Ultrasound Science
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A Geoscience Approach to Modeling Chemical Transport through Skin
by Clifford K. Ho
Full Story: www.sandia.gov/geobio/cliff.html
3.1 Introduction
Modeling chemical transport through human skin (percutaneous absorption) serves an important role in two primary arenas: (1) hazardous chemical-exposure assessments and (2) transdermal drug delivery. In the former, models are used to understand relevant features and processes of percutaneous absorption so that protective measures can be designed and implemented that minimize the risk ..(Stewart and Dodd, 1964; Bird, 1981; Flynn, 1990; EPA, 1992; Ness, 1994; Poet et al., 2000; McDougal and Boeniger, 2002; Poet and McDougal, 2002). In the latter arena, researchers are striving to enhance the viability of transdermal delivery of drugs such as analgesics, insulin, and more recently, peptides and proteins (Amsden and Goosen, 1995; Potts and Guy, 1995; Kalia and Guy, 2001). Transdermal delivery of drugs that require low dosages for long periods can be more effective, less costly, and less painful than traditional alternatives such as injection, intravenous infusion, or oral ingestion.
3.2 Anatomy of the Skin
The skin is a complex organ that serves to protect humans from chemical, physical, and biological intrusion, while retaining moisture and providing thermal regulation. It consists of three primary regions: the epidermis, the dermis, and the hypodermis (see Figure 3.1). The epidermis is the outermost layer of the skin in contact with the environment, ranging between 0.075 and 0.20 mm thick in most regions and between 0.4 and 0.6 mm thick in the palms and soles (Amsden and Goosen, 1995; Flynn, 1990). It consists of the stratum corneum, which forms the outermost layer of the epidermis, and the viable epidermis, which consists of the granular, spinous, and basal layers. The epidermis does not contain any capillary vasculature, so chemicals that transport through the epidermis must also transport partially through the dermis to reach the bloodstream. The cells in the epidermis are continually shed to the surface and replaced from the basal layer. These cells are replaced completely on the average of once every two weeks.
Figure 3.1 Skin features relevant to percutaneous absorption of chemicals.
The outermost layer of the epidermis, the stratum corneum, is the primary barrier to permeation of most drugs and chemicals (Scheuplein, 1976; Michaels et al., 1975). The stratum corneum is between 10 and 50 mm thick (15-20 cell layers thick) and contains dead keratinized cells (keratinocytes) with lipid lamellae filling the intercellular regions. It is composed of a very heterogeneous structure containing approximately 20-40% water, 20% lipids, and 40% keratinized protein. The keratinocytes, connected together in a planar array by desmosomes, are thin platelets filled with polar protein strands woven into compact and dense keratin fibers. The lipids form a continuous, albeit extremely tortuous, intercellular network between the keratinocytes. The compactness of the keratinocytes and the limited amount of intercellular lipid results in the low permeability of the stratum corneum.
The underlying dermis contains the vasculature (blood vessels and lymph vessels) that can uptake chemicals diffusing through the skin. The vasculature can reach to within a few microns of the undersurface of the epidermis. The dermis consists of a moderately dense network of connective tissue composed of collagen fibers and elastic fibers. It varies in thickness from 1 to 4 mm depending on the location of the body. Diffusion through this layer is analogous to diffusion through hydrogels (Amsden and Goosen, 1995).
Hair follicles and sweat glands, called skin appendages, break the continuity of the epidermal and dermal layers throughout most of the surface of the body. On average, 40 to 100 hair follicles and 210 to 220 sweat ducts exist per square centimeter of skin, occupying about 0.1% of the total surface area (Scheuplein, 1967). Hair follicles extend through the epidermis into the dermis, where the base of the follicle is well vascularized. Sebaceous glands attached to the sides of the follicles secrete sebum, a lipid mixture, into the region between the hair and the sheath. The sweat glands consist of tubes extending from the dermis, where the tube is coiled and vascularized, to the skin surface where a watery mixture (sweat) is excreted to provide thermal regulation.
