U.S. patent number 5,071,416 [Application Number 07/517,762] was granted by the patent office on 1991-12-10 for method of and apparatus for laser-assisted therapy.
This patent grant is currently assigned to Metalaser Technologies, Inc.. Invention is credited to Robert S. Anderson, Donald F. Heller, John C. Walling.
United States Patent |
5,071,416 |
Heller , et al. |
December 10, 1991 |
Method of and apparatus for laser-assisted therapy
Abstract
A laser beam from a tunable solid state laser such as an
alexandrite laser passes through a Raman shifter to produce a
Raman-emitted beam with wavelength shifted so as to be able to
activate a preselected photosensitizer for medical treatment. A
combination of a laser and a Raman shifter with or without
additionally a harmonic generator such as a frequency doubler may
be also selected such that radiation with two different wavelengths
can be obtained for treatment and detection.
Inventors: |
Heller; Donald F. (Warren,
NJ), Walling; John C. (White House Station, NJ),
Anderson; Robert S. (Livermore, CA) |
Assignee: |
Metalaser Technologies, Inc.
(Pleasanton, CA)
|
Family
ID: |
24061130 |
Appl.
No.: |
07/517,762 |
Filed: |
May 2, 1990 |
Current U.S.
Class: |
606/3; 606/10;
600/476 |
Current CPC
Class: |
A61N
5/062 (20130101); A61N 5/0601 (20130101); H01S
3/30 (20130101); A61N 2005/067 (20130101) |
Current International
Class: |
A61N
5/06 (20060101); A61N 5/067 (20060101); H01S
3/30 (20060101); A61B 006/00 () |
Field of
Search: |
;606/2,3,10-18
;604/20,21,49 ;128/633,395-398,665 ;372/3 ;310/426,427 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Primary Examiner: Pellegrino; Stephen C.
Assistant Examiner: Shumaker; Steven J.
Attorney, Agent or Firm: Heller, Ehrman, White,
McAuliffe
Claims
What is claimed is:
1. A method of using laser light for medical therapy comprising the
steps of
selecting a target wavelength within a certain wavelength region
for medical application,
selecting a combination of a laser and a Raman shifter such that
said laser can emit a laser beam having a preselected wavelength
which, when passed through said Raman shifter, can produce
frequency-upshifted light with said target wavelength by
anti-Stokes effect,
applying a photosensitizer to a target region,
causing said laser to emit a laser beam with said preselected
wavelength and to have said laser beam with said preselected
wavelength to pass through said Raman shifter to thereby produce
Raman-emitted frequency-upshifted light with said target
wavelength, and
causing said Raman-emitted light with said target wavelength to be
made incident on said target region for said therapy.
2. The method of claim 1 wherein said laser is a turnable solid
state laser.
3. The method of claim 2 wherein said laser is an alexandrite
laser.
4. The method of claim 1 wherein said laser is a titanium sapphire
laser.
5. The method of claim 1 wherein said target wavelength is between
630 nm and 690 nm.
6. The method of claim 1 wherein said photosensitizer is
dihematoporphyrin-ether and said target wavelength is 630 nm.
7. The method of claim 1 wherein said photosensitizer is
benzo-porphyrin derivative and said target wavelength is 690
nm.
8. The method of claim 1 wherein said photosensitizer is
tin(4)etiopurpurin dichloride and said target wavelength is 660
nm.
9. The method of claim 1 wherein said target wavelength is selected
such that laser light of said target wavelength can activate said
photosensitizer for photodynamic therapy.
10. The method of claim 1 wherein said laser is a Q-switched
laser.
11. The method of claim 1 wherein said laser is a mode-locked
laser.
12. The method of claim 1 wherein said Raman-shifter is contained
in said laser.
13. The method of claim 1 further comprising the step of
introducing a harmonic generator into said combination such that
emission at said target wavelength is produced also through passage
through said harmonic generator.
14. A method of using laser light for medical therapy comprising
the steps of
selecting a first target wavelength for laser beam to be used for
treatment,
selecting a second target wavelength for laser beam to be used for
detection of disorders,
selecting a combination of a laser and a Raman shifter such that
said laser can emit a laser beam having a preselected wavelength
which, when passed through said Raman shifter, can produce by
anti-Stokes effect frequency-upshifted emission with both said
first target wavelength and said second target wavelength,
causing said laser to emit a laser beam with said preselected
wavelength and to have said laser beam with said preselected
wavelength to pass through said Raman shifter to thereby produce
Raman-emitted frequency-upshifted light with both said first target
wavelength and said second target wavelength, and
selectably (1) applying a photosensitizer to a selected treatment
region and causing said Raman-emitted frequency-upshifted light
with said first target wavelength to be made incident on said
selected treatment region for said treatment or (2) causing said
Raman-emitted frequency-upshifted light with said second target
wavelength to be made incident on a selected detection region for
said detection of disorders.
