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    patent application phototherapy and nitric oxide

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    patent application phototherapy and nitric oxide

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    © All Rights Reserved
    Download as PDF or read online from Scribd
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    36 views75 pages

    US20170028215 KnowBio Stasko Phototherapeutic Modulation NO

    Uploaded by

    Stephen
    patent application phototherapy and nitric oxide

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
    of 75
    ‘US 2017002821581 cu») United States 2) Patent Application Publication co) Pub. No.: US 2017/0028215 A1 Medendorp, JR. et al. 4s) Pub, Dati Feb. 2, 2017 (54) SYSTEMS AND METHODS FOR Publication Classification PHOTOTHERAPEUTIC MODULATION OF ne a AGIN 506 (2006.01) S.C. 2) (71) Applicant: Photon MD, LLC, Morrisville, NC Ws) ce AGIN 5/0613 (2013.01); AGIN S601 (@O13.01}; A61N' 2005/0626 (2013.01); A61N (72) Inventors: Nicholas William Medendorp, JR. 2005/0662 (2013.01), A6IN 2005/0652 Raleigh, NC (US); Katelya P. (2013.01), 462 2005/0663 (2013.01) ighard, Chapel Hill, NC (US) ca ——— Gerald H, Negley, Chapel Hill, NC (US, Nathan Stasko. Chapel HILNC Systems and methods for phototherapeutic modulation of nivic oxide in mammalian tssve include we of @ ist ‘wavelength and fit radiant fox of ight to simulate enry~ ‘matic generation of nile oxide, and. use of a. second (21) Appl. Now 187222,243 ‘wavelength and second radiant ux of Tight to stimulate release of nic oxide from endogenous stores of nite (22) Filed: Jul 28, 2016 oxide. Pulsed light andor partially non-overlapping light impingement windows may be used. Nonscoherent ight impinged on tissue may include a peak wavelength in @ rage of fom 410 nm fo 440 nm in the absence of light (60) Provisional application No. 62/197,746, fled on Jul. emissions having a peak wavelength of from 600 am 40 900 28, 2015 am, Related U.S. Application Data 316 xe 317 303A 309 L- 318 313, 305 312 3038 id 303¢ 301 Patent Application Publication Feb. 2, 2017 Sheet 1 of 49 US 2017/0028215 AL CO -NO} | 03 Arginine hy pifelor iNOS» NO+CCo i> —+ vecr | NF-kB CCO-NO Figure 1 (Related Art) hy, hy, hy, piers Oars Blood esses Senaceous gand aerate Figure 3 Patent Application Publication Feb. 2,2017 Sheet 2 of 49 US 2017/0028215 Al Ww RSNO + R'SH — RSH + R'SNO —> R-S-S-R' +NO* Figure 2A be - Hb Hb NO, ————> NO + MetHb ————-+ HbNO Figure 2B bv CO - NO> tno; No + ¢CO | S cco -No Figure 2C¢ tion Feb. 2, 2017 Sheet 3 of 49 US 2017/0028215 AI Patent Application Publi At—o— 10. uM Hb B1—o~ Hb-NO (1 hr Incub) C1 Hb-NO 150/@530nm Absorbance ° 8 & 10610, 840 670,700 730 760 730 tty 4S te 28 Bae ae 595 625 655 685 715 745 775 Wavelength (nm) Figure 4A 05 A2—-O- 10 uM Ho 0.45 B2—o— 10 UM Hgb-NO (thr Inc) 0.4 C2—ce 10 UM Hgb-NO 150J@850nm 038 Absorbance 2 8 2 “Wo | 440 | 480. 520 | 560 420 460 500 540 580" ea0 o60 0 740 780 Wavelength (nm) Figure 4B Patent Application Publication Feb. 2,2017 Sheet 4 of 49 US 2017/0028215 Al 5% 8 0% —e— 410 nm 540 B sy -o~ 447 nm 540 8 5% i 470 nm 540 3 0% -o~ 505 nm 540 < 10% —o— 530 nm 540 $ -15% —o— 597 nm 540 e j-o- 630 nm 540 820% + 2 660 nm 540 8 5% j—o— 850 nm 540 -30% -L-4 —| -20 0 20 40 60 8 100 120 140 160 Fluence (diem?) 7 {usm} Figure 5 Cytochrome c-NO 5 z 6 = a = = 8 Fluence (Jlem?) Figure 6 US 2017/0028215 AI Feb. 2,2017 Sheet 5 of 49 Patent Application Publication 2 aunbi4 (s) oun, 009 000S = 000h = ONDE «000Z =(0F 0 (yu oe) og8 (yw 008) Arb (yw 00) ObP ztlO/MMU ed ON Patent Application Publication Feb. 2,2017 Sheet 6 of 49 US 2017/0028215 Al 410uM Hgb + 1mM Prolino, Stirred —2— 410 (300 mA) —o— 530 (300 mA) —O— 410/530 NO Per mWicm? 