Abstract:
An electro-optical system is provided for use with a target site and configured with pre-programmable energy output functions for customized TPT protocols. One or more laser sources are provided producing an output beam. A control device is coupled to the laser source. The control device includes a memory that stores at least one laser source energy output function. The laser source energy output function is used to create an intra-operatively invisible therapeutic treatment with enhanced thermotolerance which minimize iatrogenic damage to surrounding structures.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS  
       [0001]    This application claims the benefit of U.S. Serial No. 60/325,895, filed Sep. 27, 2001, and is also a continuation-in-part of U.S. Ser. No. 09/844,445, filed Apr. 27, 2001, both of which are incorporated herein by reference. 
     
    
     
       BACKGROUND OF THE INVENTION  
         [0002]    1. Field of the Invention  
           [0003]    This invention relates generally to an apparatus, and its methods of use, for delivering an intra-operatively invisible therapeutic treatment at a target site, using a novel TPT protocol, which simultaneously, with the treatment, promotes natural thermo-protective reactive mechanisms and enhances thermotolerance to minimize iatrogenic damage to adjacent non-target sites.  
           [0004]    2. Description of The Related Art  
           [0005]    Lasers are currently used for the treatment of various pathologies of the eye, such as retinal disorders and glaucoma. Glaucoma disorders treatable with laser include open angle glaucoma, angle closure glaucoma and neovascular-refractory glaucoma. Retinal disorders treatable with laser include diabetic retinopathy, macular edema, central serous retinopathy, age-related macular degeneration (AMD), and the like.  
           [0006]    Diabetic retinopathy represents the major cause of severe vision loss (SVL) for people up to 65 years of age, while AMD represents the major cause of SVL in people between 65 and 80 years of age. More than 32,000 Americans are blinded from diabetic retinopathy alone, with an estimated 300,000 diabetics at risk of becoming blind. The incidence of AMD in the USA is currently estimated at 2 million new cases per year, including 1.8 million cases with the “dry” form and 200,000 cases with the “wet” form or choroidal neovascularization (CNV). The most widely used form of laser treatment for ocular disorders is called laser photocoagulation (P.C.).  
           [0007]    Laser P.C. has become the standard treatment for a number of retinal disorders such as macular edema, central serous retinopathy, proliferative diabetic retinopathy, CNV, and the like. Laser P.C. is a photo-thermal process in which the laser energy is directed and absorbed by endogenous chromophores and converted into heat. This localized thermal elevation causes a therapeutic “damage” which can span from protein denaturation to coagulation necrosis. This photo-thermal damage has the purpose to induce physiological healing responses that mediate biological chain of events, leading to the therapeutic benefits of laser P.C.  
           [0008]    More recently, lasers have been also used for the photo-activation of exogenous photosensitizing drugs to produce localized photo-chemical therapeutic damages as in, but not restricted to, photo dynamic therapy (PDT).  
           [0009]    The human neuro-sensory retina is basically transparent and does not interact with most of the wavelengths emitted by ophthalmic lasers systems currently in use. Thus a laser photo-thermal event cannot originate in the neuro-sensory retina, and the laser irradiance levels used in conventional retinal P.C. protocols do not cause direct damage to its structure.  
           [0010]    Conventional retinal P.C. relies on some visible “blanching” of the retina as the treatment endpoint. Since the laser energy does not damage directly the neuro-sensory retina, the visible “blanching” endpoint is the sign that its normally transparent structure starts scattering light because it has been indirectly damaged by the conduction of a thermal wave caused by a thermal elevation originated elsewhere. Normally the thermal elevation originates underneath the neuro-sensory retina, where natural chromophores (i.e. melanin) contained in the retinal pigment epithelium (RPE) and in choroidal melanocytes absorb the laser energy.  
           [0011]    A visible retinal “blanching” is a convenient and practical end-point for the surgeon, but it also constitutes a iatrogenic damage to the neurosensory retina with undesirable adverse complications including some vision loss, decreased contrast sensitivity and reduced visual fields in a substantial number of patients.  
