Michael D. Sherar

Clinical Use of Ultrasound Biomicroscopy

The authors have developed a method of obtaining images of cross-sections of the intact anterior globe at microscopic resolution. High-frequency ultrasound transducers (50-100 MHz) have been developed and incorporated into a clinical B-scan device capable of producing images in the living human eye to a depth of approximately 4 mm at an axial and lateral resolution approaching 20 microns. Clinical use of this instrument is no more difficult than conventional immersion ultrasonography. The authors results in a series of 14 clinical cases have shown that this method can provide information unavailable from any other imaging technique. Anterior segment tumors difficult to define with conventional ultrasound can be measured and the extent of invasion determined. Differentiation of tissue on the basis of internal acoustic characteristics is aided by the very fine backscatter speckle patterns at these frequencies. Pathology behind anterior segment opacities can be imaged in detail and the ability to image angle structures in cross-section allows a new quantitative method of gonioscopy. The ability to define the relationship of the iris, posterior chamber, zonules, ciliary body, and lens is potentially helpful in understanding mechanisms of glaucoma. Ocular structures can be measured with increased accuracy. Clinical ultrasound biomicroscopy (UBM) has shown significant potential as an aid in diagnoses of ocular disease.

Subsurface Ultrasound Microscopic Imaging of the Intact Eye

The authors have developed a method of obtaining images of cross sections of the intact eye at microscopic resolution. High-frequency ultrasound transducers (100 MHz) have been developed and incorporated into imaging devices. These devices are capable of producing images to a depth of 4 mm at an axial and lateral resolution approaching 20 microns. Resolution exceeds that of current combined A- and B-scan imaging devices by a factor of approximately 10. Microscopic images of ocular structures including Schlemms canal, cornea, iris, ciliary muscles, and retina have been produced in eye bank eyes. These studies show the feasibility of developing an apparatus to be used in the clinical setting for examining anterior structures of the eye not visible by current techniques.

Large blood vessel cooling in heated tissues: a numerical study

Large blood vessels can produce steep temperature gradients in heated tissues leading to inadequate tissue temperatures during hyperthermia. This paper utilizes a finite difference scheme to solve the basic equations of heat transfer and fluid flow to model blood vessel cooling. Unlike previous formulations, heat transfer coefficients were not used to calculate heat transfer to large blood vessels. Instead, the conservation form of the finite difference equations implicitly modelled this process. Temperature profiles of heated tissues near thermally significant vessels were calculated. Microvascular heat transfer was modelled either as an effective conductivity or a heat sink. An increase in perfusion in both microvascular models results in a reduction of the cooling effects of large vessels. For equivalent perfusion values, the effective conductivity model predicted more effective heating of the blood and adjacent tissue. Furthermore, it was found that optimal vessel heating strategies depend on the microvascular heat transfer model adopted; localized deposition of heat near vessels could produce higher temperature profiles when microvascular heat transfer was modelled according to the bioheat transfer equation (BHTE) but not the effective thermal conductivity equation (ETCE). Reduction of the blood flow through thermally significant vessels was found to be the most effective way of reducing localized cooling.

A theoretical comparison of energy sources-microwave, ultrasound and laser-for interstitial thermal therapy

A number of heating sources are available for minimally invasive thermal therapy of tumours. The purpose of this work was to compare, theoretically, the heating characteristics of interstitial microwave, laser and ultrasound sources in three tissue sites: breast, brain and liver. Using a numerical method, the heating patterns, temperature profiles and expected volumes of thermal damage were calculated during standard treatment times with the condition that tissue temperatures were not permitted to rise above 100 degrees C (to ensure tissue vaporization did not occur). Ideal spherical and cylindrical applicators (200 microm and 800 microm radii respectively) were modelled for each energy source to demonstrate the relative importance of geometry and energy attenuation in determining heating and thermal damage profiles. The theoretical model included the effects of the collapse of perfusion due to heating. Heating patterns were less dependent on the energy source when small spherical applicators were modelled than for larger cylindrical applicators due to the very rapid geometrical decrease in energy with distance for the spherical applicators. For larger cylindrical applicators, the energy source was of greater importance. In this case, the energy source with the lowest attenuation coefficient was predicted to produce the largest volume of thermally coagulated tissue, in each tissue site.

Ultrasound imaging of apoptosis: high-resolution non-invasive monitoring of programmed cell death in vitro, in situ and in vivo

SummaryA new non-invasive method for monitoring apoptosis has been developed using high frequency (40 MHz) ultrasound imaging. Conventional ultrasound backscatter imaging techniques were used to observe apoptosis occurring in response to anticancer agents in cells in vitro, in tissues ex vivo and in live animals. The mechanism behind this ultrasonic detection was identified experimentally to be the subcellular nuclear changes, condensation followed by fragmentation, that cells undergo during apoptosis. These changes dramatically increase the high frequency ultrasound scattering efficiency of apoptotic cells over normal cells (25- to 50-fold change in intensity). The result is that areas of tissue undergoing apoptosis become much brighter in comparison to surrounding viable tissues. The results provide a framework for the possibility of using high frequency ultrasound imaging in the future to non-invasively monitor the effects of chemotherapeutic agents and other anticancer treatments in experimental animal systems and in patients.

