Photobiomodulation and low level light therapy (LLLT) research

Low Level Light / Laser Therapy (LLLT) utilises the photonic energy of light to stimulate cell and tissue responses (photobiomodulation - PBM) to promote healing, reduce inflammation and induce analgesia. Research in this area has led to several thousand publications and has significant interest from specialist groups such as NASA, the US Navy and UK military, in its therapeutic application. Notably LLLT/PBM is efficacious in a range of injuries and diseases at multiple sites in the body including the joints, connective tissues, neuronal tissues, bone, teeth, skin, muscle and the vasculature. It has been shown to promote wound healing processes including vasodilation, angiogenesis, cell proliferation, cytoprotection, adhesion, migration, differentiation and tissue formation.

Commonly LLLT utilises low power lasers or light emitting diodes (LEDs) of less than 500mW, emitting in the red to near infrared (NIR) spectrum (400-1100nm) and levels of irradiance are neither ablative nor provide a heat-based therapy (- 5-50mWcm-²_{) .} Recently cold diffuse lasers for photo-activated disinfection (PAD) or photodynamic therapy (PDT) have been developed. These local approaches utilise light indirectly to trigger photosensitive chemicals to release antibacterial or anti-cancer agents such as reactive oxygen species (ROS).

PBM is proposed to exploit natural and evolutionary preserved pathways. Cells respond to light by increasing synthesis of growth factors, nitric oxide (NO), ROS, ATP, RNA and DNA. Although exact cellular and molecular mechanisms are not yet fully understood, the current photodissociation theory' suggests specific wavelength ranges  of IR and NIR light is absorbed by the mitochondrial enzyme cytochrome c oxidase (COX) resulting in release of bound NO, which competitively displaces oxygen. NO release allows oxygen to re-bind COX enabling increases in cellular respiration and energy generation (ATP). Notably, inflammation and tissue damage can increase NO binding to COX and impede respiratory activity. The extracellular release of NO, ATP or growth factors can result in local and distant activation of tissue repair processes.

Many clinical LLLT devices utilise specific wavelengths in the 400-1000 nm spectrum (with ~660 nm and 810 – 830 nm wavelengths frequently used). Successful treatment is critically dependent on the parameters of applied irradiation including, "intensity" (properly termed, irradiance or flux, Wm^-2) , treatment/irradiation time (s), "dose" (fluence, or radiant exposure, measured in Jm^-2; the product of irradiance and exposure time), treatment frequency, treatment intervals, total number of treatments, number of treatment target points and coverage. The depth of penetration needed to irradiate target cells also needs consideration as light is reflected, absorbed, refracted and scattered to different degrees within different tissues. Light transport is significantly affected by pigments within tissues and its absorption properties. LLLT applied at the wavelengths and doses described are not harmful, however, lack of standardisation of treatment parameters can result in reduced or non-therapeutic effects, which contribute to false-negative data and the controversy that surrounds the field.

 

Currently the application of LLLT in dentistry and for the treatment of oral disease is limited despite the worldwide growing evidence for its broad efficacious application. Some evidence is however now emerging in favour of the therapeutic application of LLLT in a wide range of oral hard and soft tissues areas, including key dental specialties such as; endodontics, periodontics, orthodontics, oral medicine and oral surgery.

Further studies in this exciting therapeutic area are warranted to develop novel devices whose application is underpinned by a sound scientific basis. It is therefore the aim of our Photobiomodulation Research Group to undertake key projects and studies which will identify the physical and biological parameters necessary to enable optimal clinical efficacy.

