Photoangioplasty: An emerging clinical cardiovascular role for photodynamic therapy.

Photodynamic therapy (PDT) has been studied and applied to various disease processes. The potential of PDT for selective destruction of target tissues is especially appealing in cardiovascular disease, in which other existing interventional tools are somewhat nonselective and carry substantial risk of damage to the normal arterial wall. Enthusiasm for photoangioplasty (PDT of vascular de novo atherosclerotic and, potentially, restenotic lesions) is fueled by more effective second-generation photosensitizers and technological advances in endovascular light delivery. This excitement revolves around at least 4 significant attributes of light-activated therapy: the putative selectivity and safety of photoangioplasty, the potential for atraumatic and effective debulking of atheromatous plaque through a biological mechanism, the postulated capability to reduce or inhibit restenosis, and the potential to treat long segments of abnormal vessel by simply using fibers with longer light-emitting regions. The available nonclinical data, coupled with the observations of a new phase I trial in human peripheral atherosclerosis, suggest a promising future for photoangioplasty in the treatment of primary atherosclerosis and prevention of restenosis.

Noninvasive functional imaging of human brain using light.

Analysis of photon transit time for low-power light passing into the head, and through both skull and brain, of human subjects allowed for tomographic imaging of cerebral hemoglobin oxygenation based on photon diffusion theory. In healthy adults, imaging of changes in hemoglobin saturation during hand movement revealed focal, contralateral increases in motor cortex oxygenation with spatial agreement to activation maps determined by functional magnetic resonance imaging; in ill neonates, imaging of hemoglobin saturation revealed focal regions of low oxygenation after acute stroke, with spatial overlap to injury location determined by computed tomography scan. Because such slow optical changes occur over seconds and co-localize with magnetic resonance imaging vascular signals whereas fast activation-related optical changes occur over milliseconds and co-localize with EEG electrical signals, optical methods offer a single modality for exploring the spatio-temporal relationship between electrical and vascular responses in the brain in vivo, as well as for mapping cortical activation and oxygenation at the bedside in real-time for clinical monitoring.

Laser balloon angioplasty.

Unlike conventional transluminal percutaneous angioplasty (PTCA), which applies only intraluminal pressure, laser balloon angioplasty (LBA) employs simultaneous heat and pressure to reopen heavily occluded arterial lumens. The circumferential irradiation of Nd:YAG (1.06 microns) laser light is directly absorbed by approximately 1 to 2 mm of arterial tissue immediately adjacent to the inflated balloon. Such heating by LBA is able to seal disrupted luminal flaps, thermally remodel the luminal surface topology, reduce arterial recoil, selectively (partially) dehydrate thrombus, and possibly even reduce thrombogenicity at atherosclerotic sites. Criteria for successful LBA are defined based on earlier fundamental in vitro experiments to determine effective welding temperature, laser power doses, and exposure period; in addition, the derivation and validity of a three-part optical-thermal model and its application in parametric dosimetry analysis are presented. Though the lumen remodeled by LBA is acutely satisfactory, recurrence of the lesion is problematic chronically. Because of this, LBA is currently most useful as an adjunctive procedure whenever PTCA fails to produce optimal results or causes acute vessel closure. Perhaps, another potential application of the LBA system is to aid localized delivery of pharmacologic agents and their thermal adhesion to superficial tissue at angioplastied sites.

Stationary headband for clinical time-of-flight optical imaging at the bedside.

Conventional brain-imaging modalities may be limited by high cost, difficulty of bedside use, noncontinuous operation, invasiveness or an inability to obtain measurements of tissue function, such as oxygenation during stroke. Our goal was to develop a bedside clinical device able to generate continuous, noninvasive, tomographic images of the brain using low-power nonionizing optical radiation. We modified an existing stage-based time-of-flight optical tomography system to allow imaging of patients under clinical conditions. First, a stationary head-band consisting of thin, flexible optical fibers was constructed. The headband was then calibrated and tested, including an assessment of fiber lengths, the existing system software was modified to collect headband data and to perform simultaneous collection of data and image reconstruction, and the existing hardware was modified to scan optically using this headband. The headband was tested on resin models and allowed for the generation of tomographic images in vitro; the headband was tested on critically ill infants and allowed for optical tomographic images of the neonatal brain to be obtained in vivo.

