WO2001035881A1 - Non-contact photoacoustic spectroscopy for photoablation control - Google Patents

Non-contact photoacoustic spectroscopy for photoablation control Download PDF

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Publication number
WO2001035881A1
WO2001035881A1 PCT/EP2000/011167 EP0011167W WO0135881A1 WO 2001035881 A1 WO2001035881 A1 WO 2001035881A1 EP 0011167 W EP0011167 W EP 0011167W WO 0135881 A1 WO0135881 A1 WO 0135881A1
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tissue
non
tissue ablation
ablation method
guided non
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PCT/EP2000/011167
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French (fr)
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Thomas Bende
Benedikt Jean
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Thomas Bende
Benedikt Jean
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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/17Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/1702Systems in which incident light is modified in accordance with the properties of the material investigated with opto-acoustic detection, e.g. for gases or analysing solids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/0059Detecting, measuring or recording for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/0093Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy
    • A61B5/0095Detecting, measuring or recording by applying one single type of energy and measuring its conversion into another type of energy by applying light and detecting acoustic waves, i.e. photoacoustic measurements
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/10Eye inspection
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007Methods or devices for eye surgery
    • A61F9/008Methods or devices for eye surgery using laser
    • A61F9/00802Methods or devices for eye surgery using laser for photoablation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007Methods or devices for eye surgery
    • A61F9/008Methods or devices for eye surgery using laser
    • A61F2009/00861Methods or devices for eye surgery using laser adapted for treatment at a particular location
    • A61F2009/00872Cornea

Abstract

A method and system for non-contact laser photoablation to be utilized during vision corrective surgery. Multiple pulses of electromagnetic energy are impinged onto target tissue to ablate and generate an acoustic pressure wave while concurrently processing signals produced by the acoustic pressure wave. A representative pattern can be provided to guide the surgeon through distinct tissue layers encountered in cornea resculpting surgery. Cluster analysis may be utilized to process the acoustic wave signals to generate the representative pattern. Specifically, the representative cluster pattern provides the surgeon with a tool to discern, with increased precision, the tissue layer being ablated and reduces the likelihood of invading a deeper layer of tissue that should not be removed.

Description

NON-CONTACT PHOTO ACOUSTIC SPECTROSCOPY FOR PHOTOABLATION CONTROL

BACKGROUND OF THE INVENTION

Field Of The Invention

The present mvention relates generally to laser photoablation, and more specifically to non-contact lasei photoablation methods and systems that apply clustei analysis to photoacoustic signals foi recognizing tissue compositions during a photoablation procedure

Description ofthe Related Art

Today, it takes a highly skilled, and specially trained surgeon, with nearly a million U S dollars worth of equipment, to perfoπn complicated vision corrective procedures However, these procedures are only as good as the surgeon's ability to visualize distinctions between different types of corneal tissue For instance, the doctor must use his own eyesight to see the changes occurring m the patient's tissues occurring during the surgery Consequently, during a photoablation procedure, while the doctor is removing tissue layers of sub-micron size, it is not possible foi the surgeon to visualize the microscopic, delicate changes taking place in the tissue A well known form of vision coπective surgery removes a precise amount of tissue from the center of the cornea by utilizing a computer program The program calculates the precise amount of tissue to be removed by laser vaporization However, this method does not provide information as to the type of tissue bemg removed or guidance as to completion of the removal process As a result, a geneπc amount of tissue is removed without addressmg the specificity of the tissue Moieovei , the uniqueness of each individual is not addressed including the fact that a certain amount of tissue removal in one patient may be beneficial but ineffective and/or detrimental in another patient

Accordmgly, at the present time, a compelling need exists in the art for a photoablation method that discriminates and differentiates between tissues, such as determining corneal epithelium from stroma tissue or healthy tissue from diseased tissue, provides a \ isual output signal that is representative of the specific tissue being removed, detennines the ablation rate, and alerts the surgeon of an approachmg interface between tissue to be removed and tissue to be retamed, thereby increasing specificity and precision of the photoablation procedure

SUMMARY OF THE INVENTION

The present mvention generally relates to laser photoablation, and more specifically to a method and system for photoablation by impinging multiple pulses of electromagnetic energy onto target tissue to ablate and generate an acoustic pressure wave while concurrently processing signals produced by the acoustic pressure wave A cluster analysis algoπthm may be used to process the generated signals, and as a result, a representative pattern can be provided to guide the surgeon through distinct tissue layers

The invention, as described hereinafter in greatei detail, contemplates m various aspects

a laser photoablation method that differentiates between distinct tissue layers,

a laser photoablation method and system that togethei piovides a visual signal representative ofthe specific tissue being removed,

a laser photoablation system that alerts the surgeon of an imminent approach of an mterface between removed and retained tissue.

a laser photoablation method that reduces damage to surrounding tissue thereby providing for faster lecoveπng of the patient, increasmg success rates of corrective procedures and minimizing nsks relating to the surgery, and

a laser photoablation method that increases the specificity and precision of a photoablation procedure

In one specific aspect, the invention 1 elates to a guided non-contact tissue ablation method controllably mediated by recognition of distinct tissue composition withm a volume of tissue, the method compnsmg a) impinging multiple pulses of electromagnetic energy onto the tissue to ablate impmged tissue and generate an acoustic pressure wave m response to interaction of the tissue with the electromagnetic energy,

b) non-contactmgly sensmg the generated acoustic pressure wave and providing a plurality of corresponding signals,

c) processmg the signals by applying theieto a cluster analysis algonthm to recognize distinct tissue composition

The method may further comprise generatmg a representativ e pattern of the impinged tissue to recognize distinct layei s of tissue composition

