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Abstract: The use of gene guns in ballistically delivering DNA vaccine coated gold micro-particles to skin can potentially damage targeted cells, therefore influencing transfection efficiencies. In this paper, we assess cell death in the viable epidermis by non-invasive near infrared two-photon microscopy following micro-particle bombardment of murine skin. We show that the ballistic delivery of micro-particles to the viable epidermis can result in localised cell death. Furthermore, experimental results show the degree of cell death is dependant on the number of micro-particles delivered per unit of tissue surface area. Micro-particles densities of 0.16±0.27 (mean±S.D.), 1.35±0.285 and 2.72±0.47 per 1000μm2 resulted in percent deaths of 3.96±5.22, 45.91±10.89, 90.52±12.28, respectively. These results suggest that optimization of transfection by genes administered with gene guns is − among other effects − a compromise of micro-particle payload and cell death. [Copyright &y& Elsevier]