WO2007124602A1 - Method and device for delivering localized light energy to the eye - Google Patents

Abstract

The present invention provides a method and apparatus to deliver localized light therapy and an apparatus to do so. More particularly the present invention provides a method and apparatus to pre-correct and pre-shape in space and time a laser beam so as, after it passes through the optics of the eye, the energy in the beam is localized at the rear of the eye in depth and laterally without creating damage to adjacent tissues.

Description

METHOD AND DEVICE FOR DELIVERING LOCALIZED LIGHT ENERGY

TO THE EYE

CROSS REFERENCE TO RELATED U.S. APPLICATIONS This patent application relates to, and claims the priority benefit from,

United States Provisional Patent Application Serial No. 60/796,900 filed on May 3, 2006, in English, entitled METHODS FOR LOCALIZED LIGHT FOR APPLICATION OF THERAPY, VISUALIZATION OF THERAPY AND IMAGING IN THE EYE, and which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to methods to deliver localized light therapy to the eye and an apparatus to do so. More particularly the present invention provides a method and apparatus to pre-correct and pre-shape in space and time a laser beam so as, after it passes through the optics of the eye, the energy in the beam is localized at the rear of the eye in depth and laterally without creating damage to adjacent tissues.

BACKGROUND OF THE INVENTION

Multiphoton processes in tissue using femtosecond (fs) pulses allow the use of lower energy with high peak power to get the same result as a one photon process. When fs laser pulses are tightly focused, the intensity in the focal volume can become high enough to cause nonlinear absorption, through multiphoton processes. If ionization occurs, it can lead to a damaged region with submicron dimensions. The resulting photodisruption is more localized and the lower average powers can minimize bubble formation and shock waves compared with single photon processes. A slower pulse rate reduces thermal injury and the use of an infrared wavelength allows deeper penetration into tissue than the shorter wavelengths used for one photon processes. Other nonlinear processes such as self focusing, have the potential to further localize the light energy. Therapies delivered using multiphoton interactions have the potential to be minimally invasive and to spare adjacent, healthy tissues. The use of multiphoton processes initiated by ultrafast laser pulses as precise surgical tools has been shown in single cells [1], for corneal surgery [2,3,4], for presbyopia reversal [5] and scleral surgery[6]. Besides microsurgical applications and manipulation of viscoelastic properties, other potential multiphoton processes which could improve therapies delivered to the rear of the eye include multiphoton photo-uncaging of drugs [7] and other light based activation of therapeutic agents, laser induced breakdown of drug bearing liposomes [8], the induction of cell death [9] and two-photon photodynamic therapy [10]. Femtosecond laser pulses are thought to damage the retina [11].

Optimal delivery and localization of femtosecond pulses at the retina is necessary to fully realize the advantages of multiphoton processes at the retina and fundus. The monochromatic aberrations of the cornea and lens will blur the spatial extent of the pulse, lowering the peak power and dispersion will lengthen the pulse. Spatial localization of the light has been partially addressed by confocal scanning laser ophthalmoscopes used in conjunction with adaptive optics [12,13]. However optimal localization of light at the rear of the eye in both space and time has not been demonstrated. Furthermore, spatial localization is more complex for a short pulse because of the effects of self focusing.

In addition it is necessary to enter the eye with the pulse so that it cannot be applied outside the target body [14]. Once a single beam has been localized it will need to be scanned within the treatment volume which will also need to be visualized. Thus the methods described herein for localizing the beam will be combined with visualization and scanning of the beam. The intent is to localize the delivered light in time and space, sufficiently to allow therapy via two photon or multiphoton processes. However, the same methods of localization may be applied to reduce the damage to adjacent tissue during treatments utilizing a single photon. It would be very advantageous to provide a method and apparatus to deliver localized light to the rear of the eye (fundus) and an apparatus to do so. SUMMARY OF THE INVENTION

Embodiments of the present invention provide a method to deliver localized light therapy to the eye and an apparatus to do so. Embodiments of the invention provide a method to pre-correct and pre-shape in space and time a laser beam so that, after it passes through the optics of the eye, the energy in the beam is localized at the rear of the eye in depth and laterally without creating damage to adjacent tissues.

Thus, in one aspect of the invention there is provided a method for delivering localized light to the eye, comprising the steps of: pre-correcting and pre-shaping in space and time a laser beam so that, after it passes through the optics of the eye, the energy in the beam is localized at the rear of the eye in depth and laterally without creating damage to adjacent tissues.

