Photo-thermal targeted therapy and safety systems for efficacy, consistency and pain minimization and associated methods

Abstract

A method for determining parameters of a light source for operating within a photo-thermal targeted therapy system for calibrating chromophores embedded in a medium includes: 1) applying a laser pulse to a location to be treated at a preset power level below a known pain and injury threshold; 2) measuring the skin surface temperature at the position; 3) performing correlation fitting on the relationship between the light source parameter and the skin surface temperature at the position; 4) defining a safe operation range of the light source parameters so as to avoid pain and thermal injury at the position; 5) maintaining the skin surface temperature to be lower than the known pain and injury threshold, and increasing the peak temperature and the thermal gradient depth; and 6) applying a higher level laser pulse to raise the temperature of the target chromophore to its desired damage temperature.

Description

[0001] Reference to Related Applications

[0002] This application claims benefit of U.S. Provisional Application No. 63 / 451,991, filed March 14, 2023, and titled “Photo-Thermal Targeted Treatment System and Associated Methods for Efficacy, Consistency, and Pain Minimization.” This application is a continuation-in-part of co-pending U.S. Patent Application No. 17 / 735,056, filed May 3, 2022, and titled “Determination Process and Predictive Closed-Loop Control of Dosimetry Using Measurement of Skin Surface Temperature and Associated Methods.” The above-identified application is in turn a continuation of U.S. Patent Application No. 16 / 658,818, filed October 21, 2019, and titled “Dosimetry Determination Process via Measurement of Skin Surface Temperature and Associated Methods,” now U.S. Patent No. 11,317,969, which claims benefit of U.S. Provisional Patent Application No. 62 / 749,104, filed October 22, 2018, and titled “Dosimetry Determination Process via Measurement of Skin Surface Temperature and Associated Methods,” and U.S. Provisional Patent Application No. 62 / 771,523, filed November 26, 2018, and titled “Predictive Closed-Loop Control of Dosimetry Using Measurement of Skin Surface Temperature and Associated Methods.” The entire contents of all of the above-cited applications are incorporated herein by reference. TECHNICAL FIELD

[0003] The present disclosure relates to photothermal targeted therapy systems, and more particularly, to systems and methods for controlling the safe operation of photothermal targeted therapy systems to achieve improved efficacy, consistency, and pain minimization in the aspect of light-induced thermal treatment targeting specific chromophores embedded in a medium. BACKGROUND

[0004] Chromophores embedded in a medium, such as the dermis, can be thermally damaged by heating the chromophores with a targeted light source, such as a laser. However, applying sufficient thermal energy to damage the chromophores also damages the surrounding dermis and overlying epidermis, thus resulting in epidermal and dermal damage and subject pain. This problem also applies to targets such as sebaceous glands, where the chromophore, such as sebum, is used to heat the target to a high enough temperature to cause damage to the target.

[0005] Prior methods to prevent epidermal and dermal damage and subject pain include:

[0006] 1. Pre-cooling the epidermis followed by application of photothermal treatment; and

[0007] 2. Pre-cooling the epidermis, also pre-conditioning (i.e., pre-heating) the epidermis and dermis in a pre-heating regimen, followed by application of photothermal treatment in a different treatment regimen. In certain instances, the pre-heating regimen and treatment regimen are performed by the same laser, although the two regimens involve different laser settings and application regimens, thus resulting in further complexity of the treatment regimen and equipment.

[0008] More recent methods have involved, for example, dose determination determination using measurements of skin surface temperature and predictive closed-loop control, as discussed in the related disclosures mentioned above. Additionally, such photothermal treatment systems have shifted to providing more effective and consistent treatment results while considering patient comfort.

[0009] Accordingly, there is a need for an improved photothermal targeted therapy system and method for providing effective, consistent treatment results during a treatment procedure, and minimizing the pain experienced by the patient. SUMMARY

[0010] The following presents a simplified summary relating to one or more aspects and / or embodiments disclosed herein. As such, the following summary should not be considered an extensive overview relating to all considered aspects and / or embodiments, nor be regarded to identify key or critical elements relating to all considered aspects and / or embodiments, or to delineate the scope associated with any specific aspect and / or embodiment. The sole purpose of the following summary is to present some concepts relating to one or more aspects and / or embodiments disclosed herein in a simplified form to precede the detailed description presented below.

[0011] According to embodiments described herein, a method for determining a suitable set of parameters for operating a light source within a photothermal targeting therapy system for labeling chromophores embedded in a medium is disclosed. The method comprises, prior to administering a treatment regimen to a first subject, 1) administering at least one laser pulse to a first treatment location at a preset power level, wherein the preset power level is below a known damage threshold. The method also comprises 2) measuring a skin surface temperature at the first treatment location after administering the at least one laser pulse. The method further comprises 3) estimating a relationship between the parameters for operating the light source and the skin surface temperature at the first treatment location, and 4) defining a safe operating range of the parameters for operating the light source so as to avoid thermal damage to the medium at the first treatment location while still effectively labeling the chromophores when administering the treatment regimen.

[0012] In embodiments, steps 1) to 4) are repeated at a second treatment location on the first subject prior to administering the treatment regimen at the second treatment location. In another embodiment, steps 1) to 4) are repeated at the first treatment location on a second subject prior to administering the treatment regimen to the second subject. In yet another embodiment, the method further comprises 5) storing in a memory of the photothermal targeting therapy system the safe operating range of the parameters for operating the light source at the first treatment location on the first subject, and 6) considering the parameters so stored in the memory when later administering the treatment regimen to the first subject.

[0013] In another embodiment, a photothermal targeting therapy system for labeling chromophores embedded in a medium is disclosed. The system comprises a light source configured to provide laser pulses within a range of power levels when operated with a set of parameters, the range of power levels including a known damage threshold of the chromophores and a treatment location. The system also comprises a temperature measuring device for measuring a skin surface temperature at the treatment location, and a controller for controlling the light source and the temperature measuring device. The controller is configured for estimating a relationship between the parameters of the light source and the skin surface temperature at the treatment location, defining a safe operating range of the set of parameters of the light source so as to avoid thermal damage to the medium at the treatment location while still effectively labeling the chromophores when administering a treatment regimen, and setting the light source to administer the laser pulses within the safe operating range.

[0014] In yet another embodiment, a method for adjusting a suitable set of parameters for operating a light source within a photothermal targeting therapy system for targeting a chromophore embedded in a medium is disclosed during administration of a treatment regimen to a first subject at a first treatment location. The method comprises: 1) measuring a skin surface temperature at the first treatment location at least once; 2) predicting a skin temperature while administering the treatment regimen to the first subject at the first treatment location; and 3) adjusting at least one of the parameters for operating the light source so that a future measurement of the skin surface temperature at the first treatment location will not exceed a specified value. Predicting a skin temperature considers at least one of a heat transfer model and a series of experimental results.

[0015] In another embodiment, a method for determining a suitable set of parameters for operating a light source within a photothermal targeting therapy system for targeting a chromophore embedded in a medium is disclosed. The method comprises:

[0016] 1) administering at least one laser pulse from the light source to a to-be-treated location at a pre-set power level, the pre-set power level being below a known pain and damage threshold;

[0017] 2) measuring a skin surface temperature at the to-be-treated location;

[0018] 3) correlation fitting a relationship between the parameters for operating the light source and the skin surface temperature of the to-be-treated location;

[0019] 4) defining a safe operating range of the parameters operating the light source in order to avoid pain and thermal damage of the medium of the to-be-treated location;

[0020] 5) maintaining the skin surface temperature below the known pain and damage threshold while increasing a peak temperature and a depth of a thermal gradient until a correct depth; and

[0021] 6) administering at least one higher level laser pulse from the light source above the known pain threshold and below the damage threshold to raise a temperature of the target chromophore to its required damage temperature, effectively targeting the chromophore while administering a treatment regimen.

[0022] In yet another embodiment, a method for determining a suitable set of parameters for operating a light source within a photothermal targeting therapy system for targeting a chromophore embedded in a medium is disclosed. The method comprises, prior to administering a treatment regimen to a first subject:

[0023] 1) cooling a first treatment location, wherein the cooling comprises directing an airflow over the first treatment location;

[0024] 2) applying at least one laser pulse from the light source to the first treatment location on the first subject at a pre-set power level, the pre-set power level being below a known pain and damage threshold;

[0025] 3) measuring the skin surface temperature at the first treatment location after applying the at least one laser pulse;

[0026] 4) estimating a relationship between the parameters for operating the light source, post-pulse cooling, and the skin surface temperature at the first treatment location by fitting the skin surface temperature and the parameters for operating the light source using data correlation, wherein a priori knowledge of the correlation from clinical experiments is used to establish predictive parameters using computational analysis;

[0027] 5) defining a safe operating range of the parameters for operating the light source so as to remain below the pain threshold of the medium at the first treatment location while still effectively targeting the chromophore in applying the treatment regimen, wherein the safe operating range corresponds to the skin surface temperature between about 28°C and 34°C;

[0028] 6) measuring the skin surface temperature at the first treatment location at least once during the treatment regimen;

[0029] 7) adjusting the safe operating range of the parameters of the light source at the first treatment location, maintaining the skin surface temperature below the known pain threshold while simultaneously increasing the peak temperature and depth of thermal gradient until at the correct depth, wherein the estimating, defining, measuring, and adjusting are continually updated during treatment; and

[0030] 8) applying at least one higher level laser pulse from the light source above the known pain threshold and below the damage threshold to raise the temperature of the target chromophore to its required damage temperature, effectively targeting the chromophore in applying the treatment regimen.

[0031] In another embodiment, a method of treating a subject using a photothermal targeting treatment system comprising a light source for targeting a chromophore embedded in a medium is disclosed. The method comprises:

[0032] a) cooling a first treatment location of the subject from a first surface temperature to a second surface temperature;

[0033] b) applying a laser pulse from the light source to the first treatment location;

[0034] c) tracking the skin surface temperature at the first treatment location during application of the laser pulse using an infrared camera operating at a refresh rate of 25 Hz to 400 Hz; and

[0035] d) terminating the treatment regimen based at least in part on the skin surface temperature thus measured.

[0036] In another embodiment, a photothermal targeting therapy system for calibrating a chromophore embedded in a medium is disclosed. The system comprises a cooling unit for providing cooling at a treatment location, a light source for providing laser pulses at the treatment location, a temperature monitoring unit for monitoring a skin surface temperature at the location, and a controller for receiving the skin surface temperature as monitored by the temperature monitoring unit and accordingly controlling operating parameters of the cooling unit and the light source. In embodiments, the controller is configured for directing the light source to administer at least one laser pulse to the treatment location at a preset power level, the preset power level being below a known pain and damage threshold, directing the temperature monitoring unit to measure a skin surface temperature at the treatment location, performing a correlation fit between the operating parameters of the light source and the skin surface temperature thus measured, defining a safe operating range of the operating parameters of the light source so as to avoid pain and thermal damage to the medium at the treatment location, modifying the operating parameters of at least one of the cooling unit and the light source to administer at least one higher level laser pulse from the light source to maintain the skin surface temperature below the known pain and damage threshold while at the same time increasing a peak temperature and a depth of a thermal gradient until the peak temperature and the depth of the thermal gradient reach a desired depth within the medium at the treatment location, and directing the light source to administer at least one treatment laser pulse from the light source at a power higher than the at least one initial laser pulse to raise a temperature of the target chromophore to its required damage temperature.

[0037] These and other features and characteristics of the present technology, as well as the methods of operation and functions of the related elements of structures and the combination of parts and economies of manufacture, will become more apparent upon consideration of the following description and appended claims with reference to the accompanying drawings, all of which form a part of this specification, wherein like reference numerals designate corresponding parts in the various figures. It is to be expressly understood, however, that the drawings are for purposes of illustration and description only and are not intended as a definition of the limits of the application. As used in the specification and in the claims, the singular form of "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. BRIEF DESCRIPTION OF DRAWINGS

[0038] Figure 1 An exemplary photothermal targeting therapy system according to an embodiment is illustrated.

[0039] Figure 2 An exemplary scanner arrangement for use with a photothermal targeting therapy system according to an embodiment is illustrated.

