Cellular delivery of TGFβ1 promotes osteoinductive signalling for bone regeneration

Abstract

Administration of osteoinductive growth factors to wound sites, alone or in conjunction with a delivery vehicle, is an appealing treatment option for critical bone defects. The delivery of cells transfected with genes encoding for osteoinductive growth factors, such as TGFbeta(1), represents an attractive option to locally deliver constant levels of these growth factors to stimulate new bone formation at the defect site. Using non-viral transfection methods, we showed that osteoblasts can be genetically modified in vitro to secrete sustained therapeutic levels of TGFbeta(1) in its active form through control of the transfected cell environment. In addition, delivery of TGFbeta(1) produced by genetically modified cells that contained the proper post-translational modifications provided a more robust cellular response compared to administration of bacterially-derived recombinant TGFbeta(1). Migration and subsequent proliferation of osteoblasts are critical aspects of the initial steps in the cascade of new bone tissue formation. Exposure to mammalian-derived TGFbeta(1) induced a more pronounced chemotactic response upon administration of 10 pg/ml TGFbeta(1), whereas osteoblasts showed enhanced levels of metabolic activity at 100 pg/ml, which is indicative of greater levels of cellular proliferation when compared to addition of the same levels of recombinant TGFbeta(1). This increased efficacy of cell-derived TGFbeta(1) over recombinant forms of TGFbeta(1), combined with provision of a continual source of TGFbeta(1), highlights the advantages of delivering genetically modified cells over exogenous protein delivery for bone tissue engineering.