3.3 Skin Permeation Routes and Previous Models
Based on the physiology of the skin, three possible pathways exist for passive transport of chemicals through the skin to the vascular network (Scheuplein, 1965; Scheuplein and Blank, 1971): (1) intercellular diffusion through the lipid lamellae; (2) transcellular diffusion through both the keratinocytes and lipid lamellae; and (3) diffusion through appendages (hair follicles and sweat ducts). Figure 3.2 illustrates these potential pathways.
Figure 3.2 Skin permeation routes through the stratum corneum: (1) intercellular diffusion through the lipid lamellae; (2) transcellular diffusion through both the keratinocytes and lipid lamellae; and (3) diffusion through appendages (hair follicles and sweat ducts).
A number of models have been developed that simulate one or more of these pathways. Michaels et al. (1975) considered the first two modes of transport by modeling the steady-state behavior of the stratum corneum as a two-phase "brick and mortar" region (the aqueous protein phase in the keratinocytes was modeled as the bricks and the intercellular lipid phase was modeled as a continuous mortar). They assumed that the transport was the sum of steady diffusion (1) through the lipid and protein in series and (2) through the lipid phase via a tortuous path. They estimated tortuosities (~10:1) and diffusion coefficients through the lipid and protein. Experiments were conducted using cadaver skins and several different drug chemicals. Results showed a permeation dependence on pH (higher pH gave a higher flux for the same concentration) and mineral oil/water partition coefficient (larger partition coefficients yielded greater fluxes). They concluded that the ratio of the lipid diffusivity to the protein diffusivity (one of the two important parameters in their model) was 10-2 to 10-3, meaning that the diffusion coefficient for the lipid phase was about 500 times less than the diffusion coefficient for the protein phase, which they estimated to be about 2x10-7 cm2/s (from Michaels et al., 1975).
Flynn (1990), however, stated that the density and compactness of the intracellular protein in the keratinocytes of the stratum corneum presents a thermodynamically and kinetically impossible passageway for chemical transport. Other recent investigators also supported the belief that when comparing evidence for intercellular versus transcellular diffusion, intercellular diffusion through the lipid lamellae is the predominant mode of transport (Amsden and Goosen, 1995). As a result, Flynn (1990) proposed an alternate "aqueous pore pathway" in parallel (as opposed to in series) with the lipid pathways through the stratum corneum to represent the limited intercellular aqueous phase. Although the location of these aqueous pathways was uncertain, Flynn included these pathways to accommodate the diffusion of polar compounds. Other researchers have argued a similar phenomenon by considering both a polar and non-polar pathway through the stratum corneum. Elias (1981) described the polar pathway in terms of aqueous pores in the small aqueous phase between the lipid lamellae. Supporting this theory, Cooper (1984) found that polar molecules such as water and small ions permeated the skin and that the flux was independent of the oil/water partition coefficient. As the polarity of the molecules decreased, the flux became a function of the partition coefficient (Scheuplein and Blank, 1971).
Results of Flynn (1990) showed that diffusion was a direct function of the octanol/water partition coefficient, Kow, and molecular weight, MW (for a given Kow, chemicals with larger molecular weights exhibited lower diffusion; for a given MW, chemicals with greater Kow yielded more diffusion). The study showed that larger molecular-weight chemicals permeated slower in general, but the phase of the vehicle (water or oil) delivering the chemical was not specified. Scheuplein (1976) and Potts and Guy (1995) point out that the permeability of a chemical depends on the phase of the vehicle. If the molecular weight is high, indicating a more lipophilic compound, then the permeability will be greater if the vehicle is a water than an oil since the compound will want to partition out of the water and into the tissue. Flynn (1990) also presented a simple exposure-assessment equation using the results of his modeling that expressed the cumulative mass entering the skin. The permeability coefficient was determined from simple equations that were correlated to experimental results for different Kow and MW values. The equation assumed that the cumulative mass entering the skin took place after the lag time, which Flynn estimated could be approximately 10 minutes for MW<150 and 1 hour for MW>150.
