CN120916722A

CN120916722A - Photothermal targeted therapy and safety systems for efficacy, consistency and pain minimization and associated methods

Info

Publication number: CN120916722A
Application number: CN202480018643.0A
Authority: CN
Inventors: H·霍万德; A·J·埃克; M·J·埃斯蒂斯
Original assignee: Aikul Acne Treatment Co
Current assignee: Aikul Acne Treatment Co
Priority date: 2023-03-14
Filing date: 2024-03-14
Publication date: 2025-11-07
Also published as: WO2024196714A3; EP4680138A2; KR20250158058A; WO2024196714A2

Abstract

A method for determining parameters for operating a light source within a photothermal targeted therapy system for calibrating a chromophore embedded in a medium includes 1) applying laser pulses to a location to be treated at a preset power level below a known pain and damage threshold, 2) measuring skin surface temperature at the location, 3) fitting a correlation between the light source parameters and the skin surface temperature at the location, 4) defining a safe operating range for the light source parameters to avoid pain and thermal damage at the location, 5) maintaining the skin surface temperature below the known pain and damage threshold and increasing peak temperature and thermal gradient depth, and 6) applying higher level laser pulses to raise the temperature of a target chromophore to its desired damage temperature.

Description

Photothermal targeted therapy and safety systems for efficacy, consistency and pain minimization and associated methods

Reference to related applications

The present application claims the application at day 14, 3, 2023 and entitled "photothermal targeted therapeutic systems for efficacy, consistency, and pain minimization and associated methods (Photo-Thermal Targeted Treatment System and Associated Methods for Efficacy,Consistency,and Pain Minimization)", U.S. provisional application No. 63/451,991. The present application is filed on day 3, 5, 2022 and entitled "determination of dosimetry using measurement of skin surface temperature and predictive closed loop control and associated method (Determination Process and Predictive Closed-Loop Control of Dosimetry Using Measurement of Skin Surface Temperature and Associated Methods)", section of co-pending U.S. patent application No. 17/735,056. The above application is in turn filed on 10 month 21 of 2019 and entitled "dosimetry determination procedure via measurement of skin surface temperature and U.S. patent application serial No. 16/658,818 of the associated method (Dosimetry Determination Process via Measurement of Skin Surface Temperature and Associated Methods)", now filed on 11,317,969, which claims filed on 10 month 22 of 2018 and entitled" dosimetry determination procedure via measurement of skin surface temperature and U.S. provisional patent application serial No. 62/749,104 of the associated method (Dosimetry Determination Process via Measurement of Skin Surface Temperature and Associated Methods)", and filed on 11 month 26 of 2018 and entitled "predictive closed-loop control of dosimetry using measurement of skin surface temperature and claims of U.S. provisional patent application serial No. 62/771,523 of the associated method (Predictive Closed-Loop Control of Dosimetry Using Measurement of Skin Surface Temperature and Associated Methods)"". The entire contents of all of the above-referenced applications are incorporated herein by reference.

Technical Field

The present invention 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, uniformity, and pain minimization in providing photoinduced thermal therapy targeting specific chromophores embedded in a medium.

Background

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

Previous methods of preventing epidermal and dermal damage and pain in a subject include:

1. pre-cooling the epidermis followed by photothermal treatment, and

2. Pre-cooling the epidermis, also preconditioning (i.e., preheating) the epidermis and dermis in a pre-heating regimen, followed by application of photothermal therapy in a different treatment regimen. In some examples, the preheating and treatment protocols are performed by the same laser, although the two protocols involve different laser settings and application protocols, thus resulting in further complexity of the treatment protocols and equipment.

Newer methods have involved, for example, determination and predictive closed loop control using dosimetry of measurements of skin surface temperature, as discussed in the related publications mentioned above. In addition, while taking patient comfort into account, such photothermal treatment systems have turned to provide more effective and consistent treatment results.

Accordingly, there is a need for an improved photothermal targeted therapy system and method for providing effective, consistent therapeutic results during the course of therapy, and minimizing pain felt by the patient.

Disclosure of Invention

The following presents a simplified summary in relation to one or more aspects and/or embodiments disclosed herein. Thus, the following summary should not be considered an extensive overview of all contemplated aspects and/or embodiments, nor is it considered to identify key or critical elements of all contemplated aspects and/or embodiments, or to delineate the scope associated with any particular aspect and/or embodiment. Accordingly, the sole purpose of the summary below is to present some concepts related to one or more aspects and/or embodiments related to the mechanisms disclosed herein in a simplified form prior to the detailed description presented below.

In accordance with embodiments described herein, a method for determining an appropriate set of parameters for operating a light source within a photothermal targeted therapy system for calibrating a chromophore embedded in a medium is disclosed. The method comprises, prior to administering a treatment regimen to a first subject, 1) applying 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 further comprises 2) measuring a skin surface temperature at the first treatment location after applying the at least one laser pulse. The method further includes 3) estimating a relationship between the parameter for operating the light source and the skin surface temperature at the first treatment location, and 4) defining a safe operating range for operating the parameter of the light source so as to avoid thermal damage to the medium at the first treatment location while still effectively targeting the chromophore when the treatment regimen is administered.

In an embodiment, steps 1) through 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) through 4) are repeated at the first treatment location on the second subject prior to administering the treatment regimen to the second subject. In yet another embodiment, the method further includes 5) storing in a memory of the photothermal targeted therapy system the safe operating range of the parameters of operating the light source on the first subject at the first treatment location, and 6) taking into account the parameters so stored in the memory when administering the treatment regimen to the first subject at a later time.

In another embodiment, a photothermal targeted therapeutic system for targeting a chromophore embedded in a medium is disclosed. The system includes a light source configured to provide laser pulses within a range of power levels that includes a known damage threshold and treatment location for the chromophore when operated with a set of parameters. The system also includes a temperature measurement device for measuring a skin surface temperature at the treatment location, and a controller for controlling the light source and the temperature measurement device. The controller is configured for estimating a relationship between the parameter of the light source and the skin surface temperature at the treatment location, defining a safe operating range for the set of parameters of the light source so as to avoid thermal damage to the medium at the treatment location while still effectively targeting the chromophore when a treatment regimen is applied, and configuring the light source to apply the laser pulses within the safe operating range.

In yet another embodiment, a method of adjusting an appropriate parameter set for operating a light source within a photothermal targeted therapy system for targeting a chromophore embedded in a medium during administration of a therapeutic regimen to a first subject at a first treatment location is disclosed. The method includes 1) measuring a skin surface temperature at the first treatment location at least once, 2) predicting a skin temperature when the treatment regimen is administered to the first subject at the first treatment location, and 3) adjusting at least one of the parameters for operating the light source such that future measurements of the skin surface temperature at the first treatment location will not exceed a specified value. The predicted skin temperature considers at least one of a heat transfer model and a series of experimental results.

In another embodiment, a method for determining an appropriate set of parameters for operating a light source within a photothermal targeted therapy system for calibrating a chromophore embedded in a medium is disclosed. The method comprises the following steps:

1) Applying at least one laser pulse from the light source to a site to be treated at a preset power level, the preset power level being below a known pain and injury threshold;

2) Measuring the skin surface temperature at the location to be treated;

3) Performing a correlation fit on a relationship between the parameter for operating the light source and the skin surface temperature of the location to be treated;

4) Defining a safe operating range for operating said parameters of said light source so as to avoid painful and thermal damage to said medium at said location to be treated;

5) Maintaining the skin surface temperature below the known pain and damage threshold while increasing the peak temperature and depth of the thermal gradient until at the correct depth, and

6) At least one higher level laser pulse from the light source above the known pain threshold and below the damage threshold is applied to raise the temperature of the target chromophore to its desired damage temperature, effectively targeting the chromophore when a therapeutic regimen is applied.

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

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

2) Applying 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 injury threshold;

3) Measuring a skin surface temperature at the first treatment location after applying the at least one laser pulse;

4) Estimating a relationship between the parameter 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 parameter for operating the light source using data correlation, wherein a priori knowledge of correlation from clinical experiments is considered to establish a prediction parameter using computational analysis;

5) Defining a safe operating range for operating the parameters of the light source so as to remain below the pain threshold of the medium at the first treatment location while still effectively calibrating the chromophore when the treatment regimen is administered, wherein the safe operating range corresponds to the skin surface temperature of between about 28 ℃ and 34 ℃;

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 parameter of the light source at the first treatment location, maintaining the skin surface temperature below the known pain threshold while increasing the peak temperature and depth of the thermal gradient until at a correct depth, wherein the estimating, defining, measuring and adjusting are continuously updated during treatment, and

8) Applying at least one higher level laser pulse defining a value 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 targeting the chromophore when the treatment regimen is applied.

In another embodiment, a method of treating a subject using a photothermal targeted therapy system comprising a light source for targeting a chromophore embedded in a medium is disclosed. The method comprises the following steps:

a) Cooling a first treatment location of the subject from a first surface temperature to a second surface temperature;

b) Applying laser pulses from the light source to the first treatment location;

c) Tracking skin surface temperature at the first treatment location using an infrared camera operating at a refresh rate of 25Hz to 400Hz during application of the laser pulses, and

D) Terminating the treatment regimen based at least in part on the skin surface temperature so measured.

