Matrix immobilization enhances the tissue repair activity of growth factorgene therapy vectors

Although growth factor proteins display potent tissue repair activities, di fficulty in sustaining localized therapeutic concentrations limits their th erapeutic activity. We reasoned that enhanced histogenesis might be achieve d by combining growth factor genes with biocompatible matrices capable of i mmobilizing vectors at delivery sites. When delivered to subcutaneously imp lanted sponges, a platelet-derived growth factor B-encoding adenovirus (AdP DGF-B) formulated in a collagen matrix enhanced granulation tissue depositi on 3- to 4-fold (p less than or equal to 0.0002), whereas vectors encoding fibroblast growth factor 2 or vascular endothelial growth factor promoted p rimarily angiogenic responses. By day 8 posttreatment of ischemic excisiona l wounds, collagen-formulated AdPDGF-B enhanced granulation tissue and epit helial areas up to 13- and 6-fold (p < 0.009), respectively, and wound clos ure up to 2-fold (p < 0.05). At longer times, complete healing without exce ssive scar formation was achieved. Collagen matrices were shown to retain b oth vector and transgene products within delivery sites, enabling the trans duction and stimulation of infiltrating repair cells. Quantitative PCR and RT-PCR demonstrated both vector DNA and transgene mRNA within wound beds as late as 28 days posttreatment. By contrast, aqueous formulations allowed v ector seepage from application sites, leading to PDGF-induced hyperplasia i n surrounding tissues but not wound beds. Finally, repeated applications of PDGF-BB protein were required for neotissue induction approaching equivale nce to a single application of collagen-immobilized AdPDGF-B, confirming th e utility of this gene transfer approach. Overall, these studies demonstrat e that immobilizing matrices enable the controlled delivery and activity of tissue promoting genes for the effective regeneration of injured tissues.