Deterministic and predictive closed-loop control of dosimetry using skin surface temperature measurements and associated methods

Abstract

A method for determining a suitable set of parameters for operating a light source within a photothermal targeted therapy system for targeting chromophores embedded in a medium is disclosed. The method includes, prior to applying a treatment regimen: 1) applying at least one laser pulse from a light source to a location to be treated at a preset power level, the preset power level being below a known damage threshold; 2) after applying the at least one laser pulse, measuring the skin surface temperature at the location to be treated; 3) estimating the relationship between the parameters for operating the light source and the skin surface temperature; and 4) defining a safe operating range of the parameters for operating the light source so as to avoid thermal damage to the medium at the location to be treated while still effectively targeting the chromophores in applying the treatment regimen.

Description

Technical Field

[0001] The present invention relates to photothermal targeted therapy, and more particularly to systems and methods for determining the correct dosimetry for photoinduced thermal therapy of a target specific chromophore in an embedding medium. Background Art

[0002] Chromophores embedded in a medium such as the dermis may be thermally damaged by heating the chromophore with a targeted light source such as a laser. However, applying sufficient thermal energy to damage the chromophore may also be damaging to the surrounding dermis and overlying epidermis, resulting in epidermal and dermal damage and pain to the subject. This problem also applies to targets such as sebaceous glands, where a chromophore such as sebum is used to heat the target to a high enough temperature to cause damage to the target.

[0003] Previous approaches to preventing epidermal and dermal damage and pain in subjects include:

[0004] 1. Precooling the epidermis before applying photothermal therapy; and

[0005] 2. Precool the epidermis, also precondition (i.e., preheat) the epidermis and dermis in a preheating protocol, and then apply photothermal therapy in a different treatment protocol. In some cases, the preheating protocol and the treatment protocol are performed by the same laser, although the two protocols involve different laser settings and application protocols, thus resulting in additional complexity in the treatment protocol and equipment. Summary of the invention

[0006] According to embodiments described herein, a method for determining a suitable set of parameters for operating a light source within a photothermal targeted therapy system for targeting chromophores embedded in a medium is disclosed. The method includes, 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 also includes 2) measuring the skin surface temperature at the first treatment location after administering the at least one laser pulse. The method further includes 3) estimating the relationship between the parameters for operating the light source and the skin surface temperature at the first treatment location, and 4) defining a safe operating range of the parameters for operating the light source so as to avoid thermal damage to the medium at the first treatment location while still effectively targeting the chromophore in administering the treatment regimen.

[0007] In an embodiment, steps 1) to 4) are repeated at a second treatment location on the first subject prior to administering the treatment regimen at the second treatment location. In another embodiment, steps 1) to 4) are repeated at a first treatment location on the second subject prior to administering the treatment regimen to the second subject. In still another embodiment, the method further comprises 5) storing in a memory of the photothermal targeted therapy system a safe operating range of parameters for operating the light source of 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.

[0008] In another embodiment, a photothermal targeted therapy system for targeting chromophores embedded in a medium is disclosed. The system includes: a light source configured to provide laser pulses within a range of power levels when operated using a parameter set, the power level range including the known damage threshold of the chromophore and the treatment location. The system also includes a temperature measurement device for measuring the skin surface temperature at the treatment location, and a controller for controlling the light source and the temperature measurement device. The controller is configured to estimate the relationship between the light source parameters and the skin surface temperature at the treatment location, define a safe operating range for the light source parameter set so as to avoid thermal damage to the medium at the treatment location while still effectively targeting the chromophore in the application of the treatment regimen, and set the light source to apply the laser pulses within the safe operating range.

[0009] In yet another embodiment, a method for adjusting a suitable set of parameters for operating a light source within a photothermal targeted therapy system for targeting chromophores embedded in a medium during administration of a treatment regimen to a first subject at a first treatment location is disclosed. The method includes: 1) measuring skin surface temperature at least once at the first treatment location; 2) predicting the skin temperature while the treatment regimen is being administered to the first subject at the first treatment location; and 3) adjusting at least one parameter for operating the light source so that future measurements of the skin surface temperature at the first treatment location will not exceed a specified value. Predicting the epidermal temperature takes into account at least one of a heat transfer model and a series of experimental results. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 An exemplary photothermal targeted therapy system according to an embodiment is illustrated.

[0011] Figure 2 An exemplary scanner arrangement for use with a photothermal targeted therapy system is illustrated in accordance with an embodiment.

[0012] Figure 3 A schematic diagram of an exemplary set of light pulses suitable for use as an integrated preconditioning / light therapy regimen is shown in accordance with an embodiment.

[0013] Figure 4 Shown is the measured temperature at the skin surface as a function of time when therapeutic light pulses are applied to the skin surface, according to an embodiment.

