A novel reverse microemulsion (RM) mediated synthesis of glucose-responsive nanoparticles was developed for controlled insulin delivery. Nanoparticles were constructed using a model system comprised of dextran, poly(α-1,6 glucose), physically crosslinked with the tetrafunctional glucose-binding protein, Con A. A rapid-screening technique was used to quantify RM phase behavior in the presence of dextran, Con A and insulin. The extent of the RM existence region diminishes with increasing dextran and Con A concentrations and with increasing dextran molecular weight. Crosslinking efficiency between Con A and fluorescein isothiocyanate dextran (FITC-Dex) was found to depend on the total concentration of Con A as well as the ratio of Con A to FITC-Dex. Functionalizing dextran with higher affinity mannose ligands and increasing dextran molecular weight both improved crosslinking efficiency. The nanoparticles dissolved when dispersed in buffered saline solutions containing elevated glucose concentrations and were most responsive within the physiological range. Finally, insulin was encapsulated in select formulations and found to release preferentially at these elevated glucose concentrations. / Singapore-MIT Alliance (SMA)

Thesis (Ph. D.)--Ohio State University, 2006. / Full text release at OhioLINK's ETD Center delayed at author's request

Thesis (Ph. D.)--University of Akron, Dept. of Chemistry, 2006. / "May, 2006." Title from electronic dissertation title page (viewed 10/11/2006). Advisor, Daniel J. Smith; Committee members, Michael J. Taschner, Wiley J. Youngs, Kim C. Calvo, Darrell H. Reneker; Department Chair, Michael J. Taschner; Dean of the College, Ronald F. Levant; Dean of the Graduate School, George R. Newkome. Includes bibliographical references.

The use of polysaccharides as building blocks in the development of drugs and contrast agents delivery systems is rapidly growing. This can be attributed to the outstanding virtues of polysaccharides such as biocompatibility, biodegradability, upgradability, multiple reacting groups and low cost. The focus of this thesis was to develop and characterize novel starch based hydrogels and nanoparticles for delivery of drugs and imaging agents. To this end, two different systems were developed. The first system includes polymer and nanoparticles prepared by graft polymerization of polymethacrylic acid and polysorbate 80 onto starch. This starch based platform nanotechnology was developed using the design principles based on the pathophysiology of breast cancer, with applications in both medical imaging and breast cancer chemotherapy. The nanoparticles exhibited a high degree of doxorubicin loading as well as sustained pH dependent release of the drug. The drug loaded nanoparticles were significantly more effective against multidrug resistant human breast cancer cells compared to free doxorubicin. Systemic administration of the starch based nanoparticles co-loaded with doxorubicin and a near infrared fluorescent probe allowed for non-invasive real time monitoring of the nanoparticles biodistribution, tumor accumulation, and clearance. Systemic administration of the clinically relevant doses of the drug loaded particles to a mouse model of breast cancer significantly enhanced therapeutic efficacy while minimizing side effects compared to free doxorubicin. A novel, starch based magnetic resonance imaging (MRI) contrast agent with good in vitro and in vivo tolerability was formulated which exhibited superior signal enhancement in tumor and vasculature. The second system is a co-polymeric hydrogel of starch and xanthan gum with adjustable swelling and permeation properties. The hydrogels exhibited excellent film forming capability, and appeared to be particularly useful in controlled delivery applications of larger molecular size compounds. The starch based hydrogels, polymers and nanoparticles developed in this work have shown great potentials for controlled drug delivery and biomedical imaging applications.

Application of neural prostheses in today's medicine successfully helps patients to increase their activities of daily life and participate in social activities again. These implantable microsystems provide an interface to the nervous system, giving cellular resolution to physiological processes unattainable today with non-invasive methods. The latest developments in genetic engineering, nanotechnologies and materials science have paved the way for these complex systems to interface the human nervous system. The ideal system for neural signal recording would be a fully implantable device which is capable of amplifying the neural signals and transmitting them to the outside world while sustaining a long-term and accurate performance, therefore different sciences from neurosciences, biology, electrical engineering and computer science have to interact and discuss the synergies to develop a practical system which can be used in daily medicine practice. This work investigates the main building blocks necessary to improve the quality of acquired signal from the micro-electronics and MEMS perspectives. While all of these components will be ultimately embedded in a fully implantable recording probe, each of them addresses and deals with a specific obstacle in the neural signal recording path. Specifically we present a low-voltage low-noise low-power CMOS amplifier particularly designed for neural recording applications. This is done by surveying a number of designs and evaluating each design against the requirements for a neural recording system such as power dissipation and noise, and then choosing the most suitable topology for design and implementation of a fully implantable system. In addition a surface modification method is investigated to improve the sacrificial properties and biocompatibility of probe in order to extend the implant life and enhance the signal quality.