In another aspect, the mvention relates to a guided non-contact tissue ablation system that is controllably mediated by recognition of distinct types of tissue composition, the system compnsmg

a) at least one electiomagnetic eneig souice foi generating multiple pulses of electromagnetic energy to ablate impmged tissue and generate an acoustic pressure wave,

b) at least one non-contacting sensing means for sensmg the acoustic pressure wave and providmg a plui ahty of corresponding signals and

c) at least one processing means foi analyzing the signals of the acoustic pressure wav e by a clustei analysis algonthm to recognize distinct tissue composition In yet another aspect, the invention relates to a non-contact tissue ablation method controllably mediated by recognition of tissue composition, the method compnsmg

a) impinging multiple pulses of electromagnetic energy onto at least one location of the tissue to ablate impmged tissue and to generate at least one acoustic pressure wave in response the electromagnetic energy impinging the tissue,

b) non-contactingly sensmg the at least one generated acoustic pressure wave to provide a plurality of corresponding signals, and

c) processmg the plurality of signals by analyzing a property of the signal to detenrnne change m the ablated tissue

The signal, fonned by the generated acoustic wave, has multiple properties that can be examined and analyzed to pi ovide infoπnation concerning location of impingement, change in the ablated tissue type, and changes m the tissue due to mterference of acoustic waves The properties of the emitted signal may include, the frequency, velocity, wavelength, phase of the acoustic wave and the like If multiple locations are impmged with electromagnetic energy, responses within the tissue, caused by the generated acoustic wave, may be superimposed causing eithei constiuctive oi destructive interference This point of mterference may be located by implementmg tnangulation calculations Other aspects, features and embodurients of the mvention will be more fully apparent from the ensuing disclosure and appended clauns

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a block diagram showing the electronic components of the photoablation system accordmg to one embodiment of the present invention,

Figure 2 illustrates an acoustic signal amplitude versus time plot.

Figure 3 is an illustrative diagram of an alternative embodiment for impinging tissue with electromagnetic energ) according to the present invention,

Figure 4 shows a frequency spectrum of a smgle pulse photoacoustic signal of PMMA useful for input into a cluster analysis algorithm,

Figure 5 is a 3-dιmensιonal graph illustratmg a representative display showing 3 distinct polymenc compositions.

Figure 6 is a 2-dιmensιonal graph illustrating a repiesentative display recognizing the difference between nonnal and scaπed cornea tissue,

Figure 7 is a 3 -dimensional graph illustratmg a representative display showing 3 distinct tissue types and/or layers in nonnal cornea tissue, and

Figure 8 illustrates a smoothening process with ablation of non-homogeneities in the surface tissue and a surrounding filler material Figure 9 illustrates a multiple microphone transducer set-up to facilitate the detennination of localization of ablated tissue.

DETAILED DESCRIPTION OF THE INVENTION AND THE

PREFERRED EMBODIMENTS THEREOF

The present invention relates to a non-contact laser method and system for vision corrective surgery. It has been discovered that significant benefits are realized in cornea resculpting surgery if an acoustic pressure wave, that emulates from the impinged tissue, is sensed and monitored during the surgery. The acoustic pressure wave is a result of a flash or pulse of laser light impinging on a volume of biological tissue. Absorption of the laser light causes a photoacoustic effect that initiates a host of changes, e.g., electronic rearrangement of the absorbing molecule, vibration energy deposited in suiTounding tissue, emission of thennal energy causing expansion of liquid in the tissue, excited molecules emitting light, cleaving of bonds, and the like. All of these changes contribute to an acoustic pressure wave that propagates away from the illuminated region.

Specifically, the acoustic pressure wave has a frequency pattern, unique to each distinct tissue composition, that can be reduced to multiple data points for mathematical manipulation to generate a representative pattern for each layer of tissue during the ablation of the layer. Beneficially . this representative pattern, provides the surgeon with a tool to discern, with increased specificity, exactly which tissue layer is being removed and detennme the stratagraphic level of that tissue dunng the ablation procedure Moreover, the surgeon can view a monitor or computer screen and detennme as different tissue layers are removed and/or when an interface, with an adjacent tissue, is bemg approached Fundamentally, the surgeon is equipped with a stratagraphic map definitively showing the current level of ablation and the nearness to anothei layei of different type tissue This sh-atagraphic map increases the surgeon's ability to remove a specific layer of tissue without invading a deeper layei of tissue that should not be removed

The system can be programmed to alert the surgeon when a different layer of tissue is being approached by an alann system or coloi coding of the umque patterns generated by different tissues An alert system provides the surgeon with increased control dunng the surgery thereby providmg ample time to make adjustments to the lasing system, such as stopping the laser energy, adjustmg the laser energy, changing the repetition rate and the like

Detennmmg the umque properties of an acoustic pressure wave for each tissue layer and mathematically manipulating the data signal output can provide useful data Detenmning the speed and velocity of an acoustic wave can provide information on the location of impingement Detennmmg the frequency of a signal, especially a centei frequency peak, provides a mechamsm to detennme a change in tissue because different types of tissue generate a frequency shift The frequency shift is the result of interaction of the electromagnetic energy with different types of ablated tissue Preferably the data signal output is analyzed through cluster analysis which heretofore has been unknown Consequently the benefits realized dunng surgery have not been recogmzed and/or exploited for the benefit of the patient

A preferred embodiment of a non-contact photoablation system according to the present mvention is descnbed in connection with Figure 1 which is a block diagram of a typical photoablation device adapted accordmg to the present invention The non-contact system 10 includes a laser 12 that emits electromagnetic energy in the fonn of modulated ultraviolet, visible, infrared or microwave radiation 14 that impinges on corneal tissue 16 for absorption and mteraction therem

