Photoacoustic Waves as a Skin Permeation Enhancement Method

Fig. 11.1

Comparison between some fundamental properties of a typical ultrasound wave of 1 MHz (dashed line), a photoacoustic wave generated by Mn-TPP in polystyrene (solid line) and a shock wave generated by the ablation of a triazene polymer (dotted line). The latter two waves were experimentally detected with a 225-MHz transducer following the excitation of the materials with a nanosecond laser pulse at 355 nm. The inset is an expansion of the waves in the region close to their maximum to illustrate the different full widths at half maximum (FWHM) of the waveforms

PA waves also differ from shock waves. Shock waves are efficiently generated by lasers with high fluence rates, capable of producing optical breakdown or ablation of a target, whereas PA waves are generated in the thermoelastic regime at lower laser fluence rates. Optical breakdown occurs when the radiative energy at a certain point and in a given moment attains powers of several megawatts (MW) and produces a strong local ionization of the medium, followed by explosion. The ablation of a target is characterized by the removal of material from its surface due to vaporization or chemical transformations and produces a shock wave that travels in the bulk of the material. Both optical breakdown and ablation are destructive processes that release material together with large amounts of energy, and their light-to-pressure conversion efficiencies can be very large, even higher than 30 %. It is convenient to define the efficiency of the light-to-pressure conversion as the ratio of the energy of the stress wave (either a shock wave or an acoustic wave, E _S) over the energy of the laser pulse (E _L), i.e., η = E _S/E _L. On the other hand, thermoelastic processes are reversible thermal dilatations and contractions associated with temperature changes, which do not involve chemical transformations. The thermoelastic conversion of the radiative energy into an acoustic wave does not damage the target material but its efficiency has been reported to be less than 0.01 % (η < 10⁻⁴) (Sigrist 1986). The higher fluence rates employed in the generation of shock waves lead to higher peak pressures than those observed in PA waves. Such shock wave fronts travel with supersonic speeds and rapidly dissipate their energy. The energy dissipation in the first 10 mm of shock wave propagation amounts to nearly 90 % of the total acoustic energy, and in fact most of the shock wave energy is dissipated already within the first 200–300 μm from the source (Vogel and Noack 1998). Figure 11.1 also represents a shock wave detected with a 225-MHz transducer at a distance of 10 mm from the material that suffered ablation. In this experiment, the shock wave propagated through a quartz window between its source and the transducer, just like the PA wave shown in the same figure. The shock wave was generated by the ablation of a triazene film with a 355-nm laser pulse, making use of the exceptionally low ablation threshold of polymers made with thin triazene when excited with nanosecond laser pulses in the ultraviolet (Fardel et al. 2009). Ablation is a more efficient process than thermoelastic conversion to convert the energy of light into a stress wave that back-propagates in the target material. However, ablation also has the intrinsic limitation of making chemical changes in the target material. Thus, subsequent laser pulses will be absorbed by chemically modified target materials and will give rise to different pressure waves. The use of the same target material to convert a series of laser pulses in the ablation regime gives a series of increasingly different stress waves.

There is yet another important difference between ablation and thermoelastic expansion. The duration of the shock wave is related to the growth of cavitation bubbles or to the velocity of the materials that are ejected from its surface and produce the recoil moment. For sufficiently short laser pulses, the rise time of the shock waves will be determined by these processes and not by the duration of the laser pulse. Pressure pulse widths in the order of the 100 ns bubble growth time have been reported (Park et al. 1996). On the other hand, in the conditions detailed further below, the duration of the thermoelastic expansion can be made as short as the laser pulse. The inset in Fig. 11.1 illustrates the shift from a full width at half maximum (FWHM) of 9 ns for a photoacoustic wave to a FWHM of 140 ns for a shock wave, both generated by 8-ns laser pulse. Fast Fourier transforms (FFT, i.e., the conversion of the waveform from the domain of time to the domain of frequencies) of PA waves with such short durations show that they contain frequencies of hundreds of megahertz (MHz). Such very high frequencies are strongly attenuated by most materials because the attenuation of ultrasound waves depends on their frequency components. For example, the Food and Drug Administration (FDA) uses a value of 0.3 dB/(cm∙MHz) as a derating factor (a tissue attenuation coefficient), although this attenuation coefficient seems to be a factor of 2–3 smaller than measured values (i.e., the FDA is clearly on the safe side, as the actual attenuation is stronger than the value used or guidance) (O’Brien 2007). The selective attenuation of the higher-frequency components may lead to a broadening of the PA waves as they travel in most media.

