Biomedical subjects

Samir Mitragotri

Publications and source records attributed to Samir Mitragotri.

14 recordsLinked to original sources

PubMed2003

A reversibly switching surface.

We report the design of surfaces that exhibit dynamic changes in interfacial properties, such as wettability, in response to an electrical potential. The change in wetting behavior was caused by surface-confined, single-layered molecules undergoing conformational transitions between a hydrophilic and a moderately hydrophobic state. Reversible conformational transitions were confirmed at a molecular level with the use of sum-frequency generation spectroscopy and at a macroscopic level with the use of contact angle measurements. This type of surface design enables amplification of molecular-level conformational transitions to macroscopic changes in surface properties without altering the chemical identity of the surface. Such reversibly switching surfaces may open previously unknown opportunities in interfacial engineering.

Adsorption↗

PubMed2003

Modeling skin permeability to hydrophilic and hydrophobic solutes based on four permeation pathways.

Barrier properties of skin originate from low permeability of stratum corneum. The objective of this paper is to compile fundamentally-based analytical expressions that can be used to predict skin permeability to hydrophilic as well as hydrophobic solutes. Solute permeation through four possible routes in stratum corneum including free-volume diffusion through lipid bilayers, lateral diffusion along lipid bilayers, diffusion through pores, and diffusion through shunts was analyzed. Contribution of free-volume diffusion through lipid bilayers was determined using Scaled Particle Theory. This theory relates solute partition and diffusion coefficients to the work required to create cavities in a lipid bilayers to allow solute incorporation and motion. Contribution of lateral lipid diffusion was determined from the literature data. Contribution of pores was estimated using hindered transport theory. This theory assumes that hydrophilic solutes permeate across the skin through imperfections in the lipid bilayers modeled as pores. Finally, contribution of shunts was determined using a simple diffusion model. The model yielded a series of equations to predict skin permeability based on solute radius and octanol-water partition coefficient. Predictions of the model compare well with the experimental data.

Hydrophobic and Hydrophilic Interactions↗

PubMed2003

On the origin of size-dependent tortuosity for permeation of hydrophilic solutes across the stratum corneum.

Due to their low skin permeabilities, transdermal transport of hydrophilic solutes is poorly understood. In this study, we sought to determine the dependence of solute tortuosity on solute size and stratum corneum (SC) porosity. With porous pathway model, transdermal transport of hydrophilic solutes through the SC was modeled as diffusion through imperfections/defects that occur between/within the lipid lamellar organization of the SC. In order to seek an analytical solution, we assumed that the pores in the SC were cylindrical and organized in a cubical pattern. The proposed theoretical model describing the dependence of solute tortuosity on solute size and SC porosity is in agreement with prior experimentally derived tortuosity values.

Epithelium↗

PubMed2003

Description of transdermal transport of hydrophilic solutes during low-frequency sonophoresis based on a modified porous pathway model.

Application of low-frequency ultrasound has been shown to increase skin permeability, thereby facilitating delivery of macromolecules (low-frequency sonophoresis). In this study, we sought to determine a theoretical description of transdermal transport of hydrophilic permeants induced by low-frequency sonophoresis. Parameters such as pore size distribution, absolute porosity, and dependence of effective tortuosity on solute characteristics were investigated. Pig skin was exposed to low-frequency ultrasound at 58 kHz to achieve different skin resistivities. Transdermal delivery of four permeants [mannitol, luteinizing hormone releasing hormone (LHRH), inulin, dextran] in the presence and absence of ultrasound was measured. The porous pathway model was modified to incorporate the permeant characteristics into the model and to achieve a detailed understanding of the pathways responsible for hydrophilic permeant delivery. The slopes of the log kp(p) versus log R graphs for individual solutes changed with solute molecular area, suggesting that the permeability-resistivity correlation for each permeant is related to its size. The tortuosity that a permeant experiences within the skin also depends on its size, where larger molecules experience a less tortuous path. With the modified porous pathway model, the effective tortuosities and skin porosity were calculated independently. The results of this study show that low-frequency sonophoresis creates pathways for permeant delivery with a wide range of pore sizes. The optimum pore size utilized by solutes is related to their molecular radii.

Administration, Cutaneous↗

PubMed2003

An experimental and theoretical analysis of ultrasound-induced permeabilization of cell membranes.

