HK40060092B - Determination process and predictive closed-loop control of dosimetry using measurement of skin surface temperature and associated methods - Google Patents

Description

Determination process and predictive closed-loop control for dosing using skin surface temperature measurement and associated methods

Technical Field

This invention relates to photothermal targeted therapy, and more particularly to a system and method for determining the correct dose measurement for photoinduced thermal therapy targeting a specific chromophore in an embedding medium.

Background Technology

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

Previous methods for preventing epidermal and dermal damage and subject pain include:

1. Pre-cool the epidermis, then apply photothermal therapy; and

2. Pre-cooling the epidermis, and pre-conditioning (i.e., preheating) the epidermis and dermis in the preheating protocol, before applying 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 leading to additional complexity in the treatment protocol and equipment.

Summary of the Invention

According to embodiments described herein, a method is disclosed for determining a suitable set of parameters for operating a light source within a photothermal targeting therapy system for targeting chromophores embedded in a medium. The method includes, before administering a treatment regimen to a first subject, 1) applying at least one laser pulse to a first treatment site at a preset power level, wherein the preset power level is below a known damage threshold. The method further includes 2) measuring the skin surface temperature at the first treatment site after applying the at least one laser pulse. The method further includes 3) estimating the relationship between parameters used to operate the light source and the skin surface temperature at the first treatment site, and 4) defining a safe operating range for the parameters used to operate the light source to avoid thermal damage to the medium at the first treatment site while still effectively targeting the chromophore during the application of the treatment regimen.

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

In another embodiment, a photothermal targeting therapy system for targeting chromophores embedded in a medium is disclosed. The system includes a light source configured to provide laser pulses within a power level range when operating with a set of parameters, the power level range including a known damage threshold for the chromophore and the treatment location. The system further includes a temperature measuring device for measuring the skin surface temperature at the treatment location, and a controller for controlling the light source and the temperature measuring 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 to avoid thermal damage to the medium at the treatment location, while still effectively targeting the chromophore during the treatment administration, and set the light source to apply laser pulses within the safe operating range.

In another embodiment, a method is disclosed 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 the application of a treatment regimen to a first subject at a first treatment location. The method includes: 1) measuring skin surface temperature at the first treatment location at least once; 2) predicting skin temperature when the treatment regimen is applied to the first subject at the first treatment location; and 3) adjusting at least one parameter 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.

Attached Figure Description

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

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

Figure 3 illustrates a schematic diagram of an exemplary set of light pulses suitable for use as an integrated pre-conditioning/phototherapy scheme according to an embodiment.

Figure 4 shows the measured temperature at the skin surface as a function of time when a therapeutic light pulse is applied to the skin surface according to an embodiment.

Figure 5 shows a flowchart illustrating an exemplary process for analyzing measured skin surface temperature, predicting skin temperature when subsequent laser pulses and/or additional cooling are applied, and then modifying the treatment regimen accordingly.

Figure 6 shows the measured skin surface temperature for various applied laser pulse powers in similar treatment areas for two different individuals.

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

Figure 8 illustrates the measured skin surface temperature generated by applying four pulses to the treatment area according to an embodiment, the four pulses being used as data to predict the increase in skin temperature of the subject as subsequent pulses are applied, and the resulting curve fitting and actual temperature measurement.

Detailed Description of Embodiments of the Invention

The invention is described more fully below with reference to the accompanying drawings, in which embodiments of the invention are illustrated. However, the invention may 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 fully convey the scope of the invention to those skilled in the art. In the drawings, for clarity, the sizes and relative dimensions of layers and regions may be enlarged. The same numerals always refer to the same elements.

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

For ease of description, spatially relative terms such as “below,” “under,” “lower,” “below,” “above,” and “upper” may be used herein to describe the relationship of an element or feature to other elements(s) or features(s) illustrated in the figures. It will be understood that, in addition to the orientation depicted in the figures, 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 figures is flipped, an element described as “below,” “under,” or “below” other elements or features would then be oriented “above” other elements or features. Thus, the exemplary terms “below” and “below” can cover both the above and below orientations. The device may be oriented in other ways (rotated 90 degrees or in other orientations), and the spatially relative descriptors used herein will be interpreted accordingly. Furthermore, 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 may be one or more intermediate layers.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the invention. As used herein, the singular forms “a,” “an,” and “the” are also intended to include the plural forms unless the context clearly indicates otherwise. It will be further understood that, when used in this specification, the terms “comprising” and/or “including” specify the presence of the 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 groups thereof. As used herein, the term “and/or” includes any and all combinations of one or more associated listed items and may be abbreviated to “/”.

