LIGHT THERAPY TREATMENT METHOD AND APPARATUS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 62/753,278 filed on October 31, 2018, the contents of which are hereby incorporated in its entirety.

GOVERNMENT LICENSE RIGHTS

[0002] This invention was made with government support under contract no. HD001254 awarded by the National Institutes of Health, contract no. PR151051 awarded by other, and contract no. R01 NS091242 awarded by the National Institutes of Health. The government has certain rights in the invention.

TECHNICAL FIELD

[0003] The disclosure relates generally to infrared light therapies at selected wavelengths for reducing tissue adhesion, reducing scar formation, and promoting wound healing.

BACKGROUND

[0004] Tissue adhesions are bands of fibrous tissue that form between tissues and organs. These bands often develop as a result of surgery when tissues are handled excessively, dry out, or when the serosal surfaces are damaged, and can also arise from contact with blood, gynecological infections, or endometriosis. Of subjects who undergo abdominal surgery, a high percentage of subjects develop adhesions regardless of the surgical route (open surgery or minimally invasive surgery). In gynecologic surgery, cesarean sections (C-sections) account for nearly 30% of deliveries, and about 24-73% of women develop adhesions after a first C-section. Subsequent surgeries lead to denser and more numerous adhesions, further complicating the surgery as risks of bowl and bladder damage increase. Similar problems arise in gynecological surgery, such as myomectomies and hysterectomies.

[0005] Adhesions can lead to bowl obstruction, chronic pelvic pain, dysperonia, infertility, fistulas, complications at subsequent surgeries, and hospital readmissions. Adhesions resulting from surgery raise a significant economic burden, and a significant portion is related to prior surgical interventions in the reproductive tract of women. Therefore, there is a need in the field to reduce adhesions and improve recovery from surgery.

SUMMARY

[0006] The present disclosure is based, in part, upon the identification of infrared light at specific wavelengths that reduces tissue adhesion and wound tissue fibrosis, as well as the identification of infrared light at other specific wavelengths that impairs the reduction of tissue adhesion and wound tissue fibrosis and should be avoided when treating these diseases or conditions.

[0007] Accordingly, in one aspect, the present disclosure provides a method of reducing tissue adhesion at a location in a subject in need thereof, the method comprising applying light to tissue susceptible to tissue adhesion at the location of the subject, wherein the light has a first wavelength in the range of 730-770 nm and/or a second wavelength in the range of 930-970 nm, thereby reducing tissue adhesion in the tissue at the location.

[0008] In another aspect, the present disclosure provides a method of reducing scar formation at a location in a subject in need thereof, the method comprising applying light to tissue susceptible to scar formation at the location of the subject, wherein the light has a first wavelength in the range of 730-770 nm and/or a second wavelength in the range of 930-970 nm, thereby reducing scar formation in the tissue at the location.

[0009] In another aspect, the present disclosure provides a method of promoting wound healing at a location in a subject in need thereof, the method comprising applying light to wounded tissue at the location of the subject, wherein the light has a first wavelength in the range of 730- 770 nm and/or a second wavelength in the range of 930-970 nm, thereby promoting wound healing in the tissue at the location.

[0010] With respect to each of the foregoing aspects of the invention, it is understood that each of the following embodiments, either alone or in combination with the other embodiments, is applicable to each of the methods.

[0011] In certain embodiments of, the light has a wavelength in the range of 730-770 nm, for example, 750 nm. In certain embodiments of any one of the foregoing methods, the light has a wavelength in the range of 930-970 nm, for example, from about 940 nm to about 950 nm, for example, 940 nm, 945 nm, or 950 nm. In certain embodiments, the light has a first wavelength in the range of 730-770 nm, for example, 750 nm, and a second wavelength in the range of 930-970 nm, for example, from about 940 nm to about 950 nm, for example, 940 nm, 945 nm, or 950 nm.

[0012] In certain embodiments, the first wavelength is a peak wavelength. In certain embodiments, the second wavelength is a peak wavelength.

[0013] In certain embodiments, the light is substantially free of any wavelength in the range of 795-835 nm. In certain embodiments, the light is substantially free of a wavelength of 810 nm and/or 808 nm.

[0014] In certain embodiments, the light has a power density lower than or equal to 5 mW/cm ² at the tissue. For example, in certain embodiments, the light has a power density in the range of 0.01-0.1 mW/cm ² , 0.1-1 mW/cm ² , 0.5-5 mW/cm ² , or 3-5 mW/cm ² at the tissue.

[0015] In certain embodiments, the light is generated by one or more light emitting diodes (LEDs), lasers, laser diodes, or a combination thereof, such as a laser and a laser diode, a laser and an LED, or a laser diode and an LED. In certain embodiments, the one or more LEDs, lasers, laser diodes, or combination thereof produce light having one or more wavelengths of about 750 nm and/or in the range of about 940 nm to about 950 nm. In certain embodiments, the source or sources of the light, at the light delivery surface, has a power density in the range of 50 mW/cm ² to 2 W/cm ² . In certain embodiments, the power density is an average power density.

[0016] In certain embodiments, the light is applied to the tissue for at least 30 minutes, at least 1 hour, or at least 2 hours. In certain embodiments, the tissue comprises an abdominal tissue. In certain embodiments, the susceptibility to tissue adhesion, the susceptibility to scar formation, or the wound is caused by a surgery, for example, an open surgery or a laparoscopic surgery. In further examples, the light is applied to the tissue during and/or after the surgery.

[0017] In certain embodiments, the method reduces the activity of cytochrome c oxidase (CcO) in the tissue. In certain embodiments, the method reduces the amounts of one or more adhesion markers in the tissue, for example, one or more adhesion markers selected from the group consisting of transforming growth factor beta 1 (TGF-b 1 ), vascular endothelial growth factor (VEGF), collagen alpha- 1(1) chain (COLlal), and a combination thereof. In certain embodiments, the method reduces fibrosis in the tissue.

[0018] In another aspect, the present disclosure provides a therapeutic device suitable for reducing tissue adhesion, the device comprising a light source emitting light having a first wavelength in the range of 730-770 nm and/or a second wavelength in the range of 930-970 nm. [0019] In another aspect, the present disclosure provides a therapeutic device suitable for reducing scar formation, the device comprising a light source emitting light having a first wavelength in the range of 730-770 nm and/or a second wavelength in the range of 930-970 nm.

[0020] In another aspect, the present disclosure provides a therapeutic device suitable for promoting wound healing, the device comprising a light source emitting light having a first wavelength in the range of 730-770 nm and/or a second wavelength in the range of 930-970 nm.

[0021] With respect to each of the foregoing aspects of the invention, it is understood that each of the following embodiments, either alone or in combination with the other embodiments, is applicable to each of the therapeutic devices.

[0022] In certain embodiments of, the light has a wavelength in the range of 730-770 nm, for example, 750 nm. In certain embodiments of any one of the foregoing methods, the light has a wavelength in the range of 930-970 nm, for example, from about 940 nm to about 950 nm, for example, 940 nm, 945 nm, or 950 nm. In certain embodiments, the light has a first wavelength in the range of 730-770 nm, for example, 750 nm, and a second wavelength in the range of 930-970 nm, for example, from about 940 nm to about 950 nm, for example, 940 nm, 945 nm, or 950 nm.

[0023] In certain embodiments, the first wavelength is a peak wavelength. In certain embodiments, the second wavelength is a peak wavelength.

[0024] In certain embodiments, the light is substantially free of any wavelength in the range of 795-835 nm. In certain embodiments, the light is substantially free of a wavelength of 810 nm and/or 808 nm.

[0025] In certain embodiments, the light is generated by one or more light emitting diodes (LEDs), lasers, laser diodes, or a combination thereof, such as a laser and a laser diode, a laser and an LED, or a laser diode and an LED. In certain embodiments, the one or more LEDs, lasers, laser diodes, or combination thereof produce light having one or more wavelengths of about 750 nm and/or in the range of about 940 nm to about 950 nm. In certain embodiments, the source or sources of the light, at the light delivery surface, has a power density in the range of 50 mW/cm ² to 2 W/cm ² . In certain embodiments, the power density is an average power density.

[0026] In another aspect, the present disclosure provides a light therapy method comprising: applying to a tissue of a subject that is subjected to surgery, light having a plurality of wavelengths based on an ability of light having the plurality of wavelengths to inhibit adhesion in the tissue, wherein the method optionally further comprises, before applying the light to the tissue, the step of selecting the plurality of wavelengths, from a plurality of wavelength ranges, based on an ability of light having the plurality of wavelengths to inhibit adhesion in the identified tissue; and generating light at the plurality of wavelengths.

[0027] With respect to each of the foregoing aspects of the invention, it is understood that each of the following embodiments, either alone or in combination with the other embodiments, is applicable to each of the methods.

[0028] In certain embodiments, applying the light having the plurality of wavelengths to the tissue comprises applying the light having the plurality of wavelengths to the tissue during the surgical procedure. In certain embodiments, applying the light having the plurality of wavelengths to the tissue comprises applying the light having the plurality of wavelengths to the tissue after the surgical procedure.

[0029] In certain embodiments, each wavelength of the plurality of wavelengths is selected from a distinct wavelength range. In certain embodiments, a first wavelength of the plurality of wavelengths is in the range of 730-770 nm, for example, is 750 nm; and a second wavelength of the plurality of wavelengths is in the range of 930-970 nm, for example, from about 940 nm to about 950 nm, for example, is 940 nm, 945 nm, or 950 nm. In certain embodiments, the plurality of wavelengths comprises: a first wavelength of 750 nm; and a second wavelength of 940 nm, 945 nm, or 950 nm. In certain embodiments, the first wavelength is a peak wavelength; and the second wavelength is a peak wavelength.