[0014] Figure 5 A flow chart is shown illustrating an exemplary process for analyzing measured skin surface temperature, predicting skin temperature when subsequent laser pulses and / or additional cooling will be applied, and then modifying the treatment plan accordingly.

[0015] Figure 6 Shown are the measured skin surface temperatures for various applied laser pulse powers at similar treatment areas for two different individuals.

[0016] Figure 7 A flow chart illustrating an exemplary process for closed-loop control of laser system parameters based on real-time skin surface temperature measurements, according to an embodiment.

[0017] Figure 8 Shown are measured skin surface temperatures resulting from the application of four pulses to a treatment area, used as data for predicting a subject's skin temperature increase with subsequent pulse application, and the resulting curve fits and actual temperature measurements, according to an embodiment.

[0018] Detailed description of embodiments of the present invention

[0019] The present invention is described more fully below with reference to the accompanying drawings, in which embodiments of the invention are shown. However, the present invention may be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are provided so that the present disclosure will be thorough and complete and will fully convey the scope of the invention to those skilled in the art. In the accompanying drawings, the size and relative size of layers and regions may be exaggerated for clarity. The same numbers refer to the same elements throughout.

[0020] It will be understood that although the terms first, second, third, etc. can be used to describe various elements, components, areas, layers and / or sections herein, these elements, components, areas, layers and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, area, layer or section from another area, layer or section. Therefore, without departing from the teachings of the present invention, the first element, component, area, layer or section discussed below can be referred to as the second element, component, area, layer or section.

[0021] For ease of description, spatially relative terms such as "below", "below", "lower", "under", "above", "upper", etc. may be used herein to describe the relationship between an element or feature and another (one or more) elements or (one or more) features as illustrated in the figure. It will be understood that, in addition to the orientation depicted in the figure, the spatially relative terms are also intended to cover different orientations of the device in use or operation. For example, if the device in the figure is turned over, the elements described as "below" or "below" or "below" other elements or features will then be oriented to be "above" other elements or features. Therefore, the exemplary terms "below" and "under" can cover both the orientation above and below. The device can be oriented in other ways (rotated 90 degrees or in other orientations), and the spatially relative descriptors used herein are interpreted accordingly. In addition, it will be understood that when a layer is referred to as being "between" two layers, it can be the only layer between the two layers, or there can also be one or more intermediate layers.

[0022] The terms used herein are only for the purpose of describing specific embodiments, and are not intended to limit the present invention. As used herein, the singular forms "one", "an" and "the" are also intended to include plural forms, unless the context clearly indicates otherwise. It will be further understood that when used in this specification, the terms "include" and / or "comprise" specify the presence of stated features, integers, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components and / or their groups. As used herein, the term "and / or" includes any and all combinations of one or more associated listed items, and can be abbreviated as " / ".

[0023] 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 may be directly on, directly connected to, coupled to, or adjacent to the other element or layer, or there may be intervening elements or layers. In contrast, when an element is referred to as being "directly on," "directly connected to," "directly coupled to," or "immediately adjacent to" another element or layer, no intervening elements or layers are present. Similarly, when light is received or provided "from" an element, it may be received or provided directly from the element or from an intervening element. On the other hand, when light is received or provided "directly from" an element, no intervening elements are present.

[0024] Embodiments of the invention are described herein with reference to cross-sectional illustrations, which are schematic illustrations of idealized embodiments (and intermediate structures) of the invention. As such, variations in the illustrated shapes are expected as a result of, for example, manufacturing techniques and / or tolerances. Therefore, embodiments of the invention should not be construed as limited to the particular shapes of the zones illustrated herein, but rather to include deviations in shape, for example, resulting from manufacturing. Therefore, the zones illustrated in the figures are schematic in nature, and their shapes are not intended to illustrate the actual shapes of the device zones, and are not intended to limit the scope of the invention.

[0025] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning consistent with their meaning in the context of the relevant art and / or this specification, and will not be interpreted in an idealized or overly formal sense, unless explicitly so defined herein.

[0026] Figure 1 An exemplary photothermal targeted therapy system for targeting a target and heating the target to a sufficiently high temperature to damage the target without damaging the surrounding medium is shown, wherein the target includes a specific chromophore embedded in the medium. The system can be used, for example, to photothermally ablate sebaceous glands in a targeted manner while preserving the epidermis and dermis surrounding the targeted sebaceous glands, wherein sebum is a chromophore embedded within the sebaceous glands.

[0027] Still reference Figure 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 for a cooling effect to the treatment area (i.e., the outer skin layer area covering the target sebaceous glands), such as by contact or by direct air cooling. The cooling unit 110 is connected to a controller 122 within the phototherapy unit 120. Note that although the controller 122 is shown as being included in Figure 1 However, it is possible that the controller is located outside both cooling unit 110 and light therapy unit 122, or even within cooling unit 110.

