HK40060092A - Determination process and predictive closed-loop control of dosimetry using measurement of skin surface temperature and associated methods - Google Patents

Description

Dosimetry determination process and predictive closed-loop control using skin surface temperature measurements and associated methods

Technical Field

The present invention relates to photothermal targeted therapies, and more particularly to systems and methods for determining the correct dosimetry of photoinduced thermal therapies to target specific chromophores in an embedding medium.

Background

Chromophores embedded in media such as the dermis may be thermally damaged by heating the chromophores with a targeted light source such as a laser. However, the application of sufficient thermal energy to damage the chromophore may also cause damage to the surrounding dermis and overlying epidermis, resulting in epidermal and dermal damage and pain to the subject. The problem is also applicable 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 to the target.

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

1. precooling the epidermis and then applying photothermal therapy; and

2. precooling the epidermis, also preconditioning (i.e., preheating) the epidermis and dermis in a preheating protocol, followed by applying photothermal therapy in a different treatment protocol. In some cases, the pre-heating 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 of the treatment protocol and equipment.

Disclosure of Invention

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 a chromophore embedded in a medium is disclosed. The method includes, prior to administering the treatment regimen to the first subject, 1) administering at least one laser pulse to the first treatment location at a preset power level, wherein the preset power level is below a known damage threshold. The method further includes 2) measuring a skin surface temperature at the first treatment location after applying the at least one laser pulse. The method further comprises 3) estimating a relationship between a parameter for operating the light source and the skin surface temperature at the first treatment location, and 4) defining a safe operating range for the parameter 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 protocol.

In embodiments, steps 1) through 4) are repeated at a second treatment location on the first subject prior to administering the treatment regimen at the second treatment location. In another embodiment, steps 1) through 4) are repeated at a first treatment location on the second subject prior to administering the treatment regimen to the second subject. In yet another embodiment, the method further comprises 5) storing in a memory of the photothermal targeted therapy system a safe operating range for 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 the treatment regime is administered to the first subject at a later time.

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

In yet another embodiment, a method for adjusting a suitable set of parameters for operating a light source within a photothermal targeting therapy system for targeting chromophores embedded in a medium during administration of a therapy regimen to a first subject at a first treatment location is disclosed. The method comprises the following steps: 1) measuring the skin surface temperature at least once at the first treatment location; 2) predicting a skin temperature when a treatment regimen is administered to a first subject at a 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. Predicting the skin temperature takes into account at least one of a heat transfer model and a series of experimental results.

Drawings

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

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

Fig. 3 shows a schematic diagram of an exemplary set of light pulses suitable for use as an integrated preconditioning/phototherapy regime in accordance with an embodiment.

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

Fig. 5 shows a flow chart illustrating an exemplary process for analyzing the measured skin surface temperature, predicting the skin temperature when applying subsequent laser pulses and/or additional cooling, and then modifying the treatment regime accordingly.

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

Fig. 7 shows 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.

Fig. 8 shows measured skin surface temperature resulting from applying four pulses to a treatment region, which are used as data for predicting the increase in skin temperature of a subject with subsequent pulse applications, and the resulting curve fit and actual temperature measurement, according to an embodiment.

Detailed description of embodiments of the invention

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

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

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

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

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

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

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

Fig. 1 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 includes a specific chromophore embedded in the medium. The system can be used, for example, for photothermal ablation of sebaceous glands in a targeted manner while retaining the epidermis and dermis surrounding the targeted sebaceous glands, where sebum is a chromophore embedded within the sebaceous glands.

Still referring to fig. 1, the photothermal targeted therapy system 100 includes a cooling unit 110 and a light therapy unit 120. The cooling unit 110 provides a cooling mechanism for the cooling effect to the treatment area (i.e. the area of the outer skin layer covering the targeted sebaceous glands), such as by contact or by direct air cooling. The cooling unit 110 is connected to a controller 122 within the light treatment unit 120. It is noted that although the controller 122 is shown as being contained within the light treatment unit 120 in fig. 1, it is possible that the controller is located outside both the cooling unit 110 and the light treatment unit 122, or even within the cooling unit 110.