In another embodiment, a photothermal targeted therapeutic system for targeting a chromophore embedded in a medium is disclosed. The system includes a cooling unit for providing cooling at a treatment site, a light source for providing laser pulses at the treatment site, a temperature monitoring unit for monitoring skin surface temperature at the site, and a controller for receiving the skin surface temperature as monitored by the temperature monitoring unit and controlling operating parameters of the cooling unit and the light source accordingly. In an embodiment, the controller is configured for directing the light source to apply at least one laser pulse to the treatment site at a preset power level below a known pain and damage threshold, directing the temperature monitoring unit to measure skin surface temperature at the treatment site, relatedly fitting the relationship between the operating parameter of the light source and the skin surface temperature so measured, defining a safe operating range for the operating parameter of the light source so as to avoid pain and thermal damage to the medium at the treatment site, modifying the operating parameter 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 increasing 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 treatment site, and directing the light source to apply at least one laser pulse from the light source above the initial temperature of the at least one laser pulse to increase the target temperature thereof.

These and other features and characteristics of the present technology, as well as the methods of operation and functions of the related elements of structure and the combination of parts and economies of manufacture, will become more apparent upon consideration of the following description and the 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 the purpose of illustration and description only and are not intended as a definition of the limits of the invention. As used in the specification and in the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

Drawings

FIG. 1 illustrates an exemplary photothermal targeted therapy system according to an embodiment.

Fig. 2 illustrates an exemplary scanner arrangement for use with a photothermal targeted therapy system according to an embodiment.

Fig. 3 shows a schematic diagram of an exemplary set of light pulses suitable for use as an integrated preconditioning/phototherapy regime, according to an embodiment.

Fig. 4 shows measured temperatures at the skin surface as a function of time as therapeutic light pulses are applied to the skin surface according to an embodiment.

Fig. 5 shows a flowchart illustrating an exemplary process for analyzing the measured skin surface temperature, predicting the temperature of the skin upon application of a subsequent laser pulse and/or additional cooling, then modifying the treatment regimen accordingly.

Fig. 6 shows measured skin surface temperatures of various applied laser pulse powers at similar treatment areas for two different individuals.

Fig. 7 shows a flowchart illustrating an exemplary process for closed loop control of laser system parameters based on real-time skin surface temperature measurements, according to an embodiment.

Fig. 8 shows measured skin surface temperatures resulting from the application of four pulses to a treatment region, and the resulting curve fit and actual temperature measurements, used as data for predicting the rise in skin temperature of a subject following pulse application, according to an embodiment.

Fig. 9 is a graph showing the temperature increase as a function of depth immediately after each of the laser pulse sequences, according to an embodiment.

Fig. 10 is a graph showing a Thermal Gradient (TG) profile just prior to a subsequent continuous laser pulse, according to an embodiment.

Fig. 11 is a graph showing a TG profile immediately after each successive laser pulse is applied, according to an embodiment.

Fig. 12 is a graph showing temperature as a function of depth after each successive laser pulse is applied in a standard 6-pulse scheme, according to an embodiment.

Fig. 13 is a bar graph showing an alternative laser pulse scheme according to an embodiment.

Fig. 14 is a graph showing a TG profile immediately after each successive laser pulse is applied based on an alternative laser pulse scheme according to an embodiment.

Fig. 15 is a simplified graph showing temperature profiles of 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, according to an embodiment.

Fig. 16 is a simplified graph showing a TG profile corresponding to the CW laser application of fig. 15 according to an embodiment.

For simplicity and clarity of illustration, the drawing figures illustrate a general manner of construction, and descriptions and details of well-known features and techniques may be omitted so as to not unnecessarily obscure the embodiments detailed herein. Additionally, elements in the drawings figures are not necessarily drawn to scale. For example, the dimensions of some of the elements in the figures may be exaggerated relative to other elements to help improve the understanding of the described embodiments. Like reference symbols in the various drawings indicate like elements.

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, reference is made to the accompanying drawings, which form a part hereof, and in which is shown by way of illustration or specific examples. These aspects may be combined, other aspects may be utilized, and structural changes may be made without departing from the present disclosure. Example aspects may be practiced as methods, systems, or devices. The following detailed description is, therefore, 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

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

It will be understood that, although the terms first, second, third, etc. may 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 invention.

Spatially relative terms, such as "below," "beneath," "lower," "below," "upper," and the like, may be used herein to describe one element or feature's relationship to another element(s) or feature as illustrated in the figures. It will be understood that 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 the device in the figures is turned over, elements described as "below" or "beneath" other elements or features would then be oriented "above" the other elements or features. Thus, the exemplary terms "below" and "beneath" can encompass both an orientation of above and below. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. In addition, it will be further 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 may also be present.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. 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 may be abbreviated as "/".

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 to, coupled to, or adjacent to the other element or layer, or intervening elements or layers may be present. In contrast, when an element is referred to as being "directly on," "directly connected to," "directly coupled to," or "directly adjacent to" another element or layer, there are no intervening elements or layers present. Likewise, when light is received or provided "from" an element, it can be received or provided directly from that element or from a central element. On the other hand, when light is received or provided "directly from" one element, there are no intervening elements present.

Embodiments of the invention are described herein with reference to cross-sectional illustrations that are schematic illustrations of idealized embodiments (and intermediate structures) of the invention. Thus, variations from the illustrated shapes are expected as a result of, for example, manufacturing techniques and/or tolerances. Thus, embodiments of the invention 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. Thus, the regions illustrated in the figures are schematic in nature and their shapes are not intended to illustrate the actual shape of a region of a device and are not intended to limit the scope of the invention.

Unless defined otherwise, 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 invention 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/or the present specification and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

FIG. 1 shows an exemplary photothermal targeted therapy system for targeting a target, wherein the target comprises a specific chromophore embedded in a medium, and the target is heated to a temperature high enough 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, wherein sebum is a chromophore embedded within the sebaceous glands, while not damaging the epidermis and dermis surrounding the target sebaceous glands.

Still referring to fig. 1, the photothermal targeted therapy system 100 includes a cooling unit 110 and a phototherapy unit 120. The cooling unit 110 provides a cooling mechanism of the cooling effect on the treatment area, i.e. the area of the outer cortex covering the target sebaceous glands, for example by contact or by direct air cooling. The cooling unit 110 is connected to a controller 122 within the light treatment unit 120. It should be noted that although the controller 122 is shown as being housed within the light treatment unit 120 in fig. 1, the controller may be located external to both the cooling unit 110 and the light treatment unit 122, or even within the cooling unit 110.

The controller 122 further controls other components within the light treatment unit 120, such as the laser 124, the display 126, the temperature monitoring unit, the foot switch 130, the door interlock 132, and the emergency on-off switch. The laser 124 provides laser power to the light treatment regimen and the controller 122 adjusts specific settings of the laser, such as output power and pulse time settings. The laser 124 may 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 may include information such as the cooling unit 110, operating conditions of the laser 124, and other system states. 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 a foot switch 130 for remotely switching the laser 124 and/or the cooling unit 110 on or off. In addition, the door interlock 132 may be used as an additional safety measure such that when the door of the treatment room is half-open, the door interlock 132 detects the condition and instructs the controller 122 not to allow the light treatment unit 120 or at least the laser 124 to operate. In addition, an emergency on-off switch 134 may be provided to quickly shut down the photothermal targeted therapy system 100 in an emergency situation. In another modification, additional photodiodes or other sensors may be added to monitor the power level of the energy emitted from the laser 124.

With continued reference to fig. 1, the photothermal targeted therapy system 100 further includes a scanner 160, the scanner 160 being part of a device that is held by a user when a therapeutic regimen is applied to a subject. For example, the scanner may be formed in a gun-like or bar-like shape for ease of handling by a user. The scanner 160 is connected with the cooling unit 110 via a cooling connection 162 so that a cooling scheme can be applied using the scanner 160. In addition, the output from the laser 124 is connected to the scanner 160 via a fiber optic transmission 164 so that a 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 and feedback from the scanner may be implemented as a scanner connection 170.

Fig. 2 shows further details of scanner 160 according to an embodiment. The cooling connection 162 is connected with a cooling transfer unit 202, which cooling transfer unit 202 is configured to transfer a cooling mechanism (e.g., a flow of cold air) to the treatment area. The fiber optic transmission 164 from the laser 124 is connected to a laser energy transmission unit 204, which laser energy transmission unit 204 contains optical components for transmitting light energy for a photothermal treatment regimen to the treatment area. For example, the optical assembly may include a mirror controlled by the controller for directing optical energy in the form of a beam of light across a plurality of treatment points in an automated manner.

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

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

Power modulated CW illumination (see FIG. 15 and 16)

An example of a set of pulses suitable for use in a modulation/light therapy regimen is illustrated in fig. 3, according to an embodiment. The sequence 300 includes pulses of light 322, 324, 326, 328, 330, 332, and 334 applied at a treatment region. In one embodiment, all seven light pulses have equal power and are separated by a uniform pulse interval (represented by double arrow 342) and have the same pulse duration (represented by gap 344). In the example, the pulse duration 344 is 100 milliseconds and the pulse interval is 2 seconds. For example, a2 second pulse interval is intended to allow the epidermis and dermis in the block to cool in order to prevent damage thereto. During the pulse interval period, the laser may scan to different segments within the treatment region in order to increase laser use efficiency. It should be noted that fig. 3 is not drawn to scale.