[0028] The controller 122 further controls other components within the light therapy 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 the laser power for the light therapy regimen, and the controller 122 adjusts specific settings of the laser, such as the output power and pulse time settings. The laser 124 can be a single laser or a combination of two or more lasers. If more than one laser is used, the laser outputs are optically combined to act as one more powerful laser. The display 126 can include information such as the operating conditions of the cooling unit 110, the laser 124, and other system states. For example, the temperature monitoring unit 128 is used to monitor the temperature of the skin surface in the treatment area, and the controller 122 uses the skin surface temperature measured at the treatment area to adjust the light therapy regimen. The controller 122 also interfaces with the foot switch 130 for remotely turning the laser 124 and / or the cooling unit 110 on or off. Additionally, the door interlock 132 can be used as an additional safety measure so that when the door of the treatment room is ajar, the door interlock 132 detects this condition and instructs the controller 122 not to allow the light therapy unit 120 or at least the laser 124 to operate. In addition, an emergency on / off switch 134 can be provided to quickly shut down the photothermal targeted therapy system 100 in an emergency. In another modification, an additional photodiode or other sensor can be added to monitor the power level of the energy emitted from the laser 124.

[0029] Continue to refer Figure 1 , the photothermal targeted therapy system 100 further includes a scanner 160, which is the portion of the device held by the user in applying the treatment regimen to the subject. The scanner can be formed in, for example, a gun-like or stick-like shape to be easily held by the user. The scanner 160 is connected to the cooling unit 110 via a cooling connection 162 so that a cooling regimen can be applied using the scanner 160. Additionally, the output from the laser 124 is connected to the scanner 160 via an optical fiber delivery 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 so that the skin temperature at the treatment area is fed back to, for example, the controller 122.

[0030] Figure 2Additional details of the scanner 160 are shown according to an embodiment. The cooling connection 162 is connected to a cooling delivery unit 202, which is configured to deliver a cooling mechanism (e.g., a flow of cool air) to the treatment area. The fiber optic delivery 164 from the laser 124 is connected to a laser energy delivery unit 204, which includes optical components for delivering light energy for the photothermal therapy regimen to the treatment area. Finally, the temperature connection 166 is connected to a temperature sensor 206, which measures the temperature at the treatment area for feedback to the controller 122. Additionally, the scanner 160 includes an on / off switch 210 (such as a trigger switch that turns the laser 124 on / off) and an optional status indicator 212 that indicates the operating status of the scanner 160, such as whether the laser is operating. Although the scanner 160 is in Figure 2 Schematically shown as a box, the actual shape is configured for ease of use. For example, the scanner 160 can be shaped as a nozzle with a handle, a pistol shape, or another suitable shape that is easy for the user to aim and control.

[0031] 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 stream of cold air across the treatment area for a specified period of time (such as 10 seconds). After pre-cooling, the cooling mechanism (e.g., cold air flow or contact cooling) remains effective and a light therapy regimen is applied to the treatment area. In one embodiment, pulses of a square, "flat-top" beam are used in combination with a scanner device to sequentially apply laser pulses to the treatment area. For example, the light therapy regimen may include applying a set number of light pulses to each segment of the treatment area, wherein the segments are sequentially irradiated by the laser pulses. In another embodiment, the segments are irradiated in a random order.

[0032] An example of a pulse set suitable for use in a conditioning / phototherapy regimen is shown in Figure 3 . Sequence 300 includes light pulses 322, 324, 326, 328, 330, 332, and 334 applied at the treatment area. In one embodiment, all seven light pulses have equal power and are separated by uniform pulse intervals (indicated by double arrows 342) and have the same pulse duration (indicated by gaps 344). In the example, pulse duration 344 is 150 milliseconds and the pulse interval is 2 seconds. The 2 second pulse interval is intended, for example, to allow the epidermis and dermis in the block to cool down in order to prevent damage thereto. During the pulse separation time period, the laser can be scanned over different sections within the treatment area in order to increase the efficiency of laser use. Note that Figure 3 Not drawn to scale.

[0033] Figure 4According to an embodiment, a light pulse (such as Figure 3 Those shown in ) are applied to the treatment area to measure the skin surface temperature. Figure 4 In the example shown in , the treatment area has been pre-cooled by direct air cooling for 7 seconds, and then light pulses from a 1720 nm wavelength laser at a power of 22 Watts and a duration of 150 milliseconds are applied for a period of 2 seconds while the cooling remains on. In this particular example, the direct air cooling used for cooling and during treatment delivers a high-velocity column of air cooled to -22°C, resulting in a heat transfer coefficient between the skin and the air of approximately 350 W / m^2 K. In an embodiment, the beam size is 4.9 square mm. Depending on the size of the treatment area, the power distribution of the laser, the location of the treatment area on the body and other factors, the exact beam size can be adjusted using, for example, collimating optics.

