Biomedical subjects

John C Neu

Publications and source records attributed to John C Neu.

4 recordsLinked to original sources

PubMed2006

Singular perturbation analysis of the pore creation transient.

Electroporation, in which electric pulses create transient pores in the cell membrane, is an important technique for drug and DNA delivery. Electroporation kinetics is mathematically described by an advection-diffusion boundary value problem. This study uses singular perturbation to derive a reduced description of the pore creation transient in the form of a single integrodifferential equation for the transmembrane voltage Vt. The number of pores and the distribution of their radii are computed from Vt. The analysis contains two nonstandard features: the use of the voltage deviation to peel away the strong exponential dependence of pore creation upon the transmembrane potential, and the autonomous approximation of the pore evolution. Comparing the predictions of the reduced equation with the simulations of the original problem demonstrates that this analysis allows one to predict with good accuracy the number and distribution of pores as a function of the electric pulse strength.

Cell Membrane↗

PubMed2004

Model of creation and evolution of stable electropores for DNA delivery.

Electroporation, in which electric pulses create transient pores in the cell membrane, is becoming an important technique for gene therapy. To enable entry of supercoiled DNA into cells, the pores should have sufficiently large radii (>10 nm), remain open long enough for the DNA chain to enter the cell (milliseconds), and should not cause membrane rupture. This study presents a model that can predict such macropores. The distinctive features of this model are the coupling of individual pores through membrane tension and the electrical force on the pores, which is applicable to pores of any size. The model is used to explore the process of pore creation and evolution and to determine the number and size of pores as a function of the pulse magnitude and duration. Next, our electroporation model is combined with a heuristic model of DNA uptake and used to predict the dependence of DNA uptake on pulsing parameters. Finally, the model is used to examine the mechanism of a two-pulse protocol, which was proposed specifically for gene delivery. The comparison between experimental results and the model suggests that this model is well-suited for the investigation of electroporation-mediated DNA delivery.

Biological Evolution↗

PubMed2003

Modeling postshock evolution of large electropores.

The Smoluchowski equation (SE), which describes the evolution of pores created by electric shocks, cannot be applied to modeling large and long-lived pores for two reasons: (1) it does not predict pores of radius above 20 nm without also predicting membrane rupture; (2) it does not predict postshock growth of pores. This study proposes a model in which pores are coupled by membrane tension, resulting in a nonlinear generalization of SE. The predictions of the model are explored using examples of homogeneous (all pore radii r are equal) and heterogeneous (0<or=r<or=r(max)) distributions of pores. Pores in a homogeneous population either shrink to zero or assume a stable radius corresponding to the minimum of the bilayer energy. For a heterogeneous population, such a stable radius does not exist. All pores, except r(max), shrink to zero and r(max) grows to infinity. However, the unbounded growth of r(max) is not physical because the number of pores per cell decreases in time and the continuum model loses validity. When the continuum formulation is replaced by the discrete one, the model predicts the coarsening process: all pores, except r(max), shrink to zero and r(max) assumes a stable radius. Thus, the model with tension-coupled pores does not predict membrane rupture and the predicted postshock growth of pores is consistent with experimental evidence.

Journal Article↗

PubMed2003

Electrical energy required to form large conducting pores.

This study computes the contribution of the externally induced transmembrane potential to the energy of large, highly conductive pores. This work was undertaken because the pore energy formulas existing in the literature predict qualitatively different behavior of large pores: the original formula proposed by Abidor et al. in 1979 implies that the electrical force expanding the pore increases linearly with pore radius, while later extensions of this formula imply that this force decreases to zero for large pores. Starting from the Maxwell stress tensors, our study derives the formula for the mechanical work required to deform a dielectric body in an ionic solution with steady-state electric current. This formula is related to a boundary value problem (BVP) governing electric potentials and fields in a proximity of a pore. Computer simulations yield estimates of the electrical energy for pores of two different shapes: cylindrical and toroidal. In both cases, the energy increases linearly for pore radii above approximately 20 nm, implying that the electrical force expanding the pore asymptotes to a constant value for large pores. This result is different from either of the two energy formulas mentioned above. Our study traces the source of this disagreement to approximations made by previous studies, which are suitable only for small pores. Therefore, this study provides a better understanding of the energy of large pores, which is needed for designing pulsing protocols for DNA delivery.

Biological Transport↗