The step of pre-correcting and pre-shaping in space and time a laser beam may include a) correction of the first order chromatic aberration of the eye; b) correction of the second order and higher aberrations of the optics of the eye; c) correction of the higher order dispersion of the eye; and d) shaping the wavefront to produce the desired position of focus of the beam.

Following preshaping in space and time, the power of the beam may be chosen so as to focus the light in the best plane of the eye so as to deliver therapy in a small desired volume without damage to surrounding tissue. If the desired treatment volume is larger, the beam should be scanned within that volume.

In this aspect the step correction of the first order chromatic aberration of the eye may include using an achromatizing lens to introduce an opposite chromatic aberration to that within the target eye for the wavelengths incident on the eye.

In this aspect the step of correction of the second order and higher aberrations of the optics of the eye may include use of an adaptive optics element to pre-distort the wavefront entering the eye.

In this aspect the step c) may consist of prechirping the beam to produce the desired pulse width.

The present invention provides a method for delivering laser light pulses to a target eye by pre-correcting and pre-shaping laser pulses from a laser beam in space and time so that, after the laser pulses pass through the optics of the target eye, light energy in the laser pulses is localized at the rear of the target eye in depth and laterally without creating damage to adjacent tissues, the method comprising the steps of: a) correcting first order chromatic aberrations of the target eye for wavelengths of the laser pulses incident on the eye; b) correcting second order and higher aberrations of optics of the target eye; c) selecting a pulse width which, based on knowledge of dispersion properties of the target eye, produces the shortest pulse possible at a fundus feature of interest in the target eye; and d) adjusting a power of the laser pulses so that the laser pulses delivered at the fundus feature of interest have an intensity above a threshold intensity to activate a desired therapy.

In an another aspect of the present invention there is provided an apparatus for delivering laser light pulses to a target eye, comprising: a) a laser configured to produce laser pulses; a) means for correcting first order chromatic aberrations of the target eye for wavelengths of the laser pulses incident on the eye; b) means for correcting second order and higher aberrations of optics of the target eye; c) means for selecting a pulse width; and d) means for adjusting a power of the laser pulses so that the laser pulses delivered at the fundus feature of interest have an intensity above a threshold intensity to activate a desired therapy.

A further understanding of the functional and advantageous aspects of the invention can be realized by reference to the following detailed description and drawings. BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood from the following detailed description thereof taken in connection with the accompanying drawings, which form a part of this application, and in which: Figure 1 shows a water eye model (Paraxial) predictions of pulse widths incident on the fundus of the rat and human eyes as a function of the incident pulse width. This data is predicted from a water eye model of the eye. The central wavelength of 0.8mm.

Figure 2 shows a representation of the spherical and elliptical model is constructed in ZEMAX and this plot results;

Figure 3 shows the axial intensity along the optical axis plotted as a function of position for the natural monochromatic aberrations of the rat eye in (a) and after correction of those aberrations in (b) monochromatic aberrations present in the rat eye diminishes image quality and lowers the probability of targeted Two-Photon Excitation (TPE). An AO correction will allow for increased light intensity at the target location.

DETAILED DESCRIPTION OF THE INVENTION

Generally speaking, the systems described herein are directed to methods to deliver localized light therapy to the eye and an apparatus to do so. As required, embodiments of the present invention are disclosed herein. However, the disclosed embodiments are merely exemplary, and it should be understood that the invention may be embodied in many various and alternative forms. The Figures are not to scale and some features may be exaggerated or minimized to show details of particular elements while related elements may have been eliminated to prevent obscuring novel aspects. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention. For purposes of teaching and not limitation, the illustrated embodiments are directed to methods to deliver localized light therapy to the eye and an apparatus to do so.

As used herein, the term "about", when used in conjunction with ranges of wavelengths or other physical properties or characteristics, is meant to cover slight variations that may exist in the upper and lower limits of the ranges of dimensions so as to not exclude embodiments where on average most of the dimensions are satisfied but where statistically dimensions may exist outside this region. It is not the intention to exclude embodiments such as these from the present invention.

Methods to deliver localized light therapy are outlined along with an apparatus to do so are disclosed herein. The invention provides a method to pre-correct and pre-shape in space and time a laser beam so as, after it passes through the optics of the eye, the energy in the beam is localized at the rear of the eye in depth and laterally without creating damage to adjacent tissues.