[0040] Figure 3 A graph showing a set of exemplary light pulses suitable for use as an integrated pre-conditioning / light treatment regimen according to an embodiment.

[0041] Figure 4 A graph showing measured temperatures at a skin surface as a function of time according to an embodiment as treatment light pulses are applied to the skin surface.

[0042] Figure 5 A flowchart showing an exemplary process for analyzing measured skin surface temperatures, predicting temperatures of the skin upon application of subsequent laser pulses and / or additional cooling, then modifying a treatment regimen accordingly according to an embodiment.

[0043] Figure 6 Measured skin surface temperatures at various applied laser pulse powers at similar treatment areas of two different individuals according to an embodiment.

[0044] Figure 7 A flowchart showing an exemplary process for closed loop control of laser system parameters based on real-time skin surface temperature measurements according to an embodiment.

[0045] Figure 8 Measured skin surface temperatures resulting from the application of four pulses to a treatment area used as data for predicting the skin temperature rise of a subject upon application of subsequent pulses according to an embodiment, along with resulting curve fits and actual temperature measurements.

[0046] Figure 9 Is a graph showing temperature increase as a function of depth immediately after each of a sequence of laser pulses according to an embodiment.

[0047] Figure 10 Is a graph showing a thermal gradient (TG) profile just prior to a subsequent consecutive laser pulse according to an embodiment.

[0048] Figure 11 Is a graph showing a TG profile immediately after each consecutive laser pulse is applied according to an embodiment.

[0049] Figure 12 Is a graph showing temperature as a function of depth after each consecutive laser pulse is applied in a standard 6-pulse regimen according to an embodiment.

[0050] Figure 13 Is a bar graph showing an alternative laser pulse regimen according to an embodiment.

[0051] Figure 14 Is a graph showing a TG profile immediately after each consecutive laser pulse is applied based on an alternative laser pulse regimen according to an embodiment.

[0052] Figure 15 is a simplified plot showing the temperature profile of the dermis and skin surface temperature as a function of time when a desired thermal gradient profile is achieved and maintained using a continuous wave (CW) laser in accordance with an embodiment.

[0053] Figure 16 is a simplified plot showing the TG profile corresponding to the CW laser application of Figure 15 in accordance with an embodiment.

[0054] The accompanying drawings are included to provide a description of the general architecture of the application. Descriptions and details of well-known features and techniques can be omitted to avoid unnecessarily obscuring the embodiments described herein. Additionally, elements in the drawings can not be to scale. For example, the dimensions of some of the elements in the drawings can be exaggerated relative to other elements to help improve understanding of the described embodiments. The same reference numbers in different drawings can identify the same or similar elements.

[0055] The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments. In the following detailed description of embodiments, reference is made to the accompanying drawings, which form a part hereof, and in which are shown by way of illustration specific embodiments in which the application can be practiced. These aspects can be combined, other aspects can be utilized, and structural changes can be made without departing from the scope of the present disclosure. The example aspects can be practiced as methods, systems, or devices. Accordingly, the following detailed description is not to be taken in a limiting sense, and the scope of the present disclosure is defined by the appended claims and their equivalents. DETAILED DESCRIPTION

[0056] The present application is more fully described in the following reference to the drawings, in which embodiments of the application are shown. The application may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In fact, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the application to those skilled in the art. In the drawings, the size and relative sizes of layers and regions can be exaggerated for clarity. Like numbers refer to like elements throughout.

[0057] It is to be understood that although the terms first, second, third, etc. can be used herein to describe various elements, components, regions, layers and / or sections, these elements, components, regions, layers and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the present application.

[0058] Spatially relative terms, such as "beneath", "below", "lower", "under", "above", "upper" and the like, can be used herein for ease of description to describe one element or feature's relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as "below" or "beneath" other elements or features would then be oriented "above" the other elements or features. Thus, the exemplary term "below" can encompass both an orientation of above and below. The devices can be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. It will also be understood that when a layer is referred to as being "between" two layers, it can be the only layer between the two layers or one or more intervening layers can also be present.

[0059] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present disclosure. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and / or "comprising", when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. As used herein the term "and / or" includes any and all combinations of one or more of the associated listed items and can be abbreviated as " / ".

[0060] It will be understood that when an element or layer is referred to as being "on", "connected to", "coupled to" or "adjacent to" another element or layer, it can be directly on, connected, coupled or adjacent the other element or layer, or one or more intervening elements or layers can also be present. In contrast, when an element is referred to as being "directly on", "directly connected to", "directly coupled to", or "immediately adjacent to" another element or layer, there are no intervening elements or layers present. Likewise, when light is "received from" or "provided to" an element, it can be received from or provided to the element directly or from or to intervening elements. On the other hand, when light is "received directly from" or "provided directly to" an element, there are no intervening elements present.

[0061] Embodiments of the present application are described herein with reference to cross-section illustrations that are schematic illustrations of idealized embodiments (and intermediate structures) of the present application. As such, variations from the shapes of the illustrations as a result, for example, of manufacturing techniques and / or tolerances, are to be expected. Thus, embodiments of the present application should not be construed as limited to the particular shapes of regions illustrated herein but are to include deviations in shapes that result, for example, from manufacturing. For example, an implanted region illustrated or described as a rectangle will, typically, have rounded or curved features. Thus, the regions illustrated in the figures are schematic and their shapes are not intended to illustrate the precise shape of a region that would be formed by a method being described but are meant to be an exemplification of a region that could be formed.

[0062] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0063] Figure 1 An exemplary photothermal targeted therapy system is shown for targeting a target that includes a specific chromophore embedded in a medium and heating the target to a sufficiently high temperature to damage the target without damaging the surrounding medium. The system can be used, for example, to perform photothermal ablation of sebaceous glands in a targeted manner, where the sebum is the chromophore embedded within the sebaceous glands, while not damaging the epidermis and dermis surrounding the target sebaceous glands.

[0064] Still referring to Figure 1 , the photothermal targeted therapy system 100 includes a cooling unit 110 and a light therapy unit 120. The cooling unit 110 provides a cooling mechanism, such as by contact or by direct air cooling, that provides a cooling effect to a treatment area, i.e., an outer skin layer area that covers the target sebaceous glands. The cooling unit 110 is connected with a controller 122 within the light therapy unit 120. It should be noted that while the controller 122 is shown as housed within the light therapy unit 120 in Figure 1 , the controller can be located externally to both the cooling unit 110 and the light therapy unit 122, or even within the cooling unit 110.

[0065] The controller 122 further controls other components within the light treatment unit 120, such as the laser 124, a display 126, a temperature monitoring unit, a footswitch 130, a door interlock 132, and an emergency on-off switch. The laser 124 provides the laser power for the light treatment regimen, and the controller 122 adjusts the specific settings of the laser, such as the output power and pulse time settings. The laser 124 can be a single laser or a combination of two or more lasers. If more than one laser is used, the laser outputs are optically combined to act as one more powerful laser. The display 126 can include information such as the operating conditions of the cooling unit 110, the laser 124, and other system status. For example, the temperature monitoring unit 128 is used to monitor the temperature of the skin surface in the treatment area, and the measured skin surface temperature at the treatment area is used by the controller 122 to adjust the light treatment regimen. The controller 122 also interfaces with the footswitch 130 for remotely turning on or off the laser 124 and / or the cooling unit 110. In addition, the door interlock 132 can be used as an additional safety measure such that when the door of the treatment room is half-open, the door interlock 132 detects this condition and instructs the controller 122 not to allow the light treatment unit 120, or at least the laser 124, to operate. Furthermore, an emergency on-off switch 134 can be provided to quickly turn off the light-heat targeted therapy system 100 in an emergency situation. In another modification, additional photodiodes or other sensors can be added to monitor the power level of the energy emitted from the laser 124.

[0066] With continued reference to Figure 1 , the light-heat targeted therapy system 100 further includes a scanner 160 that is part of a device that is hand-held by a user when applying the treatment regimen to a subject. For example, to facilitate handling by the user, the scanner can be formed in a gun-like or rod-like shape. The scanner 160 is connected with the cooling unit 110 via a cooling connection 162 so that the cooling regimen can be applied using the scanner 160. In addition, the output from the laser 124 is connected with the scanner 160 via a fiber delivery 164 so that the light treatment regimen can be applied using the scanner 160. The scanner 160 is connected to the temperature monitoring unit 128 via a temperature connection 166 in order to feed back the skin temperature of the treatment area to, for example, the controller 122. In addition, the overall operation of the scanner 160, as well as the feedback from the scanner, can be implemented as a scanner connection 170.

[0067] Figure 2Further details of scanner 160 according to embodiments are shown. Cooling connection 162 is connected with cooling delivery unit 202, which is configured to deliver a cooling mechanism (e.g., a flow of cold air) to the treatment area. Fiber delivery 164 from laser 124 is connected with laser energy delivery unit 204, which includes optical components for delivering optical energy for a photothermal treatment regimen to the treatment area. For example, the optical components can include a mirror controlled by the controller for directing the optical energy in the form of a light beam in an automated manner across multiple treatment points.

[0068] Finally, temperature connection 166 is connected with temperature sensor 206, which measures the temperature at the treatment area for feedback to controller 122. In addition, scanner 160 includes an on-off switch 210 (e.g., a trigger switch to turn on / off laser 124) and optionally a status indicator 212, which indicates the operational status of scanner 160, e.g., whether the laser is being operated. Although scanner 160 is shown schematically as a box in Figure 2 the actual shape is configured for ease of use. For example, scanner 160 can be shaped as a nozzle with a handle, a pistol shape, or another suitable shape that facilitates aiming and control by a user.

[0069] In an exemplary use scenario, the entire treatment area covering sebaceous glands to be treated is cooled. The cooling regimen can include, for example, applying a flow of cold air across the treatment area for a prescribed period of time, e.g., 10 seconds. In embodiments, the cooling can be adjusted according to detection that the skin surface temperature reaches a specified temperature, e.g., -1°C. After pre-cooling, the cooling mechanism (e.g., a flow of cold air or contact cooling) remains active and a light treatment regimen is applied to the treatment area. In one embodiment, pulses of a square "flat-top" beam are used in conjunction with the scanner device to apply laser pulses sequentially to the treatment area. For example, the light treatment regimen can include applying a set number of light pulses onto each segment of the treatment area, which is sequentially illuminated by the laser pulses. In another embodiment, the segments are illuminated in a random order.

[0070] Power modulated CW illumination (see Figure 15 and 16 )

[0071] According to embodiments, an example of a set of pulses suitable for a modulation / light treatment regimen is shown in Figure 3The sequence 300 includes light pulses 322, 324, 326, 328, 330, 332, and 334 applied at the treatment area. In one embodiment, all seven light pulses have equal power and are separated by uniform pulse intervals (represented by double arrow 342) and have the same pulse duration (represented by gap 344). In an example, the pulse duration 344 is 100 milliseconds and the pulse interval is 2 seconds. The 2 second pulse interval is intended to allow the epidermis and dermis in the block to cool, so as to prevent damage thereto, for example. During the pulse interval period, the laser can be scanned to different segments within the treatment area, so as to increase laser usage efficiency. It should be noted that, Figure 3 Not drawn to scale.

[0072] Figure 4 shows measured skin surface temperature as light pulses (e.g. Figure 3 shown in FIG. 3B are applied to a treatment area. In the example shown in Figure 4 In this particular example, the cooling and direct air cooling during treatment delivers cooling to -22°C with a high velocity air column, resulting in a heat transfer coefficient of approximately 350 W / m^2K between the skin and air. In embodiments, the beam size is 4.9 mm2. Depending on the size of the treatment area, the power profile of the laser, the location of the treatment area on the body, and other factors, the exact beam size can be adjusted using, for example, collimating optics.

[0073] The resulting change in skin surface temperature is shown in graph 400, where peak 422 corresponds to the application of light pulse 322 as shown in Figure 3 FIG. 3B, and similarly for peaks 424, 426, 428, and 430. In the example shown in Figure 4 In the example shown in FIG. 3B, the average power per point is 22 W * 0.15 s / 2 s = 1.65 W. The same average power per point can be achieved by pulsing at 33 Watts for 100 ms, pulse interval of 2 s, or at 25.1 W for 125 ms, pulse interval of 1.9 s, for example. In addition, the average laser power per area should be balanced with the heat extraction achieved by the cooling system.

