A review of a strategic roadmapping exercise to advance clinical translation of photoacoustic imaging: From current barriers to future adoption.

Photoacoustic imaging (PAI), also referred to as optoacoustic imaging, has shown promise in early-stage clinical trials in a range of applications from inflammatory diseases to cancer. While the first PAI systems have recently received regulatory approvals, successful adoption of PAI technology into healthcare systems for clinical decision making must still overcome a range of barriers, from education and training to data acquisition and interpretation. The International Photoacoustic Standardisation Consortium (IPASC) undertook an community exercise in 2022 to identify and understand these barriers, then develop a roadmap of strategic plans to address them. Here, we outline the nature and scope of the barriers that were identified, along with short-, medium- and long-term community efforts required to overcome them, both within and beyond the IPASC group.

A Stable Phantom Material for Optical and Acoustic Imaging.

Establishing tissue-mimicking biophotonic phantom materials that provide long-term stability are imperative to enable the comparison of biomedical imaging devices across vendors and institutions, support the development of internationally recognized standards, and assist the clinical translation of novel technologies. Here, a manufacturing process is presented that results in a stable, low-cost, tissue-mimicking copolymer-in-oil material for use in photoacoustic, optical, and ultrasound standardization efforts. The base material consists of mineral oil and a copolymer with defined Chemical Abstract Service (CAS) numbers. The protocol presented here yields a representative material with a speed of sound c(f) = 1,481 ± 0.4 m·s-1 at 5 MHz (corresponds to the speed of sound of water at 20 °C), acoustic attenuation α(f) = 6.1 ± 0.06 dB·cm-1 at 5 MHz, optical absorption µa(λ) = 0.05 ± 0.005 mm-1 at 800 nm, and optical scattering µs'(λ) = 1 ± 0.1 mm-1 at 800 nm. The material allows independent tuning of the acoustic and optical properties by respectively varying the polymer concentration or light scattering (titanium dioxide) and absorbing agents (oil-soluble dye). The fabrication of different phantom designs is displayed and the homogeneity of the resulting test objects is confirmed using photoacoustic imaging. Due to its facile, repeatable fabrication process and durability, as well as its biologically relevant properties, the material recipe has high promise in multimodal acoustic-optical standardization initiatives.

Development and testing of a system for controlled ultrasound hyperthermia treatment with a phantom device.

Hyperthermia is the process of raising tissue temperatures in the range 40 - 45 °C for a prolonged time (up to hours). Unlike in ablation therapy, raising the temperature to such levels does not cause necrosis of the tissue but has been postulated to sensitize the tissue for radiotherapy. The ability to maintain a certain temperature in a target region is key to a hyperthermia delivery system. The aim of this work was to design and characterize a heat delivery system for ultrasound hyperthermia able to generate a uniform power deposition pattern in the target region with a closed-loop control which would maintain the defined temperature over a defined period. The hyperthermia delivery system presented herein is a flexible design with the ability to strictly control the induced temperature rise with a feedback loop. The system can be reproduced elsewhere with relative ease and is adaptable for various tumor sizes/locations and for other temperature elevation applications, such as ablation therapy. The system was fully characterized and tested on a newly-designed custom-built phantom with controlled acoustic and thermal properties and containing embedded thermocouples. Additionally, a layer of thermochromic material was fixed above the thermocouples and the recorded temperature increase was compared to the RGB (red, green, and blue) color-change in the material. The transducer characterization allowed for input voltage to output power curves to be generated, thus allowing for comparison of power deposition to temperature increase in the phantom. Additionally, the transducer characterization generated a field map of the symmetric field. The system was capable of increasing the temperature of the target area by 6 °C above body temperature and maintain the temperature to within ±0.5 °C over a defined period. The increase in temperature correlated with the RGB image analysis of the thermochromic material. The results of this work have the potential to contribute towards increasing confidence in the delivery of hyperthermia treatment to superficial tumors. The developed system could potentially be used for phantom or small animal proof-of-principle studies. The developed phantom test device may be used for testing other hyperthermia systems.

A Copolymer-in-Oil Tissue-Mimicking Material With Tuneable Acoustic and Optical Characteristics for Photoacoustic Imaging Phantoms.

Photoacoustic imaging (PAI) standardisation demands a stable, highly reproducible physical phantom to enable routine quality control and robust performance evaluation. To address this need, we have optimised a low-cost copolymer-in-oil tissue-mimickingmaterial formulation. The base material consists of mineral oil, copolymer and stabiliser with defined Chemical Abstract Service numbers. Speed of sound c(f) and acoustic attenuation coefficient α (f) were characterised over 2-10 MHz; optical absorption µa ( λ ) and reduced scattering µs '( λ ) coefficients over 450-900 nm. Acoustic properties were optimised by modifying base component ratios and optical properties were adjusted using additives. The temporal, thermomechanical and photo-stabilitywere studied, alongwith intra-laboratory fabrication and field-testing. c(f) could be tuned up to (1516±0.6) [Formula: see text] and α (f) to (17.4±0.3)dB · cm -1 at 5 MHz. The base material exhibited negligible µa ( λ ) and µs '( λ ), which could be independently tuned by addition of Nigrosin or TiO2 respectively. These properties were stable over almost a year and were minimally affected by recasting. The material showed high intra-laboratory reproducibility (coefficient of variation <4% for c ( f ), α ( f ), optical transmittance and reflectance), and good photo- and mechanical-stability in the relevant working range (20-40°C). The optimised copolymer-in-oil material represents an excellent candidate for widespread application in PAI phantoms, with properties suitable for broader use in biophotonics and ultrasound imaging standardisation efforts.