1,3-β-glucans are a class of natural polysaccharides with unique pharmacological properties and the ability to form triple helical structures and resilient gels. Curdlan and other 1,3-β-glucans have found application pharmacologically in the treatment of cancers and acceleration of wound healing in humans and in the impartation of infection resistance in animal husbandry. Structurally, these polysaccharides have found application in food science as thermal gels, in nanostructure formation as helical scaffolds, and in drug delivery as nanocarriers for drugs and as inclusion complexes with polynucleotides. A literature review of the important work on Curdlan research reveals two streams of research: investigation of the pharmacological significance of these polymers and their application in increasing host immunocompetency and investigation of the nature of the triple helix and its application in a variety of fields from food gels to drug delivery. Two significant contributions to the field of Curdlan research have been completed including 1) The development of a Curdlan nanoparticle drug delivery platform and 2) A new multi-component liquid crystalline hydrogel providing a new route to form polynucleotide inclusion complexes with Curdlan for gene delivery. The developed nanoparticle platform exhibited high encapsulation of chemotherapeutic drugs and a 24-hour controlled release with a particle size of 109.9 nm. The liquid crystalline hydrogel exhibited homogeneous inclusion of DNA into amorphous and crystalline phases of Curdlan and delayed and triggered release of polynucleotide content. This work has been a significant demonstration of the potential of Curdlan as a new polymer for multi-functional drug delivery.

Intelligent and more advanced therapeutic agents, capable of sensing and responding to their environment, are required to treat more complicated and complex diseases. Among all recently developed therapeutic agents, hydrogels are not only intelligent to sense and respond to external stimulus, but also they can be synthesized and designed in the cellular and sub-cellular size scale, which enhance their therapeutic ability. Most body physiological processes are regulated as a consequence of pH gradient in different compartments of the body; besides, changes in pH are also associated with disease or damaged sites within the body. A unique feature of hydrogels is that they can provide a network for loading and release of drugs. Therefore, the drug loaded within pH-responsive nanogels are able to locally release onto the target sites because of their small size, and capability to sense and respond to environmental changes. The goal of this research is to design and implement novel pH-responsive magnetic nanogels for drug delivery that respond to changes in pH. Semi-continuous emulsion polymerization was conducted to synthesize polyampholyte nanogels comprising of methacrylic acid (MAA) and 2-(diethylamino) ethyl methacrylate (DEAEMA) in the presence and absence of steric stabilizer poly (ethylene glycol) methacrylate (PEGMA). The synthesized nanogels demonstrated swelling behavior at both acidic and basic pHs. Herein, procaine hydro chloride (PrHy) was utilized as cationic drug to investigate the release behavior from synthesized nanogels under different conditions. PrHy was loaded within nanogels through hydrophobic interaction and hydrogen bonding, as confirmed by isothermal titration calorimetry. The release study of PrHy molecules from nanogels was conducted by applying the versatile and easy technique of drug selective electrode, in which the concentration of released drug was measured as a function of time. In order to facilitate the purification and enhance the detection of nanogels, iron oxide particles (Fe3O4) were co-precipitated within nanogels to form magnetic nanogels. Subsequently, layer-by-layer coating of polyelectrolytes were performed to control and eliminate the initial burst release of PrHy from nanogel by increasing the diffusion barrier and manipulating the permeability of nanogels. For the purpose of this research low molecular weight chitosan (CS) was used as polycation and poly (sodium 4-styrenesulfonate) (PSS) was acted as polyanion to coat magnetic nanogels. The more layers was applied, the more reduction in burst release was observed, which was revealed by using drug selective electrode to measure the concentration of the released drug from coated nanogels. Besides, layer-by-layer coating prolonged the time require to reach the steady state drug release. Therefore, this synthesized polyampholyte coated iron-oxide nanogels demonstrate great potential for use in controlled drug delivery systems.

