title: Tissue damage modeling in gene electrotransfer: the role of pH.
abstract: Optimal gene electrotransfer (GET) requires a compromise between maximum transgene expression and minimal tissue damage. GET in skeletal muscle can be improved by pretreatment with hyaluronidase which contributes to maximize transgene uptake and expression. Nevertheless, tissue damage remains severe close to the electrodes, with a concomitant loss of GET efficiency. Here we analyze the role of pH in tissue damage in GET protocols through in vivo modeling using a transparent chamber implanted into the dorsal skinfold of a mouse (DSC) and intravital microscopy, and in silico modeling using the Poisson-Nernst-Planck equations for ion transport. DSC intravital microscopy reveals the existence of pH fronts emerging from both electrodes and that these fronts are immediate and substantial thus giving rise to tissue necrosis. Theoretical modeling confirms experimental measurements and shows that in GET protocols whether with or without hyaluronidase pretreatment, pH fronts are the principal cause of muscle damage near the electrodes. It also predicts that an optimal efficiency in GET protocols, that is a compromise between obtaining maximum electroporated area and minimal tissue damage, is achieved when the electric field applied is near 183 V/cm in a GET protocol and 158 V/cm in a hyaluronidase+GET protocol.
authors.affiliation: Laboratorio de Sistemas Complejos, Departamento de Computación, FCEyN, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina.
authors.forename: N
authors.initials: N
authors.lastname: Olaiz
authors.affiliation: Laboratory of Molecular Pathology and Experimental Oncology, CNR-IFT, Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Signori
authors.affiliation: Laboratorio de Sistemas Complejos, Departamento de Computación, FCEyN, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina.
authors.forename: F
authors.initials: F
authors.lastname: Maglietti
authors.affiliation: Laboratorio de Sistemas Complejos, Departamento de Computación, FCEyN, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina.
authors.forename: A
authors.initials: A
authors.lastname: Soba
authors.affiliation: Laboratorio de Sistemas Complejos, Departamento de Computación, FCEyN, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina.
authors.forename: C
authors.initials: C
authors.lastname: Suárez
authors.affiliation: Laboratorio de Sistemas Complejos, Departamento de Computación, FCEyN, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina.
authors.forename: P
authors.initials: P
authors.lastname: Turjanski
authors.affiliation: Instituto Tecnológico de Buenos Aires, Argentina.
authors.forename: S
authors.initials: S
authors.lastname: Michinski
authors.affiliation: Laboratorio de Sistemas Complejos, Departamento de Computación, FCEyN, Universidad de Buenos Aires, C1428EGA Buenos Aires, Argentina. Electronic address: marshallg@arnet.com.ar.
authors.forename: G
authors.initials: G
authors.lastname: Marshall
mesh_terms: D000818:Animals; D002417:Cattle; D018274:Electroporation; D018014:Gene Transfer Techniques / Q000009:adverse effects*; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism
chemical_list: D006821:Hyaluronoglucosaminidase
keywords: Computational modeling; Gene electrotransfer; Hyaluronidase; pH