Joseph E. Berman PT, MHS 1,2,3 Cheryl Lasselle PT, DPT, MBA 1,2,4* Edwin P. Monroy PT, DPT, CLT, CWS 1,3

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2 RECENT RESEARCH UPDATE REGARDING THE USE OF PHOTOBIOMODULATION FOR WOUND HEALING Joseph E. Berman PT, MHS 1,2,3 Cheryl Lasselle PT, DPT, MBA 1,2,4* Edwin P. Monroy PT, DPT, CLT, CWS 1,3 1 Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, WI; 2 Wisconsin Corporation for Biomedical Research, Milwaukee, WI; 3 Marquette University; Milwaukee, WI; 4 University of Wisconsin Milwaukee, WI; (*formerly) Non-Disclosable support: Veterans Affairs Clinical Science Research & Development Service, Cooperative Study #535 (software and equipment) Clinical & Translational Science Institute of Southeast Wisconsin/ NIH Grant Number 8UL1TR (partial research support and statistical consultation)

3 DISCLOSURES Presenters have the following interest to disclose: Partial research support from QBMI, Inc. (Distributor at study initiation) QDI, Inc. (Device manufacturer) PESG and PVA staff have no interest to disclose. This continuing education activity is managed and accredited by Professional Education Services Group in cooperation with PVA. PESG, PVA, and all accrediting organization do not support or endorse any product or service mentioned in this activity.

4 CE/CME CREDIT If you would like to receive continuing education credit for this activity, please visit:

5 OTHER ACKNOWLEDGEMENTS Scientific Content Janis T. Eells PhD 4 Sandeep Ghopalakrishnan, PhD 4 Robin Schumacher 6 Medical Oversight Vaishnavi Muqeet MD 1,5 Paula Benes MD 1,5* Vicki Anderson MD 1,5* 4 University of Wisconsin Milwaukee, WI; 5 Medical College of Wisconsin; Milwaukee, WI 6 QBMI Photomedicine, LLC; Dodgeville, WI *Formerly

6 Learning Objectives At the conclusion of this activity, the participant will be able to: 1. Describe the development and application of photobiomodulation (PBM) for the treatment of chronic wounds. 2. Identify proposed mechanisms of action underlying the evidence supporting the efficacy of PBM for wound healing.

7 Learning Objectives 3. Describe recent research using similar therapies for tissue healing 4. Restate our study team s evidence supporting the therapeutic efficacy of PBM for wound healing.

8 Light Therapy Why Light Therapy? Why this device? What lead us to believe this would be useful for wound healing? Further research to come? Other applications?

9 WARP: Warfighter Accelerated Recovery by Photobiomodulation Wavelength: 670 nm (RED) Delivery: Continuous (88 sec) Direct contact LED Chips vs LED lights WARP 10 TM WARP 75 TM Manufacturer: Quantum Devices, Inc; Barneveld, WI

10 Light Therapy History Heliotherapy Light therapy sessions were well integrated in medical practice between 1920 s 1950 s.

11 Light Therapy History Endre Mester M.D. Early experimental work was to utilize laser as a tool for destroying skin cancer. He failed to destroy the cancer cells but noted that the skin incisions where laser was used were healing faster Later performed experiments in a rat model treating burns/ulcers that showed positive effects for tissue repair!

12 Light Light is a form of energy which at times behaves like a particle and as a wave. Light particles (photons) are massless, have no electric charge and are the basic units of light. Light waves are electromagnetic in nature. The wavelength demonstrates the depth of penetration by the electromagnetic radiation Individual photons have inherent energy that corresponds to their wavelength. blue>green>red>infared

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14 Electromagnetic Spectrum LED 670 +/- 15 nm

15 Light Therapy Types of Light Therapy: Ultraviolet Radiation: 1. UVA (longest wavelength : nm) 2. UVB ( nm) 3. UVC (shortest wavelength: nm) > Bactericidal vs. UVA &UVB Visible and Infrared Light: 1. Laser Diode 2. Light Emitting Diodes (LEDs) 3. Cluster Probe (Combination)

16 WARP: Warfighter Accelerated Recovery by Photobiomodulation Wavelength: 670 nm (RED) Delivery: Continuous (88 sec) Direct contact LED Chips vs LED lights WARP 10 TM WARP 75 TM Manufacturer: Quantum Devices, Inc; Barneveld, WI

17 Clinical Application Cleared by FDA (2003) : Indication for use: For treatment of chronic pain by emitting energy in the Near-IR spectrum for the temporary relief of minor muscle and joint pain, arthritis and muscle spasm; relieving stiffness; promoting relaxation of muscle tissue; and to temporarily increase local blood circulation where applied. Wound Healing

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19 Photobiomodulation The First Law of Photobiology: For light to have any effect on a living biological system, the photons must be absorbed by some molecular chromophore (or photoacceptor) 8 Chromophores Cytochrome c oxidase (Cox) is the primary photoacceptor for the red- NIR range ( nm) in Mammalian cells 11 Chlorophylls are the photoacceptor molecules Chromophores

20 Photobiomodulation *Photobiomodulation uses endogenous chromophores (or photoacceptors) to absorb light of specific wavelengths. These different wavelengths target specific chromophores within tissue: Blue Light ( nm) Green Light ( nm): Yellow Light ( nm): Flavins & Flavoprotiens Flavins & Flavoprotiens Prophyrins *Red & Near Infrared ( nm): Cytochrome c oxidase (COX)*

21 WHY????: Optimal Window ~ nm Hemoglobin/Melanin <600nm Water >1150nm

22 Mechanism of Action: Cyto-c-ox

23 Mechanism of Action: Cytochrome c oxidase(cox) Red Light effects multiple cell processes and cell signaling cascades that have significant implications on wound healing. LED Red Light 670nm Gene Transcription -Increased activity of CcOx (Photoreceptor) - Increased oxygen consumption - Restoration of mitochondrial electrochemical gradients (PSIm) - Increased ATP production Figure 4. Structure of the mitochondrial respiratory chain. Figure 3. Cell signaling pathways induced by LLLT.

