Brownian dynamics of cylindrical capsule-like particles in a nanopore in an electrically biased solid-state membrane.

We use Brownian dynamics simulations to study the motion of cylindrical capsule-like particles (capsules) as they translocate through nanopores of various radii in an electrically biased silicon membrane. We find that for all pore sizes the electrostatic interaction between the particle and the pore results in the particle localization towards the pore 's center when the membrane and the particle have charges of the same sign (case 1) while in case of the opposite sign charges, the capsule prefers to stay near and along the nanopore wall (case 2). The preferential localization leads to all capsules rotating less while inside the pore compared to the bulk solution, with a larger net charge and/or particle length resulting in a smaller range of rotational movement. It also strongly affects the whole translocation process: in the first case, the translocation is due to the free diffusion along the pore axis and is weakly dependent on the particle charge and the nanopore radius while in the second case, the translocation time dramatically increases with the particle size and charge as the capsule gets "stuck" to the nanopore surface.

A Unique Case of Lower Limb Soft Tissue Reconstruction with a Prefabricated Bipedicled Deep Inferior Epigastric Artery Flap.

Aesthetic lower-extremity reconstruction is a secondary field in lower limb reconstructive surgery. Nevertheless, it plays an important role in the final stages of patient rehabilitation after traumatic events, treatment of deformations, and oncoplastic surgery, and in unique cases of purely aesthetic reconstruction. We present a clinical case of lower limb reconstruction with a prefabricated bipedicled deep inferior epigastric artery (DIEP) flap in a young patient who underwent a massive congenital circular pigmented nevus excision surgery. Due to the lack of sufficient donor site tissues anywhere on the body, a bilateral DIEP flap was prefabricated using tissue expansion. Two expanders were used to prepare the donor site. Six months after expansion, lower limb reconstruction was performed. A large (50 × 25cm2) surgical defect was covered by a prefabricated DIEP flap. Flap positioning was regarded with extra care due to importance of proper venous outflow in accordance with lower limb venous anatomy. Treatment results were above the satisfactory level both aesthetically and therapeutically. Aesthetic and therapeutic incentives were assessed before surgical treatment decision. Large defects of the lower limbs require significant amount of excess tissue in the donor site and may require prefabrication. In young patients with low BMI, flap transfer is nearly impossible without prior expansion. In this case, we successfully performed giant pigmented nevus excision, with immediate reconstruction with a prefabricated bilateral DIEP flap. Venous outflow was problematic due to the anatomical structure of lower limb veins. This required extra venous drainage and special regard to positioning of the flap.

Multiscale simulations of charge and size separation of nanoparticles with a solid-state nanoporous membrane.

Nanoporous membranes provide an attractive approach for rapid filtering of nanoparticles at high-throughput volume, a goal useful to many fields of science and technology. Creating a device to readily separate different particles would require an extensive knowledge of particle-nanopore interactions and particle translocation dynamics. To this end, we use a multiscale model for the separation of nanoparticles by combining microscopic Brownian dynamics simulations to simulate the motion of spherical nanoparticles of various sizes and charges in a system with nanopores in an electrically biased membrane with a macroscopic filtration model accounting for bulk diffusion of nanoparticles and membrane surface pore density. We find that, in general, the separation of differently sized particles is easier to accomplish than of differently charged particles. The separation by charge can be better performed in systems with low pore density and/or smaller filtration chambers when electric nanopore-particle interactions are significant. The results from these simple cases can be used to gain insight in the more complex dynamics of separating, for example, globular proteins.

Deep Inferior Epigastric Artery Perforator Flap Breast Reconstruction in a Patient with a History of Toxic Epidermal Necrosis.

Breast reconstruction is a procedure that is in increased demand due to high incidence of breast cancer. To provide high-quality esthetic and functional results, each patient should be properly managed. Patients with comorbid conditions have become more common and account for higher difficulty in perioperative patient management. Despite the ongoing diversification of comorbidities in patients undergoing breast reconstruction, it is the patient's right to receive this final stage in rehabilitation after a mastectomy. We present a clinical vignette of a patient with a severe comorbid hypersensitivity disorder undergoing breast reconstruction with the deep inferior epigastric artery perforator flap. Despite early postoperative complications, our brigade managed to maintain flap viability without the use of surgical or pharmacological assistance in a patient with a history of toxic epidermal necrosis syndrome.

Brownian dynamics of a neutral protein moving through a nanopore in an electrically biased membrane.

