Journal of Clinical Laser Medicine & Surgery Volume 19, Number 1, 2001 Mary Ann Liebert, Inc. Pp.

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Biostimulatory Windows in Low-Intensity Laser Activation: Lasers, Scanners, and NASAs Light-Emitting Diode Array System
ANDREI P. SOMMER,1 ANTONIO L.B. PINHEIRO, 2 ADAM R. MESTER,3 RALF-PETER FRANKE,1 and HARRY T. WHELAN 4

ABSTRACT Objective: The purpose of this study was to assess and to formulate physically an irreducible set of irradiation parameters that could be relevant in the achieving reproducible light-induced effects in biological systems, both in vitro and in vivo. Background Data: Lighttissue interaction studies focusing on the evaluation of irradiation thresholds are basic for the extensively growing applications for medical lasers and related light-emitting systems. These thresholds are of central interest in the rejuvenation of collagens, photorefractive keratectomy, and wound healing. Methods: There is ample evidence that the action of light in biological systems depends at least on two threshold parameters: the energy density and the intensity. Depending on the particular light delivery system coupled to an irradiation source, the mean energy density and the local intensity have to be determined separately using adequate experimental methods. Results: From the observations of different research groups and our own observations, we conclude that the threshold parameters energy density and intensity are biologically independent from each other. Conclusions: This independence is of practical importance, at least for the medical application of photobiological effects achieved at low-energy density levels, accounting for the success and the failure in most of the cold laser uses since Mesters pioneering work.

INTRODUCTION

meliorated wound closures have been achieved at energy densities between 1 and 4 3 104 Jm22 in the therapy of ulcera cruris with 50-mW He/Ne-lasers.3 This and further evidence have led to the establishment of one basic Arndt-Schultz curve (Fig. 1) showing different modes of cell reaction at different levels of energy density.18 When energy densities were too small, there were no observable effects. Higher energy densities resulted in the inhibition of cellular functions. So far, the energy densities of reproducible photobiological effects that could be of therapeutic relevance821 were generally in accordance with the effective energy density range described in the basic Arndt-Schultz-curve. The influence of the light intensity on the irradiated cells was subsequently demonstrated in fibroblast cultures (Fig. 2),22 and possibly as well in animal experi1Central 2School

ments: The mast cells of irradiated mouse tongues showed progressive degranulation with increasing laser power (4 mW, 50 mW) where the locally administered energy density was kept at the same level.23 Assuming that the cross sections of both laser beams were of the same magnitude, this experiment would hint at the intensity dependence of photobiological cell membrane effects in vivo. This activation of mast cells could also represent a significant mechanism in the acceleration of wound healing under the correct laser light irradiation. Observations in patients also revealed that thresholds of light intensity (presumably wavelength dependent) have to be surpassed to achieve reproducible biostimulatory effects. However, there is no clinical documentation of the precise threshold values. What had been repeatedly found was that the clinical use of lasers with a power smaller than 4 mW in the field of application induced no reproducible biological effects, independent of the length of the total

Institute of Biomedical Engineering, Department of Biomaterials, ENSOMA-Laboratory, University of Ulm, 89081 Ulm, Germany. of Dentistry, Department of Diagnostic and Therapeutic, Federal University of Bahia, Salvador, BA 40110-150, Brazil. 3Semmelweis University of Medicine, Department of Radiology and Oncotherapy, 1082 Budapest, Hungary. 4NASA-Marshall Space Flight Center, Huntsville, Alabama 35812.

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Sommer et al. to the cooperative behavior of photostimulated cells,28,29 it seems to be important to irradiate the application field simultaneously to avoid adverse effects with respect to the intended aims.30 Consequently, the application field would have to be irradiated in the shortest possible period, creating a homogenously distributed mean energy density with the necessary local light intensity, as required for activation. Scanners have been developed for these practically important cases and have been used in vivo with satisfactory results. The suitability of conventional scanners for medical applications depends, besides the values of the local light intensity, on the uniformity of the mean energy density in the application field, thus implying a high scanning velocity of the laser beam. The successful application of conventional scanners is, however, hampered by an increasing energy density difference between the periphery and the center of the application field. This energy density difference was shown to increase with increasing scanner speed,8 and can easily be understood because the mean irradiation time in the vicinity of the periphery of the scan increases as the scanning speed slows down due to the approach of the laser beam to its turning point. Energy density ratios of 5:1 from the periphery to the center of the scan have been reported for linear scanners. Therefore, energy densities within

FIG. 1.

