Chronic hepatitis is accompanied by progressive deposit of hepatic fibrosis, which may lead to cirrhosis. Evaluation of liver fibrosis is, thus, of great clinical interest and, up to now, has been assessed with liver biopsy. This work aims to evaluate a new noninvasive device to quantify liver fibrosis: the shear elasticity probe or fibroscan. This device is based on one-dimensional (1-D) transient elastography, a technique that uses both ultrasound (US) (5 MHz) and low-frequency (50 Hz) elastic waves, whose propagation velocity is directly related to elasticity. The intra- and interoperator reproducibility of the technique, as well as its ability to quantify liver fibrosis, were evaluated in 106 patients with chronic hepatitis C. Liver elasticity measurements were reproducible (standardized coefficient of variation: 3%), operator-independent and well correlated (partial correlation coefficient = 0.71, p /= F2) and with cirrhosis ( = F4), respectively. The Fibroscan is a noninvasive, painless, rapid and objective method to quantify liver fibrosis.

Transient elastography: a new noninvasive method for assessment of hepatic fibrosis

Supersonic shear imaging (SSI) is a new ultrasound-based technique for real-time visualization of soft tissue viscoelastic properties. Using ultrasonic focused beams, it is possible to remotely generate mechanical vibration sources radiating low-frequency, shear waves inside tissues. Relying on this concept, SSI proposes to create such a source and make it move at a supersonic speed. In analogy with the "sonic boom" created by a supersonic aircraft, the resulting shear waves will interfere constructively along a Mach cone, creating two intense plane shear waves. These waves propagate through the medium and are progressively distorted by tissue heterogeneities. An ultrafast scanner prototype is able to both generate this supersonic source and image (5000 frames/s) the propagation of the resulting shear waves. Using inversion algorithms, the shear elasticity of medium can be mapped quantitatively from this propagation movie. The SSI enables tissue elasticity mapping in less than 20 ms, even in strongly viscous medium like breast. Modalities such as shear compounding are implementable by tilting shear waves in different directions and improving the elasticity estimation. Results validating SSI in heterogeneous phantoms are presented. The first in vivo investigations made on healthy volunteers emphasize the potential clinical applicability of SSI for breast cancer detection.

Supersonic shear imaging: a new technique for soft tissue elasticity mapping

A nuclear magnetic resonance imaging (MRI) method is presented for quantitatively mapping the physical response of a material to harmonic mechanical excitation. The resulting images allow calculation of regional mechanical properties. Measurements of shear modulus obtained with the MRI technique in gel materials correlate with independent measurements of static shear modulus. The results indicate that displacement patterns corresponding to cyclic displacements smaller than 200 nanometers can be measured. The findings suggest the feasibility of a medical imaging technique for delineating elasticity and other mechanical properties of tissue.

https://science.sciencemag.org/content/sci/269/5232/1854.full.pdf

Magnetic resonance elastography by direct visualization of propagating acoustic strain waves

Elastic Moduli of Breast and Prostate Tissues under Compression

Shear wave elasticity imaging (SWEI) is a new approach to imaging and characterizing tissue structures based on the use of shear acoustic waves remotely induced by the radiation force of a focused ultrasonic beam. SWEI provides the physician with a virtual "finger" to probe the elasticity of the internal regions of the body. In SWEI, compared to other approaches in elasticity imaging, the induced strain in the tissue can be highly localized, because the remotely induced shear waves are attenuated fully within a very limited area of tissue in the vicinity of the focal point of a focused ultrasound beam. SWEI may add a new quality to conventional ultrasonic imaging or magnetic resonance imaging. Adding shear elasticity data ("palpation information") by superimposing color-coded elasticity data over ultrasonic or magnetic resonance images may enable better differentiation of tissues and further enhance diagnosis. This article presents a physical and mathematical basis of SWEI with some experimental results of pilot studies proving feasibility of this new ultrasonic technology. A theoretical model of shear oscillations in soft biological tissue remotely induced by the radiation force of focused ultrasound is described. Experimental studies based on optical and magnetic resonance imaging detection of these shear waves are presented. Recorded spatial and temporal profiles of propagating shear waves fully confirm the results of mathematical modeling. Finally, the safety of the SWEI method is discussed, and it is shown that typical ultrasonic exposure of SWEI is significantly below the threshold of damaging effects of focused ultrasound.