The ability to separate proteins is desirable for many fields of study, and nanoporous membranes may offer a method for rapid protein filtration at high throughput volume, provided there is an understanding of the protein dynamics involved. In this work, we use Brownian dynamics simulations to study the motion of coarse-grained proteins insulin and ubiquitin in an electrically biased membrane. In our model, the protein is subjected to various biases applied to the silicon membrane equipped with a nanopore of different radii. The time each protein takes to find a cylindrical nanopore embedded in a thin silicon membrane, attempt to translocate it (waiting time), and successfully translocate it in a single attempt (translocation time) is calculated. We observe insulin finding the nanopore and translocating it faster than the electrically neutral ubiquitin due to insulin's slightly smaller size and net negative charge. While ubiquitin's dynamics is also affected by the size of the pore, surprisingly, its translocation process is also noticeably changed by the membrane bias. By investigating the protein's multipole moments, we demonstrate that this behavior is largely due to the protein's dipole and quadrupole interactions with the membrane potential.

Brownian dynamics simulations of the ionic current traces for a neutral nanoparticle translocating through a nanopore.

In this work, the ionic current blockades due to the translocation of a neutral spherical nanoparticle through a nanopore in a solid state membrane are computed. We use a Brownian dynamics approach, in conjunction with a full three-dimensional self-consistent solution of the Poisson-Nernst-Planck and Navier-Stockes system of equations to describe realistic ionic current response arising due to the random motion of a nanoparticle through a nanopore. We find that in addition to the usual geometric blockade, the variations of the current along the axis of the pore are largely caused by a concentration polarization induced by the presence of the translocating nanoparticle in the nanopore while the current changes in the radial (perpendicular to the axis) direction occur because of the local build up of the ionic charge between the particle and the nanopore surface. By performing statistical analysis of the current traces, we also observe that, in general, smaller current blockade values correspond to faster translocation times, while increased dwell times result in a larger current decrease.

Brownian dynamics of a protein-polymer chain complex in a solid-state nanopore.

We study the movement of a polymer attached to a large protein inside a nanopore in a thin silicon dioxide membrane submerged in an electrolyte solution. We use Brownian dynamics to describe the motion of a negatively charged polymer chain of varying lengths attached to a neutral protein modeled as a spherical bead with a radius larger than that of the nanopore, allowing the chain to thread the nanopore but preventing it from translocating. The motion of the protein-polymer complex within the pore is also compared to that of a freely translocating polymer. Our results show that the free polymer's standard deviations in the direction normal to the pore axis is greater than that of the protein-polymer complex. We find that restrictions imposed by the protein, bias, and neighboring chain segments aid in controlling the position of the chain in the pore. Understanding the behavior of the protein-polymer chain complex may lead to methods that improve molecule identification by increasing the resolution of ionic current measurements.

Electro-osmotic flow through nanopores in thin and ultrathin membranes.

We theoretically study how the electro-osmotic fluid velocity in a charged cylindrical nanopore in a thin solid state membrane depends on the pore's geometry, membrane charge, and electrolyte concentration. We find that when the pore's length is comparable to its diameter, the velocity profile develops a concave shape with a minimum along the pore axis unlike the situation in very long nanopores with a maximum velocity along the central pore axis. This effect is attributed to the induced pressure along the nanopore axis due to the fluid flow expansion and contraction near the exit or entrance to the pore and to the reduction of electric field inside the nanopore. The induced pressure is maximal when the pore's length is about equal to its diameter while decreasing for both longer and shorter nanopores. A model for the fluid velocity incorporating these effects is developed and shown to be in a good agreement with numerically computed results.

Protein permeation through an electrically tunable membrane.

Protein filtration is important in many fields of science and technology such as medicine, biology, chemistry, and engineering. Recently, protein separation and filtering with nanoporous membranes has attracted interest due to the possibility of fast separation and high throughput volume. This, however, requires understanding of the protein's dynamics inside and in the vicinity of the nanopore. In this work, we utilize a Brownian dynamics approach to study the motion of the model protein insulin in the membrane-electrolyte electrostatic potential. We compare the results of the atomic model of the protein with the results of a coarse-grained and a single-bead model, and find that the coarse-grained representation of protein strikes the best balance between the accuracy of the results and the computational effort required. Contrary to common belief, we find that to adequately describe the protein, a single-bead model cannot be utilized without a significant effort to tabulate the simulation parameters. Similar to results for nanoparticle dynamics, our findings also indicate that the electric field and the electro-osmotic flow due to the applied membrane and electrolyte biases affect the capture and translocation of the biomolecule by either attracting or repelling it to or from the nanopore. Our computational model can also be applied to other types of proteins and separation conditions.

