Method and apparatus for selective treatment of biological tissue
阅读说明：本技术 用于对生物组织的选择性治疗的方法和设备 (Method and apparatus for selective treatment of biological tissue ) 是由 理查德·罗克斯·安德森 迪特尔·曼施泰因 亨利·兴·利·千 文森特·左 于 2017-12-22 设计创作，主要内容包括：可以提供一种示例性治疗系统,该治疗系统可以包括：激光器系统,其被配置成发射至少一个激光束；以及光学系统,其被配置成将激光束聚焦到与组织的表面相距选定距离的聚焦区域。聚焦区域可以被配置成照射靶的至少一部分。光学系统可以使辐照能量传递到激光束的聚焦区域以(i)在组织的与靶相邻的第一区域中生成等离子体,并且(ii)避免在组织的第二区域中生成等离子体。光学系统的数值孔径在约0.5至约0.9的范围内。还可以提供一种示例性方法来控制这样的治疗系统。(An exemplary therapy system may be provided, which may include: a laser system configured to emit at least one laser beam; and an optical system configured to focus the laser beam to a focal region at a selected distance from the surface of the tissue. The focal region can be configured to illuminate at least a portion of the target. The optical system may deliver the irradiation energy to a focal region of the laser beam to (i) generate plasma in a first region of the tissue adjacent to the target, and (ii) avoid generating plasma in a second region of the tissue. The numerical aperture of the optical system is in the range of about 0.5 to about 0.9. An exemplary method may also be provided for controlling such a therapy system.)
1. A therapeutic system, comprising:
a laser system configured to emit at least one laser beam; and
an optical system configured to focus the at least one laser beam to a focal region at a selected distance from a surface of the tissue, the focal region configured to illuminate at least a portion of the target,
wherein the optical system causes irradiation energy to be delivered to the focal region of the at least one laser beam to (i) generate plasma in a first region of the tissue adjacent to the target, and (ii) avoid generating plasma in a second region of the tissue, and
wherein the numerical aperture of the optical system is in the range of about 0.5 to about 0.9.
2. The treatment system of claim 1, wherein the first region is located within the focal region, and wherein the second region is located outside the focal region.
3. The therapeutic system of claim 1, wherein the at least one laser beam has a wavelength in a range of about 600nm to about 1100nm when measured in air.
4. The treatment system of claim 1, wherein the peak intensity of the at least one laser beam in the focal region is at least about 10^8W/cm2。
5. The therapeutic system of claim 1, wherein the irradiation energy is configured to cause thermionic emission of electrons from the target.
6. The therapeutic system of claim 5, wherein the optical system configures the irradiation energy to generate plasma from the thermionic emission of electrons.
7. The therapeutic system of claim 1, wherein the at least one laser beam comprises (i) a first laser pulse configured to generate thermionic emission of electrons, and (ii) a second laser pulse configured to generate the plasma.
8. The therapeutic system of claim 1, wherein the optical system is configured to generate a further laser beam, wherein the at least one laser beam is configured to generate thermionic emission of electrons, and wherein the further laser beam is configured to generate the plasma.
9. The therapeutic system of claim 1, wherein the spot size of the focal zone is in a range of about 5 μ ι η to about 100 μ ι η when measured in air.
10. The treatment system of claim 1, wherein the optical system comprises a lens configured to change the selected distance of the focal region relative to the surface of the tissue.
11. The treatment system of claim 10, wherein the selected distance of the focal region from the surface of the tissue is in a range of about 5 μ ι η to about 1000 μ ι η.
12. The treatment system of claim 1, wherein the optical system comprises a microlens array extending along a first direction and a second direction, and wherein the microlens array is configured to focus the at least one laser beam to the focal region.
13. The treatment system of claim 12, wherein the at least one laser beam is simultaneously incident on the microlens array, thereby generating an array of focal regions.
14. The treatment system of claim 12, wherein the optical system is configured to pass the at least one laser beam from a first lens of the array of microlenses through to a second lens of the array of microlenses.
15. The treatment system of claim 12, wherein the laser system is configured to emit a plurality of laser beams, and wherein one or more of the plurality of laser beams are incident on one or more microlenses in the microlens array.
16. The therapeutic system of claim 1, wherein the target comprises a chromophore.
17. The therapeutic system of claim 16, wherein the chromophore comprises at least one of melanin, tattoo ink, hemoglobin, sebaceous glands, subcutaneous fat, hair bulbs, lipids in cell membranes, fat surrounding an organ, blood vessels, or a pharmaceutical composition.
18. The treatment system of claim 1, further comprising a sensor configured to detect one or more of a speed and a position of the treatment system relative to a tissue surface.
19. The therapeutic system of claim 18, further comprising a feedback control configuration configured to:
receiving data characterizing one or more of velocity and position data detected by the sensor; and
varying at least one of a pulse duration, a pulse frequency, or a pulse energy of the at least one laser beam.
20. The treatment system according to claim 1, wherein the laser system is configured to control a travel time of the focal region moving from a third region in the tissue to a fourth region below the tissue, the travel time being less than a time interval between temporally adjacent laser pulses of the at least one laser beam.
21. The treatment system according to claim 20, wherein the laser system is configured to control the time interval between temporally adjacent laser pulses, the time interval being less than 50 milliseconds.
22. A method of controlling a therapy system, comprising:
controlling a laser system to emit at least one laser beam; and
controlling an optical system to focus the at least one laser beam to a focus region at a selected distance from a surface of the tissue, the focus region configured to illuminate at least a portion of a target; and
controlling the optical system such that irradiation energy is delivered to the focused region of the at least one laser beam to (i) generate plasma in a first region of the tissue adjacent to the target, and (ii) avoid generating plasma in a second region of the tissue,
wherein the numerical aperture of the optical system is in the range of about 0.5 to about 0.9.
Technical Field
Exemplary embodiments of the present disclosure relate to influencing pigmented biological tissue, and more particularly to methods and apparatus for selectively generating localized plasma effects in a pigmented region of such tissue.
Background
The use of optical (light) energy to affect biological tissue has been widely used over the past few decades. Optical energy is a form of electromagnetic energy. In the electromagnetic spectrum, light energy can typically be in the infrared (longer wavelength) to ultraviolet (shorter wavelength) region. Treating biological tissue with light energy typically involves introducing light energy into the tissue.
Three major interactions may occur when directing light energy onto or into biological tissue. First, some portion of the energy may be reflected from the surface of the tissue. Such reflection may be wavelength dependent, and may be reduced, for example, by appropriate selection of the energy wavelength, reduction of the change in refractive index in the optical path (e.g., by using certain waveguide materials, providing a coating of material such as a gel on the tissue surface, etc.), and by selection of an appropriate angle of incidence of the light beam on the tissue surface.
The light energy may also be scattered by components in the tissue, which results in a local change of direction of a portion of the light beam energy. In some cases, scattering near the tissue surface may cause a portion of the light energy to be scattered back out of the tissue surface (mitigation). If the tissue is relatively thin, some of the light energy may pass through the tissue and exit the tissue, typically after some scattering has occurred.