Basic Arndt-Schultz curve.18

irradiation time.24,25 Unfortunately, the results were never correlated with the value of the laser beam cross section; otherwise, the importance of laser light intensity in low-level laser therapy (LLLT) would have been ascertained earlier.

THE LILAB EQUATION

It becomes clear that the stimulative effect of laser light in biological tissues depends on a set of at least four parameters, besides the wavelength of the light: a light intensity threshold I0, the beam cross section a, the total irradiation time Dttot, and the energy density (E/a)act required for activation. The stimulation parameters relevant for activation are interrelated according to the low-intensity laser-activated biostimulation (LILAB) equation: (E/a)act 5 Istim.Dttot, (1)

where intensities necessary for stimulation Istim have to surpass the threshold intensity I0.26,27 The majority of the published results with a negative outcome stem from ignoring the importance of the relation: Istim $ I0 (2)

in photobiological experiments. Light intensities lower than threshold values I0 obviously do not produce biostimulatory effects, even under a prolongation of the irradiation time Dttot. The effective range of (E/a)act in equation (1) is given by the particular Arndt-Schultz curve. Although equation (1) is physically surprisingly simple, the biological implications are by no means trivial. Biologically, the parameters (E/a)act and Istim are clearly independent from each other, an important consideration at least for the medical applications of photobiological effects with the use of lasers (including noncoherent light sources) at low-energy density levels.

APPLICATIONS OF THE LILAB EQUATION

In practice, it is of great importance to apply the laser light to a much greater area than the laser beam cross section itself. Due

FIG. 2. Percentage of dividing fibroblasts, 24 h after irradiation at 540 nm at a constant energy density of 4 3 104 Jm22.22 Principal result of the preliminary study was the experimental demonstration of the existence of a light intensity window in vitro.

Biostimulatory Windows in LLLT the activating fluency range8 in the central field of laser application would be followed by potentially damaging higher energy densities with opposite effects in the collateral field. Thus, an adequate aperture is used to shield and protect the peripheral tissue, a waste of expensive scanner power. Studies comparing the biological results of laser irradiation applied via scanners to the spot by spot method are missing in the accepted literature available (MedLine). In agreement with equation (1), the biologically effective light intensities can also be applied on greater areas by use of high-power lasers in combination with optical lenses (beam-diverging systems). This is presently still a very expensive solution due to the cost of high-power lasers. However, beam-diverging systems could be adequate with suitable semiconductor lasers, as reported on the successful photobiostimulation treatment of General Motors workers and other patients with carpal tunnel syndrome.31 Potential light sources promising for photobiostimulation of extended wound areas with homogeneous mean field intensities and energy densities within the activating range,8 appear to us to be light-emitting diodes (LED) and NASAs lightweight light-emitting diode array systems in particular.17,18 In contrast to the threshold intensity necessary for activation Istim, a quantity directly calculable from the technical data of the laser, the mean field intensity Ifield in any application field A greater than the cross section of the laser beam can only be determined accurately by measuring the mean energy density (E/A). The determination of this quantity is relatively simple in cases of the spot surfaces generated by beam-diverging systems, and more complicated in case of the light patterns generated by scanners as described in the literature.8,32,33 The question of whether (E/A) is an activating energy density or not depends not explicitly on the particular magnitude of the associated Ifield value, but primarily on the value of the local light intensity Istim and the total duration of the local light stimulus per activated field. The LILAB System,37 being also an exemplary model to demonstrate the interplay between biologically relevant irradiation parameters, permits, besides the periodical photobiostimulation of large surfaces, avoiding the aforementioned disadvantages commonly associated with medical lasers used in wound healing. The LILAB System is based on a very fast beam distributor designed for homogeneous irradiation of arbitrarily large application fields.8 This beam distributor (Fig. 3) consists in its simplest version of the following basic components: a

31

FIG. 4. DNA synthesis for 24 h ([3H]thymidine incorporation).16 Results as percent change relative to control: histogram from 1 R r. Control 5 100%: no LED treatment. LED treatment (670 nm) at 4.0 3 104 J/m2 and 743 W/m2. LED treatment (728 nm) at 4.0 3 104 J/m2 and 400 W/m2. LED treatment (880 nm) at 4.0 3 104 J/m2 and 530 W/m2.