Generally, any type of laser that pioduces electromagnetic l adiation in the visible, infrared and ultraviolet spectrum may be used m the present invention, mcludmg gas, solid-state, organic dye, chemical and excimer lasers Preferably, the laser generates

Figure imgf000010_0001
and infrared radiation m a wavelength band between about 150 nm and about 400 mn, and more preferably, from about 190 mn to about 353 nm It is known that within this wavelength range, the energy is strongly absorbed by most biological tissue, and thus, a photo-dissociation of the excited molecule occurs without causing necrosis of surroundmg tissue

The photoablation lasers employed in the practice of the mvention emit sufficient energy for ablating comeal tissue to modulate the shape of the cornea The strongest ultraviolet absorption in biological tissue occurs at a wavelength of 193 n without necrosis of suπounding tissue. As such, the present invention contemplates using lasers that generate an electromagnetic energy beam of photons having wavelengths in the vicinity of 193 run for the ablation of tissue. However, it is further envisioned that the methods of the present invention are applicable to the use of electromagnetic energy in a wavelength range that does not cause ablation of the tissue, but instead, merely thennal excitation of the tissue.

Regardless of the specific wavelength of the incident radiation employed, the radiation is modulated at a frequency that causes an acoustic pressure wave to be fonned. Modulation is accomplished either by using a pulse source, e.g., a pulsed laser (delivering energy in pulses that are less than 0.25seconds in duration), or a continuous beam laser source with a chopper. The frequency of the modulation should be at a rate that allows the measured photoacoustic signal to oscillate at the same frequency as that of the modulated incident radiation. Generally, modulation frequencies range fi-om about 1 Hz to about 1 kHz, and more preferably fi-om about 5 Hz to about 500 Hz.

The modulation frequency is typically adjusted to a value that is different from any natural environment oscillation that might interfere with the analysis, and more preferably, to a frequency that maximizes the intensity of the signal measured, such as an acoustically resonant frequency. Detennining the acoustic resonant frequency and the conespondmg appropriate wavelength may be calculated by known methods and equations within the skill of the art. Excimer lasers, which utilize as the excited medium rare gas hahdes such as, argon fluonde, krypton fluonde and xenon chlonde have been found to be highly effective for use in the present invention Pi eferably, an argon fluonde excimer laser is utilized because it produces very precise cuts, as narrow as 20 urn, without causing ragged edges at the cutting edge Especially preferred laser systems include a UV Excimer Laser, type UV 200L, available from Summit Technology. Inc . Waltham, MA 02451 and a UV Excimer Laser, type EISIRIS. available fiom Schwind. Klein-Osthenn, Gennany

It should be noted that the photoacoustic techmques and analysis method and system descnbed herein may be used with any laser system, mcludmg those that deliver amplified femtosecond laser pulses that generate microplasmas leading to rapid temperature and pressure inci eases in the focal spot The expansion of the hot plasma generates a shock wav e that destroys the tissue in the focal spot and this shock wave can also be sensed, measured and analyzed by the methods of the present invention

In order to target the effect of lasei radiation on the tissue of interest and provide the necessary discrimination between different types of tissue, several distinct parameters of the system should be carefully selected First, the focusing action of the lens can be selected to preferentially supply an irradiance energy of about 80 mJ/cm2 to about 300 mJ/cm2 at the pomt of impingement of the beam on the tissue Also, the sensing means should be placed at a distance from the target tissue to allow sufficient signal to reach the sensing means and cause a change therein

When ablating surface tissue, the laser may be positioned nonnal to the tissue surface and a single horizontal sweep may be sufficient However, for a larger area, the laser may be placed in a holder that is attached to a computer system programmed to scan a two dimensional pattern This may be accomplished by a honzontal sweep and a vertical displacement to place the laser beam in position to complete another horizontal sweep Providing computerized movement of the laser beam in two directions facilitates multiple pulsing regimes For mstance, the laser beam may ablate tissue at a single localized spot to the desired depth, or in the alternative, the pulsing beam may impinge on a new area of tissue every sequential pulse thereby scanning a larger area of tissue with minimal lemoval of tissue This sequential scan may be repeated until the desired depth or removal of tissue is completed

Additionally, the laser may be placed m a holder in such a way that pivoting of the laser allows for sweeping motion in at least a ninety degree arc in both the x and y direction Also, the lasei may be place on an angle to the surface thereby projecting the energy beam at a predetennmed angle

Another embodunent of the present invention provides for multiple locations of impingement by at least one electiomagnetic energy source that deliver energy to the target locations eithei simultaneously or sequentially A single laser with a split beam or multiple lasers may be used to impinge on multiple locations Several pomts oi locations of unpmgement will generate an interference response within the impinged and surrounding tissue. As discussed above, an interference pattern, fonned by supeπmposing multiple acoustic shock waves, can be used in the ablation process. Constructive interference of the acoustic waves could cause surrounding tissue to be forced into acoustic resonance and/or experience acousto-electric effects, both of which may reduce the requirements of higher intensity energy when ablating suiTounding tissue.

The beam profile of the laser may mclude any known configuration, including circular, rectangular, broad and gaussian shaped beams. Each beam geometric configuration provides unique advantages. For instance, gaussian laser beams, having a higher intensity in the center than at the edges of the beam, are able to penetrate one layer of tissue and show the transition of another layer very early in the ablation process. At the exact moment, the beam penetrates through the first layer a mixed signal is generated that indicates another layer of tissue has been penetrated. This can easily be analyzed because the amplitude of the signal for the first layer will be dampened due to the signal of the next layer of penetration which is visible on a time dependent plot.