The primary mechanism of interest for affecting tissue is absorption. The energy absorbed by the tissue elements can produce several effects. For example, energy absorption may result in vibrational modes of the molecules and the generation/enhancement of local heating effects. Local absorption of high intensity light energy, typically in the short time range (timeframe), may even result in vaporization (or ablation) of tissue, where local tissue components are decomposed and converted to a gaseous state. Such photoablation can produce small vapor bubbles in the tissue that expand rapidly, which can create mechanical (and thermal) damage to adjacent tissue, or eject tissue debris from the tissue surface. Optical energy absorption can also result in electronic transitions, in which case electrons in an atom or molecule may be excited to a higher (quantized) energy state. These absorption mechanisms are linear, with absorption being substantially independent of the intensity of the light energy. The relative extent and efficiency of the absorption process depends on many factors, including the nature of the absorbing species/component, the wavelength of the light energy, and the like.
Three types of optical energy sources commonly used to affect biological tissue are: 1) low power light sources, such as lamps and light emitting diodes; 2) an Intense Pulsed Light (IPL) source; and 3) a laser. IPL sources, such as flash lamps, typically provide high intensity pulses of a non-collimated beam of electromagnetic energy wavelengths having a range or spectrum. In contrast, lasers produce a strong collimated beam of energy composed of one or more discrete wavelengths of coherent (in-phase) light. Lasers are preferred for many types of optical treatment because the effect of the optical energy can be better controlled when the tissue is illuminated with light of a known wavelength.
The laser may provide the optical energy as a Continuous Wave (CW) with a continuous beam of energy or as a series or sequence of energy pulses. The pulsed laser may be generated by so-called Q-switching, mode locking or in some cases by a mechanical or electro-optical shutter. Pulsed lasers are known in the art and can be configured to provide many combinations of wavelength, pulse duration, and pulse interval per pulse, as well as different amounts of energy. The laser beam may also be shaped using various waveguides and/or lenses, etc., to produce energy beams having various beam shapes, widths, and focusing characteristics. Thus, a particular laser and its operating parameters can be tailored to produce a wide range of effects in biological tissue.
It has been observed that the application of certain wavelengths of light or light energy can be strongly absorbed by chromophores, which are certain molecules or parts of molecules that are particularly efficient absorbers of certain wavelengths of light. Chromophores may also determine the apparent color or appearance of certain tissue regions. Chromophores in biological tissue are typically located in certain pigmented cells or structures (e.g., melanosomes or hair follicles). One common chromophore in skin tissue is melanin, which determines the overall human skin tone. Hemoglobin in the blood is another common biological chromophore. Chromophores in tissue can also be introduced from foreign substances such as light absorbing nanoparticles of skin tattoos or some topically applied compounds. Other chromophores that may be present in biological tissue may include, for example, tattoo ink, sebaceous glands, subcutaneous fat, hair bulbs, lipids in cell membranes, fat surrounding organs, blood vessels, and pharmaceutical compositions.
A key concept for affecting biological tissue with optical energy is selective photothermolysis, in which the characteristics of the optical energy used to irradiate the biological tissue are selected to provide preferential absorption of such energy by certain chromophores, while relatively little energy is absorbed by other regions of the tissue that do not contain such chromophores. Selective or preferential absorption of light energy by chromophores can result in localized heating of adjacent tissue, which can lead to thermal damage or necrosis of cells, physical changes in the heated tissue (e.g., coagulation, collagen denaturation, etc.), and even vaporization of the tissue.
Another factor affecting the light/tissue interaction is the local thermal relaxation time. For example, in selective photothermolysis, thermal heating and tissue damage may be localized to regions containing chromophores if the duration of local illumination is relatively short compared to the local thermal relaxation time (which is the characteristic time that a small heat source will diffuse to surrounding tissue). In contrast, longer local exposure times may result in more extensive thermal damage due to heat diffusion from preferential absorption sites. The general principles of Selective Photothermolysis are described, for example, in R.R. Anderson et al, Selective Photothermolysis: precision Microsurgery by Selective adsorption of Pulsed Radiation, Science (Science), Vol.220, No. 4596, pp.524 to 527 (1983).
As previously noted, irradiation of biological tissue with high intensity light energy may vaporize or ablate the tissue. Certain ablative lasers, for example, can be used to effectively cut tissue using light energy and are common in many ophthalmic treatments such as corneal refractive surgery. For example, nanosecond pulses of an ArF excimer laser emitting light at 193nm wavelength can be used to achieve precise ablation of corneal tissue. The very short pulse duration minimizes thermal damage away from the directly illuminated focal region.
Irradiating tissue with a high intensity beam of optical energy may also result in dielectric breakdown of tissue components and formation of a plasma. For example, having a very short duration (e.g., on the order of nanoseconds or less, typically picoseconds or femtosecond pulse durations) and a very high power density (e.g., 10^ 10W/cm)2Or higher) may generate an electric field strength high enough to cause electrons to lift off atoms. At very high local workAt rate density, a plasma may form in the tissue where free electrons absorb even more energy and collide with other atoms and molecules, ejecting more electrons (ionization) that also absorb energy from the beam of optical energy. This may create a chain reaction that causes plasma formation, which is often accompanied by rapid local expansion in the tissue and mechanical shock waves. These effects can be used to create certain types of tissue damage and vaporization. Plasma formation is an example of a non-linear process that relies on the presence of high optical power density and does not occur at the low optical power densities (e.g., in W/cm) of typical lamps, IPLs, and continuous wave lasers2Optical power density in units). A pulsed laser source is used which is typically focused to achieve a sufficiently high power density in a short time interval. Once the plasma is formed, free electrons and ions within the plasma absorb incident light, which sustains the plasma until the end of the laser pulse.
There are many known uses for plasma formation in substances. For example, pulsed laser etching within glass or other transparent materials is an industry example of plasma formed by dielectric breakdown. In the medical field, cutting the posterior capsule by a focused Q-switched laser after cataract removal is an example of using dielectric breakdown to generate plasma that can locally vaporize tissue. More generally, dielectric breakdown at the focused spot of a Q-switched nanosecond or picosecond laser (depending on power density) is commonly used in ophthalmology to cut structures within the eye by locally scanning or moving the laser focus within the structure desired to be cut.
Plasma formation in tissue is often accompanied by visible sparks or flashes of light and audible sounds. Further absorption of light energy in the plasma becomes nonlinear, where absorption varies according to the fourth power of the beam intensity. The heated electrons and ions can have extremely high temperatures on the order of 10^5K and local pressures on the order of kilobars. Due to the very high power density and the mechanism of optical (or dielectric) breakdown, plasma formation in tissue tends to be non-selective with respect to the presence of chromophores.
Accordingly, it would be desirable to provide methods and devices that can selectively generate plasma and related damage mechanisms in biological tissue without generating excessive damage to non-target tissue and without generating other undesirable side effects.
Disclosure of Invention
Exemplary embodiments of methods and apparatus for treating biological tissue (e.g., selectively generating localized plasma effects in a pigmented region of such tissue) may be provided. Exemplary embodiments of the methods and devices can facilitate selective energy absorption by colored or chromophore-containing structures and/or regions within biological tissue (e.g., skin tissue) by focusing highly concentrated electromagnetic radiation (EMR) (e.g., optical energy) having appropriate wavelengths and other parameters onto regions within the tissue. This exemplary process may produce sufficient selective absorption of local energy density in tissue to cause the generation of plasma (e.g., caused by thermionic plasma initiation) in biological tissue, which is selective to tissue regions containing chromophores. The plasma thus localized can destroy pigments and/or chromophores while avoiding undesirable damage to surrounding uncolored and overlying tissues. Such systems and methods described herein may be used, for example, to improve the appearance of skin tissue.