[0030] In certain embodiments, generating the light comprises generating the light free or substantially free of any wavelength in the range of 795-835 nm. In certain embodiments, generating the light comprises generating the light free or substantially free of a wavelength of 810 nm and/or 808 nm.

[0031] In certain embodiments, the light has a power density lower than or equal to 5 mW/cm ² at the tissue. For example, in certain embodiments, the light has a power density in a range of 0.01-0.1 mW/cm ² , 0.1-1 mW/cm ² , 0.5-5 mW/cm ² , or 3-5 mW/cm ² at the tissue.

[0032] In certain embodiments, selecting the plurality of wavelengths further comprises selecting the plurality of wavelengths based on the ability of light having the plurality of wavelengths to reduce an amount of one or more adhesion markers in the identified tissue, for example, one or more adhesion markers selected from the group consisting of transforming growth factor beta 1 (TGF-b I ), vascular endothelial growth factor (VEGF), collagen alpha- 1(1) chain (COLlal), and a combination thereof.

[0033] In another aspect, the disclosure provides a light therapy method comprising applying to a tissue of a subject that is susceptible to tissue adhesion, light having a plurality of wavelengths prior to onset of tissue adhesion in the tissue, wherein prior to the step of applying the light, the method optionally further comprises selecting the plurality of wavelengths based on the ability of light having the plurality of wavelengths to inhibit tissue adhesion in the tissue.

[0034] With respect to each of the foregoing aspects of the invention, it is understood that each of the following embodiments, either alone or in combination with the other embodiments, is applicable to each of the methods.

[0035] In certain embodiments, applying the plurality of wavelengths to the tissue comprises applying the plurality of wavelengths to the tissue during a surgery. In certain embodiments, applying the plurality of wavelengths to the tissue comprises applying the plurality of wavelengths to the tissue after a surgery.

[0036] In certain embodiments, a first wavelength of the plurality of wavelengths is in the range of 730-770 nm, for example, is 750 nm; and a second wavelength of the plurality of wavelengths is in the range of 930-970 nm, for example, from about 940 nm to about 950 nm, for example, is 940 nm, 945 nm, or 950 nm. In certain embodiments, the plurality of wavelengths comprises: a first wavelength of 750 nm; and a second wavelength of 940 nm, 945 nm, or 950 nm. In certain embodiments, the first wavelength is a peak wavelength; and the second wavelength is a peak wavelength.

[0037] In certain embodiments, generating the light comprises generating the light free or substantially free of any wavelength in the range of 795-835 nm. In certain embodiments, generating the light comprises generating the light free or substantially free of a wavelength of 810 nm and/or 808 nm.

[0038] In certain embodiments, the light has a power density lower than or equal to 5 mW/cm ² at the tissue. For example, in certain embodiments, the light has a power density in a range of 0.01-0.1 mW/cm ² , 0.1-1 mW/cm ² , 0.5-5 mW/cm ² , or 3-5 mW/cm ² at the tissue.

[0039] In certain embodiments, selecting the plurality of wavelengths further comprises selecting the plurality of wavelengths based on the ability of light having the plurality of wavelengths to reduce an amount of one or more adhesion markers in the identified tissue, for example, one or more adhesion markers are selected from the group consisting of transforming growth factor beta 1 (TGF-b I ), vascular endothelial growth factor (VEGF), collagen alpha-l(I) chain (COLlal), and a combination thereof.

[0040] These and other aspects and features of the disclosure are described in the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0041] FIGS. 1A-1D illustrate light therapy apparatus for emitting infrared light and/or delivering light to a subject for treatment.

[0042] FIG. 2 illustrates an exemplary model of reducing tissue adhesion by infrared light.

[0043] FIGS. 3A-3B are graphs showing the effect of infrared light at the wavelength of 750 nm, 810 nm, 950 nm, or 750 nm in combination with 950 nm on the activity of purified cytochrome c oxidase (CcO) (FIG. 3A) and the oxygen consumption rate (OCR) of isolated mitochondria (FIG. 3B), as normalized relative to non-irradiated samples (n > 4; *p < 0.05).

[0044] FIG. 4 is a graph showing the effect of infrared light at the wavelength combination of 750 nm and 950 nm on bovine liver CcO activity in the presence or absence of N,N,N',N'- tetramethyl-p-phenylenediamine (TMPD) .

[0045] FIG. 5 is a graph showing the effect of infrared light at the wavelength of 950 nm, applied for a duration of 2 minutes (from the time point of Minute 1 to the time point of Minute 3), on normalized mitochondrial membrane potential observed in a time course.

[0046] FIGS. 6A-6B are graphs showing the effect of infrared light at the wavelength of 750 nm, 810 nm, 950 nm, or 750 nm in combination with 950 nm on the oxygen consumption rate of macrophages (FIG. 6A, n = 3) and fibroblasts (FIG. 6B).

[0047] FIGS. 7A-7B are graphs showing the effect of infrared light at the wavelength of 810 nm or 750 nm in combination with 950 nm on the generation of mitochondrial superoxide (FIG. 7A) and the mitochondrial membrane potential (FIG. 7B) in fibroblasts exposed to hypoxia (1% oxygen,“ischemia”) for 24 hours optionally followed by 21% oxygen (“reperfusion”) for 30 minutes. FIGS. 7C-7E are graphs showing the effect of the same infrared light on the induction of adhesion markers vascular endothelial growth factor (VEGF) (FIG. 7C), collagen alpha-l(I) chain (COLlal) (FIG. 7D), and TGF-b! (FIG. 7E) in fibroblasts exposed to hypoxia (1% oxygen, “ischemia”) for 24 hours optionally followed by 21% oxygen (“reperfusion”) for 3 hours. The control group did not undergo hypoxia.

[0048] FIGS. 8A-8B are graphs showing the effect of infrared light at the wavelength of 810 nm or 750 nm in combination with 950 nm on the generation of mitochondrial superoxide (FIG. 8A) and the mitochondrial membrane potential (FIG. 8B) in macrophages exposed to hypoxia (1% oxygen,“ischemia”) for 24 hours optionally followed by exposure to 21% oxygen (“reperfusion”) for 30 minutes. FIG. 8C is a graph showing the effect of the same infrared light on the induction of TGF-b I in macrophages exposed to hypoxia (1% oxygen,“ischemia”) for 24 hours optionally followed by exposure to 21% oxygen (“reperfusion”) for 3 hours. The control group did not undergo hypoxia.

[0049] FIGS. 9A-9B are graphs showing the effect of infrared light at the wavelength of 810 nm or 750 nm in combination with 950 nm on the generation of mitochondrial superoxide (FIG. 9A) and the mitochondrial membrane potential (FIG. 9B) in fibroblasts co-cultured with macrophages exposed to hypoxia (1% oxygen,“ischemia”) for 24 hours optionally followed by exposure to 21% oxygen (“reperfusion”) for 30 minutes. FIGS. 9C-9E are graphs showing the effect of the same infrared light on the induction of adhesion markers VEGF (FIG. 9C), COLlal (FIG. 9D), and TGF-b I (FIG. 9E) in a co-culture of fibroblasts and macrophages exposed to hypoxia (1% oxygen,“ischemia”) for 24 hours optionally followed exposure to by 21% oxygen (“reperfusion”) for 3 hours. The control group did not undergo hypoxia.

[0050] FIGS. 10A-10B are graphs showing the effect of infrared light at the wavelength of 810 nm or 750 nm in combination with 950 nm on the generation of mitochondrial superoxide (FIG. 10A) and the mitochondrial membrane potential (FIG. 10B) in fibroblasts exposed to hyperoxia (40% oxygen) for 30 minutes. FIGS. 10C-10E are graphs showing the effect of the same infrared light on the induction of adhesion markers VEGF (FIG. 10C), COLlal (FIG. 10D), and TGF-b! (FIG. 10E) in fibroblasts exposed to hyperoxia (40% oxygen) for 3 hours. The control group did not undergo hyperoxia.

[0051] FIGS. 11A-11C are graphs showing the effect of infrared light at the wavelength of 810 nm or 750 nm in combination with 950 nm on the generation of mitochondrial superoxide (FIG. 11 A) and release of transforming growth factor beta- 1 (TGF-b 1) (FIG. 11B) and interleukin- lbeta ( I L- 1 b) (FIG. 11C) from macrophages activated by lipopolysaccharide (LPS). [0052] FIG. 12 is a graph showing the activity of CcO from peritoneum tissue following introduction of mechanical and thermal stress on two rat adhesion models.

[0053] FIG. 13 are representative pictures of gross abdominal specimens (top panel), Haemotoxylin and Eosin (H&E) staining of the interface of normal tissue-adhesion tissue bridge, and immuno-fluorescence for TGF-bI (lower panel) in a region of inflammation and adhesion formation of animals irradiated with infrared light at 810 nm (middle column), the animals irradiated with infrared light at 750 nm and 950 nm (right column), or the control animals. In the top panel,“1” indicates left hom of the uterus;“f’ indicates filmy adhesion;“a” and arrow heads indicates very thick and extensive adhesions;“w” indicates peritoneum of the anterior abdominal wall; and indicates no adhesion at the site of surgical intervention.