Fig. 4 shows a measured skin surface temperature when a light pulse (such as the light pulse shown in fig. 3) is applied to a treatment area, according to an embodiment. In the example shown in fig. 4, the treatment area has been pre-cooled by direct air cooling for 7 seconds, then a pulse of light from a 1726nm wavelength laser at 22 watts and duration of 100 milliseconds is applied at a period of 2 seconds while cooling remains in progress. In this particular example, direct air cooling for cooling and during treatment delivers a column of high velocity air cooled to-22 ℃, resulting in a heat transfer coefficient between the skin and air of about 350W/m 2K. In an embodiment, the beam size is 4.9 square millimeters. Depending on the size of the treatment area, the power profile of the laser, the position of the treatment area of the body, and other factors, the exact beam size may be adjusted using, for example, collimating optics.

The resulting change in skin surface temperature is shown in graph 400, with peak 422 corresponding to applied light pulse 322 as shown in fig. 3, and similarly for peaks 424, 426, 428, and 430. In the example shown in fig. 4, the average power per point is 22w×0.15s/2s=1.65W. For example, the same average power per point can be achieved by pulsing at 33 watts for 100ms with a pulse interval of 2s, or pulsing at 25.1W for 125ms with a pulse interval of 1.9 s. Furthermore, the average laser power per area should be balanced against the heat extraction achieved by the cooling system.

The requirements for successful photothermal targeted therapy of a specific 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 ℃, 2) no damage to the dermis, i.e. avoiding dermal overheating by balancing the peak and average power of the therapeutic pulses with the heat extraction of the cooling system, and 3) selective heating of the chromophore and chromophore containing targets, e.g. for sebaceous gland treatment, peak temperatures greater than 55 ℃. It should be noted that the peak temperature value of 55 ℃ is highly dependent on the specific treatment regimen and can be adjusted to other temperatures to remain within safe operating ranges, thereby avoiding damage to the surrounding dermis and epidermis.

It is known in the literature that tissue parameters, such as the thickness of the epidermis and dermis, vary among individuals, depending on factors such as age, sex and race, and between different skin locations on the body. For example, even for the same person, the forehead has different tissue properties than the back, and thus requires different treatment parameter settings for different treatment positions. Such variations in tissue properties are considered in determining a particular treatment regimen, which is important for laser-based acne treatment. In addition, due to manufacturing variability and operating conditions, there may be variations between specific laser systems such as precise laser power, spot size, and cooling capacity. In fact, manufacturing variations from system to system can result in 15% or more energy density variations among different laser treatment systems. Furthermore, individual techniques used by the user to deliver the treatment may also affect the treatment, for example, by different pressures applied to the skin surface, which in turn affect, for example, blood perfusion at the treatment site.

In laser treatment of acne, the operating thermal range is typically constrained to an upper limit of the epidermis and dermis damage threshold temperatures, and a lower limit of the temperature required to bring the sebaceous glands to their damage threshold temperatures. Although there is currently no good way to directly measure the temperature of the sebaceous glands as calibrated by the treatment regimen, the skin surface temperature can be an indicator of the sebaceous gland temperature. The correlation model, which provides a correspondence between sebaceous gland temperature and skin surface temperature, can then be used to tailor the actual treatment regimen using skin surface temperature measurements to effectively map sebaceous gland lesions while maintaining a lesion threshold below the epidermis. The relevant model may be developed using, for example, an analytical heat transfer model, or by using clinical data correlating skin surface temperature to sebaceous gland lesions (e.g., via biopsy) with the application of a particular treatment regimen.

Based on clinical data, using a treatment regimen such as that illustrated in fig. 3 and 4, the operating temperature range for acne treatment expressed in terms of terminal skin surface temperature may be about 40 ℃ to 55 ℃. When the skin surface temperature is between 45 ℃ and 55 ℃ (or even 41 ℃ to 45 ℃), there is a varying degree of sebaceous gland damage, with little epidermal damage. Above 49 ℃, there is also an epidermal lesion in addition to the sebaceous gland lesion. In an example, in certain therapeutic scenarios, it may be desirable to remain in the temperature range of 40 ℃ to 50 ℃. In other cases, it may be desirable to maintain the operating temperature range within 41 ℃ to 45 ℃, for example, in order to ensure that pain and injury thresholds for sensitive patients remain below.

However, clinical data also indicate that for a particular individual, the end skin surface temperature is strongly dependent on tissue parameters at a particular treatment area. While existing treatment protocols have been based on "one treatment being suitable for all" types of methods, innovative analysis protocols can be incorporated into the treatment methods in order to directly determine individual customized treatment parameters inferred from measurements of the end skin temperature at lower laser power and/or the skin surface temperature reached during the initial part of the treatment and/or the end skin surface temperature reached during the previous treatment in order to avoid epidermal damage while effectively causing sebaceous gland damage. In this way, the treatment regimen can be tailored to a particular treatment area of a particular individual, and also mitigate treatment variations caused by variations in laser power output of a particular machine, as well as variations in treatment conditions (e.g., ambient humidity and temperature). Thus, it would be desirable to optimize a treatment regimen for different subjects and even different tissue locations of the same subject so as not to cause unwanted tissue damage while still effectively treating the target tissue component (e.g., sebaceous glands).

For example, by directly measuring the skin surface temperature during the first four pulses of fig. 3, the maximum skin surface temperature after the application of subsequent pulses can be predicted with high accuracy. This prediction may be used to modify in real time a particular treatment regimen for a particular area of skin, such as reducing the number of pulses applied for subsequent pulses, adjusting pulse width, or modifying laser power. If the laser system incorporates a cooling system that can react fast enough, the cooling can also be adjusted as part of the real-time modification of the treatment system parameters. This customization process greatly improves the comfort and safety of the subject during the course of treatment.

This analysis scheme may be performed by incorporating temperature measurements using a commercially available off-the-shelf low cost camera, such as may be built into a scanner (see, e.g., temperature sensor 206 of fig. 2) held by a medical professional to apply treatment to a subject, or by using a separate, commercially available off-the-shelf single-pixel or multi-pixel thermal measurement device. The prediction process may be performed at a highly localized level, thus adjusting the treatment plan on the fly or before the treatment begins, even adjusting the plan for each individual point in the treatment matrix. In this way, a treatment regimen may be specified to provide the necessary therapeutic laser power while remaining below the epidermis and dermis damage threshold temperatures.

Turning to FIG. 5, a flowchart illustrates an exemplary process of an analysis scheme, according to an embodiment. The analysis protocol assumes that the highest skin temperature and damage threshold temperature of the target (e.g., sebaceous glands) are known. In addition, correlation models between skin surface temperature and a target (e.g., sebaceous glands) have been established using computational analysis, such as, for example, finite element modeling of heat transfer, or by clinical experiments using biopsies. Thus, for the analysis scheme, it is assumed that the target value of the terminal skin surface temperature is known. As an example, for the treatment protocols previously described in fig. 3 and 4, the target peak skin surface temperature is known to be 51 ℃.

As shown in fig. 5, the analysis scheme 500 begins by applying a low power laser pulse to the treatment region in step 512. The laser power should be set to a value below the damage threshold of the epidermal damage. The skin surface temperature at the treatment area is then measured in step 514. For example, a low-speed infrared camera or similar device may be used to perform the temperature measurement. It is then determined in decision 516 whether enough data has been collected to fit the collected data into a pre-established correlation model. If the answer to decision 516 is no, then the process returns to step 512 where laser pulses of different, low power settings are applied to the treatment area to collect additional correlation data between the applied laser power and the skin temperature at step 512.

If the answer to decision 516 is yes, then the analysis scheme 500 continues to fit 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.

With continued reference to fig. 5, optionally, the analysis protocol 500 may continue during the actual treatment regimen. In an exemplary embodiment, after the laser parameters are set in step 522, a treatment protocol with the appropriate laser parameters is initiated in step 530. Next, 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 plan are updated based on the updated calculations. A decision 538 is then made to determine whether the treatment plan (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 scheme returns to step 532 to continue measuring skin surface temperature. If the answer to decision 538 is yes, then the treatment regimen is terminated in step 540.

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

Turning now to fig. 6, an example of an analysis protocol and subsequent treatment protocols 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 points 612, 614 and 616 show the initial three low power laser pulses applied to subject "C Carlton", after which the analysis scheme described above is used to predict peak skin surface temperature measured by the IR camera, thus defining a safe operating range as indicated by horizontal dashed line 618 and vertical dashed line 620. Points 622, 624 and 626 show data taken at a slightly higher laser power setting on the same subject "C Carlton".

With continued reference to fig. 6, to determine the applicability of the same dosimetry determination process to different subjects, the same power laser pulse is applied to a second subject "S Carlton", starting from a similar starting temperature, as shown by point 630. As shown by points 632, 634, and 636, on the second subject "S Carlton", a treatment regimen that increased laser power was immediately applied, without a dosimetry regimen at a lower temperature. While the actual measured skin temperature of the second subject "S Carlton" is different from the skin temperature of the first subject "C Carlton", the graph 600 indicates that the safe operating range indicated by the dashed lines 618 and 620 would also apply to the second subject "S Carlton" in addition. In this way, the above described analysis schemes take these individual differences into account when tailoring the treatment scheme to a particular treatment area on a particular individual. The efficacy of the assay protocol has been validated with in vivo data.