According to certain exemplary embodiments of the present disclosure, there may be provided an apparatus, which may include: a radiation emitter arrangement configured to emit EMR; and an optical arrangement configured to direct EMR onto the skin being treated and focus the EMR to a focused region within the tissue. EMR may be light energy preferably having wavelengths in the near infrared, visible, and/or ultraviolet portions of the electromagnetic energy spectrum. The EMR source may be or include, for example, a laser system or the like. The device may also include a housing and/or a handpiece that may contain these components and facilitate handling of the device during use of the device.
The EMR emitter may include, for example, an EMR source such as one or more diode lasers, fiber lasers, or the like, and optionally a waveguide or fiber configured to guide EMR from an external source. If the emitter arrangement includes an EMR source, the emitter arrangement may optionally further include a cooling arrangement configured to cool the EMR source and prevent overheating of the source. A control arrangement may be provided to control operation of the transmitter arrangement, the operation of the transmitter arrangement including: such as turning the EMR source on and off; parameters of the EMR source, such as average or peak power output, pulse length and duration, etc., are controlled or varied.
The EMR can have a wavelength preferably greater than about 600nm (e.g., between about 600nm and about 1100 nm). The selection of a particular wavelength may be based on the absorption spectrum of one or more particular chromophores. Wavelengths outside this exemplary range may be used in certain exemplary embodiments, depending on the chromophore present, the focusing characteristics of the optical energy beam, and/or the parameters of the energy beam. For example, shorter wavelengths (e.g., less than about 600nm) may be significantly scattered within skin tissue and may lack sufficient penetration depth to reach portions of the dermal layers with sufficient flux and focus, but the high absorption coefficient of a particular chromophore may offset some of these effects.
An exemplary device may include an optical arrangement configured to focus EMR in a highly focused beam. For example, the optical arrangement may comprise a focusing or converging lens arrangement having a Numerical Aperture (NA) of about 0.5 or more, for example between about 0.5 and 0.9. The correspondingly large convergence angle of the EMR can provide high flux and intensity in the focal region of the lens, and lower flux in overlying tissue above the focal region. Such a focusing geometry may help reduce undesirable thermal damage in overlying tissue above the targeted tissue region. The exemplary optical arrangement may further comprise a collimating lens arrangement configured to direct EMR from the emitting arrangement onto the focusing lens arrangement.
An exemplary device can be configured to focus EMR such that for optical energy having a wavelength of about 1060nm, the local intensity or power density of the optical energy in the focal region is about 10^10W/cm2Or higher, e.g., at about 10^10W/cm2And 10^11W/cm2In the meantime. At a certain pointIn some embodiments, if other parameters such as absorption efficiency (which depends in part on the chromophore and the wavelength of the optical energy) and energy density (which also depends in part on the pulse duration) are appropriately selected, the local power density may be lower, e.g., as low as about 0^8W/cm2. An optical arrangement may be provided to focus the EMR in a focal region to a small spot size, for example, between about 5 μm and about 100 μm (measured in air with reduced scattering). Such a small focused spot size may be advantageous for generating a sufficiently high local power density in the focus area. For example, in certain exemplary embodiments, slightly smaller or larger spot sizes may be used depending on other factors such as the wavelength of the light energy and the absorption coefficient of the particular chromophore at such wavelength.
The exemplary optical arrangement can also be configured to direct a focal region of EMR onto a location within the biological tissue (e.g., skin tissue, etc.) at a depth of between about 5 μm and 2000 μm (2mm) below the surface (e.g., between about 5 μm and 1000 μm). The depth of focus may correspond to a distance from a lower surface of the device configured to contact the tissue surface to a location of the focal region. In further embodiments, the optical arrangement may be configured to change the depth of the focal region and/or to provide multiple focal regions having different depths simultaneously.
In further exemplary embodiments of the present disclosure, the position and/or orientation of the components of the EMR emitter arrangement and/or the optical arrangement may be controllable and/or adjustable relative to each other and/or relative to the tissue, such that the position and/or path of the focal region in the tissue may be changed. Such variation of the path of the focal region may be provided using an optical arrangement with a variable focal length, a mechanical translator capable of controllably changing the position of the optical arrangement and/or the arrangement of EMR emitters relative to the tissue being treated, or the like. Such exemplary changes in the location of the focal region may facilitate treatment of larger volumes of tissue by, for example, "scanning" the focal region within the tissue in a pattern at a particular depth and/or depths. In certain exemplary embodiments, a mechanical translator may be provided that scans the tissue region to be treated at a speed, for example, in a range of about 5 mm/sec to about 5 cm/sec.
In further exemplary embodiments of the present disclosure, a handpiece configured to manually translate across tissue at a similar speed may be provided. A sensor arrangement may be provided in such a manual handpiece or mechanical translation device to detect the scan speed and to influence parameters of the optical arrangement and/or EMR source (e.g., EMR pulse duration, pulse frequency, pulse energy, etc.) based on such detection, for example to maintain a consistent range of parameters such as local power density and local dwell time during treatment. For example, the scan speed and focal zone spot size can be selected to maintain a local dwell time at the location of the focal zone in the tissue that is small enough (e.g., less than about 1ms to about 2ms) to avoid damaging uncolored tissue.
In still other exemplary embodiments of the present disclosure, an exemplary optical arrangement may include a plurality of microlenses, e.g., convex lenses, plano-convex lenses, and the like. Each microlens may have a large NA (e.g., between about 0.5 and 0.9). The microlenses may be arranged in an array, such as a square or hexagonal array, for producing multiple focal regions in the dermal tissue in a similar pattern. The width of the microlenses may be small, for example, between about 1mm and 3 mm. Microlenses that are slightly wider or narrower than this width may also be provided in some embodiments. In still other exemplary embodiments of the present disclosure, the microlenses may include cylindrical lenses, for example, convex cylindrical lenses or plano-convex cylindrical lenses. The width of such cylindrical microlenses may be small, for example, between about 1mm and 3 mm. The length of the cylindrical microlenses may be, for example, between about 5mm and 5 cm. Other exemplary arrangements of lenslets may be used in further exemplary embodiments to generate multiple focal regions within tissue, where such focal regions may be disposed at the same or different depths (e.g., one or more microlenses may have a different focal length than another microlens).
The exemplary radiation emitter arrangement and/or the exemplary optical arrangement may be configured to direct a single broad EMR beam to the entire array of such microlenses, or a portion thereof, to simultaneously generate multiple focal regions in the dermis. In further exemplary embodiments of the present disclosure, the radiation emitter arrangement and/or the optical arrangement may be configured to direct a plurality of smaller EMR beams onto respective ones of the microlenses. Such multiple beams may be provided, for example, by using multiple EMR sources (e.g., laser diodes), beam splitters or multiple waveguides, or by scanning a single beam across individual microlenses. If cylindrical microlenses are provided, one or more beams of EMR can be caused to scan such cylindrical lenses, for example, in a direction parallel to the longitudinal axis of such cylindrical lenses.
