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Biochemical and Biomedical Engineering
^ The Basis of Poly(ethylene oxide) Interactions with Biomolecules
D. Leckband,* N. Efremova, R. Gunawan
National Science Foundation, BES 98-10133

This work is aimed at understanding the molecular basis of the unusual biological compatibility of polyethylene oxide and similar water-soluble polymers used in many biological applications. This work involves a combination of polymer theory, force probe measurements of polymer films and their interactions with biological molecules, and measurements of protein interactions with grafted polymer films. These studies are providing fundamental design criteria for protein-resistant polymer surface coatings.

^ Chaotic Advection Mixing Devices for Microfluidic Biomolecular Systems
D. Leckband,* D. Beebe (Mech. Engr.), J. Santiago (Stanford Univ.), J. Moore (Chemistry), R. Adrian (Theoret. & Appl. Mech.), H. Aref (Theoret. & Appl. Mech.)
Defense Advanced Research Projects Agency, F33615-98-1-2853

The efforts of our group in this multidisciplinary team are focusing on the chemical modification of the walls of microfluidic devices in order to prevent biofouling and to selectively pattern biological receptor molecules.

^ Chemical Communication between Cells and Engineered Bioscaffolds
D. Leckband,* B. Wheeler (Elect. & Comput. Engr.), T. Eurell, D. Gross (Vet. Biosciences), R. Gunawan (Chem. Engr.)
U of I Campus Research Initiative

Patterned bioscaffolding materials are being developed for the directed growth of hippocampal neurons and endothelial cells. This cross-campus, interdisciplinary effort is aimed at controlling cell communication with engineered materials in order to direct cell growth and sustain function in artificial environments.

^ Molecular Forces Determining the Strength of Receptor-mediated Cell Adhesion
D. Leckband,* B. Zhu
National Science Foundation, BES-9503045

Cell adhesion is mediated by contacts between chemical moieties on cell surfaces. In particular, the enhanced expression of certain glycolipids on cancer cells may determine their metastatic potential. The significance of specific glycolipid interactions, however, is linked directly to the strengths of the molecular forces governing the resulting adhesion. Researchers are using direct force measurements, fluorescence microscopy, and light scattering to quantify the magnitudes and ranges of glycolipid-mediated adhesive forces and to determine the impact of those forces on the strengths of glycolipid-mediated membrane attachments. The team is testing directly the role of membrane surface components in cell adhesion and the potential utility of therapeutics designed to block their interactions.

^ Physical Mechanisms Governing Receptor-mediated Intermembrane Adhesion
D. Leckband,* S. Sivasankar, B. Zhu, A. Kloss
National Institutes of Health, RO1 GM51338-06

In these studies, the research team is determining the molecular basis of protein-mediated biological adhesion. The control of receptor-mediated cell adhesion is important in wound healing, cancer metastasis, and tissue engineering. This work uses a combination of molecular force probe measurements, theoretical modeling, and molecular biology techniques to determine the structural basis of protein-mediated adhesion. This information is used to design biological adhesion molecules and cell attachment substrates.

^ Poly(ethylene oxide) Interactions with Proteins
D. Leckband,* N. Efremova, M. Grunze (Heidelberg)
NATO Collaborative Research Grant

The unique biological activity of poly(ethlyeneglycol) is believed to be a function of intramolecular structure of the polymer backbone and of its unique interactions with water. This research program combines direct surface force measurements with several surface spectroscopies to elucidate the relationship between grafted polymer chains and short oligomers on surfaces, the structural content of the chains, and the interfacial properties that determine how these materials interact with the biological environment.

^ Structure-Function Investigations of Cell Adhesion and Membrane Proteins
D. Leckband,* S. Sivasankar, J. F. Legrand (CNRS, Grenoble)
University of Illinois

X-ray reflectivity studies of oriented monolayers of cell adhesion proteins are being used to determine the configurations of adhesion proteins in adhesive complexes with other proteins. This is a collaborative grant between the CNRS (France) and the University of Illinois.

^ Dynamics of Phase Inversion Related to Drug Delivery
A. J. McHugh,* J. R. DesNoyer, K. J. Brodbeck
National Science Foundation, CTS 97-31509; Alza Corp.

The principles of phase inversion are being applied in studies of injectable drug delivery systems consisting of a water-insoluble polymer, biocompatible solvent, and bioactive agent. In situ optical measurement techniques are used to quantify the interaction of liquid demixing, gelation, and drug release rates in solutions quenched into an aqueous environment. Water influx rates and bath-side mass transfer dynamics are correlated with the drug release rate and morphology of the formed gel. Systems under study include poly (lactide-co-glycolide) (PLGA) copolymers of various molecular weight and composition, a variety of biocompatible solvent systems, and model protein systems such as chicken egg lysozyme.

