Efficient system and method for treating biological tissue - Patents.com

Abstract

Methods, systems, and computer storage media are disclosed for efficient treatment of biological tissue. Such methods of treating tissue of a patient include irradiating a region of interest (ROI) of the patient with one or more initial doses of electromagnetic radiation. The ROI includes a matrix or array of sub-regions of interest (sROIs) of the patient's biological tissue. The method further includes determining a tissue response of the one or more sROIs, generating a tissue response matrix from the tissue responses of the one or more sROIs, and converting the tissue response matrix into a sub-clinical indicator matrix or a treatment completion matrix for the one or more sROIs. The method also includes irradiating the one or more sROIs with one or more additional doses of electromagnetic radiation or not irradiating the sROI based at least in part on the sub-clinical indicator matrix.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 317,097, filed March 7, 2022, the entire contents of which are incorporated herein by reference. [Technical field]

[0002] The technology described herein relates generally to the treatment of living tissue (eg, skin), and more specifically, to the efficient processing of tissue incorporating various imaging and control functions. [Background technology]

[0003] Some tissue (e.g., skin) conditions or diseases, such as basal cell carcinoma (BCC), are rarely fatal, but will continue to grow if not treated. Among other tissue problems and diseases, BCC is the underlying cause of more than 5.4 million treatments per year in the United States alone, resulting in a large treatment space and economic burden.

[0004] Traditional methods of treating tissue conditions such as BCC include intensive methods such as Mohs surgery, topical medications, destruction, and excision. As an example, BCC treatment may require the death of cancer cells by heat generation with a laser. BCC is characterized by being irregular in shape, hyperplastic, and having irregular increased vascularization. The current state of the art of laser treatment of BCC requires clinicians to expose patients to laser light based on guesswork and check after treatment for visual indicators of treatment effectiveness, such as tissue graying associated with coagulative damage. This approach can be highly subjective and suffers from a learning curve in clinician training. Other existing approaches to treating BCC suffer from one or more other shortcomings. Current methods and systems for the treatment of conditions other than BCC may also suffer from similar shortcomings, such as a lack of precision or complete clinical effectiveness. Summary of the Invention [Problem to be solved by the invention]

[0005] Thus, there is a therapeutic need for improved treatment systems and methods that can provide both efficacy and reduced risk of adverse events such as overtreatment of target tissue and damage to healthy tissue. Improved treatment systems and methods are needed that can achieve higher success rates, reduce clinician error, and reduce the need for additional treatments, all of which are minimally invasive to the patient. [Means for solving the problem]

[0006] This Summary is provided to introduce selected concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used solely as an aid in determining the scope of the claimed subject matter.

[0007] Embodiments of the technology described herein are directed to electromagnetic radiation-based (e.g., light-based) treatment of biological tissues, for example, of human patients in need of treatment, which achieves improved accuracy and clinical outcomes, reduces clinician error, and is less invasive to the patient, for example, through the use of various imaging and control features. The disclosed technology can be used to treat various types of biological tissues, including, for example, skin tissue or components of the skin or diseased tissue on or within the skin, of patients (such as human or animal patients) in need of treatment. Other organ tissues (e.g., liver tissue) can also be treated using the methods and systems described herein.

[0008] Although often used in the treatment of tissue pathology, it is often erroneously assumed that the dose of electromagnetic radiation and the subsequent tissue response are substantially uniform in time. In reality, many electromagnetic radiation sources are pulsed. The tissue response to the pulsed radiation dose may vary with respect to pulse duration and intensity, as in the case of laser radiation. In extreme cases, for long-duration small doses, reports of biostimulation have been made; moderate doses result in well-documented heating and / or coagulation; short-duration intense doses may cause tissue ablation; and even plasma generation may occur at extreme doses. Even in routine cases, theoretical equations can be used to design a static treatment paradigm that does not over- or under-treat tissue. This paradigm is tested, validated, and apportioned or identified as a "treatment window" for administration, similar to the dose of a chemical agent.

[0009] However, tissue responses occur on surprisingly short time scales, and minor variations in tissue responses are likely subclinical (i.e., not easily observed and recorded by clinicians without instrumentation). Furthermore, the inherent abnormal nature of pathological tissues often results in intra- and inter-patient spatial heterogeneity. The combination of spatial heterogeneity of pathology and temporal heterogeneity of tissue responses to electromagnetic radiation is likely responsible for treatment windows and a certain percentage of treatment failures when using static treatments alone. This application describes the integration of improved measurement systems into adaptive treatment methods that, in some implementations, capture patient-specific tissue responses and thus help ensure complete treatment.

[0010] In some embodiments, the methods described herein may include monitoring the biological tissue before, during, and / or after treatment with one or more spatially resolved sensors. In some embodiments, multiple registered image sensors recognize and track a physician-prescribed region of interest (herein "ROI") designated for treatment. In some such embodiments, the appropriate treatment may include spatially resolved sensing and tracking of a matrix or array of sub-regions of interest (sROI as singular or sROIs as plural), where sROIs are components of the physician-prescribed treatment region (ROI). Specialized algorithms for signal and image processing can operate on the sensor data to determine, confirm, and track ROIs while simultaneously directing the course of treatment in time, space, and intensity based on patient- and tissue-specific responses to the treatment stimuli. Additionally, as further described herein, a "treatment completion integrator" may be provided, which in some embodiments manifests as simultaneous tracking of the treatment window, as well as conversion of tissue response measurements to logical fractional markers of treatment completion (e.g., posterior probability of cell death) using rate equations.

[0011] More generally, methods, systems, and computer storage media for efficient treatment of biological tissue (e.g., skin or components thereof) are described herein. In some embodiments, a method of treating a patient's biological tissue (e.g., skin) or components thereof includes irradiating a region of interest (ROI) of the patient with one or more initial doses of electromagnetic radiation, the ROI including a matrix or array of sub-regions of interest (sROIs) of the patient's biological tissue. The method further includes determining a tissue response of the one or more sROIs, generating a tissue response matrix from the tissue responses of the one or more sROIs, and converting the tissue response matrix into a sub-clinical indicator matrix or a treatment completion matrix for the one or more sROIs. The sub-clinical indicator matrix corresponds to a degree of treatment completion of the one or more sROIs. In some embodiments, the method further includes irradiating the one or more sROIs (or no sROIs) with one or more additional doses of electromagnetic radiation based at least in part on the sub-clinical indicator matrix.

[0012] Further, in some embodiments, the sub-clinical indicator matrix includes a summary of treatment completion of one or more sROIs over time. The sub-clinical indicator matrix may also be generated based on one or more rate functions, such as at least one of an Arrhenius function, a bioheat function, and a light transport function.

[0013] Further, in some cases, two or more of the irradiating, determining, generating, and converting steps occur simultaneously, sequentially, and / or in real-time. Further, in some implementations, the one or more additional doses of electromagnetic radiation have the same or different characteristics as the one or more initial doses.

[0014] Further, in some embodiments of the methods described herein, the tissue response corresponds to the sensed temperature. Furthermore, in some cases, the treatment completeness includes achieving a benchmark temperature over time for one or more sROIs. In other examples, the treatment completeness includes achieving cell death of the living tissue of one or more sROIs. The tissue response described herein may also include or correspond to a spectral change, particularly a change in the electromagnetic spectrum. For example, in some cases, the spectral change includes a detected color (e.g., an electromagnetic radiation absorption and / or emission profile corresponding to a color perceived by a normal or healthy human eye) or a detected color change. Other spectral changes may also be used, provided that the spectral change is detectable as a tissue response within the methods and / or systems described herein.

[0015] Further, in some cases, each sROI corresponds to an actual physical location of a unit size of biological tissue having a known size and location relative to one or more other sROIs of the ROI. In some implementations, the ROI corresponds to a defined treatment area, which may be a physician-defined treatment area, as further described herein. The methods described herein may also include irradiating the matrix of sROIs a sufficient number of times to complete the treatment.

[0016] It should be understood that the methods described herein can be implemented using a variety of electromagnetic radiation sources. For example, in some cases, the electromagnetic radiation is a beam of electromagnetic radiation, such as a laser beam. In some such embodiments, the laser beam has an average wavelength λ of 700 nm to 1500 nm or 900 nm to 1300 nm. In some implementations, the laser beam includes a Nd:YAG laser beam.

[0017] In some embodiments, the methods described herein further include imaging the ROI with an imaging device, such as a camera or other imaging device described herein. Further, in some cases, the ROI is imaged in real time.

[0018] Systems for treating biological tissue (such as skin) are also described herein. In some such embodiments, a system for treating biological tissue of a patient includes an electromagnetic radiation source that irradiates a region of interest (ROI) of the patient with one or more initial doses of electromagnetic radiation, the ROI including a matrix or array of sub-regions of interest (sROIs) of the patient's biological tissue. The system also includes an imaging device and a tissue response detector for determining a tissue response of one or more of the sROIs based on the irradiation of the ROI. The imaging device can be configured to image one or more sROIs, including in real time as required. In some cases, the tissue response detector can be configured to detect a temperature of one or more sROIs. It should further be understood that in some embodiments, the tissue response detector can detect a temperature in an sROI (or a pixel in a two-dimensional image of the ROI) or multiple sROIs (or pixels) as a function of time. That is, the tissue response detector can be configured to detect a series of temperatures over time in an sROI and / or multiple sROIs. Additionally, in some embodiments described herein, one or more measured or detected sROI temperatures (or one or more time profiles of sROI temperatures) can be used to calculate, estimate, or extrapolate the bulk temperature (as opposed to surface temperature) of the ROI or sROI.