The steps include firstly the correction of the first order chromatic aberration of the eye. This can be accomplished in a number of ways with a preferred implementation being the use of an achromatizing lens to introduce the opposite chromatic aberration to that within the target eye for the wavelengths incident on the eye. This would ideally include amounts of transverse and longitudinal charomatic aberration opposite to those of the eye. The lens is then centered in front of the eye so as to reduce the amount of transverse chromatic aberration. The preferred wavelength range used has a midpoint in the infrared.

The second step is correction of the second order and higher aberrations of the optics of the eye. The first order aberrations may also be corrected. This is accomplished by the use of an adaptive optics element to pre-distort the wavefront entering the eye. The second order aberrations may be corrected by a spherocylindrical lens with the adaptive optics element correcting higher order aberrations. This device may also pre-tilt the wavefront.

The pre-distortion and pre-tilting are such that the wavefront incident on the point of interest on or close to the structure to be treated is a sphere centered at that point. In the preferred implementation, this pre-distortion

(and pre-tilt if used) is accomplished by measuring the wavefront in a feedback loop with a wavefront measuring device. The preferred implementation is a closed loop system. The position of the point of interest at which the spherical wavefront is centered may be chosen by adding or subtracting power from the instrument (either a lens or the wavefront shaping device) and observing which plane is in focus.

The imaging arm should be corrected for the difference in focus position between the wavelength used to image and that used to treat if they are different. A simpler implementation is to use an imaging wavelength at the centre of the treatment wavelength. In order to quickly reach the layer of interest in the fundus, the wavefront shaping device should be one with a large amount of stroke. The preferred implementation is to use a ferrofluidic or other magnetic mirror which has the required amount of stroke but any other wavefront shaping device or combinations of devices with similar effective strokes are possible. It is also a preferred implementation to enter through a pupil that allows the light to enter the full pupil available which may be defined (in infrared light) not by the natural or drug dilated pupil but by the aperture of the crystalline lens of the eye. The use of specific wavelengths of light may means that the light can penetrate the iris giving a larger effective aperture size. In the cases when self focusing can be induced at low powers and a singularity in power is acceptable for the therapy, the use of a narrow beam for therapy is preferred with a larger beam for visualizing the treatment location. In this case, the beam may be made smaller with a moveable iris just prior to treatment.

The third step is to choose a pulse width which will result in the shortest pulse possible at the fundus feature of interest. Based on the assumption that the dispersion of the elements of the eye is close to that of water, the ideal pulse width for the rat and human eye of average dimensions is given in Figurei . In the human eye, this is a pulse of about 55 fs and in the rat eye this is a pulse of about 27 fs. For each animal and size of eye, the ideal pulse width can be calculated.

Pulses of both shorter and longer widths will produce longer widths at the fundus (Figure 1). If a shorter pulse width is desired, first one should check that the resulting spectrum of light, centered at the therapeutic wavelength of choice, does not overlap with a known major absorption peak of the eye (usually similar to water). If not, the pulse of shorter width can be prechirped to produce a shorter pulse at the fundus.

The fourth step is to choose the power of the beam so that the localized beam at the fundus will have above threshold intensity to activate the therapy. It is however important to keep the intensity close to threshold so that the volume of treatment does not enlarge. If ionization is desired as part of the therapeutic effect, then a higher delivered intensity can be chosen which will lead to self focusing, a higher local intensity and smaller volume of treatment. Optical eye models should be used to calculate the laser energies delivered to structures away from the target structure and the therapeutic delivery should be chosen to minimize damage to other structures.

This methodology works for both animal eyes and on humans for delivery of light based therapy, for the testing of the effects of localized light therapies, for tracking of the effects of other therapies and for imaging the eye. The animal model of choice is a smaller animal model with an f# which allows better localization of the light and higher resolution of retinal features. The preferred choices are rat and mouse. These animals will require a larger stroke of the effective device for correction of the aberrations. Their refractive errors may be corrected by a secondary device or a larger effective stroke.

The power (second order) correction will depend on strain of the animal. The achromatizing lens needed for the animal model (rat or mouse) will differ from the human as will the optimum higher order dispersion correction and pulse width. The adaptive optics correction best in the preferred implementation is over the biggest possible pupil with the cornea in its natural shape. The device used should, in the preferred implementation, have about 10 microns of stroke or more. Once corrected, this animal model will allow the tracking of the effects of the therapy because of the increased f# and thus increased resolution in this model.