[0034] The resulting change in skin surface temperature is shown in graph 400, where peak 422 corresponds to Figure 3 , and similarly for peaks 424, 426, 428, and 430. Figure 4 In the example shown in , the average power per spot is 22 W * 0.15s / 2s = 1.65 W. For example, the same average power per spot can be achieved by pulsing at 33 Watts for 100 ms with a pulse interval of 2 s, or by pulsing at 25.1 W for 125 ms with a pulse interval of 1.9s. Furthermore, the average laser power per area should be balanced with the heat extraction achieved by the cooling system.

[0035] Requirements for successful photothermal targeted therapy of specific chromophores with minimal discomfort to the subject include: 1) epidermis preservation, i.e., ensuring that the peak temperature value at the skin surface is less than about 55°C; 2) dermis preservation, i.e., avoiding overheating of the dermis by balancing the peak and average power of the treatment pulses with the heat extraction of the cooling system; and 3) selective heating of chromophores and targets containing chromophores, such as a peak temperature greater than 55°C for sebaceous gland treatment. Note that the peak temperature value of 55°C is highly dependent on the specific treatment protocol and can be adjusted to other temperatures to remain within a safe operating range to avoid damage to the surrounding dermis and epidermis.

[0036] It is known in the literature that tissue parameters such as the thickness of the epidermis and dermis vary between individuals and between different skin locations on the body depending on factors such as age, gender and race. For example, even for the same individual, the forehead has different tissue properties than the back, thus necessitating different treatment parameter settings for different treatment locations. Taking such variations in tissue properties into account in determining a specific treatment regimen is important for laser-based acne treatment. Additionally, due to manufacturing variability and operating conditions, there may be variations in, for example, the exact laser power, spot size and cooling capacity between specific laser systems. In fact, manufacturing variations between systems can result in fluence variations of 15% or more between different laser treatment systems. In addition, the individual technique used by the user delivering the treatment can also affect the treatment, for example, by applying different pressures to the skin surface, which in turn affects, for example, blood perfusion at the treatment site.

[0037] In laser treatment of acne, the operating thermal range is generally defined at the upper end at the epidermal and dermal damage threshold temperatures and at the lower end by 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 targeted by the treatment regimen, the skin surface temperature can be an indicator of the sebaceous gland temperature. Then, an association model that provides a correspondence between the sebaceous gland temperature and the skin surface temperature can be used to formulate an actual treatment regimen using the skin surface temperature measurement to effectively target sebaceous gland damage while staying below the epidermal damage threshold. The association model can be developed using, for example, an analytical heat transfer model, or by using clinical data (e.g., via biopsy) to associate skin surface temperature with sebaceous gland damage given the application of a specific treatment regimen.

[0038] Based on clinical data, using e.g. Figure 3 and Figure 4 The treatment regimen illustrated in FIG. 1 has an operating temperature range of approximately 45° C. to 55° C. for acne treatment expressed as the final skin surface temperature. At skin surface temperatures below 45° C., it has been determined that there is no damage to the sebaceous glands. When the skin surface temperature is between 45° C. and 55° C., there is varying degrees of sebaceous gland damage with no epidermal damage. Above 55° C., there is epidermal damage in addition to damage to the sebaceous glands.

[0039] However, clinical data also indicate that the final skin surface temperature has a strong dependence on tissue parameters at a specific treatment area for a specific individual. While existing treatment protocols have been based on a "one treatment fits all" type of approach, innovative analytical protocols can be incorporated into the treatment method so that individually tailored treatment parameters are inferred directly from the final skin temperature at a lower laser power and / or the skin surface temperature achieved during the initial portion of the treatment and / or the measurements of the final skin surface temperature achieved during the previous treatment period to avoid epidermal damage while effectively causing sebaceous gland damage. In this way, the treatment protocol can be customized to the specific treatment area for a specific individual and also mitigate treatment variations that can be caused by variations in the laser power output of a specific machine and variations in treatment conditions (such as ambient humidity and temperature). Therefore, it would be desirable to optimize the treatment protocol for different subjects and even for different tissue locations of the same subject so as not to cause undesirable tissue damage while still effectively treating the target tissue components (e.g., sebaceous glands).

[0040] For example, by Figure 3 By directly measuring the skin surface temperature during the first four pulses of a laser, the maximum epidermal surface temperature after the subsequent pulses are applied can be predicted with a high degree of accuracy. This prediction can be used to modify a specific treatment regimen for a specific skin area in real time, such as reducing the number of pulses applied, adjusting the pulse width, or modifying the laser power for subsequent pulses. If the laser system incorporates a cooling system that can react quickly enough, the cooling is also adjustable as part of the real-time modification of the treatment system parameters. This customization process greatly enhances subject comfort and safety during the treatment process.

