This award by the Biomaterials Program in the Division of Materials Research to University of Kentucky is to develop novel gene therapy based on the use of nucleic acids - DNA or RNA - as a drug. Although the potential applications are broad, development of this technology has been hindered by a lack of safe and efficient systems for delivery of these drugs. Viruses are nature's gene delivery system and have been exploited for gene therapy, but safety concerns limit their use in humans. Synthetic gene delivery systems are also in development but typically lack the efficiency to be employed clinically. Improved synthetic gene delivery systems, in analogy to viruses, will be composed of several materials assembled in an organized fashion and will be capable of performing multiple functions. Current polymer/DNA assembly methods do not provide the necessary control of particle structure and function. To address this need, this project will develop new devices for assembling polymer/DNA complexes that will allow the incorporation of multiple polymers, each designed to perform a specific function, in a spatially defined manner and with control of important parameters such as the nanoparticle size and size uniformity. The resulting devices will be broadly applicable and will facilitate translation of human gene therapy from the bench to the clinic. High school, undergraduate and graduate students from Engineering and Pharmaceutical Sciences will receive multidisciplinary training through this project. In addition, the investigators will use this project and the underlying physical concepts during the outreach activity organized in the campus by the College of Engineering program, Girls in Engineering, Science and Mathematics, to stimulate interest in STEM disciplines among elementary school through high-school girls.
The goal of this project is to develop microfluidic systems for the assembly of non-viral gene delivery vectors, particularly multifunctional complexes of plasmid DNA with polycation and polyanion molecules. For more than two decades, polymeric gene delivery research has focused largely on the design and synthesis of the materials while the fabrication processes have received little attention. Conventional bulk mixing methods for assembling polymer/DNA complexes allow limited control of particle size, size uniformity, or spatial arrangement of the DNA and polymer(s). With this award, microfluidic systems will be developed that bring solutions of plasmid DNA and polymers into contact under laminar flow conditions, providing control of interaction times and allowing introduction of multiple materials with defined spatial arrangement in a sequential fashion. Such enhanced control of assembly including the capability of producing multilayered polyplexes comprising two or more synthetic agents that each provide specific functionality will be critical to the design of more efficient non-viral vectors and their translation. In addition, the research team will develop an interactive module on fluid dynamics for the University of Kentucky's Girls in Engineering, Mathematics and Science outreach program. This project would provide multidisciplinary training for high school, undergraduate and graduate students in fluid mechanics, biomaterials and gene therapy.