A rectangular beam profile, typically emitted by laser diodes, provides unifonn irradiance of the tissue at point of impingement. The rectangular beam is able to detect

Figure imgf000014_0001
on the surface of impmged tissue and provides infonnation concerning the different layers being ablated. Rectangular beams are especially useful when smoothening of an inegular surface is required Specifically, a surface masking matenal. such as a viscous gel, may be spread on the surface to fill void and provide a layer compnsmg the masking matenal and the lπegulaπties of the surface The ablation process will remove not only the masking matenal but also the tissue irregulanties, thereby providing a mixed signal durmg the smoothemng process When the irregularities and masking material are removed, a single signal will alert the surgeon that the ablation process is complete

Broad beam lasers emit a broad beam of electromagnetic energy that is capable of mipingmg a comparatively large surface area of tissue Advantageously, this broad coveiage of the tissue allows for detecting emitted signals of generated acoustic waves at multiple locations withm the tissue

As stated above, impinging radiation of a sufficient energy will excite tissue molecules dunng absorption and/or interaction therein After excitation, some of the molecules withm the tissue will letuni to the giound state by radiationless processes Shock waves and thennal energy emitted durmg this relaxation, will cause expansion within the tissue and/or withm the surrounding gas, which is usually an As a consequence of modulatmg the incident radiation, the tissue oi gas will periodically expand and contract This expansion and contraction can be detected by a sensing means

Sensing devices 18 are used to capture and detect acoustic signals of the generated pressure waves Generally, any transducer that converts pressure waves mto mechanical energy and/or electncal energy may be used in the present invention In one preferred embodiment, at least one microphone is used as a transducer that changes a sound wave mto an electncal signal A particularly effective transducer is a capacitoi mici ophone whei ein one of the plates is suitably flexible and responds to changing air piessuie Specifically, the changing air pressure, in the acoustic pressm e wave, causes one plate of the capacitor C to move back and forth Because C capacitance is inversely proportional to the separation of the plates, the pressure wave can cause the capacitance to change This, in turn, causes the charge Q on the plates to change (C=QV) so that an electnc current is generated at the same frequencies as the stnking pi essure wave

In Figure 1 there is shown two miciophone transducers, but it should be recognized that additional microphone transducers may be implemented to provide increased analysis of the impmged tissue, such as shown in Figure 9 Additional microphones, placed about the impmged tissue, at different locations, to capture signals, can more effectiv ely located a geneiated response by analyzing the pi opagation signal fi om one location and comparing the signal to that captuied by othei mici ophones Analysis may include tnangulation calculations, such as those utilized in detennmmg an epicenter of an earthquake Basically , the speed of an acoustic wave in biological tissue is known or can be detennmed and the speed of the wave can be used with time measurements The time measuiements may be detennmed from a tune dependent amplitude plot which aie generated individually by each of at least three microphones placed at different locations about the tissue, to pinpoint the location of ablated tissue Additionally, a Fourier analysis of the signals generated by the area of tissue being ablated and measured by a plurality of microphones can be used to locate the source of a noise

The electnc current generated by the microphone transducer, having the same frequencies as the acoustic pressure waves, is sent to a readout device 1 9 The readout device may include an x-y recorder e g , video display teπnmals, plotters and the like In alternative embodiments, the readout device 19 may include either an oscilloscope 20 or a microprocessor 24 oi a combination of both to provide an acoustic signal output repi esentation such as a frequency plot The acoustic signal output is subsequently mathematically manipulated to generate a representative pattern of a specific layer or tissue type withm the cornea Preferably a cluster analysis algorithm is used to process the signal data

To increase the electric signal generated by the capacitoi microphone, a amplifier 26 may be positioned between the microphone and oscilloscope or computer, to amply the signal output fio the sensing microphone If the laser signal is pulsed, the amplifier will typically be adjusted to respond to the acoustic signal at the pulsed frequency

The emitted and converted acoustic pressure wave can be displayed on the oscilloscope 20 Any suitable oscilloscope may be utilized m this embodiment to provide a visual output for observing an electrical signal caused by rapidly changing voltages or cunents in the acoustic pressure wave The oscilloscope display may comprise, m visual fonn, an amplitude (vertical) versus time (hoπzontal) plot as shown in Figure 2, wherein the amplitude of the peaks is in response to received signal voltage or current from the microphone This plot of peaks exhibits the interaction of a pulse of incident radiation with a layer or specific composition of tissue 16

Figure 2 provides a visual display of tissue reaction to a pulse of electromagnetic energy It should be noted that a typical A plot (amplitude of signal v tune of arrival at microphone) contams a multitude of infonnation on not only the generated acoustic wave that initially leaches the microphone but also the sound waves that reach the microphone after reflecting from internal tissue surrounding the ablation spot The electiomagnetic energy, impinging the tissue, causes an acoustic wave to travel in all directions including deeper mto the unablated tissue These internal acoustic waves may be reflected by non-homogeneities and discontinuities within the internal tissue, and the microphones will sense the reflected echoes The location of these captures echoes, for instance on an amplitude versus time plot, prov ides a visual display of different layei s of internal tissue Each internal layei will cause a reflective acoustic wave to arrive at the sensing mechanism at a different time, dependent upon the depth of interaction As such, the depth of internal tissue and approaching interfaces between different layers and types of tissue may be monitored to detennme then exact location With this infonnation in hand the surgeon is provided with another tool to increase the specificity of the photoablation process Fundamentally, the methods of the present invention, not only provide a non-contact method of photoablation, but also, may generate a 3-dιmensιonal unage of the internal structure located under the tissue bemg ablated