[0041] This analysis protocol can be performed by incorporating temperature measurements using, for example, a scanner that can be built into a scanner held by a medical professional to administer treatment to a subject (see, e.g., Figure 2 The prediction process can be performed at a highly localized level, thereby adjusting the treatment plan on the fly or before the treatment begins, or even adjusting the plan for each individual spot in the treatment matrix. In this way, the treatment plan can be specified to provide the necessary treatment laser power while staying below the epidermal and dermal damage threshold temperatures.

[0042] Go to Figure 5—— illustrates a flow chart of an exemplary process for an analysis protocol according to an embodiment. The analysis protocol assumes that the maximum epidermal temperature and the damage threshold temperature for the target (e.g., sebaceous gland) are known. Additionally, a correlation model between skin surface temperature and the target (e.g., sebaceous gland) has been established using computational analysis such as, for example, finite element modeling of heat transfer or through clinical experiments using biopsies. Therefore, for the analysis protocol, knowledge of the target value for the terminal skin surface temperature is assumed. As an example, for the earlier Figure 3 and Figure 4 The treatment protocol described in , with a target peak skin surface temperature of 51°C.

[0043] like Figure 5 As shown in , the analysis protocol 500 begins by applying low power laser pulses to the treatment area in step 512. The laser power should be set to a value below the damage threshold of epidermal damage. The skin surface temperature at the treatment area is then measured in step 514. The temperature measurement can be performed, for example, using a low speed infrared camera or similar device. A determination is then made in decision 516 whether sufficient data has been collected to fit the collected data into a pre-established correlation model. If the answer to decision 516 is no, the process returns to step 512, where laser pulses at different low power settings are applied to the treatment area to collect additional correlation data between the applied laser power and the epidermal temperature.

[0044] If the answer to decision 516 is yes, then the analysis protocol 500 proceeds to fit the measured skin surface temperature data to the established correlation model in step 518. Next, in step 520, appropriate laser parameters are determined for the particular treatment area of ​​the particular individual. Finally, in step 522, the exact treatment protocol to be used for the particular treatment area of ​​the particular individual is modified based on the appropriate laser parameters found in step 520.

[0045] Continue to refer Figure 5 , optionally, the analysis protocol 500 may continue during the actual treatment protocol. 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. The process then continues with measuring the skin surface temperature at the treatment area in step 532. In step 534, the correlation model calculation is updated using the measured skin surface temperature, and in step 536, the laser parameters of the treatment protocol are updated based on the updated calculation. A decision 538 is then made to determine whether the treatment protocol (i.e., the number of laser pulses applied to the treatment area) is complete. If the answer to decision 538 is no, the analysis protocol returns to step 532 to continue measuring the skin surface temperature. If the answer to decision 538 is yes, the treatment protocol is terminated in step 540.

[0046] In other words, until the treatment plan is completed, the analysis protocol 500 may implement optional steps 530 to 540 to continue adjusting the laser parameters even during the actual treatment plan. 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 may also be fed into the model calculations for further refinement of the laser parameters.

[0047] Now go to Figure 6 , shows an example of an analysis protocol and subsequent treatment protocol according to an embodiment. Graph 600 shows the relationship between laser power and peak skin surface temperature during a series of laser pulses applied 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 above analysis protocol was used to predict the peak skin surface temperature as measured by the IR camera, thereby 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 on the same subject "C Carlton" at a slightly higher laser power setting.

[0048] Continue to refer Figure 6 , to determine the applicability of the same dosimetry determination process on a different subject, laser pulses of the same power are applied to a second subject "S Carlton", starting with a similar starting temperature as shown at point 630. To the second subject "S Carlton", a treatment protocol of increasing laser power is immediately applied without a dosimetry protocol at a lower temperature, as shown at points 632, 634, and 636. Although the actual measured epidermal temperatures of the second subject "S Carlton" are different from those of the first subject "C Carlton", the graph 600 indicates that the safe operating ranges indicated by dashed lines 618 and 620 will also apply to the second subject "S Carlton". In this way, the above-described analysis protocol takes these individual differences into account in formulating a treatment protocol for a specific treatment area on a specific individual. The effectiveness of the analysis protocol has been verified using in vivo data.

[0049] For example, when the subject is examined at an appointment or during a pre-treatment session, the analysis protocol can be performed prior to the actual treatment session. Due to the use of low power, the analysis protocol can be performed without the need for local anesthesia with little epidermal or dermal damage occurring during the application of the analysis protocol. For example, in preparation for treatment, a trained operator can quickly pre-measure various treatment locations and develop a personalized treatment protocol with one scan per skin location.