small electric motor, two mirrors, and a swinging rod system. The electric motor, attached to the laser housing via a rubber shock absorber, drives a rotating mirror holder with mirror M2. The motor speed is continuously variable. The mirror holder is attached to the end of the shaft of the motor. The mirror holder has a ring with a sinusoidal outer-edge profile. This sinusoidal ring profile rides on a suspended swinging rod system, also attached to the laser housing via a similar rubber shock absorber. On the other end of the rod, the second mirror (M1) is mounted. The laser beam reflected by the mirror M1 paints, depending on the drive rotation speed, a dense light pattern on the mirror M2, subsequently directed toward the field of application. Using a prototype LILAB System based on a 25-mW He/Ne laser (632.8 nm), we could generate various energy density fields nearly homogenously spread over the total irradiation field. A simple variation in rotation speed of the drive allowed arbitrary high-beam velocities without the energy density gradients prevalent with conventional scanner systems.8,32 The energy density variation within the periodic light patterns generated by the LILAB system, scanned so quickly that it could mimic locally pulsed lasers, amounted to a maximum of 30%.32 For mean field intensities of biological relevance generated by the LILAB System (72 Wm22 at 632.8 nm),33 we realized and described dynamic light intensities similar to the magnitude of those administered via NASAs irradiation system, ranging from 24 Wm22 to 743 Wm22. These intensities were found to be effective in fibroblasts, osteoblasts, and skeletal muscle cells.1618 Recent laboratory results observed in murine osteoblasts irradiated with the NASA LEDs, and the associated experimental protocol, accounting for the irreducible set of the three biologically independent parameters (wavelength, energy density, intensity) necessary for complete characterization of the irradiation, are shown in Fig. 4.16

DISCUSSION
To illustrate the practical implications of the equations (1) and (2) and their implementation in irradiation systems applied in LLLT, we described the LILAB System. This irradiation system is well suited for generating homogeneous energy densities

FIG. 3. Beam distributor for lasers with principal components: drive, rotating mirror M2, and swinging rod system ending in mirror M1.26

32 at stimulating local intensities, thus satisfying the conditions and the generally accepted basic principles necessary in experimental and clinical work. The existence of an upper limit for the applicable light intensity, as found in cell culture experiments,22 could not be observed in clinical practice, presumably because of the change of the intensity with the depth of penetration due to absorption. However, with an upper limit for the stimulating light intensity, as demonstrated by Lubart,22 we could now be, in principle, in the position to evaluate effectively activating energy density thresholds/stimulating intensity windows at the surface and in deeper layers of any biological tissue. Realizing the importance of intensity and energy density, there is no way to circumvent in future laser experiments the specification of the laser beam diameter and, in using scanners, the measurement of the mean energy density. The method for the measurement of the mean energy density generated by scanners and its validation has been published.33 Besides the light intensity thresholds and the activating mean energy densities, determined in case of the scanners by the cumulation of the duration of local light stimuli, certain beam repetition frequencies with extended influence on activation seem to exist. There is also evidence from literature for their existence. The biological effect of the pulse frequency received support from the experimental side from the observation of additional Ca21 uptake in macrophages34 and an enhanced chemiluminescence in murine splenocites35 after irradiation with pulsed semiconductor lasers of suitable pulse duration and repetition frequency. There has also been support from the clinical side.36 Thus, the periodical stimulation of extended tissue areas with maximum local photon density, uniform energy density, and minimum thermal effects as realized, e.g., with the LILAB System is a powerful method for the achievement of photobiological results with lasers.37 We are now studying the molecular mechanisms behind these results, also in case of selectively stimulatory irradiation parameters. At the European Nearfield Scanning Optical Microscopy Application Laboratory (ENSOMA), we are attempting to establish a connection between low-intensity lightactivated biostimulation, and near-field optical methods. This study could facilitate our direct access to topographical changes on nanoscale levels and reveal detailed morphological responses, observable in cells reacting to their far-field stimulation with light.

Sommer et al. mechanism of accelerated wound healing processes induced by light, by co-sponsoring the 1st International Workshop on Nearfield Optical Analysis.

REFERENCES
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CONCLUSIONS
The present study suggests that the irradiation of areas exceeding the cross section of laser beams with homogenous energy densities must be paralleled in practice by the precise measurement of at least two independent threshold parameters: the local intensity of the laser beam, respective diode field, and the mean energy density in the application field.