A model for optical and thermal analysis of laser balloon angioplasty.

Laser balloon angioplasty is modeled using an infinitely long cylinder possessing axisymmetry. The balloon surface is assumed to be uniformly irradiated by diffuse light at 1060 nm delivered from within the inner balloon core. The diffusion approximation to the radiative transport equation is solved for a single layer of homogeneous medium enclosing the transparent fluid-filled balloon. The computed light fluence rate (W.cm-2) just beneath the tissue surface is 4.7 times the primary irradiance, owing to scattering and secondary irradiance from the "integrating cylinder" effect of backscattered light into the inner core. The transient temperature response of the heated tissue is then calculated using an implicit finite difference solution of the heat conduction equation for concentric layers of varying thermal properties. Finally, the extent of damage is analyzed using the Arrhenius rate process model. Changes in optical and thermal properties with temperature and thermal phase transitions have been omitted in all our analyses. Irradiances which decrease with time can produce a "temperature plateau" for a longer time period than a constant irradiance of equal total energy output. This may be clinically important. Flexible boundary conditions at the balloon interface permit simulation of a "hot contact surface," such as a black balloon absorbing all incident laser power. In this situation, the computed surface damage is consistently higher than that obtained by LBA of equivalent energy output.

Changes in birefringence as markers of thermal damage in tissues.

Light microscopy using polarized transmission illumination of routinely stained histologic sections shows changes of the native birefringence of certain tissue constituents when heated by laser irradiation or electrosurgical current. The naturally occurring birefringence of cardiac muscle disappears permanently when the muscle is frozen, thawed, and heated to temperatures in excess of 42 degrees C in vitro. This loss of birefringence is produced with temperatures at which other morphologic thermal changes are hard to detect; thus, it is a low-temperature tissue marker which can be used to observe the extent of thermal damage in tissues. Partial loss of the native birefringence of collagen occurs in canine urinary bladder coagulated by laser irradiation and pericardium heated with electrodes. In addition, thermally coagulated collagens have variable birefringence color shifts when compared to the adjacent unaffected collagens in stained histologic sections. The gradual birefringence color changes are seen at tissue temperatures higher than those at which the thermally induced hyalinization (coagulation) of collagen usually occurs (about 60-70 degrees C), but below those at which carbonization is seen (200+ degrees C). Birefringence changes can be measured to test mathematical models of thermal damage necessary for development of dosimetry models in medical applications of laser irradiation.

Laser physics and laser-tissue interaction.

Within the last few years, lasers have gained increasing use in the management of cardiovascular disease, and laser angioplasty has become a widely performed procedure. For this reason, a basic knowledge of lasers and their applications is essential to vascular surgeons, cardiologists, and interventional radiologists. To elucidate some fundamental concepts regarding laser physics, we describe how laser light is generated and review the properties that make lasers useful in medicine. We also discuss beam profile and spotsize, as well as dosimetric specifications for laser angioplasty. After considering laser-tissue interaction and light propagation in tissue, we explain how the aforementioned concepts apply to direct laser angioplasty and laser-balloon angioplasty. An understanding of these issues should prove useful not only in performing laser angioplasty but in comparing the reported results of various laser applications.

In vitro optical properties of human and canine brain and urinary bladder tissues at 633 nm.

Absorption and scattering coefficients and scattering anisotropy factor are presented for human and canine cadaver tissues at the helium-neon wavelength (633 nm). Measurements were performed with an integrating sphere arrangement and analyzed with the diffusion approximation of the equation of radiative transfer adapted to Kubelka-Munk techniques.

Forward-adjoint fluorescence model: Monte Carlo integration and experimental validation.

The adjoint form of the photon transport equation is applied to a generalized fluorescence detection problem, and its accuracy is empirically tested. This approach can be interpreted as mathematically reversing the temporal flow of fluorescent photons; that is, they are tracked from the detector back to potential sites of origin in the scattering medium. The result is a distribution of potential fluorescing sites that, when properly normalized, gives a probability field of the relative importance of the photon starting position and direction to the resulting signal. This adjoint solution can be combined with the temporally forward-derived distribution of absorbed excitation photons to evaluate the fluorescence excitation detection scheme. This bypasses the normal, temporal derivation wherein the fluorescence transport solution is dependent on the result of the excitation transport solution.

