alcohol probe showed real-time sensing of ethanol, propanol, and dimethyl sulfoxide with a response time in seconds and a saturation time around 60 s. Also, the pH probe showed high sensitivity and rapid response in the acidic region with a sensitivity near 20% pH-1. For medical applications, the pH sensor was attached to a biocompatible fiber optic and was tested for pH sensing in reflection configuration. The probe can be recommended for gastric pH detection. The fabricated optical fiber sensors may also have applications in wearable and implantable point-of-care and intensive-care continuous monitoring systems