In yet another exemplary embodiment of the present disclosure, laser pulses having a relatively short duration, for example on the order of 10 μm, may be used to selectively heat the stained cells to release some electrons via thermionic emission. A second pulse of optical energy having appropriate parameters including a pulse duration on the order of about 100ns as described herein may then be focused to irradiate the same stained cells and "pump" the released electrons before they relax and rejoin the locally ionized atoms or molecules, thereby selectively forming a plasma at or near the stained cells. Other coloured targets located in the tissue, possibly outside the cells, may also be irradiated to promote selective absorption of energy and plasma generation.
In still other exemplary embodiments of the present disclosure, a method for selectively generating plasma in a colored region of a biological tissue may be provided. An exemplary method may include: electromagnetic radiation (e.g., light energy) is directed and focused onto multiple focal regions within tissue using an optical arrangement as described herein, such that the light energy is selectively absorbed by the colored regions, thereby generating some localized ionization via thermionic emission of electrons. The beam intensity and local residence time should be large enough to allow additional energy to be absorbed by the free electrons, causing further ionization and subsequent chain reaction of the excited electrons (sometimes referred to in the physical literature as "electron avalanche"), resulting in the local formation of a plasma in the tissue.
These and other objects, features and advantages of the present disclosure will become apparent upon reading the following detailed description of exemplary embodiments of the present disclosure when taken in conjunction with the accompanying drawings and the appended claims.
Drawings
Other objects, features and advantages of the present disclosure will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate illustrative embodiments, results and/or features of exemplary embodiments of the present disclosure, and in which:
FIG. 1 is a representative side view of one or more radiation beams focused to pigmented dermal tissue;
FIG. 2 is a cross-sectional side view of an exemplary apparatus according to an exemplary embodiment of the present disclosure;
FIG. 3A is a side view of an arrangement of microlenses that may be used with certain exemplary embodiments of the present disclosure;
FIG. 3B is a top view of a first exemplary arrangement of microlenses shown in FIG. 3A;
FIG. 3C is a top view of a second exemplary arrangement of microlenses shown in FIG. 3A;
FIG. 3D is a top view of an exemplary arrangement of cylindrical microlenses that may be used with certain exemplary embodiments of the present disclosure;
FIG. 3E is a perspective view of an exemplary arrangement of cylindrical microlenses shown in FIG. 3D;
FIG. 3F is a side view of another exemplary arrangement of microlenses that can be used with further exemplary embodiments of the present disclosure;
FIG. 4 is a schematic view of a scanning pattern that may be used with exemplary embodiments of the present disclosure;
fig. 5 shows a set of exemplary images obtained at different times of an illuminated region of pig skin, according to certain exemplary embodiments of the present disclosure;
fig. 6 shows another set of exemplary images of an illuminated region of pig skin obtained at different times according to further exemplary embodiments of the present disclosure;
fig. 7A shows another set of exemplary images obtained at different times of a region of pig skin illuminated over a range of depths, according to yet other exemplary embodiments of the present disclosure;
FIG. 7B illustrates another set of exemplary images obtained at different times of the same area of the pig skin shown in FIG. 7A illuminated at a deeper depth and 2 weeks after the first illumination scan shown in FIG. 7A, according to still further exemplary embodiments of the present disclosure;
fig. 8A shows another set of exemplary images of an illuminated region of pig skin obtained at different times, according to still other exemplary embodiments of the present disclosure;
FIG. 8B shows images of a natural skin test site at various stages of treatment;
fig. 8C is an exemplary image of a biopsy (biopsy) taken by Electron Microscopy (EM) from the native skin test site shown in fig. 8B;
FIG. 9 is a side cross-sectional view of an exemplary system for in vivo plasma detection in tissue;
FIG. 10A is a graph of detected intensity spectra for irradiated melanin-containing tattooed tissue and non-melanin-tattooed tissue;
FIG. 10B is a photomicrograph image of a cross-section of a tissue sample containing a melanin tattoo that was irradiated to obtain the intensity spectrum in FIG. 10A;
FIG. 11 is a graph of detected intensity spectra for irradiated carbon-tattoo containing tissue and non-carbon-tattoo containing tissue;
FIG. 12 shows images of an exemplary test site at various stages of treatment; and
fig. 13 shows images of another exemplary test site at various stages of another treatment.
Throughout the drawings, the same reference numerals and characters, unless otherwise specified, are used to denote like features, elements, components or portions of the illustrated embodiments. Thus, similar features may be described by the same reference numerals, which indicates to those skilled in the art that feature exchanges between different embodiments may be made unless otherwise explicitly stated. Furthermore, although the present disclosure will now be described in detail with reference to the figures, it is done so in connection with the illustrative embodiments and is not limited to the specific embodiments shown in the figures. It is intended that changes and modifications may be made to the described embodiments without departing from the true scope and spirit of the present disclosure as defined by the following claims.
Detailed Description
Exemplary embodiments of the present disclosure may provide an apparatus and method for selectively generating plasma in biological tissue using thermionic plasma initiation. Thermionic plasma initiation is a thermophysical process, distinct from dielectric breakdown, that begins with the heating of a substance, releasing some thermionic electrons. Electrons rapidly recombine with the ionized molecules from which they originate, but under the proper conditions, these electrons are also able to absorb incident photons from the laser/energy source to initiate the plasma. Thermionic plasma initiation is based in part on the linear absorption mechanism of light by chromophores, and thus can occur preferentially at sites of enhanced light absorption within complex substances such as living tissue. Thermionic plasma initiation generally requires a high power density, but this power density is typically much lower (e.g., orders of magnitude) than that required for dielectric breakdown. Thus, in non-homogeneous (xenogeneous) materials such as biological tissue, a pulsed laser may induce a thermionic plasma under appropriate conditions at the site where chromophores are present within the tissue.
Thermionic plasma initiation depends on the ability to release thermal electrons from chromophores and/or nearby molecules. Some molecules have weakly bound electrons that are more likely to be released when the substance is heated, while molecules without weakly bound electrons are less likely to release hot electrons. In tissue, melanin is an example of a chromophore with many weakly bound electrons. Melanin is also a strong chromophore covering a large part of the spectrum. Thus, melanin can be a preferential site for thermionic plasma formation when exposed to sufficient power density, for example from a pulsed laser. In contrast, plasmas formed via dielectric breakdown do not rely on the presence of chromophores.
The effect of heating the chromophore to initiate the thermionic plasma depends in part on the energy density. The energy of the laser pulse is the time integral of the laser power. Femtosecond laser pulses and picosecond laser pulses capable of inducing dielectric breakdown within a short time interval tend to have a lower energy density than that required for thermo-electron plasma initiation due to the short duration of the pulses. Longer pulse durations, even in the microsecond regime (one million times longer than the femtosecond regime), can initiate thermionic plasma formation under certain conditions when suitable chromophores are present and the local power density is sufficiently high. The pulse energy is preferably focused to a degree sufficient to provide a sufficiently high local energy density in the tissue.