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

With continued reference to fig. 1, the photothermal targeted therapy system 100 further includes a scanner 160, which scanner 160 is part of a device that a user holds in the hand of applying a therapy regimen to a subject. The scanner may be formed in a gun-like or bar-like shape, for example, to be easily held by a user. The scanner 160 is connected with the cooling unit 110 via a cooling connection 162 such that a cooling scheme can be applied using the scanner 160. Additionally, the output from the laser 124 is connected to the scanner 160 via fiber optic delivery 164 so that a light therapy regimen can be applied using the scanner 160. The scanner 160 is connected to the temperature monitoring unit 128 via a temperature connection 166 in order to feed back the skin temperature at the treatment area to, for example, the controller 122.

Fig. 2 shows additional details of the scanner 160 according to an embodiment. The cooling connection 162 is connected to a cooling delivery unit 202, the cooling delivery unit 202 being configured to deliver a cooling mechanism (e.g., a flow of cold air) to the treatment region. The fiber delivery 164 from the laser 124 is coupled to a laser energy delivery unit 204, the laser energy delivery unit 204 including optical components for delivering optical energy for photothermal treatment protocols to the treatment region. Finally, the temperature connection 166 is connected to a temperature sensor 206, which temperature sensor 206 measures the temperature at the treatment area for feedback to the controller 122. Additionally, the scanner 160 includes an on/off switch 210 (such as a toggle switch that turns the laser 124 on/off) and an optional status indicator 212 that indicates an operational status of the scanner 160, such as whether the laser is operating. Although the scanner 160 is schematically shown as a box in fig. 2, the actual shape is configured for ease of use. For example, the scanner 160 may be shaped as a nozzle with a handle, a pistol shape, or another suitable shape for easy aiming and control by the user.

In an exemplary use scenario, the complete treatment area covering the sebaceous glands to be treated is cooled. The cooling protocol may include, for example, applying a cold gas flow across the treatment region for a prescribed period of time (such as 10 seconds). After pre-cooling, a cooling mechanism (e.g., cold air flow or contact cooling) remains active and a light treatment protocol 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 a treatment area. For example, a light treatment protocol may include applying a set number of light pulses to each segment of the treatment region, wherein the segments are sequentially illuminated by the laser pulses. In another embodiment, the zones are illuminated in a random order.

An example of a set of pulses suitable for use in a conditioning/light therapy regime is illustrated in fig. 3, according to an embodiment. Sequence 300 includes light pulses 322, 324, 326, 328, 330, 332, and 334 applied at a treatment region. In one embodiment, all seven light pulses have equal power and are separated by uniform pulse intervals (represented by double arrows 342) and have the same pulse duration (represented by gap 344). In an 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 mass to cool down in order to prevent damage thereto. During the pulse separation period, the laser may be scanned over different sections within the treatment region in order to increase the laser usage efficiency. Note that fig. 3 is not drawn to scale.

Fig. 4 shows measured skin surface temperatures applied to a treatment area as light pulses (such as those shown in fig. 3) according to an embodiment. In the example shown in fig. 4, the treatment region has been pre-cooled by direct air cooling for 7 seconds, then a pulse of light from a 1720 nm wavelength laser at a power of 22 watts and a duration of 150 milliseconds is applied for a period of 2 seconds while the cooling remains on. In this particular example, direct air cooling for cooling and during treatment delivers a high velocity air column cooled to-22℃, resulting in a heat transfer coefficient between skin and air of approximately 350W/m 2K. 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 body treatment area, and other factors, the exact beam size may be adjusted using, for example, collimating optics.

