Endometrial ablation has gained significant clinical acceptance over the last decade as a minimally invasive treatment
for abnormal uterine bleeding. To improve upon current thermal injury modeling, it is important to better characterize
the myometrium’s thermotolerance. The extent of myometrial thermal injury was determined across a spectrum of
thermal histories/doses (time-temperature combinations). Fresh extirpated human myometrium was obtained from 13
subjects who underwent a previous scheduled benign hysterectomy. Within two hours of hysterectomy, the unfixed
myometrium was treated in a stabilized saline bath with temperatures ranging from 45-70 °C and time intervals from 30-
150 seconds. The time-temperature combinations were selected to simulate treatment times under 2.5 minutes. A total of
six such thermal matrices, each comprised of 45 time-temperature combinations, were prepared for evaluation. The
treated myometrium was cryosectioned for nitro blue tetrazolium (NBT) staining to assess for thermal respiratory
enzyme inactivation. Image analysis was subsequently used to quantitatively assess the stained myometrium’s capacity
to metabolize the tetrazolium at each time-temperature combination. This colorimetric data was then used as marker of
cellular viability and determine survival parameters with implications for developing minimally invasive uterine
therapies.
Thermal therapy has the potential to provide a nonexcisional alternative to tonsillectomy. Clinical implementation
requires that the lymphoid tissue of tonsils is heated homogeneously to produce an amount of primary thermal injury that
corresponds to gradual postoperative tonsil shrinkage, with minimal risk of damage to underlying critical blood vessels.
Optical constants are derived for tonsils from tissue components and used to calculate the depth of 1/e of irradiance. The
1125 nm wavelength is shown to correspond to both deep penetration and minimal absorption by blood. A probe for
tonsil thermal therapy that comprises two opposing light emitting, temperature controlled surfaces is described. For ex
vivo characterization of tonsil heating, a prototype 1125 nm diode laser is used in an experimental apparatus that splits
the laser output into two components, and delivers the radiation to sapphire contact window surfaces of two temperature
controlled cells arranged to irradiate human tonsil specimens from opposing directions. Temperatures are measured with
thermocouple microprobes at located points within the tissue during and after irradiation. Primary thermal damage
corresponding to the recorded thermal histories are calculated from Arrhenius parameters for human tonsils. Results
indicate homogeneous heating to temperatures corresponding to the threshold of thermal injury and above can be
achieved in advantageously short irradiation times.
Clinical implementation of a thermal therapy requires the ability to predict tissue injury following exposures to specific
thermal histories. As part of an effort to develop a nonexcisional alternative to tonsillectomy, the degree of primary
hyperthermic tissue injury in human tonsil was characterized. Fifteen fresh pediatric hypertrophic tonsillectomy
specimens were sectioned and treated in a NIST-calibrated saline bath at temperatures of 40 to 70°C with hold times of
one to seven minutes. The treated tissues were subsequently nitroblue tetrazolium (NBT) stained to assess for thermal
respiratory enzyme inactivation as a marker of cellular injury/death. The NBT stains were quantitatively image analyzed
and used to calculate Arrhenius parameters for primary thermal injury in human tonsils.
A new approach for improving the availability of topically applied drugs by reducing the permeability of dermis has
been evaluated. The premise of this work is that photothermal vascular injury will reduce vascular uptake of drug in the
dermis. The dermal distribution of two topically applied drugs, 5-fluorouracil and mitomycin C, is calculated,
considering molecular diffusion and vascular uptake according to a distributed model, in the presence and absence of
vascular injury. Intradermal drug exposures obtained are compared to exposures known to be effective in killing tumor
cells. Combining the reduction in dermal permeability with fractional photothermal epidermal ablation to increase
epidermal permeability may allow higher drug concentrations to be achieved in the skin. A newly developed laser
handpiece for implementing the technique is described.
Photothermal injury to the sebaceous glands is a potential curative treatment for the common skin disease acne vulgaris. Accumulation of the exogenous chromophore indocyanine green in the sebaceous glands may be accomplished using an emulsion or liposomal formulation applied to the skin surface. An emulsion containing 0.09% by weight indocyanine green (ICG) was applied to the epidermis of hamster ears ex vivo and the flank organ in vivo. Fluorescence microscopy demonstrated selective accumulation of ICG in the underlying sebaceous glands. The concentration of ICG that may be expected to accumulate in sebaceous glands of humans was then estimated on the basis of the gland size and orifice area, for the case of topical application of a more concentrated 1% ICG liposomal formulation. Monte Carlo modeling and heat transfer calculations showed that the sebaceous glands containing the exogenous chromophore may be selectively damaged by pulsed 810 nm laser radiation in conjunction with cryogen spray cooling.
Vascular targeting is a recent approach to cancer therapy that aims at damaging tumor vasculature to induce tumor cell hypoxia and subsequent cell death. Squamous cell cancer arises in the superficial mucosal and cutaneous epithelial layers, and tumor microvasculature therefore may be particularly well suited for targeting by selective photothermolysis. An initial evaluation of the effect of selective eradication of microvasculature on tumor development was undertaken here using the chemically-induced hamster cheek pouch model and a 585 nm pulsed dye laser. In a first group of 6 hamsters, progression of premalignant mucosal lesions was compared between control and laser treatment groups, and laser-induced regression of established tumors was evaluated. In a second group of 12 hamsters, the number of laser treatments required to produce complete regression of tumors of the buccal mucosa was determined. The effect of the laser on tumors appearing on the skin in these animals was also investigated. These experiments showed that laser treatment inhibited tumor development and caused complete regression of established tumors 10 mm3 or smaller. Photothermal microvascular targeting may be useful in treating dyplasia and early tumors of the upper aerodigestive tract and skin, with fewer adverse sequelae than existing modalities.