Understanding the skin structure, especially its barrier function and routes of drug diffusion, and the nature of PA waves is of crucial importance to understand and predict the interaction between PA waves and living tissues. Fast and efficient light-to-pressure (piezophotonic) conversion of energy can generate PA waves with relatively high peak pressures and very short durations. In fact, as it will be shown below, it is possible to use the fluence rates of compact and lightweight lasers to generate PA waves with nanosecond durations (which lead to ultrasonic frequencies above 100 MHz) and peak pressures higher than 10 bar. The pressure in such PA waves changes very rapidly in time and space and produces strong pressure gradients (i.e., rate of pressure change per unit time or length). The physical force exerted by PA waves with large changes in pressure across very small distances can transiently disturb the barrier function of the skin and enhance the transdermal delivery of a wide range of drugs at fluence rates of simple and affordable pulsed lasers. The optimization of this process requires fast and efficient light-to-pressure thermoelastic conversion.

The structure of this chapter takes the reader from the fundamental processes of PA wave generation, through the design of devices that optimize the efficiency of photoacoustic conversion, to the mechanisms of interaction between PA waves and skin components. This chapter closes with examples of the use of such devices to increase transepidermal water loss (TEWL) and to deliver hyaluronic acid to the minipig skin.

11.2 Light-to-Pressure Conversion

Photoacoustic effects have been known since the nineteenth century with the discovery by Bell of the effect of sunlight on a selenium cell (Bell 1880). It was found that when a beam of light was rapidly interrupted by a rotating slotted disk and then focused on the selenium cell, a sound could be heard. The practical development of photoacoustics began with the advent of lasers in the 1960s, when researchers were able to exploit the short laser pulses for acoustic generation in solids and liquids (White 1963; Carome et al. 1964). The photoacoustic phenomena described by the thermoelastic expansion mechanism is the result of a photothermal conversion that consists in the ultrafast optical energy conversion into thermal energy by a strongly absorbing material. In other words, thermalization of the laser energy in the irradiated volume occurs faster than the thermal diffusion time (Karabutov et al. 2000; Schaberle et al. 2010). This means that the laser energy is totally transformed in heat in the irradiated volume before the heated volume can transfer an appreciable amount of energy to its surroundings. The ensuing expansion of the irradiated volume gives rise to the PA wave.

As mentioned above, thermoelastic expansion has been considered an inefficient method to convert light into pressure waves, and values of η < 10⁻⁵ have been reported (Sigrist 1986; Biagi et al. 2001). However, it is possible to explore the dependence of the PA waves on their properties, target materials, and laser pulses to improve the efficiency of the light-to-pressure conversion. First, constraining the energy-absorbing material by rigid and transparent windows can increase the amplitude of the PA pressure waves by a factor of 100 (von Gutfeld and Melcher 1977). Second, peak pressures obtained by thermoelastic expansion scale with the reciprocal of the thickness (h) of the absorbing material, for the same amount of energy absorbed and released per unit area (∆H _th) (Arnaut, Caldwell et al. 1992),

