Criteria for the design of tissue-mimicking phantoms for the standardization of biophotonic instrumentation

A lack of accepted standards and standardized phantoms suitable for the technical validation of biophotonic instrumentation hinders the reliability and reproducibility of its experimental outputs. In this Perspective, we discuss general criteria for the design of tissue-mimicking biophotonic phantoms, and use these criteria and state-of-the-art developments to critically review the literature on phantom materials and on the fabrication of phantoms. By focusing on representative examples of standardization in diffuse optical imaging and spectroscopy, fluorescence-guided surgery and photoacoustic imaging, we identify unmet needs in the development of phantoms and a set of criteria (leveraging characterization, collaboration, communication and commitment) for the standardization of biophotonic instrumentation

The impact of vaporized nanoemulsions on ultrasound-mediated ablation

BACKGROUND: The clinical feasibility of using high-intensity focused ultrasound (HIFU) for ablation of solid tumors is limited by the high acoustic pressures and long treatment times required. The presence of microbubbles during sonication can increase the absorption of acoustic energy and accelerate heating. However, formation of microbubbles within the tumor tissue remains a challenge. Phase-shift nanoemulsions (PSNE) have been developed as a means for producing microbubbles within tumors. PSNE are emulsions of submicron-sized, lipid-coated, and liquid perfluorocarbon droplets that can be vaporized into microbubbles using short (5 MPa) acoustic pulses. In this study, the impact of vaporized phase-shift nanoemulsions on the time and acoustic power required for HIFU-mediated thermal lesion formation was investigated in vitro. METHODS: PSNE containing dodecafluoropentane were produced with narrow size distributions and mean diameters below 200 nm using a combination of sonication and extrusion. PSNE was dispersed in albumin-containing polyacrylamide gel phantoms for experimental tests. Albumin denatures and becomes opaque at temperatures above 58°C, enabling visual detection of lesions formed from denatured albumin. PSNE were vaporized using a 30-cycle, 3.2-MHz, at an acoustic power of 6.4 W (free-field intensity of 4,586 W/cm(2)) pulse from a single-element, focused high-power transducer. The vaporization pulse was immediately followed by a 15-s continuous wave, 3.2-MHz signal to induce ultrasound-mediated heating. Control experiments were conducted using an identical procedure without the vaporization pulse. Lesion formation was detected by acquiring video frames during sonication and post-processing the images for analysis. Broadband emissions from inertial cavitation (IC) were passively detected with a focused, 2-MHz transducer. Temperature measurements were acquired using a needle thermocouple. RESULTS: Bubbles formed at the HIFU focus via PSNE vaporization enhanced HIFU-mediated heating. Broadband emissions detected during HIFU exposure coincided in time with measured accelerated heating, which suggested that IC played an important role in bubble-enhanced heating. In the presence of bubbles, the acoustic power required for the formation of a 9-mm(3) lesion was reduced by 72% and the exposure time required for the onset of albumin denaturation was significantly reduced (by 4 s), provided that the PSNE volume fraction in the polyacrylamide gel was at least 0.008%. CONCLUSIONS: The time or acoustic power required for lesion formation in gel phantoms was dramatically reduced by vaporizing PSNE into bubbles. These results suggest that PSNE may improve the efficiency of HIFU-mediated thermal ablation of solid tumors; thus, further investigation is warranted to determine whether bubble-enhanced HIFU may potentially become a viable option for cancer therapy.R21 EB009493 - NIBIB NIH HH