[0054] FIGS. 14A-14C are graphs illustrating further analysis of tissue adhesion in the animal model. FIG. 14A shows the number of adhesions in the animals irradiated with infrared light at 810 nm, the animals irradiated with infrared light at 750 nm and 950 nm, or the control animals. FIG. 14B shows the severity of the adhesions using the Mazuji scoring system. FIG. 14C shows the severity of fibrosis assessed by microscopic examination of the H&E staining of the interface of normal tissue-adhesion tissue bridge.

[0055] FIG. 15 illustrates an exemplary flowchart of a process to reduce the tissue adhesion following a surgical procedure.

[0056] FIG. 16 illustrates an exemplary flowchart of a process that may be used to design a device configured to inhibit tissue adhesion, such as the exemplary light therapy apparatus illustrated in FIGS. 1A-1D.

DETAILED DESCRIPTION

I. Definitions

[0057] As used herein, the term“about,” when used to modify a numeric value of wavelength, indicates deviations of up to 1% above and up to 1% below a given value.

[0058] As used herein, the terms“subject” and“patient” refer to an organism to be treated by the methods and compositions described herein. Such organisms preferably include, but are not limited to, mammals ( e.g ., murines, simians, equines, bovines, porcines, canines, felines, and the like), and more preferably includes humans. [0059] As used herein, the term“substantially free,” when used to describe the presence or absence of a wavelength or a range of wavelength(s), indicates that the intensity of the light at the specified wavelength or the average intensity of the light in the specified range of wavelengths is no greater than 10% of the intensity of the light at 750 nm or 950 nm, whichever is greater.

II. Therapeutic Methods

[0060] The present disclosure is based, in part, upon the identification of infrared light at specific wavelengths that reduces tissue adhesion and wound tissue fibrosis, as well as the identification of infrared light at other specific wavelengths that impairs the reduction of tissue adhesion and wound tissue fibrosis and should be avoided when treating these diseases or conditions.

[0061] Accordingly, in one aspect, the present disclosure provides a method of reducing tissue adhesion at a location in a subject in need thereof, the method comprising applying light to tissue susceptible to tissue adhesion at the location of the subject, wherein the light has a first wavelength in the range of 730-770 nm and/or a second wavelength in the range of 930-970 nm, thereby reducing tissue adhesion in the tissue.

[0062] In another aspect, the present disclosure provides a method of reducing scar formation at a location in a subject in need thereof, the method comprising applying light to a tissue susceptible to scar formation at the location of the subject, wherein the light has a first wavelength in the range of 730-770 nm and/or a second wavelength in the range of 930-970 nm, thereby reducing scar formation in the tissue.

[0063] In another aspect, the present disclosure provides a method of promoting wound healing at a location in a subject in need thereof, the method comprising applying light to wounded tissue at the location of the subject, wherein the light has a first wavelength in the range of 730- 770 nm and/or a second wavelength in the range of 930-970 nm, thereby promoting wound healing in the tissue.

[0064] In certain embodiments, the light has a wavelength in the range of 730-770 nm. Accordingly, the present disclosure provides a method of reducing tissue adhesion at a location in a subject in need thereof, the method comprising applying light to tissue susceptible to tissue adhesion at the location of the subject, wherein the light has a wavelength in the range of 730-770 nm, thereby reducing tissue adhesion in the tissue. In addition, the present disclosure provides a method of reducing scar formation at a location in a subject in need thereof, the method comprising applying light to tissue susceptible to scar formation at the location of the subject, wherein the light has a wavelength in the range of 730-770 nm, thereby reducing scar formation in the tissue. In addition, the present disclosure provides a method of promoting wound healing at a location in a subject in need thereof, the method comprising applying light to wounded tissue at the location of the subject, wherein the light has a wavelength in the range of 730-770 nm, thereby promoting wound healing in the tissue.

[0065] In certain embodiments, the light has a wavelength in the range of 930-970 nm. Accordingly, the present disclosure provides a method of reducing tissue adhesion at a location in a subject in need thereof, the method comprising applying light to tissue susceptible to tissue adhesion at the location of the subject, wherein the light has a wavelength in the range of 930-970 nm, thereby reducing tissue adhesion in the tissue. In addition, the present disclosure provides a method of reducing scar formation at a location in a subject in need thereof, the method comprising applying light to tissue susceptible to scar formation at the location of the subject, wherein the light has a wavelength in the range of 930-970 nm, thereby reducing scar formation in the tissue. In addition, the present disclosure provides a method of promoting wound healing at a location in a subject in need thereof, the method comprising applying light to wounded tissue at the location of the subject, wherein the light has a wavelength in the range of 930-970 nm, thereby promoting wound healing in the tissue.

[0066] In certain embodiments, the light has a first wavelength in the range of 730-770 nm and a second wavelength in the range of 930-970 nm. Accordingly, the present disclosure provides a method of reducing tissue adhesion at a location in a subject in need thereof, the method comprising applying light to tissue susceptible to tissue adhesion at the location of the subject, wherein the light has a first wavelength in the range of 730-770 nm and a second wavelength in the range of 930-970 nm, thereby reducing tissue adhesion in the tissue. In addition, the present disclosure provides a method of reducing scar formation at a location in a subject in need thereof, the method comprising applying light to tissue susceptible to scar formation at the location of the subject, wherein the light has a first wavelength in the range of 730-770 nm and a second wavelength in the range of 930-970 nm, thereby reducing scar formation in the tissue. In addition, the present disclosure provides a method of promoting wound healing at a location in a subject in need thereof, the method comprising applying light to wounded tissue at the location of the subject, wherein the light has a first wavelength in the range of 730-770 nm and a second wavelength in the range of 930-970 nm, thereby promoting wound healing in the tissue.

[0067] In certain embodiments, the wavelength in the range of 730-770 nm, also referred to herein as the first wavelength, is in the range of 735-765 nm, 740-760 nm, or 745-755 nm. In certain embodiments, the first wavelength is about 750 nm. In certain embodiments, the light has a wavelength of 745 nm, 746 nm, 747 nm, 748 nm, 749 nm, 750 nm, 751 nm, 752 nm, 753 nm, 754 nm, or 755 nm. In certain embodiments, the first wavelength is a peak wavelength. Accordingly, in certain embodiments, the light has a peak wavelength ( e.g ., a first peak wavelength) in the range of 730-770 nm, 735-765 nm, 740-760 nm, or 745-755 nm. In certain embodiments, the light has a peak wavelength (e.g., a first peak wavelength) of about 750 nm. In certain embodiments, the light has a peak wavelength (e.g., a first peak wavelength) of 745 nm, 746 nm, 747 nm, 748 nm, 749 nm, 750 nm, 751 nm, 752 nm, 753 nm, 754 nm, or 755 nm.

[0068] In certain embodiments, the wavelength in the range of 930-970 nm, referred to herein as the second wavelength, is in the range of 935-965 nm, 940-960 nm, 935-955 nm, 940-950 nm, or 945-955 nm. In certain embodiments, the second wavelength is about 940 nm to about 950 nm. In certain embodiments, the second wavelength is about 950 nm. In certain embodiments, the second wavelength is about 940 nm. In certain embodiments, the light has a wavelength of 935 nm, 936 nm, 937 nm, 938 nm, 939 nm, 940 nm, 941 nm, 942 nm, 943 nm, 944 nm, 945 nm, 946 nm, 947 nm, 948 nm, 949 nm, 950 nm, 951 nm, 952 nm, 953 nm, 954 nm, or 955 nm. In certain embodiments, the second wavelength is a peak wavelength. Accordingly, in certain embodiments, the light has a peak wavelength (e.g., a second peak wavelength) in the range of 930-970 nm, 935- 965 nm, 940-960 nm, 935-955 nm, 940-950 nm, or 945-955 nm. In certain embodiments, the light has a peak wavelength (e.g., a second peak wavelength) in the range of about 940 nm to about 950 nm. In certain embodiments, the light has a peak wavelength (e.g., a second peak wavelength) of about 940 nm. In certain embodiments, the light has a peak wavelength (e.g., a second peak wavelength) of about 950 nm. In certain embodiments, the light has a peak wavelength (e.g., a second peak wavelength) of 935 nm, 936 nm, 937 nm, 938 nm, 939 nm, 940 nm, 941 nm, 942 nm, 943 nm, 944 nm, 945 nm, 946 nm, 947 nm, 948 nm, 949 nm, 950 nm, 951 nm, 952 nm, 953 nm, 954 nm, or 955 nm.

[0069] In certain embodiments, the light is substantially free of a wavelength of 810 nm. In certain embodiments, the light is substantially free of a wavelength of 808 nm. In certain embodiments, the light is substantially free of a wavelength of 830 nm. In certain embodiments, the light is substantially free of any wavelength in the range of 800-810 nm, 800-820 nm, 810- 820 nm, 810-830 nm, 800-830 nm, or 795-835 nm.