0 1000 2000 3000 4000 5000 6000 Tame (s) Figure 8A 410uM Hgb + 1mM Profino, Stirred ~o- 530 Repeat 2 660 = 530/680 160 + NO per mWicm? 0 1000 2000 3000 4000 5000 6000 Time (s) Figure 8B Patent Application Publication Feb. 2,2017 Sheet 7 of 49 US 2017/0028215 Al —e— 530 (300 mA) 2 850 (300 mA) 10uM Hgb + im Proling Stirred |~2~ 530/850 Repeat —» 850 Repeat -o- 530 Repeat 0 1000 2000 3000 4000 5000 6000 Time (s) Figure 8C Patent Application Publication Feb. 2,2017 Sheet 8 of 49 US 2017/0028215 Al Figure 11 P22 22777) a Figure 12 Patent Application Publication Feb. 2,2017 Sheet 9 of 49 US 2017/0028215 Al 74 Figure 15 Patent Application Publication Feb. 2,2017 Sheet 10 of 49 US 2017/0028215 Al Figure 17 Patent Application Publication Feb. 2,2017 Sheet 11 of 49 US 2017/0028215 Al 100 cee 109 104 105 Figure 18 110 yu i 119 114 415 Figure 19 120 121 122 129 124 Figure 20 130 131 432 Figure 21 Patent Application Publication Feb. 2,2017 Sheet 12 of 49 US 2017/0028215 Al Figure 23 Figure 24 Figure 25 Patent Application Publication Feb. 2,2017 Sheet 13 of 49 US 2017/0028215 Al 180 181 182 189 183 184 182 Figure 26 ~ 191 192 197 199 194 192 Figure 27 200 = 201 202 205 209 204A 202 Figure 28 219A 215A 2198 2158 2190 215C i 2148 i. 2148 A! 214 Figure 29A Figure 29B Figure 29C Patent Application Publication Feb. 2,2017 Sheet 14 of 49 US 2017/0028215 Al 220 222 221 Figure 30 2 : 235-1 235-2 239 232 °00000°0 ©00000°e Figure 31 Patent Application Publication Feb. 2,2017 Sheet 15 of 49 US 2017/0028215 Al 240 45-1 245-2 249 A 242 ° 0° ee 36! 060 060 060 Eas) ° ° a 30 88 a O' Figure 32 \ 255-1 Figure 33 Patent Application Publication Feb. 2,2017 Sheet 16 of 49 US 2017/0028215 Al am ea Des Figure 34A 291 Figure 34B 281 2814 Patent Application Publication Feb. 2,2017 Sheet 17 of 49 US 2017/0028215 Al 317 303A 301 Figure 35 Patent Application Publication Feb. 2,2017 Sheet 18 of 49 US 2017/0028215 Al 2 2 oO £ t Figure 36A B = t Figure 36B 2 5 . a ’ Figure 36C Patent Application Publication Feb. 2, 2017 Sheet 19 of 49 US 2017/0028215 Al Figure 37 US 2017/0028215 AI Feb. 2, 2017 Sheet 20 of 49 Patent Application Publication ato Figure 38 Patent Application Publication Feb. 2,2017 Sheet 21 of 49 US 2017/0028215 Al 405 Q>) (QD Figure 39 Patent Application Publication Feb. 2,2017 Sheet 22 of 49 US 2017/0028215 Al External Part to PCB ' 526- oe LE Proximity T|_ Sensor 504- 502. | 524. Button | Temperature] T|_ Sensor 06 512 : LCD Display-—Microcontroller 5V Boost ee i] IRLED }- 508: : 514 | Buzzer } FL} Charger IC LT Battery 516~ ! Micro USB i Connector ' 518} 510 ‘12N Booet "320 LED Driver ' LED Array Figure 40 Patent Application Publication Feb. 2,2017 Sheet 23 of 49 US 2017/0028215 Al 507 503 Timers and | Application - Simple Executive Counters | 605, Hardware Drivers, Temperature Speaker ‘Sensor LED Array 520 Indicator Optical LEDs Sensor oon ae 504 509 526 Figure 41 Patent Application Publication Feb. 2,2017 Sheet 24 of 49 US 2017/0028215 Al 610 ett Figure 42 Figure 43A Figure 44A ciy LIA | ‘igure 43B Figure 44B Patent Application Publication Feb. 2,017 Sheet 25 of 49 US 2017/0028215 Al Cell Viability m0 i/em2 mi t/em2 B5J/om2 50 I/om2 4 8 24 Time Post Irradiation (h} Figure 45 18 iNOS 8 mo s/em2 2 = 10 M1 sem? 3 M5 J/em2 6 50 J/em2 A «al a-ll 0 1 4 8 Time Post Irradiation (h) Figure 46 Patent Application Publication nNOS S x 9 2 % Celis with Intraceil 100 80 60 40 20 ° nNOS il | iene! | < 4 0 Time Post Irradiation (h} Figure 47 Intracellular NO ol o 4 Time Post irradiation (h} Figure 48 Feb. 2,2017 Sheet 26 of 49 US 2017/0028215 Al mo s/om2 @is/em2 5S H/em2 G50 J/em2 MO J/em2 Bid/em2 @53/om2 £950 Jfern2 Patent Application Publication Feb. 2,2017 Sheet 27 of 49 US 2017/0028215 