[0074] The requirements for successful photothermal targeting therapy of a particular chromophore with minimal subject discomfort include: 1) no damage to the epidermis, i.e., ensuring that the peak temperature value at the skin surface is less than about 49°C; 2) no damage to the dermis, i.e., avoiding overheating of the dermis by balancing the peak and average power of the treatment pulse with the heat extraction of the cooling system; and 3) selective heating of the chromophore and the target containing the chromophore, e.g., for sebaceous gland treatment, a peak temperature greater than 55°C. It should be noted that the peak temperature value of 55°C is highly dependent on the particular treatment regime and can be adjusted to other temperatures to remain within a safe operating range to avoid damaging the surrounding dermis and epidermis.

[0075] It is known in the literature that tissue parameters, such as the thickness of the epidermis and dermis, vary among individuals according to factors such as age, gender, and ethnicity, as well as between different skin locations on the body. For example, even for the same person, the forehead has different tissue properties compared to the back, and thus different treatment parameter settings are needed for different treatment locations. Accounting for such variations in tissue properties in determining a particular treatment regime is important for laser-based acne treatment. In addition, due to manufacturing variability and operating conditions, there can be variations in, for example, the precise laser power, spot size, and cooling capability between particular laser systems. In fact, manufacturing variations between systems can result in 15% or more variation in energy density among different laser treatment systems. Furthermore, the individual technique used by the user to deliver the treatment can also affect the treatment, for example, by different pressure applied to the skin surface, which in turn affects, for example, the blood perfusion of the treatment site.

[0076] In laser treatment of acne, the operating thermal range is typically bounded on the upper end by the epidermis and dermis damage threshold temperatures, and on the lower end by the temperature required to bring the sebaceous gland to its damage threshold temperature. While there is currently no good way to directly measure the temperature of the sebaceous gland as calibrated by a treatment regime, the skin surface temperature can be an indicator of the sebaceous gland temperature. A correlation model that provides a correspondence between the sebaceous gland temperature and the skin surface temperature can then be used to tailor an actual treatment regime that uses skin surface temperature measurements to effectively target the sebaceous gland damage, while remaining below the damage threshold of the epidermis. The correlation model can be developed using, for example, analysis of heat transfer models, or by using clinical data (e.g., via biopsy) that relates skin surface temperature to sebaceous gland damage with a particular treatment regime applied.

[0077] Based on the clinical data, a correlation model is developed that relates the skin surface temperature to the sebaceous gland damage for a particular treatment regime. The correlation model can be developed using, for example, analysis of heat transfer models, or by using clinical data (e.g., via biopsy) that relates skin surface temperature to sebaceous gland damage with a particular treatment regime applied. Figure 3 and 4The treatment protocols described herein, expressed as end-skin surface temperature, allow for an operating temperature range of approximately 40°C to 55°C for acne treatment. When the skin surface temperature is between 45°C and 55°C (or even 41°C to 45°C), varying degrees of sebaceous gland damage are present, with almost no epidermal damage. Above 49°C, epidermal damage is present in addition to sebaceous gland damage. In some treatment scenarios, maintaining a temperature range of 40°C to 50°C may be desirable. In other cases, such as to ensure that the temperature remains below the pain and damage threshold of sensitive patients, it may be desirable to maintain an operating temperature range of 41°C to 45°C.

[0078] However, clinical data also indicate that, for a given individual, the distal skin surface temperature is strongly dependent on tissue parameters at the specific treatment area. While existing treatment protocols are based on a "one treatment for all" approach, innovative analytical protocols can be incorporated into treatment methods to directly determine individualized treatment parameters inferred from measurements of distal skin surface temperature at lower laser power and / or during the initial portion of treatment and / or during previous treatments, in order to avoid epidermal damage while effectively inducing sebaceous gland damage. In this way, treatment protocols can be tailored to specific treatment areas for a particular individual and also mitigate treatment variability caused by variations in the laser power output of a particular machine and variations in treatment conditions (e.g., ambient humidity and temperature). Therefore, it will be desirable to optimize treatment protocols for different subjects and even for different tissue locations within the same subject to effectively treat the target tissue component (e.g., sebaceous glands) without causing undesirable tissue damage.

[0079] For example, through Figure 3 The skin surface temperature is directly measured during the first four pulses, allowing for highly accurate prediction of the maximum epidermal surface temperature after subsequent pulses. This prediction can be used to modify specific treatment plans for specific areas of the skin in real time, such as reducing the number of pulses applied, adjusting the pulse width, or modifying the laser power for subsequent pulses. If the laser system incorporates a cooling system that reacts quickly enough, cooling can also be adjusted as part of the real-time modification of treatment system parameters. This customization process significantly improves subject comfort and safety during treatment.

[0080] This analytical protocol can be incorporated into, for example, a scanner that can be built into a handheld device used by a medical professional to administer treatment to a subject (e.g., see...). Figure 2temperature measurements by using a low-cost, off-the-shelf camera in the temperature sensor 206), or by using a separate, off-the-shelf, single-pixel or multi-pixel thermal measurement device. The prediction process can be performed at a highly localized level, thus adjusting the treatment regimen on the fly or prior to the start of treatment, even adjusting the regimen for each individual point in the treatment matrix. In this way, the treatment regimen can be specified to provide the necessary treatment laser power while remaining below the epidermal and dermal damage threshold temperatures.

[0081] Turning to Figure 5 , according to an embodiment, a flowchart illustrates an exemplary process of an analysis regimen. The analysis regimen assumes that the maximum epidermal temperature and the damage threshold temperature of the target (e.g., sebaceous gland) are known. In addition, a correlation model between the skin surface temperature and the target (e.g., sebaceous gland) has been established using computational analysis, for example, finite element modeling of heat transfer, or through clinical experiments using biopsies. Thus, for the analysis regimen, it is assumed that the target value of the end skin surface temperature is known. As an example, for the treatment regimen previously described in Figure 3 and 4 , the target peak skin surface temperature is known to be 51 °C.

[0082] As shown in Figure 5 , the analysis regimen 500 begins by applying a low-power laser pulse to the treatment area in step 512. The laser power should be set to a value below the damage threshold for epidermal damage. The skin surface temperature at the treatment area is then measured in step 514. For example, the temperature measurement can be performed using a low-speed infrared camera or similar device. It is then determined in decision 516 whether sufficient data has been collected to fit the collected data into the pre-established correlation model. If the answer to decision 516 is no, then the process returns to step 512, where a laser pulse of a different, low-power setting is applied to the treatment area to collect additional correlation data between the applied laser power and the epidermal temperature.

[0083] If the answer to decision 516 is yes, then the analysis regimen 500 continues by fitting the measured skin surface temperature data to the established correlation model in step 518. Next, in step 520, the appropriate laser parameters for the particular treatment area of the particular individual are determined. Finally, in step 522, the exact treatment regimen to be used for the particular treatment area of the particular individual is modified according to the appropriate laser parameters found in step 520.

[0084] Continuing with Figure 5, optionally, the analysis protocol 500 can continue during the actual treatment regimen. In the exemplary embodiment, after setting the laser parameters in step 522, the treatment regimen is initiated in step 530 with the appropriate laser parameters. Then, in step 532, the process continues to measure the skin surface temperature at the treatment area. In step 534, the measured skin surface temperature is used to update the relevant model calculations, and in step 536, the laser parameters of the treatment regimen are updated based on the updated calculations. Then, decision 538 is made to determine if the treatment regimen (i.e., the number of laser pulses applied to the treatment area) is complete. If the answer to decision 538 is no, then the analysis protocol returns to step 532 to continue measuring the skin surface temperature. If the answer to decision 538 is yes, then the treatment regimen is terminated in step 540.

[0085] In other words, the analysis protocol 500 can implement optional steps 530-540 to continue adjusting the laser parameters even during the actual treatment regimen, before the treatment regimen is complete. In fact, if there are other relevant data about the subject, such as laser settings from a previous treatment in the same treatment area of the same subject, they can also be fed into the model calculations for further refinement of the laser parameters.

[0086] Turning now to Figure 6 An example of the analysis protocol and subsequent treatment regimen is shown according to an embodiment. Graph 600 shows the relationship between laser power and peak skin surface temperature during the application of a series of laser pulses to two different subjects, identified as "C Carlton" and "S Carlton." Large dots 612, 614, and 616 show the initial three low-power laser pulses applied to subject "C Carlton," after which the analysis protocol described above was used to predict the peak skin surface temperature measured by the IR camera, thus defining the safe operating range as indicated by horizontal dashed line 618 and vertical dashed line 620. Dots 622, 624, and 626 show data taken at a slightly higher laser power setting on the same subject "C Carlton."

[0087] Continuing with Figure 6To determine the applicability of the same dose determination procedure to different subjects, a laser pulse of the same power was applied to a second subject, “S Carlton,” starting at a similar initial temperature, as shown in point 630. As shown in points 632, 634, and 636, an increased laser power treatment regimen was immediately applied to the second subject, “S Carlton,” without a dose determination regimen at a lower temperature. Although the actual measured skin temperature of the second subject, “S Carlton,” differed from that of the first subject, “C Carlton,” the safe operating range indicated by dashed lines 618 and 620 in graph 600 also applies to the second subject, “S Carlton.” In this way, the analytical protocol described above takes into account these individual differences when customizing treatment regimens for specific treatment areas on specific individuals. The efficacy of the analytical protocol has been validated using in vivo data.

[0088] The analysis protocol can be performed before the actual treatment period, for example, during the appointment or while examining the subject in the pre-treatment phase. When using low power, the analysis protocol can be performed without the need for local anesthesia, and virtually no epidermal or dermal damage occurs during the application of the analysis protocol. For example, during treatment preparation, a trained operator can quickly predict various treatment sites and develop a personalized treatment plan based on a single scan of each skin site. Alternatively, temperature adjustments, including adjustments to laser power and / or cooling mechanisms, can be performed in real time during the actual treatment.

[0089] Once the relationship between laser power and the resulting skin surface temperature has been established for specific subjects and / or specific skin locations and / or specific laser devices, the connection... Figure 6 The slope of the lines at points 612, 614, 616, 622, 624, and 626 indicates this relationship, which can be used to continuously adjust future treatments. Furthermore, as the treatment plan continues, all treatment data can be added to the basis for establishing the correlation between skin surface temperature and power. In this way, the correlation is continuously updated and refined even after the treatment plan has begun. For example, based on the known relationship between laser power and the resulting skin surface temperature achieved at a specific treatment location, dermatologists can be advised to adjust laser parameters (e.g., laser power) manually, or the device can automatically adjust, for example, the laser power, for the next treatment location.

[0090] The analytical approach described above can be extended to the real-time adjustment of treatment protocols using closed-loop control processes. Skin surface temperature can be measured using, for example, an infrared (IR) camera or other temperature measurement mechanisms. For instance, by fitting the measured temperature to a mathematical model of skin tissue, the measured skin surface temperature can be correlated with the temperature of target components (e.g., sebaceous glands) that cannot be directly measured.

[0091] That is, according to another embodiment, a system whereby temperature measurements of the skin surface during an initial portion of a treatment at a particular location are used to predict a future temperature of the skin surface at that particular location. The thus predicted future temperature is used to adjust the thermal energy delivered by one or more lasers, either by adjusting one or more parameters such as laser power, pulse width, number of pulses, and other parameters affecting the thermal energy delivered by the laser, or by adjusting one or more parameters of a cooling system such as gas flow, so that the future temperature of the skin surface at the particular location, and thus the temperature of underlying regions and tissue components which cannot be easily measured in a direct manner, reaches a desired value or does not exceed a specified value.