In certain embodiments of the present disclosure, electromagnetic radiation (light energy), such as light energy, at one or more specific wavelengths may be focused into tissue (where the light energy may optionally be pulsed and/or scanned) such that the light energy is selectively absorbed by regions of the tissue containing chromophores. This linear absorption of light energy can result in localized thermionic emission of electrons. With appropriate selection of optical energy parameters and beam geometry, further irradiation of the tissue region may result in further absorption of energy by the emitted electrons, followed by local plasma formation and nonlinear absorption of energy. This process may produce intense heat, localized expansion, stress waves such as intense acoustic or shock waves, and/or chemical reactions due to plasma in the chromophore-containing region of the tissue, while generating relatively little energy absorption and associated tissue damage in the unpigmented region.
Focusing a laser beam generally below the surface of a substance, such as living tissue, is known in the art as a technique for providing a high power density at a focal region, which may be adjusted to a given depth below the surface of the substance, for example, using lenses and/or other optical components. For example, confocal laser microscope imaging of living human skin can provide detailed images of tissue at the depth of the focal plane by scanning the laser beam focus within the tissue.
In exemplary embodiments of the present disclosure, laser-induced plasma may be generated at a focused spot within tissue based in part on the selective absorption of optical energy by chromophores that may be present; the pulsed laser beam may also be scanned or moved to generate a plurality of laser-induced plasmas as the focused spot changes position within the tissue. As noted herein above, thermionic plasma formation requires a threshold level of power and energy density at the site where the chromophore is present. For thermionic plasma formation, a laser focus region within the tissue may be scanned to initiate plasma formation at a depth defined by the laser focus geometry, and such plasma may be selectively formed only at the sites where chromophores are present. In this manner, the focused scanning laser can be used to selectively destroy chromophore sites within a well-defined region (e.g., within one or more focal planes) within the tissue.
Normal skin contains chromophoric melanin in the epidermis and hair follicles, and no chromophoric melanin in the dermis. However, pathological conditions may lead to melanin deposition in the dermis. These conditions include post-inflammatory hyperpigmentation and pigmentation spots. Also not present in the normal dermis but in certain cases also present are exogenous chromophores such as, for example, pigment particles (e.g., pigment particles in tattoo ink). Various precipitates that may be present in the tissue following drug treatment may also act as chromophores. Such precipitates may include, for example, gold, silver, tetracycline, iron, amiodarone, chlorpromazine, and the like. Other chromophores that may be present in biological tissues include, for example, sebaceous glands, subcutaneous fat, hair bulbs, lipids in cell membranes, fat surrounding organs, blood vessels, and certain pharmaceutical compositions.
For certain treatments and conditions, it may be desirable to achieve removal of such chromophore particles in the dermis without substantial damage to the overlying epidermis. Certain exemplary embodiments of the present disclosure may provide methods and devices for such chromophore removal, including: for example, scanning a focused spot or area of pulsed laser in one or more planes within the dermis and beneath the epidermis under conditions that selectively generate thermionic plasma formation at the site of a chromophore within the focal plane and that do not cause such plasma formation within the epidermis of the epidermis. Such plasma formation may also generate local selective damage to dermal tissue by physical and/or chemical mechanisms caused by the plasma formed at the site of chromophores in the dermis.
Indeed, as described herein, the focal region or regions capable of initiating scanning of the near infrared radiation of the thermionic plasma may reach a skin depth of up to about 2mm (2000 μm). The nominal thickness of the epidermis is 0.1mm (except for the usually thicker palms and soles) so that the focal plane of the laser with appropriate electromagnetic, temporal and optical properties can be achieved within the dermis and under the epidermis, enabling the selective formation of a thermo-electronic plasma at and/or near the chromophore sites in the dermis. Biological processes such as fluid transport, lymphatic uptake, phagocytosis, and/or enzymatic lysis may ultimately transport, remove, or lyse the altered chromophore sites from the dermis after causing physical and/or chemical damage to the target chromophore sites in the skin or tissue. Furthermore, biological cells containing or near such chromophores which are irradiated to generate plasma may be damaged, modified or killed, for example by necrosis or apoptosis.
Shorter wavelengths of optical radiation (e.g. towards the violet and ultraviolet ends of the spectrum) tend to be scattered more by inhomogeneous structures of skin tissue than longer wavelengths of optical radiation. Such scattering may result in a reduction in the effective penetration depth of optical energy directed onto the tissue, and also inhibit focusing of the optical energy beam into a small focal region as described herein. In general, the near infrared part of the spectrum (the so-called optical window) is able to penetrate deeper into the tissue, since these longer wavelengths experience less scattering. When dermal melanin is the target chromophore, wavelengths between about 600nm and 1100nm are preferred for efficient penetration into skin tissue and good absorption by melanin. In some embodiments, shorter wavelengths may be used including the ultraviolet, blue, green, and yellow regions of the spectrum. The selection of one or more wavelengths of optical energy may be based on, for example, the desired depth of focus and the type and concentration of chromophores present at one or more depths in the tissue.
The focal zone size/width, quality, and length along the beam axis of the focused laser beam directed into the biological tissue may be determined by factors such as the laser beam divergence, the laser mode structure, the numerical aperture of the beam focusing optics, the aberrations of the focusing optics, the coupling of the beam into the tissue at the tissue surface (e.g., surface reflection and refraction effects), and the optical scattering properties of the tissue.
The "rayleigh range" is a term used to describe the extent or length of the focal region along the optical axis. For example, the rayleigh range may describe the size of the focal region along the depth or z-axis of a light beam directed into skin tissue. The rayleigh range is affected by, for example, the following factors: such as laser source divergence, wavelength of the optical energy, laser mode, original beam diameter before the optical elements converge, and numerical aperture of the focusing system. For example, a highly converging light beam whose outer boundary converges at a relatively large angle (and diverges at a similar angle beyond the focal region) when the light beam reaches the focal region may exhibit a relatively small rayleigh length. A smaller focal convergence angle will result in a larger rayleigh range because the beam converges and diverges slowly with respect to distance along the beam axis. Typically, the rayleigh range is several times larger than the transversely focused spot diameter.
By varying the focusing optical design and/or laser mode structure, a variety of laser focus spots can be produced that can be characterized by geometric parameters such as spot size or width (e.g., characteristic dimension perpendicular to the axis of the beam in the focus region) and rayleigh range (e.g., dimension of the focus region along the longitudinal axis of the beam). The appropriate size of the focal region for selectively initiating plasma (via thermionic emission) in biological tissue may be selected based on factors such as the size of the chromophore as a target, the pulse energy and power of the optical energy source (which will, along with the size of the focal region, affect the local power and energy density), the rayleigh range (which will further affect the range of depths that can be scanned within a volume of tissue over a particular time interval), and the like. For example, dermal pigmentation, whether from melanin, tattoos, or drugs, is typically contained in cells that are themselves about 10 μm in diameter. Thus, for example, in certain embodiments, a spot size/diameter of about this size or larger may be required to irradiate the entire cell to facilitate energy absorption by any chromophores within the cell. In other embodiments, a smaller spot size may be used, for example, if a small area is illuminated or if the scan speed is sufficiently high.
Exemplary embodiments of the present disclosure will now be described in detail, which describe plasma formation in the melanin-rich region of the dermis. Other embodiments of the present disclosure may produce selective plasma formation in other biological tissues, with selectivity being controlled, for example, by other chromophores such as hemoglobin, certain tattoo inks, etc., that may be present in the tissue.