[0070] Effective treatment of the tissue requires application of a proper power density of the light at the tissue. The power density at the tissue may differ from the power density of the light source in view of many factors such as the distance of the light source from the tissue, the convergence or divergence of the light, the depth of the tissue under the site where the light enters the body ( e.g ., skin), and the penetration of the light through the body before reaching the tissue. In certain embodiments, the light has a power density greater than or equal to 1 pW/cm ² , 0.01 mW/cm ² , 0.02 mW/cm ² , 0.05 mW/cm ² , 0.1 mW/cm ² , 0.2 mW/cm ² , 0.5 mW/cm ² , or 1 mW/cm ² at the tissue. The power density also needs to be low enough such that it does not cause thermal injury by substantially increasing the tissue temperature. In certain embodiments, the light has a power density lower than or equal to 20 mW/cm ² , 15 mW/cm ² , 10 mW/cm ² , 5 mW/cm ² , 3 mW/cm ² , 2 mW/cm ² , or 1 mW/cm ² at the tissue. Depending upon the circumstances, the light has a power density in the range of 1 pW/ cm ² to 5 mW/cm ² , 1 pW/ cm ² to 1 mW/cm ² , 1 pW/ cm ² to 0.5 mW/cm ² , 1 pW/ cm ² to 0.2 mW/cm ² , 1 pW/ cm ² to 0.1 mW/cm ² , 1-50 pW/ cm ² , 1-20 pW/ cm ² , 1-10 pW/ cm ² , 1-5 pW/ cm ² , 0.5-20 mW/cm ² , 1-15 mW/cm ² , 2-10 mW/cm ² , 0.01-5 mW/cm ² , 0.01-1 mW/cm ² , 0.01-0.5 mW/cm ² , 0.01-0.2 mW/cm ² , 0.01-0.1 mW/cm ² , 0.01-0.05 mW/cm ² , 0.1- 5 mW/cm ² , 0.1-1 mW/cm ² , 0.1-0.5 mW/cm ² , 0.1-0.2 mW/cm ² , 1-5 mW/cm ² , or 1-3 mW/cm ² at the tissue. In certain embodiments, the light has a power density in the range of 3-5 mW/cm ² at the tissue. The tissue may have a large size (e.g., having a dimension of at least 5 mm, 1 cm, 2 cm, 5 cm, 10 cm, or 20 cm), and the power density on the tissue may be uneven. Accordingly, in certain embodiments, the light has an average power density in the range of 0.5-20 mW/cm ² , 1-15 mW/cm ² , 2-10 mW/cm ² , 1 pW/ cm ² to 5 mW/cm ² , 1 pW/ cm ² to 1 mW/cm ² , 1 pW/ cm ² to 0.5 mW/cm ² , 1 pW/ cm ² to 0.2 mW/cm ² , 1 pW/ cm ² to 0.1 mW/cm ² , 1-50 pW/ cm ² , 1-20 pW/ cm ² , 1-10 pW/ cm ² , 1-5 pW/ cm ² , 0.01-5 mW/cm ² , 0.01-1 mW/cm ² , 0.01-0.5 mW/cm ² , 0.01-0.2 mW/cm ² , 0.01-0.1 mW/cm ² , 0.01-0.05 mW/cm ² , 0.1-5 mW/cm ² , 0.1-1 mW/cm ² , 0.1-0.5 mW/cm ² , 0.1-0.2 mW/cm ² , 1-5 mW/cm ² , or 1-3 mW/cm ² at the tissue. In certain embodiments, the light has an average power density in the range of 3-5 mW/cm ² at the tissue.

[0071] In certain embodiments, the light is generated by one or more light emitting diodes (LEDs), lasers, laser diodes, or a combination thereof. In certain embodiments, the light is generated by one or more LEDs. In certain embodiments, the light is generated by one or more lasers. In certain embodiments, the light is generated by one or more laser diodes. In certain embodiments, the light is generated by a combination of a laser and a laser diode, a laser and an LED, or a laser diode and an LED. The LEDs, lasers, and/or laser diodes can be used in any manner suitable for the treatment. For example, in certain embodiments, a plurality of LEDs, lasers, and/or laser diodes are arranged in an array to produce convergent or divergent light.

[0072] In certain embodiments, the one or more LEDs, lasers, and/or laser diodes emit light having one or more wavelengths comprising a first wavelength in the range of 730-770 nm and/or a second wavelength in the range of 930-970 nm. The embodiments of wavelengths described supra in the context of applying light to a tissue also apply herein. In certain embodiments, the first wavelength ( e.g ., the first peak wavelength) is in the range of 735-765 nm, 740-760 nm, or 745-755 nm. In certain embodiments, the first wavelength (e.g. , the first peak wavelength) is about 750 nm. In certain embodiments, the second wavelength (e.g., the second peak wavelength) is in the range of 935-965 nm, 940-960 nm, 935-955 nm, 940-950 nm, or 945-955 nm. In certain embodiments, the second wavelength (e.g., the second peak wavelength) is in the range of about 940 nm to about 950 nm. In certain embodiments, the second wavelength (e.g., the second peak wavelength) is about 940 nm. In certain embodiments, the second wavelength (e.g., the second peak wavelength) is about 950 nm. In certain embodiments, the light generated by the LEDs, lasers, and/or laser diodes is substantially free of a wavelength of 808 nm, 810 nm, 830 nm, or any wavelength in the range of 800-810 nm, 800-820 nm, 810-820 nm, 810-830 nm, 800-830 nm, or 795-835 nm.

[0073] In certain embodiments, each LED, laser, or laser diode has a power output of up to 20 Watts. For example, each LED, laser, or laser diode has a power output independently selected from one of the following ranges: 1-20 Watts, 1-15 Watts, 1-10 Watts, 1-5 Watts, 5-20 Watts, 5- 15 Watts, 5-10 Watts, 10-20 Watts, 10-15 Watts, and 15-20 Watts.

[0074] In certain embodiments, each LED, laser, or laser diode has a power density at the light delivery surface in the range of 50 mW/cm ² to 2 W/cm ² . In certain embodiments, each LED, laser, or laser diode has a power density at the light delivery surface in the range of 100 mW/cm ² to 1 W/cm ² . In certain embodiments, each LED, laser, or laser diode has a power density at the light delivery surface in the range of 200-800 mW/cm ² . In certain embodiments, each LED, laser, or laser diode has a power density at the light delivery surface of about 50, 100, 200, 400, or 800 mW/cm ² . In certain embodiments, the power density at the light delivery surface is an average power density at the light delivery surface of the LEDs, lasers, and/or laser diodes.

[0075] In certain embodiments, the LEDs, lasers, and/or laser diodes are enclosed in a device that emits light. In certain embodiments, the device has a power density at the light delivery surface in the range of 50 mW/cm ² to 2 W/cm ² . In certain embodiments, the device has a power density at the light delivery surface in the range of 100 mW/cm ² to 1 W/cm ² . In certain embodiments, the device has a power density at the light delivery surface in the range of 200-800 mW/cm ² . In certain embodiments, the device has a power density at the light delivery surface of about 50, 100, 200, 400, or 800 mW/cm ² . In certain embodiments, the power density at the light delivery surface is an average power density at the light delivery surface of the device.

[0076] In certain embodiments, the light is applied to the tissue for at least 30 minutes, at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, or at least 8 hours. In certain embodiments, the light is applied to the tissue for at least 2 hours. In certain embodiments, the light is applied substantially continuously at a one-time basis.

[0077] The susceptibility to tissue adhesion, the susceptibility to scar formation, or the wound can be caused by a surgery (e.g., an open surgery or a laparoscopic surgery). In certain embodiments, the light is applied to the tissue during and/or after the surgery. For example, in certain embodiments, the light is applied during the surgery. In certain embodiments, the light is applied to the tissue immediately after (e.g., within 15 minutes, 30 minutes, 1 hour, or 2 hours after) the surgery. In certain embodiments, the light is applied to the tissue within 12 hours after (e.g., within 10 hours, 8 hours, 6 hours, 4 hours, or 3 hours after) the surgery. It is noted, however, that application of the light may be limited to the medical conditions of the subject. For example, certain subjects may need to receive another medical intervention after the surgery, which may render it impractical to apply the light immediately. In such circumstances, it is contemplated that the light is applied to the subject immediately after (e.g., within 15 minutes, 30 minutes, 1 hour, or 2 hours after) the light therapy is practically compatible with the treatment or recovery of the subject. In certain embodiments, the light is applied to the tissue within 12 hours after (e.g., within 10 hours, 8 hours, 6 hours, 4 hours, or 3 hours after) the light therapy is practically compatible with the treatment or recovery of the subject. In certain embodiments, the light is applied to the tissue both during the surgery and after (e.g., immediately after) the surgery. [0078] Alternatively or additionally, the susceptibility to tissue adhesion, the susceptibility to scar formation, or the wound can be caused by an injury. In certain embodiments, the light is applied to the tissue immediately after ( e.g ., within 15 minutes, 30 minutes, 1 hour, or 2 hours after) the injury. In certain embodiments, the light is applied to the tissue within 12 hours after (e.g., within 10 hours, 8 hours, 6 hours, 4 hours, or 3 hours after) the injury. In certain embodiments, the light is applied to the tissue immediately after (e.g., within 15 minutes, 30 minutes, 1 hour, or 2 hours after) the subject who suffers from the injury is available for treatment. In certain embodiments, the light is applied to the tissue within 12 hours after (e.g., within 10 hours, 8 hours, 6 hours, 4 hours, or 3 hours after) the subject who suffers from the injury is available for treatment. In certain embodiments, the light is applied to the tissue prior to a medical treatment (e.g., a surgery), for example, while the subject is waiting for the medical treatment.

[0079] The light can be applied in any manner suitable for the surgery and/or the recovery after the surgery or injury. For example, in certain embodiments, in an open surgery, the light is applied from a fixed light source (e.g., a surgical lamp), optionally through a light guide (e.g., a glass, plastic, liquid, or optical fiber light guide). In certain embodiments, in a laparoscopic surgery, the light is applied through a light guide (e.g., a glass, plastic, liquid, or optical fiber light guide) that transmits the light to the surgical site. In certain embodiments, after a surgery or injury, the light is applied from a light source attached to a medical bed directly or through a light guide (e.g., a glass, plastic, liquid, or optical fiber light guide). In certain embodiments, after a surgery or injury, the light is applied from a portable light source, such as a handheld device or a light- emitting blanket (e.g., an LED blanket).