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, directly connected to, coupled to, or adjacent to that other element or layer, or intermediate elements or layers may exist. 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 intermediate elements or layers exist. Similarly, when light is received or supplied "from" an element, it can be received or supplied directly from that element or from an intermediate element. On the other hand, when light is received or supplied "directly from" an element, no intermediate elements exist.

Embodiments of the invention are described herein with reference to cross-sectional views, which are schematic illustrations of idealized embodiments (and intermediate structures) of the invention. Accordingly, 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 specific shapes of the areas illustrated herein, but are to include, for example, deviations in shape due to manufacturing processes. Thus, the areas illustrated are schematic in nature, and their shapes are not intended to illustrate actual shapes of device areas, nor are they intended to limit the scope of the invention.

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

Figure 1 illustrates an exemplary photothermal targeted therapy system for targeting and heating a target to a sufficiently high temperature to damage the target without damaging the surrounding medium, wherein the target comprises a specific chromophore embedded in the medium. This system can be used, for example, to perform targeted photothermal ablation of sebaceous glands while preserving the epidermis and dermis surrounding the target sebaceous gland, where sebum is a chromophore embedded within the sebaceous gland.

Referring again to 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 the treatment area (i.e., the outer skin layer covering the target sebaceous gland), such as cooling by contact or direct air. 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 within the phototherapy unit 120 in Figure 1, it is possible that the controller is located outside of both the cooling unit 110 and the phototherapy unit 122, or even within the cooling unit 110.

The controller 122 further controls other components within the phototherapy unit 120, such as the laser 124, display 126, temperature monitoring unit, foot switch 130, door interlock device 132, and emergency on/off switch. The laser 124 provides laser power for the phototherapy program, and the controller 122 adjusts specific settings of the laser, such as 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 a 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 phototherapy program. 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 device 132 can serve as an additional safety measure, enabling it to detect when the treatment room door is half-open and instruct the controller 122 to prevent the phototherapy unit 120 or at least the laser 124 from operating. Furthermore, 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, additional photodiodes or other sensors can be added to monitor the power level of the energy emitted from the laser 124.

Referring again to Figure 1, the photothermal targeted therapy system 100 further includes a scanner 160, which is a handheld device used by the user to apply treatment protocols to the subject. The scanner may be formed, for example, in a gun-like or rod-like shape, for ease of use by the user. The scanner 160 is connected to a cooling unit 110 via a cooling connection 162, enabling the application of cooling protocols using the scanner 160. Additionally, the output from the laser 124 is connected to the scanner 160 via an optical fiber delivery 164, enabling the application of phototherapy protocols using the scanner 160. The scanner 160 is connected to a temperature monitoring unit 128 via a temperature connection 166 to feed back the skin temperature at the treatment area to, for example, a controller 122.

Figure 2 illustrates further details of the scanner 160 according to an embodiment. A cooling connection 162 is connected to a cooling delivery unit 202, configured to deliver a cooling mechanism (e.g., a stream of cool air) to the treatment area. An optical fiber delivery 164 from the laser 124 is connected to a laser energy delivery unit 204, which includes optical components for delivering light energy for a photothermal therapy protocol to the treatment area. Finally, a temperature connection 166 is connected to a temperature sensor 206, which measures the temperature at the treatment area to provide feedback to a controller 122. Additionally, the scanner 160 includes an on/off switch 210 (such as a trigger switch to turn the laser 124 on/off) and an optional status indicator 212 indicating the operating status of the scanner 160, such as whether the laser is operating. Although the scanner 160 is schematically shown as a box in Figure 2, the actual shape is configured for ease of use. For example, the scanner 160 could be shaped like a nozzle with a handle, a pistol, or another suitable shape that is easy for the user to aim and control.