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

The requirements for successful photothermal targeted therapy of specific chromophores with minimal subject discomfort include: 1) the epidermis is reserved, namely the peak temperature value at the surface of the skin is ensured to be less than about 55 ℃; 2) preserving the dermis, i.e., avoiding overheating the dermis by balancing the peak and average power of the therapy pulse with the heat extraction of the cooling system; and 3) selective heating of the chromophore and the target containing the chromophore, such as a peak temperature greater than 55 ℃ for sebaceous gland therapy. It is noted that the peak temperature value of 55 ℃ is highly dependent on the particular treatment regime, and may be adjusted to other temperatures to remain within a safe operating range to avoid 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 from individual to individual and from skin location to skin location 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 positions. In determining a particular treatment regimen, it is important to consider such changes in tissue properties for laser-based acne treatment. Additionally, due to manufacturing variability and operating conditions, there may be variations in the exact laser power, spot size, and cooling capacity, for example, between particular laser systems. In fact, manufacturing variations between systems may result in fluence variations of 15% or more between different laser treatment systems. Furthermore, the individual techniques used by the user delivering the treatment may also affect the treatment, e.g. by applying different pressures to the skin surface, which in turn affects e.g. blood perfusion at the treatment site.

In laser treatment of acne, the operating thermal range is generally defined at the upper end at the epidermal and dermal lesion threshold temperatures and at the lower end by the temperature required to bring the sebaceous glands to their lesion threshold temperature. Although there is currently no good way to directly measure the temperature of the sebaceous glands targeted by a treatment regimen, skin surface temperature may be an indicator of sebaceous gland temperature. Then, a correlation model providing correspondence between sebaceous gland temperature and skin surface temperature can be used to formulate an actual treatment plan using skin surface temperature measurements for effectively targeting sebaceous gland lesions while remaining below the epidermal lesion threshold. The correlation model may be developed using, for example, an analytical heat transfer model, or by correlating skin surface temperature with sebaceous gland lesions using clinical data (e.g., via biopsy) given a particular treatment regimen application.

Based on clinical data, the operating temperature range for acne treatment expressed as terminal skin surface temperature is approximately 45 ℃ to 55 ℃, using a treatment protocol such as that illustrated in fig. 3 and 4. At skin surface temperatures below 45 ℃, no damage to the sebaceous glands has been determined. When the skin surface temperature is between 45 ℃ and 55 ℃, there is a varying degree of sebaceous gland damage, with no epidermal damage. Above 55 ℃, there is epidermal damage in addition to sebaceous gland damage.

However, clinical data also indicate that the terminal skin surface temperature is strongly dependent on tissue parameters at a specific treatment region of a specific individual. While existing treatment protocols have been based on "one treatment fit all" type of methods, innovative analytical protocols can be incorporated into the treatment protocol to infer separately tailored treatment parameters directly from measurements of terminal skin temperature at lower laser power and/or skin surface temperature reached during the initial portion of treatment and/or terminal skin surface temperature reached during previous treatments to avoid epidermal damage while effectively causing sebaceous gland damage. In this way, the treatment plan can be tailored to the particular treatment region of a particular individual, and also mitigate treatment variations that can result from variations in the laser power output of a particular machine, as well as variations in treatment conditions (such as ambient humidity and temperature). Therefore, it would be desirable to optimize treatment regimens for different subjects and even for different tissue locations of the same subject so as not to cause unwanted tissue damage while still effectively treating the target tissue component (e.g., sebaceous glands).

For example, by directly measuring the skin surface temperature during the first four pulses of fig. 3, the maximum epidermal surface temperature after application of subsequent pulses can be predicted with a high degree of accuracy. This prediction can be used to modify in real time a particular treatment regime for a particular skin region, 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 fast 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 course of treatment.

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

Turning to FIG. 5, a flow diagram illustrating an exemplary process for analyzing a schema according to an embodiment is shown. The analysis protocol assumes that the maximum epidermal temperature and the lesion threshold temperature for the target (e.g., sebaceous glands) are known. Additionally, correlation models between skin surface temperature and targets (e.g., sebaceous glands) have been established using computational analysis such as, for example, finite element modeling of heat transfer, or by clinical trials using biopsies. Thus, for the analysis scheme, knowledge of the target value for the terminal skin surface temperature is assumed. As an example, for the treatment protocols described earlier in fig. 3 and 4, the target peak skin surface temperature is known to be 51 ℃.