[0019] Moreover, in some embodiments, the systems described herein further comprise a controller (or a network of controllers) for generating a tissue response matrix based on the information received from the tissue response detector and converting the tissue response matrix into a sub-clinical indicator matrix or a treatment completion matrix for one or more sROIs. The sub-clinical indicator matrix can correspond to the treatment completion of one or more sROIs. Furthermore, the controller (or a network of controllers) can further signal the electromagnetic radiation source to irradiate one or more sROIs with one or more additional doses of electromagnetic radiation or not irradiate the sROIs based at least in part on the sub-clinical indicator matrix. The one or more additional doses of electromagnetic radiation can have the same or different characteristics as the one or more initial doses. In some embodiments of the systems described herein, the sub-clinical indicator matrix includes a summary of the treatment completion of one or more sROIs over time. Further, in some implementations, the sub-clinical indicator matrix is ​​generated based on one or more rate functions, such as at least one of an Arrhenius function, a bioheat function, and a light transport function (or a derivative of a light transport function).

[0020] In yet another aspect, improved computer devices and storage media are also described herein. For example, computer storage media storing computer usable instructions are described herein. Such computer storage media can be used to perform the methods and / or use the systems described herein. For example, in some cases, a computer storage medium stores computer usable instructions that, when used by one or more computing devices, cause the one or more computing devices to treat a patient's biological tissue, the operations including: irradiating a region of interest (ROI) of the patient with one or more initial doses of electromagnetic radiation, the ROI including a matrix or array of sub-regions of interest (sROIs) of the patient's biological tissue; determining a tissue response of one or more of the sROIs; generating a tissue response matrix from the tissue responses of the one or more sROIs; converting the tissue response matrix into a sub-clinical indicator matrix or a treatment completion matrix for the one or more sROIs, the sub-clinical indicator matrix corresponding to a degree of treatment completion for the one or more sROIs; and irradiating or not irradiating one or more additional doses of electromagnetic radiation to the one or more sROIs based at least in part on the sub-clinical indicator matrix. In some examples, the operations further include mapping the multiple sROIs of the tissue. Moreover, in some embodiments, two or more of the illuminating, determining, generating, and converting steps occur simultaneously, sequentially, and / or in real-time.

[0021] Additional objects, advantages, and novel features of the present invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following or may be learned by practice of the invention.

[0022] Aspects of the technology presented herein are described in detail below with reference to the accompanying drawings, which are not necessarily drawn to scale. [Brief description of the drawings]

[0023] [Figure 1] FIG. 1 is a schematic diagram of an exemplary operating environment and system for tissue treatment in accordance with some implementations of the technology described herein. [Diagram 2] 1 is a flow chart illustrating a method for efficient tissue treatment in accordance with certain aspects of the technology described herein. [Diagram 3] A block diagram of an example computing environment and / or device architecture in which some implementations of the present technology may be employed. [Figure 4] FIG. 1 is a perspective view of a treatment device according to one embodiment described herein. [Diagram 5] FIG. 1 is a perspective view of a treatment device according to one embodiment described herein. [Figure 6A] FIG. 1 shows a two-dimensional thermal image of an ROI that includes multiple sROIs when processed in a manner not in accordance with the present disclosure. [Figure 6B] FIG. 1 shows a two-dimensional thermal image of an ROI containing multiple sROIs when processed with the method according to the present disclosure. [Figure 7A] FIG. 6B shows a plot of temperature as a function of distance for the ROI of FIG. [Figure 7B] FIG. 6C shows a plot of temperature as a function of distance for the ROI of FIG. 6B. [Figure 8A] FIG. 1 shows a two-dimensional output (detected image) of an RGB camera (imaging device) according to steps of one embodiment of the method described herein. [Figure 8B] FIG. 1 shows the two-dimensional output of a thermal camera (tissue response detector) according to steps of one embodiment of the method described herein. [Figure 9] FIG. 1 shows a two-dimensional thermal image of a calibration setup used in one embodiment of the method described herein. [Figure 10A] FIG. 1 shows a three-dimensional calibration plot used in one embodiment of the method described herein. [Figure 10B] FIG. 1 shows plots of error and outlier analysis used in one embodiment of the method described herein. [Figure 10C]FIG. 1 shows a calibration polynomial used in one embodiment of the method described herein. [Figure 11] FIG. 1 shows a plot of the output of a calibration process according to one embodiment of the method described herein. [Figure 12A] FIG. 1 shows an output image of a thermal camera (tissue response detector) used in one embodiment of the method described herein. [Figure 12B] FIG. 1 shows an output image of an RGB camera (imaging device) used in one embodiment of the method described herein. [Figure 13A] FIG. 1 shows an output image of a thermal camera (tissue response detector) used in one embodiment of the method described herein. [Figure 13B] FIG. 1 shows an output image of an RGB camera (imaging device) used in one embodiment of the method described herein. [Figure 14A] FIG. 1 shows an output image of a thermal camera (tissue response detector) used in one embodiment of the method described herein. [Figure 14B] FIG. 1 shows an output image of an RGB camera (imaging device) used in one embodiment of the method described herein. [Figure 15] FIG. 1 illustrates an overlay or combination of a thermal image and an RGB image according to one embodiment of the method described herein. [Figure 16] FIG. 1 illustrates a real-time display of an overlay or combination of thermal and RGB images according to one embodiment of the method described herein. [Figure 17] FIG. 1 shows a two-dimensional image provided by an imaging device during one step of an embodiment of the method described herein. [Figure 18] 1A-1D show two-dimensional images provided by an imaging device used in one embodiment of the method described herein. [Figure 19A] FIG. 1 shows two-dimensional images provided during one step of one embodiment of the method described herein. [Figure 19B] FIG. 1 shows two-dimensional images provided during one step of one embodiment of the method described herein. [Figure 20A] FIG. 1 shows a two-dimensional image provided by an imaging device during one step of one embodiment of the method described herein. [Figure 20B] FIG. 1 shows a two-dimensional image provided by an imaging device during one step of one embodiment of the method described herein. [Figure 20C] FIG. 1 shows a two-dimensional image provided by an imaging device during one step of one embodiment of the method described herein. [Figure 21A] 1. Computerized drawing of ROI according to one embodiment of the method described herein [Figure 21B] 1. Computerized drawing of ROI according to one embodiment of the method described herein [Figure 21C] FIG. 1 shows a composite image used in one embodiment of the method described herein. [Figure 21D] FIG. 1 shows a schematic diagram of the steps of one embodiment of the method described herein. [Figure 22] FIG. 1 shows a composite image of a method step according to one embodiment described herein. [Diagram 23] FIG. 1 shows a composite image of a method step according to one embodiment described herein. [Figure 24] FIG. 1 shows a schematic diagram of the steps of one embodiment of the method described herein. [Diagram 25] FIG. 1 shows a composite image of a method step according to one embodiment described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The subject matter of the aspects of the present disclosure is specifically described herein to meet legal requirements. However, the description itself is not intended to limit the scope of the present patent. Rather, the inventors contemplate that the claimed subject matter may also be embodied in other ways, including different steps or combinations of steps similar to those described herein, in conjunction with other current or future technologies. Furthermore, although the terms "step" and / or "block" may be used herein to refer to different elements of the method employed, these terms should not be interpreted to refer to a particular order between or among the various steps disclosed herein, unless the order of the individual steps is explicitly described.

[0025] Thus, the embodiments described herein can be more readily understood by reference to the following detailed description, examples, and drawings. However, the elements, features, devices, and methods described herein are not limited to the specific embodiments presented in the detailed description, examples, and drawings. It should be recognized that the exemplary embodiments herein are merely illustrative of the principles of the present invention. Numerous modifications and adaptations will be readily apparent to those skilled in the art without departing from the spirit and scope of the present invention.

[0026] Moreover, all ranges disclosed herein should be understood to encompass any and all subranges subsumed therein. For example, a range stated as "1.0-10.0" should be considered to include any and all subranges beginning with a minimum value of 1.0 or greater and ending with a maximum value of 10.0 or less, such as, for example, 1.0-5.3, or 4.7-10.0, or 3.6-7.9. All ranges disclosed herein should also be considered to include the endpoints of the range, unless expressly stated otherwise. For example, a range "between 5-10" or "from 5 to 10" or "5-10" should generally be considered to include the endpoints 5 and 10.

[0027] Additionally, the term "up to" is used in reference to an amount or quantity; it is understood that the amount is at least a detectable amount or quantity. For example, a substance present in an amount "up to" a particular amount can be present in an amount from the detectable amount up to and including the particular amount.

[0028] Additionally, in any disclosed embodiment, the terms "substantially," "approximately," and "about" can be substituted with "within [a percentage] of" what is specified, where the percentage includes 0.1, 1, 5, and 10 percent.

[0029] Similarly, unless the context clearly dictates otherwise, use of the singular forms "a" or "an" refers to "at least one."

