Controlled and sustained gene delivery from injectable, porous PLGA scaffolds

Abstract

Biodegradable poly(lactic-co-glycolic acid) (PLGA) scaffolds are widely used for the delivery of therapeutic molecules such as plasmid DNA (pDNA) and growth factors. However, many of these scaffolds must be implanted, and it would be beneficial to develop PGLA systems that can be injected in a minimally invasive manner. In this study, we present an injectable, porous PLGA scaffold that solidifies in situ for controlled gene delivery. Micro-scale porosity was engineered into the system to facilitate cell migration, proliferation and extracellular matrix elaboration. Relatively rapid release of pDNA was achieved through simple mixing into the polymer solution prior to scaffold solidification, whereas sustained release was achieved by incorporating pDNA-laden PLGA microspheres into the polymer solution. Sustained pDNA release was obtained for over 70 days. When the released pDNA was complexed with PEI and used to transfect HEK293 cells, substantial gene transfection was achieved from all time points, demonstrating that the pDNA was bioactive for the entire time course of the study. These in situ forming porous scaffolds for pDNA delivery are easy to prepare and can be injected without invasive surgery. Importantly, localized delivery of bioactive pDNA can be achieved for short to prolonged time periods, and small changes in the system composition permit facile tailoring of release profiles. In the future, this system may be used to control host cell regenerative responses by, for example, inducing cellular migration into the porous scaffold architecture via release of pDNA encoding for chemokines or pro-angiogenic molecules.