           [0012]    The thermal elevation can be controlled by (i) laser irradiance (power density), (ii) exposure time and (iii) wavelength. High thermal elevations are normally created with current clinical protocols that are aimed to produce visible endpoints ranging from intense retinal whitening (full thickness retinal burn) to barely visible retinal changes. Although laser P.C. has been proven therapeutically effective and constitutes the standard-of-care in preventing severe vision loss (SVL) in various ocular disorders, it is now recognized that any visible endpoint with retina blanching is by definition the result of an excessive thermal elevation at the RPE, often associated with irreversible changes of the RPE and with localized area of geographic atrophy, which may be unnecessary and should be avoided.  
           [0013]    A geographic atrophy represents an irreversible scotoma (blind spot) and the change of the RPE optical characteristics constitute the loss of the “absorbing chromophores” that mediate the conversion of laser energy into heat, a loss which prevents any further laser treatment in that area.  
           [0014]    Accordingly, there is a need for an apparatus and method that avoids or minimize unnecessary iatrogenic damage to the neuro-sensory retina in laser procedures. There is a further need for an apparatus, and its methods of use, that minimize unnecessary iatrogenic damage by confining the thermal elevation at the intended target tissue and by stimulating natural thermo protective mechanisms capable of increasing the thermotolerance of adjacent non-target tissue.  
         SUMMARY OF THE INVENTION  
         [0015]    Accordingly, an object of the present invention is to provide a treatment apparatus, and its methods of use, for performing laser ThermoProtectiveTreatment (TPT) procedures with minimum possible damage to surrounding non-intended targets.  
           [0016]    Another object of the present invention is to provide a treatment apparatus, and its methods of use, that produces neuroretina-sparing therapeutic photothermal and/or photochemical effects.  
           [0017]    A further object of the present invention is to provide a treatment apparatus, and its methods of use, that uses programmed variable irradiance prolonged laser exposure, which does enhance the thermotolerance while the treatment is in progress.  
           [0018]    Still another object of the present invention is to provide a treatment apparatus, and its methods of use, that allows a therapeutic treatment, which is so delicate that is intra-operatively unperceivable by the patient and invisible to the operator (lack of treatment visibility implies no damage to neuro sensory retina tissue).  
           [0019]    Another object of the present invention is to provide a treatment apparatus, and its methods of use, which is programmable to work with feedback signals proportional to intra-operative changes of physical or physiological parameters, thus with real-time detection and monitoring of treatment-induced sub-clinical (invisible) effects at the target site.  
           [0020]    These and other objects of the present invention are achieved in an electro-optical system for use with a target site and configured with pre-programmable energy output functions for customized TPT protocols. One or more laser sources are provided producing an output beam. A control device is coupled to the laser source. The control device includes a memory that stores at least one laser source energy output function. The laser source energy output function is used to create an intra-operatively invisible therapeutic treatment with enhanced thermotolerance which minimize latrogenic damage to surrounding structures.  
           [0021]    In another embodiment of the present invention, an electro-optical system is provided for use with a target tissue. One or more laser sources are included for producing an output beam. A programmable control device is coupled to the one or more laser sources. The control device includes a memory that stores at least one laser source energy output functions. A delivery device is coupled to the one or more laser sources. The delivery device delivers at least a portion of the output beam to the target tissue. A monitoring device is coupled to at least one of the control device or to an operator&#39;s device.  
           [0022]    In another embodiment of the present invention, a method for treating a target tissue provides an apparatus that produces pre-programmed energy output functions. A treatment beam is delivered that utilizes at least one of the pre-programmed energy output functions to stimulate natural thermoprotective reactive mechanisms while performing an intra-operatively invisible therapeutic treatment at the target tissue.  
           [0023]    In another embodiment of the present invention, a method for treating a target tissue provides one or more laser sources coupled to a control device. The control device has a memory that stores at least one laser source energy output function. A treatment beam is delivered from the one or more laser sources to the target tissue. Natural thermoprotective mechanisms are stimulated while creating an intra-operatively invisible thermo protected therapeutic treatment of the target tissue. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0024]    [0024]FIG. 1 depicts an embodiment of the laser apparatus of the present invention.  
         [0025]    [0025]FIGS. 2 a - 2   c  depict an example of a typical TPT variable irradiance laser output function of the present invention. 