ACKNOWLEDGMENT
We are grateful to the American Chemical Society (ACS) for supporting the advance in the investigation of the molecular

Biostimulatory Windows in LLLT

19. Pinheiro, A.L.B. personal communication. Irradiation of mouth ulcers in 57 HIV-positive patients, an average of three ulcers per patient (23 patients with lesions strongly related to the HIV infection), using 5-mW lasers (635 and 670 nm, beam cross sections , 1 mm2) and local light doses between 0.9 and 3.4 3 104 Jm22, revealed generally an approximately 50% reduction of the total healing period of the ulcers, when compared to nonirradiated cases. In the HIV related cases, the healing times depended upon the actual status of infection of the patients: AIDS-related complex (ARC) patients reacted in general better to the laser therapy than patients having developed full AIDS. 20. Pinheiro, A.L.B. personal communication. Laser irradiation of tissues contacting implants improved osteointegration (animal experiment): laser power 40 mW, wavelength 830 nm, beam cross section , 1 mm2, dose per spot 1.2 3 104 Jm22, and total dose per session 4.8 3 104 Jm22. Abstract in: Martins, P.P.M., Pinheiro, A.L.B., Oliveira, M.A.M., and Gerbi, M.E.M. (2000). P.P.M.M. implant system have osteointegration improved by LLLT. World Association for Laser Therapy, Third World Congress. Athens, 1113 May. 21. Tunr, J., and Hode, L. (1999). Low Level Laser TherapyClinical Practise and Scientific Background. Sweden: Prima Books, pp. 161162. 22. Lubart, R., Friedmann, H., Peled, I., and Grossman, N. (1993). Light Intensity Effect on Cell Proliferation. Fifth Congress of the European Society for Photobiology. Marburg/Lahn, September 1926. 23. Trelles, M.A., and Mayayo, E. (1992). Mast cells are implicated in low power laser effect on tissue. A preliminary study. Lasers Med. Sci. 7, 7377. 24. Mester, A.R. (1992). Modalities of low power laser applications. Laser Applications in Medicine and Surgery. Laser Bologna 92. Third World CongressInternational Society for Low Power Laser Applications in Medicine. Bologna, September 912. 25. Mester, A.R. (1994). Low power laser in the complex wound management. Laser Ther. 6, 39. 26. Sommer, A. (1993). Fast Surface Covering Beam Distributor for Lasers. German Patent Office, Munich, Patent Nr. 4308474/2000. 27. Lubart, R., Friedmann, H., Peled, I., and Grossman, N. (1993). Fi-

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Address reprint requests to: Dr. A.L.B. Pinheiro School of Dentistry Department of Diagnostic & Therapeutic Federal University of Bahia Av. Araujo Pinha 62 Canela Salvador, BA 40110-150, Brazil

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60. Aurelcio N. Silva Jnior , Antonio L.B. Pinheiro , Marlia G. Oliveira , Ruben Weismann , Luciana Maria Pedreira Ramalho , Renata Amadei Nicolau . 2002. Computerized Morphometric Assessment of the Effect of Low-Level Laser Therapy on Bone Repair: An Experimental Animal Study. Journal of Clinical Laser Medicine & Surgery 20:2, 83-87. [Abstract] [Full Text PDF] [Full Text PDF with Links] 61. 2002. Laser Literature Watch. Journal of Clinical Laser Medicine & Surgery 20:1, 43-49. [Citation] [Full Text PDF] [Full Text PDF with Links] 62. Harry T. Whelan , Robert L. Smits Jr. , Ellen V. Buchman , Noel T. Whelan , Scott G. Turner , David A. Margolis , Vita Cevenini , Helen Stinson , Ron Ignatius , Todd Martin , Joan Cwiklinski , Alan F. Philippi , William R. Graf , Brian Hodgson , Lisa Gould , Mary Kane , Gina Chen , James Caviness . 2001. Effect of NASA Light-Emitting Diode Irradiation on Wound Healing. Journal of Clinical Laser Medicine & Surgery 19:6, 305-314. [Abstract] [Full Text PDF] [Full Text PDF with Links] 63. Margaret T. T. Wong-Riley, Xuetao Bai, Ellen Buchmann, Harry T. Whelan. 2001. Light-emitting diode treatment reverses the effect of TTX on cytochrome oxidase in neurons. Neuroreport 12:14, 3033-3037. [CrossRef]