In an exemplary use case, the entire treatment area covering the sebaceous gland to be treated is cooled. The cooling scheme may include, for example, applying a cold airflow across the treatment area over a predetermined time period (such as 10 seconds). After pre-cooling, the cooling mechanism (e.g., cold airflow or contact cooling) remains active, and a phototherapy scheme 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 phototherapy scheme 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.

According to an embodiment, an example of a pulse set suitable for a conditioning/phototherapy regimen is illustrated in Figure 3. Sequence 300 includes light pulses 322, 324, 326, 328, 330, 332, and 334 applied to the treatment area. In one embodiment, all seven light pulses have equal power and are separated by a uniform pulse interval (indicated by double arrows 342) and have the same pulse duration (indicated by gap 344). In the example, the 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 to them. During the pulse separation period, the laser can be scanned over different segments of the treatment area to increase the efficiency of laser use. Note that Figure 3 is not drawn to scale.

Figure 4 illustrates the measured skin surface temperature as light pulses (such as those shown in Figure 3) applied to the treatment area according to an embodiment. In the example shown in Figure 4, the treatment area has been pre-cooled for 7 seconds by direct air cooling, and then a light pulse from a 1720 nm wavelength laser with a power of 22 watts and a duration of 150 milliseconds is applied for a period of 2 seconds while cooling remains on. In this particular example, the direct air cooling delivery used for cooling and during treatment is a high-speed column of air cooled to -22°C, resulting in a heat transfer coefficient between the skin and air of approximately 350 W/m² K. In this embodiment, the beam size is 4.9 mm². 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.

The resulting changes in skin surface temperature are shown in Figure 400, where peak 422 corresponds to applied light pulse 322 as shown in Figure 3, and similar patterns are observed for peaks 424, 426, 428, and 430. In the example shown in Figure 4, the average power per spot is 22 W * 0.15 s / 2 s = 1.65 W. The same average power per spot can be achieved, for example, by pulses at 33 W for 100 ms with a 2 s pulse interval, or by pulses at 25.1 W for 125 ms with a 1.9 s pulse interval. Furthermore, the average laser power per area should be balanced with the heat extraction achieved by the cooling system.

Successful photothermal targeted therapy of a specific chromophore requires minimal discomfort to the subject and includes: 1) preserving the epidermis, i.e., ensuring that the peak temperature at the skin surface is less than approximately 55°C; 2) preserving the dermis, i.e., avoiding overheating of the dermis by balancing the peak and average power of the treatment pulses with the heat extraction from the cooling system; and 3) selective heating of the chromophore and the target containing it, such as peak temperatures greater than 55°C for sebaceous gland treatment. It should be noted that the 55°C peak temperature is highly dependent on the specific treatment protocol and can be adjusted to other temperatures to remain within a safe operating range, 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 between individuals and between different skin locations on the body, depending on factors such as age, sex, and ethnicity. 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 sites. Taking into account such variations in tissue properties is important for laser-based acne treatment when determining specific treatment protocols. Additionally, due to manufacturing variability and operating conditions, such as the exact laser power, spot size, and cooling capacity between specific laser systems, variations can occur. In fact, manufacturing variations between systems can lead to infusion variations of 15% or more between different laser treatment systems. Furthermore, 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.

In laser treatment of acne, the operating thermal range is generally defined at the upper end of the epidermal and dermal damage threshold temperature and at the lower end by the temperature required to bring the sebaceous gland to its damage threshold temperature. While there is currently no good way to directly measure the temperature of the sebaceous gland targeted by the treatment regimen, skin surface temperature can serve as an indicator of sebaceous gland temperature. A correlation model providing a relationship between sebaceous gland temperature and skin surface temperature can then be used to develop practical treatment regimens using skin surface temperature measurements to effectively target sebaceous gland damage while remaining below the epidermal damage threshold. This correlation model can be developed, for example, using analytical heat transfer models or by correlating skin surface temperature with sebaceous gland damage using clinical data (e.g., via biopsy) given the application of a particular treatment regimen.

Based on clinical data, using treatment protocols illustrated in Figures 3 and 4, the operational temperature range for acne treatment, expressed as terminal skin surface temperature, is approximately 45°C to 55°C. At skin surface temperatures below 45°C, no damage to the sebaceous glands has been confirmed. When the skin surface temperature is between 45°C and 55°C, varying degrees of sebaceous gland damage exist, without epidermal damage. Above 55°C, epidermal damage occurs in addition to sebaceous gland damage.