[0092] In other words, the dosage administered to the subject (e.g., the settings of a light treatment, including the power settings of, for example, a laser source) can be adjusted in real time by using a predictive control process. For example, by measuring the skin temperature directly during the pulses 322, 324, and 326 shown in FIG. 3B, the predicted maximum epidermal surface temperature after the application of subsequent pulses can be calculated with high accuracy. This prediction is achieved by fitting a mathematical function to the measured epidermal surface temperature after the application of, for example, three or four treatment pulses. In turn, a suitable mathematical function is selected based on knowledge of the pulse plan used in the treatment regimen. For example, for the treatment regimen shown in FIG. 3B, various curve fitting methods, such as a single exponential function, can provide an accurate model of the skin surface temperature after the application of subsequent treatment pulses. This prediction can then be used to modify the particular treatment regimen for a particular skin region in real time. For example, the user can modify the number of additional pulses applied, as well as one or more of the pulse width and laser power of the subsequent pulses. Additionally, if the light treatment system includes a cooling unit that is responsive enough, the cooling applied to the treatment region can also be adjusted as part of the real-time modification of the treatment system parameters. This customization process greatly improves patient comfort and safety during the treatment process. Figure 3 Figure 3 In other words, the dosage administered to the subject (e.g., the settings of a light treatment, including the power settings of, for example, a laser source) can be adjusted in real time by using a predictive control process. For example, by measuring the skin temperature directly during the pulses 322, 324, and 326 shown in FIG. 3B, the predicted maximum epidermal surface temperature after the application of subsequent pulses can be calculated with high accuracy. This prediction is achieved by fitting a mathematical function to the measured epidermal surface temperature after the application of, for example, three or four treatment pulses. In turn, a suitable mathematical function is selected based on knowledge of the pulse plan used in the treatment regimen. For example, for the treatment regimen shown in FIG. 3B, various curve fitting methods, such as a single exponential function, can provide an accurate model of the skin surface temperature after the application of subsequent treatment pulses. This prediction can then be used to modify the particular treatment regimen for a particular skin region in real time. For example, the user can modify the number of additional pulses applied, as well as one or more of the pulse width and laser power of the subsequent pulses. Additionally, if the light treatment system includes a cooling unit that is responsive enough, the cooling applied to the treatment region can also be adjusted as part of the real-time modification of the treatment system parameters. This customization process greatly improves patient comfort and safety during the treatment process.

[0093] The analysis used in the predictive control process can be performed using temperature measurement devices, such as commercial off-the-shelf low-cost cameras incorporated into the scanner (e.g., the temperature sensor 206 of FIG. 2A), or by using separate thermal measurement devices, such as single-pixel or multi-pixel thermal imagers. Figure 2 By controlling the size of the target treatment region and specifically measuring the skin surface temperature at the target treatment region, the prediction process can be performed at a highly localized level, thus enabling the medical professional administering the treatment regimen to make adjustments before the treatment regimen begins, in real time during the treatment, or even for each individual point in the treatment matrix. In this way, the treatment regimen can be administered in a highly customizable manner to provide the necessary treatment laser power while keeping the epidermis and dermis damage threshold temperatures below.

[0094] ​For example, the Arrhenius damage function relates target damage to peak temperature exponent; subsequently, the peak temperature of the skin surface is correlated to the peak temperature of the target chromophore. In an example, for a 22 W laser irradiation on a 5 mm x 5 mm spot with 100 ms pulses, the temperature rise is approximately 180 °C / s; in this case, the skin surface measurement should be updated approximately every 2.5 ms or at 400 Hz in order to use the temperature measurement as a control input for the treatment regimen. With this fast temperature measurement method, the laser can be turned off when the measured skin surface temperature reaches a pre-set threshold.

[0095] Alternatively, a slower temperature measurement device can be used to predict the peak temperature by measuring the temperature rise and fall behavior during the early pulse application in the treatment regimen. The skin surface temperature can be measured during the first few laser pulses applied at the treatment area, and the temperature measurement is used to extrapolate the expected skin surface temperature during the subsequent pulse application, so that the energy profile of the subsequent pulses can be adjusted accordingly. For example, the laser parameters, such as laser pulse duration, power, and pulse interval, can be adjusted in order to deliver the appropriate amount of energy to the target chromophore while avoiding damage to the surrounding medium.

[0096] Figure 7 The flowchart illustrated in FIG. 7A illustrates an exemplary process for closed-loop control of laser system parameters based on real-time skin surface temperature measurements according to an embodiment. The process 700 begins with the initialization of a laser treatment regimen, in which the laser system is set to the treatment settings (i.e., treatment power level, pulse width, etc.). In step 712, laser pulses are applied to the treatment area according to the treatment regimen. The treatment regimen can involve, for example, the application of pulses with increasing power in sequence, or the repeated application of pulses at substantially the same power setting to the treatment area. An example treatment regimen involves the repeated application of laser pulses from a 22 W laser with a 5 millimeter x 5 millimeter spot size and 100 ms duration.

[0097] With continued reference to Figure 7 During the application of each laser pulse, the skin surface temperature at the treatment area is measured in step 714. Optionally, the skin surface temperature is measured during the cooling period between pulses. For example, the measurement can be made by a 25 Hz refresh rate infrared camera. Faster devices, such as a 400 Hz refresh rate temperature measurement device, can be used to more accurately measure the skin surface temperature while and after the laser pulse is applied.

[0098] Next, in decision 716, it is determined whether sufficient skin surface temperature data has been collected for curve fitting purposes. If the answer to decision 716 is no, the process returns to step 712 to apply another laser pulse. If the answer to decision 716 is yes, then in step 718, the measured skin surface temperature data is fitted to the predictive model. During step 718, a curve fit for the maximum and optionally minimum skin surface temperature is generated. For example, the predictive model can be generated by compiling a large number of temperature measurements corresponding to the application of laser pulses to test subjects in a clinical setting or by tissue analysis modeling.

[0099] Based on the curve fit generated in step 718, appropriate laser parameters for a specific treatment area on the treated individual are determined in step 720. In some embodiments, step 720 may include determining appropriate laser parameters for the next pulse. For example, if the curve fit predicts that the skin surface temperature will rise to a predetermined threshold temperature, such as above 45°C, then the laser parameters are adjusted to reduce the laser power. In this case, the skin surface temperature measurement may indicate that a specific treatment area on the subject is particularly sensitive to laser pulse energy absorption. Alternatively, if the curve fit predicts that the desired temperature for the target chromophore lesion, such as 55°C, cannot be achieved with the current laser pulse power setting, then the laser parameters may be adjusted to provide the necessary treatment power. This may occur if the epidermal and dermal characteristics make the specific treatment area less likely to absorb laser pulse energy.

[0100] Figure 8 This describes an exemplary predictive closed-loop control process based on measured skin surface temperature, according to an embodiment. Figure 8 The curve graph 800 is shown in, for example Figure 7 The document describes the various time-varying temperature measurements and calculated curves used in the predictive closed-loop control process. Figure 8 In this example, the zero point corresponds to the moment the first laser pulse is applied (in this case, from a 22W laser, a 100ms pulse, and a 5mm x 5mm square spot), preceded by approximately 15 seconds of air cooling (i.e., time -15 to zero). In this example, air cooling is applied to the treatment area throughout the laser pulse application. In this example, a 25Hz refresh rate IR camera is used to measure the skin surface temperature, but other temperature measurement devices are considered.

[0101] Continue to refer to Figure 8 The measured skin surface temperature during the initial cooling period is shown by curve 810. The measured skin surface temperature during the application of the laser pulse is shown by curve 812. The target skin surface temperature is indicated by the dashed line 816, which is shown here as 45.5°C.

[0102] Beginning at time zero, the first temperature measurements after the first four pulses (indicated by dots) are fit to the predictive model. Specifically, in the example shown in FIG. 8, the peak temperature and the cooling temperature immediately prior to the next pulse application are fit into the clinically generated predictive model. The maximum temperature peaks 822, 824, 826, and 828 and the minimum temperature troughs 823, 825, 827, and 829 are curve fit to generate a maximum temperature curve 830 and a minimum temperature curve 832 (shown as dashed curves). Optionally, temperature measurements taken during the cooling periods between laser pulse applications are used to improve the accuracy of the measurement of the maximum temperature peaks and the minimum temperature troughs. Figure 8

[0103] As shown in curve 812, the skin surface temperature is measured during the subsequent laser pulse applications. It can be seen that the maximum and minimum temperature curves 830 and 832 accurately track the measured skin surface temperature (i.e., the peaks 842, 844, 846, and 848 and the troughs 843, 845, and 847 of curve 812). It is noted that the predicted temperature rise (i.e., dashed curve 830) and the actual measured temperature (specifically, peaks 846 and 848) indicate that the desired temperature of 45.5°C has been achieved with the application of pulses 6 and 7, so the laser treatment regimen is stopped without the application of an eighth pulse.

[0104] Even with a relatively slow temperature measurement device, such as a 25 Hz refresh IR camera, fitting the temperature data during the cooling periods between laser pulse applications allows a good estimate of the rapid temperature rise achieved with each pulse application. If a faster temperature measurement device is used (e.g., 400 Hz refresh rate or faster), the temperature profile can be measured directly in real time.

[0105] The foregoing describes the present application and should not be construed as limiting the application. While several exemplary embodiments of the application have been described, those skilled in the art will readily understand that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of the application. For example, lasers with other wavelengths, such as about 1210 nm, can be used. Alternatively, the pre-treatment analysis methods described above can be used with other treatment regimens, such as those described in WIPO patent application WO / 2018 / 076011 by Sakamoto et al. and WIPO patent application WO / 2003 / 017824 by McDaniel. In fact, the methods are applicable to any thermal treatment regimen that involves equipment that can be affected by system, user, atmospheric conditions, and other inter-treatment variability.

[0106] ​Thus, many different embodiments are possible as modifications (and equivalents) of the embodiments described and illustrated herein, and all such modifications and equivalents are believed to be within the scope of the embodiments described and illustrated herein. The following claims are in no way intended to limit the scope of these embodiments to the specific embodiments described and illustrated herein. Instead, these claims are intended to cover all embodiments falling within the scope of the embodiments described and illustrated herein, and any equivalents thereto.

[0107] For example, consider embodiments such as the following:

[0108] 1. A method for determining a suitable set of parameters of a light source within a photothermal targeting therapy system for calibrating a chromophore embedded in a medium, the method comprising, prior to administering a treatment regimen: 1) administering at least one laser pulse to a location to be treated at a preset power level, the preset power level being below a known damage threshold; 2) measuring a skin surface temperature at the location to be treated after administering the at least one laser pulse; 3) estimating a relationship between parameters of the light source and the skin surface temperature; and 4) defining a safe operating range of the parameters of the light source in order to avoid thermal damage at the location to be treated.

[0109] 2. The method according to item 1, wherein steps 1) to 4) are performed on a first subject for a first treatment area, followed by repeating steps 1) to 4) on the first subject for a second treatment area.

[0110] 3. The method according to item 1, wherein steps 1) to 4) are performed on a first subject for a treatment area, followed by repeating steps 1) to 4) on a second subject for a treatment area.

[0111] 4. The method according to item 1, further comprising taking into account treatment data from previous treatments of the same subject.

[0112] 5. The method according to item 1, wherein steps 2) to 4) are repeated when performing an actual treatment regimen on a subject.

[0113] 6. A system whereby a temperature measurement of a skin surface during an initial portion of a treatment at a particular location is used to predict a future temperature of the skin surface at this particular location. This predicted future temperature is used to adjust the thermal energy delivered by one or more lasers, either by adjusting one or more parameters such as laser power, pulse width and other parameters affecting the thermal energy delivered by the one or more lasers, or by adjusting one or more parameters of a cooling system such as air flow, so that the future temperature of the skin surface at the particular location, and thus the temperature of underlying areas and tissue components which cannot easily be measured in a direct manner, reaches a desired value.

[0114] 7. A system whereby temperature measurements of the skin surface taken during treatment of one or more adjacent areas are used to predict future temperatures of the skin surface at that particular location. The future temperatures thus predicted are used to adjust the thermal energy delivered by one or more lasers, either by adjusting one or more parameters such as laser power, pulse width and other parameters affecting the thermal energy delivered by one or more lasers, or by adjusting one or more parameters of a cooling system such as airflow, so that the future skin surface temperature at the particular location, and thus the temperature of underlying areas and tissue components which cannot be easily measured in a direct manner, reaches a desired value.

