NASA Light Emitting Diode Medical Applications From Deep Space to Deep SEA

 

Harry T. Whelan1a,5,7 , Ellen V. Buchmann1a, Noel T. Whelan1a,7 Scott G. Turner1a, Vita Cevenini7, Helen Stinson7, Ron Ignatius2, Todd Martin2, Joan Cwiklinski1a, Glenn A, Meyer1c,Brian Hodgson3,4, Lisa Gould1b,MARY Kane1b, Gina Chen1b, James Caviness6

 

1cDepartments of Neurology, 1bPlastic Surgery, 1cNeurosurgery,

Medical College of Wisconsin, Milwaukee, WI 53226, (414) 456-4090

2Quantum Devices, Inc Barneveld, WI 53507 (608) 924-3000

3Children’s Hospital of Wisconsin, Milwaukee, WI 53210 (414) 266-2044

44th Dental Battalion, 4th Force Service Support Group, USMCR, Marietta, GA

5Naval Special Warfare Group TWO, Norfolk, VA 23521, (757)462-7759

6Submarine Squadron ELEVEN, San Diego, CA 92106, (619)553-8719

7NASA-Marshall Space Flight Center, AL 35812 (256)544-2121

 

Abstract. This work is supported and managed through the NASA Mashall Space Flight Center – SBIR Program. LED-technology developed for NASA plant growth experiments in space shows promise for delivering light deep into tissues of the body to promote wound healing and human tissue growth. We present the results of LED-treatment of cells grown in culture and the effects of LEDs on patients’ chronic and acute wounds. LED-technology is also biologically optimal for photodynamic therapy of cancer and we discuss our successes using LEDs in conjunction with light-activated chemotherapeutic drugs.

 

LED-ENHANCEMENT OF CELL GROWTH

 

Studies on cells exposed to microgravity and hypergravity indicate that human cells need gravity to stimulate growth. As the gravitational force increases or decreases, the cell function responds in a linear fashion. This poses significant health risks for astronauts in long-term space flight. The application of light therapy with the use of NASA LEDs will significantly improve the medical care that is available to astronauts on long-term space missions. NASA LEDs stimulate the basic energy processes in the mitochondria (energy compartments) of each cell, particularly when near-infrared light is used to activate the color sensitive chemicals (chromophores, cytochrome systems) inside. Optimal LED wavelengths include 680, 730 and 880 nm and our laboratory has improved the healing of wounds in laboratory animals by using both NASA LED light and hyperbaric oxygen. Furthermore, DNA synthesis in fibroblasts and muscle cells has been quintupled using NASA LED light alone, in a single  application combining 680, 730 and 880 nm each at 4 Joules per centimeter squared.

 

Muscle and bone atrophy are well documented in astronauts, and various minor injuries occurring in space have been reported not to heal until landing on Earth. An LED blanket device may be used for the prevention of bone and muscle atrophy in astronauts. The depth of near-infrared light penetration into human tissue has been measured spectroscopically (Chance, et al., 1988). Spectra taken from the wrist flexor muscles in the forearm and muscles in the calf of the leg demonstrate that most of the light photons at wavelengths between 630-800 nm travel 23cm through the surface tissue and muscle between input and exit at the photon detector. The light is absorbed by mitochondria where it stimulates energy metabolism in muscle and bone, as well as skin and subcutaneous tissue.

 

Long term space flight, with its many inherent risks, also raises the possibility of astronauts being injured performing their required tasks. The fact that the normal healing process is negatively affected by microgravity requires novel approaches to improve wound healing and tissue growth in space. NASA LED arrays have already flown on Space Shuttle missions for studies of plant growth and the U.S. Food and Drug Administration (FDA) has proved human trials. The use of light therapy with LEDs can help prevent bone and muscle atrophy as well as increase the rate of wound healing in a microgravith environment, thus reducing the risk of treatable injuries becoming mission catastrophes.