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

If the answer to decision 516 is yes, then the 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 particular treatment region of a particular individual. Finally, in step 522, the exact treatment protocol to be used for a particular treatment area of a particular individual is modified based on the appropriate laser parameters found in step 520.

With continued reference to fig. 5, the analysis protocol 500 may optionally continue during the actual treatment protocol. In an exemplary embodiment, after the laser parameters are set in step 522, a treatment plan with appropriate laser parameters is initiated in step 530. Then, in step 532, the process continues with measuring the skin surface temperature at the treatment area. In step 534, the correlation model calculations are updated using the measured skin surface temperature, and in step 536, the laser parameters of the treatment plan are updated based on the updated calculations. A decision 538 is then made to determine whether the treatment plan (i.e., the number of laser pulses applied to the treatment region) 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.

In other words, until the treatment plan is complete, the analysis plan 500 may implement optional steps 530 to 540 to continue adjusting 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 region of the same subject, they can also be fed into the model calculations for further refinement of the laser parameters.

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

With continued reference to fig. 6, to determine the suitability of the same dosimetry determination procedure on different subjects, 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. For the second subject, "S Carlton", the treatment regimen of increasing laser power is applied immediately without the dosimetry regimen at the lower temperature, as shown by 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 the dashed lines 618 and 620 will also apply to the second subject "S Carlton". Thus, the above analysis protocol takes these individual differences into account in formulating a treatment protocol for a particular treatment area on a particular individual. The effectiveness of the assay protocol has been validated using in vivo data.

For example, when a subject is examined at a scheduled or pre-treatment session, the analysis protocol may be performed prior to the actual treatment session. Due to the use of low power, an analysis protocol can be performed without the need for local anesthesia, with little or no epidermal or dermal damage occurring during the application of the analysis protocol. For example, in preparing a treatment, a trained operator can quickly pre-measure various treatment locations and develop personalized treatment protocols with one scan per skin location.

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

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

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

In other words, dosimetry (e.g., settings for light therapy, including, for example, power settings for a laser light source) administered to a subject can be adjusted in real time by using a predictive control process. For example, by directly measuring the skin temperature during the pulses 322, 324 and 326 shown in fig. 3, the predicted maximum epidermal surface temperature after applying subsequent pulses can be calculated with a high degree of accuracy. The prediction is achieved by fitting a mathematical function to the measured epidermal surface temperature after applying, for example, three or four treatment pulses. The appropriate mathematical function is then selected based on knowledge of the pulse regime used in the treatment regime. For example, for the treatment protocol shown in fig. 3, a single exponential function may provide an accurate model of the skin surface temperature after the application of subsequent treatment pulses. This prediction can then be used in modifying a particular treatment regime for a particular skin region in real time. For example, the user may modify the number of additional pulses applied and one or more of the pulse width and laser power of subsequent pulses. Additionally, if the light treatment system includes a sufficiently responsive cooling unit, the cooling applied to the treatment region 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 course of treatment.

The analysis for use in the predictive control process may be performed using a temperature measurement device, such as a commercially available low cost camera incorporated into a scanner (e.g., temperature sensor 206 of fig. 2), or by using a separate thermal measurement device such as a single-pixel or multi-pixel thermal imager. By controlling the size of the target treatment area and specifically measuring the skin surface temperature at the target treatment area, the prediction process can be performed at a highly localized level, enabling a medical professional applying the treatment plan to make adjustments before the treatment plan starts, in real time during the treatment, or even for each individual light point 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 epidermal and dermal damage threshold temperatures.

For example, the Arhenius lesion function derives that the target lesion is exponentially related to the peak temperature; subsequently, the peak temperature of the skin surface is correlated to the peak temperature of the target component. In the example, for radiation with a 22W laser with 150ms pulses over a 5mm by 5mm spot, the temperature rise is approximately 180 ℃/sec; in this case, the skin surface measurements should be updated approximately every 2.5ms or at 400Hz in order to use the temperature measurements as a control input for the treatment regime. With such a fast temperature measurement method, the laser can be switched off when the measured skin surface temperature reaches a preset threshold.