^ Design and Synthesis of Polymeric Materials for DNA Delivery
D. W. Pack,* M. L. Forrest
American Heart Association; National Science Foundation, BES-0120101

The goal of this project is to design novel polymers capable of safe and efficient delivery of genetic material to mammalian cells. A first step of this research is to elucidate the structure-function relationships of currently available, off-the-shelf gene-delivery polymers. Thus, researchers are developing quantitative assays that will allow the team to probe the various intracellular barriers to transport DNA from outside the cell into the nucleus. The resulting structure-function database will provide a basis for intelligent design of new materials with improved safety and efficacy.

^ Engineering of Viruses for Enhanced Gene Therapy
D. W. Pack,* J. Ramsey, H. Vu
Roy J. Carver Charitable Trust

Viruses have evolved to become extremely efficient agents of gene delivery. Unfortunately, they are not ideal for many human gene therapy applications that require, for example, targeting of the gene delivery vehicle to specific organs and cell types. Researchers are reengineering viruses using a combinatorial approach termed directed evolution. With this technique, the research team generates a diverse library of randomly mutated viruses and subsequently gleans from that library those mutants which are improved in a defined property, such as infection of a new cell type or improved thermodynamic stability.

^ Precisely Controlled Fabrication of Biodegradable Polymer Microparticles for Controlled-Release Drug Delivery
D. W. Pack,* K. Kim (Elect. & Comput. Engr.), C. Berkland, N. Varde
Campus Research Board; Alkermes, Inc.

Researchers have developed a novel technique for fabrication of microparticles of biodegradable polymers such as poly(lactic-co-glycolic acid). The research team is encapsulating therapeutic compounds in the polymer matrix such that the drug can be released at a controlled rate over a prolonged period of time in the body. The approach is unique in that researchers have precise control over particle size, size distribution, and architecture. These characteristics lead to unprecedented control of drug delivery kinetics. Furthermore, the team is pursuing advanced applications, such as passive targeting based on particle size, that have not previously been possible due to the limitations of current fabrication methods.

^ Developing a Molecular Switch for Gene Therapy
H. Zhao,* K. Chockalingam, Research Groups of J. A. Katzenellenbogen (Chem.) and B. S. Katzenellenbogen (Physiol.)
University of Illinois, Cancer Research Center

The team is interested in developing a novel receptor-based gene expression system in which activity can be precisely regulated by a synthetic ligand. Researchers will use a combined rational design and directed evolution approach to engineer a fully orthogonal ligand-receptor pair consisting of an estradiol-derived synthetic ligand and a human estrogen receptor ligand binding domain mutant. Such a system is an invaluable tool for gene therapy, temporal control of the onset of phenotypes in transgenic animals, regulated expression of genes in plants, and biological study of development and other physiological processes.

^ Directed Evolution of Antifreeze Proteins with Increased Activity
H. Zhao,* Research Groups of C. H. Cheng (Animal Biol.), D. R. Bush (Plant Biol.) and H. Huang (Biochem.)
Critical Research Initiative, University of Illinois

In this project, researchers will use DNA shuffling to recombine several antifreeze protein genes isolated from fish, insects, and plants followed by selection of variants with increased activity. The evolved antifreeze proteins could be used in low-temperature preservation of gametes and embryos of domestic animals and in the creation of cold- or frost-resistant transgenic plants.

^ Directed Evolution of Biosynthetic Pathways
H. Zhao*
University of Illinois, Department of Chemical Engineering

Biosynthetic pathways have been widely used in production of natural products. Natural products, isolated from microorganisms and plants, make up as much as 40% of the drugs in current use. Stimulated by the discovery of antibacterial agents such as penicillin, cephalosporin, and streptomycin during the 1930s and 1940s, the pharmaceutical industry has spent considerable resources to discover new biologically active natural products. However, the rate of discovering new drugs or improved ones has diminished with time. To address this limitation, researchers are developing new approaches for efficient generation of novel natural products by genetically manipulating existing biosynthetic pathways via directed evolution technologies.

^ Engineering Novel Substrate Specificity of a Hydrolytic Haloalkane Dehalogenase
H. Zhao*
University of Illinois, Department of Chemical Engineering

The study of microbial hydrolytic dehalogenases has been motivated largely by their potential use in waste treatment, bioremediation, and industrial biocatalysis. These enzymes play a crucial role in the biodegradation of aliphatic halogenated compounds, such as a broad range of chlorinated (C2-C6) alkanes. Unfortunately, as practical biocatalysts, these enzymes suffer from low activity and narrow substrate specificity. In order to understand the molecular basis of substrate specificity as well as engineer better dehalogenase mutants, researchers will apply a novel targeted combinatorial mutagenesis method to randomly mutagenize the active site of this enzyme and isolate the variants with increased activity toward the substrate of interest.


Summary of Engineering Research