by Ivan SHCHERBAKOV, Corresponding Member of the Russian Academy of Sciences and head of the Institute of General Physics of the Russian Academy of Sciences

Laser is one of the greatest discoveries of the 20th century that has changed the world. Lasers are used in industry, household electronics, space technologies, information transmission and processing systems and in medicine.

LASER BEAM INTERACTIONS WITH BIOLOGICAL TISSUE

Lasers are being widely used thanks to their unique property to maximally concentrate energy in space, time and in spectral bands. Their radiation used in practical medicine ranges from ultraviolet to middle infrared regions. The energy density can be modified by 3 orders of magnitude (from 1 to 10³ J/cm²), power density by 18 orders of magnitude (from 10^-3 to 10¹⁵ W/cm²), and time range by 16 orders of magnitude: from continuous radiation (~10 s) to femtosecond pulses (10^-15 s).

This wide range of variations makes it possible to develop quite different mechanisms of biological tissue modulation.

At the first steps of laser medicine development the biological tissue was visualized as water with "admixtures" (as we know, the human body consists of water by 75-80 percent). Hence, it was assumed that the mechanisms of radiation effect on this tissue were determined by water absorption. This concept works more or less with continuous lasers: for surface modulation, we should select radiation on a wavelength when

it is intensely absorbed by water, while if volumic effects are needed, the absorption should be slight. However, further studies revealed that other components of biological tissue also possess this property (for example, strong absorption of blood in the visible band of the spectrum). Therefore, it became clear that biological tissue is a much more complex object.

With the development of pulsed lasers and studies of their effects on biological tissue it became clear that the results depended on the combinations of wavelength, energy density, and time of radiation pulse. For example, the pulse time is an important factor, essential for separating the thermal and nonthermal exposure. Lasers with great ranges of this parameter are used in practical medicine: milli-, micro-, nano-, pico-, and femtoseconds (10^-15 s). Nonlinear processes of different kinds proved to be effective, such as optic perforation of the target surface, multiphoton absorption, formation and development of plasma, generation and propagation of shock waves. The impossibility of creating a simple universal algorithm for search of the needed laser became obvious, as each case requires an individual approach. Although the task became even more complicated, it opened up fantastic opportunities of modulating the modes of biological tissue exposure.

One more important fact to be borne in mind is diffusion during radiation interactions with biological tissue. And if absorption predominates over diffusion—the radiation fades exponentially while passing through the medium.

If diffusion predominates over absorption (which is characteristic of the majority of biological media in visible and nearest infrared wavelength bands), reliable estimation is made by using the diffuse approximation model for analysis of laser radiation propagation.

All this means that nonlinear processes and the diffusion/absorption ratio should be taken into consideration when developing a laser for concrete operations.

TWO IN ONE

A Lazurit surgical complex has been created at the Institute of General Physics by using a comprehensive approach. This complex can serve as a coagulator scalpel and a lithotriptor (device for stone destruction in human organs). Using radiation pulses of two microsecond wavelengths, the lithotriptor displays truly unique characteristics. The Nd:Ya10₃ crystal-based laser is used (wavelength 1.0796 µm) with its second harmonics (green radiation). The device is supplied with a video processing block, making it possible to monitor the operation in the real time mode.

The µs two-wave laser exposure provides for the photoacoustic mechanism of stone fragmentation, based on the optico-acoustic effect—generation of shock waves during laser interaction with liquid discovered by Academician Alexander  Prokhorov*,  Nobel  Prize

* See: A.  Prokhorov, Ye.  Dianov,  "Fiber Optics:  Problems and Prospects", Science in Russia, No. 1, 2001. —Ed.

Winner (1964) and his team. The exposure is nonlinear, multistaged, including an optical perforation on the stone surface, formation of a plasma sparkle, and of a cavitation* bubble, generation and propagation of a shock wave after the bubble's collapse. Hence, the calculus (stone) is destroyed ~700 µs after the laser beam touches its surface as a result of the shock wave generated during the collapse of the cavitation bubble.

The advantages of this method are obvious. First of all, it is safe for adjacent soft tissues, for the shock wave is not absorbed by them and hence, is not harmful to them (which is intrinsic of other laser lithotripsy methods). Moreover, this method effectively destroys calculi (stones) of any location and chemical composition. The process is very rapid: the time of hard object destruction takes 10-70 sec, depending on their chemical composition. The fibrous instrument delivering the radiation is not damaged owing to the optimal selection of pulse length. The incidence of complications and the time of postoperative treatment are minimized.

The Lazurit coagulator scalpel can be used for operations on plethoric organs (for example, kidney), for laparoscopic resection of cancerous tumors with a minimum blood loss without clamping the renal vessels and artificial ischemia, both inevitable with the use of conventional surgical methods. The effective depth of pulsed 1-µm radiation is ~1 mm; in parallel with the operation it is possible to carry out coagulation and hemostasis, and remove the tumor together with the adjacent normal tissues in order to prevent relapsing. At present the development of a new medical technology of kidney resection is in progress and permission for its clinical use is expected.

Clinical trials of the complex have been carried out at the leading medical canters of the Russian Federation, such as the Institute of Urology, of "The Russian Railways" Central Clinical Hospital in Moscow. In 2008, following these trials, Lazurit was listed in the State Register of Medical Devices and, upon obligatory permissions, its small-lot production was started.

USE IN OPHTHALMOLOGY

More than 70 million people in Russia suffer from various visual anomalies. According to statistical data, every fifth person suffers from myopia (shortsightedness); with aging, hypermetropia (farsightedness) sets in, as a rule. In a word, virtually everyone has to resort to vision correction. The need for such operations is extremely high. Just one medical center, the S. Fyodo-rov Institute of Ophthalmic Microsurgery, our partner, consults each year more than 600,000 patients with different ocular diseases.

