in vivo measurement of human skin absorption of topically applied substances by a photoacoustic...

INSTITUTE OF PHYSICS PUBLISHING PHYSIOLOGICAL MEASUREMENT

Physiol. Meas. 23 (2002) 521–532 PII: S0967-3334(02)34632-X

In vivo measurement of human skin absorption oftopically applied substances by a photoacoustictechnique

G Gutierrez-Juarez, M Vargas-Luna, T Cordova, J B Varela,J J Bernal-Alvarado and M Sosa

Instituto de Fısica, Universidad de Guanajuato, Apartado Postal E-143, 37000 Leon, Gto, Mexico

Received 7 March 2002Published 24 May 2002Online at stacks.iop.org/PM/23/521

AbstractA photoacoustic technique is used for studying topically applied substanceabsorption in human skin. The proposed method utilizes a double-chamber PAcell. The absorption determination was obtained through the measurement ofthe thermal effusivity of the binary system substance–skin. The theoreticalmodel assumes that the effective thermal effusivity of the binary systemcorresponds to that of a two-phase system. Experimental applications of themethod employed different substances of topical application in different partsof the body of a volunteer. The method is demonstrated to be an easily usednon-invasive technique for dermatology research. The relative concentrationsas a function of time of substances such as ketoconazol and sunscreen weredetermined by fitting a sigmoidal function to the data, while an exponentialfunction corresponds to the best fit for the set of data for nitrofurazona, vaselineand vaporub. The time constants associated with the rates of absorption,were found to vary in the range between 10 and 58 min, depending on thesubstance and the part of the body.

Keywords: Photoacoustic, thermal effusivity, skin

1. Introduction

For the characterization of any material, a wide variety of physical properties can be considered,including the thermal properties. Photothermal (PT) techniques have proved to be a usefultool for the thermal characterization of a large number of materials, such as crystals, liquids,gases and also biological materials (Mandelis and Hess 1997).

PT techniques are based on the heat generated in a sample by a non-radiative de-excitationprocess as a consequence of the absorption of modulated light which impinges on the sample.Among PT techniques, photoacoustic (PA) techniques are based on the sound generated by

522 G Gutierrez-Juarez et al

the pressure changes in a gas chamber surrounding the sample due to the modulated heatingof a thin layer of the chamber gas adjacent to the sample.

Despite biological systems, such as the human skin, being very complex, PT techniqueshave been used successfully to characterize them. Results have been reported on thespectroscopy of the human skin using PA techniques to study the penetration of topicallyapplied drugs (Sennhenn et al 1988) and evaluation of the human skin permeation of topicallyapplied agents by the mirage effect (Plamann et al 1992). Bindra et al (1994) have reportedmeasurements of in vivo optothermal characterization of human skin, epidermal thickness andstratum corneum hydration. Takamoto et al (1994) have measured percutaneous absorption byusing a PA cell. Kraning (1973) reported the heat conduction in blackened skin, while Gieseet al (1994) predicted the optothermal pulse response of human skin by using a mathematicalmodel.

Also, some results have been reported using pulsed photoacoustic technique (Puccetti et al1997), which allowed the authors to develop a study both in time and frequency in in vitrosamples.

On the other hand, Balderas-Lopez et al (1999) used a conventional PA cell to measurethe thermal effusivity of any kind of liquid without exposing the sample to direct radiation.In their work the authors assumed the Rosencwaig and Gersho (RG) model (1976) for theproduction of the PA signal.

More recently Raicu et al (2000) have measured radio-frequency dielectric properties ofthe human skin in vivo by using a non-invasive open-ended coaxial probe. In their work theymeasured permittivity and conductivity of both dry and wet skin; while Telenkov et al (2001)used infrared imaging techniques for non-contact in vivo determination of thermal diffusivityin epidermis.

In this paper the results are presented on in vivo measurements of human skin absorptionof topically applied substances by PA techniques, by using a modified conventional PA cell,which consists of a double cell mounted directly on the skin through a thermally thin foil. Thepurpose of this study was to demonstrate the feasibility of using a non-invasive measurement,such as the thermal effusivity, provided by PA spectroscopy, for dermatology research, to getinformation on normal human skin drug absorption.