[0030] According to aspects of the systems and methods described herein, efficient tissue treatment can be provided through the use of various imaging techniques and control systems, offering improvements over other forms of treatment. According to embodiments described herein, various imaging and control techniques can be implemented to track positions and sublocations corresponding to tissue or tissue components requiring treatment, measure tissue response to the treatment as the treatment occurs (e.g., as the tissue or its components are treated with electromagnetic radiation), and integrate over time to ensure complete and accurate treatment is achieved. It will be appreciated that in some embodiments, the tissue response can be converted into a probability of treatment completion over time, which iterates based on a drive speed or speed function.

[0031] It will be understood that treatment, e.g., of tissue or tissue components, may be required by pathology, which by definition means that the tissue is "not normal" and therefore does not have regular characteristics. Abnormal vasculature and altered cellular responses to stimuli are hallmarks of cancer, and one specific (i.e., maximum) temperature measurement to treat a pathological area may be significantly insufficient for favorable tracking and guidance. Thus, the methods and systems described herein utilize, among other components, thermal cameras, visual (RGB) cameras, laser scanners, and computing engines and components that can implement tracking indicator generation sequences that allow tracking of physical location over time as well as tissue response (e.g., temperature) over time, which can then be used to generate an aggregate probability of cell death or treatment completion per location. Additionally, as further described herein, the methods described herein can be partially or fully automated, including computer implementation, as desired.

[0032] In some embodiments, one or more sROIs or target pixels of tissue or tissue components corresponding to a patient's biological tissue can be irradiated with a dose of electromagnetic radiation (e.g., a first dose of electromagnetic radiation beam) via a light beam, e.g., a light laser beam and / or a broadband light. The one or more target sROIs can be defined by the system described herein and / or by a clinician such that the sROI is within a defined treatment region or ROI. In some embodiments, the treatment region is mapped by establishing an sROI within the defined treatment region or ROI.

[0033] It should be understood that a "laser" can refer to a single laser device that generates a single laser light beam from a single laser medium. The lasers described herein can be pulsed lasers or continuous wave (CW) lasers. Additionally, when a pulsed laser is used, the laser can generate time modulated pulses of the laser beam. For example, in some cases, the laser beam includes an ablation laser beam and the laser generates time modulated pulses of the ablation laser beam. In other cases, the laser beam includes a solidification laser beam and the laser generates time modulated pulses of the solidification laser beam.

[0034] The lasers or laser beams described herein can have any power and any peak or average emission wavelength not inconsistent with the objectives of the present disclosure. For example, in some embodiments, the lasers or laser beams of the devices described herein have a peak or average emission wavelength in the infrared (IR) region of the electromagnetic spectrum. In some such cases, the lasers or laser beams have a peak or average emission wavelength in the range of 1-4 μm, 1-3 μm, 2-4 μm, 2-3 μm, 8-12 μm, or 9-11 μm. For example, in some embodiments, the lasers or laser beams include erbium-doped yttrium aluminum garnet (Er:YAG) lasers or laser beams, or neodymium-doped YAG (Nd:YAG) lasers or laser beams having a peak or average emission wavelength of 2940 nm or 1064 nm. In other cases, the lasers or laser beams include carbon dioxide lasers or laser beams. The laser beams described herein can also have a peak or average emission wavelength in the visible region of the electromagnetic spectrum. Non-limiting examples of peak or average emission wavelengths suitable for use in some embodiments described herein include 532 nm, 695 nm, 755 nm, 1064 nm, and 1470 nm (e.g., for non-ablative applications), or 2940 nm (e.g., for ablative applications). Additionally, in some examples, the laser or laser beam of the devices described herein has an average power of 1-10 W (e.g., for non-ablative applications) or 50-200 W (e.g., for ablative applications).

[0035] Additionally, the spot size of the laser beam generated by the lasers described herein may vary. Any spot size not inconsistent with the objectives of the present disclosure may be used. In some cases, for example, the spot size is 0.1-10 mm, 0.1-1 mm, 0.1-0.5 mm, 0.5-5 mm, 1-10 mm, or 1-5 mm. Other spot sizes may also be used. The laser beam may have any cross-sectional shape not inconsistent with the objectives of the present disclosure.

[0036] The dose of electromagnetic radiation can have various characteristics, such as a determined intensity, fluence, and / or duration. In response to the dose of electromagnetic radiation, a given sROI or sROIs that are irradiated and associated with a tissue or tissue component can generate a tissue response. For example, in some cases, the tissue response may be heat generation measured as a thermal response or surface temperature. In other examples, the tissue response may be a change in fluorescence or other emission, light absorption or scattering, or a change in electrical and / or mechanical properties, among other properties. In some cases, the thermal response of the target sROI (or sROIs) can be measured directly or otherwise sensed, for example, via an infrared (IR) light input or imaging device. In some cases, the tissue response may be measured indirectly (e.g., using a surface temperature indicator).

[0037] Based on the determined and / or measured tissue responses corresponding to the target sROI (or a plurality or matrix or array of sROIs), a sub-clinical indicator matrix can be generated. In some examples, the sub-clinical indicator matrix can correspond to probabilities associated with a treatment procedure for a tissue or tissue component. In some cases, the generated sub-clinical indicator matrix can correspond to a degree of treatment completion for the associated sROI, for example, the sub-clinical indicator matrix can correspond to greater than 80% cell death, or greater than 90% cell death, or up to 100% cell death of the biological tissue associated with the biological tissue of one or more sROIs. In some examples, completion of treatment includes achieving a benchmark temperature or temperature profile within a "treatment window" of one or more sROIs. Such a "treatment window" can be described or identified as an intensity of tissue response that is sufficient to initiate a biological change to tissue function, but not strong enough to cause an adverse event.

[0038] The sub-clinical indicator matrix can be generated using the methods, systems, and components described herein. In some embodiments, the sub-clinical indicator matrix can be generated based on or otherwise using the rate function. In this manner, the rate function can utilize the determined tissue response to then generate the sub-clinical indicator matrix. In some exemplary embodiments, the rate function can include, among others, an Arrhenius function, a bioheat function, and a light transport function. In some examples, the rate function includes a derivative of the light transport function. The sub-clinical indicator matrix can be utilized to irradiate one or more sROIs with one or more additional doses of electromagnetic radiation or not irradiate the sROIs. The use of the Arrhenius function is described, for example, in WC Dewey, "Arrhenius relationships from the molecule and cell to the clinic," Int. J. Hyperthermia, February 2009; 25(1): 3-20. Thermal dosing of tissue is described, for example, in Dewhirst et al., "Thermal Does Requirement for Tissue Effect: Experimental and Clinical Findings," Proc SPIE Int Soc Opt Eng. 2003 June 2; 4954:37. As described herein, in some embodiments of the present technology, the relationship between thermal dose and tissue effect can be used to provide a sub-clinical indicator matrix or a treatment completion matrix for a ROI or one or more sROIs.

[0039] In some embodiments, the first dose can have a first fluence (f1) and a first duration (t1). The additional dose can have a second fluence (f2) and a second duration (t2). In some other examples, the dose can have a fluence (fn) and a duration (tn). It will be understood that the first fluence can be the same as the second, additional, or another fluence, and the first duration can be the same as the second, additional, or another duration. In such embodiments, one or more of a velocity-based function or equation, treatment window monitoring, and tissue response measurements can be involved in changing the intensity, fluence, or duration of the treatment dose during treatment.

[0040] In some embodiments, as described above, the electromagnetic radiation source can be a laser beam, for example having a mean wavelength λ of 700-1500 nm. In some other examples, the laser beam can have a mean wavelength λ of 900-1300 nm. In some embodiments, the laser is a Nd:YAG laser.

[0041] Other electromagnetic radiation sources may be used in conjunction with the present technology. As will be appreciated by those skilled in the art, the terms "BBL" light source and "BBL beam" can refer to a source and beam of intense broad spectrum pulses of light, respectively, including those defined and approved by the U.S. Food and Drug Administration. More specifically, the BBL beam generated by a BBL light source can include pulses of non-coherent or non-laser light having wavelengths between 500 nm and 1200 nm, as described, for example, in Raulin et al., "IPL technology: a review," Lasers Surg. Med. 2003, 32:78-87.

[0042] Any laser, BBL light source, laser beam, or BBL beam not inconsistent with the objectives of the present disclosure may be used. Furthermore, the selection of the laser, BBL light source, or laser or BBL beam may be based on the desired effect of the laser or BBL beam and / or the desired target of the laser or BBL beam. The BBL light sources described herein generally generate pulsed light output. In some cases, the BBL light source includes a xenon gas-filled chamber. In such an example, the BBL light source may generate the BBL beam by application of bursts or pulses of electrical current through the xenon-containing chamber.

[0043] The imaging of the present technology can be performed using any imaging system that is not inconsistent with the objectives of the present disclosure. For example, in some cases, the imaging system can include an optical imaging system, such as a spectrophotometer, a thermal camera, an ultrasound, an optical coherence tomography (OCT) system, a multiphoton imaging system, a reflectance confocal microscope (RCM) system, or any other imaging system that is not inconsistent with the objectives of the present disclosure. In some cases, the selectively reflective optical element can be configured to reflect both the outgoing beam and the return signal of the optical imaging system, allowing the imaging system to "probe" the target area and receive the return signal from the target area. For example, in the case of an OCT imaging system, the imaging system can include an OCT pilot or probing beam generator and an OCT detector.