Application of ultrasound transiently permeabilizes cell membranes and offers a nonchemical, nonviral, and noninvasive method for cellular drug delivery. Although the ability of ultrasound to increase transmembrane transport has been well demonstrated, a systematic dependence of transport on ultrasound parameters is not known. This study examined cell viability and cellular uptake of calcein using 3T3 mouse cell suspension as a model system. Cells were exposed to varying acoustic energy doses at four different frequencies in the low frequency regime (20-100 kHz). At all frequencies, cell viability decreased with increasing acoustic energy dose, while the fraction of cells exhibiting uptake of calcein showed a maximum at an intermediate energy dose. Acoustic spectra under various ultrasound conditions were also collected and assessed for the magnitude of broadband noise and subharmonic peaks. While the cell viability and transport data did not show any correlation with subharmonic (f/2) emission, they correlated with the broadband noise, suggesting a dominant contribution of transient cavitation. A theoretical model was developed to relate reversible and irreversible membrane permeabilization to the number of transient cavitation events. The model showed that nearly every stage of transient cavitation, including bubble expansion, collapse, and subsequent shock waves may contribute to membrane permeabilization. For each mechanism, the volume around the bubble within which bubbles induce reversible and irreversible membrane permeabilization was determined. Predictions of the model are consistent with experimental data.

3T3 Cells↗

PubMed2003

Dependence of skin permeability on contact area.

PURPOSE: We report that experimentally measured skin permeability to hydrophilic solutes increases with decreasing contact area between the formulation and the skin. Our results suggest that an array of smaller reservoirs should thus be more effective in increasing transdermal drug delivery compared to a large single reservoir of the same total area. METHODS: Experimental assessment of the dependence of skin permeability on reservoir size was performed using two model systems, an array of liquid reservoirs with diameters in the range of 2 mm to 6 mm and an array of gel disk reservoirs with diameters in the range of 3 mm to 16 mm. Full thickness pig skin was used as an experimental model. Two molecules, sodium lauryl sulfate (SLS) and oleic acid, were used as model penetration enhancers. RESULTS. Mannitol transport per unit area into and across the skin increased with a decrease in the contact area between the skin and the formulation. Mannitol permeability increased approximately 6-fold with a decrease in the reservoir size from 16 mm to 3 mm in presence of 0.5% SLS in PBS (phosphate buffered saline) as a permeability enhancer. Similar results were obtained when oleic acid was used as an enhancer. CONCLUSIONS: To explain the observed dependence of transdermal transport on contact area a simple mathematical model based on skin geometry in the reservoir was developed. The model predicts a lateral strain in the skin due to preferential swelling of skin upon penetration of water. We propose that this lateral strain is responsible for the increased skin permeability at lower reservoir sizes.

Administration, Cutaneous↗

PubMed2002

Incorporation of lipophilic pathways into the porous pathway model for describing skin permeabilization during low-frequency sonophoresis.

Application of low-frequency sonophoresis (LFS) has been shown to increase skin permeability, thereby facilitating delivery of hydrophilic solutes. We have previously shown that the modified porous pathway model provides an adequate theoretical description of transdermal delivery of hydrophilic solutes through pores in the presence and absence of ultrasound. However, small hydrophilic solutes (M(w)<400 Da) that exhibit a moderate partition coefficient, K(o/w) (0.1<K(o/w)<1), may also have a substantial contribution to permeability from transport through intercellular lipid bilayers. The aim of this note is to incorporate the lipophilic pathway into the porous pathway model to describe transdermal drug transport in the absence and presence of ultrasound.

Membrane Lipids↗

PubMed2002

Synergistic effect of low-frequency ultrasound and surfactants on skin permeability.

Low-frequency ultrasound (20 kHz) and surfactants have been individually shown to enhance transdermal drug transport. In this study, we investigated the synergistic effect of ultrasound and surfactants on transdermal drug delivery. Surfactants with different head group chemistries including anionic, cationic, and nonionic with varying tail lengths (8-16-carbon atoms) were studied. We found that surfactants possessing anionic and cationic head groups were more potent than those possessing nonionic head groups in increasing skin conductivity in the presence of ultrasound. Furthermore, for surfactants possessing the same head group, those with a 14-carbon tail length were found to be most effective in enhancing skin permeability. The data presented in this report show that ultrasound and surfactants synergistically enhance skin permeability. Two mechanisms are shown to play a role in this synergistic effect. First, ultrasound enhances surfactant delivery (enhanced delivery) into the skin and, second, ultrasound disperses surfactant (enhanced dispersion) within the skin. In general, surfactants that are potent enhancers by themselves are potent enhancers in the presence of ultrasound as well. We performed imaging experiments to assess the effect of ultrasound on delivery of a model permeant, sulforhodamine B, into the skin. These experiments show that ultrasound enhances surfactant delivery and dispersion in the skin.