The analysis protocol may be performed prior to the actual treatment session, for example, in a appointment or when the subject is examined prior to treatment. When low power is used, the analysis protocol may be performed without the need for local anesthesia, virtually no epidermal or dermal damage occurs during application of the analysis protocol. For example, in preparing a treatment, a trained operator can quickly predict various treatment locations and formulate a personalized treatment regimen by means of one scan of each skin location. Alternatively, temperature adjustments, including adjustments of laser power and/or cooling mechanisms, may be performed in real-time during an actual treatment regimen.

Once a relationship between laser power and resulting skin surface temperature has been established for a particular subject and/or a particular skin location and/or a particular laser device, this relationship, indicated by the slope of the lines connecting points 612, 614, 616, 622, 624, and 626 in fig. 6, may be used to continuously adjust future treatments. Furthermore, as the treatment plan continues, all treatment data may be added to the basis for establishing a skin surface and power correlation. In this way, the correlation is continually updated and refined even after the treatment regimen is initiated. For example, based on a known relationship between laser power and the resulting skin surface temperature achieved at a particular treatment location, a suggestion may be given to the dermatologist to adjust the laser parameters (e.g., laser power) for manual adjustment, or the device may automatically adjust for the next treatment location, e.g., laser power.

The concepts of the analysis schemes described above can be extended to real-time adjustment of treatment schemes using closed-loop control procedures. The surface temperature of the skin may be measured using, for example, an Infrared (IR) camera or other temperature measurement mechanism. For example, by fitting the measured temperature to a mathematical model of skin tissue, the measured skin surface temperature can be correlated with the temperature of a target component (e.g., sebaceous glands) that cannot be measured directly.

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

In other words, the dosimetry administered to the subject (e.g., settings of the light treatment, including, for example, power settings of the laser source) may be adjusted in real-time using a predictive control process. For example, by directly measuring skin temperature during pulses 322, 324, and 326 shown in fig. 3, the predicted maximum skin 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 skin surface temperature after application of, for example, three or four therapeutic 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 illustrated in fig. 3, various curve fitting methods, such as a single exponential function, may provide an accurate model of skin surface temperature after the subsequent treatment pulse application. This prediction can then be used to modify in real time a particular treatment regimen for a particular skin region. For example, the user may modify the number of additional pulses applied, as well as one or more of the pulse width and laser power of subsequent pulses. Additionally, if the light therapy system includes a sufficiently responsive cooling unit, the cooling applied to the treatment region may also be adjusted as part of the real-time modification of the therapy system parameters. This customization process greatly improves patient comfort and safety during the course of treatment.

Analysis used in predictive control may be performed using a temperature measurement device, such as a commercially available low cost camera incorporated into a scanner (e.g., temperature sensor 206 of fig. 2), or by using a separate thermal measurement device, such as a single-pixel or multi-pixel thermal imager. By controlling the size of the target treatment area and specifically measuring the skin surface temperature at the target treatment area, the prediction process can be performed at a highly localized level, thus enabling a medical professional administering the treatment regimen to adjust in real time, or even for each individual point in the treatment matrix, before the treatment regimen begins. In this way, the treatment regimen can be administered in a highly customizable manner to provide the necessary therapeutic laser power while remaining below the epidermis and dermis damage threshold temperatures.

For example, arrhenius (Arrhenius) lesion function gives an index of target lesions and peak temperatures, and then the peak temperature of the skin surface is correlated with the peak temperature of the target component. In the example, for irradiation of a 22W laser with 100ms pulses at a 5mm by 5mm point, the temperature rise is about 180℃per second, in which case the skin surface measurements should be updated about every 2.5ms or at 400Hz in order to use the temperature measurements as control input for the treatment regimen. With this rapid temperature measurement method, the laser may be turned off when the measured skin surface temperature reaches a preset threshold.

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

The flowchart shown in fig. 7 illustrates an exemplary process of closed loop control of laser system parameters based on real-time skin surface temperature measurements according to an embodiment. Process 700 begins with the initialization of a laser treatment protocol in which the laser system is set to a treatment setting (i.e., treatment power level, pulse width, etc.). In step 712, laser pulses are applied to the treatment region according to the treatment protocol. The treatment regimen may involve, for example, the application of pulses of sequentially increasing power, or repeated pulses of substantially the same power setting applied to the treatment area. An example treatment protocol involves repeated application of laser pulses from a 22W laser with a spot size of 5mm x 5mm and a duration of 100 ms.

With continued reference to fig. 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, measurements may be made by a 25Hz refresh rate infrared camera. Faster devices, such as 400Hz refresh rate temperature measurement devices, can be used to more accurately measure skin surface temperature during and after the application of laser pulses.

It is then determined in decision 716 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 a predictive model. A curve fit of the maximum and optionally minimum skin surface temperatures is generated during step 718. For example, predictive models may be generated by compiling a number of temperature measurements corresponding to the application of laser pulses to a test subject in a clinical setting or by analytical modeling of tissue.

Based on the curve fit generated at step 718, appropriate laser parameters for a particular treatment area on the individual being treated are determined at step 720. In certain 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, e.g., above 45 ℃, the laser parameters are adjusted to reduce the laser power. In this case, the skin surface temperature measurement may indicate that a particular treatment area on the subject is particularly sensitive to laser pulse energy absorption. Alternatively, if the curve fit predicts that the desired temperature of the target chromophore lesion, e.g., 55 ℃, will not be achievable with the current laser pulse power setting, then the laser parameters may be adjusted to provide the necessary therapeutic power. This may occur if the epidermis and dermis properties are such that a particular treatment area is not easily absorbing the laser pulse energy.

Fig. 8 illustrates an exemplary predictive closed-loop control process based on measured skin surface temperature results according to an embodiment. The graph 800 in fig. 8 shows various temperature measurements and calculated curves as a function of time for use in a predictive closed loop control process such as illustrated in fig. 7. In fig. 8, the time zero corresponds to the time instant when the first laser pulse (in this case from a 22W laser, a 100ms pulse, and a 5mm x 5mm square spot) is applied, which is preceded by an air cooling of about 15 seconds (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 skin surface temperature, but other temperature measurement devices are contemplated.

With continued reference to fig. 8, the measured skin surface temperature during initial cooling 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 dashed line 816, shown here as 45.5 ℃.

From time zero, the first temperature measurements after the first four pulses (indicated by dots) are fitted to the predictive model. Specifically, in the example shown in fig. 8, the peak temperature, as well as the cooling temperature immediately prior to the next pulse application, are fitted into a clinically-generated predictive model. Maximum temperature peaks 822, 824, 826 and 828 and minimum temperature minima 823, 825, 827 and 829 are curve fitted to produce maximum temperature curve 830 and minimum temperature curve 832 (shown as dashed curves). Optionally, temperature measurements made during the cool down period between laser pulse applications are used to improve the accuracy of the measurements of the maximum temperature peak and minimum temperature nadir.

As shown in curve 812, skin surface temperature is measured during subsequent laser pulse application. It can be seen that maximum and minimum temperature curves 830 and 832 accurately track the measured skin surface temperature (i.e., peaks 842, 844, 846, and 848 and nadir 843, 845, and 847 of curve 812). It should be noted that the predicted temperature rise (i.e., dashed curve 830) and the actual measured temperatures (specifically, peaks 846 and 848) indicate that the desired temperature of 45.5 ℃ has been achieved by applying pulses 6 and 7, thus stopping the laser treatment regimen without applying the eighth pulse.

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

The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. Although a few exemplary embodiments of this invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. For example, lasers having other wavelengths, such as about 1210nm, may be used. Alternatively, the pre-treatment analysis methods described above may be used with other treatment regimens, such as those described in WIPO patent application WO/2018/076011 to Sakamoto et al and WIPO patent application WO/2003/017824 to McDaniel. In fact, the method is applicable to any thermal treatment protocol that involves equipment that may be affected by system, user, atmospheric conditions, and other inter-treatment variability.

Thus, many different embodiments result from the above description and accompanying drawings. It should be understood that each combination and sub-combination of these embodiments described and illustrated literally will be overly repeated and confusing. Thus, the specification, including the drawings, should be construed to constitute a complete written description of all combinations and subcombinations of the embodiments described herein, as well as of the manner and process of making and using them, and should support claims to any such combination or subcombination.

For example, consider an embodiment such as the following:

1. A method for determining an appropriate parameter set for calibrating a light source within a photothermal targeted therapy system embedding a chromophore in a medium, the method comprising, prior to administration of a therapeutic regimen, 1) applying 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 application of the at least one laser pulse, 3) estimating a relationship between a parameter of the light source and the skin surface temperature, and 4) defining a safe operating range of the parameter of the light source so as to avoid thermal damage at the location to be treated.

2. The method of item 1, wherein steps 1) through 4) are performed on a first subject for a first treatment region, followed by repeating steps 1) through 4) on the first subject for a second treatment region.

3. The method of item 1, wherein steps 1) through 4) are performed on a first subject for a treatment area, followed by repeating steps 1) through 4) on a second subject for the treatment area.

4. The method of item 1, further comprising considering treatment data from previous treatments of the same subject.

5. The method of item 1, wherein steps 2) through 4) are repeated while the actual treatment regimen is performed on the subject.

6. A system whereby a temperature measurement of the skin surface during an initial portion of treatment at a particular location is used to predict a future temperature of the skin surface at that particular location. The future temperature so predicted is used to adjust the thermal energy delivered by the one or more lasers 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 the cooling system, such as air flow, so that the future temperature of the skin surface at a particular location, and thus the temperature of underlying regions and tissue components, that cannot be easily measured in a direct manner, reaches a desired value.