[0115] An improved method to define and adjust parameters of a photothermal treatment system involves establishing and manipulating a thermal gradient below the skin surface in a treatment area. Prior discussions of establishing a thermal gradient with photothermal targeted treatment involve simultaneous application of skin surface cooling with laser pulses to cause damage to chromophores at a particular depth below the skin surface (see, e.g., U.S. Patent Application Publication No. 2109-0262072 Al to Sakamoto et al., incorporated herein by reference). Others have discussed monitoring the skin surface temperature while applying laser pulses of different pulse durations and powers in a pre-treatment protocol, while inferring temperature profiles in, e.g., the dermal layer of a treatment area (see, e.g., U.S. Patent Nos. 8,974,443 B2 to Dunleavy et al. and 9,333,371 B2 to Bean et al.).

[0116] In contrast, embodiments disclosed herein provide systems and methods for controlling the peak of a thermal gradient (TG) established below the skin surface in a treatment area with closed loop control of a heating and cooling system. In embodiments, the present disclosure provides a combination of active cooling with heating that can be adjusted prior to and during the application of a treatment protocol to establish a desired TG profile below the skin surface. By controlling the TG profile in a closed loop manner, embodiments of the present disclosure provide consistent management of photothermal energy delivery by a photothermal treatment system. In this manner, the TG profile at a treatment area can be accurately controlled prior to and during treatment, thus providing a consistent, effective treatment experience for a patient while minimizing a sense of pain.

[0117] In particular, it is recognized herein that the TG profile changes over time at any given location, such that the correlation between the measured surface temperature and the peak TG temperature also changes over time. Therefore, simply monitoring the skin surface temperature as an indicator of the sub-skin TG is insufficient. The relationship between the skin surface temperature, the peak TG temperature, the TG profile below the skin surface and the photothermal energy application time must be considered to achieve consistent and effective energy delivery while ensuring patient comfort.

[0118] Embodiments described herein provide closed-loop control of the TG profile established beneath the skin surface at the treatment region, including peak TG temperature during photothermal energy application. As the TG profile at the treatment region changes over time, certain embodiments establish a correlation between skin surface temperature and peak TG temperature over time, thus enabling active control of the system's cooling and heating mechanisms to ensure that the depth of the TG profile and the peak temperature remain below the pain threshold of the patient being treated. In certain embodiments, a pre-treatment TG profile is established at the treatment region prior to any treatment regimen, such that when a treatment pulse is applied at the treatment region, the pain experienced by the patient is minimized. For example, the pre-treatment TG profile can be established such that, at a desired target depth beneath the skin surface, the temperature is less than 52°C during a pre-conditioning phase. In embodiments, the method of establishing a TG profile at the treatment region includes using a correlation function to relate the expected heating and / or cooling response to the measured change in heating and / or cooling response from a previously applied photothermal energy pulse at a given treatment location.

[0119] A key factor that distinguishes the methods described in this disclosure is the recognition that the correlation function is universal for a given heating / cooling regimen, independent of the treatment region location and patient. Prior closed-loop methods to control photothermal energy delivery require adjustment of cooling and heating parameters between different patients and between different treatment locations on the same patient. In contrast, this disclosure describes systems and methods that implement a correlation function defined and implemented as an empirically derived relationship that allows accurate prediction of the heating and cooling response across different treatment regions and patients. The correlation function can be derived from prior information obtained via laboratory and / or clinical testing, and then applied to all subsequent treatments on actual patients.

[0120] In particular, the correlation model implemented in the systems and methods described herein enables estimation of the temperature drop at a given treatment location measured between the end of a first heating pulse and just prior to the application of a second heating pulse immediately following the first heating pulse. That is, whereas prior methods focused on predictive closed-loop control of the measurable temperature rise at a particular treatment location by applying photothermal energy (e.g., laser pulses), embodiments of this disclosure also take into account the cooling drop between laser pulses to improve control of the TG established by the laser pulses.

[0121] By accurately estimating this cooling down, the starting temperature at a given treatment location prior to a second heating pulse can be predicted, thus enabling adjustment of the parameters (e.g., power, pulse duration) of this second heating pulse to ensure that the skin temperature after application of this second heating pulse can be within an acceptable range of a predetermined target temperature. This estimation of the cooling down can be based on a cooling measurement prior to the first laser pulse (i.e., a cooling temperature increment) and a heating measurement of a previous pulse (i.e., a heating temperature increment) as inputs to a correlation model. That is, the inputs to the correlation model can also take into account any laser pulses (e.g., any pre-conditioning pulses or previous treatment pulses) applied at the given treatment location prior to the first laser pulse. In this way, real-time adjustment of the photothermal energy delivery based on the correlation model can take into account both the cooling and heating temperature increments at the treatment site, enabling more consistent and accurate control of the photothermal energy delivery to the patient than was previously possible.

[0122] In certain embodiments, the heating properties (e.g., temperature increase per unit power and / or pulse duration) of the second pulse can be estimated from the heating properties of any previously applied pulses (e.g., the first pulse and / or any pre-conditioning pulses applied to the given treatment location prior to the second pulse). By incorporating this heating property estimation, the photothermal energy source parameters to achieve the target peak temperature can be determined. Additionally, the cooling mechanism can be adjusted during the treatment, such that the cumulative effect of both cooling and heating provided at the treatment location can be taken into account and adjusted in real-time during the application of the treatment protocol.

[0123] In other words, the methods described herein enable closed-loop control of any and all heating pulses (i.e., photothermal energy delivery) at a given treatment location. Thus, the described methods and systems allow for accurate control of the TG and treatment temperature at different depths. In this way, embodiments of the systems and methods described herein allow for more consistent and effective application of photothermal energy delivery at a given treatment location than was possible using previously disclosed methods.

[0124] As an example, controlling the TG profile through correlation with measured surface temperature can be performed as follows. The TG profile is defined as the profile of temperature as a function of depth in the tissue at a particular point in time. To target specific chromophores at different depths, the TG profile should be controlled to selectively heat those specific chromophores above the damage threshold, while maintaining the surrounding tissue below the damage threshold. Additionally, the pain experienced by the patient during the application of photothermal energy can be minimized by maintaining the bulk tissue temperature below a predetermined pain threshold for as long as possible.

[0125] To achieve a desired thermal gradient profile, one can start with a particular thermal profile in the tissue, then apply sufficient photothermal energy to provide a lesion at a desired location within the tissue. Additionally, a cooling mechanism can be provided prior to and / or during the application of the photothermal energy. Due to the different mechanisms and efficiencies of heating (e.g., application of energy from a pulsed laser) and cooling (e.g., air cooling that applies cold air), the heating and cooling must be carefully balanced in order to achieve an effective treatment result while avoiding tissue damage and patient discomfort. For example, to create a thermal gradient that peaks deeper in the tissue, one must balance surface heat extraction and energy deposition near the skin surface while controlling energy deposition at the desired depth for a sufficient amount of time to achieve the desired effect.

[0126] It is also recognized that the TG profile at a given treatment location changes over time. That is, the TG varies as a function of time, heat extraction rate (i.e., the cooling effect resulting from any cooling mechanism applied at the tissue surface), heat injection rate (i.e., tissue heating by the application of photothermal energy at the tissue surface), and tissue depth. Furthermore, for a given heating and cooling scheme, it is recognized that the TG profile as a function of time (i.e., the tissue temperature as a function of depth and time) can be estimated using numerical heat transfer modeling, which uses, for example, finite element analysis.

[0127] In the general three-dimensional case, numerical modeling is generally the only accurate method for estimating the spatial and temporal evolution of the TG profile at a given treatment location. However, the accuracy of this numerical modeling is only as good as the accuracy of the assumed optical and thermal parameters of the tissue used in the simulation. That is, if the actual tissue parameters are significantly different from the assumed optical and thermal parameters used in the simulation, the numerical modeling results can not accurately predict the TG profile in a patient. While numerical simulation results can be validated against clinical and / or experimental results, the simulation results can not accurately predict the TG profile for all patients.

[0128] The methods described in this disclosure overcome the shortcomings of the foregoing methods by combining the predicted TG profile from photothermal heat injection with an accurate model of the cooling extraction rate and real-time temperature measurements. In an example, the heat extraction rate of cooling can be described by a known thermodynamic relationship:

[0129] q = h A AT [Equation 1]

[0130] where q is the heat extraction rate (in Watts), h is the heat transfer coefficient (in W / m 2 x °C), A is the area being cooled (in m 2), and ΔT is the temperature difference between the tissue surface and the cooling medium in °C. Thus, the heat extraction rate can be controlled by changing the heat transfer coefficient (e.g., by changing the cooling air speed when air cooling is used) or the temperature of the cooling medium (e.g., the cooling air temperature when air cooling is used, or the temperature of the contact surface when contact cooling is used).

[0131] The depth profile of photothermal heat injection can be expressed as a function of the optical absorption and scattering coefficients of the tissue to which the photothermal energy is applied. That is, upon application of photothermal energy, the tissue at the location of application will be heated from the surface and into the tissue, with the TG profile depending on the energy and time of heat application and the specific absorption effective at each tissue layer. To provide effective photothermal targeted therapy, it is recognized herein that the damage caused to a tissue or a particular structure in a tissue (e.g., a sebaceous gland) generally follows an Arrhenius damage equation that is dependent on temperature and time, i.e., greater damage can be caused by applying higher temperatures for longer times. Thus, to selectively damage structures residing at a particular depth without causing damage to surrounding tissue, the peak temperature of the TG profile should ideally be achieved at the depth of interest where the object is to be damaged. Furthermore, the sharper the temperature peak, the more selective the expected damage that can be provided.

[0132] For short optical pulses (e.g., laser pulses with a duration of less than about 0.5 seconds), the resulting temperature profile of the injected heat is generally independent of the temperature of the surrounding tissue if the tissue temperature is above the freezing point (0°C) and below the tissue damage temperature (about 60 to 65°C for pulses with a duration of less than 0.2 seconds). In such cases, the heat deposited from the short optical pulse has not had time to diffuse into the surrounding tissue before the optical heating pulse ends, and the TG profile of the tissue remains substantially unchanged. Figure 9 To illustrate this, the temperature difference (i.e., the heating temperature increment) immediately following each of the six consecutive laser pulses applied to heat the tissue while cooling is simultaneously applied at the same location is shown. In this case, while the heating temperature increment varies with the depth of the tissue, the temperature profile varies little with the application of short laser pulses, e.g., laser pulses with a duration of about 100 milliseconds or less. Figure 9 The curve shown in FIG. 1 is consistent with the common sense that photothermal sources, e.g., lasers, microwaves, and incoherent light sources, used for heat-based dermatological procedures tend to heat tissue closer to the source most effectively due to energy absorption according to the Beer-Lambert Law and light scattering in the tissue.

[0133] Reference will now be made to Figure 9 FIG. 1 shows a temperature profile of a tissue at a given location, assuming Figure 10 and 11 , Figure 10 shows the heat gradient at a given location, assumingFigure 9 The same six optical pulses used to generate the graph in FIG. 6A are applied to a given location while a cooling mechanism (e.g., air cooling) is applied to the skin surface. Figure 11 The thermal gradient immediately after the application of the six pulses in FIG. 6A at the same given location is shown in FIG. 6B. As shown, Figure 9 The lowermost curve in FIG. 6B represents the modified TG profile immediately before the first optical pulse of the six optical pulses is applied to the given location. This initial TG profile, with cooling applied only at the skin surface, shows that the skin surface temperature is about -5°C, and rises toward normal body temperature at increasing depths as expected. Figure 10 11 Next, after the first optical pulse has been applied, The second curve from the bottom in FIG. 6B shows the modified TG profile immediately after pulse 1 of FIG. 6A has been applied to the given location. As can be seen, after the application of pulse 1, the skin surface temperature (i.e., depth of 0 mm) has increased to above 10°C, with a peak temperature of about 20°C at a depth of about 0.4 mm. Immediately before the application of pulse 2, this TG profile represented by the second curve from the bottom in FIG. 6B has stabilized to the second curve from the bottom in FIG. 6C. That is, the TG profile represented by the second curve from the bottom in FIG. 6B has cooled to a skin surface temperature of about 6°C, and the temperature peak near depth 0.4 mm has also been cooled to about 14°C by the time the second pulse is to be applied.