The use of albino animals reduces the limitations imposed by the iris and allows a larger pupil and better f# to be used. These animal models also allow the experimentation on drugs or other light activated agents before they have ideal absorption cross sections. In the cases when self focusing can be induced at low energy and a singularity in intensity is potentially acceptable and achievable for the light activated therapy, the use of a narrow beam is preferred during therapy but not during visualization.

Localization of the light in the eye for both processes based on single photon or two-photon or on multiphoton absorption is possible by putting the beam through a fundus imaging system with the beam shaping incorporated which images the full field or a reduced area or volume of the fundus or retina. The pupil used for delivery of the imaging beam may differ from that of the therapeutic beam. If the treatment is needed over an extended time period, then there should be a tracking system to stabilize the beam in the eye. If the treatment is needed over a larger area or volume, particularly an unevenly shaped area or volume, then the preferred implementation is a scanning laser system with a modulated laser beam. The possible means of laser beam modulation are numerous including direct modulation of a diode laser or Pockell cell modulation or modulation of a spatial light modulator to modulate a laser particularly an ultrafast laser.

The volume which receives the energy for treatment will be determined by the accuracy of the correction of the chromatic and monochromatic aberrations. If the volume to be treated is less than the localization obtained by the chromatic and monochromatic corrections, then there are six (6) approaches to localize the treatments further that may be used. These approaches may be used individually or used in combination or combinations with each other.

The first approach that may be used for the treatment for delivery of light energy to the superficial vessels or other superficial tissues of the retina, without damaging the underlying tissues, is to focus the treatment beam anterior in the eye to the vessel or tissue to be treated (likely within the vitreous). This allows sufficient energy from the point spread of the light to treat the vessel with a multiphoton effect while keeping the energy posterior to the target tissue low enough not to create damage due to the light to the posterior tissues.

The second methodology that may be used is to determine the shape of the volume to be treated. This shape is the produced by optically projecting a partially absorbing mask into the pupil of the eye. The Fourier transform of this mask will produce a volume of light at the rear of the eye. This can either be the desired volume for treatment or a smaller volume that can be scanning horizontally and in depth to achieve the desired treatment volume.

The third methodology that may be used if the tissue to be treated is well below the photoreceptor layer of the eye, is to direct the incident light obliquely into the pupil of the eye while still focusing it (with chromatic and aberration and dispersion correction as described previously) at the desired position at the back of the eye. Because the receptors will absorb less of obliquely incident light, they will be spared damage, while still allowing light energy to be delivered to structures posterior to the receptors in the eye.

The fourth methodology that may be used is to boast and localize the effect of the light energy via the use of structures which interact with the light in a way which localizes the absorption of the light and transfer its energy to the structures to be treated. Possibilities include but are not limited to dyes or other structures which absorb light energy. These agents can be pre- delivered to the tissue to be treated by a number of potential routes including but not limited to intravenous administration.

The fifth methodology that may be employed is the use of the waveguiding properties of the cone photoreceptors to increase the efficiency of light localization to the receptors themselves and to the retinal pigment epithelium beneath them. The funneling of light into the photoreceptors will increase the intensity of light within their structure and at the base of their structure adjacent to the RPE. If the structure to be treated is within a cone photoreceptor or just posterior to it, light should be delivered within the acceptance angle of the photoreceptor. Calculations of the threshold intensity to be delivered should also consider the intensity within a waveguide mode.

The sixth methodology that may be applied is a two photon or multiphoton, nonlinear process whereby the desired effect on the target tissue is achieved. In the case of an intrinsic agent or extrinsically delivered agent, which is stimulated to a higher energy state by 2 simultaneous or nearly simultaneous photons (in time and in space), the effective spatial localization of the effect will vary as the square of the distribution of intensity of the light energy.

In this method, an extrinsic agent with a large absorption cross section for 2 photons, should be chosen. The resulting treatment will be limited both laterally and in depth. In order to further limit the effect, a broad wavelength distribution of light which is then localized to a short (in time) pulse should be chosen for the inputted light, with a choice of wavelengths to avoid the single photon excitation of the agent and to avoid absorption by water or other structures in the eye anterior to the structure to be treated. For treatments in the posterior part of the fundus, infrared light is preferred because of its deeper penetration of tissue. For treatment of structures more anterior in the eye, shorter wavelengths may be used for better localization In this case, the energy required for treatment must be focused so that it is able to be spread in other parts of the eye so as to avoid injury to adjacent, healthy tissue.

