Disease processes that are currently among the leading causes of death now require much more than just a stethoscope for diagnosis and a pill for treatment. The next generation of therapeutics needs to possess a degree of intelligence; the ability to sense and respond to their environment. Biomedical hydrogels have the ability to sense and respond to external stimulus and with the advent of nanotechnology; these polymers can be fabricated on the same size scale as cellular and sub-cellular processes. Throughout the body gradients in pH are used at the cellular level to regulate processes such nutrient transport and to fight infection. Sites of damage or disease within the body are associated with both a change in pH and abnormal nanoporous vasculature. pH-Responsive microgels and nanogels are small enough to access these locations within the body, sense the change in environment, and locally release a therapeutic agent In this work heterogeneous, photoinitiated free radical polymerizations were developed to synthesize novel pH-responsive microgels and nanogels that could be loaded with macromolecular therapeutics and could respond to either a basic or acidic change in pH. A novel photo-dispersion polymerization scheme was developed to synthesize poly(ethylene glycol) grafted poly(methacrylic acid) (P(MAA-g-PEG)) polycomplexation gels for oral protein delivery. These ranged in size from 100- 300 nm in diameter and could swell up to a 17-fold increase in volume, in response to a rise in pH. This property allowed them to protect insulin at low pH and release the protein at neutral pH. In this way the carriers could be used to transport proteins through the stomach to the small intestine for absorption. A novel photo-emulsion polymerization scheme was developed to synthesize poly(ethylene glycol) grafted poly[2-(diethylamino)ethyl methacrylate] nanogels, between 70-150 nm in diameter. These could swell up to a 22-fold increase in volume, in response to a drop in pH. These nanostructures were able to successfully target clathrin-dependent endocytosis and deliver macromolecules to the cytosol. / text

Several polymer systems including P(MAA-g-EG) and P(MAA-co-NVP) with crosslinking agents TEGDMA and PEGDMA1000, monomer-to-solvent ratios of 67:33, 60:40, and 50:50, and particle sizes of <75 microns, 90-150 microns, and 150-212 microns were synthesized for use with protein-transporter conjugates. All synthesized systems were characterized by SEM which demonstrated the visual size, surface features, and surface textures of the polymer microparticles. Insulin-transferrin and calcitonin-transferrin conjugates were successfully synthesized using the protein crosslinker SPDP, binding the two proteins with a disulfide bond. The multi-step conjugation reactions used to create the conjugates were analyzed by the use of UV spectroscopy and HPLC to ensure the quality of the final products. In both conjugation reactions, the final product yield was found to be over 70%. The in vitro loading and release characteristics for insulin-transferrin and calcitonin-transferrin were separately investigated. By testing loading and release using a number of different polymer systems with different synthesis parameters, it was possible to optimize the hydrogel carriers for use with each of the conjugates independently. Upon optimization, the ideal system for use with insulin-transferrin and calcitonin-transferrin was found to be P(MAA-g-EG) microparticles of <75 microns formed using a PEGDMA1000 crosslinker and a 50:50 monomer-to-solvent ratio for both conjugates through separate optimization processes. This optimized polymer carrier was found to release upwards of 50% of loaded insulin-transferrin conjugate and near 90% of loaded calcitonin-transferrin conjugate. The insulin-transferrin conjugate was further evaluated through the use of cellular and animal models. Using cellular models, the insulin-transferrin conjugate was shown to increase transport relative to insulin by a factor of 7, achieving an apparent permeability of 37 x 10⁹ cm/s. Also, in the presence of polymer microparticles, the insulin-transferrin conjugate increased transport by a factor of 14 times relative to insulin, achieve an apparent permeability of 72.8 x 10⁹ cm/s. The presence of the microparticles near the cells was found to improve conjugate transport by nearly 100%. The preliminary animal studies verified the successful synthesis of the insulin-transferrin conjugate as well as demonstrated the bioactivity of the insulin portion of the molecule by achieving a drop in blood glucose level upon subcutaneous injection. / text

published_or_final_version / Orthopaedics and Traumatology / Master / Master of Medical Sciences

Not available / text

No description available.

Thesis (Master)--İzmir Institute of Technology, İzmir, 2004. / Includes bibliographical references (leaves. 55-58).

Thesis (doctoral)--Rijksuniversiteit Groningen, 1995.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2009. / Title from PDF title page (viewed Sept. 2, 2009). Additional advisors: Uday Vaidya, Burton Patterson, Susan Bellis, Mark Weaver, Vinoy Thomas. Includes bibliographical references.

Thesis (doctoral)--Rijksuniversiteit Groningen, 1995.

Thesis (Ph.D.) -- McMaster University, 2001. / Includes bibliographical references (leaves 204-228). Also available via World Wide web.