However, clinical data also indicate that terminal skin surface temperature is highly dependent on tissue parameters at specific treatment areas for a particular individual. While existing treatment protocols are based on a "one treatment fits all" approach, innovative analytical methods can be incorporated into treatment methods to infer individually tailored treatment parameters directly from measurements of terminal skin temperature at lower laser power and/or skin surface temperature reached during the initial phase of treatment and/or terminal skin surface temperature reached during previous treatments, thus avoiding epidermal damage while effectively causing sebaceous gland damage. This allows for treatment protocols to be customized for specific treatment areas of a particular individual and also mitigates treatment variability that can be caused by variations in laser power output from a particular machine and in treatment conditions such as ambient humidity and temperature. Therefore, it would be desirable to optimize treatment protocols for different subjects and even for different tissue locations within the same subject to effectively treat target tissue components (e.g., sebaceous glands) without causing undesirable tissue damage.

For example, by directly measuring the skin surface temperature during the first four pulses (Figure 3), the maximum epidermal surface temperature after the application of subsequent pulses can be predicted with high accuracy. This prediction can be used to modify specific treatment protocols for particular skin areas in real time, such as reducing the number of pulses applied for subsequent pulses, adjusting the pulse width, or modifying the laser power. If the laser system incorporates a cooling system capable of responding quickly enough, cooling can also be adjusted as part of the real-time modification of treatment system parameters. This customization process significantly enhances subject comfort and safety during treatment.

This analytical approach can be performed by incorporating temperature measurements using, for example, a commercially available, low-cost camera that can be built into a scanner held by a medical professional to administer treatment to a subject (e.g., see temperature sensor 206 in Figure 2), or by using a separate commercially available single-pixel or multi-pixel thermal measurement device. The prediction process can be performed at a highly localized level, allowing for adjustments to the treatment protocol, either online or before treatment begins, and even to the protocol for each individual spot in the treatment matrix. In this way, the treatment protocol can be specified to provide the necessary therapeutic laser power while remaining below the epidermal and dermal damage threshold temperatures.

Turning to Figure 5—this illustrates a flowchart 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, the 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 trials using biopsies. Therefore, for the analysis protocol, knowledge of the target value for the final skin surface temperature is assumed. As an example, for the treatment protocol described earlier in Figures 3 and 4, the target peak skin surface temperature is known to be 51°C.

As shown in Figure 5, the analysis scheme 500 begins by applying a low-power laser pulse to the treatment area in step 512. The laser power should be set below the damage threshold of the epidermis. Then, in step 514, the skin surface temperature at the treatment area is measured. Temperature measurement can be performed, for example, using a low-speed infrared camera or a similar device. A determination is then made in decision 516 to determine 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 with different low-power settings are applied to the treatment area to collect additional correlation data between the applied laser power and the epidermal temperature.

If the answer to decision 516 is yes, then analysis scheme 500 continues in step 518 to fit the measured skin surface temperature data to the established correlation model. Next, in step 520, appropriate laser parameters are determined for a specific treatment area for a specific individual. Finally, in step 522, based on the appropriate laser parameters found in step 520, the exact treatment plan to be used for the specific treatment area of the specific individual is modified.

Referring again to Figure 5, optionally, the analysis scheme 500 can continue during the actual treatment scheme. In an exemplary embodiment, after setting the laser parameters in step 522, a treatment scheme with appropriate laser parameters is initiated in step 530. Then, in step 532, the process continues to measure the skin surface temperature at the treatment area. In step 534, the measured skin surface temperature is used to update the correlation model calculation, and in step 536, the laser parameters of the treatment scheme are updated based on the updated calculation. Then, a decision 538 is made to determine whether the treatment scheme (i.e., the number of laser pulses applied to the treatment area) is complete. If the answer to decision 538 is no, the analysis scheme returns to step 532 to continue measuring the skin surface temperature. If the answer to decision 538 is yes, the treatment scheme is terminated in step 540.