Scheuplein (1967) developed analytical transient models of percutaneous absorption considering transport via appendages. He compared transport through appendages with transport through the intact stratum corneum, which he modeled as two single-phase regions: (1) the stratum corneum with a thickness of 10 mm and (2) the aqueous viable epidermis and papillary dermis with a combined thickness of 200 mm. To determine the cumulative amount of chemical transported, he used a composite slab solution (using resistances in series). From this he concluded that the appendages (follicles and sweat ducts), which had several orders of magnitude higher diffusion coefficients, allowed greater transport at early times, but that the bulk stratum corneum would allow greater diffusion at longer times. To determine concentrations profiles, he used a steady-state solution to determine the steady concentrations in the two slabs and a semi-infinite solution to determine the transient concentrations in the two slabs. The semi-infinite solution does not yield a concentration of zero at the boundary of the basal layer, which was inconsistent with his general formulation, but it did provide some relative comparisons. He also showed that the partitioning coefficient between the lipid and aqueous regions could also impact the concentration gradient.
Kalia and Guy (2001) developed a number of analytical solutions for transient diffusion of drugs through the skin. They treated the skin as a homogeneous slab, but they considered different scenarios for the delivery vehicle (e.g., patch with a reservoir on top, patch with drug dispersed, drug in an ointment, etc.). They concluded that a unified model that could consider the effects of molecular weight and partition coefficients was necessary. Other models have been developed that do not consider the specific routes of transport through the skin but attempt to describe the general rate of chemical transport through the skin and/or into the circulatory system using empirical observations and lumped-capacitance models. These models are generally described as physiologically-based pharmaco-kinetic models (PBPK). The general method is to correlate existing data to simple compartment models that represent the skin and various processes and regions associated with uptake into the body. Potts and Guy (1995) and Poet et al. (2000) have developed PBPK models that can predict chemical diffusion and uptake through the skin using physical properties of the chemical. Potts and Guy (1995) developed a model that provides an algorithm to predict permeability from the drug's physical properties. Multiple regression analyses were performed using previous data of the permeability coefficient for different chemicals, and the molecular volume and the hydrogen bond activity parameters were determined to be important. However, this model is only valid when the stratum corneum is the rate-limiting barrier to percutaneous absorption (i.e., for polar compounds). Poet et al. (2000) used a PBPK model to estimate skin permeability values and to predict exhaled concentrations of trichloroethylene (TCE) when subjects were exposed to TCE. Good agreement was obtained between predicted and observed TCE concentrations, but the relative importance of the various features and processes were not elucidated. In general, specific routes of permeation that contribute to the overall rate of transport through skin are not considered in PBPK models.
3.4 Model Development
Most of the models of percutaneous absorption that have been developed previously treat the skin as a homogeneous medium with an effective (average) permeability coefficient. These include many of the transient analyses (e.g., Kalia and Guy, 2001) and the PBPK analyses (e.g., Poet et al., 2000). A few models that do consider multiphase heterogeneous transport through the various layers and pathways of the skin often assume steady-state conditions (e.g., Michaels et al., 1975; Flynn, 1990). Scheuplein (1967) developed models of transient diffusion through different pathways in the skin, but deterministic models were used. In the following sections we develop a probabilistic, transient, multiphase model of chemical transport through various routes in the skin to address the inherent uncertainties in the processes and parameters associated with percutaneous absorption.
In particular, we consider the following possible pathways: (1) intercellular diffusion through the lipids and aqueous "pores" in the stratum corneum (pathway #1 in Figure 3.2); and (2) diffusion through appendages (hair follicles and sweat ducts) (pathway #3 in Figure 3.2). We do not consider the transcellular pathway across keratinocytes and lipids (pathway #2 in Figure 3.2) because the evidence presented earlier suggests that diffusion through the keratinocytes would be extremely small.
3.4.1 Intercellular Diffusion through the Stratum Corneum
Intercellular diffusion through the stratum corneum is modeled as a three-phase continuum. The keratinized cells in the stratum corneum are considered to be an immobile protein phase, which can provide reversible interactions (adsorption and desorption) with chemicals in the mobile phases. The mobile phases include the lipid (or oil) and aqueous (water) phases in between the keratinocytes. A differential control volume consisting of these three phases is shown in Figure 3.3.
Figure 3.3 Control volume for intercellular chemical diffusion through a three-phase region in the stratum corneum: p = immobile protein phase (keratinocytes), o = mobile oil (lipid) phase, w = mobile water (aqueous) phase.