15. The method of claim 14 wherein said laser is a tunable solid
state laser.
16. The method of claim 15 wherein said laser is an alexandrite
laser.
17. The method of claim 14 wherein said laser is a titanium
sapphire laser.
18. The method of claim 14 wherein said first target wavelength is
between 630 nm and 690 nm.
19. The method of claim 14 wherein said photosensitizer is
dihematoporphyrin-ether and said first target wavelength is 630
nm.
20. The method of claim 14 wherein said first target wavelength is
selected such that laser light of said first target wavelength can
activate said photosensitizer for photodynamic therapy.
21. A method of using laser light for medical therapy comprising
the steps of
selecting a first target wavelength for laser beam to be used for
treatment,
selecting a second target wavelength for laser beam to be used for
detection of disorders,
selecting a combination of a laser, a Raman shifter and a harmonic
generator such that said laser can emit a laser beam having a
preselected wavelength which, when passed through said Raman
shifter, can produce by anti-Stokes effect Raman-emitted
frequency-upshifted light with said first target wavelength and,
when passed through said harmonic generator, can produce laser
light with said second target frequency,
selectably (1) applying a photosensitizer to a selected treatment
region and causing said laser to emit a laser beam with said
preselected wavelength, causing said emitted laser beam with said
preselected wavelength to pass through said Raman shifter to
thereby produce Raman-emitted frequency-upshifted light with said
first target wavelength and causing said Raman-emitted
frequency-upshifted light with said first target wavelength to be
made incident on said selected treatment region for said treatment,
or (2) causing said laser to emit a laser beam with said
preselected wavelength, causing said emitted laser beam with said
preselected wavelength to pass through said harmonic generator to
thereby produce laser light with said second target frequency and
causing said laser light with said second target frequency to be
made incident on a selected detection region for said detection of
disorders.
22. The method of claim 21 wherein said laser is a tunable solid
state laser.
23. The method of claim 22 wherein said laser is an alexandrite
laser.
24. The method of claim 21 wherein said laser is a titanium
sapphire laser.
25. The method of claim 21 wherein said first target wavelength is
between 630 nm and 690 nm.
26. The method of claim 21 wherein said photosensitizer is
dihematoporphyrin-ether and said first target wavelength is 630
nm.
27. The method of claim 21 wherein said first target wavelength is
selected such that laser light of said first target wavelength can
activate said photosensitizer for photodynamic therapy.
Description
BACKGROUND OF THE INVENTION
This invention relates to methods of and apparatus for
laser-assisted therapy including photodynamic therapy.
Photodynamic therapy (PDT) with laser is being regarded as an
effective method for treatment of cancer and other disorders. As
with antibiotherapy, tumor cultures are initiated in laboratories
and tested for sensitivity to various sensitizing agents and
various laser wavelengths before the method is applied clinically.
Currently known examples of sensitizing compound include
dihematoporphyrin-ether activated at wavelength of 630 nm,
benzo-porphyrin derivative activated at wavelength of 690 nm and
tin [4]etiopurpurin dichloride (SnET2 purpurin) activated at
wavelength of 660-670 nm. Many other sensitizing agents and new
laser wavelengths are likely to be developed. At the present time,
argon-pumped dye lasers, copper-pumped dye lasers, gold lasers,
excimer-pumped dye lasers or the like are used but lasers of these
types are not reliable, versatile or convenient in providing a
laser beam of desired power and wavelength for the aforementioned
medical applications.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention in view of the
above to provide methods of and apparatus for laser-assisted
photodynamic and other types of therapy.
It is another object of the present invention to provide such
methods and apparatus which are efficient and convenient.
The methods and apparatus with which the above and other objects
can be achieved are based on stimulated Raman emission, sometimes
called stimulated Raman scattering. Stimulated Raman scattering is
a means for "pumping" light, or converting light at a certain
wavelength into light at longer ("Stokes") or shorter
("anti-Stokes") wavelengths. If the pump light is sufficiently
intense, the stimulated Raman scattering process can be highly
efficient. Energy conversion efficiencies into Stokes and
anti-Stokes wavelengths in excess of 70% have been reported.