     
    
     DETAILED DESCRIPTION  
       [0026]    Referring to FIG. 1, one embodiment of the present invention is a TPT ophthalmic laser apparatus  10 . Apparatus  10  can be configured to produce neuroretina-sparing therapeutic photothermal and/or photochemical effects as a result of programmed variable irradiance prolonged laser exposure incident to targeted tissue site  12 , including but not limited to an ocular tissue site. Apparatus  10  can include one or more optical source devices  14  including but not limited to a laser. Devices  14  can include one or more lasers that can operate at various wavelengths and whose emission is controlled by a ThermoProtectiveTreatment (TPT) variable irradiance, exposure, pulse regime programmer/control unit device (hereafter control device  16 ) that is delivered through a laser delivery system device  18 .  
         [0027]    Laser delivery system device  18  can be a variety of different devices including but not limited to a slit lamp delivery system, and the like. In one embodiment, device  14  can be one or more lasers known in the art including but not limited to, ion, dye lasers, Nd:YAG, frequency-doubled Nd:YAG, visible and invisible diode, infrared lasers, and the like. The output of device  14  can include various aiming and treatment beams with the same or different wavelengths. In other embodiments, device  14  can be a photocoagulation source device including but are not limited to infrared lamps, flash lamps, mercury vapor lamps, and the like.  
         [0028]    Optionally, one or more monitoring devices  20 , capable of detecting treatment-induced sub-clinical changes can be provided. Examples of different monitoring devices  20  include but are not limited to devices that are, optical (interferometry, reflectometry, light scattering, fluorescence or IR imaging), thermometric, electro-physiologic (focal ERG), and the like. Monitoring device  20  can provide feedback signals of intra-operative sub-clinical changes and thresholds (i.e. minimum therapeutic damage MTD, and maximum functional damage MFD, etc.) to the surgeon through an audio/visual device and/or optionally, to control device  16 .  
         [0029]    Apparatus  10  allows the surgeon to create and select prolonged step-by-step sequentially variable laser irradiation programs. Each program can deliver energy from one or more devices, such as lasers  14  with, (i) various spot sizes and patterns and (ii) various series of subsequent trains of repetitive laser pulses. The output of apparatus  10  can be programmed or changeable, for a sequence of changes, relative to, (i) wavelength, (ii) power, (iii) irradiance, (iv) duty cycle, (v) repetition rate, (vi) exposure time, (vii) repetition interval and the like. These sequence of changes constitute the energy output function, which can be individually set and programmed for the entire duration of the laser treatment, in accordance with various protocols (focal, grid, diffuse with large spot, and the like) requested for addressing the therapeutic needs of specific disorders.  
         [0030]    With apparatus  10 , the treatment is normally under the surgeon&#39;s control. Optionally the treatment can be assisted and/or controlled by feed-back signals from the real time monitoring of the intra-operative induced changes of physical (thermal, optical, etc.) or physiological (ERG, autofluorescence, etc.) parameters. Such feed-back signals can be used for, (i) providing the real-time detection of the sub-clinical (invisible) therapeutic treatment window, above the a) minimum therapeutic damage (MTD) threshold and not exceeding the b) maximum functional damage (MFD) threshold; (ii) providing perceptible signals (i.e. audio or others) to the physician as well as electric signals for the optional automatic control of the emission of the TPT ophthalmic laser apparatus, (iii) the recording of all successfully delivered MTD applications, their location in the ocular fundus and other relevant data pertaining to the treatment, and the like.  
         [0031]    Apparatus  10 , and its methods of use, provide a practical solution to the challenges and difficulties posed by minimum intensity photocoagulation (MIP) sub-clinical treatments of ocular pathologies requiring prolonged exposure with the minimal possible retinal damage and related iatrogenic vision impairment.  
         [0032]    The programming capabilities of apparatus  10 , particularly with control device  16 , are broad reaching. A simple example is represented by the irradiance histogram in FIGS. 2 a - c , showing a pre-programmed laser energy output function intended for, but not limited to, the occlusion of subretinal CNVs&#39; feeder vessels. This particular pre-programmed laser energy output function is designed to allow the closure of a deep vascular structure, naturally thermally protected by blood flow, through a prolonged thermal elevation (time-temperature-history) eventually causing vascular thrombosis, sclerosis or leukostasis, while auto regulating intraoperatory and temporary bio-physical changes, which allow deeper penetration and lower thermal elevation without visible permanent changes of RPE optical properties, nor scars or geographic atrophy.  