Development of Vessel Phantoms for Ultrasound Methods

Phantoms mimicking the specific mechanical and acoustic properties of human tissues are essential in the development and evaluation of novel ultrasound methods. In this work, various ultrasound phantoms are proposed to be used in the development of ultrasound methods to investigate the arterial walls longitudinal movements influence on the vasa vasorum circulation. The longitudinal movement of arteries has been shown in vivio. It has been measured to be of the same magnitude as the diameter change of the arteries. Ultrasound phantoms simulating the arterial longitudinal movement has recently been made using Polyvinyl alcohol (PVA). However, these phantoms suffered from having low temporal stability and easy degradation. This master’s thesis investigates several tissues mimicking materials and describes the design and fabrication of ultrasound phantom models that simulate the vasa vasorum (the vessels of the vessel) and the longitudinal movement of the arterial wall. The mechanical properties of phantom materials were evaluated with a mechanical test instrument and the speed of sound was measured using a method based on the time of flight, and the attenuation was also measured. We showed that copolymer-in-oil, as well as ballistic gel, are excellent alternatives for vessel phantom fabrication. The Young’s modulus for copolymer in oil and ballistic gel was measured to be 37 and 82 kPa, respectively. The attenuation coefficients were 0.83 and 0.40 dB/MHz/cm, respectively. The ultrasound speed ranged from 1433–1458 m/s. The results suggest that the best alternative is to use the commercially available styrene-ethylene/butylene-styrene (SEBS) block copolymer in mineral oil, and the clear synthetic ballistics gelatin of 10%. A walled and multi-layered vessel phantom in a cylindrical geometry and with decreasing diameter was designed and fabricated. The longitudinal and radial movements were generated by the use of pulsatile flow produced from a gear pump. The longitudinal movement was measured to 0.2 mm and the radial movement to 0.8 mm.Ultrasound Phantoms Mimicking the Vessels of the Vessels Millions of people around the world suffer and die every year due to diseases related to blood circulation. This number could be decreased significantly if better and early detection methods were developed. In order to develop advanced methods, it is important to have access to a controlled environment that mimic the phenomena of interest. Arteries are blood vessels responsible of carrying oxygenated blood from the heart out to the body and are elastic, moveable and stretchable. Since the 1970s it is known that there is an arterial diameter change, and it is what is looked for when care takers want to measure blood pressure. On the other hand, not until recently an ultrasound method was developed to detect and show that the arterial wall moves in the direction of the blood flow as well. Ultrasound is a high frequency sound and images are created from the reflected sound waves by the different body structures. Ultrasound equipment is frequently used in medical diagnosis, for example on pregnant women to check their babies. Researchers would like to develop ultrasound methods to understand how the arterial wall movements might affect the blood circulation within the micro vessels that provide blood supply and nourishment to the walls of vessels. These micro vessels are also called vasa vasorum which comes from Latin and means the vessels of the vessels and is a network of small vessels

Ultrasound metrology and phantom materials for validation of photoacoustic thermometry

High intensity focused ultrasound is an emerging non-invasive cancer therapy during which a focused ultrasound beam is used to destroy cancer cells within a confined volume of tissue. In order to increase its successful implementation in practice, an imaging modality capable of accurately mapping the induced temperature rise in tissue is necessary. Photoacoustic thermometry, a rapidly emerging technique for non-invasive temperature monitoring, exploits the temperature dependence of the Grüneisen parameter of tissues, which leads to changes in the recorded photoacoustic signal amplitude with temperature. However, the implementation of photoacoustic thermometry approaches is hindered by a lack of rigorous validation. This includes both the equipment and methodology used. This work investigates the effect of temperature on ultrasound transducers used in photoacoustic thermometry imaging as well as characterisation of potential phantom materials for its validation. The variation in transducer sensitivity with temperature is investigated using two approaches. The first one utilises a reference transducer whose output power is known as a function of temperature to characterise the sensitivity of the hydrophone. As the knowledge of variability of transducer output with temperature is not readily available, two standard metrology techniques using radiation force balances and laser vibrometry are extended beyond room temperature to characterise the effect of temperature on the output of PZT tranducers. For the second approach to transducer sensitivity calibration, a novel method is developed utilising water as a laser-generated ultrasound source and validated using the self-reciprocity calibration method. The calibrated hydrophone is then used to characterise the relevant temperature-dependent properties of several phantom materials in a custom-built setup. The measurement results are used to determine the most suitable phantom for photoacoustic thermometry. Finally, the phantom is heated and imaged in a proof-of-concept photoacoustic thermometry setup using a linear array. These contributions are of vital importance for allowing the translation of photoacoustic thermometry into clinical practice