[0044] The methods described herein may also, in some embodiments, include using imaging to identify a treatment area (e.g., a predefined treatment area) to which the method is to be applied. For example, in some cases, the treatment area may be labeled, marked, or delineated by a service provider or clinician (e.g., a physician or other health care provider). In some such embodiments, the methods described herein include labeling, marking, delineating, or otherwise identifying a treatment area on a patient prior to performing an initial therapeutic irradiation of the ROI or sROI. Such labeling, marking, delineating, or otherwise identifying may be performed in any manner not inconsistent with the technical objectives of the present disclosure. For example, in some embodiments, a perimeter is drawn around the desired treatment area using a marker or pen (e.g., for identifying a treatment area using ink placed on the skin) or using a digital device (e.g., a stylus for digitally identifying a treatment area, such as by forming a perimeter on an image of the treatment area or patient, such as may be provided by a real-time camera image).

[0045] In some cases, it is also possible to label the desired treatment area in other ways. For example, in some cases, labeling includes applying a contrast agent or dye to the patient or a portion of the patient. In some cases, the contrast agent or dye migrates to the desired structure of the patient (e.g., a component of the skin or a lesion) due to biological effects of the patient or other effects induced by application of the contrast agent or dye. In some embodiments, the contrast agent is charged or ionic. The contrast agent can also be an organic contrast agent or dye. One non-limiting example of a contrast agent that can be used in the methods described herein includes methylene blue. Other contrast agents may be used. Furthermore, in some cases, applying the contrast agent to the patient includes applying a composition (such as a solution, cream, or paste) containing the contrast agent to the surface of the skin. Furthermore, in some embodiments, the contrast agent is applied to the skin electrophoretically or using iontophoresis. For example, in some cases, the contrast agent is delivered through the local application of an electric current to the skin. The use of electric current or voltage may be particularly preferred for labeling pores with a contrast agent such as methylene blue. Intravenous or other systemic injection of contrast agents or dyes may also be used. Particular components, elements, or structures of a patient may be labeled in other manners as well, as will be appreciated by those skilled in the art.

[0046] After marking, delineating, or labeling of the desired treatment area is performed, the methods described herein may optionally include detecting the desired treatment area before irradiating the ROI or sROI as described herein. In some cases, such detection is performed using imaging software and / or hardware, possibly in combination with a controller or computer. Thus, in some embodiments, computer-assisted or computer-implemented methods are described herein. In some cases, such methods are for identifying and determining characteristics of the desired treatment area or ROI to guide appropriate delivery of irradiation to one or more sROIs as described herein. In some examples, such methods include capturing one or more images with at least one camera (such as a digital camera as described herein). The camera may have a fixed or invariant focal length. Furthermore, if multiple cameras are used, each camera may have a fixed focal length, but the fixed focal lengths of the multiple cameras may differ from each other. The methods described herein may further include correcting one or more optical distortions of the optical path of the camera that may be present. In some cases, the method also includes cropping one or more of the one or more images as necessary or desired, and retaining only the portion of any cropped image that is relevant to the treatment performed by the method. In some embodiments, the method further includes identifying therapeutically relevant sROIs. Such sROIs are optionally identified by their spatial location, size, color, estimated depth below the surface of the skin, and / or estimated angle of the shaft if a shaft is present. The method described herein may further include mapping the sROI to a mechanical model of the light source positioning system, such that the position of the light source (and / or the beam of light or electromagnetic radiation provided by the light source) is known relative to the position of the relevant sROI.Such a method may further include transmitting the sROI characteristics (e.g., location) to a controller of the light source to enable the light beam to be directed to one or more sROIs as desired by a user. It should be understood that one or more of the foregoing steps of the computer-implemented method may be performed using hardware and / or software described herein.

[0047] Referring now to the drawings and to FIG. 1, FIG. 1 depicts aspects of an efficient tissue treatment system 100 in accordance with various embodiments of the present technology. The tissue treatment system 100 can include multiple devices, components, engines, and / or modules. The treatment device 102 can include, among other components, one or more imaging devices, such as a tissue response detector 104 and an imaging device 106, and further, an electromagnetic radiation source 108. In some embodiments, the tissue response detector 104 is an infrared (IR) or thermal camera, and the imaging device 106 is an RGB or other visible light camera. The imaging devices can include, but are not limited to, any one or more of ultrasound, x-ray, cameras, sensors, or systems thereof. The sensor, in some embodiments, is a sensor of light. In other embodiments, the imaging device 106 includes a device capable of rendering three-dimensional data and applying properties, such as hardness or toughness, temperature, or other properties, to the three-dimensional data. 1 diagrammatically illustrate signals passing to and from the tissue response detector 104, the imager 106, and the electromagnetic radiation source 108 and "converging" onto an ROI (not explicitly shown) adjacent an applicator component or "standoff" of the treatment device 102. Exemplary applicator components or "standoffs" are described further below.

[0048] The tissue treatment system 100 may further include a tissue response detection engine 110 and a controller (or network of controllers) 112 that may be implemented to generate a sub-clinical indicator matrix. Any controller (or network of controllers) 112 not inconsistent with the technical objectives of the present disclosure may be used. For example, in some cases, the controller 112 includes computing hardware and / or software. In some embodiments, the controller 112 is a dedicated computer configured to improve the technical field of imaging and phototherapy diagnosis and / or treatment. Such improvements are manifested in terms of improved targeting and phototherapy of individual sROIs (e.g., individual skin cells, cancer cells, etc.). It is contemplated that the controller 112 may be a separate device (e.g., physically separate, non-integrated, discrete), entity, or component. However, systems including a controller 112 that is integrated with one or more other components described herein are also contemplated.

[0049] Further, in some cases, the controller 112 can comprise a dedicated computer or a network of dedicated computers. Furthermore, in some examples, multiple controllers 112 are used. For example, in some implementations, the imaging device described herein can be associated with a first controller (which can be represented, for example, as a "slave" device), the electromagnetic radiation source (e.g., a laser or BBL light source) can be associated with a second controller (which can be represented, for example, as a "master" device), and the first and second controllers can coordinate with each other according to steps of the methods described herein. Similarly, the controller 112 described herein can provide signals directly or indirectly to other components of the systems described herein.

[0050] The system 100 may further include a mapping component. As depicted, the tissue treatment system 100 includes a content repository 114, which may be multiple repositories, that may be in operative communication with the treatment device 102 and any associated engines or modules.

[0051] Referring now to FIG. 2, a flow chart illustrating one exemplary method 200 for treating tissue or tissue components is provided. Method 200 and other methods described herein are not limited to those illustrated, and it is contemplated that other blocks or steps may be incorporated at any point in the method according to the present disclosure. In step 210, one or more sROIs of the ROI (or the entire ROI) are irradiated with one or more initial doses of electromagnetic radiation, the one or more sROIs including the patient's biological tissue. In step 220, a tissue response, e.g., a thermal response, of the one or more sROIs is determined. The tissue response may form a tissue response matrix for the sROI, and based on the tissue response, in step 230, a sub-clinical indicator matrix may be generated that corresponds to the degree of treatment completion for the one or more sROIs. Then, in step 240, a decision may be made based at least in part on the generated sub-clinical indicator matrix as to whether to further irradiate a particular sROI, irradiate multiple sROIs, or not irradiate an sROI.

[0052] Thus, various aspects of the techniques for effectively treating tissue are described. It will be understood that various features, subcombinations, and modifications of the embodiments described herein are useful and may be employed in other embodiments without reference to other features or subcombinations. Furthermore, the order and sequence of steps shown in the exemplary method 200 is in no way intended to limit the scope of the invention, and steps may be performed in a variety of different sequences within various embodiments. Such variations and combinations thereof are also contemplated to be within the scope of the embodiments of the invention.

[0053] In some embodiments, for example, a method of treating a tissue or tissue component includes removing, ablating, vaporizing, destroying, or otherwise treating a tissue or tissue component within a target area of ​​a device described herein, including by directing a laser or BBL beam from the device onto the tissue or tissue component. Additionally, as further described herein, the methods described herein can include labeling, imaging, detecting, and / or mapping the tissue or tissue component prior to (or substantially simultaneously with) directing a laser or BBL beam onto the tissue or tissue component for therapeutic purposes. Alternatively, in other examples, the structure of the tissue is not labeled, but instead is imaged or detected in its "native" or natural state without first labeling the structure. Omitting the labeling step can be particularly desirable when the relevant structure of the tissue is visually identifiable, including in a simplified manner, without the use of a labeling agent.

[0054] The methods described herein also include a step of directing or applying electromagnetic radiation to a tissue or a particular component, component or structure of the tissue. The electromagnetic radiation can be applied to the tissue or a component, component or structure of the tissue in any manner not inconsistent with the objectives of this disclosure. For example, in some instances, the electromagnetic radiation is a laser or BBL beam or a high frequency beam generated by the device described herein. A high frequency ultrasound beam can also be used instead of the electromagnetic radiation. Any such laser, BBL light source, or other electromagnetic radiation source (or alternatively a high frequency ultrasound source) not inconsistent with the objectives of this disclosure may be used. For example, in some cases, the electromagnetic radiation is applied by a laser or BBL light source coupled to a camera (or other imaging system) and a controller.

[0055] 3 provides an exemplary operating environment for implementing embodiments of the invention, shown and designated generally as computing device 300. Computing device 300 is only one example of a suitable computing environment and is not intended to suggest any limitation as to the scope of use or functionality of the invention. Computing device 300 should not be interpreted as having any dependency or requirement relating to any one or combination of components illustrated.