Al Cell Viability 100 a 90 5 80 70 | Ee tt | m0 Jer? 50 & 4 S30 B25 sformn2 20 10 1150 j/em2 Oo o 1 6 24 Time Post-Irradiation (h} Figure 49 iNOS W125 jfem2 50 Jferm2 alla «itll. Bl | o 4 6 Time Post irradiation (h) Figure 50 Patent Application Publication Feb. 2,2017 Sheet 28 of 49 US 2017/0028215 Al WOJ/omn2 eNOS WS Sem? 100 m25 fem? 50 ema Time Post irradiation (hy Figure 51 Intracellular NO 9 lm oO i 6 Time Post Irradiation (h) Figure 52 a 3 moO jem? £ 49 5 seme 25 Jom 2 20 2 1956 J/emz & res US 2017/0028215 AI Feb. 2, 2017 Sheet 29 of 49 Patent Application Publication et a eg aunBiy (02/9) souepeny vt a or 8 9 Atta ay tet lowr at es ee ON-UIGo}BowEH ws {s/Sad) @seaay ON US 2017/0028215 AI Feb. 2, 2017 Sheet 30 of 49 Patent Application Publication yg ainBiy ON-uIgo|Goweyy eos WU O99 eee wu 6s =e wuogs — sos t= uote = | RTE wu gppeee $o+300'¢ Patent Application Publication Feb. 2,2017 Sheet 31 of 49 US 2017/0028215 Al $0 a5 0 S-nitrosoglutathione (GSNO) Figure 55 a arse irradiance ( {s/Sdd) ese0}y4 ON US 2017/0028215 AI Feb. 2, 2017 Sheet 32 of 49 Patent Application Publication 9g aunbig 291 (ONSO) euoWEIN|Boso.yU-S o0+3000 (aida) 12104 ON US 2017/0028215 AI Feb. 2, 2017 Sheet 33 of 49 Patent Application Publication dg ainbBig apueipesiy " a or 8 ¥ ’ z ° SN A OREO Ti NRO any 3 Rin ed prega ay Pet ladeh An API Aa Ri = ~ Wear enereniatnnt eee ae tealatinr sta nett saat bet mayen th tahe nmr may Abend es se ta ESE seen, | atten cetineene net AOI wel ever ate ON-uluNaly (s/ada) esvajay ON US 2017/0028215 AI Feb. 2, 2017 Sheet 34 of 49 Patent Application Publication 8g eunBiy aaueipenst ON-unWNgTy 003000 eI ppegos 1 yO#308°% sorI0g€ (add) 12301 ON Patent Application Publication Feb. 2,2017 Sheet 35 of 49 US 2017/0028215 Al Cytochrome c-NO inradian Figure 59 ddd) asvaiey ON Patent Application Publication Feb. 2,2017 Sheet 36 of 49 US 2017/0028215 Al Cytochrome c-NO Figure 60 fada) 1220 ON US 2017/0028215 AI Feb. 2, 2017 Sheet 37 of 49 Patent Application Publication Lg eunbi4 ON-28epXO -0 eUIOYDO}K 08 (s/add) ase9i2y ON US 2017/0028215 AI Feb. 2, 2017 Sheet 38 of 49 Patent Application Publication zg aunbig ON-28ep1xQ -9 ewosyoorKg LR OTP eee 083055 “300% (dda) 12201 ON US 2017/0028215 AL Feb. 2, 2017 Sheet 39 of 49 Patent Application Publication €9 aunBly ON-BupUOYoOH YY US 2017/0028215 AI Feb. 2, 2017 Sheet 40 of 49 Patent Application Publication rg aunBi4 {2t9/1) aouerpesi ON-euPUOYDONYY 70+300°S e0r3001S oi (eda) 104 04308 £0300 eoe30s'2 £0+200"¢ US 2017/0028215 AI Feb. 2, 2017 Sheet 41 of 49 Patent Application Publication (uy pajejay) gg aunBiy ZSON / £SON SEG SON / SON. Patent Application Publication Feb. 2, 2017 Sheet 42 of 49 US 2017/0028215 Al Figure 66 (Related Art) Patent Application Publication Feb. 2,2017 Sheet 43 of 49 US 2017/0028215 Al Figure 67A —O-— 660 nm LED Figure 67B Patent Application Publication Feb. 2,2017 Sheet 44 of 49 US 2017/0028215 Al LED Figure 68A —O— 530 nm LED te @ee 530 nm Laser Figure 68B Patent Application Publication Feb. 2, 2017 Sheet US 2017/0028215 AL Figure 69A : —e— 420 n LED sommes 420 nm Laser ight Transmitt & a Skin Thickness (ram) Figure 69B Patent Application Publication Feb. 2, 2017 Sheet 46 of 49 US 2017/0028215 Al Red Light ) a o o 80 60 40 20 Light Transmittance (% 0 05 115 2 25 3 35 Skin Thickness (mm) —@— LED- African American —O— LED - Caucasian =~ -@-- Laser - African American --O-- Laser - Caucasian Figure 70 Patent Application Publi —~ 100 8 80 = £ . 