3.4.2 Diffusion through Sweat Ducts
Chemical permeation through sweat ducts is modeled as a single-phase aqueous diffusion process. A control volume consisting of a sweat duct (or hair follicle) in a larger continuum is shown in Figure 3.4. For simplicity, the region around the sweat duct is assumed to be impermeable (no interactions), and the sweat duct is assumed to be filled with water. The region around the sweat duct is included in the control volume to represent a larger unit area of skin for normalization with the other transport pathways.
Figure 3.4 Control volume for diffusion through an appendage (sweat duct or hair follicle). Diffusion is assumed to occur through a single-phase fluid in the appendage.
3.5.3.2 Implications for Transdermal Drug Delivery
One of the significant problems of transdermal drug delivery is the ability to deliver sufficient doses of a particular drug through the skin. Several methods have been developed to augment the passive diffusion of water-soluble drugs such as peptides and proteins through the skin (Amsden and Goosen, 1995), and these are briefly summarized below:
- Prodrugs: Lipophilic groups are covalently bonded onto functional groups of the drug to improve partitioning into the intercellular lipid lamellae of the stratum corneum. Enzymes detach the lipophilic groups in vivo, rendering them free and active. However, prodrugs have molecular size restrictions and require synthesis.
- Chemical permeation enhancers: Compounds exist that alter the skin as a permeability barrier. Known permeation enhancers include solvents and surfactants; however, the physical basis for the method of enhancement is still unknown. No general theory of chemical enhancement has been provided.
- Iontophoresis: An iontophoretic device consists of two electrodes immersed in an electrolyte solution and placed on the skin. When an electric current is applied across the electrodes, an electric field is created across the stratum corneum that drives the delivery of ionized drugs. The primary route of ion transport appears to be through hair follicles or sweat glands, although additional uncertain pathways may be created. This method is restricted to short-term delivery.
- Electroporation: Electroporation involves the application of high-voltage electric pulses to increase the permeation through lipid bilayers. This differs from iontophoresis in the duration and intensity of the application of electrical current (iontophoresis uses a relatively constant low-voltage electric field). The high-voltage electric pulse of electroporation is believed to induce a reversible formation of hydrophilic pores in the lipid lamellae membranes that can provide a high degree of permeation enhancement, but the physics and dynamics of this process are not completely understood. This method is restricted to short-term delivery.
- Ultrasound: Ultrasound applies sound waves having a frequency greater than 16 kHz to the skin, which causes compression and expansion of the tissue through which the sound waves travel. The resulting pressure variations cause a number of processes (e.g., cavitation, mixing, increase in temperature) that may increase the permeation of drugs. Again, the exact processes and physics have not yet been determined, and this method is restricted to short-term delivery.
In all of these methods, significant uncertainty exists regarding the processes and parameters that truly cause enhanced permeation. Probabilistic simulations and sensitivity analyses coupled with mechanistic models of each of these processes can help to identify the most likely processes and parameters that are significant to drug-delivery enhancement. While models of empirical correlations are intended to provide similar information, they are not inherently based on physical processes or mechanisms. If processes or parameters are introduced that have not been used in these correlations, the results are likely to be erroneous. Therefore, mechanistic models combined with probabilistic analyses are needed to better understand and improve these methods.
3.7 References
Amsden, B. G. and Goosen, M. F. A. (1995) Transdermal delivery of peptide and protein drugs: an overview. AIChE Journal, 41(8), 1972-1997.
Bird, M. G., (1981) Industrial solvents: some factors affecting their passage into and through the skin. Ann. Occup. Hyg., 24(2) 235-244.
Cooper, R. R. (1984) Increased skin permeability for lipophilic molecules. J. Pharm. Sci., 73, 1153.
Crank, J. (1975) The Mathematics of Diffusion. 2nd Ed. Oxford University Press, Oxford.
Department of Energy (DOE) (1998) Viability assessment of a repository at Yucca Mountain, Volume 3: Total system performance assessment. Report DOE/RW-0508/V3, U.S. Department of Energy, Washington, DC.
Environmental Protection Agency (EPA), (1992) Dermal exposure assessment: principals and applications. Report EPA/600/8-91/011B, U.S. Environmental Protection Agency, Washington, DC.