Preliminary animal model experiments have been performed to test the feasibility of a new treatment for snoring. Current surgical treatments for snoring at the palatal level involve either excision of tissue to shorten the palate, or interstitial ablation of the palate to induce fibrosis and stiffening. Both shortening and stiffening of the palate are believed to be effective in reducing snoring. Mucosal surface damage and delayed tissue sloughing are the cause of considerable pain for the patient. In the new treatment proposed here, palatal stiffening with mucosal preservation is accomplished by combining evaporative cooling at the tissue surface with laser irradiation to heat subsurface tissue layers. The surface is cooled using a timed spray of tetrafluoroethane immediately prior to each pulse from a 1.54 micrometer erbium glass laser. In vivo experiments demonstrate that the technique causes significant shrinkage and decreased elasticity in hamster skin, with no tissue sloughing. In vitro experiments with canine soft palates show that laser-induced thermal damage zones ranged from approximately 0.75 to 1.75 mm below the surface, depending on laser parameters. These results suggest that the noninvasive laser technique may produce palatal stiffening with protection of the mucosal surface, for treatment of snoring with minimal morbidity.
Recurrent respiratory papillomatosis (RRP) is a viral disease characterized by the growth of benign tumors on the vocal cords. Standard management of RRP currently consists of CO2 laser microsurgical ablation of the papillomas. Because of the recurrent nature of this disease, patients are often faced with significant cumulative risk of soft tissue complications such as vocal cord scarring. As a minimally traumatic alternative to management of RRP, we have investigated the use of the 585 nm pulsed dye laser (PDL) to cause regression of the papillomas by selective eradication of the tumor microvasculature. Three patients have been treated with the PDL at fluences of 6 J/cm2 (double pulses per irradiated site), 8 J/cm2 (single pulses), and 10 J/cm2 (single pulses), at noncritical areas within the larynx, using a specially designed micromanipulator. Lesions on the true cords were treated with the CO2 laser. Clinical examination showed that PDL treatment appeared to produce complete regression of papillomas. Unlike the sites of lesions treated by the CO2 laser, the epithelial surface at the PDL treatment sites was preserved intact. The presumed mechanism for papilloma regression following PDL treatment involves acute or chronic localized hypoxia caused by loss of tumor microvasculature.
Vascular ectasias (dilatation) and vascular lesions of the larynx are difficult to treat with exciting modalities. Varix (enlarged vessel) of the vocal folds, vocal fold hemorrhage, vascular polyp, hemangioma, intubation or contact granuloma are common problems which disturb voice. Current applications of CO2 laser and cautery often damage the delicate vocal fold cover. The 585 nm dermatologic pulsed dye laser may be an ideal substitute. Two adult canines were examined under anesthesia via microlaryngoscopy technique. Pulsed dye laser (SPTL-1a, Candela Laser Corp., Wayland, MA) energy was delivered via the micromanipulator with the 3.1-mm spot size in single pulses of 6, 8, and 10 Joules/cm2 and applied to the vessels of the vocal folds, epiglottis, and arytenoid cartilage. Endoscopic examination was carried out immediately after the treatment and at 4 weeks postoperatively. The animals were sacrificed at 3 weeks, larynges excised, and whole organ laryngeal section were prepared for histology. Pulsed dye laser thrombosed vessels of the vocal fold using 6 or 8 Joules/cm2. Vascular break and leakage occurred at 10 Joules/cm2. Follow up examination showed excellent vessel obliteration or thrombosis without scarring or injury to the overlying tissues. Histologic examination shows vascular thrombosis without inflammation and fibrosis in the vocal fold cover. Pulsed dye laser may have promise in treatment of vascular lesions of the larynx and upper airway.
Ten to fifteen thousand new cases of recurrent respiratory papillomatosis (RRP) are diagnosed each year in the United States. RRP is caused by the human papillomavirus (HPV) and is characterized by recurrent, non-malignant, proliferative lesions of the larynx. Patients with RRP undergo numerous microsurgical procedures to remove laryngeal papilloma threatening airway patency and interfering with phonation. The standard surgical technique involves CO2 laser vaporization of laryngeal epithelium affected by the lesions, and requires general anesthesia. The pulsed dye laser operating at 585 nm has previously been demonstrated to be effective in clearing HPV lesions of the skin (verrucae). For treatment of RRP, the fiber- compatible pulsed dye laser radiation may be delivered under local anesthesia using a flexible intranasal laryngoscope. Potential advantages of the pulsed dye laser treatment over CO2 laser surgery include (1) reduced morbidity, especially a lower risk of laryngeal scarring; (2) lower cost; (3) reduced technical difficulty; and (4) reduced risk of viral dissemination or transmission. In vivo studies are underway to determine the effect of pulsed dye laser radiation on normal canine laryngeal tissue.
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