[0050] 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 (given by Figure 6 The slope of the line connecting points 612, 614, 616, 622, 624, and 626 in FIG. 1 may be used to continually adjust future treatments. Furthermore, as the treatment plan proceeds, all treatment data may be added to the basis for establishing the skin surface versus power association. In this way, the association continues to be updated and refined even after the treatment plan is initiated. For example, based on the known relationship between laser power and the resulting skin surface temperature achieved at a particular treatment location, a recommendation for adjusting a laser parameter (such as laser power) may be given to a dermatologist for manual adjustment, or the device may automatically adjust, for example, the laser power for the next treatment location.

[0051] The concepts of the above analysis scheme can be extended to real-time adjustments to the treatment scheme using a closed-loop control process. The surface temperature of the skin can 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 the skin tissue, the measured skin surface temperature can be correlated with the temperature of a target component that cannot be directly measured (such as a sebaceous gland).

[0052] That is, according to another embodiment, a system whereby temperature measurements of the skin surface during an initial portion of treatment at a specific location are used to predict the future temperature of the skin surface at that specific location. The future temperature so predicted is used to adjust the thermal energy delivered by the laser or lasers by adjusting one or more parameters, such as laser power, pulse width, number of pulses, and other parameters that affect the thermal energy delivered by the laser, or by adjusting one or more parameters of a cooling system, such as air flow, so that the future temperature of the skin surface at the specific location, and therefore the temperature of underlying areas and components of the tissue that cannot be easily measured in a direct manner, reaches a desired value or does not exceed a specified value.

[0053] In other words, the dosimetry (e.g., settings of light therapy, including, for example, the power setting of a laser light source) administered to a subject can be adjusted in real time using a predictive control process. For example, by directly measuring Figure 3 Based on the skin temperature during pulses 322, 324 and 326 shown in FIG, the maximum epidermal surface temperature predicted after application of subsequent pulses can be calculated with a high degree of accuracy. This prediction is achieved by fitting a mathematical function to the measured epidermal surface temperature after application of, for example, three or four treatment pulses. The appropriate mathematical function is then selected based on knowledge of the pulse regimen used in the treatment regimen. For example, for Figure 3For the treatment regimen shown in , a single exponential function can provide an accurate model of the skin surface temperature after subsequent treatment pulses are applied. This prediction can then be used in real-time modification of a specific treatment regimen for a specific skin area. For example, the user can modify the number of additional pulses applied and one or more of the pulse width and laser power of the subsequent pulses. Additionally, if the light treatment system includes a sufficiently responsive cooling unit, the cooling applied to the treatment area is also adjustable as part of the real-time modification of the treatment system parameters. This customization process greatly enhances patient comfort and safety during the treatment process.

[0054] Analysis for use in a predictive control process may use a temperature measurement device, such as incorporated into a scanner (e.g., Figure 2 The prediction process can be performed using a commercial off-the-shelf low-cost camera in the temperature sensor 206 of the target treatment area 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, allowing the medical professional administering the treatment plan to make adjustments before the treatment plan begins, in real time during treatment, or even for each individual light spot in the treatment matrix. In this way, the treatment plan can be administered in a highly customizable manner to provide the necessary therapeutic laser power while staying below the epidermal and dermal damage threshold temperatures.

[0055] For example, the Arhenius damage function derives that the target damage is related to the peak temperature index; subsequently, the peak temperature of the skin surface is correlated to the peak temperature of the target component. In the example, for irradiation with a 22W laser over a 5mm by 5mm spot with a 150ms pulse, the temperature rise is approximately 180°C / second; in this case, the skin surface measurement should be updated approximately every 2.5ms or at 400Hz in order to use the temperature measurement as a control input for the treatment plan. With such a fast temperature measurement method, the laser can be turned off when the measured skin surface temperature reaches a preset threshold.

[0056] Alternatively, a slower temperature measurement device can be used to predict the peak temperature by measuring the temperature rise and fall behavior during the application of pulses early in the treatment protocol. The skin surface temperature can be measured during the first few laser pulses applied at the treatment area, and the temperature measurement can be used to infer the expected skin surface temperature during the application of subsequent pulses so that the energy profile of subsequent pulses can be adjusted accordingly. For example, laser parameters such as laser pulse duration, power, and pulse spacing can be adjusted to deliver the appropriate amount of energy to the target chromophore while avoiding damage to the surrounding medium.

[0057] Figure 7The flowchart shown in illustrates an exemplary process for closed-loop control of laser system parameters based on real-time skin surface temperature measurement according to an embodiment. Process 700 begins with initialization of a laser treatment regimen, where the laser system is set at a treatment setting (i.e., treatment levels of power, pulse width, etc.). In step 712, laser pulses are applied to the treatment area according to the treatment regimen. The treatment regimen may involve, for example, applying pulses of sequentially increasing power, or repeatedly applying pulses of substantially the same power setting to the treatment area. An example treatment regimen involves repeatedly applying laser pulses from a 22W laser with a 5 mm by 5 mm spot size and a 150 ms duration.