24 LITERATURE REVIEW Let me splain no, there is too much. let me sum up. -Inigo Montoya

25 Light Therapy History James Carroll Described as iconic researcher and entrepreneur by London business blog Endre Mester M.D.

26 Non-tanning light bed

27 LITERATURE REVIEW Hashmi, Hamblin et al 2010 Physical Medicine and Rehabilitation Role of Low-Level Laser Therapy in Neurorehabilitation

28 LITERATURE REVIEW Hodgson, Whelan et al 2011 Supportive Care in Cancer Amelioration of Oral Mucositis Pain by NASA Near- Infrared LEDs in Bone Marrow Transplant Patients

29 LITERATURE REVIEW Prindeze, Moffatt and Shupp 2012 Experimental Biology and Medicine Mechanisms of Action for Light Therapy: A Review of Molecular Interactions

30 LITERATURE REVIEW Houreld 2014 The Scientific World Journal Shedding Light on a New Treatment for Diabetic Wound Healing: A Review on Phototherapy

31 LITERATURE REVIEW Sperandio, Sousa et al 2015 Journal of Biophotonics Low-Level Laser Irradiation Promotes the Proliferation and Maturation of Keratinocytes During Epithelial Wound Repair

32 LITERATURE REVIEW Ayuk, Abrahamse and Houreld 2016 Journal of Diabetes Research The Role of Matrix Metalloproteinases in Diabetic Wound Healing in Relation to Photobiomodulation

33 LITERATURE REVIEW Zhang, Wu et al 2016 Science Translational Medicine Noninvasive Low-Level Laser Therapy for Thrombocytopenia

34 WHAT???... effect will standard wound care plus 670 nm light have on wound area? adverse effects might we see?

35 Subjects (inclusion/ exclusion) Primary inclusion criteria Spinal cord injury At least 1 full-thickness (FT) dermal wound of known, common etiology Primary exclusion criteria Photophobia, photosensitivity, or receiving a known photosensitizing medication or supplement

36 Subjects We studied 1 wound on each of the 10 subjects with a spinal cord injury. 8 full-thickness (FT) pressure ulcers (PrUs) 1 was undermined 1 full-thickness burn 1 (undermined) dehiscence along a PrU flap incision line. Overall 4 patients with Tetraplegia and 6 with paraplegia.

37 Methods: Design Digital photos on 1 st and last days of: Baseline (BL) Phase: Standard care Mean: 27.7 days (range 21 44) Treatment (TX) Phase: Standard care plus light therapy 4x/ week inpatient 2x/ week outpatient Mean: 26.9 days (16 53) Mean: 11.8 treatments (8-17)

38 Methods: Wound Area Two-dimensional area* traced and calculated using planimetry software (VeV MD; Vista Medical Ltd, Winnipeg Manitoba). *Area included undermining and area of significant discoloration (if present).

39 Device and TX Parameters Treatment time (88+/- 8 sec) Direct Contact: transparent film Area of emission (cm 2 at 670nm) *3.6cm diameter >10cm 2 area (WARP 10) *7.6cm x 9.8cm > 75cm 2 area (WARP 75) Power Output Energy Dosage Warp 10: 50mW/cm 2 x88sec = 4.40 J/cm 2 Warp 75: 60mW/cm 2 x88sec = 5.28 J/cm 2

40 Results: Change in Wound Area PHASE Baseline (Standard care) Mean % decrease in wound area (sem) (5.6) Treatment (Standard care plus LIGHT) Increase (5.4) 2.0 x baseline Mean # of days (range) 27.7 (21-44) 26.9 (16-53) Mean % decrease per day (sem) 1.07 (0.23) 2.47 (0.27) > 2.3 x baseline P (*significant) <0.01* <0.01*

41 Results: Mean Dec in Area Mean % Decrease in Wound Area (Per Subject) PER DAY Std care + light TX *(P<0.01) Mean % Decrease in Wound Area (per subject) During Two Consecutive Periods Std care + light TX (P<0.01) Baseline (Std care) 40 Baseline (Std Care) x Baseline x Baseline

42 Results: Adverse responses to light TX NONE reported or observed. (121 treatment sessions)

43 CONCLUSIONS: Rate of mean area showed a decrease more than double of that seen during the equivalent standard care period = Clinically significant. Statistically significant (2-tailed t-test; P<0.01) + No adverse effects observed or reported = Encouraging support for this use of phototherapy.

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45 More to come.. To characterize the chronic wound microenvironment and the role of mitochondrial dysfunction and oxidative stress in non-healing chronic wounds. 1) Microenvironment and mitochondrial state in chronic wound 2) Determine the effect of 830nm to environment. - wound fluid/biopsy analysis using infrared spectroscopy.

46 Questions?... Comments?...