Hydrophone Spatial Averaging Correction for Acoustic Exposure Measurements From Arrays-Part II: Validation for ARFI and Pulsed Doppler Waveforms.

This article reports the experimental validation of a method for correcting underestimates of peak compressional pressure ( pc) , peak rarefactional pressure ( pr) , and pulse intensity integral (pii) due to hydrophone spatial averaging effects that occur during output measurement of clinical linear and phased arrays. Pressure parameters ( pc , pr , and pii), which are used to compute acoustic exposure safety indexes, such as mechanical index (MI) and thermal index (TI), are often not corrected for spatial averaging because a standardized method for doing so does not exist for linear and phased arrays. In a companion article (Part I), a novel, analytic, inverse-filter method was derived to correct for spatial averaging for linear or nonlinear pressure waves from linear and phased arrays. In the present article (Part II), the inverse filter is validated on measurements of acoustic radiation force impulse (ARFI) and pulsed Doppler waveforms. Empirical formulas are provided to enable researchers to predict and correct hydrophone spatial averaging errors for membrane-hydrophone-based acoustic output measurements. For example, for a 400- [Formula: see text] membrane hydrophone, inverse filtering reduced errors (means ± standard errors for 15 linear array/hydrophone pairs) from about 34% ( pc) , 22% ( pr) , and 45% (pii) down to within 5% for all three parameters. Inverse filtering for spatial averaging effects significantly improves the accuracy of estimates of acoustic pressure parameters for ARFI and pulsed Doppler signals.

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.

Optimisation of the transmit beam parameters for generation of subharmonic signals in native and altered populations of a commercial microbubble contrast agent SonoVue®.

The aim of this work was to establish the optimum acoustic characterisation approach and insonation transmit beam parameters for subharmonic signal generation with 'native' and 'altered' populations of a commonly-used microbubble contrast agent. Dynamic contrast-enhanced (DCE) ultrasound is a non-invasive method of imaging the microvasculature, typically implemented using harmonic imaging. Subharmonic imaging, in which echoes at half the fundamental frequency are detected, detects signals which are generated by the ultrasound contrast agents (UCAs) but not by tissue. However, optimal transmission parameters and furthermore, the optimum acoustic characterisation method have not been established. The subharmonic response of 'native' and 'altered' UCA, altered through decantation, was investigated at transmit centre frequencies 1.8-5 MHz and pulse lengths 1-8 cycles. The 'altered' UCA had reduced polydispersity (1-4 µm: 82% bubble volume), compared to 'native' (4-10 µm: 57% bubble volume). A custom-built narrow-band acoustic characterisation system was found to be more appropriate for acoustic characterisation compared to the commonly used broadband pulse-echo approach. Both UCA generated the highest subharmonic signal at pulse length of 3-cycles. The maximum 'native' subharmonic signal was generated at a transmit centre frequency of 1.9 MHz, corresponding to a subharmonic at 0.95 MHz. This optimal frequency increased in the 'altered' population to 2.3-2.5 MHz, bringing the subharmonic above 1 MHz and hence into a range amenable to clinical abdominal imaging transducers. The use of subharmonic signal detection coupled with a modified UCA size distribution has potential to significantly improve the quantification sensitivity and accuracy of DCE ultrasound imaging.

Hydrophone Spatial Averaging Artifacts for ARFI Beams from Array Transducers.

This paper reports underestimation of peak compressional pressure (p c), peak rarefactional pressure (p r ), and pulse intensity integral (pii) due to hydrophone spatial averaging of acoustic radiation force impulse (ARFI) beams generated by clinical linear and phased arrays. Although a method exists for correcting for hydrophone spatial averaging for circularly-symmetric beams, there is presently no analogous method for rectangularly-symmetric beams generated by linear and phased arrays. Consequently, pressure parameters (p c, p r , and pii) from clinical arrays are often not corrected for spatial averaging. This can lead to errors in Mechanical Index (MI) and Thermal Index (TI), which are derived from pressure measurements and are displayed in real-time during clinical ultrasound scans. ARFI beams were generated using three clinical linear array transducers. Output pressure waveforms for all three transducers were measured using five hydrophones with geometrical sensitive element sizes (dg) ranging from 85 to 1000 µm. Spatial averaging errors were found to increase with hydrophone sensitive element size. For example, if dg = 500 µm (typical membrane hydrophone), frequency = 2.25 MHz and F/# = 1.5, then average errors are approximately -20% (pc), -10% (pr), and -25% (pii). Therefore, due to hydrophone spatial averaging, typical membrane hydrophones can exhibit significant underestimation of ARFI pressure measurements, which likely compromises exposure safety indexes.