The two photon or multiphoton treatment can be further localized by the use of very short pulses of light, 100 femtoseconds or less in duration. Multiple pulses should be delivered to the eye at as rapid rate as will still minimize thermal effects until the required excitation is complete. A raster scan of the beam will reduce damage to adjacent tissues. Modeling shows that the minimum pulse width that can be delivered to the rear of the human eye (with the chromatic and aberration correction previously described) has a pulse width of between 50 and 60 femtoseconds. For treatments within the retinal and fundal tissues of the eye, this pulse width may be preferred in order to minimize damage to adjacent tissues by mechanisms such as shock waves). Pulses shorter than about 10-20 femtoseconds shorter than this minimum (in the normal eye about 30 femtoseconds) should not be used without prechirping as the second order dispersion of the human eye will cause the pulse delivered to the rear of the eye to be longer than the minimum possible. The minimum to be used can be calculated by using the second order dispersion of water and the particular eye length. If pulses longer than the ideal calculated are used or result at the retina, then the treatment will not be localized to the target tissue as well as possible because the peak intensity will need to be increased.

For treatment of the retinal vessels which are in the anterior region of the retina or abnormal structures located close to the anterior surface of the retina, shorter pulses will better localize the treatment without damaging adjacent structures, particularly if the treatment is focused slightly anterior to the target structure (possibly in the vitreous) as previously described. In this case, the pulse should be put through optics in front of the eye to preshape the input pulse (prechirp it). The resulting pulse at the retina will then be shorter than 50 femtoseconds and the treatment will be better localized to the target tissue. In the rat eye, modeling has shown that shorter pulses can be delivered to the rear of the eye without prechirping. These pulses are estimated to have a minimum duration of approximately 30 femtoseconds. In the younger, smaller rat eye or smaller eyes, (for example the mouse), the minimum pulse width that can be delivered will be smaller still. Modeling of the eye as a water eye and using the second order dispersion properties of water gives an estimate of the ideal minimum pulse width for each eye length. Pulses shorter than about 10 femtoseconds shorter than the ideal (20 femtoseconds in the young adult rat eye) should not be used as the second order dispersion of the animal model (for example rat or mouse) will cause the pulse at the retina to be longer than ideal. The use of a shorter pulse in the small animal eyes (without prechirping) allows testing of the response of the tissues of the eye and experimental therapeutic agents to shorter ultrafast pulses of light without the need for pre shaping (prechirping) these pulses. Prechirping can be used to test still shorter pulses.

This description is intended to be general in terms of any treatments for ocular diseases which employ energy delivered by light, regardless of the mechanism of action on the tissue and regardless of the disease. The mechanism may be directly on the tissue or its contents by light or on an agent delivered to the tissue by any means. The agent delivered may enclose the agent with the therapeutic effect and the light may effect the enclosure rather than the therapeutic agent.

The mechanism of action of the light energy is intended to be general by single photon or two photon or multiphoton absorption resulting in any mechanism of damage. This includes but is not limited to thermal mechanisms or other direct light treatment of the tissue, photoactivation of drugs, photoactivation of molecules that then release drugs, release of drugs from enclosures (from within a molecule or larger enclosure) via light energy, etc. The tissues at the rear of the eye that this applies to include but are not limited to nerve cells and/or their axons, photoreceptors, retinal and choroidal or other blood vessels and their contents, structures of the optic nerve head and the lamina, abnormal and normal membranes, the retinal pigment epithelium, Bruch's membrane, all structures of the choroid and all abnormal structures (including tumours) which may develop in disease. This methodology may be applied to tracking the effects of therapy within the human or animal eye by using the methods to image the structures, usually with a lower intensity of light for one photon imaging or utilizing the localization of light as described for two photon or multiphoton imaging. This methodology can also e applied to the imaging of structures within the eye which are fluorescent. If these structures are autoflourescent or filled with a fluorescent label (by any means) their imaging may be localized by localized excitation of the fluorescent molecules using the methodologies outlined above. These excitations may be via one, two or multiple photons. The image obtained may be enhanced in resolution and contrast by the application of the methods outlined above. The image may be further improved by the used of a confocal pinhole on the output path of the instrument.

