SESSION 3

THERAPEUTIC PROCESSES - III

Chairman: L.X. Xu

Lasers application in medicine (surgery, therapy, ophthalmology) emerged rapidly during the recent 20 years.¹ However the phenomena of radiation-tissue interaction is studied insufficiently. That is due to the complexity of experimental investigations, investigated material specifics, large variety of lasers with wide wavelength range, the complexity of physical and biochemical processes. So, the problem of mathematical simulation of processes that happen when the radiation interacts with tissue, is rather urgent. A number of mathematical models with different degree of complexity have been developed recently, describing the behavior of biological irradiated tissue.² These studies are mainly devoted to simulation of tissue irradiation by infrared CO₂-lasers with radiation absorption predominantly in surface layers, or by small power capacity lasers. Apparently these models are not adequate for processes occurring in tissue being irradiated with large power density laser beams and rather deep penetration (for example Ar-laser, or Cu-laser; wavelength 0.5–0.7 mm).

In present work three-dimensional transient finite difference numerical model of the biological tissue irradiated by powerful laser beam has been developed. It is used to simulate the thermal behavior of tissue assuming that radiation wavelength is chosen to give rise for volumetric heat sources. A three- dimensional seven-flow model has been used to calculate radiation propagation.³ Evaporation and burn-out of tissue resulting in a through hole along the axis of the beam has been taken into account. Besides the water boiling and corresponding changes of thermal and optical tissue properties the model takes into account one of the heat steam transfer mechanisms. Estimates have been carried out for the effects of diffusion transfer and vaporization of water from the tissue surface. Kinetics of protein denaturation process have been calculated by Arrenius equation. The problem was solved numerically using discrete grid technique and adaptive time-step control algorithm.

While the tissue temperature grows up a number of character tissue states are being passed: the denaturation of protein, the vaporization of internal tissue water, vaporization and burn-out of tissue. Each stage is described by corresponding mechanisms of heat and mass transfer. In the simulated modes it is assumed that due to the highly intensive radiation and volumetric mechanism of radiation- tissue interaction at the beginning of exposure a through hole along the axis of the symmetry of beam is formed. Since then the growth of tissue temperature becomes less intensive because only the «tails» of Gaussian radiation beam act at this stage.

Calculations were performed for a tissue sample with thickness 3 mm. The power of laser was 12 W for Gaussian beam (e^-2-level radius 10 mm) focused on the midst of tissue fragment depth (1.5 mm). For these conditions the beam radius at tissue surface is R₀=0.21 mm.

The results of temperature field calculations qualitatively agree with experimental pictures obtained using Cu-laser: in course of 0.6–1.2 s after action start a through-hole in tissue fragment has been formed. Approximately 7 s later its diameter has increased up to 0.6 mm and temperature field was practically stabilized. The analysis of the results of calculation allows to distinguish 4 characteristic zones:

1. Through-hole. Its diameter is ~0.6 mm.
2. The annular zone of the boiling of in-tissue water (temperature is equal or exceeds 100°C). The outer diameter of the ring is 1.6 mm.
3. The protein denaturation zone. The diameter of this zone is 4.3 mm.
4. «Undisturbed» zone.

Qualitatively this picture coincides with experimental observations, where distinctive rings also could be seen.

Developed model permits at least a qualitative description of temperature field distribution in biological tissue irradiated with a powerful laser beam with a wave-length at which volumetric heat sources are originated and a through-hole is formed. The preliminary results of comparison with our experiments have shown satisfying concurrence to the dynamics of processes, so as to the dimensions of distinctive zones. The model may be useful for the analysis of physical processes occurring in laser irradiated tissue and for calculation and optimization of the parameters of various surgical and therapeutical laser instruments.

REFERENCES

1. Bass L. S., Treat M. R. Laser-Tissure Welding, A Comprehensive Review of Current and Future Clinical Applications. Laser in surgery and medicine, 1995, Vol. 17, No. 4, pp 315–349.
2. Welsch A. J. The Thermal Response of Laser Irradiated Tissue, IEEE Journal of Quantum Electronics. Vol. QE-20, No. 12, December 1984, pp 1471–1481.
3. Yoon G., Welsch A. J., Motamedi M., van Gemert M. C. J. Development and Application of Three-Dimensional Light Distribution Model for Laser Irradiated Tissue, IEEE Journal of Quantum Electronics. Vol. QE-23, No. 10, October 1987, pp 1721–1733.