Shear wave elasticity imaging: a new ultrasonic technology of medical diagnostics

Elastography: A Quantitative Method for Imaging the Elasticity of Biological Tissues

An improved ultrasonic pulse-echo method and apparatus that has particular application in making precision measurements of compressibility in any backscattering material, in particular organic tissue, is disclosed. The method employs a standard transducer or transducer containing device which is translated transaxially, thereby compressing or displacing a proximal region of a target body in small known increments. At each increment, a pulse is emitted and an echo sequence (A-line) is detected from regions within the target along the sonic travel path or beam of the transducer. Resulting time shifts in echo segments corresponding to features in the target provide relative and quantitative information concerning compressibility of the target.

Method and apparatus for measurement and imaging of tissue compressibility or compliance

A method for detecting tissue abnormality, particularly precancerous cervical tissue, through fluorescence spectroscopy is disclosed. In vitro fluorescence measurements over a variety of different fluorescence spectra are used to screen tissue samples. Using a principal component analysis (PCA), it is possible to discriminate between normal and dysplastic tissues with relatively low false-positive and false-negative results.

Optical method for the detection of cervical neoplasias using fluorescence spectroscopy

The sensitivity and selectivity of UV-excited resonance Raman spectroscopy indicate that this technique may be useful in studying certain biochemical changes in cells, especially changes in DNA that occur during the development of cancer. To determine whether this technique can distinguish normal from malignant cells, we have measured UV resonance Raman spectra at 257.26 nm excitation of suspensions of normal and malignant cultured breast and cervical cells. Samples were excited with the use of an intracavity doubled argon-ion laser, and the spectra were recorded with a single grating spectrograph and a liquid nitrogen-cooled charge-coupled device. Cell spectra obtained closely resembled that of DNA, with peaks around 1330, 1480, and 1580 cm-1, due to the nucleotide bases. In addition to these, the uracil base in RNA provides a peak at 1230 cm-1. Strong tryptophan and tyrosine contributions appear in the 1520-1670 cm-1 range. The ratios of Raman spectral peaks 1480/ 1614 cm-1 and 1480/1540 cm-1, which are sensitive to the concentration of nucleic acids relative to cell proteins, were found to be higher in malignant cells than in normal cells. Normal and malignant cells could also be differentiated by using the ratio at 1330/ 1480 cm-1. This difference may be the result of decreased hypochromism due to changes in stacking of the purine bases. Changes in relative amounts of RNA may also contribute to this ratio. The results of this pilot study indicate that there may be significant differences in the UV resonance Raman spectra of normal and cancerous cells. These differences may be related to changes in nucleotide/protein concentrations in the cell, as well as changes in the vibrational structure of the nucleic acids associated with the malignant cell phenotype.

Resonance Raman Spectroscopy at 257 nm Excitation of Normal and Malignant Cultured Breast and Cervical Cells

We describe a new model of graduate education in bioengineering innovation and design- a year long Master’s degree program that educates engineers in the process of healthcare technology innovation for both advanced and low-resource global markets. Students are trained in an iterative “Spiral Innovation” approach that ensures early, staged, and repeated examination of all key elements of a successful medical device. This includes clinical immersion based problem identification and assessment (at Johns Hopkins Medicine and abroad), team based concept and business model development, and project planning based on iterative technical and business plan de-risking. The experiential, project based learning process is closely supported by several core courses in business, design, and engineering. Students in the program work on two team based projects, one focused on addressing healthcare needs in advanced markets and a second focused on low-resource settings. The program recently completed its fourth year of existence, and has graduated 61 students, who have continued on to industry or startups (one half), additional graduate education, or medical school (one third), or our own Global Health Innovation Fellowships. Over the 4 years, the program has sponsored 10 global health teams and 14 domestic/advanced market medtech teams, and launched 5 startups, of which 4 are still active. Projects have attracted over US$2.5M in follow-on awards and grants, that are supporting the continued development of over a dozen projects.

Youseph Yazdi

Papers

Elastography: A Quantitative Method for Imaging the Elasticity of Biological Tissues

Method and apparatus for measurement and imaging of tissue compressibility or compliance

Optical method for the detection of cervical neoplasias using fluorescence spectroscopy

Resonance Raman Spectroscopy at 257 nm Excitation of Normal and Malignant Cultured Breast and Cervical Cells

A new model for graduate education and innovation in medical technology.