Material Development for Ultrasound Quality Assurance

Ultrasound transducers are usually the weakest point in an ultrasonic device. Malfunction in the transducer can cause distortion in an ultrasound image. Ultrasonic devices should therefore be checked in a regular basis to prevent the usage of broken devices although there are no necessary standards for ultrasound quality assurance. Progress is slow because ultrasound is considered as a safe imaging method, which doesn’t need such accurate supervision. Studies have shown that there are several ultrasonic devices in use, which have some kind of malfunction. With the quality assurance phantom, the operation ability of ultrasonic devices and especially the functionality of the transducer can be improved via testing transducers regularly. Phantoms in clinical use are usually meant to mimic the human body or properties of tissues. Phantoms are used in studies, tests and trainings where in vivo models are inappropriate. The main objective of this thesis is to study the materials, which are used in ultrasound phantoms, and to study the functionality of materials for the application. The most common materials used in phantom materials are gelatin and agar. These materials are of animal origin and they are exposed to bacterial growth easily, which shortens their lifetime. Other materials are polymer based like polyurethane, polyvinyl alcohol and polyacrylamide. All materials mentioned are water-based, which cause hydration. Materials usually retain their acoustical properties only a few months, some couple of years. There are commercially available ultrasound phantoms but they are expensive. Therefore new materials, which would be more stable and cheaper of a price, were studied for ultrasound quality assurance. Study of more stable materials was started with silicones, which do not show property changes during a long period of time. However, the acoustical properties of silicones are not suitable for ultrasound phantom application. Next step was to study the acoustical properties of experimental material. The properties turned out suitable for the ultrasound phantom application. Study of this material was carried out and different concentrations of experimental material were tested. The experimental material still needs further studies to be able to be used as the ultrasound phanto

Tissue mimicking materials for imaging and therapy phantoms: a review

Tissue mimicking materials (TMMs), typically contained within phantoms, have been used for many decades in both imaging and therapeutic applications. This review investigates the specifications that are typically being used in development of the latest TMMs. The imaging modalities that have been investigated focus around CT, mammography, SPECT, PET, MRI and ultrasound. Therapeutic applications discussed within the review include radiotherapy, thermal therapy and surgical applications. A number of modalities were not reviewed including optical spectroscopy, optical imaging and planar x-rays. The emergence of image guided interventions and multimodality imaging have placed an increasing demand on the number of specifications on the latest TMMs. Material specification standards are available in some imaging areas such as ultrasound. It is recommended that this should be replicated for other imaging and therapeutic modalities. Materials used within phantoms have been reviewed for a series of imaging and therapeutic applications with the potential to become a testbed for cross-fertilization of materials across modalities. Deformation, texture, multimodality imaging and perfusion are common themes that are currently under development

Ferrogels ultrasonography for biomedical applications

Ferrogels (FG) are magnetic composites that are widely used in the area of biomedical engineering and biosensing. In this work, ferrogels with different concentrations of magnetic nanoparticles (MNPs) were synthesized by the radical polymerization of acrylamide in stabilized aqueous ferrofluid. FG samples were prepared in various shapes that are suitable for different characterization techniques. Thin cylindrical samples were used to simulate the case of targeted drug delivery test through blood vessels. Samples of larger size that were in the shape of cylindrical plates were used for the evaluation of the FG applicability as substitutes for damaged structures, such as bone or cartilage tissues. Regardless of the shape of the samples and the conditions of their location, the boundaries of FG were confidently visualized over the entire range of concentrations of MNPs while using medical ultrasound. The amplitude of the reflected echo signal was higher for the higher concentration of MNPs in the gel. This result was not related to the influence of the MNPs on the intensity of the reflected echo signal directly, since the wavelength of the ultrasonic effect used is much larger than the particle size. Qualitative theoretical model for the understanding of the experimental results was proposed while taking into account the concept that at the acoustic oscillations of the hydrogel, the macromolecular net, and water in the gel porous structure experience the viscous Stocks-like interaction. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.18-19-00090Ministry of Education and Science of the Russian Federation, Minobrnauka: 3.1438.2017/46Funding: The Russian Scientific Foundation (grant 18-19-00090) supported the experimental parts of this study, including the design, performance and analysis of experiments.Acknowledgments: A.Yu. Zubarev thanks the program of the Ministry of Education and Science of the Russian Federation (project 3.1438.2017/46) for the support of his mathematical studies. We thank K.R. Mekhdieva, P.A. Shabadrov, V.Ya. Krokhalev, I.V. Beketov and A.M. Murzakaev for special support