Flynn, G. L. (1990) Physicochemical Determinants of Skin Absorption. Published by Elsevier in Proceedings of the Workshop on Principles of Route-to-Route Extrapolation for Risk Assessment, Hilton Head, SC, March 19-21, 93-127.
Ho, C. K. (1997) Models of fracture-matrix interactions during multiphase heat and mass flow in unsaturated fractured porous media. In Proceedings of the ASME Fluids Engineering Division, Sixth Symposium on Multiphase Transport in Porous Media, 1997 ASME International Mechanical Engineering Congress and Exposition, FED-Vol. 244, Dallas, TX, November 16-21, pp. 401-412.
Kalia, Y. N. and Guy, R. H. (2001) Modeling transdermal drug release. Advanced Drug Delivery Reviews, 48, 159-172.
McDougal, J. N and Boeniger, M. F. (2002) Methods for assessing risks of dermal exposures in the workplace. Critical Reviews in Toxicology, 32(4), 291-327.
Michaels, A. S., Chandrasekaran, S. K., and Shaw, J. E. (1975) Drug permeation through human skin: theory and in vitro experimental measurement. AIChE Journal, 21(5), 985-1996.
Ness, S. A. (1994) Surface and Dermal Monitoring for Toxic Exposures. Van Nostrand Reinhold International Thomson Publishing Company, New York.
Poet, T. S. and McDougal, J. N. (2002) Skin absorption and human risk assessment. Chemico-biological interactions, 140, 19-34.
Poet, T. S., Corley, R. A., Thrall, K. D., Edwards, J. A., Tanojo, H., Weitz, K. K., Hui, X., Maibach, H. I., and Wester, R. C. (2000) Assessment of the percutaneous absorption of trichloroethylene in rats and humans using MS/MS real-time breath analysis and physiologically based pharmacokinetic modeling. Toxicological Sciences, 56, 61-72.
Potts, R. O. and Guy, R. H. (1995) A predictive algorithm for skin permeability: the effects of molecular size and hydrogen bond activity. Pharmaceutical Research, 12(11), 1628-1633.
Reid, R. C., Prausnitz, J. M., and Poling, B. E. (1987) The Properties of Gases and Liquids. 4th Ed., McGraw Hill, Inc., New York.
Scheuplein, R. J. (1965) Mechanism of percutaneous absorption I. routes of penetration and the influence of solubility. J. Investigative Dermatology, 45(5), 334-346.
Scheuplein, R. J. (1967) Mechanism of percutaneous absorption II. transient diffusion and the relative importance of various routes of skin penetration. J. Investigative Dermatology, 48(1), 79-88.
QUICK REFERENCE GLOSSARY
for body workers and Medical Estheticians
Click below to jump to a specific section:
Selected Prefixes
| Prefix | Meaning | Prefix | Meaning |
|---|---|---|---|
| Abdomin/o | abdomen | Embol/o | embolus |
| Adren/o | adrenal glands | Enter/o | small intestine |
| Adrenal/o | adrenal glands | Erythr/o | red |
| Albino/o | white | Galact/o | milk |
| Aliment/o | nourish | Gastr/o | stomach |
| Angi/o | blood vessel | Glomerul/o | glomerulus |
| Anter/o | front | Gloss/o | tongue |
| Arteri/o | artery | Gluc/o | sugar |
| Aque/o | water | Glyc/o | sugar |
| Audi/o | hearing | Gonad/o | sex glands |
| Audit/o | hearing | Gravid/o | pregnancy |
| Bil/I | bile | Gynec/o | woman, female |
| Blast/o | primitive cell | Hem/o | blood |
| Brachi/o | arm | Hemangi/o | blood vessel |
| Bronchi/o | bronchiole | Hemat/o | blood |
| Burs/o | sac | Hepat/o | liver |
| Calc/o | calcium | Hyster/o | uterus, womb |
| Carcin/o | cancerous | Ile/o | ileum |
| Cardi/o | heart | Ili/o | ilium, part of hip bone |
| Carp/o | wrist | Immun/o | resistant |
| Caud/o | tail | Labi/o | lip |
| Cec/o | cecum | Later/o | side |
| Cephal/o | head | Mamm/o | breast |