LASER DRUG DELIVERY METHODS

Laser optoacoustic (OA) impregnation uses a succession of short low power laser pulses of mid-infrared range at l = 2,94 mm which gives rise to OA waves of pressure. Strong irradiation absorption by water leads to an intensive OA effect. The OA wave of pressure begins to propagate towards the solution-skin interface. These ultrasonic waves of pressure make the drug solution penetrate natural physiological skin pores. Then the medicine commences to permeate epidermis and dermis intercellular liquid where it is absorbed by dermis capillary network. Another modification of this method uses a plate, transparent for mid-infrared radiation, placed over the drug solution to be impregnated. Such a technique leads to changes in boundary conditions and intensifies drug permeation into skin. In enhanced laser OA impregnation stratum corneum is removed by laser ablation before impregnation itself. After that drug solution is applied topically and then it is irradiated by successive short low power laser pulses. In laser injection drug solution is applied onto skin surface topically and then it is irradiated by a laser pulse. Strong absorption of Er:YAG laser irradiation by water leads to perforation of both drug solution and skin tissues. Parallel to the drug solution and tissue perforation there occurs drug solution penetration into the injection hole in skin. In laser OA injection after the drug solution has been injected by a laser pulse into skin a succession of short low power laser pulses creates OA waves of pressure in the rest of the drug solution remaining on the skin surface above the injection hole. These OA waves force the solution to pass deeper through the injection hole.

EXPERIMENTS AND RESULTS

In our experiments a laser perforator with an Er:YAG laser in the normal-spiking mode emitting mid-infrared photons at the wavelength of 2,94 mm with the pulse width of 250 msec was used. The pulse energy varied from 0,3 to 1,0 J. The laser beam was focused to a 0,2 mm diameter spot. To model biotissues 10% gelatinous gel was employed. Brilliant green solution was injected at different values of pulse energy. The quality of brilliant green injection was investigated by means of optical computed tomography. It was observed that the brilliant green solution was injected into gelatinous gel together with the laser pulse. The whole injection channel appeared to be filled with the brilliant green. The hole was practically cylindrical in form. The injection hole depth depended on the laser pulse energy and changed from 4 to 10 mm. It was noticed that the injection hole diameter varied from 0,3 to 1,5 mm. The volume filled with drug solution changed from approximately 0,2 to 14 mm³. In order to investigate brilliant green solution distribution in gelatin the injection hole cross-section tomogram was obtained. To investigate laser OA injection transparent aqueous suspense with opaque particles was taken. The test-tube with 10% gel was placed under the microscope vertically, so the gel surface was horizontal. A while later the suspense was dropped on the gel surface and injected by a laser pulse energy of 0,58 J. When the particles motion in the hole slowed down the solution was irradiated again. Under the microscope one could see that the particles stir in the hole increased significantly. Laser drug injection was compared to simple drug solution floating into the ablated holes. The drug solution turned out to fill only the upper part of the ablated hole, whereas at the bottom of the hole remained an air bubble. A frozen (-4^oC) autopsy piglet skin sample was taken to investigate both stratum corneum laser ablation and laser injection in skin. A polarising-interference microscope in differential mode was used for histological analysis. To obtain thin sections along injection holes a microtome was used. In order to investigate drug transport enhancement after laser ablation the stratum corneum was removed by six unfocussed laser pulses with the pulse energy of 0,3 J and then drug solution was applied topically. The sections were obtained two hours later. To investigate laser injection, brilliant green solution was dropped on the skin surface with a medicine dropper. Afterwards the solution was irradiated by the laser beam energy of 0,86 J. The stratum corneum ablation brought about enhancement in percutaneous diffusion. Brilliant green laser injection caused the drug penetration at a depth of 1 mm approximately; the diameter of the injection zone did not exceed 0,3...0,4 mm. The quality of the hole saturation with brilliant green appeared to depend on the thickness of the drop. The higher the drop was, the better saturation quality was obtained.

Laser drug injection into the autopsy skin may be concerned with the following effects. The laser beam vaporises both the drug solution and skin tissues so the ablated crater forms in the skin. Emission of microparticles at very high velocities out of the ablated crater causes the appearance of rarefaction in the crater. When the laser pulse ends the drug solution rushes into the ablated crater to fill it and the hole in the drug solution collapses. Such a collapse causes two vertical hydrodynamic waves, which propagate in two opposite directions. One of the waves propagates towards the solution- skin interface and promotes the drug penetration into the ablated crater. So laser injection is provoked by two effects, i. e. the vacuum suction of the surface solution and the hydrodynamic surface solution pressure-in.