[0080] Any tissue can be treated with the light, including but not limited to skin (e.g., epidermis, dermis, and/or hypodermis), a tissue in the thoracic cavity, and a tissue in the abdominopelvic cavity. In certain embodiments, the tissue comprises an abdominal tissue. In certain embodiments, the tissue comprises a uterus (e.g., a uterus subject to a caesarean section).

[0081] Fibrosis, which leads to overgrowth, hardening, and/or scarring of fibrous connective tissues, is often undesirable in recovery from surgery or injury. In certain embodiments, the method disclosed herein reduces fibrosis in the tissue. Various adhesion markers can be used to assess fibrosis, including but not limited to transforming growth factor beta 1 (TGE-b I ), vascular endothelial growth factor (VEGF), and collagen alpha- 1(1) chain (COLlal). Accordingly, in certain embodiments, the method reduces the amounts of one or more adhesion markers in the tissue, the one or more adhesion markers selected from the group consisting of TGF-b 1 , VEGF, COLlal, and a combination thereof. The light may reduce fibrosis by modulating one or more copper-containing enzymes, such as cytochrome c oxidase (CcO), lysyl oxidase (LOX), or superoxide dismutase CuZnSOD. For example, the effect of the light on fibrosis is correlated, at least in part, with the effect of the light on the activity of CcO. Accordingly, in certain embodiments, the method reduces the activity of CcO in the tissue.

III. Therapeutic Devices

[0082] The present disclosure also provides a therapeutic device suitable for reducing tissue adhesion in a subject, the device comprising a light source emitting light having a first wavelength in the range of 730-770 nm and/or a second wavelength in the range of 930-970 nm. In addition, the present disclosure provides a therapeutic device suitable for reducing scar formation in a subject, the device comprising a light source emitting light having a first wavelength in the range of 730-770 nm and/or a second wavelength in the range of 930-970 nm. In addition, the present disclosure provides a therapeutic device suitable for promoting wound healing in the subject, the device comprising a light source emitting light having a first wavelength in the range of 730-770 nm and/or a second wavelength in the range of 930-970 nm.

[0083] The embodiments of wavelengths described in Section II (Therapeutic Methods) also apply herein. For example, in certain embodiments, the light has a wavelength ( e.g ., a peak wavelength) in the range of 730-770 nm. In certain embodiments, the light has a wavelength (e.g. , a peak wavelength) in the range of 930-970 nm. In certain embodiments, the light has a first wavelength (e.g., a first peak wavelength) in the range of 730-770 nm and a second wavelength (e.g., a second peak wavelength) in the range of 930-970 nm. In certain embodiments, wavelength in the range of 730-770 nm, referred to as the first wavelength herein, is about 750 nm. In certain embodiments, wavelength in the range of 930-970 nm, referred to as the second wavelength herein, is in the range of about 940 nm to about 950 nm. In certain embodiments, the second wavelength is about 940 nm. In certain embodiments, the second wavelength is about 950 nm. In certain embodiments, the light is substantially free of any wavelength in the range of 795-835 nm. In certain embodiments, the light is substantially free of a wavelength of 808 nm and/or 810 nm.

[0084] In certain embodiments, the light source comprises one or more LEDs, lasers, and/or laser diodes. In certain embodiments, the one or more LEDs, lasers, and/or laser diodes emit light having one or more wavelengths comprising a first wavelength in the range of 730-770 nm and/or a second wavelength in the range of 930-970 nm. The embodiments of wavelengths supra in the context of describing the light also apply herein. In certain embodiments, the light source has a power density, at the light delivery surface, in the range of 50 mW/cm ² to 2 W/cm ² . In certain embodiments, each LED, laser, or laser diode has a power density at the light delivery surface in the range of 100 mW/cm ² to 1 W/cm ² . In certain embodiments, each LED, laser, or laser diode has a power density at the light delivery surface in the range of 200-800 mW/cm ² . In certain embodiments, each LED, laser, or laser diode has a power density at the light delivery surface of about 50, 100, 200, 400, or 800 mW/cm ² . In certain embodiments, the power density is an average power density of the LEDs, lasers, and/or laser diodes at the light delivery surface.

[0085] It is understood that the power density of the therapeutic device can be measured at the light delivery surface of the device, for example, a light outlet end (see, for example, 165 in FIG. 1C). In certain embodiments, the therapeutic device has a power density at the light delivery surface in the range of 50 mW/cm ² to 2 W/cm ² . In certain embodiments, the therapeutic device has a power density at the light delivery surface in the range of 100 mW/cm ² to 1 W/cm ² . In certain embodiments, the therapeutic device has a power density at the light delivery surface in the range of 200-800 mW/cm ² . In certain embodiments, the therapeutic device has a power density at the light delivery surface of about 50, 100, 200, 400, or 800 mW/cm ² . In certain embodiments, the power density at the light delivery surface is an average power density at the light delivery surface of the therapeutic device.

[0086] The therapeutic device can be configured in any form suitable for the surgery and/or the recovery after the surgery or injury. For example, in certain embodiments, the therapeutic device is suitable for use in an open surgery and comprises a fixed light source ( e.g ., a surgical lamp), optionally further comprising a light guide (e.g., a glass, plastic, liquid, or optical fiber light guide). In certain embodiments, the therapeutic device is suitable for use in a laparoscopic surgery and comprises a light source and a light guide (e.g., a glass, plastic, liquid, or optical fiber light guide) capable of transmitting the light to the surgical site. In certain embodiments, the therapeutic device is suitable for use after a surgery or injury and comprises a light source that can be attached to a medical bed directly or through a light guide (e.g., a glass, plastic, liquid, or optical fiber light guide). In certain embodiments, the therapeutic device is suitable for use after a surgery or injury, and comprises a portable light source, such as a handheld device or a light-emitting blanket (e.g., an LED blanket). [0087] It is disclosed herein that light at the wavelength of 810 nm, 808 nm, or 830 nm or having any wavelength in the range of 800-810 nm, 800-820 nm, 810-820 nm, 810-830 nm, 800- 830 nm, or 795-835 nm may be undesirable for recovery from surgery or injury. Light at such wavelengths can be removed by selecting a light source that is substantially free of the wavelengths. Alternatively or additionally, light at such wavelengths can be removed by one or more optical filters. Accordingly, in certain embodiments, the therapeutic device further comprises one or more optical filters that reduce the transmission of light at an undesirable wavelength by at least 50%, 60%, 70%, 80%, 90%, 95%, or 99%.

[0088] FIG. 1A illustrates an exemplary light therapy device 100 that may be used to directly or indirectly inhibit cytochrome c oxidase (CcO, sometimes also abbreviated as COX) and decrease mitochondrial membrane potential using infrared light, and thus reduce reactive oxygen species (ROS) formation and the inflammatory response in macrophages and the conversion to adhesion phenotype in fibroblasts. The light therapy device 100 includes at least one light source 105 configured to emit light at a wavelength that inhibits CcO when the light is applied to an area of tissue before, during, and/or after a surgical procedure. The light source 105 may include a light emitting diode (LED), a laser diode, optical fibers, or any other source that is configured to emit light with a wavelength that, for instance, directly or indirectly inhibits CcO when applied during a surgical procedure prior to the formation of tissue adhesion, and when applied after the surgical procedure as well. For instance, the light source 105 may include any light source 105 that is configured to output light with a wavelength of 750 nm, 870 nm, 900 nm, 940 nm, 945 nm, or 950 nm. Other light sources 105 may include quadruple diodes or a combination of individual wavelength diodes. Further, the light sources 105 may be high power or low power. The type of light source 105 may depend upon the application. For instance, optical fibers may be used to deliver light to areas of the body that may be difficult to reach with larger light sources and thus provide infrared treatment through the mouth, ears, nose, etc. In one example, diodes may be cooled during use, and before the next use, to avoid localized tissue heating that could have adverse consequences.

[0089] The light therapy device 100 may include any number of light sources 105, for instance, arranged in an array such as a diode array or a fiber optic array. Each of the light sources 105 in the array may output light with one of the wavelengths that inhibit CcO. In one exemplary implementation, some of the light sources 105 in the array may output light with one wavelength while other light sources 105 in the array may output light with a different wavelength. Therefore, the light sources 105 in combination may output light having multiple wavelengths that inhibit CcO and reduce tissue adhesion.

[0090] Moreover, the light sources 105 are configured to output light with a power density that is sufficient to at least partially penetrate one or more body tissues such as skin, bone, muscle tissue, and organs. In one exemplary approach, each light source 105 is configured to output light with a power density of at least approximately 200 mW/cm ² at the light delivery surface. For instance, each light source 105 is configured to output light with a power density of at least approximately 800 mW/cm ² at the light delivery surface when used with an adult human, and up to 0.01-0.1 mW/cm ² , 0.1-1 mW/cm ² , 0.5-5 mW/cm ² , or 3-5 mW/cm ² at the tissue in some applications. Alternatively, in another example, if the light therapy device 100 is used with, for example, a neonate (i.e., a newborn of approximately four weeks or less), the power density may be lower. One or more of the light sources 105 in the array may have a different power density than one or more of the other light sources 105 in the array. Further, the power density of each light source 105 is related to the wavelength of light generated by the light source 105. Therefore, light sources 105 generating light with the same wavelength are output with the same power density while light sources 105 generating light at different wavelengths may be output with different power densities. However, it is contemplated that the light sources in this and all disclosed exemplary embodiments may range in power output density up to 0.01-0.1 mW/cm ² , 0.1-1 mW/cm ² , 0.5-5 mW/cm ² , or 3-5 mW/cm ² at the tissue.