Multimodal and multiscale imaging of the human placental vasculature

Minimally invasive fetal interventions, such as those used for therapy of twin-to- twin transfusion syndrome (TTTS), require accurate image guidance to optimise patient outcomes. Photoacoustic imaging can provide molecular contrast based on the optical absorption of the haemoglobin, and in this dissertation, it was proposed as a novel technique to image the human placental vasculature. Normal term and in utero TTTS treated placentas were imaged post-partum using two novel photoacoustic imaging systems. With PA imaging, vasculature was resolved to a depth of approximately 7 mm from the chorionic placental surface; the photocoagulated tissue provided a negative contrast and the ablation depth of the scar was visualised. Complementary imaging of the placental vasculature in a microscopic size scale was performed with a handheld incident dark field illumination video microscope in fresh and formalin-fixed term placentas. Real time visualisation of the villus tree down to the terminal villi level was achieved without any contrast injection or extensive tissue preparation. Additionally, the novel application of photoacoustic imaging to guide minimally invasive fetal interventions motivated the development of tissue-mimicking placental phantoms for bench-top system validation and for clinical training. Ideally, phantoms for this modality comprise materials with optical and acoustic properties that can be precisely and independently controlled, which are stable over time, and which are non-toxic and low-cost. Gel wax was proposed as a novel tissue-mimicking material (TMM) that satisfies these criteria, and that it can be used to represent various soft tissues and fabricate heterogeneous phantoms with structures based on patient-specific anatomy. This dissertation sets the stage for the development of miniaturised photoacoustic imaging probes for intraoperative guidance, and new methods of understanding the placental vascular anatomy in health and disease. Gel wax has strong potential to become a next generation TMM for evaluation, and standardisation of imaging systems, and for clinical training

Monitoring dynamically the gelation phase transition of agarose with T2 qMRI as a function of concentration at 3T

The purpose of this experiment is to study as a model the gelation phase transition of agarose solutions with transverse relaxation (T2) quantitative magnetic resonance imaging (qMRI). The focus is on the reduction of T2 of agarose solution upon gelation. The sol-to-gel phase transition of agarose may provide a useful and controllable experimental model of tissue formation. Furthermore, it may provide the basis for exact mathematical models useful for understanding the much reduced transverse relaxation times (T2) observed in solid tissues relative to simple liquids. In this context, the purpose of this work was to monitor dynamically with T2 quantitative MRI the liquid-to-gel phase transition of pure agarose as a function of gel concentration. Samples of agarose at various concentrations were allowed to cool down while scanning dynamically with T2 qMRI, 32 x 10milliseconds (ms) echoes, CarrPurcell-Meiboom-Gill (CPMG), 3Tesla.T2 versus; (temperature).curves of each agarose solution show a distinct phase transition region characterized by a sharp T2 reduction. Four agarose solutions were sequentially prepared by dissolving agarose powder in distilled water at concentrations of 1%, 2%, 3%, and 4% by weight/volume. Immediately after preparation and boiling at 98°C, each liquid agarose solution was poured into a plastic container and scanned dynamically at 3.0T as it cooled down with a whole body MRI scanner (Achieva, Philips Medical Systems, Cleveland, OH). A single axial slice multi spin echo CPMG pulse sequence with the following parameters was used: 32 echoes, 10ms echo spacing, 1.5s repetition time (TR), 160 x 160 matrix size, and 2 SENSE factor. The time per dynamic scan was 1minute. The DICOM images were further processed with an adaptive T2 qMRI algorithm programed in Mathcad (Parametric Technology Corporation, Needham, MA) whereby the number of echoes used in the semi-logarithmic linear regression varies automatically from pixel to pixel depending on noise level. The T2 values of agarose gels have been measured during the entire gelation phase transition process at four different concentrations. The T2 versus time (temperature) curves of all the four concentrations shows a rapid drop at about 24 minutes (T~40°C) at which time the gelation phase transition begins. At all temperatures, T2 decreases as a function of increasing agarose concentration. The data shows similar behaviors for all concentrations with a phase transition characterized by a drastic drop in T2 occurring while the temperature drops by approximately 8°C. These results may be useful for testing theoretical models of the Nuclear Magnetic Resonance (NMR) T2 relaxation properties during tissue formation. Quantitative magnetic resonance imaging (qMRI) differs sharply from conventional directly acquired MRI in that objective measures [such as the trio of the basis MR properties: longitudinal relaxation (T1), T2 and Proton Density (PD)] are used for analysis as well as further post-processing rather than relative signal intensities. Q-MRI portrays the spatial distribution of absolute biophysical parameter measurements on a pixel-by-pixel basis; Kevin J. Chang et al 200