[0056] Embodiments of the invention may be described in the general context of computer code or machine usable instructions, including computer executable instructions, such as program modules, executed by a computer or other machine (virtual or otherwise), such as a smartphone or other handheld device. Generally, a program module or engine, including routines, programs, objects, components, data structures, etc., refers to code that performs particular tasks or implements particular abstract data types. Embodiments of the invention may be implemented in a variety of system configurations, including handheld devices, consumer electronics, general purpose computers, more specialized computing devices, etc. Embodiments of the invention may also be implemented in distributed computing environments where tasks are performed by remote processing devices linked through a communications network.

[0057] With reference to FIG. 3, a computing device 300 includes a bus 310 that directly or indirectly couples the following devices: memory 312, one or more processors 314, one or more presentation components 316, input / output ports 318, input / output components 320, and an exemplary power source 322. In some embodiments, the devices described herein utilize wired and rechargeable batteries and power sources. The bus 310 represents what may be one or more buses (e.g., an address bus, a data bus, or a combination thereof). While the various blocks in FIG. 3 are clearly drawn with lines for clarity, in practice such delineations may not be as clear and the lines may overlap. For example, a presentation component such as a display device may also be considered to be an I / O component. Also, a processor generally has memory in the form of a cache. It is recognized that such is the nature of the art, and it is reaffirmed that the diagram of FIG. 3 is merely illustrative of an exemplary computing device that may be used in connection with one or more embodiments of the present disclosure. Categories such as "workstation," "server," "laptop," "handheld device," and the like are not differentiated as all are within the scope of FIG. 3 and are considered to refer to a "computing device."

[0058] Computing device 300 typically includes a variety of computer-readable media. Computer-readable media can be any available media that can be accessed by computing device 300 and includes both volatile and nonvolatile media, removable and non-removable media. By way of example, and not limitation, computer-readable media can include computer storage media and communication media.

[0059] Computer storage media includes volatile and nonvolatile media, removable and non-removable media implemented in any method or technology for storage of information, such as computer-readable instructions, data structures, program modules, or other data. Computer storage media includes, but is not limited to, RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital versatile disks (DVD) or other optical disk storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium that can be used to store the desired information and that can be accessed by the computing device 300. Computer storage media excludes the signals themselves.

[0060] Communication media typically embodied computer-readable instructions, data structures, program modules, or other data in a modulated data signal, such as a carrier wave or other transport mechanism, and includes any information delivery media. The term "modulated data signal" means a signal that has one or more characteristics set or changed in such a manner as to encode information in the signal. By way of example, and not limitation, communication media includes wired media, such as a wired network or direct-wired connection, and wireless media, such as acoustic, RF, infrared, NFC, Bluetooth and other wireless media. Combinations of any of the above should also be included within the scope of computer-readable media.

[0061] The memory 312 includes computer storage media in the form of volatile and / or non-volatile memory. As shown, the memory 312 includes instructions 324 that, when executed by the processor 1014, are configured to cause the computing device to perform any of the operations described herein with reference to the figures above or to implement any of the program modules described herein. The memory may be removable, non-removable, or a combination thereof. Exemplary hardware devices include solid state memory, hard drives, optical disk drives, and the like. The computing device 300 includes one or more processors that read data from various entities, such as the memory 312 or the I / O components 320. The presentation component 316 presents data indications to a user or other device. Exemplary presentation components include a display device, a speaker, a printing component, a vibrating component, and the like.

[0062] The I / O ports 318 allow the computing device 300 to be logically coupled to other devices, including I / O components 320, some of which may be internal. Example components include a microphone, joystick, directional pad, monitor, scanner, printer, wireless device, battery, etc.

[0063] Referring now to FIG. 4, FIG. 4 illustrates a perspective view of a treatment device 402 according to one embodiment described herein. The treatment device 402 comprises a tissue response detector 404 and an imaging device 406. An electromagnetic radiation source 408 is also present in or coupled to the treatment device 402. In the embodiment of FIG. 4, the electromagnetic radiation source 408 is a laser beam input. The treatment device 402 also comprises a steering module or controller 410 for steering or directing the laser beam provided by the light source 408. The device 402 further comprises a connector 412 for energy supply and communication (e.g., for coupling the device 402 to a control system and other system components described herein, not shown in FIG. 4). Additionally, the treatment device 402 comprises a u-shaped applicator component 416 that can be used to align or position the treatment device 402 relative to a plane 414. The plane 414 can be defined by a surface of the ROI or treatment area. For example, the plane 414 can be defined by the skin of the patient.

[0064] FIG. 5 illustrates a different perspective view of a treatment device 502 similar or similar to the treatment device 402 of FIG. 4. The treatment device 502 of FIG. 5 includes a tissue response detector 504 and an imaging device 506. An electromagnetic radiation source 508 is also present in the treatment device 502. In the embodiment of FIG. 5, the electromagnetic radiation source 508 is a laser beam input. The treatment device 502 also includes a steering module or controller 510 for steering or directing the laser beam provided by the source 508. The device 502 further includes a connector 512 for energy supply and communication (e.g., for coupling to a control system and other system components described herein, not shown in FIG. 5). Additionally, the treatment device 502 includes a u-shaped applicator component 516 that can be used to align or position the treatment device 502 relative to a plane 514. The plane 514 can be defined by a surface of the ROI or treatment area. For example, the plane 514 can be defined by the skin of the patient. Additionally, note that the two circular apertures 518 and 520 below detector 504 in Figure 5 correspond to where the laser beam from source 508 exits toward plane 514 (aperture 518 directly below detector 504) and correspond to a high power illumination source (which may be an LED source, for example) that provides constant visible light to assist the physician and imaging device 506. This illumination source is aperture 520 below laser aperture 518 in Figure 5.

[0065] The systems, devices, and methods described herein (see, e.g., Figures 1-5) can be used to provide improved treatment to patients in need thereof. Non-limiting exemplary advantages of the systems, devices, and methods described herein are illustrated in Figures 6 and 7.

[0066] With reference to Figures 6 and 7, skin temperature profiles within a treatment plane (e.g., ROI) caused by laser shock, irradiation, or administration are illustrated. Specifically, Figures 6A and 7A, respectively, illustrate skin temperature profiles obtained by conventional methods that do not control treatment in the manner described in this disclosure. Figure 6A is a thermal image of a treated area or ROI in which temperature is shown in grayscale. Darker gray represents a higher temperature at a given pixel or spot (or sROI), and lighter gray represents a lower temperature at a given pixel or spot (or sROI). As seen in Figure 6A ("uncontrolled" case), treatment by conventional methods provides a wide range of temperatures between pixels or spots (or sROIs), even though the intended result of the method is uniform treatment across all sROIs. In contrast, the method according to the present disclosure ("controlled" case) provides an even or uniform treatment that is substantially improved by the methods and systems described herein. As can be seen in FIG. 6B (which, like FIG. 6A, is a thermal image of the treated area or ROI in grayscale), the temperature between pixels or spots within the ROI (i.e., between sROIs) is much more uniform compared to FIG. 6A. Furthermore, the improved uniformity can be seen in the curves in FIG. 7A (uncontrolled) and FIG. 7B (controlled). FIG. 7A and 7B are each plots of temperature as a function of distance across the ROI, i.e., moving from one sROI to another sROI.

[0067] The embodiments described herein can be further understood by referring to the following further examples. However, the elements, devices, and methods described herein are not limited to any particular embodiment presented in the examples. It should be recognized that these are merely illustrative of some principles of the present disclosure and are non-limiting. Numerous modifications and adaptations will be readily apparent without departing from the spirit and scope of the present disclosure.

[0068] Working Example In one exemplary embodiment, a treatment of BCC is provided, which includes spatially resolved image-guided closed-loop controlled tissue treatment. Among other components not described, the BCC treatment can incorporate the following: a display, a controller, and a laser with a 1064 nm laser module, a 1064 nm laser scanner (galvo-driven beam position), a thermal camera, an RGB camera, LED lighting, stainless steel standoffs for the laser scanner, a secondary screen for treatment observation, an imaging target, a laser microprocessor, and a computer (for handling scripts for camera input, image processing).

