where X is the thermal diffusivity, and the laser beam diameter a is taken, for the sake of definiteness, to be greater than z_o . By way of illustration, let us consider soft biotissue with A ~ 10 cm^-1 and X ~ 1.3x10^-3 cm²/s. The cooling time in this case is T cool , 2 s. Consequently, by using a laser pulse with a duration of Tp < Tcool one can, according to the data of Figure 1, heat the tissue by Δ T_max = 5-10°C without running any risk of it being damaged. This limits the fluence of a laser pulse with a duration of Tp < T cool to a value of

Φ < Φ_max ~ T_max ρc/η_o (2) where P and c are the density and heat capacity of biotissue, respectively, and η_o < A. In our example,

Φ max ~ 4 J/cm², which corresponds to a maximum permissible average laser intensity of =Φ_max/Tcool

~ 2 V/cm²

Biotissue has local absorption inhomogeneities of varying size: of the order of a few nanometers (biomolecules), a few tens of nanometers (biomolecular aggregation, membrane thickness), a few microns (cells and subcellular units), and more (microcapillaries). If a local absorption microregion has an absorptivity of δη loc exceeding the volume-averaged absorptivity η_{o '} it can be heated with a laser pulse by an amount of δT1oc exceeding the volume-averaged heating Δ T. The cooling time T1 oc of the local overheating microregion is determined by its size 1: T1oc ~ I²/4x^{( 3 )}

If the laser pulse duration T_p is shorter than this cooling time, the amount of local overheating will then be δT1oc =ΔT_{(δη1 oc/ηo}) (4) For example, the cooling time of a local absorption microregion of size 1 ~ 30 nm = 3x10^-6 cm is T1oc ~

2x10^-9 s. Consequently, to effect a pulsed local heating of such a microregion, the duration T_p of the laser pulse used must be shorter than 2 ns. If the laser pulse fluence permissible from the standpoint of the volume- averaged non-destructive heating is, according to the above numerical example, Φ_maχ ~ 4 J/cm², the peak intensity of the ultrashort laser pulse is 1_p ~ Φ_max /Tρ ~ 2 x 10⁹ W/CM². This intensity value is quite permissible, but it is fairly close to the threshold marking the onset of multiple-photon absorption effects. Even if the contrast of local absorption against the background of average absorption,K=δη_{1oc /ηo} is low, one can achieve a noticeable pulsed overheating (δT1oc ~ = 15- 50°) of local absorption microregions for a time of T_1oc ~ 2 ns , the average heating of biotissue being quite insignificant ( Δ T ~ 5-10°C). The time interval between successive ultrashort laser pulses, T_rep, must be longer than the cooling time T_cool of the entire laser-exposed bulk of biotissue. In the above numerical example, T_cool ~ 2s.

To effect a selective pulsed heating of microregions of smaller size, the laser pulse duration must be shorter, in accordance with equation (3), and to prevent multiple-photon effects in the bulk of biotissue, the laser energy must be distributed among several pulses within the time interval T cool' so as to ensure that the peak intensity does not perceptibly exceed the value of 1_P ~ 2x10⁹ W/cm². Similarly, to achieve a local pulsed heating of larger microregions, one can use, in accordance with equation (3), longer pulses, and since the peak laser intensity will be lower than 10⁹ W/cm², radiation energy can be deposited in biotissue with single pulses. The interval between them in this case must not exceed Tcool in order to avoid destructive volume-averaged heating of biotissue. Figure 3a shows the laser pulse sequence and Figure 3b, the temporal variation of the temperature of the exposed medium, caused by both the local heating δ T_1oc of the microregions of increased absoption and the volume- averaged heating ΔT of the tissue. The volume-averaged laser heating can accumulate during a long period of Tcool , if the cooling time is much longer than the interval T_rep between the pulses. At the same time, the local heating of the microregions of increased absorption rapidly vanishes within the time T1oc << T_rep . τhe average heating Δ T of the exposed region during the timeTcool must not exceed a maxium value of ΔT_max.

The therapeutic effect of laser pulses is due to, first, the local pulsed non-destructive heating of microregions in the laser-exposed biotissue by the amount defined by equation (4) and secondly, the production of the pulsed temperature gradients d ΔT/d z ~ δ T1oc/1 = (ΔT/1 (δη1oc/η_o) (5) that no other method can provide. Both these effects influence materially the course of metabolic processes on the molecular, subcellular, cellular, and above-cellular levels.

The above arguments define the region of laser radiation parameters with which pulsed laser photothermotherapy can be realised. This region is denoted by the symbol IV in Figure 2. These considerations also determine the choice of the parameters the device for implementing the technique must have.