The Photobiomodulation Research Group at Birmingham combines cell & molecular biology, photonics and clinical expertise. Our aims are to:

1) Better understand the underlying tissue, cellular and molecular mechanisms that underpin PBM

2) Build and develop novel in vitro tools for high-throughput analysis in order to study the efficacy of light therapy in a range of treatment needs

3) Establish how the therapeutic light wavelengths can be effectively transmitted through relevant wound tissue in order to optimise light dosing parameters

4) Develop simultaneous light treatment regimes to remove/inhibit infections that may impede wound repair

5) Understand patient needs and identify the most appropriate light therapy delivery approach to enable the development of novel devices for a range of clinical needs

Eukaryotic cellular responses

We have developed (with the School of Electronic, Electrical and Systems Engineering, UoB) well characterized and regulatable LED arrays for high-throughput (96-well) screening of cellular and molecular responses.

Funding support:

• NIHR i4i "A novel device for phototherapy to promote dental tissue repair." - completed.
• iCASE PhD studentship, CAPES (Brazil) & Malaysian Government (PhD studentship) - "Light irradiation modulation of oral epithelial and immune cell responses " - completed/ongoing.
• CAPES (Brazil) -"Effect of low level lightllaser/PBM therapy on mesenchymal stem cell (MSC) populations" - ongoing.
• Physical Sciences for Health (Sci-Phy-4-Health)
• "Photobiomodulatory Therapy for Cardiovascular Disease"
• "Fluorescent Nanoparticles for Mitochondrial PBM"
• Clinical trials for the use of LLLT as an adjunctive treatment for the management of periodontitis are planned.

Antibacterial screening

Higher-powered and high-throughput LED arrays have been developed for the (direct and indirect) screening of the antimicrobial effects of light.

Funding support:

• National Institute for Health Research Surgical Reconstruction and Microbiology Research Centre (NIHR SRMRC) - ongoing.
• iCASE PhD studentship "The development of novel antibacterial technologies: High throughput light delivery and characterization for optimization of photodisinfection" - ongoing.
• Joint application with Nottingham University Veterinary School relating to therapeutic device development for treatment of canine infectious otitis - ongoing.

Holder MJ, Milward MR, Palin WM, Hadis MA, Cooper PR. Effects of red light­ emitting diode irradiation on dental pulp cells. J Dent Res. 2012 Oct;91(10):961-6.

Carroll JD, Milward MR, Cooper PR, Hadis M, Palin WM. Developments in low level light therapy (LLLT) for dentistry. Dent Mater. 2014 May;30(5):465-475.

Milward MR, Holder MJ, Palin WM, Hadis MA, Carroll JD, Cooper PR. Low level light therapy (LLLT) for the treatment and management of dental and oral diseases. Dent Update 2014; 41: 763-772.

Milward MR, Hadis MA, Cooper PR, Gorecki P, Carroll JD, Palin WM (2015). Biomodulatory effects of laser irradiation on dental pulp cells in vitro. Progress in Biomedical Optics and Imaging, 9309: 930908

Palin WM, Hadis MA, Milward MR, Carroll JD, Cooper PR (2015). Beam profile measurements for dental phototherapy: The effect of distance, wavelength and tissue thickness, Progress in Biomedical Optics and Imaging, 9309: 930905

Hadis MA, Cooper PR, Milward MR, Gorecki P, Tarte E, Churm J, Palin WM (2015). The effect of UV-Vis to near-infrared light on the biological response of human dental pulp cells. Progress in Biomedical Optics and Imaging, 9309: 930906

Hadis MA, Zainal SA, Holder MJ, Carroll JD, Cooper PR, Milward MR, Palin WM. The dark art of light measurement: accurate radiometry for low-level light therapy. Lasers Med Sci. 2016 May;31(4):789-809. doi: 10.1007/s10103-016-1914-y .

Hadis MA, Cooper PR, Milward MR, Gorecki PC, Tarte E, Churm J, Palin WM. Development and application of LED arrays for use in phototherapy research. J Biophotonics. 2017 Feb 6. doi: 10.1002/jbio.201600273.

• NIHR
• Philips

• Professor Paul Cooper
• Dr Mike Milward
• Professor Will Palin
• Michelle Holder
• Dr Mo Hadis