[0091] The light therapy device 100 further includes a portion, such as a handle 110, that houses various electronics that allow the light sources 105 to operate correctly. For instance, the handle 110 may include one or more processors and circuit boards that control operation of the light sources 105, including enabling and disabling the light sources 105, adjusting the brightness of the light sources 105, etc. Alternatively, some of the electronics used to operate the light sources 105 may be housed in a separate device other than the light therapy device 100.

[0092] The light therapy device 100 illustrated is merely exemplary and may take other forms. For instance, the light therapy device may be incorporated into a helmet for brain treatments, a catheter for combined clot removal and infrared light treatment, a mouthpiece or toothbrush to treat dental/gum disorders, a massage device, diabetic socks or slippers, a headband to treat headaches, an eye mask to treat eye diseases, a glove to treat gout or arthritis, a laser pointer to treat locally (e.g., a cold sore), a cushion, a blanket, a belt, a foot bath, a belly belt to help, for example, women at risk for preterm birth, a back belt to treat back pain, or an infrared pill charged via induction to treat intestinal diseases, a tanning booth for cosmetic purposes (e.g., wrinkle reduction), an endoscopic device to be applied during minimal-invasive surgery, etc. The light therapy device 100 may be further configured to perform other tasks than described. For instance, the light therapy device 100 may be configured to act as an oximeter and monitor oxygen. Alternatively, the light therapy device 100 may be configured to work with one or more oximeters. If so, the light therapy device 100 may include a controller that prevents light used during treatment from interfering with light used to measure oxygen saturation.

[0093] Apparatus 115 of FIG. 1B includes 4 generally planar support structures 120 applicable for relatively higher power treatments such as up to 20 Watts, for example, up to 5 Watts. Each planar structure 120 includes a respective LED or laser diode array 125, and each diode array 125 may include a mix of LEDs or laser diodes having ranges of 730-770 nm and/or 930-970 nm as described. In such an example, LEDs or laser diodes may be individually turned on and off, such that specific ranges of wavelengths may be individually applied (such as, for instance LEDs or laser diodes having the range of 730-770 nm or LEDs or laser diodes having the range of 930-970 nm). In such fashion, any combination of ranges of wavelengths may be applied by selectively applying one or more wavelengths from one or more of the diode arrays 125.

[0094] In another example, diode arrays 125 may each be dedicated to one of the wavelength ranges 730-770 nm and 930-970 nm. Thus, in this example, one of the arrays 125 may have only LEDs or laser diodes having 730-770 nm as a wavelength, another array 125 may have only LEDs or laser diodes having 930-970 nm. Further, it is contemplated that each support structure 120 may be aimed toward a common focal point 130. In such fashion, apparatus 115 may be manipulated, with individual LEDs or laser diodes within arrays 125 and controllable by a controller 135, such that focal point 130 may be positioned on a subject or proximate to a subject for optimal wavelength delivery for treatment. Each structure 120 also includes, in the illustrated example, heat transfer fins 140 that serve to assist in transferring heat from diode arrays 125 during operation, to prevent self-overheating, as well as avoiding injury to a subject due to radiative or convective heat from the hot diode arrays 125.

[0095] According to another exemplary embodiment, an apparatus 150 illustrated in FIG. 1C includes a fiber optic light guide 155 that is supported by a support structure 160. Apparatus 150 is thereby positionable such that one or more LEDs or laser diodes may be positioned at an input end, the light being guided down light guide 155 to an outlet end 165, such that light can be selectively delivered while having the LEDs or laser diodes positioned at a distance. In such fashion, the light can be guided and positioned readily and without having the LEDs or laser diodes proximate to the subject, thus avoiding injury to a subject due to radiative or convective heat from the hot LEDs or laser diodes. A controller, such as controller 135 of FIG. 1B, may likewise be arranged to selectively operate the LEDs or laser diodes. Apparatus 150 may be applicable for more directed treatments, such as for neonates, such that wavelength(s) can be directed toward very specific areas.

[0096] According to another exemplary embodiment, an apparatus 170 illustrated in FIG. 1D includes one or more LEDs or laser diodes 175 positioned on a heat sink 180. A fan 185 is positioned at an end of apparatus 170 that is opposite the one or more LEDs or laser diodes 175. The one or more LEDs or laser diodes 175 may be positioned on a plate 190 having perforations 195, such that air flow may be caused to pass within apparatus 170, passing into perforations 195 and through cavities (not shown) within heat sink 180, cooling the one or more LEDs or laser diodes 175 to prevent self-overheating, as well as avoiding injury to a subject due to radiative or convective heat from the hot one or more LEDs or laser diodes 175. A controller, such as controller 135 of FIG. 1B, may likewise be arranged to selectively operate the LEDs or laser diodes. Apparatus 170 may be used for high power applications, such as 5 Watts or even more, as the combination of heat sink 180 with fan 185 direct air and heat away from the LEDs or laser diodes and in a direction opposite from a subject receiving treatment.

[0097] FIG. 2 illustrates an exemplary model showing tissue adhesion formation resulting from a surgery. At Block 200, tissue undergoing surgery or subject to a surgical procedure acquires an injury as a result of the surgery. Due to the injury and at least partially based on tissue hypoxie, anaerobic metabolism and an increase in oxidative stress (Block 205), the ROS formation increases (Block 210). The increase in ROS formation leads to a number of results. In one result, the increase in ROS formation leads to an increase in vascular endothelial growth factor (VEGF) (Block 215) that leads to a further increase in the tissue inhibitor matrix metalloproteinases (Block 220), which contributes to adhesion formation (Block 225). [0098] In another result, the increase in ROS formation leads to an increase in tumor necrosis factor alpha (Block 230) that leads to a decrease in tissue plasminogen activator (Block 235), which leads to a decrease in fibrinolysis (Block 240) and contribution to adhesion formation (Block 225).

[0099] In another result, the increase in ROS formation leads to an increase in transforming growth factor beta-l (TGF-b I ) (Block 245) that leads to an increase in collagen I (Block 250) and an increase in extracellular matrix deposition (Block 255), which contributes to adhesion formation (Block 225). The increase in TGF-b 1 (Block 245) also leads to an increase in cyclooxegenase-2 and prostaglandin E2 (Block 260) and to a decrease in matrix metalloproteinases 1,2,9 (Block 265), which both contribute to a decrease in extracellular matrix degradation (Block 270) and adhesion formation (Block 225).

[0100] According to disclosed examples described herein, application of infrared light (IRL) to the tissue negates at least some of the effects of the surgical tissue injury illustrated in FIG. 2.

EXAMPLES

[0101] The following Examples are merely illustrative and are not intended to limit the scope or content of the disclosure in any way.

Example 1: Regulation of Cytochrome c Oxidase (CcO) Activity and Mitochondrial Membrane Potential by Infrared Light

[0102] This example shows the regulation of CcO activity and mitochondrial membrane potential by infrared light at the wavelengths of 750 nm, 810 nm, and/or 950 nm.

[0103] The effect of infrared light at selected wavelengths on CcO activity and mitochondrial respiration was assessed with purified CcO protein and isolated mitochondria. Briefly, CcO protein was purified, and mitochondria was isolated from bovine liver using the method described in Lee et al. (2005) J. Biol. Chem. 280(7):6094-6l00. The CcO protein and mitochondria were irradiated with infrared light at the wavelength of 750 nm, 950 nm, 750 nm plus 950 nm, and 810 nm using light sources with intensity of 15-23 mW. The power intensity of each light source can be adjusted to reach the same total intensity. CcO activity was measured by a polarographic method; mitochondrial oxygen consumption rate (OCR) was measured by a Clark oxygen electrode. The data were obtained over a 3-min interval of irradiation.

[0104] As shown in FIGS. 3A and 3B, individual wavelengths of 750 nm and 950 nm each inhibited CcO activity by about 5% and inhibited mitochondrial respiration by about 20%. Combination of the two wavelengths had an additive effect, reducing respiration in purified CcO and isolated mitochondria by about 10% and 30%, respectively. Infrared light at the wavelength of 810 nm had an opposite effect, increasing CcO activity and mitochondrial respiration. Similar results were obtained using higher power single-wavelength light-emitting diodes operated at a power density of 200 mW/cm ² .

[0105] The copper-containing catalytic subunits I and II, which absorb infrared light, are highly conserved from bacteria to humans. To verify the effect of infrared light in various species and tissue isoforms, mitochondria and CcO protein were purified from human liver, bovine heart, and several pig tissues. The inhibitory effect of infrared light at 750 nm and 950 nm and the excitatory effect of infrared light at 810 nm were observed with CcO from all these sources.

[0106] CcO contains two copper centers that may be differentially affected by infrared light. CU _A is located in the electron acceptor site of subunit II that binds cytochrome c. N,N,N',N'- tetramethyl-p-phenylenediamine (TMPD), an electron transfer catalyst that changes the CcO kinetics from biphasic to monophasic, was used to interrogate the effect of infrared light on CUA. Under physiological conditions, cytochrome c binds to and dissociates from CcO when it transports electrons. In the presence of TMPD, however, cytochrome c can stay bound to CcO while TMPD continuously feeds electrons into cytochrome c from the reductant ascorbate. Therefore, TMPD allows bypassing of cytochrome c association/dissociation cycles.

