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U.S. Department of Health and Human Services

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Research Project: Light-Tissue Interactions and Laser Safety in Medical Devices

The objective of this key research project is to investigate fundamental working biochemical mechanisms of light-tissue interactions; non-invasive and minimally invasive optical therapeutics technologies and devices concerning critical optical parameters and laser radiation safety issues related to various medical lasers, medical fiber-optic technologies and new therapeutic monitoring systems; and methods for characterizing laser beam propagation and laser dosimetry in tissue. 

Task 1: Investigation of Light-Induced Therapy and Noninvasive Deep Tissue Optical Therapeutics

Principal Investigators:
Ronald Waynant, PhD (contact: ronald.waynant@fda.hhs.gov)
Darrell Tata, PhD

Erkinay Abliz
Sindhoora Murthy

Understanding the biological response and outcome to non-ionizing radiation for various light therapeutic devices is of keen interest to CDRH. There is a growing body of evidence in the literature to suggest that selective types of “low level light” exposures on biological systems can bring about a vast array of therapeutic responses. The manner in which the light energy is delivered, i.e., wavelength, intensity, total energy of deposition, and the location of exposure are important parameters that have been observed to bring about varying degrees of positive therapeutic effects on serious human ailments. Although laser light has unique applications in medicine, its mechanism of action for low intensity exposures on cells, tissues, and the body continues to be controversial after nearly 50 years of investigations. We have recently presented evidence for visible red and near infrared light to induce (indirect) generation of hydrogen peroxide as an important chemical messenger behind the stimulatory and inhibitory responses observed from low intensity light exposures. It is hypothesized that other ionizing or non-ionizing modalities which can either directly or indirectly induce/or generate H2O2 in an aqueous environment can also bring about similar stimulatory or inhibitory bio-effects. One of the salient parameter which governs the bio-response is the level of generated H2O2. We have studied on the mechanism which enables a small amount of hydrogen peroxide generated by light to produce beneficial effects.

Photodynamic agents such as Photofrin II (Photo II) utilized in photodynamic therapy (PDT) possess a remarkable property to become preferentially retained within the tumor’s micro-environment. Upon the photo-agent’s activation through visible light photon absorption, the agents exert their cellular cytotoxicity through type II and type I mechanistic pathways through extensive generation of reactive oxygen species (ROS): singlet oxygen 1O2, superoxide anion O2-, and hydrogen peroxide H2O2, within the intra-tumoral environment. Unfortunately, due to shallow visible light penetration depth (~ 2mm to 5mm) in tissues, the PDT strategy currently has largely been restricted to the treatments of surface tumors, such as the melanomas. Additional invasive strategies through optical fibers are currently utilized in getting the visible light into the intended deep seated targets within the body for PDT. In our investigations we have formulated a strategy for visible light production into deep seated targets for photo-activation of PDT through X-ray induced luminescence from Gadolinium oxysulfide (20 micron dimension) particles doped with Terbium: Gd2O2S:Tb.

X-ray induced visible luminescence from Gd2O2S:Tb particles was spectroscopically characterized and the ROS production levels from clinically relevant concentration (10 micro-gram/ml) of Photo II was quantified through changes in the Vitamin C absorbance. ROS kinetics through X-ray induced luminescence was found to be similar to the ROS kinetics from red He-Ne laser exposures used in the clinics. In-vitro findings herein provide the basis for future studies to determine the safety and efficacy of this non-invasive X-ray induced luminescence strategy in activating photo-agents in deep seated tumors. Similarly, near infra-red penetration depths are also significantly deeper (~ 1 – 2 cm) than visible light’s depth of penetration, and we have utilized a 980nm wavelength laser irradiation to induce visible light luminescence from engineered NaYF4:Yb,Tm “rare-earth” nano-particles. Manipulating rare-earth elements ratio and composition of the nano-particles (~ 50 nm dimension) enabled the infra-red induced visible luminescence as shown in the luminescence spectrum graph below which enables the activation of PDT agents.

Task 2: Evaluation of Safety and Efficacy of Light Sources in Scanning and Endoscopic Devices

Principal Investigators:
Do-Hyun Kim, PhD (contact: do-hyun.kim@fda.hhs.gov)
Ilko K Ilev, PhD

James Anderson (Summer, 2010)
Sean Wang (Summer, 2010)

Due to the enhanced performance and unique detection capability, more and more medical optical devices are utilizing scanning light sources. Also, due to the capability of non- or minimally-invasive diagnostic and therapeutic delivery of light source and transfer of signals from the target objects, more and more endoscopic devices are used in wide range of biomedical applications. Both scanning and endoscopic medical devices have unique characteristics in their light sources: the light source is moving across the target and is usually focused. The technology utilized in scanning and endoscopic devices is evolving fast, thus adequate evaluation methods in terms of their safety and efficacy is highly demanded.

This project investigates on the characterization of output beam profiles, irradiation distributions, and phototoxicity of light sources used for scanning and endoscopic medical devices to evaluate safety and efficacy.

Below is the list of devices under investigation:

  • Confocal Laser Scanning Microscope
  • Single-Fiber Sensor and Scanning Endoscope
  • Endoscopic Fiber-Optic Laser Delivery System
  • Multi-Photon and Nonlinear Scanning Microscope
  • Optical Coherence Tomography
  • Adaptive Optics Scanning Ophthalmoscope
  • Supercontinuum Light Source for Scanning and Endoscopic Devices
  • Photoacoustic Tomography using Endoscopic Pulse Delivery System
  • Scanning Laser Ophthalmoscope

Task 3: Laser Beam Propagation Through Biological Tissue to Evaluate Laser Dosimetry and Safety in Therapeutic Devices

Principal Investigators:
Ilko K Ilev, PhD (contact: ilko.ilev@fda.hhs.gov)
Do-Hyun Kim, PhD

Renee Naphas
Will Calhoun

To optimize the effectiveness and safety of laser and incoherent broadband light source systems used in medicine as diagnostic and therapeutic devices, knowledge on both basic irradiation parameters such as wavelength, intensity, specific temporal and spatial beam characteristics, and the optical tissue properties including its absorption and scattering characteristics is of fundamental importance. Furthermore, for accurate laser dosimetry of minimally invasive optical therapeutic devices, it is important to know the dynamic behavior of radiation and tissue properties during and after irradiation process. The primary objective of this investigation is to study the fundamental principles and effects of both continuous-wave and pulsed laser beam propagation through biological tissue. The tissues will have various optical properties including highly scattering (turbid) and thick tissue samples in order to identify key parameters that may affect the accuracy and specificity of photodosimetry in minimally invasive laser therapeutic procedures. The study will include various independent theoretical and experimental approaches for precise laser delivery into tissue areas and formation of laser beam profiles with specific intensity distributions in the ultraviolet, visible and infrared spectral ranges. The findings of this investigation will lead to a better understanding of basic laser-tissue interaction mechanisms and laser beam propagation in turbid tissue. Relevant results will be incorporated into test methods for evaluation of critical laser dosimetric parameters and safety criteria for diagnostic and therapeutic techniques and devices such as refractive corneal (LASIK) and cataract surgeries.