Ultrasonic spectral parameter characterization of apoptosis

Ultrasound (US) spectral analysis methods are used to analyze the radiofrequency (RF) data collected from cell pellets exposed to chemotherapeutics that induce apoptosis and other chemicals that induce nuclear transformations. Calibrated backscatter spectra from regions-of-interest (ROI) were analyzed using linear regression techniques to calculate the spectral slope and midband fit. Two f/2 transducers, with operating frequencies of 30 and 34 MHz (relative bandwidths of 93% and 78%, respectively) were used with a custom-made imaging system that enabled the collection of the raw RF data. For apoptotic cells, the spectral slope increased from 0.37 dB/MHz before drug exposure to 0.57 dB/MHz 24 h after, corresponding to a change in effective scatterer radius from 8.7 to 3.2 microm. The midband fit increased in a time-dependent fashion, peaking at 13dB 24 h after exposure. The statistical deviation of the spectral parameters was in close agreement with theoretical predictions. The results provide a framework for using spectral parameter methods to monitor apoptosis in in vitro and in in vivo systems and are being used to guide the design of system and signal analysis parameters.

Development of a radiofrequency based thermal therapy technique in an in vivo porcine model for the treatment of small renal masses.

PURPOSEnIncidentally detected small renal tumors appear to grow slowly and be localized to the kidney. Minimally invasive therapies are being investigated as alternatives to standard surgical techniques. Radiofrequency ablation has been reported for the treatment of small renal cell carcinomas. We developed a radiofrequency technique and established its efficacy and safety in a large animal model.nnnMETHODS AND METHODSnA total of 22 lesions were created in normal kidneys of 7 pigs. Radiofrequency energy was administered during open exposure of the kidneys or percutaneously under ultrasound guidance. Lesion development was monitored with gray-scale and power Doppler ultrasound. To avoid heating surrounding tissues new hydro-dissection and gas-dissection techniques were developed. Lesion sizes and characteristics were assessed by ultrasound and pathological examination.nnnRESULTSnNo complications were observed due to probe insertion and removal. Perirenal structures were thermally damaged before the development and application of the dissection techniques. Lesion size was accurately predicted by gray-scale ultrasound on day 7. Loss of perfusion in the ablated volume was confirmed by power Doppler ultrasound. Lesions were wedge-shaped, presumably due to the effects of heating on segmental blood flow distribution. Pathological examination revealed changes consistent with thermal injury and ischemic type infarction.nnnCONCLUSIONSnRadiofrequency thermal therapy is an effective and efficient method for ablating normal renal tissue in the pig. It may be applied percutaneously under ultrasound guidance with minimal complications provided that vital adjacent structures are protected from thermal damage. Further studies are required in humans before adopting this technique as definitive treatment for small renal cell carcinoma.

Blood flow cooling and ultrasonic lesion formation

This article examines lesion formation using focused ultrasound and demonstrates how blood flow may affect lesion dimensions using a theoretical model. The effects of blood flow on temperature distributions during ultrasonic lesioning are examined for both regional cooling by the microvasculature and localized cooling due to thermally significant vessels. Regional cooling was critically assessed using two models: the Pennes bioheat transfer equation and the scalar effective thermal conductivity equation. Localized cooling was modeled by adding an advective term in the heat diffusion equation in regions enclosed by thermally significant vessels. A finite difference approach was used to solve the basic equations of heat transfer in perfused tissues in cylindrical coordinates. The extent of the lesioned tissue was determined by the accumulated thermal dose at each location. The size of the lesion was then calculated from the boundaries of the thermal isodose curves generated by the simulations. The results were compared to published in vivo lesion data in rat liver. It was shown that even for short ultrasound exposure times (approximately 8 s), blood flow may play an important role in the thermal dose distribution.

Experimental evaluation of two simple thermal models using transient temperature analysis

Thermal models are used to predict temperature distributions of heated tissues during thermal therapies. Recent interest in short duration high temperature therapeutic procedures necessitates the accurate modelling of transient temperature profiles in heated tissues. Blood flow plays an important role in tissue heat transfer and the resultant temperature distribution. This work examines the transient predictions of two simple mathematical models of heat transfer by blood flow (the bioheat transfer equation model and the effective thermal conductivity equation model) and compares their predictions to measured transient temperature data. Large differences between the two models are predicted in the tissue temperature distribution as a function of blood flow for a short heat pulse. In the experiments a hot water needle, approximately 30 degrees C above ambient, delivered a 20 s heating pulse to an excised fixed porcine kidney that was used as a flow model. Temperature profiles of a thermocouple that primarily traversed the kidney cortex were examined. Kidney locations with large vessels were avoided in the temperature profile analysis by examination of the vessel geometry using high resolution computed tomography angiography and the detection of the characteristic large vessel localized cooling or heating patterns in steady-state temperature profiles. It was found that for regions without large vessels, predictions of the Pennes bioheat transfer equation were in much better agreement with the experimental data when compared to predictions of the scalar effective thermal conductivity equation model. For example, at a location r approximately 2 mm away from the source, the measured delay time was 10.6 +/- 0.5 s compared to predictions of 9.4 s and 5.4 s of the BHTE and ETCE models, respectively. However, for the majority of measured locations, localized cooling and heating effects were detected close to large vessels when the kidney was perfused. Finally, it is shown that increasing flow in regions without large vessels minimally perturbs temperature profiles for short exposure times; regions with large vessels still have a significant effect.

Optical phantom materials for near infrared laser photocoagulation studies

Phantoms were developed that simulate tissue with dynamic and static optical properties with which to study the effects of laser irradiation.