An exemplary schematic side view of a cross section of skin tissue is shown in fig. 1. The skin tissue includes a
In an exemplary embodiment of the present disclosure, a beam of electromagnetic radiation (light energy) 150 (e.g., light energy) may be focused into one or more
In one exemplary embodiment of the present disclosure, a Yb fiber laser with a wavelength of 1060nm may be used to generate the optical energy. In further embodiments, as described herein, sufficient focusing and/or appropriate power and energy density flux may be provided for optical energy having wavelengths between about 600nm and 1100nm to achieve sufficient intensity and selective absorption by chromophores in tissue. As described throughout this specification, certain combinations of optical energy wavelength, local power density or intensity, and local exposure time may be combined to produce desired effects.
In further exemplary embodiments of the present disclosure, a
An
The
In further exemplary embodiments of the present disclosure, the electromagnetic radiation (optical energy) 150 may be focused into one or more
The
The
As shown in fig. 2, the highly focused beam of
Exemplary beam convergence angles of about 70 to 80 degrees are shown in fig. 1 and 2. Typically, the angle of convergence may be about 40 degrees or more, for example even about 90 degrees or more. Such an untightened angle of convergence may generate a large local intensity and flux of
Thus, when the
A larger effective NA value may provide a larger angle of convergence and a correspondingly larger difference in local beam intensity and flux between the
The width (e.g., "spot size") of the
In certain exemplary embodiments, the width of the focal region 160 (e.g., the "spot size") may be less than 50 μm, such as less than 10 μm. The focused spot diameter or spot size can generally be defined as the smallest diameter of an actually focused (e.g., converging) beam that converges upon entering the focal region and diverges upon exiting the focal region. By varying the parameters, components, and configurations of the focusing optical arrangement and/or laser mode structure, a wide variety of laser focusing spot sizes can be produced. The minimum theoretical beam focus spot size can be determined by the number of optical modes present in the laser output and the sum optical diffraction and is referred to as the diffraction limited focus spot size. Typically, the minimum spot size is several times the wavelength of the corresponding light. For example, using a 1060nm single mode fiber laser (which has good focusing properties), the diffraction limited focused spot diameter of the optical system focused into the dermis will be less than about 5 μm. In practice, effects such as optical scattering in the tissue and aberrations of the optical components may produce focused spots larger than this diffraction limited minimum.
The dermal pigmentation, such as melanin, tattoo ink, or a pharmaceutical composition, is typically contained within cells that are themselves about 10 μm in diameter. Depending on the desired result and the laser/optics used, the laser focal spot diameter may be larger or smaller than the diameter of such target cells. Lasers with lower power outputs can be focused to relatively small sizes to achieve sufficient energy and power density. Alternatively, a higher power laser may thermionically ignite a plasma with a relatively larger spot size. Such a larger spot size may, for example, scan a given area or volume of tissue in a shorter time to selectively generate plasma at chromophore sites in the volume of tissue.
For example, the theoretical lower limit of the spot size may be approximately 1.22 λ/NA, where λ is the wavelength of the electromagnetic radiation and NA is the numerical aperture of the lens. For a wavelength of about 1060nm and an NA of 0.5, the theoretical minimum spot size is about 2.6 microns. The actual spot size (or width of the focal region 160) may be selected to be small enough to provide a sufficiently high power density or density of optical energy 150 (sufficient to induce thermionic emission and subsequently generate a plasma) in the
For a particular exemplary NA value of the focusing
In further exemplary embodiments of the present disclosure, a plurality of such
In certain exemplary embodiments for selectively generating plasma in skin tissue exhibiting dermal pigmented spots, the depth of the
In various exemplary embodiments of the present disclosure, the
For example, the position and/or angle of the
Exemplary adjustments and/or alterations to the geometry and/or path of the
In further exemplary embodiments, the
In one embodiment of the present disclosure, the
Each microlens may have a large NA (e.g., between about 0.5 and 0.9) such that the
The
In additional embodiments of the present disclosure, the
In still other exemplary embodiments of the present disclosure, the
The width of the
In certain exemplary embodiments of the present disclosure, any exemplary array of
In further exemplary embodiments of the present disclosure, the
According to still further exemplary embodiments of the present disclosure, the
In yet another exemplary embodiment of the present disclosure, some of the cylindrical or
In an exemplary embodiment, the
In another exemplary embodiment of the present disclosure, the
The window or contact surface 240 (if present) can be configured and/or constructed to contact the
The
In exemplary embodiments of the present disclosure, the
An index coupling fluid or gel may be used to reduce optical losses and aberrations when the laser beam passes from the optical focusing device into the tissue. For example, the refractive index of human skin in the optical region of 600nm to 1100nm is about 1.5, and the human skin surface is rough, so that the light beam meets the skin at a range of local incidence angles. Air has a refractive index of 1.0 and thus reflection and refraction are high. By applying a fluid or gel material with a refractive index close to that of the skin, losses and aberrations are smaller. For example, In "In vivo confocal scanning laser of human skin: mammalian videos strand contract concentrate" of M.Rajadhyaksha et al,J Invest Dermatol.,104(6), pages 946 to 952 (6 months 1995) describe similar situations and solutions in connection with the use of focused laser light for skin reflection confocal microscopy.
According to certain exemplary embodiments of the present disclosure, the
The
For example, the
The limitation of the illumination time (dwell time) at a specific focal zone position can be achieved in various ways. In one exemplary embodiment, the
In further exemplary embodiments of the present disclosure, the focused
The average scan speed (or range of speeds) may be determined based on the general exemplary guidelines described herein. For example, for a particular spot size (which may be primarily determined by the properties of the optical arrangement), the local dwell (illumination) time may be estimated as the spot size/width divided by the translation speed. As noted herein, such dwell times are preferably less than about 1 to 2 milliseconds to avoid undesirable thermal damage and localized heat buildup to uncolored tissue. Therefore, the minimum scan speed can be estimated as the width of the
For a pulsed laser source, the scan speed may be selected based at least in part on the pulse energy and repetition rate such that the total energy deposited into the target region may be controlled. For a pulsed laser source, the local dwell time will correspond to the pulse duration if the scan rate is low enough compared to the pulse duration that the focal region does not move significantly during the pulse (e.g., the focal region moves only a small portion of its width, such as half the spot width or less). For example, with a pulse duration of 100ns, a repetition rate of 50kHz, and a scan speed of 200mm/s, one energy pulse is deposited every 4 microns along the scan path, and the focal zone moves only about.02 microns during the pulse. Furthermore, such scanning speeds and pulse repetition rates will result in approximately 2 to 3 energy pulses to be expected to be received by a 10 μm cell, each pulse having a local dwell time of 100 ns.
