Diagnostic and Therapeutic Applications of Diode Lasers and Solid State Lasers

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DIAGNOSTIC AND THERAPEUTIC APPLICATIONS C c OF DIODE LASERS AND SOLID STATE LASERS IN MEDICINE University of Texas M. D. Anderson Cancer Center University of Texas at Austin University of Texas Medical Branch at Galveston Naval Research Laboratory UT MD Andenon Rice Univ UT Austin Laser Biology Electrical Biomedical Research Lab. and Computer Naval Engineering Network UT Medical School at Houston Texas Heart Institute cornpising Texas Medical Ganef)

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The Texas Medical Center in Houston and the nearby UT Medical Branch at Galveston together constitute a major center of medical research activities. Laser applications in medicine are under development with the engineering assistance of the colloborating engineering centers at Rice University, UT-Austin, and Texas A&M Univ. In addition, this collective is collaborating with the Naval Research Laboratory, where new developments in laser design are underway, in order to transfer promising new laser technology rapidly into the medical environment. Our research plan has not changed and we arc proceeding along the schedule of the original plan. That research plan is summarized by the following description of DIAGNOSTICS and THERAPEUTICS, which appeared in the original proposal. UTMDA-LLJUCE,UTMSH-Pd4.A.1.2 Monitoring iv lines 4.B.4 Pigmented lesion lreatment by pulscd lascrs 4.B.4.1 Prcvention of mclanoma

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where the abbreviations in the above table arc as follows: NRL Naval Research Laboratory THI Texas Heart Institute University of Texas M. D. Anderson Cancer Center University of Texas at Austin, Biomedical Engineering University of Texas Medical Branch at Galveston Texas A&M University, Bioengineering Program Rice University, Electrical and Computer Engineering University of Texas Medical School at Houston and the suffixes indicate various departments: HeadNeck Head and Neck Surgery Thoracic Thoracic Surgery Gastrointestinal Oncology and Digestive Diseases In the following sections, progress reports are presented from each of the collaborating groups. Within each group's report, the interactions between groups are mentioned. In several instances, reference is made to human studies. These studies are not OfficiaUy a part of this DOE program, which does not cite human studies. In each case, these studies were conducted under approved human protocols. They represent our efforts to translate laser technology into the clinic. This DOE program supports the basic development and design efforts using animal and phantom tissue models which catalyze this technology transfer. The goal of this project is to develop spectroscopic applications of diode lasers for the Neonatal Intensive Care Unit (NICU). We are currently conducting optical studies on prematurely newborn infants at the NICU at Herman Hospital, UTMSH-Ped (Dr. Oelberg). The method uses the optical fiber spectrophotometer and analysis algorithm described in Table 1 of the original proposal. More than 60 infants have been measured so far, and UT now have a research nurse who is routinely measuring infants. We estimate the routine measurements will reach -50 infants per week over a 6-month period, or about 1200 infants. The results of this work are to be applied in design of optical measurements that monitor three 2. monitoring iv lines (4.A.1.2)

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The aim is to establish design parameters and implement the optical techniques using diode We are also assisting RICE in development of another form of optical reflectance This topic isspectroscopy that utilizes diode lasers: Phase and Demodulation Spectroscopy. discussed in the RICE report. The god of this project is to develop endoscopic fluorescence spectroscopy as a means of locating and characterizing abnormal tissue sites, which is especially pertinent to screening for early cancer. We have begun our efforts by developing a prototype fluorescence bronchoscope in collaboration with UTMDA-Thoracic (Dr. Garret Walsh) borrowing an optical multichannel analyzer (OMA) from UTMBG (Dr. M. Motamedi). The prototype system strives to meet two The first step is to illuminate a large area with an excitation beam and use enhanced video images to locate abnormal fluorescence that indicates abnormal tissue sites. (2) Local spectroscopic characterization The second step is to obtain fluorescence spectra from specific sites using an Spectroscopic signatures have potential for characterizing tissues sitesoptical fiber catheter. more specifically than simple changes in the magnitude of fluorescence. Our current prototype system uses our new OMA (not purchased by this program) and a helium-cadmium laser at 440 nm which achieves the high average power for the surveillance task but also can excite fluorescence spectra for local characterization. At this point, we have employed the HeCd laser with a 7-surrounding-1 fiber catheter to obtain spectra from local sites. This bronchoscopic system has measured the lungs of 19 human patients under an approved protocol which is not part of this DOE proposal. Therefore, this work should not actually be considered part of our DOE program. However, it does illustrate how our DOEsponsored program is catalyzing the transfer of technology to the clinic. We have also implemented a nitrogeddye laser system for tunable excitation of fluorescence spectra using a 7-surrounding-1 fiber catheter system. This system allows acquisition of the emission spectra for a series of excitation wavelengths. The resulting data array is called an excitatiodemission matrix. We have measured such an excitatiodemission matrix obtained in uiuo from rat brain in collaboration with UTMDA-Neuro (Dr. Z. Gayan). We are measuring excitation-emission matrices from various cancer cell lines in cell culture and in tumors grown subcutaneously in rats. Such studies allow us to identify the optimum wavelengths for excitation and emission which can characterize a tissue site. Our aim is to implement fluorescence spectra using pulsed solid state lasers. We are working with both the second and third harmonics (532 and 355 nm) of the Q-switched 4.13.1.1 Photocoagulation therapy: benign prostate hyperplasia (BPH) We are collaborating with UTMBG and TAMU on the dcvelopmcnt of diode laser coagulation of the prostate. Eventual collaboration with NRL will investigate the use of solid state lasers. We have obraincd a diode laser bar from Lanircncc Livcrmore National Laboratory (LLNL) and are developing a system for coupling the bar into a fibcr bundle. O u r

