Bellamkonda This CAREER proposal presents a novel combination of educational and research initiatives in biomedical engineering in general and molecular tissue engineering in particular. The principal investigator holds a joint appointment in the Schools of Engineering and Medicine at Case Western Reserve University, and over a four year period, he proposes a program of teaching and research that will involve students and faculty from both the schools. The unifying theme of the program is the development, application and dissemination of interdisciplinary expertise on adapting biomaterials technologies as enabling tools to facilitate molecular level tissue engineering.
The four educational initiatives proposed are a) application of modern teaching methodologies to engineering education, b) curriculum revision and development, c) outreach programs for area high school students focussing on recruitment of women into engineering, and d) mentoring of bioengineering majors. All of the initiatives mentioned above are strong integrated with the research initiatives proposed.
The research initiatives proposed focus on the application of biomaterials based, drug delivery technology for the in vivo delivery of therapeutic genes to improve transfection efficiency and duration of transgene expression in vivo. In particular, the research targets proliferative vascular disorders which account for 10%-15% of all fatalities in America today. Proliferative vascular diseases are common after angioplasty, stent or graft placement or in peripheral vascular diseases. This proposal outlines a novel, versatile drug delivery system for the continuous, local, perivascular delivery of genetic agents to the arterial wall. Lipid based microcylinders can be fabricated of differing lengths and provide corresponding periods of slow release of genetic agents. It is proposed to deliver genetic agents via non-viral means to circumvent the safety issues associated with adenoviral mediated gene transfer.
It is proposed to use an organ culture system and mathematical modeling to study and optimize the kinetics of reporter gene delivery using non-viral lipid- and peptide-DNA complexes to the arterial wall. Efficiency of transfection and duration of transgene expression will be quantified in vitro in the organ culture system. Once the kinetics of gene deposition in the arterial wall are optimized, endothelial nitric oxide synthase containing plasmids will be complexed to polylysine peptides and continuously delivered to an artery previously injured by a balloon catheter in a rodent model of peripheral restenosis.
When complete, this project will shed new light on using continuous gene delivery to improve efficiency, duration of gene expression and the therapeutic outcome of delivering inhibitors of smooth muscle cell proliferation, continuously and perivascularly. It will also influence recruitment and retention of women into engineering, and impart critical biomaterials, molecular, and gene manipulation skills to undergraduate and graduate students in biomedical engineering.