| Cerebell/o | cerebellum | Mast/o | breast |
| Cerebr/o | brain | Melan/o | black |
| Cervic/o | neck, cervix | Men/o | menses, menstruation |
| Cholangi/o | bile duct | Metr/o | uterus |
| Cholecyst/o | gallbladder | Myel/o | bone marrow, spinal cord |
| Choledoch/o | common bile duct | Nat/o | birth |
| Chrondr/o | cartilage | Nephr/o | kidney |
| Coagul/o | clotting | Neur/o | nerve |
| Coccyg/o | coccyx | Onc/o | tumor |
| Colp/o | vagina | Oophor/o | ovary |
| Crani/o | head, skull | Oste/o | bone |
| Cutane/o | skin | Pancreat/o | pancreas |
| Cyan/o | blue | Patell/o | kneecap, patella |
| Cyst/o | cyst, sac | Pneum/o | lung, air |
| Cyt/o | cell | Pulmon/o | lung |
| Dactyl/o | digit, one finger or toe | Py/o | pus |
| Derm/o | skin | Pyel/o | renal (kidney) pelvis |
| Dors/o | back of body | Ren/o | kidney |
| Duoden/o | duodenum | Thorax/o | chest |
Medical Abbreviations and Symbols
| AB | abortion |
| ACTH | adrenocorticotropic hormone |
| BP | blood pressure |
| BUN | blood urea nitrogen |
| BX | bx biopsy |
| Ca | calcium |
| CAD | coronary artery disease |
| COPD | chronic obstructive pulmonary disease |
| CSF | cerebrospinal fluid |
| CT | computed tomography (also called CAT) |
| D&C | dilation and curettage |
| DM | diabetes mellitus |
| DOB | date of birth |
| Dx | diagnosis |
| ER | emergency room |
| FSH | follicle-stimulating hormone |
| GI | gastrointestinal |
| GU | genitourinary |
| GYN, gyn | gynecology |
| HGH | human growth hormone |
| IUD | intrauterine device |
| IV | intravenous |
| LH | luteinizing hormone |
| LLQ | left upper quadrant |
| OB | obstetrics |
| OB-GYN | obstetrics and gynecology |
| /p | after |
| PA | posteroanterior |
| PID | pelvic inflammatory disease |
| po | by mouth (per os) |
| prn | as the occasion arises (pro re nata) |
| RBC | red blood cell |
| RES | reticuloendothelial system |
| RLQ | right lower quadrant |
| RUQ | right upper quadrant |
| s | without |
| SOB | shortness of of breath |
| stat | immediately (statim) |
| STD | sexually transmitted disease |
| TSH | thyroid-stimulating hormone |
| UTI | urinary tract infection |
| WBC | white blood cells |
Appendix
Most commonly seen abbreviations related to ultrasound
| AAA | abdominal aortic aneurysm |
| AFP | alpha fetoprotein |
| ARC | aids related complex |
| BP | blood pressure |
| BX | biopsy |
| CBD | common bile duct |
| CNS | central nervous system |
| Cx | cervis |
| dB | decibel |
| D&C | dilatation and curettage |
| EDC | estimated date of confinement |
| EFW | estimated fetal weight |
| ETOH'er | ethanol (alcohol) abuser |
| FSH | follicle-stimulating hormone |
| FUO | fever of unknown origin |
| G | gravida |
| GB | gallbladder |
| GRD | gestational trophoblastic disease |
| Gyn | gynecology |
| HCG | human chorionic gonadotropin |
| Hydro | hydrocephalus, or hydronephrosis |
| LH | luteinizing hormone |
| LK | left kidney |
| LLQ | left lower quadrant |
| LMP | last menstrual period |
| MHz | megahertz |
| NPO | nothing by mouth |
| NST | nonstress test |
| Ob | obstetrics |
| OCP | oral contraceptives |
| Para 1234 | (1) number of pregnancies
(2) number of premature births (3) number of abortions (4) number of living children |
| PID | pelvic inflammatory disease |
| PT | pregnancy test |
| PV | portal vein |
| RBC | red blood cell |
| Rk | right kidney |
| RLQ | right lower quadrant |
| R/O | rule out |
| RUQ | right upper quadrant |
| Rx | treatment |
| SMV | superior mesenteric vein |
| WBC | white blood cell |
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