[0107] As shown in FIG. 4, 0.7 mM TMPD substantially reduced the inhibitory effect of infrared light at the combinational wavelengths of 750 nm and 950 nm. This result suggested that infrared light at 750 nm and/or 950 nm may inhibit CcO activity by modulating the interaction of CcO and cytochrome c through the CUA center next to the cytochrome c binding site.

[0108] CcO is a key protein in the mitochondrial electron transport chain, which produces a proton gradient for the generation of adenosine triphosphate (ATP). Therefore, regulation of CcO activity by infrared light may result in a change in mitochondrial membrane potential. Tetramethylrhodamine methyl ester (TMRM), a cationic dye that accumulates in negatively charged compartments, was used to measure mitochondrial membrane potential. Infrared light at the wavelength of 950 nm was applied for 2 minutes and subsequently withdrawn.

[0109] As shown in FIG. 5, mitochondrial membrane potential was reduced by infrared light at the wavelength of 950 nm and returned to control levels when irradiation was discontinued. In contrast, infrared light at the wavelength of 810 nm increased mitochondrial membrane potential.

Example 2: Regulation of Cellular Responses to Oxidative Stress and Inflammation by Infrared Light

[0110] This example shows the regulation of reactive oxygen species (ROS) production, mitochondrial membrane potential, and release of adhesion-related cytokines by infrared light at the wavelengths of 750 nm, 810 nm, and/or 950 nm.

[0111] The effect of infrared light on basal respiration rate was assessed with EL-l human macrophages, human primary neutrophils, and human primary fibroblasts under normal culture conditions. Human primary neutrophils were extracted from red cross blood filters via histopaque 1077 and 1119 density gradients (Swamydas et al. (2015) Isolation of Mouse Neutrophils, Curr Protoc Immunol, 110:3.20.1-3.20.15). Human primary fibroblasts were obtained from human buccal mucosa. The cells were cultured in modified glucose-free media containing 10 mM pyruvate and were exposed to infrared light at the wavelengths of 750 nm, 810 nm, 950 nm, or 750 nm in combination with 950 nm at the power density of 3 mW/cm ² . The rate of respiration was measured using a Clarke oxygen electrode.

[0112] As shown in FIG. 6A, macrophage respiration was increased by 810 nm irradiation, and decreased by 750 nm and/or 950 nm irradiation. Similar results were observed with primary fibroblasts (FIG. 6B) and primary neutrophils. Noteworthy, the combination of 750 nm and 950 nm irradiation resulted in an additive effect and reduced oxygen consumption rate by about 50% in the cell types tested.

[0113] Next assessed was the effect of infrared light on cellular responses to hypoxia. Human fibroblasts at about 80% confluence were incubated under 1% 0 ₂ + 5% C0 ₂ for 24 hours in a Biospherix X3 chamber (referred to as“ischemia” herein in the context of cell treatment), optionally followed by incubation under 21% 0 ₂ + 5% C0 ₂ (referred to as“reperfusion” herein in the context of cell treatment) for 30 minutes (for measuring superoxide and mitochondrial membrane potential) or 3 hours (for measuring cytokine release). The cells were exposed to infrared light at the wavelengths of 810 nm or 750 nm in combination with 950 nm at the power density of 3 mW/cm ² during reperfusion. Mitochondrial superoxide production was measured by fluorescent microscopy after staining the cells with the MitoSOX dye. Mitochondrial membrane potential was assessed by fluorescent microscopy after staining the cells with the JC-l dye. The supernatants of cell culture were collected for measuring the release of adhesion markers VEGF, COLlal, and TGF-pl by ELISA.

[0114] As shown in FIG. 7A, irradiation at a combination of 750 nm and 950 nm significantly reduced the level of mitochondrial superoxide of the cells undergoing ischemia and reperfusion, indicating that the infrared light decreased ROS production under both conditions. The infrared light at these wavelengths also significantly reduced mitochondrial membrane potential of the fibroblasts under both conditions (FIG. 7B). Additionally, this infrared light significantly reduced the production of VEGF, COLlal, and TGF-b 1 from the fibroblasts undergoing ischemia and reperfusion (FIGS. 7C-7E). In contrast, infrared light at 810 nm had the opposite effect (FIGS. 7A-7E).

[0115] The effect of infrared light on cellular responses to hypoxia was assessed in macrophages using the same methods. As shown in FIG. 8A, irradiation at a combination of 750 nm and 950 nm significantly reduced the level of mitochondrial superoxide of the cells undergoing ischemia and reperfusion, indicating that the infrared light decreased ROS production under both conditions. The infrared light at these wavelengths also significantly reduced mitochondrial membrane potential of the macrophages under both conditions (FIG. 8B). Additionally, this infrared light significantly reduced the production of TGF-b 1 from the macrophages undergoing ischemia and reperfusion (FIG. 8C). In contrast, infrared light at 810 nm generally had the opposite effect (FIGS. 8A-8C).

[0116] The effect of infrared light on cellular responses to hypoxia was also assessed in a co culture of fibroblasts and macrophages using the same methods. The fibroblasts were cultured at about 80% confluence in a 24 well plate, and about 10 ⁵ EL-l macrophages were added. The fibroblasts in the co-culture produced higher amounts of adhesion markers VEGF, COLlal, and TGF-b I than fibroblasts cultured alone, possibly due to stimulation by the factors produced by macrophages.

[0117] As shown in FIG. 9A, irradiation at a combination of 750 nm and 950 nm reduced the level of mitochondrial superoxide of the fibroblasts that are co-cultured with macrophages undergoing ischemia and reperfusion, indicating that the infrared light decreased ROS production under both conditions. The infrared light at these wavelengths also reduced mitochondrial membrane potential of the fibroblasts under both conditions (FIG. 9B). Additionally, this infrared light significantly reduced the production of VEGF, COLlal, and TGF-b! from the co-culture undergoing ischemia and reperfusion (FIGS. 9C-9E). In contrast, infrared light at 810 nm generally had the opposite effect (FIGS. 9A-9E).

[0118] Next assessed was the effect of infrared light on cellular responses to hyperoxia. Human fibroblasts were incubated under 40% 0 ₂ + 5% C0 ₂ for 30 minutes in a Biospherix X3 chamber. The cells were exposed to infrared light at the wavelengths of 810 nm or 750 nm in combination with 950 nm during hyperoxia. Mitochondrial superoxide production, mitochondrial membrane potential, and the release of adhesion markers VEGF, COLlal, and TGF-b! were measured by the methods described above.

[0119] As shown in FIG. 10A, irradiation at a combination of 750 nm and 950 nm significantly reduced the level of mitochondrial superoxide of the cells cultured in hyperoxia, indicating that the infrared light decreased ROS production. The infrared light at these wavelengths also significantly reduced mitochondrial membrane potential of the fibroblasts (FIG. 10B). Additionally, this infrared light significantly reduced the production of VEGF, COLlal, and TGF- bΐ from the fibroblasts (FIGS. 10C-10E). In contrast, infrared light at 810 nm had the opposite effect (FIGS. 10A-10E).

[0120] In addition to the effect of infrared light on cellular responses to oxidative stress, the effect on immune cell responses to a pathogen-associated molecular pattern (PAMP) molecule was also assessed. Briefly, macrophages were treated with 100 ng/mL of E. Coli lipopolysaccharide (LPS) for 24 hours and were exposed to infrared light at the wavelengths of 810 nm or 750 nm in combination with 950 nm at the power density of 3 mW/cm ² during the LPS treatment. The cells were stained with MitoSOX, and the amounts of mitochondrial superoxide were measured by fluorescent microscopy. The supernatants of cell culture were collected for measuring the release of TGF-pl and IL-lp by ELISA.

[0121] As shown in FIG. 11 A, irradiation at a combination of 750 nm and 950 nm significantly reduced the level of mitochondrial superoxide, indicating that the infrared light decreased the production of reactive oxygen species (ROS). The infrared light at these wavelengths also significantly reduced the production of TGF-b 1 and IL- 1 b (FIGS. 11B and 11C). In contrast, infrared light at 810 nm increases the production of superoxide, TGF-b!, and IL- 1 b (FIGS. 11A- 11C). Similar results were observed in neutrophils.

Example 3: Modulation of Adhesion by Infrared Light in a Rat Adhesion Model

[0122] This example shows the modulation of in vivo adhesion and fibrosis by infrared light at the wavelengths of 750 nm, 810 nm, and/or 950 nm.

[0123] Two rat adhesion models, as described in Kraemer el al. (2014) Biomed Res Int. 2014:435056, were considered. Specifically, female Sprague-Dawley (SD) rats (250-300 g) were anesthetized using 3% isoflurane. A temperature probe was inserted rectally. After shaving the abdomen with an electric clipper, the abdominal skin was sanitized with betadine and alcohol. The rat was then placed on a warming pad and draped. After a midline incision, the abdominal fascia was incised longitudinally and elevated from the underlying muscle. The rectus muscle was separated in the midline and the peritoneal cavity entered sharply. A first adhesion model employed cytobrush trauma in the peritoneum. This injury caused bleeding and damage to visceral and parietal peritoneum and represented mechanical stress in the tissue. A second adhesion model employed electrocautery and suture placement in the peritoneum. Specifically, bipolar electrocautery forceps (setting 10) were used to desiccate the parietal peritoneum as well as a 1 cm region of visceral peritoneum on the uterine horn. Four simple interrupted 4-0 Vicryl sutures were placed on the parietal peritoneum, in the region of the desiccation. This procedure mimics Bovie electrocautery use during surgery and placement of hemostatic stitches during surgical procedures. In both adhesion models, the fascia was closed with interrupted 3-0 Vicryl suture and the skin was closed with a running 4-0 Vicryl subcutaneous stitch with buried knot. The first and second models were known to result in 81% and 100% adhesions formation, respectively.