Administration, Cutaneous↗

PubMed2002

Investigations of the role of cavitation in low-frequency sonophoresis using acoustic spectroscopy.

Application of low-frequency ultrasound significantly enhances skin permeability. The enhancement of skin permeability is mediated by cavitation, oscillation, and collapse of gaseous cavities. In this article, we report detailed investigations of the occurrence of cavitation during low-frequency sonophoresis. Cavitation was monitored by recording pressure amplitudes of subharmonic emission and broadband noise at four different ultrasound frequencies in the range of 20-100 kHz and at various intensities in the range of 0-2.6 W/cm(2). Enhancement of skin conductivity, in the presence of sodium lauryl sulfate (SLS), was also measured under the same ultrasound conditions. Enhancement of skin conductivity correlated well with the amplitude of broadband noise, which suggests the role of transient cavitation in low-frequency sonophoresis. No correlation was found between the subharmonic pressure amplitude and conductivity enhancement.

Animals↗

PubMed2002

A theoretical analysis of permeation of small hydrophobic solutes across the stratum corneum based on Scaled Particle Theory.

The barrier properties of skin originate from its lipid bilayers whose ordered structure retards solute transport. The objective of this study is to develop a mathematical model that can predict skin permeability to small (MW < 500 Da), hydrophobic solutes based on the fundamental transport properties of skin lipid bilayers. We developed a mathematical model to predict two major transport properties (i.e., partition and diffusion coefficients) using important structural properties of lipid bilayers and molecular properties of the solute. The predictions are based on Scaled Particle Theory that calculates these properties using statistical mechanics of lipid chains. The calculations predict that solute partition coefficients in lipid bilayers are of the same order as those measured in isotropic solvents, such as octanol (K(o/w)). On the other hand, solute diffusion coefficients decrease exponentially with solute cross-sectional area. The resulting equation to predict skin permeability is given by P = 5.6 x 10(-6)K(0.7)(o/w)exp(-0.46r(2)(A1)--where r is solute molecular radius in Angstroms (A) and P is in cm/s. The predicted skin permeabilities compare well with the experimental data.

Algorithms↗

PubMed2002

Porous resins as a cavitation enhancer for low-frequency sonophoresis.

The application of low-frequency ultrasound enhances drug transport through the skin, a phenomenon referred to as low-frequency sonophoresis. This enhancement is mediated through cavitation, the formation and collapse of gaseous bubbles. We hypothesized that the efficacy of low-frequency sonophoresis can be significantly enhanced by provision of nuclei for cavitation. In this study, we used two porous resins, Diaion HP20 and Diaion HP2MG (2MG), as cavitation nuclei. We measured the effect of these resins on cavitation using pitting of aluminum foil. 2MG showed a higher efficacy in enhancing cavitation compared with Diaion HP20. 2MG was also effective in enhancing transdermal mannitol transport. These results confirm that the addition of cavitation nuclei such as porous resins further increases the effect of low-frequency ultrasound on skin permeability.

Administration, Cutaneous↗

PubMed2002

High throughput screening of transdermal formulations.