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 this particular location. The future temperature so predicted is used to adjust the thermal energy delivered by one or more lasers, 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 air flow, so that the future skin surface temperature at a particular location, and thus the temperature of underlying regions and tissue components, cannot be readily measured in a direct manner, reaches a desired value.

An improved method to define and adjust parameters of a photothermal treatment system involves establishing and manipulating thermal gradients below the surface of the skin in a treatment area. The previous discussion of establishing a thermal gradient with photothermal targeted therapy involved the simultaneous application of skin surface cooling and laser pulses to damage chromophores at specific depths below the skin surface (see, e.g., U.S. patent application publication 2109-0262070 A1 to Sakamoto et al, which is incorporated herein by reference). Others have discussed monitoring skin surface temperature while applying laser pulses of different pulse durations and powers in a preset application regimen, while inferring, for example, a temperature profile in the dermis of the treatment area (see, e.g., U.S. patent No. 8,974,443B2 to Deng Liwei (Dunleavy) et al and U.S. patent No. 9,333,371B2 to bine (Bean) et al).

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 an embodiment, the present disclosure provides a combination of active cooling and heating that is adjustable prior to and during application of a treatment regimen 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 transfer by the photothermal therapy system. In this way, TG profile at the treatment area can be accurately controlled before and during treatment, thus providing a consistent, effective treatment experience for the patient while minimizing pain.

In particular, it is recognized herein that at any given location, TG profile varies with time such that the correlation between measured surface temperature and peak TG temperature also varies with time. Therefore, it is not sufficient to simply monitor the skin surface temperature as an indicator of subcutaneous TG. The relationship between skin surface temperature, peak TG temperature, TG profile below the skin surface and photo-thermal energy application time must be considered to achieve consistent and efficient energy transfer while ensuring patient comfort.

The embodiments described herein provide closed loop control of TG profile established below the skin surface at the treatment area, including peak TG temperature during photo-thermal energy application. As the TG profile at the treatment area changes over time, certain embodiments establish a correlation of skin surface temperature with peak TG temperature over time, thus enabling active control of the cooling and heating mechanisms of the system to ensure that the depth and peak temperature of the TG profile remains 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 protocol such that the pain perceived by the patient is minimized when a treatment pulse is applied at the treatment region. For example, a pre-treatment TG profile may be established such that during the preconditioning phase, the temperature at a desired target depth below the skin surface is less than 52 ℃. In an embodiment, a method of establishing a TG profile at a treatment area includes using a correlation function to correlate an expected heating and/or cooling response with measured changes in heating and/or cooling response from a previously applied photo-thermal energy pulse at a given treatment location.

A key factor in distinguishing the methods described in this disclosure is the recognition that the correlation function is generic for a given heating/cooling regimen, independent of treatment region location and patient. Existing closed loop methods to control photo-thermal energy transfer require adjustment of cooling and heating parameters between different patients and between different treatment locations on the same patient. In contrast, the present disclosure describes systems and methods that enable the definition and implementation of correlation functions derived as empirical relationships that allow for accurate predictions of heating and cooling responses across different treatment areas and patients. The correlation function may be derived from a priori information obtained via laboratory and/or clinical testing, and then applied to all subsequent treatments on the actual patient.

In particular, the correlation model implemented in the systems and methods described herein enables an estimation of 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 after the first heating pulse. That is, while previous approaches focused on predictive closed loop control of a measurable temperature rise at a particular treatment location by application of photo-thermal energy (e.g., laser pulses), embodiments of the present disclosure also contemplate cooling down between laser pulses to improve control of TG established by the laser pulses.

By accurately estimating this cooling drop, the starting temperature at a given treatment location prior to the second heating pulse can be predicted, thus enabling adjustment of 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 the predetermined target temperature. This estimate of the cooling down may be based on a cooling measurement (i.e., a cooling temperature delta) prior to the first laser pulse and a heating measurement (i.e., a heating temperature delta) of the previous pulse as inputs to the correlation model. That is, the input of the correlation model may also take into account any laser pulses (e.g., any pre-conditioning pulses or previous treatment pulses) applied at a given treatment location prior to the first laser pulse. In this way, real-time adjustment of the photo-thermal energy transfer based on the correlation model may take into account both cooling and heating temperature increases at the treatment site, enabling more consistent and accurate control of the photo-thermal energy transfer of the patient than previously possible.

In certain embodiments, the heating property (e.g., temperature increase per unit power and/or pulse duration) of the second pulse may be estimated from the heating property of any previously applied pulse (e.g., the first pulse and/or any preconditioning pulse applied to a given treatment site prior to the second pulse). By incorporating this heating property estimate, the photo-thermal energy source parameters to achieve the target peak temperature can be determined. In addition, the cooling mechanism may be adjusted during treatment such that the cumulative effect of both cooling and heating provided at the treatment site may be considered and adjusted as needed in real time during application of the treatment regimen.

In other words, the methods described herein enable closed loop control of any and all heating pulses (i.e., photo-thermal energy transfer) at a given treatment site. Thus, the described methods and systems allow for accurate control of TG and treatment temperature at different depths. In this way, embodiments of the systems and methods described herein allow for more consistent and efficient application of photo-thermal energy transfer at a given treatment site than is possible using the previously disclosed methods.

As an example, controlling the TG profile by correlation with the measured surface temperature may be performed as follows. TG profile is defined as the profile of the temperature that varies at a specific point in time depending on the depth in the tissue. 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 surrounding tissue below the damage threshold. In addition, pain experienced by the patient during the application of photo-thermal energy can be minimized by maintaining the overall tissue temperature below a predetermined pain threshold for as long as possible.

To achieve a desired thermal gradient profile, one may start with a specific thermal profile in the tissue, followed by application of sufficient photo-thermal energy to provide a lesion at a desired location within the tissue. Additionally, a cooling mechanism may be provided before and/or during application of the photo-thermal energy. Because of the different mechanisms and efficiencies of heating (e.g., application of energy from a pulsed laser) and cooling (e.g., application of air cooling of cold air), the heating and cooling must be carefully balanced in order to achieve effective therapeutic results while avoiding tissue damage and patient discomfort. For example, to create a thermal gradient that peaks deeper in the tissue, it is necessary to 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.

It is also recognized that TG profile at a given treatment site varies over time. That is, TG varies depending on time, heat extraction rate (i.e., cooling effect produced by any cooling mechanism applied at the tissue surface), heat injection rate (i.e., tissue heating produced by application of photo-thermal energy at the tissue surface), and tissue depth. Furthermore, for a given heating and cooling scheme, it is recognized that TG profiles that vary over time (i.e., tissue temperature that varies over depth and time) can be estimated using numerical heat transfer modeling (which uses, for example, finite element analysis).

In the generalized three-dimensional case, numerical modeling is typically 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 hypothetical optical and thermal parameters of the tissue used in the simulation. That is, if the actual tissue parameters are significantly different from the hypothetical optical and thermal parameters used in the simulation, the numerical modeling results may not accurately predict TG profiles in the patient. Although numerical simulation results may be validated against clinical and/or experimental results, simulation results may not accurately predict TG profiles for all patients.

The method described in this disclosure overcomes the drawbacks of the previous methods by combining predicted TG profiles from photo-thermal injection with accurate models of cooling extraction rates and real-time temperature measurements. In an example, the heat extraction rate of cooling can be described by a known thermodynamic relationship:

q=haΔT [ equation 1]

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 ℃). Thus, the heat extraction rate may be controlled by varying the heat transfer coefficient (e.g., by varying the cooling air velocity when air cooling is used) or the temperature of the cooling medium (e.g., cooling air temperature when air cooling is used, or the temperature of the contact surface when contact cooling is used).

The depth profile of photothermal injection may 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 photo-thermal energy, the tissue at the applied location 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 that is effective at each tissue layer. In order to provide effective photothermal targeted therapy, it is recognized herein that damage to a tissue or a specific structure in a tissue (e.g., sebaceous glands) generally follows the temperature and time dependent arrhenius damage equation, i.e., greater damage can be caused by the application of higher temperatures over longer periods of time. Thus, in order 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 at which the subject to be damaged is located. In addition, the more acute the temperature peak, the more selective the expected damage can be provided.

For short optical pulses (e.g., laser pulses of less than about 0.5 seconds in duration), if the tissue temperature is above the freezing point (0 ℃) and below the tissue damage temperature (about 60 to 65 ℃ for pulses of less than 0.2 seconds in duration), the resulting temperature profile of the injection heat is generally independent of the temperature of the surrounding tissue. In such cases, the deposition heat 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. Fig. 9 illustrates this case, showing the temperature difference (i.e., the heating temperature delta) immediately after each of the application of six consecutive laser pulses to heat the tissue while simultaneously applying cooling at the same location. In this case, although the heating temperature increase varies with the depth of the tissue, the temperature profile varies little with the application of a short laser pulse, for example a laser pulse having a duration of about 100 milliseconds or less. The curve shown in fig. 9 is in line with the common sense that light and heat sources for heat-based dermatological processes, such as lasers, microwaves and incoherent light sources, tend to heat tissue closer to the source most effectively due to energy absorption and light scattering in tissue according to Beer-Lambert Law.