[0058] Continue to refer Figure 7 During the application of each laser pulse, the skin surface temperature at the treatment area is measured in step 714. Optionally, the skin surface temperature is measured during the cool down period between pulses. For example, the measurement can be made by a 25 Hz refresh rate infrared camera. A faster device, such as a 400 Hz refresh rate temperature measurement device, can be used to make more accurate measurements of the skin surface temperature during and after the application of the laser pulses.

[0059] A determination is then made 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 the predictive model. During step 718, a curve fit of the maximum skin surface temperature and optionally the minimum skin surface temperature is generated. For example, the predictive model can be generated by compiling a large number of temperature measurements corresponding to applying laser pulses to a test subject in a clinical setting, or by analytical modeling of the tissue.

[0060] Based on the curve fit generated in step 718, appropriate laser parameters are determined in step 720 for a particular treatment area of ​​the individual being treated. For example, if the curve fit predicts that the skin surface temperature will rise above a predetermined threshold temperature (such as 45°C), the laser parameters are adjusted to reduce the laser power. In this case, the surface temperature measurement of the skin surface 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 a desired temperature (such as 55°C for targeted chromophore damage) will not be achieved at the current laser pulse power setting, the laser parameters may be adjusted to provide the necessary treatment power. Such a situation may arise if the characteristics of the epidermis and dermis are such that a particular treatment area does not readily absorb laser pulse energy.

[0061] Figure 8An exemplary predictive closed-loop control process based on measured skin surface temperature results is illustrated in accordance with an embodiment. Figure 8 The diagram 800 in FIG. 1 shows that in a case such as Figure 7 The various temperature measurements and calculations used in the predictive closed-loop control process are shown in Figure 2 as a function of time. Figure 8 , time zero corresponds to the application instant of the first laser pulse (in this case, from a 22W laser, 150ms pulse and 5 mm by 5 mm square spot), which is preceded by approximately 15 seconds of air cooling (i.e., time -15 to zero). In this example, air cooling is applied to the treatment area throughout the laser pulse application. In this example, a 25Hz update rate IR camera is used to measure the skin surface temperature, although other temperature measurement devices are contemplated.

[0062] Continue to refer Figure 8 , the skin surface temperature measured during the initial cooling period is shown by curve 810. The skin surface temperature measured during the application of the laser pulses is shown by curve 812. The target skin surface temperature is indicated by dashed line 816, here shown at 45.5°C.

[0063] Starting at time zero, the first temperature measurement after the first four pulses (indicated by dots) is fitted to the prediction model. Figure 8 In the example shown in , the peak temperature and the cool down temperature immediately before the next pulse application are fitted into the clinically generated prediction model. Maximum temperature peaks 822, 824, 826 and 828 and minimum temperature nadirs 823, 825, 827 and 829 are curve fitted to generate maximum temperature curve 830 and minimum temperature curve 832 (as shown by the dashed curves). Optionally, temperature measurements taken during the cool down period between laser pulse applications are used to improve the measurement accuracy of the maximum temperature peaks and minimum temperature nadirs.

[0064] As shown in curve 812, the skin surface temperature is measured during the subsequent laser pulse application. It can be seen that the maximum and minimum temperature curves 830 and 832 accurately track the measured skin surface temperature (i.e., peaks 842, 844, 846 and 848 and nadirs 843, 845 and 847 of curve 812). Note that the predicted temperature rise (i.e., dashed curve 830) and the actual measured temperature (specifically peaks 846 and 848) indicate that the desired temperature of 45.5°C has been achieved by applying pulses 6 and 7, so the laser treatment protocol is stopped without applying an eighth pulse.

[0065] Even with a relatively slow temperature measurement device, such as a 25 Hz refresh IR camera, fitting the temperature data during the cool down period between laser pulse applications allows a good estimate of the rapid temperature rise achieved with each pulse application. If a faster temperature measurement device is used (e.g., 400 Hz refresh rate or faster), the temperature distribution can be measured directly in real time.

[0066] The foregoing is illustrative of the present invention and should not be construed as limiting the present invention. Although several exemplary embodiments of the present 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 the present invention. For example, lasers having other wavelengths (such as approximately 1210 nm) may be used. Alternatively, the above-described pre-treatment analysis method 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 regimen involving equipment that may be affected by system, user, atmospheric conditions, and other variability between treatments.

[0067] Thus, many different embodiments emerge from the above description and drawings. It will be appreciated that literally describing and illustrating every combination and subcombination of these embodiments would be unduly repetitive and obfuscating. As such, this specification, including the drawings, should be construed as constituting a complete written description of all combinations and subcombinations of the embodiments described herein, as well as the manner and process of making and using them, and should support claims to any such combination or subcombination.