[0134] Figure 11 Next, after the first optical pulse has been applied, Figure 9 The second curve from the bottom in FIG. 6B shows the modified TG profile immediately after pulse 1 of FIG. 6A has been applied to the given location. As can be seen, after the application of pulse 1, the skin surface temperature (i.e., depth of 0 mm) has increased to above 10°C, with a peak temperature of about 20°C at a depth of about 0.4 mm. Immediately before the application of pulse 2, this TG profile represented by the second curve from the bottom in FIG. 6B has stabilized to the second curve from the bottom in FIG. 6C. That is, the TG profile represented by the second curve from the bottom in FIG. 6B has cooled to a skin surface temperature of about 6°C, and the temperature peak near depth 0.4 mm has also been cooled to about 14°C by the time the second pulse is to be applied. Figure 11 Figure 10 Figure 10

[0135] In other words, as shown in FIG. 6A, immediately after each optical pulse is applied, the TG profile of the given location fluctuates between a higher peak temperature at a depth between 0.5 mm and 1 mm, and then stabilizes to the slightly flattened curve in FIG. 6B. This flattening, corresponding to the cooling temperature increment provided by the continued cooling of the skin surface during the application of the photothermal energy, can lead to errors in the adjustment of the photothermal energy parameters if the cooling is not taken into account. Figure 11 Figure 10 As referenced above, in the previous method, the parameter variations were based on peak temperature measurements made immediately after the application of the optical pulses, without taking into account the subsequent cooling temperature increment that occurs between the optical pulses. Thus, although the resulting adjustment of the laser parameters resulted in providing inconsistent treatment results, as the photothermal energy provided can not have been sufficient to achieve an effective treatment result.

[0136] As referenced above, in the previous method, the parameter variations were based on peak temperature measurements made immediately after the application of the optical pulses, without taking into account the subsequent cooling temperature increment that occurs between the optical pulses. Thus, although the resulting adjustment of the laser parameters resulted in providing inconsistent treatment results, as the photothermal energy provided can not have been sufficient to achieve an effective treatment result.

[0137] ​​​​​However, the embodiments described herein consider both the heating temperature increment provided by optical pulses and the cooling temperature increment provided by continuous application of cooling at the skin surface. It is recognized that the time required to cool a given location to a certain depth and desired temperature varies depending on the cooling power and the tissue's thermal diffusion time, a generally fixed property of the tissue determined by its thermal conductivity, specific heat capacity, and density. While lowering the temperature of the cooling mechanism and increasing the heat transfer coefficient at the tissue surface will accelerate cooling deep beneath the skin surface, the upper layers of tissue can suffer frostbite due to overcooling. Therefore, the amount of cooling that can be provided at the skin surface is limited, and it is important to balance the cooling provided with the heating resulting from the application of photothermal energy. Taking all these factors into account results in a more accurate prediction of the photothermal energy required for adequate heating of the target chromophore, and thus more reliable and effective photothermal targeted therapy outcomes.

[0138] For example, using thermal model estimation, such as Figures 9 to 11 The curves shown illustrate how a TG profile generated by applying photothermal pulses can be designed to balance the thermal extraction rate (i.e., the cooling power provided by cooling applied at the skin surface) and cooling time with the thermal injection and heating times, thereby positioning the peak temperature of the TG profile at a desired temperature and depth below the skin surface. Since the depth profile of thermal injection with short optical pulses is fixed, the peak temperature is at a relatively shallow depth (e.g., approximately 0.3 mm for a 1726 laser, such as...). Figure 9 As shown in the diagram, the targeting of deeper chromophores (e.g., sebaceous glands located at depths of approximately 0.5 to 1.5 mm below the skin surface) requires a balance between skin surface cooling and time to keep the epidermis and superficial papillary dermis sufficiently cool to remain below the patient's pain and damage threshold during laser pulse application. Utilizing prior knowledge of the dynamically changing TG profile during photothermal energy application, the peak temperature and depth of the TG profile can be correlated with the skin surface temperature, thus allowing the peak TG temperature to be aimed at the desired location below the skin surface.

[0139] This article also recognizes that both excessive heating and excessive cooling during preconditioning and treatment can lead to increased pain perception in patients. Typical pain relief procedures include providing adequate skin cooling, applying local anesthetic creams or gels, and administering anesthetics (such as lidocaine-containing anesthetics) or gaseous analgesics such as PRO-NOX. TMPain relief and the like. Combinations of various pain relief processes can also help reduce the perception of pain (see, e.g., co-pending U.S. Patent Application No. 17 / 564,836, filed December 29, 2021, which is incorporated herein by reference). While the various pain management techniques listed above are effective for most photothermal targeting therapy procedures, the injection process of the injectable anesthetic is painful in itself, various other anesthetics require a prescription, and a physician specialist is typically required to perform or supervise the procedure. Thus, it would be beneficial if the pain associated with the photothermal targeting therapy itself could be reduced fundamentally.

[0140] Specifically taking the example of photothermal targeting therapy for acne, sebaceous glands located 0.5 mm to 1.5 mm below the skin surface need to be heated to temperatures above 65 °C with, for example, 100 ms laser pulses to achieve effective results. In general, the perception of pain is driven by the temperature that is too high (i.e., temperature above the pain threshold), the duration of the elevated temperature, and the volume of tissue at these elevated temperatures. That is, the pain receptors of the elevated temperature are different depending on the temperature profile. For example, exceeding the pain threshold at the skin surface will result in a sensation of heat, while exceeding the pain threshold at a depth of about 1 mm below the skin surface will result in a “prickling” sensation at that location. In general, a person will perceive pain based on, for example, the following factors: 1) the temperature profile in the tissue, e.g., the volume of tissue exposed to temperatures above the threshold temperature associated with pain receptors residing at the applicable depth; and 2) the duration spent above the pain threshold. At the depth of a typical sebaceous gland, the pain threshold for an average person is about 52 °C (see, e.g., Basbaum et al., Cellular and Molecular Mechanisms of Pain, Cell 139, October 16, 2009), and if the temperature spike is less than 52 °C and the duration is less than 250 milliseconds, pain is typically not perceived at this depth. Since 52 °C is below the damage threshold for sebaceous glands, photothermal targeting therapy protocols for treating acne typically require additional pain mitigation.

[0141] As a specific example, consider a photothermal therapy protocol that is calibrated to target sebaceous glands residing at a depth of 0.8 mm without damaging the dermis above or below. The Arrhenius model shows that sebaceous gland damage is dependent on temperature and time, as is damage to the dermis. Taking a time period of 100 milliseconds as an example, the required temperature to damage a target sebaceous gland is 65 °C. However, in the same 100 milliseconds, the surrounding dermis must be kept below 60 °C.

[0142] Ideally, by exploiting the differential absorption between the sebaceous gland and the surrounding dermis, a TG profile that produces a peak temperature above 65°C at approximately 0.8 mm is generated, thus allowing the sebaceous gland to be brought to a temperature above 65°C while maintaining the dermis temperature below 60°C for maximum sebaceous gland damage without damaging the surrounding tissue. This TG profile can be achieved by cooling the skin surface using a cooling source with a constant heat transfer coefficient in combination with a photo-thermal energy source (e.g. laser) that deposits energy in a constant manner (pulsed wave or continuous wave). Using a 1726 nm laser, with tissue pre-cooling to 1°C at the skin surface and continuous cooling during the application of the laser energy, a peak temperature of the TG profile at a depth of 0.8 mm can be achieved in approximately 7 seconds. Figure 12 The temperature change at depth is illustrated over a typical six-pulse laser application protocol. However, the time period can be too long to be tolerable by the patient without experiencing excessive pain and / or the need for additional pain mitigation techniques, such as the use of topical or injected anesthetics.

[0143] Upon viewing the graph 1200 of Figure 12 it is noted that the temperature at the peak of the thermal gradient exceeds the pain threshold of 52°C at depth for more than 5.5 seconds. To avoid this extended period of temperature above the pain threshold, embodiments of the present disclosure instead employ a method that first pre-regulates the initial TG profile, then applies photo-thermal energy in such a way that the peak TG temperature at depth does not exceed the pain threshold until the last pulse. In other words, once a pre-regulated TG profile has been established at the treatment location, and the peak temperature of the pre-regulated TG profile is at the desired depth while below the pain threshold temperature, a single higher power pulse is delivered to definitively damage the sebaceous gland with a shorter pulse duration than would normally be perceptible. Figure 13 An example of a pulse sequence according to an embodiment is shown in Figure 14 Figure 13 The resulting TG profile after pulses 1, 5, and 6 of

[0144] It is noted that the laser parameters of the pulse sequence demonstrated in Figures 9 to 11 can be specified using the TG profile design method illustrated in Figure 13 . Figure 13 and 14 The methods demonstrated in Figure 14 minimize the time spent above the pain threshold of 52°C, thus minimizing the amount of pain experienced by the patient while still achieving the desired TG profile peak at the target depth. In the example curves shown in Figure 13 a single high power pulse is shown, but can be immediately after the last emission shown in Figure 13 , or by repeating Figure 13 ​The pulse sequence shown in the image can be used to apply additional higher-level pulses, either in whole or in part.

[0145] In some embodiments, when applying Figure 13 Cooling may be provided at the skin surface before and / or during the pulses shown. As a specific example, it should be noted that if a fixed cooling mechanism with a fixed heat transfer coefficient is used, care must be taken to avoid reducing the skin surface temperature below -4°C for more than approximately 6 seconds to prevent frostbite. Therefore, assuming a 7-second laser pulse application sequence, the application of a cooling mechanism at the skin surface can be limited to a 5-second pre-cooling, followed by continuous cooling during the 7-second laser pulse application period. In some cases, additional time for the application of a cooling mechanism at the skin surface may be provided during the pre-cooling cycle, and the cooling provided at the skin surface may be adjusted in real time during application (e.g., by adjusting the cooling airflow rate).

[0146] In an alternative approach, the combination of cooling and photothermal heating pulses can be adjusted to rapidly achieve a peak thermal gradient just below the 52°C pain threshold at the desired depth early in the 7-second laser application cycle, followed by reducing heating (e.g., by reducing the power and / or duration of subsequent pulses) to maintain the peak temperature at the desired depth while allowing time for heat diffusion, thus heating deeper tissue. In yet another approach, pre-cooling and treatment time can be further reduced by increasing cooling power through lowering the temperature of the cooling mechanism or increasing the heat transfer coefficient (e.g., increasing the cooling air velocity in an air-cooling system). If the skin surface temperature can be maintained just above the frostbite temperature during photothermal energy application, additional cooling can reduce the temperature at deeper depths more quickly, thus pushing the peak of the TG profile deeper below the skin surface. This effect will allow for the application of greater heating power (e.g., increased laser pulse power or duration), effectively resulting in deeper penetration of the heating power into the tissue for a given pulse application sequence, while preventing damage to shallower tissues.

[0147] In the embodiments, the purpose of the process described herein is to maintain the dermal temperature below the generally accepted pain threshold temperature of 52°C. Skin surface temperature and its correlation with dermal temperature can be determined using the process described herein and used as an indicator of temperature at a certain depth below the skin surface (e.g., in the dermis).

[0148] Figure 15 This is a simplified graph illustrating the temperature profile of the dermis and skin surface as a function of time when a desired thermal gradient profile is achieved and maintained using a continuous wave (CW) light source according to an embodiment. In other words, instead of using laser pulses to establish the initial thermal gradient, a CW light source can be used to establish and maintain the initial thermal gradient profile.

[0149] likeFigure 15 As shown in the figure, graph 1500 illustrates the changes over time and their correlation with the pain threshold T. pain and the target chromophore damage threshold T damage The relevant applied CW power and dermal temperature T dermis With skin surface temperature T surface The temperature relationship between them. T pain and T damage It is indicated as a horizontal dashed line.

[0150] A CW laser source can be applied at the treatment site, such as by... Figure 15 The dashed curve in the diagram indicates this. Therefore, T dermis and T dermis It also increases over time. In an embodiment, the CW power can initially increase rapidly to above T. pain The pain level then gradually decreases over time. In some embodiments, an increase in CW power above the pain threshold can be alleviated by appropriate pre-cooling and / or continuous cooling of the skin surface.