Ice-Front Propagation Monitoring in Tissue by the use of Visible-Light Spectroscopy.

For demonstrating that visible-light spectroscopy can be used for ice-front detection within freezing tissue, proton magnetic resonance images were correlated to time-evolving transmittance spectra as an ice front progressed across a tissue sample. The experimental apparatus was designed to be compatible with magnetic resonance imaging, to produce one-dimensional freezing, and to allow both reflectance and transillumination emitter-detector configurations about a normally progressing planar ice front in chicken muscle. This demonstration has potentially important medical applications in cryopreservation (freezing of biological materials for preservation) and cryosurgery (destruction of tissue by freezing).

Heat generation in laser irradiated tissue.

Many medical applications involving lasers rely upon the generation of heat within the tissue for the desired therapeutic effect. Determination of the absorbed light energy in tissue is difficult in many cases. Although UV wavelengths of the excimer laser and 10.6 microns wavelength of the CO2 laser are absorbed within the first 20 microns of soft tissue, visible and near infrared wavelengths are scattered as well as absorbed. Typically, multiple scattering is a significant factor in the distribution of light in tissue and the resulting heat source term. An improved model is presented for estimating heat generation due to the absorption of a collimated (axisymmetric) laser beam and scattered light at each point r and z in tissue. Heat generated within tissue is a function of the laser power, the shape and size of the incident beam and the optical properties of the tissue at the irradiation wavelength. Key to the calculation of heat source strength is accurate estimation of the light distribution. Methods for experimentally determining the optical parameters of tissue are discussed in the context of the improved model.

Bedside imaging of intracranial hemorrhage in the neonate using light: comparison with ultrasound, computed tomography, and magnetic resonance imaging.

Medical optical imaging (MOI) uses light emitted into opaque tissues to determine the interior structure. Previous reports detailed a portable time-of-flight and absorbance system emitting pulses of near infrared light into tissues and measuring the emerging light. Using this system, optical images of phantoms, whole rats, and pathologic neonatal brain specimens have been tomographically reconstructed. We have now modified the existing instrumentation into a clinically relevant headband-based system to be used for optical imaging of structure in the neonatal brain at the bedside. Eight medical optical imaging studies in the neonatal intensive care unit were performed in a blinded clinical comparison of optical images with ultrasound, computed tomography, and magnetic resonance imaging. Optical images were interpreted as correct in six of eight cases, with one error attributed to the age of the clot, and one small clot not seen. In addition, one disagreement with ultrasound, not reported as an error, was found to be the result of a mislabeled ultrasound report rather than because of an inaccurate optical scan. Optical scan correlated well with computed tomography and magnetic resonance imaging findings in one patient. We conclude that light-based imaging using a portable time-of-flight system is feasible and represents an important new noninvasive diagnostic technique, with potential for continuous monitoring of critically ill neonates at risk for intraventricular hemorrhage or stroke. Further studies are now underway to further investigate the functional imaging capabilities of this new diagnostic tool.

Quantitative angioscopy: a novel method of measurement of luminal dimensions during angioscopy with the use of a "lightwire".

PURPOSE: To determine the accuracy and reproducibility of luminal dimension measurements of a newly developed method of quantitative angioscopy. METHODS: A method was developed for quantitation of luminal dimensions during angioscopy, as variation in magnification with lens-object distance and ambiguity associated with identification of corresponding points about the circumference of a given discrete cross-section render subjective estimates unreliable. A transverse ring of fiberoptically transmitted light was emitted from a guidewire or its housing at a known distance from the distal end of an angioscope and discrete cross-sections of interest were observed as the ring of light was reflected from the luminal surface. Caliper measurement of the diameter of the light ring image (< 50 mW at 488/515 nm), obtained on angioscopic video recordings of cylindrical phantom vessels of known dimensions, was performed by three observers on five occasions. RESULTS: The mean absolute difference between measured and known luminal diameter (n = 405 observations) was 65 microns +/- 35 microns and the mean coefficient of variation was 4.2%, and the mean difference between measured and known areas (n = 195 observations) was 0.4 mm2, with a mean coefficient of variation of 6.5%. CONCLUSION: By use of this new lightwire method, luminal dimensions can now be measured in vitro with a high degree of accuracy and reproducibility during angioscopy.