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

Turning now to Figure 6, an example of the analysis protocol and subsequent treatment protocol according to an embodiment is shown. Figure 600 illustrates the relationship between laser power and peak skin surface temperature during a series of laser pulses applied to two different subjects (labeled “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 aforementioned analysis protocol was used to predict the peak skin surface temperature, such as that measured by an IR camera, thereby defining the safe operating range indicated by horizontal dashed line 618 and vertical dashed line 620. Points 622, 624, and 626 show data obtained on the same subject “C Carlton” at a slightly higher laser power setting.

Referring again to Figure 6, to determine the applicability of the same dosing determination procedure to different subjects, laser pulses of the same power were applied to a second subject, “S Carlton,” starting at a similar initial temperature as shown at point 630. For the second subject, “S Carlton,” a treatment regimen with increased laser power was immediately applied, without the dosing regimen at a lower temperature, as shown at points 632, 634, and 636. Although the actual measured skin temperatures of the second subject, “S Carlton,” differed from those of the first subject, “C Carlton,” the safe operating range indicated by dashed lines 618 and 620 in Figure 600 will also apply to the second subject, “S Carlton.” Thus, the above analytical protocol takes into account these individual differences when developing treatment regimens for specific treatment areas on specific individuals. The validity of the analytical protocol has been validated with in vivo data.

For example, the analysis protocol can be executed before the actual treatment period when the subject is scheduled for examination or during the pre-treatment period. Due to the use of low power, the analysis protocol can be executed with minimal epidermal or dermal damage during its application without the need for local anesthesia. For instance, in treatment preparation, trained operators can quickly predict various treatment sites and develop personalized treatment plans with only one scan per skin site.

Once a relationship between laser power and the resulting skin surface temperature has been established for a specific subject and/or a specific skin location and/or a specific laser device, this relationship (indicated by the slope of the line connecting points 612, 614, 616, 622, 624, and 626 in Figure 6) can be used to continuously adjust future treatments. Furthermore, as the treatment plan progresses, all treatment data can be added to the basis for establishing the skin surface contrast power correlation. In this way, the correlation is continuously 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 specific treatment location, dermatologists can be advised to adjust laser parameters (such as laser power) manually, or the device can automatically adjust the laser power, for example, for the next treatment location.

The concept of the above-described analytical approach can be extended to real-time adjustments of the treatment plan using a closed-loop control process. Skin surface temperature can be measured using, for example, an infrared (IR) camera or other temperature measurement mechanisms. For instance, by fitting the measured temperature to a mathematical model of skin tissue, the measured skin surface temperature can be correlated with the temperature of target components that cannot be directly measured, such as sebaceous glands.

In other words, according to another embodiment, a system in which temperature measurements of the skin surface during the initial portion of treatment at a particular location are used to predict the future temperature of the skin surface at that particular location. By adjusting one or more parameters, such as laser power, pulse width, number of pulses, and other parameters affecting the heat energy delivered by the laser, or by adjusting one or more parameters of the cooling system, such as airflow, the predicted future temperature is used to adjust the heat energy delivered by one or more lasers so that the future temperature of the skin surface at the particular location, as well as the temperature of the underlying tissue and components that cannot be easily measured directly, reaches a desired value or does not exceed a specified value.

In other words, the dose measurements applied to the subject (e.g., phototherapy settings, including, for example, the power settings of the laser source) can be adjusted in real time using a predictive control process. For example, by directly measuring the skin temperature during pulses 322, 324, and 326 shown in Figure 3, the predicted maximum epidermal surface temperature after the application of subsequent pulses can be calculated with high accuracy. This prediction is achieved by fitting a mathematical function to the measured epidermal surface temperature after, for example, three or four treatment pulses. The appropriate mathematical function is then selected based on knowledge of the pulse pattern used in the treatment protocol. For example, for the treatment protocol shown in Figure 3, a single exponential function can provide an accurate model of the skin surface temperature after the application of subsequent treatment pulses. This prediction can then be used in real-time modification of specific treatment protocols for specific skin areas. For example, the user can modify the number of additional pulses applied, as well as one or more of the pulse width and laser power of subsequent pulses. Additionally, if the phototherapy 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 procedure.