 

Space flight has provided a laboratory for studying wound healing problems due to microgravity, which mimic traumatic wound healing problems here on earth. Improved wound healing may have multiple applications that benefit civilian medical care, military situations and long-term space flight. Laser light and hyperbaric oxygen have been widely acclaimed to speed wound healing in ischemic, hypoxic wounds. An excellent review of recent human experience with near-infrared light therapy for wound healing was published by Conlan, et al (Conlan, 1996). Laser provide low energy stimulation of tissues which results in increased cellular activity during wound healing (Beauvoit, 1994, 1995: Eggert, 1993; Karu, 1989; Lubart, 1992, 1997; Salansky, 1998; Whelan, 1999; Yu, 1997) including increased fibroblast proliferation, growth factor syntheses, collagen production and angiogenesis. Lasers, however, have some inherent characteristics that make their use in a clinical setting problematic, such as limitations in wavelength capabilities and beam width. The combined wavelengths of light optimal for wound healing cannot be efficiently produced, and the size of wounds that may be treated by lasers is limited. Light-emitting diodes (LEDs) offer an effective alternative to lasers. These diodes can be made to produce multiple wavelengths, and can be arranged in large, flat arrays allowing treatment of large wounds. Potential benefits to NASA, military, and civilian populations include treatment of serious burns, crush injuries, non-healing fractures, muscle and bone atrophy, traumatic ischemic wounds, radiation tissue damage, compromised skin grafts, and tissue regeneration.

 

Combat casualty care in Special Operations already have adopted the NASA LED technology for submarines deployed in training with risk of injury. The USS Salt Lake City is currently underway with an LED Array in the Pacific. Special Operations are characterized by lightly equipped, highly mobile troops entering situations requiring optimal physical conditioning at all times. Wounds are an obvious physical risk during combat operations. Any simple and light weight equipment that promotes wound healing and musculoskeletal rehabilitation and conditioning has potential merit. NASA LEDs have proven to stimulate wound healing at near-infrared wavelengths of 680, 730 and 880 nm in laboratory animals, and have been approved by the U.S. Food and Drug Administration (FDA) for human trials. The NASA LED arrays are light enough and mobile enough to have already flown on the Space Shuttle numerous times. LED arrays may be used for improved wound healing and treatment of problem wounds as well as speeding the return of deconditioned personnel to full duty performance. Examples include; 1. Promotion of the rate of muscle regeneration after confinement or surgery. 2. Personnel spending long periods of time aboard submarines may use LED arrays to combat muscle atrophy during relative inactivity. 3. LED arrays may be introduced early to speed wound healing in the field. Human trials have began at the Medical College of Wisconsin, Naval Special Warfare Command, Submarine Squadron ELEVEN and NASA-Marshall Space Flight Center.

 

LED-PHOTODYNAMIC THERAPY FOR CANCER

 

Astronauts in deep space are subjected to increased-levels of radiation, compared to low-earth orbit environments. Cancer protection strategies are therefore a subject of our NASA-LED photodynamic therapy program. Photodynamic therapy (PDT) is a cancer treatment modality that recently has been improved using LED space technology. PDT consists of intravenously injecting a photo sensitizer, which preferentially accumulates in tumor cells, into a patient and then activating the photo sensitizer with a light source. This results in free radical generation followed by cell death. LED’s are an effective alternative to lasers for PDT. Laser conversion to near-infrared wavelengths is inherently costly and inefficient, using an argon ion or KTP/YAG laser beam that is converted by a dye module, usually to 630 nm. LED’s have been frequently used to emit longer wavelength broad spectrum near-infrared light of 25-30 nm bandwidths. LED lamps traditionally consist of an array of semi conducting LED chips.