[0151] As CW power decreases, the wavelength of the CW light source can be selected to promote heating of deeper dermis while maintaining skin surface temperature at an acceptable level for the subject. This time period is within... Figure 15 The middle is indicated as t ETG Next, using the same CW light source or by using a separate pulsed laser, the laser power can be pulsed to target the chromophore to initiate the treatment protocol. Establishing a thermal gradient using CW power allows sufficient power to be delivered to raise the temperature of the target chromophore above the damage threshold T0. damage At the same time, it keeps the skin surface temperature below the pain threshold T. pain .

[0152] In the embodiments, replacing such as Figure 15 The initial surge in CW laser power shown herein allows for gradual increases in CW power from low to high to establish a thermal gradient. Suitable CW sources may include, for example, infrared CW lasers, light-emitting diodes, and others. Other CW power application schemes may be considered and are considered part of this disclosure.

[0153] Figure 16 This is to demonstrate the corresponding embodiment. Figure 15 A simplified curve of the TG profile applied by a CW laser. (See diagram below.) Figure 16 As shown in the figure, the depth of the peak temperature below the skin surface over time is displayed during the application of CW power.

[0154] At time t0, when the peak CW power is applied, as Figure 15As shown in the middle, the peak temperature is closer to the skin surface. When the CW power is gradually decreased over time (e.g., at ti and t2), the peak temperature under the skin surface at time t ∞ moves gradually deeper towards the steady state thermal gradient.

[0155] The use of CW power can be advantageous because the steady state temperature at the depth of the target chromophore can be maintained at a higher temperature than with a pulsed pre-heat protocol. In addition, CW power can be applied over a larger surface area at and around the target treatment location, thus enabling more extensive heating and earlier establishment of thermal gradients over a larger surface area.

[0156] In addition to the embodiments listed above, additional embodiments are contemplated, such as the following:

[0157] 1. A method for determining a suitable set of parameters for operating a light source within a photothermal targeting therapy system for marking a chromophore embedded in a medium, the method comprising:

[0158] 1) administering at least one laser pulse from the light source to a location to be treated at a preset power level, the preset power level being below a known pain and damage threshold;

[0159] 2) measuring a skin surface temperature at the location to be treated;

[0160] 3) correlation fitting a relationship between the parameters for operating the light source and the skin surface temperature of the location to be treated;

[0161] 4) defining a safe operating range of the parameters for operating the light source so as to avoid pain and thermal damage to the medium at the location to be treated;

[0162] 5) maintaining the skin surface temperature below the known pain and damage threshold while increasing a peak temperature and depth of thermal gradient until at a correct depth; and

[0163] 6) administering at least one higher level laser pulse from the light source above the known pain threshold and below the damage threshold to raise the temperature of the target chromophore to its desired damage temperature, effectively marking the chromophore when administering a treatment protocol.

[0164] 2. A method for determining a suitable set of parameters for operating a light source within a photothermal targeting therapy system for marking a chromophore embedded in a medium, the method comprising, prior to administering a treatment protocol to a first subject:

[0165] 1) cooling a first treatment location, wherein the cooling comprises directing an air flow over the first treatment location;

[0166] 2) applying at least one laser pulse from the light source to the first treatment location on the first subject at a pre-set power level, the pre-set power level being below a known pain and damage threshold;

[0167] 3) measuring the skin surface temperature at the first treatment location after applying the at least one laser pulse;

[0168] 4) estimating a relationship between the parameters for operating the light source, post-pulse cooling, and the skin surface temperature at the first treatment location by fitting the skin surface temperature and the parameters for operating the light source using data correlation, wherein a priori knowledge of the correlation from clinical experiments is used to establish predictive parameters using computational analysis;

[0169] 5) defining a safe operating range of the parameters for operating the light source so as to remain below the pain threshold of the medium at the first treatment location while still effectively targeting the chromophore in applying the treatment regimen, wherein the safe operating range corresponds to a skin surface temperature between about 28°C and 34°C;

[0170] 6) measuring the skin surface temperature at the first treatment location at least once during the treatment regimen;

[0171] 7) adjusting the safe operating range of the parameters of the light source at the first treatment location, maintaining the skin surface temperature below the known pain threshold while simultaneously increasing the peak temperature and depth of thermal gradient until at the correct depth, wherein the estimating, defining, measuring, and adjusting are continually updated during treatment; and

[0172] 8) applying at least one higher level laser pulse from the light source that is above the known pain threshold and below the damage threshold to raise the temperature of the target chromophore to its desired damage temperature, effectively targeting the chromophore in applying the treatment regimen. For example, the laser pulse can provide a temperature rise above the chromophore damage threshold while remaining below the damage threshold of surrounding tissue.

[0173] 3. The method of item 2, further comprising: repeating steps 1) through 8) at a second treatment location on the first subject prior to applying the treatment regimen at the second treatment location.

[0174] 4. The method of item 2, further comprising: repeating steps 1) through 8) at the first treatment location on a second subject prior to applying the treatment regimen to the second subject.

[0175] 5. The method of item 2, further comprising:

[0176] 9) storing in a memory of the photothermal targeting therapy system the safe operating range of the parameters of the light source operated at the first treatment location on the first subject; and

[0177] 10) considering the parameters so stored in the memory when later administering the treatment regimen on the first subject.

[0178] 6. The method of item 2, further comprising:

[0179] 9) adjusting the parameters of the light source to reduce the effective power incident at the first treatment location if the skin surface temperature at the first treatment location reaches a pre-set threshold temperature.

[0180] 7. The method of item 2, wherein defining the safe operating range of the parameters of the light source comprises setting at least one of laser power, pulse width, pulse interval, maximum power output, and skin surface cooling mechanism.

[0181] 8. The method of item 2, further comprising repeating steps 1) through 8) at a second treatment location on the first subject during administration of the treatment regimen at the second treatment location.

[0182] 9. The method of item 2, further comprising repeating steps 1) through 8) at a first treatment location on a second subject during administration of the treatment regimen on the second subject.

[0183] 10. The method of item 9, further comprising:

[0184] 9) storing in a memory the parameters of the light source operated for the first subject at the first treatment location of the second subject; and

[0185] 10) considering the parameters so stored in the memory for operating the light source when later administering the treatment regimen on the second subject.

[0186] 11. A method for determining a suitable set of parameters for operating a light source within a photothermal targeting therapy system for chromophores embedded in a calibration medium, the method comprising:

[0187] a) cooling a first treatment location;

[0188] b) applying at least one laser pulse from the light source to the first treatment location at a pre-set power level, the first laser pulse having thermal energy below a known pain and damage threshold of the medium;

[0189] c) tracking skin surface temperature at the first treatment location at a refresh rate of 25 Hz to 400 Hz while applying the first laser pulse;

[0190] d) estimating a relationship between the parameters for operating the light source, post-pulse cooling, and the skin surface temperature at the first treatment location by using data correlation to fit the skin surface temperature and the parameters for operating the light source, wherein a priori knowledge of the correlation from clinical experiments is used to establish predictive parameters using computational analysis;

[0191] e) defining a "safe" operating range of the parameters operating the light source (i.e., related to pain) in order to keep below the pain threshold of the medium at the first treatment location while still effectively targeting the chromophore in applying the treatment regimen, wherein the safe operating range corresponds to the skin surface temperature between about 28°C and 34°C;

[0192] f) continuing to track skin surface temperature at the first treatment location at a refresh rate of 25 Hz to 400 Hz while applying additional laser pulses;

[0193] g) adjusting the safe operating range of the parameters of the light source at the first treatment location, maintaining the skin surface temperature below the known pain threshold while simultaneously increasing the peak temperature and depth of thermal gradient until at the correct depth, wherein the estimating, defining, measuring, and adjusting are continuously updated during treatment; and

[0194] h) defining at least one higher level laser pulse from the light source above the known pain threshold and below the damage threshold to raise the temperature of the target chromophore to its required damage temperature, effectively targeting the chromophore.

[0195] 12. The method of item 11, further comprising repeating steps a through h at a second treatment location on the first subject.

[0196] 13. The method of item 11, further comprising repeating steps a) through h) on a second subject.

[0197] 14. The method of item 11, wherein adjusting the parameters for operating the light source comprises adjusting at least one of laser power, pulse width, pulse separation, maximum power output, and skin surface cooling mechanism for performing the cooling.

[0198] 15. A method of treating a subject using a photothermal targeting therapy system comprising a light source for calibrating a chromophore embedded in a medium, the method comprising:

[0199] a) cooling a first treatment location of the subject from a first surface temperature to a second surface temperature;

[0200] b) administering a laser pulse from the light source to the first treatment location;

[0201] c) tracking a skin surface temperature at the first treatment location during application of the laser pulse using an infrared camera operating at a refresh rate of 25 Hz to 400 Hz; and

[0202] d) terminating the treatment regimen based at least in part on the skin surface temperature so measured.

[0203] 16. The method of item 15, wherein cooling the first treatment location comprises cooling the first treatment location from the first surface temperature of body temperature to a second surface temperature that is less than body temperature.

[0204] 17. The method of item 15, wherein cooling comprises using a contact cooling mechanism. In embodiments, the cooling can comprise cooling by a stream of cooling air. In other embodiments, other cooling mechanisms can be used, such as refrigerant spray cooling.

[0205] 18. The method of item 15, wherein tracking a skin surface temperature comprises determining the skin surface temperature at a refresh rate of at least 400 Hz.

[0206] 19. The method of item 15, wherein terminating the treatment regimen comprises fitting the skin surface temperature so tracked to a data correlation, wherein a predictive parameter is established using computational analysis taking into account a priori knowledge of the correlation from clinical experiments, appropriate laser parameters of the light source are determined, and the treatment regimen is modified according to the appropriate laser parameters.

[0207] 20. The method of item 19, wherein terminating the treatment regimen further comprises determining appropriate cooling parameters of the cooling mechanism, and modifying the cooling parameters during the treatment regimen.

[0208] 21. The method of item 17, wherein terminating the treatment regimen comprises fitting the skin surface temperature so tracked to a data correlation, wherein the predictive parameter is established using computational analysis taking into account a priori knowledge of the correlation from clinical experiments, a peak skin surface temperature is predicted, and at least one of laser power, pulse width, number of pulses, and cooling system parameters are adjusted.

[0209] 22. The method of item 21, wherein the peak skin surface temperature is a temperature in the range of 40°C and 55°C. In embodiments, the peak skin surface temperature can be maintained between 41°C and 45°C in order to remain below the pain threshold of a broad patient population.

[0210] 23. The method of item 22, wherein the peak skin surface temperature is about 51°C.

[0211] 24. The method of item 15, wherein the pulse duration of the laser pulses is 100 milliseconds.

[0212] 25. The method of item 15, wherein terminating the treatment regimen comprises fitting the skin surface temperature so tracked to a data correlation, wherein the predictive parameters are established using computational analysis taking into account a priori knowledge of the correlation from clinical experiments, determining appropriate laser parameters for the light source, and modifying the treatment regimen according to the appropriate laser parameters.

[0213] 26. The method of item 25, wherein terminating the treatment regimen further comprises determining appropriate cooling parameters for the cooling mechanism, and modifying the cooling parameters during the treatment regimen.

[0214] 27. The method of item 26, wherein terminating the treatment regimen comprises fitting the skin surface temperature so tracked to a data correlation, wherein the predictive parameters are established using computational analysis taking into account a priori knowledge of the correlation from clinical experiments, predicting a peak skin surface temperature, and adjusting at least one of laser power, pulse width, number of pulses, and cooling system parameters.

[0215] 28. The method of item 27, wherein the peak skin surface temperature is a temperature in the range of 40°C and 55°C.

[0216] 29. The method of item 28, wherein the peak skin surface temperature is in the range of 41°C and 45°C.

[0217] 30. The method of item 15, wherein the pulse duration of the laser pulses is 100 milliseconds.