Referring now to fig. 10 and 11 in conjunction with fig. 9, fig. 10 shows the thermal gradient at a given location, assuming that the same six optical pulses used to generate the graph in fig. 9 are applied to the given location while a cooling mechanism (e.g., air cooling) is applied to the skin surface. Fig. 11 shows the thermal gradient at the same given location immediately after the six pulses of fig. 9 are applied. As shown, the bottom-most curves in fig. 10 and 11 represent the modified TG profile immediately before the first of the six optical pulses is applied to a given location. This initial TG profile, with cooling applied only at the skin surface, shows that the skin surface temperature is about-5 ℃ and rises toward normothermia at increasing depth as expected.

Next, after the first optical pulse has been applied, the second bottom-up curve of fig. 11 shows the modified TG profile immediately after pulse 1 of fig. 9 has been applied to the given location. As can be seen, after pulse 1 was applied, the skin surface temperature (i.e., 0mm depth) had increased above 10 ℃ with a peak temperature of about 20 ℃ at a depth of about 0.4 mm. Immediately before the application of pulse 2, this TG profile, represented by the second bottom-up curve of fig. 11, stabilizes to the second bottom-up curve of fig. 10. That is, the TG section represented by the second curve from bottom up in fig. 10 has cooled to a skin surface temperature of about 6 ℃, and by the time the second pulse is to be applied, the temperature peak around 0.4mm in depth has also cooled to about 14 ℃.

In other words, as shown in fig. 11, immediately after each optical pulse is applied, the TG profile for a given location continuously fluctuates between the higher peak temperatures at a depth of between 0.5mm and 1mm, then stabilizes to the slightly flattened curve in fig. 10. This flattening, corresponding to the increase in cooling temperature provided by the continuous cooling of the skin surface during the application of photo-thermal energy, may lead to errors in the adjustment of the photo-thermal energy parameters without taking into account the cooling.

As referenced above, in previous approaches, the parameter change is based on a peak temperature measurement taken immediately after the application of the optical pulses, without regard to subsequent cooling temperature increases that occur between the optical pulses. Thus, although the resulting adjustment of the laser parameters results in inconsistent therapeutic results being provided, the photo-thermal energy provided may not be sufficient to achieve effective therapeutic results.

However, the embodiments described herein contemplate both the heating temperature increase provided by the optical pulse and the cooling temperature increase provided by the continuous application of cooling at the skin surface. It is recognized herein that the time desired to cool a given location to a depth and a given temperature varies depending on the cooling power and the thermal diffusion time of the tissue, which is a generally fixed property of the tissue determined by the thermal conductivity, specific heat capacity, and density of the tissue. While lowering the temperature of the cooling mechanism and increasing the heat transfer coefficient at the surface of the tissue will accelerate cooling deep below the skin surface, the upper layers of the tissue may be frostbitten by excessive cooling. Thus, there is a limit to the amount of cooling that can be provided at the skin surface, and it is important to balance the cooling provided with the heating due to the application of photo-thermal energy. Taking all these factors into account, the result is a more accurate prediction of the required photothermal energy for adequate heating of the target chromophore, and thus a more reliable and efficient photothermal targeted therapeutic result.

For example, using thermal model estimation, such as exemplified in the graphs shown in fig. 9-11, a TG profile generated by the application of a photo-thermal energy pulse may be designed to balance the heat extraction rate (i.e., cooling power provided by cooling applied at the skin surface) and cooling time with heat injection and heating time to locate the peak temperature of the TG profile at a desired temperature and depth below the skin surface. Since the depth profile of the thermal injection of the short optical pulse is fixed, the peak temperature is at a relatively shallow depth (e.g., about 0.3mm for the 1726 laser, as shown in fig. 9), calibration of the deeper chromophores (e.g., sebaceous glands located at a depth between about 0.5 and 1.5mm below the skin surface) requires a balance of skin surface cooling and time to keep the epidermis and shallow papillary dermis sufficiently cool to remain below the pain and injury threshold of the patient during application of the laser pulse. With a priori knowledge of the TG profile that dynamically changes during the application of photo-thermal energy, the temperature and depth of the peak temperature of the TG profile can be correlated to the skin surface temperature, thus allowing the peak TG temperature peak to be aimed at a desired location below the skin surface.

It is also recognized herein that during preconditioning and treatment regimens, both overheating and overcooling can result in enhanced perception of pain by the patient. Pain relief procedures typically provided include providing adequate skin cooling, using local anesthetic creams or gels, injecting anesthetics (e.g., lidocaine-containing anesthetics), applying gaseous analgesics such as PRO-NOX ^TM to relieve pain, and the like. Combinations of various pain relief procedures may also help reduce pain sensations (see, e.g., co-pending U.S. patent application Ser. No. 17/564,836, filed on, 12, 29, 2021, which is incorporated herein by reference). While the various pain management techniques listed above are effective for most photothermal targeted therapeutic procedures, the injection process of injectable anesthetic agents is itself painful, various other anesthetic agents require prescription, and physician specialists are typically required to perform or supervise the process. It would therefore be beneficial if the pain associated with photothermal targeted therapy itself could be substantially reduced.

In particular for photothermal targeted treatment of acne, sebaceous glands located 0.5mm to 1.5mm below the skin surface require heating to a temperature above 65 ℃ with, for example, a laser pulse of 100ms to achieve effective results. In general, the perception of pain is driven by excessive temperatures (i.e., temperatures above the pain threshold), the duration of the elevated temperatures, and the volume of tissue at these elevated temperatures. That is, pain receptors of elevated temperature differ depending on the temperature profile. For example, exceeding the pain threshold at the skin surface will result in a hot sensation, while exceeding the pain threshold at a depth of about 1mm below the skin surface will result in a "needlestick" sensation of the location. In general, a person will perceive pain based on factors such as 1) a temperature profile in the tissue, such as a volume of tissue exposed to a temperature above a threshold temperature associated with pain receptors residing at an applicable depth, and 2) a duration of time spent above the pain threshold. At the depth of a typical sebaceous gland, the pain threshold of an average person is about 52 ℃ (see, e.g., the "cellular and molecular mechanism of pain (Cellular and Molecular Mechanisms of Pain) of Basbaum (Basbaum) et al)", cell 139,2009, 10 months 16 days), and if the temperature increases dramatically below 52 ℃ for a duration of less than 250 milliseconds, pain is typically not perceived at this depth. Because 52 ℃ is below the damage threshold of the sebaceous glands, photothermal targeted treatment regimens for treating acne typically require additional pain remediation.

As a specific example, consider a photothermal treatment regimen that targets sebaceous glands residing at a depth of 0.8mm without damaging the dermis above or below. The Arrhenius model shows that sebaceous gland damage is temperature and time dependent, as is damage to the dermis. Taking a 100 millisecond period as an example, the required temperature to damage the target sebaceous glands is 65 ℃. However, within the same 100 milliseconds, the surrounding dermis must remain below 60 ℃.

Ideally, by taking advantage of the absorption difference between the sebaceous glands and the surrounding dermis, a TG profile with peak temperature above 65 ℃ is produced at about 0.8mm, thus bringing the sebaceous glands to a temperature above 65 ℃ while maintaining the dermis temperature below 60 ℃ to achieve 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 or continuous wave). The peak temperature of the TG profile can be achieved at a depth of 0.8mm in about 7 seconds using a 1726nm laser, pre-cooling of the tissue to 1 ℃ at the skin surface, and continuous cooling during application of the laser energy. Fig. 12 illustrates the temperature variation deep within a typical six pulse laser application scheme. However, the time period may be too long for the patient to tolerate without experiencing excessive pain and/or without requiring additional pain relief techniques, such as the use of local or injected anesthetics.

In looking at graph 1200 of fig. 12, it should be noted that the temperature at the peak of the thermal gradient exceeding 5.5 seconds is above the pain threshold of 52 ℃ deep. To avoid this prolonged period of time above the pain threshold temperature, embodiments of the present disclosure instead employ a method of first preconditioning the initial TG profile, followed by applying photo-thermal energy in such a way that the deep peak TG temperature does not exceed the pain threshold until the last pulse. In other words, once the preconditioned TG profile has been established at the treatment site, and the peak temperature of the preconditioned TG profile is at the desired depth while below the pain threshold temperature, a single higher power pulse is delivered to explicitly damage the sebaceous glands with a pulse duration shorter than normally perceptible. An example of a pulse sequence according to an embodiment is shown in fig. 13. Fig. 14 shows the resulting TG profile after pulses 1, 5 and 6 of fig. 13.

It should be noted that the laser parameters of the pulse sequence exemplified in fig. 13 may be specified using the TG profile design method illustrated in fig. 9 to 11. The methods exemplified in fig. 13 and 14 minimize the time spent above the pain threshold of 52 ℃, 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 plot shown in fig. 14, it should be noted that the peak of the preconditioning thermal gradient and the peak of the final thermal gradient are at different depths. Further, it should be noted that although a single high power pulse is shown in fig. 13, additional higher level pulses may be applied immediately after the last transmission shown in fig. 13, or by repeating all or part of the pulse sequence shown in fig. 13.

In certain embodiments, cooling may be provided at the skin surface before and/or during application of the pulses shown in fig. 13. 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 ℃ for more than about 6 seconds to prevent frostbite of the skin. Thus, assuming a 7 second laser pulse application sequence, the application of the cooling mechanism at the skin surface may be limited to 5 seconds of pre-cooling followed by a continuous cooling during the laser pulse application for a 7 second period. In some cases, the application of the cooling mechanism at the skin surface may be provided for additional time during the pre-cooling period, and the cooling provided at the skin surface may be adjusted in real-time during the application (e.g., by adjusting the cooling air flow rate).