The photoacoustic signals comprising a time domain spectrum (Figure 2) of the emitted electrical signal provide v aluable infonnation relating to the umqueness of ablated tissue Prefei ably. Founei ti ansfonnation is used to convert the time domain spectrum to a frequency domain spectrum such as shown m Figure 4 thereby pioviding a frequency fingerprint of the absorbing and/or affected tissue containing multiple frequency data points The center frequency, substantially unique for different types of tissue can be used to indicate a transition from one layer oi type of tissue to another layer or type The center frequency may be calculated by mathematically integrating the frequency depending amplitude over the fi equency Further the frequency shift, that occurs when different tissue are ablated, may be detected by Fourier analysis Additionally and preferably, sensed multiple frequency data points, typically in the lange between 20 Hz and 250 kHz. are mathematically manipulated by clustei analysis to distinguish similai tissues

Cluster analysis is implemented in ordei to analyze and classify the photoacoustic frequency data into meaningful gi oups and to provide a representative cluster pattern for each distinct tissue Cluster analysis is a method that uses classification algoπthms to group objects mto clusters There are a numbei of different clustei algoπthms that may be applicable, e g , joining, two way )oining and K-means clusteπng When the number of classifications is known or hypothesized, such as four classes corresponding to the four layers of tissue in the cornea, which includes the epithelium, Bowman, stroma and endothehum, then apply mg the k-means clustermg algonthm is the most appropnate In general, the k-means method will produce exactly k different clusters of greatest possible distinction

There are several vanants of the k-means clustering algorithm, but most involve an iterative scheme that operates ovei a fixed numbei of clusters, while attempting to satisfy the following properties

1 Each class has a center which is the mean position of all the samples in that class, and

2 Each sample is m the class having a center that it is closest to

The basis k-means algorithm consists of the following steps when using a fixed number of classes, such as 4

1 Initialize This involves picking a numbei of pixels (frequency data pomts) at random from all the data points (for instance, picking 10 out of total of 50), then picking 4 out of the 10 so that the chosen 4 data points have values that are distant from one anothei These 4 pixels are used to initialize the 4 classes

2 All the remaining data points aie assigned to a class such that the distance from the data point to the centei of the class is minimized Then the mean of the class is recalculated based on the new data point added to that class If a data point is no longer in the appiopπate class, because the distance to the center is increased, it is moved to another class wherein the distance to the center is decreased The distance between the data point and center of the class may be detennmed by using either the Manhattan distance or Euclidean distance equations

3 Repeat the steps until a teπnination condition is met which theoretically occurs when data points cease changing classes However, this may require an unreasonable amount of iterations Thus an end point, such as 50 iterations may be implemented to provide a reasonable tennmation point

The cluster analysis as set forth abov e can be manually calculated or for a large set of data points a softwaie pi ogram may be utilized A particularly effective software program is commeicially available from The MathWorks, Inc , Natick, MA 0 1760. under the trademaik MATLAB

When utilizmg a clustei analysis algonthm foi classification of materials, different groups of similar material ai e discernible For substantially sunilar materials, local maxima aie used foi data point input into the cluster algonthm and dependmg on the numbei of local maxima it can lead to a multiple clusters groups As shown in Figure 5. the application of cluster analysis with the photoacoustic signals generated foi the three cheimcally similar materials, polymethyl-meth-acrylate (PMMA), polyacrylate (PA), and polyvinylchlonde (PVC), yields a visual output that can be displayed on a computei screen to provide recognition of distinct tissue compositions that are easily separable and discernible Figure 7 provides a v isual output that shows positively that corneal epithelium, Bowman' s and stroma tissue can be successfully identified and separated in layers Adv antageously, this visible representation illustrates that separation and discrimination of the three corneal layers is possible, and thus, can limit the amount of tissue removal in typical clinical PRK /TPK procedures with the concomitant effect of limiting the amount of induced latrogemc hyperopia

Figure 8 illustrates another aspect of the present invention which provides for a smoothemng of a surface havmg lπ egulaπties oi non-homogeneities Th s is accomplished by covering the surface tissue 40, that is to be ablated, with a material filler layer 42 that fills voids oi valleys 44 in the surface tissue thereby fonmng a film-like mask To ensure a smooth surface, the film-like mask is ablated along with the surface tissue Initially, the film and irregulanties in the surface tissue will fonn a mixed signals of acoustic waves generated by the ablated tissue and the material filing the voids When only a smgle signal is sensed, the smoothemng pi ocess is complete Any filer material may be used that has a similai ablation rate as the surface layer to be ablated Preferably, the material has gel-like properties, such as water soluble film fonn g polymers A list of some representative useful polymers are the water soluble alkyl celluloses, the hydroxyalkyl celluloses, cyclic ohgosacchaπdes ,polydextrose, and the like

Additionally a fluid may be used as a fillei The fluid is not ablated dunng the smoothemng process, but instead, merely fills voids in the surface to be smoothened The tissue' s watei content may be monitored by the photoacoustic signal and the laser' s pulse repetition rate may be adjusted, in order to control the water content and/or the amount of water set free, leading to a surface smoothing effect The fluid may be water that is set free dunng the ablation process, I e , cellular water of destroyed body cells or the like The generated watei will fill the voids, but some runoff must be expected dunng surgery due to the shape of the eye To compensate for any water lost dunng the surgery, the pulse rate of the emitted electi omagnetic energy source may be increased and/oi vaπed Foi example, as watei concentration decreases, the pulse rate may be increased to provide additional water The amount of water can be easily determined by signal analysis, because the measured amplitude of the watei signal is deteπnmative of the amount of water set free durmg the ablation

The following examples illustrate the various aspects of the present invention for ophthahnic use as a lasei ablation method to detennme and distmguish similar tissues dunng an ablation procedure