[0069] In this example, various control systems and modules can be implemented to treat the BCC, as well as for calibration and control of the components listed above. For example, the system may include a thermal camera calibration module (to adjust the camera pixel or sub-region intensity, account for environmental variables, and enable object temperature imaging) and an image registration module (to allow for overlaying a thermal image on a visible image for operator visibility, i.e., homography techniques), thereby allowing the user to view the treatment in real time and perform the treatment, for example, on a secondary screen. The system can further include a coordinate system mapping module (to convert the "sub-region space" or "pixel space" from the camera image to "real space" distances and dimensions on the tissue). The camera and image processing engine and module can provide feedback on the pixel or sub-region location. Galvos that steer the beam can use applied voltages, thus moving the beam to the desired location. A beam localization and position correction module can be incorporated to account for variations in beam trajectory due to device configuration. This will utilize an aiming beam to ensure alignment between the coordinate system and the laser beam location for each treatment. The system may further include a contour detection module (the computer analyzes the image to identify and trace marker areas drawn or painted on the tissue by the physician or clinician indicating the desired treatment zone). This device does not necessarily diagnose, but helps guide the operator towards a complete treatment after the physician has determined what to treat. The system may further include a path planning module (which divides the contour into several spots and determines the spot order and travel path). At the initial treatment, this path may determine the first treatment pass to start the control loop. This utilizes the contour and coordinate system mapping described above. The system may further include patient motion tracking (e.g., as a safety feature), which may be implemented in an "interlock" style, which may use image monitoring of the visible wavelength camera to determine if the contour (patient) moves.The system may further include a core control loop that includes the thermal video feed (sensor), image processing (heating over time), an accumulation matrix of Arrhenius rates at each location (spatial tracking), the current temperature matrix of the physical treatment locations, a decision tree (where to go next, such as minimum temperature location / sROI, and radiation dose intensity to place each sROI within the treatment window). The system may further include a drive rate or speed function, as further described herein. Instead of using an exact temperature or a representation of temperature over time, this equation converts the sensed tissue response into a likelihood or other partial probability of a treatment outcome (e.g., cell death), with a spatially resolved accumulator matrix tracking this likelihood for each location. This can be used to drive a control loop that treats all locations to completion and determines which location to treat next among available locations midway through treatment. In this exemplary embodiment, the Arrhenius equation is implemented as a velocity function to convert the sensed temperature in each frame for each sROI into an accumulation of the likelihood of cell death, which is then used to: 1) track each location and ensure all are treated to completion; 2) ensure that temperatures remain within the treatment window to prevent adverse events; and 3) deliver custom-tailored treatment in real time, taking into account differential tissue responses within and around the lesion.

[0070] In another example, production level tasks may be incorporated into the system or method, and may include the following: align, focus, and calibrate both the thermal and RGB cameras and the visible light source; perform and verify homography image registration between the thermal and RGB cameras and store the homography transfer matrix in memory (automated using an error minimization algorithm to optimize common settings for registration); perform coordinate system mapping (transform "subregion space" to "real space") and map each camera's coordinate system to real space using information from the target and standoffs (subregion space and real space are expected to be non-uniform in x and y due to angular offsets from the target); perform beam localization and position correction to account for beam trajectory variations due to device configuration, and further include tasks of positioning the aiming beam centroid at a defined location or list of defined locations (often treatment contours or targets if manufactured), calculating the beam position "offset", and looping until accurate; test the offset protocol against a defined target where the system directs the aiming beam onto the tops of a series of targets.

[0071] Certain steps of the aforementioned exemplary implementation are illustrated in more detail by FIGS. 8-16. Specifically, the thermal camera, the RGB camera, and the visible light source were aligned and calibrated as described above. FIG. 8A shows the two-dimensional output (detected image) of the RGB camera (imaging device) oriented within the treatment device (not shown). The RGB camera is positioned within the treatment device in a manner similar to the positioning of the imaging device 406 within the treatment device 402 of FIG. 4. In FIG. 8A, an applicator component or standoff component similar to the applicator component 416 of FIG. 4 is visible within the detected image. An Air Force 1951 style resolution target is visible adjacent to (or "behind") the applicator component or standoff. FIG. 8B shows the two-dimensional output (detected temperature) of the thermal camera (tissue response detector) oriented within the treatment device (not shown) in a manner similar to the tissue response detector 404 within the treatment device 402 of FIG. 4, directed at the same resolution target as FIG. 8A. The tissue response detector, whose output is shown in Figure 8B, is present in the same overall treatment device as the imaging device, whose output is shown in Figure 8A. In Figure 8B, the same applicator or standoff components are visible as in Figure 8A.

[0072] FIG. 9 shows a two-dimensional image of a calibration rig or setup captured by the same thermal camera described in FIG. 8. The calibration rig or setup of FIG. 9 is a blackbody radiator whose temperature can be varied as desired to create a calibration surface for the RGB and thermal cameras of FIG. 8. The square near the center of FIG. 9 shows a two-dimensional spatial region (which can be referred to as the calibration region) whose temperature is detected over time by the thermal camera. The minimum, maximum, and average temperatures of this calibration region at a given time are shown in FIG. 9. The exact construction of the calibration rig is not particularly important, and the wires and other features shown in FIG. 9 are not critical to the calibration process, provided that the temperature of the calibration region can be tracked over time, as will be appreciated by those skilled in the art.

[0073] 10A-C show further steps in the alignment and calibration process. The temperature of the calibration area in FIG. 9 changes over time and stabilizes between desired temperature points (stabilization can be achieved, for example, by waiting 5 minutes). In FIG. 10, the desired temperature points span physiologically relevant temperatures. FIG. 10A shows a three-dimensional plot of ordered triplets corresponding to the detected temperatures of pixels in the calibration area using a thermal camera, the temperature of the thermal camera itself, and the temperature of the blackbody radiator itself, which is measured in a different way than when using a thermal camera. The plot of FIG. 10A can be referred to as a calibration surface. FIG. 10B illustrates a plot of the error or outlier analysis, where the ordered triplets, indicated with an "x" in both FIG. 10A and FIG. 10B, were rejected as outliers. FIG. 10C shows a modeling polynomial based on the calibration surface of FIG. 10A. FIG. 11 shows a plot of the output of the calibration process.

[0074] Figures 12-14 further illustrate aspects of the performance of homography image registration between thermal and RGB cameras. More specifically, Figures 12A and 12B show output images of the thermal camera (Figure 12A) and the RGB camera (Figure 12B) with reference to the same calibration target (Air Force 1951) as above. After the output images are taken, they are resized, intensity normalized, filtered, and / or thresholded. Additionally, edge detection is performed on both images, as shown in Figures 13A and 13B. Figure 13A shows the thermal camera output image, and Figure 13B shows the RGB camera output image. Figure 14 illustrates feature matching based on random sample consensus of edges (eliminating bad matches). In Figure 14, features from the thermal camera output image (Figure 14A) are matched to features from the RGB camera output image (Figure 14B). In this example, homography (or rigid registration or affine transformation, as necessary or preferred depending on the system optics) is used to register and overlay the images from the thermal and RGB camera outputs, and the homography coordinates are stored in the system's memory (e.g., as described above).

[0075] In this exemplary embodiment, the defined thermal gradients and / or isotherms are then used to show an overlay of thermal and RGB camera images, performed in real time during treatment and calibration, using the stored coordinates. See FIG. 15 for an overlay with good registration. The combined images can also be streamed or otherwise provided continuously and / or simultaneously to provide real time visualization (e.g., on a secondary screen or monitor) for physician guidance and safety. FIG. 16 shows a live streaming image of a calibrated thermal camera imaging a heated Air Force 1951 target in thermal imaging mode, displayed via WiFi LAN on a secondary screen.

[0076] Another exemplary treatment method includes: scanner calibration is checked and confirmed, the physician encircles the lesion plus clinical margins with a tissue pen, the scanner standoff is placed on the tissue centered on the lesion, and the camera scans the lesion margins and identifies the lesion border. The laser then traces the border with the aiming beam. The physician verifies that the correct area is highlighted. The laser then calculates a path for the beam to scan the entire enclosed area, processes the area in a "first pass" to increase the temperature, and starts the control loop. The control loop then processes the following steps: the location of the lesion is tracked and ensures that the patient has not moved relative to the treatment beam. Correct if necessary, or stop treatment if necessary for safety. The location of the aiming beam is checked against the desired location and corrected if necessary. Calculate the tissue response (temperature) for each sROI. The temperature map is updated. The incremental likelihood of cell death in the region is calculated via the Arrhenius rate equation. A matrix of the likelihood of cell death is updated at each location. The next location to treat is selected based on temperature and likelihood of cell death (areas with high likelihood of complete, i.e., death are excluded), the location with the lowest remaining temperature is selected, the difference between the current temperature and the target temperature is calculated, and the pulse fluence is calculated to bring the "next target" location to the desired temperature. The laser moves to the next selected location and irradiates with the prescribed fluence. The camera checks the tissue response and the loop is repeated. A termination sequence can also be performed, which can include the following steps: all locations are registered as above the threshold for high likelihood of cell death, and treatment data is recorded for review.

[0077] Certain steps of the aforementioned embodiments are further illustrated and described with reference to Figures 17-25. Systems similar to those described above (e.g., in connection with Figures 4, 5, and 8-16) can be used in the context of Figures 17-25.

[0078] Referring to FIG. 17, this figure shows an RGB image (e.g., captured by the RGB camera imaging device described above) with an example of how a physician can use a skin marking pen or marker to encircle, define, or otherwise identify pathological areas and clinically relevant edges of the skin (see the approximate hexagonal perimeter marked on the skin in FIG. 17). FIG. 18 shows a circled area on a patient's hand where image registration (e.g., as described above in connection with FIGS. 8-16) identifies the skin and markers, and uses filtering and edge detection. FIG. 19A shows overlaid thermal and RGB images, showing a computer-generated tracing of the outer boundary of the treatment area (e.g., ROI) on the skin. In an alternative embodiment (FIG. 19B), the physician may choose to draw on the touch screen interface of the image instead of using a physical or traditional handheld marker on the skin.

[0079] Returning again to the exemplary implementation of FIG. 17, once the boundary is drawn and the system recognizes the markings, the laser traces the defined boundary and the physician verifies that the region is correctly identified and also verifies system alignment. FIGS. 20A-C illustrate the laser tracing the edge of the region of FIG. 17 in each frame sequentially. In FIG. 20A, the laser spot is seen in the lower left quadrant of the boundary defined by the marked region. In FIG. 20B, the laser is seen in the upper center of the boundary defined by the marked region. In FIG. 20C, the laser is seen in the lower right quadrant of the boundary defined by the marked region.