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

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

With continued reference to fig. 7, during the application of each laser pulse, the skin surface temperature at the treatment area is measured in step 714. Optionally, the skin surface temperature is measured during the cool down period between pulses. For example, the measurements may be made by a 25Hz refresh rate infrared camera. Faster devices, such as 400Hz refresh rate temperature measurement devices, can be used to make more accurate measurements of skin surface temperature at and after the application of the laser pulses.

A determination is then made in decision 716 as to whether sufficient skin surface temperature data has been collected for curve fitting purposes. If the answer to decision 716 is no, the process returns to step 712 to apply another laser pulse. If the answer to decision 716 is yes, then in step 718, the measured skin surface temperature data is fitted to a predictive model. 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 may be generated by compiling a number of temperature measurements corresponding to the application of laser pulses to a test subject in a clinical setting, or by analytical modeling of tissue.

Based on the curve fit generated in step 718, appropriate laser parameters are determined in step 720 for the particular treatment region of the individual being treated. For example, if the curve fitting predicts that the skin surface temperature will rise above a predetermined threshold temperature (such as 45 ℃), the laser parameters are adjusted to reduce the laser power. In this case, surface temperature measurements 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 the desired temperature (such as 55 ℃ for targeted chromophore damage) will not be reached at the current laser pulse power setting, the laser parameters may be adjusted to provide the necessary therapeutic power. This may occur if the properties of the epidermis and dermis are such that the laser pulse energy is not readily absorbed by a particular treatment area.

Fig. 8 illustrates an exemplary predictive closed-loop-control process based on measured skin surface temperature results, according to an embodiment. Graph 800 in FIG. 8 shows various temperature measurement and calculation curves as a function of time used in a predictive closed-loop-control process such as that illustrated in FIG. 7. In fig. 8, time zero corresponds to the time of application of the first laser pulse (in this case, from a 22W laser, a 150ms pulse and a 5mm by 5mm square spot) that 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 application of the laser pulses. In the present example, a 25Hz update rate IR camera is used to measure the skin surface temperature, although other temperature measurement devices are contemplated.

With continued reference to fig. 8, the skin surface temperature measured during the initial cooling is shown by curve 810. The skin surface temperature measured during the application of the laser pulse is shown by curve 812. The target skin surface temperature, here shown at 45.5 ℃, is indicated by the dashed line 816.

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

As shown in curve 812, the skin surface temperature was 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 ℃ has been achieved by applying pulses 6 and 7, and thus the laser treatment protocol is stopped without applying the eighth pulse.

Even with a relatively slow temperature measurement device, such as a 25Hz refreshed IR camera, fitting 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., 400Hz refresh rate or faster), the temperature profile can be measured directly in real time.

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

Accordingly, many different embodiments are possible in light of the above description and the accompanying drawings. It will be understood that each combination and sub-combination of the embodiments described and illustrated in the text is intended to be unduly repetitious and confusing. As such, this specification, including the drawings, should be construed to constitute a complete written description of all combinations and subcombinations of the embodiments described herein, and of the manner and process of making and using them, and should support claims to any such combination or subcombination.

For example, embodiments such as the following are envisaged:

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

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

3. The method of clause 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.

4. The method of clause 1, further comprising taking into account treatment data from a prior treatment of the same subject.

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

6. A system whereby temperature measurements of a skin surface during an initial portion of a treatment at a particular location are used to predict a future temperature of the skin surface at the particular location. The so predicted future temperature 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 the cooling system, such as air flow, so that the future temperature of the skin surface at a specific location and thus the temperature of the underlying layer region and component parts of the tissue, which cannot easily be measured in a direct manner, reach the desired value.

7. A system whereby skin surface temperature measurements taken during treatment of an adjacent region or regions are used to predict the future temperature of the skin surface at that particular location. The so predicted future temperature 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 the cooling system, such as air flow, so that the future skin surface temperature at a specific location and thus the temperature of the underlying layer region and component parts of the tissue, which cannot easily be measured in a direct manner, reach the desired value.