The power output of the
Based on some experimental observations, for
A typical scan speed of a handpiece that is manually translated over the area of skin to be treated may be on the order of about 5 mm/sec to about 5 cm/sec, for example. Such a speed corresponds to a distance of 5cm (about 2 inches) in about 1 to 10 seconds. Thus, for a handpiece that is manually translated across the skin to illuminate a portion of the dermis as described herein, the power output and focusing geometry of the
Such an exemplary power calculation may be based on the entire output of a laser diode focused into one focal region. If the output from a single optical energy source is focused onto multiple focal regions (e.g., in the case of using a wide beam or optical splitter directed onto multiple microlenses), the power output of that optical energy source should be multiplied by the number of
In certain exemplary embodiments of the present disclosure, the
The
As described herein, once one or more of the exemplary parameters of the
In still other exemplary embodiments, two consecutive pulses may be used to selectively form a plasma at or near a chromophore as described herein. For example, a laser with modulated laser intensity may be used, or two or more lasers with different parameters and focused to the same region may be used to selectively induce thermionic emission at a chromophore under a first set of local energy conditions, and then "pump out" the thermionic electrons under a second set of local energy conditions to produce a local plasma. The absorptive heating of melanin is a linear process, while pumping out thermionic electron avalanches to form and sustain a plasma is a nonlinear process. The thermal relaxation time of melanosomes (i.e. the main structure with which biological melanin is essentially associated) is a few hundred nanoseconds. As described in certain embodiments herein, the laser used to selectively generate plasma in tissue may have a pulse duration on the order of about 100ns less than the thermal relaxation time of melanosomes. These timescales allow for efficient heating of the melanosome to induce emission of hot electrons, but operate at much higher short femtosecond and picosecond ranges than associated with dielectric breakdown. The thermal relaxation time of the stained cells is much longer, about 10 to 100. mu.s.
Thus, based on the principles described herein, laser pulses having a duration on the order of, for example, 10 μ s may be used to selectively heat the stained cells to release some electrons via thermionic emission. As described herein, a second pulse of optical energy having appropriate parameters including a pulse duration on the order of about 100ns may thus be focused to illuminate the same stained cell and "pump out" the released electrons before they relax and rejoin the locally ionized atoms or molecules, thereby forming a plasma at the stained cell. Other pigmented targets located in the tissue, possibly outside the cells, may also be irradiated to promote selective absorption of energy and plasma generation.
In further exemplary embodiments of the present disclosure, a method for selectively generating plasma in a colored region of a biological tissue may be provided. The exemplary method may include:
Example 1
Animal studies using an exemplary point-focused laser apparatus and model system were used to test the efficacy of selective plasma formation in skin tissue using optical radiation. This study was performed on female yucatan pigs as described below.
First, the deep pigmented macules condition was simulated by tattooing the dermis using melanin-based ink. Ink was prepared by mixing the synthesized melanin at a concentration of 20mg/mL in a 50:50 saline/glycerol solution. The resulting suspension was then stirred before being injected into approximately 1 "x 1" test sites on animal subjects using a standard tattoo gun at a depth ranging from about 200 μm to 400 μm. Ink was used to provide a dark black tattoo frame for each test site to facilitate identification of each test site.
An exemplary pigmented plaque treatment system was constructed based on the exemplary embodiments of the present disclosure described herein, which included a Q-switched 1060nm Yb-fiber laser with an average power of up to 10W, operating at a pulse rate between 20kHz and 100kHz and a pulse duration of 100 ns. The laser is mounted on an x-y scanning platform. The measured focused spot size was about 4 μm. The collimated output of the fibre laser is focussed with an effective focal length of 8mm and a Numerical Aperture (NA) of 0.5.
A table of exemplary scan parameters for establishing the selective formation of plasma in biological tissue is shown in table 1 below. The laser power is 2W or 4W, the grating linear velocity of the focusing spot is between 50mm/s and 800mm/s, and the spacing between adjacent grating scan lines (which determines the overall coverage per plane) ranges between 0.0125mm and 0.05 mm. These parameter ranges are selected to cover the range in which some parameter sets generate plasma (as evidenced by visible white sparks and audible popping sounds) while other parameter sets do not. In general, at these power levels, no plasma formation was observed at scan rates of about 400mm/s or greater.
The energy and scan parameters shown in table 1 represent exemplary test parameters for evaluating the function of prototype devices described herein and improving the approximate parameter combinations for further study. For these power levels of 2 watts and 4 watts, plasma formation was observed at scan speeds less than about 100mm/s, while higher scan speeds generally did not result in the observed plasma formation.
Exemplary system parameters and procedures for producing a visible effect in biological tissue are as follows: the laser beam was scanned at a speed of 200mm/s using a scanner over a 1cm x 1cm area within the test site of each melanin tattoo, which was prone to significant plasma formation. Different test scans were run using laser power outputs of 1W, 2W, 3W, 4W and 10W. Scanning multiple depths in each test site, wherein the beam focal region is scanned in a raster scan pattern at a single depth of focus, followed by varying the depth of focus and repeating the raster scan pattern. Most test treatments were performed at a 50kHz pulse repetition rate, and some tests were performed at 20kHz for comparison. A schematic diagram of the scanning pattern used for 3 separate depths is shown in fig. 4.
The distance between successive focal depth planes is about 50 μm and provides a "dwell" interval of about 4 to 5 minutes between the raster scans of the region at each focal depth to allow tissue cooling. Between successive scans of different depths, wiping alcohol was sprayed onto the treatment area and massaged to help dissipate the white cavitation observed when the laser interacted with the tissue layer containing melanin. Without such alcohol wiping, it was observed that the white film took a considerable amount of time to self-dissipate (e.g., about 10 to 15 minutes compared to about 4 to 5 minutes for wiping with alcohol).
Exemplary results of exemplary treatments of melanin tattoo test sites according to exemplary embodiments of the present disclosure are shown in fig. 5. The Yb-fiber laser was set to average a power output of 2W, and the pulse repetition rate was 50kHz and the scan rate was 200 mm/s. The distance between adjacent grating lines is 12.5 μm and 6 different depths in the range of 300 μm to 550 μm are illuminated at 50 μm intervals.
For example, image 510 provided in FIG. 5 shows the test site just prior to scanning with the laser device, and image 512 shows the test site just after scanning is completed. Images 514, 516, 518 and 520 show the appearance of the test sites at 2 hours, 1 day, 1 week and 4 weeks post irradiation treatment, respectively. The illuminated area was observed to brighten immediately after treatment and persisted after 4 weeks.
Table 1: exemplary parameters for raster scanning the focal area of the optical energy beam at each constant depth plane within the test area. A rectangular raster pattern is shown in fig. 4.
Example 2
Fig. 6 shows additional scanned melanin tattoo test sites irradiated at different times with 1W of fiber laser output using the general scanning parameters described above (e.g., scan rate of 200mm/s, repetition rate of 50kHz and six (6) consecutive scan layer depths of 550 μm, 500 μm, 450 μm, 400 μm, 350 μm, and 300 μm, and distance between adjacent scan lines in each plane of 25 μm), according to additional embodiments of the present disclosure. An
Example 3
Fig. 7A and 7B show images of a test site of a melanin tattoo scanned twice during two treatment sessions spaced two weeks apart. Both treatments used a fiber laser with an average power output of 6W and a pulse repetition rate of 20 kHz. The first scan session targets a shallower layer (300 μm to 550 μm) and the second scan session targets a deeper layer (550 μm to 850 μm).
In particular, fig. 7A shows an exemplary result of a first scan irradiation treatment.