2 60 3 6 40 E ‘& 20 = ) tion Feb. 2, 2017 Sheet 47 of 49 US 2017/0028215 AI Green Light 05 1 15 2 25 3 3.5 Skin Thickness (mm) —®— LED - African American —O— LED - Caucasian --@-- Laser - African American =-O-- Laser - Caucasian Figure 71 Patent Application Publication Feb. 2,2017 Sheet 48 of 49 US 2017/0028215 Al Blue Light 100 oo ° D ° 40 * » 20 \ Veron Light Transmittance {(%) 0 05 115 2 25 3 35 Skin Thickness (mm) —@— LED - African American —®— LED - Caucasian --@-- Laser - African American --O-- Laser - Caucasian Figure 72 Patent Application Publication Feb. 2,2017 Sheet 49 of 49 US 2017/0028215 Al 140.0 1200 #1000 | 2 200 = coo 2 10.0 20.0 0 a 0 025 05d 1050 NO-Donor Concentration (mM) Figure 73 140.0 120.0 @ Dark oy 420 nm Light 100.0 80.0 60.0 & Eb a 40.0 20.0 0 1 NO-Donor Concentration (mM) Figure 74 US 2017/0028215 Al SYSTEMS AND METHODS FOR. PHOTOTHERAPEUTIC MODULATION OF NITRIC OXIDE STATEMENT OF RELATED APPLICATIONS {0001} This application claims the benefit of provisional patent application Ser. No, 62/197,746, fled Jul 28, 018, the disclosure of which is hereby incorporated herein by reference in its entirety. ‘TECHNICAL FIELD [0002] This disclosure relates to systems and methods for phototherapeutie simulation of nitric oxide produetion and! ‘or release in tissues of mammalian subjects BACKGROUND [0003] ‘The term “phototherapy” relates to the therapeutic ‘use of fight. Various light therapies (eg. including low level light therapy (LLLT) and photodynamic therapy (PDT)) have been publicly reported or claimed to provide various health related! medical benefits—including, but not Fimited (©: promoting hair growth; twatment of skin or dssue inflammation; promoting tissue or skin healing or rejuvens- ‘ion; enhancing wound healing pain management; reduction ‘of wrinkles, sears, stretch matks, varioase veins, nd spider veins; treating cardiovascular disease; rating erectile dys- function: treating microbial infections; treating byperbilira- binemia; and treating various oncologial and non-oncologi- cal diseases or disorders [000$) Various mechunisms by which phototherapy has boon suggested 1 provide therapeutic benefits include: increasing circulation (eg. by inereasing formation of new ) followed by photomodulated release of nitric oxide from the CCO-NO and CCO-NO- 10043] FIG. 3 is a cross-sectional view of epidermis and ‘dermis layers of human skin with sehematie illustration of ‘overlappniz zones in which NO is released from endogenous stores of NO by photomodulation. [0044] FIG. 44 includes superimposed plots of absor- bance versis wavelength for hemoglobin (11), nitric oxide- Joaded hemoglobin (I1b-NO) prior to irradiation, and Hb- Feb. 2, 2017 NO following absopion of 150 J of light emissions of a arsen LED having peak wavelength of 530 nm. [0045] FIG. 48 inciodes superimposed plots of absor- bance versus wavelength for, H-NO prior wo iradiation, and i5-NO following sbsorption of 150 J of ght emissions Of an IR LED souree having a peak wavelength of 850 nm. [0046] FIG. § is @ plot of perentoze change in peak absorbance for the $40 nm peak of Hb-NO versus fluence (Goules per square centimeter) for nine diferent wavelengths of light (rom 410 nm to 850 nm. [0047] FG. 6 is plot of percentage change in peak absorbance for Cytochrome e-NO vert hence (oles per Square centimeter) for nine diffrent wavelengths of light {Grom 410 am vo 850 any, [0048] FIG. 7 is plot of released NO (ppb) per milliwat er square centimeter vests time forthe photomodulated release of NO from Th-NO fornine different wavelengths of light (from 410 nm to $50 nm). {0049} FIG. 8A includes superimposed plots of released NO (ppb) per millwat per square centimeter versus ine for ination of Hb-NO with ()) 8 410 1m peak wavelenath biue LED device, ia $30 am peak wavelength green LED device, and Gi) the 410 nm peak wavelength blue LED device in combination with the $30 nm peak wavelength sreen LED device. {0050} FIG. $B includes superimposed pots of released NO (ppb) pr millwat