In contrast to some other investigations which deal with in vitro samples, and irradiatethem directly, and carry out a detailed deep profile analysis on a wide variety of substances, inthis work the emphasis on in vivo measurements, for a best approach to the actual conditions,requires indirect light incidence on the skin, especially if a significant energy absorbance isrequired to get a good PA signal. The thermal penetration is of the same order as in the workby Puccetti et al (1997), because of the use, in this work, of low modulation frequencies. Ourmain goal is to study the global behaviour of the substance penetration phenomenon.

2. Theoretical concerns

2.1. The human skin

The human skin is a complex and dynamic multilayered medium in which two layers dominate:the dermis has a thickness of ∼3 mm and the epidermis is ∼0.1 mm thick. However, theepidermis is in fact a system comprising four layers in most of the body, the outermost layerbeing the stratum corneum, whose thickness varies from ∼0.01 mm at the forearm to muchgreater values at the heel.

The stratum corneum plays an important role in the attenuation of radiation throughthe skin. Radiation must pass through this outer layer of the epidermis before reaching

Measurement of human skin absorption of topically applied substances 523

other tissues. In fact, results reported in the literature reveal that the stratum corneum is thediffusional barrier in the skin.

On the other hand, it has been demonstrated that the water concentration across the stratumcorneum results in relevant effects on the thermal properties of the skin. PA spectroscopy issensitive to the presence of water in a sample. For dry skin the thermal diffusion length µ givenas µ = √

2α/ω, where α is the thermal diffusivity and ω is the modulation angular frequencyof the light, which is much greater than the stratum corneum thickness, that is ∼0.01 mm,for the frequency range used in our experiment; while for hydrated skin the thermal diffusionlength decreases.

Also, from an electrical point of view, the skin can be considered as a two-layered structure,namely the poorly conducting stratum corneum and the more conductive epidermis/dermislayers taken together.

In the work by Raicu et al (2000) the authors claim that the stratum corneum doesnot impair the dielectric property measurements of the deeper skin layers, especially whena suitable interface between the probe and the skin is produced by using a conductivephysiological solution. However, when the skin surface is dry, measurements correspondto the dielectric properties of the superficial layers. Therefore, the registration of the electricalproperties of the skin layers depends, among other factors, on the degree of hydration of thestratum corneum, which affects the electric field penetration into the tissue.

It has also been shown by other authors (Alanen et al 1999) that the frequency dependenceof the contributions of the two skin layers can have an important impact upon dielectricmeasurements.

2.2. Skin binary model

The key variable we propose to use in our experiment is the thermal effusivity ε, which isdefined by the equation

ε = √κρc, (1)

where κ , ρ and c stand for the thermal conductivity, the density and the specific heat,respectively. Recently, this thermal parameter has been determined by using the PA techniquein liquids and binary mixtures of liquids (Balderas-Lopez et al 1999).

To measure the effusivity we make use of the RG model, which gives the evolution Qof the pressure changes in the gas column of the PA cell. The function Q which is the resultof applying the RG model to a sample within a PA chamber (completely sealed) on whichimpinges a modulated light beam, is given by

Q = Y e−π/4

(b + 1) eσsls − (b − 1) e−σs ls

[(g + 1)(b + 1) eσsls − (g − 1)(b − 1) e−σs ls ], (2)

where Y is a coefficient independent of the modulation frequency which depends exclusively onthe thermal properties of the gas column, f is the modulated radiation frequency,σs is a complexthermal diffusion coefficient of the sample given by σs = (1 + j)as , where as = √

ω/2αs , lsis the thickness of the sample, while the parameters b and g are the ratios of effusivities betweenthe reference material and the sample, and between the gas and the sample, respectively. Inother words

b = εr

and g = εg

Now, taking into account the fact that we are interested in determining the amplitude ofthe PA signal, equation (2) is written after some algebra as

√[(b + 1)2 exp(2als) − (b − 1)2 exp(−2als) + 4(b2 − 1)2 sin2(2als)

](b + 1)2 exp(2als) + (b − 1)2 exp(−2als) + 2(b2 − 1) cos(2als)

where the approximation g � 1 was taken into account.From equation (4) different cases can be considered:

(a) Case in which the sample is the air. For this case b = g, and remembering that g � 1,b can be approximated to zero. Therefore, the amplitude of the PA signal becomes

Sr = Y

2π, (5)

where it was also assumed that al � 1, which means that the reference material behavesas thermally thin in the range of frequencies used. Note that, for a system like this, thePA signal amplitude varies as f −3/2.