In an alternative approach, the combination of cooling and photo-thermal heating pulses may be adjusted to rapidly achieve a peak of thermal gradient just below the 52 ℃ pain threshold at the desired depth early in the 7 second laser application period, followed by reduced heating (e.g., by reducing the power and/or pulse duration of subsequent pulses) to maintain peak temperature at the desired depth while allowing time for heat supply to diffuse, thus heating deeper tissue. In yet another approach, pre-cooling and treatment time may be further reduced by increasing cooling power by decreasing the temperature of the cooling mechanism or increasing the heat transfer coefficient (e.g., increasing the cooling air speed in an air cooling system). If the skin surface temperature can be maintained just above the frostbite temperature during the application of photo-thermal energy, the additional cooling can reduce the temperature deeper 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 tissue in a given pulse application sequence, while preventing damage at shallower tissue.

In an embodiment, the purpose of the process described herein is to maintain the dermis temperature below the generally accepted pain threshold temperature of 52 ℃. The skin surface temperature and its correlation with the dermis temperature may be determined using the processes described herein and used as an indicator of the temperature at a depth below the skin surface (e.g., at the dermis).

Fig. 15 is a simplified graph showing temperature profiles of dermis and skin surface temperature as a function of time when a Continuous Wave (CW) light source is used to achieve and maintain a desired thermal gradient profile, according to an embodiment. That is, instead of using laser pulses in the establishment of the initial thermal gradient, a CW light source may be used to establish and maintain the initial thermal gradient profile.

As shown in fig. 15, graph 1500 shows the temperature relationship between applied CW power, dermis temperature T _dermis, and skin surface temperature T _surface as a function of time and in relation to pain threshold T _pain and target chromophore damage threshold T _damage. T _pain and T _damage are indicated as horizontal dashed lines.

A CW laser source may be applied at the treatment site as indicated by the dashed curve in fig. 15. Thus, T _dermis and T _dermis also rise over time. In an embodiment, the CW power may initially increase rapidly above T _pain and then decrease gradually over time. In certain embodiments, an increase in CW power above the pain threshold may be alleviated by appropriate pre-cooling and/or continuous application of cooling to the skin surface.

As the CW power is reduced, the wavelength of the CW light source may be selected to promote heating of the deeper dermis while maintaining the skin surface temperature at an acceptable level for the subject. This period of time is indicated as t _ETG in fig. 15. 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 regimen. Establishing a thermal gradient using CW power allows sufficient power to be delivered to raise the target chromophore temperature above the damage threshold T _damage while maintaining the skin surface temperature below the pain threshold T _pain.

In an embodiment, instead of an initial spike in CW laser power as shown in fig. 15, the CW power may be gradually increased from a low power to a higher power to establish a thermal gradient. Suitable CW light 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.

Fig. 16 is a simplified graph showing a TG profile corresponding to the CW laser application of fig. 15 according to an embodiment. As shown in fig. 16, the depth of the peak temperature below the skin surface is shown over time during the application of CW power.

At time t ₀, when peak CW power is applied, as shown in fig. 15, the peak temperature is closer to the skin surface. As the CW power gradually decreases over time (e.g., at t ₁ and t ₂), the peak temperature below the skin surface gradually moves deeper toward the steady-state thermal gradient at time t _∞.

The use of CW power may be advantageous because the steady-state temperature at the depth of the target chromophore may be maintained at a higher temperature than with a pulsed preheat schedule. Furthermore, CW power may be applied over a larger surface area at and around the target treatment site, thus enabling more extensive heating over a larger surface area and earlier establishment of thermal gradients.

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

1. A method for determining an appropriate set of parameters for operating a light source within a photothermal targeted therapy system for calibrating a chromophore embedded in a medium, the method comprising:

2) Measuring the skin surface temperature at the location to be treated;

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

2. A method for determining an appropriate set of parameters for operating a light source within a photothermal targeted therapy system for targeting a chromophore embedded in a medium, the method comprising, prior to administering a treatment regimen to a first subject:

8) Applying at least one higher level laser pulse defining a value 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 targeting the chromophore when the treatment regimen is applied. For example, the laser pulse may provide a temperature rise above the chromophore damage threshold while remaining below the damage threshold of surrounding tissue.

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

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

5. The method of item 2, further comprising:

9) Storing in a memory of the photothermal targeted therapy system the safe operating range of the parameter for operating the light source on the first subject at the first treatment location, and

10 The parameters so stored in the memory are considered when the treatment regimen is later administered to the first subject.

6. The method of item 2, further comprising:

9) If the skin surface temperature at the first treatment location reaches a preset threshold temperature, the parameters of the light source are adjusted to reduce the effective power incident at the first treatment location.

7. The method of item 2, wherein defining the safe operating range for the parameter 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 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.

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 to the second subject.

10. The method of item 9, further comprising:

9) Storing in memory the parameters for operating the light source for the first subject at the first treatment location of the second subject, and

10 When the treatment regimen is later administered to the second subject, the parameters for operating the light source so stored in the memory are considered.

11. A method for determining an appropriate set of parameters for operating a light source within a photothermal targeted therapy system for calibrating a chromophore embedded in a medium, the method comprising:

a) Cooling the first treatment site;

b) Applying at least one laser pulse from the light source to the first treatment site at a preset power level, the first laser pulse having a thermal energy below a known pain and injury threshold of the medium;

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

d) Estimating a relationship between the parameter 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 a parameter for operating the light source using a data correlation, wherein a priori knowledge of correlation from a clinical experiment is considered to establish a prediction parameter using computational analysis;

e) Defining a "safe" operating range (i.e., related to pain) of the parameter for operating the light source so as to remain below the pain threshold of the medium at the first treatment location while still effectively calibrating the chromophore when the treatment regimen is administered, wherein the safe operating range corresponds to the skin surface temperature of between about 28 ℃ and 34 ℃;

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

g) Adjusting the safe operating range of the parameter of the light source at the first treatment location, maintaining the skin surface temperature below the known pain threshold while increasing the peak temperature and depth of the thermal gradient until at a correct depth, wherein the estimating, defining, measuring and adjusting are continuously updated during treatment, 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 target chromophore to its desired damage temperature, effectively calibrating the chromophore.

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

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

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

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

b) Applying laser pulses from the light source to the first treatment location;

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

17. The method of item 15, wherein cooling comprises using a contact cooling mechanism. In an embodiment, the cooling may include cooling by a cooling air flow. In other embodiments, other cooling mechanisms may be used, such as refrigerant spray cooling.

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

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 priori knowledge of the correlation from a clinical trial is considered to establish a predictive parameter using computational analysis, determining an appropriate laser parameter for the light source, and modifying the treatment regimen according to the appropriate laser parameter.

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

21. The method of item 17, wherein terminating a treatment regimen includes fitting the skin surface temperature so tracked to a data correlation, wherein prior knowledge of the correlation from a clinical trial is considered to establish the predicted parameters using computational analysis, predict peak skin surface temperature, and adjust at least one of laser power, pulse width, pulse number, and cooling system parameters.

22. The method of item 21, wherein the peak skin surface temperature is a temperature in the range of 40 ℃ and 55 ℃. In an embodiment, the peak skin surface temperature may be maintained between 41 ℃ and 45 ℃ in order to maintain below the pain threshold for a broad patient population.

23. The method of item 22, wherein the peak skin surface temperature is about 51 ℃.

24. The method of item 15, wherein the laser pulse has a pulse duration of 100 milliseconds.

25. The method of item 15, wherein terminating the treatment regimen comprises fitting the skin surface temperature so tracked to a data correlation, wherein a priori knowledge of the correlation from a clinical trial is considered to establish the predicted parameters using computational analysis, determine appropriate laser parameters for the light source, and modify the treatment regimen according to the appropriate laser parameters.

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.

27. The method of item 26, wherein terminating a treatment regimen includes fitting the skin surface temperature so tracked to a data correlation, wherein prior knowledge of the correlation from a clinical trial is considered to establish the predicted parameters using computational analysis, predict peak skin surface temperature, and adjust at least one of laser power, pulse width, pulse number, and cooling system parameters.

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

29. The method of item 28, wherein the peak skin surface temperature is in the range of 41 ℃ and 45 ℃.

30. The method of item 15, wherein the laser pulse has a pulse duration of 100 milliseconds.

As used herein, recitation of "at least one of A, B and C" is intended to mean "any combination of A, B, C or A, B and C". The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present disclosure. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may 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 embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof. Each of the various elements disclosed herein may be implemented in a variety of ways. The disclosure should be understood to cover each such variation, provided that it is a variation of an embodiment of any apparatus embodiment, a variation of a method or process embodiment, or even merely a variation of any element of these. In particular, it is to be understood that the words of each element may be expressed in terms of equivalent apparatus or method, even if only the function or result is the same. Such equivalent, broader, or even more generic terms should be considered to be encompassed in the description of each element or action. Such terms may be substituted as desired to clarify the underlying broad scope of the invention to which the invention is entitled.