According to the present invention, a combination consisting of a
laser and a Raman shifter is selected such that the beam of
radiation having a certain wavelength which can be caused to be
emitted from the laser, when traversed through the Raman shifter,
produces frequency-shifted scattered laser light (or Raman-emitted)
having a desired wavelength. If the method or apparatus is for
photodynamic therapy with the use of dihematoporphyrin-ether, the
desired wavelength is approximately 630 nm. If benzo-porphyrin
derivative is the sensitizing agent to be used, the desired
wavelength will be approximately 690 nm. If SnET2 purpurin is to be
used, the desired wavelength will be approximately 660 nm. For
treatment of vascular lesions, a laser beam with a much shorter
wavelength (say, 578 nm) may be desirable. A tunable solid state
laser such as an alexandrite laser or a titanium sapphire laser is
preferably used in such a combination. Since many different Raman
shifters with different scattering media, and hence different shift
characteristics, are available, different combinations of a laser
and a Raman shifter are capable of outputting laser radiation with
a desired wavelength but a selection is made according to the
present invention such that the scattered frequency-shifted
Raman-emitted beam with the desired wavelength is outputted in an
optimum condition for the intended use.
Such a frequency-shifted Raman-emitted laser light can be used not
only for the purpose of photodynamic or other kind of therapy but
also for detection, for example, of a malignant condition. For such
a purpose, a laser beam with lower intensity and different
wavelength may be used to cause fluorescence of an injected
tumor-seeking agent. Thus, a Raman shifter capable of producing
Raman-emitted light having two different wavelengths may be
selected such that the same combination of a laser and a Raman
shifter can be used both for treatment at one wavelength and for
detection and localization of a condition at another
wavelength.
As an alternative, a harmonic generator such as a frequency doubler
may be selectably used in combination with the laser to produce a
beam of radiation suited for such detection separate from the beam
which is intended for treatment.
It has not been known or appreciated that pulsed laser sources
having sufficient intensity to produce efficient stimulated Raman
scattering are compatible with the requirements for efficacious
photodynamic therapy, and thus can prove useful as sources for
photodynamic therapy.
BRIEF DESCRIPTION OF THE DRAWING
The accompanying drawings, which are incorporated in and form a
part of the specification, illustrate embodiments of the present
invention and, together with the description, serve to explain the
principles of the invention. In the drawings:
FIGS. 1A and 1B are block diagrams schematically showing the
structure and operation of apparatus embodying the present
invention for laser-assisted photodynamic therapy using
dihematoporphyrin-ether and FIG. 1C is a schematic drawing for
showing the structure of the Raman shifter in FIGS. 1A and 1B,
FIG. 2 is a block diagram schematically showing the structure and
operation of another apparatus embodying the present invention,
and
FIGS. 3A, 3B and 3C are block diagrams schematically showing the
structures and operations of still other apparatus embodying the
present invention.
In these figures, components which are substantially identical or
at least similar to each other are indicated by the same
numeral.
DETAILED DESCRIPTION OF THE INVENTION
With reference to FIGS. 1A and 1B which schematically show systems
for laser-assisted photodynamic therapy using
dihematoporphyrin-ether, numeral 11 indicates a source of a laser
beam including an alexandrite laser such as a PAL.TM. system
(produced and sold by Light Age, Inc. of Warren, N.J.) which is a
tunable solid state laser with output wavelength in the range of
about 720-800 nm. Numeral 12 generally indicates a Raman shifter
with means (not shown) for applying Raman-shifted radiation on a
target region, having a typical optical arrangement shown
schematically in FIG. 1C and only for the purpose of illustration.
Monochromatic radiation from the laser 11 impinges on an emitting
medium in an appropriate transparent cell. The impinging laser
light may be condensed by a lens L.sub.1 and collimated by another
lens L.sub.2, and unwanted radiation from the beam may be removed
by a narrow-band optical filter F.
Use as the Raman shifter 12 may be made, for example, of Model
LAI101 PAL-RC (produced and sold by Light Age, Inc.) with hydrogen,
deuterium, methane, nitrogen, oxygen or other gases used as the
Raman emitting medium. Table 1 shows the wavelengths of
Raman-shifted beams (first, second, etc.) emitted from such
shifters using different kinds of gas when laser beams of different
initial wavelengths impinge thereupon. Liquid and solid media may
also be employed but their use is generally less preferable. If
deuterium gas is employed in the Raman shifter 12 in combination
with monochromatic pump radiation of wavelength near 777 nm as
shown in FIG. 1A, anti-Stokes light is generated at a wavelength
near 630 nm. Pump beams having low spatial divergence and powers of
several megawatts are preferred.
The foregoing description of a preferred embodiment of the
invention has been presented for purposes of illustration and
description. It is not intended to be exhaustive or to limit the
invention to the precise form disclosed, and many modifications and
variations are possible in light of the above teaching. For
example, the source of laser radiation need not be an alexandrite
laser. A titanium sapphire laser and other kinds of tunable solid
state laser may be used as the source of laser radiation. Other
examples of sensitizing agent to be activated by a laser beam in
photodynamic therapy according to the present invention include but
are not limited to benzo-porphyrin derivative and SnET2 purpurin
although only such agents that can be activated by radiation in the
wavelength range of 630 nm-690 nm are considered herein.