(b) Case in which the sample is the human skin. From equation (4), again considering al � 1,the amplitude is given by

Ss = Y√2f ε

√1 + 2bal + 2b2(al)2√b2 + 2bal + 2(al)2

From equation (6) it can be seen that the PA signal amplitude varies as f −1, instead off −3/2 as in the air case.

Experimentally, to determine the effusivity of the sample, we measure in fact Ss and Sr

as a function of frequency. From these values one obtains the function q = Ss/Sr, which isgiven by

(al)r+

)2]−1/2

Because a, l, and ε are known parameters for the reference material, we can fit the ratioof amplitudes taking b as the fitting parameter. Once we get the value of b, the effusivity ofthe skin is determined through equation (3).

On the other hand, essential to the basic understanding of the thermal properties of skinis the development of a heat conduction model for this system. Recently Gutierrez-Juarez(1998) proposed a model to determine the thermal effusivity of binary mixtures, in which it wasassumed that the effective thermal effusivity behaves as the thermal conductivity for a systemof two phases (Maroulis et al 1991). The two phases that make up the system are randomlymixed. This means that if k1 and k2 are the conductivities of media 1 and 2, respectively, thenthe effective conductivity of the system is

k = k1

where x is the volume fraction of medium 2.In the work by Gutierrez-Juarez (1998) a mixture of water and acetone was used and

assuming that (ρc)1 and (ρc)2 are similar, the effective effusivity was given as

ε = ε1

where ε1 and ε2 are the effusivities of water and acetone, respectively.

In our work, a similar two-phase model to the one given in equation (9) is used. Ourbinary system is composed of applied substance and human skin. The relative absorption ofsubstances through the skin can therefore be calculated from equation (9) and are given by theequation

X = ln(εm/εp)

ln(εs/εp), (10)

where εm is the measured effective effusivity, εp is the clean skin effusivity and εs is thesubstance effusivity.

3. Experimental set-up

The double PA cell used in this experiment was a redesigned model of the differential cellproposed by Guy and Bernengo (1986). In the design of the cell, special care was takento optimize the relation between the sensitivity and the dimensions of the cell to get themaximum PA signal. The cell was a two cylindrical chamber system with radius r = 0.3 cmand height h = 0.4 cm, which gives a volume V = 0.113 cm3, which is in agreement withthe values suggested by Aamodt et al (1977). Both chambers are identical within a 1 µmuncertainty. Each chamber was connected to a microphone and sealed hermetically. On thetop of the chambers a transparent window allowing light penetration was placed. A collimatedlight beam was produced by using a 100 mW Ar+ laser modulated by an optical chopperat frequencies between f = 6 Hz and 40 Hz, which was controlled by a lock-in amplifier.The material which seals the bottom face was stainless steel of thickness lb = 0.0104 ±0.0002 cm. This value allowed a cut-off frequency fc = 206 Hz, where fc is the limit of thethermal regimes.

To calibrate the PA cell, a reference material with known thermal properties was employed.The reference material was required to be thermally thin in the frequency range between6 Hz and 40 Hz and optically opaque for the magnitude of the light used. A silicon sampleof thickness 85 µm is a material that satisfies both properties. The diffusivity α and thermalconductivity κ of this material can be found elsewhere in the literature (Touloukian 1989). Itsvalues are α = 0.88 cm2 s−1 and κ = 1.47 W cm−1 K−1, respectively. With these values it ispossible to determine its thermal effusivity ε by using equation (1) and the relation betweenthe conductivity κ and the diffusivity α given by

α = κ

ρc. (11)

A value of ε = 1.56 W s1/2 cm−2 K−1 was obtained for this reference material. With theparameters for the silicon, the effusivities of two well-known substances such as distilled waterand ethyl alcohol were measured. The values obtained were 0.161 and 0.067 W s1/2 cm−2 K−1,respectively. These values are in good agreement with those reported in the literature(Balderas-Lopez et al 1999). Measuring against distilled water we now obtained the effusivityof the stainless steel, giving εss = 1.000 ± 0.004 W s1/2 cm−2 K−1. Once calibrated thestainless steel cell of ≈100 µm thickness was finally used as a reference material, due to itsrigidity. The diffusivity of this kind of stainless steel was measured by using a beam deflectiontechnique. The value was α = 0.0700 ± 0.0004 cm2 s−1. It is important to emphasize thatthe lower thermal conductivity of stainless steel compared to other metals did not represent aproblem due to the fact that the measurements were performed in the thermally thin regime.To confirm this measurement, some proofs were performed using other materials that donot corrode, such as gold coated stainless steel as reference materials instead of stainless

Sample

Double PA cell

Lock in

Chopper

Figure 1. Schematic diagram of the experimental set-up.

steel alone. No significant difference in the signal was found. After that, measurementsof the effusivity of the systems, stainless steel–air and stainless steel–skin–substance, wereperformed separately. Taking the ratio of the signals from the systems described above, andmaking use of equation (7), the value of the parameter b was obtained, determining in thisway the effusivity of the system skin–substance.