per square centimeter versus ine for ination of HsNO with () a $30 nm peak wavelength zreen LED device (i) a 660 nm peak wavelength red LED device, and Gi) the $30 nm peak wavelength green LED device in combination with the 660 nm peak Wavelength red LED device [0081] FIG. 8€ includes superimposed plots of released NO (ppb) per milwat per square centimeter versus ine for inadation of HNO with () a $30 nm peck wavelength green LED device (inching one repeat nin), (i) a 80 nm peak wavelength infared LED device inliding one repeat rin) and (ii) the $30 1m peak wavelength green LED device in combination with the 880 nm peak Wavelenath infrared LED deve. [0082] FIG. 9 is aside erss-setonal schematic view of 4 portion ofa device for delivering light energy’ wo living ‘nammalian ts, the device including multiple eect view Tih emitting sourees supported bya substrate and covered with an cacapsulant material layer. [0083] FIG. 10 aside eros-sctonal schematic view of 4 portion ofa device for delivering light energy to living ‘otmmulian sue, the device including mulple diet view Jit emitingsourees supported bya substate and covered ‘with an encapsulant material layer, wherein at least one functional material (.@, wavelength conversion and eat tegatana r aver [0088] FIG. 11 side cross-sectional schematic view of 4 portion of a device for delivering light energy’ to living ‘mammalian ts, the device including mie dizect view light cating sources supported by a sobstate and covered with two eocapslant material layers, with at least one Tunetional material, wavelengts eoaversion and/or cate tering. material} layer disposed between the encapsulant smatrialLayers [0085] FIG. 12s side ess-scotiona schematic view of 4 potion of a device for delivering light energy t living malian sue, the dvieeinluding lip direct view US 2017/0028215 Al light emitting sources supported by a substrate and covered by an encapsulant layer, wherein the encapsulant layer is ‘covered witha diffusion oF seattering material layer 10056] FIG. 13 isa sido cross-sectional schematie view of 8 portion of a device for delivering light energy to living ‘mammalian tise, the device ineluding multiple direct view light emiting sources supported by a substrate, multiple molded features overlying the light emitting sources, and an ‘encapsulant or light coupling material arrnged between the Tight emitting sources and dhe molded features. 10057] FIG. 14 isa sido cross-sectional schematic view of 8 portion of a device for delivering light energy to living ‘mammalian tissue, the device ineluding a flexible substrate, ‘one oF more organic light emitting diode layers arranged between san anode and cathode, and an encapsulant layer arranged over the cathode. [0058] FIG. 13 is side cross-sectional schematie view of 4 ponion of a device for delivering light energy to living ‘mammalian tise, the device including a flexible substrate, ‘multiple direct view light emitting sources supported by the substrate, encapsulant material layers seranged above and below the substrate and over the lit emitting sourees, and holes or perforations defined through both the substrate and the encapsulant material layers, 10059] FIG. 16 isa side cross-sectional schematic view of 8 portion of a device for delivering light energy to living mammalian tissue, wherein the device includes multiple direct view light emitting sources supported by a substrate ‘and covered by an encapsulant layer, and the deviee is arranged in a concave configuration [0060] FIG. 17 isa side cross-sectional schematie view of 4 ponion of a device for delivering light energy to living ‘mammalian tissue, wherein the device includes multiple

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