Two-Photon Excitation Photodynamic Therapy (TPE-PDT) occurs when two photons are simultaneously absorbed and their energies are combined to cause the transition to the excited state of the photosensitizer. Two-Photon processes require short, intense pulses of light (fs duration). They are used in imaging and therapy to provide a temporally and spatially localized effect. An animal model can be used to study two-photon therapies in the in vivo retina. The animal model is necessary to determine the potential of different drugs to be excited by 1 photons and to succeed in treating abnormal vessels in eye disease. We also asses whether Adaptive Optical (AO) correction of the eye for spatial localization and pulse pre-chirping for temporal control are necessary for targeted TPE in animal or human eyes. As TPE varies as the inverse of the fourth power of the f# of an eye, the rat eye with its small f# is an excellent model as is our approach to decrease the f# of the human eye by putting light through a larger aperture than that defined by the dilated pupil. Smaller FMs permit more light to reach the image plane, increase the out of focus blur and causing the longitudinal intensity to drop off faster away from focus thus reducing the probability of damaging healthy tissue. The tighter focus that can be produced if the wavefront is perfect (or corrected with adaptive optics) increases the opportunity for TPE.

An optical model of the rat eye shown schematically in Figure 2 was analyzed to determine the best pupil for imaging the retina and also delivering therapy in the absence of adaptive optics correction, which differ. This optical model was also used to calculate the spatial localization of light on the fundus prior to a following adaptive optical correction. The localization in depth is greatly improved by the use of adaptive optics (see Figure 3). This analysis shows that the adaptive optics element required for aberration correction must have a stroke greater than 10 microns.

As used herein, the terms "comprises" and "comprising" are to be construed as being inclusive and open ended, and not exclusive. Specifically, when used in this specification including claims, the terms "comprises" and

"comprising" and variations thereof mean the specified features, steps or components are included. These terms are not to be interpreted to exclude the presence of other features, steps or components.

The foregoing description of the preferred embodiments of the invention has been presented to illustrate the principles of the invention and not to limit the invention to the particular embodiment illustrated. It is intended that the scope of the invention be defined by all of the embodiments encompassed within the following claims.

REFERENCES

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Claims

THEREFORE WHAT IS CLAIMED IS:

1. A method for delivering laser light pulses to a target eye by pre- correcting and pre-shaping laser pulses from a laser beam in space and time so that, after the laser pulses pass through the optics of the target eye, light energy in the laser pulses is localized at the rear of the target eye in depth and laterally without creating damage to adjacent tissues, the method comprising the steps of: a) correcting first order chromatic aberrations of the target eye for wavelengths of the laser pulses incident on the eye; b) correcting second order and higher aberrations of optics of the target eye; c) selecting a pulse width which, based on knowledge of dispersion properties of the target eye, produces the shortest pulse possible at a fundus feature of interest in the target eye; and d) adjusting a power of the laser pulses so that the laser pulses delivered at the fundus feature of interest have an intensity above a threshold intensity to activate a desired therapy.

2. The method according to claim 1 wherein step a) of correcting the first order chromatic aberration of the target eye includes using an achromatizing lens to introduce an opposite chromatic aberration to that within the target eye for wavelengths incident on the target eye.

3. The method according to claim 2 wherein the step of using an achromatizing lens to introduce an opposite chromatic aberration to that within the target eye for the wavelengths incident on the target eye includes amounts of transverse and longitudinal chromatic aberration opposite to those of the target eye and the achromatizing lens is centered in front of the eye to minimize any tranverse chromatic aberration of the eye.

4. The method according to claim 2 or 3 wherein the wavelengths are in a wavelength range which has a midpoint in an infrared portion of the spectrum, and is selected such that these wavelengths do not overlap with major absorption peaks of water and is appropriate to the therapeutic agent.

5. The method according to claim 1 , 2, 3 or 4 wherein the step b) of correcting the second order and higher aberrations of the optics of the target eye includes pre-distorting a wavefront of the laser pulses entering the eye.

6. The method according to claim 1 , 2, 3, 4 or 5 wherein the step b) of correcting the second order and higher aberrations of the optics of the target eye includes pre-tilting a wavefront of the laser pulses entering the eye.

7. The method according to claim 5 wherein the step of pre-distorting the wavefront of the laser pulses entering the eye is performed using an adaptive optics element configured to pre-distort the wavefronts.