Nanopore gating with an anchored polymer in a switching electrolyte bias.

In this work, we theoretically study the interaction between a solid state membrane equipped with a nanopore and a tethered, negatively charged polymer chain subjected to a time-dependent applied electrolyte bias. In order to describe the movement of the chain in the biomolecule-membrane system immersed in an electrolyte solution, Brownian dynamics is used. We show that we can control the polymer's equilibrium position with various applied electrolyte biases: for a sufficiently positive bias, the chain extends inside the pore, and the removal of the bias causes the polymer to leave the pore. Corresponding to a driven process, we find that the time it takes for a biomolecular chain to enter and extend into a nanopore in a positive bias almost increases linearly with chain length while the amount of time it takes for a polymer chain to escape the nanopore is mainly governed by diffusion.

Charged nanoparticle in a nanochannel: Competition between electrostatic and dielectrophoretic forces.

Nanochannels made in solid-state materials are used for various applications such as nanoparticle separation or DNA manipulation. In this work we examine the effects of the electric and dielectrophoretic forces on a charged nanoparticle confined in a nanochannel. To this end, we solve the Poisson equation for the nanochannel with a wedgelike geometry and consider how channel geometry and electrolyte concentration affect the electrostatic potential distribution and forces acting on nanoparticles of various sizes. On the basis of our calculations, we establish conditions necessary for the particle's attraction to the corners of a channel. We find that for large particles, the net force is attractive only for low concentrations of the electrolyte irrespective of the wedge angle, while small enough particles are attracted to the vertex for either larger electrolyte concentrations or small wedge angle.

Pores with longitudinal irregularities distinguish objects by shape.

The resistive-pulse technique has been used to detect and size objects which pass through a single pore. The amplitude of the ion current change observed when a particle is in the pore is correlated with the particle volume. Up to date, however, the resistive-pulse approach has not been able to distinguish between objects of similar volume but different shapes. In this manuscript, we propose using pores with longitudinal irregularities as a sensitive tool capable of distinguishing spherical and rod-shaped particles with different lengths. The ion current modulations within resulting resistive pulses carry information on the length of passing objects. The performed experiments also indicate the rods rotate while translocating, and displace an effective volume that is larger than their geometrical volume, and which also depends on the pore diameter.

Charged particle separation by an electrically tunable nanoporous membrane.

We study the applicability of an electrically tunable nanoporous semiconductor membrane for the separation of nanoparticles by charge. We show that this type of membrane can overcome one of the major shortcomings of nanoporous membrane applications for particle separation: the compromise between membrane selectivity and permeability. The computational model that we have developed describes the electrostatic potential distribution within the system and tracks the movement of the filtered particle using Brownian dynamics while taking into consideration effects from dielectrophoresis, fluid flow, and electric potentials. We found that for our specific pore geometry, the dielectrophoresis plays a negligible role in the particle dynamics. By comparing the results for charged and uncharged particles, we show that for the optimal combination of applied electrolyte and membrane biases the same membrane can effectively separate same-sized particles based on charge with a difference of up to 3 times in membrane permeability.

Filtering of nanoparticles with tunable semiconductor membranes.

Translocation dynamics of nanoparticles permeating through the nanopore in an n-Si semiconductor membrane is studied. With the use of Brownian Dynamics to describe the motion of the charged nanoparticles in the self-consistent membrane-electrolyte electrostatic potential, we asses the possibility of using our voltage controlled membrane for the macroscopic filtering of the charged nanoparticles. The results indicate that the tunable local electric field inside the membrane can effectively control interaction of a nanoparticle with the nanopore by either blocking its passage or increasing the translocation rate. The effect is particularly strong for larger nanoparticles due to their stronger interaction with the membrane while in the nanopore. By extracting the membrane permeability from our microsopic simulations, we compute the macroscopic sieving factors and show that the size selectivity of the membrane can be tuned by the applied voltage.

Slowing down and stretching DNA with an electrically tunable nanopore in a p-n semiconductor membrane.

We have studied single-stranded DNA translocation through a semiconductor membrane consisting of doped p and n layers of Si forming a p-n-junction. Using Brownian dynamics simulations of the biomolecule in the self-consistent membrane-electrolyte potential obtained from the Poisson-Nernst-Planck model, we show that while polymer length is extended more than when its motion is constricted only by the physical confinement of the nanopore. The biomolecule elongation is particularly dramatic on the n-side of the membrane where the lateral membrane electric field restricts (focuses) the biomolecule motion more than on the p-side. The latter effect makes our membrane a solid-state analog of the α-hemolysin biochannel. The results indicate that the tunable local electric field inside the membrane can effectively control dynamics of a DNA in the channel to either momentarily trap, slow down or allow the biomolecule to translocate at will.