Measurements were performed by using a PA double cell on different parts of the bodyof a volunteer: forearm, calf and heel. With this cell simultaneous measurements of the cleanskin and the binary system substance–skin were performed. In each case data were taken fouror five times, with an interval of 10 min. In this way we were able to monitor the effusivity asa function of time while the substance was penetrating through the skin.

In order to determine if the contact pressure between chamber and skin make a differenceto the results, some measurements were made applying different pressures by hanging differentmasses of 100 g, 200 g and 300 g. It was observed that low and high pressures tended tointroduce some instabilities in the signal, compared to an obtained optimal pressure for whichthe signal was quite stable. However, despite this fact, the fits of all the data including thoseat low and high pressures show that the general features did not change significantly.

It is important to emphasize that using the experimental system described above light didnot impinge directly on the skin, thus avoiding possible damage to the tissue.

In figure 1 a schematic diagram of the experimental set-up is shown.

4. Results and discussion

By using the experimental arrangement described above, measurements of the effusivity andhence skin absorption of topically applied substances were performed.

In table 1 the mean values for the measured thermal effusivities, as compared to the valuesreported in the literature (Kraning 1973), for different parts of the body are shown; whiletable 2 shows the effusivities for different substances employed in the experiment. A totalof five substances of topical application were used: nitrofurazona, ketoconazol, vaporub,vaseline and sunscreen with a solar protection factor of 15 (SPF15).

As can be seen from table 1, the values of the effusivities obtained from our experimentfor the skin are less than those reported by Kraning (1973). We attribute this discrepancy tothe fact that in Kraning’s experiment the skin was blackened, introducing a possible strongcontribution from the paint.

Figure 2 shows a comparison between the effusivity and the relative concentration, bothas a function of time, for ketoconazol applied on the forearm. From this figure, it is seenthat the effusivity and the relative concentration show similar behaviour. This result is also

1 10 100 1000

MINUTES

Figure 2. (a) Thermal effusivity as a function of time of the binary system ketoconazol–skinmeasured in the forearm. (b) Relative concentration of ketoconazol through the skin. The fulllines correspond to logistic fit behaviour. The lower tick corresponds to the asymptotic value.

Table 1. Mean thermal effusivity of the human skin in different parts of the body.

Measured [ε (W s1/2 cm−2 K−1)] Reported [ε (W s1/2 cm−2 K−1)]Parts of the body (our experiment) (Kraning 1973)

Forearm 0.053 ± 0.004 0.209Calf 0.056 ± 0.002 —Heel 0.023 ± 0.001 0.147

expected from equation (10). The same behaviour is obtained for the other substances appliedon the other parts of the body. According to this behaviour, in the following, we will restrictthe discussion to the relative concentration of the topically applied substances.

In figure 3, the relative concentrations of ketoconazol applied on: (a) the calf, (b) theforearm and (c) the heel are shown. It is important to emphasize that, in this figure, the finalpoint corresponds to the clean skin, and it is used as a reference. To determine the functional

1 10 100 1000

MINUTES

Figure 3. Relative concentrations as a function of time of the binary system ketoconazol–skinmeasured: (a) in the calf, (b) in the forearm and (c) in the heel. The full lines correspond to logisticfit behaviour.

Table 2. Mean thermal effusivity of different substances topically applied.

Measured ε (W s1/2 cm−2 K−1)Topically applied drug (our experiment)

Nitrofurazona 0.106 ± 0.003Ketoconazol 0.123 ± 0.004SPF15 0.119 ± 0.004Vaporub 0.082 ± 0.003Vaseline 0.095 ± 0.003

relation of the relative concentrations, a fit was performed for the different cases. A sigmoidalfunction, given by f (t) = a/[1 + exp(k(t − t0))] + c, corresponds to the best fit in all cases. Aflat behaviour for times larger than 100 min is also observed, which can be explained assumingcomplete substance absorption through the skin. In terms of the thermal effusivity, this meansthat the effusivity of the system substance–skin tends to the effusivity of the clean skin at largetimes. This result is in agreement with what one expects.

