Date of Award

Summer 2005

Document Type


Degree Name

Doctor of Philosophy (PhD)


Biomedical Engineering

First Advisor

Michael J. McShane


In this dissertation, the modeling, design, and function of fluorescent spherical enzymatic microsensors for minimally-invasive diabetic monitoring are described. The devices reported herein are novel and their experimental construction and theoretical analysis have not been previously reported, thus laying the foundation for an intensive set of studies. These sensors are based on the encapsulation of an enzymatic fluorescent assay for glucose within hydrogel alginate microspheres with diameters on the order of tens of microns, which are of the appropriate size for intradermal implantation. A novel feature of these sensors is the use of multifunctional nanoengineered ultrathin multilayer polyelectrolyte coatings on the surface of the microspheres, which play a key role in the proper function of the sensors. These sensors are designed to be implanted in the dermis for continuous monitoring of interstitial glucose, with either discrete or continuous transdermal interrogation using an external light source and emission detector. These minimally-invasive sensors could eliminate some of the pain and bother associated with self blood glucose monitoring, thereby increasing patient compliance and decreasing the incidence of deleterious complications.

The work presented here describes the development and implementation of computational tools for sensor characterization and design, as well as the construction and testing of actual sensor prototypes. The fundamental behavior of spherical enzymatic glucose microsensors with micro- and nanoscale features was investigated using a novel computational model of the sensors, and a genetic algorithm was used for evolutionary design optimization of fluorescent glucose sensors with predefined response characteristics. A major finding of the mathematical modeling work was that the response of the sensors can be improved dramatically with the application of polyelectrolyte nanofilm coatings as thin as 12 nm. Genetic algorithm results demonstrated that sensors with diameters on the order of 100 μm, enzyme concentrations in the 1–3 mM range, and 10–60 nm thick nanofilm coatings are predicted to result in highly desirable response characteristics. Sensor prototypes were characterized with regard to their physicochemical attributes, spectral characteristics, stability, and reversible ratiometric response to glucose transients in vitro. The sensors exhibited sensitive (0.02% change in ratio per mg/dL) and linear responses to glucose over the physiologically significant 0–600 mg/dL glucose range, and for the first time, true continuous sensing of glucose using enzymatic bead-based fluorescent glucose sensors was demonstrated, with response times on the order of two minutes. As a consequence of this work, it has been determined that the concept of enzymatic-based fluorescent microsphere glucose sensors for intradermal monitoring is feasible, and warrants further research.