A device for laser photothermotherapy is shown in Figure 4 and includes a pulsed laser 1 whose wavelength λ corresponds to that of local absorption by microregions of average size 1 (λ) in biotissue, a laser pulse duration control unit 2 providing for the generation of laser pulses with a duration of T_P satisfying the condition

T_P < T_1oc=/2(λ)/4X (6) and a repetition period of T_rep meeting the requirement for the absence of any noticeable volume-averaged heating of biotissue:

T_rep <Tcool =

(λ)/4X <1/[4η

(λ) ]X (7) a delivery system 3 to deliver radiation to a biotissue treatment region that ensures the necessary laser pulse fluence Φ_p ~ ΔT max Pc/η_o ( 8 ) with which the volume-averaged heating of biotissue falls within permissible limits, Δ T_{max '} while the pulsed local heating of the microregions in the tissue reaches therapeutic levels (δT1oc > 15-50°C), and a rise and fall measurement unit 4 for measuring the local heating by a single laser pulse and the average heating ΔT by a train of laser pulses, which controls, by way of feedback to the control unit 2, the pulse energy and repetition period and the total exposure dose in order to provide for therapeutic effect without running the risk of thermal damage to the exposed tissue region. For this purpose, use can be made, for example, of a small-time- constant radiometer registering the heat emission intensity of the heated tissue regions. To measure the pulsed heating of local microregions, use is made of the fast component (1 in Figure 3b) of the temperature variation following the laser pulse, whereas the volume- averaged heating is determined from the slow temperature variation component (2 in Figure 3b).

It will be understood that the construction and parameters of the units 1, 2, 3, 4 will be clear- to those skilled in the associated art and, therefore, do not require detailed description in this specification.

Table 1

An example of selecting laser pulse parameters for the laser photothermotherapy of biotissue withfe. = 10 Cm^-1 and X = 1.3x10^-3 cm² /s as a function of the average size 1(λ) of local microregions of increased absorption

Table 1 lists the laser pulse parameters necessary for treating biotissue, for example, with an absorptivity of η_o = 10 cm^-1 and a thermal diffusivity of X = 1.3x10-³ cm²/s, as a function for the average size 1 (λ ) of local microregions of increased absorption at the laser wavelength λ . For 1 > 30 n = 300 A, the laser pulse repetition period is determined by the cooling time Tcool' whereas for 1 < 30 n, the pulse repetition period is selected to be shorter in order to limit the peak pulse intensity to a non-destructive level of some 2x10⁹ W/cm² . In that case, the laser pulse fluence is limited to a safe average heating level of around 4 J/cm².

The device can also be used in a method of laser photothermotherapy where tissue is injected by exogenak non-toxic dye or drug comprised by chromophores of suitable size to enable local micro-heating, on absorbing the effective wavelength, of the microregion where the chromophores of the dye or drug are situated and cause therapeutic or destructive effects according to the condition treated.

Claims

CLAIMS :

1. A device for laser photothermotherapy comprising a pulsed laser constructed to operate in the ultraviolet, visible or infrared part of the spectrum, and a system arranged to deliver pulsed irradiation generated from said laser to a targeted area of living human or animal tissue, characterised in that control means (2) are provided for controlling said laser (1) to generate pulses of variable duration, repetition rate and pause duration between the pulses, and that measuring means (4) responsive to the tissue, when irradiated, are provided for operating said control means for the pulse duration and wavelength delivered by said laser to correspond to the size and nature of one or more targeted absorbing exogenous or endogenous chromophores in the tissue, said measuring means being responsive to local microheating of an absorbing said chromophore or chromophores and the surrounding local microregion, significantly higher than the average temperature of the entire targeted tissue, for actuating said control means to render the pauses between consecutive laser pulses to be sufficiently long to permit cooling of the temperature elevation in said local microregion between each pulse and the next.

2. A device according to Claim 1, characterised in that said measuring means (4) comprises a short-time constant radiometer arranged to register the heat emission of the tissue region, when targeted, the radiometer comprising a fast component to measure pulsed heating of local microregions following each laser pulse and a slow temperature variation component for detecting volume-averaged heating of the targeted area.

3. A device according to Claim 1 or Claim 2, characterised in that said control system is contrived for each pulse to have a duration complying with the relation T_P < T_1oc=I²(y)/4X and for each pulse to have energy complying with the relations

Φ < Φ max ~ ΔT_max Pc/η

and

δT1oc = ΔT (δη1oc/η_o)

4. A method of effective laser photothermotherapy comprising delivering ultraviolet, visible or infrared laser pulse energy to a targeted area of living human or animal tissue characterised in that the method is effected by means of a device according to any one of the preceding claims.