[0080] In this particular non-limiting exemplary embodiment, after the ROI is confirmed by the physician, the computer system then plans a path for the initial pass of treatment, both in the direction the galvo laser will scan the desired space, as well as the direction the laser will fire in the pattern. This process is illustrated in Figures 21A-D. Figure 21A shows a computer drawing of the detected region boundary. The spot inside the boundary corresponds to the planned laser pulse deposition (or "fire") location within the ROI. Figure 21B illustrates the waypoints for the galvo scan through the pattern of Figure 21A, adjusted for a known laser beam diameter or spot size. Figure 21C shows the different regions (ROIs) drawn by the physician on the touch screen, with the boundaries and planned treatment locations overlaid on the live image feed. As illustrated in Figure 21D, an alternative strategy for planning may include known beam locations that encompass the margin lines. Figure 21D shows the u-shaped standoff (or applicator component) and potential beam locations, as well as dotted lines for the drawn margins, and the filled beam location utilized to deliver the treatment energy.

[0081] 22 illustrates an alternative embodiment of a planned treatment path. As shown in FIG. 22 (top to bottom), the planned raster pattern "fills" the ROIs of the patient's hand with sequential irradiations by the laser as part of the initial irradiation of multiple sROIs.

[0082] FIG. 23 further illustrates the steps of the processing method. With reference to FIG. 23, in order from left to right and top to bottom, the first pass of the treatment determines the tissue response to a known dose for each individual unit area (e.g., sROI) within the defined and confirmed treatment region (e.g., ROI). In the embodiment of FIG. 23, the accumulated or applied energy causes a temperature rise that exists beyond a single camera frame. That is, the temperature rise caused by the initial dose at a given pixel or sROI spreads out in time from frame to frame in FIG. 23. During this and all portions of the treatment in the embodiment of FIG. 23, the RGB images and thermal images are processed to determine the cumulative time-resolved dose as described herein. The initial pass serves to both bring the tissue to the target treatment window (e.g., based on a rate equation) and to determine any variability in the tissue response due to many factors, such as slight variations in energy delivery, differences in heat generated per unit energy delivered, and variations in the thickness or severity of the pathology at each location (e.g., sROI). Each of the foregoing sources of variation can potentially be anticipated, but likely will not be precisely known prior to providing the treatment. Subsequent exposures, "passes," or irradiation of one or more sROIs based on the methods described herein can provide a desired therapeutic effect or degree of treatment completion.

[0083] 24 and 25 further illustrate steps of an exemplary treatment method. FIG. 24 shows a schematic of an ROI (amorphous periphery in FIG. 24) with reference to a u-shaped standoff or applicator component described herein. According to the method described herein, the scanner can routinely create aiming beam alignment illumination (dots in FIG. 24) that is recognized by an RGB camera as described herein. The position of the aiming beam relative to the standoff and the defined region of interest is checked to be within known boundaries and corrected to ensure proper treatment, minimizing the effect of slight movements by the patient or the physician guiding the laser placement on the skin. FIG. 25 shows an RGB output of an ROI similar to that shown diagrammatically in FIG. 24. More specifically, FIG. 25 illustrates an RGB image of the skin and aiming beam, as well as a projected overlay of the available treatment space (dotted circles in FIG. 25). Each RGB output in FIG. 25 shows the laser aimed at one of the target circles. However, in three of the RGB outputs (top three in FIG. 25), the laser does not perfectly target the desired target circle (each of which may be, for example, an sROI). The white arrows in FIG. 25 indicate the center of the actual laser spot in each case. Thus, as described herein, the method of this example corrects this misalignment (based on the detected tissue response) and corrects the "miss" in the subsequent treatment step.

[0084] Some additional non-limiting exemplary embodiments are described below.

[0085] Embodiment 1. A method of treating biological tissue in a patient in need of treatment, comprising: irradiating one or more initial doses of electromagnetic radiation to a region of interest (ROI) of a patient, the ROI comprising a matrix or array of sub-regions of interest (sROI) of the patient's biological tissue; determining a tissue response of one or more of said sROIs; generating a tissue response matrix from the tissue responses of the one or more sROIs; converting the tissue response matrix into a sub-clinical indicator matrix or a treatment completion matrix for the one or more sROIs, the sub-clinical indicator matrix corresponding to a treatment completion degree of the one or more sROIs; and applying one or more additional doses of electromagnetic radiation to the one or more sROIs or not applying one or more additional doses of electromagnetic radiation to the one or more sROIs based at least in part on the sub-clinical indicator matrix. A method comprising:

[0086]

[0023] Embodiment 2. The method of embodiment 1, wherein said sub-clinical indicator matrix comprises a summary of treatment completion of said one or more sROIs over time.

[0087] Embodiment 3. The method of embodiment 1 or embodiment 2, wherein two or more of the illuminating, determining, generating, and converting steps are performed simultaneously, sequentially, and / or in real time.

[0088] Embodiment 4. The method of any of the preceding embodiments, wherein the one or more additional doses of electromagnetic radiation have the same or different characteristics as the one or more initial doses.

[0089] Embodiment 5. The method of any of the preceding embodiments, wherein the sub-clinical indicator matrix is ​​generated based on one or more rate functions.

[0090]

[0023] Embodiment 6. The method of embodiment 5, wherein the one or more rate functions include at least one of an Arrhenius function, a bioheat function, a light transport function, and a derivative of a light transport function.

[0091] Embodiment 7. The method of any of the preceding embodiments, wherein the tissue response corresponds to a sensed temperature, a detected color or color change, or another detected spectral change.

[0092]

[0023] Embodiment 8. The method according to any of the preceding embodiments, wherein each sROI corresponds to an actual physical location of a unit size of biological tissue having a known size and location relative to one or more other sROIs of said ROI.

[0093]

[0023] Embodiment 9. The method of any of the preceding embodiments, wherein the ROI corresponds to a defined treatment region.

[0094]

[0023] Embodiment 10. The method of any of the preceding embodiments, wherein the electromagnetic radiation is a laser beam.

[0095] Embodiment 11. The method of embodiment 10, wherein the laser beam has a mean wavelength in the ultraviolet (UV), visible or infrared (IR) region of the electromagnetic spectrum, for example with a mean wavelength λ between 190 nm and 10.6 μm or between 190 nm and 3 μm.

[0096]

[0023] Embodiment 12. The method of embodiment 10, wherein the laser beam has an average wavelength λ of 700 nm to 1500 nm or 900 nm to 1300 nm.

[0097]

[0023] Embodiment 13. The method of embodiment 10, wherein the laser beam comprises a Nd:YAG laser beam.

[0098]

[0023] Embodiment 14. The method of any of the preceding embodiments, wherein the treatment completeness comprises achieving a benchmark temperature over time for one or more sROIs.

[0099]

[0036] Embodiment 15. The method of any of the preceding embodiments, wherein the treatment completeness comprises achieving cell death in the biological tissue of one or more sROIs.

[0100] Embodiment 16. The method of any of the preceding embodiments, further comprising imaging said ROI with an imaging device.

[0101]

[0023] Embodiment 17. The method of embodiment 16, wherein the ROI is imaged in real time.

[0102] Embodiment 18. The method of any of the preceding embodiments, further comprising irradiating the matrix of sROIs a sufficient number of times to complete the treatment.

[0103] Embodiment 19. A system for treating biological tissue of a patient, the system comprising: an electromagnetic radiation source that delivers one or more initial doses of electromagnetic radiation to a region of interest (ROI) of a patient, the ROI comprising a matrix or array of sub-regions of interest (sROIs) of the patient's biological tissue; Imaging devices; an imaging device and a tissue response detector for determining a tissue response of one or more of the sROIs based on illumination of the ROIs; and a control unit for generating a tissue response matrix based on information received from the tissue response detector and converting the tissue response matrix into a sub-clinical indicator matrix or a treatment completion matrix for one or more sROIs. Equipped with the sub-clinical indicator matrix corresponds to a treatment completion degree for the one or more sROIs; The controller further signals the electromagnetic radiation source to irradiate the one or more sROIs with one or more additional doses of electromagnetic radiation or to not irradiate a sROI based at least in part on the sub-clinical indicator matrix. A system characterized in that

[0104]

[0023] Embodiment 20. The system of embodiment 19, wherein said sub-clinical indicator matrix comprises a summary of treatment completion of one or more sROIs over time.

[0105]

[0041] Embodiment 21. The system of embodiment 19 or embodiment 20, wherein the one or more additional doses of electromagnetic radiation have the same or different characteristics as the one or more initial doses.

[0106] Embodiment 22. The system of any of embodiments 19-21, wherein the sub-clinical indicator matrix is ​​generated based on one or more rate functions.

[0107]

[0023] Embodiment 23. The system of embodiment 22, wherein the one or more rate functions include at least one of an Arrhenius function, a bioheat function, and a light transport function.

[0108]

[0023] Embodiment 24. The system of any of embodiments 19-23, wherein the tissue response detector is configured to detect a temperature of one or more sROIs.

[0109]

[0031] Embodiment 25. The system of any of embodiments 19-24, wherein the electromagnetic radiation source is a Nd:YAG laser.