EXAMPLE 1

This example describes a method and system to detennme and distinguish sunilar chemicals accoiding to the pi esent invention A UV excimer laser ( 193 mn, from Summit Technology, Inc , type UV 200L) was used for photoablation The laser parameters weie as follows 10 Hz repetition rate, beam diameters 5 0 mm. fluence 180 mJ/cnr The fluence was detennmed by measuring the lasei output energy with an external power meter Organic polymers, polymethyl-meth-acrylate (PMMA), polyacrylate (PA), and polyvmylchlonde (PVC) were examined to detennme the photoacoustic frequency spectrum for each polymer Then subsequently the frequency data pomts were mathematically manipulated through cluster analysis to clearly distinguish the separate polymers The system configuration and set up, as shown m Figure 3, included a 193 nm Excimer laser, microphone, amplifier, PC with an A D converter and pπntei The photoacoustic signal was sensed by a capacitor microphone w ith a frequency range from about 20 Hz to about 200 kHz and an attenuation of 92 dB (Broel & Kjaei , type 2839. pi eamphfier 2809, microphone power supply 2804) The microphone was positioned 1 0 cm from the target at an angle of 90° The signal was amplified up to 10 times The linearly amplified analog signal was analyzed by an A/D converter for further processing to avoid deterioration of the signal quality A smgle slot full length 16 bit ISA PC board (CompuScope 2 125. GageScope Gage Applied Sciences, Inc . Canada) was used to process the signal output Two signals were obtained in this manner, the time signal as shown in Figure 2 and the Founer transfoπned signal (frequency spectrum) of Figure 4 The frequency spectrum from the Founer transfoπn signal was investigated by inputting frequency data points into a cluster analysis algonthm (k-means) Specifically, the center maximum fi-equencv and the four (4) closest local frequency maxima were selected, that bemg f(x) 1 , 2, 3, 4, and 5 as shown in Figure 4 The converted data was analyzed with the MatLab1'11 language program (MatLab 5 2. fi-om The Mathworks. Inc ) The frequency spectrums for PMMA, PA and PVC were analyzed by cluster analysis and the results transferred to a 3-dunensιonal cluster plot as shown in Figure 5

Results Implementmg clustei analysis provides for a visual output illustratmg the separate polymers The center frequency, fx (3) in Figure 4, was used to imtiahze the cluster analysis for PMMA and the remaimng frequency maxima were grouped according to the distance to the central frequency (It should be noted that PMMA is composed of several points and each point represents a vaπation of laser parameters, e g . fluence, beam diameter ) Frequency signals fi-om the othei polymers were entered and analyzed accordingly In this manner, very similai polymers were distinguished Moreover, it is shown that vanations of laser parameters m the same target material results in insignificantly small shifts within a cluster cloud for the same target matenal. and the cluster is easily separable from chemically similar mateπals

EXAMPLE 2

This Example descnbes detennining and distinguishing nonnal porcme cornea tissue from scar porcme cornea tissue To discnminate nonnal corneal tissue from corneal scar tissue, the photoacoustic signal for two freshly removed porcme corneas were compai ed to corneas with photothennally induced scar tissue Stromal coagulation was induced by contact application with a LTK laser by meandering the contact band piece in an aiea measuring 7 by 7 mm The same laser, sensing and computer set-up used in Example 1 was used herem except that the laser beam diameter w as increased to 6 0 mm and the microphone was placed 16 cm fi-om the tissue at an angle of 20°. Cluster analysis was perfonned on the frequency spectrums and the results are shown in Figure 6.

Results: For essentially different tissue, such as corneal scar tissue and nonnal cornea tissue, a 2-dimensional cluster plot suffices for reproducible discrimination. Such 2-dimensional cluster analysis reduces the time and complexity of signal processing and thus provides an easily identified representation of different materials that can easily transfer to an operating room environment.

EXAMPLE 3

This example describes detennining and distinguishing the different layers of cornea tissue including comeal epithelium. Bowman's layer and sn'oma during an in vivo and in situ photoablation (PRK) procedure. The same laser, sensing and computer set-up used in Example 1 was used during the surgery except that the laser beam diameter was increased to 6.0 mm and the microphone was placed 16 cm fi-om the tissue at an angle of 20°. Cluster analysis was perfonned on the data of the frequency spectrums generated during the ablation process with the results shown in Figure 7.

Results: The successful identification and separation of the comeal layers has been demonstrated by using the non-contact photoacoustic methods of the present invention in a typical clinical PRK/TRK procedure. The three comeal layers are easily discernible, in contrast to the use of a surgical microscope, and as such, the method of the present invention provides for recognition of a transition interface between scar tissue and nonnal stroma tissue. Thus, the methods of the present invention could minimize unnecessary tissue removal and consequently limit the amount of induced latrogemc hyperopia.

The ablation methods of the present invention may be used for any surface. Especially, it may be used for restoration of paintings or other historically important surfaces. Further, it may be used to clean metallic surfaces, like steel to remove oxidations layers, such as rust.

While the invention has been described herein with reference to specific features, aspects and embodiments, it will be recognized that the invention may be widely varied, and that numerous other vaπations, modifications and other embodiments will readily suggest themselves to those of ordinary skill in the art. Accordingly, the ensuing claims are to be broadly construed, as encompassing all such other variations, modifications and other embodiments, withm their spirit and scope.