${p}_{\max}\propto \frac{g}{h}\varDelta {H}_{\mathrm{th}}$

(11.1)

where γ = c _a ²α/C _p (α is the volumetric thermal expansion coefficient, c _a is the adiabatic speed of sound, and C _p is the specific heat capacity) is the dimensionless Grüneisen coefficient (Childs 2002), which reflects how a change in temperature changes the volume of a material. Third, Eq. (11.1) shows that absorbing materials with high Grüneisen coefficients can give proportionally higher peak pressures, which is the case of elastomers with high thermal expansion coefficients (Buma et al. 2001). Fourth, absorbing materials with ultrafast radiationless processes insure that all the laser energy is transformed into heat within the duration of the laser pulse and maximize the conversion efficiency (Schaberle et al. 2010). Fifth, the conversion efficiency increases with the fluence rate of the laser pulse up to the ablation threshold limit (Sa et al. 2013), and proper shaping of the laser pulse and selection of materials with high ablation thresholds will increase this efficiency. It was shown that in taking advantage of all these factors, it was possible to attain η = 10⁻⁵ with a laser fluence rate I _L = 5 MW/cm² (Sa et al. 2013). This laser fluence is in the thermoelastic regime and could still be substantially increased before reaching the ablation threshold, which means that higher efficiencies are attainable.

In view of the factors that control the conversion of the optical energy in a laser pulse into the acoustic energy of a PA wave, the maximization of η requires:

(i)

Confining the absorbing material between a rigid window and a rigid (preferably reflective) support
(ii)

Very thin absorbing materials with very high linear absorption coefficients (μ _a), capable of absorbing >90 % of the incident light in a short optical path
(iii)

Materials with large Grüneisen coefficients
(iv)

Materials that convert the laser pulse energy into heat within the duration of the laser pulse (τ _L)
(v)

Materials with relatively high ablation thresholds

In addition to the peak pressure, the distribution of the ultrasonic frequencies in the PA wave is also a very important factor to consider in the interaction between PA waves and the skin. When the absorbing material converts the light energy in thermal energy within the duration of the laser pulse (τ _L) and, additionally, has a linear absorption coefficient sufficiently high to meet the condition μ _a c _a τ _L > > 1, the duration of the PA is as short as that of the laser pulse, and the spectral band of the PA transient is determined by the spectral band of the laser pulse (Karabutov et al. 2000). Under these conditions the acoustic relaxation time is shorter than the laser pulse duration and we call this the limit of optical confinement. In this limit, duration of the laser pulse and its peak power determine the bandwidth and intensity of the acoustic transient. For example, Dubois and coworkers showed that going from a 200-ns to a 10-ns laser pulse generates five times more amplitude at 5 MHz, whereas the same pulse reduction will increase the amplitude at 1 MHz only by a factor of 1.3 (Dubois et al. 2000). Figure 11.2 shows simulated laser pulses with various pulse durations and the corresponding FFT to emphasize the large increase in the high-frequency components of the ultrasound waves when the laser pulse duration τ _L is decreased. Although this indicates that higher amplitude and frequency PA waves can be generated with picosecond lasers, the practical difficulties of meeting the limit of optical confinement and the dramatic attenuation in most materials of acoustic waves with GHz frequencies limit the applications of picosecond lasers.

Fig. 11.2

Simulated laser pulses of 1-μs, 8-ns, or 1-ps durations (a) and respective bandwidths (b)

The theoretical limit of maximum pressure amplitude generated by thermoelastic expansion after absorption of a laser pulse with the fluence rate I _L is given by (Simonin 1995)

${p}_{\max }=\frac{g}{c_{\mathrm{a}}}{I}_{\mathrm{L}},$

(11.2)

and for a modest fluence rate I _L = 4 MW/cm² (e.g., a 40-mJ/cm² laser pulse with τ _L = 10 ns), a silicone elastomer such as polydimethylsiloxane (Sylgard 184®, Dow Corning, USA) (γ = 0.9, c _a = 1100 m/s and ρ = 1010 kg/m³ (Millett et al. 2011)) could produce a PA wave with p _max = 330 bar. The corresponding average sound power density (Simonin 1995)