[0218] As used herein, recitation of "at least one of A, B, and C" is intended to mean "A, B, C, or any combination of A, B, and C." The foregoing description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the disclosure. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein can be applied to other embodiments without departing from the spirit or scope of the disclosure. Thus, the present disclosure is not intended to be limited to the disclosed embodiments, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

[0219] The terminology and phraseology employed herein are for descriptive purposes and not limiting, and any equivalents for the terms and expressions used herein are to be considered within the scope of the disclosure. Each of the various elements disclosed herein can be implemented in various ways. The disclosure should be understood to encompass every variation within the scope of the disclosure, whether or not the variation is expressly disclosed. In particular, it is understood that the word "element" can be expressed as an equivalent term, such as "means," even if only a function or result is the same. Such equivalents, broader or even more general terms, should be considered to be encompassed in the description of each element or action. Such terms can be substituted as desired to explicitly give the disclosure the full breadth of the implied scope.

[0220] As just one example, it is understood that all actions can be expressed as a means or element that takes the action or causes the action. Similarly, each physical element disclosed should be understood to encompass the disclosure of the action facilitated by the physical element. In this last regard, as just one example, the disclosure of a "protrusion" should be understood to encompass the disclosure of the action of "protruding" (whether or not explicitly discussed) and conversely, if there is merely a disclosure of the action of "protruding," this disclosure should be understood to encompass the disclosure of a "protrusion." Such variations and alternative terms are to be understood to be expressly included in the description.

[0221] In the description, embodiments of the application have been disclosed with reference to specific terminology. However, the description is not intended to limit the scope of the application in that specific terminology. While several exemplary embodiments have been described, it should be apparent that many modifications are possible in the exemplary embodiments without departing from the spirit or scope of the application. Accordingly, it is intended that the foregoing description be considered as illustrative only of the principles of the application and not in a limiting sense, and that modifications of the disclosed embodiments, as well as other embodiments, within the scope of the present disclosure, are intended to be included.

Claims

1. A method for determining a suitable set of parameters for operating a light source within a photothermal targeting therapy system for targeting a chromophore embedded in a medium, the method comprising: 1) administering at least one initial laser pulse from the light source to a location to be treated at a preset power level, the preset power level being below a known pain and damage threshold; 2) measuring a skin surface temperature at the location to be treated; 3) correlation fitting a relationship between the parameters for operating the light source and the skin surface temperature at the location to be treated; 4) defining a safe operating range of the parameters operating the light source so as to avoid pain and thermal damage to the medium at the location to be treated; 5) maintaining the skin surface temperature below the known pain and damage threshold while simultaneously increasing a peak temperature and depth of a thermal gradient until the peak temperature and depth of the thermal gradient reaches a desired depth within the medium at the location to be treated; and 6) administering at least one treatment laser pulse from the light source having a power higher than the at least one initial laser pulse to raise a temperature of the target chromophore to its required damage temperature to effectively target the chromophore upon administration of a treatment regimen.

2. A method for determining a suitable set of parameters for operating a light source within a photothermal targeting therapy system for targeting a chromophore embedded in a medium, the method comprising, prior to administering a treatment regimen on a first subject: 1) cooling a first treatment location, wherein the cooling includes directing an airflow over the first treatment location; 2) administering at least one laser pulse from the light source to the first treatment location on the first subject at a preset power level, the preset power level being below a known pain and damage threshold; 3) measuring a skin surface temperature at the first treatment location after administering the at least one laser pulse; 4) estimating a relationship between the parameters for operating the light source, post-pulse cooling, and the skin surface temperature at the first treatment location by fitting the skin surface temperature and parameters for operating the light source using a data correlation, wherein a priori knowledge of a correlation from a clinical experiment is used to establish predictive parameters using computational analysis; 5) defining a safe operating range of the parameters operating the light source so as to remain below the pain threshold of the medium at the first treatment location while still effectively targeting the chromophore upon administration of the treatment regimen, wherein the safe operating range corresponds to a skin surface temperature between about 28°C and 34°C; 6) measuring the skin surface temperature at the first treatment location at least once during the treatment regimen; 7) adjusting the safe operating range of the parameters of the light source at the first treatment location, maintaining the skin surface temperature below the known pain threshold while simultaneously increasing a peak temperature and depth of a thermal gradient until at a correct depth, wherein the estimating, defining, measuring, and adjusting are continually updated during treatment; and 8) administering a treatment regimen to the first subject. 8) applying at least one higher level laser pulse from the light source, defined above the known pain threshold and below the damage threshold, to raise the temperature of the chromophore to its desired damage temperature.

3. The method of claim 2, further comprising: repeating steps 1) through 8) at a second treatment location on the first subject prior to applying the treatment regimen at the second treatment location.

4. The method of claim 2, further comprising: repeating steps 1) through 8) at the first treatment location on a second subject prior to applying the treatment regimen to the second subject.

5. The method of claim 2, further comprising: 9) storing in a memory of the photothermal targeting therapy system the safe operating range of the parameters of the light source operated at the first treatment location on the first subject; and 10) considering the parameters so stored in the memory when later applying the treatment regimen to the first subject.

6. The method of claim 2, further comprising: 9) adjusting the parameters of the light source to reduce the effective power incident at the first treatment location if the skin surface temperature at the first treatment location reaches a pre-set threshold temperature.

7. The method of claim 2, wherein defining the safe operating range of the parameters of the light source includes setting at least one of laser power, pulse width, pulse interval, maximum power output, and skin surface cooling mechanism.

8. The method of claim 2, further comprising: prior to the determining, at repeating steps 1) through 8) at a second treatment location on the first subject prior to applying the treatment regimen at the second treatment location.

9. The method of claim 2, further comprising: repeating steps 1) through 8) at a second treatment location on the first subject prior to applying the treatment regimen at the second treatment location.

10. The method of claim 9, further comprising: 9) storing in a memory the parameters of the light source operated for the first subject at the first treatment location of the second subject; and 10) considering the parameters so stored in the memory for operating the light source when later applying the treatment regimen to the second subject.

11. A method for determining a suitable set of parameters for operating a light source within a photothermal targeting therapy system for targeting a chromophore embedded in a medium, the method comprising: a) cooling a first treatment location; b) applying at least one laser pulse from the light source to the first treatment location at a pre-set power level, the first laser pulse having thermal energy below known pain and damage thresholds of the medium; c) tracking a skin surface temperature at the first treatment location at a refresh rate of 25 Hz to 400 Hz while applying the first laser pulse; d) estimating a relationship between the parameters for operating the light source, post-pulse cooling, and the skin surface temperature at the first treatment location by fitting the skin surface temperature and the parameters for operating the light source using data correlation, wherein a priori knowledge of the correlation from clinical experiments is used to establish predictive parameters using computational analysis. e) defining an operating range of the parameters operating the light source to maintain below the pain threshold of the medium at the first treatment location while still effectively targeting the chromophore in administering the treatment regimen, wherein the safe operating range corresponds to the skin surface temperature between about 28°C and 34°C; f) continuing to track the skin surface temperature at the first treatment location with a refresh rate of 25 Hz to 400 Hz while administering additional laser pulses; g) adjusting the operating range of the parameters of the light source at the first treatment location, maintaining the skin surface temperature below the known pain threshold while simultaneously increasing the peak temperature and depth of the thermal gradient at the first treatment location to a desired depth, wherein the estimating, defining, measuring, and adjusting are continuously updated during the treatment regimen; and h) defining at least one higher level laser pulse from the light source above the known pain threshold and below the damage threshold to raise the temperature of the chromophore to its required damage temperature.

12. The method of claim 11, further comprising repeating steps a) through h) at a second treatment location on the first subject.

13. The method of claim 11, further comprising repeating steps a) through h) on a second subject.

14. The method of claim 11, wherein adjusting the parameters for operating the light source includes adjusting at least one of laser power, pulse width, pulse separation, maximum power output, and a skin surface cooling mechanism for performing the cooling.

15. A method of treating a subject using a photothermal targeting treatment system including a light source for targeting a chromophore embedded in a medium, the method comprising: a) cooling a first treatment location of the subject from a first surface temperature to a second surface temperature; b) administering a laser pulse from the light source to the first treatment location; c) tracking a skin surface temperature at the first treatment location during application of the laser pulse using an infrared camera operating with a refresh rate of 25 Hz to 400 Hz; and d) terminating the treatment regimen based at least in part on the skin surface temperature so measured.

16. The method of claim 15, wherein cooling the first treatment location includes cooling the first treatment location from the first surface temperature of body temperature to a second surface temperature less than body temperature.

17. The method of claim 15, wherein cooling includes using at least one of contact cooling, a stream of cooling air, and a spray of refrigerant.

18. The method of claim 15, wherein tracking a skin surface temperature includes determining the skin surface temperature with a refresh rate of at least 400 Hz.

19. The method of claim 15, wherein terminating the treatment regimen includes fitting the skin surface temperature so tracked to a data correlation, wherein a priori knowledge of the correlation from clinical experiments is used to establish predictive parameters using computational analysis, determine appropriate laser parameters of the light source, and the method further comprising: modifying the treatment regimen according to the appropriate laser parameters.

20. The method of claim 19, wherein terminating the treatment regimen further comprises determining appropriate cooling parameters of the cooling mechanism, and modifying the cooling parameters during the treatment regimen.

21. The method of claim 17, wherein terminating the treatment regimen comprises fitting the skin surface temperature so tracked to a data correlation, wherein the prior knowledge of the correlation from clinical experiments is used to establish the predictive parameters using computational analysis, the method further comprising: predicting a peak skin surface temperature, and adjusting at least one of laser power, pulse width, number of pulses, and cooling system parameters according to the peak skin surface temperature so predicted.

22. The method of claim 21, wherein the peak skin surface temperature is a temperature in the range of 40°C and 55°C.

23. The method of claim 22, wherein the peak skin surface temperature is 45°C.

24. The method of claim 15, wherein the pulse duration of the laser pulses is 100 milliseconds.

25. The method of claim 15, wherein terminating the treatment regimen comprises fitting the skin surface temperature so tracked to a data correlation, wherein the appropriate laser parameters of the light source are determined taking into account prior knowledge of the correlation from clinical experiments, and the treatment regimen is modified according to the appropriate laser parameters using computational analysis to establish the predictive parameters.

26. The method of claim 25, wherein terminating the treatment regimen further comprises determining appropriate cooling parameters of the cooling mechanism, and modifying the cooling parameters during the treatment regimen.

27. The method of claim 26, wherein terminating the treatment regimen comprises fitting the skin surface temperature so tracked to a data correlation, wherein the predictive parameters are established using computational analysis, including taking into account prior knowledge of the correlation from clinical experiments, predicting a peak skin surface temperature, and adjusting at least one of laser power, pulse width, number of pulses, and cooling system parameters.

28. The method of claim 27, wherein the peak skin surface temperature is a temperature in the range of 40°C and 55°C.

29. The method of claim 28, wherein the peak skin surface temperature is in the range of 41°C and 45°C.

30. The method of claim 15, wherein the pulse duration of the laser pulses is 100 milliseconds.

31. A photothermal targeting therapy system for calibrating a chromophore embedded in a medium, the system comprising: a cooling unit for providing cooling at a treatment location; a light source for providing laser pulses at the treatment location; a temperature monitoring unit for monitoring a skin surface temperature at the location; and a controller for receiving the skin surface temperature as monitored by the temperature monitoring unit, and controlling operation parameters of the cooling unit and the light source accordingly, wherein the controller is configured for: terminating the treatment regimen when the skin surface temperature so monitored reaches a predetermined threshold, directing the light source to apply at least one laser pulse to the treatment site at a preset power level, the preset power level being below a known pain and damage threshold, directing the temperature monitoring unit to measure a skin surface temperature at the treatment site, correlation fitting a relationship between the operating parameters of the light source and the skin surface temperature thus measured, defining a safe operating range of the operating parameters of the light source so as to avoid pain and thermal damage to the medium at the treatment site, modifying the operating parameters of at least one of the cooling unit and the light source to apply at least one higher level laser pulse from the light source to maintain the skin surface temperature below the known pain and damage threshold while at the same time increasing the peak temperature and depth of the thermal gradient until the peak temperature and depth of the thermal gradient reaches a desired depth within the medium at the treatment site, and directing the light source to apply at least one treatment laser pulse from the light source at a power higher than the at least one initial laser pulse to raise the temperature of the target chromophore to its required damage temperature.

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