Claims

THE CLAIMS
1 A guided non-contact tissue ablation method controllably mediated by recognition of distinct tissue composition within a tissue volume, the method comprising a) impinging multiple pulses of electromagnetic energy onto the tissue to ablate impmged tissue and generate an acoustic pressure wave in response to the electromagnetic energy interacting with the impinged tissue, b) non-contactingly sensing the geneiated acoustic pressure wave to provide a plurality of coπesponding signals, c) processmg the plurality of signals by applying thereto a cluster analysis algonthm to recognize distinct tissue composition
2 The guided non-contact tissue ablation method of claim 1 further comprising generating a repi esentati e pattern of the impinged tissue illustrating distinct tissue layei s
3 The guided non-contact tissue ablation method of claim 1 or 2 wherem the plurality of signals is an acoustic signal sensed from the acoustic pressure wave
4 The guided non-contact tissue ablation method of claim 3 wherem the acoustic signal is Fouπei transfoπned and a maximum peak is chosen as a center frequency and at least foui closest fiequency maxima are chosen to be piocessed in the clustei analysis algonthm The guided non-contact tissue ablation method of anyone of clauns 1 to 4 wherem the electromagnetic energy has a wavelength m a range of from about 1 50 mn to about 400 mn
The guided non-contact tissue ablation method of anyone of claims 1 to 5 wherein the electromagnetic energy is emitted by a laser
The guided non-contact tissue ablation method of claim 6 wherein the laser is an excimei lasei tienei atnm the electi omaimetic energy with a wavelength of 193 nm
The guided non-contact tissue ablation method of anyone of clauns 1 to 7 wherein the generated acoustic pressure wave is non-contactingly sensed by a transducei
The guided non-contact tissue ablation method of claim 8 wherem the transducer comprises is a capacitor microphone
The guided non-contact tissue ablation method of anyone of claims 1 to 9 wherein the geneiated acoustic piessui e wav e is generated by the absorption of the electromagnetic energy by the impinged tissue
The guided non-contact tissue ablation method of anyone of claims 1 to 10 wherein the clustei analysis compnses perfonning a k-means algorithm A non-contact tissue ablation method conti ollably mediated by recognition of tissue composition, the method compnsmg
a) impinging multiple pulses of electromagnetic energy onto at least one location of the tissue to ablate impinged tissue and to generate at least one acoustic pressm e wave in response the electromagnetic energy impinging the tissue.
b) non-contactingly sensing the at least one generated acoustic pressure wave to prov ide a pluiahty of coπespond ng signals, and
c) piocessing the plui ahty of signals by analyzing at least one signal property to detennme change in the ablated tissue
The guided non-contact tissue ablation method of claim 12 further comprising generating a repi esentative pattern of the impinged tissue illustratin Όg distinct tissue lavei s
The guided non-contact tissue ablation method of claims 12 or 13 wherem the plurality of signals compnse acoustic signals sensed fi-om the acoustic pressme wav e
The guided non-contact tissue ablation method of claim 14 wherem the acoustic signals aie Founei tiansfoπned and a maximum is chosen as a center frequency and at least foui closest fiequency maxima are chosen to be processed m the clustei analysis algonthm The guided non-contact tissue ablation method of anyone of claims 12 to 15 wherem the electromagnetic energy has a wavelength from about 150 mn to about 400 mn
The guided non-contact tissue ablation method of claun 16 wherein the electromagnetic energy is emitted by a laser
The guided non-contact tissue ablation method of claim 1 7 wherein the laser comprises an excimer laser generating the electromagnetic energy having a wavelength of 1 93 nm
The guided non-contact tissue ablation method of anyone of claims 12 to 1 8 wherein the generated acoustic pressure wave is non- contactingly sensed by at least one microphone transducer
The guided non-contact tissue ablation method of claim 1 8 wherein the processing of the plurality of signals compnses perfoπning cluster analysis using a k-means algorithm
The guided non-contact tissue ablation method of anyone of claims 12 to 20 wherem at least two electromagnetic energy sources impinge at least two locations on the tissue to generate multiple acoustic waves that superimposed to provide an interference response
The guided non-contact tissue ablation method of claun 2 1 wherein the pulse are emitted simultaneously oi sequentially The guided non-contact tissue ablation method of anyone of claims 12 or 2 wherein the signal property to be analyzed is frequency
The guided non-contact tissue ablation method of anyone of claims 12 to 23 wherem the electromagnetic energy is emitted by a laser have a beam configuration selected from the group consisting of gaussian, rectangular, circular, point beam and broad beam
The guided non-contact tissue ablation method of claim 24 wherein the beam comprises a broad beam to impinge electromagnetic energy onto an area of tissue and signals fonned by the generated acoustic wave are sensed at multiple locations of the impinged tissue
The guided non-contact tissue ablation method of claims 24 or 25 further comprising applying a matenal filer to the tissue before impinging area with the laser, the laser having the rectangular beam configuration to ablate impinged tissue and matenal fillei
The guided non-contact tissue ablation method of anyone of claims 12 to 26 further compnsmg adjusting impinging electromagnetic energy accordmg to fluid content of tissue
A guided non-contact tissue ablation system that is controllably mediated by recognition of distinct types of tissue composition, the system comprising a) at least one electromagnetic energy' emitting source to generate multiple pulses of electromagnetic energy to ablate impmged tissue and generate an acoustic pressure wave in response to the electromagnetic energy impinging the tissue, b) at least one non-contacting sensing means for sensing the acoustic pressure wave and providing a plurality of conespondmg signals, and c) at least one piocessing means foi analyzing the signals of the acoustic pressure wave to recognize distinct tissue composition
The guided non-contact tissue ablation system of claim 28 further compnsmg a display means for displaying a representative pattern of the impmged tissue illustratmg distinct tissue layers
The guided non-contact tissue ablation system of claims 28 or 29 wherem the at least one electromagnetic energy source comprises a laser
The guided non-contact tissue ablation system of anyone of claims 28 to 30 wherem the processing means analyzes by a cluster analysis algorithm
The guided non-contact tissue ablation system of claim 3 1 wherem the laser comprises an excimei laser generating the electromagnetic energy having a wavelength of 193 nm
The guided non-contact tissue ablation system of anyone of clauns 28 to 32 wherein the at least one non-contacting sensing means comprises a microphone transducer
34. The guided non-contact tissue ablation system of anyone of claims 28 to 33 wherein the processing means comprises an oscilloscope operatively coupled with a computer.
PCT/EP2000/011167 1999-11-12 2000-11-12 Non-contact photoacoustic spectroscopy for photoablation control WO2001035881A1 (en)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001097692A1 (en) * 2000-06-22 2001-12-27 Richard James Dewhurst Ophthalmic uses of lasers
DE10128650B4 (en) * 2001-06-15 2004-03-11 Jurca Optoelektronik Gmbh & Co. Kg Measuring device for the treatment radiation beam parameters of a device for photorefractive correction of vision defects and device for correction of vision defects photorefractive
WO2004092714A1 (en) * 2003-04-16 2004-10-28 Koninklijke Philips Electronics N.V. Method for measuring thin films
DE102005013252A1 (en) * 2005-03-22 2006-09-28 Carl Zeiss Meditec Ag Ablation program establishing method for correcting ametropia of human eye, involves establishing ablation program based on water concentration of surface to be ablated and pre-compensated set-point ablation profile
WO2007039208A1 (en) * 2005-09-27 2007-04-12 Bausch & Lomb Incorporated Apparatus, system and method of controlling and monitoring the energy of a laser
DE102006053269A1 (en) * 2006-11-06 2008-05-08 Forschungsgesellschaft für Strahlwerkzeuge -FGSW- mbH A method for detecting a stock removal
WO2010031395A1 (en) * 2008-09-19 2010-03-25 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Laser-based apparatus and method for the non-contact scanning of eyes
WO2011107117A1 (en) * 2010-03-04 2011-09-09 Fotona D.D. Laser system for ablative treatment of body tissue
CN104000624A (en) * 2014-04-24 2014-08-27 温州医科大学 Ultrasonic probe attaching to ocular surface and used for measuring eye axis
US9078732B2 (en) 2009-03-12 2015-07-14 Carl Zeiss Meditec Ag Ophthalmologic laser system
DE102015008127A1 (en) * 2015-06-24 2016-12-29 Wavelight Gmbh Device for laser eye surgery and method for performing a transepithelial photorefractive keratectomy