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goal is to establish a distributed light source about 1.5-cm long which can be inserted into the urethra via an urethroscope. Current methods use the Nd:YAG laser from a single fiber, which leads to overheating of the site of irradiation and causes much vaporization. We estimate that as much as 87% of the applied energy is going into steam formation rather than into coagulation of - the prostate. By distributing the laser energy source, the overheating can be mitigated. We have also been chosen by the Diomed Ltd. of Cambridge, England, as a test site for their new 25-W diode laser system. This system is portable, self-contained, operates on 110 VAC wall outlet power, and delivers 25 W through a single 400-pm core diameter fiber. We have purchased a fiber splitter (Canstar Inc., Canada) to split the 25 W into four 5-W fiber outputs. These four output fibers are being hcorporated into a catheter system which uses a gold mirror to deflect the four fiber outputs at 90' to yield a distributed irradiance. We have modeled the optical propagation and thermal diffusion process in prostate for practitioners are attempting to achieve photocoagulation too rapidly. Rather than irradiate for 60 s at 60 W, our modeling suggests that 180 s at 20 W (or 360 s at 10 W)would achieve essentially the same spatial distribution of heat, and minimize the overheating of the surface. Therefore, we are developing and testing in dogs (initially at UTMBG and later at UTMDA) dosimetry protocols for optimal photocoagulation in the prostate. Human studies of laser photocoagulation have begun at UTMDA-Urol (Dr. D. Johnson), under approved protocols which are not part of this DOE program. Again, the results of our animal testing under this DOE program are catalyzing the transfer of new laser applications into I n this project, we are testing the use of near-UV lasers, the third harmonic of the Nd:YAG laser (355 nm) and the doubled alexandrite laser (365-400 nm), to achieve tissue ablation. The eventual application is angiosurgery, however the application of laser ablation is quite broad. The choice of near-UV lasers is that protein absorption is utilized rather than water absorption as for the mid-IR lasers. Many have observed that multiple pulses from a midIR laser will dessicate tissue, lowering the tissue abosrption and interfering with the ablation process. In contrast, any dessication during multiple 355-nm pulses will serve only to increase the absorption coefficient and enhance ablation. Therefore, the problem of dessication is selfcorrecting when near-UV wavelengths are used. Our preliminary findings are that 355-nm ablation is more efficient than anticipated on the basis of tissue optical properties at 355 nm under low-irradiance conditions. Therefore, we have been exploring the relative roles of (1) laser-induced increases of absorbance due to excited state absorption and (2) laser-induced spallation due to induced thermoclastic strcss. The goal of this project is to use laser-induced acoustic pressure waves to cause relaxation of blood vessels, Our progress so far has been implementation of a sputtered lithiumniobate detector for measurement of laser-induced pressure waves. The very thin detector allows very high frequency response. We have been studying the acoutic signals generated in bovine liver, chicken breast, and dog prostate by the 355,532, 630, and 1064 nm wavelengths of generated by the laser propagates through the tissue sample to thc rear surface where the