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

Claims (15)

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

1) applying at least one laser pulse from a light source to a first treatment location on a first subject at a preset power level, the preset power level being below a known damage threshold;

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

3) estimating a relationship between a parameter for operating the light source and a skin surface temperature at the first treatment location; and

4) a safe operating range of parameters for operating the light source is defined 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.

2. The method of claim 1, further comprising:

repeating steps 1) through 4) at a second treatment location on the first subject prior to administering the treatment regimen at the second treatment location.

3. The method of claim 1, further comprising:

repeating steps 1) through 4) at a first treatment location on a second subject prior to administering the treatment regimen to the second subject.

4. The method of claim 1, further comprising:

5) storing in a memory of the photothermal targeted therapy system a safe operating range for operating a parameter of a light source of a first subject at a first treatment location, an

6) The parameters so stored in the memory are taken into account when the treatment regime is administered to the first subject at a later time.

5. The method of claim 1, further comprising, during administration of the treatment regimen:

5) measuring the skin surface temperature at least once at the first treatment location;

6) safe operating ranges of light source parameters are adjusted at the first treatment location while still providing effective photothermal targeting therapy in continuing the treatment regimen.

6. The method of claim 5, further comprising:

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

7. The method of claim 1, wherein defining a safe operating range for the light source parameters comprises setting at least one of laser power, pulse width, pulse interval, maximum power output, and skin surface cooling mechanism.

8. A photothermal targeted therapy system for targeting a chromophore embedded in a medium, the system comprising:

a light source configured to provide laser pulses over a range of power levels including a known damage threshold and a treatment location of a chromophore when operating using a set of parameters;

a temperature measuring device for measuring the skin surface temperature at the treatment site; and

a controller for controlling the light source and the temperature measuring device,

wherein the controller is configured for

The relationship between the light source parameters and the skin surface temperature at the treatment location is estimated,

defining a safe operating range for the set of light source parameters so as to avoid thermal damage to the medium at the treatment site while still effectively targeting the chromophore in administering the treatment regimen, and

the light source is arranged to apply laser pulses within a safe operating range.

9. A method for adjusting a suitable set of parameters for operating a light source within a photothermal targeting therapy system for targeting a chromophore embedded in a medium during administration of a therapy regime to a first subject at a first treatment location, the method comprising:

1) measuring the skin surface temperature at least once at the first treatment location;

2) predicting a skin temperature when a treatment regimen is administered to a first subject at a 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,

wherein predicting the skin temperature takes into account at least one of a heat transfer model and a series of experimental results.

10. The method of claim 9, further comprising:

4) the parameters for operating the light source are further adjusted to reduce the effective power incident at the first treatment location if the skin surface temperature at the first treatment location reaches a preset threshold temperature.

11. The method of claim 9, further comprising:

repeating steps 1) -3) at a second treatment location on the first subject during administration of the treatment regimen at the second treatment location.

12. The method of claim 9, further comprising:

repeating steps 1) -3) at a first treatment location on a second subject during administration of the treatment regimen to the second subject.

13. The method of claim 9, further comprising:

4) storing in a memory parameters for operating a light source of a first subject at a first treatment position; and

5) the parameters for operating the light source so stored in the memory are taken into account when the treatment regime is administered to the first subject at a later time.

14. A photothermal targeted therapy system for targeting a chromophore embedded in a medium at a treatment site, the system comprising:

a light source configured to provide laser pulses over a range of power levels including a known damage threshold and a treatment location of a chromophore when operating using a set of parameters;

a temperature measuring device for measuring the skin surface temperature at the treatment site; and

a controller for controlling the light source and the temperature measuring device,

wherein the controller is configured for

The relationship between the light source parameters and the skin surface temperature at the treatment location is estimated,

predicting a future skin surface temperature at the treatment location based on a relation between the light source parameters and the skin surface temperature so estimated, an

At least one parameter of the light source is adjusted such that future measurements of the skin surface temperature will not exceed a specified value.

15. The photothermal targeted therapy system of claim 14, wherein the light source parameters comprise at least one of laser power, pulse width, number of pulses, and cooling air flow.