[0124] Peritoneum tissues were collected from the first and second rat models 7 days after the surgery. Lysates of the tissues were used to measure respiration rates. As shown in FIG. 12, both adhesion surgeries increased CcO activity in the injured issues.

[0125] The electrocautery and suture placement model was used to further characterize the effect of infrared on post-surgery recovery. After the surgery, the rats were irradiated with infrared light at the wavelength of 810 nm or 750 nm in combination with 950 nm for 2 hours. The formation of tissue adhesions was examined after 7 days. In contrast to the control animals, which exhibited a 100% adhesion rate and thick adhesions, the rats irradiated with 750 nm and 950 nm infrared light were virtually free of adhesions (FIGS. 13, 14 A, and 14B). Examination of H&E stained histological slides by a board-certified pathologist revealed that tissues from the rats receiving 750 nm and 950 nm irradiation showed less fibrosis (FIG. 14C). These results demonstrated an inhibitory effect of infrared light at 750 nm and 950 nm on adhesion formation.

Example 4: Processes

[0126] FIG. 15 illustrates an exemplary flowchart of a process 300 that may be used to reduce the formation of tissue adhesion following a surgical procedure. Block 305 includes identifying a target tissue of a patient subject to a surgical procedure. The target tissue may be a tissue particularly susceptible to adhesion formation or scar formation post-surgery. The surgery may be, for example, an open surgery or a laparoscopic surgery. Block 310 includes selecting light wavelengths based on an ability of light having the plurality of light wavelengths to inhibit adhesion, reduce scar formation, or promote wound healing in the identified tissue. One or more of the wavelengths in the range may inhibit or decrease CcO and mitochondrial membrane potential to reduce tissue adhesion formation and/or fibrosis in the tissue when applied during and/or after exposure of a tissue to surgery. The light wavelengths are preferably selected from a plurality of wavelength ranges such as 730-770 nm and 930-970 nm that promote tissue adhesion suppression. For instance, the light source 105 may output light with a wavelength of approximately 750 nm or 950 nm where 750 nm and 950 nm are peak wavelengths. Additionally, the light source 105 may output light at both of these wavelengths as well as other wavelengths that inhibit CcO and mitochondrial membrane potential. Outputting light containing wavelengths of 750 nm or 950 nm also promotes a reduction in ROS formation and inflammatory response in macrophages. Thus, the conversion to adhesion phenotype in fibroblasts can be reduced. A light wavelength selection in the range of 795-835 nm, and in particular at 810 nm, is preferable avoided as light in this range negates some of the effects that are beneficial to reducing tissue adhesion. In a preferred embodiment, a light wavelength from each range is selected to be simultaneously applied to the target tissue.

[0127] Block 315 includes generating light at the selected wavelengths using, for instance, one or more light sources 105. The light source 105 may include a light emitting diode (LED), an optical fiber, a laser, or any other light source 105 configured to output light having a wavelength that directly or indirectly inhibits CcO. Furthermore, the light source 105 is configured to output light with a range that includes multiple wavelengths selected at block 310.

[0128] Moreover, the light source 105 is configured to output light having a power density sufficient to penetrate one or more body tissues. For instance, the power density may be sufficient to penetrate one or more of bone, skin, muscle tissue, and organ tissue. In one exemplary approach, the light source 105 may generate the light with a power density of at least approximately 200 mW/cm ² . For example, the light source 105 may generate the light with a power density at the light delivery surface of at least approximately 800 mW/cm ² when used on an adult human or less than 200 mW/cm ² when used on, for instance, neonates. Alternatively, the light source may have a power density at the light delivery surface in the range of 50 mW/cm ² to 2 W/cm ² .

[0129] Block 320 includes applying light to an area of tissue during a surgical procedure involving the tissue. As previously discussed, various wavelengths of infrared light, alone or in combination, modulate CcO activity and mitochondrial membrane potential when applied, for example, prior to the onset of tissue adhesion, reducing the effects thereof. The light may be applied for at least 2 hours in one example. In one exemplary approach, using the exemplary light therapy device 100 illustrated in FIG. 1A, a physician or other surgical staff member may direct the light generated by the light source 105 toward the tissue subjected to the surgical procedure during and/or after the surgical procedure. As previously discussed, tissue adhesions are bands of fibrous tissue that form between tissues and organs. The onset of tissue adhesion is defined as the instant in which formation of these bands of fibrous tissue begin to form between tissues and organs. Prior to the onset of tissue adhesion, the physician may direct the light onto the patient's tissue either directly or via a passing of the light through the patient's skin, bone, muscle tissue, organs, or any other tissue prior to reaching the targeted tissue area. The physician may apply glycerol to the patient's skin to help the light penetrate the patient's skin. Glycerol helps make the skin transparent to infrared light.

[0130] Block 325 includes applying the light at least partially after the surgical procedure. In addition to applying the light during the surgical procedure as illustrated at block 320, applying the light to the tissue at least partially after the surgical procedure may further inhibit CcO and further reduce the effects of, for instance, tissue adhesion.

[0131] Block 330 includes inhibiting CcO and mitochondrial membrane potential using the light from the light therapy device 100. As previously discussed, applying light at various frequencies to tissue subjected to a surgical procedure during and at least partially after the surgical procedure directly or indirectly inhibits CcO and mitochondrial membrane potential. Inhibiting CcO and mitochondrial membrane potential indirectly prevents the generation of tissue adhesion. As previously discussed, the CcO enzyme include photoacceptors that receive the light generated by the light therapy device 100. When the light output by the light therapy device 100 penetrates the various body tissues and reaches the affected tissue, the light inhibits CcO and mitochondrial membrane potential and thus reduces the amount of formed tissue adhesions.

[0132] Block 335 includes gradually reducing the light to the treated tissue. For instance, the light output by the light therapy device 100 may be gradually reduced following the surgical procedure. In one exemplary approach, the physician may manually reduce the light output of the light therapy device 100 by disabling one or more of the light sources 105 in the array or by moving the light therapy device 100 further away from the patient. Alternatively, the light therapy device 100 may be configured to gradually reduce the brightness of one or more of the light sources 105 or disable the light sources 105 one at a time or in discrete groups so that the light applied to the target tissue area is automatically reduced.

[0133] FIG. 16 illustrates an exemplary flowchart of a process 400 that may be used to design a device configured to inhibit CcO and mitochondrial membrane potential, such as the light therapy device 100 illustrated in FIG. 1A.

[0134] Block 405 includes selecting at least one light source 105. The light source 105 is configured to generate light having a wavelength that, for example, inhibits CcO and mitochondrial membrane potential to reduce tissue adhesion formation. The selected light source 105 may generate light having a wavelength that includes one or more of approximately 750 nm, 940 nm, and 950 nm. Selecting the light source 105 may further include arranging a plurality of light sources 105 in an array. In this exemplary approach, each of the light sources 105 may have a wavelength that inhibits CcO and mitochondrial membrane potential. Some light sources 105 in the array may be selected to include different wavelengths than other light sources 105 in the array. For instance, some of the light sources 105 may output light with a wavelength of about 750 nm, and some of the light sources 105 may output light with a wavelength of about 940 nm or about 950 nm. Of course, other wavelengths of light may inhibit CcO and may be used in the array. Also, the array need not include equal numbers of each type of light source 105.

[0135] Block 410 includes selecting a power density of the light source 105 sufficient for the light generated by the light source 105 to penetrate a body tissue. If the light sources 105 are arranged in an array, one or more of the light sources 105 may output light with a different power density than another of the light sources 105. The power density may further depend upon how the light is applied by the physician. For instance, if the physician applies the light to the patient through the patient’s skin, bone, muscle tissue, and organs, then a higher power density may be necessary than if the light is applied directly to the ischemic tissue through, for instance, a surgical opening.

[0136] Another consideration when selecting power density may include reducing the amount of thermal damage to the patient. For instance, the power density may be selected so that the tissue to which the treatment is applied does not heat by more than one degree Celsius during the treatment. In one exemplary approach, the power density may, for instance, be at least approximately 200 mW/cm ² . In another exemplary approach, for instance in an adult human patient, the power density may be at least approximately 800 mW/ cm ² . However, the power density may be lower than 200 mW/ cm ² when used with other human patients, such as neonates.

[0137] With regard to the processes, systems, methods, heuristics, etc. described herein, it should be understood that, although the steps of such processes, etc. have been described as occurring according to a certain ordered sequence, such processes could be practiced with the described steps performed in an order other than the order described herein. It further should be understood that certain steps could be performed simultaneously, that other steps could be added, or that certain steps described herein could be omitted. In other words, the descriptions of processes herein are provided for the purpose of illustrating certain embodiments and should in no way be construed so as to limit the claims.

[00120] Accordingly, it is to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments and applications other than the examples provided would be apparent upon reading the above description. The scope of the disclosure should be determined, not with reference to the above description, but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. It is anticipated and intended that future developments will occur in the technologies discussed herein, and that the disclosed systems and methods will be incorporated into such future embodiments. In sum, it should be understood that the disclosure is capable of modification and variation.

[0138] The disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing disclosure is therefore to be considered in all respects illustrative rather than limiting on the disclosure described herein. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.