[0110] Embodiment 26. The system of any of embodiments 19 to 25, wherein the electromagnetic radiation source has a mean wavelength in the ultraviolet (UV), visible, or infrared (IR) region of the electromagnetic spectrum, for example, with a mean wavelength λ of 190 nm to 10.6 μm, 190 nm to 3 μm, 700 nm to 1500 nm, or 900 nm to 1300 nm.

[0111]

[0023] Embodiment 27. The system of any of embodiments 19-26, wherein the imaging device is configured to image the one or more sROIs.

[0112]

[0031] Embodiment 28. The system of embodiment 27, wherein the imaging is performed in real time.

[0113]

[0023] Embodiment 29. A computer storage medium storing computer usable instructions that, when used by one or more computing devices, cause the one or more computing devices to treat biological tissue of a patient, the operations including: irradiating one or more initial doses of electromagnetic radiation to a region of interest (ROI) of the patient, the ROI comprising a matrix or array of sub-regions of interest (sROIs) of the patient's biological tissue; determining a tissue response of one or more of said sROIs; generating a tissue response matrix from the tissue responses of the one or more sROIs; converting the tissue response matrix into a sub-clinical indicator matrix or a treatment completion matrix for the one or more sROIs, the sub-clinical indicator matrix corresponding to a degree of treatment completion for the one or more sROIs; and irradiating the one or more sROIs with one or more additional doses of electromagnetic radiation or not irradiating the sROI based at least in part on the sub-clinical indicator matrix. A computer storage medium.

[0114]

[0021] Embodiment 30. The computer storage medium of embodiment 29, wherein the operations further comprise mapping a plurality of sROIs of the tissue.

[0115]

[0023] Embodiment 31. The computer storage medium of embodiment 29 or embodiment 30, wherein the sub-clinical indicator matrix comprises a summary of treatment completion of one or more sROIs over time.

[0116]

[0036] Embodiment 32. The computer storage medium of any of embodiments 29-31, wherein two or more of the illuminating, determining, generating, and converting steps are performed simultaneously, sequentially, and / or in real time.

[0117] Embodiment 33. The computer storage medium of any one of embodiments 29-32, wherein the one or more additional doses of electromagnetic radiation have the same or different characteristics as the one or more initial doses.

[0118]

[0023] Embodiment 34. The computer storage medium of any of embodiments 29-33, wherein the sub-clinical indicator matrix is ​​generated based on one or more rate functions.

[0119]

[0023] Embodiment 35. The computer storage medium of embodiment 34, wherein the one or more rate functions include at least one of an Arrhenius function, a bioheat function, and a light transport function.

[0120]

[0023] Embodiment 36. The computer storage medium of any of embodiments 29-35, wherein the tissue response corresponds to a sensed temperature.

[0121] Many different arrangements of the various components and / or steps shown and described, as well as those not shown, are possible without departing from the scope of the following claims. The embodiments of the present technology have been described with the intent to be illustrative and not limiting. Alternative embodiments will become apparent from reference to this disclosure. Alternative ways of implementing the above may be accomplished without departing from the scope of the following claims. Certain features and subcombinations are useful and can be employed without reference to other features and subcombinations and are contemplated within the scope of the claims.

Claims

1. A method for treating biological tissue of a patient in need of treatment, comprising: irradiating a region of interest (ROI) of a patient with one or more initial doses of electromagnetic radiation, said ROI comprising a matrix or array of sub-regions of interest (sROIs) of said patient's biological tissue; determining the tissue response of one or more of said sROIs; generating a tissue response matrix from the tissue responses of the one or more sROIs; converting the tissue response matrix into a sub-clinical indicator matrix or a treatment completion matrix for the one or more sROIs, the sub-clinical indicator matrix corresponding to the treatment completion of the one or more sROIs; and applying one or more additional doses of electromagnetic radiation to the one or more sROIs or not applying one or more sROIs based at least in part on the sub-clinical indicator matrix. A method comprising:

2. 10. The method of claim 1, wherein the sub-clinical indicator matrix comprises a summary of treatment completion of the one or more sROIs over time.

3. 10. The method of claim 1, wherein two or more of the illuminating, determining, generating, and converting steps are performed simultaneously, sequentially, and / or in real time.

4. 10. The method of claim 1, wherein the one or more additional doses of electromagnetic radiation have the same or different characteristics as the one or more initial doses.

5. 2. The method of claim 1, wherein the sub-clinical indicator matrix is ​​generated based on one or more rate functions.

6. 6. The method of claim 5, wherein the one or more velocity functions include at least one of an Arrhenius function, a bioheat function, a light transport function, and a derivative of a light transport function.

7. 10. The method of claim 1, wherein the tissue response corresponds to a sensed temperature, a detected color or color change, or another detected spectral change.

8. 2. The method of claim 1, wherein each sROI corresponds to an actual physical location of a unit-sized portion of biological tissue having a known size and location relative to one or more other sROIs of said ROI.

9. The method of claim 1 , wherein the ROI corresponds to a defined region of interest.

10. 2. The method of claim 1, wherein the electromagnetic radiation is a laser beam.

11. 11. The method of claim 10, wherein the laser beam has a mean wavelength λ between 190 nm and 10.6 μm.

12. 11. The method of claim 10, wherein the laser beam has a mean wavelength λ between 700 nm and 1500 nm.

13. 11. The method of claim 10, wherein the laser beam comprises a Nd:YAG laser beam.

14. The method of claim 1, wherein processing completion includes achieving a benchmark temperature over time for one or more sROIs.

15. The method described in claim 1, characterized in that the degree of processing completion includes achieving cell death of biological tissue in one or more sROIs.

16. 10. The method of claim 1, further comprising imaging the ROI with an imaging device.

17. 17. The method of claim 16, wherein the ROI is imaged in real time.

18. The method of claim 1, further comprising illuminating the matrix of sROIs a sufficient number of times to complete the process.

19. 1. A system for processing biological tissue of a patient, the system comprising: an electromagnetic radiation source that delivers one or more initial doses of electromagnetic radiation to a region of interest (ROI) of a patient, the ROI comprising a matrix or array of sub-regions of interest (sROIs) of the patient's biological tissue; imaging devices; an imaging device and a tissue response detector for determining a tissue response of one or more of the sROIs based on illumination of the ROIs; and a control unit for generating a tissue response matrix based on information received from the tissue response detector and converting the tissue response matrix into a sub-clinical indicator matrix or a treatment completion matrix for one or more sROIs; Equipped with the sub-clinical indicator matrix corresponds to treatment completion for the one or more sROIs; The controller further signals the electromagnetic radiation source to irradiate the one or more sROIs with one or more additional doses of electromagnetic radiation or to not irradiate an sROI based at least in part on the sub-clinical indicator matrix. A system characterized by:

20. 20. The system of claim 19, wherein the sub-clinical indicator matrix includes a summary of treatment completion of one or more sROIs over time.

21. 20. The system of claim 19, wherein the one or more additional doses of electromagnetic radiation have the same or different characteristics as the one or more initial doses.

22. 20. The system of claim 19, wherein the sub-clinical indicator matrix is ​​generated based on one or more rate functions.

23. 23. The system of claim 22, wherein the one or more velocity functions include at least one of an Arrhenius function, a bioheat function, and a light transport function.

24. 20. The system of claim 19, wherein the tissue response detector is configured to detect a temperature of one or more sROIs.

25. 20. The system of claim 19, wherein the electromagnetic radiation source is a Nd:YAG laser.

26. 20. The system of claim 19, wherein the electromagnetic radiation source has a mean wavelength λ between 700 nm and 1500 nm.

27. 20. The system of claim 19, wherein the imaging device is configured to image the one or more sROIs.

28. 28. The system of claim 27, wherein the imaging is performed in real time.

29. A computer storage medium storing computer usable instructions that, when used by one or more computing devices, cause the one or more computing devices to process patient tissue, the operations including: irradiating one or more initial doses of electromagnetic radiation to a region of interest (ROI) of the patient, the ROI comprising a matrix or array of sub-regions of interest (sROIs) of the patient's biological tissue; determining a tissue response in one or more of said sROIs; generating a tissue response matrix from the tissue responses of the one or more sROIs; converting the tissue response matrix into a sub-clinical indicator matrix or a treatment completion matrix for the one or more sROIs, the sub-clinical indicator matrix corresponding to treatment completion for the one or more sROIs; and irradiating the one or more sROIs with one or more additional doses of electromagnetic radiation, or not irradiating an sROI, based at least in part on the sub-clinical indicator matrix. a computer storage medium,

30. 30. The computer storage medium of claim 29, wherein the operations further comprise mapping a plurality of sROIs of the tissue.

31. 30. The computer storage medium of claim 29, wherein the sub-clinical indicator matrix includes a summary of treatment completion of one or more sROIs over time.

32. 30. The computer storage medium of claim 29, wherein two or more of the illuminating, determining, generating, and converting steps occur simultaneously, sequentially, and / or in real time.

33. 30. The computer storage medium of claim 29, wherein the one or more additional doses of electromagnetic radiation have the same or different characteristics as the one or more initial doses.

34. 30. The computer storage medium of claim 29, wherein the sub-clinical indicator matrix is ​​generated based on one or more rate functions.

35. 35. The computer storage medium of claim 34, wherein the one or more velocity functions include at least one of an Arrhenius function, a bioheat function, and a light transport function.

36. 30. The computer storage medium of claim 29, wherein the tissue response corresponds to a sensed temperature.

Images