[0068] For example, embodiments such as the following are contemplated:

[0069] 1. A method for determining a suitable set of parameters for a light source within a photothermal targeted therapy system, wherein the photothermal targeted therapy system is used to target chromophores embedded in a medium, the method comprising, before applying a treatment regimen: 1) applying at least one laser pulse to a location to be treated at a preset power level, wherein the preset power level is below a known damage threshold; 2) after applying the at least one laser pulse, measuring the skin surface temperature at the location to be treated; 3) estimating the relationship between the light source parameters and the skin surface temperature; and 4) limiting a safe operating range of the light source parameters to avoid thermal damage at the location to be treated.

[0070] 2. The method of item 1, wherein steps 1) to 4) are performed on a first subject for a first treatment area, and then steps 1) to 4) are repeated on the first subject for a second treatment area.

[0071] 3. The method of item 1, wherein steps 1) to 4) are performed on a first subject for a treatment area, and then steps 1) to 4) are repeated on a second subject for the treatment area.

[0072] 4. The method of item 1, further comprising taking into account treatment data from previous treatments of the same subject.

[0073] 5. The method of item 1, wherein steps 2) to 4) are repeated while the actual treatment regimen is being implemented on the subject.

[0074] 6. A system whereby temperature measurements of the skin surface during an initial portion of treatment at a specific location are used to predict the future temperature of the skin surface at that specific location. The future temperature so predicted is used to adjust the thermal energy delivered by the laser or lasers by adjusting one or more parameters, such as laser power, pulse width and other parameters that affect the thermal energy delivered by the laser or lasers, or by adjusting one or more parameters of a cooling system, such as air flow, so that the future temperature of the skin surface at the specific location, and therefore the temperature of underlying areas and components of the tissue that cannot be easily measured in a direct manner, reaches a desired value.

[0075] 7. A system whereby skin surface temperature measurements taken during treatment of an adjacent area or areas are used to predict the 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 laser or lasers by adjusting one or more parameters, such as laser power, pulse width and other parameters affecting the thermal energy delivered by the laser or lasers, or by adjusting one or more parameters of a cooling system, such as air flow, so that the future skin surface temperature at the particular location, and therefore the temperature of underlying areas and components of the tissue that cannot be easily measured in a direct manner, reaches a desired value.

[0076] In the specification, embodiments of the present invention have been disclosed, and although specific terms are employed, they are used only in a general and descriptive sense and not for the purpose of limitation. Although several exemplary embodiments of the present invention have been described, it will be readily appreciated by those skilled in the art that many modifications are possible in the exemplary embodiments without substantially departing from the novel teachings and advantages of the present invention. Therefore, all such modifications are intended to be included within the scope of the present invention as defined in the claims. Therefore, it should be understood that the foregoing is an illustration of the present invention and should not be interpreted as being limited to the specific embodiments disclosed, and modifications to the disclosed embodiments and other embodiments are intended to be included within the scope of the appended claims. The present invention is defined by the following claims, which will include equivalents of the claims.

Claims

1. A photothermal targeted therapy system for targeting a chromophore embedded in a medium, the system comprising: a light source configured to provide laser pulses within a range of power levels that includes known damage thresholds of the chromophore and treatment locations when operated using the parameter set; a temperature measuring device for measuring the skin surface temperature at the treatment site; a cooling system including a stream of air directed toward the treatment site; as well as A controller for controlling the light source and the temperature measuring device, The controller is configured for cooling the treatment location by directing a flow of air toward the treatment location using a cooling system; measuring a skin surface temperature at the treatment location after applying at least one laser pulse from a light source to the treatment location at a preset power level, the preset power level being below a known damage threshold; estimating a relationship between light source parameters and skin surface temperature at a treatment location by fitting the skin surface temperature at a treatment location and parameters for operating the light source to a correlation model, wherein the correlation model is established by computational analysis using finite element modeling taking into account heat transfer or by clinical experimentation using a biopsy; The controller is further configured to defining a safe operating range for a set of light source parameters in order to avoid thermal damage to the medium at the treatment site while still effectively targeting the chromophore in administering the treatment regimen, and Set the light source to deliver laser pulses within safe operating range.

2. The photothermal targeted therapy system according to claim 1, wherein the controller is further configured to predicting the future skin surface temperature at the treatment location based on the relationship between the light source parameters and the skin surface temperature so estimated, and At least one parameter of the light source is adjusted so that future measurements of skin surface temperature will not exceed a specified value. 3 . The photothermal targeted therapy system according to claim 1 , wherein the light source parameters include at least one of laser power, pulse width and pulse number.

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