8. The method according to claim 6 wherein the step of pre-tilting the wavefront of the laser pulses entering the eye is performed using an adaptive optic element configured to pre-tilt the wavefronts.

9. The method according to claim 7 or 8 wherein the adaptive optic element is configured to measure the wavefront in a feedback loop with a wavefront measuring device, and pre-tilt or pre-distort the wavefront accordingly.

10. The method according to claim 7, 8 or 9 wherein the adaptive optic element includes a spherocylindrical lens.

11. The method according to claim 8 wherein the pre-distortion of the wavefronts is such that each wavefront incident on the fundus feature of interest in the target eye is a sphere centered at the fundus feature of interest.

12. The method according to claim 5 wherein the pre-tilting is such that each wavefront incident on the fundus feature of interest in the target eye is a sphere centered anterior to the fundus feature of interest.

13. The method according to claim 11 or 12 wherein the fundus feature of interest at which the wavefront is centered may be chosen by adding or subtracting power from the laser pulses and observing which plane is in focus.

14. The method according to any one of claims 1 to 13 wherein in step c) of choosing a pulse width which will result in the shortest pulse possible at the fundus feature of interest includes determining if the wavelength of the laser light pulses overlaps with a known major absorption peak of the eye, and if not, pre-chirping the laser light pulses to produce a shorter pulse at the fundus.

15. The method according to any one of claim 14, wherein the target eye is a human eye, and wherein in step c) said pulse width is selected to be about about 55 fs.

16. The method according to any one of claims 1 to 15 including scanning the laser beam across the fundus for delivering the laser light pulses to a larger cross sectional area of the fundus of the eye than a cross section of the laser pulses.

17. The method according to any one of claims 1 to 16 wherein said fundus feature of interest includes vessels or other tissues of the retina, and including localizing a volume to be irradiated by the laser pulses by focusing the laser pulses at an anterior position in the eye relative to the vessels or tissues such that sufficient energy from a region which absorbs the lasers pulses spread by way of a multiphoton effect while keeping the energy posterior to the vessels or tissue low enough so as to not induce damage due to any light delivered to the posterior tissues.

18. The method according to claim 17 wherein anterior position in the eye to the vessel or tissue to be irradiated is in a vitreous portion of the target eye.

19. The method according to any one of claims 1 to 16 including localizing a volume to be irradiated by the laser pulses by determining a shape of the volume to be treated by optically projecting a partially absorbing mask into a pupil of the target eye, and taking a Fourier transform of this mask to produce a selected volume at the rear of the target eye, and wherein this selected volume can a volume to be irradiated or a smaller volume that can be scanned horizontally and in depth to achieve the desired volume to be irradiated.

20. The method according to any one of claims 1 to 16 wherein the region of the fundus to be irradiated is below a photoreceptor layer of the eye, and including localizing a volume to be irradiated by the laser pulses by directing the laser pulses obliquely into the pupil of the eye while focusing the laser pulses at the fundus feature of interest, and wherein since photoreceptors in the photoreceptor layer absorb less of obliquely incident light damage is reduced while still allowing light energy to be delivered to structures posterior to the photoreceptors in the eye.

21. The method according to any one of claims 1 to 16 including localizing a volume to be irradiated by the laser pulses by injecting a material which absorbs the laser pulses into the target eye into a desired volume to be irradiated.

22. The method according to claim 21 wherein said material which absorbs the laser pulses has a pre-selected absorption cross section for 2 photon absorption.

23. An apparatus for delivering laser light pulses to a target eye, comprising: a) a laser configured to produce laser pulses; a) means for correcting first order chromatic aberrations of the target eye for wavelengths of the laser pulses incident on the eye; b) means for correcting second order and higher aberrations of optics of the target eye; c) means for selecting a pulse width; and d) means for adjusting a power of the laser pulses so that the laser pulses delivered at the fundus feature of interest have an intensity above a threshold intensity to activate a desired therapy.

24. The apparatus according to claim 23 wherein said means for correcting the first order chromatic aberration of the target eye includes an achromatizing lens.

25. The apparatus according to claim 23 or 24 wherein said means for means for correcting second order and higher aberrations of optics of the target eye includes an adaptive optics element and a wavefront measuring device in a feedback loop configured to pre-distort and/or pre-tilt wavefronts of the laser pulses.

26. The apparatus according to claim 25 wherein the adaptive optic element includes a spherocylindrical lens.