The analysis used in the predictive control process can be performed using temperature measurement devices, such as commercially available, low-cost cameras incorporated into a scanner (e.g., temperature sensor 206 in Figure 2), or by using separate thermal measurement devices such as single-pixel or multi-pixel thermal imagers. By controlling the size of the target treatment area and specifically measuring the skin surface temperature at that area, the predictive process can be performed at a highly localized level, allowing medical professionals administering the treatment regimen to adjust it before treatment begins, in real-time during treatment, or even for each individual spot in the treatment matrix. 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 epidermal and dermal damage threshold temperatures.

For example, the Arhenius damage function derives an exponential correlation between the target damage and the peak temperature; subsequently, the peak temperature of the skin surface is correlated with the peak temperature of the target component. In the example, for radiation using a 22W laser with 150ms pulses over a 5mm x 5mm spot, 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 to allow the temperature measurement to be used as a control input for the treatment protocol. Using such a rapid temperature measurement method, the laser can be shut off when the measured skin surface temperature reaches a preset threshold.

Alternatively, slower temperature measurement devices can be used to predict peak temperature by measuring the temperature rise and fall behavior during the early pulse application in the treatment protocol. Skin surface temperature can be measured during the first few laser pulses applied to the treatment area, and these measurements can be used to infer the expected skin surface temperature during subsequent pulse applications, allowing the energy distribution of subsequent pulses to be adjusted accordingly. For example, laser parameters such as pulse duration, power, and pulse interval 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 Figure 7 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 the initialization of the laser treatment protocol, where the laser system is set to treatment settings (i.e., power, pulse width, and other treatment levels). In step 712, laser pulses are applied to the treatment area according to the treatment protocol. The treatment protocol may involve, for example, applying pulses with sequentially increasing power, or repeatedly applying pulses with essentially the same power setting to the treatment area. An example treatment protocol involves repeatedly applying laser pulses from a 22W laser with a spot size of 5 mm by 5 mm and a duration of 150 ms.

Referring again to Figure 7, during each laser pulse application, the skin surface temperature at the treatment area is measured in step 714. Optionally, the skin surface temperature is measured during the cooling-down period between pulses. For example, this can be done using a 25Hz refresh rate infrared camera. Faster devices, such as 400Hz refresh rate temperature measurement devices, can be used for more accurate measurements of the skin surface temperature during and after the application of the laser pulse.

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

Based on the curve fit generated in step 718, appropriate laser parameters for a specific treatment area of the individual being treated are determined in step 720. 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 can indicate that a specific treatment area on the subject is particularly sensitive to laser pulse energy absorption. Alternatively, if the curve fit predicts that the desired temperature (such as 55°C for targeted chromophore damage) will not be reached with the current laser pulse power setting, the laser parameters can be adjusted to provide the necessary treatment power. This may occur if the characteristics of the epidermis and dermis make a particular treatment area less likely to absorb laser pulse energy.

Figure 8 illustrates an exemplary predictive closed-loop control process based on measured skin surface temperature results according to an embodiment. Graph 800 in Figure 8 shows various temperature measurement and calculation curves as a function of time used in predictive closed-loop control processes such as those illustrated in Figure 7. In Figure 8, time zero corresponds to the application moment of the first laser pulse (in this case, from a 22W laser, a 150ms pulse, and a 5mm x 5mm square spot), preceded by approximately 15 seconds of air cooling (i.e., time -15 to zero). In this example, air cooling is applied to the treatment area throughout the laser pulse application. In this example, a 25Hz refresh rate IR camera is used to measure the skin surface temperature, although the use of other temperature measurement devices is contemplated.

Referring again to Figure 8, curve 810 shows the skin surface temperature measured during the initial cooling period. Curve 812 shows the skin surface temperature measured during the application of the laser pulse. The dashed line 816 indicates the target skin surface temperature, shown here at 45.5°C.

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

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

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

The foregoing is illustrative of the invention and should not be construed as limiting it. Although several exemplary embodiments of the invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without departing from the novel teachings and advantages of the invention. For example, lasers with other wavelengths (such as approximately 1210 nm) may be used. Alternatively, the above-described pre-treatment analysis method can be used in conjunction with other treatment protocols, such as those described in WIPO patent applications WO/2018/076011 by Sakamoto et al. and WO/2003/017824 by McDaniel. In fact, the method is applicable to any thermotherapy protocol involving equipment that may be affected by other variability in the system, user, atmospheric conditions, and treatment.