Therapeutic operation risk has been reduced by the use of micro-robots, allowing highly invasive surgery to be replaced by low invasive surgery (LIS), which provides an effective tool even in previously inaccessible parts of the human body. LIS techniques help delivering drugs effectively via micro-carriers. The micro-carriers are divided into two groups: tethered devices, which are supported by internally supplied propulsion mechanism, and untethered devices. Remote actuation is the critical issue in micro-device navigation, especially through blood vessels. To achieve remote control within the cardiovascular system, magnetic propulsion offers an advantage over other proposed actuation methods. In the literature, most research has focused on micro-device structural design, while there is a lack of research into design and analysis of combined structure and control. As the main part, integrating the principle of electromagnetic induced force by feedback control design will lead to the desired automatic movement. An actuator configuration should thus first be designed to initiate the desired force. The design is basically defining the type and placement of a set of coils to achieve an operational goal. In this project, the magnetic actuation is initiated by a combination of four electromagnets and two sets of uniform coils. Preliminary studies on 2D navigation of a ferromagnetic particle are used to show the effect of actuator structure on controller performance. Accordingly, the performance of the four electromagnets combination is compared to the proposed augmented structure with uniform coils. The simulation results show the improved efficiency of the augmented structure. In more general cases, the arrangement and number of electromagnets are unknown and should be defined. An optimization method is suggested to find these variables when the working space is maximized. Finally, the problem of robust output regulation of the electromagnetic system driven by a linear exosystem, is also addressed in this project. The exosystem is assumed to be neutrally stable with unknown frequencies. The parallel connection of two controllers, a robust stabilizer and an internal model-based controller, is presented to eliminate the output error. In the latter one, an adaptation is used to tune the internal model frequencies such that a steady-state control is produced to maintain the output-zeroing condition. The robust regulation with a local domain of convergence is achieved for a special class of decomposable MIMO nonlinear minimum-phase system. The simulation results show the effectiveness and robustness of this method for the electromagnetic system when two different paths are considered.

The principal goal of this research is to achieve the chemical labeling and surface modification of block copolymer vesicles (polymersomes) made from amphiphilic diblock copolymer Poly(butadiene-b-ethylene oxide) (PBd120- PEO89, MW 10400 g/mol) with the aim of developing possible drug carrier vehicles for controlled release of molecules triggered by stimuli-responsive environments. The terminal hydroxyl group of poly(ethylene oxide) (PEO), or poly(ethylene glycol) is converted into its corresponding carboxylic acid by a novel one-pot two-phase oxidation reaction. This regioselective and catalytic reaction assures the preservation of important structural characteristic of the block copolymers. Vesicles formed by a mixture of the carboxylate and unmodified block copolymer exhibit an increment in the critical aggregation concentration (CAC) value while the averaged vesicle size decreases demonstrating that the negative charges in the modified diblock copolymer disrupt the vesicle formation process. The carboxylated reactive intermediates are subsequently subjected to a covalent coupling reaction in organic solvent to replace the terminal hydroxyl of the PEO block. The obtained functionalized diblock copolymers are effectively incorporated into the vesicle bilayer. Also, surface density control in polymersomes of fluorescently modified diblock copolymers, synthesized by the amination reaction, is achieved. To demonstrate the ability of this polymersomes as carrier vehicles, a Noradrenaline functionalized vesicle is placed in closed contact with rat aortic smooth muscle cells (RASMC) using the micropipette aspiration technique. A distinctive increase in fluorescent intensity of cells is observed. It indicates that the drug molecule has been transported by the polymersome and internalized by the cell. In addition, diblock copolymers containing a disulfide moiety and a fluorophore are synthesized and studied through fluorescent microscopy. Vesicles are formed with this polymer and a decrease in fluorescent intensity is observed in the vesicle's bilayer after its exposure to a reductive environment. These results indicate that fluorophore molecules are successfully released into solution.

The skin serves as a semi-permeable barrier that protects the body from pathogens and water loss. The stratum corneum, the upper 10-15 µm layer of skin, is the primary barrier layer. Due to its structure, only drugs that are lipophilic and with a low molecular weight (<500 Da) can penetrate intact skin. This study examines the use of microdermabrasion as a method of removing the stratum corneum to increase the skin's permeability to hydrophilic molecules, proteins, and vaccines. Microdermabrasion is a FDA-approved cosmetic skin resurfacing procedure that removes the stratum by bombarding it with abrasive particles under vacuum. The aims of this thesis are focused on optimizing the microdermabrasion conditions that will selectively remove stratum corneum, evaluating the transport of different sized molecules through abraded skin in vitro, examining drug efficacy in vivo by delivering insulin to diabetic rats, and examining the rate of skin healing after treatment. Microdermabrasion can be used as a non-invasive transdermal drug technique to safely remove stratum corneum to make the skin more permeable to waters soluble drugs and proteins.