PURPOSE: Applications of transdermal drug delivery are limited by low skin permeability. Many chemicals have been used to enhance skin permeability, however, only a handful are actually used in practice. Combinations of chemicals are likely to be more efficient in enhancing skin permeability compared to individual enhancers. However, identification of efficient enhancer combinations is quite challenging because many chemical enhancers interact with each other and with the skin in a complex manner. In the absence of a fundamental knowledge of such interactions, we need to rely on rapid methods to screen various enhancer combinations for their effectiveness. In this paper, we report a novel high throughput (HTP) method that is at least 50-fold more efficient in terms of skin utilization and up to 30-fold more efficient in terms of holdup times than the current methods for formulation screening (Franz diffusion cells). METHODS: A high throughput method was developed based on skin conductivity and mannitol penetration into the skin. This method was used to perform at least 100 simultaneous tests per day. Detailed studies were performed using two model enhancers, sodium lauryl sulfate (SLS) and dodecyl pyridinium chloride (DPC). The predictions of the high throughput method were validated using Franz diffusion cells. RESULT: High throughput screening revealed that mixtures of SLS and DPC are significantly more effective in enhancing transdermal transport compared to each of them alone. Maximum efficiency was observed with near-equimolar mixtures of SLS: DPC. The predictions of the HTP method compared well against those made using Franz diffusion cells. Specifically, the effect of surfactant mixtures on skin conductivity and mannitol permeability measured using Franz cells also showed a maximum at near-equimolar mixtures of SLS: DPC. CONCLUSIONS: The novel HTP method allows rapid screening of enhancer formulations for transdermal applications. This method can be used to discover new and effective enhancer mixtures. At the same time, these data may also broaden our understanding of the effect of enhancers on skin permeability.

Adjuvants, Pharmaceutic↗

PubMed2002

Transdermal drug delivery by jet injectors: energetics of jet formation and penetration.

PURPOSE: Pressure-driven jets have been used for intradermal delivery of a variety of drugs. Despite their introduction into clinical medicine, variability and occasional bruising have limited their widespread acceptance. Although numerous clinical studies of jet injectors have been reported in the literature, surprisingly little is known about the mechanisms of jet penetration into the skin. In this article, we report results of our studies aimed at determining the dependence of drug delivery on jet velocity and diameter. These studies were performed using two experimental models, porcine skin and human skin. Our rationale for using two models was to explore the possibility of using porcine skin as a model for human skin. METHODS: Dermal penetration of jets possessing a range of diameters from 76 microm to 559 microm and a range of velocities from 80 m/s to 190 m/s was studied into human and porcine skin. Penetration was quantified using radiolabeled mannitol. Pressure and velocity of the jets were measured using a calibrated pressure transducer and high-speed photography. RESULTS: Penetration of the jet into the skin was determined by two main parameters, jet diameter and average jet velocity. Substantial variation in jet penetration into porcine skin was observed for skin pieces obtained from different anatomic locations. For porcine skin, a parabolic dependence of jet delivery on velocity and diameter was observed. The threshold velocity is suggested to be between 80 and 100 m/s for a jet diameter of 152 microm. Above the threshold velocity, the delivery increased for velocities up to 150 m/s, after which delivery decreased with increasing velocity. At a constant velocity of 150 m/s, jet delivery exhibited a maximum at a diameter of 152 microm. Results obtained with human skin were qualitatively similar but quantitatively different. The threshold velocity for jet penetration into human skin was comparable with that in porcine skin; however, the maxima observed in jet delivery into porcine skin with respect to jet velocity was not apparent for human skin over the range of velocities explored. CONCLUSIONS: These studies offer a quantitative analysis of jet penetration into the skin.

Administration, Cutaneous↗

PubMed2002

A theoretical analysis of low-frequency sonophoresis: dependence of transdermal transport pathways on frequency and energy density.

PURPOSE: Application of low-frequency ultrasound has been shown to increase skin permeability, thereby facilitating delivery of macromolecules (low-frequency sonophoresis). In this study, we seek to determine the dependence of transport pathways during low-frequency sonophoresis on ultrasound parameters. METHODS: Pig skin is exposed to low-frequency ultrasound over a range of frequencies to achieve different skin resistivities. The porous pathway model is used to study the dependence of average pore size, porosity, and tortuosity on ultrasound parameters. Imaging experiments are also carried out to visualize the transport pathways created by ultrasound. RESULTS: The data show that the average pore size, determined from the porous pathway model, does not depend on application frequency. Both in the presence and absence of ultrasound the average pore size determined from mannitol delivery is the same (28 +/- 12 A). With the application of ultrasound the skin porosity could be increased by up to 1700-fold. The effect of ultrasound on skin is heterogeneous thereby creating localized transport pathways (LTP). The porosity of these transport pathways is of the same order of magnitude as that of the dermis. CONCLUSIONS: With this study it is shown that low-frequency ultrasound increases skin permeability by increasing skin porosity rather than by increasing the size of the pores that are responsible for permeant delivery.

Administration, Cutaneous↗