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3918629A1 (en) * 1989-06-07 1990-12-13 Juergen Spahn Contactlessly registering internal pressure of eye - illuminating eye by modulated IR radiation to use photo-acoustic effects
WO1996011655A1 (en) * 1994-10-14 1996-04-25 Chiron/Technolas Gmbh Ophthalmologische Systeme Excimer laser system for correction of vision
US5840023A (en) * 1996-01-31 1998-11-24 Oraevsky; Alexander A. Optoacoustic imaging for medical diagnosis
EP0919180A1 (en) * 1997-11-25 1999-06-02 TRW Inc. Method and apparatus for noninvasive measurement of blood glucose by photoacoustics

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3918629A1 (en) * 1989-06-07 1990-12-13 Juergen Spahn Contactlessly registering internal pressure of eye - illuminating eye by modulated IR radiation to use photo-acoustic effects
WO1996011655A1 (en) * 1994-10-14 1996-04-25 Chiron/Technolas Gmbh Ophthalmologische Systeme Excimer laser system for correction of vision
US5840023A (en) * 1996-01-31 1998-11-24 Oraevsky; Alexander A. Optoacoustic imaging for medical diagnosis
EP0919180A1 (en) * 1997-11-25 1999-06-02 TRW Inc. Method and apparatus for noninvasive measurement of blood glucose by photoacoustics

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001097692A1 (en) * 2000-06-22 2001-12-27 Richard James Dewhurst Ophthalmic uses of lasers
DE10128650B4 (en) * 2001-06-15 2004-03-11 Jurca Optoelektronik Gmbh & Co. Kg Measuring device for the treatment radiation beam parameters of a device for photorefractive correction of vision defects and device for correction of vision defects photorefractive
WO2004092714A1 (en) * 2003-04-16 2004-10-28 Koninklijke Philips Electronics N.V. Method for measuring thin films
DE102005013252A1 (en) * 2005-03-22 2006-09-28 Carl Zeiss Meditec Ag Ablation program establishing method for correcting ametropia of human eye, involves establishing ablation program based on water concentration of surface to be ablated and pre-compensated set-point ablation profile
WO2007039208A1 (en) * 2005-09-27 2007-04-12 Bausch & Lomb Incorporated Apparatus, system and method of controlling and monitoring the energy of a laser
DE102006053269A1 (en) * 2006-11-06 2008-05-08 Forschungsgesellschaft für Strahlwerkzeuge -FGSW- mbH A method for detecting a stock removal
WO2010031395A1 (en) * 2008-09-19 2010-03-25 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Laser-based apparatus and method for the non-contact scanning of eyes
US9918874B2 (en) 2009-03-12 2018-03-20 Carl Zeiss Meditec Ag Ophthalmological laser system
EP2521519B1 (en) * 2009-03-12 2015-08-19 Carl Zeiss Meditec AG Ophthalmologic laser system
US9078732B2 (en) 2009-03-12 2015-07-14 Carl Zeiss Meditec Ag Ophthalmologic laser system
WO2011107117A1 (en) * 2010-03-04 2011-09-09 Fotona D.D. Laser system for ablative treatment of body tissue
CN104000624A (en) * 2014-04-24 2014-08-27 温州医科大学 Ultrasonic probe attaching to ocular surface and used for measuring eye axis
CN104000624B (en) * 2014-04-24 2016-04-13 温州医科大学 Affixed to one kind of ultrasonic probe for ocular axial length measurement
DE102015008127A1 (en) * 2015-06-24 2016-12-29 Wavelight Gmbh Device for laser eye surgery and method for performing a transepithelial photorefractive keratectomy

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