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detector is located. We have experimentally established the effects of geometry on such photomechanical measurements, for example how do beam size, tissue thickness, and optical penetration interact. We have used the technique to measure the absorption and reduced scattering coefficients of the tissues, which constitutes a new optical method similar to classical - photoacoustic spectroscopy but applicable to scattering medium. Wc have also implemented the theory of laser-induced stress wave propagation for comparison with the experimental results. In summary, we have established the behavior of laser-induced acoustic waves in tissues, both theoretically and experimentally. We are poised to intiate experiments on blood vessel relaxation using our dorsal rat skin window chamber model which allows real-time video recording of the vessels during the laser irradiation. 4.B.4 Pigmented lesion treatment by pulsed lasers This project has not yet been initiated. However, we have established a collaboration with Dr. M. Levy a t Texas Childrens Hospital where pulsed dye lasers are used for treatment portwinc stain lesions. Dr. Levy and Dr. Jacques (LTMD:Q arc preparing a human protocol for investigation of Q-switched second-harmonic Nd:YAG laser treatment of superficial pigmented lesions. The UTMDA-LL intends to conduct experimental tests in animals and phantom tissues to elucidate the proper dosimetry for such treatments. The human studies are not part of this DOE program, but illustrate how our DOE program is actively catalyzing the transfer of laser technology into the clinic. We have been conducting PDT on several cancer cell lines grown as subcutaneous tumors in the flanks of rats using the Nd:YAG/harmonic crystalldye laser (630 nm) and two porphyrin sensitizers: (I)Photofrin 11 from Quadralogic Technologies Inc., Canada, and (2) protoporphyrin IX (PPIX) whose de novo synthesis in cells in stimulated by administration of the metabolic precusor 6-aminolevulenic acid (5-ALA). We are quantrfying the degree of dye saturation and dye photodestruction caused by the high-irradiance Q-switched pulsed laser exposure in comparison to low-irradiance continuous light exposure. Our preliminary results show a 3-fold lower efficiency of PDT using the pulsed laser system, suggesting saturation effects. Future work will be investigating the optimal duty cycle (on-off light exposure) which allows reperfusion of oxygen into the cancer cells from nearby blood vessels during the off cycle. We are using fluorescence spectroscopy to monitor the rate constants for PPIX de n o m synthesis in cell cultures and animal tumors, and the rate constant for photodestruction during laser irradiation. Our preliminary results are guiding development of dosimetry protocols that optimize PDT using PPIX. We are considering the logistics of implementing such PPIX-PDT for treatment of prostate cancer and breast cancer. We are collaborating with UTMGB-LL to obtain and test new diode lasers from an industrial source that will generate light in the 630-nm region suitable for PDT. 4.A.2.1 Diagnosis of Cervical Pre-cancer or Dysplasia The goal of this project is to develop a spectroscopic technique to bcttcr direct biopsy placcmcnt during colposcopic screening for cervical dysplasia. W'c h a x conducted studies to determine which excitation wavelengths are most promising for this work. We have recorded fluorescence cxcitation emission matrices of 16 samples of normal and neoplastic human

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cervical tissue in uitro. Following spectroscopic interrogation, samples were submitted for histologic analysis. A prelininary analysis of the data indicates that 360 nm excitation is a promising wavelength for discriminating normal, inflammatory and neoplastic tissue. We conducted fluorescence microscopy studies to identify the morphologic stmctures responsible for this fluorescence. At this excitation wavelength, collagen fibers in the stroma and eosinophils in the epithelium and stroma contributed significant fluorescence in normal, inflammatory and neoplastic tissues. In inflammatory and neoplastic tissues, eosinophilic infiltration was more marked. In normal and inflammatory tissues, no sgnificant fluorescence was observed from epithelial cells. However, carcinoma in situ was associated with. a significant epithelial cell fluorescence. To aid in deconvolving tissue spectra at 360 nm excitation, we determined the fluorescence properties of eosinophils. Eosinophils were isolated from human whole blood. Fluorescence excitation emission matrices were measured, and an excitation emission maxima was observed at 360 mi1 excitation, 420 r u n emission. tliz fluorescence cf scrum dwclling eosinophils lippeared visually different than that of tissue dwelling eosinophils. At 360 nm excitation, tissue dwelling cells exhibited a yellow fluorescence, while serum dwelling cells exhibited bluish fluorescence. !%'e are currently investigating the reasons for this difference. We are presently building a prototype system to record fluorescence spectra from human cervix in uivo. We are constructing a biopsy forceps with an attached optical fiber probe to measure fluorescence emission spectra from normal and abnormal appearing areas a t colposcopy. Initial studies will be conducted at 360 nm excitation based on the results of the preliminary studies described above. 4.A2.2 Examination of the Atherosclerotic Process a t the Molecular Level Our ultimate goal in this project is to develop a combined spectroscopic and ultrasonic imaging system to determine the chemical composition and morphological structure of atherosclerotic plaque in uiuo. We will utilize this system to image coronary artery atherosclerosis in symptomatic patients to predict in advance the least invasive, most effective form of therpay. Two major advances were made in the past year. 1) At UTA we have constructed a prototype imaging system which is capable of recording spectroscopic and ultrasonic images of coronary artery in vitro. This system consists of a mechanical ultrasound catheter with a torroidally shaped piezo-electric transducer. The transducer sends and receives 20 MHz ultrasound pulses to the arterial wall via a rotating concave mirror at a 45" angle with respect to the lumenal axis. The piezo-electric transducer can either be coupled to a pulser-receiver to provide A mode ultrasound scans from pixels of interest or to a commercially available ultrasound imaging system (CVIS, Sunnyvale, CA) available at UTMBG to provide B mode images of the arterial cross section. An optical fiber bundle is epoxied into the central hole of this transducer and uses the …