The same result, shown in figure 3 for ketoconazol, was also observed for SPF15.Figure 4 shows the time constant τ = 1/k, in minutes, determined from the fits described

above for ketoconazol and SPF15, respectively. From this figure, values for ketoconazol andSPF15 of 11.7 and 10.9 min at the forearm, 31.0 and 17.7 min at the calf, and 29.6 and25.0 min at the heel, are obtained. These results mean that the rate of absorption, given by theparameter k for these substances, is large at the forearm and decreases significantly at the calfand heel.

In figure 5, the relative concentrations of: (a) nitrofurazona, (b) vaseline and (c) vaporub,applied in the forearm, are shown. For these substances the best fit corresponds to anexponential function, given by f (t) = d exp(bx) + g, in contrast to the ketoconazol andSPF15 cases. It is important to stress that the fits shown in this figure roughly describe the

FOREARM CALF HEEL

Figure 4. Time constants τ = 1/k, determined for: (a) the ketoconazol and (b) SPF15, whenthese substances were applied on the forearm, calf and heel.

1 10 100 1000

MINUTES

Figure 5. Relative concentrations of: (a) nitrofurazona, (b) vaseline and (c) vaporub, applied onthe forearm. The full lines correspond to an exponential function.

data, especially in the time between 15 and 45 min. However, no other function was found togive a better description.

The time constants τ = 1/b are shown in figure 6, for nitrofurazona, vaseline and vaporubapplied on the forearm. The values of the time constants determined from the fits shown infigure 5 are 58.0, 31.0 and 14.7 min, respectively. These results show a rapid absorption ofvaporub through the skin, compared to vaseline and nitrofurazona.

Finally, figure 7 shows the measurements of the clean skin for six different experimentsperformed on the forearm of the volunteer on different days are shown. As can be seen fromthe figure, the thermal effusivity does not change significantly, showing the stability of theexperimental set-up.

NITROFURAZONA VASELINE VAPORUB

Figure 6. Time constants τ = 1/b determined for nitrofurazona, vaseline and vaporub applied onthe forearm.

1 2 3 4 5 60.00

NUMBER OF EXPERIMENT

Figure 7. Thermal effusivity of clean skin for six different experiments performed on the forearmof the volunteer. The full line is the average value.

5. Conclusions

A double-chamber PA cell, constructed in our laboratory, was used to study the in vivoabsorption of substances of topical application. Different substances, such as nitrofurazona,ketoconazol, SPF15, vaseline and vaporub, were applied on the forearm, calf and heel of avolunteer, and the effusivity of the binary system substance–skin was measured. A theoreticalmodel, assuming that the effective thermal effusivity of the binary system corresponds to thatof a two-phase system, was employed.

The measurement of the effusivity allowed the determination of the rate of absorptionthrough the skin. The relative concentrations of substances were determined by fitting a

sigmoidal function for the data corresponding to ketoconazol and SPF15, and an exponentialfunction for the data of nitrofurazona, vaseline and vaporub.

The time constants τ , in minutes, were also determined for the different substances andfor different parts of the body, giving values which vary from 10 min to 58 min, depending onthe substance and the part of the body.

The effusivities of the clean skin in different parts of the body were also measured andcompared to the values reported in the literature.

The method used was shown to be an easily used non-invasive technique for dermatologyresearch.

It is clear that several factors can affect this kind of experiment, such as the degree ofhydration, involuntary movements, excessive transpiration, roughness of the skin, etc. Someof them were avoided or at least diminished by the rigid layer material (stainless steel). Thesefactors must be considered and require more research. Nevertheless, we believe that the resultsof this paper show enough generality and, above all, it is important to stress that themethod is an easily used non-invasive technique, which avoids direct light incidence onthe skin. Of course, the method requires knowledge of those factors which can introduce somevariations in the results, as appear in many physiological measurements, to establish a standardmethodology.

Acknowledgments

The work was partially supported by CONACyT under grant no 27603E, CONCyTEG undergrant no 00-16-203-008, and grant no 00-16-CONCyTEG/CONACyT-075. The authors thankM Munoz, J M Noriega and R Martınez for technical support. They also thank the volunteerJ J Camacho.

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in vivo measurement of human skin absorption of topically applied substances by a photoacoustic...

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