${I}_{\mathrm{s}}=\frac{p_{\max}^2}{c_{\mathrm{a}}\rho}$

(11.3)

is only 98 kW/cm² and η = 0.024, but this is a sufficiently large pressure to perturb the skin structure. In fact, it is possible to produce pressure gradients to permeabilize the skin with peak pressures in the tens of bars, if the PA waves generated by thermoelastic processes upon the absorption of nanosecond laser pulses have bandwidths in the hundreds of MHz. For example, a τ _L = 10-ns laser pulse generating a PA wave with an amplitude p _max = 15 bar and with the duration of the laser pulse has a rate of pressure change per unit time of 1.5 bar/ns, which is comparable to that of shock waves (Kodama et al. 2000; Menon et al. 2003). Considering that the sound velocity in soft tissues is c _s ≈ 1500 m/s, this corresponds to a pressure gradient of 1 bar/μm. More precisely, the calculation for an ultrasonic frequency component of f _US = 100 MHz present in that PA wave shows that the pressure gradient can increase to 2 bar/μm for the acoustic wavelength λ _ac = 30 μm (λ _ac = 2c _s τ _L), assuming a sinusoidal PA wave. Such large pressure gradients imply that one layer of corneocytes will experience a substantially different pressure than the next layer of corneocytes and that some layers will be subject, for example, to a 10-bar compressive stress, while others are subject to a 5-bar tensile stress. The difference in compressive/tensile stress from one layer of corneocytes to the next one may perturb the packing of the layers of corneocytes. These disrupting physical forces exerted at the cellular level may expand the extracellular domains of the stratum corneum. Thus, moderately intense PA waves with ultrasonic components above 100 MHz produce very large pressure gradients that can disturb the tightly packed layers of the SC.

11.3 Principles of Piezophotonic Materials

The development of materials capable of rapidly and efficiently converting the energy in a laser pulse into high-frequency broadband ultrasound using the photoacoustic effect has been eluded by the lack of fundamental understanding of the processes involved and by the inability to develop adequate chromophores and substrates. Initially the nature of the converter was almost always a self-standing thin metallic film, a metal evaporated into a transparent support or commercial plastics (Doukas and Kollias 2004). Further evolution considered the use of metallic films evaporated onto the tip of optical fibers (Guo et al. 2011). Only in the last decade, alternative materials (mainly carbon-polymer composites) were described (Visuri et al. 2002), and the importance of the thermoelastic properties and thickness (Sa et al. 2011) of the materials was revealed. We take advantage of the relations between the properties of the materials and the intensity of the pressure waves to design materials that further improve the light-to-pressure conversion. We define piezophotonic (piezo, pressure; photonic, light; both derived from Greek words) materials as those that strongly absorb an incident laser pulse and use thermoelastic processes to produce broadband ultrasonic PA waves with high peak pressures.

Piezophotonic materials must have strong absorption bands at the laser wavelength, excited states with very short lifetimes due to the presence of ultrafast (radiationless) transition processes that thermalize their energy, and large Grüneisen coefficients and, additionally, must be very thin. The amount of light absorbed by the material is intimately related to its thickness, and strong absorption of the laser pulse by a thin film requires that the optical penetration depth, δ = 1/(2.3μ _a), of the light in the film is very small. A value of δ = 10 μm means that 10 μm beneath the surface of the material, the light intensity is 1/e ≈ 0.37 of its value at the surface. Due to the exponential nature of the decay of the light intensity in the material, δ = 10 μm (i.e., μ _a = 435 cm⁻¹) also means that 23 μm beneath the surface, the light intensity is only 10 % of its value at the surface. A practical approach to obtain such short penetration depths is to incorporate suitable dyes in the piezophotonic materials.

Suitable dyes for piezophotonic materials must strongly absorb the light of the laser pulse and transform it very rapidly into heat. These are also properties required for calorimetric references employed in photoacoustic calorimetry (PAC) (Arnaut et al. 1992; Pineiro et al. 1998; Schaberle et al. 2010). By definition, a PAC reference compound is a molecule that strongly absorbs the incident laser pulse and uses ultrafast radiationless processes to convert all the absorbed optical energy into heat within the duration of the laser pulse. The applications of such compounds in PAC are not of interest here, but it is relevant to note that it is simple to screen for PAC reference compounds (Pineiro et al. 1998) and that the compounds passing that screening are good candidates to make piezophotonic materials. It is also interesting to note that such compounds do not have measurable photochemistry, that is, they can repeatedly absorb laser pulses without changing their response, which is useful to make long-lasting piezophotonic materials.