As just one example, it should be understood that all actions may be expressed as a means for taking the action or as an element which causes the action. Similarly, each physical element disclosed should be understood to encompass the disclosure of actions facilitated by that physical element. With respect to this last aspect, by way of example only, disclosure of "a protrusion" should be understood to encompass disclosure of an action of "protruding" (whether or not explicitly discussed) and conversely, if there is only disclosure of an action of "protruding", then this disclosure should be understood to encompass disclosure of "a protrusion". Such variations and alternative terms are to be understood to be expressly included in the description.

In the specification, embodiments of the invention have been disclosed and, although specific terms are employed, they are used in a generic and descriptive sense only and not for purposes of limitation. Although a few exemplary embodiments of this invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Therefore, it is to be understood that the foregoing is illustrative of the present invention and is not to be construed as limited to the specific embodiments disclosed, and that modifications to the disclosed embodiments, as well as other embodiments, are intended to be included within the scope of the disclosure.

Claims

1. A method for determining a suitable set of parameters for operating a light source within a photothermal targeted therapy system for calibrating chromophores embedded in a medium, the method comprising:

1) Apply at least one initial laser pulse from the light source to the treatment site at a preset power level, the preset power level being below a known pain and injury threshold;

2) Measure the skin surface temperature at the treatment site;

3) Perform correlation fitting on the relationship between the parameters used to operate the light source and the skin surface temperature at the treatment location;

4) Define a safe operating range for the parameters of the light source to avoid pain and thermal damage to the medium at the treatment site;

5) Maintain the skin surface temperature below the known pain and injury thresholds while simultaneously increasing the peak temperature and depth of the thermal gradient until the peak temperature and depth of the thermal gradient reach the desired depth within the medium at the site to be treated; and

6) Apply at least one therapeutic laser pulse from the light source having a power higher than that of the at least one initial laser pulse to raise the temperature of the target chromophore to its desired damage temperature in order to effectively calibrate the chromophore when the treatment regimen is applied.

2. A method for determining a suitable set of parameters for operating a light source within a photothermal targeted therapy system for calibrating chromophores embedded in a medium, the method comprising, prior to administering a treatment regimen to a first subject:

1) Cooling a first treatment site, wherein the cooling includes guiding airflow at the first treatment site;

2) Apply at least one laser pulse from the light source to the first treatment site on the first subject at a preset power level, the preset power level being lower than a known pain and injury threshold;

3) After applying the at least one laser pulse, measure the skin surface temperature at the first treatment location;

4) The relationship between the parameters used to operate the light source, post-pulse cooling, and the skin surface temperature at the first treatment location is estimated by fitting the skin surface temperature and the parameters used to operate the light source using data correlation, wherein prior knowledge of correlation from clinical trials is considered to establish predictive parameters using computational analysis.

5) Define a safe operating range for the parameters of the light source to remain below the pain threshold of the medium at the first treatment location, while still effectively calibrating the chromophore when the treatment is applied, wherein the safe operating range corresponds to the skin surface temperature between approximately 28°C and 34°C.

6) Measure the skin surface temperature at the first treatment site at least once during the treatment regimen;

7) Adjust the parameters of the light source within the safe operating range 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 until the correct depth is reached, wherein the estimation, definition, measurement, and adjustment are continuously updated during treatment; and

8) Apply at least one high-level laser pulse defined from the light source as being 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) to 8) at the second treatment site before applying the treatment regimen to the second treatment site on the first subject.

4. The method of claim 2, further comprising: repeating steps 1) to 8) at the first treatment site on the second subject before administering the treatment regimen to the second subject.

5. The method of claim 2, further comprising:

9) The safe operating range of the parameters for operating the light source on the first subject at the first treatment position is stored in the memory of the photothermal targeted therapy system; and

10) When the treatment regimen is administered to the first subject later, the parameters stored in the memory are taken into consideration.

6. The method of claim 2, further comprising:

9) If the skin surface temperature at the first treatment location reaches a preset threshold temperature, then adjust the parameters of the light source to reduce the effective power incident on the first treatment location.

7. The method of claim 2, wherein the safe operating range for defining 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: during the application of the treatment regimen to a second treatment site on the first subject, repeating steps 1) to 8) at the second treatment site.

9. The method of claim 2, further comprising: repeating steps 1) to 8) at a first treatment site on the second subject during the administration of the treatment regimen to the second subject.

10. The method of claim 9, further comprising:

9) Storing in memory the parameters of the light source used for the first subject at the first treatment position of the second subject; and

10) When the treatment regimen is later administered to the second subject, the parameters for operating the light source stored in the memory are taken into consideration.

11. A method for determining a suitable set of parameters for operating a light source within a photothermal targeted therapy system for calibrating chromophores embedded in a medium, the method comprising:

a) Cool the primary treatment site;

b) Apply at least one laser pulse from the light source to the first treatment location at a preset power level, wherein the first laser pulse has thermal energy below the known pain and injury threshold of the medium;

c) While applying the first laser pulse, track the skin surface temperature at the first treatment location at a refresh rate of 25Hz to 400Hz.

d) Estimate the relationship between the parameters used to operate 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 used to operate the light source using data correlation, wherein computational analysis is used to establish predictive parameters taking into account prior knowledge of correlations from clinical trials.

e) Define the operating range of the parameters for operating the light source so as to keep it below the pain threshold of the medium at the first treatment location, while still effectively calibrating the chromophore when the treatment is applied, wherein the safe operating range corresponds to the skin surface temperature between approximately 28°C and 34°C;

f) While applying additional laser pulses, continue to track the skin surface temperature at the first treatment site at a refresh rate of 25Hz to 400Hz;

g) Adjusting the operating range of the parameters of the light source at the first treatment location to maintain the skin surface temperature below a known pain threshold, while simultaneously increasing the peak temperature and depth of the thermal gradient at the first treatment location until a desired depth is reached, wherein estimations, definitions, measurements, and adjustments are continuously updated during the treatment regimen; and

h) Define 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 chromophore to its desired damage temperature.

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

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

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

15. A method of treating a subject using a photothermal targeted therapy system comprising a light source for calibrating chromophores embedded in a medium, the method comprising:

a) Cool the first treatment site of the subject from a first surface temperature to a second surface temperature;

b) Apply laser pulses from the light source to the first treatment site;

c) During the application of the laser pulse, the skin surface temperature at the first treatment site is tracked using an infrared camera operating at a refresh rate of 25 Hz to 400 Hz; and

d) The treatment regimen is terminated at least in part based on the skin surface temperature measured in this way.

16. The method of claim 15, wherein cooling the first treatment site comprises cooling the first treatment site from a first surface temperature of body temperature to a second surface temperature lower than body temperature.

17. The method of claim 15, wherein cooling comprises using at least one of contact cooling, a cooling airflow, and a refrigerant spray.

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

19. The method according to claim 15,

Terminating the treatment regimen includes fitting the skin surface temperature, which is thus tracked, to a data correlation.

This involves using computational analysis to establish predictive parameters, taking into account prior knowledge of the correlations derived from clinical trials, to determine appropriate laser parameters for the light source, and

The method further includes:

The treatment plan is modified according to the appropriate laser parameters.

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

21. The method according to claim 17,

The treatment termination protocol includes fitting the skin surface temperature, which is thus tracked, to the data correlation.

The predictive parameters are established using computational analysis, taking into account prior knowledge of the correlations derived from clinical trials.

The method further includes:

Predicting peak skin surface temperature, and

Adjust at least one of the laser power, pulse width, pulse number, and cooling system parameters based on the predicted peak skin surface temperature.

22. The method of claim 21, wherein the peak skin surface temperature is a temperature in the range of 40°C to 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 pulse is 100 milliseconds.

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

26. The method of claim 25, wherein terminating the treatment regimen further comprises

Determine the appropriate cooling parameters for the cooling mechanism, and

The cooling parameters were modified during the treatment regimen.

27. The method according to claim 26,

The treatment termination protocol includes fitting the skin surface temperature, which is thus tracked, to a data correlation, wherein computational analysis is used to establish the predictive parameters, which include...

Taking into account prior knowledge of the aforementioned relevance from clinical trials,

Predicting peak skin surface temperature, and

Adjust at least one of the following: 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 to 55°C.

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

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

31. A photothermal targeted therapy system for calibrating chromophores embedded in a medium, the system comprising:

A cooling unit that provides cooling at the treatment site;

A light source, used to provide laser pulses at the treatment location;

A temperature monitoring unit is used to monitor the skin surface temperature at the location; and

A controller is configured to receive the skin surface temperature, as monitored by the temperature monitoring unit, and accordingly control the operating parameters of the cooling unit and the light source.

The controller is configured to:

The light source is guided to apply at least one laser pulse to the treatment site at a preset power level, which is below a known pain and injury threshold.

The temperature monitoring unit is guided to measure the skin surface temperature at the treatment site.

Correlation fitting is performed on the relationship between the operating parameters of the light source and the measured skin surface temperature.

Define a safe operating range for the operating parameters of the light source to avoid pain and thermal damage to the medium at the treatment site.

The operating parameters of at least one of the cooling unit and the light source are modified to apply at least one higher-level laser pulse from the light source to maintain the skin surface temperature below the known pain and injury thresholds, while simultaneously increasing the peak temperature and depth of the thermal gradient until the peak temperature and depth of the thermal gradient reach the desired depth within the medium at the treatment site.

The light source is guided to apply at least one therapeutic laser pulse with a power higher than that of the at least one initial laser pulse, in order to raise the temperature of the target chromophore to its desired damage temperature.