Therefore, many different embodiments are derived from the above description and drawings. It will be understood that it would be excessive and confusing to literally describe and illustrate each combination and sub-combination of these embodiments. Accordingly, this specification, including the drawings, should be construed as constituting a complete written description of all combinations and sub-combinations of the embodiments described herein, as well as the ways and processes of making and using them, and should support the claims for any such combination or sub-combination.

For example, an embodiment such as the following is conceivable:

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

2. The method of Project 1, wherein steps 1) through 4) are performed on a first subject for a first treatment area, and then steps 1) through 4 are repeated on the first subject for a second treatment area.

3. The method of Project 1, wherein steps 1) through 4) are performed on a first subject for a treatment area, and then steps 1) through 4) are repeated on a second subject for the treatment area.

4. The method of Project 1 further includes taking into account treatment data from previous treatments of the same subject.

5. The method of Project 1, wherein steps 2) through 4 are repeated while the actual treatment regimen is administered to the subject.

6. A system in which temperature measurements of the skin surface during the initial portion of treatment at a particular location are used to predict the future temperature of the skin surface at that particular location. The predicted future temperature is used to adjust the heat 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 one or more lasers, or by adjusting one or more parameters of a cooling system, such as airflow, so that the future temperature of the skin surface at the particular location, as well as the temperature of the underlying tissue and components that cannot be readily measured directly, reaches a desired value.

7. A system by which skin surface temperature measurements obtained during treatment of one or more adjacent regions are used to predict the future temperature of the skin surface at that particular location. The predicted future temperature is used to adjust the heat energy delivered by one or more lasers, such as laser power, pulse width, and other parameters affecting the thermal energy delivered by one or more lasers, or by adjusting one or more parameters of a cooling system, such as airflow, so that the future skin surface temperature at the particular location, as well as the temperature of the underlying tissue and components that cannot be readily measured directly, reaches a desired value.

Embodiments of the invention have been disclosed in this specification, and although specific terminology has been used, it is used only in a general and descriptive sense and not for limiting purposes. While several exemplary embodiments of the invention have been described, those skilled in the art will readily appreciate that many modifications are possible in these exemplary embodiments without departing from the novel teachings and advantages of the invention in essence. Therefore, all such modifications are intended to be included within the scope of the invention as defined in the claims. It should therefore be understood that the foregoing is illustrative of the invention and should not be construed as limiting to the specific embodiments disclosed, and modifications to the disclosed and other embodiments are intended to be included within the scope of the appended claims. The invention is defined by the following claims—which will include equivalents of the claims.

Claims (3)

1. A photothermal targeted therapy system for targeting chromophores embedded in a medium, the system comprising: The light source is configured to provide laser pulses within a power level range when operating with a set of parameters, the power level range including the known damage threshold of the chromophore and the treatment location; Temperature measuring device for measuring the skin surface temperature at the treatment site; The cooling system includes an airflow directed toward the treatment site; and Controller used to control light sources and temperature measuring devices. The controller is configured for The treatment area is cooled by directing airflow toward it using a cooling system. After applying at least one laser pulse from a light source to the treatment site at a preset power level, the skin surface temperature at the treatment site is measured, wherein the preset power level is below a known damage threshold. The relationship between light source parameters and skin surface temperature is estimated by fitting the skin surface temperature at the treatment site and the parameters used to operate the light source to an association model, wherein the association model is established by computational analysis using finite element modeling that takes heat transfer into account or by using clinical experiments using biopsy. The controller is further configured to be used for To limit the safe operating range of the light source parameter set in order to avoid thermal damage to the medium at the treatment site, while still effectively targeting the chromophore during the application of the treatment plan, and Set the light source to apply laser pulses within safe operating limits. 2. The photothermal targeted therapy system of claim 1, wherein the controller is further configured for... Based on the relationship between the light source parameters and the estimated skin surface temperature, the future skin surface temperature at the treatment site is predicted, and Adjust at least one parameter of the light source so that future measurements of the 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.