Example 4
A more direct skin whitening effect is observed at higher power output. For example, the tattoo test site was scanned at a fiber laser power output of 10W, with the other scan parameters matching the scan parameters used to obtain the results shown in FIGS. 7A and 7B. Whitening of the scanned area at the center of the tattooed area was observed immediately after the scanning process, as shown in fig. 8A. The plasma observed at this higher power level is more intense, indicating a correlation between (peak) power level and plasma intensity where plasma is selectively generated in tissue.
The general guidelines for selectively generating plasma at the site of melanin chromophores can be estimated from the various test scans performed. For example, in the case of a spot size of 4 μm, an average fiber laser power output of 4W, a pulse duration of 100ns, and a repetition rate of 50kHz (as shown in FIG. 5, which produces a visible plasma effect and may have some skin whitening at a later time), the local peak power density may be calculated to be about 6.37 × 109W/cm2And the peak power is about 800W.
At the higher end of the applied power density (e.g., average power of 10W and repetition rate of 20kHz, corresponding to the case of FIG. 8A), the peak power density is about 3.98 × 1010W/cm2And the corresponding peak power is about 5 kW. These higher power levels result in more direct tissue whitening and a stronger visible plasma.
For the scan speed used (typically 200mm/s), the pulse duration of 100ns is short enough that the focused spot does not move more than a few nanometers before the off pulse. At a scan speed of 200mm/s, each 10mm scan line takes 0.05 seconds to complete. At a pulse rate of 50kHz, there are 2500 pulses per scan line, so that the distance between successive pulses is about 4 μm. Because the spot width used is 4 μm and the distance between the centers of adjacent pulses along a scan line is also 4 μm, this set of scan parameters generates a substantially continuous train of pulses (e.g., consecutive scan lines with little overlap) that just touch each other. Thus, for melanocyte phagocytosis (melanophage) or other chromophore sites of about 10 μm in diameter or width, each melanocyte phagocytosis will be subjected to about 2 to 3 pulses. With an exemplary pulse duration of 100ns, the total local residence (exposure) time for such melanocytes is about 250 ns.
Example 5
FIG. 8B shows a set of images of a pig skin test site scanned with a laser beam having a scan rate of 200mm/s along a scan line, a repetition rate of 20kHz, a wavelength of about 1060nm, a pulse duration of about 100 nanoseconds, and an output power of 8W. The distance between adjacent scan lines is about 25 μm. The focal area of the laser beam is approximately at the surface of the natural skin.
Example 6
Fig. 8C shows an exemplary image of a biopsy taken from a native skin test site taken by an Electron Microscope (EM) described in example 5 and shown in fig. 8B. Destroyed cells 820 and unaltered cells 830 can be observed. The destroyed cell 820 contains melanin and the destruction is believed to be caused by laser beam therapy. Unaltered cells 830 are located near about 5 microns from destroyed cells 820. Unaltered cells 830 typically do not contain melanin and are believed to remain viable after treatment.
Example 7
Fig. 9 illustrates a cross-sectional view of a
The optical element 914 may be selected based on the spectral composition of the laser beam 912 and the emitted radiation 913. For example, exemplary properties of optical element 914 can be selected to substantially reflect a spectral component of laser beam 912 and substantially transmit a spectral component of emitted radiation 913. In an exemplary embodiment, the laser beam 912 may include a wavelength of 1060 nm. The corresponding optical element 914 used was a Thorlabs NB1-K14 Nd: YAG mirror, which reflects wavelengths ranging from about 1047nm to about 1064 nm. The reflected portion of the laser beam 912 is imaged and focused by the focusing arrangement 916. The diffractive limit aspheric lens used in this
Radiation 913 emitted from the plasma generated in the tissue 918 at the focal region 920 may be imaged by the focusing arrangement 916 and transmitted by the optical element 914 to impinge on a first end of an optical fiber (not shown) through a fiber coupler 922. The fiber couplers used in the
The tissue sample 918 may be mounted on a motorized stage that is capable of independent movement along the x-axis, y-axis, and z-axis. With such exemplary movement, the motorized stage may place a particular portion of the tissue sample 918 into a focal region 920 of the focused laser beam 912. For example, the working distance between the tissue sample 918 and the focusing optics 916 can be varied (e.g., varied along the z-axis) to control the depth of the focal region 920 of the laser beam 912 within the tissue sample 918. The motorized stage also moves in the x-y plane and can move certain portions of the tissue sample 918 (e.g., portions including target chromophores) into the focal region 920.
Fig. 10A shows an exemplary graph of an intensity spectrum detected by the spectrometer of the
The horizontal axis set in fig. 10A represents the wavelength (in nanometers) of the detected radiation. The vertical axis represents the intensity of the radiation detected at each wavelength. In fig. 10A, there are two spectra, a
The operating parameters of
Fig. 10B shows a photomicrograph image of a cross-section of a tissue sample containing a melanin tattoo that was illuminated to obtain
Example 8
Fig. 11 shows an exemplary plot of additional intensity spectra detected by the spectrometer of the
The horizontal axis set in fig. 11 represents the wavelength (in nanometers) of the detected radiation. The vertical axis represents the intensity of the radiation detected at each corresponding wavelength. Two spectra are shown in fig. 11: a
The operating parameters of the
Example 9
Fig. 12 shows exemplary images of an exemplary test site at various stages of treatment using the
The
Example 10
Fig. 13 shows exemplary images of an exemplary test site at various stages of treatment by the
The exemplary parameters and calculations described in the examples herein and other portions of the present disclosure may be used to determine other parameter combinations that may also generate selective plasma formation at chromophore sites using conventional geometry-to-energy relationships. For example, the amount of energy delivered to each location in the tissue can be reduced by half by doubling the scan speed or by reducing the average laser power output by half. However, faster scan speeds reduce the local dwell (exposure) time by half, while reducing the average laser output power does not affect the dwell time. Doubling the spot size/diameter (all other laser parameters remain fixed) will reduce the local power and energy density by a factor of four. Such a larger spot size (at a fixed scanning speed) will also double the local dwell time at a location in the tissue, since a wider spot will take twice as long to pass a particular point in the tissue.
Thus, additional combinations of pulse durations, power outputs, pulse frequencies, scan rates, focused spot sizes, etc., that cause selective plasma formation can be readily estimated as one or more parameters vary within the exemplary set of values presented herein. Parameters that should be kept close to the parameters presented here to achieve a similar effect in tissue include local power and energy density and local dwell time. Further variations in such parameters may also be estimated to account for changes in other factors such as different wavelengths or other chromophores, for example by accounting for changes in the energy absorption efficiency of the chromophores, and so forth.
Furthermore, although the examples herein are described primarily with respect to selective plasma formation at chromophore sites in biological tissue, such as skin, similar principles may be applied to selectively generate plasma in other irradiated tissue (e.g., brain tissue, etc.) and in other substances (e.g., non-biological substances having relatively weak absorption coefficients and containing regions of highly absorbing chromophores).
The foregoing merely illustrates the principles of the disclosure. Various modifications and alterations to the described embodiments will be apparent to those skilled in the art in view of the teachings herein. It will thus be appreciated that those skilled in the art will be able to devise numerous techniques which, although not explicitly described herein, embody the principles of the disclosure and are thus within its spirit and scope. All patents and publications cited herein are incorporated by reference in their entirety.