Polymer translocation through an electrically tunable nanopore in a multilayered semiconductor membrane.

We have developed a two-level computational model that enables us to calculate electrostatic fields created by a semiconductor membrane submerged in electrolytic solution and investigate the effects of these fields on the dynamics of a polymer translocating through a nanopore in the membrane. In order to calculate the electrostatic potentials and the ionic concentrations in a solid-state nanopore, we have self-consistently solved Poisson equation within the semiclassical approximation for charge carrier statistics in the membrane and electrolyte. The electrostatic potentials obtained from these simulations are then used in conjunction with Langevin (Brownian) dynamics to model polymer translocation through the nanopore. In this work, we consider single-stranded DNA (ssDNA) translocation through semiconductor membranes consisting of heavily doped p- and n-layers of silicon forming a pn-junction which is capable of creating strong electric fields. We show that the membrane electric field controls dynamics of a biomolecule inside the channel, to either momentarily trap it, slow it down, or allow it to translocate at will.

DNA translocation through a nanopore in a single-layered doped semiconductor membrane.

Recently, we developed a computational model that allowed us to study the influence a semiconductor membrane has on a DNA molecule translocating through a nanopore in this membrane. Our model incorporated both the self-consistent Poisson-Nernst-Planck simulations for the electric potential of a solid state membrane immersed in an electrolyte solution together with the Brownian dynamics of the biomolecule. In this paper, we study how the applied electrolyte bias, the semiconductor membrane bias, and the semiconductor material type (n-Si or p-Si) affect the translocation dynamics of a single-stranded DNA moving through a nanopore in a single-layered semiconductor membrane. We show that the type of semiconductor material used for the membrane has a prominent effect on the biomolecule's translocation time, with DNA exhibiting much longer translocation times through the p-type membrane than through the n type at the same electrolyte and membrane potentials, while the extension of the biomolecule remains practically unchanged. In addition, we find the optimal combination for the membrane-electrolyte system's parameters to achieve the longest translocation time and largest DNA extension. With our single-layered electrically tunable membranes, the DNA translocation time can be manipulated to have an order of magnitude increase.

Towards biochemical filters with a sigmoidal response to pH changes: buffered biocatalytic signal transduction.

We realize a biochemical filtering process by introducing a buffer in a biocatalytic signal-transduction logic system based on the function of an enzyme, esterase. The input, ethyl butyrate, is converted into butyric acid--the output signal, which in turn is measured by the drop in the pH value. The developed approach offers a versatile "network element" for increasing the complexity of biochemical information processing systems. Evaluation of an optimal regime for quality filtering is accomplished in the framework of a kinetic rate-equation model.

Biochemical filter with sigmoidal response: increasing the complexity of biomolecular logic.

The first realization of a designed, rather than natural, biochemical filter process is reported and analyzed as a promising network component for increasing the complexity of biomolecular logic systems. Key challenge in biochemical logic research has been achieving scalability for complex network designs. Various logic gates have been realized, but a "toolbox" of analog elements for interconnectivity and signal processing has remained elusive. Filters are important as network elements that allow control of noise in signal transmission and conversion. We report a versatile biochemical filtering mechanism designed to have sigmoidal response in combination with signal-conversion process. Horseradish peroxidase-catalyzed oxidation of chromogenic electron donor by H(2)O(2) was altered by adding ascorbate, allowing to selectively suppress the output signal, modifying the response from convex to sigmoidal. A kinetic model was developed for evaluation of the quality of filtering. The results offer improved capabilities for design of scalable biomolecular information processing systems.

Enzymatic AND logic gates operated under conditions characteristic of biomedical applications.

Experimental and theoretical analyses of the lactate dehydrogenase and glutathione reductase based enzymatic AND logic gates in which the enzymes and their substrates serve as logic inputs are performed. These two systems are examples of the novel, previously unexplored class of biochemical logic gates that illustrate potential biomedical applications of biochemical logic. They are characterized by input concentrations at logic 0 and 1 states corresponding to normal and pathophysiological conditions. Our analysis shows that the logic gates under investigation have similar noise characteristics. Both significantly amplify random noise present in inputs; however, we establish that for realistic widths of the input noise distributions, it is still possible to differentiate between the logic 0 and 1 states of the output. This indicates that reliable detection of pathophysiological conditions is indeed possible with such enzyme logic systems.