In recent years, improvements in semiconductor technology have substantially increased the light output of LED chips. A novel type of LED chip is based on the semiconductor Aluminum Gallium Arsenide (ALGaAs).These LED chips have been manufactured to emit light with peak wavelengths of 680 and 730 nm, which are optimal wavelengths for the absorption spectrum of the new photo sensitizers used for cancer PDT

 

The development of more effective light sources for PDT of brain rumors has been facilitated by applications of space light-emitting diode array technology; thus permitting deeper tumor penetration of light and use of better photo sensitizers. Lutetium Texaphyrin (Lutex) and Benzoporphyrin Derivative (BPD) are new, second generation photo sensitizers that can potentially improve PDT for brain tumors. Lutex and BPD have major absorption peaks at 730 nm and 680 nm respectively, which gives them two distinct advantages. First, longer wavelengths of light penetrate brain tissue easily so that larger tumors could be treated; and second, the major absorption peaks mean that more of the drug is activated upon exposure to light. In deep space the LED-PDT technology may be capable of early cancer surveillance and treatment before radiation-induced tumors can develop in astronauts.

 

Tumoricidal effects of Lutex and BPD have been studied in vitro using canine glioma and human glioblastoma cell cultures. Using light-emitting diodes (LED) with peak emissions of 728 nm and 680 nm as a light source, a greater then 50 percent cell kill was measured in both cell lines by tumor DNA synthesis reduction. The effectiveness of Lutex and BPD against tumor cells in vitro thus established, we have taken the first step toward determining their in vivo efficacy by performing experiments to determine the largest doses of both Lutex, or BPD, and light that can be administered to dogs before toxicity is seen, i.e. the maximum tolerated dose (MTD). Using this dose allows us to effect maximum tumor cell destruction during in vivo studies.

 

Photodynamic Therapy with NASA LED Human Subjects

 

Preclinical and clinical studies of LED-photodynamic therapy were reported previously (Whelan, et al., 1993, 1999, 2000; Schmidt, 1996,1999), and continue under our FDA approval.

 

Improvements Realized from LED Arrays

 

Red laser light is frequently produced using an argon ion or KTP/YAG laser beam that is converted by a dye module, usually to 630 nm. For longer wavelengths of light improved technology is required. Laser conversion to near-infrared wavelengths is inherently costly and inefficient, but allows for light to be delivered by fiberoptics. For non-fiberoptic delivery of light, LEDs offer an alternative. LEDs have been frequently used to emit low power, broad spectrum light of 25-30 nm bandwidths in an array of semiconductor chips. In recent years, improvements in semi conductor technology have substantially increased the light output of LED chips. Dr. Whelan’s laboratory has already used LED array light successfully in cancer treatment (Whelan, et al., 2000), with Photofrin, and has published animal data with Photofrin, Benzoporphyrin Derivative (BPD) and lutetium texaphyrin (Schmidt, et al., 1996, 1999; Whelan, et al., 2000). Resulting human skin cancer treatment trials with LED-based PDT using BPD have occurred, and FDA approval for use of LED-based PDT in children and adults with brain tumors has prompted an further human studies. BPD has a spectral photo activation/ absorption peak of 680 nm and lutetium texaphyrin has an absorption peak at 730 nm, both involving high, long-lived quantum yields for triplet states that produce singlet oxygen cytotoxic to cancer cells.

 

Currently, PDT with Photofrin has become standard therapy for lung cancer (superficial microinfiltrating, palliative endobronchial) and advanced esophageal cancer (adenocarcinoma, squamous cell carcinoma). Furthermore, balloon adapters developed by Quantum Devices and tested in Dr. Whelan’s laboratory and in his brain tumor patients show promise for adaptation to esophageal use to flatten out the folds of tissue lining, in which cancer cells could otherwise hide from light. Barrett’s esophagus investigators at University of Tennessee (Knoxville) have already displayed an interest in this LED balloon adaptor application. LED arrays, and LED probes for skin cancer, psoriasis and theumatoid arthritis treatment using BPD, and advances of the other cancer PDT regimens to use of the newer photo sensitizers all promise to launch the NASA LED Medical Program to full PDT commercialization rapidly, with the test-site strategy described.