There are a variety of chemical processes that occur in the picosecond time scale and lead to ultrafast radiationless processes. Such processes are the basis for the development of materials as diverse as sunscreens and laser safety glasses. Although the principles of strong light absorption and ultrafast energy dissipation are the same as for piezophotonic materials, the latter have the additional purpose of producing broadband ultrasonic PA waves with high peak pressures. Thus, piezophotonic materials must be able to incorporate dyes with the properties of PAC references and have large Grüneisen coefficients.

The Grüneisen coefficient γ is a dimensionless quantity that tells how a change in temperature of a given material dictates its change in volume. It is a measure of the thermoelasticity of that material. Higher values of γ mean that larger volume changes occur for the same change in ΔT and, for materials constrained by rigid boundaries, higher amplitude pressure waves will be generated. The Grüneisen coefficients of various materials of potential interest for the fabrication of piezophotonic materials have been reported in the literature, and representative examples are presented in Table 11.1.

Table 11.1

Grüneisen coefficients of various materials at room temperature

Material	Grüneisen coefficient, γ	References
Water	0.11	Boehler and Kennedy (1977)
Pentane	0.74	Boehler and Kennedy (1977)
Epoxy resin	0.7	Casalini et al. (2001); Sundqvist et al. (1977)
Polystyrene	0.7	Childs (2002)
Polyethylene	0.9	Childs (2002)
Polydimethylsiloxane	0.9	Dattelbaum et al. (2005)
Glasses	1.1–1.5	Sanditov et al. (2012)
Pyrolytic graphite	0.026	Childs (2002)

Efficient piezophotonic materials can be fabricated incorporating PAC reference compounds in thin support materials with high Grüneisen coefficients. A compound with μ _a > 300 cm⁻¹ at the laser excitation wavelength incorporated in a substrate with γ > 0.7 and a thickness of 50 μm will absorb 97 % of the laser pulse and is a good candidate for a piezophotonic material. The efficiency of such a piezophotonic material below its ablation threshold increases with the laser fluence rate. For a fluence rate of I _L = 20 MW/cm² (e.g., a 200-mJ/cm² laser pulse with τ _L = 10 ns) that can be obtained with small lasers, the theoretical efficiency is η > 0.01.

11.4 Devices Which Use Photoacoustic Waves for Penetration Enhancement

The incorporation of large quantities of such dyes in polymers can produce thin films of piezophotonic materials by different physical techniques, such as (1) spin coating gives films with thicknesses between a few tens of nanometers (nm) and 10 micrometers (μm) and (2) casting techniques with highly controlled thicknesses in the micrometer range. The most promising dyes for light-to-sound conversion should have a strong absorption at the wavelength of the laser pulse in a reduced thickness of a specific material (μ_a ≤ 500 cm⁻¹) and a total conversion of the absorbed energy into heat during the laser pulse duration (≤8 ns).

The light-to-pressure transducer polymer films employed in this work were casted from a mixture of polystyrene and a PAC reference compound using a cube film applicator 35050 (Elcometer®, UK). The PAC reference compounds employed were either Mn^III5,10,15,20-tetraphenylporphyrinate (Mn-TPP), Mn^III5,10,15,20-tetraundecylporphyrinate (Mn-TUP), or Mn^III5,10,15,20-tetrakis (4-sulfonylphenyl) porphyrinate acetate (Mn-TPPS). Polystyrene and toluene (3:10, V/V) were mixed and stirred until complete solubilization of the polymer. The PAC reference compound was then added to polystyrene/toluene solution, and all the mixture was stirred until the dye was completely dissolved. Air bubbles resulting from stirring were eliminated placing the polystyrene/toluene/dye in an ultrasonic bath for 2 min. Finally, the mixture was poured into the mold and spread on a clean glass lamina. The film deposited by casting was dried at room temperature and then removed from the lamina. The thicknesses of the films were measured with a digital micrometer. Table 11.2 represents some examples of films prepared with this method.

Table 11.2

Representative examples of light-to-pressure (piezophotonic) materials

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