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Research Interests
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| Cell and Tissue Engineering | Drug Delivery | Gene Therapy | |||||||||||||||||||||||||||||||||||||||||||||||||||
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The need for new materials for the treatment of human disease presents many exciting research opportunities. The field of biomaterials and tissue engineering has recently experienced a paradigm shift due to a rapid increase in the understanding of the biological mechanisms underlying many diseases. My research interests focus on cellular and molecular aspects of biomaterials and tissue engineering. This research is highly interdisciplinary, combining an understand of biology, chemistry, and biomedical engineering to develop new bioactive materials, which can enhance wound healing and tissue regeneration. The bioactive signals that will be provided by integrated tissue engineering scaffolds include signals for cell-type specific adhesion and migration, growth factors to promote cell proliferation and differentiation, and vehicles for gene
therapy.
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| Spinal Cord Regeneration | |||||||||||||||||||||||||||||||||||||||||||||||||||
| The overall goal is to use novel biomaterials to allow controlled release of growth factors from scaffolds that facilitate the regeneration of adult spinal cord axons through and beyond spinal cord lesions. These “tissue engineering” scaffolds will provide two critical mechanisms for enhancing spinal cord regeneration: 1) they will provide a permissive scaffold for cellular migration and axonal outgrowth of host and/or grafted cells across the lesion site (thus reducing the inhibitory environment normally found in the glial scar of spinal cord lesions), and 2) they will serve as a drug delivery vehicle for the controlled release of one or more neurotrophic factors to promote axonal regrowth and neuronal survival during regeneration. The scaffolds are drug-delivery systems consisting of fibrin matrices containing growth factors that are released in a sustained manner during tissue regeneration. By providing both a permissive matrix to serve as a substrate for axonal regeneration and soluble stimuli, in the form of neurotrophic factors, to enhance fiber sprouting, both the extracellular and the cellular environment within the spinal cord will be dramatically altered thereby enhancing the potential for regeneration within the central nervous system (CNS). These scaffolds can be further modified through the addition of embryonic stem (ES) cells during polymerization. The ES cells can repopulate the injured spinal cord and serve as a source of neurotrophic factors during regeneration. | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Embryonic stem cells grown on fibrin matrices. TujI (red) staining denotes neurons, Dapi (blue) staining denotes cell nuclei. These preliminary results demonstrate the ability of ES cell to differentiate into neurons and glial cell (not pictured) within fibrin matrices. |
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Cell and Tissue Engineering | Drug Delivery | Gene Therapy |
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| Growth factors are potent protein drugs that are powerful regulators of biological function. Their presence in tissues is highly regulated in both time and space. The ability to tightly regulate the release of growth factors is essential in the development of tissue engineering scaffolds. My laboratory is using combinatorial methods to design novel materials for affinity-based protein delivery. The release of proteins from affinity-base delivery systems can be optimized by changing the number of protein-binding sites in the material or by changing the affinity of the interaction between the protein and the material. The libraries of compounds developed in this project can provide a new method for the regulation of drug release profiles - regulation of the affinity of the delivery vehicle for the drug. Based on an understanding of the time course of key events required for tissue regeneration, these affinity-based protein delivery vehicles can be incorporated into tissue engineering scaffolds to provide the signals necessary to stimulate tissue regeneration on a relevant time scale. | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Cell and Tissue Engineering | Drug Delivery | Gene Therapy |
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| Gene therapy is another powerful tool in tissue engineering, which can be used to regulate the expression of both secreted and intracellular proteins vital to tissue regeneration. Previously, 80% of gene therapy clinical trials have used viral vectors, however recent safety concerns with viral vectors will limit their use in the future. Non-viral transfection agents have varying efficiencies of transfection, and commonly used agents such as liposomes and polycationic polymers are highly toxic to mammalian cells. My research focuses on the development of non-toxic alternatives to current non-viral gene therapy vehicles. The goal of this project is to develop an "artificial histone" transfection agent, which retains the histone's ability to efficient compact DNA while avoiding the toxicity problems that plague linear polycationic polymers. These artificial histone vehicles can provide a safe, simple and flexible DNA delivery vehicle within tissue engineering scaffolds. The materials developed in this project can be used to provide the signals necessary for tissue regeneration and can be tailored for applications in many different types of tissue. | |||||||||||||||||||||||||||||||||||||||||||||||||||
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B |
Live/dead
assay comparing cytotoxic effects of PEG-based vectors,
poly(L-Lysine), and polyethylenimine following transfection
of CHO cells. These
are the results for the LIVE/DEAD Viability/Cytotoxicity
assay. Green
fluorescence indicates live cells, red indicates dead.
Row A) Cells transfected with DBP-PEG.
B) PLL. C)
PEI. D)
Control – no polymer added |
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C
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D |
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