Raman-emitted radiation outside this wavelength range may be
utilized for different medical purposes and the method and
apparatus therefor, such as shown in FIG. 2, are also to be
considered within the scope of this invention. Some additional
combinations of initial laser wavelength and the kind of gas used
in a Raman shifter which may produce useful Raman-emitted radiation
within the broad meaning of the present invention are also included
in Table I.
Another method embodying the present invention is based on the
observation that the Raman spectrum of many scattering (emitting)
substances contains a plurality of anti-Stokes lines. In such a
case, a high-intensity line may be used for treatment and a
low-intensity line corresponding to a different wavelength may be
used for detection and/or localization, say, of a malignancy by
causing a photosensitizer to fluoresce. For example, under typical
conditions of intensity, pressure and focussing geometry where pump
light at 777 nm, as can be generated by using an alexandrite laser,
is anti-Stokes Raman-shifted to produce light at 630 nm as
described above, light is also produced at higher-order anti-Stokes
wavelengths of 530 nm, 457 nm, 402 nm, etc. as shown in FIG. 3A and
Table 1. Although the light intensity at these wavelengths is
significantly lower than at 630 nm, there is more than enough
intensity generated for use for tumor detection and localization.
With dihematoporphyrin-ether, light with wavelengths in the 450-350
nm region is particularly well suited to this application as it is
strongly absorbed, is well transmitted by optical fibers, and is
non-mutagenic. In FIG. 3A, F indicates a filter which may be used
for selectively allowing Raman-emitted radiation in a specified
wavelength range.
According to still another method embodying the present invention
and schematically illustrated in FIG. 3B, the laser radiation from
the laser 11 is passed selectably through a Raman shifter 12 and a
harmonic generator such as a frequency doubler 13 wherein numeral
15 indicates a device of any known type for selectably directing
the laser beam emitted from the laser 11 to the Raman shifter 12 or
the frequency doubler 13. The Raman shifter 12 can serve to
activate a photosensitizer for treatment as described above. The
frequency doubler 15 serves to provide a beam with a higher
frequency (shorter wavelength) that may be used for the purpose of
detection and/or localization as above.
The methods described above by way of FIGS. 3A and 3B can be
combined to form another combination as illustrated in FIG. 3C
which is characterized as having another Raman shifter 12' inserted
between the frequency doubler 13 and the beam-splitting means 15.
Table 2 shows examples of combination of wavelengths that may thus
be obtained from an initial laser beam and a combination of a Raman
shifter and a frequency doubler. In FIGS. 3B and 3C, F and F'
indicate individual optical filters which can be operated such that
laser light of a different wavelength cab be selectably caused to
be outputted.
In all examples described above, furthermore, it is believed
preferable to use a Q-switched laser but use may well be made of a
mode-locked laser. Lasers of other types are not intended to be
precluded. In all block diagrams presented above, the boxes
representing a laser and those representing a Raman shifter were
drawn separately but this is not intended to preclude the designs
whereby the Raman shifter 12 is located inside the resonator cavity
of the laser 11. In summary, any such modifications and variations
that may be apparent to a person skilled in the art are intended to
be included within the scope of this invention.
TABLE 1 ______________________________________ 1st 2nd 3rd 4th Gas
Fundamental Shift Shift Shift Shift
______________________________________ Oxygen 720 nm 647 nm 588 nm
539 nm 497 nm Oxygen 740 664 601 550 507 Oxygen 760 680 615 561 516
Oxygen 780 696 628 572 525 Oxygen 800 711 641 582 534 Deuterium 720
592 503 437 387 Deuterium 740 606 513 445 393 Deuterium 760 619 522
452 398 Deuterium 780 632 532 459 403 Deuterium 800 646 541 466 409
Nitrogen 720 617 539 479 431 Nitrogen 740 631 550 488 438 Nitrogen
760 646 561 496 445 Nitrogen 780 660 572 505 452 Nitrogen 800 674
583 513 458 Hydrogen 720 554 450 379 328 Hydrogen 740 566 458 385
332 Hydrogen 760 578 466 390 336 Hydrogen 780 589 473 395 340
Hydrogen 800 600 481 401 343 Hydrogen 760 578 466 390 336 Deuterium
777 630 530 458 403 Oxygen 735 660 598 547 504 Oxygen 773 690 623
568 522 Nitrogen 739 630 550 487 438 Nitrogen 780 660 572 505 452
______________________________________
TABLE 2 ______________________________________ Fundamental 1st
Shift Doubled Doubled ______________________________________
Hydrogen 735 nm 1058 nm 529 nm 368 nm Hydrogen 780 1154 577 390
Deuterium 735 942 471 368 Deuterium 780 1017 509 390 Oxygen 735 830
415 368 Oxygen 780 888 444 390 Nitrogen 735 887 443 368 Nitrogen
780 953 477 390 ______________________________________
* * * * *