         [0033]    Control device  16  can provide a variety of pre-programmed laser energy output functions, in the form of software programs, databases and the like that can be stored in one or more memories  22 . Memory  22  is configured to store laser energy output functions programs, data, data sets and databases, including but not limited to achieved MTD thresholds that can be confirmed by monitoring device  20 . Examples of programs include control algorithms such as proportional, proportional derivative and proportional derivative integral (PID) algorithms. Suitable memories  22  include but are not limited to, RAM, ROM, PROM, flash memory and the like. Suitable data and databases that can be stored include but are not limited to, optical interference patterns and profiles data, other optical data and the like. A database of such information can be both for a population or an individual patient and may include baseline (e.g. pretreatment), treatment and post-treatment profiles.  
         [0034]    In various embodiments, apparatus  10  is an ophthalmic apparatus, and its methods of use, for delivering TPT for retina-sparing subthreshold minimum intensity photocoagulation (MIP). Apparatus  10  achieves this while minimizing iatrogenic damage. TPT is a variable-irradiance long exposure protocol in which natural thermo protective mechanisms are stimulated during the delivery of the therapeutic treatment.  
         [0035]    In one embodiment, apparatus  10  is a TPT ophthalmic laser apparatus with irradiance that can be time-step-programmed. The time-step-preprogrammed creates localized time-temperature-histories and produces photothermal and/or photochemical therapeutic effects. This can be achieved while simultaneously inducing biochemical and biophysical changes which increase the thermotolerance and thermoresistance, the temporary state of resistance to heat killing of the retina. TPT allows for completion of an intended therapeutic tasks with reduced thermal hazards and with minimal or no signs of damage visible during the treatment.  
         [0036]    More specifically, apparatus  10  can include an ophthalmic laser device  14 , which can include one or more laser sources. All or a portion of the laser parameters, including but not limited to power, irradiance, pulse “ON” time, inter-pulse “OFF” time, exposure duration, number of pulses, repetition interval and the like, can be set individually in order to create a variety of pre-programmed laser energy output functions. Each output function&#39;s program can be designed to gradually produce the intended photothermal and/or photochemical therapeutic effects while simultaneously, (i) modulating natural protective mechanisms capable of increasing the thermal tolerance of the retina (vascular auto-thermo-regulation, upregulation of neuroprotective agents, synthesis of heat shock proteins, and the like) and (ii) altering biophysical and bio-chemical properties of endogenous and exogenous laser absorbing chromophores, for effectively sparing the sensory retina while addressing the targeted sub retinal structures, whose treatment can benefit from prolonged exposures.  
         [0037]    The combined processes of, (i) photo-thermal and/or photo-chemical sub-retinal therapeutic damage and (ii) photo-thermal inner-retina protection and conditioning, can be simultaneously or sequentially accomplished with laser energy output functions that are programmed to deliver the laser energy in series of subsequent trains of laser pulses. The output of laser devices  14  has parameters, including but not limited to, wavelength, power, irradiance, duty cycle, repetition rate, repetition interval, exposure time, and the like, can be individually programmed with control device  16  for the entire duration of the laser treatment. Furthermore, intra-operative monitoring of induced changes of physical (thermal, optical, and the like) or physiological (ERG, autofluorescence, etc.) parameters can provide feed-back signals. Such feedback signals can assist the surgeon in the completion of the sub-clinical (invisible) treatment or, alternatively, utilized for the automatic control of laser devices  14 . Intra-operative physical and/or physiological monitoring techniques to assist subclinical threshold treatments include, but are not limited to, the use of thermometry, reflectometry, interferometric reflectometry, light scattering, focal electroretinography, fluorescence, autofluorescence imaging, SLO imaging, and the like.  
         [0038]    With apparatus  10 , and its methods of use, minimally invasive TPT protocols can be performed where, (i) the therapeutic application can be administered in such a way to effectively treat the target and while changing (ii) biochemical and biophysical properties that enhance the thermal protection and/or thermotolerance of overlying non-targets. Apparatus  10 , and its methods of use, are particularly useful for minimally invasive and clinically effective treatments of selected tissue and/or structures within the eye, without the need for visible endpoints, while minimizing injury, such as thermal injury, to surrounding structures including the neurosensory retina. It will be appreciated, that apparatus  10 , and its methods of use, can be utilized with any tissue target.  
         [0039]    While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not limited to the disclosed embodiment, but on the contrary it is intended to cover various modifications and equivalent arrangement included within the spirit and scope of the claims which follow.