We have created a Microscan ophthalmologic laser system based on the ArF excimer laser** with a wave-

* Cavitation (Lat. cavitas, empty space)-formation of cavities (cavitation bubbles filled by gas or vapor) in liquid. Moving with the stream into a higher pressure area, they burst forming a shock wave.—Ed.

** Excimer laser—a variety of gaseous laser. -Ed.

length of 193 nm for correction of myopia, hyperme-tropia, and astigmatism. The so-called "flying spot" method is realized. The cornea of the eye is exposed to a radiation spot ~0.7 mm in diameter and the corneal shape is modified by scanning this spot according to an algorithm preset by computer. Vision correction by 1 diopter is carried out within 5 seconds at pulse frequency of 300 Hz. The exposure is superficial one, as the radiation of 193 nm wavelength is vigorously absorbed by the cornea. The monitoring system ensures high quality of the operation irrespective of the patient's eye mobility.

Microscans certified in Russia, CIS countries, Europe, and China are now working at 45 Russian hospitals. They hold 55 percent of the Russian market.

One more example of fruitful collaboration of research and educational institutions: an ophthalmologic complex consisting of the updated Micro-scan device, Microscan Visum, Femto Visum (femtosecond laser system), and diagnostic equipment. The Institute of Physics has developed a surgical instrument for this complex, while the Institute of Problems of Laser and Information Technologies of the Russian Academy of Sciences (at Shatura) and Lomono-sov Moscow State University have provided diagnostic facilities within the framework of the program supported by the Federal Agency for Science and Innovations.

The Femto Visum laser deserves special attention. The device is based on a neodymium laser with a radiation wavelength of 1.06 µm. The cornea vigorously absorbs the radiation emitted by excimer laser, while at radiation on a wavelength of ~ 1 µm the linear absorption is slight. However, because of the short time of the pulse (400 fs), high power density is realized in focused radiation and hence, multiphoton processes become effective. Appropriate focusing makes it real to realize an exposure not involving the corneal surface, while multiphoton absorption proceeds in the entire volume of the cornea. Thus, the mechanism of exposure in this case is in the photodestruction of tissues. The adjacent layers are not subjected to thermal damage, whereas the intervention is carried out at high precision.

PHOTODYNAMIC DIAGNOSIS IN THERAPY

Photodynamic diagnosis and therapy of cancer are the methods intensely developing at present. They are based on the use of a laser with the monochromatic radiation stimulating the fluorescence of the photosensitizer stain (pharmaceutical in this case) and initiating selective photochemical reactions, causing biochemical transformation of tissues. Injected in a dose of 0.2-2.0 mg/kg, the photosensitizer is accumulated mainly in a tumor and its fluorescence shows the location of the tumor. Due to the energy transfer effect and amplification of laser power, singlet oxygen* (a potent oxidizer) is formed, which leads to tumor destruction. In a word, using this method, it is possible not only to diagnose, but also to treat cancer.

It is noteworthy that injection of a photosensitizer is a procedure not quite inoffensive for the patient, and in some cases it is possible to use the so-called laser-induced autofluorescence. It was found that normal cells do not fluoresce in some cases (particularly with short-wave laser radiation), while cancer cells exhibit this effect. This method is preferable, but it is used mainly for diagnosis, though recently attempts at realization of its therapeutic effect have been made.

A series of devices for fluorescent diagnosis and photodynamic therapy has been developed at our Institute. The leading therapeutic institutions of Moscow are equipped with them: the Sechenov Moscow Medical Academy, the Blokhin Oncological Center, the Hertzen Oncological Institute as well as hospitals in Nizhni Novgorod and Saransk. More than 30 diagnostic and

* Singlet oxygen is a common name for two metastable states of molecular oxygen (O₂) with energy higher than in the main (triplet) state. -Ed.

20 therapeutic systems are in use in Russia and in former Soviet republics as well as in Germany, Japan, Israel, Greece, South Korea and Poland.

Obligatory components of the laser complex for endoscopic and laparoscopic operations are devices for radiation delivery and formation of a radiation field at the site of exposure. Devices of this kind, based on multimode optical fibers working in a 0.2-16 µm spectrum, have been created at our Institute of General Physics.

In collaboration with other institutions and with support from the Federal Agency for Science and Innovations we are developing a method for determining the size of nanoparticles in liquid, specifically, in human blood, by using quasielastic light diffusion spectroscopy. The presence of minite particles leads to a widening of the central peak of Rayleigh scattering*. The size of these particles can be determined by measuring this value. Studying the nanoparticles' spectra in cardiovascular patients' blood serum, we detected large protein and lipid clusters. The presence of these particles is characteristic of cancer patients as well. Moreover, the component indicating the presence of clusters disappeared after effective treatment but was back again in case of a relapse. No doubt, this technology will be useful in the diagnosis of cancer and cardiovascular diseases.

Several years ago our Institute suggested a new device for detection of threshold low concentrations of organic compounds. Its major components include a laser, a time-flow mass spectrometer, and a nanostructurized plate for adsorption of the examined gas. At present this device is being modified for blood analysis, and it could be used for early diagnosis of cancer and cardiovascular diseases.

Solution of many medical problems is possible only in conjunction with basic studies in laser physics, radiation—substance interactions, energy transfer processes, biomedical research, and development of therapeutic medical technologies.

Let us emphasize that one of the pioneers of medical uses of lasers was the founder and first head of the Institute of General Physics (1982-2002) Alexander Prokhorov. Many studies mentioned in the present article were initiated by him.

* Rayleigh scattering—diffusion of light on objects whose size is smaller than its wavelength. -Ed.